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Page 168 Appendix B Ascertaining Information on the Reproductive and Developmental Toxicity of Agent Exposures Information on potential reproductive and developmental toxicity of exposures to chemical and physical agents can be obtained from a variety of resources that vary greatly in their approach, coverage, and manner of presentation. Some resources include only bibliographic information; others provide critical evaluations of the available data sets. Some resources emphasize investigations in humans; others focus on experimental animal studies. Some resources take a quantitative approach; others provide only qualitative descriptions of available data. Some resources include only information published in the open literature; others emphasize studies, often unpublished, that have been submitted for regulatory review. This appendix describes many of the information resources available on reproductive and developmental toxicology that should be useful to the Navy for conducting evaluations. These resources are listed in Box B-1 and Box B-2. The amount of relevant information varies greatly from resource to resource and from agent to agent and for different specific reproductive and developmental outcomes. The following section provides descriptions of several documents and databases that are designed specifically to evaluate reproductive and developmental toxicity data. Generally, except for the bibliographic databases and primary data sources, an expert or committee of experts in reproductive and developmental toxicology has either written or reviewed each document or database. The final section describes additional sources of information that might be useful for assessing agent exposures for potential reproductive and developmental toxicity. Quality control, including the extent of peer review, is noted for each source, as well as the subcommittee's evaluation of the usefulness of the source in identifying exposures that pose a substantial risk of reproductive or developmental toxicity in humans.
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Page 169 Box B-1 Sources of Information Specific to Reproductive and Developmental Toxicity Detailed Evaluations Informational Summaries Bibliographic Resources Primary Data California Environmental Protection Agency Hazard Identification Documents for Reproductive and Developmental Toxicity Evaluative Process (Moore et al. 1995 a,b; 1997) National Institute of Environmental Health Sciences Center for the Evaluation of Risks to Human Reproduction Documents Reproductive Hazards of Industrial Chemicals: An Evaluation of Animal and Human Data REPROTEXT REPROTOX Chemically Induced Birth Defects Shepard's Catalog of Teratogenic Agents Teratogen Information System Developmental and Reproductive Toxicology (DART) and Environmental Teratology Information Center (ETIC) Database National Toxicology Program Teratology Studies National Toxicology Program Short-Term Developmental and Reproductive Toxicity Studies National Toxicology Program Continuous Breeding Studies
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Page 170 Box B-2 Additional Sources That May Include Information on Reproductive and Developmental Toxicity Detailed Evaluations Informational Summary Bibliographic Resource Primary Data Agency for Toxic Substances and Disease Registry Toxicological Profiles National Institute for Occupational Safety and Health Criteria Documents International Agency for Research on Cancer Monographs on the Evaluation of Carcinogenic Risks to Humans International Programme on Chemical Safety Environmental Health Criteria Documents Environmental Protection Agency Integrated Risk Information System Environmental Protection Agency National Center for Environmental Assessment Documents Chemical Hazards in the Workplace National Institute for Occupational Safety and Health Registry of Toxic Effects of Chemical Substances MEDLINE TOXLINE PUBMED National Toxicology Program Toxicology Report Series Organization for Economic Cooperation and Developmental Screening Information Data Set Profiles
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Page 171 No single source of information exists that includes everything needed for a comprehensive evaluation of the reproductive and developmental toxicity of exposures to most agents. It is usually necessary to review several secondary information sources as well as a large amount of primary data to obtain an adequate overall assessment. Even such a thorough review of available information is inadequate in most cases because all of the necessary studies to fully delineate the reproductive and developmental toxicity of an agent have not been conducted. The most complete screening data sets are for pesticides, pharmaceutical agents, food and color additives, and some environmental chemicals (e.g., lead, methylmercury, and polychlorinated biphenyls). The proprietary nature of the data for the first three cases may require the Navy to request information from the appropriate regulatory agencies. SOURCES OF INFORMATION SPECIFIC TO REPRODUCTIVE AND DEVELOPMENTAL TOXICITY Detailed Evaluations California Environmental Protection Agency Hazard Identification Documents on Reproductive and Developmental Toxicity Description The Safe Drinking Water and Toxic Enforcement Act of 1986 (Proposition 65, California Health and Safety Code 25249.5 et seq.) requires that the governor cause to be published a list of those chemicals
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Page 172 “known to the state” to cause cancer or reproductive (including developmental) toxicity. Substances can be added to that list if they have been classified as reproductive toxicants by an authoritative body (e.g., the World Health Organization, WHO), by the state or federal government, or by a state expert panel, including the California Office of Environmental Health Hazard Assessment Science Advisory Board Developmental and Reproductive Toxicant (DART) Identification Committee. That DART Identification Committee evaluates selected agents for reproductive toxicity using a set of criteria adapted from the U.S. Environmental Protection Agency (EPA). The products of the evaluations are Hazard Identification Documents that can be found on the Internet at < http://www.oehha.org/prop65.html>. Thus far, only a few agents (methyl-tert-butyl ether, benzene, inorganic arsenic, and cadium) have been evaluated by the DART Identification Committee. Reproductive and Developmental Toxicity The DART Identification Committee evaluated each selected agent for male and female reproductive toxicity and developmental toxicity in humans and experimental animals. It also reviews other types of available toxicity data (e.g., acute and carcinogenicity) and pharmaco-kinetic data. Quality Control The documents are initially prepared by scientists with expertise in reproductive toxicity from the California EPA Reproductive and Cancer Hazard Assessment Section. They are then reviewed by the DART Identification Committee and open to public comment. The final documents are used to determine whether an agent should be placed on the state's list. Usefulness in Identifying Exposures that Pose a Substantial Risk of Reproductive or Developmental Toxicity in Humans The DART Identification Committee's evaluation is comprehensive in assessing reproductive toxicity. Although currently there are only a few documents available, they can be useful for providing a comprehensive review and evaluation for each agent.
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Page 173 Evaluative Process (Mooreet al. 1995a,b; 1997) Description An expert committee has produced documents that assess lithium and boric acid for reproductive and developmental toxicity (J.A. Moore et al. 1995b, 1997). That committee used the evaluative process developed by Moore et al. (1995a); Chapter 2 and Chapter 3 of this report are based on that process. The reviews of lithium and boron follow a systematic approach for assessing agents for reproductive and developmental toxicity: (1) reviewing the conditions of exposure; (2) reviewing and summarizing the agent's toxicological and biological properties; (3) reviewing and summarizing human and experimental animal studies on reproductive and developmental toxicity; (4) integrating the reproductive and developmental toxicity data with information derived from the review of toxicological and biological properties, including pharmacokinetic data and exposure information; and (5) determining the certainty of the judgments about an agent's potential reproductive and developmental risk to humans. The expert committee's conclusions are stated in a summary. Reproductive and Developmental Toxicity The evaluative process was used to assess lithium and boric acid for their potential to cause reproductive and developmental toxicity (J.A. Moore et al. 1995b, 1997). The final product is a summary statement that integrates reproductive and developmental data and exposure data. The summary also makes a statement about the certainty of judgment about an agent's reproductive and developmental risk, and critical data needed for reducing uncertainty and improving the risk assessment. Quality Control The evaluative process was conducted by a team of scientists with expertise in a variety of disciplines related to reproductive and developmental toxicology.
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Page 174 Usefulness in Identifying Exposures That Pose a Substantial Risk of Reproductive and Developmental Toxicity in Humans The evaluative process provides a comprehensive assessment of human reproductive and developmental toxicity of agent exposures. National Institute of Environmental Health Sciences Center for the Evaluation of Risks to Human Reproduction Description Only recently established, the National Institute of Environmental Health Sciences (NIEHS) Center for the Evaluation of Risks to Human Reproduction will provide comprehensive, unbiased, and scientifically sound assessments of reproductive health hazards (including developmental health hazards) associated with human exposures to environmental agents. The assessment process to be used will be based on the evaluative process developed by J.A. Moore et al. (1995a). The center's product will be reports published in the peer-reviewed literature. The reports will be produced by expert panels in reproductive and developmental toxicology and reviewed by a committee composed of scientists from the center, NIEHS, and other institutions. Agents to be assessed are selected by an oversight committee composed of NIEHS scientists and representatives of federal and state agencies, public interest groups, and cofunders. Several phthalates have been reviewed and the assessments will be released to the public via the Center's website ( http://cerhr.niehs.nih.gov). No other reports are available yet. Reproductive and Developmental Toxicity Reports produced by the center will assess environmental agent exposures for their potential to cause reproductive and developmental toxicity in humans. All relevant data are evaluated. Quality Control Center reports are prepared by an expert panel that comprehen-
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Page 175 sively evaluates the relevant data, reviewed by a committee of scientists from NIEHS, the center, and other institutions, and approved by an oversight committee. Usefulness in Identifying Exposures That Pose a Substantial Risk of Reproductive or Developmental Toxicity in Humans The center reports will be comprehensive assessments of potential reproductive and developmental toxicity in humans for selected environmental agent exposures. Informational Summaries Reproductive Hazards of Industrial Chemicals: An Evaluation of Animal and Human Data Description Reproductive Hazards of Industrial Chemicals: An Evaluation of Animal and Human Data (Barlow and Sullivan 1982) is a classic reference book that provides detailed reviews of the reproductive and developmental toxicity of about 50 common occupational exposures. Each substance is treated in a separate chapter introduced by a description of the chemical, its general pharmacology, and its overall toxicity. Extensive citations to literature published before 1982 are included. Reproductive and Developmental Toxicity Reproductive Hazards of Industrial Chemicals provides detailed discussions of the full range of reproductive toxicity. Data from animal studies and investigations in humans are considered separately. Overall interpretations are provided, whenever possible, for reproductive endpoints in the context of general maternal toxicity. Quality Control S.M. Barlow and F.M. Sullivan are internationally-recognized
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Page 176 authorities in reproductive and developmental toxicology. There is no formal external peer review of the book's contents. Usefulness in Identifying Exposures That Pose a Substantial Risk of Reproductive or Developmental Toxicity in Humans Reproductive Hazards of Industrial Chemicals is a valuable guide to information available prior to 1982 on the reproductive toxicity of the chemicals included. Unfortunately, the book is out of date and has not been revised. REPROTEXT Description REPROTEXT is an electronic knowledge base developed by B. Dabney. It includes reviews of more than 850 commonly encountered industrial agents. Most are chemicals, but some physical agents are also covered. Subscriptions to REPROTEXT are available on CD-ROM from MICROMEDEX, Inc., as a component of its REPRORISK system. Reproductive and Developmental Toxicity REPROTEXT summaries provide information on the physical characteristics, use, and monitoring of agents as well as detailed discussions of the full range of general and reproductive toxicity. An extensive list of bibliographic citations is provided, reflecting the breadth of the material included. A grading system gives overall ratings of the general toxicity and reproductive hazard associated with each agent. Quality Control REPROTEXT summaries are written by an expert reproductive and developmental toxicologist. There is no formal external peer review of the summaries.
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Page 177 Usefulness in Identifying Exposures That Pose a Substantial Risk of Reproductive or Developmental Toxicity in Humans REPROTEXT summaries provide a comprehensive overview of the information available on the reproductive and developmental toxicity of many important occupational exposures. The data are interpreted in the context of human reproductive hazards. REPROTOX Description The REPROTOX knowledge base was developed by A. R. Scialli and associates at the Reproductive Toxicology Center, Bethesda, MD. REPROTOX is available on CD-ROM as part of the REPRORISK package distributed by MICROMEDEX, Inc. Subscriptions in other electronic formats are available through the Reproductive Toxicology Center. The knowledge base also has been published as a book, Reproductive Effects of Chemical, Physical and Biologic Agents (Scialli et al. 1995), but the electronic versions are more current. Reproductive and Developmental Toxicity REPROTOX has information on the reproductive and developmental toxicology of some 3000 chemical and physical agents. Each entry summarizes available data on a variety of reproductive outcomes in males and females. Each study is briefly described, and bibliographic citations are provided. The emphasis is on investigations in humans, but experimental animal data also are summarized. The primary intended audience is obstetricians and other physicians. Quality Control REPROTOX is written by clinical teratologists who have recognized expertise in the interpretation of reproductive and developmental toxicology studies in the context of actual human exposures. The summaries are revised, if necessary, in response to concerns raised by
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Page 178 users and are frequently reviewed to ensure that the information included is up to date. There is no formal external peer review of REPROTOX summaries. Usefulness in Identifying Exposures That Pose a Substantial Risk of Reproductive or Developmental Toxicity in Humans REPROTOX is useful clinically. It provides succinct, authoritative overviews of the reproductive and developmental toxicity of a large number of chemical exposures, including many important occupational exposures. The system is designed for use by health professionals who are familiar with the general principles of risk assessment and is intended to assist in the counseling of individual patients. Chemically Induced Birth Defects Description Chemically-Induced Birth Defects (Schardein 2000) describes mammalian teratology studies on more than 3300 chemicals, including those found in occupational exposures and in drugs. Each chapter deals with a group of related agents, such as industrial solvents. Literature citations are extensive. Reproductive and Developmental Toxicity Chemically-Induced Birth Defects contains information on human and other conventional mammalian teratology studies. Other kinds of reproductive toxicology are not usually covered. Full discussions are provided on chemicals for which substantial data exist, but most chemicals, for which information is much more limited, are listed in tables that summarize studies by species as “+” (developmental abnormalities observed), “−” (developmental abnormalities not observed), and “±” (equivocal results). Quality Control Chemically-Induced Birth Defects is written by an internationally-
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Page 187 profile has a public health statement that describes toxicological properties in nontechnical terms. The profile also provides information about the amounts of significant human exposure and, where known, significant health effects for acute, subchronic, and chronic exposures. The adequacy of information also is described. Responsibility for the content and views expressed in a profile resides with ATSDR. A list of substances covered can be found on the Internet at <http://www.atsdr.cdc..gov/toxpro2.html>. The profiles are used by federal, state and local health officials and health professionals, interested private-sector organizations and groups; and members of the public. The agency's intent is to revise and republish profiles as newer data become available. Reproductive and Developmental Toxicity Pertinent information on reproductive and developmental effects is presented in a narrative summary and in tabular form for species, route, dose, no-observed-adverse-effect level (NOAEL), and lowest-observed-adverse-effect level (LOAEL). Quality Control Draft profiles are usually prepared by contractors with demonstrated technical expertise. The drafts are reviewed by several groups within ATSDR, published for public comment, and peer reviewed by several experts. ATSDR evaluates peer reviewers' comments, and comments not incorporated in the profile are made part of the administrative record with a brief explanation of the rationale for their exclusion. Usefulness in Identifying Exposures That Pose a Substantial Risk of Reproductive or Developmental Toxicity in Humans Information presented in the profiles can be useful for identifying and summarizing studies relevant to reproductive and developmental toxicity. Significant exposures to substances are reported.
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Page 188 National Institute for Occupational Safety and Health Criteria Documents Description The National Institute for Occupational Safety and Health (NIOSH) develops criteria documents to describe the scientific basis for occupational safety and health standards. They contain critical reviews of the available literature on physical and chemical properties, uses and occurrence, toxicokinetics, general toxicity, toxic effects on various organs, genotoxicity, carcinogenicity, and developmental and reproductive toxicity of particular agents. Data are evaluated in the context of potential human occupational exposures, and recommendations for minimizing safety and health risks are provided. Most of these documents were written more than 10 years ago, and many are more than 20 years old. Criteria documents are developed primarily for the U.S. Department of Labor, but they are also distributed to health professionals, industry, organized labor, public interest groups, and federal state, and local government agencies. More than 140 NIOSH criteria documents are available on the Internet at <www.cdc.gov/niosh>. Individual documents or the entire set on CD-ROM can be obtained from NTIS. Reproductive and Developmental Toxicity Available information on reproductive and developmental effects is presented and critically evaluated. Human data and animal studies are considered separately and assessed in terms of potential implications for human occupational exposures. Quality Control NIOSH criteria documents are developed by NIOSH staff and reviewed by external expert consultants.
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Page 189 Usefulness in Identifying Exposures That Pose a Substantial Risk of Reproductive or Developmental Toxicity in Humans NIOSH criteria documents provide information that is useful for identifying exposures that might be associated with reproductive and developmental toxicity. Unfortunately, most of the documents are out of date. International Agency for Research on Cancer Monographs on the Evaluation of Carcinogenic Risks to Humans Description These monographs are prepared and published by the International Agency for Research on Cancer (IARC), which is part of WHO. Qualitative evaluations of published literature are made by international working groups of independent scientists. A list of agents covered can be found on the Internet at <http://www.iarc.fr>. Reproductive and Developmental Toxicity Each agent evaluation has a section that briefly summarizes reproductive and developmental effects using the traditional IARC format of presenting human data separately from data in experimental systems. Quality Control IARC working groups are composed of individuals with expertise related to cancer. There usually is a member with expertise on reproductive and developmental toxicity who prepares that section, but the working group is not constituted to provide a peer review of reproductive or developmental toxicity. Usefulness in Identifying Exposures That Pose a Substantial Risk of Reproductive or Developmental Toxicity in Humans Information presented in the IARC evaluations can be useful for
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Page 190 identifying and summarizing studies relevant to reproductive and developmental toxicity. International Programme on Chemical Safety Environmental Health Criteria Documents Description The International Program on Chemical Safety (IPCS) has been preparing and issuing Environmental Health Criteria Documents since 1976. More than 170 documents have been issued. IPCS is a joint effort of the United Nations Environmental Program (UNEP), International Labor Organization (ILO), and WHO. The documents provide critical reviews on the effects on human health and the environment of chemicals, or combinations of chemicals, and physical and biological agents. The documents assist national and international authorities in making risk assessments and risk management decisions. Information about the documents, including a list of agents covered, can be found on the Internet at < http://www.who.int/pcs/>. IPCS Environmental Health Criteria Documents reflect the collective view of an international group of experts and do not necessarily represent the decision or stated policy of UNEP, ILO, or WHO. The reports summarize and interpret the pertinent published literature. Unpublished information is used when published information is absent or when data are pivotal to the risk assessment. Adequate human data are preferred to animal data. Topics include physical chemistry; sources of exposure; environmental fate and transport; concentrations in the environment and in humans; pharmacokinetics; effects from acute, subacute, and long-term exposure; toxic effects on skin, eye, and reproduction; mutagenesis; and cancer. Reproductive and Developmental Toxicity Summary statements are provided under the heading of reproductive toxicity, embryotoxicity, and teratogenicity. Data from individual studies usually are not presented.
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Page 191 Quality Control Typically, a draft is prepared by an expert and presented to an IPCS official. The draft is communicated to approximately 150 contact persons who have an opportunity to provide comments. A revised draft is then prepared and submitted to a technical group of international experts. Further changes are made to reflect their deliberations, and, after editing and approval by the director of IPCS, the document is issued. Usefulness in Identifying Exposures That Pose a Substantial Risk of Reproductive or Developmental Toxicity in Humans The Environmental Health Criteria Documents provide information on reproductive and developmental effects for selected agents that can be useful for identifying important studies. EPA Integrated Risk Information System Description The Integrated Risk Information System (IRIS), prepared and maintained by EPA, is an electronic knowledge base containing information on human health effects that might result from exposure to various chemicals in the environment. IRIS was initially developed for EPA staff in response to a growing demand for consistent information on chemical substances for use in risk assessments, decision-making, and regulatory activities. The information in IRIS is intended for those without extensive training in toxicology but with some knowledge of health sciences. IRIS includes chronic reference doses (RfDs), reference concentrations (RfCs), and cancer unit risks and slope factors for more than 500 substances. It is searchable on the Internet at <http://www.epa.gov/iris>. Reproductive and Developmental Toxicity The review of data for setting chronic RfDs and RfCs is comprehensive and includes a review of reproductive and developmental toxicity
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Page 192 data. Two prenatal developmental toxicity studies in two species and a two-generation reproduction study are considered part of the minimum database for setting the chronic RfD-RfC. If such studies are not available, a database deficiency factor (ranging from 1 to 10) may be applied. Quality Control Draft IRIS summaries and support documents undergo rigorous internal and external peer review, followed by an agency-scientific consensus review. The IRIS program manager oversees the consensus process and provides quality control of all documents. A senior science manager provides scientific authority. Usefulness in Identifying Exposures That Pose a Substantial Risk of Reproductive or Developmental Toxicity in Humans Information in the files for the RfD and RfC can be useful for identifying a risk of reproductive and developmental toxicity in humans, if such data have been used in setting the RfD or RfC. The review of data in establishing RfDs and RfCs is comprehensive, and newer assessments have detailed support documents that can be downloaded from the IRIS Internet site, < http://www.epa.gov/iris>. EPA National Center for Environmental Assessment Documents Description The National Center for Environmental Assessment (NCEA), which is part of the EPA Office of Research and Development (ORD), serves as the national resource center for the overall process of human health and ecological risk assessments; the integration of hazard, dose-response, and exposure data; and models to produce risk characterizations. NCEA prepares a variety of documents, many of which are the source of scientific information used by EPA decision makers in developing or revising regulations. The documents can pertain to a specific medium, such as air or water, or they can be comprehensive analyses of scientific data. Many NCEA documents contain analyses
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Page 193 of reproductive and developmental toxicity data. The documents are available on the NCEA web site, http://www.epa.gov/ncea, and from NCEA's technical information staff. Reproductive and Developmental Toxicity Available reproductive and developmental toxicity data are reviewed and summarized. Quality Control All NCEA documents undergo internal and external peer review according to EPA, ORD, and NCEA policies. Each document is cleared by a senior manager before publication. Usefulness in Identifying Exposures that Pose a Substantial Risk of Reproductive and Developmental Toxicity in Humans The review of data is comprehensive, and information in the documents can be useful for identifying a risk of reproductive and developmental toxicity in humans. Informational Summary Chemical Hazards of the Workplace Description Proctor and Hughes' Chemical Hazards of the Workplace (Hathaway et al. 1996) is a standard reference that provides summaries of the toxicity of more than 500 frequently encountered occupational chemicals. Each summary includes American Conference of Governmental Industrial Hygienists Threshold Limit Values (when available); a statement describing physical properties, uses, and usual routes of exposure; and selected literature citations. Brief descriptions of the clinical effects of toxic exposure are given along with the doses at which the effects have been observed. Emphasis is placed on data obtained from human studies.
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Page 194 Reproductive and Developmental Toxicity The summaries for chemical exposures that have been associated with human reproductive or developmental toxicity usually include a paragraph describing those effects. Quality Control Chemical Hazards of the Workplace is written by internationally recognized authorities in occupational toxicology. There is no formal external peer review of the summaries. Usefulness in Identifying Exposures That Pose a Substantial Risk of Reproductive or Developmental Toxicity in Humans The book provides a short, authoritative overview of the information available on the occupational toxicology of many important chemical exposures. Consideration of reproductive and developmental toxicology is limited. Bibliographic Resources Bibliographic resources that may contain information on reproductive and developmental toxicity include the NIOSH Registry of Toxic Effects of Chemical Substances (RTECS), TOXLINE, MEDLINE, and PUBMED. RTECS is a NIOSH database of toxicological information — including mutagenic effects, reproductive effects, tumorgenic effects, and other toxicity — obtained from the open scientific literature. RTECS includes study summaries (route, species, study type, dose, effect) and bibliographic information on reproductive effects, if available. RTECS does not evaluate the studies included. Considerable expertise is required to interpret the information obtained in terms of risks related to human exposure. Originally published in 1971 as the “Toxic Substances List,” RTECS contains information on more than 130,000 substances. It is available on the Internet at http://www.cdc.gov/niosh/rtecs.html, on CD-ROM, and on computer tape. TOXLINE is NLM's collection of online bibliographic information covering the biochemical, pharmacological, physiological, and toxico-
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Page 195 logical effects (including effects on reproduction and development) of drugs and other chemicals. It contains more than 2.5 million bibliographic citations, most with abstracts and/or indexing terms and CAS Registry Numbers. It is available on the Internet at http://toxnet.nlm.nih.gov/. MEDLINE is an NLM bibliographic database covering the fields of medicine, nursing, dentistry, veterinary medicine, the health care system, and the preclinical sciences. MEDLINE contains bibliographic citations and author abstracts from more than 4,000 biomedical journals published in the United States and 70 other countries. The file contains over 11 million citations dating back to the mid-1960's. MEDLINE can be accessed on the Internet at: http://igm.nlm.nih.gov/. PubMed was developed by the National Center for Biotechnology Information (NCBI) at NLM. PubMed provides access to bibliographic biomedical-related information, which is drawn primarily from MEDLINE, PreMEDLINE, HealthSTAR, and publisher-supplied citations. PubMed also provides access and links to the integrated molecular biology databases included in NCBI's Entrez retrieval system. These databases contain DNA and protein sequences, 3-D protein structure data, population study data sets, and assemblies of complete genomes in an integrated system. PUBMED can be accessed on the Internet at: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi. Primary Data National Toxicology Program Toxicology Report Series Description Acute or repeated dose studies of up to 90 days are conducted in rats and mice on selected agents under the direction of NIEHS. Results from genetic toxicity testing and pharmacokinetic studies are frequently presented. Reproductive and Developmental Toxicity Reports of 90-day repeated-dose studies usually incorporate an evaluation of sperm morphology and vaginal cytology. The proce-
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Page 196 dures are performed on 10 animals per dose group. Data from males are collected at time of necropsy. For females, vaginal swabs are collected daily for the last 12 days of the study. Typically, tables for males include data for weight of the left testis, left epididymis, and cauda epididymis and data on sperm count, concentration, and motility. Data from females also are expressed as mean estrus cycle length and the percent of cycle in diestrus, proestrus, estrus, or metestrus. It is standard for a histological examination of testis and ovary to be performed in each study on animals from the highest dose groups and from control groups. Lower dose groups may be evaluated when effects are observed at the high dose. Quality Control Studies since the mid-1980s have generally been performed in conformance with good laboratory practice regulations. Histological examinations are reviewed by a pathology working group. Each draft report is reviewed independently. The reviewers determine whether the design and conditions of the studies are appropriate and ensure that toxicity reports present results and conclusions fully and clearly. The comments of the reviewers are not summarized or otherwise presented in reports, but the comments of peer reviewers are reviewed and addressed. Usefulness in Identifying Exposures That Pose a Substantial Risk of Reproductive or Developmental Toxicity in Humans The NTP toxicology reports can be useful for identifying agents that cause male or female reproductive (but not developmental) effects in those parameters examined. Organization for Economic Cooperation and Development Screening Information Data Set Profiles Description The Organization for Economic Cooperation and Development (OECD) has committed to the development and assessment of a core
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Page 197 set of toxicological and environmental data on 2000 chemical substances with high production and use throughout the world. The Screening Information Data Set (SIDS) represents the core data that are assessed to determine whether a substance can be set aside with low priority for additional evaluation or needs further study because of possible environmental or human health effects. The data address physical and chemical properties and acute and repeated dose (28-day) mammalian toxicity. SIDS dossiers are reviewed by a committee of technical and scientific experts from OECD-member countries. More than 100 dossiers have been completed. Information on SIDS can be found on the Internet at <http://www.oecd.org/ehs/hpv.htm>. Reproductive and Developmental Toxicity The core data requirements include assessment of fertility and reproduction. This requirement is commonly met through a 28-day repeated-dose protocol in rats, which requires treated members of both sexes to be mated and females observed for pregnancy, parturition, and survival of pups through postnatal day 4. Histological evaluations of testis and ovary also are required. Positive test results are not considered definitive, in part because of the limited numbers of animals used, but they signal the need to confirm and expand the characterization of possible effects using more traditional protocols. Quality Control The studies are done according to a standardized OECD protocol and in compliance with good laboratory practices. Test results are reviewed by the responsible government entity within the country with lead responsibility. Dossiers are subsequently reviewed by an international committee of experts. Usefulness in Identifying Exposures That Pose a Substantial Risk of Reproductive or Developmental Toxicity in Humans The SIDS profiles rank chemical substances based on their potential environmental and human health effects. Some information on reproductive and developmental toxicity is included in each profile.
Representative terms from entire chapter: