Chapter 2, Chapter 3, and Chapter 4 of this report describe the process recommended by the Subcommittee on Reproductive and Developmental Toxicology for evaluating exposures to agents for reproductive and developmental toxicity. Appendix A illustrates how that process can be used. This chapter contains a discussion of several general recommendations and areas of research that the subcommittee believes would improve the Navy's ability to evaluate exposures to agents.
Agents should not be classified simply as toxic or nontoxic to reproduction and development; rather, potential risks should always be considered in the context of exposure.
The risk of adverse reproductive or developmental effects from exposure to a given substance should be considered only in the context of the exposure situation. In this way, both the agent itself and the conditions of exposure, including the dose, route, timing, and duration of exposure are considered, rather than “labeling” an agent either as “toxic” or as “safe.”
The subcommittee acknowledges that the Navy might need to use a screening process in which decisions are made in a dichotomous
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Page 86 5 Recommendations Chapter 2, Chapter 3, and Chapter 4 of this report describe the process recommended by the Subcommittee on Reproductive and Developmental Toxicology for evaluating exposures to agents for reproductive and developmental toxicity. Appendix A illustrates how that process can be used. This chapter contains a discussion of several general recommendations and areas of research that the subcommittee believes would improve the Navy's ability to evaluate exposures to agents. GENERAL RECOMMENDATIONS Agents should not be classified simply as toxic or nontoxic to reproduction and development; rather, potential risks should always be considered in the context of exposure. The risk of adverse reproductive or developmental effects from exposure to a given substance should be considered only in the context of the exposure situation. In this way, both the agent itself and the conditions of exposure, including the dose, route, timing, and duration of exposure are considered, rather than “labeling” an agent either as “toxic” or as “safe.” The subcommittee acknowledges that the Navy might need to use a screening process in which decisions are made in a dichotomous
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Page 87 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. The evaluative process describes an approach by which an exposure level that is unlikely to be associated with reproductive and developmental toxicity (the unlikely effect level; UEL) can be estimated. If the workplace scenario is anticipated to result in human exposures sufficiently lower than that estimate, then for policy decisions, the exposure can be regarded as acceptable. If the anticipated human exposure is higher than the estimated UEL, the use of the agent in question can be regarded as unacceptable, and alternative agents can be evaluated or exposure control measures can be put into place. The evaluative process should be implemented by a team of scientists with training and experience in assessing reproductive and developmental toxicity. The process described by the subcommittee requires expertise in the intricacies and relationships of several integrated processes involved in reproduction and development and the exercise of considerable judgment based on the body of scientific knowledge in these areas. That judgment is brought to bear in interpreting data and making decisions concerning the adequacy of available data sets for estimating the potential reproductive and developmental toxicity of agents under specific conditions of exposure. In addition, once there has been a determination of the exposure at which adverse effects are unlikely, judgment is required in the evaluation of other characteristics of the agent or exposure conditions that might make it advisable to alter the estimate for a given workplace scenario. In cases in which the data set is incomplete or insufficient, evaluators should assume that susceptibility to reproductive or developmental toxicity may be greater than susceptibility to any known toxicity of the agent, and apply additional uncertainty factors to reflect the degree of uncertainty attributable to missing data. When the reproductive and developmental risks of a particular exposure cannot be fully characterized, a conservative approach is to assume that such risks exist with exposure conditions below those that produce toxicity for the most sensitive system known for the agent.
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Page 88 The most sensitive system is the kind of toxicity produced by exposure to the agent at the lowest effective dose in any relevant species studied. The confidence with which one can apply this assumption to a particular exposure that has not been adequately studied depends on the amount of relevant information available about the exposure in general. The less that is known, the greater the uncertainty, and the greater the degree of concern. When the database for reproductive and developmental toxicity is inadequate, the total uncertainty factor applied should result in an exposure limit that is lower than that based on known toxicity of other kinds. An exposure to an agent that is known not to be associated with substantial reproductive or developmental toxicity should be substituted for an exposure to an agent associated with unknown risks. The decision to substitute one agent for another or to eliminate a particular agent altogether always involves many factors, including other kinds of toxicity, ease and safety of storage, availability, and cost. Although reproductive and developmental toxicity can never be the only issue considered in such decisions, it must never be ignored. When use of an agent with demonstrated toxicity is necessary, minimize the potential risk by limiting the potentially absorbed dose. Reproductive and developmental toxicity is less likely to be associated with exposures that minimize absorption of the agent. Exposures associated with an unknown risk of reproductive and developmental toxicity should be as brief and as infrequent as possible. The amount of an agent used should be minimized, and reasonable safety procedures and engineering safeguards should be used to limit the exposure. The Navy should consider using the National Library of Medicine's Developmental and Reproductive Toxicology (DART) database as the primary source of bibliographic information in this area. DART is a bibliographic database that covers the literature on teratology and other aspects of reproductive and developmental toxicology. DART is an essential resource to the Navy for gathering information on the potential reproductive and developmental effects of agents because it greatly simplifies the process for searching for literature in this area.
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Page 89 In addition to DART, there are a number of additional sources of information that the Navy should consider using to evaluate the reproductive and developmental toxicity potential of agents. These sources are described in Appendix B. RESEARCH RECOMMENDATIONS The Navy should conduct or commission studies that are necessary to obtain sufficient data sets for the agents it is considering for use. As noted in Chapter 1, for a data set to be considered sufficient, it should include consideration of potential adverse reproductive and developmental effects of male and female exposure. The absence or inadequacy of data on one or more of the components of reproductive toxicity (male reproductive effects, female reproductive effects, developmental effects) does not equate with lack of effect. Data on the reproductive and developmental toxicity of exposures to agents are often sparse and, when data are available, there can be variability in the quality of the studies from which they are obtained. To account for such incomplete or inadequate data sets, an uncertainty factor is applied to the no-observed-adverse-effect level, lowest-observed-adverse-effect level, or benchmark dose. It is possible that such uncertainty could lead to the calculation of an exposure limit that is more conservative than necessary and, based on those limits, the Navy could decide to curtail use of specific substances or institute costly exposure control measures. Uncertainty could be reduced by filling in data gaps and improving exposure estimates so that the potential toxicity of agents that the Navy is considering for use is better understood. Developing a sufficient data set on a particular exposure to an agent could provide a cost savings to the Navy and reduce the risk of reproductive and developmental toxicity. Because there are exposure scenarios that are unique to the Navy's work environment, the subcommittee also recommends that the Navy consider developing a research program to meet needs that are not being met by civilian research (e.g., the study of reproductive and developmental toxicity in the context of naval operations). Such a program would allow the Navy to anticipate and rank the agents it would like to use and to study the reproductive and developmental toxicity of those agents before its personnel are exposed.
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Page 90 The Navy should monitor Navy personnel for reproductive and developmental outcomes. The Navy is well equipped to design, implement, and conduct epidemiological studies that focus on various reproductive and developmental outcomes. Such studies should include male and female military and civilian personnel as well as other populations at risk (e.g., partners of naval personnel and residents of communities affected by naval operations). Naval ships provide a unique opportunity to study a well-defined population, and one in which many confounders that affect community or occupational studies (e.g., lifestyle factors thought to affect reproductive health such as alcohol consumption and cigarette smoking) can be documented. As such, the Navy is well suited to conduct surveillance, record linkage, and etiological studies. Specifically, the following activities could be conducted: A complete and up-to-date reproductive history should be obtained and available for all naval personnel (men and women; active duty and reservists). Such a history should be updated annually or after a reproductive outcome. This would provide important baseline information and permit study of maternally and paternally mediated effects. The reproductive history should address sexual activity and inactivity, sexual libido, sexual dysfunction, semen analysis, menstruation history, pregnancy intentions, time-to-pregnancy (conception delays, fecundability, infertility), and pregnancy outcomes (e.g., ectopic pregnancy, spontaneous loss, fetal demise, birth size, secondary sex ratios, birth defects, mental retardation, developmental disabilities). Recording this information is in keeping with the definition for reproductive health and the need to address all health aspects of individuals. Surveillance of reproductive health could be obtained via record linkages with live birth or fetal death registeries or via the establishment of outcome-specific registries (such as a congenital malformation registry for the navy). Baseline prevalence figures for various outcomes are urgently needed for military populations; the U.S. general population might not be an appropriate reference group. Hypothesis-driven etiological studies can be designed on an ad hoc basis in response to concerns or based on associations
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Page 91 observed in linkage or surveillance studies. The studies should be designed to address questions of utmost concern, and they should be grounded within the epidemiological method or framework for study. The Navy should conduct toxicity studies on chemical mixtures. In many cases, exposure is not to an individual chemical, but to mixtures of chemicals. Risks to human health from multichemical exposures often are not well understood. Because multichemical exposures are found in the Navy workplace, the Navy should conduct research on the toxicity of these mixtures. Research also should be conducted to illuminate exposure scenarios associated with chemical mixtures.