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The mechanism of action of reproductive toxicants. Toxicol Pathol Meyer, UA. Quantitative estimation and prediction of risk at the International Agency for Research on Cancer. Moolenaar, RJ. Default assumptions in carcinogen risk assessment used by regulatory agencies. Regul Toxicol Pharmacol Moser, VC. Screening approaches to neurotoxicity: A functional observational battery. J Am Coll Toxicol Biological Markers in Reproductive Toxicity. Biologic Markers in Immunotoxicology.
Subcommittee on Toxicology. Nebert, DW. Genes encoding drug-metabolizing enzymes: Possible role in human disease. New York: Plenum Publishing. Drug-metabolizing enzymes in ligand-modulated transcription. Biochem Pharmacol In Principles of Drug Action. New York: Churchill-Livingstone.
P gene nomenclature based on evolution. In Methods of Enzymology. Orlando, Fla: Academic Press. Cytochrome P Evolution and functional diversity. Prog Liv Dis The P gene superfamily: Recommended nomenclature. The P superfamily: Update on new sequences, gene mapping, and recommended nomenclature. Role of the Ah receptor and the dioxin-inducible [Ah] gene battery in toxicity, cancer, and signal transduction.
Ann NY Acad Sci The P superfamily: Update on new sequences, gene mapping, accession numbers, early trivial names of enzymes, and nomenclature. Nature Toxicologic data in chemical safety evaluation. Nordberg, GF. Reproductive Hazards in the Workplace. Document No. Paris: OECD. Technology review; an overview of cancer risk assessment. Toxicol Methods Comparing alternative approaches to establishing regulatory levels for reproductive toxicants: DBCP as a case study.
In vitro study on lead and alcohol interaction and the inhibition of erythrocyte delta-aminolevulinic acid dehydratase in man. Scand J Work Environ Health Development of multispecies, multiroute pharmacokinetic models for methylene chloride and 1,1,1-trichloroethane. London: Gower Medical Publishing. Sato, A. The effect of environmental factors on the pharmacokinetic behaviour of organic solvent vapours. Ann Occup Hyg Silbergeld, EK.
Developing formal risk assessment methods for neurotoxicants: An evaluation of the state of the art. Chelsea, Mich. Experimental and Clinical Neurotoxicology. Evaluation of methods for the prospective identification of early fetal losses in environmental epidemiology studies. Am J Epidemiol Genetic analysis of resistance to cadmium-induced testicular damage in mice. Proc Soc Exp Biol Med Arh rig rada toksikol Lead interference in zinc metabolism and the lead and zinc interaction in humans as a possible explanation of apparent individual susceptibility to lead.
Edinburgh: CEP Consultants. In vivo study on lead and alcohol interaction and the inhibition of erythrocyte delta-aminolevulinic acid dehydratase in man. Strategies for the assessment of neurobehavioral consequences of environmental factors. Cell injury and cell death. New York: Oxford Univ. Curr Opin Cell Biol Calcium-mediated cell injury and cell death.
Cell death and the disease process. The role of cell calcium. Weber, WW. The Acetylator Genes and Drug Response. Technical Report Series, No. Environmental Health Criteria, No. Air Quality Guidelines for Europe. European Series, No. Environmental Health Criteria, unedited draft.
Cell death: The significance of apoptosis. Int Rev Cytol Toxicol Molecular Biology of the Cell. New York: Garland Publishing. Ariens, EJ. Molecular Pharmacology. New York: Academic Press. Allgemeine Toxicologie [General Toxicology]. Stuttgart: Georg Thieme Verlag. Prediction of rodent carcinogenicity for 44 chemicals: Results.
Mutagenesis Monitoring the Worker for Exposure and Disease. Baltimore: Johns Hopkins Univ. Nakoplenie radioaktivnih elementov v organizme I ih vivedenie [Accumulation of Radioactive Elements in the Organism and their Excretion]. Moskva: Medgiz. Dordrecht: Martinus Nijhoff. Boyhous, A. Brandau, R and BH Lippold. Dermal and Transdermal Absorption. Stuttgart: Wissenschaftliche Verlagsgesellschaft. Brusick, DJ. Methods for Genetic Risk Assessment. Boca Raton: Lewis Publishers. Burrell, R. Human immune toxicity. Mol Aspects Med Madrid, Spain: Farmaindustria. Chapman, G. Body Fluids and their Functions.
London: Edward Arnold. Biological markers in environmental health research. New York: Witey.
Behavioral Measures of Neurotoxicity: Report of a Symposium.
Immunotoxicity of Metals and Immunotoxicology. New York: Plenum Press. Djuric, D. In Part 1 Toxicokinetics. Environmental Toxicology. Pharmakologie und Toxikologie. Mannheim: Biblio- graphische Institut. Frazier, JM. Scientific criteria for Validation of in VitroToxicity Tests. New York: Marcel Dekker. Gad, SC. In Vitro Toxicology. Gadaskina, ID.
Zhiroraya tkan I yadi [Fatty Tissues and Toxicants]. Gaylor, DW. The use of safety factors for controlling risk. J Toxicol Environ Health Goldberg, AM. Alternatives in Toxicology. New York: Mary Ann Liebert. Grandjean, P. Individual susceptibility to toxicity. Hanke, J and JK Piotrowski. Biochemyczne podstawy toksikologii [ Biochemical Basis of Toxicology ].
Warsaw: PZWL. Hatch, T and P Gross. Pulmonary Deposition and Retention of Inhaled Aerosols. Risk assessment of carcinogenic chemicals in The Netherlands. Molekulaere Pharmakologie. Huff, JE. Chemicals and cancer in humans: First evidence in experimental animals. Principles of toxicology. Kossover, EM. Molecular Biochemistry. New York: McGraw-Hill. Kundiev, YI. Kiev: Zdorovia. Komvinovanie deistvie promishlenih yadov [Combined Effects of Industrial Toxicants]. Moskva: Medicina. Lauwerys, R. Toxicologie industrielle et intoxications professionelles.
Paris: Masson. Genetic Toxicology. Loewey, AG and P Siekewitz. Cell Structure and Functions. New York: Holt, Reinhart and Winston. Loomis, TA. Essentials of Toxicology. Mutation and the Environment, Parts A-E. New York: Wiley Liss. Mettzler, DE. Principles and Practice of Immunotoxicology. Oxford: Blackwells Scientific. Ministry of International Trade and Industry. Handbook of Existing Chemical Substances.
Tokyo: Chemical Daily Press. In Japanese and in English. Tokyo: Kagaku Kogyo Nippo Press. Montagna, W. The Structure and Function of Skin. Carcinogen risk assessment: international comparison. R egul Toxicol Pharmacol National Research Council. Neuman, WG and M Neuman. The Chemical Dynamic of Bone Minerals. Chicago: The Univ. Clinical Immunotoxicology. Pacheco, H. La pharmacologie moleculaire. Paris: Presse Universitaire. Piotrowski, JK. Biochemical interactions of heavy metals: Methalothionein. Proceedings of the Arnold O.
Clin Chem 40 7B. The Principles of Humane Experimental Technique. Reprinted by Universities Federation for Animal Welfare, Textbook of Contact Dermatitis. Berlin: Springer-Verlag. Schubert, J. Estimating radioelements in exposed individuals. Nucleonics Shelby, MD and E Zeiger. Activity of human carcinogens in the Salmonella and rodent bone-marrow cytogenetics tests.
Stone, R. A molecular approach to cancer risk. Teisinger, J. US Congress. Kleine Enzyklopaedie: Leben [Life]. Weil, E. Elements de toxicologie industrielle [Elements of Industrial Toxicology]. Paris: Masson et Cie. Environmental Health Criteria, no. Combined Exposure to Chemicals, Interim Document no. Principles of Toxicokinetic Studies. Limphatics, Lymph and Lymphoid Tissue. Cambridge: Harvard Univ. Zakutinskiy, DI. Voprosi toksikologii radioaktivnih veshchestv [Problems of Toxicology of Radioactive Materials].
Moscow: Medgiz. Tools and Approaches Toxicology Mechanisms of Toxicity. Mechanisms of Toxicity. Why Understand Mechanisms of Toxicity? Techniques for Studying Mechanisms of Toxicity The majority of mechanistic studies start with a descriptive toxicological study in animals or clinical observations in humans.
Exposure The route of exposure in mechanistic studies is usually the same as for human exposure. Role of Pharmacokinetics in Toxicity Pharmacokinetics describes the time relationships for chemical absorption, distribution, metabolism biochemical alterations in the body and elimination or excretion from the body. Figure 2. Reresentation of mechanisms of toxicity Examples of Mechanisms of Toxicity Mechanisms of toxicity can be straightforward or very complex.
Acute Toxicity Mechanisms The following examples are specific to high-dose, acute effects which can lead to death or severe incapacitation. Subchronic and Chronic Toxicity Mechanisms When given as a single high dose, some chemicals do not have the same mechanism of toxicity as when given repeatedly as a lower but still toxic dose. Conclusion The intent of this article is to give a perspective on several known mechanisms of toxicity and the need for future study. Published in Mechanisms of Toxicity. Read more Definitions Cell injury Cell injury is defined as an event or stimulus, such as a toxic chemical, that perturbs the normal homeostasis of the cell, thus causing a number of events to occur figure 1.
Cell injury Lethal injuries result in the death of a cell after a variable period of time, depending on temperature, cell type and the stimulus; or they can be sublethal or chronic—that is, the injury results in an altered homeostatic state which, though abnormal, does not result in cell death Trump and Arstila ; Trump and Berezesky ; Trump and Berezesky ; Trump, Berezesky and Osornio-Vargas Apoptosis Apoptosis is derived from the Greek words apo , meaning away from, and ptosis , meaning to fall. Oncosis Oncosis, derived from the Greek word onkos , to swell, is so named because in this type of prelethal change the cell begins to swell almost immediately following the injury Majno and Joris Necrosis Necrosis refers to the series of changes that occur following cell death when the cell is converted to debris which is typically removed by the inflammatory response.
Mechanisms Initial stimulus In the case of lethal injuries, the most common initial interactions resulting in injury leading to cell death are interference with energy metabolism, such as anoxia, ischaemia or inhibitors of respiration, and glycolysis such as potassium cyanide, carbon monoxide, iodo-acetate, and so on.
Signalling pathways With many types of injury, mitochondrial respiration and oxidative phosphorylation are rapidly affected. The a primary, b secondary and c tertiary organization of human hereditary information Using RNA and an array of different proteins, the cell ultimately deciphers the information encoded by the linear sequence of bases within specific regions of DNA genes and produces proteins that are essential for basic cell survival as well as normal growth and differentiation.
Bioactivation of: a benzo a pyrene; and b N-nitrosodimethylamine Because of their relative abundance in cells, proteins are the most frequent target of toxicant interaction. Figure 3. Primary sites of chemically-induced DNA damage Compounds that contain one electrophilic moiety typically exert genotoxicity by producing mono-adducts in DNA. Figure 4. Various types of damage to the protein-DNA complex Over the past thirty to forty years, a variety of techniques have been developed to monitor the type of genetic damage induced by various chemicals.
Table 1. Hereditary, cancer-prone disorders that appear to involve defects in DNA repair Syndrome Symptoms Cellular phenotype Ataxia telangiectasia Neurological deterioration Immunodeficiency High incidence of lymphoma Hypersensitivity to ionizing radiation and certain alkylating agents. The Immune System The major function of the immune system is defence against bacteria, viruses, parasites, fungi and neoplastic cells. Non-specific defence A first line of defence to micro-organisms is executed by a physical and chemical barrier, such as at the skin, the respiratory tract and the alimentary tract.
Specific immunity After initial contact of the host with the pathogen, specific immune responses are induced. Two arms of specific immunity are recognized—humoral immunity and cell-mediated or cellular immunity: Humoral immunity. Mechanisms of Immunotoxicity Immunosuppression Effective host resistance is dependent upon the functional integrity of the immune system, which in turn requires that the component cells and molecules which orchestrate immune responses are available in sufficient numbers and in an operational form.
Allergy Allergy may be defined as the adverse health effects which result from the induction and elicitation of specific immune responses. The drug can alter the red-cell membrane so that the immune system regards the cell as foreign. The drug and its specific antibody form immune complexes that adhere to the red-cell membrane to produce injury.
Red-cell sensitization occurs due to the production of red-cell autoantibody. Human Risk Assessment The assessment of human immune status is performed mainly using peripheral blood for analysis of humoral substances like immunoglobulins and complement, and of blood leukocytes for subset composition and functionality of subpopulations. Classification of tests for immune markers Test category Characteristics Specific tests Basic-general Should be included with general panels Indicators of general health and organ system status Blood urea nitrogen, blood glucose, etc.
Preface Part I. The Body Part II. Chemicals Part X.
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Toxicology Additional Resources. Click the Button below to view additional resources for this topic. Toxicology References. Cellular phenotype. Neurological deterioration Immunodeficiency High incidence of lymphoma. Hypersensitivity to ionizing radiation and certain alkylating agents. Developmental abnormalities Lesions on exposed skin High incidence of tumours of the immune system and gastrointestinal tract. High frequency of chromosomal aberrations Defective ligation of breaks associated with DNA repair.
Growth retardation High incidence of leukaemia. Hypersensitivity to crosslinking agents High frequency of chromosomal aberrations Defective repair of crosslinks in DNA. Hereditary nonpolyposis colon cancer.
High incidence of colon cancer. Defect in DNA mismatch repair when insertion of wrong nucleotide occurs during replication. High incidence of epithelioma on exposed areas of skin Neurological impairment in many cases. Class of chemical. Source of exposure. Probable genotoxic lesion. Mono-adducts, interstrand crosslinks and single-strand breaks in DNA.
Metals and metal compounds. Both intra- and inter-strand crosslinks in DNA. Mono-adducts and single-strand breaks in DNA. Mono-adducts and interstrand crosslinks in DNA. Polycyclic aromatic hydrocarbons. Test category. Specific tests. Basic-general Should be included with general panels. Per Page. Include Forthcoming Titles. Developmental Toxicology 3rd Edition. Neurotoxicology 3rd Edition.
Toxicology of the Skin 1st Edition. Endocrine Toxicology 3rd Edition. Adrenal Toxicology 1st Edition. Toxicology of the Lung 4th Edition. Ophthalmic Toxicology 2nd Edition. Toxicant-Receptor Interactions: Modulations of signal transduction and gene expression 1st Edition. Toxicology of the Liver 2nd Edition. Endocrine Toxicology 2nd Edition.
Carcinogenesis 1st Edition. Developmental Toxicology 3rd Edition Deborah K. Abbott November 14, Highlighting latest advances in genetics and biochemistry, the completely revised Third Edition reviews the field from basic science, clinical, epidemiological, and regulatory perspectives.
Toxicology of the Gastrointestinal Tract, Second Edition 2nd Edition Shayne Cox Gad October 30, The gastrointestinal tract is the most important of the three major routes of entry and clearance of xenobiotics and biologic entities into the bodies of mammals. Neurotoxicology 3rd Edition G. Toxicology of the Skin 1st Edition Nancy A. Monteiro-Riviere February 17, This key volume of the Target Organ Toxicology Series provides a fresh and modern approach to the subject of skin toxicology from the perspective of how the skin forms a barrier that protects the body from the external environment and how chemicals and drugs interact with the barrier properties of Endocrine Toxicology 3rd Edition J.
Stevens February 15, With contributions by international experts in academia, chemical manufacturing, government research laboratories, regulatory agencies, and private consulting, this guide explores the potentially damaging influence of environmental agents on the endocrine system. Adrenal Toxicology 1st Edition Philip W. Springall October 22, Despite being regarded as the most common toxicological target in the endocrine system, the adrenal gland has often been neglected in regulatory testing.
Toxicology of the Lung 4th Edition Donald E. Gardner December 20, The most up-to-date treatment of inhalation toxicology available, Toxicology of the Lung, Fourth Edition examines the subject from a target-organ perspective.
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Ophthalmic Toxicology 2nd Edition G. Chiou July 01, Thoroughly revised and updates, this new edition of Ophthalmic Toxicology retains its uniqueness in covering all aspects of ophthalmic toxicology. Thus, agencies and Congress have developed a number of ingenious means to regulate carcinogens while not seeming to acquiesce in exposure of the general population to a carcinogen.
In contrast, occupational standards, which also take into account feasibility, permit exposure to known human carcinogens. A generally outmoded approach for environmental or indoor air guidelines has been to divide the permissible OSHA standard by a factor accounting for the presumed lifetime exposure to the environmental chemical compared with 45 years at a hour workweek. For a thorough discussion of the methods of clinical diagnosis, see John B. Wong et al. See also Jerome P. In some instances, the reporting of symptoms can be in itself diagnostic of exposure to a specific substance, particularly in evaluating acute effects.
Other reported symptoms are muscle twitching, weakness, and hypersecretion with sweating, salivation, and tearing. Acute exposure to many toxic agents produces a constellation of nonspecific symptoms, such as headaches, nausea, lightheadedness, and fatigue. These types of symptoms are part of human experience and can be triggered by a host of medical and psychological conditions.
Thus, these symptoms can be attributed mistakenly to an exposure to a toxic agent or discounted as unimportant when in fact they reflect a significant exposure. Kopelman, Learning Clinical Reasoning Office of Tech. Congress, supra note 17, at — But see Moore v. Ashland Chem. Durango Georgia Paper Co. The issue of whether the development of nonspecific symptoms may be related to pesticide exposure was considered in Kannankeril v. The court ruled that the trial court abused its discretion in excluding expert opinion that considered, and rejected, a negative laboratory test. See also Kerner v.
Ohio Feb. In taking a careful medical history, the expert focuses on the time pattern of symptoms and disease manifestations in relation to any exposure and on the constellation of symptoms to determine causation. It is easier to establish causation when a symptom is unusual and rarely is caused by anything other than the suspect chemical e.
However, many cancers and other conditions are associated with several causative factors, complicating proof of causation. Two types of laboratory tests can be considered: tests that are routinely used in medicine to detect changes in normal body status and specialized tests that are used to detect the presence of the chemical or physical agent. Even when available from a hospital or a clinical laboratory, a test such as that for carbon monoxide combined to hemoglobin is done so rarely that it may raise concerns regarding its accuracy. Other tests, such as the test for blood lead levels, are required for routine surveillance of potentially exposed workers.
With few exceptions, acute and chronic diseases, including cancer, can be caused by either a single toxic agent or a combination of agents or conditions.
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In taking a careful medical history, the expert examines the possibility of competing causes, or confounding factors, for any disease, which leads to a differential diagnosis. In addition, ascribing causality to a specific source of a chemical requires that a history be taken concerning other sources of the same chemical. The failure of a physician to elicit such a history or of a toxicologist to pay attention to such a.
Rail Corp. Intel Corp. Valley Bus. Forms, F. Three types of toxicological approaches are pertinent to understanding the effects of mixtures of agents. One is based on the standard toxicological evaluation of common commercial mixtures, such as gasoline. The second approach is from studies in which the known toxicological effect of one agent is used to explore the mechanism of action of another agent, such as using a known specific inhibitor of a metabolic pathway to determine whether the toxicity of a second agent depends on this pathway.
The third approach is based on an understanding of the basic mechanism of action of the individual components of the mixture, thereby allowing prediction of the combined effect, which can then be tested in an animal model. Swift Adhesives, Inc. See generally Edward J. Calabrese, Multiple Chemical Interactions 97—, — Courts have been called on to consider the issue of synergy.
See generally Calabrese, supra note EPA has been addressing the issue of multiple exposures to different agents within a community under the heading of cumulative risk assessment. This approach is particularly of importance in dealing with environmental justice concerns.
Individuals who exercise inhale more than sedentary individuals and therefore are exposed to higher doses of airborne environmental toxins. Moreover, for any given level of a toxic agent that reaches a target organ, damage may be greater because of a greater response of that organ. In addition, for any given level of target-organ damage, there may be a greater impact on particular individuals.
For example, an elderly individual or someone with preexisting lung disease is less likely to tolerate a small decline in lung function caused by an air pollutant than is a healthy individual with normal lung function. Multiple avenues of deductive reasoning based on scientific data lead to acceptance of causation in any field, particularly in toxicology. However, the basis for this deductive reasoning is also one of the most difficult aspects of causation to describe quantitatively. The problem of differences in chemical sensitivity was addressed by the court in Gulf South Insulation v.
Consistency of research results was considered by the court in Marsee v. United States Tobacco Co. The defendant, the manufacturer of snuff alleged to cause oral cancer, moved to exclude epidemiological studies conducted in Asia that demonstrate. The more difficult problem is how to evaluate conflicting research results.
To arrive at an opinion, the expert assesses the strengths and weaknesses of the research studies. The expert also bases an opinion on fundamental concepts of toxicology relevant to understanding the actions of chemicals in biological systems. As the following series of questions indicates, no single academic degree, research specialty, or career path qualifies an individual as an expert in toxicology. Toxicology is a heterogeneous field. A number of indicia of expertise can be explored, however, that are relevant to both the admissibility and weight of the proffered expert opinion.
A graduate degree in toxicology demonstrates that the proposed expert has a substantial background in the basic issues and tenets of toxicology. Many universities have established graduate programs in toxicology. These programs are administered by the faculties of medicine, pharmacology, pharmacy, or public health. Although most recent toxicology Ph. The defendant also moved to exclude evidence demonstrating that the nitrosamines and polonium contained in the snuff are cancer-causing agents in some 40 different species of laboratory animals.
The court denied both motions, finding:. Further, defendant conceded that animal studies have accurately and consistently demonstrated that these substances cause cancer in test animals. Finally, the Court found evidence based on experiments with animals particularly valuable and important in this litigation since such experiments with humans are impossible.
Under all these circumstances, the Court found this evidence probative on the issue of causation. For a person with this type of background, a single course in toxicology is unlikely to provide sufficient background for developing expertise in the field. A proposed expert should be able to demonstrate an understanding of the discipline of toxicology, including statistics, toxicological research methods, and disease processes.
A physician without particular training or experience in toxicology is unlikely to have sufficient background to evaluate the strengths and weaknesses of toxicological research. Most practicing physicians have little knowledge of environmental and occupational medicine. The cause of these effects, particularly if they are unrelated to the treatment of the disease, is generally of little concern to the practicing physician.
Subspecialty physicians may have particular knowledge of a cause-and-effect relationship e. For recent documentation of how rarely an occupational history is obtained, see B. Politi et al. Fuller Co. Treating physicians also become involved in considering cause-and-effect relationships when they are asked whether a patient can return to a situation in which an exposure has occurred. The answer is obvious if the cause-and-effect relationship is clearly known. However, this relationship is often uncertain, and the physician must consider the appropriate advice.
In such situations, the physician will tend to give advice as though the causality was established, both because it is appropriate caution and because of fears concerning medicolegal issues. Before , the American Board of Medical Toxicology certified physicians, but beginning in , medical toxicology became a subspecialty board under the American Board of Emer-. Some physicians who are occupational health specialists also have training in toxicology. Knowledge of toxicology is particularly strong among those who work in the chemical, petrochemical, and pharmaceutical industries, in which the surveillance of workers exposed to chemicals is a major responsibility.
Of the occupational physicians practicing today, only about have successfully completed the board examination in occupational medicine, which contains some questions about chemical toxicology. As of January , more than individuals had received board certification from the American Board of Toxicology. To sit for the examination, the candidate must be involved full time in the practice of toxicology, including designing and managing toxicological experiments or interpreting results and translating them to identify and solve human and animal health problems.
Diplomats must be recertified every 5 years. The Academy of Toxicological Sciences aTs was formed to provide credentials in toxicology through peer review only. It does not administer examinations for certification. Approximately individuals are certified as Fellows of ATS.
Clinical ecologists, another group of physicians, have offered opinions regarding multiple chemical hypersensitivity and immune system responses to chemical exposures. These physicians generally have a background in the field of allergy, not toxicology, and their theoretical approach is derived in part from classic concepts of allergic responses and immunology. This theoretical approach has often led clinical ecologists to find cause-and-effect relationships or low-dose effects that are not generally accepted by toxicologists.
Clinical ecologists often belong to the American Academy of Environmental Medicine. In Bradley v. Brown, 42 F. See also Kropp v. Maine School Adm. Union No. New York, F. But see Elam v. Alcolac, Inc. The Society of Toxicology SOT , the major professional organization for the field of toxicology, was founded in and has grown dramatically in recent years. It now has members. There are also societies of forensic toxicology, such as the International Academy of Forensic Toxicology. Other organizations in the field are the American College of Toxicology, for which experience in the active practice of toxicology is the major membership criterion; the International Society of Regulatory Toxicology and Pharmacology; and the Society of Occupational and Environmental Health.
For membership, the last two organizations require only the payment of dues. The success of academic scientists in toxicology, as in other biomedical sciences, usually is measured by the following types of criteria: the quality and number of peer-reviewed publications, the ability to compete for research grants, service on scientific advisory panels, and university appointments.
Publication of articles in peer-reviewed journals indicates an expertise in toxicology. The number of articles, their topics, and whether the individual is the principal or senior author are important factors in determining the expertise of a toxicologist. Most research grants from government agencies and private foundations are highly competitive. Successful competition for funding and publication of the research findings indicate competence in an area.
Selection for local, national, and international regulatory advisory panels usually implies recognition in the field. There are currently 21 specialty sections of SOT that represent the different specialty areas involved in understanding the wide range of toxic effects associated with exposure to chemical and physical agents.
These sections include mechanisms, molecular biology, inhalation toxicology, metals, neurotoxicology, carcinogenesis, risk assessment, and immunotoxicology. Because of a growing interest in environmental issues, the demand for scientific advice has outgrown the supply of available toxicologists. It is thus common for reputable toxicologists to serve on advisory panels. Finally, a university appointment in toxicology, risk assessment, or a related field signifies an expertise in that area, particularly if the university has a graduate education program in that area.
The authors greatly appreciate the excellent research assistance provided by Eric Topor and Cody S. The following terms and definitions were adapted from a variety of sources, including Office of Technology Assessment, U. The taking up of a chemical into the body orally, through inhalation, or through skin exposure. An immediate toxic response following a single or short-term exposure to an agent or dosing. When exposure to more than one toxic agent results in the same effect as would be predicted by the sum of the effects of exposure to the individual agents.
When exposure to one toxic agent causes a decrease in the effect produced by another toxic agent. A test for measuring the toxicity of an agent by exposing laboratory animals to the agent and observing the effects. Measurement of toxic agents or the results of their metabolism in biological materials, such as blood, urine, expired air, or biopsied tissue, to test for exposure to the toxic agents, or the detection of physiological changes that are due to exposure to toxic agents.
A biological explanation for the relationship between exposure to an agent and adverse health outcomes. Limited or long-term tests using laboratory animals to evaluate the potential carcinogenicity of an agent. A toxic response to long-term exposure or dosing with an agent. Physicians who believe that exposure to certain chemical agents can result in damage to the immune system, causing multiple-. Clinical ecologists often have a background in the field of allergy, not toxicology, and their theoretical approach is derived in part from classic concepts of allergic responses and immunology.
There has been much resistance in the medical community to accepting their claims. The study and treatment of humans exposed to chemicals and the quantification of resulting adverse health effects. Clinical toxicology includes the application of pharmacological principles to the treatment of chemically exposed individuals and research on measures to enhance elimination of toxic agents. In chemistry, the combination of two or more different elements in definite proportions, which when combined acquire properties different from those of the original elements.
Variables that are related to both exposure to a toxic agent and the outcome of the exposure. A confounding factor can obscure the relationship between the toxic agent and the adverse health outcome associated with that agent. Agents that cause toxic effects without metabolic activation or conversion. Movement of a toxic agent throughout the organ systems of the body e. The rate of distribution is usually determined by the blood flow through the organ and the ability of the chemical to pass through the cell membranes of the various tissues. A product of both the concentration of a chemical or physical agent and the duration or frequency of exposure.
A graphic representation of the relationship between the dose of a chemical administered and the effect produced. The extent to which a living organism responds to specific doses of a toxic substance. For example, a small dose of carbon monoxide will cause drowsiness; a large dose can be fatal.
The study of the occurrence and distribution of disease among people. Epidemiologists study groups of people to discover the cause of a disease, or where, when, and why disease occurs. Pertaining to nongenetic mechanisms by which certain agents cause diseases, such as cancer. A branch of medical science concerned with the causation of diseases. The process by which toxicants are eliminated from the body, including through the kidney and urinary tract, the liver and biliary system, the fecal excretor, the lungs, sweat, saliva, and lactation.
The intake into the body of a hazardous material. The main routes of exposure to substances are through the skin, mouth, and lungs. Codes developed by the federal government in consultation with the laboratory testing industry that govern many aspects of laboratory standards. In risk assessment, the qualitative analysis of all available experimental animal and human data to determine whether and at what dose an agent is likely to cause toxic effects.
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Scientists who specialize in the movement of ground and surface waters and the distribution and movement of contaminants in those waters. A branch of toxicology concerned with the effects of toxic agents on the immune system. Agents that require metabolic activation or conversion before they produce toxic effects in living organisms. The study of the effect of toxic agents that are absorbed into the body through inhalation, including their effects on the respiratory system. A research or testing methodology that uses living cells in an artificial or test tube system, or that is otherwise performed outside of a living organism.
A bioassay in which doses of an agent are given to experimental animals throughout their lifetime. See bioassay. The highest dose of an agent to which an organism can be exposed without it causing death or significant overt toxicity. The sum total of the biochemical reactions that a chemical produces in an organism.
The study of how toxic agents interact with cellular molecules, including DNA. A physical condition whereby individuals react to many different chemicals at extremely low exposure levels. A model for understanding certain diseases, including some cancers, based on the postulate that more than one event is necessary for the onset of disease.
A substance that causes physical changes in chromosomes or biochemical changes in genes. The process by which agents cause changes in chromosomes and genes. A branch of toxicology concerned with the effects of exposure to toxic agents on the central nervous system. The highest level of exposure to an agent at which no effect is observed. It is the experimental equivalent of a threshold. A model for understanding disease causation that postulates that any exposure to a harmful chemical such as a mutagen may increase the risk of disease.
A theory of cancer risk in which each molecule of a chemical mutagen has a possibility, no matter how tiny, of mutating a gene in a manner that may lead to tumor formation or cancer. A mathematical model that expresses the movement of a toxic agent through the organ systems of the body, including to the target organ and to its ultimate fate. The process by which the addition of one agent, which by itself has no toxic effect, increases the toxicity of another agent when exposure to both agents occurs simultaneously.
The study of the effect of toxic agents on male and female reproductive systems, including sperm, ova, and offspring. The use of scientific evidence to estimate the likelihood of adverse effects on the health of individuals or populations from exposure to hazardous materials and conditions. The final step of risk assessment, which summarizes information about an agent and evaluates it in order to estimate the risks it poses. Toxicological research that tests the toxic potential of a chemical in vivo or in vitro using standardized techniques required by governmental regulatory agencies or other organizations.
A method used by toxicologists to predict the toxicity of new chemicals by comparing their chemical structures with those of compounds with known toxic effects. When two toxic agents acting together have an effect greater than that predicted by adding together their individual effects.
The organ system that is affected by a particular toxic agent. The dose to the organ that is affected by a particular toxic agent. An agent that changes eggs, sperm, or embryos, thereby increasing the risk of birth defects. The ability to produce birth defects. Teratogenic effects do not pass to future generations. See teratogen. The level above which effects will occur and below which no effects occur.
See no observable effect level. An agent or substance that causes disease or injury. The science of the nature and effects of poisons, their detection, and the treatment of their effects. Val Roloff ed. Michael A. Frank C. Rodricks eds. Chang eds. The Reference Manual on Scientific Evidence, Third Edition , assists judges in managing cases involving complex scientific and technical evidence by describing the basic tenets of key scientific fields from which legal evidence is typically derived and by providing examples of cases in which that evidence has been used.
First published in by the Federal Judicial Center, the Reference Manual on Scientific Evidence has been relied upon in the legal and academic communities and is often cited by various courts and others.
Judges faced with disputes over the admissibility of scientific and technical evidence refer to the manual to help them better understand and evaluate the relevance, reliability and usefulness of the evidence being proffered. The manual is not intended to tell judges what is good science and what is not. Instead, it serves to help judges identify issues on which experts are likely to differ and to guide the inquiry of the court in seeking an informed resolution of the conflict. The core of the manual consists of a series of chapters reference guides on various scientific topics, each authored by an expert in that field.
The topics have been chosen by an oversight committee because of their complexity and frequency in litigation. Each chapter is intended to provide a general overview of the topic in lay terms, identifying issues that will be useful to judges and others in the legal profession. They are written for a non-technical audience and are not intended as exhaustive presentations of the topic.
Rather, the chapters seek to provide judges with the basic information in an area of science, to allow them to have an informed conversation with the experts and attorneys. Based on feedback from you, our users, we've made some improvements that make it easier than ever to read thousands of publications on our website. Jump up to the previous page or down to the next one. Also, you can type in a page number and press Enter to go directly to that page in the book. Switch between the Original Pages , where you can read the report as it appeared in print, and Text Pages for the web version, where you can highlight and search the text.
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Goldstein and Mary Sue Henifin. Get This Book. Visit NAP. Looking for other ways to read this? No thanks. Green, D. Reference Guide on Toxicology bernard d. GoldsTein and mary sue henifin Bernard D. Introduction A. Toxicology and the Law B. Purpose of the Reference Guide on Toxicology C. Toxicological Study Design 1. In vivo research 2. In vitro research D. Safety and Risk Assessment 1. The use of toxicological information in risk assessment F. Toxicology and Exposure Assessment H. Page Share Cite. Medical History A. Expert Qualifications A. Acknowledgments Glossary of Terms References on Toxicology.
Introduction The discipline of toxicology is primarily concerned with identifying and understanding the adverse effects of external chemical and physical agents on biological systems. Carbon monoxide is not only an external poison but is a product of normal internal metabolism such 1. Second, each chemical or physical agent tends to produce a specific pattern of biological effects that can be used to establish disease 2. What degree of risk is associated with chemical exposure at any given dose? Toxicology and the Law The growing concern about chemical causation of disease is reflected in the public attention devoted to lawsuits alleging toxic torts, as well as in litigation concerning the many federal and state regulations related to the release of potentially toxic compounds into the environment.
In tort litigation, toxicologists offer evidence that either supports 5. Purpose of the Reference Guide on Toxicology This reference guide focuses on the scientific issues that arise most frequently in toxic tort cases. Toxicological Study Design Toxicological studies usually involve exposing laboratory animals in vivo research or cells or tissues in vitro research to chemical or physical agents, monitoring the outcomes such as cellular abnormalities, tissue damage, organ toxicity, or tumor formation , and comparing the outcomes with those for unexposed control groups.
See infra Section I. In vivo research Animal research in toxicology generally falls under two headings: safety assessment and classic laboratory science, with a continuum between them. See infra Sections I. Dose—response relationships An important component of toxicological research is dose—response relationships. No observable effect level A dose—response study also permits the determination of another important characteristic of the biological action of a chemical—the no observable effect level NOEL. D, II. Benchmark dose For regulatory toxicology, the NOEL is being replaced by a more statistically robust approach known as the benchmark dose BD.
No-threshold model and determination of cancer risk Certain genetic mutations, such as those leading to cancer and some inherited disorders, are believed to occur without any threshold. Maximum tolerated dose and chronic toxicity tests Another type of study uses different doses of a chemical agent to establish over a day period what is known as the maximum tolerated dose mTd the highest dose that does not cause significant overt toxicity.
To test risks of 1 in 1,,, a researcher would have to either increase the lifetime dose from 10 times to , times the realistic dose or Occurring Substances v. In vitro research In vitro research concerns the effects of a chemical on human or animal cells, bacteria, yeast, isolated tissues, or embryos. Extrapolation from Animal and Cell Research to Humans Two types of extrapolation must be considered: from animal data to humans and from higher doses to lower doses. Safety and Risk Assessment Toxicological expert opinion also relies on formal safety and risk assessments.
The use of toxicological information in risk assessment Risk assessment as practiced by government agencies involved in regulating exposure to environmental chemicals is highly dependent upon the science of toxicology and on the information derived from toxicological studies. Toxicological Processes and Target Organ Toxicity The biological, chemical, and physical phenomena that are the basis of life are astounding in their complexity.
Organ System Examples of End Points Examples of Agents of Concern Endocrine system thyroid toxicity radioactive iodine, perchlorate Cardiovascular system heart toxicity anthracyclines, cobalt high blood pressure lead arrhythmias plant glycosides e. Researchers may look for changes in the nucleus of the cell suggestive of DNA damage that could IARC uses the following classifications: Group 1, The agent mixture is carcinogenic to humans; Group 2A, The agent mixture is probably carcinogenic to humans, Group 2B, The agent mixture is possibly carcinogenic to humans; Group 3, The agent mixture is not classifiable as to its carcinogenicity to humans; and Group 4, The agent mixture is probably not carcinogenic to humans.
Toxicology and Exposure Assessment In recent decades, exposure assessment has developed into a scientific field with the usual trappings of journals, learned societies, and research funding processes. Toxicology and Epidemiology Epidemiology is the study of the incidence and distribution of disease in human populations. Such studies generate hypotheses that can then be evaluated more thoroughly by subsequent studies that more narrowly focus on the potential cause-and-effect Yet there are more than known animal carcinogens for which there is no valid epidemiological database, and others for which the epidemiological database has been To do so, the expert relies on the principles of toxicology to provide a scientifically valid Through evolution, a very efficient and specific mechanism has developed that No matter how strong the temporal relationship between exposure and the development of disease, or the supporting epidemiological evidence, it is difficult to accept an association between a compound and a health effect when no of specific toxic metabolic products of benzene in comparison with the alkyl benzenes.
The law e. For example, mathematical models take into account such factors as wind variations to allow calculation of Elec. Thus the rate of distribution depends on the rate of blood flow to various organs For example, in acute myelogenous leukemia, the adult form of acute leukemia, at least 1 to 2 years must elapse from initial exposure to radiation, benzene, or The failure of a physician to elicit such a history or of a toxicologist to pay attention to such a numbness, tingling, burning sensations, and paresthesia ; Wicker v.
See also sources cited supra note Acknowledgments The authors greatly appreciate the excellent research assistance provided by Eric Topor and Cody S. Glossary of Terms The following terms and definitions were adapted from a variety of sources, including Office of Technology Assessment, U. A chemical substance or other agent that causes cancer. The process of estimating unknown values from known values. A research or testing methodology that uses living organisms. Of, relating to, or caused by a poison—or a poison itself.
Environmental Toxicants Morton Lippmann ed. Waters et al. Principles and Methods of Toxicology A. Joseph V. Rodricks, Calculated Risks 2d ed. Toxic Interactions Robin S. Goldstein et al.
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Toxicology Hans Marquardt et al. This page intentionally left blank. Login or Register to save! Giannelli, Edward J. Imwinkelried, and Joseph L.