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Suggested Citation:"Introduction." National Research Council. 2001. Evaluating Chemical and Other Agent Exposures for Reproductive and Developmental Toxicity. Washington, DC: The National Academies Press. doi: 10.17226/10007.
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1

Introduction

Disorders of human reproduction and development affect a substantial number of individuals of all ages and have long-standing implications for the public in terms of both quality of life issues and economic costs. Although reproductive disorders typically affect younger individuals, they also have implications for long-term health status. For example, men with impaired fecundity (the biological capacity for reproduction) could be at increased risk for testicular cancer (Moller and Skakkebaek 1999) and women with early onset of menopause could be at increased risk of osteoporosis (Bagur and Mautalen 1992; Ohta et al. 1996).

In assessing reproductive and developmental toxicity, a spectrum of endpoints in adult men and women, embryos, fetuses, infants, and children need to be considered. Reproductive outcomes are typically measures related to fertility (the ability to conceive) and fecundity. Adverse reproductive outcomes include abnormal male and female hormone profiles, altered menstrual and ovarian cycles, longer than normal time-to-pregnancy, abnormal semen characteristics, gynecological and urological disorders, spontaneous abortion, ectopic pregnancy (i.e., a pregnancy occurring elsewhere than in the uterus), and premature reproductive senescence. Major manifestations of abnormal development include pre- and postnatal deaths (e.g., spontaneous abortions, still births, and infant deaths), birth defects, altered growth,

Suggested Citation:"Introduction." National Research Council. 2001. Evaluating Chemical and Other Agent Exposures for Reproductive and Developmental Toxicity. Washington, DC: The National Academies Press. doi: 10.17226/10007.
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and functional deficiency (e.g., neurological, respiratory, and immune deficiencies) in the offspring (Wilson 1973).

Known causes of reproductive and developmental disorders include genetic defects; maternal metabolic imbalances; infection; and occupational, therapeutic, and environmental exposures to chemical and physical agents. This report primarily addresses reproductive and developmental defects that might be attributable to chemical and other agent occupational exposures.

The number of individuals affected by reproductive disorders is difficult to assess, and few population-based data are available for either men or women. Noticeably absent are data on fecundity and fertility impairments affecting men and only limited information on male-mediated developmental outcomes exists. Population-based data for impaired female fertility are available for select endpoints from the National Surveys of Family Growth (NSFG), which are conducted periodically and most recently in 1995. Data from the NSFG show that 6.2 million women (10.2%) between the ages of 15 and 44 in the United States had impaired fertility in 1995 (Stephen 1996). This number was estimated to increase to 6.3 million women in 2000 (Stephen and Chondra 1998). Other reproductive disorders in females that impact fecundity include endometriosis and polycystic ovarian syndrome (PCOS). The prevalence of endometriosis in women of reproductive age is reported to be 10% (Houston 1984; Olive and Schwartz 1993), and no population-based prevalence data exist for PCOS.

With respect to developmental outcomes, population-based data are available regarding the prevalence of birth defects. Approximately 2-3% of infants are born with major birth defects (Holmes 1997). The full impact of prenatal testing on the prevalence of birth defects has not been delineated. The prevalence of birth defects increases (approximately 5%) when all defects (i.e., major and minor) are included. However, identifying the prevalence of minor defects is problematic, given differences in clinical assessment, recognition and reporting of defects, and variations across state-birth-defects registries in the recording of minor defects. Other developmental outcomes that need to be considered in assessing developmental toxicity include fetal and infant growth and developmental disabilities during infancy and childhood. Boyle et al. (1994), citing data from the 1988 National

Suggested Citation:"Introduction." National Research Council. 2001. Evaluating Chemical and Other Agent Exposures for Reproductive and Developmental Toxicity. Washington, DC: The National Academies Press. doi: 10.17226/10007.
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Health Interview Survey, found that 17% of children in the United States were reported to have a developmental disability. The prevalence rates for specific developmental disabilities per thousand 10-year-old children were 10.3 for mental retardation, 2.0 for cerebral palsy, 1.0 for hearing impairments, and 0.6 for visual impairments. Another study found that about 4% of U.S. children aged 17 years or younger are reported by their parents to have delays in growth and development, and that 6.5% of children have learning disabilities (Zill and Schoenborn 1990).

The causes of many developmental abnormalities are unknown. As an example, Nelson and Holmes (1989), through a careful evaluation of approximately 70,000 children and their families, were able to account for 57% of birth defects: mutations (28%), multifactorial conditions (23%), uterine factors and twinning (3%), and exposure to chemical and physical agents found in the environment (3%). Thus, the etiology of at least 43% of all birth defects could not be determined. Prevention of developmental defects depends on understanding their causes and is important in reducing the tremendous societal and financial burden.

Economic costs for adverse reproductive and developmental outcomes are noteworthy and expected to grow. Annual costs for infertility treatment in the United States exceed one billion dollars (U.S. Congress 1988). According to the Centers for Disease Control and Prevention (CDC), the cost to society for developmental defects is massive (i.e., the lifetime costs for children born annually with 17 of the most common birth defects and cerebral palsy is over $8 billion (CDC 1995)). However, these abnormalities affect only 22% of children with birth defects, and the cost estimate does not consider costs associated with many other developmental disorders. A recent study estimated the total lifetime costs for persons born in 1996 with mental retardation, autism, or cerebral palsy to be $47 billion, $4.9 billion, and $12 billion, respectively (Honeycutt et al. 1999).

To reduce the number of reproductive and developmental disorders caused by exposure to chemical and physical agents, reproductive and developmental toxicity testing generally is conducted in laboratory animals because at present no other approach is considered predictive of reproductive and developmental effects and, also, data in humans

Suggested Citation:"Introduction." National Research Council. 2001. Evaluating Chemical and Other Agent Exposures for Reproductive and Developmental Toxicity. Washington, DC: The National Academies Press. doi: 10.17226/10007.
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are often not available. Several regulatory agencies and other organizations have developed evaluative guidelines and processes for identifying and assessing reproductive and developmental toxicity (U.S. Environmental Protection Agency (EPA) 1991, 1996a; European Commission (EC) 1992; J.A. Moore et al. 1995a; California Environmental Protection Agency 1991). Each agency or organization has established criteria for evaluating data on the reproductive and developmental effects of exposures to agents, as summarized in Table 1-1. The International Programme on Chemical Safety (IPCS) (1994) identified current differences in risk assessment procedures for reproductive and developmental toxicity among several countries. IPCS also has proposed ways to improve the international harmonization of those procedures.

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 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.

With respect to health surveillance for deployed forces, The National Academies Institute of Medicine recommends the development of strategies for the protection of reproductive health in men and women and fetal development and well-being of offspring (IOM 1999). In sum, assessment of reproductive and developmental toxicity requires consideration of a wide spectrum of possible endpoints in both men and women and their offspring. Appreciation of the subtle and methodological nuances underscoring successful human reproduction need to be appreciated in the systematic evaluation for assessing reproductive and developmental toxicity.

Suggested Citation:"Introduction." National Research Council. 2001. Evaluating Chemical and Other Agent Exposures for Reproductive and Developmental Toxicity. Washington, DC: The National Academies Press. doi: 10.17226/10007.
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TABLE 1-1 Comparison of the Criteria for Evaluating the Data on the Reproductive and Developmental Effects of Agent Exposures

Document (in chronological order)

Intended Purpose

Definitions

Criteria

EPA – Developmental Toxicity Risk Assessment Guidelines (EPA 1991)

Provide guidance on the evaluation of human and animal data on developmental toxicity. Guidelines describe the procedures EPA follows in evaluating potential developmental toxicity by analyzing and organizing data for risk assessments.

Developmental toxicology–The study of adverse effects on the developing organism that may result from exposure prior to conception (either parent), during prenatal development, or postnatally to the time of sexual maturation. Adverse developmental effects may be detected at any point in the lifespan of the organism. The major manifestations of developmental toxicity include death of the developing organism, structural abnormality, altered growth, and functional deficiency.

Sufficient versus insufficient evidence. Sufficient human evidence includes data from epidemiological studies that provide convincing evidence that a causal relationship is or is not supported. A case series with strong supporting evidence may also be used. Sufficient experimental animal evidence-limited human data includes data from experimental animal studies and/or limited human data that provide convincing evidence that the potential for developmental toxicity exists. Insufficient evidence refers to a data set that provides less than the minimum sufficient evidence necessary for assessing the potential for developmental toxicity (e.g., there are no developmental toxicity data available or there are methodological limits of studies).

Suggested Citation:"Introduction." National Research Council. 2001. Evaluating Chemical and Other Agent Exposures for Reproductive and Developmental Toxicity. Washington, DC: The National Academies Press. doi: 10.17226/10007.
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California Proposition 65 (1991)

Protect people of California from reproductive (including developmenal)toxicants to ensure their health and well-being.

Reproductive toxicity includes developmental toxicity, female reproductive toxicity, and male reproductive toxicity. Developmental toxicity includes adverse effects on the products of conception.

The Safe Drinking Water and Toxic Enforcement Act of 1986 (Proposition 65) provides three mechanisms for listing a chemical as a reproductive toxicant: (1) if an authoritative body (e.g., EPA, National Institute for Occupational Safety and Health recognized by the DARTa scientific advisory board identifies a chemical as such, (2) if a state or federal government formally requires labeling as a reproductive toxicant, and (3) a de novo listing based on the opinion of the DART scientific advisory board using a “weight-ofevidence” approach. The total body of evidence is categorized as sufficient, limited, deficient, and null.

European Commission (EC 1992)

Develop a system of classification for substances that might be considered toxic to reproduction.

Reproductive toxicity includes impairment of male and/or female fertility and effects on development of the progeny (developmental toxicity). Developmental toxicity includes nonheritable adverse effects on the further development of the offspring up to attainment of sexual maturity and adult life.

Agents that cause adverse effects on reproduction are classified as those that affect fertility and those that affect offspring. Each classification is subdivided into three categories: (1) agents known to impair fertility or development in humans, (2) agents that should be regarded as though they impair fertility or development in humans, and (3) agents that cause concern for humans because of possible fertility or developmental toxic effects. Evidence required to place an agent in each category is listed. If an agent does not meet criteria of a category, it should not be classified.

Suggested Citation:"Introduction." National Research Council. 2001. Evaluating Chemical and Other Agent Exposures for Reproductive and Developmental Toxicity. Washington, DC: The National Academies Press. doi: 10.17226/10007.
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International Programme on Chemical Safety (IPCS 1994)

Harmonization of risk assessment for reproductive and developmental toxicity by establishing a glossary for terminology, identifying minimum database requirements, identifying areas of difference in risk assessment procedures and approaches for reconciliation; and consider harmonized formats for data reporting.

Merged EC and EPA definitions. Reproductive toxicity includes adverse effects on sexual function and fertility in males and females as well as developmental toxicity. The toxicity might be expressed as alterations to the female or male reproductive organs, the related endocrine system, or pregnancy outcomes. Developmental toxicity in its widest sense includes any effect interfering with normal development before or after birth. The occurrence of adverse effects on the developing organism might result from exposure before conception (either parent), during prenatal development, or postnatally to the time of sexual maturation. Adverse developmental effects may be detected at any point in the lifespan of the organism.

Establishes criteria for low to high concern using a minimum data set. A standardized format for the summary would comment on the sufficiency and quality of data to draw conclusions.

Suggested Citation:"Introduction." National Research Council. 2001. Evaluating Chemical and Other Agent Exposures for Reproductive and Developmental Toxicity. Washington, DC: The National Academies Press. doi: 10.17226/10007.
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Evaluative Process (J.A. Moore et al. 1995a)

To develop an evaluative process for assessing reproductive and developmental toxicity.

Developmental toxicity consists of adverse effects on the developing organism that might result from exposure before conception (either parent), exposure during prenatal development, or exposure during postnatal development from birth to sexual maturation. Reproductive toxicity can involve alterations in the reproductive organs or in the related endocrine systems resulting in a variety of effects among men and women.

Sufficient versus insufficient evidence. Three generic criteria are applied to describe data that are insufficient: (1) there are no data, (2) deficiency in study design or insufficient detail available to allow analysis, and (3) data are insufficient to reach a definitive conclusion. The evaluative process requires a weight of evidence approach to determine (in)sufficiency of data as summarized in a narrative document. The evaluation process determines whether the collective toxicity data are (in)sufficient to judge that there is an adverse effect under specified exposure conditions or whether the data are (in)sufficient to conclude the absence of adverse effects under specified exposure condition.

EPA – Reproductive Toxicity Risk Assessment Guidelines (EPA 1996a)

Provide guidance for assessing the effects of environmental agents that might adversely affect human health, including the reproductive system.

Reproductive toxicity is the occurrence of biologically adverse effects on the reproductive systems of females or males that might result from exposure to harmful substances in the environment. The toxicity might be manifested in various ways. Developmental toxicity is the occurrence of adverse effects on the developing organisms that might result from exposure prior to conception (either parent), during prenatal development, or postnatally to the time of sexual maturation. These adverse effects can be manifested in various ways over the lifespan of the organism.

Sufficient versus insufficient evidence. Sufficient evidence includes data that collectively provide enough information to judge whether or not a reproductive hazard exists within the context of effect as well as dose, duration, timing, and route of exposure. Both human and animal evidence may be included. Insufficient evidence refers to data less than the minimum for sufficient evidence of reproductive toxicity, largely reflecting methodological limits of reported studies or the absence of studies.

Suggested Citation:"Introduction." National Research Council. 2001. Evaluating Chemical and Other Agent Exposures for Reproductive and Developmental Toxicity. Washington, DC: The National Academies Press. doi: 10.17226/10007.
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a DART refers to reproductive and developmental toxicity.

Suggested Citation:"Introduction." National Research Council. 2001. Evaluating Chemical and Other Agent Exposures for Reproductive and Developmental Toxicity. Washington, DC: The National Academies Press. doi: 10.17226/10007.
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SUBCOMMITTEE'S TASK

Every year, the U.S. Navy screens hundreds of chemical substances for potential toxicity to determine whether they can be used safely in the workplace. Although the Navy reviews available data on the reproductive and developmental toxicity potential of those agents, its health hazard evaluation process is not currently designed to emphasize assessment of reproductive and developmental effects.

Because the Navy wishes to protect its male and female military and civilian personnel from reproductive and developmental hazards, it seeks to incorporate a formalized, state-of-the-art process for identifying hazards in its current health hazard evaluation process. Therefore, the Navy requested that the National Research Council (NRC) recommend an approach that can be used to evaluate agents for 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 charged with 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 demonstrations 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.

For the purposes of this study, the primary focus is on avoiding occupational exposures to agents that potentially cause reproductive and developmental toxicity. Therefore, this report recommends a process that focuses on evaluating exposures to adult male and female military and civilian personnel and on predicting the effects of those exposures on those adults and their children. It does not specifically address direct exposures to children of military and civilian personnel, including children living on military bases.

Suggested Citation:"Introduction." National Research Council. 2001. Evaluating Chemical and Other Agent Exposures for Reproductive and Developmental Toxicity. Washington, DC: The National Academies Press. doi: 10.17226/10007.
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Agents that have the potential to cause reproductive and developmental toxicity should be substituted with less hazardous materials or surveillance should be increased in an effort to control exposures. The Subcommittee on Reproductive and Developmental Toxicology believes it is inadvisable to designate agents as toxic or nontoxic; rather, the agent and the risk of adverse reproductive or developmental effects should be considered only in the context of exposure. Assessment of exposure accounts for both the agent itself and for the conditions of exposure, including the amount, route, timing, duration, and pattern of exposure.

The subcommittee recognizes the need for the Navy 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. In this report, the subcommittee describes a process by which an exposure can be estimated that is unlikely to be associated with reproductive and developmental toxicity. If the Navy workplace scenario is anticipated to result in human exposures appreciably 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 nontoxic level, the use of the agent in question can be regarded as unacceptable, and alternative agents can be evaluated or exposure control measures (e.g., use of masks and protective clothing) can be used.

Data on the reproductive and developmental effects of the agents of interest often are sparse. When they are available, the quality of the studies from which the information is obtained can be highly variable. The quality and quantity of the data are related to the level of confidence in assessing concern about exposure to an agent. When adequate data sets are available, there is a high level of confidence in determining a low (if no significant toxicity is expected at anticipated exposures) or high (if toxicity is expected at anticipated exposures) degree of concern. When the data set is inadequate, the level of confidence in assessing the degree of concern in lessened.

The process described by the subcommittee requires the exercise of considerable judgment, brought to bear in assessing the adequacy of data for estimating potential reproductive and developmental toxicity of agents under specific conditions of exposure. Once there has been a determination of the exposure at which adverse effects are unlikely,

Suggested Citation:"Introduction." National Research Council. 2001. Evaluating Chemical and Other Agent Exposures for Reproductive and Developmental Toxicity. Washington, DC: The National Academies Press. doi: 10.17226/10007.
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Page 22

judgment is required in the evaluation of other characteristics of the agent or exposure conditions that might make it advisable to alter the exposure estimate for a given workplace scenario. Therefore, the subcommittee believes the process should be implemented by a team of scientists who have training and experience in assessing reproductive and developmental toxicity.

Reproductive and developmental toxicity often is equated with pregnancy effects (maternal and developmental effects) of exposures of interest. The subcommittee believes that pregnancy effects of exposures are important, but attention also should be directed to the potential for reproductive toxicity in males and nonpregnant females, and to the potential for paternally mediated adverse effects of exposures. Although examples of the latter toxicity in humans are not readily available, several agents have been shown to have such effects in experimental animals; therefore, it is important to take seriously any data that suggest a paternally mediated effect. Reproductive systems of elderly adults also could be susceptible to adverse effects. In such cases, the concern is not with procreative competence but with biological function maintained by the gonads (e.g., hormone production) and with reproductive senescence. Any data that suggest such an effect should be considered. The subcommittee recommends that an assessment not be considered complete unless it includes consideration of potential adverse reproductive and developmental consequences of exposure of both the male and the female. The absence or inadequacy of data on one or more of the components of reproductive toxicity (i.e., male reproductive effects, female reproductive effects, or developmental effects) does not equate with lack of effect.

ORGANIZATION OF THE REPORT

In addition to this Introduction, this report is organized into four chapters. Chapter 2 and Chapter 3 outline the process the subcommittee recommends for evaluating the potential reproductive and developmental effects of exposures to agents. Chapter 2 outlines the principles for evaluating reproductive and developmental toxicity data. The product of that evaluative process is typically an exposure level– called the unlikely effect level (UEL)–that is assumed not to pose

Suggested Citation:"Introduction." National Research Council. 2001. Evaluating Chemical and Other Agent Exposures for Reproductive and Developmental Toxicity. Washington, DC: The National Academies Press. doi: 10.17226/10007.
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appreciable risk of reproductive and developmental effects, adjusted for the exposure scenario of concern. The UEL is similar to the EPA's acute and chronic Reference Doses (RfD) and the U.S. Food and Drug Administration's Acceptable Daily Intake (ADI) except that it is specific for reproductive and developmental effects and is derived specifically for the exposure duration of concern in humans. Chapter 3 discusses how the UEL is derived in the evaluative process and how it can be compared with an anticipated human exposure such as found in the workplace. Chapter 4 sets forth a strategy for evaluating exposures for which there are few or no data on reproductive or developmental toxicity. The subcommittee's recommendations are presented in Chapter 5. This report also contains four appendixes: Appendix A contains examples of the application of the proposed evaluative process to two specific chemical agents, Appendix B describes and evaluates various sources of information on reproductive and developmental toxicity, Appendix C describes and evaluates human study designs, and Appendix D describes experimental animal study designs and discusses qualities and limitations for each type of study.

Suggested Citation:"Introduction." National Research Council. 2001. Evaluating Chemical and Other Agent Exposures for Reproductive and Developmental Toxicity. Washington, DC: The National Academies Press. doi: 10.17226/10007.
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Suggested Citation:"Introduction." National Research Council. 2001. Evaluating Chemical and Other Agent Exposures for Reproductive and Developmental Toxicity. Washington, DC: The National Academies Press. doi: 10.17226/10007.
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Suggested Citation:"Introduction." National Research Council. 2001. Evaluating Chemical and Other Agent Exposures for Reproductive and Developmental Toxicity. Washington, DC: The National Academies Press. doi: 10.17226/10007.
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Suggested Citation:"Introduction." National Research Council. 2001. Evaluating Chemical and Other Agent Exposures for Reproductive and Developmental Toxicity. Washington, DC: The National Academies Press. doi: 10.17226/10007.
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Suggested Citation:"Introduction." National Research Council. 2001. Evaluating Chemical and Other Agent Exposures for Reproductive and Developmental Toxicity. Washington, DC: The National Academies Press. doi: 10.17226/10007.
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Suggested Citation:"Introduction." National Research Council. 2001. Evaluating Chemical and Other Agent Exposures for Reproductive and Developmental Toxicity. Washington, DC: The National Academies Press. doi: 10.17226/10007.
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Suggested Citation:"Introduction." National Research Council. 2001. Evaluating Chemical and Other Agent Exposures for Reproductive and Developmental Toxicity. Washington, DC: The National Academies Press. doi: 10.17226/10007.
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Suggested Citation:"Introduction." National Research Council. 2001. Evaluating Chemical and Other Agent Exposures for Reproductive and Developmental Toxicity. Washington, DC: The National Academies Press. doi: 10.17226/10007.
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Suggested Citation:"Introduction." National Research Council. 2001. Evaluating Chemical and Other Agent Exposures for Reproductive and Developmental Toxicity. Washington, DC: The National Academies Press. doi: 10.17226/10007.
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Suggested Citation:"Introduction." National Research Council. 2001. Evaluating Chemical and Other Agent Exposures for Reproductive and Developmental Toxicity. Washington, DC: The National Academies Press. doi: 10.17226/10007.
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Suggested Citation:"Introduction." National Research Council. 2001. Evaluating Chemical and Other Agent Exposures for Reproductive and Developmental Toxicity. Washington, DC: The National Academies Press. doi: 10.17226/10007.
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Suggested Citation:"Introduction." National Research Council. 2001. Evaluating Chemical and Other Agent Exposures for Reproductive and Developmental Toxicity. Washington, DC: The National Academies Press. doi: 10.17226/10007.
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Suggested Citation:"Introduction." National Research Council. 2001. Evaluating Chemical and Other Agent Exposures for Reproductive and Developmental Toxicity. Washington, DC: The National Academies Press. doi: 10.17226/10007.
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Next: The Evaluative Process: Part I. Assessing the Available Data »
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The United States Navy has been concerned for some time with protecting its military and civilian personnel from reproductive and developmental hazards in the workplace. As part of its efforts to reduce or eliminate exposure of Naval personnel and their families to reproductive and developmental toxicants, the Navy requested that the National Research Council (NRC) recommend an approach that can be used to evaluate chemicals and physical agents for their potential to cause reproductive and developmental toxicity. The NRC assigned this project to the Committee on Toxicology, which convened the Subcommittee on Reproductive and Developmental Toxicology, to prepare this report. In this report, the subcommittee recommends an approach for evaluating agents for potential reproductive and developmental toxicity and demonstrates how that approach can be used by the Navy.

This report has been reviewed in draft form by individuals chosen for their diverse perspectives and technical expertise, in accordance with procedures approved by the NRC's Report Review Committee. The purpose of this independent review is to provide candid and critical comments that will assist the institution in making its published report as sound as possible and to ensure that the report meets institutional standards for objectivity, evidence, and responsiveness to the study charge. The review comments and draft manuscript remain confidential to protect the integrity of the deliberative process. We wish to thank the following individuals for their review of this report: James Chen (National Center for Toxicological Research), George Daston (Procter and Gamble Company), Jerry Heindel (National Institute of Environmental Health Sciences), Grace Lemasters (University of Cincinnati), and John Young (National Center for Toxicological Research).

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