Reference Manual on Scientific Evidence Third Edition (2011) / Chapter Skim
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Reference Guide on Toxicology--Bernard D. Goldstein and Mary Sue Henifin
Reference Guide on Toxicology--Bernard D. Goldstein and Mary Sue Henifin
Pages 633-686
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From page 633... ...
In vitro research, 645 D. Extrapolation from Animal and Cell Research to Humans, 646 E. Safety and Risk Assessment, 646 1. The use of toxicological information in risk assessment, 650 F. Toxicological Processes and Target Organ Toxicity, 651 G. Toxicology and Exposure Assessment, 656 H. Toxicology and Epidemiology, 657 II.
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From page 634... ...
669 IV. Medical History, 670 A. the Medical History of the Individual Consistent with the Is Toxicologist's Expert Opinion Concerning the Injury?
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From page 635... ...
For the most part, toxicological study begins with a chemical or physical agent and asks what impact it will have, while toxic tort cases begin with an individual or a group that has suffered an adverse impact and makes claims about its cause. A particular challenge is that only rarely is the adverse impact highly specific to the toxic agent; for example, the relatively rare lung cancer known as mesothelioma is almost always caused by asbestos.
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From page 636... ...
Second, each chemical or physical agent tends to produce a specific pattern of biological effects that can be used to establish disease 2. Direct-acting toxic agents are those whose toxicity is due to the parent chemical entering the body. A change in chemical structure through metabolism usually results in detoxification.
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From page 637... ...
6. Forensic toxicology, a subset of toxicology generally concerned with criminal matters, is not addressed in this reference guide, because it is a highly specialized field with its own literature and methodologies that do not relate directly to toxic tort or regulatory issues. 7. In standard risk assessment terminology, hazard is an intrinsic property of a chemical or physical agent, while risk is dependent both upon hazard and on the extent of exposure.
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. Courts have held that toxicologists can testify as to disease causation related to chemical exposures.
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From page 639... ...
, and comparing the outcomes with those for unexposed control groups. As explained below,15 the extent to which animal and cell experiments accurately predict human responses to chemical exposures is subject to debate.16 However, because it is often unethical to experiment on humans by exposing them to known doses of chemical agents, animal toxicological evidence often provides the best scientific information about the risk of disease from a chemical exposure.17 In contrast to their exposure to drugs, only rarely are humans exposed to environmental chemicals in a manner that permits a quantitative determination of adverse outcomes.18 This area of toxicological study may consist of individual or multiple case reports, or even experimental studies in which individuals or groups of individuals have been exposed to a chemical under circumstances that permit analysis of dose–response relationships, mechanisms of action, or other aspects of 14. The use of toxicological evidence in regulatory decisionmaking is discussed in Casarett and Doull's Toxicology: The Basic Science of Poisons, supra note 3, at 13–14; Barbara D
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21. W.J. White et al., The Use of Laboratory Animals in Toxicology Research, in Principles and Methods of Toxicology 1055–1102 (A.
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From page 641... ...
.25 The NOEL sometimes is called a threshold, because it is the level above which observable effects in test animals are believed to occur and below which no toxicity is observed.26 Of course, because the NOEL is dependent on the ability to 23. See infra Sections I.D, II.A. 24. Committee on Toxicity Testing and Assessment of Environmental Agents, National Research Council, Toxicity Testing in the 21st Century: A Vision and a Strategy (2007)
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May 11, 2006) (benchmark dose should not be equated with LOEL (lowest observable effect level)
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. Although the one-hit model explains the response to most carcinogens, there is accumulating evidence that for certain cancers there is in fact a multistage process and that some cancer-causing agents, so-called epigenetic or nongenotoxic agents, act through nonmutational processes, Commit tee on Risk Assessment Methodology, National Research Council, Issues in Risk Assessment 34–35, 187, 198–201 (1993)
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From page 644... ...
Consider the situation in which a realistic dose of a chemical causes a tumor in 1 in 100 laboratory animals. If the lifetime background incidence of tumors in animals without exposure to the chemical is 6 in 100, a toxicological test involving 100 control animals and 100 exposed animals who were fed the realistic dose would be expected to reveal 6 control animals and 7 exposed animals with the cancer.
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From page 645... ...
Inevitably, then, animal studies must trade statistical power for extrapolation from higher doses to lower doses. Accordingly, proffered toxicological expert opinion on potentially ancer‑causing chemicals almost always is based on a review of research studies c that extrapolate from animal experiments involving doses significantly higher than that to which humans are exposed.30 Such extrapolation is accepted in the regulatory arena.
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From page 646... ...
Through the study of factors that modify the toxic effects of chemicals, including absorption, distribution, metabolism, and excretion, researchers can improve the ability to extrapolate from laboratory animals to humans and from higher to lower doses.35 The mathematical depiction of the process by which an external dose moves through various compartments in the body until it reaches the target organ is often called physiologically based pharmacokinetics or toxicokinetics.36 Extrapolation from studies in nonmammalian species to humans is much more difficult but can be done if there is sufficient information on similarities in absorp (Toxicologist qualified to testify on relationship between welding fumes and Parkinson's disease including epidemiology and animal and in vitro toxicology studies)
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From page 647... ...
As discussed in Section I.F, in vitro or animal data for elucidating the mechanisms of toxicity are more persuasive when positive human epidemiological data or toxicological information also exists.38 E Safety and Risk Assessment Toxicological expert opinion also relies on formal safety and risk assessments.
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From page 648... ...
The lack of toxicity data for most chemicals in commerce has led EPA to propose methods of evaluation using in vitro toxicity pathway testing, followed by whole-animal testing where warranted. See Committee on Toxicity Testing and Assessment of Environmental Agents, National Research Council, Toxicity Testing in the 21st Century: A Vision and a Strategy (2007)
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From page 649... ...
In recent years, codification of the methodology used to assess risk has increased confidence that the process can be reasonably free of bias; however, significant controversy remains, particularly when actual data are limited and generally conservative default assumptions are used.46 Although risk assessment information about a chemical can be somewhat useful in a toxic tort case, at least in terms of setting reasonable boundaries regarding the likelihood of causation, the impetus for the development of risk assessment has been the regulatory process, which has different goals.47 Because of their 43. See John S Applegate, The Perils of Unreasonable Risk: Information, Regulatory Policy, and Toxic Substances Control, 261 Colum.
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From page 650... ...
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. EPA, FDA, OSHA, the Consumer Product Safety Commission, and other international (e.g., the World Trade Organization)
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52. Some toxic agents pass through the lung without producing any direct effects on this organ. For example, inhaled carbon monoxide produces its toxicity in essence by being treated by the body as if it is oxygen.
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This interaction is even more complex when dealing with estrogenic agents that are naturally occurring as well as made within the body at different levels in response to different external and internal stimuli and at different time intervals. 56. The complexity of the interaction of a mixture of dioxins with receptors governing the endocrine system can be contrasted with that of the reaction of carbon monoxide with the hemoglobin oxygen receptor discussed in note 52.
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From page 653... ...
asthma toluene diisocyanate chronic obstructive cigarette smoke pulmonary disease fibrosis, pneumoconiosis silica, mineral dusts, cotton dust cancer cigarette smoke, arsenic, asbestos, nickel Blood and the anemia arsine, lead, methyldopa immune system secondary polycythemia cobalt methemoglobinemia nitrites, aniline dyes, dapsone pancytopenia benzene, radiation, chemotherapeutic agents secondary lupus hydralazine erythematosus leukemia benzene, radiation, chemotherapeutic agents Liver and hepatic damage (hepatitis) acetaminophen, ethanol, carbon gastrointestinal tetrachloride, vitamin A tract cancer aflatoxin, vinyl chloride Urinary tract kidney toxicity ethylene and diethylene glycols, lead, melamine, aminoglycoside antibiotics bladder cancer aromatic amines Nervous system nervous system toxicity cholinesterase inhibitors, mercury, lead, n-hexane, bacterial toxins (botulinum, tetanus)
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digitalis) aThis table presents only examples of toxicological end points and examples of agents of concern in humans and is provided to help illustrate the variety of toxic agents and end points.
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From page 655... ...
have formal processes to evaluate the weight of evidence that a chemical causes cancer.62 Each classifies chemicals on the basis of epidemiological evidence, toxicological findings in laboratory animals, and mechanistic considerations, and then assigns a specific category of carcinogenic potential to the individual chemical or exposure situation (e.g., employment as a painter) .63 Only a small percentage of 59. All of these tests require validation regarding their relevance to predicting human carcinogenesis, as well as to their technical reproducibility.
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From page 656... ...
In recent years, with improved understanding of the mechanism of action of chemical carcinogens, there has been increased use of mechanistic data.64 For example, higher credence is given to the likelihood that a chemical is a human carcinogen if the metabolite found to be responsible for carcinogenesis in a laboratory animal is also found in the blood or urine of humans exposed to this chemical, or if there is evidence of the same type of DNA damage in humans as there is in laboratory animals in which the agent does cause cancer.65 G 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.
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From page 657... ...
In this continuum of exposure metrics, the closer to the human body, the greater the overlap with toxicology.66 Exposure assessment is central to epidemiology as well. Many of the causal associations between chemicals and human disease have been developed from epidemiological studies relating a workplace chemical to an increased risk of the specific disease in cohorts of workers, often with only a qualitative assessment of exposure.
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From page 658... ...
Green et al., Reference Guide on Epidemiology, in this manual. 70. Both commonalities and differences between animal responses and human responses to chemical exposures were recognized by the court in International Union, United Automobile, Aerospace and Agricultural Implement Workers of America, UAW v.
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From page 659... ...
Even though there is little toxicological data on many of the 75,000 compounds in general commerce, there is far more information from toxicological studies than from epidemiological studies.73 It is much easier, and more economical, to expose an animal to a chemical or to perform in vitro studies than it is to perform epidemiological studies. This difference in data availability is evident even for cancer causation, for which toxicological study is particularly expensive and time-consuming.
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From page 660... ...
To do so, the expert relies on the principles of toxicology to provide a scientifically valid 74. The absence of epidemiological data is due, in part, to the difficulties in conducting cancer epidemiology studies, including the lack of suitably large groups of individuals exposed for a sufficient period of time, long latency periods between exposure and manifestation of disease, the high variability in the background incidence of many cancers in the general population, and the inability to measure actual exposure levels. These same concerns have led some researchers to conclude that "many negative epidemiological studies must be considered inconclusive" for exposures to low doses or weak carcinogens.
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From page 661... ...
Comparative information concerning factors that modify the toxic effects of chemicals, including absorption, distribution, metabolism, and excretion, in the laboratory test animals and humans enhances the expert's ability to extrapolate from laboratory animals to humans.76 The expert should review similarities and differences between the animal species in which the compound has been tested and humans. This analysis should form the basis of the expert's opinion regarding whether extrapolation from animals to humans is warranted.77 76. See generally supra notes 35–36 and accompanying text.
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Will Humans Be Affected Similarly? Some toxic agents affect only specific organs and not others.
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The unfolding of the human genome already is beginning to provide information pertinent to understanding the wide variation in human risk from environmental chemicals. The impact of this understanding on toxic tort causation issues remains to be explored.81 C
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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. Thus SAR is predictive of neurotoxic effects but not bone marrow effects.
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From page 665... ...
Regulatory standards are set for purposes far different than determining the preponderance of evidence in a toxic tort case. For example, if regulatory standards are discussed in toxic tort cases to provide a reference point for assessing exposure levels, it must be recognized that there is a great deal of variability in the extent of evidence required to support different regulations.88 The extent of evidence required to support regulations depends on 85. However, theories of bioplausibility, without additional data, have been found to be insufficient to support a finding of causation.
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. See also John Endicott, Interaction Between Regulatory Law and Tort Law in Controlling Toxic Chemical Exposure, 47 SMU L
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("[g] uesses, even if educated, are insufficient to prove the level of exposure in a toxic tort case")
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Metabolism is complex, because a variety of pathways compete for the same agent; some produce harmless metabolites, and others produce toxic agents.93 D hat Excretory Route Does the Compound Take, and W How Does This Affect Its Toxicity?
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For agents that produce effects other than through mutations, it is assumed that there is some level that is incapable of causing harm. If the level of exposure was below this no observable effect, or threshold, level, a relationship between the exposure and disease cannot be established.95 When only laboratory animal 94. The temporal relationship between exposure and causation is discussed in Rolen v.
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From page 670... ...
Is the Medical History of the Individual Consistent with the Toxicologist's Expert Opinion Concerning the Injury? One of the basic and most useful tools in diagnosis and treatment of disease is the patient's medical history.98 A thorough, standardized patient information ques 2d 863, FN101 (N.D.
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The following information is relevant to a patient's medical history: past and present occupational and environmental history and exposure to toxic agents; lifestyle characteristics (e.g., use of nicotine and alcohol) ; family medical history (i.e., medical conditions and diseases of relatives)
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W 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. 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.
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1989) , the court found that OSHA failed to sufficiently explain its findings that formaldehyde presented no significant carcinogenic risk to workers at exposure levels of 1 part per million or less.
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If animal studies, pharmacological research on mechanisms of toxicity, in vitro tissue studies, and epidemiological research all document toxic effects of exposure to a compound, an expert's opinion about causation in a particular case is much more likely to be true.111 109. See generally Calabrese, supra note 106. 110. The problem of differences in chemical sensitivity was addressed by the court in Gulf South Insulation v.
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From page 675... ...
The defendant also moved to exclude evidence demonstrating that the nitrosamines and polonium-210 contained in the snuff are cancer-causing agents in some 40 different species of laboratory animals. The court denied both motions, finding: There was no dispute that both nitrosamines and polonium-210 are present in defendant's snuff prod ucts.
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An exception is a physician who is certified in medical toxicology as a subspeciality under the American Board of Medical Specialties' requirements, based on substantial training in toxicology and successful completion of rigorous examinations, including recertification exams.114 112. For recent documentation of how rarely an occupational history is obtained, see B.J. Politi et al., Occupational Medical History Taking: How Are Today's Physicians Doing?
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From page 677... ...
115. 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.
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From page 678... ...
Recognized industrial organizations, including the American Petroleum Institute and the Electric Power Research Institute, and public interest groups, such as the Environmental Defense Fund and the Natural Resources Defense Council, 116. 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.
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From page 679... ...
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.
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From page 680... ...
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. biologically plausible theory.
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From page 681... ...
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 elimina tion of toxic agents.
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inhalation toxicology. The study of the effect of toxic agents that are absorbed into the body through inhalation, including their effects on the respiratory system.
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reproductive toxicology. The study of the effect of toxic agents on male and female reproductive systems, including sperm, ova, and offspring.
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See no observable effect level. toxic.
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From page 685... ...
. Short-Term Toxicity Tests for Nongenotoxic Effects (Philippe Bourdeau et al.
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