Evaluating Chemical and Other Agent Exposures for Reproductive and Developmental Toxicity (2001) / Chapter Skim
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The Evaluative Process: Part I. Assessing the Available Data
The Evaluative Process: Part I. Assessing the Available Data
Pages 24-56
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In that chapter, the interpretation of toxicity data, integration of toxicity and exposure data, and quantitative assessment steps are covered. PRINCIPLES AND OBJECTIVES Use of Data and Judgment The evaluative process uses both scientific data and scientific judgment.
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Using a weight-of-evidence approach to communicate a judgment about human risk, taking into consideration exposure potential, should diminish reliance on the assumption that reproductive and developmental toxicity observed in animals predicts similar effects in humans. Because the evaluative process requires a judgment about human risk potential based on the weight of the evidence, its approach and its results will be useful to the Navy.
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lARC and NIP clearly state that their deliberations do not represent a complete assessment of human risk potential, but their monographs and lists continue to be misused for that purpose. Threshold Assumption Use of a threshold assumption for low dose-response relationships implies that there is an exposure level below which an adverse effect is not expected to occur.
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Certainty Documents produced under the evaluative process will clearly describe the level of confidence in the evaluative judgment. The need to invoke a series of default assumptions will signify progressively greater degrees of uncertainty.
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Other factors that should be considered include statistical power, analytical approaches, data presentation, and consistency with other results. Qualities and Limitations of Reproductive and Developmental Toxicity Studies Developmental toxicity studies typically assess whether structural abnormalities are associated with administration of an agent to a pregnant female during major organogenesis in the developing embryo.
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Alone, however, those studies might not provide enough evidence to be considered sufficient to identify an adverse effect. A judgment that data are insufficient to establish an adverse effect does not mean that they are sufficient to establish lack of an adverse effect.
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The section on deveZopmentaZ and reproductive toxicity reviews data from human and animal studies. To ensure adequate assessments of both types of data, experts review each type of data independently and prepare synopses of individual studies.
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The last step is a listing of references for papers and studies of the agent of interest. DETAILS OF THE EVALUATIVE PROCESS The sections below detail the steps of the evaluative process recommended by the subcommittee.
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General Toxicological and Biological Parameters 2.1 Chemistry 2.2 Basic Toxicity 2.3 Pharmacokinetics 3. Reproductive and Developmental Toxicity Data 3.1 Human Data 3.1 .1 Developmental Toxicity 3.1 .1 .1 Register Studies 3.1 .1 .2 Prospective Studies 3.1 .1 .3 Retrospective Studies 3.1 .1 .4 Clinical Case Reports 3.1.2 Reproductive Toxicity 3.1 .2.1 Developmental Toxicity 3.1 .2.2 Reproductive Toxicity 3.2 Experimental Animal Toxicity 3.2.1 Developmental Toxicity 3.2.1 .1 Studies in Mice 3.2.1 .2 Studies in Rats 3.2.1.3 Studies in Rabbits, Monkeys, and Pigs 3.2.2 Reproductive Toxicity 3.2.2.1 Female Reproductive Toxicity 3.2.2.2 Male Reproductive Toxicity 4.
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Thus, there is uncertainty in the exposure component of the evaluative process, even as there is in hazard characterization. When toxicity data indicate the potential for an adverse effect, the need to estimate the nature of human exposure becomes imperative.
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considers the range of estimates and provides a probabilit~v distribution of exposures. Data sets are rarely complete and, therefore, exposure estimates are developed using various default assumptions (combined with the modeling estimates)
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can vary in susceptibility. For male and female reproductive toxicity, exposure assessments should consider the duration and period of exposure during development (prenatal, prepubescent, and reproductive)
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Data on real or estimated levels of exposures should be collected, as should information on population distributions, intensity, routes, timing, and durations. Other data of value include industrial hygiene measurements at the point of manufacture, materials balance (input, products, waste)
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Observations from studies of other toxicity endpoints might either strengthen or weaken the conclusions to be drawn from a reproductive or developmental study and provide information about target organs that should be evaluated further in developing animals. Relevant toxicity data typically originate from acute (single dose)
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Although acute lethality data are not predictive of reproductive or developmental toxicity, they are useful indicators of divergences in species or route sensitivity. When there are significant species differences in acute toxicity, for example, one would also expect differences between species in the doses that would cause reproductive or developmental toxicity.
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Changes in the weight or morphology of the reproductive organs must be interpreted in the context of other systemic or general toxicity. Such effects must be considered in the overall evaluation of reproductive toxicity, especially if there is no evidence of other systemic toxicity.
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The correlation of pharmacokinetic parameters and reproductive and developmental toxicity data might enhance our understanding of both the effects observed and of their predictive value (Kimme] and Young 1983; Hansen et al.
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Because human pharmacokinetic data are often minimal, absorption data from studies of experimental animals—by any relevant route of exposure—might assist those who must apply animal toxicity data to risk assessment. Results of a dermal developmental toxicity study that shows no adverse developmental effects are potentially m~sleading if uptake through the skin is not documented.
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It will be helpful to understand whether an agent that causes reproductive or developmental toxicity acts by exceeding a threshold concentration for a brief period of time or whether a protracted exposure is required to initiate an adverse effect. Such information could be helpful in judging the potential hazards posed by human exposure.
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1999~. In that study, animals exposed to short, high concentrations of ethylene oxide by inhalation on day 7 of gestation were found to have more adverse developmental effects than did animals exposed to the same concentration X time multiple but at longer, lower exposures.
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to conclude that there is no adverse effect under specified conditions. To ensure systematic rigor, the process evaluates the experimental animal data and the human data independently.
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Chapter 3 of this report describes the integrative process. Human Data Given that the goal of the evaluative process is to protect human health, including reproductive and developmental processes in men and women, human data are critical.
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Those design features help to ensure the scientific validity of human data, and they underscore the added strength and utility of epidem~olog~cal data that contribute to assessment of human health risk from toxicological hazards. Weighing the Evidence All epidem~ological studies should be critically evaluated with respect to research design (especially in relation to study purposes)
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Causality Necessary, sufficient Risk factors
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Selection of a health outcome for study depends in part upon the exposure of interest and methodological considerations such as the ability to define, measure, and validate adverse outcomes, especially if self-reported. Operational definitions for outcomes can be general or specific in nature (e.g., ah birth defects versus spine bifida, respectively)
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Studies that discuss results in relationship to chance findings, random errors, possible confounders, or sources of bias should be weighed more heavily than are studies that ignore or incompletely address those issues. Case Reports and Clinical Series Almost all exposures that are currently recognized as having unequivocal developmental or reproductive toxicity in humans were initially recognized in case reports and cynical series.
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The observation of adverse developmental or reproductive outcomes in a few case reports or clinical series is, therefore, never sufficient by itself to establish the reproductive toxicity of an exposure in humans.
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Multivariate modeling or stratification procedures can be used in observational studies to assess for confounding, interaction, or effect modification and, thereby, to help rule out alternative explanations. The existing literature is used to assess the remaining criteria for causality: replication of findings in other populations, biological plausibility to aid in interpreting risk factors, cessation of exposure, specific
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Investigators have developed a standard series of animal test procedures that domestic and international regulatory bodies require, for example, for approval to market drugs, pesticides, and, to a lesser degree, other industrial and commercial substances. Data showing adverse effects from such animal reproductive and developmental toxicity studies are assumed to be predictive of a potential human reproductive or developmental effect, although the precise manifestations may not be the same.
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Thus, because experimental animal toxicity data can be misinterpreted, it is imperative that the evaluative process include a review and interpretation of animal data by scientists with appropriate training and experience. The logic that underpins their interpretation of data should be stated clearly in the evaluation so that other experts can understand the basis for the evaluative judgment.
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That study might have noted a decrease in production of progesterone by cultured granulosa ceils. Although the study is adequate in every technical respect, the data themselves are insufficient for rendering an assessment of animal hazard because the relationship of this effect to an adverse effect in viva cannot be predicted.
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To support a conclusion that a given exposure does not cause developmental toxicity, the available studies must be conducted in at least two mammalian species and must test for a wide variety of pre- and postnatal outcomes (EPA 1991~. A minimum data set for a conclusion of no reproductive toxicity would normally consist of at least one two-generation reproductive toxicity study.
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Similarly, the absence of adverse effects in a two-generation reproductive study would not preclude the possibility of significant reproductive toxicity that is not manifested as a fertility problem, unless more detailed sperm evaluations, estrous cycling, ovarian histology, and endocrine function were included. Detailed description of animal testing protocols, and their qualifications and limitations are discussed in Appendix D
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