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Summary

Reproductive disorders and developmental defects (including birth defects) are significant public health problems, with enormous personal and economic costs. Reproductive disorders may include altered menstrual and ovarian cycles, increased time-to-pregnancy, decreased sperm count, reduced libido, and infertility. Developmental defects may be manifested as prenatal and postnatal death, structural abnormalities (e.g., neural tube and heart defects), altered growth (e.g., low birth weight), and functional deficiencies (e.g., mental retardation). The known causes of reproductive and developmental disorders include genetic mutations; maternal metabolic imbalances; infection; and occupational, therapeutic, and environmental exposure to harmful chemical and physical agents.

Concern regarding reproductive and developmental hazards in the workplace, including military facilities, has increased significantly in recent years. In 1997, Congress passed a law, as part of the National Defense Authorization Act, concerning health care coverage for children with medical conditions caused by parental exposure to hazardous materials while serving as members of the Armed Services (Public Law 104-201, Section 704). The law states, in part, that a plan would be developed for ensuring the provision of medical care to any natural child of a member of the Armed Forces who has a congenital defect or catastrophic illness, proven to a reasonable degree of scientific certainty on the basis of scientific research to have resulted from exposure



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Page 1 Summary Reproductive disorders and developmental defects (including birth defects) are significant public health problems, with enormous personal and economic costs. Reproductive disorders may include altered menstrual and ovarian cycles, increased time-to-pregnancy, decreased sperm count, reduced libido, and infertility. Developmental defects may be manifested as prenatal and postnatal death, structural abnormalities (e.g., neural tube and heart defects), altered growth (e.g., low birth weight), and functional deficiencies (e.g., mental retardation). The known causes of reproductive and developmental disorders include genetic mutations; maternal metabolic imbalances; infection; and occupational, therapeutic, and environmental exposure to harmful chemical and physical agents. Concern regarding reproductive and developmental hazards in the workplace, including military facilities, has increased significantly in recent years. In 1997, Congress passed a law, as part of the National Defense Authorization Act, concerning health care coverage for children with medical conditions caused by parental exposure to hazardous materials while serving as members of the Armed Services (Public Law 104-201, Section 704). The law states, in part, that a plan would be developed for ensuring the provision of medical care to any natural child of a member of the Armed Forces who has a congenital defect or catastrophic illness, proven to a reasonable degree of scientific certainty on the basis of scientific research to have resulted from exposure

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Page 2 of the member to a chemical warfare agent or other hazardous material to which the member was exposed during active military service. The Department of Defense is required to develop a plan for compliance. As a part of its efforts to protect military and civilian personnel from reproductive and developmental hazards in the workplace, the Navy requested that the National Research Council (NRC) recommend an approach that can be used to evaluate sources of potential reproductive and developmental toxicity. The NRC assigned this project to the Committee on Toxicology, which convened the Subcommittee on Reproductive and Developmental Toxicology. The subcommittee was assigned the following tasks: Develop a process for assessing the reproductive and developmental toxicity potential from exposures to chemicals and physical agents. Develop a strategy for dealing with the potential reproductive and developmental toxicity of exposures to chemicals and physical agents for which little or no information is available. Conduct pilot evaluations on two chemicals using the process developed by the subcommittee. Identify reliable sources for assessment of reproductive and developmental toxicity. Identify areas of needed research. In this report, the subcommittee recommends an approach to assess potential reproductive and developmental toxicity from exposures to substances encountered in workplaces operated by the United States Navy. CONCLUSIONS AND RECOMMENDATIONS The subcommittee's major conclusions and recommendations, organized in response to each of its tasks, are presented below. Evaluative Process The subcommittee's recommended approach for evaluating exposures to chemicals and physical agents for reproductive and develop-

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Page 3 mental toxicity is based on a process published in 1995 by Moore and colleagues. 1 As it is described and expanded on in the subcommittee's report, the process undertakes a systematic review of data on reproductive and developmental toxicity in humans and experimental animals, on general toxicity, and on the conditions of use that result in human exposure. The toxicity and exposure data are integrated, and the result is an estimate of an exposure that is unlikely to cause reproductive or developmental toxicity. The subcommittee recommends against an attempt to classify agents as “toxic” or “nontoxic.” Instead, the potential toxicity of a substance should be considered in the context of exposure (e.g., amount, route, timing, and duration of exposure). The subcommittee recognizes that the Navy might want to use a screening process in which decisions are made in a dichotomous manner (to use or not to use a particular agent). Such decisions can be made by considering the exposure scenario that is anticipated in the workplace. An exposure level of an agent that is unlikely to be associated with reproductive and developmental toxicity can be estimated, and if the anticipated workplace exposure is sufficiently lower than that estimate, the Navy can regard the exposure as acceptable. If the anticipated human exposure is higher than the estimate, then the use of the agent under consideration can be regarded as unacceptable and exposure control measures can be implemented or alternative agents can be evaluated. The subcommittee recommends that the evaluative process be implemented by a team of scientists with training and experience in assessing agents for their potential to cause reproductive and developmental toxicity. Such evaluation requires expertise in the intricacies and relationships of the integrated processes of reproduction and development. Considerable scientific judgment is needed to interpret data and make informed decisions about the adequacy of available data sets for estimating the potential reproductive and developmental toxicity of specific substances under specific conditions of exposure. 1 Moore, J.A., G.P. Daston, E. Faustman, M.S. Golub, W.L. Hart, C. Hughes Jr., C.A. Kimmel, J.C. Lamb IV, B.A. Schwetz, and A.R. Scialli. 1995. An evaluative process for assessing human reproductive and developmental toxicity of agents. Reprod. Toxicol. 9(1):61-95.

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Page 4 Assessing the Available Data When conducting an evaluation of an agent for potential reproductive and developmental toxicity, the Navy should assess several types of data: human exposure data, general toxicity data in humans and experimental animals, and reproductive and developmental toxicity data in humans and experimental animals. Complete assessments should consider potential adverse effects on the male and female reproductive systems and on the embryo, fetus, and child. Human exposure data are evaluated to identify populations that might be exposed, to identify potential pathways of exposure, and to estimate the range of exposure so that quantitative estimates of exposure can be made that are associated with each pattern of use. Exposure conditions that are unique for reproductive and developmental toxicity should be considered because the embryo, fetus, neonate, juvenile, young adult, and older adult differ in susceptibility. Human exposure data are important for accurate evaluation of the risk potential of an agent, but data of sufficient quality and quantity are often unavailable. Chemical data (e.g., physical and chemical properties, structureactivity relationships, and environmental fate and transport), basic toxicity data, and pharmacokinetic data (information on absorption, distribution (including placental and lactational transfer), metabolism, and excretion) should be reviewed. These data are particularly important because reproductive and developmental effects are interpreted in the context of general toxicity data in humans or experimental animals. Pharmacokinetic data for both animals and humans can be helpful in extrapolating exposure levels from one species to another. Reproductive and developmental toxicity data from animal experiments and human studies should be assessed based on defined criteria. One of the following judgments can be made: either the toxicity data are sufficient (or insufficient) to ascribe an adverse effect to a specific agent under specified conditions, or the data are sufficient (or insufficient) to conclude that there is no adverse effect. To be characterized as sufficient, the database must include information on the full range of potential adverse male and female reproductive effects and developmental effects, and the actual range of conditions of exposure must be known in sufficient detail to determine whether the dose, duration,

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Page 5 route, timing, and other characteristics of exposure pose a substantial reproductive risk. A designation of sufficient (or insufficient) data is inadequate by itself to identify a substance as having the potential to cause (or not cause) reproductive or developmental toxicity; the reproductive and developmental toxicity information must be integrated with the exposure and general toxicity information before the evaluative process can be considered complete. The integration step is described below. Integration of Toxicity and Exposure Information The integration step of the evaluation is conducted in three stages. In the first stage, the evaluators examine the data for relevance to potential human toxicity. Then, if the data are determined to be relevant to human exposures, a quantitative assessment is conducted. Finally, the concluding step of the evaluative process is the integration of toxicity and exposure information to characterize the risk of potential reproductive and developmental toxicity. This step involves combining information from the review of animal and human reproductive and developmental toxicity data with information from the review of general toxicity, pharmacokinetic, and exposure data. A weight-of-evidence approach is used to formulate judgments about potential hazards to humans. Three separate judgments should be developed: one each to address developmental toxicity, female reproductive toxicity, and male reproductive toxicity. Once an assessment has determined that the data indicate human risk potential for reproductive and developmental toxicity, the next step is to perform a quantitative evaluation. Dose-response data from human and experimental animal reproductive and developmental toxicity studies are reviewed to identify a no-observed-adverse-effect level (NOAEL) or a lowest-observed-adverse-effect level (LOAEL), and/or to derive a benchmark dose (BMD). Duration adjustments of the NOAEL, LOAEL, or BMD are often made, particularly for inhalation exposures when extrapolating to different exposure scenarios. Such adjustments have not been routinely applied to developmental toxicity data. The subcommittee recommends that duration adjustments be considered for both reproductive and developmental toxicity

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Page 6 assessments. Uncertainty factors (UF) are then applied to the NOAEL, LOAEL, or BMD to account for various uncertainties in the data. Uncertainty factors for reproductive and developmental toxicity commonly applied to the NOAEL or BMD include a 10-fold factor for interspecies variability and a 10-fold factor for intraspecies variability. If only a LOAEL is available, an additional factor of up to 10-fold would be applied. The magnitude of the UFs can be adjusted, depending on the type and quantity of data, including pharmacokinetic and pharmacodynamic data, available and other modifying factors can be used to account for other uncertainties (e.g., insufficiencies in the database). To calculate an unlikely effect level (UEL) for reproductive and developmental toxicity, the NOAEL, LOAEL, or BMD is divided by the composite UF. UELs can be calculated for different exposure durations or adjusted to account for length of exposure. A UEL can be compared with a human exposure estimate to determine whether the exposure is sufficient to cause concern. If the UEL is higher than the human exposure estimate, there will be little or no cause for concern. If the UEL is lower than the human exposure estimate, then there is a possibility that adverse effects may occur. A margin of exposure (MOE; the ratio of the NOAEL or BMD to the anticipated human exposure) also can be calculated. In that case, the higher the ratio, the greater the numerical distance between the human exposure estimate and the highest dose that is without adverse effect in the species tested. The choice of an MOE for regulatory action should be based on the level of confidence in the underlying data and on judgment about other factors that might influence human risk, similar to the judgment made in the selection of appropriate UFs. It would be inappropriate to use a particular MOE as a default action level. Each evaluation should conclude with a summary of the risk posed by a substance. The summary can consist of background information on the chemical and toxicological parameters of the agent; human exposure information; a summary of the male and female reproductive toxicity data and the developmental toxicity data; a list of the quantitative values derived from the data; a description of the default assumptions and UFs used in the process; the data needs to reduce uncertainty; and a reference section.

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Page 7 Insufficient Data Sets In practice, sufficient data are rarely available to inform a judgment about the potential reproductive or developmental toxicity of an exposure to an agent. In such cases, steps can be taken to minimize the risk of an adverse effect. Obviously, the only way to completely eliminate the risk of an adverse effect is to eliminate exposure to the agent, but that is often not feasible. If use of a given agent is unavoidable, the risk can be minimized by assuming that susceptibility to reproductive and developmental toxicity may be greater than susceptibility to any other known toxicity of the agent and applying additional UFs to reflect the lack of data. The risk can also be minimized by substituting an agent that is known not to be associated with substantial reproductive or developmental toxicity or by limiting the potentially absorbed dose by the use of respirators, gloves, and protective clothing. Application of the Evaluative Process To demonstrate how the subcommittee's recommended evaluative process can be applied to specific agents, the subcommittee evaluated two compounds of interest to the Navy: jet propulsion fuel 8 (JP-8) and hydrofluorocarbon (HFC) 134a. These assessments demonstrate that the subcommittee's recommended process can be used to evaluate compounds for which varying amounts of data are available. For example, several reproductive and developmental toxicity studies have been conducted for HFC 134a; however, just one developmental toxicity study has been conducted for JP-8. The subcommittee calculated a UEL based on at least one endpoint for each compound, accounting for uncertainties due to deficiencies in the database. Regardless of the quantity of data available, the subcommittee found that considerable scientific judgment was needed to conduct the evaluations. Although these assessments are examples of how to use the evaluative process, they are not complete–largely because the subcommittee was unable to assess thoroughly the conditions of use that result in human exposure. For example, JP-8 is a complex chemical mixture and although the subcommittee did evaluate toxicity data for the fuel, it did

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Page 8 not evaluate the constituents separately. The Navy should evaluate data on the individual components of JP-8 because the composition of the fuel mixture can vary from batch to batch. The subcommittee recommends that the Navy examine how various environmental conditions (e.g., temperature extremes and humidity) might affect exposure patterns to HFC 134a and JP-8. Sources of Information To assist the Navy in gathering information on chemicals and physical agents, the subcommittee reviewed many of the information sources available on reproductive and developmental toxicology. For most exposures, no single source includes all the information needed for a comprehensive evaluation of reproductive and developmental toxicology, and it is usually necessary to review several different sources of information. The subcommittee reviewed sources of information that are specifically designed to assess reproductive and developmental toxicity and sources of information that are not as specific, but often contain some information. The subcommittee's summaries briefly describe the type of information provided by each source, the quality-control procedures (e.g., peer review), and how useful that source is in identifying exposures that pose a risk of reproductive and developmental toxicity in humans. Sources specific to reproductive and developmental toxicity include detailed evaluations on specific agents (e.g., the California Environmental Protection Agency Hazard Identification Documents on Reproductive and Developmental Toxicity), informational summaries on specific agents that are not as comprehensive as the detailed evaluations (e.g., electronic databases such as REPROTEXT and reference books such as J.L. Schardein's Chemically Induced Birth Defects), bibliographic sources (e.g., the Developmental and Reproductive Toxicology Database (DART) maintained by the National Library of Medicine), and primary data (e.g., the National Toxicology Program reproductive and developmental toxicology study reports). The subcommittee believes that DART, which covers the literature on teratology and some aspects of reproductive and developmental toxicology, is, in particular,

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Page 9 an essential resource to the Navy because it greatly simplifies the process for searching for literature in this area. Sources that are not specifically designed to evaluate reproductive and developmental toxicity, but contain some useful information on such toxicity (e.g., the Agency for Toxic Substances and Disease Registry Toxicological Profiles and the Environmental Protection Agency Integrated Risk Information System) are evaluated as well. Research Recommendations The subcommittee recommends that the Navy conduct research to obtain sufficient data sets on agents in use or considered for use. Specifically, the Navy should conduct the following tasks: Conduct experimental studies in animals to assess the potential for agents to cause reproductive and developmental effects on the male and female reproductive systems and on the embryo, fetus, and child. Fill data gaps that would reduce uncertainties in data sets and, thereby, eliminate or reduce the need for default uncertainty factors. Conduct toxicity studies on chemical mixtures. Design, implement, and conduct epidemiological studies that focus on various reproductive and developmental outcomes. Naval ships provide a unique environment in which to study a well-defined population–one in which many confounders that affect community or occupational studies (e.g., life-style factors thought to affect reproductive health such as alcohol consumption and cigarette smoking) can be documented. Conduct studies to estimate exposures and, in particular, consider exposure scenarios that are unique to the Navy's work environment.

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