Introduction ToxTutor is a self-paced tutorial covering key principles of toxicology and was adopted from the National Library of Medicine (NLM) chemical and toxicology databases. While a knowledge of anatomy and physiology is not required for viewing ToxTutor, theIntroduction to the Human Bodyfrom the National Cancer Institute provides a good introduction to the topic.
The basic principles of toxicology described in ToxTutor are similar to those taught in university programs and are well described in toxicology literature. A list of the textbooks used as the primary resources for the tutorials is found in theBibliography.
MLA Continuous Education Credit Eligibility Instructions on how to claim the credits can be found in our survey after completing the End Of Module Certification Quiz.
Using ToxTutor
Getting Around It will take approximately three hours to complete this self-paced tutorial. There are a variety of ways you can navigate ToxTutor. You can:
Use the Glossary button in the upper right corner of each page to access the glossary.
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Toxicants gain entrance into the body by absorption. The body considers ingested and inhaled materials as being outside of it until those materials cross the cellular barriers of the gastrointestinal tract or respiratory system. A substance must be absorbed to exert an effect on internal organs, although local toxicity, such as irritation, may occur.
Absorption Variability Absorption varies greatly by specific chemicals and the route of exposure.
For skin, oral or respiratory exposure, the absorbed dose is only a fraction of the exposure dose (external dose).
For substances injected or implanted directly into the body, exposure dose is thesameas the absorbed or internal dose.
Several factors affect the likelihood that a xenobiotic will be absorbed. The most important factors are the:
Route of exposure.
Concentration of the substance at the site of contact.
Chemical and physical properties of the substance.
The route of exposure influences how the concentration and properties of the substance vary. In some cases, a high percentage of a substance may not be absorbed from one route whereas a low amount may be absorbed via another route.
For example, very littleDDT powderwill penetrate the skin whereas a high percentage will be absorbed when it is swallowed.
Due to such route-specific differences in absorption, xenobiotics are often ranked for hazard in accordance with the route of exposure. A substance may be categorized as relatively non-toxic by one route and highly toxic via another route.
Routes of Exposure Theprimary routes of exposureby which xenobiotics can gain entry into the body are:
Gastrointestinal (GI) tract— important for environmental exposure to contaminants from food and water; the main route for many pharmaceuticals.
Respiratory tract— important for environmental and occupational exposure to air contaminants; some pharmaceuticals (such as nasal or oral aerosol inhalers) use this route.
Skin— important environmental and occupational exposure route; many consumer and pharmaceutical products are applied directly to the skin.
Other routes of exposure– used primarily for specific medical purposes:
Injections— primarily used for pharmaceuticals.
Implants— pharmaceuticals may be implanted to permit slow, time-release (for example, hormones). Many medical devices are implanted for which minimal absorption is desired (such as artificial lens or tendons). Some materials enter the body via skin penetration as the result of accidents or weapons.
Conjunctival instillations (eye drops)— primarily for treating ocular conditions; however, in some cases, considerable absorption can occur and cause systemic toxicity.
Suppositories— used for medicines that may not be adequately absorbed after oral administration or that are intended for local therapy; usual locations for suppositories are the rectum and vagina.
Cell Membranes Cell membranes(often referred to as plasma membranes) surround all body cells and are similar in structure. They consist of two layers of phospholipid molecules arranged like a sandwich, referred to as a "phospholipid bilayer." Each phospholipid molecule consists of a phosphate head and a lipid tail. The phosphate head is polar, meaning it is hydrophilic(attracted to water). In contrast, the lipid tail is lipophilic(attracted to lipid-soluble substances).
The two phospholipid layers are oriented on opposing sides of the membrane so that they are approximate mirror images of each other. The polar heads face outward and the lipid tails face inward in the membrane sandwich (Figure 2).
Figure 2. Each phospholipid molecule consists of a phosphate head and lipid tail (Image Source: Adapted from Wikimedia Commons, obtained under Public Domain,original image)
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The cell membrane is tightly packed with these phospholipid molecules interspersed with various proteins and cholesterol molecules. Some proteins span across the entire membrane which can create openings for aqueous channels or pores.
A typical cell membrane structure is illustrated in Figure 3.
Figure 3. Typical cell membrane structure (Image Source: Adapted from Wikimedia Commons, obtained under Public Domain,original image)
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Role of Cell Membranes in Absorption For a xenobiotic to enter the body (as well as move within, and leave the body) it must pass across cell membranes (cell walls). Cell membranes are formidable barriers and a major body defense that prevents foreign invaders or substances from gaining entry into body tissues. Normally, cells in solid tissues (such as skin, or mucous membranes of the lung or intestine) are so tightly compacted that substances cannot pass between them. This requires that the xenobiotic have the ability to penetrate cell membranes. It must cross several membranes to go from one area of the body to another.
For a substance to move through one cell requires that it first move across the cell membrane into the cell, pass across the cell, and then cross the cell membrane again to leave the cell. This is true whether the cells are in the skin, the lining of a blood vessel, or an internal organ such as the liver. In many cases, in order for a substance to reach the site where it exerts toxic effects, it must pass through several membrane barriers.
Animation 1 depicts how a chemical from a theoretical consumer product called a "Shower Gel" might get to the surface of the skin during showering and then pass through several membranes before coming in contact with the inside of a liver cell.
Movement of Toxicants Across Cell Membranes Some toxicants move across a membrane barrier with relative ease while others find it difficult or impossible. Those that can cross the membrane use one of two general methods: 1)passive transferor 2)facilitated transport. Passive transfer consists ofsimple diffusion(or osmotic filtration) and is "passive" because no cellular energy or assistance is required. Some toxicants cannot simply diffuse across the membrane but require assistance by specialized transport mechanisms. The primary types of specialized transport mechanisms are:
Facilitated diffusion
Active transport
Endocytosis (phagocytosis and pinocytosis)
Passive Transfer Passive transfer is the most common way that xenobiotics cross cell membranes. Two factors determine the rate of passive transfer:
The difference in concentrations of the substance on opposite sides of the membrane (this occurs when a substance moves from a region of high concentration to one having a lower concentration. Diffusion will continue until the concentration is equal on both sides of the membrane).
The ability of the substance to move either through the small pores in the membrane or the lipophilic interior of the membrane.
Properties affecting a chemical substance's ability for passive transfer are:
Lipid solubility
Molecular size
The degree of ionization
Substances with high lipid solubility readily diffuse through the phospholipid membrane. Small water-soluble molecules can pass across a membrane through the aqueous pores, along with normal intracellular water flow.
Large water-soluble molecules usually cannot make it through the small pores, although some may diffuse through the lipid portion of the membrane, but at a slow rate.
Most aqueous pores are about 4 Angstrom (Å) in size and allow chemicals of molecular weight 100-200 to pass through. Exceptions are membranes of capillaries and kidney glomeruli which have relatively large pores (about 40 Angstrom [Å]) that allow molecules up to a molecular weight of about 50,000 (molecules slightly smaller than albumin which has a molecular weight of 60,000) to pass through.
In general, highly ionized chemicals have low lipid solubility and pass with difficulty through the lipid membrane.
Figure 4 demonstrates the passive diffusion and filtration of xenobiotics through a typical cell membrane.
Facilitated diffusion is similar to simple diffusion in that it does not require energy and follows a concentration gradient. The difference is that it is a carrier-mediated transport mechanism (Figure 5)—that is, special transport proteins, which are embedded within the cell membrane, facilitate movement of molecules across the membrane. The results are similar to passive transport but faster and capable of moving larger molecules that have difficulty diffusing through the membrane without a carrier.
Examples are the transport of sugar and amino acids into RBCs and the CNS.
Active Transport Some substances are unable to move with diffusion, unable to dissolve in the lipid layer, and are too large to pass through the aqueous channels. For some of these substances,active transportprocesses exist in which movement through the membrane may beagainstthe concentration gradient, that is, from low to higher concentrations. Cellular energy from adenosine triphosphate (ATP) is required in order to accomplish this. The transported substance can move from one side of the membrane to the other side by this energy process. Active transport is important in the transport of xenobiotics into the liver, kidney, and central nervous system and for maintenance of electrolyte and nutrient balance.
Figure 6 shows sodium and potassium moving against concentration gradient with the help of the ATP sodium-potassium exchange pump.
Endocytosis (Phagocytosis and Pinocytosis) Many large molecules and particles cannot enter cells via passive or active mechanisms. However, some may still enter by a process known asendocytosis.
In endocytosis, the cell surrounds the substance with a section of its cell wall. This engulfed substance and section of membrane then separates from the membrane and moves into the interior of the cell. The two main forms of endocytosis are 1) phagocytosis and 2) pinocytosis.
Inphagocytosis(cell eating), large particles suspended in the extracellular fluid are engulfed and either transported into cells or are destroyed within the cell. This is a very important process for lung phagocytes and certain liver and spleen cells.
Pinocytosis(cell drinking) is a similar process but involves the engulfing of liquids or very small particles that are in suspension in the extracellular fluid.
Figure 7 demonstrates the types of membrane transport by endocytosis.
Figure 7. Types of Endocytosis (Image Source: Wikimedia Commons, obtained by Public Domain License,original image)
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Knowledge Check (Solutions on next page)
1) The process whereby a substance moves from outside the body into the body is known as: a) Distribution b) Biotransformation c) Absorption
2) For a xenobiotic to move from outside the body to a site of toxic action requires that it: a) Possess hydrophilic (water-soluble) properties b) Possess hydrophobic (lipophilic) properties c) Pass through several cell membranes
3) The basic structure of the cell membrane consists of: a) A thick protein layer containing phospholipid channels b) A bilayer of phospholipids with scattered proteins within the layers c) Cholesterol outer layer with a phospholipid inner layer
4) The membrane transport process by which large hydrophobic molecules cross membranes via the lipid portion of the membrane, follow the concentration gradient, and do not require energy or carrier molecules is known as: a) Simple diffusion b) Active transport c) Facilitated diffusion
5) Endocytosis is a form of specialized membrane transport in which the cell surrounds the substance with a section of its cell membrane. The specific endocytosis process by which liquids or very small particles are engulfed and transported across the membrane is known as: a) Phagocytosis b) Pinocytosis c) Exocytosis
1) Absorption-This is the correct answer. Absorption is the first and crucial step in the toxicokinetics of a xenobiotic. Without absorption, a toxic substance does not represent a human health hazard.
2) Pass through several cell membranes-This is the correct answer. In order for a xenobiotic to move from outside the body to an internal site of toxic action (target cells), a xenobiotic must pass through several membrane barriers. The first membranes are those at the portal of entry, for example, lung or intestinal tract.
3) A bilayer of phospholipids with scattered proteins within the layers-This is the correct answer. The typical cell membrane consists of two layers of phospholipids with polar head groups consisting of phospholipid molecules and the lipid inner portion consisting primarily of cholesterol molecules. The phospholipid layers are oriented on opposing sides of the membrane so that they are approximate mirror images of each other. Various proteins are scattered throughout the lipid bilayers of the membrane.
4) Simple diffusion-This is the correct answer. Large hydrophobic molecules must diffuse through the lipid portion of the membrane, with the rate of transport correlating with its lipid solubility. In general, highly ionized chemicals have low lipid solubility and do not readily pass through the lipid membrane.
5) Pinocytosis-This is the correct answer. Pinocytosis (cell drinking) involves the engulfing of liquids or very small particles that are in suspension within the extracellular fluid.
The gastrointestinal (GI) tract can be viewed as a tube going through the body (Figure 1). Its contents are considered exterior to the body until absorbed. Salivary glands, liver, and the pancreas are considered accessory glands of the GI tract as they have ducts entering the GI tract and secrete enzymes and other substances. For foreign substances to enter the body, they must pass through the gastrointestinal mucosa, crossing several membranes before entering the bloodstream.
Substances must be absorbed from the gastrointestinal tract in order to exert a toxic effect throughout the whole body, although local gastrointestinal damage may occur from direct exposures to toxicants. Absorption can occur at any place along the entire gastrointestinal tract. However, the degree of absorption depends on the site.
Three main factors affect absorption within the various sites of the gastrointestinal tract:
Type of cells at the specific site.
Period of time that the substance remains at the site.
Mouth and Esophagus Under normal conditions, xenobiotics are poorly absorbed within themouthandesophagus, due mainly to the very short time that a substance resides within these portions of the gastrointestinal tract. There are some notable exceptions. For example:
Nicotine readily penetrates the mouth mucosa.
Nitroglycerin is placed under the tongue (sublingual) for immediate absorption and treatment of heart conditions.
The sublingual mucosa under the tongue and in some areas of the mouth is thin and highly vascularized and allows some substances to be rapidly absorbed.
Stomach Thestomach, with its high acidity (pH 1-3), is a significant site for the absorption of weak organic acids, which exist in a diffusible, nonionized and lipid-soluble form. In contrast, weak bases will be highly ionized and therefore poorly absorbed. The acidic stomach may chemically break down some substances. For this reason, those substances must be administered in gelatin capsules or coated tablets, which can pass through the stomach into the intestine before they dissolve and release their contents.
Another determinant that affects the amount of a substance that will be absorbed in the stomach is the presence of food in the stomach. Food ingested at the same time as the xenobiotic may result in a considerable difference in absorption of the xenobiotic.
Intestine The greatest absorption of chemicals, as with nutrients, takes place in theintestine, particularly in the small intestine. The intestine has a large surface area consisting of outward projections of the thin (one-cell thick) mucosa into the lumen of the intestine (the villi) (Figure 2). This large surface area facilitates diffusion of substances across the cell membranes of the intestinal mucosa.
Since the pH is near neutral (pH 5-8), both weak bases and weak acids are nonionized and are usually readily absorbed by passive diffusion. Lipid soluble, small molecules effectively enter the body from the intestine by passive diffusion.
In addition to passive diffusion, facilitated and active transport mechanisms move certain substances across the intestinal cells into the body, including essential nutrients such as glucose, amino acids, and calcium. These mechanisms also transport strong acids, strong bases, large molecules, and metals, including some important toxins.
For example, lead, thallium, and paraquat (herbicide) are toxins that active transport systems move across the intestinal wall.
The slow movement of ingested substances through the intestinal tract can influence their absorption. This slow passage increases the length of time that a compound is available for absorption at the intestinal membrane barrier.
Intestinal microflora and gastrointestinal enzymes can affect the toxicity of ingested substances. Some ingested substances may be only poorly absorbed but they may be biotransformed within the gastrointestinal tract. In some cases, their biotransformed products may be absorbed and be more toxic than the ingested substance.
An important example is the formation of carcinogenic nitrosamines from non-carcinogenic amines by intestinal flora.
Colon and Rectum Very little absorption takes place in thecolonandrectum. As a rule, if a xenobiotic has not been absorbed after passing through the stomach or small intestine, very little further absorption will occur. However, there are some exceptions, as some medicines may be administered as rectal suppositories with significant absorption.
An example is Anusol (hydrocortisone preparation) used for the treatment of local inflammation which is partially absorbed (about 25%).
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Knowledge Check (Solutions on next page)
1) The most important factor that determines whether a substance will be absorbed within the stomach is the: a) Physical form as a solid or liquid b) Molecular size c) pH
2) The primary routes for absorption of environmental agents are: a) Gastrointestinal tract, respiratory tract, and skin b) Conjunctival exposures and skin wounds
3) The site of the gastrointestinal tract where most absorption takes place is: a) Stomach b) Small intestine c) Colon and rectum
1) pH-This is the correct answer. The most important factor that determines absorption within the stomach is pH. Weak organic acids, which exist in a diffusible, nonionized and lipid-soluble form are readily absorbed in the high acidity of the stomach (pH 1-3). In contrast, weak bases will be highly ionized and therefore poorly absorbed.
2) Gastrointestinal tract, respiratory tract, and skin-This is the correct answer. Environmental agents may be found in contaminated food, water, or air. As such, they may be ingested, inhaled, or present on the skin.
3) Small intestine-This is the correct answer. By far, the greatest absorption takes place in the intestine. This is due to the neutral pH and the large, thin, surface area that allows easy penetrable by passive diffusion. Weak bases, weak acids, lipid soluble substances and small molecules effectively enter the body from the intestine. In addition, special carrier-mediated and active transport systems exist.
Many environmental and occupational agents as well as some pharmaceuticals enter the respiratory tract through inhalation. Absorption can occur at any place within the upper respiratory tract. However, the amount of a particular xenobiotic that can be absorbed at a specific location depends highly on its physical form and solubility.
There are three basic regions to the respiratory tract:
Mucociliary Escalator The mucociliary escalator covers most of the bronchi, bronchioles, and nose. It contains mucus-producing goblet cells and ciliated epithelium. The movements of the cilia push it and anything in it such as inhaled particles or microorganisms up and out into the throat, which can either get swallowed or removed through the mouth.
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Pulmonary Region By far, the most important site for absorption is the pulmonary region consisting of the very small airways called bronchioles and the alveolar sacs of the lung.
The alveolar region has a very large surface area, about 50 times that of the skin. In addition, the alveoli consist of only a single layer of cells with very thin membranes that separate the inhaled air from the blood stream. Oxygen, carbon dioxide, and other gases readily pass through this membrane. Gases and particles, which are water-soluble (and thus blood-soluble), are absorbed more efficiently from the lung alveoli compared to their absorption via the gastrointestinal tract or through the skin. Water-soluble gases and liquid aerosols can pass through the alveolar cell membrane by simple passive diffusion.
Impact of Physical Form on Absorption In addition to solubility, the ability to be absorbed depends highly on the physical form of the agent (that is, whether the agent is a gas/vapor or a particle). The physical form determines the extent of its penetration into the deep lung.
Gases and Vapors Agasorvaporcan be inhaled deep into the lung and if it has high solubility in the blood, it is almost completely absorbed in one respiration (a single breath). Absorption through the alveolar membrane is by passive diffusion, following the concentration gradient. As the agent dissolves in the circulating blood, it leaves the lung and a large amount of gas or vapor can be absorbed and enter the body.
Blood-solublegases or vapors can often be exhaled instead of absorbed right away. For blood-soluble gases, the equilibrium between the concentration of the agent in the inhaled air and that in the blood is difficult to achieve. Inhaled gases or vapors, which have poor solubility in the blood, have a limited capacity for absorption. The main reason for this is that the blood can become quickly saturated. Once saturated, blood will not be able to accept the gas and it will remain in the inhaled air and then get exhaled. One way that the amount of gas absorbed could increase is if the rate and depth of breathing were increased (this concept is known as ventilation limitation). More specifically, the amount of gas absorbed could be increased if the rate of blood supply to the lung were increased byflow limitation.
In contrast,insolublegases or vapors can be absorbed into the body by the lungs before getting exhaled (for example, nitrogen dioxide and carbon monoxide). This is because the equilibrium between the inhaled air and the blood is reached more quickly for relatively insoluble gases than for soluble gases.
Airborne Particles The absorption of airborne particles is usually quite different from that of gases or vapors. The absorption of solid particles, regardless of solubility, depends upon particle size:
Large particles (>5 μM) are generally deposited in the nasopharyngeal (head airways region) region with little absorption.
Particles 2-5 μM can penetrate into the tracheobronchial region.
Very small particles (<1 μM) are able to penetrate deep into the alveolar sacs where they can deposit and be absorbed.
Differences in Absorption Among Regions of the Respiratory Tract
Nasopharyngeal Region Minimal absorption takes place in the nasopharyngeal region due to the cell thickness of the mucosa and the rapid movement of gases and particles through the region.
Tracheobronchial Region Relatively soluble gases can quickly enter the blood stream. Most deposited particles are moved back up to the mouth where they are swallowed.
Pulmonary Region Absorption in thealveoliof the pulmonary region is quite efficient compared to other areas of the respiratory tract. Relatively soluble materials (gases or particles) are quickly absorbed into systemic circulation. Pulmonary macrophages exist on the surface of the alveoli. They are not fixed and not a part of the alveolar wall. They can engulf particles just as they engulf and kill microorganisms. These alveolar macrophages can scavenge and clear some insoluble particle into the lymphatic system.
Some other particles may remain in the alveoli indefinitely. For example:
Coal dust and asbestos fibers may lead to black lung or asbestosis, respectively.
Carbon nanotubes (CNT), tiny tube-shaped structures smaller than a human hair, have been found in the lungs long after exposure. CNT are used in materials like polymers and anti-static packaging for their electric, magnetic, and mechanical properties. Studies of what happens to different forms of single-walled and multi-walled carbon nanotubes (CNT) found that pristine CNT could remain in the lung for months or even years after pulmonary deposition. However, some CNT can move to the gastrointestinal (GI) tract via the mucocilary escalator where, if swallowed, there appears to be no uptake of CNT from the GI tract (with a possible exception of the smallest functionalized single-walled CNT). In addition, under some experimental conditions in animals, some carbon nanotubes moved from the alveolar space to the nearby pulmonary region including lymph nodes, subpleura and pleura, and smaller amounts went to distal organs including the liver, spleen, and bone marrow.
Factors Affecting the Toxicity of Inhaled Materials The nature of toxicity of inhaled materials depends on whether the material is absorbed or remains within the alveoli and small bronchioles. If the agent is absorbed and is lipid soluble, it can rapidly distribute throughout the body, passing through the cell membranes of various organs or into fat depots. Lipid-soluble substances take a longer time to reach equilibrium than water soluble substances. Chloroform and ether are examples of lipid-soluble substances with high blood solubility.
Non-absorbed foreign material can also cause severe toxic reactions within the respiratory system. These reactions may take the form of chronic bronchitis, alveolar breakdown (emphysema), fibrotic lung disease, and even lung cancer. In some cases, the toxic particles can kill the alveolar macrophages, which results in lowering the body's respiratory defense mechanism.
Pharmaceuticals Targeted to the Respiratory Tract Inhaled drug delivery devices can be very effective and safe for getting active agents directly to their site of action. Inhalation is used to deliver locally acting drugs to treat respiratory conditions, including asthma, chronic obstructive pulmonary disease (COPD), and airway infections. Advantages of targeted delivery to the lungs include a more rapid onset of action and an increased therapeutic effect. Depending on the drug inhaled, there can be reduced systemic side effects since a lower dose can deliver the required local concentration.
Toxicogenomics and Toxicity Testing Toxicogenomics applies genomics concepts and technologies to study gene and protein activities within a type of tissue or type of cell in response to a chemical exposure. Toxicogenomics helps in the understanding of what genes and proteins interact with a chemical, and what diseases are associated with various genes, proteins, and chemicals. This example used toxicogenomics to evaluate the response of the respiratory tract to one type of inhaled material:
For example, titanium dioxide nanoparticles (TiO2NPs) induce lung inflammation in experimental animals andone studyincluded a comprehensive toxicogenomic analysis of lung responses in mice exposed to six individual TiO2NPs exhibiting different sizes, crystalline structure, and surface modifications. The goal was to investigate whether the mechanisms leading to TiO2NP-induced lung inflammation are property specific. The results suggest that the severity of lung inflammation is property specific; however, the underlying mechanisms (genes and pathways perturbed) leading to inflammation were the same for all particle types. While the particle size clearly influenced the overall acute lung responses, a combination of small size, crystalline structure, and hydrophilic surface contributed to the long-term pathological effects observed at the highest dose.
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Knowledge Check (Solutions on next page)
1) An inhaled material will most likely be absorbed into the body if it has the following characteristics: a) High lipid solubility and poorly ionized b) Large particle size and low water solubility c) High water solubility and small particle size
2) Particles of size 2-5 μM are most likely to settle out in which location of the respiratory tract? a) Nasopharyngeal region b) Tracheobronchial region c) Pulmonary region
1) High water solubility and small particle size-This is the correct answer. In contrast to absorption via the gastrointestinal tract or through the skin, gases and particles, which are water-soluble (and thus blood soluble), will be absorbed more efficiently from the lung alveoli. Very small particles (<1 μM) are able to penetrate deep into the alveolar sacs where they can deposit and be absorbed.
2) Tracheobronchial region-This is the correct answer. Particles 2-5 µM can penetrate into the tracheobronchial region. Very small particles (<1 μM) are able to penetrate deep into the alveolar sacs where they can deposit and be absorbed.
In contrast to the thin membranes of the respiratory alveoli and the gastrointestinal villi, the skin is a complex, multilayer tissue. It is relatively impermeable to most ions and aqueous solutions, and serves as a barrier to most xenobiotics.
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Did you know?
Dimethyl sulfoxide (DMSO)has been used in research, human and veterinary medicine, and as a solvent. After applying to the skin, some people can quickly detect a garlic taste as the DMSO is absorbed and enters the body. DMSO also increases the rate of absorption of some other compounds through the skin.
For transdermal drug delivery (TDD), the big challenge is the barrier property of skin, especially the stratum corneum (SC). Different methods have been developed to enhance the penetration of drugs through the skin, with the most popular approach being the use of penetration enhancers (PEs), including natural terpenes. Terpenes, a large and diverse class of organic compounds produced by a variety of plants, are a very safe and effective class of PEs.Limoneneis one example of a terpene used as a penetration enhancer. The main mechanism for the penetration enhancing action of terpenes is the interaction with SC intercellular lipids. The key factor affecting the enhancement is the lipophilicity of the terpenes and the drug molecules.
Epidermis and Stratum Corneum The epidermis (and particularly the stratum corneum) is the only layer that is important in regulating the penetration of a skin contaminant. It consists of an outer layer of cells, packed with keratin, known as thestratum corneumlayer. The stratum corneum is devoid of blood vessels. The cell walls of the keratinized cells are apparently double in thickness due to the presence of the keratin, which is chemically resistant and an impenetrable material. The blood vessels are usually about 100 μM from the skin surface. To enter a blood vessel, an agent must pass through several layers of cells that are generally resistant to penetration by chemicals.
Factors Influencing Penetration of the Stratum Corneum
Thickness The thickness of the stratum corneum varies greatly with regions of the body. The stratum corneum of the palms and soles is very thick (400-600 μM) whereas that of the arms, back, legs, and abdomen is much thinner (8-15 μM). The stratum corneum of the axillary (underarm) and inguinal (groin) regions is the thinnest with the scrotum especially thin. As expected, the ability of toxicants to penetrate that stratum corneum inversely relates to the thickness of the epidermis.
Damage Any process that removes or damages the stratum corneum can enhance penetration of a xenobiotic. Abrasion, scratching, or cuts to the skin will make it more penetrable. Some acids, alkalis, and corrosives can injure the stratum corneum and make it easier for agents to penetrate this layer. The most prevalent skin conditions that enhance dermal absorption are skin burns and dermatitis.
Passive Diffusion Toxicants move across the stratum corneum by passive diffusion. There are no known active transport mechanisms functioning within the epidermis. Polar and nonpolar toxicants diffuse through the stratum corneum by different mechanisms:
Polar compounds,which are water soluble, appear to diffuse through the outer surface of the hydrated keratinized layer.
Nonpolar compounds,which are lipid soluble, dissolve in and diffuse through the lipid material between the keratin filaments.
Water Water plays an important role in dermal absorption. Normally, the stratum corneum is partially hydrated (approximately 7% by weight). Penetration of polar substances is about 10 times more effective than when the skin is completely dry. Additional hydration on the skin's surface increases penetration by 3–5 times, which further increases the ability of a polar compound to penetrate the epidermis.
Species Skin penetration can vary by species which can influence the selection of species used for safety testing. Penetration of chemicals through the skin of the monkey, pig, and guinea pig is often similar to that of humans. The skin of the rat and rabbit is generally more permeable whereas the skin of the cat is generally less permeable. For practical reasons and to assure adequate safety, the rat and rabbit have been used for dermal toxicity safety tests.
Other Sites of Dermal Absorption In addition to the stratum corneum, small amounts of chemicals may be absorbed through the sweat glands, sebaceous glands, and hair follicles. However, since these structures represent only a very small percentage of the skin's total surface area, they are not ordinarily viewed as important contributors to dermal absorption.
Dermis and Subcutaneous Tissue Once a substance penetrates through the stratum corneum, it enters lower layers of the epidermis, the dermis, and subcutaneous tissue. These layers are far less resistant to further diffusion. They contain a porous, nonselective aqueous diffusion medium which can be penetrated by simple diffusion. Most toxicants that have passed through the stratum corneum can now readily move through the remainder of the skin and enter the circulatory system via the large numbers of venous and lymphatic capillaries in the dermis.
Semivolatile Organic Compounts (SVOCs) Exposure tosemivolatile organic compounds (SVOCs)via the dermal route can occur. The amount of SVOCs absorbed via air-to-skin uptake has been estimated to be comparable to or larger than the amount taken in via inhalation for many SVOCs encountered indoors, including:
Butylated hydroxytoluene (BHT)
Chlordane
Chlorpyrifos
Diethyl phthalate
Nicotine (in free-base form)
Other chemicals
The influence of particles and dust on dermal exposure, the role of clothing and bedding as transport vectors, and the potential significance of hair follicles as transport shunts through the epidermis are all areas of research interest.
Human exposure to indoor SVOCs through the dermal pathway has often been underestimated and not considered in exposure assessments. However, exposure scientists, risk assessors, and public health officials are increasingly aware of and interested in the health impacts of dermal exposure. Further, experts seek to understand how health consequences can vary by the exposure pathway. For example, an SVOC that enters the blood through the skin does not encounter the same detoxification pathways that it would encounter when ingested and processed by the stomach, intestines, and liver before entering the blood; its direct entry into the blood can make it potentially more toxic.
1) The main barrier to dermal absorption is the: a) Stratum corneum b) Dermis c) Subcutaneous tissue
2) The two primary factors that can increase dermal penetration are: a) Neutralizing pH and aerosolizing b) Increasing hydration and disruption of the stratum corneum c) Dehydrating a substance and increasing particle size
1) Stratum corneum-This is the correct answer. The epidermis (and particularly the stratum corneum) is the only layer that is important in regulating penetration of a skin contaminant.
2) Increasing hydration and disruption of the stratum corneum-This is the correct answer. Water plays an important role in dermal absorption. Normally, the stratum corneum is partially hydrated (~7% by weight). Penetration of polar substances is about 10 times as effective as when the skin is completely dry. Additional hydration can increase penetration by 3-5 times which further increases the ability of a polar compound to penetrate the epidermis. Any process that removes or damages the stratum corneum can enhance penetration of a xenobiotic.
In addition to the common routes of environmental, occupational, and medical exposure (oral, respiratory, and dermal), other routes of exposure may be used for medical purposes. Many pharmaceuticals are given by parenteral routes via injection into the body using a syringe and hollow needle.
Other Exposure Routes Intradermal injectionsare made directly into the skin, just under the stratum corneum. Tissue reactions are minimal and absorption is usually slow. Asubcutaneous injectionis beneath the skin. Since the subcutaneous tissue is quite vascular (consisting of vessels especially those carrying blood), absorption into the systemic circulation is generally rapid. Tissue sensitivity is also high and thus irritating substances may induce pain and an inflammatory reaction.
Theintramuscularroute is used to inject many pharmaceuticals, especially antibiotics and vaccines, directly into muscle tissue. It is an easy procedure and the muscle tissue is less likely to become inflamed compared to subcutaneous tissue. Absorption from muscle is about the same as from subcutaneous tissue.
Theintravenous(vein) orintra-arterial(artery) routes are used to inject substances directly into large blood vessels when they are irritating or when an immediate action is desired, such as anesthesia.
Parenteralinjections may also be made directly into body cavities, rarely in humans but frequently in laboratory animal studies. Anintraperitoneal injectiongoes directly into the abdominal cavity and anintrapleural injectiondirectly into the chest cavity. Since the pleura and peritoneum have minimal blood vessels, irritation is usually minimal and absorption is relatively slow.
Implantationis another route of exposure of increasing concern. A large number of pharmaceuticals and medical devices are now implanted in various areas of the body. Implants may be used to allow slow, time-release of a substance such as hormones. Implanted medical devices and materials like artificial lenses, tendons, and joints, and cosmetic reconstruction do not involve absorption.
Some materials enter the body viaskin penetrationas the result of accidents or violence (weapons, etc.). The absorption in these cases depends highly on the nature of the substance. Metallic objects (such as bullets) may be poorly absorbed whereas more soluble materials that thrust through the skin and into the body from accidents may be absorbed rapidly into the circulation.
Novel methods of introducing substances into specific areas of the body are often used in medicine. For example,conjunctival instillations(eye drops) treat ocular conditions where high concentrations are needed on the outer surface of the eye, not possible by other routes.
Therapies for certain conditions require that a substance is deposited in body openings where high concentrations and slow release may be needed while keeping systemic absorption to a minimum. For these substances, the pharmaceutical agent is suspended in a poorly absorbed material such as beeswax with the material known as asuppository. The usual locations for use of suppositories are the rectum and vagina.
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Did you know? Cinnamic aldehyde, also calledcinnamaldehyde, gives cinnamon its flavor and odor. It occurs naturally in the bark of cinnamon trees and other species. Cinnamic aldehyde and cinnamic alcohol are well known in the scientific literature as being associated with skin allergy in humans. Skin allergy is also called skin sensitization or allergic contact dermatitis. Cinnamic aldehyde is a more potent sensitizer than cinnamic alcohol. The skin absorption and metabolism of cinnamic aldehyde and cinnamic alcohol play an important role in the development of skin sensitization following skin exposures. Cinnamic alcohol applied to human skin is converted to cinnamic aldehyde and cinnamic acid.
Cinnamic aldehyde is a good example of how an assessment of the risk of skin sensitization can be conducted prior to the introduction of new ingredients and products into the marketplace.Apublished quantitative risk assessmentfor cinnamic aldehyde used the understanding of its chemical, cellular, and molecular properties. By estimating the exposure to cinnamic aldehyde and knowing its allergenic potency, it was possible to assess the sensitization risk of cinnamic aldehyde in different types of consumer products. This publication applied exposure-based risk assessment tools to two hypothetical products containing cinnamic aldehyde. The risk assessment predicted that an eau de toilette leave-on product containing 1000 ppm or more of cinnamic aldehyde would pose anunacceptable riskof skin sensitization getting induced. However, a shampoo containing the same level of cinnamic aldehyde would pose anacceptable riskof skin sensitization getting induced, based on there being limited exposure to the ingredient from a rinse-off product application.
1) If an immediate therapeutic effect is needed, the route of exposure that would most likely be used is the: a) Intradermal route b) Intramuscular injection c) Intravenous injection
2) A pharmaceutical may be implanted in the body to: a) Allow slow-release over a long period of time b) Assure that the substance is distributed equally throughout the body c) Reduce irritation from the substance
1) Intravenous injection-This is the correct answer. Substances injected into the circulatory system go directly to the target tissue where immediate reactions can occur.
2) Allow slow-release over a long period of time-This is the correct answer. Treatment with pharmaceuticals in time-release implants is a relatively new therapeutic technique that has gained popularity for long-term chronic chemotherapy.
What We've Covered This section made the following main points:
Absorption is the process by which toxicants gain entrance into the body.
Ingested and inhaled materials are considered outside the body until they cross the cellular barriers of the gastrointestinal tract or respiratory system.
The likelihood of absorption depends on the:
Route of exposure.
Concentration of the substance at the site of contact.
Chemical and physical properties of the substance.
Exposure routes include:
Primary routes:
Gastrointestinal (GI) tract
Mouth and esophagus — poorly absorbed under normal conditions due to short exposure time (nicotine and nitroglycerin are notable exceptions).
Stomach — significant site for absorption of weak organic acids, but weak bases are poorly absorbed.
Intestine — greatest absorption of both weak bases and weak acids, particularly in the small intestine.
Colon and rectum — very little absorption, unless administered via suppository.
Respiratory tract
Mucociliary escalator — movements of the cilia push mucus and anything contained within up and out into the throat to be swallowed or removed through the mouth.
Pulmonary region — most important site for absorption with about 50 times the surface area of the skin and very thin membranes.
Skin
Epidermis and stratum corneum — the only layer important in regulating the penetration of a skin contaminant.
Toxicants move across the stratum corneum by passive diffusion.
If a toxicant penetrates through the stratum corneum, it enters lower layers of the epidermis, dermis, and subcutaneous tissue, which are far less resistant to further diffusion.
Other exposure routes:
Injections
Implants
Conjunctival instillations (eye drops)
Suppositories
Cell membranes surround all body cells and are made up of a phospholipid bilayer in which each molecule contains a:
Polar (hydrophilic, or attracted to water) phosphate head
Lipophilic (attracted to lipid-soluble substances) lipid tail
Xenobiotics must pass across cell membranes to enter, move within, and leave the body. This movement can be either:
Passive transfer (most common) — simple diffusion or osmotic filtration with no cellular energy or assistance required.
Facilitated transport — similar to passive transport, but a carrier-mediated transport mechanism and thus faster and capable of moving larger molecules.
Active transport — movement against the concentration gradient (from lower to higher concentrations), requiring cellular energy from ATP.
Endocytosis — the cell surrounds the substance with a section of its cell wall, separating from the membrane and moving into the interior of the cell.
Toxicology is traditionally defined as "the science of poisons." Over time, our understanding of how various agents can cause harm to humans and other organisms has increased, resulting in a more descriptive definition of toxicologyas "thestudy of the adverse effects of chemical, physical, or biological agents on living organisms and the ecosystem, including the prevention and amelioration of such adverse effects." These adverse effects can take many forms, ranging from immediate death to subtle changes not appreciated until months or years later. They may occur at various levels within the body, such as an organ, a type of cell, or a specific biochemical. Our understanding of how toxic agents damage the body has progressed along with medical knowledge. We now know that various observable changes in anatomic or bodily functions actually result from previously unrecognized changes in specific biochemicals in the body.
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Did you know?
The study of toxicology may appear to focus only on poisonings or disasters, but some toxic chemicals can have positive effects. Animal venoms, whether from bees, wasps, snakes, or Gila monsters, are composed of hundreds of chemicals that are being studied as treatments for human diseases.
For example, exantide, a drug derived from Gila monster saliva, has been approved for use in Type 2 diabetes. Captopril, which is used to treat hypertension and heart failure, was developed from studies on the chemical bradykinin-potentiating factor (BPF) in the venom of a South American snake Bothrops jararaca. Melitten, which comes from honeybee venom, is being investigated for its anticancer and antifungal properties.
Xenobiotic is the general term that is used for a foreignsubstance taken into the body. It is derived from the Greek term xeno which means "foreigner." Xenobiotics may produce beneficial effects (such as pharmaceuticals) or they may be toxic (such as lead).
As Paracelsus proposed centuries ago, dose differentiates whether a substance will be a remedy or a poison. A xenobiotic in small amounts may be nontoxic and even beneficial, but when the dose is increased, toxic and lethal effects may result.
The following image provides some examples that illustrate this concept.
Figure 3. Examples of varying doses of the same substance as non-toxic or beneficial, toxic, and lethal (Image Source: Adapted from Gossel, T.A. (2001). Principles Of Clinical Toxicology (3rd ed.). CRC Press. https://doi.org/10.1201/9780203742167)
So far, we have described the absorption of substances into the body. Now we will focus on what happens next to substances in the body after they are absorbed.
Distribution Defined Distributionis the process in which an absorbed chemical moves away from the site of absorption to other areas of the body. In this section, we will answer the following questions:
How do chemicals move through the body?
Does distribution vary with the route of exposure?
Is a chemical distributed evenly to all organs or tissues?
How fast is a chemical distributed?
Why do some chemicals stay in the body for a long time while others are eliminated quickly?
Body Fluids When a chemical is absorbed, it passes through cell linings of the absorbing organ (skin, lung, or gastrointestinal tract) into theinterstitial fluid(fluid surrounding cells) of that organ.
The other body fluids areintracellular fluid(fluid inside cells) andblood plasma. However, the body fluids are not isolated but represent one large pool. The interstitial and intracellular fluids, in contrast to fast moving blood, remain in place with certain components (for example, water and electrolytes) moving slowly into and out of cells. A chemical, while immersed in the interstitial fluid, is not mechanically transported the way it is in blood. Table 1 lists the approximate percentage of body weight each of these body fluids comprise.
A toxicant can leave the interstitial fluid by entering:
Local tissue cells.
Blood capillaries and the blood circulatory system.
The lymphatic system.
Blood Plasma If the toxicant gains entrance into the blood plasma, it travels along with the blood, either in a bound or unbound form. Blood moves rapidly through the body via the cardiovascular circulatory system. In contrast, lymph (fluid) moves slowly through the lymphatic system. The major distribution of an absorbed chemical is by blood with only minor distribution by lymph. Since virtually all tissues have a blood supply, all organs and tissues of the body are potentially exposed to the absorbed chemical.
Distribution of a chemical to body cells and tissues requires that the toxicant penetrate a series of cell membranes. It must first penetrate the cells of the capillaries (small blood vessels) and later the cells of the target organs. Thefactors pertaining to passage across membranesapply to these other cell membranes as well. For example, important factors include the concentration gradient; molecular weight; lipid solubility; and polarity, with the smaller, nonpolar toxicants in high concentrations being most likely to gain entrance.
The distribution of a xenobiotic can be affected by whether it binds to plasma protein. Some toxicants may bind to these plasma proteins (especially albumin), which removes the toxicant from potential cell interaction. Within the circulating blood, the non-bound (free) portion is in equilibrium with the bound portion. However, only the free substance is available to pass through the capillary membranes. Those substances that are extensively bound are limited in terms of equilibrium and distribution throughout the body. Protein binding in the plasma greatly affects distribution, prolongs the half-life within the body, and affects the dose threshold for toxicity.
The plasma level of a xenobiotic is important since it generally reflects the concentration of the toxicant at the site of action. The passive diffusion of the toxicant into or out of these body fluids will be determined mainly by the toxicant's concentration gradient.
Volume of Distribution (written as V subscript D - see example in formula below) Theapparent volume of distribution (VD)is the total volume of body fluids in which a toxicant is distributed. The VDis expressed in liters.
If a toxicant is distributed only in the plasma fluid, the plasma concentration will remain high and a low VDresults; however, if a toxicant is distributed in all sites (blood plasma, interstitial, and intracellular fluids) there is greater dilution in plasma concentration and a higher VDwill result. Binding in effect reduces the concentration of free toxicants in the plasma or VD. Toxicants that undergo rapid storage, biotransformation, or elimination further affect the VD. Toxicologists determine the VDof a toxicant in order to know how extensively a toxicant is distributed in the body fluids. The volume of distribution can be calculated by the formula:
The volume of distribution may provide useful estimates as to how extensive the toxicant is distributed in the body. For example, a very high apparent VDmay indicate that the toxicant has distributed to a particular tissue or storage area such as adipose tissue. In addition, the body burden for a toxicant can be estimated from knowledge of the VDby using the formula:
It may be biotransformed into different chemicals (metabolites).
Its metabolites may be excreted or stored.
The chemical or its metabolites may interact or bind with cellular components.
Most chemicals undergo some biotransformation. The degree with which various chemicals are biotransformed and the degree with which the parent chemical and its metabolites are stored or excreted vary with the nature of the exposure (dose level, frequency, and route of exposure).
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Knowledge Check (Solutions on next page)
1) When an ingested toxicant is absorbed, it passes through the cells lining the GI tract into the: a) Intracellular fluid b) Gastric fluid c) Interstitial fluid
2) The apparent volume of distribution represents the: a) Total volume of body fluids in which a toxicant is distributed b) Amount of blood plasma in which a toxicant is dissolved c) Amount of interstitial fluid that contains a toxicant
1) Interstitial fluid-This is the correct answer. When a chemical is absorbed it passes through cell linings of the absorbing organ (in this case, the gastrointestinal tract) into the interstitial fluid (fluid surrounding cells) within that organ.
2) Total volume of body fluids in which a toxicant is distributed-This is the correct answer. The apparent volume of distribution (VD) represents the total volume of body fluids in which a toxicant is distributed. It consists of the interstitial fluid, intracellular fluid, and the blood plasma. Soon after absorption, a toxicant may be distributed to all three types of fluids, although the concentrations may be quite different. Rarely will a toxicant be distributed to only one type of fluid.
Theroute of exposureis an important factor that can affect the concentration of the toxicant (or its metabolites) at any specific location within the blood or lymph. This can be important since the time and path taken by the chemical as it moves through the body influences the degree of biotransformation, storage, and elimination (and thus toxicity).
For example, if a chemical goes to the liver before going to other parts of the body, much of it may be biotransformed quickly. In this case, the blood levels of the toxicant "downstream" may be diminished or eliminated. This way of processing the chemical right away can dramatically affect its potential toxicity.
Gastrointestinal Tract and Peritoneum When toxicants are absorbed through thegastrointestinal (GI) tract, a similar biotransformation process occurs. Blood carries absorbed toxicants entering the vascular system of the GI tract directly to the liver via the portal system. This is also true for those drugs administered by intraperitoneal injection. Blood from most of the peritoneum also enters the portal system and goes immediately to the liver. Blood from the liver then flows to the heart and then on to the lung, before going to other organs.
Thus, toxicants entering from the GI tract or peritoneum are immediately subject to biotransformation or excretion by the liver and elimination by the lung. This is often referred to as the "first-pass effect."
For example, first-pass biotransformation of the drug propranolol (cardiac depressant) is about 70% when given orally. This means the blood level of this medication is only about 30% of a comparable dose administered intravenously.
Lung and Skin Drugs and other substances that are absorbed through thelungsorskinenter the bloodstream to be carried throughout the body. Thus, they avoid the liver (hepatic) first-pass effect that would have occurred if they had been absorbed from the gastrointestinal tract. These substances can have local effects in the lungs or skin in addition to having systemic effects, and some cells in the lungs and skin may metabolize the drug or other substance. Examples of a "local first-pass effect" in the skin due to metabolism are when nitroglycerin and cortisol applied to the skin. Drugs administered intravenously or intramuscularly also enter the bloodstream to be carried throughout the body and avoid the liver (hepatic) first-pass effect.
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Did you know? Some advantages of transdermal drug delivery (skin patches):
They are a better way to deliver substances that are broken down by the stomach acids, not well absorbed from the gut, or extensively broken down by the liver.
They are a substitute for oral route.
They permit constant dosing rather than the peaks and valley in medication level associated with orally administered medication.
They can minimize undesirable side effects.
They can be used to prescribe drugs that have short biological half-lives or a narrow therapeutic window.
They can be removed, thereby terminating therapy easily.
They are noninvasive, avoiding the inconvenience of IV therapy or injections.
They can be used with patients who are nauseated or unconscious.
Lymph The delivery of drugs and bioactive compounds via the lymphatic system avoids first-pass metabolism by the liver and increases oral bioavailability. It is also a way to deliver drugs for diseases that spread through the lymphatic system such as certain types of cancer and the human immunodeficiency virus (HIV). For example,liposomes (see below) composed of phosphatidylethanol can enhance the oral bioavailability of poorly absorbed hydrophilic drugs such as cefotaxime.
Liposomes are small sphere-shaped vesicles which consist of one or more bilayers created from cholesterol and phospholipids. They were first described in the mid-1960s. Liposomes offer several advantages for delivery of some drugs. They:
Are non-toxic, flexible, biocompatible, completely biodegradable, and non-immunogenic for systemic and non-systemic administrations.
Can provide increased efficacy, stability, and therapeutic index for some drugs.
Can reduce the toxicity of the encapsulated drug.
Can help reduce the exposure of sensitive tissues to toxic drugs.
Can be used with other molecules to offer site-specific "ligand-targeted liposome design" for delivery of a drug to a tumor or elsewhere in the body.
Blood The blood levels of a drug or other substance depend on the site of absorption, whether being absorbed after subcutaneous injection or more quickly from intramuscular injection. These blood levels also depend on the individual's rate of local and systemic biotransformation, and the rate of excretion. Uptake and release can occur in areas of the body away from the first site of absorption. Some anesthetics can be taken up by the lungs and later released, impacting blood levels. Lidocaine, given intravenously, is one example of this later release. Further, as noted elsewhere in ToxTutor, the metabolism of a substance can vary widely from person-to-person due to factors such as genetic differences, age, diet, and diseases that affect metabolism.
Some advantages of intramuscular injections:
They are absorbed faster than subcutaneous injection, partly because muscle tissue has a larger blood supply than tissue just under the skin.
They can hold a greater injected volume of drug (or vaccine) than a subcutaneous tissue injection can.
They can be used instead of intravenous injection if a drug is irritating to veins or if a suitable vein cannot be located.
They may be used instead of oral delivery if a drug is known to be degraded by stomach acids.
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Knowledge Check (Solutions on next page)
1) The main difference in distribution of a toxicant absorbed from the gastrointestinal tract from toxicants absorbed through the skin or from inhalation is: a) The toxicant is distributed to more organs b) A greater amount of the toxicant that is absorbed will be distributed to distant parts of the body c) The toxicant enters the systemic circulatory system after first passing through the liver
1) The toxicant enters the systemic circulatory system after first passing through the liver-This is the correct answer. Toxicants that enter the vascular system of the gastrointestinal tract are carried directly to the liver by the portal system. Thus, toxicants are immediately subject to biotransformation or excretion by the liver. This is often referred to as the "first pass effect."
Dispositionis the term often used to describe the combined processes of distribution, biotransformation, and elimination. The most used disposition models are compartmental models, which are categorized as one-compartment, two-compartment, and multicompartment models. Compartmental models can be used to predict the time course of drug concentrations in the body. These compartments could represent a group of similar tissues or fluids.
For example:
Blood is a compartment.
Fat (adipose) tissue, bone, liver, kidneys, and brain are other major compartments.
Kinetic models may be a 1) one-compartment open model; 2) two-compartment open model; or 3) multiple compartment model.
One-Compartment Model Aone-compartment open modelmay be used for drugs like aminoglycosides which rapidly distribute (equilibrate) to tissues and fluids within the body. In other words, the entire body acts like one uniform compartment. This model is also called a one-compartment open model, with "open" being the assumption that the drug can enter and leave the body via excretion. The figure below shows the disposition of a drug or other substance that distributes instantaneously and evenly in the body, and is eliminated at a rate and amount that is proportional to the amount left in the body. This is known as a "first-order" rate and represented as the logarithm of concentration in blood as a linear function of time (Figure 1).
Figure 1. One-compartment open model (Image Source: NLM)
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Thehalf-lifeof the chemical that follows a one-compartment model is simply the time required for half of the chemical to be lost from the plasma. Only a few chemicals actually follow the simple, first-order, one compartment model.
Two-Compartment Model For most chemicals, it is necessary to describe the kinetics in terms of at least a two-compartment model. A two-compartment model is used for drugs which distribute slowly within the body. This model is also called a two-compartment open model, with "open" being the assumption that the drug can enter and leave the body.
For example, a one-time (bolus) intravenous administration over a short time period could lead to a drug distributing rapidly in the blood and also to highly perfused (by blood) organs like the liver and kidneys. This would be one compartment of the two-compartment model. There would be a slower distribution to other parts of the body as the second compartment.
Two examples are vancomycin and digoxin. As shown in Figure 2, the drug or other substance enters and distributes in the first compartment. It is then distributed to another compartment. The concentration in the first compartment declines with time while the concentration in the second compartment rises, peaks, and declines as the chemical is eliminated from the body.
Figure 2. Two-compartment open model (Image Source: NLM)
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A half-life for a chemical whose kinetic behavior fits a two-compartment model is often referred to as the "biological half-life." This is the most commonly used measure of the kinetic behavior of a xenobiotic.
Multiple Compartment Model Frequently the one- and two-compartment models cannot adequately describe the kinetics of a chemical within the body since there may be several peripheral body compartments to which the chemical may go, including long-term storage. In addition, biotransformation and elimination of a chemical may not be simple processes but subject to different rates as blood levels change.
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Knowledge Check (Solutions on next page)
1) Disposition models describe: a) How a toxicant moves within the body over time b) How the body eliminates the toxicant c) The pathway for biotransformation of the toxicant within the liver
1) How a toxicant moves within the body over time-This is the correct answer. Disposition models, also known as kinetic models, describe how a toxicant moves within the body compartments with time.
Organs or tissues differ in the amount of a chemical that they receive or to which they are exposed. This is primarily due to two factors: the 1)volume of bloodflowing through a specific tissue and the 2)presence of special barriersto slow down a toxicant's entrance.
Volume of Blood and Tissue Affinity Organs that receive largerblood volumescan potentially accumulate more of a given toxicant. Body regions that receive a large percentage of the total cardiac output include the liver (28%), kidneys (23%), heart muscle, and brain. Bone and adipose tissues have relatively low blood flow, even though they serve as primary storage sites for many toxicants. This is especially true for toxicants that are fat-soluble and those that readily associate (or form complexes) with minerals commonly found in bone.
Tissue affinitydetermines the degree of concentration of a toxicant. In fact, some tissues have a higher affinity for specific chemicals and accumulate a toxicant in great concentrations despite a rather low flow of blood.
For example, adipose tissue, which has a meager blood supply, concentrates lipid-soluble toxicants. Once deposited in these storage tissues, toxicants may remain for long periods, due to their solubility in the tissue and the relatively low blood flow.
Structural Barriers During distribution, the passage of toxicants from capillaries into various tissues or organs is not uniform.Structural barriersexist that restrict the entrance of toxicants into certain organs or tissues. The primary barriers are those of the brain, placenta, and testes.
Blood-Brain Barrier Theblood-brain barrierprotects the brain from most toxicants. Specialized cells called astrocytes possess many small branches, which form a barrier between the capillary endothelium and the neurons of the brain. Lipids in the astrocyte cell walls and very tight junctions between adjacent endothelial cells limit the passage of water-soluble molecules. The blood-brain barrier is not completely impenetrable and its penetrability can vary with health status/disease state, but it does slow down the rate at which toxicants cross into brain tissue while allowing essential nutrients, including oxygen, to pass through.
Placental Barrier Theplacental barrierprotects the sensitive, developing fetus from most toxicants distributed in the maternal circulation. This barrier consists of several cell layers between the maternal and fetal circulatory vessels in the placenta. Lipids in the cell membranes limit the diffusion of water-soluble toxicants. However, nutrients, gases, and wastes of the developing fetus can pass through the placental barrier. As in the case of the blood-brain barrier, the placental barrier is not completely impenetrable but effectively slows down the diffusion of most toxicants from the mother into the fetus.
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Knowledge Check (Solutions on next page)
1) Organs may differ greatly in the concentration of a toxicant in them, due primarily to the: a) Rate of elimination of the toxicant by the kidneys b) Distance of the organ from the heart since the toxicant disintegrates quickly in the blood plasma c) Volume of blood flow and the presence of special barriers
2) The placental barrier protects the fetus from toxicants in the maternal blood because: a) Substances in the maternal blood must move through several layers of cells in order to gain entrance to placental blood b) The placenta does not contain circulating fetal blood that can absorb toxicants from the maternal blood c) Toxicants in maternal blood are usually lipid soluble and must be water-soluble in order to penetrate through the placental cell layers
1) Volume of blood flow and the presence of special barriers-This is the correct answer. Organs or tissues differ in the amount of a chemical that they receive or to which they are exposed. This is primarily due to two factors, thevolume of bloodflowing through a specific tissue and thepresence of special "barriers"to slow down toxicant entrance. Organs that receive larger blood volumes can potentially accumulate more of a given toxicant.
2) Substances in the maternal blood must move through several layers of cells in order to gain entrance to placental blood-This is the correct answer. The placental barrier protects the developing and sensitive fetus from most toxicants distributed in the maternal circulation. This barrier consists of several cell layers between the maternal and fetal circulatory vessels in the placenta. Lipids in the cell membranes limit the diffusion of water-soluble toxicants.
Storageof toxicants in body tissues sometimes occurs. Initially, when a toxicant enters the blood plasma, it may be bound to plasma proteins. Toxicants attached to proteins are considered a form of storage because they do not contribute to the chemical's toxic potential. Albumin is the most abundant plasma protein that binds toxicants. Normally, the toxicant is only bound to the albumin for a relatively short time.
The primary sites for toxicant storage are adipose tissue, bone, liver, and kidneys.
Adipose Tissue Lipid-soluble toxicants are often stored inadipose tissues. Adipose tissue is located in several areas of the body but mainly in subcutaneous tissue. Lipid-soluble toxicants can be deposited along with triglycerides in adipose tissues. The lipids are in a continual exchange with blood and thus the toxicant may be mobilized into the blood for further distribution and elimination, or redeposited in other adipose tissue cells.
Bone Boneis another major site for storage. Bone is composed of proteins and the mineral salt hydroxyapatite. Bone contains a sparse blood supply but is a live organ. During the normal processes that form bone, calcium and hydroxyl ions are incorporated into the hydroxyapatite-calcium matrix. Several chemicals, primarily elements, follow the same kinetics as calcium and hydroxyl ions and therefore can be substituted for them in the bone matrix.
For example, strontium (Sr) or lead (Pb) may be substituted for calcium (Ca), and fluoride (F-) may be substituted for hydroxyl (OH-) ions. Bone is continually being remodeled under normal conditions. Calcium and other minerals are continually being resorbed and replaced, on the average about every 10 years. Thus, any toxicants stored in the matrix will eventually be released to re-enter the circulatory system.
Liver and Kidneys Theliveris a storage site for some toxicants. It has a large blood flow and its hepatocytes (that is, liver cells) contain proteins that bind to some chemicals, including toxicants.
As with the liver, thekidneyshave a high blood flow, which preferentially exposes these organs to toxicants in high concentrations. Storage in the kidneys is associated primarily with the cells of the nephron (the functional unit for urine formation).
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Knowledge Check (Solutions on next page)
1) The areas of the body which most frequently store toxicants are: a) Adrenal gland, thyroid gland, and pancreas b) Adipose tissue, bone, liver, and kidney c) Skeletal muscle, tendons, and leg joints
1) Adipose tissue, bone, liver, and kidney-This is the correct answer. The primary sites for toxicant storage are adipose tissue, bone, liver and kidneys. Lipid-soluble toxicants store in adipose tissues; chemicals that follow calcium or hydroxyl ion kinetics store in bone; and the liver and kidney cells are subjected to high concentrations of toxicants.
What We've Covered This section made the following main points:
Distribution is the process in which an absorbed chemical moves away from the site of absorption to other areas of the body.
An absorbed chemical passes through cell linings of the absorbing organ (skin, lung, or gastrointestinal tract) into the interstitial fluid of that organ.
The toxicant can leave the interstitial fluid by entering local tissue cells, blood capillaries and the blood circulatory system, or the lymphatic system.
If the toxicant gains entrance into the blood plasma, it:
Travels bound or unbound along with the blood.
May be excreted, stored, or biotransformed, or may interact or bind with cellular components.
The volume of distribution (VD) is the total volume (in liters) of body fluids in which a toxicant is distributed.
The route of exposure is an important factor affecting the concentration of the toxicant or its metabolites at any specific location within the blood or lymph.
Toxicants entering from the GI tract or peritoneum are immediately subject to biotransformation or excretion by the liver and elimination by the lung (this is often called the "first-pass effect").
Toxicants absorbed through the lung or skin enter the blood and go directly to the heart and systemic circulation, thus being distributed to various organs before going to the liver (not subject to the first-pass effect).
Toxicants that enter the lymph will not go to the liver first, but will slowly enter systemic circulation.
The blood level of a toxicant depends on the site of absorption and the rate of biotransformation and excretion.
Disposition is the combined processes of distirbution, biotransformation, and elimination. Disposition models can be:
One-Compartment Open Model — disposition of a substance introduced and distributed instantaneously and evenly in the body and eliminated proportionally to the amount left in the body ("first-order" rate).
Two-Compartment Open Model — the chemical enters and distributes in the first compartment (usually blood), then distributed to another compartment where it can be eliminated or may return to the first compartment.
The biological half-life, the most commonly used measure of the kinetic behavior of a xenobiotic, is the half-life for a chemical in a two-compartment model.
Multiple Compartment Model — the chemical involves several peripheral body compartments, including long-term storage, or biotransformation and elimination at varying rates as blood levels change.
Organs or tissues differ in the amount of a chemical they may receive, depending on:
Volume of blood — organs that receive larger blood volumes potentially accumulate more of a given toxicant.
Tissue affinity — some tissues have a higher affinity for specific chemicals, accumulating a toxicant in great concentrations despite a rather low flow of blood.
Structural barriers to distribution include the blood-brain barrier and the placental barrier.
Toxicology Defined Toxicology is an evolving medical science and toxicology terminology is evolving with it. Most terms are very specific and will be defined as they appear in the tutorial. However, some terms are more general and used throughout the various sections. The most commonly used terms are introduced in this section.
Toxicology is the study of the adverse effects of chemicals or physical agents on living organisms.
A toxicologist is a scientist who determines the harmful effects of agents and the cellular, biochemical, and molecular mechanisms responsible for the effects.
Toxinology, a specialized area of study, looks at microbial, plant and animal venoms, poisons, and toxins.
Terminology and definitions for materials that cause toxic effects are not always consistently used in the literature. The most common terms are toxicant, toxin, poison, toxic agent, toxic substance, and toxic chemical. Toxicant, toxin, and poison are often used interchangeably in the literature but there are subtle differences as shown below:
Toxic Agents A toxic agent is anything that can produce an adverse biological effect. It may be chemical, physical, or biological in form. For example, toxic agents may be:
The toxicity of the agent is dependent on the dose.
A distinction is made for diseases people get from living organisms. Organisms that invade and multiply within another organism and produce their effects by biological activity are not classified as toxic agents but as biological agents. An example of this is a virus that damages cell membranes resulting in cell death.
If the invading organisms excrete chemicals which are the basis for their toxicity, the excreted substances are known as biological toxins. In that case, the organisms are called toxic organisms. A specific example is tetanus. Tetanus is caused by a bacterium,Clostridium tetani. The bacteria C. tetani itself does not cause disease by invading and destroying cells. Rather, a toxin (neurotoxin) that the bacteria excrete travels to the nervous system and produces the disease (Figure 8).
Figure 8. Micrograph of a group of Clostridium tetani bacteria (Image Source: CDC)
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Toxic Substances
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A toxic substance is simply a material that has toxic properties. It may be a discrete toxic chemical or a mixture of toxic chemicals. For example, lead chromate, asbestos, and gasoline are all toxic substances. More specifically:
Lead chromate is a discrete toxic chemical.
Asbestos is a toxic material that does not have an exact chemical composition but comprises a variety of fibers and minerals.
Gasoline s a toxic substance rather than a toxic chemical in that it contains a mixture of many chemicals. Toxic substances may not always have a constant composition. The composition of gasoline varies with octane level, manufacturer, time of season, and other factors.
Toxic substances may be systemic toxicants or organ toxicants.
A systemic toxicant affects the entire body or many organs rather than a specific site. For example, potassium cyanide is a systemic toxicant in that it affects virtually every cell and organ in the body by interfering with the cells’ ability to use oxygen. Toxicants may also affect only specific tissues or organs while not producing damage to the body as a whole. These specific sites are known as the target organsor target tissues.
Benzene is a specific organ toxicantin that it is primarily toxic to the blood-forming tissues.
Lead is also a specific organ toxicant; however, it has three target organs:the central nervous system, the kidneys, and the hematopoietic system.
A toxicant may affect a specific type of tissue (such as connective tissue) that is present in several organs. The toxic site is then considered thetarget tissue.
Types of Cells The body is composed of many types of cells, which can be classified in several ways. Table 1 shows examples of one classification of one type of cells.
Germ cellsare involved in reproduction and can give rise to a new organism. They have only a single set of chromosomes peculiar to a specific sex. Male germ cells give rise to sperm and female germ cells develop into ova. Toxicity to germ cells can cause effects in a developing fetus that lead to outcomes such as birth defects or miscarriage.
Somatic cellsare all body cells except the reproductive germ cells. (Somatic cells include the "basic structure" and "tissue type" cells listed in Table 1). They have two sets (or pairs) of chromosomes. In an exposed individual, toxicity to somatic cells causes a variety of toxic effects, such as dermatitis, death, and cancer. Figure 11 illustrates the differences between germ cells and somatic cells.
Figure 11. Germ cells and somatic cells (Image Source: National Human Genome Research Institute,http://www.genome.gov)
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Natural and Man-Made Chemicals Often, people mistakenly assume that all man-made chemicals are harmful and natural chemicals are beneficial. In reality, natural chemicals can be just as harmful to human health as man-made chemicals, and in many cases, more harmful. Figure 12 compares the toxicity of several natural and man-made chemicals.
Biotransformationis the process by which a substance changes from one chemical to another (transformed) by a chemical reaction within the body.Metabolismormetabolic transformationsare terms frequently used for the biotransformation process. However, metabolism is sometimes not specific for the transformation process but may include other phases of toxicokinetics.
Importance of Biotransformation Biotransformation is vital to survival because it transforms absorbed nutrients (food, oxygen, etc.) into substances required for normal body functions. For some pharmaceuticals, it is a metabolite that is therapeutic and not the absorbed drug.
For example, phenoxybenzamine, a drug given to relieve hypertension caused by pheochromocytoma, a kind of tumor, is biotransformed into a metabolite, which is the active agent.
Biotransformation also serves as an important defense mechanism since toxic xenobiotics and body wastes are converted into less harmful substances and substances that can be excreted from the body.
Toxicants that are lipophilic, non-polar, and of low molecular weight are readily absorbed through the cell membranes of the skin, GI tract, and lung. These same chemical and physical properties control the distribution of a chemical throughout the body and its penetration into tissue cells. Lipophilic toxicants are hard for the body to eliminate and can accumulate to hazardous levels. However, most lipophilic toxicants can be transformed into hydrophilic metabolites that are less likely to pass through membranes of critical cells. Hydrophilic chemicals are easier for the body to eliminate than lipophilic substances. Biotransformation is thus a key body defense mechanism.
Fortunately, the human body has a well-developed capacity to biotransform most xenobiotics as well as body wastes.
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Did you know? Hemoglobin, the oxygen-carrying iron-protein complex in red blood cells, is an example of a body waste that must be eliminated. The normal destruction of aged red blood cells releases hemoglobin. Bilirubin is one of several hemoglobin metabolites. If the body cannot eliminate bilirubin via the liver because of disease, medicine, or infection, bilirubin builds up in the body and the whites of the eyes and the skin may look yellow. Bilirubin is toxic to the brain of newborns and, if present inhigh concentrations, may cause irreversible brain injury. Biotransformation of the lipophilic bilirubin molecule in the liver results in the production of water-soluble (hydrophilic) metabolites excreted into bile and eliminated via the feces.
Potential Complications The biotransformation process is not perfect.Detoxificationoccurs when biotransformation results in metabolites of lower toxicity. In many cases, however, the metabolites are more toxic than the parent substance, a process calledbioactivation. Occasionally, biotransformation can produce an unusually reactive metabolite that may interact with cellular macromolecules like DNA. This can lead to very serious health effects such as cancer or birth defects.
An example is the biotransformation of vinyl chloride into vinyl chloride epoxide, which covalently binds to DNA and RNA, a step leading to cancer of the liver.
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Knowledge Check (Solutions on next page)
1) The term "biotransformation" refers to: a) An increase in electrical charge in tissues produced by a biological transformer b) Chemical reactions in the body that create a new chemical from another chemical c) The transformation of one type of cell in a tissue to another type of cell
2) Detoxification is a biotransformation process in which: a) Metabolites of lower toxicity are produced b) Metabolites of higher toxicity are produced
3) Bioactivation is a biotransformation process in which: a) Metabolites of lower toxicity are produced b) Metabolites of higher toxicity are produced
1) Chemical reactions in the body that create a new chemical from another chemical-This is the correct answer. Biotransformation is the process whereby a substance is changed from one chemical to another (transformed) by a chemical reaction within the body.
2) Metabolites of lower toxicity are produced-This is the correct answer. When biotransformation results in metabolites of lower toxicity, the process is known as detoxification.
3) Metabolites of higher toxicity are produced-This is the correct answer. When biotransformation results in metabolites of higher toxicity, this is known as bioactivation.
Chemical reactions are continually taking place in the body. They are a normal aspect of life, participating in the:
Building up of new tissue.
Tearing down of old tissue.
Conversion of food to energy.
Disposal of waste materials.
Elimination of toxic xenobiotics.
Within the body is a magnificent assembly of chemical reactions, which is well orchestrated and called upon as needed. Most of these chemical reactions occur at significant rates only because specific proteins, known as enzymes, are present to catalyze them, that is, accelerate the reaction. A catalyst is a substance that can accelerate a chemical reaction of another substance without itself undergoing a permanent chemical change.
Enzymes Enzymesare the catalysts for nearly all biochemical reactions in the body. Without these enzymes, essential biotransformation reactions would take place slowly or not at all, causing major health problems.
Did you know? Phenylketonuria (PKU) is the genetic condition in which the enzyme that biotransforms phenylalanine to tyrosine (another amino acid) is defective. As the result, phenylalanine can build up in the body and cause severe mental retardation. Babies are routinely checked at birth for PKU. If they have PKU, they need to follow a special diet to restrict the intake of phenylalanine in infancy and childhood.
Figure 1. Phenylketonuia (PKU) testing in an infant (Image Source:Wikimedia Commons, obtained under Public Domain license. Author: U.S. Air Force Photographic Archives)
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These enzymatic reactions are not always simple biochemical reactions. Some enzymes require the presence of cofactors or coenzymes in addition to thesubstrate(the substance to be catalyzed) before their catalytic activity can be exerted. These co-factors exist as a normal component in most cells and are frequently involved in common reactions to convert nutrients into energy (vitamins are an example of co-factors). It is the drug or chemical transforming enzymes that hold the key to xenobiotic transformation. The relationship of substrate, enzyme, coenzyme, and transformed product can be shown as:
Most biotransforming enzymes are high molecular weight proteins, composed of chains of amino acids linked together by peptide bonds. A wide variety of biotransforming enzymes exist. Most enzymes will catalyze the reaction of only a few substrates, meaning that they have high specificity. Specificity is a function of the enzyme's structure and its catalytic sites. While an enzyme may encounter many different chemicals, only those chemicals (substrates) that fit within the enzyme's convoluted structure and spatial arrangement will be locked on and affected. This is sometimes referred to as the "lock and key" relationship.
As shown in Figure 2, when a substrate fits into the enzyme's structure, an enzyme-substrate complex can be formed. This allows the enzyme to react with the substrate with the result that two different products are formed. If the substrate does not fit into the enzyme ("incompatible"), no complex will be formed and thus no reaction can occur.
Figure 2. If the substrate does not fit into the enzyme, no complex will be formed and no reaction will occur. (Image Source: NLM)
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Enzyme Specificity Enzymes range from having absolute specificity to broad and overlapping specificity. In general, there are three main types of specificity:
Absolute— the enzyme will catalyze only one reaction. Examples:
Formaldehyde dehydrogenase catalyzes only the reaction for formaldehyde.
Acetylcholinesterase biotransforms the neurotransmitting chemical, acetylcholine.
Group— the enzyme will act only on molecules that have specific functional groups, such as amino, phosphate, or methyl groups.
For example, alcohol dehydrogenase can biotransform several different alcohols, including methanol and ethanol.
Linkage— the enzyme will act on a particular type of chemical bond regardless of the rest of the molecular structure.
For example, N-oxidation can catalyze a reaction of a nitrogen bond, replacing the nitrogen with oxygen.
Enzyme Naming Convention The names assigned to enzymes may seem confusing at first. However, except for some of the originally studied enzymes (such as pepsin and trypsin), a convention has been adopted to name enzymes. Enzyme names end in "ase" and usually combine the substrate acted on and the type of reaction catalyzed.
For example, alcohol dehydrogenase is an enzyme that biotransforms alcohols by the removal of a hydrogen. The result is a completely different chemical, an aldehyde or ketone.
The biotransformation of ethyl alcohol to acetaldehyde is depicted in Figure 3.
ADH = alcohol dehydrogenase, a specific catalyzing enzyme
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Figure 3. Biotransformation of ethyl alcohol (Image Source: NLM)
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Beneficial or Harmful?
At this point in ToxTutor you likely see that the transformation of a specific xenobiotic can be either beneficial or harmful, and perhaps both depending on the dose and circumstances.
A good example is the biotransformation of acetaminophen (Tylenol®). When the prescribed doses are taken, the desired therapeutic response is observed with little or no toxicity. However, when excessive doses of acetaminophen are taken, hepatotoxicity can occur. This is because acetaminophen normally undergoes rapid biotransformation with the metabolites quickly eliminated in the urine and feces.
At high doses, the normal level of enzymes may be depleted and the acetaminophen is available to undergo the reaction by an additional biosynthetic pathway, which produces a reactive metabolite that is toxic to the liver. For this reason, a user of Tylenol®is warned not to take the prescribed dose more frequently than every 4–6 hours and not to consume more than four doses within a 24-hour period.
Biotransforming enzymes, like most other biochemicals, are available in a normal amount and in some situations can be "used up" at a rate that exceeds the body's ability to replenish them. This illustrates the frequently used phrase, the "dose makes the poison."
Biotransformation Reaction Phases Biotransformation reactions are categorized not only by the nature of their reactions, for example, oxidation, but also by the normal sequence with which they tend to react with a xenobiotic. They are usually classified as Phase I and Phase II reactions.
Phase I reactionsare generally reactions which modify the chemical by adding a functional structure. This allows the substance to "fit" into a second, or Phase II enzyme, so that it can become conjugated (joined together) with another substance.
Phase II reactionsconsist of those enzymatic reactions that conjugate the modified xenobiotic with another substance. The conjugated products are larger molecules than the substrate and generally polar in nature (water soluble). Thus, they can be readily excreted from the body. Conjugated compounds also have poor ability to cross cell membranes.
In some cases, the xenobiotic already has a functional group that can be conjugated and the xenobiotic can be biotransformed by a Phase II reaction without going through a Phase I reaction.
For example, phenol can be directly conjugated into a metabolite that can then be excreted. The biotransformation of benzene requires both Phase I and Phase II reactions. As illustrated in Figure 5, benzene is biotransformed initially to phenol by a Phase I reaction (oxidation). Phenol has a structure including a functional hydroxyl group that is then conjugated by a Phase II reaction (sulfation) to phenyl sulfate.
Figure 5. Biotransformation of benzene into phenol in Phase 1 (oxidation), which is then conjugated by a Phase 2 reaction (sulfation) to phenyl sulfate (Image Source: NLM)
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Table 1 lists the major transformation reactions for xenobiotics broken into Phase I and Phase II reactions. These reactions are discussed in more detailed below.
Phase I Reactions Phase I biotransformation reactions are simple reactions compared to Phase II reactions. In Phase I reactions, a small polar group (containing both positive and negative charges) is either exposed on the toxicant or added to the toxicant. The three main Phase I reactions are 1) oxidation; 2) reduction; and 3) hydrolysis.
Oxidation Oxidationis a chemical reaction in which asubstrate loses electrons. There are a number of reactions that can achieve the removal of electrons from the substrate.
Theaddition of oxygen, oroxygenation, was the first of these reactions discovered and thus the reaction was named oxidation. However, many of the oxidizing reactions do not involve oxygen.
The simplest type of oxidation reaction isdehydrogenation, which is the removal of hydrogen from the molecule.
Another example of oxidation iselectron transferthat consists simply of the transfer of an electron from the substrate.
Figure 6 shows these types of oxidizing reactions.
Figure 6. Three types of oxidation reactions (Image Source: NLM)
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The specific oxidizing reactions and oxidizing enzymes are numerous and several textbooks are devoted to this subject. Most of the reactions are described by the name of the reaction or enzyme involved. Some of these oxidizing reactions include:
Alcohol dehydrogenation
Aldehyde dehydrogenation
Alkyl/acyclic hydroxylation
Aromatic hydroxylation
Deamination
Desulfuration
N-dealkylation
N-hydroxylation
N-oxidation
O-dealkylation
Sulphoxidation
Reduction Reductionis a chemical reaction in which thesubstrate gains electrons. Reductions are most likely to occur with xenobiotics in which oxygen content is low. Reductions can occur across nitrogen-nitrogen double bonds (azo reduction) or on nitro groups (NO2). Frequently, the resulting amino compounds are oxidized which forms toxic metabolites. Some chemicals such as carbon tetrachloride can be reduced to free radicals, which are quite reactive with biological tissues. Thus, reduction reactions frequently result in activation of a xenobiotic rather than detoxification. An example of a reduction reaction in which the nitro group is reduced is illustrated in Figure 7.
Figure 7. Reduction reaction in which the nitro group is reduced (from NO2to NH2) ** NO2 and NH2 written with subscripts as seen in the Figure above
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There are fewer specific reduction reactions than oxidizing reactions. The nature of these reactions is also described by their name. Some reducing reactions include:
Azo reduction
Dehalogenation
Disulfide reduction
Nitro reduction
N-oxide reduction
Sulfoxide reduction
Hydrolysis Hydrolysisis a chemical reaction in which theaddition of watersplits the toxicant into two fragments or smaller molecules. The hydroxyl group (OH-) is incorporated into one fragment and the hydrogen atom is incorporated into the other. Larger chemicals such as esters, amines, hydrazines, and carbamates are generally biotransformed by hydrolysis.
An example of hydrolysis is illustrated in the biotransformation of procaine (local anesthetic) which is hydrolyzed to two smaller chemicals (Figure 8).
Figure 8. Hydrolysis of procaine (Image Source: Adapted from Humboldt State University, Department of Chemistry. Author: Richard A. Paselk, Professor Emeritus.
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Toxicants that have undergone Phase I biotransformation are converted to metabolites that are sufficiently ionized, or hydrophilic, to be either eliminated from the body without further biotransformation or converted to an intermediate metabolite that is ready for Phase II biotransformation. The intermediates from Phase I transformations may be pharmacologically more effective and in many cases more toxic than the parent xenobiotic.
Phase II Reactions A xenobiotic that has undergone a Phase I reaction is now a new intermediate metabolite that contains a reactive chemical group such as hydroxyl (-OH), amino (-NH2), and carboxyl (-COOH). Many of these intermediate metabolites do not possess sufficient hydrophilicity to permit elimination from the body. These metabolites must undergo additional biotransformation as a Phase II reaction.
Phase II reactions are conjugation reactions where a molecule normally present in the body is added to the reactive site of the Phase I metabolite. The result is a conjugated metabolite that is more water soluble than the original xenobiotic or Phase I metabolite. Usually, the Phase II metabolite is quite hydrophilic and can be readily eliminated from the body. The primary Phase II reactions are:
Glucuronide conjugation – most important reaction (detailed below)
Sulfate conjugation – important reaction (detailed below)
Acetylation
Amino acid conjugation
Glutathione conjugation
Methylation
Glucuronide Conjugation Glucuronide conjugationis one of the most important and common Phase II reactions. The glucuronic acid molecule is used in this reaction. It is derived from glucose, a common carbohydrate (sugar) that is the primary source of energy for cells. In this reaction, glucuronic acid is added directly to the toxicant or its phase I metabolite. The sites of glucuronidation reactions are substrates having an oxygen, nitrogen, or sulfur bond, which apply to a wide array of xenobiotics as well as endogenous substances, such as bilirubin, steroid hormones, and thyroid hormones.
Glucuronidation is a pathway that conjugates xenobiotics at a high capacity ("high-capacity pathway"). Glucuronide conjugation usually decreases toxicity although there are some notable exceptions, for example, where it can result in producing carcinogenic substances. The glucuronide conjugates are generally quite hydrophilic and are excreted by the kidney or bile, depending on the size of the conjugate. The glucuronide conjugation of aniline is illustrated in Figure 9.
Figure 9. Glucuronide conjugation of aniline (which is used to make polyurethane, pharmaceuticals, and industrial chemicals) (Image Source: NLM)
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Sulfate Conjugation Sulfate conjugationis another important Phase II reaction that occurs with many xenobiotics. In general, sulfation decreases the toxicity of xenobiotics. Unlike glucuronic acid conjugates that are often eliminated in the bile, the highly polar sulfate conjugates are readily secreted in the urine. In general, sulfation is a low-capacity pathway for xenobiotic conjugation. Often glucuronidation or sulfation can conjugate the same xenobiotics.
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Knowledge Check (Solutions on next page)
1) The substances in the body that accelerate chemical reactions are known as: a) Amino acids b) Enzymes c) Substrates
2) The convention used to name specific enzymes consists of combining: a) The substrate name with the type of chemical reaction b) The target organ and the type of chemical reaction c) The substrate name with the form of toxicity
3) Biotransformation reactions are classified as Phase I and Phase II. The basic difference is: a) Phase I reactions conjugate a substrate whereas Phase II reactions oxidize the substance b) Phase I reactions generally add a functional structure whereas Phase II reactions conjugate the substance c) A Phase I reaction generally makes a substance more hydrophilic than a Phase II reaction
4) The difference between oxidation and reduction reactions is: a) A substrate gains electrons from an oxidation reaction whereas it loses electrons by a reduction reaction b) Oxygen is removed from a substrate in oxidation and added in the reduction reaction c) A substrate losses electrons from an oxidation reaction whereas it gains electrons by a reduction reaction
5) Which conjugation reaction is the most common in the biotransformation of xenobiotics? a) Amino acid conjugation b) Glucuronide conjugation c) Methylation
1) Enzymes-This is the correct answer. Enzymes are proteins that catalyze nearly all biochemical reactions in the body.
2) The substrate name with the type of chemical reaction-This is the correct answer. Enzyme names end in "ase" and usually combine the substrate acted on and the type of reaction catalyzed.
3) Phase I reactions generally add a functional structure whereas Phase II reactions conjugate the substance-This is the correct answer. Phase I reactions are generally reactions which modify the chemical by adding a functional structure. This allows the substance to "fit" into the Phase II enzyme so that it can become conjugated (joined together) with another substance. Phase II reactions consist of those enzymatic reactions that conjugate the modified xenobiotic with another substance.
4) A substrate losses electrons from an oxidation reaction whereas it gains electrons by a reduction reaction-This is the correct answer. Oxidation is a chemical reaction in which a substrate loses electrons. Reduction is a chemical reaction in which the substrate gains electrons.
5) Glucuronide conjugation-This is the correct answer. Glucuronide conjugation is one of the most important and common Phase II reactions. Glucuronidation is a high-capacity pathway for xenobiotic conjugation.
Biotransforming enzymes are widely distributed throughout the body.
The liver is the primary biotransforming organ due to its large size and high concentration of biotransforming enzymes.
The kidneys and lungs are next with 10-30% of the liver's capacity.
A low capacity exists in the skin, intestines, testes, and placenta.
Primary Biotransformation Site: The Liver Since the liver is the primary site for biotransformation, it is also potentially vulnerable to the toxic action of a xenobiotic that is activated to a more toxic compound.
Within the liver cell, the primary subcellular components containing the transforming enzymes are themicrosomes (small vesicles) of the endoplasmic reticulumand the soluble fraction of thecytoplasm (cytosol). The mitochondria, nuclei, and lysosomes contain a small level of transforming activity.
Microsomal enzymes are associated with most Phase I reactions. Glucuronidation enzymes are also contained in microsomes.
Cytosolic enzymes are non-membrane-bound and occur free within the cytoplasm. They are generally associated with Phase II reactions, although some oxidation and reduction enzymes are contained in the cytosol.
The most important enzyme system involved in Phase I reactions are thecytochromes P450, also called the cytochrome P-450 system or the mixed function oxidase (MFO) system, but now mostly called CYP450 or CYPs by scientists and in research publications. It is found in microsomes and is responsible for oxidation reactions of a wide array of chemicals.
Susceptibility of the Liver The liver is particularly susceptible to damage by ingested toxicants because it biotransforms most xenobiotics and receives blood directly from the gastrointestinal tract. Blood leaving the gastrointestinal tract does not flow directly into the general circulatory system. Instead, it flows into the liver first via the portal vein. This process is known as the "first pass." Blood leaving the liver is eventually distributed to all other areas of the body; however, much of the absorbed xenobiotic has undergone detoxification or bioactivation. The liver may have removed most of the potentially toxic chemical. On the other hand, some toxic metabolites are highly concentrated in the liver.
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Knowledge Check (Solutions on next page)
1) The organ that has the greatest ability to biotransform xenobiotics is the: a) Liver b) Pancreas c) Skin
2) The "first pass" phenomenon pertains to: a) The situation where xenobiotics that are absorbed from the GI tract first enter the circulating blood before going to the liver b) A condition where the liver first biotransforms a xenobiotic by Phase II reaction before it is biotransformed by a Phase I reaction c) An anatomical arrangement in which xenobiotics absorbed from the intestine go to the liver first rather than into the systemic circulation
1) Liver-This is the correct answer. Biotransforming enzymes are widely distributed throughout the body. However, the liver has the largest concentration of all organs and thus has a very high capacity for biotransformation.
2) An anatomical arrangement in which xenobiotics absorbed from the intestine go to the liver first rather than into the systemic circulation-This is the correct answer. Blood leaving the gastrointestinal tract does not directly flow into the general circulatory system. Instead, it flows into the liver first via the portal vein. This is known as the "first pass" phenomena.
The relative effectiveness of biotransformation depends on several factors that can inhibit or induce enzymes and dose levels. Factors include:
Species
Age
Gender
Genetic variability
Nutrition
Disease
Exposure to other chemicals
Species It is well known that the capability to biotransform specific chemicals varies byspecies. These differences are termed selective toxicity, which refers to differences in toxicity between species similarly exposed. Research uses what is known about selective toxicity to develop chemicals that are effective but relatively safe in humans.
For example, the pesticide malathion in mammals is biotransformed by hydrolysis to relatively safe metabolites, but in insects, it is oxidized to malaoxon, which is lethal to insects.
Age and Gender Agemay affect the efficiency of biotransformation. In general, human fetuses and newborns have limited abilities to carry out xenobiotic biotransformations. This limitation is due to inherent deficiencies in many of the enzymes responsible for catalyzing Phase I and Phase II biotransformations. While the capacity for biotransformation fluctuates with age in adolescents, by early adulthood the enzyme activities have essentially stabilized. The aged also have decreased biotransformation capability.
Gendermay influence the efficiency of biotransformation for specific xenobiotics. This is usually limited to hormone-related differences in the oxidizing cytochrome P-450 enzymes.
Genetic Variability Genetic variabilityin biotransforming capability accounts for most of the large variation among humans. In particular, human genetic differences influence the Phase II acetylation reaction. Some persons have rapid acetylation ("rapid acetylator") while others have a slow ability to carry out this reaction ("slow acetylator"). The most serious drug-related toxicity occurs in those who have slow acetylators, often referred to as "slow metabolizers." With slow acetylators, acetylation is so slow that blood or tissue levels of certain drugs (or Phase I metabolites) exceed their toxic threshold.
Table 1 includes examples of drugs that build up to toxic levels in slow metabolizers who have specific genetic-related defects in biotransforming enzymes.
Nutrition Poornutritioncan have a detrimental effect on biotransforming ability. Poor nutrition relates to inadequate levels of protein, vitamins, and essential minerals. These deficiencies can decrease a person's ability to synthesize biotransforming enzymes. Many diseases can impair an individual's capacity to biotransform xenobiotics.
For example, hepatitis (a liver disease) is well known to reduce hepatic biotransformation to less than half of its normal capacity.
Prior or Simultaneous Exposure Prior or simultaneous exposure to xenobiotics can cause enzyme inhibition and enzyme induction. In some situations, exposure to a substance will inhibit the biotransformation capacity for another chemical due toinhibition of specific enzymes. A major mechanism for the inhibition is competition between the two substances for the available oxidizing or conjugating enzymes. The presence of one substance uses up the enzyme needed to metabolize the second substance.
Exposure to Other Environmental Chemicals and Drugs Enzyme induction is a situation where prior exposure to certain environmental chemicals and drugs results in an enhanced capability for biotransforming a xenobiotic. The prior exposures stimulate the body to increase the production of some enzymes. This increased level of enzyme activity results in increased biotransformation of a chemical subsequently absorbed.
Examples of enzyme inducers include:
Alcohol
Isoniazid
Polycyclic halogenated aromatic hydrocarbons (for example, dioxin)
Phenobarbital
Cigarette smoke
The most commonly induced enzyme reactions involve the cytochrome P450 enzymes.
Dose Level Dose levelcan affect the nature of the biotransformation. In certain situations, the biotransformation may be quite different at high doses compared to low dose levels. This difference in biotransformation contributes to a dose threshold for toxicity. The existence of different biotransformation pathways can usually explain what causes this dose-related difference in biotransformation. At low doses, a xenobiotic may follow a biotransformation pathway that detoxifies the substance. However, if the amount of xenobiotic exceeds the specific enzyme capacity, the biotransformation pathway is saturated. In that case, it is possible that the level of parent toxin builds up. In other cases, the xenobiotic may enter a different biotransformation pathway that may end up producing a toxic metabolite.
An example of a dose-related difference in biotransformation occurs with acetaminophen (Tylenol®):
At normal doses:
About 96% of acetaminophen is biotransformed to non-toxic metabolites by sulfate and glucuronide conjugation.
About 4% of the acetaminophen oxidizes to a toxic metabolite.
That toxic metabolite is conjugated with glutathione and excreted.
At 7-10 times the recommended therapeutic level:
The sulfate and glucuronide conjugation pathways become saturated and more of the toxic metabolite is formed.
The glutathione in the liver may also be depleted so that the toxic metabolite is not detoxified and eliminated.
It can react with liver proteins and cause fatal liver damage.
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Knowledge Check (Solutions on next page)
1) Selective toxicity refers to a difference in the toxicity of a xenobiotic to different species. This selective toxicity can usually be attributed to differences in: a) The ability to absorb the xenobiotic b) Organ systems between species c) Capability to biotransform the xenobiotic
1) Capability to biotransform the xenobiotic-This is the correct answer. A difference between species in their capability to biotransform a specific chemical is normally the basis for a chemical's selective toxicity.
What We've Covered This section made the following main points:
Biotransformation is the process by which a substance changes from one chemical to another (transformed) by a chemical reaction within the body.
Biotransformation is vital to survival because it transforms absorbed nutrients into substances required for normal body functions.
Potential complications of biotransformation include:
Detoxification — biotransformation results in metabolites of lower toxicity than the parent substance.
Bioactivation — biotransformation results in metabolites of greater toxicity than the parent substance.
Chemical reactions continually occur in the body to build up new tissue, tear down old tissue, convert food to energy, dispose of waste materials, and eliminate toxic xenobiotics.
Enzymes are catalysts for nearly all biochemical reactions in the body; essential biotransformation reactions would be slowed or prevented without these enzymes, causing major health problems.
There are generally three types of enzyme specificity:
Enzymes with absolute specificity catalyze only one reaction.
Enzymes with group specificity act only on molecules that have specific functional groups.
Enzymes with linkage specificity act on a particular type of chemical bond regardless of the rest of the molecular structure.
There are two biotransformation reaction phases:
Phase I reactions modify the chemical by adding a functional structure, allowing the substance to "fit" into a second (Phase II) enzyme:
Oxidation — the substrate loses electrons.
Reduction — the substrate gains electrons.
Hydrolysis — the addition of water splits the toxicant into two fragments or smaller molecules.
Phase II reactions conjugate (join together) the modified xenobiotic with another substance. The most important Phase II reactions are:
Glucuronide conjugation, a high-capacity pathway — glucuronic acid is added directly to the toxicant or its Phase I metabolite, generally resulting in hydrophilic conjugates excreted by the kidney or bile.
Sulfate conjugation, a low-capacity pathway — decreases the toxicity of xenobiotics, resulting in highly polar sulfate conjugates readily secreted in the urine.
Biotransformation sites are the:
Liver (primary site, which also makes it the most susceptible to damage by ingested toxicants).
Kidneys (about 10-30% of the liver's capacity).
Skin, intestines, testes, and placenta (low capacity).
Biotransformation effectiveness depends on factors that can inhibit or induce enzymes and dose levels, including species, age, gender, genetic variability, nutrition, disease, exposure to other chemicals, and the dose level.
What We've Covered In this section, we covered several important concepts:
Toxicology is the study of adverse effects of chemicals and physical agents on living organisms.
A xenobiotic is a foreign substance taken into the body.
A toxic agent is any chemical, physical, or biological agent that can produce an adverse biological effect.
Toxic substances can be systemic toxicants, which affect the entire body or multiple organs, or organ toxicants, which affect a specific organ or tissues.
The dose of a substance is the most important determinant of toxicity.
Coming Up... In the next section, we will explore the concept of dose and its importance to toxicology in greater detail.
Elimination from the body is very important in determining the potential toxicity of a xenobiotic. When the body rapidly eliminates a toxic xenobiotic (or its metabolites), it is less likely that they will be able to concentrate in and damage critical cells. The terms excretion and elimination are frequently used to describe the same process in which a substance leaves the body.Eliminationis sometimes used in a broader sense and includes the removal of the absorbed xenobiotic through metabolic pathways as well as through excretion.Excretion, as used here, pertains to the elimination of the xenobiotic and its metabolites by specific excretory organs.
Except for the lung, polar (hydrophilic) substances are more likely than lipid-soluble toxicants to be eliminated from the body. Chemicals must again pass through membranes in order to leave the body, and the same chemical and physical properties that governed passage across other membranes apply to excretory organs as well.
Primary Routes of Excretion The body uses several routes to eliminate toxicants or their metabolites. The main routes of excretion are via urine, feces, and exhaled air. Thus, the primary organ systems involved in excretion are the:
Urinary system
Gastrointestinal system
Respiratory system
A few other avenues for elimination exist but they are relatively unimportant, except in exceptional circumstances.
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Knowledge Check (Solutions on next page)
1) The three major routes of excretion are: a) Gastrointestinal tract, sweat, and saliva b) Mother's milk, tears, and semen c) Urinary excretion, fecal excretion, and exhaled air
The primary route in which the body eliminates substances is through the kidneys. The main function of the kidney is the excretion of body wastes and harmful chemicals into the urine. The functional unit of the kidney responsible for excretion is the nephron. Each kidney contains about one million nephrons. The nephron has three primary regions that function in the renal excretion process: the glomerulus, proximal tubule, and the distal tubule (Figure 2).
Figure 2. Nephron of the kidney (Image Source: Adapted from Wikimedia Commons, obtained by Public Domain, Creative Commons CC0 1.0 Universal Public Domain Dedication. View original image.)
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Filtration Filtrationtakes place in the glomerulus, which is the vascular beginning of the nephron. Approximately one-fourth of the blood flow from cardiac output circulates through the kidney, the greatest rate of blood flow for any organ. A considerable amount of the blood plasma filters through the glomerulus into the nephron tubule. This results from the large amount of blood flow through the glomerulus, the large pores (40 Angstrom [Å]) in the glomerular capillaries, and the hydrostatic pressure of the blood. Small molecules, including water, readily pass through the sieve-like filter into the nephron tubule. Both lipid soluble and polar substances will pass through the glomerulus into the tubule filtrate. The amount of filtrate is very large, about 45 gallons per day in an adult human. About 99% of the water-like filtrate, small molecules, and lipid-soluble substances, are reabsorbed downstream in the nephron tubule. This means that the amount of urine eliminated is only about one percent of the amount of fluid filtrated through the glomeruli into the renal tubules.
Molecules with molecular weights greater than 60,000 (which include large protein molecules and blood cells) cannot pass through the capillary pores and remain in the blood. If urine contains albumin or blood cells, it indicates that the glomeruli have been damaged. Binding to plasma proteins will influence urinary excretion. Polar substances usually do not bind with the plasma proteins and thus can be filtered out of the blood into the tubule filtrate. In contrast, substances extensively bound to plasma proteins remain in the blood.
Secretion Secretion, which occurs in the proximal tubule section of the nephron, is responsible for the transport of certain molecules out of the blood and into the urine. Secreted substances include potassium ions, hydrogen ions, and some xenobiotics. Secretion occurs by active transport mechanisms that are capable of differentiating among compounds based on polarity. Two systems exist, one that transportsweak acids(such as many conjugated drugs and penicillins) and the other that transportsbasic substances(such as histamine and choline).
Reabsorption Reabsorptiontakes place mainly in the proximal convoluted tubule of the nephron. Nearly all of the water, glucose, potassium, and amino acids lost during glomerular filtration reenter the blood from the renal tubules. Reabsorption occurs primarily by passive transfer based on a concentration gradient, moving from a high concentration in the proximal tubule to the lower concentration in the capillaries surrounding the tubule (Figures 4-6).
A factor that greatly affects reabsorption and urinary excretion is the pH of the urine. This is especially the case with weak electrolytes. If the urine is alkaline, weak acids are more ionized and excretion is increased. Weak acids (such as glucuronide and sulfate conjugates) are less ionized if the urine is acidic and undergo reabsorption and renal excretion is reduced. Since the urinary pH varies in humans, the urinary excretion rates of weak electrolytes also vary.
Examples are phenobarbital (an acidic drug) which is ionized in alkaline urine and amphetamine (a basic drug) which is ionized in acidic urine. Treatment of barbiturate poisoning (such as an overdose of phenobarbital) may include changing the pH of the urine to facilitate excretion.
Diet may have an influence on urinary pH and thus the elimination of some toxicants. For example, a high-protein diet results in acidic urine.
The physical properties (primarily molecular size) and polarity of a substance in the urinary filtrate greatly affect its ultimate elimination by the kidney. Small toxicants (both polar and lipid-soluble) are filtered with ease by the glomerulus. In some cases, large molecules (including some that are protein-bound) may be secreted (by passive transfer) from the blood across capillary endothelial cells and nephron tubule membranes to enter the urine. The major difference in ultimate fate is governed by a substance's polarity. Those substances that are ionized remain in the urine and leave the body. Lipid-soluble toxicants can be reabsorbed and re-enter the blood circulation, which lengthens their half-life in the body and potential for toxicity.
Kidneys, which have been damaged by toxins, infectious diseases, or because of age, have diminished ability to eliminate toxicants thus making those individuals more susceptible to toxins that enter the body. The presence of albumin in the urine indicates that the glomerulus filtering system is damaged, letting large molecules pass through. The presence of glucose in the urine is an indication that tubular reabsorption has been impaired.
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Knowledge Check (Solutions on next page)
1) The reason that much of the blood plasma filters into the renal tubule is due to: a) The large amount of blood, under relatively high pressure, that flows through kidney glomerulae whose capillaries have large pores b) Its high lipid content c) The high binding content of plasma
2) In which area of the nephron does active secretion take place? a) The collecting duct of the nephron b) The proximal tubule of the nephron c) The glomerulus of the nephron
3) Most of the material filtered through the glomerulus is reabsorbed in the proximal convoluted tubule of the nephron. The primary property of a xenobiotic that determines whether it will be reabsorbed is: a) Protein binding b) Molecular size c) Polarity
1) The large amount of blood, under relatively high pressure, that flows through kidney glomerulae whose capillaries have large pores-This is the correct answer. A considerable amount of the blood plasma filters through the glomerulus into the nephron tubule. This results from the large amount of blood flow through the glomerulus, the large pores (40 Angstrom [Å]) in the glomerular capillaries, and the hydrostatic pressure of the blood.
2) The proximal tubule of the nephron-This is the correct answer. Secretion occurs in the proximal tubule section of the nephron and is responsible for the transport of certain molecules out of the blood and into the urine.
3) Polarity-This is the correct answer. The ultimate fate of a substance filtered into the renal tubule is governed by its polarity. Those substances that are ionized remain in the urine and leave the body.
Elimination of toxicants in the feces occurs from two processes:
Excretion in bile, which then enters the intestine ("biliary excretion").
Direct excretion into the lumen of the gastrointestinal tract ("intestinal excretion").
Biliary Excretion Thebiliary routeis an important mechanism for fecal excretion of xenobiotics and is even more important for the excretion of their metabolites. This route generally involves active secretion rather than passive diffusion. Specific transport systems appear to exist for certain types of substances, for example, organic bases, organic acids, and neutral substances. Some heavy metals are excreted in the bile, for example, arsenic, lead, and mercury. However, the most likely substances to be excreted via the bile are comparatively large, ionized molecules, such as those having a large molecular weight (conjugates greater than 300).
Once a substance has been excreted by the liver into the bile, and then into the intestinal tract, it can be eliminated from the body in the feces, or it may be reabsorbed. Since most of the substances excreted in the bile are water soluble, they are not likely to be reabsorbed as such. However, enzymes in the intestinal flora are capable of hydrolyzing some glucuronide and sulfate conjugates, which can release the less polar compounds that may then be reabsorbed. This process of excretion into the intestinal tract via the bile and reabsorption and return to the liver by the portal circulation is known as theenterohepatic circulation(Figure 1).
Enterohepatic circulation prolongs the life of the xenobiotic in the body. In some cases, the metabolite is more toxic than the excreted conjugate. Continuous enterohepatic recycling can occur and lead to very long half-lives of some substances. For this reason, drugs may be given orally to bind substances excreted in the bile.
For example, a resin can be taken orally to bind with dimethylmercury, which had been secreted in the bile. The binding of the resin to dimethylmercury prevents its reabsorption and further toxicity.
Changes in the production and flow of bile into the liver affect the efficiency of biliary excretion.
Liver disease usually causes a decrease in bile flow.
Some drugs such as phenobarbital can produce an increase in bile flow rate. Administration of phenobarbital has been shown to enhance the excretion of methylmercury by this mechanism.
Intestinal Excretion Another way that xenobiotics can be eliminated via the feces is by directintestinal excretion. While this is not a major route of elimination, a large number of substances can be excreted into the intestinal tract and eliminated via feces. Some substances, especially those that are poorly ionized in plasma (such as weak bases), may passively diffuse through the walls of the capillaries, through the intestinal submucosa, and into the intestinal lumen to be eliminated in feces.
Figure 2. Layers of the Alimentary Canal (Image Source: Wikimedia Commons, obtained under Creative Commons Attribution-Share Alike 3.0 Unported license. Author:Goran tek-en. View original image.)
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Intestinal excretion is a relatively slow process and therefore, it is an important elimination route only for those xenobiotics that have slow biotransformation, or slow urinary or biliary excretion. Increasing the lipid content of the intestinal tract can enhance intestinal excretion of some lipophilic substances. For this reason, mineral oil (liquid paraffin, derived from petroleum) is sometimes added to the diet to help eliminate toxic substances, which are known to be excreted directly into the intestinal tract.
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Knowledge Check (Solutions on next page)
1) Substances excreted in the bile are primarily: a) Small, lipid soluble molecules b) Comparatively large, ionized molecules c) Large, lipid soluble molecules
2) Many substances excreted in bile undergo enterohepatic circulation, which involves: a) Excretion of substances into the circulating system rather than into the intestine b) Excretion into the intestinal tract and reabsorption and return to the liver by the portal circulation c) The recycling of xenobiotics between the liver and gall bladder
1) Comparatively large, ionized molecules-This is the correct answer. The most likely substances to be excreted via the bile are comparatively large, ionized molecules, such as large molecular weight (greater than 300) conjugates.
2) Excretion into the intestinal tract and reabsorption and return to the liver by the portal circulation-This is the correct answer. The process of excretion into the intestinal tract via the bile and reabsorption and return to the liver by the portal circulation is known as the enterohepatic circulation. The effect of this enterohepatic circulation is to prolong the life of the xenobiotic in the body.
The lungs are an important route of excretion for xenobiotics (and metabolites) that exist in a gaseous phase in the blood.
Passive Diffusion Blood gases are excreted by passive diffusion from the blood into the alveolus, following a concentration gradient. This type of excretion occurs when the concentration of the xenobiotic dissolved in capillary blood is greater than the concentration of the substance in the alveolar air. Gases with a low solubility in blood are more rapidly eliminated than those gases with a high solubility. Volatile liquids dissolved in the blood are also readily excreted via the expired air.
For example, breathalyzer devices can measure blood alcohol concentration because as alcohol in the blood moves across the alveoli the alcohol in the blood evaporates and is exhaled. The concentration of alcohol in the exhaled air relates to the level of alcohol in the blood.
Impact of Vapor Pressure The amount of a liquid excreted by the lungs is proportional to its vapor pressure. Exhalation is an exception to most other routes of excretion in that it can be a very efficient route of excretion for lipid soluble substances. This is due to the very close proximity of capillary and alveolar membranes, which are thin and allow for the normal gaseous exchange that occurs in breathing.
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Knowledge Check (Solutions on next page)
1) Xenobiotics are eliminated in exhaled air by: a) Passive diffusion b) Active transport c) Facilitated transport
1) Passive diffusion-This is the correct answer. Blood gases are excreted by passive diffusion from the blood into the alveolus, following a concentration gradient. This occurs when the concentration of the xenobiotic dissolved in capillary blood is greater than the concentration of the substance in the alveolar air.
Several minor routes of excretion occur including mother's milk, sweat, saliva, tears, and semen.
Excretion into Breast Milk Excretion into milk can be important since toxicants can be passed with milk to the nursing offspring. In addition, toxic substances can pass from cow's milk to people. Toxic substances are excreted into milk by simple diffusion. Both basic substances and lipid soluble compounds can beexcreted into milk (The National Library of Medicine'sLactMedis a resource for information on drugs, dietary supplements, and herbs that pass into breast milk).
Basic substances can be concentrated in milk since milk is more acidic (pH approximately 6.5) than blood plasma. Since milk contains 3–4% lipids, lipid soluble xenobiotics can diffuse along with fats from plasma into the mammary gland and thus can be present in mother's milk. Substances such as lead, mercury, Bisphenol A (BPA), and phthalates that are chemically similar to calcium can also be excreted into milk along with calcium.
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Did you know? Volatile organic compounds (VOCs) found in indoor air can also be found in breast milk.
Examples include MTBE (methyl tert-butyl ether), chloroform, benzene, and toluene. For benzene, toluene, and MTBE, the levels in breast milk followed the indoor air concentrations. However, the infant average daily dose by inhalation exceeded ingestion rates by 25-to-135 fold. Thus, the amount of VOC exposure from indoor air in nonsmoking households is much greater than the VOC exposure from breast milk. Strategies to lessen infant VOC exposure should focus on improving indoor air quality.
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Excretion into All Other Body Secretions or Tissues Excretion of xenobiotics inall other body secretions or tissues(including the saliva, sweat, tears, hair, and skin) are of only minor importance. Under conditions of great sweat production, excretion in sweat may reach a significant degree. Some metals, including cadmium, copper, iron, lead, nickel, and zinc, may be eliminated in sweat to some extent. Xenobiotics that passively diffuse into saliva may be swallowed and absorbed by the gastrointestinal system. The excretion of some substances into saliva is responsible for the unpleasant taste that sometimes occurs with time after exposure to a substance.
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Knowledge Check (Solutions on next page)
1) The following are minor routes of excretion: a) Sweat and saliva b) Urinary excretion, fecal excretion, and exhaled air
1) Sweat and saliva-This is the correct answer. Several minor routes of excretion exist, primarily via mother's milk, sweat, saliva, tears, and semen. The main routes of excretion are via urine, feces, and exhaled air.
What We've Covered This section made the following main points:
Excretion, as used in ToxTutor, pertains to the elimination of a xenobiotic and its metabolites by specific excretory organs.
The primary organ systems involved in excretion are the:
Urinary system, which involves:
Filtration in the glomerulus.
Secretion in the proximal tubule section of the nephron to transport certain molecules out of the blood and into the urine.
Reabsorption in the proximal convoluted tubule of the nephron to reenter nearly all of the water, glucose, potassium, and amino acids lost during filtration back into the blood.
Gastrointestinal system, which occurs from two processes:
Biliary excretion — generally active secretion by the liver into the bile and then into the intestinal tract, where it can be eliminated in the feces or reabsorbed.
Intestinal excretion — an important elimination route only for xenobiotics that have slow biotransformation or slow urinary or biliary excretion.
Respiratory system, which is important for xenobiotics and metabolites that exist in a gaseous phase in the blood:
Excreted by passive diffusion from the blood into the alveolus.
Minor routes of excretion occur including breast milk, sweat, saliva, tears, and semen.
This section discusses cellular effects yet cell and chemical effects cannot be conveniently separated because cells are constructed of a variety of chemicals of diverse types. Specific intracellular chemical changes may occur as changes in the cell and may affect either its appearance or function. The actual mechanisms leading to cell damage are usually biochemical in nature.
Adaptation Explained To maintain homeostasis, cells and tissues:
"Cope" with new demands placed on them by constantly adapting to changes in the tissue environment.
Are usually capable of an amazing degree of cellular adaptability.
Adapt in a way that may be beneficial in nature (physiological) or detrimental (pathological).
Examples ofphysiological adaptationare:
An increase in skeletal muscle cells in athletes due to exercise and increased metabolic demand.
The increase in number and size of epithelial cells in breasts of women resulting from endocrine stimulation during pregnancy.
When these cells or tissues are damaged, the body attempts to adapt and repair or limit the harmful effects. Often the adaptive changes result in cells or organs that cannot function normally. This imperfect adaptation is a pathological change. Examples ofpathological adaptationsare:
Cellular changes in people who smoke cigarettes: The ciliated columnar epithelium changes to non-ciliated squamous epithelium in the trachea and bronchi of cigarette smokers. The replacement of squamous epithelium can better withstand the irritation of the cigarette smoke. However, the loss of cilia and mucous secretions of columnar epithelium diminish the tracheobronchial defense mechanisms.
Replacement of normal liver cells by fibrotic cells in chronic alcoholics (known as cirrhosis of the liver): A severely cirrhotic liver is incapable of normal metabolism, maintenance of nutrition, and detoxification of xenobiotics.
If the change is minor, cellular adaptation may result and the cells return to normal. When damage is very severe, the result may be cell death or permanent functional incapacitation.
Cellular adaptation to toxic agents includes three basic types:
Increase in cell activity.
Decrease in cell activity.
Alteration in cell morphology (structure and appearance) or cell function.
Specific Types of Cellular Adaptations
Atrophy Atrophyis adecrease in the size of cells. If a sufficient number of cells are involved, the tissue or organ may also decrease in size. When cells atrophy, they have:
Reduced oxygen needs.
Reduced protein synthesis.
Decreased number and size of the organelles.
The most common causes of atrophy are reduced use of the cells, lack of hormonal or nerve stimulation, decrease in nutrition, reduced blood flow to the tissue, and natural aging.
An example of atrophy is the decrease in the size of muscles and muscle cells in persons whose legs are paralyzed, in a cast, or infrequently used as when a patient is on bedrest.
Hypertrophy Hypertrophyis anincrease in the size of individual cells. This frequently results in an increase in the size of a tissue or organ. When cells hypertrophy, components of the cell increase in numbers with increased functional capacity to meeting increased cell needs. Hypertrophy generally occurs in situations where the organ or tissue cannot adapt to an increased demand by formation of more cells. This is commonly seen in cardiac and skeletal muscle cells, which do not divide to form more cells. Common causes for hypertrophy are increased work or stress placed on an organ or hormonal stimulation.
An example of hypertrophy is the compensatory increase in the size of cells in one kidney after the other kidney has been removed or is in a diseased state.
Hyperplasia Hyperplasiais anincrease in the number of cells in a tissue. This generally results in an enlargement of tissue mass and organ size. It occursonlyin tissues capable of mitosis such as the epithelium of skin, intestine, and glands. Some cells do not divide and thus cannot undergo hyperplasia, for example, nerve and muscle cells. Hyperplasia is often a compensatory measure to meet an increase in body demands. Hyperplasia is a frequent response to toxic agents and damage to tissues such as wounds or trauma. In wound healing, hyperplasia of connective tissue (for example, fibroblasts and blood vessels) contributes to the wound repair. In many cases, when the toxic stress is removed, the tissue returns to normal. Hyperplasia may result from hormonal stimulation, for example, breast and uterine enlargement due to increased estrogen production during pregnancy.
Metaplasia Metaplasiais theconversionfrom one type of mature cell to another type of mature cell. It is a cellular replacement process. A metaplastic response often occurs with chronic irritation and inflammation. This results in a tissue more resistant to the external stress since the replacement cells are capable of survival under circumstances in which the original cell type could not survive. However, the cellular changes usually result in a loss of function, which was performed by the original cells that were lost and replaced. Examples of metaplasia are:
The common condition in which a person suffers from chronic reflux of acid from the stomach into the esophagus (Gastroesophageal Reflux Disease). The normal esophageal cells (squamous epithelium) are sensitive to the refluxed acid and die. They are replaced with the columnar cells of the stomach that are resistant to the stomach's acidity. This pathological condition is known as "Barrett's Esophagus."
The change in the cells of the trachea and bronchi of chronic cigarette smokers from ciliated columnar epithelium to non-ciliated stratified squamous epithelium. The sites of metaplasia frequently are also sites for neoplastic transformations. The replacement cells lack the defense mechanism performed by the cilia in moving particles up and out of the trachea.
With cirrhosis of the liver, which is a common condition of chronic alcoholics, the normal functional hepatic cells are replaced by nonfunctional fibrous tissue.
Dysplasia Dysplasiais a condition ofabnormal cell changes or deranged cell growthin which the cells are structurally changed in size, shape, and appearance from the original cell type. Cellular organelles also become abnormal. A common feature of dysplastic cells is that the nuclei are larger than normal and the dysplastic cells have a mitotic rate higher than the predecessor normal cells. Causes of dysplasia include chronic irritation and infection. In many cases, the dysplasia can be reversed if the stress is removed and normal cells return. In other cases, dysplasia may be permanent or represent a precancerous change.
An example of dysplasia is the atypical cervical cells that precede cervical cancer. Routine examination of cervical cells is a routine screening test for dysplasia and possible early stage cervical cancer (Papanicolaou test).
Cancer occurs at the site of Barrett's syndrome and in the bronchi of chronic smokers (bronchogenic squamous cell carcinoma).
Anaplasia Anaplasiarefers tocells that are undifferentiated. They have irregular nuclei and cell structure with numerous mitotic figures. Anaplasia is frequently associated with malignancies and serves as one criterion for grading the aggressiveness of a cancer. For example, an anaplastic carcinoma is one in which the cell appearance has changed from the highly differentiated cell of origin to a cell type lacking the normal characteristics of the original cell. In general, anaplastic cells have lost the normal cellular controls, which regulate division and differentiation.
Neoplasia Neoplasiais anew growth of tissueand is commonly referred to as a tumor. There are two types of neoplasia: benign and malignant. Malignant neoplasia are cancers. Since cancer is such an important and complex medical problem, aseparate sectionis devoted to cancer.
Interactions Interactions between two or more toxic agentscan produce damage by chemical-chemical interactions, chemical-receptor interactions, or by modification, by a first agent, of the cell and tissue response to a second agent. Interactions may occur by simultaneous exposure and if exposure to the two agents is separated in time.
Chemical-chemical interactionshave been mostly studied in the toxicology of air pollutants, where it was shown that the untoward effect of certain oxidants may be enhanced in the presence of other aerosols.
Interactions at thereceptor sitehave been found in isolated perfused lung experiments. Oxygen tolerance may be an example, when pre-exposure to one concentration of oxygen mitigates later exposure to 100% oxygen by modifying cellular and enzymatic composition of the lung.
Damage of the alveolar zone by the antioxidant butylated hydroxytoluene (BHT) in mice can be greatly enhanced bysubsequent exposureto oxygen concentration which, otherwise, would have little if any demonstrable effect.
Thesynergistic interactionbetween BHT and oxygen in mice results in interstitial pulmonary fibrosis. Acute or chronic lung disease may then be caused not only by one agent, but also in many instances by the interaction of several agents.
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Knowledge Check (Solutions on next page)
1) An increase in skeletal muscle cells in athletes due to exercise and increased metabolic demand is an example of: a) Pathological adaptation b) Physiological adaptation
2) A cellular response in which there is an increase in the number of cells in a tissue is known as: a) Atrophy b) Hypertrophy c) Hyperplasia d) Metaplasia
3) A condition of abnormal cell changes or deranged cell growth in which the cells are structurally changed in size, shape, and appearance from the original cell type is known as: a) Dysplasia b) Anaplasia c) Neoplasia
1) Physiological adaptation-This is the correct answer. The increase in skeletal muscle cells in athletes due to exercise and increased metabolic demand is an example of physiological adaptation since the increased muscle is beneficial rather than harmful.
2) Hyperplasia-This is the correct answer. Hyperplasia is an increase in the number of cells in a tissue.
3) Dysplasia-This is the correct answer. Dysplasia is a condition of abnormal cell changes or deranged cell growth in which the cells are structurally changed in size, shape, and appearance from the original cell type.
Toxic damage to cells can cause individual cell death and if sufficient cells are lost, the result can be tissue or organ failure, ultimately leading to death of the organism. It is nearly impossible to separate a discussion of cellular toxicity and biochemical toxicity. Most observable cellular changes and cell death are due to specific biochemical changes within the cell or in the surrounding tissue. However, there are a few situations where a toxic chemical or physical agent can cause cell damage without actually affecting a specific chemical in the cell or its membrane. Physical agents such as heat and radiation may damage a cell by coagulating their contents (similar to cooking). In this case, there are no specific chemical interactions. Impaired nutrient supply (such as glucose and oxygen) may deprive the cell of essential materials needed for survival.
Toxic Effects The majority of toxic effects, especially due to xenobiotics, are due to specific biochemical interactions without causing recognizable damage to a cell or its organelles. Examples of these toxic effects include:
Interference with a chemical that transmits a message across a neural synapse such as the inhibition of the enzyme acetylcholinesterase by organophosphate pesticides.
When one toxic chemical inhibits or replaces another essential chemical such as the replacement of oxygen on the hemoglobin molecule with carbon monoxide.
The human body is extremely complex. In addition to over 200 different cell types and about as many types of tissues, there are literally thousands of different biochemicals, which may act alone or in concert to keep the body functions operating correctly. To illustrate the cell's structures and functions and the chemical toxicity of all tissues and organs would be impossible in this brief tutorial. This section presents only a general overview of toxic effects along with some specific types of toxicity that include cancer and neurotoxicity.
Capacity for Repair Some tissues have a great capacity for repair, such as most epithelial tissues. Others have limited or no capacity to regenerate and repair, such as nervous tissue. Most organs have a functional reserve capacity so that they can continue to perform their body function although perhaps in somewhat diminished ability. For example:
Half of a person's liver can be damaged, and the body can regenerate sufficient new liver or repair the damaged section by fibrous replacement to maintain most of the capacity of the original liver.
The hypertrophy of one kidney to assume the capacity lost when the other kidney has been lost or surgically removed.
Toxic Damage to Cells and Tissues Toxic damage to cells and tissues can be transient and non-lethal or, in severe situations, the damage may cause death of the cells or tissues. The following diagram illustrates the various effects that can occur with damage to cells. There are four main final endpoints to the cellular or biochemical toxicity:
The tissue may be completely repaired and return to normal.
The tissue may be incompletely repaired but is capable of sustaining its function with reduced capacity.
Death of the organism or the complete loss of a tissue or organ. In some instances, the organism can continue to live with the aid of medical treatment, for example, replacement of insulin or by organ transplantations.
Neoplasm or cancers may result, many of which will result in death of the organism and some of which may be cured by medical treatment.
Figure 1. Toxic damage to cells (Image Source: NLM)
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Reversible Cell Damage The response of cells to toxic injury may be transient and reversible once the stress has been removed or the compensatory cellular changes are made. In some cases, the full capability of the damaged cells returns. In other cases, a degree of permanent injury remains with a diminished cellular or tissue capacity. In addition to the adaptive cell changes discussed previously, two commonly encountered specific cell changes are associated with toxic exposures, cellular swelling, and fatty change.
Cellular swelling, which is associated with hypertrophy, is due to cellular hypoxia, which damages the sodium-potassium membrane pump. This in turn changes the intracellular electrolyte balance with an influx of fluids into the cell, causing it to swell. Cell swelling is reversible when the cause is eliminated.
Fatty changeis more serious and occurs with severe cellular injury. In this situation, the cell has become damaged and is unable to adequately metabolize fat. The result is that small vacuoles of fat accumulate and become dispersed within the cytoplasm. While fatty change can occur in several organs, it is usually observed in the liver. This is because most fat is synthesized and metabolized in liver cells. Fatty change can be reversed but it is a much slower process than the reversal of cellular swelling.
Lethal Injury (Cell Death) In many situations, the damage to a cell may be so severe that the cell cannot survive. Cell death occurs mainly by two methods: necrosis and apoptosis.
Necrosisis a progressive failure of essential metabolic and structural cell components usually in the cytoplasm. Necrosis generally involves a group of contiguous cells or occurs at the tissue level. Such progressive deterioration in structure and function rapidly leads to cell death or "necrotic cells." Necrosis begins as a reduced production of cellular proteins, changes in electrolyte gradient, or loss of membrane integrity (especially increased membrane permeability). Cytoplasmic organelles (such as mitochondria and endoplasmic reticulum) swell while others (especially ribosomes) disappear. This early phase progresses to fluid accumulation in the cells making them pale-staining or showing vacuoles, which pathologists call "cloudy swelling" or "hydropic degeneration." In some cells, they no longer can metabolize fatty acids so that lipids accumulate in the cytoplasmic vacuoles, referred to as "fatty accumulation" or "fatty degeneration." In the final stages of "cell dying," the nucleus becomes shrunken (pyknosis) or fragmented (karyorrhexis).
Apoptosisor "programmed cell death" is a process of self-destruction of the cell nucleus. Apoptosis is an individual or single cell death in that dying cells are not contiguous but are scattered throughout a tissue. Apoptosis is a normal process in cell turnover in that cells have a finite lifespan and spontaneously die. During embryonic development, certain cells are programmed to die and are not replaced, such as the cells between each developing finger. If the programmed cells do not die, the fetus ends up with incomplete or fingers joined together in a web fashion.
In apoptosis, the cells shrink from a decrease of cytosol and the nucleus. The organelles (other than the nucleus) appear normal in apoptosis. The cell disintegrates into fragments referred to as "apoptotic bodies." These apoptotic bodies and the organelles are phagocytized by adjacent cells and local macrophages without initiation of an inflammatory response as is seen in necrosis. The cells undergo apoptosis and just appear to "fade away." Some toxicants induce apoptosis or, in other cases, they inhibit normal physiological apoptosis.
Following necrosis, the tissue attempts to regenerate with the same type of cells that have died. When the injury is minimal, the tissue may effectively replace the damaged or lost cells. In severely damaged tissues or long-term chronic situations, the ability of the tissue to regenerate the same cell types and tissue structure may be exceeded, so that a different and imperfect repair occurs.
An example of this is with chronic alcoholic damage to liver tissue in which the body can no longer replace hepatocytes with hepatocytes but rather connective tissue replacement occurs. Fibrocytes with collagen replace the hepatocytes and normal liver structure with scar tissue. The fibrotic scar tissue shores up the damage but it cannot replace the function of the lost hepatic tissue. With constant fibrotic change, the liver function is continually diminished so that eventually the liver can no longer maintain homeostasis. This fibrotic replacement of the liver is known as cirrhosis (Figure 2). The normal dark-red, glistening smooth appearance of the liver has been replaced with light, irregular fibrous scar tissue that permeates the entire liver.
We have so far discussed primarily changes to individual cells. However, a tissue and an organ consist of different types of cells that work together to achieve a particular function. As with a football team, when one member falters, the others rally to compensate. It is the same with a tissue. Damage to one cell type prompts reactions within the tissue to compensate for the injury. Within organs, there are two basic types of tissues: the parenchymal and stromal tissues. Theparenchymal tissuescontain the functional cells (for example, squamous dermal cells, liver hepatocytes, and pulmonary alveolar cells). Thestromal cellsare the supporting connective tissues (for example, blood vessels and elastic fibers).
Cell Repair Repair of injured cells can be accomplished by either:
Regeneration of the parenchymal cells.
Repair and replacement by the stromal connective tissue.
The goal of the repair process is to fill the gap that results from the tissue damage and restore the structural continuity of the injured tissue. Normally a tissue attempts to regenerate the same cells that are damaged; however, in many cases, this cannot be achieved so that replacement with a stromal connective tissue is the best means for achieving the structural continuity.
The ability toregeneratevaries greatly with the type of parenchymal cell. The regenerating cells come from the proliferation of nearby parenchymal cells, which serve to replace the lost cells. Based on regenerating ability, there are three types of cells:
Labile cells— cells that routinely divide and replace cells that have a limited lifespan (for example, skin epithelial cells, and hematopoietic stem cells).
Stable cells— cells that usually have a long lifespan with normally a low rate of division; they can rapidly divide upon demand.
Permanent cells— cells that never divide and do not have the ability for replication even when stressed or when some cells die.
The labile cells have a great potential for regeneration by replication and repopulation with the same cell type so long as the supporting structure remains intact. Stable cells can also respond and regenerate but to a lesser degree and are quite dependent on the supporting stromal framework. When the stromal framework is damaged, the regenerated parenchymal cells may be irregularly dispersed in the organ resulting in diminished organ function. The tissue response for the labile and stable cells is initially hyperplasia until the organ function becomes normal again. When permanent cells die they are not replaced in kind but instead connective tissue (usually fibrous tissue) moves in to occupy the damaged area. This is a form of metaplasia.
Examples of replacement by metaplasia are:
Cirrhosis of the liver— liver cells (hepatocytes) are replaced by bands of fibrous tissue, which cannot carry out the metabolic functions of the liver.
Cardiac infarcts— cardiac muscle cells do not regenerate and thus are replaced by fibrous connective tissue (scar). The scar cannot transmit electrical impulses or participate in contraction of the heart.
Pulmonary fibrosis— damaged or dead epithelial cells lining the pulmonary alveoli are replaced by fibrous tissue. Gases cannot diffuse across the fibrous cells and thus gas exchange is drastically reduced in the lungs.
Figure 3. Activation of Toxicity Pathways (Image Source: Adapted from Dr. Andrew Maier, adapted from National Research Council (NRC) 2007a.)
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Knowledge Check (Solutions on next page)
1) The process of self-destruction of the cell nucleus(often referred to as "programmed cell death")is known as: a) Necrosis b) Apoptosis c) Cellular swelling d) Fatty change
2) The category of cells that routinely divide and replace cells that have a limited lifespan is known as: a) Labile cells b) Stable cells c) Permanent cells
1) Apoptosis-This is the correct answer. Apoptosis(referred to as "programmed cell death")is a process of self-destruction of the cell nucleus.
2) Labile cells-This is the correct answer. Labile cells are cells that routinely divide and replace cells that have a limited lifespan (e.g., skin epithelial cells and hematopoietic stem cells).
Cancer has long been considered a cellular disease since cancers are composed of cells that grow without restraint in various areas of the body. Such growths of cancerous cells can replace normal cells or tissues causing severe malformations (such as with skin and bone cancers) and failure of internal organs which frequently leads to death. How do cells become cancerous? The development of cancer is an enormously complex process. For once a cell has started on the cancer path, it progresses through a series of steps, which continue long after the initial cause has disappeared.
Overview There are about as many types of cancers as there are different types of cells in the body (over 100 types). Some cell types constantly divide and are replaced (such as skin and blood cells). Other types of cells rarely or never divide (such as bone cells and neurons). Sophisticated mechanisms exist in cells to control when, if, and how cells replicate. Cancer occurs when these mechanisms are lost and replication takes place in an uncontrolled and disorderly manner. It can arise when one cell or a small group of cells multiplies too many times because of damage to its DNA.
Recent research has begun to unravel the extremely complex pathogenesis of cancer. There is an intricate array of biochemical changes that take place within cells and between cells underlying the progression of cancer that transforms normal cells into cancerous cells. These biochemical changes lead a cell through a series of steps, changing it gradually from a normal to a cancer cell. The altered cell is no longer bound by the regulatory controls that govern the life and behavior of normal cells.
Cancer is not a single disease but a large group of diseases. The common aspect is that all cancers have the same basic property: they are composed of cells that no longer conform to the usual constraints on cell proliferation. In other words, they are uncontrolled growths of cells.
Terminology The terminology associated with cancer can be confusing and may be used differently among the public and medical communities. Here are definitions of the most frequently used cancer terms:
Cancer— a malignant tumor that has the ability to metastasize or invade into surrounding tissues.
Tumor— a general term for an uncontrolled growth of cells that becomes progressively worse with time. Tumors may be benign or malignant.
Neoplasm— same as a tumor.
Neoplasia— the growth of new tissue with abnormal and unregulated cellular proliferation.
Benign Tumor— a tumor that does not metastasize or invade surrounding tissue.
Malignant Tumor— a tumor that has the ability to metastasize or invade into surrounding tissues (same as cancer).
Metastasis— ability to establish secondary tumor growth at a new location away from the original site.
Carcinogenesis— the production of a carcinoma (epithelial cancer). Sometimes carcinogenesis is used as a general term for production of any type of tumor.
How are Cancers Named? While most tumors are generally named in accordance with aninternationally agreed-upon classification scheme, there are exceptions. Tumors are generally named and classified based on:
The cell or tissue of origin
Whether benign or malignant
Most tumor names end with the suffix "oma" which indicates a swelling or tissue enlargement. [Note: some terms ending with -oma are not cancers; for example, a hematoma is merely a swelling consisting of blood].
In naming tumors, qualifiers may be added in addition to the tissue of origin and structural features. For example, a "poorly-differentiated bronchogenic squamous cell carcinoma" is a malignant tumor (carcinoma) of squamous cell type (original cell type), which arose in the bronchi of the lung (site where the cancer started), and in which the cancer cells are poorly differentiated, meaning they have lost much of the normal appearance of squamous cells.
There are several historical exceptions to the standard nomenclature system, often based on their early and accepted use in the literature.
Examples include:
Some tumors are named after the person that first described the tumor, for example, Wilms tumor (kidney tumor) and Hodgkin lymphoma (a specific form of lymphoid cancer).
A few cancers are named for their physical characteristics such as pheochromocytomas (dark-colored tumors of the adrenal gland).
A few cancers are composed of mixtures of cells, for example, fibrosarcoma and carcinosarcoma.
Most malignant tumors fall into one of two categories: carcinomas or sarcomas. The major differences between carcinomas and sarcomas are listed in Table 1:
Common Sites for Cancer Cancer can occur in almost any tissue or organ. Some cells and tissues are more likely to become cancerous than others are, particularly thosecells that normally undergo proliferationto replace cells that have been lost due to injury or cell death. Those cells that don't proliferate (for example, neurons and heart muscle cells) rarely give rise to cancers. Figure 1 illustrates the most frequent occurrence of cancers in various body sites.
Figure 1. Top 10 Cancer Sites for Males and Females from All Races in the United States in 2013 (Image Source: CDC) ‡ Rates are age-adjusted to the 2000 U.S. standard population (19 age groups – Census P25–1130)
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While the prostate is the most common type of cancer that occurs in men, most survive with treatment. In contrast, other types of cancer are more often fatal. For example, the most common cancer, which causes death in men, even with treatment, is lung cancer. With women, a similar situation exists in that the breast is the most common site for cancer but more women die as a result of lung cancer.
What Do Cancers Look Like? Cancer is a general term for more than 100 different cellular diseases, all with the same characteristic – the uncontrolled abnormal growth of cells in different parts of the body. Cancers appear in many forms. A few types are visible to the unaided eye but others grow inside the body and slowly destroy or replace internal tissues.
Skin Cancer An example of a cancer that can be easily seen by the unaided eye is skin cancer. Skin cancers appear as raised, usually dark-colored, irregularly-shaped growths on the skin. As the cancer grows, it spreads to nearby areas of the skin. In advanced cases, the cancer metastasizes to lymph nodes and organs far away from the original site. The skin cancer illustrated in Figure 2 is known as a basal cell carcinoma. Melanomas and squamous cell carcinomas are other common skin cancers. Melanomas are usually the most malignant of the skin cancers.
Figure 2. Photograph of basal cell carcinoma of the skin (Image Source: NLM)
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Other Cancers
Most cancers involve internal organs and require elaborate diagnostic tests to diagnose. Some large internal tumors can be felt or will push the skin outward and can be detected by noting abnormal bulges or an abnormal feel (for example, a hard area) to the body. Thyroid tumors, bone tumors, breast tumors, and testicular tumors are cancers that might be felt or observed by the patient. Other internal tumors may only be suspected based on diminished organ function (such as difficulty breathing with lung cancers), pain, bleeding (for example, blood in feces with colon cancer), weakness, or other unusual symptoms. To confirm the actual existence of a cancer may require diagnostic tests. This is especially the case where the cancer is not growing as a single large lump, but rather as a series of small tumors (metastatic foci) or when widely dispersed throughout the body (such as leukemia).
A few examples of internal cancers are presented in the following figures.
Liver Cancer Numerous cancer nodules can be seen showing that much of the liver has been destroyed (Figure 3).
Figure 3. A liver with numerous cancer nodules (Image Source: NLM)
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Lung Cancer An early developing squamous cell carcinoma can be seen growing in the middle of the lung (Figure 4). As the cancer develops, it will consume more of the lung and metastasize to other areas of the body.
Figure 5. A kidney with cancer (Image Source: NLM)
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Historical Changes in Incidence of Cancer
Cancer has been recognized in humans for centuries. However, the incidence of various types of cancer has changed since the mid-1900s. This is especially true for lung and stomach cancer. Deaths from lung cancer hit a peak in the early 1990s and have been slowly declining since 2001. During that same period, deaths from stomach cancer decreased substantially. Breast cancer caused more deaths than any other type cancer in women for many decades. However, when women began smoking cigarettes, deaths from lung cancer outpaced deaths from breast cancer. These changes in types and incidences of cancer reflect the increased longevity of people as well as personal habits and environmental changes.
Latency Period for Cancer Development Cancer is a chronic condition, which develops gradually over a period of time, and may become a clinical concern many years following the initial exposure to a carcinogen. This period of time is referred to as thelatency period. The latency period varies with the type of cancers and may be as short as a few years to over 30 years. For example, the latency period for leukemia after benzene or radiation exposure may only be five years. In contrast, the latency period may be 20–30 years for skin cancer after arsenic exposure and mesothelioma (cancer of the pleura around the lungs) after asbestos exposure.
Survival Time Success in treating cancer varies greatly with the type of cancer with some cancers responding to treatment whereas others do not. For example, medical treatment of cancers of the pancreas, liver, esophagus, and lung are largely unsuccessful. In contrast, cancers of the thyroid, testes, and skin respond quite well to treatment. Table 3 shows the 5-year survival rate by cancer location.
A large number of industrial, pharmaceutical, and environmental chemicals have been identified as potential carcinogens by animal tests. Human epidemiology studies have confirmed that many are human carcinogens as well. However, whileit is apparentthat chemicals and radiation play a substantial role, it appears that lifestyle factors (such as diet, obesity, and smoking), and infections (such as hepatitis B, hepatitis C, andHuman Papillomaviruses) are also major factors leading to the likelihood that a person will develop cancer. Additional factors that are involved in the development of cancer include aging and heredity.
Pathogenesis of Cancer Carcinogenesisis a multi-step, multi-factorial genetic disease. All known tumors are composed of cells with genetic alterations that make them perform differently from their progenitor (parent) cells. The carcinogenesis process is very complex and unpredictable consisting of several phases and involving multiple genetic events (mutations) that take place over a very long period of time, at least 10 years for most types of cancer.
Cancer cells do not necessarily proliferate faster than their normal progenitors. In contrast to normal proliferating tissues where there is a strict and controlled balance between cell death and replacement, cancers grow and expand since more cancer cells are produced than die in a given time period. For a tumor to be detected it must attain a size of at least one cubic centimeter (about the size of a pea). This small tumor contains 100 million to a billion cells at that time. The development from a single cell to that size also means that the mass has doubled at least 30 times. During the long and active period of cell proliferation, the cancerous cells may have become aggressive in growth and have reverted to a less differentiated type cell that is not similar to the original cell type.
While knowledge of carcinogenesis continues to evolve, it is clear that there are at least three main phases in cancer development:
Figure 6. Phases of carcinogenesis (Image Source: NLM)
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1. Initiation Theinitiationphase consists of the alteration of the DNA (mutation) of a normal cell, which is an irreversible change. The initiated cell has developed a capacity for individual growth. At this time, the initiated cell is indistinguishable from other similar cells in the tissue. The initiating event can consist of a single exposure to a carcinogenic agent or, in some cases, it may be an inherited genetic defect.
An example is retinoblastoma in which some children who develop the disease may have inherited an altered copy of the gene involved and are at risk of passing the altered gene to successive generations.
The initiated cell, whether inherited or newly mutated, may remain dormant for months to years and, unless a promoting event occurs, may never develop into a clinical cancer case.
2. Promotion/Conversion Thepromotion/conversionphase is the second major step in the carcinogenesis process in which specific agents (referred to as promoters) enhance the further development of the initiated cells. Promoters often, but not always, interact with the cell's DNA and influence the further expression of the mutated DNA so that the initiated cell proliferates and progresses further through the carcinogenesis process. The clone of proliferating cells in this stage takes a form consistent with a benign tumor. The mass of cells remains as a cohesive group and physically keeps in contact with each other.
3. Progression Progressionis the third recognized step and is associated with the development of the initiated cell into a biologically malignant cell population. In this stage, a portion of the benign tumor cells may be converted into malignant forms so that a true cancer has evolved. Individual cells in this final stage can break away and start new clones of growth distant from the original site of development of the tumor. This is known asmetastasis.
Genetic Activity While the three-stage pathogenesis scheme describes the basic sequence of events in the carcinogenesis process, the actual events that take place in these various steps are due to activities of specific genes within the DNA of the cells. Cellular DNA contains two types of genes:
Structural genesdirect the production of specific proteins within the cell.
Regulatory genescontrol the activity of the structural genes and direct the proliferation process of the cell.
The three classes of regulatory genes considered to have major roles in the carcinogenesis process are known as:
Proto-oncogenes
Oncogenes
Suppressor genes
Proto-oncogenesare normal cellular genes that encode and instruct the production of the regulatory proteins and growth factors within the cell or its membrane. The proteins encoded by proto-oncogenes are necessary for normal cellular cell growth and differentiation. Activation of a proto-oncogene can cause the alteration in the normal growth and differentiation of cells, which leads to neoplasia. Several agents can activate proto-oncogenes. This is the result ofpoint mutationsor by DNA rearrangements of the proto-oncogenes. The product of this proto-oncogene activation is an oncogene. Many proto-oncogenes have been identified and have usually been named after the source of their discovery, for example, the KRAS proto-oncogene was named for the discovery using the Kirsten rat sarcoma virus. HRAS, MYC, MYB, and SRC are other examples of proto-oncogenes. The proto-oncogenes are not specific for the original species but have been found in many other species, including humans. These proto-oncogenes are present in many cells but remain dormant until activated. Either a point mutation or chromosomal damage of various types can induce activation. Once activated they become an oncogene.
Oncogenesare altered or misdirected proto-oncogenes which now have the ability to direct the production of proteins within the cell that can change or transform the normal cell into a neoplastic cell. Most oncogenes differ from their proto-oncogenes by a single point mutation located at a specific codon (a group of three DNA bases that encodes for a specific amino acid) of a chromosome. The altered DNA in the oncogene results in the production of an abnormal protein that can alter cell growth and differentiation. It appears that a single activated oncogene is not sufficient for the growth and progression of a cell and its offspring to form a cancerous growth. However, it is a major step in the carcinogenesis process.
Tumor suppressor genes, sometimes referred to as anti-oncogenes, are present in normal cells and serve to counteract and change the proto-oncogenes and altered proteins that they are responsible for. The tumor suppressor genes serve to prevent a cell with damaged DNA from proliferating and evolving into an uncontrolled growth. They actively function to effectively oppose the action of an oncogene. If a tumor suppressor gene is inactivated (usually by a point mutation), its control over the oncogene and transformed cell may be lost. Thus the tumor-potential cell can now grow without restraint and is free of the normal cellular regulatory control. The suppressor gene most frequently altered in human tumors is the p53 gene. Damaged p53 genes have been identified in over 50% of human cancers.
Thep53 genenormally halts cell division and stimulates repair enzymes to rebuild and restore the damaged regions of the DNA. If the damage is too extensive, the p53 commands the cell to self-destruct. An altered p53 is incapable of these defensive actions and cannot prevent the cell with damaged DNA from dividing and proliferating in an erratic and uncontrolled manner. This is the essence of cancer.
This section represents only a brief overview of an enormously complex process for which knowledge is continuously evolving with the tools of molecular biology. New factors are continuously being identified; however, many pieces of this cancer puzzle remain elusive at this time.
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Knowledge Check (Solutions on next page)
1) A body growth with the ability to metastasize or invade into surrounding tissues is known as a: a) Benign tumor b) Malignant tumor c) Hyperplasia
2) Most cancers are thought to be due to the following: a) Infections b) Food additives c) Lifestyle factors d) Pollution
3) The initial stage in carcinogenesis in which there is an alteration of the DNA (mutation) is referred to as the: a) Progression stage b) Promotion stage c) Initiation stage
4) The cellular gene which is present in most normal cells and serves as a balance to the genes for tumor expression is known as a: a) Tumor suppressor gene b) Oncogene c) Proto-oncogene
1) Malignant tumor-This is the correct answer. A malignant tumor that has the ability to metastasize or invade into surrounding tissues. It is the same as cancer.
2) Lifestyle factors-This is the correct answer. Lifestyle (including diet, tobacco use, reproductive and sexual behavior, and alcohol consumption) is considered to cause about 75% of all cancers.
3) Initiation stage-This is the correct answer. The initiation phase consists of the alteration of the DNA (mutation) of a normal cell, which is irreversible change.
4) Tumor suppressor gene-This is the correct answer. Tumor suppressor genes, sometimes referred to as anti-oncogenes, are present in normal cells and serve as a balance to the genes for expression or proto-oncogenes.
The nervous system is very complex and toxins can act at many different points in this complex system. The focus of this section is to provide a basic overview of how the nervous system works and how neurotoxins affect it. Due to the complexity of these topics, this section does not include extensive details related to the anatomy and physiology of the nervous system or the many neurotoxins in our environment and the subtle ways they can damage the nervous system or interfere with its functions.
Since the nervous system innervates all areas of the body, some toxic effects may be quite specific and others generalized depending upon where in the nervous system the toxin exerts its effect. Before discussing how neurotoxins cause damage, we will look at the basic anatomy and physiology of the nervous system.
Anatomy and Physiology of the Nervous System The nervous system has three basic functions:
Specialized cells detect sensory information from the environment and relay that information to other parts of the nervous system.
It directs motor functions of the body usually in response to sensory input.
It integrates the thought processes, learning, and memory.
All of these functions are potentially vulnerable to the actions of toxicants.
The nervous system consists of two fundamental anatomical divisions:
Central nervous system (CNS)
Peripheral nervous system (PNS)
Central Nervous System The CNS includes the brain and spinal cord. The CNS serves as the control center and processes and analyzes information received from sensory receptors and in response issues motor commands to control body functions. The brain, which is the most complex organ of the body, structurally consists of six primary areas (Figure 1):
Cerebrum— controls thought processes, intelligence, memory, sensations, and complex motor functions.
Diencephalon(thalamus, hypothalamus, pituitary gland)— relays and processes sensory information; controlls emotions, autonomic functions, and hormone production.
Midbrain— processes auditory and visual data; generates involuntary motor responses.
Pons— a tract and relay center which also assists in somatic and visceral motor control.
Cerebellum— voluntary and involuntary motor activities based on memory and sensory input.
Medulla oblongata— relays sensory information to the rest of the brain; regulates autonomic function, including heart rate and respiration.
Peripheral Nervous System The PNS consists of all nervous tissue outside the CNS (Figure 2). The PNS contains two forms of nerves:
Afferent nerves, which relay sensory information to the CNS.
Efferent nerves, which relay motor commands from the CNS to various muscles and glands.
Efferent nervesare organized into two systems. One is thesomatic nervous systemthat is also known as the voluntary system and which carries motor information to skeletal muscles. The second efferent system is theautonomic nervous system, which carries motor information to smooth muscles, cardiac muscle, and various glands. The major difference between these two systems pertains to conscious control.
The somatic system is under our voluntary control such as moving our arms by consciously telling our muscles to contract.
In contrast, we cannot consciously control the smooth muscles of the intestine, heart muscle, or secretion of hormones. Those functions are automatic and involuntary as controlled by the autonomic nervous system.
Figure 2. Structures of the central nervous system and peripheral nervous system (Image Source: NLM)
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Cells of the Nervous System There are two categories of cells found in the nervous system: neurons and glial cells.Neuronsare the functional nerve cells directly responsible for transmission of information to and from the CNS to other areas of the body.Glial cells(also known as neuroglia) provide support to the neural tissue, regulate the environment around the neurons, and protect against foreign invaders.
Neuronscommunicate with all areas of the body and are present within both the CNS and PNS. They serve to transmit rapid impulses to and from the brain and spinal cord to virtually all tissues and organs of the body. As such, they are an essential cell and their damage or death can have critical effects on body function and survival. When neurons die, they are not replaced. As neurons are lost, so are certain neural functions such as memory, ability to think, quick reactions, coordination, muscular strength, and our various senses such as sight, hearing, and taste. If the neuron loss or impairment is substantial, severe and permanent disorders can occur, such as blindness, paralysis, and death.
A neuron consists of a cell body and two types of extensions, numerous dendrites, and a single axon (Figure 3).Dendritesare specialized in receiving incoming information and sending it to the neuron cell body with transmission (electrical charge) on down the axon to one or more junctions with other neurons or muscle cells (known as synapses). Theaxonmay extend long distances, over a meter in some cases, to transmit information from one part of the body to another. Themyelin sheathis a multi-layer coating that wraps some axons and helps insulate the axon from surrounding tissues and fluids, and prevents the electrical charge from escaping from the axon.
Figure 4. Complete neuron cell diagram (Image Source: Adapted from Wikimedia Commons, obtained under Public Domain. Author: LadyofHats.)
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Information passes along the network of neurons between the CNS and the sensory receptors and the effectors by a combination of electrical pulses and chemical neurotransmitters. The information (electrical charge) moves from the dendrites through the cell body and down the axon. The mechanism by which an electrical impulse moves down the neuron is quite complex. When the neuron is at rest, it has a negative internal electrical potential. This changes when a neurotransmitter binds to a dendrite receptor. Protein channels of the dendrite membrane open allowing the movement of charged chemicals across the membrane, which creates an electrical charge. The propagation of an electrical impulse (known as action potential) proceeds down the axon by a continuous series of openings and closings of sodium-potassium channels and pumps. The action potential moves like a wave from one end (dendritic end) to the terminal end of the axon.
However, the electrical charge cannot cross the gap (synapse) between the axon of one neuron and the dendrite of another neuron or an axon and a connection with a muscle cell (neuromuscular junction). Chemicals called neurotransmitters move the information across the synapse.
Neurons do not make actual contact with one another but have a gap, known as asynapse. As the electrical pulse proceeds up or down an axon, it encounters at least one junction or synapse. An electrical pulse cannot pass across the synapse. At the terminal end of an axon is a synaptic knob, which contains the neurotransmitters.
Neurotransmitters Vesicles releaseneurotransmittersupon stimulus by an impulse moving down the presynaptic neuron. The neurotransmitters diffuse across the synaptic junction and bind to receptors on the postsynaptic membrane. The neurotransmitter-receptor complex then initiates the generation of an impulse on the next neuron or the effector cell, for example, a muscle cell or secretory cell.
After the impulse has again been initiated, the neurotransmitter-complex must be inactivated or continuous impulses (beyond the original impulse) will be generated. Enzymes perform this inactivation, which serves to break down the complex at precisely the right time and after the exact impulse has been generated. There are several types of neurotransmitters and corresponding inactivating enzymes. One of the major neurotransmitters is acetylcholine with acetylcholinesterase as the specific inactivator.
There are over 100 known neurotransmitters. Among the most well-known are:
Acetylcholine
Dopamine
Serotonin
Norepinephrine
GABA (gamma-aminobutyric acid)
Types of Neurons Neurons are categorized by their function and consist of three types:
Sensory neurons (afferent neurons)carry information from sensory receptors (usually processes of the neuron) to the CNS. Some sensory receptors detect external changes such as temperature, pressure, and the senses of touching and vision. Others monitor internal changes such as balance, muscle position, taste, deep pressure, and pain.
Motor neurons (effector neurons)relay information from the CNS to other organs terminating at the effectors. Motor neurons make up the efferent neurons of both the somatic and autonomic nervous systems.
Interneurons (association neurons)are located only in the CNS and provide connections between sensory and motor neurons. They can carry either sensory or motor impulses. They are involved in spinal reflexes, analysis of sensory input, and coordination of motor impulses. They also play a major role in memory and the ability to think and learn.
Glial Cells Glial cellsare important as they provide a structure for the neurons by protecting them from outside invading organisms, and maintaining a favorable environment (nutrients, oxygen supply, etc.). The neurons are highly specialized and do not have all the usual cellular organelles to provide them with the same life-support capability. They are highly dependent on the glial cells for their survival and function. For example, neurons have such a limited storage capacity for oxygen that they are extremely sensitive to decreases in oxygen (anoxia) and will die within a few minutes. The list below describes the types of glial cells:
Astrocytesare big cells, only in the CNS, and maintain the blood-brain barrier that controls the entry of fluid and substances from the circulatory system into the CNS. They also provide rigidity to the brain structure.
Schwann cells and oligodendrocyteswrap themselves around some axons to formmyelin, which serves like insulation. Myelinated neurons usually transmit impulses at high speed, such as needed in motor neurons. Loss of myelination causes a dysfunction of these cells.
Microgliaare small, mobile, phagocytic cells.
Ependymal cellsproduce the cerebrospinal fluid (CSF) which surrounds and cushions the central nervous system.
Figure 7. Comparison of somatic and visceral reflects (Image Source: Wikimedia Commons, obtained under Creative Commons Attribution 3.0 Unported License. Author: OpenStax College.View original image. Source: Anatomy & Physiology, Connexions Web site.http://cnx.org/content/col11496/1.6/, Jun 19, 2013.)
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Toxic Damage to Nervous System The nervous system is quite vulnerable to toxins since chemicals interacting with neurons can change the critical voltages, which must be carefully maintained. However, the nervous system has defense mechanisms that can protect it from toxins.
Most of the CNS is protected by an anatomical barrier between the neurons and blood vessels, known as theblood-brain barrier. It is protected from some toxin exposures by tightening junctions between endothelial cells of the blood vessels in the CNS and having astrocytes surround the blood vessels. This prevents the diffusion of chemicals out of the blood vessels and into the intracellular fluid except for small, lipid-soluble, non-polar molecules. Specific transport mechanisms exist to transport essential nutrients (such as glucose and amino acids and ions) into the brain. Another defense mechanism within the brain to counter chemicals that pass through the vascular barrier is the presence of metabolizing enzymes. Certain detoxifying enzymes, such as monoamine oxidase, can biotransform many chemicals to less toxic forms as soon as they enter the intercellular fluid.
The basic types of changes due to toxins can be divided into three categories – 1) sensory; 2) motor; and 3) interneuronal – depending on the type of damage sustained.
Damage can occur to sensory receptors andsensory neurons, which can affect the basic senses of pressure, temperature, vision, hearing, taste, smell, touch, and pain.
For example, heavy metal poisoning (especially lead and mercury) can cause deafness and loss of vision.
Several chemicals including inorganic salts and organophosphorus compounds can cause a loss of sensory functions.
Damage tomotor neuronscan cause muscular weakness and paralysis.
Isonicotinic hydrazide (used to treat tuberculosis) can cause such damage.
Interneuronaldamage can cause learning deficiencies, loss of memory, incoordination, and emotional conditions.
Low levels of inorganic mercury and carbon monoxide can cause depression and loss of memory.
Mechanisms for Toxic Damage to the Nervous System Toxic damage to the nervous system occurs by the following basic mechanisms:
Direct damage and death of neurons and glial cells.
Interference with electrical transmission.
Interference with chemical neurotransmission.
A. Death of Neurons and Glial Cells The most common cause of death of neurons and glial cells isanoxia, an inadequate oxygen supply to the cells or their inability to utilize oxygen. Anoxia may result from the blood's decreased ability to provide oxygen to the tissues (impaired hemoglobin or decreased circulation) or from the cells unable to utilize oxygen.
For example, carbon monoxide and sodium nitrite can bind to hemoglobin preventing the blood from being able to transport oxygen to the tissues.
Hydrogen cyanide and hydrogen sulfide can penetrate the blood-brain barrier and is rapidly taken up by neurons and glial cells.
Another example is sodium fluoroacetate (commonly known as Compound 1080, a rodent pesticide) which inhibits a cellular enzyme.
Those chemicals interfere with cellular metabolism and prevent nerve cells from being able to utilize oxygen. This is calledhistoxic anoxia.
Neurons are among the most sensitive cells in the body to inadequate oxygenation. Lowered oxygen for only a few minutes is sufficient to cause irreparable changes leading to the death of neurons.
Several other neurotoxins directly damage or kill neurons, including:
Lead
Mercury
Some halogenated industrial solvents including methanol (wood alcohol)
While some neurotoxic agents affect neurons throughout the body, others are quite selective.
For example, methanol specifically affects the optic nerve, retina, and related ganglion cells while trimethyltin kills neurons in the hippocampus, a region of the cerebrum.
Other agents can degrade neuronal cell function by diminishing its ability to synthesize protein, which is required for the normal function of the neuron.
Organomercury compounds exert their toxic effect in this manner.
With some toxins, only a portion of the neuron is affected. If the cell body is killed, the entire neuron will die. Some toxins can cause death or loss of only a portion of the dendrites or axon while the cell itself survives but with diminished or total loss of function. Commonly axons begin to die at the very distal end of the axon with necrosis slowly progressing toward the cell body. This is referred to as "dying-back neuropathy."
Some organophosphate chemicals (including some pesticides) cause this distal axonopathy. The mechanism for the dying back is not clear but may be related to the inhibition of an enzyme (neurotoxic esterase) within the axon.
Other well-known chemicals can cause distal axonopathy include ethanol, carbon disulfide, arsenic, ethylene glycol (in antifreeze), and acrylamide.
B. Interference with Electrical Transmission There are two basic ways that a foreign chemical can interrupt or interfere with the propagation of the electrical potential (impulse) down the axon to the synaptic junction:
To interfere with the movement of the action potential down the intact axon.
To cause structural damage to the axon or its myelin coating. Without an intact axon, transmission of the electrical potential is not possible.
Agents that can block or interfere with the sodium and potassium channels and sodium-potassium pump cause interruption of the propagation of the electrical potential. This will weaken, slow, or completely interrupt the movement of the electrical potential. Many potent neurotoxins exert their toxicity by this mechanism.
Tetrodotoxin (a toxin in frogs, pufferfish, and other invertebrates) and saxitoxin (a cause of shellfish poisoning) blocks sodium channels. Batrachotoxin (a toxin in South American frogs used as arrow poison) and some pesticides (DDT and pyrethroids) increases the permeability of the neuron membrane preventing closure of sodium channels which leads to repetitive firing of the electrical charge and an exaggerated impulse.
A number of chemicals can causedemyelination. Many axons (especially in the PNS) are wrapped with a protective myelin sheath that acts as insulation and restricts the electrical impulse within the axon. Agents that selectively damage these coverings disrupt or interrupt the conduction of high-speed neuronal impulses. Loss of a portion of the myelin can allow the electrical impulse to leak out into the tissue surrounding the neuron so that the pulse does not reach the synapse with the intended intensity.
In some diseases, such as Multiple Sclerosis (MS) and Amyotrophic Lateral Sclerosis (ALS), the myelin is lost, causing paralysis and loss of sensory and motor function.
A number of chemicals can cause demyelination:
Diphtheria toxin causes loss of myelin by interfering with the production of protein by the Schwann cells that produce and maintain myelin in the PNS.
Triethyltin (used as a biocide, preservative, and polymer stabilizer) interrupts the myelin sheath around peripheral nerves.
Lead causes loss of myelin primarily around peripheral motor axons.
C. Interference with Chemical Neurotransmission Synaptic dysfunctionis a common mechanism for the toxicity of a wide variety of chemicals. There are two types of synapses:those between two neurons(axon of one neuron and dendrites of another) and thosebetween a neuron and a muscle cell or gland. The basic mechanism for the chemical transmission is the same. The major difference is that the neurotransmitting chemical between a neuron and muscle cell is acetylcholine whereas there are several other types of neurotransmitting chemicals involved between neurons, depending on where in the nervous system the synapse is located.
There are four basic steps involved in neurotransmission at the synapse:
Synthesis and storage of neurotransmitter (synaptic knob of axon).
Release of the neurotransmitter (synaptic knob with movement across synaptic cleft).
Receptor activation (effector membrane).
Inactivation of the transmitter (enzyme breaks down neurotransmitter stopping induction of action potential).
The arrival of the action potential at the synaptic knob initiates a series of events culminating in the release of the chemical neurotransmitter from its storage depots in vesicles. After the neurotransmitter diffuses across the synaptic cleft, it complexes with a receptor (membrane-bound macromolecule) on the post-synaptic side. This binding causes an ion channel to open, changing the membrane potential of the post-synaptic neuron or muscle or gland. This starts the process of impulse formation or action potential in the next neuron or receptor cell. However, unless this receptor-transmitter complex is inactivated, the channel remains open with continued pulsing. Thus, the transmitter action must be terminated. Specific enzymes that can break the bond and return the receptor-membrane to its resting state do this.
Drugs and environmental chemicals can interact at specific points in this process to change the neurotransmission. Depending on where and how the xenobiotics act, the result may be either an increase or a decrease in neurotransmission. Many drugs (such as tranquilizers, sedatives, stimulants, beta-blockers) are used to correct imbalances to neurotransmissions (such as occurs in depression, anxiety, and cardiac muscular weakness). The mode of action of some analgesics is to block receptors, which prevent transmission of pain sensations to the brain.
Exposure to environmental chemicals that can perturb neurotransmission is a very important area of toxicology. Generally, neurotoxins affecting neurotransmission act to:
Increase or decrease the release of a neurotransmitter at the presynaptic membrane.
Block receptors at the postsynaptic membrane.
Modify the inactivation of the neurotransmitter.
This is a list of only a few examples of neurotoxins to show the range of mechanisms:
α-Bungarotoxin (a potent venom of elapid snakes) prevents the release of neurotransmitters.
Scorpion venom potentiates the release of a neurotransmitter (acetylcholine).
Black widow spider venom causes an explosive release of neurotransmitters.
Botulinum toxin blocks the release of acetylcholine at neuromuscular junctions.
Atropine blocks acetylcholine receptors.
Strychnine inhibits the neurotransmitter glycine at postsynaptic sites resulting in an increased level of neuronal excitability in the CNS.
Nicotine binds to certain cholinergic receptors.
A particularly important type of neurotoxicity is the inhibition of acetylcholinesterase. The specific function of acetylcholinesterase is to stop the action of acetylcholine once it has bound to a receptor and initiated the action potential in the second nerve or at the neuro-muscular or glandular junction. If the acetylcholine-receptor complex is not inactivated, continual stimulation will result leading to paralysis and death.
Many commonly used chemicals, especially organophosphate and carbamate pesticides, poison mammals by this mechanism.
The major military nerve gases are also cholinesterase inhibitors.
Acetylcholine is a common neurotransmitter. It is responsible for transmission at all neuromuscular and glandular junctions as well as many synapses within the CNS.
Events Involved in a Typical Cholinergic Synapse The complexity of the sequence of events that takes place at a typical cholinergic synapse is indicated below:
The nervous system is the most complex system of the body. There are still many gaps in understanding how many neurotoxins act, yet research is discovering their possible effects on the body's structures and functions. It is important to understand that the most potent toxins (on a weight basis) are neurotoxins with extremely minute amounts sufficient to cause death.
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Knowledge Check (Solutions on next page)
1) The two fundamental anatomical divisions of the nervous system are the: a) Cerebrum and cerebellum b) Central nervous system and peripheral nervous system c) Brain and spinal cord
2) The two major categories of cells found in the nervous system are: a) Neurons and glial cells b) Astrocytes and microglia c) Schwann cells and oligodendrocytes
3) The propagation of an electrical impulse (action potential) down an axon consists of: a) The transmission of the action potential by chemical neurotransmitters b) The movement of sodium ions from the dendrite to the axon c) A continuous series of opening and closing of sodium-potassium channels and pumps
4) The type of neuron that relays information from the CNS to other organs is a: a) Motor neuron b) Sensory neuron c) Interneuron
5) The primary cause of death to neurons and glial cells is: a) Interference with chemical transmission b) Interference with electrical transmission c) Anoxia
6) A major mechanism that prevents the action potential (impulse) from moving down an axon is: a) Blockage or interference with movement of sodium and potassium ions in and out of neuron membrane, changing the action potential b) Excessive release of chemical neurotransmitters c) Blocking receptors at the post-synaptic membrane
7) What are the two basic types of synapses? a) Neuro-muscular and neuro-glandular b) CNS and PNS synapses c) Those between two neurons and a neuron and effector
1) Central nervous system and peripheral nervous system-This is the correct answer. The two fundamental anatomical divisions of the nervous system are the Central Nervous System (brain and spinal cord) and the Peripheral Nervous System, which consists of all nerves outside the brain and spinal cord.
2) Neurons and glial cells-This is the correct answer. The two major categories of cells found in the nervous system are neurons and glial cells. Neurons are the functional nerve cells directly responsible for transmission of information to and from the CNS to other areas of the body. Glial cells (also known as neuroglia) provide support to the neural tissue, regulate the environment around the neurons, and protect against foreign invaders.
3) A continuous series of opening and closing of sodium-potassium channels and pumps-This is the correct answer. The propagation of an electrical impulse (action potential) down an axon consists of a continuous series of opening and closing of sodium-potassium channels and pumps. The action potential moves like a wave from one end (dendritic end) to the terminal end of the axon.
4) Motor neuron-This is the correct answer. Motor Neurons (effector neurons) relay information from the CNS to other organs terminating at the effectors.
5) Anoxia-This is the correct answer. The most common cause of death of neurons and glial cells is anoxia, an inadequate oxygen supply to the cells or their inability to utilize oxygen.
6) Blockage or interference with movement of sodium and potassium ions in and out of neuron membrane, changing the action potential-This is the correct answer. Interruption of the propagation of the electrical potential is caused by agents that can block or interfere with the sodium and potassium channels and sodium-potassium pump. This will weaken, slow, or completely interrupt the movement of the electrical potential.
7) Those between two neurons and a neuron and effector-This is the correct answer. The two basic types of synapses are those between two neurons and those between a neuron and effectors, such as muscle cell or gland. The major difference in the two basic types is that the neurotransmitting chemical between a neuron and muscle cell is acetylcholine whereas there are several other types of neurotransmitting chemicals involved between neurons, depending on where in the nervous system the synapse is located.
What We've Covered This section made the following main points:
To maintain homeostasis, cells and tissues undergo:
Physiological adaptation, which is beneficial in nature — for example, increased skeletal muscle cells in athletes.
Pathological adaptation, which is detrimental — for example, cellular changes in people who smoke cigarettes.
Specific types of adaptation include:
Atrophy — a decrease in the size of cells.
Hypertrophy — an increase in the size of individual cells.
Hyperplasia — an increase in the number of cells in a tissue.
Metaplasia — the conversion from one type of mature cell to another type.
Dysplasia — abnormal cell changes or deranged cell growth.
Anaplasia — cells that are undifferentiated.
Neoplasia — new growth of tissue.
Most toxic effects, especially due to xenobiotics, are due to specific biochemical interactions without causing recognizable damage to a cell or its organelles. Cellular or biochemical toxicity leads to:
The tissue being completely repaired and returned to normal.
The tissue being incompletely repaired but capable of functioning with reduced capacity.
Death of the organism or complete loss of a tissue or organ.
Neoplasm or cancers.
Tumors are either:
Benign — similar to the cell of origin, slow-growing, and usually without systemic effects.
Malignant — dissimilar from the cell of origin, rapid-growing, and commonly with systemic effects and life-threatening. Most malignant tumors are either:
Carcinomas — arising in epithelium, the most common form of cancer, usually spread in the lymphatic system.
Sarcomas — arising in connective or muscle tissue, usually spread by the blood stream.
Carcinogenesis is a multi-step, multi-factorial genetic disease consisting of at least three main phases:
Initiation — irreversible alteration of the DNA (mutation) of a normal cell.
Promotion/Conversion — promoters enhance further development of the initiated cells, often influencing further expression of the mutated DNA such that the initiated cell proliferates and progresses further.
Progression — development of the initiated cell into a biologically malignant cell population, often with metastasis to other areas of the body.
Regulatory genes control the activity of structural genes and direct the proliferation process of the cell. Regulatory genes that play roles in carcinogenesis include:
Proto-oncogenes — normal cellular genes that encode and instruct the production of regulatory proteins and growth factors within a cell or its membrane.
Oncogenes — altered or misdirected proto-oncogenes with the ability to direct the production of proteins within the cell that change or transform the normal cell into a neoplastic cell.
Tumor suppressor genes (anti-oncogenes) — present in normal cells and counteract and change the proto-oncogenes and altered proteins, preventing a cell with damaged DNA from proliferating and evolving into an uncontrolled growth.
The p53 gene normally halts cell division, stimulates repair enzymes, and if necessary, commands the mutated cell to self-destruct
p53 is the most frequently altered in human tumors and is incapable of its defense mechanisms
Toxic damage to the nervous system is divided into three categories:
Damage to sensory receptors and sensory neurons impacting the sensory functions.
Damage to motor neurons causing muscular weakness and paralysis.
Intuitivecan be defined as "using or based on what one feels to be true even without conscious reasoning." Humans have always been intuitive toxicologists via the use of the senses of sight, taste, and smell to try to detect harmful or unsafe food, water, and air.
Intuition and Professional Judgment in Toxicology Even well-established scientific approaches used in human risk assessment depend on extrapolations and judgments when assessing human, animal and other toxicology data. This led to the study ofintuitive toxicology—the intuitive elements of expert and public risk judgments involved with exposure assessment, toxicology, and risk assessment.
Figure 1. Albert Einstein understood the importance of intuition along with knowledge and experience (Image Source: Wikimedia Commons, Public Domain -original image)
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Studies of Intuitive Toxicology The studies of intuitive toxicology have surveyed toxicologists (for example, members of the Society of Toxicology) and others about a wide range of attitudes, beliefs, and perceptions regarding risks from chemicals. These have included basic concepts, assumptions, and interpretations related to the effects of chemical concentration, dose, and exposure on risk, and the value of animal studies for predicting the effects of chemicals on humans.
Two questions that have been studied repeatedly in intuitive toxicology are:
Would you agree or disagree that the way an animal reacts to a chemical is a reliable predictor of how a human would react to it?
If a scientific study produces evidence that a chemical causes cancer in animals, can we can then be reasonably sure that the chemical will cause cancer in humans?
Examples of Findings from Intuitive Toxicology Examples of the findings from studies of intuitive toxicology in the United States, Canada, and the United Kingdom include:
The public is more likely than toxicologists to think chemicals pose greater risks.
The public finds it difficult to understand the concept of dose–response relationships.
Much disagreement between toxicologists about how to interpret various results.
Technical judgments of toxicologists were also found to be associated with factors such as their type of employment (for example, academia, government, or industry), gender, and age.
These types of studies have identified misconceptions that experts should try to clarify in interactions with the public. The results also suggest that disagreement among experts, especially as perceived by the news media and the public, can play a key role in controversies over toxicology-related risks.
Click on any of the links below to learn moreabout Intuitive Toxicology
1) Intuitive toxicology studies show that: a) All toxicologists think the same b) Members of the public usually think like toxicologists c) There can be meaningful differences among toxicologists in how they look at the same set of toxicology study results d) Intuitive toxicology is not important to consider in communication efforts
2) Which of the following statements is correct? a) The concept of dose-response relationships is easily understood by the public b) The public and toxicologists tend to agree about the risks of chemicals c) Technical judgments of toxicologists have been found to not be associated with factors such as their type of employment (for example, academia, government of industry, gender, and age) d) Technical judgments of toxicologists have been found to be associated with factors such as their type of employment (for example, academia, government of industry, gender, and age)
1) There can be meaningful differences among toxicologists in how they look at the same set of toxicology study results-This is the correct answer. Intuitive toxicology studies show that there can be meaningful differences among toxicologists in how they look at the same set of toxicology study results.
2) Technical judgments of toxicologists have been found to be associated with factors such as their type of employment (for example, academia, government of industry, gender, and age)-This is the correct answer. Technical judgments of toxicologists have been found to be associated with factors such as their type of employment (for example, academia, government of industry, gender, and age).
Risk communication is the exchange of information about risks.
Rules for Communicating Risk Much information about how risks could be communicated is available. Some key points about risk communication are identified in the "Seven Cardinal Rules for Communicating Risk" from the work of Dr. Vincent Covello and used by U.S. EPA and others:
Accept and involve the public as a legitimate partner.
Listen to the public’s specific concerns.
Be honest, frank, and open.
Coordinate and collaborate with other credible sources.
Meet the needs of the media.
Speak clearly and with compassion.
Plan carefully and evaluate your efforts.
Lessons Learned About Communicating Risk Some of the lessons that organizations have learned about communicating exposure and health effects information to study subjects, the community, and the public include:
Communication is not a "cheap add-on" to a study. It must be planned and budgeted at the start. The researcher must know the community and establish relationships early in the project. Communications should be tailored to the project and should contain what people really need to know. The study results that are most significant for the community should be emphasized. Moreover, results should be communicated in a format and a manner that subjects can readily understand. Researchers should evaluate and learn from each study.
Ignoring communication may lead to legal problems.
Communicating risk is part of societal accountability.
Principles and guidelines, including proper terminology, are needed.
Guidelines should be enforceable.
Communication requires resources.
It should be determined early in the project who has control of the release of results, and whether results will be presented in stages or all at once.
A professional's credibility is at risk when decisions about communication of study results are being made.
Mechanisms may be needed to proactively consider communication.
The role of Institutional Review Boards (IRBs) must be considered in developing communication.
Six principles of effective crisis and risk communication are:
Be first
Be right
Be credible
Express empathy
Promote action
Show respect
"The CDC acknowledges that less-than-clear communication about what was known and not known about the possible health effects of the Elk River spill may have affected communities' trust in government."Learn more
Uncertainty is defined as "imperfect knowledge concerning the present or future state of an organism, system, or (sub)population under consideration." In other sources (EFSA, 2018), "uncertainty is defined as referring to all types of limitations in the knowledge available to assessors at the time an assessment is conducted and within the time and resources available for the assessment." There are different types of uncertainty, some quantifiable and others not, some reducible and others not.
Due to lack of knowledge, variability adds to the overall uncertainty. Ignoring uncertainty may lead to incomplete risk assessments, poor decision-making, and poor risk communication (European Commission, 2015). The degree to which characterization of uncertainty (and variability) is needed will depend on the risk assessment and risk management contexts as determined in the questions asked (problem formulation).
Uncertainty should be acknowledged and described, such as outlining any data gaps or issues relating to methodology. What is being done to address the areas of uncertainty is also important. In its guidelineWhen Food Is Cooking Up a Storm, the European Food Safety Authority provides a framework to assist decision-making about appropriate communications approaches in a wide variety of situations that can occur when assessing and communicating on risks related to food safety in Europe. It is directed towards governmental agencies that regulate the food sector.
EFSA has developed a harmonized approach to assessing and taking account of uncertainties in food safety, and animal and plant health. In 2018, EFSA published itsGuidance on Uncertainty Analysis in Scientific Assessmentwhich offers a diverse toolbox of scientific methods and technical tools for uncertainty analysis. It is sufficiently flexible to be implemented in such diverse areas as plant pests, microbiological hazards and chemical substances. Further, in a separate document EFSA (2018)describes the principles and methods behind its guidance. It provides a flexible framework within which different methods may be selected, according to the needs of each risk assessment. It is recommended that assessors should systematically identify sources of uncertainty, checking each part of their assessment to minimize the risk of overlooking important uncertainties.
Communicating Uncertainty in Risk Assessments and in Risk Management
By late 2018, EFSA is expected to have apractical guidance for communication specialistson how to communicate the results of uncertainty analysis to different target audiences, including the public. The document aims to help EFSA to communicate scientific uncertainties to its different audiences by using more accessible language tailored to their needs.
Click any of the links below to learn moreabout uncertainty and communicating about it
1) Which of the following isnottrue about communicating risk to a community about exposures and health effects? a) Results should be communicated in a format and a manner that subjects can readily understand b) Results do not need to be communicated in a format and a manner that subjects can readily understand c) Communications should be tailored to the project and should contain what people really need to know d) Researchers and others can learn from studying good and bad risk communication efforts
2) According to the European Commission, ignoring uncertainty may lead to: a) Great decision-making b) Poor decision-making c) Effective risk communication d) Use of the most accurate knowledge available
Environmental Toxicology is the multidisciplinary study of the effects of manmade and natural chemicals on health and the environment. This includes the study of the effects of chemicals on organisms in their natural environments and in the ecosystems to which they belong.
Branches of Environmental Toxicology Environmental Toxicology covers a wide range of interdisciplinary studies, as illustrated in Figure 1:
Figure 1. Environmental Toxicology interdisciplinary core (not comprehensive) (Image Source: Adapted from Wikipedia under the Creative Commons Attribution-ShareAlike 3.0 License)
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Scope of Work and Study Environmental toxicologists work in academia, companies, government agencies, and elsewhere. The work can include laboratory studies, computer modeling, and work "in the field." It is not unusual for an environmental toxicologist to also have training in other areas—for example, public health, environmental chemistry, and pharmacology. Some examples of what Environmental Toxicologists study include:
The effects of a chemical or other substance at various concentrations on various species.
Whether a chemical or other substance can bioaccumulate (increase over time) in animals or other organisms. This is important for human exposures if the bioaccumulation occurs in animals that are part of the human food chain, such as fish.
Emerging issues such as the study of the sources and effects of microplastics that could become part of the human food chain.
Click any of the links below to learn more about microplastics
Figure 2. Microplastics are plastic debris less than five millimeters in length (Image Source: National Ocean Service, National Oceanic and Atmospheric Administration.Original image)
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Another emerging global issue is the health of bees. In the news in recent years are terms like the Colony Collapse Disorder (CCD), pesticides like the neonicotinic pesticides (also called neonicotinoids), and parasites that only reproduce in bee colonies. About 75% of all flowering plants rely on animal pollinators and about one-third of our food production is dependent on animal pollinators. The general declining health of honeybees and other bees is thought to be related to complex interactions among multiple stressors, including pesticides and parasites, and stressors like poor nutrition due to declining foraging habitats, bee management practices, and a lack of genetic diversity.
Neonicotinoids have been a focus of international attention and their mode of action is on the central nervous system of insects. Neonicotinoids are highly toxic to honeybees and also native bees like bumble bees and blue orchard bees, and sub-lethal levels can affect foraging and the ability to reproduce. Further, neonicotinoids can be persistent in the environment, and can be absorbed by plants and found in pollen and nectar.
1) The interdisciplinary core ("branches") of environmental toxicology includes: a) Environmental sciences; physics; toxicology; chemistry; biology b) Environmental sciences; engineering; toxicology; biology; computer and math c) Environmental sciences; computer and math; toxicology; biology; law d) Environmental sciences; biology; toxicology; chemistry; computer and math
2) Which issues in environmental toxicology relate to the human food supply? a) Bioaccumulation of substances in fish b) Effects of neonicotinic pesticides on bees c) Both the bioaccumulation of substances in fish and effects of neonicotinic pesticides on bees
1) Environmental sciences; biology; toxicology; chemistry; computer and math-This is the correct answer. The interdisciplinary core ("branches") of environmental toxicology includes environmental sciences; biology; toxicology; chemistry; computer and math.
2) Both the bioaccumulation of substances in fish and effects of neonicotinic pesticides on bees-This is the correct answer. Both the bioaccumulation of substances in fish and effects of neonicotinic pesticides on bees relate to the human food supply.
Environmental health is a branch of public health. It focuses on the relationships between people and their environment, and promotes human health and well-being. Further, it fosters healthy and safe communities and is a key part of any comprehensive public health system. The field works to advance policies and programs to reduce chemical and other environmental exposures in air, water, soil, and food to protect people and provide communities with an healthier environments.
Toxicology vs. Environmental Health The two fields are closely connected, with a large intersection. The terminology is loose. For example, is environmental health about the health of the environment and/or the effect of the environment on health?
Scope of Work and Study Environmental health specialists identify and evaluate environmental hazards and their sources. They also limit exposures to physical, chemical, and biological agents in air, water, soil, food, and other environmental media or settings that may adversely affect human health (Source).
National Center for Environmental Health (NCEH) The CDC National Center for Environmental Health (NCEH) plans, directs, and coordinates a program to protect the American people from environmental hazards. The NCEH seeks to prevent premature death, avoidable illness, and disability caused by non-infectious, non-occupational environmental and related factors. One focus is on safeguarding the health of venerable populations, such as children, the elderly, and people with disabilities, from certain environmental hazards.
Click any of the links below to learn moreabout environmental health
1) Which of the following are important environmental health issues? a) Radon in air b) Lead contamination in drinking water c) Foodborne illness from contaminated food d) All of these are important for human health
One Health is a worldwide concept and strategy recognizing that the health of people, animals, and the environment are all connected. For example, the Centers for Disease Control and Prevention (CDC) works with physicians, veterinarians, ecologists, and many others to monitor and control public health threats and to learn about how diseases spread among people, animals, and the environment.
Link Between Human, Animal, and Environmental Health One Health is important at the local, regional, national, and global levels, and there are many examples of its importance. One example of how human, animal, and environmental health are linked involves bacteria, cows, farms, food, lettuce, and humans:
People eat contaminated lettuce and can become infected withE. coli. Serious illness or sometimes death can result.
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Figure 1. Human, animal, and environmental health are linked (Image Source: CDC -original image)
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Another example of One Health involving animals and humans is the shared susceptibility to some diseases and environmental hazards. Animals can serve as early warning signs of potential human illness. An example is birds dying from West Nile virus before people in the same areas get sick from exposures to this virus.
Factors that Affect Human and Animal Health Some interactions between people, animals, and the environment have changed in recent years and these changes have impacted animal and human health.
1) One Health is a concept and strategy recognizing that the health of ________, ________, and __________ are all connected. a) People, plants, the environment b) People, animals, the environment c) People, animals, microbes
2) Which of the following factors that affect human and animal health isnotcorrect? a) Fewer people in recent years live in close contact with wild and domestic animals b) Disruptions in environmental conditions and habitats provide new opportunities for diseases to pass to animals c) International travel and trade have increased, and diseases can spread quickly across the globe
1) People, animals, the environment-This is the correct answer. One Health is a concept and strategy recognizing that the health of people, animals, and the environment are all connected.
2) Fewer people in recent years live in close contact with wild and domestic animals-This is the correct answer. The statement "Fewer people in recent years live in close contact with wild and domestic animals" is incorrect.
Thank you for completing ToxTutor!We trust it has given you a strong foundation of understanding in this important area of science. In conclusion, we have now covered the following topics throughout this course:
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Dose by definition is the amount of a substance administered at one time. However, other parameters are needed to characterize the exposure to xenobiotics. The most important are the number of doses, frequency, and total time period of the treatment.
For example:
650 mg acetaminophen (Tylenol®products) as a single dose.
500 mg penicillin every 8 hours for 10 days.
10 mg DDT per day for 90 days.
Substances can enter the body from either:
Encountering them in the environment (exposure).
Intentionally consuming or administering a certain quantity of a substance.
Environments in which xenobiotics are present include outdoor air, indoor air, and water. Xenobiotics can travel into the body through the skin, eyes, lungs, and digestive tract.Exposure to a xenobiotic (see below)can occur in any environment where a substance can enter the:
Skin through dermal absorption (air and water).
Respiratory tract through inhalation.
Digestive tract through ingestion.
Exposure to a xenobiotic Measuring the amount of a substance a person encountered in the surrounding environment often is difficult, but a person's exposure to a xenobiotic can be estimated by collecting samples from the environment and analyzing which substances are present in them and at what amounts.
The amount of a substance administered over a period of time.
Types of doses include:
Absorbed dose— the amount of a substance that entered the body through the skin, eyes, lungs, or digestive tract and was taken up by organs or particular tissues. Absorbed dose can also be called internal dose.
Administered dose— the quantity administered usually orally or by injection (note that an administered dose taken orally may not necessarily be absorbed).
Total dose— the sum of all individual doses.
Not all substances that enter the body are necessarily absorbed by it. This concept applies to water intake. When a person drinks a large quantity of water at one time, some of it is absorbed while the rest of the water is eliminated.
If an individual drinks 1 liter of water every hour for 3 hours, eachadministered dosewould be 1 liter. Thetotal dosewould be the amount the person drank over the time period that the water was consumed. Theabsorbed dose, however,would likely be less than the total dose because it would depend on how much of the water the individual's body absorbed which can be affected by various factors. The water intake example is represented in Table 1.
The terms for types of doses help account for the amount of a substance that entered the body by different means, but the amount absorbed is what is most important.
In a later section, we will review specifics about how the body handles substances after they enter the body.
Fractionating Doses
Fractionating a total dose usually decreases the probability that the total dose will cause toxicity. The reason is that the body often can repair the effect of eachsubtoxic (adosewhich elicits effects that are below the level of detection with standard toxicological parameters) dose if sufficient time elapses before the next dose is received. In that case, a total dose that would be harmful if received all at once is non-toxic when administered over a period of time. For example, 30 mg of strychnine swallowed at one time could be fatal to an adult whereas 3 mg of strychnine swallowed each day for 10 days is not considered a fatal dose. The units used in toxicology are basically the same as those used in medicine. The gram (g) is the standard unit. Because most exposures are in smaller quantities, the milligram (mg) is commonly used. For example, the common adult dose of acetaminophen is 650 mg.
Importance of Age, Body Size, and Time A person’s age and body size affect the clinical and toxic effects of a given dose. Age and body size usually are connected, particularly in children. This relationship is important because a person's body size can affect the burden that a substance has on it. For example, a 650-mg dose of acetaminophen is typical for adults but it would be toxic to young children. Therefore, a tablet of an acetaminophen product designed for children (Children's Tylenol®) contains only 80 mg of the drug.
One way to compare the effectiveness of a dose and its toxicity is to assess the amount of a substance administered with respect tobody weight. A common dose measurement is mg/kg which stands for mg of substance per kg of body weight. Another method used to compare doses among different species is to usebody surface area (see below), rather than simply body weight.
Body Surface Area Intoxicologystudies, toxic effects are tested in animals before any testing is done with humans. Information learned from animal studies about toxicdosesfor one species cannot be directly applied to another species based on body weight alone.Body surface areais another method used for comparingdosesamong different species. Body surface area calculations can help estimate the conversion of animaldosesinto equivalentdosesin humans. Information abouttoxicityfrom particulardosesadministered to animals can be used to inform the startingdosefor humans in an attempt to prevent toxic effects from occurring in humans. Find out more from theFDAGuidance for Industry Estimating the Maximum Safe StartingDosein Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers.
Time Another important aspect is the time over which a dose is administered. That is especially important for exposures that occur over several days or that are chronic. Because the most common time unit is 1 day, the usual dosage unit is mg/kg/day.
Units Because some xenobiotics are toxic in quantities much smaller than the milligram, smaller fractions of the gram, such as microgram (µg). Table 2 shows other units.
Concentration Environmental exposure units are expressed as the amount of a xenobiotic in a unit of the media, which could be liquid, solid, or air. Concentration is the amount of a substance found in a certain amount of another substance, such as water, air, soil, food, blood, hair, urine, or breath. For example, the weight of a toxic substance found in a certain weight of food is indicated as a measure of concentration rather than the total amount. Knowing how concentrated the toxic substance is in a sample of food that weighs 100 g allows for easy comparison when testing for that toxic substance in other samples of food that weigh more or less than 100 g.
Figure 7 illustrates this concept. The two glasses contain samples of juice that are being tested for contamination with lead. The volume of juice in Glass A is 100 mL and the volume of juice in Glass B is 50 mL. The concentration of lead is the same in both samples of juice: 20 parts per billion (ppb). The total amount of lead would be higher in Glass A but the concentration of lead per unit volume is the same in both glasses.
Assessing Exposure An individual’s exposure to a substance can be assessed based on the relationship between the person'sbody weight and these factors:
Concentrationof the substance in the environmental media (for example, in µg/ml).
Amount of the substance taken into the body.
Duration and frequency of individual events during which the body was in contact with the environmental media.
Environmental exposure units used in toxicology include:
mg/liter (mg/L) for liquids.
mg/gram (mg/g) for solids.
mg/cubic meter (mg/m3) for air.
Smaller units are used as needed; for example, µg/mL. Other commonly used dose units for substances in media are parts per million (ppm), parts per billion (ppb), and parts per trillion (ppt). When smaller units are used to quantify exposure, the mg/kg/day unit can be adapted to the smaller unit. For example, parts per billion per kg per day (ppb/kg/day) could be used.
An important thing to remember is that the use of a small dose unit is not related to the burden a substance has on the body. An exposure unit describes only the quantity of the substance.
The dose-response relationship is an essential concept in toxicology. It correlates exposures with changes in body functions or health.
In general, the higher the dose, the more severe the response. The dose-response relationship is based on observed data from experimental animal, human clinical, or cell studies.
Knowledge of the dose-response relationship establishes:
Causality— that the chemical has induced the observed effects.
Thethreshold effect— the lowest dose where an induced effect occurs.
Theslopefor the dose response — therateat which injury builds up.
Within a population, the majority of responses to a toxicant are similar; however, there are differences in how responses may be encountered – some individuals are susceptible and others resistant. As demonstrated in Animation 1, a graph of the individual responses can be depicted as a bell-shaped standard distribution curve. There is a wide variance in responses as demonstrated by the mild reaction in resistant individuals, the typical response in the majority of individuals, and the severe reaction in sensitive individuals.
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Animation 1.A graph of individual responses to a substance, which generally take the form of a bell-shaped curve. (view full-text, PDF version)
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The dose-response curve is a visual representation of the response rates of a population to a range of doses of a substance, as demonstrated in Animation 2.
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Animation 2. The graph of a dose-response relationship typically has an "s" shape. (view full-text, PDF version)
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A threshold for toxic effects occurs at the point where the body's ability to detoxify a xenobiotic or repair toxic injury has been exceeded. Most organs have a reserve capacity such that loss of some organ function does not result in decreased performance. For example, development of cirrhosis in the liver may not result in a clinical effect until over 50% of the organ has been replaced by fibrous tissue.
Knowledge Check (Solutions on next page)
1) The quantity of a substance administered to an individual over a period of time or in several individual doses is known as the: a) administered dose b) absorbed dose c) total dose
2) Fractionation of a total dose so that the total amount administered is given over a period of time usually results in: a) decreased toxicity b) increased toxicity
3) The usual dosage unit that incorporates the amount of material administered or absorbed in accordance with the size of the individual over a period of time is: a) PPM/hour b) mg/kg/day c) kg/100 lb/week
4) The dose at which a toxic effect is first encountered is called the: a) median toxic dose b) absorbed dose c) threshold dose
5) The dose-response relationship helps a toxicologist determine: a) whether exposure has caused an effect b) the threshold dose c) the rate of increasing effect with increasing dose levels d) all of the above
1) The total dose is the quantity of a substance administered to an individual over a period of time or in several individual doses. It is particularly important when evaluating cumulative poisons.
2) Fractionation of a total dose so that the total amount administered is given over a period of time usually results in decreased toxicity. This applies to most forms of toxicity but not necessarily to carcinogenicity or mutagenicity.
3) The usual dosage unit that incorporates the amount of material administered or absorbed in accordance with the size of the individual over a period of time is mg/kg/day. In some cases, much smaller dosage units, such as µg/kg/day, are used.
4) The threshold dose is the dose at which a toxic effect is first encountered.
5) All of these answers are correct. The dose-response relationship demonstrates whether any effect has occurred, the threshold dose, and the rate at which the effect increases with increasing dose levels.
Dose Estimates Dose-response curves are used to derive dose estimates of chemical substances.
Historically,LD50(Lethal Dose 50%) has been a common dose estimate for acute toxicity. It is astatistically derived maximum doseat which 50% of the group of organisms (rat, mouse, or other species) would be expected to die. LD50 testing is no longer the recommended method for assessing toxicity because of the ethics of using large numbers of animals, the variability of responses in animals and humans, and the use of mortality as the only endpoint. Regulatory agencies use LD50 only if it is justified by scientific necessity and ethical considerations.
The Three Rs The current practice for estimating acute toxicity emphasizes the following approaches, known as the Three Rs:
Replacinganimals in science byin vitro,in silico (performed on computer or via computer simulation), and other approaches.
Reducingthe number of animals used. For example, the oral LD50 approach has been replaced in some circumstances by anup-and-down method (definition below) in which animals are dosed one at a time.
Refiningcare and procedures to minimize pain and distress.
Other dose estimates also may be used.
Up-and-down-method - Animals are dosed one at a time. If an animal survives, the dose for the next animal is increased; if it dies, the dose is decreased. The up-and-down procedure would require only 6 to 10 animals, provided that the initial estimate of the LD50 is within a factor of two of the true LD50.
Lethal Doses/Concentrations
Lethal Dose 0% (LD0)— represents the dose at which no individuals are expected to die. This is just below the threshold for lethality.
Lethal Dose 10% (LD10)— refers to the dose at which 10% of the individuals will die.
Lethal Concentration 50% (LC50)— for inhalation toxicity, air concentrations are used for exposure values. The LC50 refers to the calculated concentration of a gas lethal to 50% of a group. Occasionally LC0 and LC10 are also used.
Effective Doses (EDs) Effective Doses(EDs) are used to indicate the effectiveness of a substance. Normally, effective dose refers to a beneficial effect such as relief of pain. It may also stand for a harmful effect such as paralysis. Thus, the specific endpoint must be indicated. The usual terms are:
Determining the Relative Safety of Pharmaceuticals
Toxicologists, pharmacologists, and others useeffectiveand toxic doselevels to determine the relative safety of pharmaceuticals. As shown in Figure 1, two dose-response curves are presented for the same drug, one for effectiveness and the other for toxicity. In this case, a dose that is 50% to 75% effective does not cause toxicity. However, a 90% effective dose may result in a small amount of toxicity.
The Therapeutic Index (TI) is used to compare the therapeutically effective dose to the toxic dose of a pharmaceutical agent. The TI is a statement of relative safety of a drug. It is the ratio of the dose that produces toxicity to the dose needed to produce the desired therapeutic response. The common method used to derive the TI is to use the 50% dose-response points, including TD50 (toxic dose) and ED50 (effective dose).
However, the use of the ED50and TD50doses to derive the TImay be misleading about a drug's safety, depending on the slope of the dose-response curves for therapeutic and toxic effects. To overcome this deficiency, toxicologists often use another term to denote the safety of a drug: the Margin of Safety.
Margin of Safety (MOS) TheMargin of Safety (MOS)is usually calculated as the ratio of the toxic dose to 1% of the population (TD01) to the dose that is 99% effective to the population (ED99).
The graph in Figure 2 shows the relationship between effective dose response and toxic dose response. The shaded area represents the doses at which the substance produces an effective dose response while the toxic dose response remains below the TD50. The slope of a curve shows how dose increases result in responses to the effective or toxic dose.
Figure 2. Relationship between effective dose response and toxic dose response (Image Source: NLM)
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Because of differences in slopes and threshold doses, low doses may be effective without producing toxicity. Although more patients may benefit from higher doses, that is offset by the probability that toxicity will occur.
The toxicity of various substances can be compared using the slopes for each curve (Figure 3).
Figure 3. Comparison of the toxicity of two substances (Image Source: NLM)
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For some substances, a small increase in dose causes a large increase in response, which is seen in Toxicant A's steep slope. For other substances, a much larger increase in dose is required to cause the same increase in response, as indicated in Toxicant B's shallow slope.
NOAEL and LOAEL Results from research studies establish the highest doses at which no toxic effects were identified and the lowest doses at which toxic or adverse effects were observed. The terms often used to describe these outcomes are:
No Observed Adverse Effect Level (NOAEL)
Lowest Observed Adverse Effect Level (LOAEL)
These terms refer to the actual doses used in human clinical or experimental animal studies. They are defined as follows:
NOAEL --Highest doseat which therewas notan observed toxic or adverse effect.
LOAEL --Lowest doseat which therewasan observed toxic or adverse effect.
Figure 1 shows a dose-response curve where the NOAEL occurs at 10 mg and the LOAEL occurs at 18 mg.
Figure 1. A dose-response curve showing doses where the NOAEL and LOAEL occur for a substance (Image Source: NLM)
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Sometimes the termsNo Observed Effect Level (NOEL)andLowest Observed Effect Level (LOEL)are also used. NOELs and LOELs do not necessarily imply toxic or harmful effects and can be used to describe beneficial effects of substances.
The NOAEL, LOAEL, NOEL, and LOEL are commonly used in risk assessments and research. For example,this U.S. Food and Drug Administration (FDA) publicationfor industry describes a process for estimating the maximum safe starting dose of drugs tested in clinical trials. It provides extensive information about these concepts and their utility when developing new drugs.
NOAELs and LOAELs are also included in theNoncarcinogenic Risk Assessment sectionwhere they are applied using the benchmark dose (BMD) method.
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Knowledge Check (Solutions on next page)
1) Which of the following isnotone of the Three Rs of estimating acute toxicity? a) Replace animals in science byin vitro,in silico, and other approaches b) Reduce the number of animals used c) Refine care and procedures to minimize pain and distress d) Randomize the selected test animals
2) The Therapeutic Index (TI) is used to: a) Compare the therapeutically effective dose to the toxic dose of a pharmaceutical agent b) Calculate the lethal dose level for different pharmaceuticals c) Compare the lethal dose to the therapeutically effective dose of a pharmaceutical agent
3)The Margin of Safety (MOS) of a drug is the: a) Amount of a pharmaceutical that can be given before toxicity first appears b) Difference between the Effective Dose to 50% of the population (ED50) and the Toxic Dose to 50% of the population (TD50) c) Ratio of the Toxic Dose to 1% of the population (TD01) to the Effective Dose to 99% of the population (ED99)
4) The No Observed Adverse Effect Level (NOAEL) is the: a) Lowest doseat which therewas noobserved toxic or adverse affect b) Highest doseat which therewas noobserved toxic or adverse effect c) Highest doseat which therewasan observed adverse effect
5) The Lowest Observed Adverse Effect Level (LOAEL) is the: a) Lowest doseat which therewasan observed toxic or adverse effect b) Lowest doseat which therewas noobserved toxic or adverse effect c) Highest doseat which therewasan observed adverse effect
1) Randomize the selected test animals-This is the correct answer. The Three Rs involve replacing animals in science byin vitro,in silico, and other approaches; reducing the number of animals used in testing; and refining care and procedures to minimize pain and distress.
2) Compare the therapeutically effective dose to the toxic dose of a pharmaceutical agent-This is the correct answer. The Therapeutic Index (TI) is used to compare the therapeutically effective dose to the toxic dose of a pharmaceutical agent.
3) Ratio of the Toxic Dose to 1% of the population (TD01) to the Effective Dose to 99% of the population (ED99)-This is the correct answer. The Margin of Safety (MOS) is the ratio of the Toxic Dose to 1% of the population (TD01) to the Effective Dose to 99% of the population (ED99).
4) Highest doseat which therewas noobserved toxic or adverse effect-This is the correct answer. The No Observed Adverse Effect Level (NOAEL) is the highest dose at which there was no observed toxic or adverse effect.
5) Lowest doseat which therewasan observed toxic or adverse effect-This is the correct answer. The Lowest Observed Adverse Effect Level (LOAEL) is the lowest dose at which there was an observed toxic or adverse effect.
What We've Covered In this section, we explored the following main points:
Dose is the amount of a substance administered; however, several parameters are required to characterize exposure to xenobiotics, including the:
Number of doses
Frequency of doses
Total time period of exposure
The dose-response relationship helps establish causality, or that the chemical induced the observed effects; the threshold effect, or the lowest dose that induced effects; and the slope, or the rate at which effects increase with dose increases.
Estimating doses for toxic effects involves:
Lethal Doses/Concentrations, such as LD0, LD10, and LC50, which denote doses or concentrations that are expected to lead to death in specific percentages of a population.
Effective Doses, such as ED50 and ED90, which denote doses that are effective in achieving a desired endpoint in specific percentages of a population.
Toxic Doses, such as TD0 and TD50, which denote doses that cause adverse toxic effects in specific percentages of a population.
The Therapeutic Index (TI) compares the effective dose to the toxic dose of a drug.
The Margin of Safety (MOS) compares the toxic dose to 1% of the population to the effective dose to 99% of the population.
NOAEL is thehighestdose at which thereis noobserved toxic effect.
LOAEL is thelowestdose at which thereisan observed toxic effect.
Did you know? In December 1984, the world's worst industrial accident occurred in Bhopal, India. More than 40 tons ofmethyl isocyanateleaked from a pesticide plant, killing thousands of people and injuring hundreds of thousands. Follow-up studies have shown that the incident caused increased mortality and continued effects on health, including airway disease, eye diseases, and pregnancy losses.
The company involved in the leak tried to distance itself from the accident and prevent those affected from learning the true nature of the accident. The legal case went on for years. Eventually, families of the dead received an average of about $2,200. While the company ceased operation at its Bhopal plant after the disaster, it did not clean up the site completely. The plant continues to leak several toxic chemicals and heavy metals into local aquifers.
Types of Toxic Effects Many factors play a potential role in toxicity. The dosage (or amount of exposure) is the most important factor. A well-known saying,"the dose makes the poison" speaks to this principle. The full saying credited toParacelsusis "All things are poison and nothing is without poison; only the dose makes a thing not a poison."
Toxicity can result from adverse cellular, biochemical, or macromolecular changes. Some examples are noted below.
Many chemicals distribute in the body and often affect only specifictarget organs. However, other chemicals can damage any cell or tissue that they contact. The target organs that are affected may vary depending on dosage and route of exposure. For example, the central nervous system may be the target organ for toxicity from a chemical after acute exposure whereas the liver may be affected after chronic exposures.
Chemicals can cause many types of toxicity by a variety of mechanisms. Some act locally such as when direct exposure triggers skin or eye irritation, whereas other chemical cause systemic effects in the body in sites remote from where the actual exposure occurred. Toxicity can act directly affect subcellular components, such as cell receptors, or it can cause problems at the cellular level, such as with exposures to caustic or corrosive substances.
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For example, chemicals might:
Themselves be toxic or require metabolism (chemical change within the body) before they cause toxicity.
Cause damage leading to fibrosis as the body attempts to repair the toxicity.
Damage or disrupt an enzyme system or protein synthesis.
Produce reactive chemicals in cells.
Cause changes in hormone signaling or other effects.
Mercuryis a naturally occurring heavy metal.Methylmercury, the most common organic mercury compound, can be formed in water and soil by bacteria. It builds up in the tissues of fish. Exposure to high levels of mercury and mercury compounds can cause death or permanently damage the brain and kidneys.
In the late 1950s, people living around Japan's Minamata Bay developed symptoms of severe methylmercury poisoning, some of whom died. Children exposedin uterowere born with disabilities. Investigations showed that heavily contaminated sludge from a factory had been released into the bay, contaminating fish and shellfish. People who ate the fish and shellfish became ill. The events led to a better understanding of industrial pollution and how heavy metals can accumulate in systems.
In January 2013 theMinamata Convention on Mercuryglobal treaty was agreed to by an intergovernmental committee. It seeks to protect human health and the environment from the adverse effects of mercury.
Because chemicals can affect organisms by different mechanisms and at the molecular level, there are new ways to conduct toxicity testing. An emerging approach is to useAdverse Outcome Pathways (AOPs), which evaluate changes in normal cellular pathways. AOPs reflect the move away from high-dose studies in laboratory animals for toxicity testing to in vitro methods that evaluate changes in normal cellular pathways using human-relevant cells or tissues.
Other terms that describe changes resulting from the exposure of a living organism to a substance include mode of action (MoA) and mechanism of action (MOA).
Mode of action (MoA)(older term) — describes a functional or anatomical change at thecellularlevel.
In some instances, individuals can have unpredictable reactions, oridiosyncratic responses, to a drug or other substance. An idiosyncratic response is uncommon, and it is sometimes impossible to understand whether it is the result of a genetic predisposition or has some other cause such as the status of the immune system. It could result in an abnormally small or short, or abnormally large or long response to the drug or other substance. Or, the response could be qualitatively different than what has been observed in most other individuals. The toxicity of a substance usually depends on the following factors:
Form and innate chemical activity
Dosage, especially dose-time relationship
Exposure route
Species
Life stage, such as infant, young adult, or elderly adult
Gender
Ability to be absorbed
Metabolism
Distribution within the body
Excretion
Health of the individual, including organ function and pregnancy, which involves physiological changes that could influence toxicity
Nutritional status
Presence of other chemicals
Circadian rhythms (the time of day a drug or other substance is administered)
Factors Related to the Substance
Form and Innate Chemical Activity Theformof a substance may have a profound impact on its toxicity especially for metallic elements, also termed heavy metals. For example, the toxicity of mercury vapor differs greatly from methyl mercury. Another example is chromium. Cr3+is relatively nontoxic whereas Cr6+causes skin or nasal corrosion and lung cancer.
Theinnate chemical activityof substances also varies greatly. Some can quickly damage cells causing immediate cell death. Others slowly interfere only with a cell's function. For example:
Hydrogen cyanide binds to the enzyme cytochrome oxidase resulting in cellular hypoxia and rapid death.
Nicotine binds to cholinergic receptors in the central nervous system (CNS) altering nerve conduction and inducing gradual onset of paralysis.
Dosage Thedosageis the most important and critical factor in determining if a substance will be anacuteor achronictoxicant. Virtually all chemicals can be acute toxicants if sufficiently large doses are administered. Often the toxic mechanisms and target organs are different for acute and chronic toxicity. Examples are:
Exposure Route The way an individual comes in contact with a toxic substance, orexposure route, is important in determining toxicity. Some chemicals may be highly toxic by one route but not by others. Two major reasons are differences in absorption and distribution within the body. For example:
Ingested chemicals, when absorbed from the intestine, distribute first to the liver and may be immediately detoxified.
Inhaled toxicants immediately enter the general blood circulation and can distribute throughout the body prior to being detoxified by the liver.
Different target organs often are affected by different routes of exposure.
Absorption Theability to be absorbedis essential to systemic toxicity. Some chemicals are readily absorbed and others are poorly absorbed. For example, nearly all alcohols are readily absorbed when ingested, whereas there is virtually no absorption for most polymers. The rates and extent of absorption may vary greatly depending on the form of a chemical and the route of exposure to it. For example:
Ethanol is readily absorbed from the gastrointestinal tract but poorly absorbed through the skin.
Organic mercury is readily absorbed from the gastrointestinal tract; inorganic lead sulfate is not.
Factors Related to the Organism
Species Toxic responses can vary substantially depending on the species. Most differences between species are attributable to differences in metabolism. Others may be due to anatomical or physiological differences. For example, rats cannot vomit and expel toxicants before they are absorbed or cause severe irritation, whereas humans and dogs are capable of vomiting. Selective toxicityrefers to species differences in toxicity between two species simultaneously exposed. This is the basis for the effectiveness of pesticides and drugs. For example:
An insecticide is lethal to insects but relatively nontoxic to animals.
Antibiotics are selectively toxic to microorganisms while virtually nontoxic to humans.
Life Stage An individual's age orlife stagemay be important in determining his or her response to toxicants. Some chemicals are more toxic to infants or the elderly than to young adults. For example:
Parathion is more toxic to young animals.
Nitrosamines are more carcinogenic to newborn or young animals.
Gender Gender can play a big role in influencing toxicity. Physiologic differences between men and women, including differences in pharmacokinetics and pharmacodynamics, can affect drug activity.
In comparison with men, pharmacokinetics in women generally can be impacted by their lower body weight, slower gastrointestinal motility, reduced intestinal enzymatic activity, and slower kidney function (glomerular filtration rate). Delayed gastric emptying in women may result in a need for them to extend the interval between eating and taking medications that require absorption on an empty stomach. Other physiologic differences between men and women also exist. Slower renal clearance in women, for example, may result in a need for dosage adjustment for drugs such as digoxin that are excreted via the kidneys.
In general, pharmacodynamic differences between women and men include greater sensitivity to and enhanced effectiveness, in women, of some drugs, such as beta blockers, opioids, and some antipsychotics.
Studies in animals also have identified gender-related differences. For example:
Male rats are 10 times more sensitive than females to liver damage from DDT.
Female rats are twice as sensitive to parathion as are male rats.
Metabolism Metabolism, also known as biotransformation, is the conversion of a chemical from one form to another by a biological organism. Metabolism is a major factor in determining toxicity. The products of metabolism are known as metabolites. There are two types of metabolism:
Detoxification
Bioactivation
Indetoxification, a xenobiotic is converted to a less toxic form. This is a natural defense mechanism of the organism. Generally, detoxification converts lipid-soluble compounds to polar compounds.
Inbioactivation, a xenobiotic may be converted to more reactive or toxic forms. Cytochrome P-450 (CYP450) is an example of an enzyme pathway used to metabolize drugs. In the elderly, CYP450 metabolism of drugs such as phenytoin and carbamazepine may be decreased. Therefore, the effect of those drugs may be less pronounced. CYP450 metabolism also can be inhibited by many drugs. Risk of toxicity may be increased if a CYP450 enzyme-inhibiting drug is given with one that depends on that pathway for metabolism.
There is awareness that the gut microbiota can impact the toxicity of drugs and other chemicals. For example, gut microbes can metabolize some environmental chemicals and bacteria-dependent metabolism of some chemicals can modulate their toxicity. Also, environmental chemicals can alter the composition and/or the metabolic activity of the gastrointestinal bacteria, thus contributing in a meaningful way to shape an individual's microbiome. The study of the consequences of these changes is an emerging area of toxicology.
Learn moreabout human exposure to pollutants and their interaction with the GI microbiota. Learn moreabout the microbiome and toxicology.
Distribution Within the Body Thedistributionof toxicants and toxic metabolites throughout the body ultimately determines the sites where toxicity occurs. A major determinant of whether a toxicant will damage cells is its lipid solubility. If a toxicant is lipid-soluble, it readily penetrates cell membranes. Many toxicants are stored in the body. Fat tissue, liver, kidney, and bone are the most common storage sites. Blood serves as the main avenue for distribution. Lymph also distributes some materials.
Excretion The site and rate ofexcretionis another major factor affecting the toxicity of a xenobiotic. The kidney is the primary excretory organ, followed by the gastrointestinal tract, and the lungs (for gases). Xenobiotics may also be excreted in sweat, tears, and milk.
A large volume of blood serum is filtered through the kidney. Lipid-soluble toxicants are reabsorbed and concentrated in kidney cells. Impaired kidney function causes slower elimination of toxicants and increases their toxic potential.
Health Status The health of an individual or organism can play a major role in determining the levels and types of potential toxicity. For example, an individual may have pre-existing kidney or liver disease. Certain conditions, such as pregnancy, also are associated with physiological changes in kidney function that could influence toxicity.
Nutritional Status Diet (nutritional status) can be a major factor in determining who does or does not develop toxicity. For example:
Consumption of fish that have absorbed mercury from contaminated water can result in mercury toxicity; an antagonist for mercury toxicity is the nutrient selenium.
Some vegetables can accumulate cadmium from contaminated soil; an antagonist for cadmium toxicity is the nutrient zinc.
Grapefruit contains a substance that inhibits the P450 drug detoxification pathway, making some drugs more toxic.
Find out more about nutrition and chemical toxicityhere.
Circadian Rhythms Circadian rhythms can play a role in toxicity. For example, rats administered an immunosuppressive drug had severe toxicity in their intestines 7 hours after light onset compared to controls and to other times in the day. The rats had changes in their digestive enzyme activity and other physiological indicators at this dosing time.
Find out more about circadian rhythm and gut toxicityhere.
Other Factors
Presence of Other Chemicals The presence of other chemicals, at the same time, earlier, or later may:
Decrease toxicity(antagonism)
Add to toxicity(additivity)
Increase toxicity(synergism or potentiation)
For example:
Antidotes used to counteract the effects of poisons function through antagonism (atropine counteracts poisoning by organophosphate insecticides).
Alcohol may enhance the effect of many antihistamines and sedatives.
A synergistic interaction between the antioxidant butylated hydroxytoluene (BHT) and a certain concentration of oxygen results in lung damage in the form of interstitial pulmonary fibrosis.
Information on additional examples of lung damage from chemical interactions can be foundhere.
Knowledge Check (Solutions on next page)
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1) A target organ is an organ that: a) Absorbs a toxic substance b) Stores an absorbed substance or its metabolite c) Is damaged by a toxic substance
2) What are the important factors that influence the degree of toxicity of a substance? a) Innate chemical activity, form, dosage, and exposure route b) The species, life stage, gender, health status, nutritional status, and circadian rhythms of the organism c) Absorption, metabolism, distribution within the body, excretion, and presence of other chemicals d) All of the above
3) Metabolism, or biotransformation, of a xenobiotic: a) Always results in reduced toxicity of the xenobiotic b) May result in detoxification or bioactivation c) Has no influence on the toxicity of the xenobiotic
4) An antibiotic administered to humans kills bacteria in the body but does not harm human tissues. This is an example of: a) Selective toxicity b) Acute toxicity c) Varying absorption of the antibiotic
5) A major determinant of whether a toxicant will damage cells is its: a) Acidity b) Biotransformation c) Lipid solubility
1) Is damaged by a toxic substance-This is the correct answer. A target organ is an organ in which a substance exerts a toxic effect.
2) All of the above-This is the correct answer. All of these are important factors influencing the toxicity of a substance.
3) May result in detoxification or bioactivation-This is the correct answer. Metabolism of a xenobiotic results in either detoxification, which converts the xenobiotic to a less toxic form, or bioactivation, which converts the xenobiotic to more reactive or toxic forms. For example, a xenobiotic itself might not be carcinogenic, but a metabolite of the xenobiotic might be.
4) Selective toxicity-This is the correct answer. Selective toxicity refers to differences in toxicity between two species simultaneously exposed, much like the antibiotic in this example.
5) Lipid solubility-This is the correct answer. A major determinant of whether or not a toxicant will damage cells is its lipid solubility. If a toxicant is lipid-soluble, it readily penetrates cell membranes.
Types of Systemic Toxic Effects Toxic effects are generally categorized according to the site of the toxic effect. In some cases, the effect may occur at only one site. This site is termed the specific target organ.
In other cases, toxic effects may occur at multiple sites. This is known as systemic toxicity. Types of systemic toxicity include:
Acute Toxicity
Subchronic Toxicity
Chronic Toxicity
Carcinogenicity
Developmental Toxicity
Genetic Toxicity (somatic cells)
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Acute Toxicity Acute toxicityoccurs almost immediately (seconds/minutes/hours/days) after an exposure. An acute exposure is usually a single dose or a series of doses received within a 24-hour period. Death can be a major concern in cases of acute exposures. For example:
In 1989, 5,000 people died and 30,000 were permanently disabled due to exposure to methyl isocyanate from an industrial accident in India.
Many people die each year from inhaling carbon monoxide from faulty heaters.
Subchronic Toxicity Subchronic toxicityresults from repeated exposure for several weeks or months. This is a common human exposure pattern for some pharmaceuticals and environmental agents. For example:
Ingestion of warfarin (Coumadin®) tablets (blood thinners) for several weeks as a treatment for venous thrombosis can cause internal bleeding.
Workplace exposure to lead over a period of several weeks can result in anemia.
Chronic Toxicity Chronic toxicity represents cumulative damage to specific organ systems and takes many months or years to become a recognizable clinical disease. Damage due to subclinical individual exposures may go unnoticed. With repeated exposures or long-term continual exposure, the damage from this type of exposure slowly builds up (cumulative damage) until the damage exceeds the threshold for chronic toxicity. Ultimately, the damage becomes so severe that the organ can no longer function normally and a variety of chronic toxic effects may result. Chronic toxic effects include:
Cirrhosis in alcoholics who have ingested ethanol for several years.
Chronic kidney disease in workmen with several years of exposure to lead.
Chronic bronchitis in long-term cigarette smokers.
Pulmonary fibrosis in coal miners (black lung disease).
Carcinogenicity Carcinogenicityis acomplex multistage processof abnormal cell growth and differentiation that can lead to cancer. The two stages of carcinogenicity are:
Initiation— a normal cell undergoes irreversible changes.
Promotion— initiated cells are stimulated to progress to cancer.
Chemicals can act asinitiatorsorpromoters.
The initial transformation that causes normal cells to undergo irreversible changes results from the mutation of the cellular genes that control normal cell functions. The mutation may lead to abnormal cell growth. It may involve a loss of suppresser genes that usually restrict abnormal cell growth. Many other factors are involved, such as growth factors, immune suppression, and hormones.
Atumor (neoplasm)is simply an uncontrolled growth of cells:
Benign tumorsgrow at the site of origin; do not invade adjacent tissues or metastasize; and generally are treatable.
Malignant tumors (cancer)invade adjacent tissues or migrate to distant sites(metastasis). They are more difficult to treat and often cause death.
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Developmental Toxicity Developmental toxicity pertains to adverse toxic effects to the developing embryo or fetus. It can result from toxicant exposure to either parent before conception or to the mother and her developing embryo or fetus. The three basic types of developmental toxicity are:
Embryolethality— failure to conceive, spontaneous abortion, or stillbirth.
Embryotoxicity— growth retardation or delayed growth of specific organ systems.
Teratogenicity— irreversible conditions that leave permanent birth defects in live offspring, such as cleft palette or missing limbs.
Chemicals cause developmental toxicity in two ways:
They act directly on cells of the embryo, causing cell death or cell damage, leading to abnormal organ development.
They induce a mutation in a parent's germ cell, which is transmitted to the fertilized ovum. Some mutated fertilized ova develop into abnormal embryos.
Genetic Toxicity Genetic toxicityresults from damage to DNA and altered genetic expression. This process is known as mutagenesis. The genetic change is referred to as a mutationand the agent causing the change is called a mutagen. There are three types of genetic changes:
Gene mutation— change in DNA sequence within a gene.
Chromosome aberration— changes in the chromosome structure.
Aneuploidyorpolyploidy— increase or decrease in number of chromosomes.
If the mutation occurs in a germ cell, the effect is heritable. This means there is no effect on the exposed person; rather, the effect is passed on to future generations.
If the mutation occurs in a somaticcell, it can cause altered cell growth (for example, cancer) or cell death (for example, teratogenesis) in the exposed person.
Blood and Cardiovascular/Cardiac Toxicityresults from xenobiotics acting directly on cells in circulating blood, bone marrow, and the heart. Examples of blood and cardiovascular/cardiac toxicity are:
Hypoxia due to carbon monoxide binding of hemoglobin preventing transport of oxygen.
Decrease in circulating leukocytes due to chloramphenicol damage to bone marrow cells.
Leukemia due to benzene damage of bone marrow cells.
Arteriosclerosis due to cholesterol accumulation in arteries and veins.
Dermal Toxicitycan occur when a toxicant comes into direct contact with the skin or is distributed to it internally. Effects range from mild irritation to severe changes, such as irreversible damage, hypersensitivity, and skin cancer. Examples of dermal toxicity include:
Dermal irritation from skin exposure to gasoline.
Dermal corrosion from skin exposure to sodium hydroxide (lye).
Dermal itching, irritation, and sometimes painfulrashfrom poison ivy, caused byurushiol.
Skin cancer due to ingestion of arsenic or skin exposure to UV light.
Epigenetics is an emerging area in toxicology. In the field of genetics, epigenetics involves studying how external or environmental factors can switch genes on and off and change the programming of cells.
More specifically, epigenetics refers to stable changes in the programming of gene expression which can alter the phenotype without changing the DNA sequence (genotype). Epigenetic modifications include DNA methylation, covalent modifications of histone tails, and regulation by non-coding RNAs, among others.
Toxicants are examples of factors that can alter genetic programming.
In the past, toxicology studies have assessed toxicity without measuring its impact at the level where gene expression occurs. Exogenous agents could cause long-term toxicity that continues after the initial exposure has disappeared, and such toxicities remain undetected by current screening methods. Thus, a current challenge in toxicology is todevelop screening methods that would detect epigenetic alterationscaused by toxicants.
Research is being done to assess epigenetic changes caused by toxicants. For example, theNational Institutes of Health (NIH) National Institute of Environmental Health Sciences (NIEHS) Environmental Epigenetics programprovides funding for a variety of research projects that use state-of-the-art technologies to analyze epigenetic changes caused by environmental exposures. NIEHS-supported researchers use animals, cell cultures, and human tissue samples to pinpoint how epigenetic changes can lead to harmful health effects and can potentially be passed down to the next generation.
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Eye Toxicity
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Eye Toxicityresults from direct contact with or internal distribution to the eye. Because the cornea and conjunctiva are directly exposed to toxicants, conjunctivitis and corneal erosion may be observed following occupational exposure to chemicals. Many household items can cause conjunctivitis. Chemicals in the circulatory system can distribute to the eye and cause corneal opacity, cataracts, and retinal and optic nerve damage. For example:
Acids and strong alkalis may cause severe corneal corrosion.
Corticosteroids may cause cataracts.
Methanol (wood alcohol) may damage the optic nerve.
Hepatotoxicityis toxicity to the liver, bile duct, and gall bladder. Because of its extensive blood supply and significant role in metabolism, the liver is particularly susceptible to xenobiotics Thus, it is exposed to high doses of the toxicant or its toxic metabolites. The primary forms of hepatotoxicity are:
Steatosis— lipid accumulation in the hepatocytes.
Chemicalhepatitis— inflammation of the liver.
Hepaticnecrosis— death of the hepatocytes.
Intrahepaticcholestasis— backup of bile salts into the liver cells.
Hepaticcancer— cancer of the liver.
Cirrhosis— chronic fibrosis, often due to alcohol.
Hypersensitivity— immune reaction resulting in hepatic necrosis.
Related Resource: LiverTox® The National Library of MedicineLiverTox: Clinical and Research Information on Drug-Induced Liver Injury®has information on liver injury caused by prescription and nonprescription drugs and herbal and dietary supplements, including clinical information on diagnosis and management of drug-induced liver injury and a registry of clinical case reports.
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Immunotoxicity
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Immunotoxicityis toxicity of the immune system. It can take several forms:
Hypersensitivity (allergy and autoimmunity)
Immunodeficiency
Uncontrolled proliferation (leukemia and lymphoma)
The normal function of the immune system is to recognize and defend against foreign invaders. This is accomplished by production of cells that engulf and destroy the invaders or by antibodies that inactivate foreign material. Examples include:
Contact dermatitis due to exposure to poison ivy.
Systemic lupus erythematosus ("lupus") in workers exposed to hydrazine.
The kidney is highly susceptible to toxicants because a high volume of blood flows through the organ and it filters large amounts of toxins which can concentrate in the kidney tubules.
Nephrotoxicityis toxicity to the kidneys. It can result in systemic toxicity causing:
Decreased ability to excrete body wastes.
Inability to maintain body fluid and electrolyte balance.
Decreased synthesis of essential hormones (for example, erythropoietin, which increases the rate of blood cell production).
Neurotoxicityrepresents toxicant damage to cells of the central nervous system (brain and spinal cord) and the peripheral nervous system (nerves outside the CNS). The primary types of neurotoxicity are:
Respiratory Toxicityrelates to effects on the upper respiratory system (nose, pharynx, larynx, and trachea) and the lower respiratory system (bronchi, bronchioles, and lung alveoli). The primary types of respiratory toxicity are:
1) Toxic effects are primarily categorized into two general types: a) Systemic or organ-specific effects b) Carcinogenic or teratogenic effects c) Hepatic or nephrotoxic effects
2) What is the main difference between acute and chronic toxicity? a) Different organs are involved b) Acute toxicity occurs only after a single dose, whereas chronic toxicity occurs with multiple doses c) Acute toxicity appears within hours or days of an exposure, whereas chronic toxicity takes many months or years to become a recognizable clinical disease d) Acute toxicity is less likely to lead to death than is chronic toxicity
3) Police respond to a 911 call in which two people are found dead in an enclosed bedroom heated by an unvented kerosene stove. There was no sign of trauma or violence. A likely cause of death is: a) Excess oxygen generated by the combustion of kerosene b) Acute toxicity due to uncombusted kerosene fumes c) Acute toxicity due to carbon monoxide poisoning
4) Genetic toxicity can result in: a) Gene mutation b) Changes in the structure and/or number of chromosomes c) Epigenetic alterations d) All of the above
1) Systemic or organ-specific effects-This is the correct answer. Toxic effects are broadly categorized as either systemic or organ- specific effects.
2) Acute toxicity appears within hours or days of an exposure, whereas chronic toxicity takes many months or years to become a recognizable clinical disease-This is the correct answer. 3) Acute toxicity due to carbon monoxide poisoning-This is the correct answer. The victims most likely died as a result of acute toxicity from exposure to carbon monoxide.
4) All of the above-This is the correct answer. Genetic toxicity can cause gene mutations, changes in chromosome structure (aberration), increases or decreases in the number of chromosomes (aneuploidy or polyploidy), and changes to genetic programming (epigenetic alterations).
What We've Covered This section made the following main points:
Toxicity can result from adverse cellular, biochemical, or macromolecular changes.
Some chemicals affect only specific target organs; others can damage any cell or tissue they contact.
Chemicals can affect organisms by multiple mechanisms and at the molecular level, leading to modern approaches such as Adverse Outcome Pathways (AOPs) and Mechanism of Actions (MOAs).
Several factors influence toxicity, including form and innate chemical activity, dosage, exposure route, species, life stage, gender, absorption ability, metabolism, distribution, excretion, health and nutritional status, the presence of other chemicals, and circadian rhythms.
Systemic toxic effects, which can occur at multiple sites, include:
Acute toxicity, which occurs almost immediately (seconds/minutes) after a single dose or series of doses within 24 hours.
Subchronic toxicity, which results from repeated exposure for several weeks or months.
Chronic toxicity, which damages specific organ systems over the course of many months or years.
Carcinogenicity, or abnormal cell growth and differentiation that can lead to cancer.
Developmental toxicity, which adversely affects the developing embryo or fetus.
Genetic toxicity, caused by damage to DNA and altered genetic expressions.
Organ specific toxic effects include:
Blood/cardiovascular toxicity, affecting the blood, bone marrow, or heart.
Did you know? Gasoline is a volatile, complex mixture of hydrocarbon compounds. The mixture is easily vaporized during handling in normal conditions. People are exposed to this complex substance during refueling at service stations.More informationis available on consumer exposure to gasoline.
In this section, we will look into the effects of interactions among such chemicals.
Sources of Interactions Humans are normally exposed to many chemicals at one time. For example, the use of consumer products, medical treatments, and exposures from the diet and environment (such as from soil, air, and water) can consist of exposures to hundreds, if not thousands, of chemicals. Other examples include:
Hospital patients receive an average of six drugs daily.
Consumers may use five or more consumer products before breakfast (for example, soap, shampoo, conditioner, toothpaste, and deodorant).
Home influenza treatment consists of aspirin, antihistamines, and cough syrup taken simultaneously.
Drinking water may contain small amounts of pesticides, heavy metals, solvents, and other organic chemicals.
Air often contains mixtures of hundreds of chemicals such as automobile exhaust and cigarette smoke.
Gasoline vapor at service stations is a mixture of 40-50 chemicals.
Toxicology studies and human health risk assessments have traditionally focused primarily on a single chemical. However, as noted above, people are exposed to many chemicals every day. They are also exposed to non-chemical stressors every day and throughout a lifetime.
In addition, non-chemical stressors include infectious agents, diet, and psychosocial stress, all of which have potential roles in contributing to the health effects associated with chemical exposures.
Approaches for Assessing Interactions Development of methods to assess the health effects associated with complex exposures is underway atvarious organizations (EPA, NIEHA).
Non-animal tools and approaches are demonstrating high potential for use in assessing combined effects of chemicals on humans and the environment. These tools and approaches may help uncover information about new mixture components or entire mixtures, which can promote understanding of the underlying mechanisms of their combined effects. The strategies for assessing interactions rely less on in vivo testing and more on non-animal studies and computational tools and incorporate emerging approaches such as:
The adverse outcome pathway (AOP) concept.
In vitromethods.
“Omics” techniques.
In silicoapproaches such as quantitative structure activity relationships (QSARs).
Read-across.
Toxicokinetic modeling.
Integrated approaches to testing and assessment (IATA).
The goals include the development of more effective and comprehensive regulatory assessments while reducing the reliance on animal testing.
1) The presence of one chemical decreasing toxicity of another chemical is called: a) Additivity b) Antagonism c) Synergism
2) TRUE or FALSE? Additivity is when the combined toxic effects of two chemicals when given together is less than the sum of their individually measured toxic effects. a) True b) False
3) TRUE or FALSE? Piperonyl butoxide is not an insecticide; however, it can greatly increase the effects of a pyrethrum insecticide. Thus, piperonyl butoxide can be called a synergist and this interaction can be called synergism. a) True b) False
1) Antagonism-This is the correct answer. When the presence of another chemical decreases toxicity of a chemical, this is called antagonism.
2) False-This is the correct answer. An additive effect occurs when the combined effects of two or more chemicals is equal to the sum of the effects of each chemical given alone.
3) True-This is the correct answer. The interaction of this combination is synergism. Synergists are used to enhance the toxicity of several commonly used insecticides.
Alternatives to animal testing have emerged in recent years.
Since about 1990, numerous attempts have been made around the world to reduce the use of and replace laboratory animals in toxicology and other studies. These efforts have involved finding alternatives to animal testing and incorporating the "3Rs" concept (Replace,Reduceand Refine), which means using test methods that:
Replacethe use of animals with other types of studies and approaches.
Reducethe number of animals in studies.
Refinethe procedures to make studies less painful or stressful to the animals.
Regulatory authorities, companies, and others have endorsed the principle of the 3Rs, and alternative testing methods have been and are being developed. An international group that has played a key role is the International Cooperation on Alternative Test Methods (ICATM). Established in 2009, ICATM includes representatives oforganizations from various countries as seen below.
The International Cooperation on Alternative Test Methods (ICATM) includes representatives from:
Korean Centre for the Validation of Alternative Methods (KoCVAM)
U.S. Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM)
U.S. National Toxicology Program (NTP) Interagency Center for the Evaluation of Alternative Toxicological Methods (NICEATM)
Japanese Center for the Validation of Alternative Methods (JaCVAM)
Health Canada
European Union Reference Laboratory for Alternatives to Animal Testing (EURL ECVAM)
Other organizations working on alternative methods, such as from Brazil and China.
Finding Information about Alternatives to Animal Testing
Many countries including the United States, Canada, and the European Union member states, require that a comprehensive search for possible alternatives be completed before some or all research involving animals is begun. Because numerous Web resources are now available to provide guidance and other information on in vitro and other alternatives to animal testing, completing such searches and keeping current with information associated with alternatives to animal testing is much easier than it used to be.
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ALTBIB, from NLM
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The NLM ALTBIB ("Resources for Alternatives to the Use of Live Vertebrates in Biomedical Research and Testing") portal is a comprehensive starting point for finding information related to alternatives to animal testing. ALTBIB is available athttps://www.nlm.nih.gov/enviro/altbib.html.
It provides access toPubMed®/MEDLINE®citations relevant to alternatives to use of live vertebrates in biomedical research and testing.
ALTBIB's topicsand subtopics are aligned with current approaches. For example, information is provided on in silico, in vitro, and improved (refined) animal testing methods and on testing strategies that incorporate these methods and other approaches.
ALTBIB also provides access to news and additional resources, including information on the status of the evaluation and acceptance of alternative methods. Main categories include:
Animal Alternatives News
Additional Resources
Evaluation/Acceptance of Test Methods
Links to Specific Resources(Sources Providing Animal Alternatives News, Key Organizations Providing Resources, and the Regulatory Acceptance of Specific Alternative Methods and Milestones in Non-animal Toxicity Testing)
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Animal Tests
NOTE:This information is provided for historical and other reasons, especially since animal testing is still being done in some cases, and because toxicologists, risk assessors, and others are faced with interpreting the results of new and old studies that used animals.
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Animal tests for toxicity have been conducted prior to and in parallel with human clinical investigations as part of the non-clinical laboratory tests of pharmaceuticals. For pesticides and industrial chemicals, human testing is rarely conducted. Years ago, results from animal tests were often the only way to effectively predict toxicity in humans. Animal tests were developed and used because:
Chemical exposure can be precisely controlled.
Environmental conditions can be well-controlled.
Virtually any type of toxic effect can be evaluated.
The mechanism by which toxicity occurs can be studied.
Animal methods to evaluate toxicity have been developed for a wide variety of toxic effects. Some procedures for routine safety testing have been standardized. Standardized animal toxicitytests have been highly effective in detecting toxicity that may occur in humans. As noted above, concern for animal welfare has resulted in tests that use humane procedures and only as many animals as are needed for statistical reliability.
To be standardized, a test procedure must have scientific acceptance as the most meaningful assay for the toxic effect. Toxicity testing can be very specific for a particular effect, such as dermal irritation, or it may be general, such as testing for unknown chronic effects.
Standardized testshave been developed for the following effects:
Acute Toxicity
Subchronic Toxicity
Chronic Toxicity
Carcinogenicity
Reproductive Toxicity
Developmental Toxicity
Dermal Toxicity
Ocular Toxicity
Neurotoxicity
Genetic Toxicity
Species Selection
Species selectionvaries with the toxicity test to be performed. There is no single species of animal that can be used for all toxicity tests. Different species may be needed to assess different types of toxicity. The published literature (such as via PubMed) and online databases (such as TOXNET) should be searched for information from non-animal and animal studies, as well as for possible best approaches, most applicable species, and strains and gender of a species. Here are two examples:
It would have been invaluable years ago for toxicologists and risk assessors to have known that carcinogenic effects in male rats are considered irrelevant for humans if the α(2u)-globulin protein is involved because humans lack that protein. Seeanother example
Many physiological, pharmacological, and toxicological findings related to organic anion and cation transport and transporters in rodents and rabbits do not apply to humans.Learn more
In some cases, it may not be possible to use the most desirable animal for testing because of animal welfare or cost considerations.
For example, use of dogs and non-human primates is now restricted to special cases or banned by some organizations, even though they represent the species that may respond the closest to humans in terms of chemical and other exposures (however, note the examples above).
Rodents and rabbits are the most commonly used laboratory species because they are readily available, inexpensive to breed and house, and they have a history of producing reliable results in experiments.
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The toxicologist attempts to design an experiment to duplicate the potential exposure of humans as closely as possible. For example:
The route of exposureshould simulate that of human exposure. Most standard tests use inhalation, oral, or dermal routes of exposure.
The age of test animalsshould relate to that of humans. Testing is normally conducted with young adults, although in some cases, newborn or pregnant animals may be used.
For most routine tests, both sexesare used. Sex differences in toxic response are usually minimal, except for toxic substances with hormonal properties.
Dose levelsare normally selected so as to determine the threshold as well as a dose-response relationship. Usually, a minimum of three dose levels are used.
Historically, acute toxicity tests were the first tests conducted. They provide data on the relative toxicity likely to arise from a single or brief exposure, or sometimes multiple doses over a brief period of time. Standardized tests are available for oral, dermal, and inhalation exposures, and many regulatory agencies still require the use of all or some of these tests. Table 1 lists basic parameters historically used in acute toxicity testing.
Subchronic toxicity testsare employed to determine toxicity likely to arise from repeated exposures of several weeks to several months. Standardized tests are available for oral, dermal, and inhalation exposures. Detailed information is obtained during and after the study, ranging from body weight, food and water consumption measurements, effects on eyes and behavior, composition of blood, and microscopic examination of selected tissues and organs.
Table 2 lists basic parameters previously used in subchronic toxicity testing.
Chronic toxicity testsdetermine toxicity from exposure for a substantial portion of a subject's life. They are similar to the subchronic tests except that they extend over a longer period of time and involve larger groups of animals.
Table 3 includes basic parameters previously used in chronic toxicity testing.
Carcinogenicity Carcinogenicity testsare similar to chronic toxicity tests. However, they extend over a longer period of time and require larger groups of animals in order to assess the potential for cancer.
Table 4 lists basic parameters used in the past in carcinogenicity testing.
Reproductive Toxicity Reproductive toxicity testing is intended to determine the effects of substances on gonadal function, conception, birth, and the growth and development of offspring. The oral route of administration is preferable.
Table 5 lists basic parameters historically used in reproductive toxicity testing.
Dermal toxicity testsdetermine the potential for an agent to cause irritation and inflammation of the skin. Those reactions may be a result of direct damage to the skin cells by a substance or an indirect response due to sensitization from prior exposure.In vitroapproaches to dermal toxicity testing are being developed, in part because this type of testing has received so much publicity.
Table 7 lists basic parameters historically used in dermal toxicity testing.
Ocular Toxicity Ocular toxicitywas at one time determined by applying a test substance for 1 second to the eyes of 6 test animals, usually rabbits. The eyes were then carefully examined for 72 hours, using a magnifying instrument to detect minor effects. An ocular reaction can occur on the cornea, conjunctiva, or iris. It may be simple irritation that is reversible and quickly disappears. This eye irritation test was commonly known as the "Draize Test."This test has received much attention, such as the development of a"low volume" variation andin vitroapproaches.
Neurotoxicity
A battery of standardized neurotoxicity testswere developed to supplement the delayed neurotoxicity testin domestic chickens (hens). The hen assay determines delayed neurotoxicity resulting from exposure to anticholinergic substances, such as certain pesticides. The hens are protected from immediate neurological effects of the test substance and observed for 21 days for delayed neurotoxicity.
Table 8 lists measurements included in other neurotoxicity tests.
Genetic Toxicity Genetic toxicityis determined using a wide range of test species including whole animals and plants (for example, rodents, insects, and corn), microorganisms, and mammalian cells. A large variety of tests have been developed to measure gene mutations, chromosome changes, and DNA activity.
Table 9 lists parameters used for common gene mutation tests.
Chromosomal effectscan be detected with a variety of tests, some of which utilize entire animals (in vivo) andsome which use cell systems (in vitro). Several assays are available to test for chemically induced chromosome aberrations in whole animals. Table 10 lists common in vivo means oftesting chromosomal effects.
In VitroTesting In vitro tests for chromosomal effects involve exposure of cell cultures and followed by microscopic examination of them for chromosome damage.
The most commonly used cell lines are Chinese Hamster Ovary (CHO) cells and human lymphocyte cells. The CHO cells are easy to culture, grow rapidly, and have a low chromosome number (22), which makes for easier identification of chromosome damage.
Human lymphocytes are more difficult to culture. They are obtained from healthy human donors with known medical histories. The results of these assays are potentially more relevant to determine effects of xenobiotics that induce mutations in humans.
Two widely used genotoxicity tests measure DNA damage and repair that is not mutagenicity. DNA damage is considered the first step in the process of mutagenesis. Common assays for detecting DNA damage include:
Unscheduled DNA synthesis (UDS)— involves exposure of mammalian cells in culture to a test substance. UDS is measured by the uptake of tritium-labeled thymidine into the DNA of the cells. Rat hepatocytes or human fibroblasts are the mammalian cell lines most commonly used.
Exposure of repair-deficientE. coliorB. subtilis— DNA damage cannot be repaired so the cells die or their growth may be inhibited.
Emerging Approaches and Methods
In the future, there will likely be additional and refined in vitro methods, and the emergence of in silicoand "chip" approaches. Many current efforts are underway to refine, develop, and validate in vitro methods.
Did you know? The Human Toxicology Project Consortium provides a video series calledPathways to a Better Future. These videos discuss the future of toxicology, if you would like to know more about where the field is headed.
In SilicoMethods Also emerging are in silico methods, meaning "performed on computer or via computer simulation." This term was developed as an analogy to the Latin phrases in vivo and in vitro.
Advanced computer models called "Virtual Tissue Models" are being developed by the U.S.EPA's National Center for Computational Toxicology (NCCT).The EPA's Virtual Tissue Models are described as using "new computational methods to construct advanced computer models capable of simulating how chemicals may affect human development. Virtual tissue models are some of the most advanced methods being developed today. The models will help reduce dependence on animal study data and provide much faster chemical risk assessments" (source).
One example is the Virtual Embryo (v-Embryo™)research effort, aimed at developing prediction models to increase our understanding of how chemical exposure may affect unborn children. Researchers are integrating new types of in vitro, in vivo, and in silico models that simulate critical steps in fetal development. Virtual Embryo models simulate biological interactions observed during development and predict chemical disruption of key biological events in pathways that is believed to lead to adverse effects.
"Chip" Models Also emerging are microphysiological systems (MPS) that are used in "tissue chip" and "organs-on-chips" models. Chip models include human cell cultures that are placed on a computer chip and studied there. TheWyss (pronounced "Veese") Institute for Biologically Inspired Engineeringis a helpful resource for more information.
For example, the "Lung-on-a-chip" is described as "combining microfabrication techniques with modern tissue engineering, lung-on-a-chip offers a new in vitro approach to drug screening by mimicking the complicated mechanical and biochemical behaviors of a human lung." To learn more, watch avideofrom the Wyss Institute that shows a human lung-on-a-chip.Another Wyss Institute videoillustrates how researches have used long-on-a-chip to mimic pulmonary edema.
Figure 5. Lung-on-a-chip used to mimic pulmonary edema (Image Source: The Wyss Institute for Biologically Inspired Engineering)
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Using a connected series of tissue chips as an integrated multi-organ system can allow for the creation of a "human-on-a-chip," to be used to model the metabolism and effects of drugs and other substances moving through a human. For example, a liver chip could provide fluids and metabolites to a kidney chip, allowing for the assessment of the nephrotoxic (kidney damage) potential of a substance metabolized in the liver.
Induced Pluripotent Stem Cells (iPSCs) Induced pluripotent stem cells (iPSCs) are an emerging approach usingin vitrocultures of cells. The cells of mammals and plants can be reprogrammed via "cellular reprogramming" to generate iPSCs. Like human embryonic stem cells, iPSCs are pluripotent (capable of giving rise to several different cell types) and these cells can renew themselves. As examples, iPSC-derived hepatocytes, cardiomyocytes, and neural cells can serve as tools for the screening of drugs and other substances for potential toxicity, and also can be used to study disease mechanisms and pathways. Further, iPSCs have been studied in immunotherapy and regenerative cellular therapies.
Figure 6. Promise of hiPSCs. Schematic representation of how somatic cells taken from a patient can be reprogrammed into induced pluripotent stem cells (iPSCs) using the ‘Yamanaka’ factors, OCT4, KLF4, c-MYC and SOX2. Subsequent differentiation of human iPSCs (hiPSCs) into neurons of define lineage allow for investigations into disease pathophysiology and identification of potential drug targets. In addition, hiPSC derived neurons may function as a cellular platform in which drug screens can be carried out using disease relevant neurons. (Image Source:Adapted under Creative Commons Attribution License (CC BY). doi:10.1016/j.yhbeh.2015.06.014 Original image:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4579404/figure/f0005/)
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Did you know? Professor Shinya Yamanaka (Kyoto University, Japan) received the 2012 Nobel Prize in Physiology or Medicine for discovering that mature cells can be reprogrammed to iPSCs that can differentiate into any type of cell. Key to this discovery was his use of four "reprogramming factors" referred to as c-Myc, Klf4, Oct3/4, and Sox2. Learn more
Combining "Chips" and iPSCs The emerging approaches of "chips" and iPSCs are being combined. One example is for the evaluation of drugs as potential countermeasures for biological and chemical threats that can be a substitute for human clinical trials. The "chips" and "humans on a chip" can be used as complexin vitrohuman models to simulate the biology and function of an organ.
Links to Specific Resources Animal Alternatives News
ICCVAM/NIEHS: Interagency Coordinating Committee for the Validation of Alternative Methods
Altweb News: Johns Hopkins University (includesFrequently Asked Questionsabout Animal Testing Alternatives; Resources for Scientists, Researchers, and Technicians; Resources for Teachers and Students, from K-12 to University Level; and Other Resources)
Additional Resources
AltTox.org- Non-animal Methods for Toxicity Testing
Clinical Investigations and Other Types of Human Data
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Several approaches exist for determining how toxic drugs and consumer products are to humans.
For Drugs
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The focus of this section is on the U.S. Food and Drug Administration (FDA), but regulatory agencies worldwide have very similar approaches. The main methods of determining the toxicity of drugs to humans are:
Clinical investigations— administration of chemicals to human subjects with careful clinical observations and laboratory measurements.
Epidemiological studies— observation of humans who have been exposed to xenobiotics in the normal course of their life or occupation.
Adverse reactions to drug reports— reports voluntarily submitted by physicians to the FDA after a drug has been approved and is in widespread use.
Clinical Investigations Clinical investigationsare a component ofInvestigational New Drug Applications (INDs) submitted to the FDA. Clinical investigations are conducted only after a minimal battery of nonclinical laboratory studies has been completed.
Toxicity studies using human subjects require strict ethical considerations. They are primarily conducted for new pharmaceutical applications submitted to the FDA for approval.
Generally, toxicity found in animal studies occurs with similar incidence and severity in humans. Differences sometimes occur, thus clinical tests with humans are needed to confirm the results of nonclinical laboratory studies.
FDA clinical investigations are conducted in three phases, as outlined below.
For Consumer Products Health-related data for a chemical in a consumer product (and for the consumer product itself for the human studies) can come from the following types of studies:
In silico data — from computer programs that estimate toxic properties based on data for similar chemicals, and/or from the physical chemical properties.
In vitro data — from the results of alternatives to animal tests, such as from cell cultures used to assess the potential for eye or skin irritation.
Animal (toxicological) study data — for example, from studies that assessed eye or skin irritation potential.
Human data – from studies conducted before (premarketing) and after (postmarketing) a product had been sold to consumers. More specifically, from:
Premarketing clinical studies, such as from patch tests to assess skin irritation potential.
Premarketing "controlled use" studies that are designed to assess the skin effects from using a new type of personal care product.
Postmarketing studies conducted by physicians or dermatologists, such as testing a diagnostic patch with their patients.
Postmarketing epidemiological studies, including studies developed by Poison Control Centers, companies, and academia that look at the "real world" health reports of effects associated with consumer use of a product.
Did you know? Bisphenol A (BPA)andphthalatesare chemicals that have been widely found in consumer products. BPA has been used in some food can linings, polycarbonate food and beverage containers, tooth sealants applied to dentists, and even in cash register receipts! Examples of potential exposures to BPA include eating or drinking foods or liquids from those containers, and skin exposures from handing the cash register receipts. Workers involved in making products with BPA can be exposed during production.
Often called plasticizers, phthalates are used to make plastics more flexible. Some phthalates are used as solvents. They can be found in vinyl flooring and shower curtains, children's toys, personal care products, and as contaminants in the food supply. As with BPA, exposures can come from many sources.
Toxicologists and others are still assessing the full extent of the potential impacts on health. Studies suggest that BPA and phthalates affect the reproductive system, impacting how hormones such as estrogen and testosterone work in the body. The impact of fetal or early childhood exposures is still being assessed. Because of the ubiquity of the possible products containing these chemicals, thorough assessments of potential exposures, toxicities, and potential substitutes are essential.
Epidemiology studies are conducted using human populations to evaluate whether there is acorrelation or causal relationship (see definition at end of section)between exposure to a substance and adverse health effects.
These studies differ from clinical investigations in that individuals have already been administered the drug during medical treatment or have been exposed to it in the workplace or environment.
Epidemiological studies measure the risk of illness or death in an exposed population compared to that risk in an identical, unexposed population (for example, a population the same age, sex, race and social status as the exposed population).
Correlation or Causal Relationship Acorrelationshows the degree of relationship between two variables. It can show if there are trends between two sets of values, for example, if one set of values tends to increase when another set of values also increases.
Acausal relationshipexists if one event causes the occurrence of a second event.
Types of Studies There are four primary types of epidemiology studies. They are:
Cohort studies— A cohort (group) of individuals with exposure to a chemical and a cohort without exposure are followed over time to compare disease occurrence.
Case control studies— Individuals with a disease (such as cancer) are compared with similar individuals without the disease to determine if there is an association of the disease with prior exposure to an agent.
Cross-sectional studies— The prevalence of a disease or clinical parameter among one or more exposed groups is studied, such as:
The prevalence of respiratory conditions among furniture makers.
Ecological studies– The incidence of a disease in one geographical area is compared to that of another area, such as:
Cancer mortality in areas with hazardous waste sites as compared to similar areas without waste sites.
Cohort Studies Cohort studies are the most commonly conducted epidemiology studies and they frequently involve occupational exposures. Exposed persons are easy to identify and their exposure levels are usually higher than in the general public. There are two types of cohort studies:
Prospective, in which cohorts are identified based on current exposures and followed into the future.
Retrospective,in which cohorts are identified based on past exposure conditions and study "follow-up" proceeds forward in time; data come from past records.
Common Statistical Measures Standard, quantitative measures are used to determine if epidemiological data are meaningful. The most commonly used measures are:
Odds Ratio (O/R)— The ratio of risk of disease in a case-control study for an exposed group to an unexposed group. An odds ratio equal to 2 (O/R = 2) means that the exposed group has twice the risk as the non-exposed group.
Standard Mortality Ratio (SMR)— The relative risk of death based on a comparison of an exposed group to non-exposed group. A standard mortality ratio equal to 150 (SMR = 150) indicates that there is a 50% greater risk.
Relative Risk (RR)— The ratio expressing the occurrence of disease in an exposed population to that of an unexposed population. A relative risk of 175 (RR = 175) indicates a 75% increase in risk.
Study Design When designing an epidemiology study, the most critical aspects include:
An appropriate control group.
An adequate time span.
The statistical ability to detect an effect.
More specifically, the control population used as a comparison group must be as similar as possible to that of the test group, for example, same age, sex, race, social status, geographical area, and environmental and lifestyle influences.
Many epidemiology studies evaluate the potential for an agent to cause cancer. Because most cancers require long latency periods, the study must cover that period of time.
The statistical ability to detect an effect is referred to as thepowerof the study. To gain precision, the study and control populations should be as large as possible.
Bias Errors Epidemiologists attempt to control errors that can occur in the collection of data, which are known as bias errors. The three main types of bias errors are:
Selection bias, which occurs when the study group is not representative of the population from which it came.
Information bias, which occurs when study subjects are misclassified as to disease or exposure status. Recall bias occurs when individuals are asked to remember exposures or conditions that existed years before.
Confounding factors, which occur when the study and control populations differ with respect to factors which might influence the occurrence of the disease. For example, smoking might be a confounding factor and should be considered when designing studies.
Postmarketing Studies Finally, for consumer products,postmarketingepidemiological studies can be performed. Examples include studies developed by Poison Control Centers, companies, academia, and other sources to look at the "real world" health reports of effects associated with consumer use of a product or article under reasonably foreseeable conditions.
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Knowledge Check (Solutions on next page)
1) While animal testing was historically the primary method used in testing for toxicity, modern testing methods prefer: a) In silico b) In vitro c) Refined animal testing d) All of the above
2) In testing a pharmaceutical to comply with FDA requirements, the initial testing consists of: a) Clinical investigations b) Non-clinical laboratory studies c) Epidemiology studies d) All of the above
3) The primary goal of a Phase 1 clinical investigation is to: a) Obtain information to design a more definitive Phase 2 clinical investigation b) Evaluate the effectiveness of a drug for treating disease c) Provide the basis for pharmaceutical labeling
4) Determining the overall risk versus the benefit of a new pharmaceutical is part of: a) Phase 2 clinical investigation b) Phase 3 clinical investigation c) Epidemiology study
5) The type of epidemiology study in which individuals are identified according to exposure and followed to determine subsequent disease risk is known as: a) Cohort study b) Case control study c) Cross-sectional study d) Ecological study
6) An epidemiological study in which the individuals that make up the test cohort are identified according to past exposures is known as: a) Case control study b) Prospective cohort study c) Retrospective cohort study
1) All of the above-This is the correct answer. Modern approaches to testing for toxicity includein silico,in vitro, and improved (refined) animal testing.
2) Non-clinical laboratory studies-This is the correct answer. Investigational New Drug Applications (IND) require clinical investigations. Before clinical investigations begin, a minimal battery of non-clinical laboratory studies must be completed.
3) Obtain information to design a more definitive Phase 2 clinical investigation-This is the correct answer. The primary goal of a Phase 1 clinical investigation is to obtain information that is used to design more extensive, Phase 2 studies.
4) Phase 3 clinical investigation-This is the correct answer. Determining the overall risk versus the benefit of a new pharmaceutical is part of Phase 3 clinical study. The risk versus benefit is one of the last steps in the drug evaluation process.
5) Cohort study-This is the correct answer. The type of epidemiology study in which individuals are identified according to exposure and followed to determine subsequent disease risk is known as a cohort study. In a cohort study individuals are selected to be part of the group based on their exposure to a particular substance.
6) Retrospective cohort study-This is the correct answer. This is known as a retrospective cohort study. As the name implies, retrospective cohorts are identified according to past exposure conditions and the follow-up study proceeds forward in time.
What We've Covered This section made the following main points:
The 3Rs concept of using test methods replace the use of animals with other types of studies and approaches, reduce the number of animals used in studies, and refine study procedures to cause less pain or stress to animals.
ALTBIB is a comprehensive starting point provided by NLM to find information related to alternatives to animal testing.
Animal tests for toxicity have been conducted prior to and in parallel with human clinical investigations.
Standardized animal tests have been developed for testing:
Acute toxicity
Subchronic toxicity
Chronic toxicity
Carcinogenicity
Reproductive toxicity
Developmental toxicity
Dermal toxicity
Ocular toxicity
Neurotoxicity
Genetic toxicity
Modern approaches to toxicity testing are preferred over animal testing and include:
In vitromethods, which are performed outside living organisms.
In silicomethods, which are performed using computers and computer simulation.
Chip models, which include human cell cultures placed on computer chips for study.
Approaches used for testing pharmaceuticals include:
Clinical investigations, in which human subjects are studied with clinical observations and laboratory measurements.
Epidemiological studies, involving observation of humans exposed to xenobiotics in their regular life or occupation.
Reports of adverse reactions to drugs.
Consumer products and the chemicals they contain are tested through:
In silicodata from computer models.
In vitrodata from tests performed as alternatives to animal testing.
Animal study data.
Human data from premarketing and postmarketing studies.
For many years, the terminology and methods used in human risk or hazard assessment were inconsistent, which led to confusion among scientists, the public, and others.
In 1983, the (U.S.) National Academy of Sciences (NAS) publishedRisk Assessment in the Federal Government: Managing the Process.Often called the "Red Book" by toxicologists and others, it addressed the standard terminology and concepts for risk assessments.
Figure 1. Toxicology-based approaches to hazard identification, dose-response assessment, exposure analysis, and characterization of risks were described in the 1983 Red Book (Image Source: National Academies Press)
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Key Terms The following terms are routinely used in risk assessments:
Hazard— capability of a substance to cause an adverse effect.
Risk— probability that the hazard will occur under specific exposure conditions.
Risk assessment— the process by which hazard, exposure, and risk are determined.
Risk management— the process of weighing policy alternatives and selecting the most appropriate regulatory action based on the results of risk assessment and social, economic, and political concerns.
Risk Assessment Steps The four basic steps in the risk assessment process as defined by the NAS are:
Hazard identification— characterization of innate adverse toxic effects of agents.
Dose-response assessment— characterization of the relation between doses and incidences of adverse effects in exposed populations.
Exposure assessment— measurement or estimation of the intensity, frequency, and duration of human exposures to agents.
Risk characterization— estimation of the incidence of health effects under the various conditions of human exposure.
Once risks are characterized in step 4, the process of risk management begins (Figure 2).
"Silver Book" for Advancing Risk Assessment (2009) A newer book by the NAS,Science and Decisions: Advancing Risk Assessment(2009), often called the “Silver Book” by toxicologists and others, emphasizes uncertainty and variability and cumulative risk, and notes that risk assessment "is at a crossroads.
Figure 3. The 2009 Silver Book includes approaches for improving risk analysis and a framework for risk-based decision-making (Image Source: National Academies Press)
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Risk-Based Decision Making The co-authors of this Silver Book proposed a framework for risk-based decision-making (Figure 4). The framework consists of three phases:
The core of the framework, as noted in the Silver Book, includes the risk assessment paradigm of the Red Book, but differs primarily in its initial and final steps:
"The framework systematically identifies problems and options that risk assessors should evaluate at the earliest stages of decision-making."
"It expands the array of impacts assessed beyond individual effects (for example, cancer, respiratory problems, and individual species) to include broader questions of health status and ecosystem protection."
"It provides a formal process for stakeholder involvement throughout all stages but has time constraints to ensure that decisions are made."
"It increases understanding of the strengths and limitations of risk assessment by decision-makers at all levels, for example, by making uncertainties and choices more transparent."
Figure 4. Framework for risk-based decision-making National Research Council. 2009. Science and Decisions: Advancing Risk Assessment. Washington, DC: The National Academies Press. https://doi.org/10.17226/12209.
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Latest Approaches
Other parts of ToxTutor highlight the latest approaches used in risk assessment. For example:
Testing for, and Assessing Toxicitydescribes the numerous global efforts made, since approximately 1990, to reduce and replace use of laboratory animals in toxicology studies. Included are efforts to develop and validate in vitro methods and the emerging use ofin silico methods.
Knowledge Check (Solutions on next page)
1) Risk is the: a) Capability of a substance to cause an adverse effect b) Weighing of possible alternatives and selecting the most appropriate regulatory actions c) Probability that a hazard will occur under specific exposure conditions
2) In the risk assessment process, what happens during the hazard identification step? a) Characterization of the relation between doses and incidences of adverse effects b) Characterization of innate adverse toxic effects of agents c) Measurement or estimation of intensity, frequency, and duration of human exposures to agents d) Estimation of the incidence of health effects under the various conditions of human exposure
3) What are the phases of the risk-based decision-making framework proposed by the co-authors of the "Silver Book?" a) Enhanced problem formulation and scoping; planning and assessment; and risk management b) Hazard identification; dose-response assessment; exposure assessment; risk characterization c) Hazard identification; risk assessment; action planning
1) Probability that a hazard will occur under specific exposure conditions-This is the correct answer. Risk is theprobabilitythat a hazard will occur.
2) Characterization of innate adverse toxic effects of agents-This is the correct answer. Hazard identification is the first step in the risk assessment process as defined by the National Academy of Sciences.
3) Enhanced problem formulation and scoping; planning and assessment; and risk management-This is the correct answer. The framework proposed by the co-authors of the "Silver Book" involves enhanced problem formulation and scoping; planning and assessment; and risk management.
The goal of hazard identification in toxicology is to identify or develop information suggesting or confirming that a chemical (or, for example, a consumer product) poses or does not pose a potential hazard to humans.
During earlier years of toxicology, this process relied primarily on human epidemiology data and on various types of animal testing data, supplemented in more recent years with the development of in vitromethods such as those focused on assessing the potential for mutations and DNA damage. The future of hazard identification is promising and toxicologists now have various types of in vitro methods to explore for hazard identification, along with the emergence of"chip"approaches.
These emerging methods are based, in part, on (Quantitative) Structure Activity, or (Q)SAR methods. Q(SAR) methods, such as computer models, help toxicologists and others to consider closely related chemicals as a group, or chemical category, rather than as individual chemicals. Not every chemical needs to be tested for every toxicity endpoint, and the data for chemicals and endpoints that have been tested are used to estimate the corresponding properties for other chemicals and endpoints of interest. Data from a chemical category must be judged as adequate to support at least a "screening-level" hazard identification. One approach involves using endpoint information for one chemical to predict the same endpoint for another chemical that is considered "similar" in some way (such as having structural similarity and similar properties and/or activities).
Read-Across Another approach for hazard identification used since about 2000 isread-across.Read-across can be qualitative or quantitative:
Inqualitative read-across, the presence (or absence) of a property/activity such as a particular type of toxic effect for the chemical of interest is inferred from the presence (or absence) of the same property/activity for one or more other chemicals. This qualitative approach provides a "yes/no" answer.
Quantitative read-acrossuses information for one or more chemicals to estimate what the chemical of interest will be like. Thus, quantitative read-across can be used to obtain a quantitative value for an endpoint, such as a dose-response relationship.
Adverse Outcome Pathways (AOPs)
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An emerging approach to hazard identification is the use ofAdverse Outcome Pathways (AOPs). AOPs reflect the move in toxicity testing from high-dose studies in laboratory animals to in vitro methods that evaluate changes in normal cellular signaling pathways using human-relevant cells or tissues. The AOP concept has emerged as a framework for connecting high throughput toxicity testing (HTT, or high throughput toxicity screening, HTS) and other results.
Other Computer Models Another emerging term is(quantitative)in vitrotoin vivoextrapolation, or (Q)IVIVE, used together with what are being calledIntegrated Testing Strategiesand Integrated Approaches to Testing and Assessment (IATA).
Toxicology Testing in the 21st Century - A New Strategy
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The High Throughput Screening (HTS) Initiative is part of the new toxicology testing strategy developed from the 2004 National Toxicology Program (NTP)Vision and Roadmap for the 21st Century.
Traditional toxicological testing is based largely on the use of laboratory animals. However, this approach suffers from low throughput, high cost, and difficulties inherent to inter-species extrapolation – making it of limited use in evaluating the very large number of chemicals with inadequate toxicological data.
NTP recognized that the dramatic technological advances in molecular biology and computer science offered an opportunity to use in vitro biochemical- and cell-based assays and non-rodent animal models for toxicological testing. These assays allow for much higher throughput at a much reduced cost. In some assays, many thousands of chemicals can be tested simultaneously in days.
The goal is to move toxicology from a predominantly observational science at the level of disease-specific models to a predominantly predictive science focused upon broad inclusion of target-specific, mechanism-based, biological observations.
The High Throughput Screening program represents a new paradigm in toxicological testing. The HTS program approach to toxicological testing screens for mechanistic targets active within cellular pathways considered critical to adverse health effects such as carcinogenicity, reproductive and developmental toxicity, genotoxicity, neurotoxicity, and immunotoxicity in humans.
As described in theTesting for, and Assessing Toxicitysection, the EPA is developing "Virtual Tissue Models" such as the Virtual Embryo (v-Embryo™). These types of advanced computer models are being designed to be capable of simulating how chemicals may affect human development and will help reduce dependence on animal study data. They will also provide faster ways of developing chemical risk assessments.
Finally, also noted in the Testing for and Assessing Toxicity section, emerging in the toxicologist's tool box are "chip" models (for example, an "organ on a chip"). One example is the "Lung-on-a-chip" that "…offers a new in vitro approach to drug screening by mimicking the complicated mechanical and biochemical behaviors of a human lung."
Figure 3. Lung-on-a-chip used to mimic pulmonary edema (Image Source: The Wyss Institute for Biologically Inspired Engineering)
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Knowledge Check (Solutions on next page)
1) Modern approaches to hazard identification are based in part on: a) Extensive animal testing for toxicity b) Computer models like (Q)SAR c) Risk assessment strategies
2) Adverse Outcome Pathways (AOPs) are methods of hazard identification that: a) Evaluate changes in normal cellular signaling pathways using human-relevant cells or tissues b) Identify adverse outcomes in test subjects administered increasing doses of potential toxicants c) Measure the intensity, frequency, and duration of human exposures to agents d) Evaluate the health effects under various conditions of human exposure
3) Can quantitative read-across be used to determine the value of an endpoint, such as dose-response relationship? a) Yes b) No
1) Computer models like (Q)SAR-This is the correct answer. Part of the basis for emerging approaches to hazard identification, such as assessing for potential mutations and DNA damage, relies on (Quantitative) Structure Activity (Q)SAR methods.
2) Evaluate changes in normal cellular signaling pathways using human-relevant cells or tissues-This is the correct answer. Adverse Outcome Pathways (AOPs) arein vitromethods that evaluate changes in normal cellular signaling pathways using human-relevant cells or tissues.
3) Yes-This is the correct answer. Quantitative read-across can lead to a measurable value for an endpoint, such as a dose-response relationship.
The dose-response assessment step of the risk assessment process quantitates the hazards that were identified in the previous step. It determines the relationship between dose and incidence of effects in humans. There are normally two major extrapolations required:
From high experimental doses to low environmental doses.
From animal doses to human doses.
The procedures used to extrapolate from high to low doses are different for assessing carcinogenic effects and noncarcinogenic effects:
Mathematical models are used to extrapolate from high to low doses to provide estimates of risk if there is not a threshold for carcinogenicity. However,some carcinogenic effects (e.g., for nongenotoxic compounds)are considered or known to have a threshold and this type of extrapolation is not appropriate.
Noncarcinogenic effects(for example neurotoxicity)are considered to have dose thresholds below which the effect does not occur. The lowest dose with an effect in animal or human studies is divided by safety factors to provide a margin of safety.
Carcinogen (Cancer) Risk Assessment Cancer risk assessmentinvolves two steps:
Perform qualitative evaluation of all epidemiology studies, animal bioassay data, and biological activity(for example, mutagenicity).The substance is classified as to its carcinogenic risk to humans based on the weight of evidence. If the evidence is sufficient, the substance may be classified as a definite, probable or possible human carcinogen.
Quantitate the risk for those substances classified as definite or probable human carcinogens.Mathematical models are used to extrapolate from the high experimental doses to the lower environmental doses.
1. Qualitative Evaluation of Cancer Risk The EPA's cancer assessment procedures have been used by several Federal and State agencies. The Agency for Toxic Substances and Disease Registry (ATSDR) relies on EPA's carcinogen assessments. A substance is assigned to one of five descriptors shown below in Table 1.
Cancer Data for Humans The basis forsufficient human evidenceis an epidemiology study that clearly demonstrates a causal relationship between exposure to the substance and cancer in humans. The data are determined to belimited evidence in humansif there are alternative explanations for the observed effect. The data are considered to beinadequate evidence in humansif no satisfactory epidemiology studies exist.
Cancer Data for Animals An increase in cancer in more than one species or strain of laboratory animals or in more than one experiment is consideredsufficient evidence in animals. Data from a single experiment can also be considered sufficient animal evidence if there is a high incidence or unusual type of tumor induced. Normally, however, a carcinogenic response in only one species, strain, or study is considered as only limited evidence in animals.
2. Quantitative Evaluation of Cancer Risk When an agent is classified as a Human or Probable Human Carcinogen, it is then subjected to a quantitative risk assessment. For those designated as a Possible Human Carcinogen, the risk assessor can determine on a case-by-case basis whether a quantitative risk assessment is warranted.
The key risk assessment parameter derived from the EPA carcinogen risk assessment is the cancer slope factor. This is a toxicity value that quantitatively defines the relationship between dose and response. The cancer slope factor is a plausible upper-bound estimate of the probability that an individual will develop cancer if exposed to a chemical for a lifetime of 70 years. The cancer slope factor is expressed as mg/kg/day.
Linearized Multistage Model (LMS) Mathematical models are used to extrapolate from animal bioassay or epidemiology data to predict low-dose risk. Most assume linearity with a zero threshold dose.
Figure 2. The Linearized Multistage Model is used to extrapolate cancer risk from a dose-response curve using the cancer slope factor (Image Source: NLM)
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EPA uses theLinearized Multistage Model (LMS)illustrated in Figure 2 to conduct its cancer risk assessments. It yields a cancer slope factor, known as theq1*(pronounced "Q1-star"), which can be used to predict cancer risk at a specific dose. It assumes linear extrapolation with a zero dose threshold from the upper confidence level of the lowest dose that produced cancer in an animal test or in a human epidemiology study.
Other Models Other models that have been used for cancer assessments include:
One-hit model, which assumes there is a single stage for cancer and that one molecular event induces a cell transformation. This is a very conservative model.
Multi-hit model, which assumes several interactions are needed before a cell can be transformed. This is one of the least conservative models.
Probit model, which assumes log normal distribution (Probit) for tolerances of exposed population. This model is sometimes used, but generally considered inappropriate for assessing cancer risk.
Physiologically Based Pharmacokinetic (PBPK) Models, which incorporate pharmacokinetic and mechanistic data into the extrapolation process. This model requires extensive data and is becoming commonly used.
Application of Models to Estimate Chemical Concentrations in Drinking Water The chemical chlordane has been found to cause a lifetime risk of one cancer death in a million persons. Different cancer risk assessment models vary in their estimates of drinking water concentrations for chlordane as illustrated in Table 2:
Table 2. Estimates of drinking water chlordane concentrations by various cancer assessment models
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PBPK models are relatively new and are being employed when biological data are available. They quantitate the absorption of a foreign substance, its distribution, metabolism, tissue compartments, and elimination. Some compartments store the chemical (such as bone and adipose tissue) whereas others biotransform or eliminate it (such as liver or kidney). All these biological parameters are used to derive the target dose and comparable human doses.
Noncarcinogenic Risk Assessment Historically, the Acceptable Daily Intake (ADI)procedure has been used to calculate permissible chronic exposure levels for humans based on noncarcinogenic effects. The ADI is the amount of a chemical to which a person can be exposed each day for a long time (usually lifetime) without suffering harmful effects. It is determined by applying safety factors (to account for the uncertainty in the data) to the highest dose in human or animal studies that has been demonstrated not to cause toxicity (NOAEL).
The EPA has slightly modified the ADI approach and calculates aReference Dose (RfD)as the acceptable safety level for chronic noncarcinogenic and developmental effects. Similarly, the ATSDR calculatesMinimal Risk Levels(MRLs) for noncancer endpoints.
Thecritical toxic effectused in the calculation of an ADI, RfD, or MRL is the serious adverse effect that occurs at the lowest exposure level. It may range from lethality to minor toxic effects. It is assumed that humans are as sensitive as the animal species unless evidence indicates otherwise.
Assessment of Chronic Exposures In determining the ADIs, RfDs or MRLs, theNOAELis divided by safety factors (uncertainty factors) in order to provide a margin of safety for allowable human exposure.
When a NOAEL is not available, aLOAELcan be used to calculate the RfD.
An additional safety factor is included if a LOAEL is used. A Modifying Factor of 0.1–10 allows risk assessors to use scientific judgment in upgrading or downgrading the total uncertainty factor based on the reliability and quality of the data. For example, if a particularly good study is the basis for the risk assessment, a modifying factor of <1 may be used. If a poor study is used, a factor of >1 can be incorporated to compensate for the uncertainty associated with the quality of the study.
Figure 3. Dose-response curve for noncarcinogenic effects (Image Source: NLM)
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Figure 3 above shows a dose-response curve for noncarcinogenic effects which also identifies the NOAEL and LOAEL. Any toxic effect might be used for the NOAEL/LOAEL so long as it is the most sensitive toxic effect and considered likely to occur in humans.
TheUncertainty FactorsorSafety Factorsused to derive an ADI or RfD are listed in Table 3.
Table 3. Uncertainty/Safety factors used to derive an Acceptable Daily Intake (ADI) or Reference Dose (RfD)
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The modifying factor is used only in deriving EPA Reference Doses. The number of factors included in calculating the ADI or RfD depends upon the study used to provide the appropriate NOAEL or LOAEL.
The more uncertain or unreliable the data become, the higher the total uncertainty factor that is applied. An example of an RfD calculation is provided below. A subchronic animal study with a LOAEL of 50 mg/kg/day was used in the numerator. Uncertainty factors used in the denominator are 10 for human variability, 10 for an animal study, 10 for less than chronic exposure, and 10 for use of an LOAEL instead of a NOAEL.
In addition to chronic effects, RfDs can also be derived for other long-term toxic effects, including developmental toxicity.
Traditionally, theNOAEL method has been used to determine thepoint of departure (POD - represents a dose derived from observed data that is associated with an extra risk for a specific endpoint)from animal toxicology data for use in risk assessments. However, this approach has limitations such as a strict dependence on the dose selection, dose spacing, and sample size of the study from which the critical effect has been identified. Also, using the NOAEL does not take into consideration the shape of the dose-response curve and other related information.
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Benchmark Dose Method The benchmark dose (BMD) method, first proposed as an alternative in the 1980s, addresses many limitations of the NOAEL method. It is less dependent on dose selection and spacing and takes into account the shape of the dose-response curve (Figure 4). In addition, the estimation of a BMD 95% lower bound confidence limit (BMDL) results in a POD that appropriately accounts for study quality (i.e., sample size). With the availability of user-friendly BMD software programs, including the EPA’s Benchmark Dose Software (BMDS), the BMD has become the method of choice for many health organizations worldwide.
Figure 4. Extrapolated values using the benchmark dose method reflect the shape of a dose-response curve (Image Source: EPA)
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Assessment of Noncancer Toxicity Effects While the Agency for Toxic Substances and Disease Registry (ATSDR) does not conduct cancer risk assessments, it does derive Minimal Risk Levels (MRLs)for noncancer toxicity effects (such as birth defects or liver damage). The MRL is defined as an estimate of daily human exposure to a substance that is likely to be without an appreciable risk of adverse effects over a specified duration of exposure. For inhalation or oral routes, MRLs are derived for acute (14 days or less), intermediate (15–364 days), and chronic (365 days or more) durations of exposures.
The method used to derive MRLs is a modification of the EPA's RfD methodology. The primary modification is that the uncertainty factors of 10 may be lower, either 1 or 3, based on scientific judgment. These uncertainty factors are applied for human variability, interspecies variability (extrapolation from animals to humans), and use of a LOAEL instead of NOAEL. As in the case of RfDs, the product of uncertainty factors multiplied together is divided into the NOAEL or LOAEL to derive the MRL.
Assessment of Acute or Short-Term Exposures Risk assessments are also conducted to derive permissible exposure levels for acute or short-term exposures to chemicals. Health Advisories (HAs) are determined for chemicals in drinking water. HAs are the allowable human exposures for 1 day, 10 days, longer-term, and lifetime durations. The method used to calculate HAs is similar to that for the RfDs using uncertainty factors. Data from toxicity studies with durations of length appropriate to the HA are being developed.
Assessment of Occupational Exposures Foroccupational exposures, Permissible Exposure Levels (PELs), Threshold Limit Values (TLVs), and National Institute for Occupational Safety and Health (NIOSH) Recommended Exposure Levels (RELs) are developed. They represent dose levels that will not produce adverse health effects from repeated daily exposures in the workplace. The method used to derive is conceptually the same. Safety factors are used to derive the PELs, TLVs, and RELs.
Conversion of Animal Doses to Human Dose Equivalents Animal doses must be converted to human dose equivalents. The human dose equivalent is based on the assumption that different species are equally sensitive to the effects of a substance per unit of body weight or body surface area.
Historically, the FDA used a ratio of body weights of humans to animals to calculate the human dose equivalent. The EPA has used a ratio of surface areas of humans to animals to calculate the human dose equivalent. Some current approaches include multiplying the animal dose by the ratio of human to animal body weight raised to either the 2/3rd or 3/4th power (to convert from body weight to surface area). Toxicologists and risk assessors should check to make sure that the approach they are using is the one mandated or recommended by the regulatory agency of most relevance to their efforts.
Allowable Exposures to Contamination Sources The last step in risk assessment is to express the risk in terms of allowable exposure to a contaminated source. Risk is expressed in terms of the concentration of the substance in the environment where human contact occurs. For example, the unit for assessing risk in air is risk per mg/m3whereas the unit for assessing risk in drinking water is risk per mg/L.
For carcinogens, the media risk estimates are calculated by dividing cancer slope factors by 70 kg (average weight of a man) and multiplying by 20 m3/day (average inhalation rate of an adult) or 2 liters/day (average water consumption rate of an adult).
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Knowledge Check (Solutions on next page)
1) The default procedures used to extrapolate from high to low doses primarily depend upon the: a) Potency of the substance b) Rate of lethality in laboratory animals c) Genotoxic carcinogenicity of the substance
2) According to EPA, a substance is classified as likely to be carcinogenic to humans when: a) There is strong evidence of human carcinogenicity b) Evidence is adequate to demonstrate potential carcinogenicity to humans, but not strongly enough to definitively classify as carcinogenic c) The weight of evidence suggests human carcinogenicity, but the data are determined not to be sufficient for a stronger conclusion d) Robust data lead to the conclusion that a substance is clearly carcinogenic to humans
3) The primary cancer risk assessment model used by the EPA is known as the: a) Linearized Multistage Model (LMS) b) Probit Model c) Physiologically Based Pharmacokinetic Model (PB-PK)
4) The Acceptable Daily Intake (ADI) is calculated by: a) Dividing the NOAEL by safety factors b) Dividing the NOAEL by the LOAEL c) Multiplying the RfD by a modifying factor d) Linear extrapolation from the LOAEL to the zero intercept
5) Animal doses must be converted to human dose equivalents for risk assessment. When doing this, toxicologists and risk assessors must: a) Multiply the animal dose by the ratio of human to animal body weight raised to the2⁄3power b) Ensure they use the conversion method mandated or recommended by the regulatory agency most relevant to their efforts c) Multiply the animal dose by the ratio of human to animal body weight raised to the3⁄4power
6) Minimal Risk Levels (MRLs) are derived: a) Similarly to deriving the RfD, but with a potentially lower uncertainty factor b) By multiplying the cancer slope factor by the lowest exposure dose c) By multiplying the LOAEL by safety factors
1) Genotoxic carcinogenicity of the substance-This is the correct answer. The procedure for extrapolation from high to low doses depend on whether or not the effects are carcinogenic. Carcinogenic effects are not considered to have a threshold dose and mathematical models are used to estimate the risk of carcinogenicity at very low doses. Noncarcinogenic effects are considered to have threshold doses and the margin of safety (MOS) is calculated.
2) Evidence is adequate to demonstrate potential carcinogenicity to humans, but not strongly enough to definitively classify as carcinogenic-This is the correct answer. A substance is classified as likely to be carcinogenic to humans when evidence is adequate to demonstrate carcinogenic potential to humans but does not reach the weight of evidence for the descriptor Carcinogenic to Humans.
3) Linearized Multistage Model (LMS)-This is the correct answer. EPA uses the Linearized Multistage Model (LMS) to conduct its cancer risk assessments, producing the q1* that is used to predict cancer risk at a specific dose.
4) Dividing the NOAEL by safety factors-This is the correct answer. The ADI is calculated by dividing the NOAEL by safety factors.
5) Ensure they use the conversion method mandated or recommended by the regulatory agency most relevant to their efforts-This is the correct answer. Toxicologists and risk assessors should check to ensure they use the approach mandated or recommended by the regulatory agency most relevant to their efforts.
6) Similarly to deriving the RfD, but with a potentially lower uncertainty factor-This is the correct answer. The MRL is calculated much like the RfD, except that the uncertainty factors of 10 may be lower (1 or 3), based on scientific judgment.
An expression used in toxicology is "no exposure = no risk." Exposure assessment is a key step in the risk assessment process because without an exposure, even the most toxic chemical does not present a threat. Our understanding of potential exposures to chemicals has grown significantly since approximately 1980. For example, research has identified previously "missing" sources and pathways of potential indoor air exposures such as chemicals from consumer products or elsewhere that end up in household dust.
Environmental contaminants are analyzed according to their releases, movement and fate in the environment, and the exposed populations. Consumer products and pharmaceuticals are analyzed in terms of reasonably foreseeable potential exposures.
Other residential sources of chemicals can come from household air and water. For example, chemicals in air can deposit on, absorb into, oradsorb (Adsorption occurs when molecules of a gas, liquid, or dissolved solid adhere to a surface and create a thin film around it)onto household materials (such as carpets and foods and food packaging), which can lead to dermal and oral exposures. When chemicals are confined to indoor spaces and not diluted in outdoor air, there can be large differences in indoor versus outdoor levels of a chemical.
Figure 4 illustrates some other residential exposures to chemicals via water.
Exposure Pathways The route a substance takes from its source (where it began) to its endpoint (where it ends), and how people can come into contact with (or be exposed to) it is defined as an exposure pathway. An exposure pathway has five parts:
Asource of exposure, such as using a consumer product for a household task or a chemical spilled from a truck onto a highway.
The main variables in the exposure assessment are:
Exposed populations.
Types of substances.
Single substance or mixture of substances.
Frequency and duration of exposure.
Pathways and types of exposure.
All possible types of reasonably foreseeable exposures are considered in order to assess the toxicity and risk that might occur.
Considerations for Environmental Exposure For an environmental exposure, the risk assessor would look at the physical environment and the potentially exposed populations. The physical environment may include considerations about climate, vegetation, soil type, groundwater and surface water. Populations that may be exposed as the result of chemicals that migrate from the site of pollution are also considered.
Subpopulations may be at greater risk due to a higher level of exposure or because they have increased sensitivity. Examples include infants, the elderly, pregnant women, and those with chronic illness.
Pollutants may be transported away from the source and may be physically, chemically, or biologically transformed. They may also accumulate in various materials. Assessment of the chemical fate requires knowledge of many factors, including:
Organic carbon and water partitioning at equilibrium (Koc).
Chemical partitioning between soil and water (Kd).
Partitioning between air and water (Henry's Law Constant).
Solubility constants.
Vapor pressures.
Partitioning between water and octanol (Kow).
Bioconcentration factors.
These factors are integrated with the data on sources, releases, and routes of the pollutants to determine the exposure pathways of importance, such as groundwater, surface water, air, soil, food, and/or breastmilk.
Use of Exposure Models Because actual measurements of exposures are often not available, exposure models may be used. For example:
In air quality studies, chemical emission and air dispersion models are used to predict the air concentrations to downwind residents.
Residential wells downstream from a site may not currently show signs of contamination. They may become contaminated in the future as chemicals in the groundwater migrate to the well site.
In these situations, groundwater transport models can be used to estimate when chemicals of potential concern will reach the wells.
Information Sources on Chemical Exposures and Health
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The future of exposure assessment promises to involve more information and more approaches. Find out more information about:
Figure 5. Topics covered by CTD (Image Source: Davis AP, Grondin CJ, Johnson RJ, Sciaky D, Wiegers J, Wiegers TC, Mattingly CJ The Comparative Toxicogenomics Database: update 2021. Nucleic Acids Res. 2020 Oct 17.)
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Considerations when Reading About a New Exposure Study
When reading about a new exposure study, there are several questions you can consider to critically evaluate studies about everyday chemical exposures.
Is the study published in a peer-reviewed journal?
Are there other publications that lend or do not lend support to the current research, or is this study possibly the first of its kind that suggests an emerging issue for regulators, chemical companies, consumer product manufacturers, and others to consider?
In addition to scientific journal publications, is there information available from government or other Web sites that provides perspectives about the exposures and potential risks?
How was the study conducted? For example, is it a preliminary or "pilot" study involving a small number of people who were studied, and did the participants represent a narrow or broad, wide range of the types of potentially affected consumers?
Did the study use household products/materials or food to which some consumers are likely to be exposed? If yes, are there geographical or other limitations that should be noted by the authors such as the products or food being likely to be sold only in one country or region of the world?
Did the study try to approach "reasonably foreseeable" consumer exposure conditions?
Is there a known or reasonably foreseeable association between these types of exposures and human adverse effects?
Approaches to risk characterization continue to evolve. The final stage in the risk assessment process involves predicting the frequency and severity of effects in exposed populations. The conclusions reached from the stages of hazard identification and exposure assessment are integrated to determine the probability of effects likely to occur in humans exposed under similar conditions.
Because most risk assessments include major uncertainties, it is important to describe biological and statistical uncertainties in risk characterization. The assessment should identify which components of the risk assessment process involve the greatest degree of uncertainty.
For Carcinogenic Risks Potential human carcinogenic risks associated with chemical exposure are expressed in terms of an increased probability of developing cancer during a person's lifetime. For example, a 10-6increased cancer risk represents an increased lifetime risk of 1 in 1,000,000 for developing cancer. For carcinogenicity, the probability of an individual developing cancer over a lifetime has historically been estimated by multiplying the cancer slope factor(mg/kg/day)for the substance by the chronic(70-year average)daily intake(mg/kg/day).
For Noncarcinogenic Effects For noncarcinogenic effects, the exposure level has historically been compared with an ADI, RfD, or MRL derived for similar exposure periods. Three exposure durations are considered: acute, intermediate, or chronic. For humans:
Acute effects— arise within days to a few weeks.
Intermediate effects— evident in weeks to a year.
Chronic effects— manifest in a year or more.
For Multiple Exposures In some complex risk assessments, such as for hazardous waste sites, the risk characterization must consider multiple chemical exposures andmultiple exposure pathways(described in Exposure Assessments).
Simultaneous exposures to several chemicals, each at a subthreshold level, can often cause adverse effects by "adding" the multiple exposures together, calleddose additivity.
The assumption of dose additivity is most acceptable when substances induce the same toxic effect by the same mechanism. When available, information on mechanisms of action and chemical interactions are considered and are useful in deriving more scientific risk assessments.
Individuals are often exposed to a substance by more than one exposure pathway(for example, drinking contaminated water and inhaling contaminated dust).
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Knowledge Check (Solutions on next page)
1) A major component of exposure assessment involves: a) Identifying the exposure pathways b) Measuring the amount of a substance that is metabolized in the body c) Determining the amount of exposure that must be reduced to comply with the acceptable risk level
2) The movement of substances in environmental media is primarily predicted by: a) Tagging substances with radioactive tracers and measuring radioactivity at various times and locations within the environmental media b) Using exposure models to derive scientific estimates c) Performing actual measurements of exposure pathways
3) Which of the following isnottrue about risk characterization? a) It involves predicting the frequency and severity of effects in exposed populations b) It determines the amount of exposure that must be reduced to comply with the acceptable risk level c) It integrates conclusions reached in hazard identification and exposure assessment d) It yields probabilities of effects likely to occur in humans exposed under similar conditions
4) An increased cancer risk of 2.0 X 10^-6 (^ indicates to the -6 power)means that: a) It is likely that two people out of one million will develop the specific type of cancer in their lifetime due to exposure to the chemical b) The xeniobiotic for which the cancer risk assessment was performed is likely to cause cancer in two people on a yearly basis c) It is likely that two people out of one thousand will develop the specific type of cancer in their lifetime due to exposure to the chemical d) It is probable that two million people will develop cancer if they are continuously exposed to the chemical for life
1) Identifying the exposure pathways-This is the correct answer. Exposure pathways are key to exposure assessment because they identify the route a substance takes from its source to its end point, as well as how people can be exposed to the substance.
2) Using exposure models to derive scientific estimates-This is the correct answer. Since actual measurements of exposures are often unavailable, exposure models may be used.
3) It determines the amount of exposure that must be reduced to comply with the acceptable risk level-This is the correct answer. Risk characterization involves predicting the frequency and severity of effects in exposed populations. It integrates conclusions reached in hazard identification and exposure to yield probabilities of effects likely to occur in humans exposed under similar conditions.
4) It is likely that two people out of one million will develop the specific type of cancer in their lifetime due to exposure to the chemical-This is the correct answer. An increased cancer risk of 2 times 10^-6means two in a million people will likely develop the specific type of cancer in their lifetime due to exposure to the chemical.
What We've Covered This section made the following main points:
Ahazardis the capability of a substance to cause an adverse effect. Ariskis the probability that the hazard will occur under specific conditions.
Risk assessmentis the process of determining hazard, exposure, and risk. Risk managementis the process of weighing policy alternatives and deciding on the most appropriate regulatory action.
There arefour basic steps to risk assessment:
Hazard Identification
Identify or develop information suggesting or confirming whether a chemical poses a potential hazard to humans.
(Quantitative) Structure Activity, or (Q)SAR methods, including computer models, help consider closely related chemicals as a group or category.
Read-across involves estimating what a chemical may be like, including the presence or absence of certain properties or activities, based on one or more other chemicals.
Adverse Outcome Pathways (AOPs) involvein vitromethods that evaluate changes in normal cellular signaling pathways.
Other emerging methods include (Quantitative) in vitro to in vivoextrapolation, or (Q)IVIVE, Integrated Testing Strategies, and Integrated Approaches to Testing and Assessment (IATA).
Dose-Response Assessment
Carcinogenic (cancer) risk assessment involves two steps:
Perform qualitative evaluation of all epidemiology studies, animal bioassay data, and biological activity.
Quantitation of the risk for substances classified as definite or probably human carcinogens.
Non-carcinogenic risk assessment includes:
Acceptable Daily Intake (ADI), which divides the NOAEL by uncertainty/safety factors.
Reference Dose (RfD), which divides the NOAEL or LOAEL by uncertainty/safety factors.
Benchmark Dose Method (BMD), which extrapolates data to determine a point of departure (POD) that accounts for study quality.
Assessments for noncancer toxicity effects, acute or short-term exposures, and occupational exposures.
Exposure Assessment
People are exposed to mixtures of hundreds of chemicals in everyday life.
Anexposure pathwaydescribes the:
Route a substance takes from its source to its endpoint.
How people can be exposed to the substance.
The three steps of exposure assessment are to:
Characterize the point of exposure setting and exposure scenario.
Identify exposure pathways.
Quantify the exposure.
Exposure models are commonly used because actual exposure measurements are often not available.
Risk Characterization
This final phase predicts the frequency and severity of effects in exposed populations.
Biological and statistical uncertainties are described.
For carcinogenic risks, the probability of a person developing cancer over a lifetime is estimated by multiplying the cancer slope factor for the substance by the chronic, 70-year average daily intake.
For noncarcinogenic effects, the exposure level is compared with an ADI, RfD, or MRL derived for similar exposure periods.
1) Legally enforceable acceptable exposure levels or controls-This is the correct answer. Exposure standards are legally enforceable acceptable exposure levels or controls resulting from Congressional or Executive mandate.
2) Recommended maximum exposure levels which are voluntary and not legally enforceable-This is the correct answer. Exposure guidelines are recommended maximum exposure levels that are voluntary and not legally enforceable.
1) U.S. Consumer Product Safety Commission (CPSC)-This is the correct answer. The U.S. Consumer Product Safety Commission (CPSC) is charged with protecting the public from unreasonable risks of injury or death associated with the use of the consumer products under its jurisdiction.
2) Recommended guidance developed by the U.S. Food and Drug Administration (FDA)-This is the correct answer. The FDA does not issue exposure standards for drugs, but rather approves a New Drug Application containing guidance for usage and warnings that the manufacturer must provide to physicians and others.
3) An antibiotic administered to cattle-This is the correct answer. Indirect food additives are not intentionally added to foods and are not natural constituents of foods. Examples include antibiotics administered to cattle, pesticide residues remaining after production or processing of foods, and chemicals that migrate from packaging into foods.
4) Prohibited the addition of any substance to food that has been shown to induce cancer in humans or animals-This is the correct answer. The Delaney Clause prohibits addinganysubstance to food that has been shown to induce cancer in humans or animals. The lowest level of concern for an additive used at 0.05 ppm is irrelevant in this case.
5) European Chemicals Agency (ECHA)-This is the correct answer. The European Chemicals Agency (ECHA) has regulatory authority for chemicals and biocides in the EU.
1) Pesticide tolerance for food use-This is the correct answer. The pesticide tolerance for food use standard established by the EPA specifies the pesticide residue allowed to remain in or on treated food products.
2) Maximum Contaminant Levels (MCLs)-This is the correct answer. The EPA conducts risk assessments and issues Maximum Contaminant Levels (MCLs) for naturally-occurring and man-made contaminants in drinking water.
3) Primary NAAQS set limits to protect public health; secondary NAAQS relate to public welfare-This is the correct answer. Primary NAAQS set limits to protect public health. Secondary NAAQS relate to public welfare, such as crops, animals, and structures.
4) Minimal Risk Levels (MRLs)-This is the correct answer. Minimal Risk Levels (MRLs) for noncancer toxic effects estimate the daily human exposures that are likely to be without an appreciable risk of adverse effects over a specific duration of exposure.
Exposure standards and guidelines are developed by governments to protect the public from harmful substances and activities that can cause serious health problems. This section describes standards and guidelines relating to protection from the toxic effects of chemicals only.
Exposure standards and guidelines are determined by risk management decisions. Risk assessments provide regulatory agencies with estimates of numbers of persons potentially harmed under specific exposure conditions. Regulatory agencies then propose exposure standards and guidelines designed to protect the public from "unacceptable risk" levels.
Exposure standards and guidelines usually provide numerical exposure levels for various media (such as food, consumer products, water, and air) that should not be exceeded. Alternatively, these standards may be preventive measures to reduce exposure (such as labeling, special ventilation, protective clothing and equipment, and medical monitoring).
Standards and Guidelines More specifically, standards and guidelines for chemical exposure levels consist of the following:
Standards— legally acceptable exposure levels or controls issued as the result of Congressional or Executive mandate. They result from formal rulemaking and are legally enforceable. Violators are subject to punishment, including fines and imprisonment.
Guidelines— recommended maximum exposure levels which are voluntary and not legally enforceable. Guidelines may be developed by regulatory and non-regulatory agencies, or by some professional societies.
Federal and state regulatory agencies have the authority to issue permissible exposure standards and guidelines in the following categories:
Consumer Product Exposure Standards and Guidelines
Environmental Exposure Standards and Guidelines
Occupational Exposure Standards and Guidelines
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Knowledge Check (Solutions on next page)
1) Exposure standards are: a) Developed by chemical manufacturers b) Recommended maximum exposure levels which are voluntary and not legally enforceable c) Legally enforceable acceptable exposure levels or controls
2) Exposure guidelines are: a) Developed by chemical manufacturers b) Recommended maximum exposure levels which are voluntary and not legally enforceable c) Legally enforceable acceptable exposure levels or controls
Consumer products are often called household products. It is important to know what a category of product is called in the area of the world of interest.
For example, in the United States, cosmetic products are defined by theFDAas those products "intended to be applied to the human body for cleansing, beautifying, promoting attractiveness, or altering the appearance without affecting the body's structure or functions." While cosmetics are often thought of as being make-up products such as eye-liner, lipstick, or nail polish, the FDA definition includes skin-care creams, lotions, powders, and perfumes. However, soap products are excluded from FDA's definition of cosmetics.
In comparison, in the European Union (EU), the European Commission's definition of cosmetic products includes soap, shampoo, deodorant, toothpaste, perfumes, and makeup.
It is also important to keep in mind that some products are known by different names. For example, what is known as a cloth or disposable diaper in the United States is called a nappy in several other countries.
The U.S.Consumer Product Safety Commission(CPSC) is charged with "protecting the public from unreasonable risks of injury or death associated with the use of the consumer products" under its jurisdiction such as toys, cribs, power tools, cigarette lighters, and household chemical-containing products. The CPSC considers if a product could pose a fire, electrical, chemical, or mechanical (such as choking) hazard. CPSC's work, including research, product recalls, education, and administration of regulations, laws, and standards, has resulted in a decline in the rate of deaths and injuries associated with consumer products over the past several decades.
Consumer exposure standards are developed for hazardous substances and articles by the CPSC. The authority under theFederal Hazardous Substance Act(FHSA) pertains to substances other than pesticides, drugs, foods, cosmetics, fuels, and radioactive materials. The CPSC-required warning labels on containers of household products that are toxic, corrosive, irritants, or sensitizers help consumers to safely store and use those products and to give them information about immediate first aid steps to take if an accident happens. Highly toxic substances are labeled with DANGER; less toxic substances are labeled with WARNING or CAUTION.
Figure 2. CPSC danger label for a gas-powered generator (Image Source: CPSC)
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The CPSC’s basis for a determination of highly toxic has been death in laboratory rats at an oral dose of 50 mgs, or an inhaled dose in rats of 200 ppm for one hour, or a 24-hour dermal dose in rabbits of 200 mg/kg. A substance is corrosive if it causes visible destruction or irreversible damage to the skin or eye. If it causes damage that is reversible within 24 hours, it is designated an irritant. An immune response from a standard sensitization test in animals is sufficient for designating the substance a sensitizer.
CPSC is a member of the U.S. Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM), a permanent committee of the National Institutes of Environmental Health Science (NIEHS) under the National Toxicology Program Interagency Center for the Evaluation of Alternative Toxicological Methods (NICEATM). ICCVAM was created "to establish, wherever feasible, guidelines, recommendations, and regulations that promote the regulatory acceptance of new or revised scientifically valid toxicological tests that protect human and animal health and the environment while reducing, refining, or replacing animal tests and ensuring human safety and product effectiveness."
European Commission General Product Safety Directive (GPSD) In the EU, the European Commission'sGeneral Product Safety Directive(GPSD) requires producers and distributors to place only safe consumer products on the market and to take all necessary measures to prevent risks to consumers. The GPSD excludes certain product categories covered by specific European safety regulations. It provides an alert system (Rapid Alert System for non-food dangerous products – "RAPEX") between the Commission and EU Member States, Norway, Iceland and Liechtenstein.
U.S. Food and Drug Administration (FDA) The FDA oversees food safety, tobacco products, dietary supplements, prescription and non-prescription drugs, vaccines, blood products, medical devices, electromagnetic radiation emitting devices, cosmetics, animal foods, and veterinary products.
Drugs Manufacturers of new pharmaceuticals must obtain formal FDA approval before their products can be marketed. Drugs intended for use in humans must undergo animal studies and human clinical trials to determine toxic dose levels prior to filing aNew Drug Application(NDA).
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Did you know? During the late 1950s the drugThalidomidewas used to control nausea and vomiting in pregnancy in Canada, Europe, Australia, and parts of Asia. After the drug came on the market, reports appeared of children born with missing limbs, with upper limbs usually more affected than lower limbs. In addition to damage to arms and legs, faces, eyes, ears, and genitalia, internal organs including the heart, kidney, and gastrointestinal tract were damaged.
Thalidomide did not reach the US market due to the efforts of an astute FDA drug reviewer, Dr. Frances Oldham Kelsey, who insisted that thalidomide be fully tested before approval. In response to the episode, the Kefauver Harris Amendment to the Federal Food, Drug, and Cosmetic Act became law in 1962. The amendment requires drug manufacturers to give proof of the effectiveness and safety of a drug before it can be approved.
Thalidomide continues to be prescribed under strict supervision as a treatment for multiple myeloma, leprosy, certain complications of human immunodeficiency virus (HIV), and autoimmune disorders. In the 2000s, children with thalidomide-related birth defects were noted in Brazil due to the use of thalidomide to treat leprosy. Pregnant women were being exposed when family members took the drug.
An NDA covers all aspects of a drug's effectiveness and safety, including:
Pharmacokinetics and pharmacological effects.
Metabolism and postulated mechanism of action.
Associated risks of the drug.
Intended uses and therapeutic efficacy.
Risk:benefit relationship.
Basis for package inserts supplied to physicians.
The FDA does not issue exposure standards for drugs. Instead, it approves an NDA that contains guidance for usage and warnings concerning potential side effects of a drug. The manufacturer is required to provide this information to physicians prescribing the drug as well as to others that may purchase or use the drug. Information on a drug's harmful side effects is provided in three main ways:
Labeling and package inserts that accompany a drug and explain approved uses, recommended dosages, and effects of overexposure.
Publication of information in the Physicians' Desk Reference (PDR) and other publically available databases.
Figure 5. Sample package insert for a fictional prescription drug (Image Source:FDA)
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Food Additives The FDA is responsible for the approval of food additives. Standards are different depending on whether they are direct food additives or indirect food additives.
Direct food additives are intentionally added to foods for functional purposes. Examples of direct food additives include:
Processing aids
Texturing agents
Preservatives
Flavoring and appearance agents
Nutritional supplements
Approval usually designates the maximum allowable concentrations in a food product.
Indirect food additives are not intentionally added to foods and they are not natural constituents of foods. They become a constituent of the food product from environmental contamination during production, processing, packaging, and storage. Examples of indirect food additives are:
Antibiotics administered to cattle.
Pesticide residues remaining after production or processing of foods.
Chemicals that migrate from packaging materials into foods.
Exposure standards indicate the maximum allowable concentration of these substances in food.
New direct food additives must undergo stringent review by FDA scientists before they can be approved for use in foods. The manufacturer of a direct food additive must provide evidence of the safety of the food additive in accordance with specified uses. The safety evaluation is conducted by the toxicity testing and risk assessment procedures previously discussed with derivation of the ADI. In contrast to pharmaceutical testing, virtually all toxicity evaluations are conducted with experimental laboratory animals.
FDA approval of all new food additives has been requires since the Food, Drug and Cosmetic Act (FDCA) was amended in 1958. At that time, all existing food additives wereGenerally Recognized as Safe(GRAS)and no exposure standard was developed. Many of GRAS substances have since been reevaluated and maximum acceptable levels have been established. However, under the law, a substance may be determined to be GRAS for an intended use and introduced into the food supply as such without prior approval by FDA. FDA maintains a searchable database ofGRAS substances.
Figure 7. Select Committee on GRAS Substances searchable database
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The FDA reevaluation of GRAS substances requires that specific toxicity tests be conducted based on the level of the GRAS substance in a food product. For example, the lowest level of concern is for an additive used at 0.05 ppm in the food product. Only short-term tests (a few weeks) are required for those compounds. In contrast, a food additive used at levels higher than 1.0 ppm must be tested for carcinogenicity, chronic toxicity, reproductive toxicity, developmental toxicity, and mutagenicity.
The 1958 amendment to the Food, Drug and Cosmetic Act law is known as the Delaney Clause. This clause prohibited the addition of any substance to food that has been shown to induce cancer in man or animals. The implication was that any positive result in an animal test, regardless of dose level or mechanism, is sufficient to prohibit use of the substance. In this case, the allowable exposure level is zero. In 1958, chemical levels could only be measured in parts per thousand whereas analytical methods today allow some chemical levels to be measured down to parts per trillion or quintillion. Such levels might represent negligible cancer risks and Congress has repeatedly amended the Delaney Clause to create more and more exceptions. In 1996, the Delaney Clause was repealed, and the "zero–risk" standard was changed to one of "reasonable certainty."
Food Safety in the European Union (EU)
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General Food Law The basic principles for the EU's food safety policy are defined in the EU's General Food Law (Regulation (EC) No 178/2002), adopted in 2002. This regulation:
Lays down general principles, requirements and procedures that underpin decision making in matters of food and feed safety, covering all stages of food and feed production and distribution.
Sets up an independent agency responsible for scientific advice and support, theEuropean Food Safety Authority (EFSA) - see below for more information.
TheEuropean Food Safety Authority (EFSA)was set up in 2002 and is based in Parma, in Italy. It carries out risk assessments before certain foods are allowed to be sold in the EU. The agency was legally established by the EU under theGeneral Food Law - Regulation 178/2002. The General Food Law created a European food safety system in which responsibility for risk assessment (science) and for risk management (policy) are kept separate.EFSAis responsible for the former area, and also has a duty to communicate its scientific findings to the public.
EFSA provides scientific advice to the European Commission and EU countries, to help them take effective decisions to protect consumers. It also plays an essential role in helping the EU respond swiftly to food safety crises. EFSA's remit covers:
Most ofEFSA's workis undertaken in response to requests for scientific advice from the European Commission, the European Parliament and EU Member States. EFSA also carry out scientific work on own initiative, in particular to examine emerging issues and new hazards and to update our assessment methods and approaches. This is known as "self-tasking." EFSA's quality management system (QMS) has been awarded an ISO 9001:2015 certificate, the international standard for quality management.
EFSA's Scientific Panels of experts are responsible for the bulk of EFSA's scientific assessment work. Each of the 10 Panels is dedicated to a different area of the food and feed chain. The Scientific Committee has the task of supporting the work of the Panels on cross-cutting scientific issues. It focuses on developing harmonized risk assessment methodologies in fields where EU-wide approaches are not yet defined.
The EU General Food Law deals with a wide range of issues related to food in general and food safety in particular, including food information and animal welfare. It covers all parts of the food chain from animal feed and food production to processing, storage, transport, import and export, as well as retail sales. It also establishes the principles for risk analysis. These stipulate how, when, and by whom scientific and technical assessments should be carried out in order to ensure that humans, animals, and the environment are properly protected.
The EU's food safety policy covers food from farm to fork. The EU food policy comprises:
Comprehensive legislation on food and animal feed safety and food hygiene.
Sound scientific advice on which to base decisions.
Enforcement and checks.
Where specific consumer protection is justified, there may be special rules on:
Use of pesticides, food supplements, colorings, antibiotics, or hormones.
Food additives, such as preservatives and flavorings
Substances in contact with foodstuffs, for example, plastic packaging.
Labeling of ingredients that may cause allergies.
Health claims such as "low-fat" or "high-fiber."
The EU'sRapid Alert System for Food and Feed (RASFF)was launched in 1979 and allows information on food and feed to be shared quickly and efficiently between all the relevant bodies at national and EU-level. In a similar vein, theEU Notification System for Plant Health Interceptions (EUROPHYT)is the EU's notification and rapid alert system for plant products entering and being traded within the EU. It helps to prevent the introduction and spread of plant disease and plant pests.
The EU'sTrade Control and Expert System (TRACES)is a system for tracking live animals and food and feed of animal origin as they enter the EU and are traded within the EU. It links veterinary authorities across and outside the EU, and enables veterinary services and businesses to react swiftly when a health threat is discovered.
Regulatory Science in the European Union The following tables describe regulatory science in the EU, including links to the relevant agencies. The list is a work in progress.
List above shows regulatory authorities over cross-cutting science in the European Union.
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Knowledge Check (Solutions on next page)
1) Consumer exposure standards are developed for hazardous substances and articles by the: a) U.S. Food and Drug Administration (FDA) b) U.S. Consumer Product Safety Commission (CPSC) c) General Product Safety Directive (GPSD)
2) Exposure standards for pharmaceuticals are: a) Issued by the U.S. Food and Drug Administration (FDA) b) Developed by the Environmental Protection Agency c) Recommended guidance developed by the U.S. Food and Drug Administration (FDA)
3) The FDA develops exposure standards for both direct and indirect food additives. Which of the following is an example of an indirect food additive? a) A preservative added to food products b) An antibiotic administered to cattle c) Natural and artificial flavorings d) A nutritional supplement, such as Vitamin A
4) Under the Delaney Clause of 1958, the FDA: a) Required physicians to strictly adhere to exposure standards for pharmaceuticals b) Prohibited the addition of any substance to food that has been shown to induce cancer in humans or animals c) Authorized the addition of potentially carcinogenic substances to food as long as the concentration is at 0.05 ppm or less
5) In the European Union, what regulatory authority is responsible for chemicals and biocides? a) European Centre for Disease Prevention and Control (ECDC) b) European Food Safety Authority (EFSA) c) European Chemicals Agency (ECHA)
The Environmental Protection Agency (EPA) is responsible for US-widelawsthat require determination and enforcement of environmental exposure standards. In addition, EPA has the authority to prepare recommended exposure guidelines for selected environmental pollutants. Similar organizations exist in US states, and in other countries and groups of countries (such as the European Commission for European Union member countries). The EPA is responsible for developing exposure standards for:
Pesticides
Water pollutants
Air pollutants
Hazardous wastes
Pesticides
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Pesticides cannot be marketed until they have been registered by the EPA in accordance with theFederal Insecticide, Fungicide, and Rodenticide Act(FIFRA). In order to obtain registration, a pesticide must undergo an extensive battery of toxicity tests, chemistry analyses, and environmental fate tests.
TheFood Quality Protection Actof 1996 (FQPA) changed the way that pesticides were regulated by requiring investigation of:
Nonoccupational exposure to pesticides.
The cumulative effects of pesticides having a common toxicity mechanism.
Any increased susceptibility in infants, children and other sensitive groups.
Whether the pesticide has endocrine-disrupting effects.
Certain pesticides have been determined by the EPA to pose minimal risk to health or to the environment and areexemptfrom FIFRA registration.
A primary exposure standard for pesticides is thepesticide tolerance for food useThis standard specifies the pesticide residue allowed to remain in or on each treated food product. The EPA residues risk assessment covers:
Toxicity.
Amount used and how often.
How much residue remains by the time a product reaches the market.
Other ways of being exposed to the pesticide, if any.
Access to safe drinking water and control of water pollution are regulated by theSafe Drinking Water Act(SDWA) and theClean Water Act(CWA). Under the SDWA, the EPA conducts risk assessments and issuesMaximum Contaminant Levels(MCLs)for naturally-occurring and man-made contaminants in drinking water. The MCL is the acceptable exposure level which, if exceeded, requires immediate water treatment to reduce the contaminant level.
In addition to establishing MCLs, the EPA can propose recommended exposure guidance for drinking water contamination. As an interim procedure, maximum contaminant level goals(MCLGs)may be recommended for long-term exposures to contaminants in drinking water. Generally, no allowable exposure can be recommended for a carcinogenic chemical. When the MCL is issued, an acceptable exposure level based on a cancer risk assessment may be proposed for the MCL.
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EPA prepareshealth advisories(HAs)as voluntary exposure guidelines for drinking water contamination. The HAs provide exposure limits for 1-day, 10-day, longer-term, or lifetime exposure periods. They pertain to both cancer and noncancer risks. The formula used to derive a health advisory differs from that for the ADI or RfD in that the HAs pertain to short-term as well as long-term exposures. In addition, human body weight and drinking water consumption are included in the formula.
Data from toxicology studies such as the duration of exposure and the exposure route (such as oral) must be represented in the HAs. For example, the 10-day HA must be based on a NOAEL or LOAEL derivation that was obtained from an animal toxicology study of approximately 10 days duration (routinely 7- to 14-day toxicity studies).
A longer-term HA applies to humans drinking contaminated water for up to 7 years (which could represent 10% of a human's 70-year lifespan). Because 90 days is about 10% of a rat's expected lifespan, the 90-day subchronic study with rats is considered appropriate for providing the basis for the longer-term HA assessment.
A life-time HA (representing lifetime exposure to a toxicant in drinking water) is also determined for noncarcinogens. The procedure uses the RfD risk assessment with adjustments for body weight of an adult human (70 kg) and drinking water consumption of 2 L/day.
Figure 3. EPA issues health advisories as voluntary exposure guidelines for drinking water contamination (Image Source: Adapted from EPA)
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In addition to drinking water standards, the EPA is authorized under the Clean Water Act (CWA) to issue exposure guidance for controlling pollution in ground water. The intent is to provide clean water for fishing and swimming rather than for drinking purposes. It provides a scheme for controlling the introduction of pollutants into navigable surface water. The recommendations for ground water protection are known as ambient water quality criteria.
The ambient water quality criteria are intended to control pollution sources at the point of release into the environment. While these criteria may be less restrictive than the drinking water standards, they usually are the same numeric value. For example, the MCL for drinking water and the ambient water quality criteria for ground water for lead are the same: 0.05 mg/L of water.
Air Pollutants Air emission standards are issued by EPA under theClean Air Act(CAA). The CAA authorizes the issuance ofNational Ambient Air Quality Standards(NAAQS)for air pollution. There are two types of NAAQS:
Primary NAAQS standardsset limits to protect public health, including people at increased risk (preexisting heart or lung disease, children, older adults).
Secondary NAAQS standardsrelate to public welfare, such as crops, animals, and structures.
NAAQS have been established for the following major atmospheric pollutants:
Carbon monoxide
Sulfur oxide
Oxides of nitrogen
Ozone
Hydrocarbons
Particulates
Lead
When air emissions exceed the NAAQS levels, the polluting industry must take action to reduce emissions to acceptable levels.
The main purpose of CERCLA is to clean up hazardous waste disposal sites. EPA has established standards known asReportable Quantities(RQs). Companies must report to EPA any chemical release that exceeds the RQ. RQs evaluate physical, chemical, and toxicological properties of a substance. These are called primary criteria and include aquatic toxicity, acute mammalian toxicity (oral, dermal, and inhalation), ignitability, reactivity, chronic toxicity, and potential carcinogenicity. Secondary criteria evaluate how a substance degrades in the environment.
Minimal Risk Levels(MRLs) for noncancer toxic effects are derived by theAgency for Toxic Substances and Disease Registry(ATSDR), which has a congressional mandate to investigate the health effects of hazardous substances in the environment. MRLs are estimates of daily human exposures that are likely to be without an appreciable risk of adverse effects over a specified duration of exposure. MRLs are derived for acute (14 days or less), intermediate (15–364 days), and chronic (365 days or more) exposures for inhalation or oral routes.
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Knowledge Check (Solutions on next page)
1) The exposure standard established by the EPA for the pesticide residue allowed to remain in or on each treated food product is called the: a) Pesticide tolerance for food use b) Reportable quantity of pesticides c) Maximum Contaminant Level (MCL)
2) The EPA establishes exposure standards for natural and man-made contaminants in drinking water. These standards are called: a) Ambient Water Quality Criteria b) Maximum Contaminant Level Goals (MCLGs) c) Maximum Contaminant Levels (MCLs)
3) What is the difference between primary National Ambient Air Quality Standards (NAAQS) and secondary NAAQS? a) Primary NAAQS relate to public welfare (for example, crops, animals, and structures); secondary NAAQS set limits to protect public health b) Primary NAAQS set limits to protect public health; secondary NAAQS relate to public welfare c) Primary NAAQS are legally enforceable; secondary NAAQS are not
4) The Agency for Toxic Substances and Disease Registry (ATSDR) estimates levels for daily human exposure to chemicals that are likely to be without an appreciable risk of adverse effects for specified periods of exposure. These are known as: a) Minimal Risk Levels (MRLs) b) Maximum Contaminant Levels (MCLs) c) Reportable Quantities (RQs)
Occupational Safety and Health Administration (OSHA) Standards Recommended or mandatoryoccupational exposure limits (OELs)for chemicals exist in many countries. For example, legal standards in the United States are established by the Occupational Safety and Health Administration (OSHA). These standards are known asPermissible Exposure Limits(PELs). The majority of PELs were issued after the 1970Occupational Safety and Health (OSH) Act.
OSHA maintains the "Permissible Exposure Limits – Annotated Tables" that contain comparative information taken from federal, state, and professional organizations such as the:
California Division of Occupational Safety and Health (Cal/OSHA) PELs.
These tables list air concentration limits for chemicals but do not include notations for skin absorption or sensitization. The PEL Annotated Tables include the following:Table Z-1,Table Z-2, andTable Z-3.
Figure 1. Screenshot of a portion of OSHA PEL Annotated Table Z-2
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Most OSHA PELs are for airborne substances with allowable exposure limits averaged over an 8-hour day in a 40-hour week. This is known as theTime-Weighted-Average (TWA)PEL. While adverse effects are not expected to be encountered with repeated exposures at the PEL, OSHA recommends that employers consider using thealternative occupational exposure limitsbecause it believes levels above some of the alternative occupational exposure limits may be hazardous to workers even when the exposure levels are in compliance with the relevant PELs.
Short Term Exposure Limits, Ceiling Limits, and Skin Designations OSHA also issues Short Term Exposure Limit (STELs) PELs, Ceiling Limits, and PELs that carry a skin designation.
Short Term Exposure Limit(STELs)--PEL STELs are concentration limits of substances in the air that a worker may be exposed to for 15 minutes without suffering adverse effects. The 15-minute STEL is usually considerably higher than the 8-hour TWA exposure level.
Ceiling Limitsare concentration limits for airborne substances that should never be exceeded.
Askin designationindicates that the substance can be readily absorbed through the skin, eye or mucous membranes, and substantially contribute to the dose that a worker receives from inhalation of the substance. OSHA standards do not include surface contamination criteria or quantifications for skin absorption.
Theoretically, an occupational substance could have PELs as TWA, STEL, and Ceiling Value, and with a skin designation, but that is rare. Usually, an OSHA-regulated substance will have only a PEL as a time-weighted average.
Immediately Dangerous to Life or Health (IDLH) TheImmediately Dangerous to Life or Health(IDLH)occupational exposure guideline was developed jointly by the OSHA and NIOSHStandards Completion Programin 1974. IDLH represents:
An airborne exposure "likely to cause death or immediate or delayed permanent adverse health effects or prevent escape from such an environment" (NIOSH).
"An atmosphere that poses an immediate threat to life, would cause irreversible adverse health effects, or would impair an individual's ability to escape from a dangerous atmosphere" (OSHA).
IDLH values can be used in assigning respiratory protection equipment.
Recommended Exposure Limits and Biological Exposure Indices The NIOSHRecommended Exposure Limits(RELs) are also designated as time-weighted average, short-term exposure limits, and ceiling limits. NIOSH also uses immediately dangerous to life or health (IDLH) values.
ACGIH®also has developedBiological Exposure Indices (BEIs®)as guidance values for assessing biological monitoring results (concentration of a chemical in biological media such as blood or urine). The OSHAPolicy Statementon the Uses of TLVs®and BEIs®provides an overview on using these guidelines.
Control Banding (CB) Control banding(CB)is an emerging area internationally for guiding the assessment and management of workplace chemical risks. CB is a technique that determines a control measure such as dilution by air ventilation or engineering controls based on a range or “band” of hazards such as skin irritation or carcinogenic potential and exposures such as an assessment of a small, medium, or large exposure. It is based on the fact that there are a limited number of control approaches, and a history of having many problems solved in the past. CB is used with other health and safety practices such as chemical substitution. It is not a replacement for the use of experts in occupational safety and health and it does not eliminate the need to perform exposure monitoring.
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Knowledge Check (Solutions on next page)
1) The Occupational Safety and Health Administration (OSHA) develops legal standards for workplace exposure. These standards are called: a) Threshold Limit Values (TLVs) b) Recommended Exposure Limits (RELs) c) Permissable Exposure Limits (PELs)
2) What exposure standards can be used to assign respiratory protection equipment? a) Immediately Dangerous to Life or Health (IDLH) b) Short Term Exposure Limits (STELs) c) Biological Exposure Indices (BEIs)
1) Permissable Exposure Limits (PELs)-This is the correct answer. OSHA establishes Permissable Exposure Limits, or PELs, which are legal standards for workplace exposure.
2) Immediately Dangerous to Life or Health (IDLH)-This is the correct answer. Immediately Dangerous to Life or Health (IDLH) values can be used in assigning respiratory protection equipment.
What We've Covered This section made the following main points:
Standardsare legally acceptable exposure levels or controls set by Congressional or Executive mandate.
Guidelinesare recommended maximum exposure levels and are voluntary and not legally enforceable.
Consumer products
The U.S. Consumer Product Safety Commission (CPSC) protects the public from unreasonable risks of harm connected with consumer products.
The CPSC establishes consumer exposure standards for hazardous substances and articles.
The CPSC requires warning labels on containers of household products that are toxic, corrosive, irritating, or sensitizing.
Drugs
FDA approval is required before pharmaceuticals can be marketed.
Animal studies and human clinical trials are required to determine toxic dose levels.
The New Drug Application (NDA) contains guidance for drug usage and warnings regarding side effects and interactions.
Information about a drug's harmful side effects must be provided through labeling and package inserts, publication in the Physicians' Desk Reference (PDR), and direct-to-consumer marketing.
Food additives
The FDA is responsible for approving food additives.
Direct additivesare intentionally added to foods for functional purposes and include processing aids, flavors, appearance agents, and nutritional supplements.
Indirect additivesare not intentionally added to foods and are not natural constituents of foods, but become constituents during production, processing, packaging, and storage.
FDA scientists must review new direct food additives before they can be used in foods.
Generally Recognized as Safe (GRAS) additives are generally accepted as safe for an intended use and can be introduced into the food supply without prior FDA approval.
Environment
The EPA establishes exposure standards for pesticides, water pollutants, air pollutants, and hazardous wastes.
Pesticides must be registered with EPA after undergoing extensive analyses.
The EPA prepares health advisories (HAs) as voluntary exposure guidelines for drinking water contamination.
Ambient water quality criteria help control pollution sources at the point of release into the environment.
National Ambient Air Quality Standards (NAAQS) protect public health and welfare from air pollution.
Hazardous wastes are regulated under the Resource Conservation and Recovery Act (RCRA) and Superfund.
RCRA regulates hazardous and non-hazardous solid waste.
Occupational Safety
The Occupational Safety and Health Administration (OSHA) establishes legal standards for worker exposure in the United States.
Permissible Exposure Limits (PELs) list air concentration limits for chemicals, but not skin absorption or sensitization.
Short Term Exposure Limit (STELs) PELs are concentration limits of substances in the air that workers may be exposed to for 15 minutes without adverse effects.
Ceiling limits are concentration limits for airborne substances that must not be exceeded.
Immediately dangerous to life or health (IDLH) designates an airborne exposure or atmosphere that could lead to death or immediate or delayed permanent adverse health effects.
Control banding (CB) determines a control measure based on a band of hazards, such as skin irritation or carcinogenic potential, and exposures.
In order to understand how toxic substances cause harmful changes in organs, tissues, or cells, knowledge of normal physiology and anatomy is needed. This section is an overview of normal physiology, especially as related to the normal body components and how they function. While we show how some xenobiotics can damage the different body components, detailed examples of toxic cellular and biochemical reactions will be covered in later sections.
Complexity of the Body The body is immensely complex with numerous components, all of which perform precise functions necessary for the body to maintain health and well-being. Malfunction of any component can result in disease or a breakdown of a portion of the body. Toxic substances can damage an organ or organ system so that it cannot function properly, leading to death or sickness of the organism (for example, liver or kidney failure). However, in nearly all cases, the toxic substance actually exerts its harmful effect directly on specific cells or biochemicals within the affected organ. These cell and chemical changes in turn cause the tissue or organ to malfunction.
Specific Toxic Effects Most toxic substances are usually specific in their toxic damage to particular tissues or organs, referred to as the "target tissues" or "target organs." Toxic effects may affect only a specific type of cell or biochemical reaction. For example:
The toxic effect of carbon monoxide is due to its binding to a specific molecule (hemoglobin) of a specific cell (red blood cell).
Organophosphate toxic substances, which inhibit an enzyme (acetylcholinesterase) responsible for modulating neurotransmission at nerve endings.
Systemic Toxic Effects On the other hand, the effect of some toxic substances may be generalized and potentially damage all cells and thus all tissues and all organs.
An example is the production of free radicals by whole body radiation. Radiation interacts with cellular water to produce highly reactive free radicals that can damage cellular components. The result can be a range of effects from the death of the cell, to cell malfunction, and to the failure of normal cell division (for example, cancer).
An example of a multi-organ chemical toxic substance is lead, which damages several types of cells, including kidney cells, nerve cells, and red blood cells.
The body is a remarkable complex living "machine" consisting of trillions of cells and multitudes of biochemical reactions. Each cell has a specific function and cells work together to promote the health and vitality of the organism. The number and types of toxic reactions are likewise very large. While this tutorial cannot possibly present all these types of cellular and biochemical toxic reactions, it is our goal to provide an overview of the primary toxic mechanisms with a few examples that illustrate these mechanisms. It is important to understand that changes at one level in the body can affect homeostasis at several other levels.
Homeostasisis the ability of the body to maintain relative stability and function even though drastic changes may take place in the external environment or in one portion of the body. A series of control mechanisms, some functioning at the organ or tissue level and other centrally controlled, maintain homeostasis. The major central homeostatic controls are the nervous and endocrine systems.
Physical and mental stresses, injury, and disease continually challenge us and any of them can interfere with homeostasis. When the body loses its homeostasis, it may plunge out of control, into dysfunction, illness, and even death. Homeostasis at the tissue, organ, organ system, and organism levels reflects the combined and coordinated actions of many cells. Each cell contributes to maintaining homeostasis.
Maintaining Homeostasis To maintain homeostasis, the body reacts to an abnormal change (induced by a toxic substance, biological organism, or other stress) and makes certain adjustments to counter the change (a defense mechanism). The primary components responsible for the maintenance of homeostasis include:
Stimulus— a change in the environment, such as an irritant, loss of blood, or presence of a foreign chemical.
Receptor— the site within the body that detects or receives the stimulus, senses the change from normal, and sends signals to the control center.
Control center— the operational point at which the signals are received, analyzed, and an appropriate response is determined. This is sometimes referred to as the integration center since it integrates the signals with other information to determine if a response is needed and the nature of a response.
Effector— the body site where a response is generated, which counters the initial stimulus and thus attempts to maintain homeostasis.
Feedback mechanisms— methods by which the body regulates the degree of response that has been elicited. A negative feedback depresses the stimulus to shut off or reduce the effector response, whereas a positive feedback has the effect of increasing the effector response.
Example: Reaction to a Toxin An example of a homeostatic mechanism can be illustrated by the body's reaction to a toxin that causes anemia and hypoxia (low tissue oxygen) (Figure 1). The production of red blood cells (erythropoiesis) is controlled primarily by the hormone, erythropoietin. When the body goes into a state of hypoxia (the stimulus), it prompts the heme protein (the receptor) that signals the kidney to produce erythropoietin (the effector). This, in turn, stimulates the bone marrow to increase red blood cells and hemoglobin, raising the ability of the blood to transport oxygen and thus raises the tissue oxygen levels in the blood and other tissues. This rise in tissue oxygen levels serves to suppress further erythropoietin synthesis (feedback mechanism). In this example, cells and chemicals interact to produce changes that can either disturb homeostasis or restore homeostasis. Toxic substances that damage the kidney can interfere with the production of erythropoietin or toxic substances that damage the bone marrow can prevent the production of red blood cells. This interferes with the homeostatic mechanism described resulting in anemia.
Figure 1. Homeostatic mechanism to restore levels of red blood cells (Image Source: NLM)
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Knowledge Check (Solutions on next page)
1) The ability of the body to maintain relative stability and function even though drastic changes may take place in the external environment or in one portion of the body is known as: a) Physiology b) Homeostasis c) Toxicity
2) To maintain homeostasis, the body reacts to an abnormal change(induced by a toxin, biological organism, or other stress)and makes certain adjustments to counter the change(a defense mechanism). The component of the homeostasis process which detects the change in the environment is known as the: a) Effector b) Stimulus c) Receptor
Grace Ansah is a senior at Iowa State University majoring in Biology. She loves to learn about human anatomy and physiology. One of her major interests is reproductive health. On her free time Grace likes to exercise, cooking, photography, dancing, eating, and spending time with friends and family
As a fun fact she can sing in several languages, including Portuguese, Spanish, and Arabic.
Another interesting fact about Grace is that she is Ghanaian; Ghana is a country in located in west Africa.
1) Homeostasis-This is the correct answer. Homeostasis is the ability of the body to maintain relative stability and function even though drastic changes may take place in the external environment or in one portion of the body. In good health, homeostasis is maintained at all levels of the body hierarchy, including organs, tissues, cells, and biochemicals.
2) Receptor-This is the correct answer. A receptor is the site within the body that detects or receives the stimulus, senses the change from normal, and sends signals to the control center.
Before one can understand how xenobiotics affect these different body components, it's important to understand normal body components and how they function. For this reason, this section provides a basic overview of anatomy and physiology as it relates to toxicity mechanisms.
Basic Body Structure and Organization We can think of the basic structure and functional organization of the human body as a pyramid or hierarchical arrangement in which the lowest level of organization (the foundation) consists of cells and chemicals. Organs and organ systems represent the highest levels of the body's organization (Figure 1).
Figure 1. Pyramid represents a hierarchical organization of human body components (Image Source: NLM)
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Simplified definitions of the various levels of organization within the body are:
Organ system— a group of organs that contribute to specific functions within the body. Examples include:
Gastrointestinal system
Nervous system
Organ— a group of tissues precisely arranged so that they can work together to perform specific functions. Examples include:
Liver
Brain
Tissue— a group of cells with similar structure and function. There are only four types of tissues:
Epithelial
Connective
Muscle
Nerve
Cell— the smallest living units in the body. Examples include:
Hepatocyte
Neuron
Chemicals— atoms or molecules that are the building blocks of all matter. Examples include:
Oxygen
Protein
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Organ Systems of the Human Body The human body consists of eleven organ systems, each of which contains several specific organs. An organ is a unique anatomic structure consisting of groups of tissues that work in concert to perform specific functions. Table 1 includes the structures and functions of these eleven organ systems.
1) Groups of cells with similar structure and function are known as: a) Tissues b) Organs c) Organ systems
2) The organ system that transports oxygen and nutrients to tissues and removes waste products is the: a) Urinary system b) Integumentary system c) Cardiovascular system
3) The organ system that regulates body functions by chemicals (hormones) is known as the: a) Nervous system b) Reproductive system c) Endocrine system
1) Tissues-This is the correct answer. Tissues are groups of cells with similar structure and function. There are only four types of tissues: epithelial tissue, connective tissue, muscle tissue, and nerve tissue.
2) Cardiovascular system-This is the correct answer. The cardiovascular system functions to transport oxygen and nutrients to tissues and removes waste products. The primary organs are the heart, blood, and blood vessels.
3) Endocrine system-This is the correct answer. The endocrine system functions to regulate body functions by chemicals (hormones). It contains several organs including the pituitary gland, parathyroid gland, thyroid gland, adrenal gland, thymus, pancreas, and gonads.
There are four types of tissues dispersed throughout the body, as described below. A type of tissue is not unique for a particular organ and all types of tissue are present in most organs, just as certain types of cells are found in many organs. For example, nerve cells and circulating blood cells are present in virtually all organs.
An "Orchestra" of Tissues Tissues in organs are precisely arranged so that they can work in harmony in performing organ functions. This is similar to an orchestra that contains various musical instruments, each of which is located in a precise place and contributes exactly at the right time to create harmony. Like musical instruments that are mixed and matched in various types of musical groups, tissues and cells also are present in several different organs and contribute their part to the function of the organ and the maintenance of homeostasis.
Kinds of Tissues in the Body The four types of tissues are:
Epithelial tissue
Connective tissue
Muscle tissue
Nerve tissue
The four types of tissues are similar in that each consists of cells and extracellular materials. However, the types of tissues have different types of cells and differ in the percentage composition of cells and the extracellular materials. Figure 1 illustrates how tissues fit into the hierarchy of body components.
Figure 1. Hierarchy of body components (Image Source: NLM)
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Epithelial Tissue Epithelial tissueis specialized to protect, absorb, and secrete substances, as well as detect sensations. It covers every exposed body surface, forms a barrier to the outside world, and controls absorption. Epithelium forms most of the surface of the skin, and the lining of the intestinal, respiratory, and urogenital tracts. Epithelium also lines internal cavities and passageways such as the chest, brain, eye, inner surfaces of blood vessels, the heart, and the inner ear.
Functions of epithelium include:
Providing physical protection from abrasion, dehydration, and damage by xenobiotics.
Controlling the permeability of substances in entering or leaving the body.
Some epithelia are relatively impermeable; others are readily crossed.
Various toxins can damage this epithelial barrier.
Detecting sensation (sight, smell, taste, equilibrium, and hearing) and conveying this information to the nervous system.
For example, touch receptors in the skin respond to pressure by stimulating adjacent sensory nerves.
The epithelium also contains glands and secretes substances such as sweat or digestive enzymes. Others secrete substances into the blood (hormones), such as the pancreas, thyroid, and pituitary gland.
The epithelial cells are classified according to the shape of the cell and the number of cell layers. Three primary cell shapes exist: squamous (flat), cuboidal, and columnar. There are two types of layering: 1) simple and 2) stratified. Figure 2 illustrates these types of epithelial cells.
Connective Tissue Connective tissuesprovide support and hold the body tissues together. They contain more intercellular substances than the other tissues. Connective tissues include blood; bone; cartilage; adipose (fat); and the fibrous and areolar (loose) connective tissues that give support to most organs. The blood and lymph vessels are immersed in the connective tissue media of the body. The blood-vascular system is a component of connective tissue.
In addition to connecting, the connective tissue plays a major role in protecting the body from outside invaders. The hematopoietic tissue is a form of connective tissue responsible for the manufacture of all the blood cells and immunological capability. Phagocytes are connective tissue cells and produce antibodies. If invading organisms or xenobiotics get through the epithelial protective barrier, the connective tissue acts to defend against them.
Figure 3. Connective tissues (Image Source: Adapted from Wikimedia Commons, Public Domain)
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Muscle Tissue Muscular tissueis specialized for an ability to contract. Muscle cells are elongated and called muscle fibers. When one end of a muscle cell receives a stimulus, a wave of excitation is conducted through the entire cell so that all parts contract in harmony. There are three types of muscle cells:
Skeletal muscle— attached to bone and contracts causing the bones to move.
Cardiac muscle— contracts to force blood out of the heart and around the body.
Smooth muscle— can be found in several organs, including the digestive tract, reproductive organs, respiratory tract, and the lining of the bladder. Examples of smooth muscle activity are the:
Contraction of the bladder to force urine out.
Peristaltic movement to move feces down the digestive system.
Contraction of smooth muscle in the trachea and bronchi which decreases the size of the air passageway.
Nerve Tissue Nervous tissueis specialized with a capability to conduct electrical impulses and convey information from one area of the body to another. Most of the nervous tissue (98%) is located in the central nervous system, the brain, and spinal cord.
There are two types of nervous tissue: 1) neurons and 2) neuroglia. Neurons (Figure 5) actually transmit the impulses. Neuroglia (Figure 6) provide physical support for the neural tissue, control tissue fluids around the neurons, and help defend the neurons from invading organisms and xenobiotics. Receptor nerve endings of neurons react to various kinds of stimuli (for example, light, sound, touch, and pressure) and can transmit waves of excitation from the farthest point in the body to the central nervous system.
Figure 6. Types of neuroglia (Image Source: Adapted from Wikimedia Commons. Blausen.com staff (2014). "Medical gallery of Blausen Medical 2014".WikiJournal of Medicine1 (2). DOI:10.15347/wjm/2014.010. ISSN2002-4436.View original image.)
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Knowledge Check (Solutions on next page) 1) There are only four types of tissues in the body. The type of tissue that is specialized to protect, absorb and secrete substances, detect sensations, covers every exposed body surface, and forms a barrier to the outside world is: a) Nerve tissue b) Epithelial tissue c) Connective tissue d) Muscle tissue
1) Epithelial tissue-This is the correct answer. Epithelial tissue is specialized to protect, absorb and secrete substances, and detect sensations. It covers every exposed body surface, forms a barrier to the outside world and controls absorption. Epithelium forms most of the surface of the skin, and the lining of the intestinal, respiratory, and urogenital tracts. Epithelium also lines internal cavities and passageways such as the chest, brain, eye, inner surfaces of blood vessels, and heart and inner ear.
Cells are the smallest component of the body that can perform all of the basic life functions. Each cell performs specialized functions and plays a role in the maintenance of homeostasis. While each cell is an independent entity, it is highly affected by damage to neighboring cells. These various cell types combine to form tissues, which are collections of specialized cells that perform a relatively limited number of functions specific to that type of tissue. Several trillion cells make up the human body. These cells are of various types, which can differ greatly in size, appearance, and function.
Primary Cell Components While there are approximately 200 types of cells, they all have similar features: cell membrane, cytoplasm, organelles, and nucleus. The only exception is that the mature red blood cell does not contain a nucleus. Toxins can injure any of the components of the cell causing cell death or damage and malfunction.
Figure 1 shows the various components of a composite cell.
Figure 1. Basic cell structure (Image Source: adapted from National Cancer Institute -SEER Training)
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The primary components of a typical cell include the following:
Cell membrane— a phospholipid bilayer which also contains cholesterol and proteins; its functions are to provide support and to control entrance and exit of all materials. We will discuss the structure of the cell membrane and the mechanisms by which chemicals can penetrate or be absorbed into or out of the cell in theIntroduction to Absorptionsection later in ToxTutor.
Cytoplasm— a watery solution of minerals, organic molecules, and gases found between the cell membrane and nucleus.
Nucleus— a membrane-bound part of a cell that contains nucleotides, enzymes, and nucleoproteins; the nucleus controls metabolism, protein synthesis, and the storage and processing of genetic information.
Cytosol— the liquid part of the cytoplasm which distributes materials by diffusion throughout the cell.
Nucleolus— a dense region of the nucleus which contains the RNA and DNA; It is the site for rRNA synthesis and assembly of the ribosome components.
Endoplasmic reticulum— an extensive network of membrane-like channels that extends throughout the cytoplasm; it synthesizes secretory products and is responsible for intracellular storage and transport.
Ribosomes— very small structures that consist of RNA and proteins and perform protein synthesis; some ribosomes are fixed (bound to the endoplasmic reticulum) while other ribosomes are free and scattered within the cytoplasm.
Mitochondria— oval organelles bound by a double membrane with inner folds enclosing important metabolic enzymes; they produce nearly all (95%) of the ATP and energy required by the cell.
Lysosomes— vesicles that contain strong digestive enzymes; lysosomes are responsible for the intracellular removal of damaged organelles or pathogens.
Peroxisomes— very small, membrane-bound organelles which contain a large variety of enzymes that perform a diverse set of metabolic functions.
Golgi apparatus— stacks of flattened membranes containing chambers; they synthesize, store, alter, and package secretory products.
Centrioles— there are two centrioles, aligned at right angles, each composed of 9 microtubule triplets; they organize specific fibers of chromosomes during cell division, which move the chromosomes.
Cilia— thread-like projections of the outer layer of the cell membrane, which serve to move substances over the cell surface.
Cell Components Most Susceptible to Xenobiotics While all components of the cell can be damaged by xenobiotics or body products produced in reaction to the xenobiotics, the components most likely to be involved in cellular damage are the cell membrane, nucleus, ribosomes, peroxisomes, lysosomes, and mitochondria.
Agents that can lead to changes in the permeability of the membrane and the structural integrity of a cell can damagecell membranes. The movement of substances through cell membranes is precisely controlled to maintain homeostasis of the cell. Changes in toxin-induced cell membrane permeability may directly cause cell death or make it more susceptible to the entrance of the toxin or to other toxins that follow. The effects in this case may be cell death, altered cell function, or uncontrolled cell division (neoplasia).
Nucleicontain the genetic material of the cell (chromosomes or DNA). Xenobiotics can damage thenucleus, which in many cases lead to cell death, by preventing its ability to divide. In other cases, the genetic makeup of the cell may be altered so that the cell loses normal controls that regulate division. That is, it continues to divide and become a neoplasm. How this happens is described in theCancer sectionof ToxTutor.
Ribosomesuse information provided by the nuclear DNA to manufacture proteins. Cells differ in the type of protein they manufacture. For example, the ribosomes of liver cells manufacture blood proteins whereas the ribosomes of fat cells manufacture triglycerides. Ribosomes contain RNA, structurally similar to DNA. Agents capable of damaging DNA may also damage RNA. Thus, toxic damage to ribosomes can interfere with protein synthesis. In the case of damage to liver cell ribosomes, a decrease in blood albumin may result with impairment in the immune system and blood transport.
Lysosomescontain digestive enzymes that normally function in the defense against disease. They can break down bacteria and other materials to produce sugars and amino acids. When xenobiotics damage lysosomes, the enzymes can be released into the cytoplasm where they can rapidly destroy the proteins in the other organelles, a process known asautolysis. In some hereditary diseases, the lysosomes of an individual may lack a specific lysosomal enzyme. This can cause a buildup of cellular debris and waste products that is normally disposed of by the lysosomes. In such diseases, known as lysosomal storage diseases, vital cells (such as in heart and brain) may not function normally resulting in the death of the diseased person.
Peroxisomes, which are smaller than lysosomes, also contain enzymes. Peroxisomes normally absorb and neutralize certain toxins such as hydrogen peroxide (H2O2) and alcohol. Liver cells contain considerable peroxisomes that remove and neutralize toxins absorbed from the intestinal tract. Some xenobiotics can stimulate certain cells (especially liver) to increase the number and activity of peroxisomes. This, in turn, can stimulate the cell to divide. The xenobiotics that induce the increase in peroxisomes are known as "peroxisome proliferators." Their role in cancer causation are discussed in theCancer sectionof ToxTutor.
Mitochondriaprovide the energy for a cell (required for survival), by a process involving ATP synthesis. If a xenobiotic interferes with this process, the death of the cell will rapidly ensue. Many xenobiotics are mitochondrial poisons.
Examples of poisons that cause cell death by interfering with mitochondria include cyanide, hydrogen sulfide, cocaine, DDT, and carbon tetrachloride.
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Knowledge Check (Solutions on next page)
1) There are several different types of cellular organelles. The very small structures(fixed to the endoplasmic reticulum or free within the cytoplasm)that consist of RNA and proteins, and function in protein synthesis, are: a) Nucleus b) Peroxisomes c) Lysosomes d) Ribosomes
2) The organelle that produces nearly all (95%) of the energy required by the cell is the: a) Nucleolus b) Golgi apparatus c) Mitochondria d) Centioles
1) Ribosomes-This is the correct answer. Ribosomes are very small structures that consist of RNA and proteins. Some ribosomes are fixed, i.e., bound to the endoplasmic reticulum. Other ribosomes are free and scattered within the cytoplasm. They function in protein synthesis.
2) Mitochondria-This is the correct answer. Mitochondria are oval organelles bound by a double membrane with inner folds enclosing important metabolic enzymes. They produce nearly all (95%) of the ATP and energy production required by the cell.
Most toxic effects are initiated by chemical interactions in which a foreign chemical or physical agent interferes with or damages normal chemicals of the body. This interaction results in a body chemical being unable to carry out its function in maintaining homeostasis.
There are many ways this can happen; for example:
Interference with absorption or disposition of an essential nutrient.
Interference with nerve transmission (seeNeurotoxicity).
Types of Physiological Chemicals There are three categories of chemicals normally functioning in the body:
Elements— substances made up of only one atom; for example:
Hydrogen
Calcium
Singlet oxygen (O)
Inorganic compounds— simple molecules that usually consist of one or two different elements; for example:
Water (H2O) - N.B - written with 2 as a subscript
Carbon dioxide (CO2) - N.B - written with 2 as a subscript
Bimolecular oxygen (O2) - N.B - written with 2 as a subscript
Sodium chloride (NaCl)
Organic compounds— substances that contain covalently-bonded carbon and hydrogen and often other elements; for example:
Sugars
Lipids
Amino acids
Proteins
Elements Elementsare components of all chemical compounds. Of the 92 naturally occurring elements, only 20 are normally found in the body. Seven of these, carbon, oxygen, hydrogen, calcium, nitrogen, phosphorous, and sulfur make up approximately 99% of the human body weight. In most cases, the elements are components of inorganic or organic compounds. However, in a few cases the actual elements may enter into chemical reactions in the body, such as oxygen during cell respiration, sodium in neurotransmission, and arsenic and lead in impaired mitochondrial metabolism.
Inorganic Compounds Inorganic compoundsare important in the body and responsible for many simple functions. The major inorganic compounds are water (H2O), bimolecular oxygen (O2), carbon dioxide (CO2), and some acids, bases, and salts. The body is composed of 60–75% water. Oxygen is required by all cells for cellular metabolism and circulating blood must be well oxygenated for maintenance of life. Carbon dioxide is a waste product of cells and must be eliminated or a serious change in pH can occur, known as acidosis. A balance in acids, bases, and salts must be maintained to assure homeostasis of blood pH and electrolyte balance.
Organic Compounds Organic compoundsare involved in nearly all biochemical activities related to normal cellular metabolism and function. The mechanisms by which xenobiotics cause cellular and biochemical toxicity are predominantly related to changes to organic compounds. The main feature that differentiates organic compounds from inorganic compounds is that organic compounds always contain carbon. Most organic compounds are also relatively large molecules. There are five major categories of organic compounds involved in normal physiology of the body:
Figure 1. Organic compounds are involved in numerous structures and functions of biochemical processes in the body (Image Source: NLM)
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Carbohydrates Mostcarbohydratesserve as sources of energy for the body. They are converted to glucose, which in turn is used by the cells in cellular respiration. Other carbohydrates become incorporated as structural components of genetic macromolecules.
For example, deoxyribose is part of DNA, the genetic material of chromosomes, and ribose is part of RNA, which regulates protein synthesis.
Lipids Lipidsare essential substances of all cells and serve as a major energy reserve. They may be stored as fatty acids or as triglycerides. Other types of lipids are the steroids and phospholipids.
Cholesterol is a lipid that is a component of cell membranes and is used to produce sex hormones such as testosterone and estrogen.
Phospholipids serve as the main components of the phospholipid bilayer cell membrane.
Proteins The most diverse and abundant of organic compounds in the body is the group ofproteins. There are about 100,000 different kinds of proteins, which account for about 20% of the body weight. The building blocks for proteins are the 20 amino acids, which contain carbon, hydrogen, oxygen, nitrogen, and sometimes sulfur. Most protein molecules are large and consist of 50–1000 amino acids bonded together in a very precise structural arrangement. Even the slightest change in the protein molecule alters its function.
Proteinsperform a large variety of important functions. Some proteins have a structural function such as the protein pores in cell membranes, keratin in skin and hair, collagen in ligaments and tendons, and myosin in muscles.
Hemoglobin and albumin are proteins that carry oxygen and nutrients in the circulating blood.
Antibodies and hormones are proteins.
A particularly important group of proteins are the enzymes.
Enzymes,which are catalysts, are compounds that accelerate chemical reactions, without themselves being permanently changed. Each enzyme is specific in that it will catalyze only one type of reaction. Enzymes are vulnerable to damage by xenobiotics and many toxic reactions occur by changing the shape of the enzyme ("denaturation") or by inhibiting the enzyme ("inhibition").
Nucleic Acids Nucleic acidsare large organic compounds that store and process information at the molecular level inside virtually all body cells. Three types of nucleic acids are present:
Deoxyribonucleic acid (DNA)
Ribonucleic acid (RNA)
Adenosine triphosphate (ATP)
Nucleic acids are very large molecules composed of smaller units known as nucleotides. A nucleotide consists of a pentose sugar, a phosphate group, and four nitrogenous bases. The sugar in DNA is deoxyribose while the bases are adenine, guanine, cytosine, and thymine. RNA consists of the sugar, ribose, plus the four bases adenine, guanine, cytosine, and uracil. These two types of molecules are known as the molecules of life. For without them, cells could not reproduce and animal reproduction would not occur.
DNA is in the nucleus and makes up the chromosomes of cells. It is the genetic code for hereditary characteristics. RNA is located in the cytoplasm of cells and regulates protein synthesis, using information provided by the DNA. Some toxic agents can damage the DNA causing a mutation, which can lead to the death of the cell, cancer, birth defects, and hereditary changes in offspring. Damage to the RNA causes impaired protein synthesis, responsible for many types of diseases. Figure 2 shows the structure of DNA and RNA. Note that DNA is double-stranded and known as the double helix. RNA is a single strand of nucleotides.
High-Energy Compounds Adenosine triphosphate (ATP)is the most important high-energy compound. It is a specialized nucleotide located in the cytoplasm of cells that serves as a source of cellular energy. ATP contains adenine (amino acid base), ribose (sugar), and three phosphate groups. ATP is created from adenine diphosphate using the energy released during glucose metabolism. One of the phosphates in ATP can later be released along with energy from the broken bond induced by a cellular enzyme.
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Knowledge Check (Solutions on next page)
1) A substance in the body that contains covalently-bonded carbon and hydrogen is an: a) Organic compound b) Inorganic compound c) Element
2) The nucleic acid located in the nucleus, which makes up the chromosomes of cells, is: a) ATP b) RNA c) DNA
1) Organic compound-This is the correct answer. Organic compounds contain covalently-bonded carbon and hydrogen and often other elements. For example, sugars, lipids, amino acids, and proteins are organic compounds.
2) DNA-This is the correct answer. DNA is in the nucleus and makes up the chromosomes of cells. It is the genetic code for hereditary characteristics.
What We've Covered This section made the following main points:
In most cases, toxic substances exert their harmful effects directly on specific cells or biochemicals within the affected organ (specific toxic effects).
Homeostasis is the ability of the body to maintain relative stability and function despite drastic changes in the external environment or one portion of the body. The primary components of homeostasis include:
Stimulus — a change in the environment.
Receptor — the site within the body that detects or receives the stimulus.
Control center — the operational point at which the signals are received, analyzed, and an appropriate response is determined.
Effector — the body site where a response is generated.
Feedback mechanisms — methods by which the body regulates the response
The basic structure and functional organization of the human body is: Chemicals → Cells → Tissues → Organs → Organ Systems → Organism
The human body consists of eleven organ systems.
Tissues in organs are precisely arranged to work in harmony to perform organ functions.
There are four types of tissues in the body:
Epithelial tissue protects, absorbs, and secretes substances, and detects sensations.
Connective tissue provides support and holds body tissues together.
Muscle tissue has the ability to contract.
Nerve tissue conducts electrical impulses and conveys information from one area of the body to another.
The cell is the smallest component of the body that can perform all of the basic life functions.
Cell components that are most susceptible to cellular damage include the cell membrane, nucleus, ribosomes, peroxisomes, lysosomes, and mitochondria.
The three categories of physiological chemicals normally functioning in the body are:
Elements — made up of only one atom (examples include hydrogen and oxygen).
Inorganic compounds — simple molecules made up of one or two different elements (examples include water and carbon dioxide).
Organic compounds — contain covalently-bonded carbon and hydrogen and often other elements (examples include DNA, RNA, ATP, and proteins).
Toxicokineticsis essentially the study of "how a substance gets into the body and what happens to it in the body." Before this term was used, the study of the kinetics (movement) of chemicals was originally conducted with pharmaceuticals and the term pharmacokinetics became commonly used. Similarly, toxicology studies were initially conducted with drugs. Toxicokinetics deals with what the body does with a drug when given a relatively high dose relative to the therapeutic dose. Read more aboutdifferences between pharmacokinetics and toxicokinetics.
Processes
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Four processes are involved in toxicokinetics:
Absorption— the substance enters the body.
Distribution— the substance moves from the site of entry to other areas of the body.
Biotransformation— the body changes (transforms) the substance into new chemicals (metabolites).
Excretion— the substance or its metabolites leave the body.
The science of toxicology has evolved to include environmental and occupational chemicals as well as drugs. Toxicokinetics is thus the appropriate term for the study of the kinetics of all substances at toxic dose/exposure levels.
Frequently the terms toxicokinetics, pharmacokinetics, or disposition have the same meaning. Disposition is often used in place of toxicokinetics to describe the movement of chemicals through the body over the course of time, that is, how the body disposes of a xenobiotic.
The disposition of a toxicant and its biological reactivity are the factors that determine the severity of toxicity that results when a xenobiotic enters the body. The most important aspects of disposition include:
Duration and concentrationof a substance at the portal of entry.
Rate and amountof the substance that can be absorbed.
Distributionin the body andconcentrationof the substance at specific body sites.
Efficiencyof biotransformation and nature of the metabolites.
Abilityof the substance or its metabolitesto pass through cell membranesand come into contact with specific cell components (for example, DNA).
Amount and duration of storageof the substance (or its metabolites) in body tissues.
Rate and sites of excretionof the substance.
Age and health statusof the person exposed.
Here are some examples of how toxicokinetics of a substance can influence its toxicity:
Absorption— A highly toxic substance that is poorly absorbed may be no more hazardous than a substance of low toxicity that is highly absorbed.
Biotransformation— Two substances with equal toxicity and absorption may differ in how hazardous they are depending on the nature of their biotransformation. A substance that is biotransformed into a more toxic metabolite (bioactivated) is a greater hazard than a substance that is biotransformed into a less toxic metabolite (detoxified).
Inter-Related Processes of Absorption, Distribution, Biotransformation, and Elimination Absorption, distribution, biotransformation, and elimination are inter-related processes as illustrated in Figure 2 below. After the substance is absorbed, it is distributed through the blood, lymph circulation, and extracellular fluids into organs or other storage sites and may be metabolized. Then, the substance or its metabolites are eliminated through the body's waste products.
Figure 2. Absorption, Distribution, Metabolism, and Elimination (Image Source: NLM)
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What are Transporters? Transporters, also called transporter proteins, play an important role in the processes of absorption, distribution, metabolism, and elimination (ADME). They are important to pharmacological, toxicological, clinical, and physiological applications. For example:
In theliver— transmembrane transporters, together with drug metabolizing enzymes, are important in drug metabolism and drug clearance by the liver. Xenobiotics, endogenous metabolites, bile salts, and cytokines affect the levels (or "expression") of these transporters in the liver. Adverse reactions in the liver to a xenobiotic such as a drug could be caused by genetic or disease-induced variations of transporter expression or drug-drug interactions at the level of these transporters.
In thekidneys— renal proximal tubules are targets for toxicity partly because of the expression of transporters that mediate the secretion and reabsorption of xenobiotics. Changes in transporter expression and/or function could enhance the accumulation of toxicants and make the kidneys more susceptible to injury, for example, when xenobiotic uptake by carrier proteins is increased or the efflux of toxicants and their metabolites is reduced. The list of nephrotoxic chemicals is a long one and includes:
Environmental contaminants such as some hydrocarbon solvents, some heavy metals, and the fungal toxin ochratoxin.
Some antibiotics.
Some antiviral drugs.
Some chemotherapeutic drugs.
The competition of xenobiotics for transporter-related excretion and genetic polymorphisms affecting transporter function affect the likelihood of nephrotoxicity.
Because of concerns that such changes to transporter expression and function can adversely affect clinical outcomes and physiological regulation, increased drug transporter activity is important to study and understand. There is clinical and laboratory research includingin vitro,ex vivo, andin vivostudies that shows how powerful drug-drug interactions can be.
For example, drugs might compete with each other for binding to a transporter, which can lead to changes in serum and tissue drug levels and possible side effects.
This is one possible explanation for the rare occurrence of potentially severe toxicity when the drug methotrexate and nonsteroidal anti-inflammatory drugs are given at the same time.
The drug probenecid, which competitively inhibits some transporters, has been used to increase the half-life of antibiotics such as penicillin and antiviral drugs and improve their therapeutic value.
Pharmacokinetics and Toxicokinetics: Now and in the Future Current research priorities suggest that we can anticipate important strides in the following areas of pharmacokinetics and toxicokinetics:
An increased understanding of human variability of pharmacokinetics and pharmacodynamics in the population.
Further exploration of mode of action hypotheses(MoA).
Is a MoA the same as a MOA? No. Amode of action (MoA)describes a functional or anatomical change, at the cellular level, resulting from exposure to a substance. Amechanism of action (MOA)describes changes at the molecular level.
Further application of biological modeling in the risk assessment of individual chemicals and chemical mixtures.
Further identification and discussion of uncertainties in the modeling process.
Further use of "Reverse Toxicokinetics," also called"IVIVE" (In vitrotoin vivoextrapolation).IVIVEin vitrodata to estimate exposures that could be associated with adverse effectsin vivo.
The Toxicology Mentoring and Skills Development Training Program is a 5-year program funded by the National Institutes of Health to provide career development opportunities for STEM undergraduates from diverse underserved backgrounds. Successful candidates will complete the 1 yr. program from their home institutions. It is mostly a virtual program accessible 24/7. The goal of the NIH funding is to support educational activities that complement and/or enhance the training of a diverse workforce to meet the nation’s biomedical, behavioral and clinical research needs. Toxicology is an essential component of the nation’s biomedical research enterprise. However, there is a critical lack of underrepresented populations in toxicology.
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The University of California, Davis, The Society of Toxicology, Iowa State University, Tuskegee University, the Ohio State University, and Michigan State University are collaborating to deliver this unique Toxicology Mentoring and Skills Development Training program targeting undergraduate underrepresented populations to build a pathway for entering graduate school and the toxicology workforce. Core concepts of the program are structured mentoring activities, skills development, and public outreach in toxicology.
Student Applications for 2022-23 are now closed.
Mentors application and requirements can be found here.
This is a one-year toxicology mentoring and skills development training program. For the structured mentoring component, mentees are matched 1:1 with mentors primarily from industry, government, and nongovernmental organizations. Mentors are trained to provide a holistic mentoring experience to mentees. Mentees shadow mentors at their places of work. Participants will meet at the University of California Davis to open the program, attend the Society of Toxicology Annual Meeting in San Diego, California, and participate in capstone activities at Tuskegee University, Tuskegee, Alabama. There is travel, per diem, room and board support provided to all mentees and mentors for all program activities.
Skills development includes sessions at the inaugural workshop at University of California, Davis, completion of case study modules in toxicology, knowledge gained through job shadowing activities, and activities to enhance communication skills.
One of the challenges of recruiting undergraduates into toxicology graduate research programs is a lack of toxicology courses at the undergraduate level. Course content developed through this program is accessible to other undergraduate students, educators, and the interested public, which will increase the availability of an introduction to the discipline of toxicology and interest in toxicology careers.
Adamarie S. Marquez Acevedo is a junior at Iowa State University where she studies Animal Sciences and Global Resource Systems. Originally from Carolina, Puerto Rico her desire on expanding her horizons brought her to the Midwest. During her time at college, she hopes to work within the dairy industry in hopes of learning how to lessen it's ecological footprint! She also loves working with farmers and problem solving challenges that arise within agriculture. She is hoping that learning about toxicology will not only help her improve her critical analysis skills, but will also enlighten her on how to make sure toxins from dairy farms do not harm the surrounding ecosystems.
Hi, my name is Adriana Le Compte. I am a Junior majoring in Biology at Iowa State University. I was born and raised in Ponce, Puerto Rico, and recently studied abroad in Rome, Italy this past spring. Some of my hobbies include being outdoors, taking pictures, traveling, reading, and making other people laugh. I'm also very excited to be a part of the ToxMSDT program this year.
Hi! My name is Tej Akavaram. I am currently a sophomore in chemical engineering at Iowa State University in Ames, Iowa. I’m from West Des Moines, IA where I’ve lived basically my entire life. I decided to pursue chemical engineering because math and science, especially chemistry, were my favorite subjects in high school. On campus, I have the privilege of working with faculty currently involved with biomedical research. I am also involved with an on-campus organization called BioBus, tasked with the responsibility of recycling used cooking oil into biofuel for our campus bus system. Following my undergraduate degree, I hope to pursue a doctorate and conduct research in the field of pharmaceuticals. I believe that having an understanding of toxicology will better prepare me for a career in the pharmaceutical industry since I will be working with various types of compounds whose effects on organisms and the environment are important to be aware of.
Prof. Bonaventure A. Akinlosotu is a Regulatory Scientist/Environmental Protection Specialist at U.S. EPA, Office of Chemical Safety and Pollution Prevention (OCSPP), Office of Pesticides Program (OPP), Registration Division (RD), Chemistry, Inerts and Toxicology Assessment Branch (CITAB). He serves as (1) the Agency’s acute toxicity data review “Point of Contact - POC” for NAFTA and Global Joint Review (GJR) for the registration of pesticide chemicals/products; (2) the Agency’s expert on Child Resistant Packaging (CRP) for pesticide products. Prof. Akinlosotu also served as technical lead for the US/Canada Joint Project on “OECD Guidance for Waiving or Bridging of Mammalian Acute Toxicity Tests for Pesticides”.
Dr. Lauren Aleksunes is a board-certified toxicologist with expertise in both basic and clinical toxicology. The research of her laboratory focuses on mechanisms of toxicity including the role that membrane transporters play in regulating cellular responses to drugs and environmental chemicals. Dr. Aleksunes is particularly interested in elucidating mechanisms underlying heterogeneity in toxicity responses due to life stage, genetics, diet, environment, and pre-existing disease.Dr. Aleksunes is Director of the T32-funded Joint Graduate Program in Toxicology and Lead of the Workforce Development Core of the NJ Alliance for Clinical and Translational Sciences (NJACTS) CTSA Program. She is also Director of the NIH R25-funded Summer Undergraduate Research Fellowship (SURF) at Rutgers that trainees the next generation of toxicologists.
Dr. Deloris Alexander is a Professor in Microbiology and Molecular Biology and the Director of Integrative Biosiences PhD Program at Tuskegee University, Alabama. Dr. Alexander has been intimately involved in the launching of Tuskegee’s PhD Program in Integrative Biosciences (IBS), which seeks to address the lack of well-trained, graduate-level, U.S. scientists. Serving as the program Director, she has worked with integrative teams in procuring grants to cover student training and to improve institutional and research infrastructure. The IBS program has provided a mechanism for fostering a more intensive biomedical research and training atmosphere at Tuskegee. Dr. Alexander has many research interests, all related to microbial ecology. This area of research has implications for biomedical challenges as well as agricultural and biofuels applications. Dr. Alexander, who also serves as the Deputy Director for Research for Tuskegee University’s Health Disparities Institute for Research and Education (HDIRE), has additionally been actively involved in research that seeks to reduce health disparities as it relates to the Alabama Black Belt Counties (ABBC). Dr. Alexander is also a joint faculty member in the College of Agriculture, Environment and Nutrition Sciences (CAENS) and the College of Veterinary Medicine, and Allied Health (CVMNAH). Her research fields are Parasitology and Health Disparities.
Dr. Chidozie (Dozie) Amuzie is a Scientific Director within the global pathology team at Janssen R&D. He received a PhD comparative medicine and integrative biology, combined with integrative toxicology at Michigan State University in 2009, and subsequently completed an anatomic pathology residency the same institution. He is board-certified in both toxicology and pathology, and enjoys combining the tools of toxicology and pathology to solve scientific problems. In his current role, Dozie provides scientific input in the design, conduct, and interpretation of experiments that focus on characterizing the safety of novel therapeutics and/or understanding mode(s) of action for toxicity in nonclinical studies. He also helps to ensure that pathology data from FIH-enabling studies for Janssen’s biologics portfolio are integrated and decision-quality. In addition, he is the therapeutic area pathologist for Janssen’s immunology portfolio, providing end to end nonclinical pathology support for the portfolio. Prior to joining Janssen R&D, Dozie was the Associate Director of Pathology at MPI Research (Mattawan, MI), where he spent about 5 years, in various pathology roles, working on diverse nonclinical safety assessment studies, and providing scientific leadership for the biomarker and investigative pathology unit. Dozie also assisted the Director of Pathology in pathology operations and pathologists. Dozie has authored/co-authored 5 books/book chapters, 15 peer-reviewed manuscripts and over 25 abstracts in toxicology and related disciples- immunotoxicology, biomarker identification and use, toxicokinetics, biopharmaceutical safety assessment, and animal models of cardiovascular and metabolic diseases. He has been invited to speak at several toxicology and pathology conferences globally. He is active in professional toxicology and toxicologic pathology organizations, and is currently the Vice President the Toxicology and Exploratory Pathology Specialty Section within the Society of Toxicology and Chair of the Immune System Interest Group within the Society of Toxicologic Pathology.
Dr. Ansari completed his Ph.D. from Kanpur University, India in the area of Reproductive Toxicology and conducted several postdoctoral studies at University of Nebraska Medical Center, University of Pittsburgh and Case Western Reserve University. Dr. Ansari was Research faculty at University of Arkansas for Medical Sciences, Little Rock, AR and New York Medical College, Valhalla, NY. Dr. Ansari has published more than 30 peer-reviewed articles in reputed journals, has written book chapters and contributed to text books. He has presented his research work in several meetings of national and international repute. Dr. Ansari serves as a reviewer for several journals and is the editorial board member for many journals. Presently, his research focuses on defining the role of environmental factors especially xenobiotics in regulation of human angiotensinogen gene and CYP11B2 as the models of hepatotoxicity and hypertension.
Are you interested in joining the ToxMSDT program?
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We are now recruiting undergraduate students from around the United States to participate in the 2021-2022 program. The Student Application and Reference Form deadline is May 1, 2021.
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Eligibility
STEM major
Minimum cumulative GPA of 3.0
At least a second-year undergraduate student
Completion of at least one semester of general biology and general chemistry
Currently enrolled in an accredited undergraduate institution and continuing enrollment for the 2021-2022 academic year
Member of a group under-served in the biomedical sciences (for example, under-represented racial/ethnic groups; those from disadvantaged backgrounds such as low socioeconomic status, or grew up in a rural or inner-city setting; NIH notice).
The tremendous advancement at technological level has made it possible to generate data at “high-throughout” levels. It has also enabled scientists to study toxicological processes from a more holistic approach. Instead of answering single questions at a time, a more comprehensive approach is now being applied to understand toxicological responses. “Systems” approach is being effectively used in industry, government and clinical settings.
In biopharmaceutical/chemical industries, thousands of molecules are screened in the early discovery phase to select target compounds with efficacy. Similarly, compounds can also be screened based on their toxicity fingerprints. Molecular fingerprints generated for each class of compounds/ specific chemistries can be used to screen compounds for different indications for future uses. This has also significantly reduced the time and increased efficiency in discovery programs in industry settings.
The government has also been using “the systems” approach successfully for safety assessment programs. Efforts such as the ToxCast and Tox 21 are examples where “systems” toxicology is being efficiently used to prioritize animal testing towards chemicals that pose the greatest risk to human health and safety.
In the clinical setting more and more information is becoming available via the “systems” approach for specific disease states that enable physicians and researchers to develop personalized medicines based on specific needs of patients.
While, all these efforts mark the beginning of a very promising future, there is still a lot of research necessary to utilize these tools and technologies to their full potential.
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References
Systems Biology in Toxicology and Environmantal Health. First Edition. Editor Rebecca Fry. Chapters 1 and 4
Incorporating Human Dosimetry and Exposure into High-Throughput In Vitro Toxicity Screening. Rotroff et al., Toxicological Sciences; 117(2), 348–358 (2010)
Danniel Arriaga was born in Texas but raised in the freezing winters of Iowa, currently studying Chemical Engineering and Chemistry at Iowa State University. Serving as a TA in general chemistry, his understanding of the subject has improved along with his communication and chalkboard skills. While he would love to spend his evenings and weekends doing chemistry problems, his interests in creative writing, music, and art do appear to take some priority. Danniel's career interests are in the realm of pharmaceuticals meshing well with toxicology topics.
References The following books were used during the development of the original Toxicology Tutors which were launched in 1998. New material based on books and journal articles was added in 2016 and 2017.
Casarett LJ, Klaassen CD, Amdur MO, Doull J, eds. Casarett and Doull's Toxicology: The Basic Science of Poisons. New York, NY: McGraw-Hill, Health Professions Division; 1996.
My name is Danae Biddle from Los Angeles, California. I currently attend Tuskegee University, Alabama where I am junior chemistry major. My favorite class so far has been organic chemistry. My professor taught it in such a way that was enjoyable and easier to understand. For fun I enjoy singing, swimming, and spending time with family and friends. I hope to give back to the communities that I have grown in by becoming a teacher after retiring from my future career in toxicology.
Bethany Bogan is a native of Snellville, Georgia. She is currently a junior at Georgia Southern University, where she is pursuing a degree in Chemistry, with a concentration in Biochemistry, and a minor in Digital Photography. On campus, Bethany serves as the president of the National Organization of Black Chemist and Chemical Engineers, and the historian of the Alpha Chi Sigma Professional Chemistry Organization. Within the ToxMSDT program, she is most looking forward to meeting other students who are also interested in the field of toxicology, and gain more professional insight on the best way to approach future graduate-level Toxicology programs.
The Graduate Group in Pharmacology and Toxicology (PTX) at the University of California, Davis, is an interdisciplinary program that combines coursework and experimental training in modern approaches to pharmacological and toxicological problems.
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Now in its fourth year, the Envision UC Davis campus visit program enables California's most promising grad school hopefuls to develop an understanding and appreciation of graduate education. The program sponsors California senior undergraduates and recent bachelor's degree grads for an action-packed weekend on the Davis campus, allowing them to envision their future as a graduate student.
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In PREP@UC Davis, we prepare postbaccalaureate students from disadvantaged backgrounds and historically marginalized groups (including individuals who have a disability that limits major life activities) to succeed in PhD programs in the biomedical sciences.
The University of Illinois’ Research Training Program in Toxicology and Environmental Health is a part of the larger, campus-wide Interdisciplinary Environmental Toxicology Program (IETP), which provides toxicology training to students and postdoctoral fellows trained in basic sciences such as endocrinology and reproductive biology. Our program is ideal for students who are interested in applying their basic knowledge in four areas of toxicological research: reproductive/endocrine toxicology, neurotoxicology, nutritional toxicology, and nanotoxicology. The Research Training Program is a T32 NIEHS Environmental Toxicology Training Program.
Dr. Clay Comstock is a faculty member in the Department of Life Sciences at Salish Kootenai College (SKC), a tribal college in western Montana. He is responsible for advising undergraduates in the environmental health sciences track and teaches core departmental courses in chemistry such as introductory, general, organic, and biological. He also teaches environmental chemistry and environmental toxicology courses, that infuse indigenous perspectives, to seniors in the environmental health sciences track.
Committed to providing undergraduates a competitive research experience, he has mentored undergraduates at every level of his education and training. He currently heads an R25 from the NIH-NIEHS to advance the resource and research opportunities for indigenous students in the environmental health sciences. He is also funded by the NSF to evaluate methyl-mercury levels in the local watershed and has an ongoing collaboration with Montana Tech to understand wildfire smoke exposure and control on the Flathead Indian Reservation.
Complementing his environmental-based teaching and research endeavors, he has previously served as a full-time, professional editor for well-respected journals devoted to the molecular mechanisms and epidemiology of cancer. Dr. Comstock’s previous editorial experience combined with his current service on the Institutional Review Board (IRB) for SKC provides additional mentoring capacity in the areas of publishing ethics and research integrity.
For more information, please reach out to the program manager Pia van Benthem. Pia van Benthem School of Veterinary Medicine Department of Molecular Biosciences University of California Davis Davis, CA 95616-8741 Email: toxmsdt@gmail.com
Dr. de Conti is a staff fellow researcher in the U.S. Department of Health and Human Services at the National Center for Toxicological Research (NCTR) of the U.S. Food and Drug Administration (FDA). Dr. de Conti has knowledge in key areas for cancer research, specifically, in the field of elucidation of mechanism(s) by which dietary factors and other environmental exposures that contributes for development or prevention of cancer. Dr. de Conti received a graduate degree in Pharmacy from the Faculty of Pharmacy Oswaldo Cruz, and Ph.D. in Food Science, from the University of Sao Paulo, Brazil. After this period Dr. de Conti moved to United States for a postdoctoral position at FDA-NCTR. In 2015, she was selected her to be a member of the NCTR research program to investigate the contribution of epigenetic changes to the process of cancer development. Dr. de Conti is author of 28 peer peer-reviewed articles. During recent years, significant effort has been devoted to elucidating the fundamental mechanisms associated with the development of liver cancer, which incidence and mortality steady increases in the United States. At NCTR, Dr. de Conti, initially studied the mechanisms by which bioactive food components exert cancer-preventing activity. She then expanded the scope of her investigations to study the mechanisms by which furan, a food contaminant, can induce cancer. Specifically, she conducted an extension of National Toxicology Program study on furan. The average exposure of the U.S. consumers to furan is considered high. Importantly, relatively high furan levels have been detected in infant formulas and baby foods. Despite a large body of evidence for furan-induced liver cancer, the mechanism leading to liver tumor development is still unclear. Dr. de Conti, developed and applied high-throughput methodologies, such as microarrays for global gene expression analysis, chromatin immunopreciptation (Chip) and methylated DNA immunopreciptation analysis (MeDIP), to provide significant new information about new epigenetic targets. Specifically, Dr. de Conti determined specific epigenetic alterations associated with furan carcinogenicity, which represent novel targets for cancer prevention. These studies provide important baseline information for the FDA to formulate guidelines that consider the impact of epigenetic changes in evaluating susceptibility to human diseases, including cancer. Dr. de Conti is an elected member of the Society of Toxicology (SOT), a professional and scholarly organization of scientists in the U.S. and abroad, which mission is “developing knowledge for the improvement of the health and safety of living beings, as well as, and the protection of their environment.” Moreover, Dr. de Conti is the editor in-chief of the Hispanic Organization of Toxicologist (HOT) newsletter. HOT is Special Interest Group within the SOT. Its main goal is to provide a forum, for the awareness and dissemination of toxicological information and issues as they relate to the Hispanic/Latino community.
Dr. Ana-Paula Correia is a Professor of Learning Technologies in the Department of Educational Studies at the Ohio State University. She is also the Director for the Center on Education and Training for Employment. She has more than 25 years of experience in learning design and instructional systems technology. Specifically, Dr. Correia has expertise in distance education, online and mobile learning, collaborative learning and entrepreneurial education. She has presented more than 150 academic papers around the world and published over 90 refereed articles and book chapters.
She has been involved with research projects funded by Bill & Melinda Gates Foundation, National Science Foundation, U.S. Department of Agriculture, Pappajohn Center/Kauffman Foundation, U.S. Department of Education and National Institutes of Health.
During her academic career, Dr. Correia’s research was awarded for excellence several times by the Association for Educational Communication and Technology as well as the Association for the Advancement of Computing in Education. Dr. Correia earned her PhD from Indiana University-Bloomington.
Ms. Angela Curry currently serves as a specialist/consultant to agency staff and the public concerning toxicology and risk assessment issues. She makes technical recommendations regarding agency permitting, monitoring, and enforcement activities based on analysis and interpretation of environmental and toxicologic data. Ms Curry also serves as an expert toxicologist/risk assessor in agency hearings, courts proceedings, and public meetings and prepares technical reports and fact sheets on chemicals posing risks to human health or threats to the environment. She has co-authored 3 scientific publications, and is also a member of Delta Sigma Theta Sorority, Incorporated.
Dr. Jared Danielson is the Associate Dean for Academic and Student Affairs at the Iowa State University College of Veterinary Medicine (ISUCVM), and is a Professor in the Department of Veterinary Pathology. He received a Bachelor’s degree in English from Brigham Young University, a Master’s degree in Instructional Design, Development and Evaluation from Syracuse University, and a PhD in Curriculum and Instruction from Virginia Tech. Jared has twenty-one years of experience designing educational interventions and assessments in Veterinary Medical Education, emphasizing practical research-based solutions to learning and assessment problems in higher education. Jared has served in a variety of leadership roles nationally and internationally, including as chair of the Academic Affairs Council of the AAVMC, and as a member of the AAVMC’s Council on Outcomes-based Veterinary Education. He conducts research in the areas of diagnostic problem solving and veterinary medical education and assessment, publishing his results in journals such as Computers and Education, Educational Technology, Research and Development, Computers in Human Behavior, the Journal of the American Veterinary Medical Association, the Journal of Veterinary Medical Education, and Frontiers in Veterinary Science. He reviews for numerous scholarly journals, and is an Associate Editor for Frontiers in Veterinary Science. He has published 64 journal articles, proceedings and/or book chapters and has presented nationally and internationally to hundreds of audiences. As PI or co-PI Jared has directed or co-directed 31 funded research projects.
Dr. Das has expertise, leadership, training, and motivation to successfully carry out research in toxicology and molecular cancer stem cell biology. He has a broad background in area of molecular signaling pathways of cancer stem cells, and anti-cancerous drugs, apoptosis, antioxidant and free radical research. Dr. Das research includes molecular cancer stem cell biology. As postdoctoral cancer researcher on several universities, institutes and NIH, NIA-funded grants, he did his research work in cancer treatment, anti-cancerous drug development, signaling pathway detection for cancer treatment and his research works were documented over time as in several publications. In addition, he successfully collaborated with other scientists, and produced several peer-reviewed publications as co-author from these collaborations.
Dr. Aline de Conti received a graduate degree in Industrial Pharmacy from the Oswaldo Cruz College in Sao Paulo, Brazil in 2005 and a Ph.D. degree in Food Sciences from the University of Sao Paulo, Sao Paulo, Brazil in 2009. During 2009-2012, Dr. de Conti conducted postdoctoral research on nutrition and cancer at University of Sao Paulo, Sao Paulo, Brazil, including six months as a Visiting Researcher at NCTR’s Division of Biochemical Toxicology. In 2012, Dr. de Conti joined NCTR as postdoctoral fellow and in 2015 she was converted to an FDA Staff Fellow. Dr. de Conti has published more than 40 research articles and 2 book chapters and has served as a reviewer for more than 30 scientific articles. In 2018, she received the NCTR Scientific Achievement Award as Outstanding Junior Investigator and the NCTR Director’s Award for providing outstanding service to NCTR/FDA. She has been invited to be a member of a working group for International Agency for Cancer Research to evaluate carcinogenic risks to humans. She is the vice-president of the Hispanic Organization of Toxicologists, a Special Interest Group of the Society of Toxicology. Dr. de Conti’s research interests are related to the identification of molecular mechanisms of carcinogenesis, with a focus on the role of epigenetic alterations. Dr. de Conti has investigated the role of epigenetic alterations in liver carcinogenesis induced by several non-genotoxic and genotoxic carcinogens. The results of Dr. de Conti’s research demonstrate the importance of epigenetic alterations as contributing factors to carcinogenesis and indicate that epigenetic alterations may represent a class of biomarkers with a great potential for the identification of exposure status, damage response, and/or disease state, and may become an essential tool for hazard identification. Another major area of Dr. de Conti’s research has been investigating the genomic and epigenomic drivers of nonalcoholic fatty liver disease (NAFLD) and NAFLD-associated liver cancer. Currently, NAFLD is the most prevalent form of chronic liver disease in the United States and other countries worldwide, affecting approximately one-quarter of the world's population. Using in vivo models of NAFLD-related hepatocarcinogenesis, Dr. de Conti demonstrated the significance of epigenetic abnormalities, including alterations in histone modifications, DNA methylation, and chromatin structure, in the development of NAFLD-related HCC. In addition, Dr. de Conti is interested in the elucidation of chemopreventive bioactive food components against liver carcinogenesis, including farnesol, β-ionone, tributyrin, and folic acid, as well as, in the investigation of the mechanisms of action involved in the prevention of liver cancer.
Dr. Bryan Delaney is a Research Fellow and Toxicologist working at DuPont Pioneer since 2003. He obtained a B.A. in Chemistry from the University of Nebraska, a Ph.D. in Pharmacology and Toxicology at the Medical College of Virginia with Dr. Norbert Kaminski and did a postdoctoral research fellowship at the McArdle Laboratory for Cancer Research at the University of Wisconsin with Dr. Henry Pitot. He specializes in the safety assessment of food and feed ingredients with emphasis on agricultural biotechnology and has authored more than 60 peer reviewed publications in that area. He is a Diplomate of the American Board of Toxicology, a Fellow of the Academy of Toxicological Sciences and has been Editor of the Elsevier journal Food and Chemical Toxicology since 2011.
Thomata Doe is originally from Liberia, West Africa, but her family now resides in Des Moines, Iowa. She is currently a junior at Iowa State University with majors in Nutritional Science and Global Resource Systems with prospective graduation in May of 2018. Her plan after graduation involves attending graduate school with a focus in community or global health. She hopes to work with an agency that works to reduce health disparities and increase prevention efforts among underrepresented groups.
Dr. Dong-suk Kim obtained his doctor of philosophy on toxicology at Iowa State University. His research focused on characterizing the mechanisms by which chronic exposure to manganese induces neurotoxicity similar to Parkinson’s disease. He is currently a post-doctoral research associate. His current research focuses on characterization of mechanisms by which acute exposure to toxic gas such as hydrogen sulfide induces neurotoxicity and neurological sequalae.
Dr. Ingrid Druwe received her BS in Chemistry from Northeastern Illinois University in Chicago, Il. She then attended the University of Arizona where she studied the diabetogenic effects of arsenic and earned her doctorate degree in Pharmacology & Toxicology under the guidance of Dr. Richard R. Vaillancourt. She was the recipient of an NIH Ruth R Kirschstein National Research Service Award (NRSA). Her research also earned the University of Arizona College of Pharmacy Caldwell Award. After earning her doctorate degree Dr. Druwe joined Dr. Bill Mundy’s group at the US EPA National Health Effects and Exposure Laboratory as postdoctoral fellow through a cooperative agreement with the University of North Carolina- Chapel Hill. Under Dr. Mundy’s guidance, Dr. Druwe developed high throughput (HTP) screening assays to screen potential developmental neurotoxicants. She earned the Cellular Dynamics Innovative Research grant award in 2013 for her work using Induced Pluripotent Stem cells to screen chemicals for hazard prioritization. She joined the US EPA National Center for Environmental Assessment (NCEA) as an ORISE postdoctoral fellow in the Fall of 2014. As a postdoctoral trainee Dr. Druwe worked on the Arsenic IRIS assessment and developed Adverse Outcome Pathway’s (AOPs) for various Adverse Outcomes related to arsenic exposure. She has also worked on developing and incorporating Bayesian methods to integrate high throughput data for chemical risk prioritization. Dr. Druwe recently accepted a position as a staff Toxicologist at the US EPA to support Integrated Risk Information System (IRIS) where she will be using her expertise in Toxicology, neurobiology, molecular mechanism biology and bioinformatics to support US EPAs IRIS human health assessments.
Anwar Y. Dunbar is a Regulatory Scientist within the Environmental Protection Agency’s Office of Pesticide Programs Human Health Effects Division, Washington, DC. His duties are those of a Hazard Assessor and Risk Assessor where his role is to identify the critical effect levels for pesticide active ingredients generated by Chemical Registrants and then predicting the potential human exposures. Dr. Dunbar further sits on numerous peer review groups within his division where he helps other scientists in his division with their hazard assessments, determining new data requirements, and the cancer potential of pesticides that show indicators of carcinogenicity. Dr. Dunbar earned his Ph.D. in Pharmacology from the University of Michigan and his Bachelor’s Degree in General Biology from Johnson C. Smith University (JCSU). He published and contributed to numerous research articles in competitive scientific journals reporting on his research from his graduate school and postdoctoral years. Dr. Dunbar is the founder of the Big Words Blog Site (www.bigwordsarepowerful.com) where he writes about education, STEM, and financial literacy-related topics.
Dr.Alex Eapen is the Director of the R&D – Scientific & Regulatory Affairs Team – North America at Cargill. He has over 20 years of experience as a toxicologist and risk assessor for FDA-regulated products. His team, with diverse backgrounds in toxicology, nutrition, dietetics and animal science, are responsible for the safety and regulatory substantiation for new products entering the marketplace. He received his BS degree in biochemistry from the University of Dayton and a PhD in Pharmacology from the University of Iowa. In addition, he completed a post-doctoral fellowship at the Mayo Clinic Division of Oncology Research. He has been an active member of the Society of Toxicology as well as the American College of Toxicology since 2004. He has been board-certified in toxicology since 2005 and currently serves on the Board of Directors for the American Board of Toxicology.
Dr. Betty Eidemiller is the Director of Education for the Society of Toxicology (SOT), headquartered in Reston, Virginia. She received her MS and PhD in Ecology and Evolutionary Biology from the University of California, Irvine, and her bachelor’s degree in biology from Whitman College (Washington). In twenty-plus years with SOT, she has coordinated the range of education-related activities of the Society, from continuing education for professionals, programs for trainees, and outreach to students in grades K-12. A primary focus has been managing activities for educators and undergraduate students, including the SOT Undergraduate Diversity Program, for which she serves as co-investigator on the NIH/NIEHS grant that supports the program. Among current responsibilities, she is the staff liaison for the Faculty United for Toxicology Undergraduate Recruitment and Education (FUTURE) Committee which leads SOT strategic activities for educators and students.
Previous roles with scientific societies include serving as executive director for the Toxicology Education Foundation and for the International Association of Environmental Mutagenesis and Genomics Societies. Dr. Eidemiller also managed faculty initiatives at the American Society for Microbiology. Before her roles in education at the national level, she was division chair at Lamar University, Orange (Texas) where she taught biology, was principal investigator on multiple professional development grants for K-12 science teachers, and conducted science enrichment activities for students. She also held faculty positions at College of the Holy Cross (Massachusetts) and Albion College (Michigan). Publications include a number of education-related articles and environmental impact studies.
M Anthony is a third year dual degree student at The Ohio State University. He is currently pursuing a PhD in Educational Psychology, a Master of Learning Technologies and an interdisciplinary specialization in Quantitative Research, Evaluation and Measurement. M Anthony is a first-generation university student who taught Mathematics and Computer Science which molded his research interests in classroom technology integration, instructional design, curriculum development, project management and teacher technology training especially for persons in underrepresented populations who have limited opportunities for advancements in academia.
My name is Morgan Fair and I’m from Aiken, SC. Currently, I’m a sophomore Chemistry major with a minor in mathematics attending Tuskegee University. This past summer I was selected to participate in the 2016 NSF (REU) Program in the Engineering Research Center for Biorenewables Chemicals for Iowa State. I was also selected to lead a research team that focused on field research and creating educational modules to present at area schools. During the past year I earned certification as a certified Alabama Water Watch monitor which allows me to monitor Alabama’s lakes, streams, and coasts. I am dedicated and have consistent work ethics. I have always been a go-getter and I’m striving to reach the level necessary for me to succeed in life.
Dr. Fernandez-Surumay is a Médico Veterinario (equivalent to DVM), Universidad del Zulia, Maracaibo, Venezuela. He holds a Ph.D. in Toxicology with Minor in Statistics from Iowa State University, Ames, Iowa. He is currently a Principal Scientist in the Dept. of Safety Assessment and Laboratory Animal Sciences, Preclinical Development at Merck & Co., Inc., West Point, Pennsylvania. He works as a toxicologist/study director in GLP and non-GLP animal toxicity studies that enable clinical trials in humans with new candidate drugs. Dr. Fernandez-Surumay is also an electrocardiography (EKG) contributing scientist in toxicity studies and safety assessment representative in interdisciplinary early development research teams for two drug development programs (one investigational, one marketed). Additionally he supervises four scientists in the Toxicological Sciences group within the department and lead/participate in teams continuously working on process improvement within the laboratory.
Dr. Jodi A. Flawsis a Professor in Comparative Biosciences at the University of Illinois-Urbana/Champaign. She received a B.S. in Biology from St. Xavier University, a M.S. in Biology from Loyola University of Chicago, and a Ph.D. in Physiology from the University of Arizona. Following completion of the Ph.D. degree, Dr. Flaws performed postdoctoral research at Johns Hopkins University and the University of Maryland. Following postdoctoral training, Dr. Flaws accepted an Assistant Professor position at the University of Maryland, where she subsequently was promoted to Associate Professor. In 2006, Dr. Flaws accepted a position as Professor of Comparative Biosciences at the University of Illinois-Urbana/Champaign. Dr. Flaws’ research program is mainly focused on determining the mechanisms by which environmental chemicals affect the development and function of the ovary. Her research is funded by grants from the National Institutes of Health. She has published over 250 peer-reviewed papers that have involved extensive participation and authorship by graduate students, postdoctoral fellows, veterinary medical students, and undergraduate students. She is the recipient of the Department of Epidemiology and Preventive Medicine, University of Maryland Student Mentoring Award, the Patricia Sokolove Outstanding Mentor Award, the Dr. Gordon and Mrs. Helen Kruger Research Excellence Award, the Pfizer Animal Health Award for Research Excellence, the University Scholar Award, the Women in Toxicology Mentoring Award from the Society of Toxicology, and the Society for the Study of Reproduction Trainee Mentor Award.
Gustavo Flores is a sophomore at Iowa State University majoring in Nutritional Science on the Pre-Pharmacy track. Born and raised in a small town Denison, Iowa. Gustavo loves to bike and run. He has biked across the whole state of Iowa. He is currently active in many organizations: president of Mariachi Los Amigos de ISU, member of Science Bound, MANRRS, Next Generation Scholar and SHPEP. His goal is to strive towards making a difference in the world and to pursue a PharmD degree so he can become a clinical pharmacist because he wants to improve people’s lives by providing better medicines and being able to recommend the appropriate drug and dosage to the people who needs them. He also would like to educate people on how to stay healthy and making healthy life decisions.
Dr. Eric Gato is currently employed by the Department of Chemistry and Biochemistry, Georgia Southern University as an Assistant Professor of Biochemistry. The primary responsibility of his position is to; teach environmental carcinogenesis, toxicology, biochemistry, general chemistry to undergraduate and graduate students, develop appropriate courses for upper level undergraduate and graduate students, seek internal and external research funding to support research projects and research assistantships for graduate and undergraduate students and publish our research findings in appropriate international scientific journals.
Dr. Eric Gato has had the opportunity to combine biomedical research with teaching at major universities in the United States of America. This has enabled him to present over 20 abstracts at prestigious international scientific meetings, often as an invited speaker. He has exhibited his work at such international conferences as Society of Toxicology, Environmental Mutagenesis and Genomics Society and the American Chemical Society meetings. He has also published more than 15 manuscripts in major international journals within the last few years. He has been involved in mentoring and training a number of undergraduate and graduate students. These students have all gone on into biomedical related careers.
My name is Faith Gaye. I am originally from Liberia, but was raised in Des Moines Iowa. I am a Kinesiology and Health major, focus in premed. I'm studying to become an obstetrician Gynecologist. I am second year student at Iowa State University, and is ecstatic to be part of the toxicology mentoring skill development program.
Dr. Ebony Gilbreath obtained her Doctor of Veterinary Medicine degree in 2004 from Tuskegee University, followed by a one year Anatomic Pathology internship, also at Tuskegee University, Alabama. She completed an Anatomic Pathology Residency in 2008 and a PhD in Pathology in 2011, both at Michigan State University. Dr. Gilbreath is a Diplomate of the American College of Veterinary Pathologists and is a Professor in the Pathobiology Department at the Tuskegee University College of Veterinary Medicine.
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A
Absorbed Dose The amount of a substance that actually enters the body, usually expressed as milligrams of substance per kilogram of body weight(mg/kg).
Absorption The process whereby a substance moves from outside the body into the body.
Acceptable Daily Intake (ADI) The amount of a chemical to which a person can be exposed each day over a long period of time(usually lifetime)without suffering harmful effects.
Acetylcholine An important chemical in the body having physiological functions, including the neurotransmission of electrical impulses across synapses of nerve endings.
Acetylcholinesterase An enzyme present in nervous tissue, muscle, and red blood cells that catalyzes the hydrolysis of acetylcholine to choline and acetic acid.
Acetylcholinesterase Inhibitors Chemicals that inhibit the enzyme acetylcholinesterase at neural synapses. This prevents the acetylcholinesterase from stopping the action of acetylcholine and allows for continued stimulation of the effector. The result is spasms and paralysis, which can cause paralysis and death. Some important acetylcholinesterase inhibitors are organophosphate pesticides, carbamates, and some chemical warfare agents.
ACGIH® Formerly called American Conference of Governmental Industrial Hygienists. ACGIH is a professional society for industrial hygienists that recommends safety and health guidelines.
Acid A substance with one or more hydrogen atoms that are readily replaceable by electropositive atoms. It is a donator of protons. In aqueous solution, it will undergo dissociation with the formation of hydrogen ions. It has a pH of less than 7.0.
Action potential A conducted change in the membrane potential of cells, initiated by an alteration of the membrane permeability to sodium ions, and subsequent propagation of an electrical impulse down an axon. Same as nerve impulse.
Active Transport The movement of a substance across a membrane requiring energy. The substance moves against a concentration gradient, from a less concentrated region to a more concentrated region.
Acute Effect An effect that occurs almost immediately(seconds/minutes/hours/days)after a single or brief exposure to a toxic agent. Generally, acute effects will be evident within 14 days.
Adenosine triphosphate (ATP) An important high-energy compound located in the cytoplasm of cells, which serves as a source of cellular energy.
ADI seeAcceptable Daily Intake
Adsorption The process of attracting and holding a substance to a surface. For example, a substance may adsorb onto a soil particle.
Aerosols Airborne particulate which may be solids or liquid droplets.
Afferent nerve A nerve that relays sensory information to the CNS.
Albumin A simple protein soluble in water and distributed throughout body tissues. It is the most abundant plasma protein.
Allergy An immune hypersensitivity reaction of body tissues to allergens that can affect the skin(urticaria), respiratory tract(asthma), and gastrointestinal tract(vomiting and nausea)or produce a systemic circulatory response(anaphylactic response).
Alveoli The air sacs at the ends of the tracheobronchial tree in which gases are exchanged between inhaled air and the pulmonary capillary blood.
Ames Test A test for mutagenesis using the bacteriumSalmonella typhimurium.
Amyotrophic Lateral Sclerosis A disease in which the myelin around nerves is lost causing paralysis and loss of sensory and motor function. Same as Lou Gehrig's disease.
Anaplasia An alteration of cells from normal appearance to poorly-differentiated or undifferentiated morphology. They have irregular nuclei and cell structure with numerous mitotic figures. Anaplasia is frequently associated with malignancies and serves as one criterion for grading the aggressiveness of a cancer.
Anemia A condition in which there is reduced or impaired red blood cells or hemoglobin resulting in an inadequate capacity of the blood to transport oxygen to body tissues.
Aneuploidy Any deviation from an exact multiple of the haploid number of chromosomes. This may involve missing or extra chromosomes or parts of chromosomes.
Anoxia An insufficient(below normal)supply of oxygen in the body tissues.
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Antagonism An interaction between two chemicals in which one decreases the expected toxic effect of the other.
Antibody An antibody is a protein molecule (immunoglobulin with a unique amino acid sequence) that only interacts with a specific or closely related foreign substances (antigen). The antibody is induced (a response of the immune system) as a result of prior exposure to the antigen.
Anticholinergic Effects Neurological effects resulting from the blockage of acetylcholine, which transmits impulses across nerve junctions.
Antidote A remedy for counteracting a poison.
Anxiety A feeling of apprehension, uncertainty, and fear without apparent stimulus, and associated with tachycardia, sweating and tremors.
Apoptosis Individual or single cell death by a process of self-destruction of the cell nucleus. In apoptosis, dying cells are not contiguous but are scattered throughout a tissue. Often referred to as "programmed cell death."
Aqueous Of a watery nature. Prepared with water.
Asphyxiant A substance, which in high concentrations in air, replaces or reduces the oxygen level such that a person inhaling the air mixture suffers hypoxia.
Astrocyte A type of glial cell in the CNS. They are big cells that maintain the blood-brain barrier and provide rigidity to the brain structure.
Atrophy A decrease in the size of cells. If a sufficient number of cells are involved, the tissue or organ may also decrease in size.
Atropine An anticholinergic drug that blocks acetylcholine receptors.
ATSDR Agency for Toxic Substances and Disease Registry, a US federal agency responsible for emergency response to chemical spills and assessment of health effects of hazardous waste sites.
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Autoimmunity An immune response in which the constituents of the body's own cells are seen as foreign, resulting in hypersensitivity to its own tissues.
Autonomic Nervous System The part of the nervous system involved in the unconscious regulation of visceral functions by transmitting motor information to smooth muscles, cardiac muscle, and various glands.
Axon The elongation of a neuron that conducts an action potential. It may extend long distances from one part of the body to another.
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Base A substance that dissociates in water to yield a hydroxyl ion. A donator of electrons.
Batrachotoxin A potent neurotoxin of some South American frogs that has been used as arrow poisons.
Benign tumor A tumor that grows only at the site of origin and does not invade adjacent tissues or metastasize. It is generally treatable.
Bias Systematic error that may be introduced in sampling by selecting or encouraging one outcome over another.
Biliary Pertaining to bile, an excretion produced by the liver, stored in the gall bladder, and released into the small intestine.
Bioactivation The metabolic process whereby a parent substance is chemically changed to a daughter substance with enhanced biological activity.
Bioassay A laboratory study used to determine the ability of a substance to produce a particular biological effect.
Bioavailability The physical and/or biological state of a substance rendering it capable of being absorbed into the body.
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Biological Half-Life The time required to eliminate one-half the quantity of a substance from the body.
Biotransformation Conversion of a chemical from one form to another by a biological organism.
Blood-Brain Barrier The anatomical barrier that isolates the CNS from the general circulation. The cell responsible is the astrocyte, which forms, layers around capillaries and regulates diffusion of substances from the blood circulation to the neurons.
Body Burden The concentration of a substance that has accumulated in the body.
Bone Marrow The tissue within the internal open space of bones (e.g., shaft of long bones) in which the blood-forming elements exist.
Botulinum toxin A potent neurotoxin that blocks the release of acetylcholine at neuromuscular junctions.
Bronchioles The very small branches of the tracheobronchial tree of the respiratory tract which terminate in the alveoli.
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Cancer An uncontrolled growth of abnormal cells, creating a tumor that can invade surrounding tissues and may spread (metastasize) to distant organs.
Cancer Slope Factor A key risk assessment parameter derived by the EPA. It is an estimate of the probability that an individual will develop cancer if exposed to a specified amount of chemical (mg/kg) every day for a lifetime.
Capillaries The very small blood vessels that take blood from small arteries to small veins.
Carbohydrates Organic compounds that serve as sources of energy for the body. They are converted to glucose, which in turn is used by the cells in cell respiration.
Carcinogen A compound that is capable of causing cancer.
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Carcinogenesis A general term for production of any type of tumor.
Carcinogenic The ability of a substance to cause cancer.
Carcinogenicity The complex process whereby normal body cells are transformed into cancer cells.
Carcinoma A malignant tumor arising in epithelium. It is the most common form of cancer and usually spreads via the lymphatic system.
Cardiovascular System The organ system that transports oxygen and nutrients to tissues and removes waste products. The main components are the heart, blood, and blood vessels.
Case-Control Study A type of study in which subjects that have a disease or outcome [cases] are compared to subjects that do not have the disease or outcome [controls]. In toxicology, a case-control study compares the exposure histories of humans who have a particular toxic effect with that of normal individuals
Catalyst A substance that accelerates a reaction.
Cell The smallest living unit in the body.
Cell membrane The membrane composed of phospholipids, proteins, and cholesterol that form the outer boundary of a cell and regulates the movement of substances into and out of the cell.
Cell Proliferation The process by which cells undergo mitosis and divide into similar cells.
Cell Transformation The change of a cell from one form to another. The term is generally used to denote the change from normal to malignant.
Cellular Swelling A pathologic condition of a cell that is associated with hypertrophy. It is due to cellular hypoxia, which damages the sodium-potassium membrane pump. This in turn changes the intracellular electrolyte balance causing an influx of fluids into the cell and resultant swelling.
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Centrioles Organelles composed of nine microtubule triplets that organize specific fibers of chromosomes and move the chromosomes during cell division. There are two centrioles, aligned at right angles to each other.
Cerebellum A posterior portion of the brain that is responsible for voluntary and involuntary motor activities based on memory and sensory input.
Cerebrum The largest portion of the brain that controls thought processes, intelligence, memory, sensations, and complex motor functions.
Chemicals Atoms or molecules that are the building blocks of all matter.
Cholestasis A liver condition in which excretion of bile salts via the bile duct is inhibited, resulting in bile salts backing up into liver cells.
Chromosome One of a group of structures that form in the nucleus of a cell during cell division. Chromosomes bear DNA and carry an organism’s genetic code.
Chromosome Aberration Changes in chromosome structure.
Chronic Effect An effect that either shows up a long time after an exposure (the latency period) or an effect that results from a long-term (chronic) exposure.
Cilia Thread-like projections of the outer layer of the cell membrane, which serve to move substances over the cell surface.
Cirrhosis A chronic condition of the liver in which liver cells are replaced by fibrous cells.
CNS The central nervous system consisting of the brain and spinal cord.
Compartment As used in toxicokinetics, compartment is a hypothetical volume of a body system wherein a chemical acts homogeneously in transport and transformation. The body is composed of organs, tissues, cells, cell organelles, and fluids, any one or several of which may be referred to as a compartment.
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Concentration Gradient The relative amounts of a substance on either side of a membrane. Diffusion occurs from a region of high concentration to a region of low concentration.
Cohort Study A type of study in which a cohort (group) of individuals who have been exposed to a substance or had treatment for a disease and a cohort without that exposure or that treatment are followed over time to compare disease occurrence. In toxicology, a cohort (group) of individuals with exposure to a chemical and a cohort without exposure are followed over time to compare disease occurrence.
Conjugation A metabolic process in which chemical groups are attached to foreign substances in the body, usually making the conjugated chemical more water soluble and easier to eliminate from the body.
Conjugate A metabolite that results from the joining of a Phase II molecule with a xenobiotic. It is generally more water soluble that the original substance.
Connective Tissue One of the four tissues of the body. It is specialized to provide support and hold the body tissues together (i.e., they connect). It contains more intercellular substances than the other tissues. Bones, cartilage, and fat are types of connective tissue. The blood and lymph vessels are immersed in the connective tissue media of the body.
Control Group A group of animals or humans in a study that are treated the same as the exposed groups but without receiving the specific exposure.
Cornea The transparent front surface of the eye.
Corrosion Direct chemical action that results in irreversible damage at the site of contact. It is manifested by ulceration, necrosis, and scar formation.
Covalent Bond The joining together of atoms that results from sharing electrons.
CPSC Consumer Product Safety Commission. It is a US federal agency responsible for protecting the public from toxins and other hazards present in consumer products.
Cytochrome P-450 An iron-protein complex with a maximum absorbance of visible light at 450 nm that functions as a nonspecific enzyme system during Phase I biotransformation reactions.
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Cytoplasm The fluid matrix of a cell exclusive of the nucleus. Cytoplasm consists of a continuous aqueous solution (cytosol) and the organelles and inclusions suspended in it. This is the site of most chemical activities within the cell.
Cytosol The liquid medium of the cytoplasm, that is, cytoplasm without the organelles and non-membranous insoluble components.
D
Demyelination The loss of the myelin sheath (insulation) around a nerve.
Dendrites Sensory processes of a neuron that are specialized to receive incoming information and send it to the neuron cell body.
Dermal Toxicity Toxicity of the skin, which can range from mild irritation to corrosivity, hypersensitivity, and skin cancer. It can result from direct contact or internal distribution of the xenobiotic to the skin.
Deoxyribonucleic Acid (DNA) A nucleic acid known as the molecule of life that makes up the chromosomes. It is composed of a chain of nucleotides containing the sugar deoxyribose and the nitrogen bases, adenine, guanine, cytosine, and thymine wound in a double helix and held together by weak bonds between complementary nitrogen base pairs.
Depression A clinical psychiatric condition in which a person has a dejected mood, psychomotor retardation, insomnia and weight loss, sometimes associated with guilt feelings and often with delusional preoccupations.
Detoxification A metabolic process whereby a parent substance is changed to a daughter product (metabolite) that has less toxicity.
Diencephalon A portion of the brain that contains the thalamus, hypothalamus, and pituitary gland. It relays and processes sensory information; control of emotions, autonomic functions, and hormone production.
Diffusion The spontaneous movement of a substance from a high concentration gradient to a lower concentration gradient.
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Digestive System The organ system that functions to process foods that are ingested, absorb nutrients into body, and provide metabolized nutrients to the body cells. Consists of the mouth, salivary glands, esophagus, stomach, intestinal tract, liver, and pancreas.
Disease A malfunction of any component of the body that can result in an abnormal and undesirable physiological or anatomical change.
Disposition The term used to describe the kinetics of a substance in the body. It encompasses absorption, distribution, metabolism, and elimination of a chemical.
Distal Away from a point of reference. As used in medicine, something distal is farther away from the main body. For example, the foot is distal to the knee.
Distribution Movement of a substance from the site of entry to other parts of the body.
DNA (Deoxyribonucleic acid) A nucleic acid known as the molecule of life that makes up the chromosomes. It is composed of a chain of nucleotides containing the sugar deoxyribose and the nitrogen bases, adenine, guanine, cytosine, and thymine wound in a double helix and held together by weak bonds between complementary nitrogen base pairs.
Dosage The determination of quantity of a substance received, which incorporates the size, frequency, and duration of doses (e.g., 10 mg every 8 hours for 5 days).
Dose The amount of a substance received at one time. Dose is usually expressed as administered or absorbed dose (e.g., milligrams material/kilogram of body weight).
Dose-Response Assessment The relation between dose levels and associated effects.
Dose-Response Curve A graphical representation of the quantitative relationship between doses of a substance and specific biological effects.
Draize Test The test for eye irritation in which the test substance is placed on the eyes of white rabbits and observed for 72 hours.
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Dying-back Neuropathy A neurological condition in which axons begin to die at the very distal end of the axon with necrosis slowly progressing toward the cell body.
Dysplasia A condition of abnormal cell change or deranged cell growth in which the cells are structurally changed in size, shape, and appearance from the original cell type.
E
ED50 Effective dose 50%. The estimated dose that causes some specific effect (usually desirable) for 50% of the population.
ED99 Effective dose 99%. The estimated dose that causes some specific effect (usually desirable) for 99% of the population.
Effector The body site where a response occurs which counters an initial stimulus and thus attempts to maintain homeostasis.
Efferent Nerve A nerve that relays motor commands from the CNS to various muscles and glands.
Edema Retention of fluid in an organ or in the body.
Element A chemical substance composed of only one atom, e.g., hydrogen, calcium, or singlet oxygen.
Elimination The toxicokinetic process responsible for the removal or expulsion of a substance from the body.
Embryo An early stage of the development of the unborn offspring in which cell differentiation proceeds rapidly along with the formation of major organs. In humans this stage occurs from about 3 weeks until 8 to 9 weeks after conception.
Embryotoxic The harmful effects of a substance on the developing embryo.
Endocrine System The organ system that regulates body functions by use of chemicals, known as hormones. Endocrine organs are the pituitary gland, parathyroid gland, thyroid gland, adrenal gland, thymus, pancreas, and gonads.
Endocytosis The process whereby a substance is engulfed and taken into a cell by an inward folding of the cell membrane, which detaches and moves into the cytoplasm.
Endoplasmic Reticulum A cell organelle, which provides an extensive network of membrane-like channels that, extends throughout the cytoplasm. It synthesizes secretory products and is responsible for intracellular storage and transport.
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Enterohepatic circulation Also known as enterohepatic recirculation. The cycling of a substance from the blood into the liver, then into the bile and gastrointestinal tract. This is followed by re-uptake into the blood stream from the gastrointestinal tract, possibly after chemical or enzymatic breakdown.
Environmental Fate The fate of a substance following its release into the environment. It includes the movement and persistence of the substance.
Enzyme A protein formed in living cells that acts as a catalyst for chemical reactions in cells.
Enzyme Activation The increase in levels of an enzyme as the result of stimulation by another chemical substance. Same as enzyme induction.
Enzyme Inhibitor A substance which causes a decrease in levels of an enzyme.
Enzymes A chemical (protein) that catalyzes (accelerates) specific biochemical reactions without themselves being permanently changed.
EPA Environmental Protection Agency. A US federal agency responsible for regulation of most chemicals that can enter the environment. The EPA administers the following acts: Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA), the Toxic Substances Control Act (TSCA) which was amended in June 2016 by the Frank R. Lautenberg Chemical Safety for the 21st Century Act, the Resource Conservation and Recovery Act (RCRA), the Safe Drinking Water Act (SDWA), Clean Air Act (CAA), and the Comprehensive Environmental Response, Compensation and Liabilities Act (CERCLA) (Superfund Act).
Ependymal Cells A type of glial cell in the CNS that produces a special fluid, known as the cerebral spinal fluid (CSF).
Epidemiology The study of the relative characteristics of exposed and non-exposed human populations for the purpose of detecting harmful effects.
Epidermis The outer layer of the skin.
Epithelial Tissue One of the four types of tissue in the body that is specialized to protect, absorb and secrete substances, as well as detect sensations. It covers every exposed body surface, forms a barrier to the outside world, and controls absorption.
Equilibrium A state of balance. Opposing forces exactly counteract each other.
Excretion A process whereby substances(or metabolites)are eliminated from the body.
Exposure Contact with a foreign substance, usually by inhalation, ingestion, or skin contact.
Exposure Assessment Analysis or estimation of the intensity, frequency, and duration of human exposures to an agent.
Exposure Dose The amount of a substance in the environment to which a person is subjected.
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F0Generation (0 is written as a subscript) The parent generation in a multigeneration reproduction study.
F1Generation (1 is written as a subscript) The first filial generation(offspring)in a multigeneration reproduction study. It is produced by breeding individuals of the F0generation.
F2Generation (2 is written as a subscript) The second filial generation(offspring)in a multigeneration reproduction study. It is produced by breeding individuals of the F1generation.
Facilitated diffusion The passage of molecules and ions across a cell membrane with the aid of a specific carrier protein. It is dependent on concentration gradient.
Fatty Change A toxic cellular change that occurs with severe cellular injury. The cell has become damaged and is unable to adequately metabolize fat, resulting in development of small vacuoles of fat that accumulate and become dispersed within the cytoplasm. It is usually observed in the liver.
FDA Food and Drug Administration. A US federal agency responsible for evaluating the safety of drugs, cosmetics, food additives, and medical devices.
Feedback Mechanism A part of the homeostasis in which the body regulates the degree of response to a stimulus. A negative feedback depresses the stimulus to shut off or reduce the effector response whereas a positive feedback has the effect of increasing the effector response.
Femtogram (fg) An extremely minute quantity, 1x10^-15gram (N.B- ^ means to the power).
Fetus The unborn offspring in the postembryonic period, after major structures have been outlined. In humans this occurs from 8 to 9 weeks after conception until birth.
Fibrosis The formation of scar tissue in an organ, generally by replacement of functional organ cells with nonfunctional fibrous tissue.
FIFRA Federal Insecticide, Fungicide, and Rodenticide Act. A US federal law administered by the EPA for evaluation and registration of pesticides.
Filtrate A substance that has passed through a filter. As used in toxicokinetics, it usually pertains to the material that has passed through the glomerulus into the renal tubule.
Filtration The passage of a solvent and dissolved substance through a membrane or filter. In excretion, a portion of the plasma and dissolved materials undergo filtration through the glomerular filter (capillary bed).
First-pass Effect The biotransformation of a substance in the liver after absorption from the intestine and before it reaches the systemic circulation.
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Gamma Aminobutyric Acid (GAMA) A neurotransmitter of the CNS whose effects are usually inhibitory.
Gene The smallest subunit of a chromosome that contains a genetic message.
Gene Mutation A change in the DNA sequence within a gene.
Genetic Toxicity Toxic effects that result from damage to DNA and altered genetic expression.
Germ Cell Reproductive cells that give rise to sperm or ova.
Glial cells The supporting cells of the neural tissue. They regulate the environment around the neurons and protect against foreign invaders. They are also known as neuroglia.
Glomerular filtration The first step in urine formation in which blood enters the vascularized glomerulus where water and small molecules are forced by hydrostatic pressure across the glomerular filter and into the filtrate of the Bowman's capsule of the renal tubule.
Glomerulus The highly vascular structure in the kidney where much of the fluid portion of the blood (serum) is filtered and passes into the kidney tubules, carrying with it toxins and many other materials present in the serum.
Glucuronidation The process of adding glucuronide to a toxicant or Phase I metabolite during Phase II biotransformation.
Glucuronide A glycosidic compound of glucuronic acid. Generally inactive. Constitutes the major portion of some metabolites.
Glutathione The tripeptide glutamyl-cysteinyl-glycine. It is found in most tissue, especially the liver. It plays a major role in detoxication and cellular protection.
Golgi Apparatus Cell organelles composed of stacks of flattened membranes containing chambers. They synthesize, store, alter, and package secretory products and lysosomes.
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Half-Life The time required for a concentration of a substance in a body fluid (usually blood plasma) to decrease by half.
Hazard The inherent adverse effect of a substance.
Hazard Identification Characterization of the innate adverse toxic effects of an agent.
Hepatic Cancer Cancer of the liver.
Hepatic Necrosis Death of liver cells(hepatocytes).
Hepatitis Inflammation of the liver
Hepatotoxicity Toxicity of the liver and associated bile duct and gall bladder.
Hepatotoxin A systemic poison whose target organ is the liver.
Heritable Translocation Assay A test for mutagenicity in which exposed male fruit flies(Drosophila)or mice are bred to non-exposed females. The offspring males(F1generation)are then bred to detect the presence of chromosomal translocations indicating this specific type of mutation.
Herpes Simplex Virus A virus that causes a disease marked by vesicles of the skin, usually on the lips, nares, or genitals.
High Throughput Screening Involvesin vitroassays (often called High throughput assays), many of which use human proteins or cells (primary cells or cell lines). The automated methods allow for a large number of chemicals to be rapidly evaluated for a specific type of bioactivity at the molecular or cellular level. The assays can be run for a range of test chemical concentrations and produce concentration-response information representing the relationship between chemical concentration and bioactivity. For toxicity testing for human health effects, these assays primarily use human cells and focus on assessing disruptions to key biological pathways.
Human Dose Equivalent A calculation of the dose in humans that produces a specific effect based on the dose that produces the effect in animals. A conversion formula comparing animal to human body weight or animal to human body surface is used.
Hydrolysis The chemical process in which water is used to split a substance into smaller molecules. The hydrogen and hydroxyl parts of a water molecule bond to opposite locations on a chemical bond at the site where the split occurs.
Hydrophilic Water loving. Substance that has strong polar groups that readily interacts with water.
Hyperplasia An increase in the number of cells in a tissue. This generally results in an enlargement of tissue mass and organ size.
Hypersensitivity A state of altered immune reactivity in which the body reacts with an exaggerated response to a foreign agent.
Hypertrophy An increase in size of individual cells. This frequently results in an increase in the size of a tissue or organ.
Hypoxia A partial reduction in the oxygen concentration supplied to cells or tissues.
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IDLH Immediately Dangerous to Life and Health. A National Institute of Occupational Safety and Health estimate for the maximum level of exposure from which a person could exit in 30 minutes without escape-impairing symptoms or irreversible health effects.
Immunotoxicity Toxicity of the immune system. It may take several forms: hypersensitivity(allergy and autoimmunity), immunodeficiency, and uncontrolled proliferation(leukemia and lymphoma).
In Silico Testing done via computer or computer simulation.
In Vitro Testing done in a controlled environment outside of a living organism, for example, in a test tube.
In Vivo Testing done using a whole living organism.
Inhibition A reduction in the activity of a reaction. In toxicokinetics, it normally refers to enzyme inhibition.
Initiation Phase The initial stage in the carcinogenesis process, which consists of the alteration of the DNA (mutation) of a normal cell. The initiated cell has thus developed a capacity for unregulated growth.
Inorganic Compounds Simple molecules that usually consist of one or two different elements. For example, water (H2O), carbon dioxide (CO2), bimolecular oxygen (O2), and sodium chloride (NaCl).
Integumentary System The organ system that serves as a barrier to invading environmental organisms and chemicals and serves in temperature control. Organs include the skin, hair, nails, and exocrine glands.
Interactions Refers to measures of effects of simultaneous exposure to two or more substances. The four types of interactions are additive, antagonistic, potentiation, and synergistic.
Interneurons Interneurons are neurons located only in the CNS and provide connections between sensory and motor neurons. They can carry either sensory or motor impulses. They are involved in spinal reflexes, analysis of sensory input, and coordination of motor impulses. They play a major role in memory and the ability to think and learn. They are also known as association neurons.
Interstitial fluid The fluid in the space between cells. Same as intercellular fluid.
Intracellular Fluid The fluid within a cell. It is also known as the cytoplasm.
Ionized Separated into ions. Normally, an ionized substance will dissolve in water.
Irritation Local tissue reaction without involvement of an immunologic mechanism. It is a reversible inflammation.
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Karyorrhexis The rupture of the cell nucleus with the disintegration of the chromatin into granules which are extruded from the cell.
Kilogram (kg) A measure of weight consisting of 1000 grams.
Kinetics Refers to turnover, movement, or rate of change of a specific factor, e.g., chemical reaction. It is commonly expressed in units of amount per unit time.
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Labile Cells Body cells that have a limited lifespan and are capable of routine division and replacement. The squamous epithelium of skin, mouth, vagina and cervix, columnar epithelium of intestinal tract, transitional epithelium of urinary tract, and hematopoietic stem cells of the bone marrow are examples of labile cells.
Latency Period The period of time between an exposure and onset of toxicity.
LC0 Lethal Concentration 0%. The calculated concentration of a gas at which none of the population is expected to die.
LC10 Lethal Concentration 10%. The calculated concentration of a gas at which 10% of the population is expected to die.
LC50 Lethal Concentration 50%. The calculated concentration of a gas at which 50% of the population is expected to die.
LC90 Lethal Concentration 90%. The calculated concentration of a gas at which 90% of the population is expected to die.
LD0 Lethal Dose 0%. The estimated dose at which none of the population is expected to die.
LD10 Lethal Dose 10%. The estimated dose at which 10% of the population is expected to die.
LD50 Lethal Dose 50%. The estimated dose at which 50% of the population is expected to die.
LD90 Lethal Dose 90%. The estimated dose at which 90% of the population is expected to die.
Lethal Injury Damage to a cell or the body so severe that death results.
Leukemia Cancer of the hematopoietic system, the blood-forming organs.
Linearized Multistage Model A conservative quantitative cancer assessment model used by the EPA. It assumes linear extrapolation with a zero dose threshold from the upper confidence level of the lowest dose that produced cancer in an animal test or in a human epidemiology study.
Lipid Soluble Capable of being dissolved in fat or in solvents that dissolve fat. Usually nonionized compounds.
Lipid A large and diverse group of organic compounds that contain primarily carbon and hydrogen atoms with a lesser amount of oxygen. Most lipids are insoluble in water but will readily dissolve in other lipids and in organic solvents.
Lipids Essential substances of all cells and a major energy reserve for the body. Lipids may be stored as fatty acids or as triglycerides.
Lipophilic Having an affinity for fats or lipids. A substance that is lipophilic has high lipid solubility and can penetrate cell membranes by passive diffusion.
Lipophilicity A term used to describe the ability of a substance to dissolve in, or associate with, fat and therefore living tissue. This usually applies to substances that are non-ionized or non-polar or have a non-polar portion. High lipid solubility usually implies low water solubility.
LOAEL Lowest Observed Adverse Effect Level. The lowest dose in a study in which there was an observed toxic or adverse effect.
Lou Gehrig's Disease A disease in which the myelin around nerves is lost causing paralysis and loss of sensory and motor function. Same as Amyotrophic Lateral Sclerosis.
Lymphatic System An organ system that returns tissue fluid to blood and defends against foreign organisms. Organs include the spleen, lymph nodes, thymus, and the lymphatic vessels.
Lysosomes Organelles that consist of vesicles that contain strong digestive enzymes. Lysosomes are responsible for the intracellular removal of damaged organelles or pathogens.
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Macrophage Large phagocytic cells of the blood or lymph systems that can engulf particles or small organisms.
Malignant Cell A cancer cell that has the potential to invade surrounding tissues or spread to other areas of the body(metastasize).
Malignant Tumor A tumor that can invade surrounding tissues or metastasize to distant sites, resulting in life-threatening consequences.
Margin of Safety (MOS) The ratio of the dose that is just within the lethal range(LD01)to the dose that is 99% effective(ED99), LD01/ED99. A ratio of greater than 1 gives comfort to the physician whereas a ratio of less than 1 denotes caution.
Mechanism of Action The specific manner by which a substance causes a particular effect.
Medulla Oblongata The segment of the brain that is attached to the spinal cord. It relays sensory information to the rest of the brain and regulates autonomic function, including heart rate and respiration.
Metabolism The conversion of a chemical from one form to another. Same asBiotransformation.
Metabolite A chemical produced when a substance is metabolized by a biological organism.
Metaplasia The conversion from one type of mature cell to a different type of mature cell. It is a cellular replacement process. An example is cirrhosis of the liver.
Metastasis The movement of diseased cells, in particular cancer cells, from the site of origin to another location in the body.
Metastatic Foci Secondary tumors in an organ different from the original site of cancer development.
mg/kg A commonly used dose that stands for mg of a substance per kg of body weight.
mg/kg/day A commonly used dosage that stands for mg of a substance per kg of body weight on a daily basis.
mg/m^3 (N.B ^ indicates to the power) An exposure unit used to express concentrations of particulates in the air, standing for milligrams of compound per cubic meter of air.
Microglia A type of glial cell. The microglia are small, mobile, phagocytic cells that function in defense against invading organisms and xenobiotics.
Microgram (µg) A commonly used unit of weight consisting of 1 millionth (1 x 10^-6) of a gram. N.B In 10^-6 (N.B -^ indicates to the power)
Micronucleus Test A test for mutagenicity in which bone marrow or peripheral blood cells are examined for the presence of micronuclei(broken pieces of chromosomes surrounded by a nuclear membrane).
Microsomes The subcellular organelles that are a part of the smooth endoplasmic reticulum.
Midbrain The area of the brain between the cerebrum and brain stem. It contains the centers that process auditory and visual data and generates involuntary motor responses.
Milligram (mg) The most commonly used unit of measure in medicine and toxicity consisting of one thousandth of a gram (1x10^-3g). N.B ^ indicates superscript.
Minimal Risk Levels (MRLs) A risk level calculated by the ATSDR for noncancer end points. The MRL is an estimate of daily human exposure to a substance that is likely to be without an appreciable risk of adverse effects over a specified duration of exposure. MRLs are derived for acute(14 days or less), intermediate(15-364 days), and chronic(365 days or more)duration exposures for either inhalation or oral routes.
Mitochondria Oval organelles bound by a double membrane with inner folds enclosing important metabolic enzymes. They produce nearly all (95%) of the ATP and energy required by the cell.
Monooxygenase Enzyme system (such as cytochrome P450) involved in the oxidation of compounds.
Motor Neurons The neurons that relay information from the CNS to other organs, terminating at the effectors. Motor neurons are the efferent neurons of both the somatic and autonomic nervous systems. They are also referred to as effector neurons.
Multiple Sclerosis A disease in which the myelin around nerves is lost causing paralysis and loss of sensory and motor function.
Muscular System The organ system involved with movement or locomotion and heat production. The main organs are the skeletal muscles and tendons.
Muscular Tissue One of the four types of tissue. It is specialized for an ability to contract. Muscle cells are elongated and referred to as muscle fibers. When a stimulus is received at one end of a muscle cell, a wave of excitation is conducted through the entire cell so that all parts contract in harmony.
Mutagen A substance that causes mutations(genetic damage).
Mutagenesis The process whereby a substance damages DNA and produces alterations in or loss of genes or chromosomes.
Mutation DNA damage resulting in genetic alterations ranging from changes in one or a few DNA base pairs(gene mutations)to gross changes in chromosomal structures(chromosome aberrations)or in chromosome number.
Myelin Protein layers that surround neurons and serves like insulation. Myelinated neurons usually transmit impulses at high speed, such as needed in motor neurons. Loss of myelination allows interruption of the action potential (like leakage) and causes a dysfunction of these cells. This can cause paralysis and loss of sensory and motor function.
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Nanogram (ng) A unit of weight consisting of 1 billionth of a gram (1 x 10^-9g). N.B ^ indicates to the power
Necrosis The death of a cell caused by a progressive failure of essential metabolic and structural cell components, usually in the cytoplasm. Necrosis generally involves a group of contiguous cells or occurs at the tissue level.
Neonates Newborn animals.
Neoplasia A new growth of tissue with abnormal and unregulated cellular proliferation. There are two types of neoplasia, benign and malignant. Same as a tumor.
Neoplasm An uncontrolled and progressive growth of cells which may be benign or malignant. Same asTumor.
Neoplastic Pertaining to or like a neoplasm or neoplasia(tumor).
Neoplastic Conversion The second major step in the carcinogenesis process in which specific agents (referred to as promoters) enhance the further development of the initiated cells.
Nephron The functional unit of the kidney that produces urine. The primary areas are the glomerulus, convoluted tubule, and collecting duct.
Nephrotoxin A systemic poison whose target is the kidney.
Nervous System The organ system that coordinates activities of other organ systems and responds to sensations. It is composed of the central nervous system and peripheral nervous system.
Nervous Tissue One of the four body tissues that is specialized so as to be capable to conduct electrical impulses and convey information from one area of the body to another. Most of the nervous tissue (98%) is located in the central nervous system, the brain, and spinal cord.
Neural Synapse The junction between the axon of one neuron and the dendrite of another neuron or an axon and a connection with a muscle cell (neuromuscular junction).
Neuroglia Cells of the nervous system that provide physical support for the nervous tissue, control tissue fluids around the neurons, and help defend the neurons from invading organisms and xenobiotics. Same as glial cells.
Neurons The functional nerve cells directly responsible for transmission of information to and from the CNS to other areas of the body.
Neurotoxicity Toxicity to cells of the central nervous system(brain and spinal cord)and the peripheral nervous system(nerves outside the CNS).
Neurotoxin A systemic poison whose target organ is the nervous system.
Neurotransmitters These are chemicals that move information across a synapse by diffusing across the synaptic junction, binding to receptors on the postsynaptic membrane, and stimulating generation of an action potential.
New Drug Application (NDA) The process by which a manufacturer of a new drug applies to the FDA for formal approval to market the drug.
Nicotine A neurotoxin that binds to certain cholinergic receptors thus preventing normal neural function and stimulation.
NIOSH National Institute of Occupational Safety and Health. It is an institute in the U.S. Department of Health & Human Services that conducts research on health hazards in the workplace.
NOAEL No Observed Adverse Effect Level. The highest dose in a toxicity study at which there were no toxic or adverse effects observed.
Non-polar A term used to describe a molecule, which is neutral or possesses neither a positive or negative charge.
Norepinephrine A chemical neurotransmitter of adrenergic nerves of both the central and peripheral nervous systems. It is also produced by the adrenal medulla in response to stimulation. It is the same as noradrenaline.
Nucleic acids These are large organic compounds inside virtually all body cells (RBCs is an exception) that store and process information at the molecular level.
Nucleolus This is a dense region of the nucleus, which contains the RNA and DNA. It is the site for rRNA synthesis and assembly of the ribosome components.
Nucleus A membrane-bound part of a cell that contains nucleotides, enzymes, and nucleoproteins. The nucleus controls metabolism, protein synthesis, and the storage and processing of genetic information.
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Octanol/Water Partition Coefficient The ratio of the amount of a substance that will dissolve in octanol versus the amount that will dissolve in water. The higher the octanol/water partition coefficient the greater the tendency of substance to be stored in fatty tissues.
Odds Ratio (O/R) A statistical calculation in a case-control study involving the ratio of risk of an exposed group to that of an unexposed group. An O/R=2 means that the exposed group has twice the risk of the non-exposed group.
Oligodendrocyte A type of glial cell in the CNS that wraps itself around an axon to form myelin, which serves like insulation.
Oncogene Altered or misdirected proto-oncogene which then has the ability to transform the normal cell into a neoplastic cell. Most oncogenes differ from their proto-oncogenes by a single point mutation.
Organ System A group of organs that contribute to specific functions within the body.
Organelle A subcellular structure such as the mitochondria or nucleus of a cell.
Organic Compound A substance that contains covalently-bonded carbon and hydrogen and often other elements.
Organophosphate Chemical Organic chemicals that contain a phosphate group. Many are highly toxic, as they are capable of inhibition of the enzyme acetylcholinesterase at neural synapses. Many pesticides and some warfare agents are organophosphate chemicals.
Organs A group of tissues precisely arranged so that so they can work together to perform specific functions.
OSHA Occupational Safety and Health Administration. The component of the U.S. Department of Labor responsible for ensuring safe working conditions.
Oxidation A change in a chemical characterized by the loss of electrons. This is a primary Phase I type biotransformation reaction.
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p53 Gene A normal suppressor gene that controls cell division and stimulation of repair enzymes to rebuild and restore damaged regions of the DNA. Damage or inactivation of the p53 gene is considered a contributing cause of most cancers.
Partition Coefficient See Octanol/water partition coefficient.
Passive Transfer The movement across a membrane by simple diffusion.
Pathology The branch of medicine that involves the functional and structural changes in tissues and organs that are caused by disease.
PEL Permissible Exposure Level. The standard stipulated by the Occupational Safety and Health Administration for the highest safe level of exposure to a chemical in the workplace.
Percutaneous absorption The transfer of a substance from the outer surface of the skin through the corneum and outer layers and into the systemic circulation.
Peripheral Nervous System (PNS) All nervous tissue outside the central nervous system.
Peripheral Neuropathy Abnormal and detrimental changes to nervous tissue outside the brain or spinal cord.
Permanent Cells Body cells that never divide and do not have the ability for replication even when stressed or when some cells die. Examples are neurons and muscle cells.
Peroxisomes Very small, membrane-bound organelles which contain a large variety of enzymes that perform a diverse set of metabolic functions.
Phagocytosis The engulfing of particles by certain cells of the circulatory and lymphatic systems, known as phagocytes. Phagocytosis is a primary cellular defense mechanism against foreign particles or organisms.
Pharmacokinetics Quantitation of the time course of chemical absorption, distribution, metabolism, and elimination.
Pharmacology The science that deals with the origin, nature, chemistry, effects and uses of drugs.
Phospholipids Molecules containing phosphates and lipids found in the cell membrane. The phosphate head is hydrophilic, whereas the lipid tail is hydrophobic.
Physiological Adaptation The ability of the body to adapt to changes or stresses so that the change is beneficial. Increase in muscle mass with exercise is an example of physiological adaptation.
Picogram (pg) A unit of weight consisting of 1 quadrillionth of a gram (1 x 10^-12g). N.B ^ Indicates to the power.
Pinocytosis The process whereby a liquid is engulfed and taken into a cell by an inward folding of the cell membrane, which detaches and moves into the cytoplasm.
Plasma membrane The membrane composed of phospholipids, proteins, and cholesterol that forms the outer boundary of a cell and regulates the movement of substances into and out of the cell. Same as cell membrane.
Plasma The non-cellular, fluid portion of whole blood.
Point Mutation A change in the DNA sequence in a gene.
Poison A substance capable of causing toxicity when absorbed into the body in a relatively small quantity.
Polar A term used to describe a molecule which is charged or ionized. Polar substances are usually the easiest for the body to excrete.
Polyploidy An increase in the normal number of chromosomes.
Pons A section of the brain that functions as a relay center and assists in somatic and visceral motor control.
Poorly-differentiated The change in a cell so that it has lost much of the normal appearance.
Portal circulation The term applied to the venous circulation draining the tissues of the gastrointestinal tract into the liver.
Power of the Study The statistical ability of a study to detect an effect.
PPB Parts per billion. The number of units of a substance in 1 billion units. PPB is a common concentration unit for dilute samples of dissolved substances or airborne substances.
PPM Parts per million - the number of units of a substance in a million units. PPM is a common concentration unit for dilute samples of dissolved substances or airborne substances.
Probit Model A risk assessment model that assumes log normal distribution for tolerances of an exposed population. It is generally considered inappropriate for the assessment of cancer risk.
Progression Stage The third recognized step in the carcinogenic process that is associated with the development of the initiated cell into a biologically malignant cell population.
Proliferation The reproduction or multiplication of similar forms, especially cells.
Promotion Phase The second step in the carcinogenesis process in which specific agents (referred to as promoters) enhance the further development of the initiated cells.
Prospective Cohort Study An epidemiology study in which cohorts are identified according to current exposures. The cohort is followed over time for the development of specific effects, such as cancer.
Protein A complex nitrogenous substance which constitutes the main building material in cells.
Proteins The most diverse and abundant of organic compounds in the body. There are about 100000 different kinds of proteins that perform a large variety of important functions, such as the protein pores in cell membranes, keratin in skin and hair, collagen in ligaments and tendons, myosin in muscles, and hemoglobin in RBCs. The building blocks for proteins are the 20 amino acids.
Proto-oncogenes Normal or good cellular genes that instruct the production of the regulatory proteins and growth factors within the cell or its membrane. Activation of a proto-oncogene can cause alteration in the normal growth and differentiation of cells, which leads to neoplasia.
Pulmonary Fibrosis Changes in the lining of the pulmonary alveoli in which the normal epithelial cells are replaced by fibrous tissue. Gases poorly diffuse across the fibrous tissue and thus gas exchange is drastically reduced in the lungs.
Pyknosis A degenerative change in a cell in which it thickens with a shrinking of the nucleus and the chromatin condenses to a solid, structureless mass or masses.
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Read-across A testing method that uses known chemical endpoints to estimate or predict unknown endpoints for chemicals similar in structure or mechanism of action.
Receptor The site within the body that detects or receives the stimulus, senses the change from normal, and sends signals to the control center.
Reduction A change in a chemical characterized by the gain of electrons. This is one of the main Phase I biotransformation reactions.
Reference Dose (RfD) The EPA estimate of a lifetime daily exposure level for humans that is likely to be without risk of harmful effects. RfDs are acceptable safety levels for chronic noncarcinogenic and developmental effects. The process used to derive an RfD is a modification of that used to derive an ADI.
Relative Risk (RR) A statistical calculation of the ratio of disease in an exposed population to that of an unexposed population.
Reproductive System The organ system that produces germ cells (eggs and sperm) and provides the environment for growth of the fetus (women). The main reproductive organs are the ovaries, uterus, mammary glands, testes, prostate gland, and the external genitalia.
Reproductive Toxicity Toxicity of the male or female reproductive system. Toxic effects can include damage to the reproductive organs or offspring.
Respiratory System The organ system responsible for oxygen and carbon dioxide exchange. The main organs are the lungs, trachea, larynx, nasal cavities, and pharynx.
Respiratory Toxicity Toxicity of the upper(nose, pharynx, larynx, and trachea)or lower(bronchi, bronchioles, and lung alveoli)respiratory system.
Retrospective Cohort Study An epidemiology study in which cohorts are identified according to past exposure conditions and follow-up proceeds forward in time.
Reversible Cell Damage A type of cellular damage in which the response of the cell to toxic injury may be transient and once the stress has been removed or the compensatory cellular changes made, it returns to full capability.
RfD seeReference Dose
Ribonucleic Acid (RNA) A nucleic acid consisting of a chain of nucleotides that contain the sugar ribose and the nitrogen bases adenine, guanine, cytosine, and uracil.
Ribosomes Very small cell organelles that consist of RNA and proteins, and function in protein synthesis.
Risk The probability that a hazard or effect will occur at a specific level of exposure.
Risk Assessment The process by which the probability that an adverse effect will occur at a defined exposure level is determined.
Risk Characterization The final stage in the risk assessment process, which involves predicting the frequency and severity of effects in exposed populations.
Risk Management The process of weighing policy alternatives and selecting the most appropriate regulatory action based on the results of risk assessment and social, economic, and political concerns.
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Safety Factor Factors used in the calculation of acceptable human or environmental exposures. They are applied to data from laboratory experiments or epidemiology studies. Factors of 10 are normally used to account for such uncertainties in the data on which risk assessments are made. Similar to uncertainty factors.
Sarcoma A malignant tumor arising in connective or muscle tissue. They are usually spread by the blood stream and frequently metastasize to the lung.
Saxitoxin A potent neurotoxin present in some shellfish poisoning that produces its effect by blocking sodium channels.
Schwann Cells A very important glial cell present in the peripheral nervous system. They wrap themselves around all axons outside the CNS and form myelin, which serves like insulation.
Secretion A process in which molecules are actively transported out of an organ.
Selection Bias Systematic error that may be introduced in sampling by selecting one population over another.
Selective Toxicity Differences in toxicity between two species simultaneously exposed to the same substance.
Sensitization An immune capability that develops after an individual is exposed to a specific antigen. Subsequent exposure results in an immune reaction.
Sensitizer A substance that causes an allergic immune response.
Sensory Neurons Neurons that carry information from sensory receptors (usually processes of the neuron) to the CNS. They are also known as afferent neurons.
Sister Chromatid Exchange Assay (SCE) A mutation test in which bone marrow cells or lymphocytes of exposed individuals are microscopically examined for complete chromosome breakage and errors in rejoining of chromatid fragments. Errors are detected by demonstrating that there has been an exchange in the sister chromatids during the rejoining process.
Skeletal System The organ system that supports and moves the body, protects internal organs, provides for mineral storage, and provides for blood formation. The main organs are the bones, cartilage, ligaments, and bone marrow.
Slope of the Dose-Response Curve Rate of buildup of toxic effects with increasing doses.
Solubility Ability of a substance to be dissolved in a solvent. The solubility is expressed according to the solvent, such as water solubility or solubility in acetone.
Somatic Cell A body cell other than a germ cell.
Somatic System The part of the nervous system under voluntary control.
Stable Cells Body cells that have a long lifespan with normally a low rate of division but the ability to rapidly divide upon demand. Examples are liver cells, alveolar cells of the lung, and kidney tubule cells.
Standard Deviation The statistical calculation denoting the variability of responses to an exposure. One standard deviation incorporates 68% of the responses while two standard deviations incorporates 95% of the responses.
Steatosis Lipid accumulation in hepatocytes.
Stimulus A change in the environment, such as an irritant, loss of blood, or presence of a foreign chemical.
Strychnine An extremely poisonous natural substance that inhibits the neurotransmitter glycine at postsynaptic sites, resulting in an increased level of neuronal excitability in the CNS.
Subchronic Toxicity The adverse effects of a substance resulting from repeated exposure to a toxic agent over a period of several weeks or months.
Subclinical Showing no, or undetectable, signs or symptoms of a disease or condition. Also, the period of time between exposure and onset of symptoms.
Substance Physical material of which something is made. It may be element, compound, or a mixture of materials.
Substrate A substance acted upon. It often refers to the chemical that undergoes reaction with an enzyme.
Synapse The junction between the axon of one neuron and the dendrite of another neuron or an axon and a connection with a muscle cell (neuromuscular junction).
Systemic toxin A toxin that affects the entire body or many organs.
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Target Organ An organ in which a xenobiotic exerts a toxic effect.
TD0 Toxic Dose 0%. The estimated dose at which none of the population is expected to exhibit toxic effects.
TD50 Toxic Dose 50%. The estimated dose at which 50% of the population exhibits toxic effects.
TD90 Toxic Dose 90%. The estimated dose at which 90% of the population exhibits toxic effects.
Teratogenesis The process by which a substance causes abnormal development of tissues or organs in a developing fetus.
Teratogenicity The development of birth defects as the result of exposure to a teratogenic toxicant.
Tetrodotoxin A potent neurotoxin produced in some species of frogs, puffer fish and other invertebrates.
Therapeutic Index (TI) The ratio of the dose needed to produce the desired therapeutic response to the dose producing toxicity
Threshold Dose The dose at which a toxic effect is first encountered.
Threshold Limit Value (TLV) A recommendation by the ACGIH for the highest level of exposure to a chemical that is safe.
Tissue A group of cells with similar structure and function. There are four types of tissues: epithelial tissue, connective tissue, muscle tissue, and nerve tissue.
TLV seeThreshold Limit Value
Tolerance The ability to endure unusually large doses of a substance without ill effect. Toxic effects are decreased with continued exposure to the substance.
Total Dose The sum of all individual doses which may be received over a period of time.
Toxicant An agent that produces adverse effects when absorbed into the body.
Toxicokinetics The pharmacokinetics of a toxic chemical.
Toxicologist A person who studies harmful effects of chemicals including the mechanisms by which the effects are produced and the probability that the effects will occur under specific exposure conditions.
Toxicology The study of the harmful interactions of chemicals on living organisms and biological systems.
Toxin A specific protein produced by certain plants, animals and microorganisms that is highly toxic to other organisms(e.g.,snake venom).
Tumor seeNeoplasm
Tumor Suppressor Gene Genes present in normal cells that serve to prevent a cell with damaged DNA from proliferating and evolving into an uncontrolled growth. Sometimes referred to as anti-oncogenes. The p53 gene is a tumor suppressor gene.
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Uncertainty Factors Factors used in the calculation of acceptable human or environmental exposures, which are applied to data from laboratory experiments or epidemiology studies. Factors of 10 are normally used to account for uncertainties in the data on which risk assessments are made. Similar to safety factors.
Unscheduled DNA Synthesis (UDS) The synthesis of DNA outside the normal mitotic process, which is considered an indication of DNA damage and the first step in the process of mutagenesis. The most commonly used test for UDS measures uptake of tritium-labeled thymidine into the DNA of rat hepatocytes or human fibroblasts.
Urinary System The organ system responsible for the elimination of wastes; regulation of pH and the volume of blood. The main organs are the kidneys, urinary bladder, and urethra.
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Vapor Pressure The pressure exerted when a solid or liquid is in equilibrium with its own vapor. The higher the vapor pressure the higher the volatility.
Volatility The ability of a substance to change from liquid or solid form to a gaseous form.
Volume of distribution (V*D) *N.B - D is written as a subscript The volume of body fluid in which a compound is apparently distributed. It may consist of plasma, interstitial fluid, and intercellular fluid.
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Xenobiotic A chemical foreign to the body.
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β-Bungarotoxin A potent neurotoxin (venom) of elapid snakes that prevents the release of neurotransmitters, thus causing paralysis and death.
My name is Ebony Hargrove-Wiley, a senior biology major at Tuskegee University by way of Kansas City. I became interested in toxicology will working in a reproductive lab under my university's School of Veterinary Medicine. I wish to continue my education to pursue a dual degree working as a medical scientist.
Dr.Esther Haugabrooks is a toxicology manager in the North American Scientific & Regulatory Affairs division of the Coca-Cola Company. Her role is to ensure the safety of food ingredients and support innovation initiatives. Previously, Esther worked in the non-profit sector reviewing and promoting the implementation of new approach methodologies for US and international regulatory use. Esther has also worked for the Florida state government as a Health Educator Consultant and Medical Research Manager. From her professional experiences working for state government, a nonprofit organization, and now industry, Esther has cultivated and lent her unique perspectives to the development of public outreach programs, scientific presentations, publications, and various expert groups. Esther earned a PhD in Toxicology from Iowa State University, a MS in Environmental Sciences from Tuskegee University, and a BS in Biology from Oakwood University. She is an active member of the Society of Toxicology since 2013, American Society for Cellular and Computational Toxicology since 2016, and the Toxicology Forum since 2017.
Dr. Tamara House-Knight is a toxicologist for the environmental consulting firm Ramboll Environ. She received her doctorate in Interdisciplinary Toxicology from the University of Arkansas for Medical Sciences in 2004. She has worked in the environmental consulting business for over 13 years and specializes in human and environmental risk assessment. She has been involved in project planning, development of risk assessment work plans, management and implementation of risk assessments, and community relations/public participation providing toxicological support following chemical exposures to client employees and health care workers. As an environmental consultant she has responded to hundreds of worker exposure incidents involving a wide variety of chemicals including: diesel fuel, battery acid fumes, exhaust fumes, ammonia, and pesticides. She has been a member of the Society of Toxicology (SOT) since 2004 as a graduate student, post-doctoral student, associate member and full member. She is a member of the SOT special interest group TAO (Toxicologist of African Origin) and has been the Secretary/Treasurer of the SOT specialty section ELSI (Ethical, Legal and Social Issues) for the last 3 years.
SURE Tox The Summer Undergraduate Research Experience in Toxicology program at the University of Illinois will provide high quality research experiences for under-represented minority junior and senior undergraduate students during the summer academic break.
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The Undergraduate Research and Mentoring Opportunities Tuskegee University DAES is excited to offer students a number of undergraduate research opportunities through faculty-funded projects by DAES faculty and its partners at Tuskegee University and other institutions across the U.S. and beyond. Due to the nature of funded for such opportunities, undergraduate research programs are always evolving, thus, we encourage you to visit our site often to learn about these and other opportunities.
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List of biotech/pharmaceutical companies with summer internship opportunities:
I am Daenique Jengelley; a senior from McDonough, GA studying at Tuskegee University. I am majoring in Biology Pre-Health. On campus, I serve as the president for the Biology and MAPS club; I mentor girls at Booker T. Washington High School interested in careers in health professions; and I am a university student ambassador. I am currently applying to graduate programs in biomedical sciences. I look forward to being a part of the ToxMSDT program because of my prior research internship with the American Physiological Society which has motivated me to discover more aspects of research and science.
We are deeply saddened by the news of Ms. Kayla Marie Jones passing. Kayla Marie was a graduate of our ToxMSDT program, 2nd cohort and a graduate from Tuskegee University. She passed away suddenly in a single car accident on October 25, 2020. There have been many comments and tributes shared regarding the life of Kayla Marie Jones. Kayla Marie's life is a shining example of how to make the most of the time we have on this earth. As we mourn the loss of our young scholar, leader, role model, and friend, we are asking that you support the family with a donation as they prepare the final service arrangements. All donations will be sent to the family to help with this unexpected tragedy.
I am Kayla-Marie Jones, an animal science major attending Tuskegee University and I grew - up in Hayward, California. My interest in animal science started when I was of the age 8 I would babysit and give aid to pets. That’s when I decided to tell everyone I wanted to be a “vegetarian,” but I meant a veterinarian. Thus, the reason I was excited to hear about the ToxMSDT program. I’m hoping to add my diverse skills to the program as well as implement it as a holistic veterinarian. My background includes research as an undergraduate in nutrition, cancer biology, renewable energy and marine biology research. Furthermore, I placed 3rd at the Professional Agriculture Workers Conference, I placed 2nd at the Joint Annual Research Symposium, and earlier this year I placed 1st at the Joint Annual Research Symposium. Being a winner and a leader in various organizations on and off campus and serving on a few e-boards has inspired me to explore all aspects of my major. Overall, I thank God for the opportunity to progress within the ToxMSDT program.
I, Kelsea Williams, am currently a Junior Biology Pre-Medicine major at Tuskegee University. I am from the small town of Uniontown, Alabama. Opportunities within my hometown are limited, therefore, I have always strived to be remembered a small individual, from a small town, with big ambitions. I am currently a member of Tuskegee Universities' National Association for the Advancement of Colored People Chapter Pre-Health Committee, Thurgood Marshall College Fund Mentoring Program, and other organizations. My interest in Biology sparked at an early age. I have an aunt who suffers from Cerebral Palsy and has never been able to speak a complete sentence. I have always yearned to be apart of the medical fight.
After completing my undergraduate studies, I will seek my Masters degree in Rural Community Health, and utilmately become a medical doctor.
Dr. Lau is the Manager of Allergens and Toxicology at The Hershey Company where she is the corporate subject matter expert in the management and labeling of food allergens, assessing chemical contaminants in food, and evaluating the safety of novel ingredients. She received her doctorate in Pharmacology and Toxicology from the University of Arizona in 2012 where she obtained 16 publications in peer-reviewed journals. Prior to Hershey, she was a Sr. Associate, Toxicology at S.C Johnson & Son, Inc. Dr. Lau has served on several committees for industry trade associations, such as the Grocery Manufacturers Association and National Confectioners Association. She has been a member of the Society of Toxicology since 2010 and is actively involved with the Women in Toxicology Special Interest Group.
Mu G. Lay, Microbiology Major, Iowa State University.
I like microbiology because microbes amazed me with their roles in other living organisms. My favorite topic would be the usage of microbes in therapeutic treatments and how gut microbes influence human's brain. Some of my hobbies are that I like to play tennis, enjoy swimming and watching historical dramas. Fun facts: I can speak/write/read in three languages : Burmese, Karen and English. My favorite microbe is Pseudomonas aeruginosa mainly because it smell like grapes, without considering other microbiological things that it is capable of doing.
Dr. Pamela (Pam) Lein earned a B.S. degree in Biology from Cornell University in Ithaca, NY, USA, a M.S. degree in Environmental Health Sciences from East Tennessee State University in Johnson City, TN, USA, and a Ph.D. in Pharmacology and Toxicology from the University of Buffalo in Buffalo, NY, USA. She completed postdoctoral training in Molecular Immunology at the Roswell Park Cancer Institute in Buffalo, NY. Currently, Dr. Lein is Professor of Neurotoxicology and Chair of the Department of Molecular Biosciences in the School of Veterinary Medicine at the University of California, Davis (UC Davis) in Davis, CA, USA. In addition, she holds a faculty appointment in the UC Davis MIND Institute. Dr. Lein’s research focuses on the cellular and molecular mechanisms by which environmental stressors, including persistent organic pollutants, organophosphorus cholinesterase inhibitors, and traffic-related air pollution contribute to the pathogenesis of neurodevelopmental and neurodegenerative disorders. Her research has been continuously funded by the U.S. National Institutes of Health over the past 20 years, and she has > 225peer-reviewed publications and book chapters. Dr. Lein is actively engaged in teaching and mentoring veterinary, graduate and undergraduate students in neuropharmacology and neurotoxicology. Her service activities include Director and PI of the NIH-funded training program in environmental health sciences at UC Davis, Director of the Career Development Program in the NIEHS-funded Environmental Health Sciences Center at UC Davis, Director and PI of the NIH-funded UC Davis CounterACT Center of Excellence, and Co-Editor-in-Chief of the journal NeuroToxicology. She recently was recognized for her mentoring with an award from the UC Davis Office of Graduate Studies.
Kennady Lilly is a Junior majoring in biology at Iowa State University. She is from Des Moines, Iowa and has known she wanted to pursue a career in science since a young age. She loves learning about cell biology, anatomy and physiology, and horticulture. Her hobbies include cooking, hiking, as well as practicing and performing with the Iowa State Juggling and Unicycling Club which she has been involved in since the start of her freshman year. Her experiences tutoring introductory biology for underrepresented students have given her a broader understanding and valuable experience in teaching and communicating science. Kennady wishes to do research that aims to create a safer world for future generations, and hopes learning about toxicology can help her achieve her goals.
Kennedy Mayfield-Smith is originally from San Francisco, California. She is a senior at Tuskegee University, AL where she is pursuing a degree in Animal Science. She is part of numerous volunteer organizations on campus and her favorite thing to do is get young minds interested in science. She hopes to learn more about toxicology in relation to animal studies and she is looking forward to meeting with animal health professionals that have toxicology backgrounds.
Dr. J. Eric McDuffie is heading the Mechanistic & Investigative Toxicology (MIT) team at Janssen’s La Jolla site. He joined Janssen in 2007, after a 7-year tenure at Pfizer’s Ann Arbor and Plymouth, MI sites. At Pfizer, he was responsible for providing investigative pathology and immunotoxicology support for Antibacterial, Cardiovascular/Atherosclerosis, Neuroscience, Dermatology, Inflammation, and Oncology projects. At Janssen, Dr. McDuffie’s team provides support to early discovery teams and work as part of a global group of preclinical safety assessment scientists to implement discovery toxicology strategies that enable rapid selection and progression of drug candidates to clinical trials, mostly for the Immunology and Neuroscience Therapeutic Areas. Dr. McDuffie has 17 years of experience in preclinical toxicology, including applications of novel toxicity mechanism-based assays and integrated models to support early target safety as well as to investigate potentially translatable organ-specific liabilities for late stage drug candidates. He earned a BS degree in Biology from Benedict College in Columbia, SC, a PhD degree in Pharmacology from Meharry Medical College in Nashville, TN and an MBA from the University of Phoenix, San Diego, CA. As postdoctoral research fellow at The University of Michigan Medical School in Ann Arbor, Michigan, he collaboratively investigated the role of pro- and anti-inflammatory cyto- and chemokines in liver, kidney, heart, and lung injury responses. He has co-authored over 30 peer‑reviewed manuscripts; presented numerous posters/platform presentations; authored book chapters; and served as book editor. Dr. McDuffie co-edited the benchmark book, Drug Discovery Toxicology: From Target Assessment to Translational Biomarkers (2016). He is the Vice President-Elect to the Southern California Chapter of the Society of Toxicology (SCCSOT). Dr. McDuffie is also a Mentor in the 2017-2018 ToxMSDT Program which is funded by the NIH.
My name is William Mejía and I am a junior majoring in Biology at Iowa State University. I am from San Juan, Puerto Rico and although it is extremely different, I have absolutely loved these past 3 years that I have been in Iowa.
I started as a pre-med student but halfway through my college journey I developed an interest in research, which Is why I applied for the ToxMSDT program. This semester I am starting to do research on the evolutionary relationship between fig wasps and their hosts, which I am extremely excited about.
Adelina Rolea is from Hagerstown, Maryland. She is currently a senior in the Chemistry department at Princeton University pursuing a minor in Environmental Studies. On campus, Adelina is involved with SIFP, an organization that provides professional development opportunities and fosters community for first generation and/or low-income students at Princeton. She is also the co-director of the Princeton chapter of Camp Kesem, a non-profit organization that supports children through and beyond their parent or caregiver’s cancer. Within the ToxMSDT program, Adelina is looking forward to exploring her interest in toxicology and exposure science while also getting to know other students in the program.
Aellah Kaage is currently a senior at Princeton University, where she is pursuing a degree in Molecular Biology. On campus, her research focuses on marsupial antimicrobial peptides and their effects on the immune system. As a Peer Health Advisor, she connects students with health-related resources; as a Mend Leader, she teaches classmates how to repair damaged clothes. She has worked with the Freshman Scholars Institute at Princeton and the Kick-Start event at the University of Kent, both programs designed to help first years acclimate to university life. Aellah is specifically interested in developmental toxicology and exposure to toxicants in food, and is excited to meet other students who are likewise curious about toxicology.
Aellah Kaage is being mentored by Tamara House-Knight.
Alma Avila Oropeza is a senior majoring in Biochemistry with a minor in Spanish at California State University-San Marcos. As a first-generation college student, she is originally from Tijuana, Mexico but lives in San Diego, California. On-campus, she serves as President of the American Chemical Society Student Chapter and a member of the Hispanic Honor Society (Sigma Delta Pi). What she is looking forward to in the ToxMSDT program is meeting students interested in the field of toxicology, as well as gaining professional development. She aspires to learn more and become a better scientist and knows this program will help her to achieve that. She hopes to go to Graduate School and pursue a Ph.D. in Toxicology and have a career as a Forensic/Investigative Toxicologist.
Alyssa Juenke is native to Delano, Minnesota. She is currently a junior at the University of Wisconsin - Madison, studying Microbiology and Pharmacology/Toxicology. On campus, Alyssa works as a lab assistant in the Hyunh Lab, where she is investigating antibiotic resistance. She is most excited to meet people with similar interests and make professional connections in her future field.
Amy Gathings is from Bloomington, California. She currently is a senior at King University in Bristol, Tennessee. She is pursuing a degree in biochemistry with a minor in exercise science. On campus she is a member of the Toxicology Worm Lab where she does research using nematodes. She is extremely interested in the transgenerational effects of chemical exposure on progeny. She is unsure of how she will continue her education after graduation next year but knows that ToxMSDT will help to guide her passions. She is excited to learn about the professions in toxicology and the many innerworkings that go on in the toxicology world.
Andrea P. Maisonet-Sanchez is a senior Microbiology major at the Ana G. Mendez University Carolina campus. Currently she’s the president of the UAGM-Carolina Student Microbiology Chapter (Affiliated with ASM). Her most recent research experience with the USDA-NIFA HSI-BIO Program made her discovered her interest on Toxicology research in Agricultural sciences. One of her goals is to continue her studies and pursue a PhD. She has some knowledge in fields of her interest such as microbiology, soil studies, plant biology, and toxicology as the most recent. From the ToxMSDT program, she is looking forward to exploring and learning more about the field of toxicology as well as gaining experience and learn from professionals in her field of interest.
Andrea Maisonet Sanchez is being mentored by Kristin Licko.
Antonio Aviles is a senior at John Jay College for Criminal Justice majoring in forensic science. He was born in the Bronx but currently lives in Brooklyn. He is currently active in a research program called PRISM at his school where he studied the effect of atrazine and curcumin on PC-12 cells. His hobbies are mainly just binge-watching YouTube and playing basketball. Through this program, his goal is to learn more about the toxicology field and attempt to convert what he learns from the program into a work setting since he has no plans currently of going to graduate school.
Antonio Aviles is being mentored by Saber Hussain.
Besan Khader is Honor chemistry senior at NC A&T in Greensboro, NC. During her experience as an undergraduate student, she is currently working on an organic chemistry research project, where she is developing organic cathode material for rechargeable aluminum/magnesium batteries. Also, she is a member of the Golden Key International Honour Society, the American Chemical Society, and the American Academy of Forensic Science. Inside the ToxMSDT program, she is looking forward to meeting people from all around the country who are either interested in toxicology like her or mentors/professors that will guide her to successfully approach graduate school with enriched knowledge about toxicology. Also, as an outcome of the program, Besan is hoping to network with toxicologists from various field areas and different backgrounds.
Carolyn Billings is a Senior at the University of Nebraska-Lincoln where she majors in Forensic Science. She is a part of the University Honors Program and is also attaining a minor in Chemistry. Carolyn is currently working on a research project at UNL to optimize extraction and analytical methods for N-nitrosoatrazine (NNAT) in blood and tissue samples. Carolyn is excited to be part of the ToxMSDT mentoring program and believes it will help her with plans for after graduation. Throughout the program, she hopes to learn more about all fields of toxicology and make great connections with other mentees and mentors.
Carolyn Billings is being mentored by Saurabh Vispute.
Cassandra Myers is a rising junior at the University of Arizona that is deeply interested in pharmacology and toxicology. She is majoring in Pharmaceutical Science and minoring in Biochemistry. At the University of Arizona, she is a part of the Honors College and the Undergraduate Biology Research Program. Her interest in pharmacology and toxicology was sparked once she became involved in research focusing on toxicity in liver disease—specifically non-alcoholic steatohepatitis. Additionally, she is involved with the University of Arizona's Black Girls' Fitness Club. Cassandra believes that ToxMSDT will prepare her for her pursuit of a Ph.D. in pharmacology and toxicology and career later in life. Through this program, she hopes to learn from professionals in the field and become more confident in her ability to conduct research.
Chanel Staton is a senior at Norfolk State University majoring in Pre-professional Biology. She is interested in Environmental toxicology. She earned a four-year bowling scholarship to NSU and bowl on the NSU Women’s Bowling Team. When she is not studying for academic subjects, she is working out or at bowling practice or competing in Collegiate Bowling tournaments. She is also a member of the National Society of Leadership and Success, the NSU Biology Society and the NSU Beta Kappa Chi National Scientific Honor Society.
Charles Ezenwanne is a senior at Montclair State University (MSU) Majoring in Molecular Biology and minoring in Chemistry. He was born in Lagos, Nigeria and currently lives in Edgewater Park New Jersey. He is currently the President of Global Medical Brigades, conducts research in a genetic toxicology lab, and is a scholar of the Garden State Louis Stokes Alliance for Minority Participation (LSAMP) at MSU. When he is not studying or participating in extracurricular activities, you can find him playing basketball or swimming. Through this program he is looking forward to networking with other students and scientists, to further develop his professionalism, and most importantly to gain insight on the intersection and interdisciplinary roles between toxicology and medicine.
Daniyal Atiq is currently a junior at St. Francis College, Brooklyn NY. He’s pursuing a BS in Biology and minors in Chemistry and Mathematics. His interests in pharmacology, toxicology, and pharmacy stem from his own experience as a patient with a chronic condition. Being diagnosed with systemic lupus at a young age gave him early experiences with healthcare and pharmacy. He later went on to explore different facets of healthcare and research leading him to work as a medical assistant, nursing assistant, and more recently as a laboratory technician and cancer biology research assistant. He learned more about the field of Pharmacy in Summer 2022 via the SHPEP program and discovered his passion for pharmaceutical/drug development research. He hopes to pursue a PharmD and Ph.D. in Pharmacology and Toxicology. Through this, he hopes to impact people’s lives, by developing effective cures and treatments for some of the most problematic conditions, including systemic lupus.
Through TOXMSDT, he hopes to explore his interests in pharmacology, toxicology, and drug development while also building lasting relationships with his mentors and fellow mentees.
Elelta Sisay is a senior at Pomona College, majoring in Molecular Biology. Her chemistry courses in high school were what lit a spark in her and started her fascination with biochemical pathways and biomedical research. Courses in cell biology and medical anthropology in college further drew her towards biomedical research and public health research addressing health disparities. She is interested in pursuing an MD/PhD after college to pursue a career as a physician-scientist. Outside of class, she is a member of her school’s cross-country team and enjoys reading, writing, and drinking coffee. Through ToxMSDT, Elelta hopes to gain further exposure to the various fields of toxicology.
Ember Suh is from Southaven, MS and was raised by her parents who emigrated from South Korea. She is a senior at the University of Mississippi, pursuing a B.S. in Forensic Chemistry with a minor in Biology. At the university, Ember is a member of the Sally McDonnell Barksdale Honors College, the president of Ole Miss Korean Students Association, a Ronald E. McNair Scholar, and a Forensic Chemistry Student Ambassador. Ember has also won several awards at the university, including the 2019 Cynthia Krieser Outstanding Freshman Writing Award for her narrative about her Korean-American identity and the ACS Analytical Chemistry Division Award. Currently, she is researching biocompatibility of ionic liquids and squaraine dyes with blood (particularly DNA) for forensic blood detection. Ember wants to obtain a Ph.D. degree in Toxicology with interests in environmental toxicology (especially air pollution), reproductive toxicology, cancer toxicology, and neurotoxicology, and she wants to apply toxicology to population/community health policies.
Emory Hoelscher-Hull is a current undergraduate student at Montana State University in Bozeman, MT where she is pursuing a degree in Microbiology with a concentration in Environmental Health and a minor in Economics. As a Seattle native, she has witnessed firsthand the burden of environmental health issues disenfranchised groups face. This experience, along with a love of science and a penchant for public service has led her to consider a career in public health. A particular area of interest for her is the way our food systems contribute to health outcome inequality, and she sees toxicology as an exciting way to approach this issue. She is particularly excited to learn more about the regulatory and governmental/non-profit watchdog side of Toxicology and to meet other mentees and learn from their experiences.
Fahad Nassam is a first-generation student attending North Carolina A&T State University. He is a senior biology student with a minor in chemistry. He lives in Greensboro North Carolina, but is originally from Togo, a small country located in west Africa. Fahad is pursuing a Ph.D. in microbiology/immunology. His hobbies include eating and sleeping. He is an athlete, so he likes to work out and play soccer. Fahad is looking forward to making new connections, being exposed to new things, and gaining new skills. He wants to better himself as a scientist and explore the different fields of toxicology.
Fahad Nassam is being mentored by Nathan Pechacek.
Fatina Mulumba is an African Muslim woman from Burundi. She is an incoming sophomore at Bates College and plans to major in Biochemistry with a minor in a Language on the Pre-Med track. On Campus she is on the student advisory committee for Equity, Inclusion, and Antiracism at Bates College. She is also involved in the Public Health Initiative as well as Chinese Club. She is super excited to meet other BIPOC individuals who are interested in STEM related careers and the opportunities that she will gain from participating in the ToxMSDT program. After completing her undergraduate studies, she plans to enroll in medical school to become a heart surgeon. Being in the ToxMSDT program will help her forge the path that she needs to get there.
Cristina M Santana Maldonado is a PhD Candidate in the Interdepartmental Toxicology Program at Iowa State University as part of Wilson K Rumbeiha’s laboratory. She received her B.S. in Biological Sciences at Iowa State University and joined Dr. Wilson Rumbeiha’s team to study the toxic effects of hydrogen sulfide on the respiratory system. She was a mentee in the 2017-2018 cohort which led her to pursue a career in toxicology and will be serving as the teaching assistant to guide mentees with module questions.
Gabriel Rosario-Ortiz is a senior Natural Sciences major at the University of Puerto Rico, Cayey. Currently he is the Historian of the Beta Beta Beta National Biological Honor Society (Tribeta). He discovered research in his freshman year with the RISE program and a summer internship at Tufts University. These experiences convinced him that research is the best option for his future. One of his goals is to continue his studies and pursue a PhD. He has some knowledge in fields that interest him such as cancer research, neuroscience, and toxicology as the most recent. He wanted to be part of the ToxMSDT program to gain experience and decide the right field for his future.
Gisselle Soberanes Rodriguez is a senior at Arizona State University, majoring in Pharmacology and Toxicology with a minor in Human Nutrition. Gisselle was born and raised in Phoenix, Arizona. She is a first-generation college student and is very passionate about Environmental Toxicology. Gisselle is involved in research at ASU that pertains to doing Dose-Response and Phyto-accumulation tests on Trifluoroacetic acid (TFA) in desert plants native to Arizona. She also takes part in the New College Environmental Health Science Scholars at ASU. She is eager to meet her other peers and mentors in the ToxMSDT program. As well as further her knowledge on Toxicology through the program.
Grant Fleming is a native of Harrisburg, Pennsylvania, and a junior at the Lincoln University of Pennsylvania. Lincoln is the first historically black college and is in Chester County, Pennsylvania. Grant is pursuing a major in Biology and a minor in the Visual Arts. On campus, Grant is a member of both the Japanese and the Esports Interest Club. During the Summer of 2021, Grant served as a research intern under Dr. Thomas Gluodenis, his former Organic Chemistry professor. Grant’s research was focused on investigating the toxicity of metals commonly found in consumer products. Through ToxMSDT Grant is looking forward to connecting with a mentor, traveling, and meeting other mentees. After graduation Grant would like to pursue his post graduate studies in Toxicology, Virology, or Medicine. In his spare time Grant likes to cultivate his herb garden and play videogames.
Harriet Akyen-Odoom was born in Ghana and raised in New York. She is currently attending Bates College, planning to major in BioChemistry with a minor in Japanese language. She enjoys reading and listening to music in her spare time. Harriet is most looking forward to the extra experience she will get from the program that will lead to her desired career path, Pathology.
Ivy Thompson is a native of Southern, California and is a senior at San Diego State University. In May 2023, she will be finishing her B.S. in Biology with a concentration in Cell and Molecular. Ivy is heavily interested in the impression of toxicology impacting oncological/disease research, forensic studies and pharmaceuticals allowing for an improving quality of life. Growing up and driving through areas of Los Angeles exposed her to high, dense levels of pollution in an industrial, overpopulated setting. This grew her interest in toxicology and how these toxins can be catastrophic to the environment and living organisms. Because of this, she is a strong advocate for being eco-friendly and expanding on health policies, holding a passion for finding more sustainable ways of living and being mindful of exposure to harmful toxins and chemicals. More importantly, the loss of her mother due to brain cancer is the strongest driving factor that opened her into pursuing a career in toxicology, regarding the discovery of new drugs and the design of clinical trials. With the broadness of her interests in toxicology, she plans to take this experience to dive deeper into specifics with expanding her knowledge in concepts of toxicology alongside mentors and mentees. Being a woman of Filipino-American descent, she is driven to be an advocate to other women of underrepresented ethnic backgrounds within STEM and the toxicology field. Outside of her studies, she enjoys playing the piano and bass guitar, yoga and dancing. Ivy plans on applying for graduate school and achieving her master’s degree in Toxicology. Through ToxMSDT, she plans on broadening her knowledge in various Toxicology fields as well as networking with other like-minded individuals.
Jarett Reyes George grew up in North Plainfield, New Jersey and is now entering his senior year at Rutgers University. He is currently pursuing a BS in Biochemistry with a focus in toxicology. He is a first gen student, EOF scholar, a brother of Lambda Sigma Upsilon Latino Fraternity Inc. (LSU). Jarett has worked for the Chemistry department and held office hours for general chemistry, has been a tutor for the learning center for general/ and organic chemistry as well as general physics. Has Served as a mentor for other EOF students aspiring to get into research. Jarett discovered research after his freshman year of college and has continued down that path ever since. After graduation, he aspires to obtain a PhD in toxicology. His goal is to conduct clinical trials or do medical research. He wanted to be part of the ToxMSDT program to gain experience and keep a good head on his shoulders as well as meeting professionals that can guide him in the wright direction.
Jarett Reyes George is being mentored by Nagaraju Anreddy.
Jennae Whitted is a senior at Trinity Washington University that is interested in pharmacology and toxicology, as well as environmental toxicology. Jennae is majoring in Biology and minoring in Bioinformatics. Her interest in pharmacology and toxicology peaked once she attended the SOT Conference meeting last year. She is involved in Trinity Washington University's Ladies Fierce. In. Research. Science. and Technology Stem Club. Jennae believes that ToxMSDT will prepare her for a pursuit of a Ph.D. in pharmacology and toxicology and government or industry research career later in life. She hopes to learn from professionals in the field and build my professional network.
Jennae Whitted is being mentored by Doug Donahue.
Jera Wongsrijan was born and raised in Arvin, CA. She is a third year at University of California, Los Angeles, majoring in Biochemistry and minoring in Film and Television. On campus, she is a part of the Southeast Asian (SEA) Admit Program that invites newly admitted Southeast Asian students to explore campus and learn about the different opportunities and experiences of current UCLA students. Off campus, she works part-time at Nike and leads their merchandising as well as the Diversity & Inclusion program. From the ToxMSDT program, she is looking forward to exploring and learning more about the field of toxicology and building a strong network within the community.
Jonathan Patruno is currently in his senior year at St. Francis College in Brooklyn, New York. Residing in Queens, New York, he is in pursuit of a Chemistry degree, with he plans to use to expand his overall knowledge in said field. In preparation of his upcoming graduation, he is making an effort to stay busy within the field of Chemistry doing his best to hone his laboratory skills by participating in independent research which allows him to become proficient in HILIC processes as well as other modes of chromatography. His passion for chemistry has allowed him to confidently state that his career will involve a form of intensive research in a lab environment. Having said that, ToxMSDT will allow him to be exposed to many career paths and possibilities that await him in the future. He believes that his hard work in his undergraduate journey has granted him this opportunity, and he intends to continue working hard to make his dreams become a reality with ToxMSDT.
Kaitlynne (Katie) Eggleston is a senior at King University in Bristol, Tennessee. She is majoring in biology and psychology. On campus she worked in the Toxicology Worm Lab researching with nematodes. She focused on pesticide's effects on neurons, specifically Parkinson's Disease. This led to her larger interest in neurotoxicology. After her time at King, she is unsure of how she will continue her education but knows this program will lead her in the right direction. During the ToxMSDT program, she is excited to learn more about career paths that are available and building networks in the field.
Kaitlynne Eggleston is being mentored by Jason Cannon.
Kathy De La Torre is a senior at the University of Illinois at Urbana-Champaign majoring in Biochemistry with a minor in Bioengineering and Chemistry. She is currently a lab assistant in Dr. Jodi Flaws' lab studying reproductive toxicology. In the future, Kathy hopes to pursue an M.D./PhD to help advance medicine meanwhile attending to patients. In the ToxMSDT program, Kathy is looking forward to exploring the different fields of toxicology.
Lily Hoang is a sophomore at the University of Louisville, KY, where she is pursuing a degree in Biology and Anthropology, with a concentration in Genetics, and a minor in Spanish. Although born-and-raised in Louisville, Kentucky, she is a first-generation American of Vietnamese descent; this had led to her dedication to become involved in assisting her cultural heritage of their past tribulation— this specifically being Vietnam’s exposure to Agent Orange during the Vietnam War. With her participation in the ToxMSDT program, she hopes to develop dynamic relationships with her mentor and peers as well as expand her knowledge of toxicology. Currently, she is studying under Dr. Wise’s Laboratory of Environmental & Genetic Toxicology in which she is researching if hexavalent chromium targets separase in human lung cells. During her free time, she loves to give back to her community by volunteering at medical sites, anthropological centers, and immigration and refugee centers. Although she currently contemplates pursuing medical science or academic research within the realms of genetics, toxicology, and environmental health, her ultimate goal is to help and forward society to a better future.
Mahmoud Salem is a sophomore majoring in Clinical Laboratory Sciences at Stony Brook University. He is very passionate about the clinical applications of science and biochemistry. He aims to complete a MSc in Analytical Toxicology after he graduates and wants to be involved in research. One of his most foundational values is a passion for learning and curiosity. The human body and the way chemistry can affect it is something he aspires to master and gain a deeper understanding of. He hopes to use this knowledge in a practical sense to help those who are vulnerable and sick.
Marieli Jimenez is from Passaic, New Jersey. She is currently a junior at New Jersey Institute of Technology (NJIT), where she is pursuing a degree in Biomedical Engineering. Outside campus she is a mother. As a mother she strives to be a great example for her children and prove that anyone can achieve their goals. Within the toxicology program she is looking forward to learning about this interesting field of toxicology, meeting other students with the same interests and becoming a mentor for future generations.
Matthew Fehrle is native to Bensalem, Pennsylvania, and is currently a Sophomore at Penn State University studying Biochemistry and Molecular Biology. On campus, Matthew is a lab assistant in the Okafor Lab, using Python and Molecular Dynamics (MD) simulations to study protein receptors and their interactions with different ligands. Post Graduation, he is interested in pursuing a career in Medical Lab Sciences and Drug Development, and is excited to learn more about the field of toxicology, especially in regards to public safety and quality assurance. Matthew Fehrle is being mentored by Dan Arrieta.
Melanie Madrigal is a rising junior in Environmental Toxicology at UC Davis. On campus, she’s a part of the Chondronikola Lab where they study the effects of time-restricted eating on metabolism. Growing up in the San Fernando Valley she got to see the effects that water pollution has on public health. This interested her in the field of toxicology and the role that toxins can play in our bodies. Her current interest is in pharmaceutical toxicology but she’s excited to learn more about toxicology and get to learn from mentors and mentees. After graduation, she plans on pursuing post-graduate studies in toxicology. During her free time, Melanie enjoys cooking, reading, and making a good cup of coffee.
Melanie Madrigal is being mentored by Archit Rastogi.
Melissa Rosas is a Senior at CUNY John Jay College of Criminal Justice majoring in Forensic Science with a concentration in Toxicology. She is currently a research assistant at Dr. Champeils lab at John Jay. When Melissa is not at school or at work, she enjoys going to the gym and boxing. Melissa hopes to obtain her masters in toxicology and to work with the DEA. Through the program she hopes to learn more about the different fields of toxicology and to continue to grow professionally.
Midori Flores is a San Antonio, Texas native entering her senior year at St. Mary's University. She is currently pursuing a BS in Environmental Science with a minor in Biology. Her academic affairs at StMU include being the President of the university's National Society of Leadership and Success (NSLS) chapter, Founder and Vice President of StMU Humanitarians, and MARC U*STAR Scholar. Midori's extracurriculars include hiking, spending time with friends and family, and writing; she has published a children's book titled, "We Are All Human". Midori plans to pursue a Ph.D. in Toxicology/Environmental Health and is committed to a journey of life-long learning. She is ecstatic about being in the ToxMSDT program and learning from professionals in her field of interest.
Mikayla Ortiz is from Olmsted Falls, Ohio. She is currently a sophomore at Ashland University, where she is pursuing a degree in Toxicology. On campus, Mikayla was a part of Ashland University’s Pathways Pre-Orientation Program, is the Social Media Manager for the Sustainability Club, and will be conducting undergraduate independent research in the fall on ‘Improving Methods of Extraction of Hydrophobic Pesticide Contaminants from Sediment’. During the ToxMSDT program, Mikayla is most excited about learning about all the different occupations a Toxicologist can do and meeting many different professionals who work in them.
Nader Abdalla is a sophomore at the University of South Florida, majoring in Biomedical Sciences. He was born in Florida but has often visited his home country of Egypt. Nader currently performs research in the Oxidative Stress Group under Dr. Marcus Cooke studying the activity of DNA repair mechanisms in both in vitro and in vivo models. The ToxMSDT program will provide him the perfect opportunity to further his understanding of the field of toxicology and research in general. Nader is looking forwards to preparing for his future studies and excited to see everyone in the field during the annual SOT meeting.
Nader Abdalla is being mentored by Nicole Soucy.
Neiah Richard is from Houston, TX. She is currently a junior at the University of St. Thomas in Houston, TX. She is pursuing a biology degree on the premed track. On campus she is a member of the Beta Beta Beta (Tribeta) Honor Society. Currently, she is a part of a research group studying the Correlation Between Fruit Fly Mortality and Offspring Development After Exposure Toluene. After graduating from undergrad, she plans to attend medical school and specialize in Infectious Disease. By participating in the ToxMSDT program, she hopes to expand her knowledge about toxicology and form positive relationships with her mentors and peers.
Neiah Richard is being mentored by Samuel Buxton.
Nicole Rivera Acevedo is currently a senior in the InterAmerican University of Puerto Rico, Aguadilla campus majoring in Biology. She currently offers on-campus tutoring services to academically strengthen students in Biology and Math courses for college success. At the same time, she gets involved with her communities through student associations such as: Society for the Advancement of Chicanos/Hispanic (SACNAS), MEDLIFE Movement, Leaders of Honor Association, etc... As a Puerto Rican, she has seen that there is a lack of representation for the development of toxicology. This is why she is interested in pursuing a career in clinical toxicology. Being part of the ToxMSDT makes her have the objective of expanding her knowledge, networking and delving into what it means to be a toxicologist in all its facets.
Nicole Rivera is being mentored by Acevedo ArgelIslas-Robles.
Noha Elbedwihy is a Biomedical Engineering major at New Jersey Institute of Technology. She is currently a member of the NJIT prosthetics club, where she designs prosthetics that are safe and functional for injured animals to use. She has always had an interest in helping others, whether that be directly or indirectly, and that’s why ToxMSDT is the perfect program for her. The ToxMSDT will provide her with the great opportunity of doing just that and more. She is excited to gain more experience in the biology (specifically toxicology) field to be more prepared for graduate school which will help her in perusing her goals of providing safe to use medical devices for others in need.
Olesia Headen is a rising senior at North Carolina Central University. She is a chemistry student with a concentration in Forensic Science and a minor in Biology. After graduating from undergrad, she plans to pursue a Master's in Forensic Toxicology and possibly a Ph.D. also. In the future, she hopes to become a toxicologist and work in a forensics lab for a federal agency.
Renata Montanez Lopez born in Tepic, Nayarit, Mexico and raised in Arbuckle, California. She is currently enrolled in Woodland Community College, in hopes to transfer to UC Davis and obtain a major in animal science. Her greatest goal is to go to veterinary school. As she attends school, she also works as a registered veterinary technician at a veterinary hospital. In her free time she enjoys riding horses and spending time with her pets. Renata is looking forward to gaining experience and learning about different career paths and this program is helping gain the experience she desires.
Renata Montanez Lopez is being mentored by Logeswari Ponnusamy.
Savannah White is a sophomore majoring in Biology at the University of Mississippi. While being a first-gen premed is tough, she is willing to put in the work in order to fulfill her ultimate goal of becoming an emergency medicine physician. Around middle school is when her interest in the medical field began. Learning about how the different systems worked together to sustain the body intrigued her and the more she learned, the more her interest solidified. She is excited for the knowledge she will gain from this program as in the emergency room, she is sure to encounter an array of cases including those involving toxic substances. When she is not studying or preparing for med school, she can be found oil painting, sketching, or reading.
Shreya Sharma is a senior attending the University of Colorado Boulder. She is majoring in Biochemistry and Spanish for the professions. Currently, Shreya works as a medical assistant in an allergy clinic and as a registered behavioral technician where she helps deliver ABA therapy to individuals who have been diagnosed with autism or have experienced severe trauma. On campus, she is a co-president of a student run non-profit called Globemed that focuses on making healthcare more accessible to marginalized groups, both locally and internationally. She is passionate about working with communicates of underserved background and is heavily involved in the multicultural program at her university. She is an instructional assistant and a peer mentor for undergraduate students within this program and works to provide more resources and support to her students.
Shreya Sharma is being mentored by Monica Langley.
Taina Moore is a native of Northern, Illinois and a senior at Tuskegee University. In May 2023, she will have achieved a B.S in Chemistry with a Concentration in Biochemistry. Taina is heavily interested in the impact pharmacology and toxicology can have on producing healthier living conditions and products, especially in the cosmetic industry. She sees this program as an opportunity to learn more about various types of toxicology and a learning environment that will push her to build the fundamentals as a researcher, leader, and overall person. During her time at Tuskegee, Taina has served as the Vice-President of the TU Student Chapter of the American Chemical Society, Sophomore Representative in the Student Government Association, and she is a new initiate of the Marching Crimson Piperettes Dance Team. This semester she intends on working in the chemistry department as a laboratory assistant. Taina plans on applying to graduate school to pursue a PhD degree in toxicology.
Taina Moore is being mentored by Esther Haugabrooks.
Tasnia Hossain is a junior at Rutgers SEBS, pursuing a BS in Biochemical Toxicology and a minor in Philosophy. She recently joined an on-campus lab with projects focused on developmental toxicology using the zebrafish model. Tasnia was born and raised in NJ, the oldest of four. When she isn’t studying/sleeping, she loves to swim, cook, and write. Tasnia is very pleased to be a mentee this academic year and hopes that the ToxMSDT program will help her grow closer to achieving a career in medical toxicology, so that she can affect change for those suffering from illness and disease.
Tasnia Hossain is being mentored by Cindy Roegge.
Tiffani Roberts is from Chesterfield, Virginia. She is currently a Junior at the University of North Carolina at Pembroke. She is majoring in Chemistry with a concentration in Forensics. She is also minoring in Criminal Justice and Psychology. She isn't quite sure how toxicology will fit into her future academic career, but she would love to continue learning about the subject as it widely interests her. In the future she hopes to work in Forensic Chemistry for a Federal Agency.
Tiffani Roberts is being mentored by Colleen McLoughlin.
Tre’Von Williams hails from Ellenwood, Georgia. He attends Albany State University currently as a sophomore this upcoming semester. He is currently majoring in Forensic Science and finished his first semester as a freshman with a 3.5 GPA. When at school he works as a Student Assistant for a NASA Outreach program and a member of the M.A.L.E.S Mentors at ASU. Being a member of the ToxMSDT Program, he is looking to have a strong bond with his mentor that surpasses this program and to gain a better understanding of the toxicology field.
Vanessa Grifford is a senior at Arizona State University majoring in Pharmacology and Toxicology. She has a keen interest in researching psychedelics and will soon be applying to PhD programs. She is a returning first-generation college student. Through Students for Sensible Drug Policy, she has completed the certification to be a peer drug educator and have open, honest conversations with the public about drugs and drug users. Currently, she is a laboratory assistant in Dr Pamela Marshall’s eukaryotic genetics lab where they are working on improving an existing T Cell lymphoma drug that also shows promise in treating other types of cancers as well as Alzheimer’s disease. Her part of this project involves testing analogs for efficacy, cytotoxicity, and mutagenicity. In her free time, Vanessa likes to be out in nature and near water. She is hoping this mentorship will allow her the opportunity to network with other scientists and students to gain further skills that will benefit her future career path.
Vanessa Grifford is being mentored by Ahmed Abdelmoneim.
To get the ToxMSDT program started, 15 undergraduate student mentees were recruited into the program in spring 2017. Of these eight students were recruited from ISU and seven from Tuskegee University. Students were sophomores, juniors and seniors enrolled in STEM subjects. They all were meritorious students with a GPA of at least 3.0 or higher. Students applied competitively to to enter the program. The best candidates were selected and matched to a mentor who is an established toxicologist in academia or industry.
Benefits to mentees:
Knowledge and skills gained through this year-long program will position mentees to compete effectively for graduate school training positions
Mentees will gain a supportive network of mentors and fellow mentees
Knowledge gained through this program will apply to the broader biomedical, behavioral, and clinical research enterprise, all relevant to NIH
Fifteen undergraduate student mentees from historically underrepresented ethnic/racial backgrounds were recruited into the program in the spring and summer of 2017. Student mentees were recruited from Iowa State University, Tuskegee University, Georgia Southern University, Agnes Scott College, and Florida International University. Students are sophomores, juniors and seniors enrolled in STEM majors. The candidates are meritorious students with a GPA of at least 3.0 or higher. Students applied competitively to enter the program. The best candidates were selected and matched to a mentor who is an established toxicologist in academia or industry. Benefits to mentees:
Knowledge and skills gained through this year-long program will position mentees to compete effectively for graduate school training positions
Mentees will gain a supportive network of mentors and fellow mentees
Knowledge gained through this program will apply to the broader biomedical, behavioral, and clinical research enterprise, all relevant to NIH
For the 2021/22 cohort, twenty-five Science, Technology, Engineering, and Math (STEM) sophomore, juniors, or seniors from underserved communities were selected to participate in the year-long mentoring program. Candidateswere selected from a competitive pool of applicants andmatched 1:1 with an established toxicologist inindustry, academia, government, or nonprofit entities from across the country. Mentee training is provided at the University of California Davis inaugural kick-off workshop preparing mentees for regular meetings with their mentor to receivecareer guidance. A job shadowing visit offers insight into mentor’s career path in toxicology and on the skills needed at the mentor’s current place of work. In addition, mentees attend the annual Society of Toxicology conference to continue networking efforts with professionals and to discover future career opportunities.
To conclude the annual program, mentees attend the capstone event at Tuskegee University where successful candidates will receive a Certificate of Completion at the culmination of the program.This certificate marks successful accomplishment of other program components including training in research ethics and the completion of six online learning modules providing knowledge about important topics in toxicology ranging from ‘Principles of Toxicology’ to ‘Applied Systems Toxicology’.
Are you interested in joining the ToxMSDT program...
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Application Process
Fill out the application when it reopens.
Upload unofficial undergraduate transcripts, including all coursework and current enrollment, with the application
Send the Reference Form to a faculty who knows you and your academic performance well. For example, you can send it to a faculty member who supervised or assessed you in a class, on an internship or on a research project.
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Applications for 2023-2024 will open February 15, 2023.
Eligibility
Minimum cumulative GPA of 3.0
Completion of at least one semester of general biology and general chemistry
Enrolled in an accredited undergraduate institution at the time of application, with continuing enrollment for the next academic year concurrent with the ToxMSDT program
Member of a group underserved in the biomedical sciences (for example, underrepresented racial/ethnic groups; those from disadvantaged backgrounds such as low socioeconomic status, or grew up in a rural or inner-city setting; NIH notice).
US citizen or US permanent resident
Due to institutional requirements we encourage applications from fully vaccinated COVID-19 individuals only.
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Role of a Mentee: Each mentee will attend the mentee training provided at the University of California Davis inaugural kick-off workshop preparing mentees for monthly meetings with their mentor to receive career guidance. A job shadowing visit offers insight into mentor’s career path in toxicology and on the skills needed at the mentor’s current place of work. In addition, mentees attend the annual Society of Toxicology conference to continue networking efforts with professionals and to discover future career opportunities. To conclude the annual program, mentees attend the capstone event at Tuskegee University where successful candidates will receive a Certificate of Completion at the culmination of the program. This certificate marks successful accomplishment of other program components including training in research ethics and the completion of six online learning modules providing knowledge about important topics in toxicology ranging from ‘Principles of Toxicology’ to ‘Applied Systems Toxicology’. Throughout the year we also use the National Research Mentoring Network (NRMN) platform to enhance further communication between all members of our community.
Benefits to Mentees:
Knowledge and skills development to compete effectively for graduate school toxicology programs
Individualized guidance and support to foster career development in toxicology
Building a supportive network of mentors and fellow mentees
Participation in the largest meeting in the field of toxicology, the Society of Toxicology’s annual conference
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Meet the 2022-2023 Mentees
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For the 2022/23 cohort, twenty-five Science, Technology, Engineering, and Math (STEM) sophomore, juniors, or seniors from underserved communities were selected to participate in the year-long mentoring program. Candidates were selected from a competitive pool of applicants and matched 1:1 with an established toxicologist in industry, academia, government, or nonprofit entities from across the country. Mentee training is provided at the University of California Davis kick-off workshop preparing mentees for regular meetings with their mentor to receive career guidance. A job shadowing visit offers insight into mentor’s career path in toxicology and on the skills needed at the mentor’s current place of work. In addition, mentees attend the annual Society of Toxicology conference to continue networking efforts with professionals and to discover future career opportunities.
To conclude the annual program, mentees attend the capstone event at Tuskegee University where successful candidates will receive a Certificate of Completion at the culmination of the program. This certificate marks successful accomplishment of other program components including training in research ethics and the completion of online learning modulesand case studies providing knowledge about important topics in toxicology ranging from ‘Principles of Toxicology’ to ‘Applied Systems Toxicology’.
Role of a Mentee: Each mentee will attend the mentee training provided at the University of California Davis inaugural kick-off workshop preparing mentees for monthly meetings with their mentor to receive career guidance. A job shadowing visit offers insight into mentor’s career path in toxicology and on the skills needed at the mentor’s current place of work. In addition, mentees attend the annual Society of Toxicology conference to continue networking efforts with professionals and to discover future career opportunities. To conclude the annual program, mentees attend the capstone event at Tuskegee University where successful candidates will receive a Certificate of Completion at the culmination of the program. This certificate marks successful accomplishment of other program components including training in research ethics and the completion of six online learning modules providing knowledge about important topics in toxicology ranging from ‘Principles of Toxicology’ to ‘Applied Systems Toxicology’. Throughout the year we also use the National Research Mentoring Network (NRMN) platform to enhance further communication between all members of our community.
Benefits to Mentees:
Knowledge and skills development to compete effectively for graduate school toxicology programs
Individualized guidance and support to foster career development in toxicology
Building a supportive network of mentors and fellow mentees
Participation in the largest meeting in the field of toxicology, the Society of Toxicology’s annual conference
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Meet the 2021-2022 Mentees
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For the 2021/22 cohort, twenty-five Science, Technology, Engineering, and Math (STEM) sophomore, juniors, or seniors from underserved communities were selected to participate in the year-long mentoring program. Candidateswere selected from a competitive pool of applicants andmatched 1:1 with an established toxicologist inindustry, academia, government, or nonprofit entities from across the country. Mentee training is provided at the University of California Davis inaugural kick-off workshop preparing mentees for regular meetings with their mentor to receivecareer guidance. A job shadowing visit offers insight into mentor’s career path in toxicology and on the skills needed at the mentor’s current place of work. In addition, mentees attend the annual Society of Toxicology conference to continue networking efforts with professionals and to discover future career opportunities.
To conclude the annual program, mentees attend the capstone event at Tuskegee University where successful candidates will receive a Certificate of Completion at the culmination of the program.This certificate marks successful accomplishment of other program components including training in research ethics and the completion of six online learning modules providing knowledge about important topics in toxicology ranging from ‘Principles of Toxicology’ to ‘Applied Systems Toxicology’.
Are you interested in joining the ToxMSDT program...
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Application Process
Fill out the application when it reopens.
Upload unofficial undergraduate transcripts, including all coursework and current enrollment, with the application
Send the Reference Form to a faculty who knows you and your academic performance well. For example, you can send it to a faculty member who supervised or assessed you in a class, on an internship or on a research project.
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+
+
+
+
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Applications for 2023-2024 will open February 15, 2023.
Eligibility
Minimum cumulative GPA of 3.0
Completion of at least one semester of general biology and general chemistry
Enrolled in an accredited undergraduate institution at the time of application, with continuing enrollment for the next academic year concurrent with the ToxMSDT program
Member of a group underserved in the biomedical sciences (for example, underrepresented racial/ethnic groups; those from disadvantaged backgrounds such as low socioeconomic status, or grew up in a rural or inner-city setting; NIH notice).
US citizen or US permanent resident
Due to institutional requirements we encourage applications from fully vaccinated COVID-19 individuals only.
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Role of a Mentee: Each mentee will attend the mentee training provided at the University of California Davis inaugural kick-off workshop preparing mentees for monthly meetings with their mentor to receive career guidance. A job shadowing visit offers insight into mentor’s career path in toxicology and on the skills needed at the mentor’s current place of work. In addition, mentees attend the annual Society of Toxicology conference to continue networking efforts with professionals and to discover future career opportunities. To conclude the annual program, mentees attend the capstone event at Tuskegee University where successful candidates will receive a Certificate of Completion at the culmination of the program. This certificate marks successful accomplishment of other program components including training in research ethics and the completion of six online learning modules providing knowledge about important topics in toxicology ranging from ‘Principles of Toxicology’ to ‘Applied Systems Toxicology’. Throughout the year we also use the National Research Mentoring Network (NRMN) platform to enhance further communication between all members of our community.
Benefits to Mentees:
Knowledge and skills development to compete effectively for graduate school toxicology programs
Individualized guidance and support to foster career development in toxicology
Building a supportive network of mentors and fellow mentees
Participation in the largest meeting in the field of toxicology, the Society of Toxicology’s annual conference
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Meet the 2022-2023 Mentees
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For the 2022/23 cohort, twenty-five Science, Technology, Engineering, and Math (STEM) sophomore, juniors, or seniors from underserved communities were selected to participate in the year-long mentoring program. Candidates were selected from a competitive pool of applicants and matched 1:1 with an established toxicologist in industry, academia, government, or nonprofit entities from across the country. Mentee training is provided at the University of California Davis kick-off workshop preparing mentees for regular meetings with their mentor to receive career guidance. A job shadowing visit offers insight into mentor’s career path in toxicology and on the skills needed at the mentor’s current place of work. In addition, mentees attend the annual Society of Toxicology conference to continue networking efforts with professionals and to discover future career opportunities.
To conclude the annual program, mentees attend the capstone event at Tuskegee University where successful candidates will receive a Certificate of Completion at the culmination of the program. This certificate marks successful accomplishment of other program components including training in research ethics and the completion of online learning modulesand case studies providing knowledge about important topics in toxicology ranging from ‘Principles of Toxicology’ to ‘Applied Systems Toxicology’.
Dr. Ahmed Abdelmoneim is an assistant professor and clinical veterinary toxicologist at the Department of Comparative Biomedical Sciences, Louisiana State University. His research program focuses on understanding how environmental contaminants and chemicals of concern may impact the early development of organisms, and on developing new technologies and techniques in an effort to advance the field of toxicology and address some of the challenges facing its community. In particular, he is interested in assessing impacts on the neuroendocrine system of organisms through investigations performed at different levels of biological organization. He earned his BVMS (2007) from the Faculty of Veterinary Medicine, Assiut University (Egypt), and his M.Sc. in Ecotoxicology (2011) from the University of Poitiers (France). Dr. Abdelmoneim received his Ph.D. (2012) in Aquatic Toxicology from Purdue University and went on to complete two postdoctoral fellowships with a focus in toxicology at Cornell University. He authored/co-authored more than nine peer-reviewed journal articles and has been a member of several professional societies, including the Society of Toxicology and the Society of Environmental Toxicology and Chemistry. He provided mentorship to a number of undergraduate and graduate students who have grown to be scientists and health professionals.
Dr. Rastogi is an Assistant Director of Preclinical Development at Ionis Pharmaceuticals with expertise in mechanistic and developmental toxicology. At Ionis, he drives comprehensive, integrated safety assessments of drug candidates. Prior to joining Ionis, Dr. Rastogi worked at Gradient Corporation, an environmental toxicology consulting firm based in Boston. In this role, he served as a subject matter expert on a variety of projects in the environmental, pharmaceutical, and medical device field. He earned his doctorate in Molecular and Cellular Biology from the University of Massachusetts, Amherst. His research focused on identifying the mechanisms by which endocrine disrupting chemicals exert toxicity in the developing embryo. He has won over 15 awards from the Society of Toxicology, Society for Redox Biology and Medicine and the American Association for the Advancement of the Sciences for his research, including the Carl C Smith Award and the Sheldon D Murphy Award from Mechanisms SS. Dr. Rastogi has been an active SOT member since 2016, and is the current Vice-President Elect of the Mechanisms Specialty Section. He has authored several peer-reviewed research articles and presented his work to diverse scientific and non-scientific audiences, including US legislators.
Dr. Argel Islas-Robles works as Toxicologist and Study Director at the Institute for In vitro Sciences Inc. (IIVS). Additionally he is appointed as Program Leader for the Skin Sensitization program at IIVS. Dr. Islas-Robles oversees the design, conduction, data analysis, and reporting of pre-clinical in vitro toxicology safety testing including skin and eye irritation and corrosion and multiple endpoints for skin sensitization. Additionally, he direct studies aimed to assess the efficacy of cosmetic products such as ocular nociception. He works with industry, government, and other non-profit organizations for the implementation, use and promotion of novel non-animal methods in toxicology for the testing of cosmetics, personal use products, agrochemicals, pharmaceuticals, pesticides, among others. He earned a Bachelor’s degree in Biopharmaceutical Chemistry (2012) from the University of Guanajuato (Mexico), and his Ph.D. in Pharmacology and Toxicology (2019) from the University of Arizona (USA). Dr. Islas-Robles is an active member of the Society of Toxicology, and the Hispanic Organization of Toxicologists.
Dr.Betina J. Lew is a Board Certified (DABT) and European Registered (ERT) Toxicologist with broad experience in Medical Devices and Consumer Goods Industry. She is currently an Associate Director of Toxicology and Biocompatibility at Johnson&Johnson (J&J) where she manages the Ethicon Inc (Somerville, NJ) team and oversees the safety of a diverse portfolio which includes the wound closure and healing, biosurgery and mentor breast implants business units. Betina manages the team and provides scientific input in all aspects of the toxicological assessments of the medical devices and biologics. She worked as a Toxicologist and Safety Manager in other companies (such as Procter and Gamble and Reckitt Benckiser). Dr. Lew was a Postdoctoral Trainee in Toxicology at the Department of Environmental Medicine, University of Rochester (NY) for more than four years. She earned a PhD through a joint program from São Paulo State and Michigan State University, a M.S. from The Hebrew University of Jerusalem (Israel) and a B.S. from São Paulo State University. Since 2006, Dr. Lew has been an active member of the SOT and served on several committees. Currently the Co-Chair (2020-2021) and Incoming Chair (2021– 2022) of the Membership committee, which she was elected member in 2019. She was President of Women in Toxicology (WIT, 2016-2018), Councilor of Risk Assessment Specially Session (RASS, 2016-2019). She was a member of CRAD (2013-2016), President of the Hispanic Organization of Toxicologists (HOT) from 2011 – 2013, their Councilor (2009–2011) and Chair of the Awards and Education committees (2010–2012). She has also served as the Chair (2008–2010) for the Postdoctoral Assembly (PDA). Throughout her career, Dr. Lew received many awards and grants support. Betina is a strong supporter of trainees at the SOT. She co-chaired numerous sessions focused on career development of younger toxicologists and mentored several students and postdocs.
Prof.Bonaventure A. Akinlosotu is a Regulatory Scientist/Environmental Protection Specialist at U.S. EPA, Office of Chemical Safety and Pollution Prevention (OCSPP), Office of Pesticides Program (OPP), Registration Division (RD), Chemistry, Inerts and Toxicology Assessment Branch (CITAB). He serves as (1) the Agency’s acute toxicity data review “Point of Contact - POC” for NAFTA and Global Joint Review (GJR) for the registration of pesticide chemicals/products; (2) the Agency’s expert on Child Resistant Packaging (CRP) for pesticide products. Prof. Akinlosotu also served as technical lead for the US/Canada Joint Project on “OECD Guidance for Waiving or Bridging of Mammalian Acute Toxicity Tests for Pesticides.
Dr.Christina Zuch de Zafra received her PhD in Toxicology from the University of Rochester and conducted a post-doctoral research fellowship at the University of Colorado; her research utilized rodent models to study the impact of toxins (lead) or neurodegenerative disease (Parkinson’s disease) on dopaminergic pathways in the central nervous system. Christina has been a part of the nonclinical toxicology departments at Genentech and Amgen, supporting the development of multi-modality biotherapeutics (including mAbs, fusion proteins, ADCs, and oncolytic viruses), and is currently a Director in the Nonclinical Sciences department at Seagen (based in South San Francisco). She has specialized in oncology, and has experience in neuroscience-, ophthalmic- and infectious disease-focused drug development. Her other areas of focus include product quality risk assessments, nonclinical abuse liability assessment, and the 3Rs of ethical animal use. Christina is a member of the Society of Toxicology and is a Diplomate of the American Board of Toxicology.
Dr.Cindy Roegge completed her Ph.D. from the University of Illinois at Urbana-Champaign in Neuroscience. Her thesis work was on the neurodevelopmental effects of environmental contaminants such as polychlorinated biphenyls (PCBs) and methyl mercury in the laboratory of Dr. Susan Schantz. Dr. Roegge completed post-doctoral work with Dr. Ed Levin at Duke University Medical Center before taking an industry position as GLP study director at the contract research organization WIL Research in Ashland, Ohio (later purchased by Charles River). Dr. Roegge was also an Oak River Institute for Science and Education (ORISE) fellow in the Neurotoxicology Division at the FDA National Center for Toxicological Research in Jefferson, Arkansas, working with Dr. Merle Paule. Dr. Roegge then began her career in Medical Device Toxicology at Medtronic in 2011. She also worked as a toxicologist in drug development for central nervous system diseases at Upsher-Smith Laboratories and later as part of Proximagen, where the team received FDA approval for the combination product Nayzilam nasal spray containing midazolam as a rescue medication for the short-term treatment of seizure clusters. Dr. Roegge returned to Medtronic in 2018 to join the Targeted Drug Delivery Research team working on therapy expansion for the SynchroMed™ II fully implantable and programmable drug infusion pump along with the Ascenda™ intrathecal catheter for targeted drug delivery to the intrathecal space surrounding the spinal cord for current treatment of severe pain and spasticity. Dr. Roegge holds DABT board certification, has published 10 articles in peer-reviewed journals, co-authored a book chapter, presented numerous scientific posters, and has recently served as Councilor for the Northland Society of Toxicology Regional Chapter.
Dr Colleen E. McLoughlin is Scivera’s Director of Toxicology. She received her doctorate in Biomedical Engineering from Virginia Commonwealth University in 2012. Her dissertation research focused on immunotoxicity testing of a polymer used in tissue engineered constructs and development of a novel drug delivery system. Subsequently she was a postdoctoral fellow at the National Institute for Occupational Safety and Health (NIOSH)/Centers for Disease Control (CDC) in Morgantown, WV. Colleen has over 15 years of experience in toxicology and is a US board-certified toxicologist and a European Registered Toxicologist. Her role at Scivera is day-to-day management of Toxicology Team projects and personnel as well as conducting chemical hazard assessments, risk assessments, and product certifications. Dr. McLoughlin works closely with other business units to support client success, product development and product testing, amongst others. She is also very active in the scientific community, including the Society of Toxicology (SOT) where is the current SOT-National Capital Area Chapter President. She is also the Vice Chair and webmaster for a local volunteer organization Health Equity and Access in Rural Regions.
Dr Daniel E. Arrieta earned his PhD in pharmacology and toxicology from the University of California, Davis in 2005. Upon graduating he spent one year working at the National Institute of Occupational Safety and Health (NIOSH) as an Associate Service Fellow studying the effects of chemical allergens using a murine (mouse) model. In 2006, Daniel accepted a position at Chevron Phillips Chemical LP as a staff toxicologist where he manages and provides technical support to the Specialty Chemicals and Drilling Specialties business lines in matters related to chemical management programs (e.g. EU, UK and South Korea REACH) and global registrations (e.g. Australia, Canada, China, United States, and Offshore Drilling in The North Sea), coordinates and monitors toxicity testing, and participates in various trade associations. Daniel chairs the American Chemistry Council (ACC) Hydrocarbon Solvents Panel. He is a Diplomat of the American Board of Toxicology (DABT®), European Registered Toxicologist (ERT), member of the Society of Toxicology, American Industrial Hygiene Association, and the Workplace Environmental Exposure Level (WEEL®) committee (former chair). He also participates on the Industry Advisory Committee for the Environmental & Occupational Health Department and Ergonomics Center at the Texas A&M School of Public Health, has taught courses at professional scientific meetings, assisted with the K-12 Outreach initiatives sponsored by the Society of Toxicology, and co-authored a book chapter on hazard identification for beginners.
Douglas Donahue (Doug) obtained his MS in Biological Sciences from Bowling Green State University in 2004 with emphasis on general toxicology, endocrinology, and environmental pollutants. He holds both DABT and ERT certifications. He currently serves as the Head of Preclinical Toxicology for GSK Vaccines, supporting key mRNA-based vaccines. For the past 18 years, Doug’s career has focused on practical applications for industrial, cosmetic, device, pharma and vaccine product development. Positions held at GSK, WIL Research, KAO, Covance, and Becton-Dickenson have allowed Doug to shepherd more than 300 successful global product registrations/approvals with major Regulatory agencies including REACh, TSCA, EPA, FDA and EMA. Significant areas of expertise include DART, medical device registrations, and rare disease treatments. Although he has worked primarily in an industry setting, Doug actively contributes to the academic community through peer-reviewed journal publications and serves as a guest lecturer for University of Texas Medical Branch at Galveston. He is also grant reviewer for Alternatives Research & Development Foundation (ARDF), which supports novel, viable strategies to in-vivo animal testing. Doug mentored many early-career toxicologists at Covance, Becton-Dickinson and now at GSK; helping train the next generation of toxicology professionals. Doug also formally participates in the ACT Mentorship program meeting with his Mentee on a quarterly basis. Doug is an active member of ACT (since 2008) serving as an elected member of the ACT Membership committee (2020-2023) and an appointed member of the ACT Program Committee (2018-2020), co-chairing sessions and continuing education courses. He remains a full member of the Society of Toxicology (SOT) and the British Toxicology Society (BTS).
Dr. Jason Cannon received his Ph.D. in Toxicology from the University of Michigan and was a postdoctoral fellow at the University of Pittsburgh. He is an Professor of Toxicology at Purdue University, where he studies mechanisms of environmentally induced neurodegeneration and teaches several toxicology courses. More recently, his laboratory has developed a multi-species approach to study the comparative biology of neurodegeneration, where he utilizes rodent, amphibian, nematode and in vitro models to test mechanistic hypotheses and advance understanding of human neurodegeneration. Further, Dr. Cannon leads multiple graduate programs as Director of the Purdue Toxicology Graduate Program and Head, Purdue University Interdisciplinary Life Sciences Program. He is currently the President for the Neurotoxicology Specialty Section (NTSS) for the Society of Toxicology. Dr. Cannon serves the field of toxicology in many other ways, such as on the following editorial boards: Neurotoxicology (Associate Editor), Neurotoxicology & Teratology; Frontiers in Toxicology (Associate Editor), Frontiers in Genetics, Toxicology, Toxicological Sciences, and Toxics. The most rewarding part of Dr. Cannon’s career is the success of his trainees.
Dr. Jayanta Das has expertise, leadership, training, and motivation to successfully carry out research in toxicology and molecular cancer stem cell biology. He has a broad background in area of molecular signaling pathways of cancer stem cells, and anti-cancerous drugs, apoptosis, antioxidant, and free radical research. Dr. Das research includes molecular cancer stem cell biology. As postdoctoral cancer researcher on several universities, institutes and NIH, NIA-funded grants, he did his research work in cancer treatment, anti-cancerous drug development, signaling pathway detection for cancer treatment and his research works were documented over time as in several publications. In addition, he successfully collaborated with other scientists, and produced several peer-reviewed publications as co-author from these collaborations.
Dr.John Wise.Sr. is a scientist, and a person who embraces all that a scientist can be – explorer, detective, artist, dreamer, educator and mentor- all packaged together to make a career, a life, filled with thrills, wonders and discoveries. For him, being a scientist is one part explorer- venturing into the unknown and discovering things never seen or considered before. One part detective- solving mysteries and puzzles to help explain the new discoveries. One part artist- experiencing the beauty and wonder of scientific discovery and illustrating it for others in images, words, ideas and song. One part dreamer- always imagining what might be next. One part educator and mentor- teaching and sharing the scientific journey and helping others find their scientific footing and vision. Yes, he is a scientist, working both in the tiny, microscopic world of the cell and in the wild with some of the most amazing creatures on earth. He is a successful scientist having mentored and trained over 200 diverse people in his laboratory in toxicology including faculty, postdoctoral fellows, graduate students, undergraduates and high school students. In his research, he identified signature ways that chromium, an environmental pollutant with widespread exposure, destabilizes chromosomes to cause lung cancer, which has contributed to improvements in health protection. He pioneered understanding how metal pollution impacts the health of whales, sea turtles, sea lions and alligators and, in doing so, demonstrated that chromium pollution is a global problem. He discovered novel adaptations in whale cells that protect against chromium toxicity, which may lead to new breakthroughs in human cancer. His work has led to numerous awards for himself and his students, more than over $20 million in grant funding, over 130 peer reviewed research papers and over 700 abstracts and has attracted widespread media coverage.” Currently, he is a Professor of Toxicology and Pharmacology, Distinguished University Scholar, Director of the Center for Environmental and Occupational Health Sciences, Deputy Director of the Center for Integrative Environmental Health Sciences and Multi-Principal Investigator for the UofL Environmental Health Sciences Training Program. His formal education includes a Bachelor's degree in Biology with high distinction and recognition from George Mason University and a Ph.D. in Pharmacology from the George Washington University. His postdoctoral training focused on molecular epidemiology under Curtis Harris at the National Cancer Institute, followed by experience with occupational health and risk assessment as a Senior Toxicologist at Jonathan Borak and Company. He has served on the faculty of Yale University’s School of Medicine and School of Public Health, the University of Southern Maine, and now the University of Louisville, School of Medicine.
Dr Karen Riveles is a Toxicologist and Emergency Response Coordinator with the Office of Environmental Health Hazard Assessment (OEHHA) in the California Environmental Protection Agency (CalEPA) and an assistant adjunct professor at UC Davis. Her research focuses on accidental releases of hazardous chemicals, the role of toxicology in emergency response, wildfire smoke, chemical emissions from refineries, and the risk assessment of toxic air contaminants. She earned her Bachelor of Arts and Science (BAS) in Biological Sciences and Spanish (1992) from the University of California, Davis, and her Master of Public Health in Environmental Health (1997) from the Graduate School of Public Health (GSPH), San Diego State University. Dr. Riveles received a Ph.D. (2004) in Environmental Toxicology from the University of California, Riverside and went on to complete a postdoctoral fellow at the Parkinson’s Institute. Dr. Riveles joined the OEHHA in 2006 and assumed her role as the Emergency Response Coordinator in 2009. She is also an Adjunct Professor at UC Davis Department of Environmental Toxicology where she mentors undergraduate students through OEHHA and teaches. Additional research interests include protection of vulnerable populations, including children; environmental justice and health equity; and regulatory toxicology and how science influences policies and regulation.
Ms. Kristin Licko is a native of northern Illinois and obtained her bachelor’s degree in Environmental Science from Benedictine University in Lisle, Illinois. She received her master’s degree in Pharmacology and Toxicology from Michigan State University. Kristin is a toxicologist with experience in material safety evaluations, human health chemical risk assessments, management, and higher education. For over a decade, she has worked to develop and assess safe human health levels for drinking water contaminants at the Water Quality Association (WQA), a third-party certification body that evaluates drinking water treatment products. At WQA, Kristin manages a diverse team with skills that range from project management to technical product reviews and chemical risk assessment. Within the drinking water treatment industry, she organizes a committee with participants from competing organizations to harmonize drinking water contaminant evaluation criteria and risk assessment approaches and reduce duplication of efforts. In addition, Kristin is a voting member of two Joint Committees that develop and maintain drinking water industry standards: the Joint Committee on Drinking Water Additives – System Components and the Joint Committee on Drinking Water Additives – Treatment Chemicals. In this capacity, she has contributed to efforts that have streamlined information and clarified guidance for the drinking water industry. Kristin also teaches portions of a graduate-level Food Safety Toxicology course at Michigan State University, covering topics that range from risk communication to individual contaminant case studies. Throughout each semester, she guides students in developing a human health chemical risk assessment, encouraging students to understand and justify a weight of evidence approach to evaluating research. Kristin has been a member of the Society of Toxicology (SOT) since 2013, participating as a member of the Women in Toxicology (WIT) special interest group and the following specialty sections: Risk Assessment, Regulatory and Safety Evaluation, Food Safety, and Computational Toxicology. In 2016 Kristin was one of the first recipients of the WIT special interest group Celebrating Women in Toxicology award. From a personal perspective, Kristin immensely appreciates the organizations that gave her the opportunity and stability to overcome homelessness and attend college after fleeing an abusive relationship: Bridge Communities and Families Helping Families.
Dr.Lauren Lewis, is currently a Senior Scientist, Project Toxicologist at Bristol Myers Squibb. Previously, she wasan investigative toxicologist in the Drug Safety Research and Evaluation group at Takeda Pharmaceuticals who specializes in preclinical safety strategies. Currently, she focuses on developing in vitro models for safety assessment across new pharmaceutical modalities. Dr. Lewis is an active member of the Society of Toxicology and American College of Toxicology. She received her doctorate in Toxicology from Texas A&M University in 2019.
Dr. Linval DePass is Executive Director of Nonclinical Safety at Durect Corporation in Cupertino, California. He is responsible for designing and managing most of the nonclinical studies that are required for the successful development of new drug candidates. These include toxicology, safety pharmacology, pharmacokinetic and general pharmacology studies. He earned his B.S. with a biology major from Georgetown University in Washington, D.C., an M.S. in biology from the University of Miami in Coral Gables, FL, and a Ph.D. in toxicology at the University of Arkansas for Medical Sciences in Little Rock, AR. After completing his Ph.D., he did chemical industry toxicology at the Bushy Run Research Center of Union Carbide Corporation near Pittsburgh, PA. He then moved to the pharmaceutical industry working first for Syntex Corporation in Palo Alto, CA. When Syntex was acquired by Hoffmann LaRoche, he stayed and worked for Roche for several years before moving to Durect Corporation. Dr. DePass has authored or co-authored 26 peer-reviewed journal articles and is a member of several professional societies, including the Society of Toxicology, the American College of Toxicology, the Safety Pharmacology Society, and the American Association for the Advancement of Science. Dr. DePass was certified by the American Board of Toxicology (DABT) and is currently certified by the Academy of Toxicological Sciences.
Dr. Ponnusamy is a Veterinarian and board-certified industry toxicologist currently leading the Toxicology group within Zoetis, a global veterinary pharmaceutical company in Michigan. In her current role, Dr. Ponnusamy develops regulatory strategy for human food toxicology and user safety programs, and performs toxicology assessments for drug substances, excipients, residual solvents, and impurities. She is also an industry representative for the VICH-Human Food Safety Working Group. Dr. Ponnusamy started her career as a clinical veterinarian and transitioned to a research career in pharmacology and toxicology. For her doctoral research, she investigated epigenetic mechanisms of chemoresistance and authored several publications. She has won several fellowships, grants, and research and leadership excellence awards. Dr. Ponnusamy has been an active member of the Society of Toxicology (SOT) and American College of Toxicology (ACT) and has been an elected officer on several committees and specialty groups within SOT and ACT since 2013. Currently, she is the President of the SOT- Food Safety Specialty section and a member of the SOT Awards Committee. In addition, she has dynamically been engaged in science/toxicology outreach and diversity initiatives with several organizations since 2013 and serves on the ACT Outreach Committee. Besides, as a SOT-International ToxScholar, she has visited multiple institutions to promote toxicology sciences and has been mentoring veterinary students for career development, including careers in toxicology globally.
Prof.Madhumita Das, completed her Bachelor of Science with Honors and Master of Science degree from University of Kalyani, India in Zoology. Prof. Das moved USA in 2009 and volunteered in research work at John D. Dingel. VA Medical Center, Detroit, MI, USA. Prof. Das, started her teaching job at Miami Dade College in 2019 at Hialeah, Pardon and Wolfson campuses. She mentored many undergraduate students in basic cancer research and toxicology. Her research works titled, “Identification of the underlining relationship of bivalent histone modifications with pancreatic cancer stem cells by bioinformatic analysis”, conducted with both her students and collaborators was accepted to the 2020 AACR annual conference (DOI: 10.1158/1538-7445.AM2020-2431); and another research abstract titled, “Bivalent histone modifications: Clinical targets against pancreatic cancer stem cell heterogeneity” (DOI: 10.1158/1538-7445.TUMHET2020-PO-003) was accepted to the virtual conference in 2020. In 2021, she published the research work with her students and Collaborators, titled, “3D spheroid: A rapid drug screening model for epigenetic clinical targets against heterogenic cancer stem cells” (DOI: 10.1158/1538-7445.AM2021-2104).
Dr. Marquea King is the Director of the Office of Scientific Quality Review (OSQR) at the U.S. Department of Agriculture’s (USDA) Agricultural Research Service (ARS). She communicates and enforces Agency policy and requirements regarding the quality peer review over three distinct programmatic areas. The classification of nearly 1500 research scientists, the review of 690 intramural research projects, and the retrospective review of 16 national programs. Marquea completed her B.S. degree in Chemistry from Delaware State University and a Ph.D. in Toxicology from Virginia Polytechnic Institute & State University, where she was trained in immunotoxicology and heavy metals. She began her career with the Environmental Protection Agency (USEPA) in Washington, DC in 2002 as a research toxicologist. She has been a member of SOT since 1999 and is a past president of the Toxicologists of African Origin as well as a participant in the Committee for Diversity Initiatives; past chair of the Undergraduate Consortium Task Force; 15+ ToxScholar visits. She is also a member of the Hispanic Organization of Toxicologists, Women in Toxicology, and her regional chapter area. She is actively involved in community outreach and mentoring and is often sought after as a motivational speaker. She is actively involved in community outreach and mentoring. She is the board Vice-President at her local Boys & Girls Club as well as an invited speaker at various universities giving guidance and advice to graduate and undergraduate students. She is also a member of Delta Sigma Theta Sorority, Incorporated and a hands-on mother of three zealous sons.
Mr. Peterson is a Principal at Gradient more than 20 years of experience specializing in human health risk assessment of cancer and non-cancer endpoints, critical analysis of human and animal toxicology and epidemiology studies, and multimedia assessment of exposure to chemicals. He has applied these skills primarily in the areas of product safety, occupational safety and health, and risk assessment. He has extensive experience evaluating the toxicity of asbestos and other fibers. He also has experience evaluating exposures to chemicals in a variety of different consumer products and developing toxicity guidelines for those chemicals. Many of his projects have involved preparing risk communication materials to effectively convey chemical exposure risks in appropriate context for a variety of stakeholders. He is an appointed member of the Washington Governor's Industrial Safety and Health Advisory Board, a past President of the Occupational and Public Health Specialty Section of the Society of Toxicology, and the Chairperson of the Washington Agriculture Safety Day Committee. While earning a Master of Environmental Management degree at Duke University, Mr. Peterson researched the oral bioavailability of polycyclic aromatic hydrocarbons from soil. Outside of his work at Gradient, he is an alternate member of the local Board of Health as well as a volunteer and board member of the local mountain rescue association.
Dr.Mohamed Ghorab works for U.S. Environmental Protection Agency (EPA), the Office of Chemical Safety and Pollution Prevention (OCSPP), the Office of Pesticide (OPP), Chemistry, Inerts, and Toxicology Assessment Branch (CITAB) as a toxicologist scientist since December 2020. Where he is responsible for Researching, reviewing, and evaluating toxicological scientific data and/or pesticide-based studies and all collateral information regarding health effects of pesticides and other related chemicals; assessing pesticide exposures in community, occupational, and residential settings; and evaluating environmental monitoring data under the Pesticide Registration Improvement Act (PRIA) and the Federal Insecticide, Fungicide, and Rodenticide Act (FIRFA) apply the US EPA risk assessment models and Preparing exposure assessment, toxicity evaluation, and risk assessment documents under US EPA regulations.” Before coming to OCSPP/US EPA, Dr. Ghorab was a Research Toxicologist working as a contractor for EPA’s Office of Research and Development (ORD) in Cincinnati, OH. where he was responsible for a number of acute and chronic toxicity projects at ORD’s Aquatic Research Facility. He also headed the Toxicology group as Team leader and played a key role in the continued development and validation of toxicity methods. Mohamed earned his B.S. degree in Agriculture Science with a major in Chemistry and his M.S. degree in Pesticide Chemistry and Toxicology from Alexandria University and obtained his Ph.D. in Environmental Toxicology from Alexandria University and Michigan State University. After receiving his Ph.D., Dr. Ghorab served as a postdoctoral fellow at Michigan State University’s Wildlife Toxicology Lab (WTL), where he focused on research on the fate and effects of potentially toxic compounds, particularly in the area of ecological risk assessment. Additionally, his work at WTL included research in the movement, bioaccumulation, and effects of toxic substances at different levels of biological organization, ranging from terrestrial to aquatic and biochemical to the ecosystem. Mohamed was awarded the Postdoctoral and early career award from the Society of Environmental Chemistry and Toxicology (SETAC) in 2020 and earned the Outstanding Professional Award from special-interest group SOT-ATA, 2021. Dr. Ghorab has been selected to serve The Society of Toxicology (SOT) as Vice-Chair in the postdoctoral and early career committee for 2021.
I am an Assistant Professor of Pharmacology and Research Associate in the Department of Physical Medicine and Rehabilitation at the Mayo Clinic in Rochester, MN. I have been studying the role of diet and glial interactions on myelin repair in models of multiple sclerosis for the past 5 years. During graduate school at Iowa State, my work focused on the contribution of environmental factors and the efficacy of novel therapeutic strategies in translational models of Parkinson’s disease. Before that, I had some experience at a Biotech company, hospital pathology lab, and contract research organization. My work so far has resulted in 20 publications, 10 oral presentations, and more than 30 poster presentations. Overall, my research interest has been on neurotoxicology as it pertains to risk and progression of neurological diseases and finding new therapeutic approaches for neural repair. I have helped mentor students from various educational levels, including serving as a mentor through Mayo’s Summer Undergraduate Research Fellows program and through the American Society for Pharmacology and Experimental Therapeutics (ASPET)’s Peer Mentoring Program. I was recently a Guest Associate Editor for “Environmental Effects on Neuroinflammation and Neurodegeneration” in Frontiers in Cellular Neuroscience. Also, to help promote advancement of women and young scientists in STEM, I currently serve as guest editor for research topics entitled “Women in Neurotoxicology” and “Emerging Talents in Toxicology: Neurotoxicology” through Frontiers in Toxicology. I currently serve on several special interest group committees at Mayo Clinic and have been active in professional societies like SOT, SfN, and ASPET since graduate school.
Dr.Moumita Dutta received her PhD in general toxicology and graduated in 2017 from the University of Burdwan, India. During 2018-2020, she did her postdoctoral training from the at University of Washington, USA. Currently she is working as a Research Scientist at the University of Washington, Seattle. Her persistent goal is to explore the role of environmental toxicant in the host health and disease pathogenesis, using in-vivo model and application of cell and molecular biology techniques. She has already published 16 articles at several high throughput journals of pharmacology and toxicology and presented her research work at more than 25 scientific meetings. She was awarded with 2 best poster presentation awards in both India and USA while presenting her research works in front of scientific community. She is a current member of Society of Toxicology and Center for Microbiome Sciences & Therapeutics (CMiST), University of Washington. At her current role, Dr. Dutta is interested to investigate the role of gut-liver interaction focusing xenobiotic biotransformation, nuclear receptor, and metabolites association in the progression of host health and disease pathogenesis.
Dr. Nagaraju Anreddy a Lead Pharmacologist/Toxicologist at Viatris in Pittsburgh, PA, where he contributes to non-clinical safety assessment of small molecules and complex injectables within Global pharmacology and toxicology department. He is primarily involved in design, conduct, interpretation, and reporting of exploratory, mechanistic, and regulatory toxicology studies in rodent and non-rodent animal models. Dr. Anreddy obtained PhD in Pharmacology from St. John’s University, NY and BS in Pharmacy from Kakatiya University, India. He is board-certified toxicologist and enjoys utilizing the tools of toxicology to solve scientific problems. He is a member of the Society of Toxicology, and American Association for Cancer Research. He is an author/co-author of several peer-reviewed publications. In addition, he serves as an ad hoc reviewer for peer reviewed journals.
Dr. Nicole Soucy is the Director of Global Toxicology and Biocompatibility in the Preclinical Sciences Department at Boston Scientific. She has nearly 20 years of experience as a toxicologist and risk assessor for products regulated as medical devices, pharmaceuticals, and cosmetics. In her current role, Nicole built and now leads a team of 42 scientists to ensure all products developed and manufactured by Boston Scientific meet or exceed global regulatory requirements for the biological safety evaluation of medical devices - a key safety input for regulatory approval in all regions. In her prior role, Nicole provided technical support, leadership, and guidance to a team of scientists supporting 3M Health Care Business Group, a diverse group of businesses developing and commercializing active pharmaceutical ingredients, drug delivery systems, medical devices, combination products, and cosmetics. Nicole received a PhD in pharmacology and toxicology from Dartmouth College in 2003, where her research investigated mechanisms for cardiovascular disease following exposure to metals and metalloids. This was followed by a post-doctoral fellowship at the Chemical Industry Institute of Toxicology (CIIT) where her research focus was on gestational pharmacokinetics of endocrine disrupting compounds. Nicole has been an active member of the Society of Toxicology since 2000; serving in leadership roles in the Northland Regional Chapter and participating as a member of the RC Collaboration and Communication Committee and former Education Committee. In 2022 Nicole was elected to a role on the SOT Nominating Committee. A Diplomate of the American Board of Toxicology since 2012, Nicole has served on the Board of Directors since 2019 where she is currently serving as President.
Dr. Pallavi McElroy is a Senior Scientist within the Global Toxicology team in Nonclinical Safety at Janssen R&D where she has been employed as a Toxicologist since 2019. She completed her PhD from the University of Colorado Denver in Toxicology in 2016, following which she worked at Charles River Laboratories in Ashland, OH, as a Study Director in Developmental and Reproductive Toxicology until 2019. In her current role, Dr. McElroy is involved in assessing the nonclinical safety of large and small molecule multi-modality drug candidates including design of in vivo toxicology studies, integrated scientific data interpretation and report generation, engagement in multi-disciplinary teams to provide scientific and technical expertise, and participation on issue-resolution teams. In addition, she is a member of the Global DART-Pediatric team at Janssen and is involved in strategy discussions for DART and juvenile tox studies for various programs. She is an active member of the Society of Toxicology, Society for Birth Defects Research and Prevention where she is part of the 2022 Program committee and the Membership committee, the Mid-Atlantic Reproduction and Teratology Association for which is serving as the Secretary, and a member of a HESI DART committee.
I am fortunate to be associated with both Wright State University (WSU) and the US Air Force Research Laboratory (AFRL) where I was given the opportunity to direct a multidisciplinary research team conducting state of the art research. The ultimate goal is to establish a network of research and engineering capabilities to directly address AF challenges. I enjoy creating a collaborative research experience between students, faculty, and government to solve challenging problems which are the focus of the AFRL in Warfighter health, performance, and sustainment. I particularly enjoy mentoring students and building research collaborations with WSU and other academic partners that will accelerate student participation and diversity. Main Research thrusts
Assessing the Impact of Operational Stressors on Cellular Functions
Understanding the Effects of Inhaled Chemical & Particle Mixtures on Lung Surfactant (LS) Function: Linkage to Adverse Health Effects
Utilizing the Mitochondria as a Diagnostic and Predictive Tool to Identify Cellular Susceptibilities
Advance In Vitro Dermal Models: Uncovering Mechanisms of Key Events in the Sensitization Process
Harnessing Artificial Intelligence based in silico Modeling for Rapid Hazard Identification of AF Related Contaminants
Dr. Samuel Buxton (prefers to be called Samuel) received his PhD in Toxicology from Iowa State University, Iowa and a PhD in Science de la Vie et de la Santé (Life and Health Sciences) from University of Tours, France in 2012. His graduate school and postdoctoral research at Iowa State University were focused on characterizing mainly acetylcholine receptors as drug target sites in human endoparasites. Another postdoctoral stint at Baylor College of Medicine was focused on characterizing ryanodine receptors and its subunits as drug target sites for treating atrial fibrillation in humans. Samuel is a board-certified Toxicologist, currently working as a Human Health Toxicologist in the non-ferrous metal industry. Samuel’s work at NiPERA, the science division of the global Nickel Institute, involves designing and monitoring studies conducted at contract research laboratories on in vitro and in vivo genotoxicity, carcinogenicity, and inhalation toxicity. His work extends to using the study results in regulatory submissions and/or to author peer-reviewed publications, responding to regulatory requests, authoring white papers and fact sheets, and defending regulatory positions before regulators. Outside work, you will find Samuel tending to his garden of flowers and vegetables, running and/or hiking in nature, and volunteering at food and clothing donation centers.
Dr.Shakil Saghir is a Senior Toxicologist at The Scotts Miracle-Gro. He holds a PhD in Toxicology and Pharmacology from the University of Illinois, MSPH from the University of Alabama and MSc and BSc in Zoology from the University of Karachi. He holds certifications from American Board of Toxicologist (DABT) and Eurotox (ERT), he is also a fellow of the Academy of Toxicological Sciences (ATS) and the Royal Society of Biology (RBS). Prior to joining Scotts Miracle-Gro, Dr. Saghir served as an ecotoxicologist at the Pakistan Agricultural Research Council, as a Research Assistant Professor in the Department of Pharmacology, Toxicology and Therapeutics of the University of Kansas Medical Center, as a Research Scientist at the Pacific Northwest National Laboratory, as a Senior Toxicology Specialist at the Dow Chemical Company and Syngenta, and as a Chief Scientific Officer at Smithers Avanza. He also holds a visiting professorship in the Departments of Biological and Biomedical Sciences at the Aga Khan University Hospital. Dr. Saghir has authored over 90 peer reviewed papers/book chapters, over 100 conference presentations and over 300 technical reports in the area of toxicokinetics, mechanism of toxicity and ways to improve toxicity testing. He is also member of the editorial board of several leading journals.
Dr. Tamara House-Knight is a Senior Toxicologist/Risk Assessor with over 18 years specializing in human and environmental risk assessment. She became a Diplomate of the American Board of Toxicology (DABT) in 2016. Dr. House-Knight has been involved in assessing human health risks for redevelopment projects, brownfield sites, and household and pharmaceutical products. She has provided toxicological support following chemical exposures to client employees and health care workers and responding to hundreds of worker exposure incidents involving a wide variety of chemicals. She works with industrial and pharmaceutical clients to meet regulations in the U.S. (Toxic Substances Control Act and OSHA Hazard Communication Standard) and European Community (REACH). In addition, she has assisted with community relations/public participation following environmental releases.
Dr. House-Knight has provided toxicological support for litigation teams related to causation involving asbestos, petroleum products, VOC (benzene, trichloroethylene) and coal ash exposures. She currently serves as the GHD lead of the Americas Emerging Contaminants Technical Team. She is also a member of the Society of Toxicology and ITRC Chemicals of Emerging Concern Working Group.
Dr.Toufan Parman is the Senior Director of Nonclinical Safety Evaluations at Sangamo Therapeutics where she is responsible for the management of Pharmacology, Toxicology, and Pharmacokinetic Programs. As the nonclinical lead, Dr. Parman provides preclinical drug development strategy and safety assessment expertise for various cell and gene therapy programs. She has produced seminal results and contributed both conceptually and technically to her fields of expertise, with over 30 peer reviewed publications, a patent, and several book chapters in high-ranking journals. Dr. Parman received her Ph.D. in Pharmaceutical Sciences from the University of Toronto, Canada specializing in mechanistic reproductive toxicology. She received Postdoctoral Fellowship awards from the Canadian Institutes of Health Research and the National Cancer Institute (NCI) to conduct postdoctoral training in the areas of cell signaling and cancer at the NCI, University of Arizona, and Stanford University. Prior to joining Sangamo, Dr. Parman worked at SRI International where she translated several novel male contraceptives, as well as small molecule drugs, biologic therapeutics, and vaccines for the treatment of infectious and neurodegenerative diseases, and cancer from discovery to clinical trials. Dr. Parman has been certified by the American Board of Toxicology since 2007.
Dr. Vivek Lawana is currently working as senior study director at world leading medical device CRO, NAMSA. Dr. Lawana received his Bachelor in Pharmacy degree from India in 2008 and MS in Pharmacology/toxicology degree from Long Island University in 2012. He completed his PhD from Iowa State University in 2018 and postdoctoral training from Purdue University in 2019. Dr. Lawana’s doctoral and postdoctoral research involved understanding the role of pesticide and food-derived toxicants in Pakrinson’s diasese (PD) pathogenesis. Using advanced molecular biology and mechanistic toxicology technique, his work demonstrated the role of c-Abl kinase enzyme in causing neuroinflammation and neurodegeneration in preclinical lab PD models. His work was published in several top peer-reviewed journals and he also received many national awards from Society of Toxicology for his research. Since 2019, Dr. Lawana has been with NAMSA working as study director and subject matter expert for toxicology. In his current role, he works with Sponsors (i.e. medical device and biotech industries across the world) to design, execute and determine the safety for their therapeutic product using small and large animal models (nonclinical). As study director he has lead several of such risk assessment study over the years ranging from class III implantable devices to small molecule pharmaceutical drugs and biologics (gene therapy). Beside this, Dr. Lawana has been a leader in various SOT committees. He is a stout advocate for increasing diversity in STEM field and has volunteered on various such task force. Importantly, he has also been serving as mentor for SOT’s commitment to diversity initiative program since 2012. He has mentored more than 50 undergraduate students through this opportunity.
National Research Mentoring Network (NRMN) Through the national network, NRMN implements and disseminates innovative, evidence-based best practices to improve mentoring relationships at institutions across the country. NRMN connects highly knowledgeable and skilled mentors with motivated and diverse mentees, ranging from undergraduate students to early-career faculty, and facilitate long-term, culturally responsive interactions between them. NRMN is committed to establishing a culture in which historically underrepresented mentees successfully progress in their careers and contribute to the biomedical research enterprise.
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The Science of Effective Mentoring in STEMM Effective mentors are critical in the development of undergraduate and graduate students in science, technology, engineering, mathematics, and medicine (STEMM)—especially for many members of underrepresented and marginalized populations. The Science of Effective Mentoring in STEMM committee systematically compiled and analyzed current research on the characteristics, competencies, and behaviors of effective mentors and mentees in STEMM and developed a practical resource guide for mentoring practitioners to create and support viable, sustainable mentoring support systems.
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The Science of Mentorship Podcast In this series from the National Academies of Sciences, Engineering, and Medicine, you’ll hear personal stories about mentorship experiences from STEMM leaders, in their own words, to help you learn how evidence-based mentorship practices can help you develop the skills to engage in the most effective mentoring relationships possible.
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Mentoring Videos
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'Meet your ToxMSDT Mentor' by Dr. Barbara Johnson, Executive Vice President and Provost at Talladega College, AL; Director of the Leadership and Mentoring Institute.
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Mentor Training to Improve Diversity in Science Culturally Aware Mentoring Part 1 and Part 2
Fifteen mentors were selected to the ToxMSDT program from different settings: academia, industry and government. Mentors give presentations on their career paths into toxicology and on skills they use currently at work. They interact with mentees through group roundtable discussions. Group activities such as tours of toxicology laboratories on Iowa State University campus, meals, and mixers are used to build relationships among mentors and mentees. Benefits to mentors:
Personal satisfaction
Helping NIH achieve its noble goals of a diverse workforce
Sixteen mentors were selected to the ToxMSDT program from different settings: academia, industry and government. Mentors give presentations on their career paths into toxicology and on skills they use currently at work. They interact with mentees through group roundtable discussions. Group activities such as campus tours, meals, and mixers are used to build relationships among mentors and mentees. They also organize a shadowing experience for their mentees. Benefits to mentors:
Personal satisfaction
Helping NIH achieve its noble goals of a diverse workforce
Dr. Rais Ansari, PhD Associate Professor, Department of Pharmaceutical Sciences College of Pharmacy, Health Professions Divisions, Nova Southeastern University, Fort Lauderdale, FL
Dr. Guillermo E. Fernandez-Surumay, DVM, PhD, DABT Principal Scientist, Merck & Co. Inc., Safety Assessment and Laboratory Animal Resources, Toxicological Sciences West Point, PA
Dr. Worlanyo Eric Gato, PhD Assistant Professor of Biochemistry, Department of Chemistry and Biochemistry, Georgia Southern University Statesboro, GA
Dr. Wilson Rumbeiha, BVM, PhD, DABT, DABVT, ATS Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, CA.
We are now recruiting toxicologists from around the United States to serve as mentors for the 2022/23 program season starting September 2022 through June 2023. Eligibility requirements:Mentor’s place of work must be located within the United States. Graduate students and postdoctoral scholars are not eligible to apply. Due to institutional requirements we encourage applications from fully vaccinated COVID-19 individuals only.
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Role of a Mentor: Each mentor will commit meeting virtually once every month with the mentee, hosting the mentee at their worksite for the “2 days in the life of a toxicologist” job shadowing visit, and participating in three conferences. These include the inaugural workshop at the University of California Davis, Davis; the Society of Toxicology (SOT) Annual Meeting, and the capstone workshop at Tuskegee University, Tuskegee, AL. In addition, mentors are expected to participate in program evaluation surveys to assess program activities. Throughout the year we also use the National Research Mentoring Network (NRMN) platform to enhance further communication between all members of our community.
Benefits to Mentors:
Career advancement through leadership skill development
Supporting career development of the future generation of toxicologists
Networking with other mentors and professionals in toxicology
Increased visibility and recognition within the mentor’s place of work
Giving back to the next generation of toxicologists
Support NIH to diversify the biomedical workforce
Travel support to the annual Society of Toxicology conference
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Meet the 2021-2022 Mentors
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For the 2021/22 cohort twenty-five mentors fromindustry, academia, government, or nonprofit entities from across the countrywere matched 1:1 with undergraduate student participants.A mentor training is provided at the University of California Davis’ inaugural kick-off workshop to preparementors to subsequently offer career guidance during monthly meetings with their mentee.Mentorsprovide insight into their own career paths in toxicology and on the skills, they currently use at their places of work during the mentee’s job shadowing work site visit.In addition, mentors attend the annual Society of Toxicology conference.To conclude the year-long program, mentors join the capstone event at Tuskegee University where group activities such as campus tours, poster presentations,and mixers are used to continuously build relationships among mentors and mentees.
Prof. Bonaventure Akinlosotu, Senior Regulatory Scientist, Office of Chemical Safety and Pollution Prevention, U.S. Environmental Protection Agency (EPA)
Dr. Rais Ansari, PhD Associate Professor, Department of Pharmaceutical Sciences College of Pharmacy, Health Professions Divisions, Nova Southeastern University, Fort Lauderdale, FL
Dr. Mohamed Ghorab, Toxicologist Scientist, Chemistry, Inerts and Toxicology Assessment Branch, Office of Pesticide Programs (OPP), Office of Chemical Safety and Pollution Prevention (OCSPP), U.S. Environmental Protection Agency (EPA)
Ms. Kristin Licko, Toxicology Manager; Instructor, Water Quality Association (WQA), Professional Certification; Michigan State University, Department of Large Animal Clinical Sciences
We are now recruiting toxicologists from around the United States to serve as mentors for the 2022/23 program season starting September 2022 through June 2023. Eligibility requirements:Mentor’s place of work must be located within the United States. Graduate students and postdoctoral scholars are not eligible to apply. Due to institutional requirements we encourage applications from fully vaccinated COVID-19 individuals only.
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Role of a Mentor: Each mentor will commit meeting virtually once every month with the mentee, hosting the mentee at their worksite for the “2 days in the life of a toxicologist” job shadowing visit, and participating in three conferences. These include the inaugural workshop at the University of California Davis, Davis; the Society of Toxicology (SOT) Annual Meeting, and the capstone workshop at Tuskegee University, Tuskegee, AL. In addition, mentors are expected to participate in program evaluation surveys to assess program activities. Throughout the year we also use the National Research Mentoring Network (NRMN) platform to enhance further communication between all members of our community.
Benefits to Mentors:
Career advancement through leadership skill development
Supporting career development of the future generation of toxicologists
Networking with other mentors and professionals in toxicology
Increased visibility and recognition within the mentor’s place of work
Giving back to the next generation of toxicologists
Support NIH to diversify the biomedical workforce
Travel support to the annual Society of Toxicology conference
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Meet the 2022-2023 Mentors
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For the 2022/23 cohort twenty-five mentors from industry, academia, government, or nonprofit entities from across the country were matched 1:1 with undergraduate student participants. A mentor training is provided at the University of California Davis’ kick-off workshop to prepare mentors to subsequently offer career guidance during monthly meetings with their mentee. Mentors provide insight into their own career paths in toxicology and on the skills, they currently use at their places of work during the mentee’s job shadowing work site visit. In addition, mentors attend the annual Society of Toxicology conference. To conclude the year-long program, mentors jointhe capstone event at Tuskegee University forthe mentee’s final poster presentations.
Ms. Kristin Licko, Associate Director of Product Certification-Toxicology; Instructor, Water Quality Association (WQA), Product Certification; MSU, Department of Large Animal Clinical Sciences
Dr. Karen Riveles, Staff Toxicologist & Emergency Response Coordinator Office of Environmental Health Hazard Assessment, California Environmental Protection Agency and University of California Davis
Sam Merlus is a first-generation Haitian and the first in his family to attend college. He graduated from Miami Dade College with Associate of Arts with distinct honors in April 2016. Afterwards, Merlus matriculated to Tuskegee University in August 2016 where he received Transfer Scholarship covering his cost for tuition to concentrate in Chemistry & Chemical Engineering. In addition, he is conducting undergraduate research for Howard Hughes Medical Institute in Curry group aegis to Center for Sustainable Nanotechnology at Tuskegee University. Besides school, Merlus is actively involved in tutoring students at Tuskegee Public School, posting blogs on his website, running on track field, and advising others to aim to do what seems impossible to man but possible to God.
I am Nathalie Lancy Momplaisir. Being originally from Haiti, I am a first-generation student. I am a transfer student from Miami Dade College and currently attending Tuskegee University where I am on a pathway to a major in chemistry. My passion for chemistry has been increased exponentially ever since I started taking chemistry in college, especially organic chemistry. Lat year, I had the opportunity to work on a research project in which I was able to synthesize polymers for the purification of water. As I am going through my undergraduate career, I still want to pursue the highest level of education in my field. I eventually want to go to medical school and earn a PhD in toxicology. I believe that having an understanding in toxicology will equip me for my career. As I am a goal-oriented woman in the STEM field, I am determined to work hard to be an important element in the scientific field and the society.
I am Nathalie Lancy Momplaisir. Being originally from Haiti, I am a first-generation student. I am a transfer student from Miami Dade College and currently attending Tuskegee University where I am on a pathway to a major in chemistry. My passion for chemistry has been increased exponentially ever since I started taking chemistry in college, especially organic chemistry. Lat year, I had the opportunity to work on a research project in which I was able to synthesize polymers for the purification of water. As I am going through my undergraduate career, I still want to pursue the highest level of education in my field. I eventually want to go to medical school and earn a PhD in toxicology. I believe that having an understanding in toxicology will equip me for my career. As I am a goal-oriented woman in the STEM field, I am determined to work hard to be an important element in the scientific field and the society.
Dr Annette O'Connor is a quantitative epidemiologist who works in food production, public health, food safety, and animal uses for food, companionship, and biomedical research. She conducts primary research and synthesis research in these areas. This work involves combining research in transparent and comprehensive ways that ensure maximum value is obtained from society's investment in research funding. She has worked in a diverse set of fields, including food-borne pathogens of animal proteins, statistical approaches to antibiotic resistance data, food production, biomedical uses of animals, and veterinary public health. The main aim of her work is to help end-users better understand the results of research so decision makers such as industry bodies, veterinary practitioners, and government officials can incorporate primary research into decisions, i.e., science-supported decision making. She is also particularly interested in reproducible research, study design, assessing the bias of observational studies. Her work on study design and risk-of-bias assessment is closely related to toxicology because much of the toxicology data relates to experimental studies assessing toxins or observational studies assessing associations with human or animal health states. She has over 150 publications on topics as diverse as primary research, study design, systematic reviews, and meta-analysis.
Nathan Pechacek is a Director of Product Safety & Stewardship at Ecolab where he provides toxicological and risk assessment support for the company’s business units, as well as manages toxicologists and regulatory specialists. In terms of technical support, Nathan monitors and interprets toxicity studies, authors chemical-specific evaluations and summaries, and develops global strategies for regulatory compliance. In regards to staff management, Nathan trains and mentors staff on toxicology and regulatory affairs-related tasks, helps prioritize work tasks and ensure on-time delivery, promotes professional development, and conducts performance reviews. In addition to this work, Nathan is a visiting lecturer at the University of Minnesota and a member of specialty committees (i.e., California Proposition 65, Asthma, Ingredient Safety) for the Consumer Specialty Products Association (CSPA) and American Cleaning Institute (ACI). Prior to joining Ecolab, Nathan had experience as a toxicologist and risk assessor in academic (Oregon State University), regulatory (Texas Commission on Environmental Quality) and industrial (3M) settings. Overall, he has over 20 years of experience in the practice of toxicology and risk assessment. Nathan earned a B.S. in Environmental Science and Ecology from Minnesota State University, Mankato (1996), an M.S. in Toxicology and Microbiology from Iowa State University (1998), and an MBA from the University of Wisconsin-River Falls. He is a Diplomate of the American Board of Toxicology (certified 2006, re-certified 2011, 2016) and a member of the following professional and trade group associations: Society of Toxicology (SOT) (2006-Present), Northland regional chapter of SOT (2006-present, 2-year Councilor: 2007-2009, President-Elect: 2009-2010, President: 2010-2011, Past-President: 2011-2012, Secretary/Treasurer: 2015-2017), Risk Assessment Specialty Section of SOT (2007-present), Regulatory and Safety Evaluation Specialty Section of SOT (2007-present), Consumer Specialty Products Association (2007-present), American Cleaning Institute (2011-present), Midwest Section of the Society of Environmental Toxicology and Chemistry (2013-present), Upper Midwest Section of the American Industrial Hygiene Association (2013-present).
Jesenia Perez is a sophomore enrolled at Florida International University (FIU) majoring in Biological Sciences. Born and raised in Miami, Florida, she is an active member of the community. She participates in STEM-oriented volunteering projects, including the March for Science event hosted in April 2017. Her current research investigates the effects of oxidative stress on genetic stability and cellular senescence, and has strong potential for medical applications. Jesenia is a member of the Quantifying Biology in the Classroom (QBIC) Program, an honors track for Biological Science majors. She aspires to pursue a PhD researching the causes of genomic instability caused by environmental factors.
My name is Tanya Pierre and I am currently a junior at Agnes Scott College in Decatur, Georgia majoring in Biochemistry & Molecular Biology on the Pre-Med track. For as long as I can remember I have had an interest in becoming a medical doctor, but upon entering college my desire to pursue research has grown. Currently I am considering the idea of pursuing a MD-PHD, but struggling to find a field that interests me among all the exciting research opportunities. I look forward to learning more about toxicology and finding an area of research that is perfect for me. Aside from school I enjoy volunteering with local community organizations and making science appealing as a member of my campus Chemistry and Biochemistry club.
Dr. Pizzurro is a senior toxicologist with expertise in diverse areas, including molecular and general toxicology, in vitro and in vivo systems, neurodevelopment, human health risk assessment, chemical hazard assessment, and regulatory comment. Dr. Pizzurro performs critical analysis of toxicology studies and mode-of-action data, provides toxicological support for litigation and human health risk assessment projects, conducts chemical hazard assessment for evaluation and registration of new chemicals under GHS, and develops toxicity criteria and health-based exposure levels. She is also regularly involved in assessments of certain NAAQS pollutants for regulatory comment and weight-of-evidence analyses. Before joining Gradient, Dr. Pizzurro earned her doctoral degree at the University of Washington in Seattle, where she used primary rodent cell culture models to explore the mechanisms by which organophosphorus insecticides impair brain development. In addition to her technical work, Dr. Pizzurro participates in outside organizations such as the Society of Toxicology (SOT) and Women in Toxicology at SOT, as well as various mentoring programs for undergraduates and minorities in science. Education Ph.D. Toxicology, University of Washington ‒ Seattle B.S. Chemistry, University of Massachusetts ‒ Amherst
Areas of Expertise General & Molecular Toxicology Mode-of-action Analyses GHS Chemical Hazard Assessment Neurotoxicology Human Health Risk Assessment
Dr. Robert Poppenga is Professor of Clinical Veterinary Toxicology and Section Head, Toxicology Laboratory at the California Animal Health and Food Safety Laboratory (CAHFS), School of Veterinary Medicine, University of California at Davis. He has been at UCD since 2004.
He received his DVM and PhD (veterinary toxicology) degrees from the University of Illinois. He is board-certified by the American Board of Veterinary Toxicology and has served that organization in a number of roles including President. He has almost 33 years of experience as a diagnostic veterinary toxicologist including previous faculty and diagnostic laboratory positions at Michigan State University and the University of Pennsylvania.
The Toxicology Laboratory at CAHFS is one of the busiest of its kind in the world and offers comprehensive diagnostic toxicology testing. The Laboratory is a member of the Food Emergency Response Network sponsored by the U.S. Food and Drug Administration. FERN is involved in ensuring the safety of human and animal food. The Laboratory also works closely with the CA Department of Food and Agriculture to provide livestock feed testing for a variety of organic and inorganic chemicals.
His research interests include diagnostic veterinary toxicology, wildlife toxicology, and development of biomarkers for chemical exposure. He was a member of the Morris Animal Foundation’s Wildlife Scientific Advisory Board. He teaches veterinary toxicology to veterinary students at the School of Veterinary Medicine, mentors Residents in diagnostic veterinary toxicology at CAHFS and oversees thesis projects of graduate students in the UCD Forensic Science Graduate Group. He is also a member of the UCD Pharmacology and Toxicology Graduate Group.
Dr. Jennifer Rayner attended the North Carolina School of Science and Mathematics, Durham, NC during her junior and senior high school years which helped develop her love for science. Before starting college, Jennifer conducted research in the laboratory of Dr. Goldie Byrd at North Carolina Central University (NCCU), Durham, NC. Upon entering NCCU, she continued to conduct research during the academic year as well as during the summers at MIT and the University of North Carolina at Chapel Hill (UNC), Chapel Hill, NC. Jennifer graduated in 2001 from NCCU with B.S. degrees in Biology and Environmental Science. She then started her graduate studies at UNC-Chapel Hill and graduated in 2006 with a Ph.D. in Environmental Sciences and Engineering. Jennifer conducted her dissertation research with Dr. Suzanne Fenton in the Reproductive Toxicology Division of the U.S. Environmental Protection Agency, Research Triangle Park, NC. During her graduate studies, she found time to conduct research at The Proctor & Gamble Company, Cincinnati, OH as a pre-doctoral intern. Her research expertise and interests include developmental/reproductive outcomes from gestational exposure with emphasis on reproductive organ development and fetal basis of adult disease. She is currently working as a toxicologist at SRC, Inc. in Arlington, VA where she works with a team to develop toxicity assessments and technical documents to protect human health risks and decrease environmental impacts. On a day-to-day basis, she conducts critical analysis of scientific literature, toxicological studies, and reports and writes summaries, technical documents, and literature reviews to present findings to external audiences. She has several published peer-reviewed journal articles, book chapters, and abstracts. In 2010, Jennifer was certified in General Toxicology by the American Board of Toxicology and works to maintain her certification. During her free time, she volunteers with the Society of Toxicology and various community groups and travels.
Collaborative Institutional Training Initiative The Collaborative Institutional Training Initiative (CITI Program) is dedicated to serving the training needs of colleges and universities, healthcare institutions, technology and research organizations, and governmental agencies, as they foster integrity and professional advancement of their learners.
National Research Mentoring Network (NRMN) Through the national network, NRMN implements and disseminates innovative, evidence-based best practices to improve mentoring relationships at institutions across the country. NRMN connects highly knowledgeable and skilled mentors with motivated and diverse mentees, ranging from undergraduate students to early-career faculty, and facilitate long-term, culturally responsive interactions between them. NRMN is committed to establishing a culture in which historically underrepresented mentees successfully progress in their careers and contribute to the biomedical research enterprise.
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The Science of Effective Mentoring in STEMM Effective mentors are critical in the development of undergraduate and graduate students in science, technology, engineering, mathematics, and medicine (STEMM)—especially for many members of underrepresented and marginalized populations. The Science of Effective Mentoring in STEMM committee systematically compiled and analyzed current research on the characteristics, competencies, and behaviors of effective mentors and mentees in STEMM and developed a practical resource guide for mentoring practitioners to create and support viable, sustainable mentoring support systems.
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The Science of Mentorship Podcast In this series from the National Academies of Sciences, Engineering, and Medicine, you’ll hear personal stories about mentorship experiences from STEMM leaders, in their own words, to help you learn how evidence-based mentorship practices can help you develop the skills to engage in the most effective mentoring relationships possible.
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Mentoring Videos
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Mentor Training to Improve Diversity in Science Culturally Aware Mentoring Part 1 and Part 2
The ASPET Summer Undergraduate Research Fellow (SURF) Awards introduce undergraduate students to pharmacology research. Our goal is to use authentic, mentored research experiences in pharmacology to heighten student interest in careers in research and related health care disciplines.
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SURE Tox The Summer Undergraduate Research Experience in Toxicology program at the University of Illinois will provide high quality research experiences for under-represented minority junior and senior undergraduate students during the summer academic break.
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The Undergraduate Research and Mentoring Opportunities Tuskegee University DAES is excited to offer students a number of undergraduate research opportunities through faculty-funded projects by DAES faculty and its partners at Tuskegee University and other institutions across the U.S. and beyond. Due to the nature of funded for such opportunities, undergraduate research programs are always evolving, thus, we encourage you to visit our site often to learn about these and other opportunities.
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Research Ethics Training Resources
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Collaborative Institutional Training Initiative The Collaborative Institutional Training Initiative (CITI Program) is dedicated to serving the training needs of colleges and universities, healthcare institutions, technology and research organizations, and governmental agencies, as they foster integrity and professional advancement of their learners.
The Graduate Group in Pharmacology and Toxicology (PTX) at the University of California, Davis, is an interdisciplinary program that combines coursework and experimental training in modern approaches to pharmacological and toxicological problems.
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Now in its fourth year, the Envision UC Davis campus visit program enables California's most promising grad school hopefuls to develop an understanding and appreciation of graduate education. The program sponsors California senior undergraduates and recent bachelor's degree grads for an action-packed weekend on the Davis campus, allowing them to envision their future as a graduate student.
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In PREP@UC Davis, we prepare postbaccalaureate students from disadvantaged backgrounds and historically marginalized groups (including individuals who have a disability that limits major life activities) to succeed in PhD programs in the biomedical sciences.
The University of Illinois’ Research Training Program in Toxicology and Environmental Health is a part of the larger, campus-wide Interdisciplinary Environmental Toxicology Program (IETP), which provides toxicology training to students and postdoctoral fellows trained in basic sciences such as endocrinology and reproductive biology. Our program is ideal for students who are interested in applying their basic knowledge in four areas of toxicological research: reproductive/endocrine toxicology, neurotoxicology, nutritional toxicology, and nanotoxicology. The Research Training Program is a T32 NIEHS Environmental Toxicology Training Program.
Dr. Zadok Ruben received his B.S. in zoology (honors program 1969), Doctor of Veterinary Medicine (1972) and M.S, in veterinary pathology (1973) from Iowa State University, A.M. in experimental pathology (1975) from Harvard University and Ph.D. in pathobiology (1980) from the University of Connecticut. He became board certified in anatomical pathology (Diplomate, American College of Veterinary Pathology, 1983) and in general toxicology (Diplomate, American Board of Toxicology, 1985).
In 1973-1975 he was a Research Fellow in Experimental Pathology at Harvard Medical School and a Research Associate at the Division of Tumor Immunology, Dana-Farber Cancer Institute (Boston, Massachusetts); this included training in comparative pathology at Angell Memorial Animal Hospital. In 1975-1979 he was a Research Associate (diagnostic pathology of all animals, research in reproductive pathology) in the Department of Pathobiology at the University of Connecticut (Storrs, Connecticut). In 1979 he was also in small animal practice at Belmont Animal Hospital (Belmont, Massachusetts). In 1980-1989 he was at the Department of Product Safety Assessment of G. D. Searle & Co. (Skokie, Illinois) and in 1989-1985 in the Department of Toxicology of Hoffmann-La Roche Inc. (Nutley, New Jersey).
In this period, he worked in nonclinical toxicological evaluation and in investigative research projects related to development and discovery of novel drugs, served as director of general pathology, study pathologist, study director, principal investigator/collaborator, reviewer of drug resumes, author of toxicology summaries, presenter of toxicology-pathology data at the FDA, member of R&D project teams and various committees and task forces. In 1995-present, he is Founder and Principal at Patoximed Consultants (Westfield, New Jersey), providing consulting and educational services to industry, government, law firms, educational and other support organizations in nonclinical development strategies, regulatory registration, pathology/toxicology/safety assessment, and biomedical R&D.
Since 1991, Dr. Ruben has been with the Davis-Thompson Foundation (formerly, the Charles Louis Davis, D.V.M. Foundation for the advancement of veterinary and comparative pathology) as a Program Director of the Northeast Sub-Division, Vice President of toxicological and environmental Pathology, and a member on the faculty and the Board of Directors. Recently, he has been focusing on guidance for careers in pharmacological and toxicological pathology. Dr. Ruben has been member of many national and international professional societies for pathology, toxicology, pharmacology, laboratory animals, tissue culture, experimental biology and medicine, active in the organizations of the A.C.V.P., S.T.P. and S.O.T. at the national level and regional chapters. He is an author/co-author of over 50 publications in refereed journals, book chapters, review articles and referenced abstracts; numerous presentations in U.S.A. and abroad in scientific meetings and in academic, research and industrial institutions; manuscript reviewer for several professional journals and book chapters; symposia chairman/co-chairman; chairman/reviewer of pathology nomenclature committees. He has served on the editorial board member of J. Toxicol. Environ. Health and Exp. Biol. Med. (Proc. Soc.). In addition, he was adjunct faculty, Laboratory Animal Research Center, Rockefeller University, New York, a visiting assistant professor of pathology (Rush Medical College, Chicago), and consultant/advisor to academic institutions.
Dr. Wilson Rumbeiha is a Professor of One Environmental Health Toxicology, Dept. of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis. He is the ToxMSDT project Director. Dr. Rumbeiha is first in his family to go to college and graduated in 1982 with a BVM (DVM equivalent) from Makerere University, Kampala Uganda and with a PhD in Biomedical Sciences from the Ontario Veterinary College, University of Guelph, Guelph, Ontario Canada in 1991. After completing a Residency/Post doc at Kansas State University in Manhattan KS, in 1993, Dr. Rumbeiha joined Industry, serving as Staff Scientist at Embro Corporation in Minneapolis, MN, and as a Study Director, Comparative Toxicology Division, White Sands Research Center, Alamogordo, NM. Following the 2-year stint in industry, Dr. Rumbeiha returned to academia. He worked as a Clinical Toxicologist at Michigan State University (MSU), East Lansing MI, from January 1996 to August 2011 in the Department of Pathobiology and Diagnostic Investigation. During tenure at MSU he served as the Section Chief of Toxicology in the Diagnostic Center for Population and Animal Health, (DCPAH) at the same time. From August of 2011 to September 2019 Dr. Rumbeiha served as a Professor of Toxicology in the Department of Veterinary Diagnostic and Production Animal Medicine (VDPAM). Dr Rumbeiha joined UC Davis in October 2019. Currently, at UC Davis Dr. Rumbeiha is engaged in research, teaching and service. The current focus of his research is to understand the basic and translational aspects of hydrogen sulfide-induced neurotoxicology and neurodegeneration, and translational veterinary clinical and diagnostic toxicology. He is an author on > 60 peer reviewed publications, and over 40 book chapters. Dr. Rumbeiha has also served on several leadership positions in professional organizations and is currently section editor for the Journal of Medical Toxicology.
Dr. Ashish Sachan is a Veterinarian licensed in 'toxicology' by the College of Veterinarians of Ontario (CVO). Dr. Sachan has more than fifteen years of toxicology experience in both the university and industrial settings. Dr. Sachan completed his DVM in 1996 and Masters in Veterinary Pharmacology in 1998, from Veterinary College, Bangalore, India.
Dr. Sachan received his PhD in Toxicology from the Department of Biochemistry, Biophysics and Molecular Biology, Iowa State University, USA. His PhD involved development of nanosensor technologies to detect toxic chemical species of forensic significance. During his tenure as an Assistant Professor his research focused on ethnopharmacology and genetic toxicology. Dr. Sachan has also been inducted to the Iowa State University chapter of the Honors Society of Gamma-Sigma-Delta.
Dr. Sachan is a Director of Toxam Inc., Ontario, Canada and he also serves on the board of directors for the Society of Toxicology of Canada. His current professional interests involve regulatory affairs and, scientific and business development of agricultural and veterinary products.
Cristina M Santana Maldonado is a PhD Candidate in the Interdepartmental Toxicology Program at Iowa State University as part of Wilson K Rumbeiha’s laboratory. She received her B.S. in Biological Sciences at Iowa State University and joined Dr. Wilson Rumbeiha’s team to study the toxic effects of hydrogen sulfide on the respiratory system. She was a mentee in the 2017-2018 cohort which led her to pursue a career in toxicology and will be serving as the teaching assistant to guide mentees with module questions.
My name is Cristina Santana and I’m a Senior in Biology at Iowa State. I’m originally from Puerto Rico and came to Iowa for the first time three years ago for college. I have worked with a toxicology laboratory for the past year and that experience made me interested in doing the ToxMSDT program. I hope to go to Grad School after college and do toxicology research. Hopefully in the future I pursue an MD/PhD which has always been a dream of mine. On campus I’m very involved in my sorority, Alpha Omicron Pi, volunteering within the Ames community and participating in a number of philanthropic events throughout the year.
The ASPET Summer Undergraduate Research Fellow (SURF) Awards introduce undergraduate students to pharmacology research. Our goal is to use authentic, mentored research experiences in pharmacology to heighten student interest in careers in research and related health care disciplines.
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NACME (National Action Council for Minorities in Engineering) is the largest provider of college scholarships for underrepresented minorities pursuing degrees at schools of engineering. Their scholarship program for under-represented minorities serves as a catalyst to increase the proportion of Black/African American, Native/American Indian, and Latinx/Hispanic American young women and men in STEM careers.
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The American Indian College Fund invests in Native students and tribal college education to transform lives and communities. For over 31 years, the College Fund has been the nation’s largest charity supporting Native student access to higher education. They provide scholarships, programming to improve Native American student access to higher education, and the support and tools for them to succeed once they are there. (collegefund.org)
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AISES (American Indian Science and Engineering Society) is a national nonprofit organization providing internships and scholarships focusing on substantially increasing the representation of Indigenous peoples of North America and the Pacific Islands in science, technology, engineering, and math (STEM) studies and careers.
Dr. Shubhra Chaudhuri is a Research Scientist in the Toxicology and Safety Assessment Division of Charles River Laboratories in Horsham since 2015. Dr. Chaudhuri obtained her Ph.D. in Toxicology from the University of Arkansas for Medical Sciences followed by a Post Doctoral Fellowship at The Dow Chemical Company prior to joining Charles River Laboratories. Dr. Chaudhuri worked in ADME, Toxicokinetics (TK) and medium –high throughput modeling for margin of safety assessments at The Dow Chemical Company. She was also involved in conducting regulatory safety assessment studies. Currently, in her role as a Study Director Dr. Chaudhuri is involved in study management, oversight, data analysis , interpretation and report writing for safety assessment studies of pharmaceutical compounds.
The ToxMSDT online component comprises of six learning modules: pathophysiology, biochemistry and molecular genetics, principles of genetic toxicology, applied systems toxicology, regulatory toxicology, and principles of toxicology.
The primary target audience of these toxicology modules is the student mentees who are enrolled in the Toxicology Mentoring and Skill Development Training Program. However, these online modules are open to the biomedical community and the public in general and not restricted to students enrolled in the program. The aim of these case study modules are to train and educate the general public about toxicology and toxicology research.
In this case study module you will learn the fundamental principles of toxicology, including dose-response relationships, how chemicals enter the body and how they are metabolized and excreted, major health outcomes of intoxications, basics of physiology, toxicokinetics, and cellular toxicology. ToxTutor was adopted from theU.S National Library of Medicinein 2021.
Pathophysiology is the study of the physical and functional changes that occur during a disease process. In this case study module you will learn about the concept of pathophysiology, types of toxicity, repair and adaptation, and patterns of toxic injury.
Biochemistry is the study of chemical processes within and related to living organisms. In this case study module you will learn about biomolecules and cell components, cell structure and subcellular compartments, DNA and RNA metabolism, and epigenetic mechanisms.
The genetic toxicology methodology or assay technique helps to test or evaluate the level of damages of the genetic information caused by toxicants or agents within the cells. In this case study module you will learn about different genetic toxicology assays, different genetic damages, and cytotoxicity and epigenetics assays.
Systems toxicology is a branch of science that utilizes data from different branches of toxicology and integrates them to provide a holistic approach for safety assessment. In this case study module you will learn about the concept of systems toxicology, dose level in toxicology, and different approaches to traditional and new toxicology.
Regulatory toxicology is where the science of toxicology meets the regulations, policies and guidelines that protect human health and the environment from chemicals. In this case study module you will learn about global, regional, national, state, and non-governmental regulatory toxicology.
Dr. Sonya K. Sobrian is an Associate Professor of Pharmacology at the Howard University College of Medicine and Director of the Developmental Neurobehavioral Pharmacology Laboratory.
The major focus of Dr. Sobrian's research is developmental neuropharmacology and behavioral toxicology. Previous research has involved the life-span consequences of prenatal exposure to cocaine and nicotine, alone and in combination, with an emphasis on drug addiction in the aging organism. As a visiting scientist at the National Center for Toxicological Research, she was instrumental in establishing a prenatal model of cocaine toxicity. Currently her research involves the multi- and trans- generational inheritance of addiction-like behaviors following prenatal exposure to synthetic cannabinoids.
Dr. Sobrian served as Director of the Behavioral Neuroscience Program at the National Science Foundation and was President of the Developmental Neurotoxicology Society. She currently serves as Section Editor of Developmental Toxicology for the scientific journal, Neuroteratology and Toxicology. She was also guest editor of a special issue of NTT entitled “Developmental Marijuana”. Dr. Sobrian was formerly on the Board of Scientific Counselors for the Department of Health and Human Services National Toxicology Program. She was also a permanent member of EPA’s Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel from 2016 to 2020.
During her tenure at the College of Medicine, Dr. Sobrian has successfully mentored medical, pharmacy, and graduate and undergraduate students, whom she has involved in developmental neurotoxicological research. Moreover, as a former AAAS Science and Technology Fellow and Fulbright Research Scholar, she has served on fellowship selection committees for both organizations.
Megan Taylor is a senior chemistry major at Tuskegee University. Megan was born and raised in the beautiful Kansas City, MO. Her interest in the field of chemistry stemmed from her 10th grade chemistry class and realizing that she actually understood it. She is actively involved on campus by participating in STEM outreach, president of the Student Chapter of The American Chemical Society, Golden Key International Honour Society, the Tuskegee University Honors Program, and other campus organizations. She aspires to use her knowledge of chemistry to advance the world of medicine. I like to think that I’m using all my skills learned at Tuskegee to help make me a better me.
Director of the Office of Undergraduate Research (OUR), Assistant Biology Faculty, and Media Technology Specialist for the Department of Health Disparities Institute for Research and Education
PhD Candidate/ Junior Specialist Department of Veterinary Diagnostic and Production Animal Medicine/ Molecular Biosciences Iowa State University/UC Davis Ames, IA 50010/Davis, CA 95616 Email: Cristina Santana Maldonado
Director of the T32-funded Joint Graduate Program in Toxicology Lead of the Workforce Development Core of the NJ Alliance for Clinical and Translational Sciences (NJACTS) CTSA Program. Director of the NIH R25-funded Summer Undergraduate Research Fellowship (SURF) at Rutgers University Email: Lauren Aleksunes
Faculty member, Department of Life Sciences at Salish Kootenai College (SKC), Western Montana Institutional Review Board (IRB) member for SKC Head of an R25 from the NIH-NIEHS
Scientist (Toxicologist), Monographs Programme Evidence Synthesis and Classification Branch International Agency for Research on Cancer World Health Organization
Tamia Tolson is a junior chemistry major at Tuskegee University. Tamia was born and raised in the beautiful city of Los Angeles, CA. Her love for science began at a young age so chemistry was an easy choice when it came to choosing a major. After exploring the many things one can do with a degree in chemistry, toxicology became her top choice. Aside from academics, Tamia enjoys volunteering with children and has been doing so since high school. She is a member of Tuskegee University's STEM outreach program as well as a member of SAACS.
1. Systems toxicology approach involves: Correct answer: D. All of the above. 2. Systems toxicology is usually applicable in the Correct answer: A. Early discovery phases of drug development
LEARNING OBJECTIVES After completing this lesson, you will be able to:
Understand the concept of systems toxicology.
Understand the approaches of traditional toxicology approaches vs. the new toxicity testing paradigm.
Recognize the driving force behind the growth of this field.
Applications of this field.
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The word “systems” originates from the Latin word “systema” which means a complete concept that has several parts.
Similarly systems toxicology is a branch of science that utilizes data from different branches of toxicology and integrates them to provide a holistic approach for safety assessment.
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Toxicology is the science on understanding the adverse effects of xenobiotics (drugs, chemicals etc.) on biological systems
Biological systems are extremely complex
Due to the vast number of toxicology research approaches over the years, a lot of data have been generated in different systems- in vivo, in vitro, in silico (especially due to “omics” approaches)
However, there is currently a lack of interpreting/utilizing that data for efficient safety assessment of xenobiotics
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Systems toxicology aims to fill this gap and utilize these data from different systems and integrate them into meaningful assessment for safety.
Systems toxicology relies heavily on mathematical and computational models to link the data from various systems. So, in order to have fully validated systems toxicology approaches it is important to have “real” (in life) data from animal models to validate the hypothesis.
The main driving force behind the development of systems toxicology approaches is the fact that the whole “safety assessment” process is a very lengthy, time consuming and expensive process in case of chemicals as well as the pharmaceutical industry. In order to make this process more efficient, it is important for early pharmaceutical/chemical (especially pharmaceuticals)candidate selection/screening. Screening thousands of compounds is a lengthy process and current high-throughput screening approaches together with large volume data analysis techniques have helped in more efficient selection of target molecules.
1. Enzymes are: Correct answer: A. specialized proteins that accelerate a chemical reaction by serving as a biological catalyst.
2. Lipid molecules are mainly hydrophilic molecules. Correct answer: B. False
3. A nucleotide consist of? Correct answer: A. a sugar (either deoxyribose or ribose), a phosphate group, and one of the 4 nitrogen bases.
4. Which sentence is true? Correct answer: B.RNA stands for ribonucleic acid and is composed of ribose, phosphates and the nitrogen bases cytosine (C), guanine (G), adenine (A) and uracil (U)
Topic 1: Introduction to Biomolecules and Cell Components
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LEARNING OBJECTIVES After completing this lesson, you will be able to:
Define the basic structure of biomolecules, such as: amino acids and proteins, carbohydrates, fatty acids, triacylglycerol, phospholipids, steroids and nucleic acids.
Define the meaning and significance of essential and non-essential amino acids?
Understand the function of enzymes.
Define the basic structure of ribonucleic acid (RNA) and deoxyribonucleic acid (DNA).
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Topic 1: Key Points In this section, we explored the following main points:
Amino acids link together, in a reaction known as peptide bond, to form proteins.
One important function of protein is to act as enzymes to accelerate chemical reactions.
Carbohydrates are important energy source required for various metabolic activities and may bind to proteins and lipids that play important roles in cell interactions
Lipid molecules serve as storage of biological energy and provide the building blocks for biological membranes
DNA and RNA structures have 3 main differences .The nitrogenous bases (DNA has thymine and RNA has uracil). The DNA molecule is usually double stranded and most of the RNA molecules are single stranded. In the DNA molecule the sugar is deoxyribose and in the RNA molecule the sugar is ribose.
Topic 1: Introduction to Biomolecules and Cell Components
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LEARNING OBJECTIVES After completing this lesson, you will be able to:
Define the basic structure of biomolecules, such as: amino acids and proteins, carbohydrates, fatty acids, triacylglycerol, phospholipids, steroids and nucleic acids.
Define the meaning and significance of essential and non-essential amino acids.
Understand the function of enzymes.
Define the basic structure of ribonucleic acid (RNA) and deoxyribonucleic acid (DNA).
Topic 1: Introduction to Genetic-Toxicology Assay
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LEARNING OBJECTIVES After completing this lesson, you will be able to:
In this introduction, you will know about the definition of genetic toxicology assay.
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Subtopic: 1.1. What is Genetic-Toxicology Assay?
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The genetic-toxicology methodology or assay technique which helps to test or evaluate the level of damages of the genetic information caused by toxicants or agents within the cells (Figure 1). Damages resulted as induced mutations, which may lead to different diseases including cancer. The causative toxic agents are know as mutagens. Mutagens caused for cancer disease, is known as carcinogens.
LEARNING OBJECTIVES After completing this lesson, you will be able to:
Define pathophysiology
Summarize the various host responses to toxicant-induced injury
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Pathophysiology describes the changes that occur during a disease process, with “patho-“ referring to the physical changes that are observed and “physio-“ referring to the functional processes or mechanisms that occur during a disease process. In toxicology, pathophysiology encompasses the biochemical and physical alterations that occur upon exposure of an individual (generally termed the “host”) to harmful amounts of a toxicant.
In toxicology, pathophysiology takes into account how the characteristics of the toxicant (for example, dosage, physical properties and chemical properties) and the characteristics of the host (including species, life stage, health/reproductive status, metabolism, and individual sensitivity) interact to produce physical and/or biochemical changes in the host. Pathophysiology also encompasses the host response to the effects a toxicant. With acutely lethal intoxications, the physical and chemical injury may be sufficient to cause rapid death of the organism. In non-lethal toxic exposures, toxicant-induced injury results in dysfunction of cells, tissues and/or organs that may persist or that may progress to death. Persistent toxic injury that does not result in death generally leads to attempts at repair of toxicant-induced damage. With some toxicants, the host is able to develop strategies to adapt to continued exposure to toxicants. Dysfunction, repair and adaptive processes that occur in response to exposure to certain toxicants may trigger development of unregulated cell growth leading to tumor formation in a process termed carcinogenesis.
In many cases the toxicant is the unchanged xenobiotic to which the host was exposed, but in some cases the xenobiotic itself may be relatively innocuous and requires bioactivation to more toxic metabolites before toxic effects occur. A variety of endogenous systems have evolved to mitigate the effects of many toxicants and/or their metabolites. However, when these systems fail or when the dose of toxicant exceeds the capacity of the system to neutralize the toxic effects, poisoning occurs. The clinical syndrome associated with a poisoning is referred to as toxicosis.
Most toxicants exert their effects on specific molecules, tissues or organs based on the physical and chemical makeup of the toxicant as well as the absorption, distribution and metabolism of the toxicant within the body. Toxicants such as some strong acids or alkalis (e.g. concentrated hydrochloric acid) are not systemically absorbed, so are limited to causing local injury upon contact with skin, eyes or mucous membranes. Toxicants that are ingested and absorbed from the gastrointestinal tract are shuttled via the portal vein to the liver, where they may cause direct injury, where they may be bioactivated to toxic metabolites, or where they may be detoxified before they reach the general circulation (a process termed “first pass effect”). Inhaled toxicants such as smoke may cause local tissue injury due irritants or corrosive components as well as systemic intoxication from toxic gases such as carbon monoxide or cyanide.
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Topic 1: Key Points In this section, we explored the following main points:
Pathophysiology is the study of the physical and functional changes that occur during a disease process.
Toxic insults can result in physical and biochemical alterations that may lead to cellular dysfunction, repair, adaptation, carcinogenesis and/or death.
1. What is regulatory toxicology? Correct answer: C. The intersection of the science of toxicology with the regulatory world protecting human health and the environment. 2. Which of the following have the force of law? Correct answer: A. A regulation.
LEARNING OBJECTIVES After completing this lesson, you will be able to:
Identify regulatory toxicology inside and outside of government.
Give examples of regulatory toxicology at various scales and locales.
Explain the difference between a regulation and guidance.
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What is Regulatory Toxicology?
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Regulatory Toxicology is where the science of toxicology meets the regulations, policies and guidelines that protect human health and the environment from chemicals. Regulatory toxicology commonly is associated with government agencies. These agencies may vary dramatically in their size and scope. For example, the United Nations covers the entire globe, while agencies within a city are limited to the area covered by the municipality.
Regulatory agencies generally have specific focus areas that they address. For example, the U.S. Occupational Safety and Health Administration (OSHA) covers hazardous chemicals in the workplace, while the U.S. Consumer Product Safety Commission (CPSC) addresses chemical hazards in consumer products. Lastly, regulatory toxicology also occurs in non-governmental agencies such as professional societies, private industry and various advocacy groups. Further discussion of these is provided later in the module.
What is the difference between a regulation, policy and guideline?
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A regulation is a rule or order issued by a governmental authority that has the force of law. Often regulations are developed by experts in a governmental authority to enforce legislation. An example of a regulation is the Food Quality Protection Act (FQPA) passed by the U.S. Congress and signed into law by the President in 1996.
Policies and guidelines are principles and approaches that clarify and interpret regulations. As such, policies and guidelines do not carry the force of law but provide important direction.
The Federal Insecticide, Fungicide and Rodenticide Act (FIFRA) is a U.S. regulation that regulates the broad class of chemicals used as pesticides (i.e., substances used to combat “pests”). The U.S. Environmental Protection Agency (EPA) has authority of over FIFRA, and has in turn established many policies and guidelines concerning pesticides.
One area that EPA has established multiple policies and guidelines is in the registration of pesticides(i.e., EPA review and approval).
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Topic 1: Key Points In this section, we explored the following main points:
What is Regulatory Toxicology?
What is the difference between a regulation, policy and guidance?
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+Figure 1. Basic structure of an amino acid.
+Credit: Aline de Conti
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Amino acids are the basic units of proteins. All amino acids present in proteins carry a carboxyl- and an amino group, hydrogen and variable side chains (R) at a single α – carbon atom. Amino Acid Basic Structure: Every amino acid has four components linked together with a central carbon atom α – carbon (Figure 1):
Amino group (NH2)
Carboxylic acid group (COOH)
Hydrogen atom (H)
R-group, which varies with each amino acid (R)
R groups may be:
Hydrophobic
Hydrophilic
Charged R-groups: positive or negative charged
Special R-groups: conjugated with other molecules
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Amino Acids are classified as:
Essential: humans can not synthesize them and must be obtained directly from food (phenylalanine, valine, threonine, tryptophan, methionine,leucine, isoleucine, lysine, histidine, cysteine and arginine).
Non-essential: the human body is able to produce them (glycine, alanine, serine, asparagine, glutanine, tyrosine, aspartic acid, glutanic acid and proline).
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See bellow different structures of the most common amino acids in humans.
Levels of Protein Structure: Primary (1°) Structure: The sequence of amino acids in a protein is named as primary structure. The amino acids are linked via peptide bonds formed with the carboxylic acid group of one amino acid and the amino group of a other amino acid. Secondary (2°) Structure: The secondary structure is the way a polypeptide folds to form α-helix, β-strand, or β-turn. Tertiary (3°) Structure: The tertiary structure is the way the polypeptide chain coils and turns to form a complex molecular shape. Additionally, tertiary structure starts to develop an active sites of proteins where critical actions and interactions will take place. Quaternary (4°) Structure: The quaternary structure is the combination of the multiple protein subunits that interact to form a single, larger, biologically active protein.
Protein Functions: Proteins have several functions in the human body including hormonal, enzymes, structural proteins in cell membranes, proteins also receive signals from outside the cell and mobilize intracellular response, and they are part of the immune system.
Enzymes are specialized proteins that accelerate a chemical reaction by serving as a biological catalyst. By catalyzing these reactions, enzymes cause them to take place one million or more times faster than in their absence. Several biochemical reactions important for cellular maintenance occur due to with enzymes activity. For example: environmental response and metabolic pathways.
Carbohydrates are made of molecules of carbon (C), Hydrogen (H) and Oxygen (O), and are composed of recurring monomers called monosaccharides (which typically form ring structures). A common name of monomers and dimers is ‘sugar’.
Carbohydrates are classified into three subtypes: monosaccharides, disaccharides, and polysaccharides.
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Monosaccharides: 1 unit of monomer. Examples: fructose, glucose, galactose.
Disaccharides: 2 units of monosaccharides. Examples: lactose, maltose and sucrose.
Polysaccharides: Many monosaccharides units. Examples: cellulose, glycogen and starch.
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Carbohydrates are a group of macromolecules that are important energy source required for various metabolic activities. Carbohydrates may bind to proteins and lipids that play important roles in cell interactions e.g. receptor molecules and immune system e.g. antigens.
Lipid molecules are mainly hydrophobic molecules i.e. found in areas away from water molecules, but also present smaller hydrophilic parts that are important for its biological function. The major roles of lipid molecules are to serve as storage of biological energy (Example: triacylglycerols) and provide the building blocks for biological membranes (Example: phospholipids and cholesterol). Although there are other types of lipids, in this topic we will discuss the structure and function of these main groups of lipids. Triacylglycerols
Triacylglycerols are composed of fatty acids and glycerol.
Glycerol is a simple three-carbon molecule with hydroxyl groups at each carbon.
Fatty acids are chains of carbon molecules with a carboxylic acid (COOH) in the first carbon and a CH3 (methyl) group at the end of the chain.
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Fatty acidscan be saturated or unsaturated.
Saturated fatty acids contain only single carbon–carbon bonds, and all of the carbon molecules are bonded to the maximum number of hydrogen molecules.
Unsaturated fatty acids have at least one double carbon–carbon bond with the potential for additional hydrogen atom bonding still existing for some of the carbon atoms in the backbone chain. If more than one double bond is present, the term polyunsaturated is used.
Figure 7. Saturated and unsaturated fatty acids. Credit: Aline de Conti
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Essential Fatty Acids
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Examples of two essential fatty acids, linoleic acid (known as omega-6;ω-6) and linolenic acid (known as omega-3; ω-3). These fatty acids present double bonds at the sixth and third carbon atoms, respectively, counting from the methyl end of their chains. They are considered essential because humans do not have the ability to produce double bonds at these locations and, therefore, must obtain these two fatty acid from vegetable oils.
Phospholipids Phospholipids are the major component of cell membranes. They form lipid bilayers because of their amphiphilic characteristic. The structure of the phospholipid molecule generally consists of two hydrophobic fatty acid "tails" and a hydrophilic "head" consisting of a phosphate group (PO4−3) attached to the third glycerol carbon. This head group is usually charged, creating a part of the lipid that is hydrophilic, and wants to be near water, a quality that is essential for the formation of biological membranes and many lipid functions.
Steroids Steroids are lipids that have four rings made of carbon atoms—three rings have six sides and one has five sides—with a six-carbon ring tail. Examples: bile salts, cholesterol, the sexual hormones estrogen, progesterone and testosterone, corticosteroids and pro-vitamin D.
Cholesterol is an important molecule found only in eukaryotic organisms with a variety of functions. Cholesterol is also a component of biological membranes and its main function is to control the fluidity of membranes. Cholesterol does not like to be exposed to water environments, preferring to be shielded by other hydrophobic molecules such as lipids or hydrophobic parts of proteins Cholesterol also serves as the primary source for the production of steroid hormones, bile salts, and vitamin D.
Nucleosides and nucleotides are involved in the preservation and transmission of the genetic information of all living creatures. In addition, they play roles in biological energy storage and transmission, signaling and regulation of various aspects of metabolism.
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These molecules can be divided into two major families:
Purines: are two-ring structures (adenine and guanine);
Pyrimidines: are one ring structure (thymine, cytosine and uracil).
The unique structure and interaction of these molecules serve as the fundamental building block of RNA and DNA molecules and allow fundamental processes of DNA replication and protein synthesis to occur.
Components of Nucleotides:
Nitrogenous base: The nitrogenous base of a nucleoside or nucleotide may be either a purine or a pyrimidine.
Carbohydrate: The carbohydrate component of nucleosides and nucleotides is usually the sugar ribose for RNA molecules and deoxyribose for DNA molecule
Phosphate Group: One or more phosphate groups (PO4−3) may be attached to the carbon 5 of the carbohydrate molecule.
DNA stands for deoxyribonucleic acid. DNA is an extremely long molecule that forms a double-helix.
DNA components:
Sugars - Deoxyribose
Phosphates - (PO4−3)
Base - cytosine (C), guanine (G), adenine (A) and thymine (T).
The DNA consists of two strands attached to each other by hydrogen bond created by nucleotide pairing (A-T and C-G). The double-helix structure of DNA is important for its function because these two bonded strands can temporarily separate to allow for DNA replication.
The sequences of nucleotides (A, C, T, G) in the DNA molecule will make up the genes and, subsequently, proteins are referred to as “expressed sequences” or “exons.” Sequences that do not code for a protein are called “intervening sequences” or “introns.”
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Human Genome
The genome of humans is estimated to contain approximately 20,000–25,000 different genes arranged on multiple chromosomes. Twenty three pairs of chromosomes: Twenty two pairs (autosomes). One pair (sex chromosome) (xx) (female) or (xy) (male). Humans have 23 pairs of chromosome in every cell (except mature red blood cells); Gametes or sex cells (sperm and eggs) have half the normal complement of chromosomes.
RNA stands for ribonucleic acid. RNA molecules are single strands.
RNA components:
Sugars - Ribose
Phosphates - (PO4−3)
Base: cytosine (C), guanine (G), adenine (A) and uracil (U)
RNA molecules often form secondary (2°) structures and may interact with DNA, other RNA molecules, and proteins. These interactions help to define the particular function of each type of RNA.
Types of RNA molecules and functions:
Messenger RNA (mRNA): molecules which function as the transmitter of genetic information from the DNA genetic code to the resulting protein.
Transfer RNA (tRNA): molecules that carry amino acids and match them with a specific mRNA sequence during protein synthesis.
Ribosomal RNA (rRNA): molecules associated with proteins and are responsible for the synthesis of protein molecules.
Regulatory RNA: molecules involved in regulation of DNA expression, posttranscriptional mRNA processing, and the activity of the transcribed mRNA message.
The basic structure of DNA and RNA are similar, however with 3 main differences:
1. Three of the nitrogenous bases are the same in the DNA and RNA: adenine, cytosine, and guanine. The fourth base for DNA is thymine while for RNA is uracil.
2. The DNA molecule is usually double stranded and most cellular RNA molecules are single stranded.
3. In the DNA molecule the sugar is deoxyribose and in the RNA molecule the sugar is ribose
1. Traditional LD 50 studies evaluated: Correct answer: B. Death in 50 % of the population. 2. Utilizing very high dose levels in animal models are not useful because Correct answer: A. It causes forced toxicity due to saturation of the absorption and elimination processes.
LEARNING OBJECTIVES After completing this lesson, you will be able to:
Assess toxicity in response to dose levels.
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The dose makes the poison. -Paracelsus
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As students of toxicology it is critically important to understand that everything including water and oxygen has the potential to act as poison. It is only the dose that determines the toxic/beneficial effect.
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Dose level and Applied Toxicology
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While traditional toxicology approaches in many academic laboratories and also in industry utilized very high dose levels of xenobiotics in order to study various mechanisms of toxicity, it has been identified recently that this is not a very ideal approach especially for industrial applications.
Using very high dose levels may saturate the physiological processes in a living system and hence may cause “forced toxicity” which is not very relevant in terms of real life exposures (could be valid in case of overdose/accidental overexposure).
In industry, a lot of preliminary research is conducted in order to determine dose levels for toxicology experiments. Typically, in case of pharmaceutical compounds a lot of pharmacokinetic modeling and simulations is performed to come up with exposure levels that are multiples of the real drug exposure level in humans. In the chemical industry relevant exposure levels that human beings may be exposed to based on the use of the chemical is determined
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Dose Level Selection
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Traditional toxicity testing involved using a large number of animals and using very high dose levels. Study designs such as LD 50 (Lethal Dose for 50% animals in the study) are no longer used. It is not feasible from a scientific or animal welfare point of view
Nowadays, dose level selection often involves mathematical simulation and modeling utilizing various forms of in vitro data that are analyzed with the help of medium and high-throughput modeling tools. This is a systems toxicology approach where data from different platforms is utilized to come up with relevant dose levels that are scientifically justifiable and also to refine and minimize animal experiments
1. Which sentence is true? Correct answer: A. Membranes are composed of lipids arranged in a lipid bilayer, with the hydrophilic glycerol and phosphate “head” groups of the lipid molecules forming the two outside layers and the hydrophobic “tail” groups arranged inside.
2. Histones are proteins present in the nucleus of the cells with the function of: Correct answer: A. Interact with the DNA to form nucleosomes.
1. In base-pair substitution mutation, single base nucleotide is replaced by another nucleotide. Correct answer: A. True
2. Frame shift mutation, resulted to shift or change of entire DNA or amino acid sequence by: Correct answer: C. addition or deletion of nucleotide in the DNA.
3. What is monosomy? Correct answer: B. single missing chromosome from diploid set.
4. What are the structural changes in chromosomes caused by toxicants? Correct answer: E. All of the above.
5. Micronuclei (MN) changes are the damaged chromosome fragments or whole chromosomes that were not incorporated into the cell nucleus and stayed as the extra-nuclear bodies after the cell division. Correct answer: A. True
Electrophilic compounds binding to nucleophilic compounds to form adducts is an example of which type of targeted toxicity: Correct answer: A. Covalent binding
Compared to covalent binding of a toxicant to its target molecule, noncovalent bonds tend to be: Correct answer: C. Weaker
Antioxidants mitigate cellular injury by donating electrons to: Correct answer: C. Free radicals
The binding of the acetaminophen metabolite NAPQI with cellular DNA is an example of: Correct answer: B. Adduct formation
Mechanical kidney injury caused by precipitation of crystals within renal tubules is an example of: Correct answer: C. Non-targeted toxicity
LEARNING OBJECTIVES After completing this lesson, you will be able to:
Discuss the differences between targeted and non-targeted toxicity.
Explain how absorption, distribution, and metabolism of a toxicant might influence its effects in the body.
Discuss types of interactions that can occur between a toxicant and its target molecule and how they impact the host.
Explain the importance of bioactivation in the pathophysiology of acetaminophen toxicosis.
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Toxic effects occur when the ultimate toxicant reacts with a host molecule, cell or tissue, triggering a secondary series of events leading to toxic injury. The ultimate toxicant may be the original xenobiotic to which the host was exposed, a metabolite of the original xenobiotic, a reactive species generated by the original xenobiotic or its metabolite, or an altered or unchanged endogenous compound. Some toxicants can interact with any compound they encounter, while other toxicants exert their effects by interacting with specific sites (targets) on molecules. The types of interaction between toxicants and their targets include:
Covalent binding
Noncovalent binding
Electron transfer
Hydrogen abstraction
Enzymatic reactions
Covalent binding forms practically irreversible bonds between the toxicant and target molecule; the resulting toxicant-target molecule is termed an adduct. Covalent binding occurs most commonly when electrophilic (electron-seeking) compounds join with nucleophilic (electron-donating) compounds. Nucleophilic compounds are abundant in biological systems, and include cellular macromolecules such as proteins, nucleic acids, and phospholipids. Covalent binding of toxicants to cellular proteins can inhibit vital enzyme reactions, alter protein function, inhibit or stimulate membrane receptors, or damage membrane proteins. Covalent binding of toxicants to nucleic acids such as RNA and DNA can inhibit or alter protein synthesis or induce DNA mutations that can lead to cellular dysfunction or carcinogenesis. Covalent binding of toxicants to phospholipids can result in direct damage to cellular or organelle membranes or can trigger lipid peroxidation, which will be discussed later.
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DID YOU KNOW?
Exposure to the analgesic drug acetaminophen is the most common cause of drug-induced liver injury in humans, accounting for 30,000 hospitalizations and approximately 1200 liver transplants performed every year in the United States. Most cases of acetaminophen-induced liver injury are the result of accidental or intentional overdoses. However, certain risk factors can increase the chance of liver injury developing at therapeutic doses of acetaminophen. These risk factors include chronic alcohol consumption, ingestion of drugs or herbs that alter liver antioxidant levels or pathways, malnourishment or advancing age with subsequent impairment or decline of normal liver metabolic pathways, and presence of chronic liver disease (e.g. viral hepatitis).
Figure 2.1 Liver transplantation surgery. Acetaminophen toxicosis is the leading cause of drug-induced liver injury leading to transplantation.
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Acetaminophen itself does not itself cause liver injury. Under normal circumstances, acetaminophen is converted in the liver primarily into non-toxic metabolites that are then excreted from the body. However, about 10% of acetaminophen is bioactivated by CYP450 enzymes to a toxic metabolite called N-acetyl-p-benzoquinoneimine (NAPQI); under normal circumstances, the liver can neutralize NAPQI by binding it to the antioxidant molecule glutathione. However, in overdose situations or when glutathione levels are low (as in chronic liver disease or malnutrition), the amount of NAPQI formed exceeds the capacity of glutathione to bind it, and instead NAPQI covalently binds onto macromolecules in the hepatocyte, causing hepatocellular injury and death. Treatment of acetaminophen overdose frequently involves administering antioxidants and glutathione precursors, such as N-acetylcysteine, in an attempt to provide alternative molecules to which NAPQI may bind.
Figure 2.2 The acetaminophen metabolite NAPQI is normally detoxified through binding with glutathione. If glutathione becomes depleted, NAPQI can then bind to cellular macromolecules, resulting in cell injury. Providing the glutathione precursor n-acetylcysteine helps to replenish glutathione stores and mitigate NAPQI-induced injury to cellular structures.
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Noncovalent binding of toxicants to target molecules involves the formation of relatively weak hydrogen or ionic bonds. Because of the relatively weak bonds formed, noncovalent binding is usually reversible. Noncovalent binding is commonly seen with toxicants that interact with cellular membrane receptors, intracellular receptors, some enzyme systems and membrane ion channels. Noncovalent bonding to these structures may result in over- or under stimulation of normal function. These interactions can result in alteration of inter- and intracellular signalling, organelle dysfunction, alteration of enzyme function, interference with normal homeostatic ion movement, general cellular dysfunction, or cell death. Electron transfer can result in oxidation of some endogenous macromolecules, altering their function. For example, chemicals that oxidize ferrous iron (Fe++) to ferric iron (Fe+++) in the hemoglobin molecule cause a condition termed methemoglobinemia, resulting in lowered ability of the hemoglobin in red blood cells to deliver oxygen to body tissues. Electron transfers can result in the formation of radicals, highly reactive atoms or molecules with unpaired electrons that can bind to and damage cellular molecules and structures. Oxygen-derived free radicals ("free" because they are not attached to larger molecules) such as superoxide ion (•O2-) and hydroxyl radical (HO•) are produced during normal physiological processes, but when present in excess can cause significant cellular injury due to their ability to self-perpetuate. Antioxidants present in living organisms help mitigate this “snowball effect” by donating electrons without forming radical species. Important antioxidants present within cells include superoxide dismutase, catalase, vitamin A, and glutathione.
Figure 2.3 The formation and effects of free radicals.
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Toxicant-induced hydrogen extraction from membrane phospholipids can induce lipid peroxidation which results in membrane injury leading to leakage and/or cell death. Lipid peroxidation occurs when an electrophilic compound steals an electron from a membrane phospholipid, producing a fatty acid radical. This fatty acid radical is relatively unstable and will react readily with molecular oxygen to produce a peroxyl-fatty acid radical. The peroxyl fatty acid radical then reacts with another fatty acid, producing yet another lipid peroxide and fatty acid radical that continues the cycle in a chain reaction-type mechanism. When present in sufficient quantities, antioxidants such as vitamin E can help terminate lipid peroxidation.
Figure 2.4 Cartoon of lipid peroxidation. An electrophilic radical interacts with the fatty acid chain of the cell membrane, extracting a hydrogen atom and producing a fatty acid radical which in turn interacts with other cell membrane fatty acids, propagating the production of radicals within the membrane. Lipid peroxidation may result in severe membrane injury if not terminated through interaction with an antioxidant.
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Some toxicants act enzymatically with target molecules to exert their adverse effects. Ricin, a toxin from the castor bean plant, enzymatically hydrolyzes a bond in the ribosomal RNA molecule, thus blocking protein synthesis. Many snake venoms contain a variety of enzymes that can destroy cells and tissues of the body; for example, hyaluronidase cleaves connective tissue via hydrolysis of hyaluronic acid, an essential polysaccharide in connective tissue.
Figure 2.5 Rattlesnake venom contains a variety of enzymes and enzyme co-factors that cause tissue destruction
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Non-Targeted Toxicity Not all toxic effects are mediated through direct action of toxicant at the site of injury. Some toxicants exert their effects by altering the biological microenvironment of the affected cells or tissues, and the resulting injury may be distant from the site of toxicant action. For instance toxic ergot alkaloids produced by the fungus Claviceps purpurea act on blood vessels to cause vasoconstriction, resulting in reduced blood circulation and gangrene of the extremities. Other toxicants may exert their effects merely by being physically present, as when inert gases such as methane displace oxygen in the environment, resulting in asphyxia. Some xenobiotics can precipitate as crystals in the kidney tubules, resulting in mechanical damage to the tubular epithelium, leading to kidney injury.
Figure 2.6 Precipitation of melamine-cyanuric acid crystals (M) causes mechanical damage to cells in the distal tubules of a canine kidney. A necrotic (dead) cell (N) has detached from the basement membrane. Melamine contamination of pet food caused kidney injury to hundreds of dogs and cats in 2007. (Courtesy of University of California, Davis Anatomic Pathology.)
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Topic 2: Key Points In this section, we explored the following main points:
Toxicants may interact with host molecules in a targeted or non-targeted fashion.
Targeted interactions include covalent and noncovalent binding, electron transfer, hydrogen abstraction and enzymatic reactions.
Covalent bonding of toxicant and target molecules form adducts, which can cause physical or functional damage to macromolecules such as proteins and nucleic acids.
The covalent binding of the acetaminophen metabolite, NAPQI, to macromolecules in hepatocytes can result in severe liver injury requiring liver transplantation.
Noncovalent binding between toxicant and target molecules form relatively weak, reversible bonds.
Electron transfer can result in formation of self-perpetuating radicals that can cause significant damage to cellular structures.
Antioxidants such as superoxide dismutase bind free radicals and help prevent perpetuation of free radical formation.
Lipid peroxidation begins with extraction of hydrogen from membrane phospholipids, resulting in fatty acid radical formation and damage to membranes.
Toxicants can act as enzymes, damaging cellular or tissue structures or interfering with normal cellular function.
Non-targeted interactions include alterations in biological microenvironment of cell and tissues and impairment of normal function by physical obstruction or mechanical damage.
1. Which of the following is an example of a global regulatory toxicology initiative? Correct answer: C. Globally Harmonized System. 2. Which of the following generally is involved with establishing a global regulatory toxicology initiative? Correct answer: B. United Nations (UN).
LEARNING OBJECTIVES After completing this lesson, you will be able to:
Define what is meant by “global regulatory toxicology”
Give an example of a global regulatory guideline
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What is Global Regulatory Toxicology
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Global regulatory toxicology is exactly as it sounds, it deals with regulatory toxicology on a global scale (i.e., the entire planet). Relative to other jurisdictions (e.g., nations, states, cities), there are few regulatory toxicology initiatives that are global in nature. Some initiatives (e.g., clean drinking water, clean air) with similar intent may span many parts of the globe and appear global, but they lack a global consensus.
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Global regulatory toxicology initiatives often originate from activities by the United Nations (UN), a global organization bringing together member countries to confront common challenges.
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Example of Global Regulatory Toxicology: Globally Harmonized System (GHS)
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Full name is the Globally Harmonized System of Classification and Labelling of Chemicals (GHS)
Created by the UN. Work on GHS began in 1992 and the first edition was released in 2003. GHS is updated every two years.
The goal is to harmonize the criteria by which chemicals are classified in terms of their hazards. Hazards include physical (e.g., flammability), environmental (e.g., toxicity to fish), and human heath (e.g., acute toxicity people).
Prior to Globally Harmonized System (CHS), each country had its own criteria for hazard classification, and some countries had multiple criteria. This provided challenges and confusion to the general public and other stakeholders.
GHS is a guideline, not a regulation. However, once adopted by a country, GHS generally becomes a regulation.
Membrane: Plasma membrane, nuclear envelope, and membranes provide separation of different environments to permit a variety of biological functions. Membranes are dynamic and fluid structures that allow selective movement of ions, energy sources, vitamins and cofactors, and waste. Membrane components include lipid, carbohydrates and protein molecules. Membrane fluidity is very important for its functions and, as a consequence, is important in disease processes, as well as, treatments.
Membranes are composed of lipids arranged in a lipid bilayer, with the hydrophilic glycerol and phosphate “head” groups of the lipid molecules forming the two outside layers and the hydrophobic “tail” groups arranged inside. Proteins are the second major part of biological membranes and make up approximately 20%–80% of both the structural and functional components of these membranes. Many of these proteins are embedded into the membrane and stick out on both sides; these are called transmembrane proteins.
Cytoskeleton is a structure that helps cells maintain their shape and internal organization, and it also provides mechanical support that enables cells to carry out essential functions like division and movement. The cytoskeleton is made up of microtubules, actin filaments, and intermediate filaments. Endoplasmic reticulum (ER): It consists of a system of sac- and tube-like structures, which locally expand into cisterns. Its internal lumen is connected with the intermembrane space of the nuclear membrane. Part of the ER is studded on the outside with ribosomes (rough ER), which take part in protein synthesis. The other part of the ER is free of ribosomes (smooth ER). Enzymes of the smooth ER are involved in the synthesis of fatty acids. The smooth ER also plays a role in detoxification by hydroxylation reactions.
Golgi apparatus: This organelle consists of stacks of flattened membrane sacs. Their main function is the further processing and sorting of proteins and their export to the final targets. In most cases, these are secreted or membrane proteins. In addition, the Golgi apparatus also produces polysaccharides.
Lysosomes: Lysosomes are vesicles enclosed by a lipid bilayer. These organelles are filled with many enzymes for polysaccharide, lipid, protein and nucleic acid degradation. They act also on intracellular material to be removed and even contribute to the apoptosis of their own cell. Lysosomes of special cells (e.g., macrophages) destroy bacteria or viruses as a defense mechanism.
Peroxisomes: Peroxisomes are surrounded by a single membrane. They are generated from components of the cytosol and do not bud from other membranes. The main task of these organelles is the performance of monooxygenase (hydroxylase) or oxidase reactions, which produce hydrogen peroxide (H2O2).
Mitochondria: In a typical eukaryotic cell, there are in the order of 2000 of these organelles, which are often of ellipsoidal shape. They have a smooth outer membrane and a highly folded inner membrane with numerous invaginations (cristae), which contain most of the membrane-bound enzymes of mitochondrial metabolism. Mitochondria are the site of respiration and ATP synthesis, but also of many other central reactions of metabolism, e.g., citrate cycle, fatty acid oxidation, glutamine formation, and part of the pathway leading to steroid hormones. Mitochondria are the only organelles which are equipped with their own (circular) DNA, RNA and ribosomes and thus can perform their own protein synthesis. Nucleus: All eukaryotic cells show the presence of a separate nucleus, which contains the major portion of the genetic material of the cell (DNA). The nuclear DNA is organized in a number of chromosomes. The nucleus is surrounded by a double membrane of lipid bilayers with integrated proteins, called the nuclear membrane (also known as the nuclear envelope). Nuclear pores span the nuclear membrane and enable the transport of proteins, rRNA etc.
Macro lesions are chromosomal mutations with mutagens and are with distinct morphological changes in the phenotype.
These morphological changes of chromosomes can be cytologically visible under microscope.
Macro lesions are following types:
2.2a. Numerical changes in chromosomes (Figure 2): i) Polyploidy: Duplication of entire set of chromosome to triploid or tetraploid. ii) Aneuploidy: Changes of single missing chromosome to monosomy or three copies of a single chromosome to trisomy.
2.2b. Structural changes in chromosomes (Figure 3): i) Deletion: loss of chromosome segment ii) Translocation: A segment of one chromosome becomes attached to a non homologous chromosome. It can be one way transfer as simple translocation and two way transfer as reciprocal translocation. iii) Inversion: A change in the direction of material along a single chromosome. iv) Duplication: Repetition of chromosome segment
2.2c. Micronuclei changes (Figure 4):
Micronuclei (MN) are the damaged chromosome fragments or whole chromosomes that were not incorporated into the cell nucleus and stayed as the extra-nuclear bodies after the cell division.
MN can be resulted by the defects of the cell repair machinery and by the accumulation of damaged DNA and chromosomal aberrations.
Chromosomal DNA is packaged inside microscopic nuclei by its association of histones H2A, H2B, H3, and H4. These are positively-charged proteins that strongly adhere to negatively-charged DNA and form complexes called nucleosomes. (11-nm “beads on a string” structure). Each nucleosome is composed of DNA wound 1.65 times around eight histone proteins. Nucleosomes fold up to form a 30-nanometer chromatin fiber, which forms loops averaging 300 nanometers in length. The 300 nm fibers are compressed and folded to produce a 250 nm-wide fiber, which is tightly coiled into the chromatid of a chromosome. The level of structure varies depending on the cell cycle stage and, as a result, the requirement for DNA transcription or replication.
Chromatin: The most important structure inside the nucleus is chromatin, consisting, in humans, of the 46 chromosomes. Chromatin is the combination or complex of DNA and proteins that make up the contents of the nucleus of a cell. The most abundant protein in the nucleus are histones. Histones are rich in basic amino acids (positively charged), which interact with negative charges of the DNA.
Cell signaling consists in the ability of cells to respond to environment changes through signals received outside their borders. Cells may receive many signals simultaneously and also send out messages to other cells. Cells have proteins called receptors, that are generally transmembrane proteins, which bind to signaling molecules outside the cell and subsequently transmit the signal through a sequence of molecular switches to internal signaling pathways and initiate a physiological response. Different receptors are specific for different molecules. In fact, there are hundreds of receptor types found in cells, and varying cell types have different populations of receptors.
Examples of receptors membrane:
G-protein-coupled receptors
Ion channel receptors
Enzyme-linked receptors
Receptor may be located in the cellular membrane (important to receive extracellular signals) but also may be present inside the cell or inside the nucleus.
1. Adverse Outcome Pathway (AOP) Programme was launched by: Correct answer: D. Organization for Economic Co-Operation and Development. 2. The ToxCast program utilizes which kind of assays: Correct answer: C. In vitro.
Topic 3: Tools and Technologies in Systems Toxicology
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LEARNING OBJECTIVES After completing this lesson, you will be able to:
Understand tools and technologies used in systems toxicology, the concept of adverse effects and Adverse Outcome Pathways.
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Tools and Technologies
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Tools at molecular level: Omics technologies such as genomics, protemics, metabolomics.
Tools at cellular level include highly refined high-throughput in vitro model systems.
Modeling softwares that can utilize in vitro data and mathematically translate that into relevant in vivo information utilizing pharmacokinetic (PK) or physiologically based pharmacokinetic models (PBPK). This is known as in vitro to in vivo extrapolation (IVIVE).
Modeling softwares that can perform sophisticated species scaling (prediction of human parameters from non clinical species such as rat, dog, monkey etc.).
Risk assessment and exposure modeling tools that enable calculation of hazard and risk in populations on a whole and specific subpopulations.
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Toxicity Testing in Chemicals Vs. Pharmaceuticals
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Regulatory based toxicity testing is different for pharmaceutical based compounds versus chemical and agrochemical compounds.
Non clinical safety assessment for phamaceutical products is governed by the different stages of drug development while the toxicological data requirement for chemicals/agrochemicals is based on the amount (tonnage) produced.
While most pharmaceutical compounds undergo extensive animal toxicity testing, there are thousands of chemicals in commerce today that have undergone very limited or non toxicity testing. In order to address this several governmental mandates are being put into action.
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Government Initiatives and Mandates for 21st Century Toxicity Testing
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In Europe the Registration Evaluation Authorization and Restriction of Chemicals (REACH) was initially implemented in 2007.
This substancially altered the safety testing performed on new as well as existing chemicals.
In The United States too several initiatives to increase safety testing on more and more chemicals are underway which would increase the cost of safety assessments astronomically.
The regulations under REACH have been directly estimated to cost the industry more than 4.2 billion dollars (Brown, 2003).
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Brown, V. J. (2003). REACHing for chemical safety. Environ. Health Perspect. 111, A766–A769.
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21st Century Toxcity Testing
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Traditional toxicity testing involves the use of a lot of animals and is an extremely expensive and time consuming process.
In order to address the large number of untested chemicals the US Environmental Protection Agency (EPA) initiated the ToxCast program.
The ToxCast Program is a high-throughput screening program that would enable the prioritization of chemicals so that resources can be channelized towards those chemicals that possess the greatest risk to human safety.
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The ToxCast Program
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The ToxCast program developed and utilized automated in vitro assays ( to test effects of chemicals on various biological processes using living cells, isolated proteins etc.).
The assay designs included endpoints such as cytotoxicity, enzyme activity, endocrine endpoints, gene expression etc.
A total of approximately 600 endpoints were evaluated.
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The biggest question to answer was how relevant was this data to human safety and how to utilize this in vitro information to predict human safety.
Figure 1. National Institute of Environmental Health Sciences – NIH, 50th Anniversary
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The Overall Perspective
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In vitro assays may be relevant in the light of the fact that overall disesase/toxicology processes are actually mediated by molecular and cellular perturbations.
However, the overall picture at the whole organism level includes several other complex factors such as pharmacokinectics of the compound, metabolism, clearance etc.
This gap could be filled by utilizing computational modeling tools that would utilize the in vitro data and integrate them into human physiology with the help of pharmacokinetic (PK) or physiologically based pharmacokinetic models (PBPK).
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Understanding the concept of effects Vs. adverse Effects
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In order to conduct safety assessments it is important to understand the concept of “adverse effects” versus simply “effects”. It is also important to understand the significance of biological relevance of isolated in vitro, molecular assays as it pertains to the whole organism
Adverse Outcome Pathways (AOPs) have been developed to try and link the causal molecular initiating event to a host of intermediate processes at the cellular level that finally leads to adverse outcome (AO) in the whole organism that can be used for safety assessment purposes
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Adverse Outcome Pathways
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The AOP programme was launched by the Organization for Economic Co-operation and Development (OECD) in 2012. The objective was to link the main molecular initiating event with the phenotypic/functional toxicity/adverse effect at the organism level.
Using Systems Toxicology Approach For Toxicity Predictions
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The molecular initiating events could be used in selecting in vitro assays that could have possible potential for predicting toxicity at the whole organism level .
1. Which of the following does not belong to the process od DNA replication? Correct answer: C. RNA Polymerase.
2. RNA splicing is the process where occur the removal of introns present in the pre-mRNA and splicing of the remaining exons. Correct answer: A. True
3. During protein translation, the sequence of codons (triplets of bases) of mRNA is important to: Correct answer: B. Translated the correct a sequence of amino acids.
LEARNING OBJECTIVES After completing this lesson, you will be able to:
Understand the mechanism of DNA replication.
Understand the process of gene expression.
List the main types of DNA mutation and mechanism of DNA repair.
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Topic 3: Key Points In this section, we explored the following main points:
The process of DNA replication is controlled by several proteins that act together to assure the correct base pairing for creation of the new DNA strand.
Transcription is the first step of gene expression, in which a particular segment of DNA is copied into RNA (mRNA) by the enzyme RNA polymerase.
In translation, messenger RNA (mRNA)—produced by transcription from DNA—is decoded by a ribosome and tRNA to produce a specific amino acid chain, or protein.
Mutations are changes in the genetic sequence (DNA or RNA sequence), that can be beneficial or may result in damage, if not repaired.
1. The Ames technique uses several strains of the bacterium Salmonella typhimurium which carry mutations in genes involved in: Correct answer: B. Histidine synthesis.
2.In Allele-Specific PCR, fluorescent reporter probes are added to the reaction mixture and one fluorescent reporter probe is selected for wild type and other fluorescent probe is used for mutant. Correct answer: A. True.
3. Which instrument is used to measure the terminating nucleotides in Sanger Dideoxy Sequencing? Correct answer: A. Fluorescence spectroscopy .
4. Cytogenetic assays of mammalian cells are performed to detect different types of structural and numerical chromosomal aberrations caused by a genotoxic chemicals. The structural chromosomal aberrations are: Correct answer: E. All of the above.
LEARNING OBJECTIVES After completing this lesson, you will be able to:
Know different types of genetic-toxicology assays.
Know how different genetic-toxicology assays are used in toxicology when cells are exposed to mutagens.
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The goal of genetic toxicology assay is to determine whether any chemical or mutagen will do any adverse effect on genetic material or may cause different diseases including cancer. The assays can be performed using bacterial, yeast, or mammalian cells. One can early control and save vulnerable organisms from genotoxic chemicals by preforming genetic toxicology assay.
Following different types of genetic toxicology assays are used now a days:
Whether the effect of a given xenobiotic is therapeutic or toxic is entirely dependent upon its: Correct answer: B. Dose
Highly reactive toxicant molecules have a predilection for which moiety on a protein molecule? Correct answer: D. Sulfhydryl (S-H) moiety
The process of a xenobiotic binding a larger protein molecule, resulting in a new molecule that triggers an immune response is termed: Correct answer: C. Haptenization
Topic 3: Outcomes of Targeted and Non-Targeted Toxicity
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LEARNING OBJECTIVES After completing this lesson, you will be able to:
Discuss the various effects that toxicants have on target molecules and how these effects result in injury to the host.
Discuss the pathogenesis of the rash that occurs following exposure to poison ivy.
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The interaction of toxicants with host molecules may lead to the dysfunction or destruction of the target molecule, or it may result in formation of adducts that the immune system identifies as “foreign,” triggering immune responses against these neoantigens.
Target molecule dysfunction is a common mechanism by which xenobiotics, particularly drugs, exert their effects; remember it is the dose of xenobiotic that determines whether the effect will be therapeutic (pharmacologic) or harmful (toxicologic). Target molecule dysfunction may occur through activation of cellular membrane receptors, resulting in over-stimulation of some cellular function. For instance, the toxic effects of methomyl, a carbamate insecticide, include over-stimulation of cells of excretory glands, resulting in excessive salivation, excessive tear formation and excessive secretion of mucus by goblet cells within the respiratory tract.
Conversely, other toxicants may inhibit or impede the action of cellular receptors; the resulting clinical effects will depend on the type of receptor affected and what action is impeded. For example, there are channels in nerve cell membranes that allow sodium to pass into and out of the cell; when exposed to pyrethrins, insecticides extracted from chrysanthemum flowers, these channels are unable to close, which results in excessive stimulation seen as muscle twitches, tremors and convulsions. However, when these channels are exposed to tetrodotoxin, the infamous puffer fish toxin, these channels are unable to open, which prevents stimulation of muscle and results in paralysis.
Figure 3.1 Pufferfish (fugu) is a delicacy in some countries, but if not prepared correctly it can cause paralysis and even death.
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Toxicants may induce target molecule dysfunction by altering protein structure such that the protein is no longer functional, resulting in disruption of membrane protein channels, interference with transmembrane signaling or loss of enzyme function. Many of these types of effects involve the toxicant or its metabolite binding to reactive moieties on the protein molecule; the sulfhydryl or thiol (S-H) moiety is particularly susceptible to binding with other reactive compounds. Toxicant-induced alteration of DNA structure can lead to mispairing of nucleotides during mitosis, with potential effects ranging from altered protein synthesis to initiation of carcinogenesis.
Destruction of target molecules by toxicants can occur via chemical degradation by radicals or by cross-linking and fragmentation by electrophiles, radicals, and ionizing radiation. Cross-linking and strand breaks can occur in proteins but are more commonly associated with toxicant-induced nucleic acid (particularly DNA) injury.
Figure 3.2 DNA strand breaks may result in cell death, genetic mutation or development of cancers
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Neoantigen formation results when a xenobiotic or its metabolite binds to a larger protein to form a novel molecule that elicits an immune response. Molecules that trigger an immune response upon binding to carrier proteins are termed haptens, and the process of neoantigen formation in this manner is termed haptenization. Neoantigens can trigger humoral immune responses resulting in the development of antibodies that can trigger acute allergic reactions such as hives or anaphylaxis. Neoantigens that trigger cellular-mediated immune responses cause injury to specific tissues or organs such as skin, liver or blood vessels in a process termed autoimmunity.
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DID YOU KNOW?
The rash caused by poison ivy (Toxicodendron spp.) is caused by urushiol, an oily mixture of chemicals called catechols, in the plant of the sap. Upon exposure to human skin, urushiols bind to membranes on skin cells and serve as haptens, changing the shape of proteins in the membranes. The body’s immune cells no longer recognize these skin cells as normal parts of the body and mount an immune response, resulting in inflammation, itching, blisters, swelling and redness at the site of urushiol contact. In addition to local irritation, serious, systemic reactions to urushiol can occur if the leaves are ingested, or if smoke from burning poison ivy is inhaled.
Figure 3.3 Skin contact with leaves of poison ivy can result in a blistering rash.
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Topic 3: Key Points In this section, we explored the following main points
Toxicant-induced target molecule dysfunction can occur through activation or inhibition of cellular receptors, denaturing of membrane proteins, and destruction of target molecules.
Haptenization results in the formation of neoantigens that can trigger immune responses against cells and tissues of the body, resulting in allergic or autoimmune reactions.
The rash caused by poison ivy is an autoimmune reaction against skin cells whose membranes have bound to the toxicant urushiol from the plant.
1. Which of the following is an example of a regional regulatory toxicology initiative? Correct answer: B. REACH. 2. Which of the following generally is a trait commonly found in a regional regulatory toxicology initiative? Correct answer: D. Involvement of two or more countries in a regulatory initiative.
LEARNING OBJECTIVES After completing this lesson, you will be able to:
Define what is meant by a “regional regulatory toxicology”.
Give an example of a regional regulatory regulation.
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What is Regional Regulatory Toxicology?
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Regional regulatory toxicology exists between global and national regulatory toxicology. It deals with regulatory toxicology that includes multiple countries. Often these countries are adjacent or in close proximity (e.g., United States and Canada) but that is not a requirement.
A group of nations that frequently exert regulations on a regional scale is the European Union (EU). The EU started in 1951 with six European countries agreeing to cooperate and has expanded over the ensuing decades to the current list of 28 member countries. -One current member of the EU, the United Kingdom, through a popular vote, has decided through a popular vote to eventually exit the EU (i.e., Brexit).
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Example of Regional Regulatory Toxicology: Registration, Evaluation, Authorization and restriction of CHemicals (REACH)
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Started as a paper in 2001 and entered into force on June 1, 2007.
New approach for the regulation of chemicals in the EU.
Required key hazard information to be obtained for existing chemicals to remain in commerce, or for a new chemicals to enter into commerce.
Information falls into three broad hazard categories: physical-chemical, human health and environmental health.
The types and amounts of information varies depending on the volume of chemical used in commerce. The more the chemical is used, the more the data.
In addition to hazard information, REACH requires assessments to determine if chemicals in commerce pose unreasonable risk(s).
The process of DNA replication consists in uncoiling double-stranded DNA, copying each DNA strand and then separating the two, new, double-stranded copies. The process starts at an origin of replication (ori), a nucleic acids sequence where the replication can start. There are around 100,000 origins of replication in each human cell. This means that the DNA replication may starts simultaneously in different positions at the same time. The replication fork is the point where two DNA strands, one termed the leading strand and the other the lagging strand, are separated and DNA copying occurs. The coiled-coil, double-helical DNA structure is initially unwound by the enzyme DNA helicase by breaking the hydrogen bonds between complementary nucleic acids. Single-stranded binding proteins attach to the new DNA strands to keep them separated.
An enzyme termed primase then produces a short strand of RNA to serve as a primer for the remainder of the process. The enzyme DNA polymerase replicates each DNA strand in the 5′ to 3′ direction by adding the correct, matching nucleotide triphosphate to the 3′-hydroxyl end of the primer strand. As each new nucleic acid is added, a new phosphodiester bond is formed, utilizing the energy contained in the remaining diphosphate group.
This process is continuous on the leading strand but, as DNA polymerase can only add in the 5′ to 3′direction. For the lagging strand short chains of nucleic acids, called Okazaki fragments, are generated and the enzyme DNA ligase joins the Okazaki fragments together as lagging strand replication proceeds. The process of replication along the coiled-coil structure of DNA soon leads to an unfavorable DNA conformation that is wound about itself. To relieve this problem, a DNA topoisomerase efficiently cuts the phosphate backbone, “untangles” the DNA strands, and then repairs the cut, leaving the DNA otherwise unaltered.
This assay was discovered by Bruce Ames in 1970. This assay is widely used to test for gene mutation. The technique uses several strains of the bacterium Salmonella typhimurium which carry mutations in genes involved in histidine synthesis. These strains are auxotrophic mutants and they require histidine for growth and they cannot produce it. This assay examine the ability of the chemical or mutagen in creating mutations or a "prototrophic" state of strains, when the strains can grow on a histidine-free medium (Figure 1).
RNA Transcription is the process whereby a particular segment of DNA is transcripted into an equivalent RNA sequence
mRNA: for genes that codes for a protein.
tRNA: for a transfer RNA.
rRNA: for assembly of a ribosome.
miRNA: (micro RNA) which binds to mRNA and inhibits its translation
siRNA: (small-interfering RNA) which binds to mRNA and aids in its degradation.
snRNA: (small nuclear RNA) which participates in RNA processing as part of the spliceosomes.
snoRNA: (small nucleolar RNA) which participate in nucleolar RNA processing.
The transcription starts with binding of the enzyme RNA polymerase to a promoter sequence on the DNA, a regulatory region that dictate where the transcription should start. The DNA is transcribed from 3′ to 5′ and occurs only on one of the DNA strands, the template strand . The enzyme RNA polymerase travels down the DNA from 3′ to 5′ while matching the appropriate RNA to its DNA counterpart, utilizing uracil matched with adenine instead of thymine. As in DNA replication, energy for the formation of the phosphodiester bond is derived from hydrolysis of the two terminal phosphate bonds of the nucleoside triphosphate. Multiple RNA polymerases can transcribe on a single DNA gene sequence, allowing rapid production of the RNA product.
Promoter region: are specific DNA sequences, usually located upstream and near the transcription start sites of genes and serves as a binding site for proteins called transcription factors that recruit RNA polymerase. Example: TATA box, CpG island.
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Transcription factors (TFs): include a wide number of proteins, excluding RNA polymerase, that promotes (as an activator), or blocks (as a repressor) the recruitment of RNA polymerase to DNA. TFs bind to promoter regions of DNA.
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Enhancer is a short region of DNA that can be bound by transcription factors to increase or facilitate the transcription of a particular gene. They can be located up away from the gene, upstream or downstream from the start site.
Following are the different molecular assay to study nucleotide variants or alternation of genetic material caused by mutagens: 3.2a. Allele-Specific PCR :
Single nucleotide polymorphism (SNP) resulted from base substitution mutation can be analyzed by this method. In this real-time PCR, fluorescent reporter probes are added to the reaction mixture and one fluorescent reporter probe is selected for wild type and other fluorescent probe is used for mutant. The PCR primers with fluorescent probe will match or mismatch one of the alleles at 3’ end of the primer. DNA polymerase extends the probes in a complementary fashion and releasing the reporter fluorescent molecules for detection. The PCR cycles with the reporter probes show the amplified signals and allow for precise measurement of one or both alleles of interest. Similarly, the 3’ end of the mutant-specific primer is extended only in the presence of DNA with that mutation (Figure 2).
The goal of this method is to detect unknown mutations including single nucleotide variants (SNVs) and small duplications, insertions, deletions, and indels of interest caused by mutagens. In this method, sequencing primers hybridized to the PCR product and are extended using the four deoxynucleotides (dNTPs), a mixture of fluorescently labeled dideoxynucleotides (ddNTPs) and DNA polymerase. Four ddNTPs are marked with a different fluorescent dye. Random incorporation of the marked ddNTPs shows in termination of strands at each location along the sequence. The gel electrophoresis separates the strands by size. Fluorescence spectroscopy measured the terminating nucleotides (Figure 3).
The newly synthesized RNA transcripts are processed prior to their use in the cell as mature RNA.
A 7-methyl guanosine nucleic acid is added to the 5′-end (known as a 5′ cap) of the pre-mRNA as it emerges from RNA polymerase II (Pol II). The cap protects the RNA from being degraded by enzymes and serves as an assembly point for the proteins to begin translation to protein.
Removal of introns present in the pre-mRNA and splicing of the remaining exons, in a process called RNA splicing. The continuous series of DNA bases coding for a protein are interrupted by base sequences that are not translated. The translated sequences are referred to as exons (expressed sequences) and the nontranslated sequences as introns (intervening sequences).
Synthesis of the poly(A) tail. This is a stretch of adenine (A) nucleotides. When a special poly(A) attachment site in the pre-mRNA emerges from Pol II, the transcript is cut there, and the poly(A) tail is attached to the exposed 3′ end.
This completes the mRNA molecule, which is now ready for export to the cytosol. (The remainder of the transcript is degraded, and the RNA polymerase leaves the DNA.)
Cytogenetic assays of mammalian cells are performed to detect different types of structural and numerical chromosomal aberrations caused by a genotoxic chemicals. The clastogenic or aneugenic effects from the genotoxic chemicals will result an increase in frequency of structural (premature centric separation, chromosome breaks, dicentric chromosomes, ring) complex rearrangements (Figure 4) or numerical aberrations of the genetic material in mammalian cells.
Protein synthesis requires the interaction of mRNA, tRNA, several accessory proteins, called initiation factor (IF) and elongation (EF) factor, and ribosomes.
The large ribosomal subunit binds to the small ribosomal subunit to complete the initiation complex. The tRNA molecule bind to one amino acids at the top of the structure. In the base if the tRNA there is the three base sequence known as the anticodon. This anticodon binds, through base pairing, to a three base codon on mRNA. It is this interaction between the mRNA and the amino acid-tRNA that provides the high degree of fidelity observed in the transfer of genetic information from DNA to proteins.
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The Triplet Code (Genetic Code) A sequence of three bases in DNA identifies each of the 20 amino acids that are to be incorporated into the newly synthesized protein. This information is incorporated into mRNA which is synthesized using DNA as the template. Considering that three bases are required at a minimum, and we have 4 nucleotides ( 43 = 64 code words are possible). This is more than the 20 amino acids. In fact, many triplets are used to define one same amino acid. In addition, some “extra” triplet sequences are used as stop codons to terminate protein synthesis. AUG is used as the start codon for the N-terminal amino acid in eukaryotes.
Using the same binding rules as DNA double strands (e.g., a tRNA that binds the starting mRNA codon AUG has an anticodon sequence of UAC), insuring the specific order of AAs required for proper production of the protein.
RNA plays three distinct and important roles:
mRNA – the intermediary between gene and protein – provides the message.
tRNA – the key or adaptor – reads the genetic code, brings amino acids to the growing polypeptide chain
rRNA – in ribosome, provides a scaffold for protein synthesis, catalyzes peptide bond formation
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The IF and EF accessory proteins serve a number of roles, including enabling binding of the mRNA molecule to the ribosome, movement of the mRNA along the ribosome to the start point of the synthesis, docking of the tRNA–amino acid, and movement of the mRNA and growing peptide chain, as well as accuracy assurance
The protein biosynthesis, can be divided into three phases: initiation, elongation, and termination.
Initiation of protein synthesis begins when the protein initiator factor IF-3 binds to the small subunit of the ribosome and causes its dissociation. The small ribosomal subunit then binds to the 5’ side of mRNA which carries information in a triplet code from DNA. The small subunit is then translocated where it meets the large ribosomal subunit, other protein initiator factors, and initiator tRNA. The tRNA is bound to methionine at a site in the ribosome known as the P site.
In the elongation phase of protein synthesis, a specific aminoacyl-tRNA, directed by hydrogen bonding interactions between the anticodon region of the aminoacyl-tRNA and the codon region of mRNA, adds to a site distinct from the P site, the A site. The A and P sites are in close proximity, allowing the peptide bond formation between the amino acids. The newly synthesized tRNA bound dipeptide then moves from the A site to the P site. After a translocation of the ribosome in the 5’ - 3’ direction along the mRNA occurs to expose a new codon. Then, another amino acid-tRNA identity and binds to the mRNA at the A site and the peptidyl transferase reaction is again initiated. As the polypeptide chain grows through subsequent cycles of amino acid residue incorporation, it emerges from the ribosome and undergoes folding into its native secondary and tertiary conformations.
In termination step, the peptide bond synthesis ceases when a stop codon on the mRNA is reached. This termination site will not bind aminoacyl-tRNA and peptide synthesis stops. Release factors allow the newly synthesized protein to dissociate from the ribosome.
Micronucleus assay is used as a tool to evaluate genetic damage caused by a genotoxic chemicals. The number of micronuclei (Figure 5) generated directly related to the amount of DNA damage in the cells.
Gene expression is a two-step process in which DNA is converted into a protein.
The first step is DNA transcription to RNA. In this step, the information from the archival copy of DNA is imprinted into mRNA. The structure of RNA is a little different, it contains ribose instead of deoxyrybose, and the four bases that bind to it are cytosine (C), guanine (G), adenine (A) and uracil (U). During transcription, DNA unfolds, and mRNA is created by pairing mRNA bases with the bases of DNA. In this process C in DNA translates to G, G to C, A to U, and T to A. After mRNA is transcripted, it is transported to the ribosome.
The second step, protein translation occurs at the ribosome. During translation, the sequence of codons (triplets of bases) of mRNA is, with the help of tRNA, translated into a sequence of amino acids.
Gene expression seems to be a straightforward process, the mechanism that control the gene expression that causes most phenotypic differences in organisms.
Mutations are changes in the genetic sequence (DNA or RNA sequence) , and they are a main cause of diversity among organisms. Although some of mutations are beneficial, offering resistance to disease or improved structure and/or function, some other specific mutations can lead to disease and/or death of the cell or organism.
Mutations can occur due to assaults from the environment or spontaneous mutation may occur during the DNA replication. Mutations are estimated to occur at an approximate rate of 1000–1,000,000 per cell per day in the human genome, and every new cell is believed to contain approximately 120 new mutations.
Types of mutation Point mutations when only a single base pair is changed into another base pair. They can be classified as:
Transition when a purine nucleotide is changed to a different purine (A ↔ G) or a pyrimidine nucleotide is changed to a different pyrimidine nucleotide [C ↔ T(U)].
Transversion when the orientation of a single purine and pyrimidine nucleotide is reversed [A/G ↔ C/T(U)].
Silent when the same AA is coded.
Missense when a different AA is coded.
Neutral when an AA change occurs but does not affect the protein's structure or function.
Nonsense when a stop codon results, terminating translation and shortening the resulting protein.
Insertion and deletion mutations, which are together known as indels. Indels can have a wide variety of lengths. At the short end of the spectrum, indels of one or two base pairs within coding sequences have the greatest effect, because they will inevitably cause a frameshif, i.e. change the entire reading of the mRNA sequence. At the intermediate level, indels can affect parts of a gene or whole groups of genes. At the largest level, whole chromosomes or even whole copies of the genome can be affected by insertions or deletions. At this high level, it is also possible to invert or translocate entire sections of a chromosome, and chromosomes can even fuse or break apart. If a large number of genes are lost as a result of one of these processes, then the consequences are usually very harmful.
The human body have mechanisms to detect and repair the various types of damage that can occur to DNA, no matter whether this damage is caused by the environment or by errors in replication. Because DNA is a molecule that plays an active and critical role in cell division, during the cell cycle, checkpoint mechanisms ensure that the DNA is intact before permitting DNA replication and cell division to occur. Failures in these checkpoints can lead to an accumulation of damage, which in turn leads to mutations.
UV radiation causes DNA lesions that may distort DNA's structure, introducing bends or kinks and thereby impeding transcription and replication. These lesions may be repaired through a process known as nucleotide excision repair (NER), a mechanism where a enzyme catalyze the removal of damaged nucleotides, and replacement of the correct sequence, guided by the intact complementary DNA strand. Defects in this mechanism is related to human diseases like skin cancer.
Another repair mechanism that handles the spontaneous DNA damage caused oxidation or hydroxylation generated by metabolism is the base excision repair (BER). In this mechanism, enzymes known as DNA glycosylases remove damaged bases by literally cutting them out of the DNA strand through cleavage of the covalent bonds between the bases and the sugar-phosphate backbone. The resulting gap is then filled by a specialized repair polymerase and sealed by ligase.
DNA damage also may occur in form of double-strand breaks, which are caused by ionizing radiation, including gamma rays and X-rays. Double-strand breaks may be repaired through one of two mechanisms: nonhomologous end joining (NHEJ), where an enzyme called DNA ligase IV uses overhanging pieces of DNA adjacent to the break to join and fill in the ends; or homologous recombination repair (HRR) where the homologous chromosome itself is used as a template for repair.
1. QSAR databases link: Correct answer: A. Relationship between chemical structures of compounds and their activity/toxicity. 2. Development of efficient QSAR tools depend on: Correct answer: C. A large database of validation training sets.
1. Epigenetic mechanisms are considered: Correct answer: A. Reversible.
2. DNA methylation may inhibit the binding of transcription factors to their recognition site, at promoter regions resulting in: Correct answer: A. Inhibition of gene transcription.
3. DNA methylation and histone post-translational modifications play important role in the establishment of chromatin structure and in consequence in the gene expression modulation. Correct answer: B. True.
LEARNING OBJECTIVES After completing this lesson, you will be able to:
Identify the main epigenetic mechanisms related to control of gene expression.
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Topic 4: Key Points In this section, we explored the following main points:
Epigenetic mechanisms may influence gene expression without alteration in the DNA sequence.
Main epigenetic mechanisms are DNA methylation, histones post-translational modification and alteration in the expression of microRNAs.
Epigenetic change is a regular and natural occurrence but can also be influenced by several factors including age, the environment/lifestyle, and disease state.
Different from genetic alterations, epigenetic alterations are considered reversible.
1. Ladder assay are performed for following reason: 1) to simply characterize the toxicity of the chemicals or drugs in cells, or 2) to determine the maximum doses of the test chemicals or drugs that can be used for cells without causing too much cell death. Correct answer: A. True.
2. The Comet Assay is used to detect DNA damage by using a micro gel electrophoresis: Correct answer: A. True.
3. The cells are considered in the stage of necrosis, if the cells lose membrane integrity and die promptly due to cell lysis when exposed to chemicals, drugs, toxins or foreign antigens Duplication of entire set of chromosome . Correct answer: A. True.
4. What are the proteomic assays to know the effect of toxicants in cellular toxicity signaling pathway or mechanism? Correct answer: D. All of the above.
5. The expression array is the chip based microarray of more gene expressions (finger print of genes) by the effect of cellular toxicants. Correct answer: A. True.
LEARNING OBJECTIVES After completing this lesson, you will be able to:
Know different types of cytotoxicity assays.
Know how different cytotoxicity assays are used when cells are exposed to toxicants or mutagens.
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Topic 4: Key Points In this section, we explored the following main points:
Different types of cytotoxicity assays.
How different cytotoxicity assay namely DNA fragmentation/ladder assay, Comet assay, Necrosis assay, Enzyme assay, Proteomics assay, and Expression array assay are used when cells are exposed to cytotoxic agents.
LEARNING OBJECTIVES After completing this lesson, you will be able to:
Know different types of cytotoxicity assays.
Know how different cytotoxicity assays are used when cells are exposed to toxicants or mutagens.
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The goal of cytotoxicity assay is to determine whether any chemicals or drugs will do any toxic effect or load on milieu or genetic material of the cells caused for lethality of the cells or caused for different diseases.
Followings are the different types of cytotoxicity assays:
The accumulation of excess lipid within liver cells is termed: Correct answer: A. Steatosis
Cellular degeneration secondary to a toxic insult is seen microscopically as: Correct answer: A. Cellular swelling
Loss of organelle function, hydrolytic degradation of intracellular membranes and lysis of cells are characteristics of: Correct answer: D. Necrosis
The orderly decommissioning of cellular organelles without loss of energy and protein synthesis leading to fragmentation into membrane-bound packets is characteristic of: Correct answer: A. Apoptosis
Topic 4: Cellular Response to Toxicant-Induced Injury
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LEARNING OBJECTIVES After completing this lesson, you will be able to:
Describe the range of cellular injury that may occur following exposure to a toxicant.
Discuss the major mechanisms of toxicant-induced cell death.
Compare the processes of necrosis and apoptosis in terms of inciting causes and the cellular changes that occur with each.
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Toxicants can exert a variety of effects at the molecular level that have significant repercussions at the cellular, tissue and organ levels. The effects of a toxic exposure can range from reversible cellular dysfunction to irreversible cellular injury to cell death, all of which can alter normal organ function and have significant impact on the health and well-being of the body as a whole. The ability of cells, tissues and organs to overcome the effect of a toxicant through repair and/or adaptation will dictate the ultimate outcome of a toxic exposure.
Following toxic insult, cells have a limited repertoire of responses. Nonlethal cell injury may lead to cellular degeneration, seen microscopically as swelling of the cells. Toxicant-injured cells may accumulate water, lipid, pigments, glycogen or metabolic waste products due to impairment of normal maintenance functions. Accumulation of lipids in hepatocytes, termed steatosis or hepatic lipidosis, is a common toxic effect seen in cases of alcohol-related liver disease. Degenerative changes in cells are often reversible if the inciting cause is removed. When cell injury proceeds beyond the self-repair capability of the cell, cell death ensues.
Figure 4.1 Lipid accumulation in the liver comparing normal liver (left) to liver with steatosis (right). In the photomicrographs at the bottom, the white spaces are areas of lipid accumulation.
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Mechanisms of Cell Death Major mechanisms of toxicant-induced cell death include disruption of cell membrane structure and/or function, loss of cellular maintenance functions, and impairment of cellular energy production. Loss of membrane structural or functional integrity can result in uncontrolled passage of water, ions and other compounds into or out of the cell. The subsequent loss of normal cytosolic environment interferes with normal biochemical processes necessary for cell function and/or survival. Loss of ability to synthesize proteins and other macromolecules impedes maintenance of organelles and enzymatic pathways vital to cellular survival. Impairment of cellular energy production generally occurs when toxic effects alter mitochondrial function and/or structure and can lead to cell death due to failure to produce sufficient ATP to power essential cellular functions.
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Necrosis is the term used to describe cell death due to irreversible injury. Necrotic cells undergo degenerative processes including swelling of organelles, loss of organelle function, oxidative and hydrolytic degradation of intracellular membranes and macromolecules by electophiles and free radicals, and, ultimately, lysis (loss of cellular constituents to surrounding tissues due to cell membrane rupture). Necrosis generally results in the generation of an inflammatory response as cellular components and free radicals that are released to the extracellular matrix attract inflammatory cells.
In contrast, apoptosis (sometimes nicknamed “cell suicide” or “programmed cell death”) is a more orderly form of cell death. Apoptosis is an active process involving activation of specific enzymes which triggers the systematic fragmentation of cell constituents into blebs of cell membrane that pinch off of the main cell to form apoptotic bodies. During this fragmentation, the cell continues to produce energy and proteins, unlike necrosis where organelle and energy production cease prior to cellular fragmentation. The end result of apoptosis is numerous apoptotic bodies, each composed of a cellular membrane surrounding intact and functional cellular components. Apoptosis can be triggered by various forms of oxidative stress, particularly the presence of excessive oxygen-derived free radicals, due to excessive free radical generation and/or to lack or exhaustion of endogenous antioxidants. Because intracellular components are not spilled into the extracellular matrix, apoptosis generally does not incite an inflammatory response; instead the apoptotic bodies are removed by local phagocytes.
Figure 4.2 Apoptosis and Necrosis are two very different forms of cell death.
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Whether a given toxic insult will lead to apoptosis or necrosis is not always known, and there are many toxicants, such as the heavy metal cadmium, that can induce both apoptosis and necrosis at the same time. A general rule of thumb for apoptosis is that it is more commonly seen at lower levels of toxicant exposure while necrosis occurs more frequently at relatively higher toxicant levels. This makes sense, as at high levels of exposure, cells may not have time to undergo apoptosis before cell death occurs. However, for some toxicants, apoptosis may occur early on during high levels of exposure, with necrosis developing later. The distinction between apoptotic and necrotic outcomes for various disease conditions is the subject of extensive current research.
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Topic 4: Key Points In this section, we explored the following main points:
Toxicant-induced cellular injury can range from reversible cellular dysfunction to irreversible cellular injury to cell death.
Cellular responses to toxic injury may include cellular degeneration and accumulation of substrates within the cell.
Steatosis is lipid accumulation within hepatocytes and is a common toxic effect secondary to alcohol exposure.
Major mechanisms of cell death include disruption of cell membrane structure and/or function, loss of cellular maintenance functions, and impairment of cellular energy production.
Necrosis is cell death resulting from cessation of organelle function, degradation of intracellular structures and culminating in lysis of the cell and attraction of inflammatory cells.
Apoptosis is an active form of cell death whereby cellular function is maintained as the cell components are compartmentalized and packaged into apoptotic bodies that pinch off of the main cell.
Apoptosis can be triggered by oxidative stresses caused by oxygen-derived free radicals.
Apoptosis is not generally associated with an inflammatory response.
1. EPA regulates chemicals that are in: Correct answer: B. Environmental media (e.g., water, air). 2. True or False: US States can choose not to comply with regulations set by the FDA. Correct answer: B. False – FDA sets federal regulations that are enforceable by law and all US States are required to comply with these laws.
Epigenetics is defined as potentially heritable and reversible and changes in gene expression mediated by methylation of DNA, modifications of histone proteins or by non-coding RNAs that are not due to any alteration in the DNA sequence. These processes singularly or jointly affect transcript stability, DNA folding, nucleosome positioning, chromatin compaction, and ultimately nuclear organization. They determine whether a gene is silenced or activated and when and where this occurs. Epigenetic change is a regular and natural occurrence, essential for normal cell development, but can also be influenced by several factors including age, the environment/lifestyle, and disease state.
DNA fragmentation or ladder assay are used to know the fragmented DNA of the cells caused by chemicals or drugs. Fragmented DNA can be separated agarose gel electrophoresis and can be visualized as “ladder” by ethidium bromide staining (Figure 1).
The evaluation of cytotoxicity through cell death is an acceptable common assessment.
Ladder assay are performed for following reason:
to simply characterize the toxicity of the chemicals or drugs in cells, or
to determine the maximum doses of the test chemicals or drugs that can be used for cells without causing too much cell death.
DNA methylation is a covalent modification of DNA, in which a methyl group is transferred from S-adenosylmethionine (SAM), that is converted to S-adenosylhomocisteine (SAH), to the 5 position of cytosine by a family of enzymes known as DNA methyltransferases (DNMT).
Figure 1. DNA methylation – Credit Aline de Conti
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DNA methylation occurs predominantly in cytosines located in proximity of guanines, known as CpG dinucleotides (CpGs) or CpG island. These CpG island are found in promoter region of genes. The methyl group inhibits the binding of transcription factors to their recognition site, resulting in inhibition of gene transcription. Furthermore, the methyl group may attract other proteins know as transcriptional repressors that contributes for inhibition of gene transcription.
The Comet Assay (single cell gel electrophoresis /SCGE) is used to detect DNA damage by using a micro gel electrophoresis. The image of the damaged DNA shows a comet with head and tail. The analysis of image for comet assay is calculated for the “tail length” of the comet which is the measurement from the point of highest intensity within the comet head as well as the “tail moment” which is the product of the tail length and the fraction of total DNA present within the tail.
The nucleosome is composed of five histone proteins (H1, H2A, B, H3, and H4). The N-terminus of these histone proteins are subject to covalent modifications such as methylation, phosphorylation, acetylation, ubiquitination or sumoylation by a group of histone-modifying enzymes . Alterations in these proteins contribute to the accessibility and compactness of the chromatin, and result in activation or suppression of particular genes.
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EXAMPLES OF TYPES AND ROLES OF HISTONE MODIFICATIONS
Figure 3. Histone sites of post-translational modifications.
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DNA methylation and histone post-translational modifications play important role in the establishment of chromatin structure and in consequence in the gene expression modulation. These epigenetic mechanisms can be independent or can happen together to control the gene expression. They also may influence each other, for example the histone methylation can help to direct DNA methylation patterns, and DNA methylation might serve as a template for some histone modifications after DNA replication.
The necrosis assay is performed by flow cytometry analysis with staining of Annexin V and propidium iodide (PI) in the cells. The cells are considered in the stage of necrosis, if the cells lose membrane integrity and die promptly due to cell lysis when exposed to chemicals, drugs, toxins or foreign antigens. In necrosis, cells show swelling, loss of membrane integrity and disruption of metabolism. Cells with necrosis do not go to stage of apoptosis, apoptotic cell may undergo secondary necrosis. These necrotic cell will shut down metabolism, lose membrane integrity, lyse and formed cell injury autolysis.
The flow cytometric analysis for necrosis assay showed that the cells stained positive for both FITC Annexin V and PI are in the end stage of apoptosis and are undergoing to the stage of necrosis as dead cells stained PI positive. Cells that stain negative for both FITC Annexin V and PI are alive and not undergoing apoptosis or necrosis (Figure 3).
miRNAs have an important role in gene regulation and they can influence biological functions including cell differentiation and proliferation during normal development and pathological responses.
miRNAs are small non-coding RNA molecules (containing about 22 nucleotides), derived from regions of RNA transcripts that fold back on themselves to form short hairpins.
miRNAs regulate gene expression at the post transcriptional level.
A number of miRNAs may bind to specific regions of the messenger RNA (mRNA) and block its translation to proteins. Alteration of the expression of miRNAs is believed to contribute to the progression of tumorigenesis and other diseases.
The enzyme assay is used to monitor passaging of lactate dehydrogenase (LDH), due to loss of cell membrane integrity when cells are exposed to cytotoxic compounds. LDH reduces NAD to NADH which generates a color change by interaction with a specific probe (Figure 4a). In other enzyme assay, Adenosine triphosphate (ATP )-based assay combined with bioluminescent assay are used to measure cytotoxicity of the cells in which ATP is the reagent for the luciferase reaction (Figure 4b).
The proteomic assay is performed to know the mechanism of cellular toxicity by measuring expression of a specific protein which may consider as a biomarker for particular toxic mechanism or cellular toxicity signaling pathway. Immunofluorescence, immunoprecipitation and immunoblot assay are mainly used to know the effect of toxicants in cellular toxicity signaling pathway or mechanism (Figure 5).
The expression array is the chip based microarray of more gene expressions (finger print of genes) by the effect of cellular toxicants. This is a rapid and sensitive detection method which allows to detect all toxicological end points at wide range of molecular level changes in the cell at single assay. The microarray process can be divided into two main parts. First is the printing of known gene sequences onto glass slides or other solid support followed by hybridization of fluorescently labeled cDNA (containing the unknown sequences to be interrogated) to the known genes immobilized on the glass slide. After hybridization, arrays are scanned using a fluorescent microarray scanner. Analyzing the relative fluorescent intensity of different genes provides a measure of the differences in gene expression (Figure 6).
Figure 6. Schematic representation of gene expression array showed that Cy5(red) and Cy3 (green) labeled cDNA hybridized to a DNA microarray. Yellow spots indicate the genes are expressed in both samples. The intensity and different types of color at each spot indicate the level and presence of genes in samples. Black spots show low level of expression or do not show any expression of genes.
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1. Liquid Chromatography mass spectroscopy is used for: Correct answer: D. Proteomics and metabolomics. 2. Which of the following technologies is used to study complete RNA profiles: Correct answer: B. Microarrays.
3. The central dogma of molecular biology states: Correct answer: A. DNA to RNA and RNA to protein.
4. Which of the following processes is a non destructive process in which samples can reused or returned back to the biorepository: Correct answer: C. NMR.
Topic 5: Technologies Used In Systems Biology/Toxicology
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LEARNING OBJECTIVES After completing this lesson, you will be able to:
Understand the different omics technologies and how they are used.
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Systems biology/toxicology uses very powerful high-throughout platforms/tools such as the “omics” technologies. The human genome was first sequenced in 2003. It took 13 years and was extremely expensive. Advancement in technology has now made it possible to have genome sequencing completed in less than a day. It has also made handling and interpretation of large volumes of data at different levels (gene, transcriptome, protein, metabolic) possible. Scientists across different disciplines are now using these technologies to provide a more holistic approach to disease and toxicity.
Systems Biology in Toxicology and Environmental Health; First Edition, Chapter 1
Figure 1. A schematic approach for “omics” technologies. Parts of illustration from www.pixabay.com
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Technologies Used In Systems Biology/Toxicology
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Genomics: This refers to the technology which allows us to study the complete genetic material of an organism. This involves DNA sequencing and analysis. Some of the most common methods used for high-throughput genotyping for genome wide association studies (GWAS) include Illumina Omni Arrays which can simultaneously analyze upto 5 million markers per sample. Other examples are the HumanOmni 5 Quad (Omni 5) and the Affymetrix platforms.
A GWAS involves analysis of genetic variants in different individuals to study particular traits associated with genetic variations. This enables scientists to study the underlying mechanisms of different diseases at the genomic level. Single base pair changes are the most common form of variants of the genome and are known as single nucleotide polymorphisms (SNP). While most of them are functionally harmless, rare ones can lead to changes at the protein level leading to functional impairment and diseases.
Systems Biology in Toxicology and Environmental Health; First Edition, Chapter 4
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Genomics: Example Application
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SNPs that results in functional changes at the protein level thereby causing a difference in phenotype such as a disease state is known as a mutation. These are considered rare genetic variants. An example of a disease state is cystic fibrosis which is cause by multiple mutation in the CFTR gene. This was made possible by genotyping families that were affected by this disease and identifying markers (genetic variants) that could be linked to this disease. This is known as linkage analysis. This type of analysis was also successfully used to identify unique mutations that lead to rare diseases like Huntington’s disease. While this approach has been successful for rare diseases it has been a challenge to utilize this for more common disease states such as cancer, heart and liver disease etc.
Transcriptomics is the study of all transcriptomes (RNA) in a genome. In other words it the study that enables us to study large volumes (> 200,000) of data related to gene expression at the RNA level.
Traditionally RNA expression was studies through a technique known as Northern blots. But this technique could not handle large volume of data. Current techniques used for high-throughput data analysis are different kinds of microarrays and biochips. The most commonly used are the DNA based microarrays.
Quantitative gene expression analysis helps us understand the difference in expression of genetic product between different cells,tissues, species etc. Such microaarays are commercially made available from companies lilke Affymetrix, Agilent, Applied Microarrays, Illumina etc.
Systems Biology in Toxicology and Environmental Health; First Edition, Chapter 4
Figure 2. Different kinds of microarrays. Rebecca C. Fry. Systems Biology in Toxicology and Environmental Health, Chapter 4 (Kindle Location 1954). Elsevier Inc..
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Analysis of microarray data
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Microarray data is provides relative expression levels of various genes. Quantitaive analysis of microarray data require sophisticated statistical tools and is expressed in the form of a “heat map” which provides expression patterns (upregulation/downregulation of genes) in the form of various colors. Significance analysis of microarrays (SAM is common technique) is a statistical tools that allows for quantitative determination of expression patterns.
The output which is the heatmap has different colors signifying differential expression patterns. In the example given below red color signifies upregulated gene expression while green signifies downregulation.
Figure 4. Heatmap generated from microarray. Rebecca C. Fry. Systems Biology in Toxicology and Environmental Health, Chapter 4 (Kindle Location 1954). Elsevier Inc..
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Proteomics
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Proteomics is the field that studies total proteins in a system. This involves high-throughput profiling of proteins. This kind of expression pattern is especially useful since it allows us to study post translational effects, since all transcription products are not always converted to proteins; however, all functional aspects at the phenotypic level are almost always driven by proteins.
Proteomics is a powerful tool that can help us in identification of protein biomarkers specific to toxicity due to particular exposures or specific diseases states. Mass spectrometers are commercially sold by several companies such as Waters, Thermofisher, Agilent, Shimadzu, Perkin Elmer etc.
A mass spectrometer is used for analysis of protemics data. Interpretation requires sophisticated bioinformatics tools.
Rebecca C. Fry. Systems Biology in Toxicology and Environmental Health, Chapter 4 (Kindle Location 1954). Elsevier Inc..
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Sample processing and workflow for proteomics studies:
Figure 5. Sample processing and workflow for proteomics studies. Rebecca C. Fry. Systems Biology in Toxicology and Environmental Health, Chapter 4 (Kindle Location 1954). Elsevier Inc..
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Metabolomics
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Metabolomics refers to the study of metabolites (low molecular weight products of cellular /biological processes that are found in cells, tissues, biological fluids etc.). Metabolomics provides an understanding of the differences in the biochemistry between different variants (such as diseased and healthy patient populations, control group versus treatment group, high dose group versus low dose group etc.)
Metabolic profiling can be easily performed in biological matrices such as urine, blood, plasma, serum and also a wide variety of tissues. Hence this can be used very efficiently in human health and safety assessment for evaluating biomarkers for exposure to toxicity to various agents. It can be used in drug discovery in the pharmaceutical industry for comparing metabolic profile between different dose level and control groups. In the clinical setting metabolomics can provide an understanding of differences in metabolite products in diseased versus healthy patient populations.
Platforms/tools used in metabolomics is similar to proteomics. Liquid chromatography mass spectrometers (MS) are broadly used for metabolite profiling of different biological matrices. Additionally, nuclear magnetic resonance (NMS) imaging is also widely used for metabolomics analysis. A major difference between the two tools is that NMR is a non destructive process and samples used for NMR can be reused for other purposes or returned to the biorepository whereas this is not possible with the LCMS method.
Metabolomic studies can be conducted using a “targeted approach” where a few selected analytes (metabolites) are analyzed based on hypothetical research. Such studies are mainly performed in early discovery phases. Alternatively, a more “broad spectrum” approach may be used in order to develop biomarkers for certain treatments or specific disease states.
As with other “omics” approaches, state-of-the art bioinformatics and statistical tools are used for quantitative interpretation of the data generated from metabolomics platforms (LCMS, NMR).
Rebecca C. Fry. Systems Biology in Toxicology and Environmental Health, Chapter 4 (Kindle Location 1954). Elsevier Inc.
1. DNA methylation assays are important to know the non-epigenetic modification. Correct answer: B. False.
2. Histone modification assays are useful to find the modification of histone proteins which have important roles in epigenetic inheritance: Correct answer: A. True.
3. MicroRNAs assays are used to know the non-coding RNAs. These non-coding RNAs are : Correct answer: A. 17 to 25 nucleotides.
LEARNING OBJECTIVES After completing this lesson, you will be able to:
Know different types of epigenetic assays.
Know how different epigenetic assays are used when cells are exposed to toxicants or mutagens.
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Topic 5: Key Points In this section, we explored the following main points:
Different types of Epigenetic assays.
How different Epigenetic assays namely DNA methylation assay, histone modification assay and MicroRNAs assay are used when cells are exposed to toxic chemicals or agents.
LEARNING OBJECTIVES After completing this lesson, you will be able to:
Know different types of epigenetic assays.
Know how different epigenetic assays are used when cells are exposed to toxicants or mutagens.
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The aim of epigenetic assay is to determine whether any chemicals or drugs will cause any toxic effect or load on the genome which do not involve a change in the nucleotide sequence.
Followings are the different types of Epigenetic assays:
LEARNING OBJECTIVES After completing this lesson, you will be able to:
Explain cell and tissue repair mechanisms and how toxicants may alter these processes.
Discuss adaptation mechanisms that may occur with exposures to toxicants.
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Repair The ability of cells to repair toxicant-induced damage plays a large role in the outcome of exposure to toxicants. Repair mechanisms include molecular repair such as reversal of thiol oxidation, removal of damaged units with replacement by newly synthesized units, and degradation followed by resynthesis of damaged structures. Cellular repair mechanisms include autophagy of damaged organelles and resynthesis/regeneration of damaged structures. Tissue repair mechanisms include active removal of damaged cells via apoptosis, regeneration of cells by hyperplasia (increase in cell numbers) or hypertrophy (increase in cell size), and resynthesis of extracellular matrix. When cellular or tissue repair is unable to restore original tissue architecture, production of extracellular connective tissue to results in fibrosis.
Figure 5.1 Normal cells (at left) that are exposed to a toxic insult may undergo degeneration, characterized by cellular swelling. Repair responses to cellular injury include increased cell numbers (hyperplasia) and increased cell size (hypertrophy). When exposed to continued toxic insult or when cellular injury is severe, the repair process may include formation of excessive extracellular connective tissue (fibrosis).
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Some toxicants can interfere with the normal cellular repair mechanisms, resulting in early cellular senescence and death. Inability to repair damage to DNA can result in disruption of normal protein synthesis or initiation of carcinogenesis. Other toxicants trigger exaggerated repair mechanisms which themselves pose a hazard to the survival of the individual. For instance, the herbicide paraquat causes lung injury mediated by oxygen-derived free radicals; because the lung is a highly oxygenated organ, this damage can be quite extensive as the ready availability of oxygen provides plenty of fuel for the snowballing generation of free radicals such as superoxide anions. The immediate effect of paraquat on the lung is damage to alveolar walls, resulting in stimulation repair mechanisms that cause intense, progressive fibrosis of the lung over several weeks, which ultimately leads to the death of the patient from asphyxia. Intense fibrosis is also seen in alcoholic cirrhosis of the liver, with normal liver parenchyma being replaced by fibrous connective tissue that impedes normal liver function.
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Adaptation Adaptation mechanisms have evolved at the cellular, tissue and organ levels that allow the individual to survive in the face of exposure to levels of toxicants that might otherwise result in serious or lethal injury. Adaptation requires time to develop, so generally occurs upon multiple exposures to levels of toxicants that are too low to cause severe acute injury. Adaptation mechanisms include alteration of toxicant delivery to target sites, decreasing reactivity of the target site to the toxicant, increasing local repair mechanisms, and development of compensatory mechanisms to mitigate toxicant-induced injury.
Decreasing toxicant delivery to target site may include decreasing toxicant absorption, detoxification of the toxicant before it can reach the target site, or binding of the toxicant with a neutral molecule. The opioid fentanyl is a powerful narcotic when injected, but it is quickly metabolized in the liver if ingested, greatly reducing the amount that enters the systemic circulation and reaches the central nervous system; this “first pass effect” occurs with many substances and is often the reason why some drugs must be administered via injection rather than the oral route. Similarly, chronic ingestion of ethyl alcohol can result in the induction (increased expression) of the enzyme alcohol dehydrogenase in the gastrointestinal tract and liver, resulting in more alcohol being metabolized before it can reach the systemic circulation.
Some toxic heavy metals that reach the bloodstream become bound to metal-binding proteins called metallothioneins; because only unbound metals are free to react, metallothioneins prevent the toxic metals from interacting with their target sites. Many sea-dwelling mammals such as killer whales (Orca spp.) bind organic mercury to selenium-containing metallothioneins which allows them to accumulate large amounts of organic mercury that would be lethal to terrestrial mammals. Adaptation by decreased reactivity to the target site is classically illustrated by the tolerance that can develop in people addicted to opioids such as heroin. Constant stimulation of opioid receptors results in downregulation (decreased expression) of those receptors and increased amounts of opioids required to stimulate remaining receptors.
Figure 5.2 Orcas have evolved a means of adapting to the high levels of organic mercury in their diet.
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Adaptive mechanisms may include increased function or number of cells to compensate for the loss of function of similar cells due to toxic insult. A variety of toxicants can cause injury to kidney tubules, and as a result, other kidney tubules may undergo hypertrophy and/or hyperplasia in an attempt to provide adequate kidney function.
Adaptive and repair mechanisms frequently occur simultaneously, resulting in characteristic lesions in some organs or tissues, For example, toxic hepatocellular injury from chronic alcohol exposure may result in nodular areas of regenerating hepatocytes (adaptation) surrounded by fibrous connective tissue formed to replace lost hepatocytes (repair), resulting in the characteristic “bubbly” look of hepatic cirrhosis.
Figure 5.3 Hepatic cirrhosis, a combination of repair and adaptive changes.
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Topic 5: Key Points In this section, we explored the following main points
Tissue repair mechanisms include removal of damaged cells via apoptosis, regeneration of cells by hyperplasia (increase in cell numbers) or hypertrophy (increase in cell size), and regeneration of extracellular matrix.
Fibrosis may result when tissue repair is incomplete.
Adaptation mechanisms may allow the host to survive in the face of continuous exposure to toxicants and include:
alteration of toxicant delivery to target sites.
decreasing reactivity of target site to toxicant
increasing local repair processes
compensatory mechanisms to mitigate toxicant-induced injury
1. Which of the following could explain some of the variability observed between states in terms of regulatory toxicology? Correct answer: D. All of the above. 2. Proposition 65 is a regulation established in: Correct answer: C. California
LEARNING OBJECTIVES After completing this lesson, you will be able to:
Define what is meant by “State Regulatory Toxicology”.
Give an example of a state regulatory regulation.
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What is State Regulatory Toxicology?
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Deals with regulatory toxicology for the US on a state level (e.g. Texas, Delaware, Arizona).
Established by authorities applicable to a given state.
State regulatory toxicology only applies with the state’s boundaries; however, they may influence adjacent states or even national regulatory toxicology.
Under the layer of the US national government sits a complex web of state and local laws and policies, in addition to regulatory authorities.
The make-up of state and local governments varies widely across the US; while they have mutual specific features, their organizations differ.
Whatever their design, state and local governments can sometimes have a much greater impact on people's lives than the federal government.
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The Federal-State Toxicology and Risk Analysis Committee (FSTRAC) is made up of representatives from U.S. state health and environmental agencies and U.S. EPA personnel.
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Is an integral part of EPA’s communication strategy with states and tribes for human health risks associated with water contamination.
Fosters cooperation, consistency, and an understanding of EPA’s and different states’ goals and problems in human health risk assessment.
Allows states and the federal government to work together on issues related to the development and implementation of regulations and criteria under the Safe Drinking Water Act and Clean Water Act.
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FSTRAC members have supported development of:
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Human Health Benchmarks for Pesticides (HHBP)
-Represent levels of pesticides in drinking water that are not anticipated to cause health effects. -Used to help assess drinking water quality for pesticides that do not have other regulatory toxicology standards .
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Example agencies that set state toxicology regulations:
The goal of state agencies is the same as federal agencies, protect people and the environment from health effects associated with chemical exposures.
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States have differing regulatory toxicology requirements and focuses. Reasons for the differences could be due to: state history, geography, culture, population size and diversity, major industries, etc…
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Examples of state regulatory toxicology as it concerns chemicals in air:
Texas
Effects Screening Levels (ESLs) – Air concentrations generally applicable to a specific chemical set by the Texas Commission on Environmental Quality (TCEQ). Play an important role in the regulation of air emissions from companies located in the state. List of ESLs.
California
Reference Exposure Levels (RELs) – Air concentrations generally applicable to a specific chemical set by the California Environmental Protection Agency (CalEPA). Represent an air concentration that does not pose a health risk to people. List of RELs.
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Example state toxicology regulations and the requirement that must be followed:
Figure 1: An example of a State Regulatory Agency signal.
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Proposition 65
Purpose:
Enable consumers to make informed decisions regarding chemical exposures.
Why?
Established to protect California citizens from chemicals known to the state to cause cancer, birth defects, or other reproductive harms.
Scope:
Addresses chemical exposures to the citizens of California that may occur through consumer products, workplace exposures, and exposures occurring via the environment.
OEHHA publishes a list of chemicals known to cause cancer, birth defects or other reproductive harm
The list is updated regularly and currently contains approximately 900 chemicals
Once a chemical is listed, companies have 12 months to comply with warning requirements under the regulation
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Proposition 65 is referred to as a “risk-based” regulation in that the warning requirements only apply if the risk from chemical exposure are too high as defined by the regulation.
The regulation has undergone revisions, New Proposition 65 Warnings, that will now require companies to add a symbol and change the phrasing of the warning. For example: “WARNING: This product can expose you to chemicals including arsenic, which is known to the State of California to cause cancer. For more information, go to www.P65Warnings.ca.gov.”
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Topic 5: Key Points In this section, we explored the following main points:
What is State Regulatory Toxicology?
An example of how federal and state agencies work together
What is the Federal-State Toxicology and Risk Analysis Committee (FSTRAC) Two example outcomes of the FSTRAC’s workgroup
Example of State Agencies
Highlight two state specific guidance and rules as it concerns chemicals in air
DNA methylation assays are important to know the epigenetic modification which is a heritable, enzyme-induced modification without alteration the nucleotide base pairs. The transfer of a methyl-group to the 5-carbon on the cytosine in a CpG dinucleotide happens in the DNA methylation by DNA methyltransferases (DNMT1, DNMT3A, and DNMT3B). The high level of promoter CpG island methylation results in gene silencing. The methylated DNA immunoprecipitation (MeDIP)-chip technique is used for DNA methylation assay.
In brief, the MeDIP-chip procedure is mentioned as follows. The genomic DNA is sheared to low molecular weight fragments (approximately 400 bp) by sonication. Then, the methylated DNAs are immunoprecipitated with the anti-methyl-cytosine antibody, and are amplified with PCR, if source material is less. Input and methylated DNA are labeled with fluorescent dyes Cy3 (green) and Cy5 (red), pooled, denatured, and are hybridized to a microarray slide containing all the annotated human CpG islands or other whole genome or promoter microarray designs. Then the slide is scanned using a scanner and each image is analyzed with the image analysis software ( Figure 1).
Histone modification assays are useful to find the modification of histone proteins (e.g. lysine acetylation, lysine and arginine methylation, serine and threonine phosphorylation, and lysine ubiquitination and sumoylation) which have important roles in epigenetic inheritance. The chromatin immunoprecipitation (ChIP) assay followed by hybridization to microarrays (ChIP-chip) (Figure 2) or by high-throughput sequencing (ChIP-seq) (Figure 3) are both powerful techniques to find histone modification.
MicroRNAs assays are used to know the non-coding RNAs (17 to 25 nucleotides) which target messenger RNAs (mRNAs) and decayed the mRNAs or downregulated at the level of translation into protein. Almost, 60% of human protein coding genes are controlled by miRNAs and these miRNAs are epigenetically regulated. About 50% of miRNA genes are related with CpG islands, which may be repressed by epigenetic methylation. Other miRNAs are epigenetically controlled by either histone modifications or by DNA methylation. The expression of microRNAs are quantified by RT-PCR followed by quantitative PCR (qPCR). Then, miRNAs are hybridized to microarrays, slides or chips with probes to hundreds or thousands of miRNA targets. The microRNAs can be both invented and profiled by sequencing methods (microRNA sequencing) (Figure 4).
Which features make the centrilobular region of the liver lobule more susceptible to toxic insult? Correct answer B. Relatively high levels of biotransformation enzymes and relatively low oxygenation
Which of the following patterns of injury would be consistent with a toxicant that is directly injurious to liver and kidney cells? Correct answer D. Periportal hepatic injury, proximal tubular renal injury
1. Which of the following is an example of non-governmental regulatory toxicology? Correct answer: D. All of the above. 2. Which of the following is a trait found in a non-governmental entities? Correct answer: C. Is not a government agency or formally associated with a government agency.
ToxTutor Principles of Toxicology Certification Quiz
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Quiz Instructions: This quiz marks the end of the ToxTutor Principles of Toxicology modules. For certification, you are required to complete all 40 questions as seen in the quiz below. There is no time limit and you can attempt it as many times as desired. Your grade will be displayed immediately upon submission.
Compatibility: Works best in Mozilla Firefox, Google Chrome and Microsoft Edge.
Pass Mark: 80% (32/40) for certification.
Certification Instructions: Once you have achieved at least 80% on this quiz, your certificate will be automatically generated and sent to the email address entered at the beginning of the quiz.
If you have any questions feel free to contact us at toxmsdt@gmail.com
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When you are finished and press submit, click "view score" at the top of the screen to see your score and your graded answers.
Pia van Benthem is the program manager for the ToxMSDT program and she oversees all logistical and programmatic aspects of the training grant. She is housed in the Department of Molecular Biosciences at the University of California Davis and brings more than 10 years of experience in leading outreach and education programs in STEM sciences to the program.
Specifically, her expertise is in establishing and advancing innovative undergraduate student programs. She has collaborated with experts from Institutions of Higher Education, industry, and professional societies from across the globe to advance student access to higher education. Pia has developed and published K-16 STEM education materials and held teacher training workshops across the US. Pia van Benthem earned her MS from the University of Applied Sciences in Stuttgart, Germany.
Dr. Laura S Van Winkle is a Professor of Respiratory Toxicology in the School of Veterinary Medicine Department of Anatomy, Physiology and Cell Biology at UC Davis. She received a BS with honors from UC Santa Barbara in Pharmacology and worked in the biotech sector for several years before earning her PhD in Pharmacology and Toxicology from UC Davis. Following completion of her American Lung Association Research Training Fellowship, she joined the faculty at UC Davis. Her laboratory is at the Center for Health and the Environment where she is the Director of the Cellular and Molecular Imaging Core. She is a Diplomate of the American Board of Toxicology (DABT) and is a current member of the American Thoracic Society (ATS) Environmental Occupational and Public Health program committee. She has served on numerous NIH Study Sections and as an Associate Editor for the SOT society journal Toxicological Sciences. She was the recipient of the SOT Inhalation and Respiratory Specialty Section Young Investigator and the Women in Toxicology Mentoring Awards. She has published over 95 research articles in the fields of inhalation toxicology, developmental lung biology, chemical bioactivation and lung injury and repair. Her research has focused on the interaction of environmental pollutants and specific lung regions, such as the distal conducting airway epithelium of the lung and how that contributes to lung remodeling. She studies chemical exposures relate to lung diseases such as cancer and asthma by investigating how chemical exposures alter life-span health. She is currently the Chair of the Graduate Group in Pharmacology and Toxicology at UC Davis and Director of the NIEHS T32 for Advanced Training in Environmental Health Sciences at UC Davis. Her research lab has mentored over 75 undergraduate students in STEM.
Dr. Saurabh Vispute is a Principal Scientist at Pfizer contributing to the safety assessment of novel biopharmaceuticals. Prior to his career at Pfizer, Dr. Vispute was a Research Scientist in Toxicology Department at Charles River Laboratories, Reno, NV. He was primarily involved in design, conduct, interpretation, and reporting of toxicology studies. Prior to joining Charles River, Dr. Vispute earned his doctorate in Pharmacology from St. John’s University, New York in 2015. His graduate research focused on characterizing the regulation of Fibroblast growth factor (Fgf) 21 and its pharmacological/toxicological implications. Dr. Vispute is a registered Pharmacist with a Bachelor’s degree in Pharmacy from Mumbai University, India (2009). He is an author/co-author of several publications in peer reviewed journals and presentations at international scientific meetings. Dr. Vispute’s achievements have been recognized by scientific organizations and he is recipient of graduate student awards, scholarships, early career toxicologist awards, and ToxScholar grants. In addition, Dr. Vispute volunteers as a reviewer for peer‑reviewed journals and scientific abstract screening committees. He is actively involved in leadership positions in various component groups and committees within Society of Toxicology and American College of Toxicology.
I am Quentoria Walton, a sophomore chemistry major at Tuskegee University from Columbus, GA. My interest in the field of chemistry stemmed from taking high school level chemistry courses and thoroughly enjoying the subject. I am actively involved on campus by participating in STEM outreach, being a member of Tuskegee University's Pre-Alumni Council, and other campus activities and organizations. I aspire to enter into a field that allows me to apply my knowledge in chemistry as well as grow while doing so. I like to describe myself as a humble, motivated, and enthusiastic young woman striving to become the best version of myself.
Dr. Rueben C. Warren is currently the Director of the National Center for Bioethics in Research and Health Care and Professor of Bioethics at Tuskegee University in Tuskegee, Alabama. He is also former Director of the Institute for Faith-Health Leadership and Adjunct Professor of Public Health, Medicine and Ethics at the Interdenominational Theological Center (ITC) in Atlanta, GA. From 1988 to 1997, Dr. Warren served as Associate Director for Minority Health at the Centers for Disease Control and Prevention (CDC). From 1997 to 2004, he was Associate Director for Urban Affairs at the Agency for Toxic Substances and Disease Registry (ATSDR). From 2005 to 2007, Dr. Warren served part-time as the Director of Infrastructure Development for the National Center on Minority Health and Health Disparities at the National Institutes of Health in Bethesda, MD. From 2004 to 2009, he was on leave from the National Center for Environmental Health-CDC/ATSDR) in Atlanta, where he served as Associate Director for Environmental Justice. As Associate Director at CDC/ATSDR Dr. Warren had lead agency responsibility for Environmental Justice and Minority Health.
Prior to joining CDC, Dr. Warren served as Dean and Associate Professor in the School of Dentistry, Department of Preventive Dentistry and Community Health, at Meharry Medical College in Nashville, Tennessee. He is also Clinical Professor, Department of Community Health/Preventive Medicine, Morehouse School of Medicine and Adjunct Professor, Department of Behavioral Sciences and Health Education, Rollins School of Public Health, Emory University, both in Atlanta, Georgia. Dr. Warren is also Adjunct Professor in the Department of Dental Public Health, School of Dentistry and Adjunct Professor in the School of Graduate Studies and Research at Meharry Medical College in Nashville, TN and Georgia Health Sciences University in Augusta, GA. His extensive public health experience at community, state, local, national, and international levels range from clinical and research work in the Lagos University Teaching Hospital in Lagos, Nigeria, to heading the Public Health Dentistry Program at the Mississippi State Department of Health. Dr. Warren has contributed to the scientific literature in public health, oral health, ethics, and health services research. His professional associations include: the Health Braintrust of the Congressional Black Caucus of the United States, National Dental Association, American Board of Dental Public Health, American Public Health Association United Nations Children's Fund, and World Health Organization. Dr. Warren’s membership in health related associations has expanded his perspective on health. In 1996-97, he served as Chairperson of the Caucus on Public Health and Faith Communities, an affiliate of the American Public Health Association.
Dr. Richard Whittington is the HBCU-Up/HHMI Director of the Office of Undergraduate Research (OUR), Assistant Biology Faculty, and Media Technology Specialist for the Department of Health Disparities Institute for Research and Education at Tuskegee University, AL. The majority of his time is focused on increasing the number of students in STEM disciplines who are engaged in mentored, authentic research that revolves around disease prevention. In addition, his energy is geared toward activities to enhance exposure of students to science and health related issues that impact communities, creating an environment with abundant research opportunities with outcomes that impact the world. While serving as Director, the Office of Undergraduate Research has focused on three major activities (professional development, visibility, and research exposure) to enhancing student knowledge of graduate programs and research opportunities. Dr. Whittington has successfully accomplishes this with annual workshops, seminars, and conferences to create a professional environment at increases exposure and knowledge. Some of the essential activities involved research seminars by guest faculty, review of the program application process, presentation of scholarships and fellowships, professional and graduate program information, and discussion of summer internship opportunities to enhance awareness. The Interdisciplinary Meeting of Professionals for the Awareness of Careers and Training of Undergraduate Students (IMPACTUS) and Distinguished Scholar Seminar Series are held annually since 2010, involving professionals from various disciplines presenting research and knowledge to guide student toward a research-based career. The Joint Annual Research Symposium (JARS) allowed for student to present research conducted throughout the year while networking with Tuskegee University faculty, visiting faculty, and plenary speakers. As a result of outreach activities, the OUR experienced an average of 248 individual sessions made by students per semester since 2010. To enhance his connection to the community, he is an active part of the Macon County Civitan Club (Community Associate), Black Belt Community Foundation (President), and Tuskegee United Women’s League Inc (Coordinator). In addition, his background includes coordinating science academies and creating summer enrichment programs. Dr. Whittington has collaborated in educational enrichment programs such as GROW CELLS, VET STEP I, VET STEP II, Project GRAD Knoxville, AMACHI Leadership Foundation, Southeast Science Partnership, Fast Track Science Camp, and Science America Camp.
As an Assistant Professor of Biology at Tuskegee University, Dr. Whittington has focused on the disease prevent and understanding of the pathogenic mechanisms of important fish pathogens, particularly bacterial diseases of tilapia and channel catfish. Early investigations aimed improving survival rates against Streptococcus iniae and Flavobacterium columnare utilizing vaccines for enhanced resistance and the development of diagnostic techniques for early detection. Recent studies have focus on Aeromonas hydrophila in channel catfish, due to outbreaks of Aeromonad septicemia resulting in industry-wide losses of catfish totaling over 8 million pounds. He has conducted experimental disease challenges to demonstrate the virulence of this microbe and immune boosting capabilities of nutritional supplementation. In addition, his research as allow for him to expose several undergraduates to aquatic research and the techniques associated microbial disease analysis.
I am Justin Williams, a Junior Biology Pre-Medicine major at Tuskegee University, and from the “Rocket City” Huntsville, Alabama. My interest in Biology began in third grade when I received a kids microscope kit for Christmas. I am currently a member of my Universities Biology club, Minority Association for Pre-Health Students(MANRRS), an Undergraduate Research assistant, and many other campus organizations and clubs. . I know being fortuned with the opportunity to gain insight on toxicology and research in disease control will aid me in my driving efforts to better the medical field. By obtaining my doctorate, I will improve the medical field and work to increase the morale of medical professionals by enhancing devices for medical practices and creating a better patient-doctor relationship by providing understanding from the knowledge I would gain from completing the Toxicology Mentor and Skills Development program. I’d describe myself as Enthusiastic, Eager, and Excited to see the growth of myself and others!
As Vice President of the American Chemistry Council’s (ACC) Regulatory and Technical Affairs Division, Dr. White oversees the development of ACC’s policy positions in response to regulatory and legislative proposals. She also leads a staff of experts to identify, analyze and create technical and policy materials to serve as the foundation for ACC’s activities.
Dr. White has more than a decade of experience in the chemical industry, focused on managing science policy issues, scientific research, and product stewardship programs to inform regulatory decision-making. Most recently, she served as Senior Director for ACC’s Chemical Products and Technology Division. In this role, Dr. White supported federal, state and congressional advocacy on specific chemistries and led the development and communication of science policy and research. She also represented industry in chemical policy discussions with various audiences, including testimony to U.S. House of Representatives and U.S. Senate Committees.
Previously, she served as a Scientific Advisor for the oil and natural gas industry where she was responsible for regulatory efforts and research programs focused on environmental, health, and safety.
Dr. White received Bachelor of Science and Master of Science degrees in biology and a Doctor of Philosophy degree in Environmental Toxicology from Texas Southern University
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