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NOTICE: The project that is the subject of this report was approved by the Governing Board of the National Research Council, whose members are drawn from the councils of the National Academy of Sciences, the National Academy of Engineering, and the Institute of Medicine. The members of the committee responsible for the report were chosen for their special competences and with regard for appropriate balance.
This project was supported by Contract Nos. DAMD 17-89-C9086 and DAMD 17-99-C9049 between the National Academy of Sciences and the U.S. Department of Defense. Any opinions, findings, conclusions, or recommendations expressed in this publication are those of the author(s) and do not necessarily reflect the view of the organizations or agencies that provided support for this project.
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THE NATIONAL ACADEMIES
National Academy of Sciences
National Academy of Engineering
Institute of Medicine
National Research Council
The National Academy of Sciences is a private, nonprofit, self-perpetuating society of distinguished scholars engaged in scientific and engineering research, dedicated to the furtherance of science and technology and to their use for the general welfare. Upon the authority of the charter granted to it by the Congress in 1863, the Academy has a mandate that requires it to advise the federal government on scientific and technical matters. Dr. Bruce M. Alberts is president of the National Academy of Sciences.
The National Academy of Engineering was established in 1964, under the charter of the National Academy of Sciences, as a parallel organization of outstanding engineers. It is autonomous in its administration and in the selection of its members, sharing with the National Academy of Sciences the responsibility for advising the federal government. The National Academy of Engineering also sponsors engineering programs aimed at meeting national needs, encourages education and research, and recognizes the superior achievements of engineers. Dr. William A. Wulf is president of the National Academy of Engineering.
The Institute of Medicine was established in 1970 by the National Academy of Sciences to secure the services of eminent members of appropriate professions in the examination of policy matters pertaining to the health of the public. The Institute acts under the responsibility given to the National Academy of Sciences by its congressional charter to be an adviser to the federal government and, upon its own initiative, to identify issues of medical care, research, and education. Dr. Kenneth I. Shine is president of the Institute of Medicine.
The National Research Council was organized by the National Academy of Sciences in 1916 to associate the broad community of science and technology with the Academy's purposes of furthering knowledge and advising the federal government. Functioning in accordance with general policies determined by the Academy, the Council has become the principal operating agency of both the National Academy of Sciences and the National Academy of Engineering in providing services to the government, the public, and the scientific and engineering communities. The Council is administered jointly by both Academies and the Institute of Medicine. Dr. Bruce M. Alberts and Dr. William A. Wulf are chairman and vice chairman, respectively, of the National Research Council.
SUBCOMMITTEE ON REPRODUCTIVE AND DEVELOPMENTAL TOXICOLOGY
CAROLE A. KIMMEL (Chair), U.S. Environmental Protection Agency, Washington, D.C.
GERMAINE M. BUCK, University at Buffalo, State of New York
MAUREEN H. FEUSTON, Sanofi Pharmaceuticals, Inc., Malvern, Pa.
PAUL M.D. FOSTER, Chemical Industry Institute of Toxicology, Research Triangle Park, N.C.
J. M. FRIEDMAN, University of British Columbia, Vancouver
JOSEPH F. HOLSON, WIL Research Laboratories, Inc., Ashland, Ohio
CLAUDE L. HUGHES, JR., Cedars-Sinai Medical Center, Los Angeles, Calif.
JOHN A. MOORE, Institute for Evaluating Health Risks, Washington, D.C., and Sciences International, Alexandria, Va.
BERNARD A. SCHWETZ, National Center for Toxicological Research, Rockville, Md.
ANTHONY R. SCIALLI, Georgetown University Medical Center, Washington, D.C.
WILLIAM J. SCOTT, JR., University of Cincinnati College of Medicine, Cincinnati, Ohio
CHARLES V. VORHEES, University of Cincinnati College of Medicine, Cincinnati, Ohio
BARRY R. ZIRKIN, The Johns Hopkins University School of Hygiene and Public Health, Baltimore, Md.
KULBIR S. BAKSHI, Program Director for the Committee on Toxicology
ABIGAIL STACK, Project Director
KATE KELLY, Editor
MIRSADA KARALIC-LONCAREVIC, Information Specialist
LEAH PROBST, Senior Project Assistant
EMILY SMAIL, Project Assistant
U.S. DEPARTMENT OF DEFENSE
COMMITTEE ON TOXICOLOGY
BAILUS WALKER, JR. (Chair), Howard University Medical Center and American Public Health Association, Washington, D.C.
MELVIN E. ANDERSEN, Colorado State University, Denver
GERMAINE M. BUCK, National Institutes of Health, Washington, D.C.
ROBERT E. FORSTER II, University of Pennsylvania, Philadelphia
WILLIAM E. HALPERIN, National Institute for Occupational Safety and Health, Cincinnati, Ohio
CHARLES H. HOBBS, Lovelace Respiratory Research Institute and Lovelace Biomedical and Environmental Research Institute, Albuquerque, N.M.
SAM KACEW, Department of Pharmacology Faculty of Medicine and University of Ottawa, Ontario
NANCY KERKVLIET, Oregon State University, Agricultural and Life Sciences, Corvallis
MICHAEL J. KOSNETT, University of Colorado Health Sciences Center, Denver
MORTON LIPPMANN, New York University School of Medicine, Tuxedo
ERNEST E. MC CONNELL, ToxPath, Inc., Raleigh, N.C.
THOMAS E. MCKONE, Lawrence Berkeley National Laboratory and University of California, Berkeley
HARIHARA MEHENDALE, The University of Louisiana at Monroe, Monroe
DAVID H. MOORE, Battelle Memorial Institute, Bel Air, Md.
LAUREN ZEISE, California Environmental Protection Agency, Oakland
BOARD ON ENVIRONMENTAL STUDIES AND TOXICOLOGY
GORDON ORIANS (Chair), University of Washington, Seattle
JOHN DOULL, University of Kansas Medical Center, Kansas City
DAVID ALLEN, University of Texas, Austin
INGRID C. BURKE, Colorado State University, Fort Collins
THOMAS BURKE, The Johns Hopkins University, Baltimore, Md.
GLEN R. CASS, Georgia Institute of Technology, Atlanta
WILLIAM L. CHAMEIDES, Georgia Institute of Technology, Atlanta
CHRISTOPHER B. FIELD, Carnegie Institute of Washington, Stanford, Calif.
JOHN GERHART, University of California, Berkeley
J. PAUL GILMAN, Celera Genomics, Rockville, Md.
DANIEL S. GREENBAUM, Health Effects Institute, Cambridge, Mass.
BRUCE D. HAMMOCK, University of California, Davis
ROGENE HENDERSON, Lovelace Respiratory Research Institute, Albuquerque, N.M.
CAROL HENRY, American Chemistry Council, Arlington, Va.
ROBERT HUGGETT, Michigan State University, East Lansing
JAMES F. KITCHELL, University of Wisconsin, Madison
DANIEL KREWSKI, University of Ottawa, Ottawa, Ontario
JAMES A. MACMAHON, Utah State University, Logan
CHARLES O'MELIA, The Johns Hopkins University, Baltimore, Md.
WILLEM F. PASSCHIER, Health Council of The Netherlands, The Hague
ANN POWERS, Pace University School of Law, White Plains, N.Y.
KIRK SMITH, University of California, Berkeley
TERRY F. YOSIE, American Chemistry Council, Arlington, Va.
JAMES J. REISA, Director
DAVID J. POLICANSKY, Associate Director and Senior Program Director for Applied Ecology
RAYMOND A. WASSEL, Senior Program Director for Environmental Sciences and Engineering
KULBIR BAKSHI, Program Director for the Committee on Toxicology
ROBERTA M. WEDGE, Program Director for Risk Analysis
K. JOHN HOLMES, Senior Staff Officer
COMMISSION ON LIFE SCIENCES
MICHAEL T. CLEGG (Chair), University of California, Riverside
PAUL BERG (Vice Chair), Stanford University, Stanford, Calif.
FREDERICK R. ANDERSON, Cadwalader, Wickersham & Taft, Washington, D.C.
JOANNA BURGER, Rutgers University, Piscataway, N.J.
JAMES E. CLEAVER, University of California, San Francisco
DAVID S. EISENBERG, University of California, Los Angeles
NEAL L. FIRST, University of Wisconsin, Madison
DAVID J. GALAS, Keck Graduate Institute of Applied Life Science, Claremont, Calif.
DAVID V. GOEDDEL, Tularik, Inc., South San Francisco, Calif.
ARTURO GOMEZ -POMPA, University of California, Riverside
COREY S. GOODMAN, University of California, Berkeley
JON W. GORDON, Mount Sinai School of Medicine, New York, N.Y.
DAVID G. HOEL, Medical University of South Carolina, Charleston
BARBARA S. HULKA, University of North Carolina, Chapel Hill
CYNTHIA J. KENYON, University of California, San Francisco
BRUCE R. LEVIN, Emory University, Atlanta, Ga.
DAVID M. LIVINGSTON, Dana-Farber Cancer Institute, Boston, Mass.
DONALD R. MATTISON, March of Dimes, White Plains, N.Y.
ELLIOT M. MEYEROWITZ, California Institute of Technology, Pasadena
ROBERT T. PAINE, University of Washington, Seattle
RONALD R. SEDEROFF, North Carolina State University, Raleigh
ROBERT R. SOKAL, State University of New York, Stony Brook
CHARLES F. STEVENS, The Salk Institute for Biological Studies, La Jolla, Calif.
SHIRLEY M. TILGHMAN, Princeton University, Princeton, N.J.
RAYMOND L. WHITE, DNA Sciences, Inc., Mountain View, Calif.
WARREN R. MUIR, Executive Director
JACQUELINE K. PRINCE, Financial Officer
BARBARA B. SMITH, Administrative Associate
LAURA T. HOLLIDAY, Senior Program Assistant
OTHER REPORTS OF THE BOARD ON ENVIRONMENTAL STUDIES AND TOXICOLOGY
Toxicological Effects of Methylmercury (2000)
Strengthening Science at the U.S. Environmental Protection Agency: Research-Management and Peer-Review Practices (2000)
Scientific Frontiers in Developmental Toxicology and Risk Assessment (2000)
Modeling Mobile-Source Emissions (2000)
Toxicological Risks of Selected Flame-Retardant Chemicals (2000)
Copper in Drinking Water (2000)
Ecological Indicators for the Nation (2000)
Waste Incineration and Public Health (1999)
Hormonally Active Agents in the Environment (1999)
Research Priorities for Airborne Particulate Matter: I. Immediate Priorities and a Long-Range Research Portfolio (1998); II. Evaluating Research Progress and Updating the Portfolio (1999)
Ozone-Forming Potential of Reformulated Gasoline (1999)
Risk-Based Waste Classification in California (1999)
Arsenic in Drinking Water (1999)
Brucellosis in the Greater Yellowstone Area (1998)
The National Research Council's Committee on Toxicology: The First 50 Years (1997)
Toxicologic Assessment of the Army's Zinc Cadmium Sulfide Dispersion Tests (1997)
Carcinogens and Anticarcinogens in the Human Diet (1996)
Upstream: Salmon and Society in the Pacific Northwest (1996)
Science and the Endangered Species Act (1995)
Wetlands: Characteristics and Boundaries (1995)
Biologic Markers (5 reports, 1989-1995)
Review of EPA's Environmental Monitoring and Assessment Program (three reports, 1994-1995)
Science and Judgment in Risk Assessment (1994)
Ranking Hazardous Waste Sites for Remedial Action (1994)
Pesticides in the Diets of Infants and Children (1993)
Issues in Risk Assessment (1993)
Setting Priorities for Land Conservation (1993)
Protecting Visibility in National Parks and Wilderness Areas (1993)
Dolphins and the Tuna Industry (1992)
Hazardous Materials on the Public Lands (1992)
Science and the National Parks (1992)
Animals as Sentinels of Environmental Health Hazards (1991)
Assessment of the U.S. Outer Continental Shelf Environmental Studies Program, Volumes I-IV (1991-1993)
Human Exposure Assessment for Airborne Pollutants (1991)
Monitoring Human Tissues for Toxic Substances (1991)
Rethinking the Ozone Problem in Urban and Regional Air Pollution (1991)
Decline of the Sea Turtles (1990)
Copies of these reports may be ordered from
the National Academy Press
OTHER REPORTS OF THE COMMITTEE ON TOXICOLOGY
Acute Exposure Guideline Levels for Selected Airborne Contaminants, Volume 1 (2000)
Review of the US Navy's Human Health Risk Assessment of the Naval Air Facility at Atsugi, Japan (2000)
Methods for Developing Spacecraft Water Exposure Guidelines (2000)
Review of the U.S. Navy Environmental Health Center's Health-Hazard Assessment Process (2000)
Review of the U.S. Navy's Exposure Standard for Manufactured Vitreous Fibers (2000)
Re-Evaluation of Drinking-Water Guidelines for Diisopropyl Methylphosphonate (2000)
Submarine Exposure Guidance Levels for Selected Hydrofluorocarbons: HFC-236fa, HFC-23, and HFC-404a (2000)
Review of the U.S. Army's Health Risk Assessments for Oral Exposure to Six Chemical-Warfare Agents (1999)
Toxicity of Military Smokes and Obscurants, Volume 1(1997), Volume 2 (1999), Volume 3 (1999)
Assessment of Exposure-Response Functions for Rocket-Emission Toxicants (1998)
Toxicity of Alternatives to Chlorofluorocarbons: HFC-134a and HCFC-123 (1996)
Permissible Exposure Levels for Selected Military Fuel Vapors (1996)
Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants, Volume 1 (1994), Volume 2 (1996), Volume 3 (1996), Volume 4 (2000)
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.
Several individuals assisted the subcommittee by providing information on Naval operations, particularly on the Navy's health hazard evaluation program. We thank Captain David Macys (Office of Naval Research), Captain Lawrence Betts (Navy Environmental Health Center), Commander Victoria Cassano (Navy Environmental Health Center), Captain David Sack (Navy Environmental Health Center), Captain Kenneth Still (Navy Health Research Center's Toxicology Detachment), and James Crawl (Navy Environmental Health Center)
for their interest and support of this project. We also gratefully acknowledge the following persons who provided valuable background information to the subcommittee: Stacy Arnesen (National Library of Medicine), George Daston (Procter and Gamble Company), James Donald (California Environmental Protection Agency), Elaine Faustman (University of Washington), Michael Shelby (National Institute of Environmental Health Sciences), and John Weiner (University at Buffalo, State of New York). The subcommittee thanks R. Woodrow Setzer, Jr. (U.S. Environmental Protection Agency) for providing guidance on statistical methods discussed in this report.
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).
Although the reviewers listed above have provided many constructive comments and suggestions, they were not asked to endorse the conclusions or recommendations, nor did they see the final draft of the report before its release. The review of this report was overseen by Donald Mattison (March of Dimes Birth Defects Foundation), appointed by the Commission on Life Sciences, who was responsible for making certain that an independent examination of this report was carried out in accordance with institutional procedures and that all review comments were carefully considered. Responsibility for the final content of this report rests entirely with the authoring committee and the institution.
We are also grateful for the assistance of NRC staff in the prepara-
tion of this report. The subcommittee acknowledges Kulbir Bakshi, program director of the Committee on Toxicology and, in particular, Abigail Stack, project director for this report, without whose leadership and assistance this project could not have been completed. Other staff members contributing to this report were James Reisa, director of the Board on Environmental Studies and Toxicology (BEST); Carol Maczka, formerly BEST's senior program director for toxicology and risk assessment; Ruth Crossgrove, publications manager; Leah Probst, senior project assistant; and Emily Smail, project assistant.
Finally, we thank all the members of the subcommittee for their expertise and dedicated effort throughout the study.
Carole A. Kimmel, Ph.D.
Chair, Subcommittee on Reproductive and Developmental Toxicology
Bailus Walker Jr., Ph.D., M.P.H.
Chair, Committee on Toxicology
ACGIH American Conference of Governmental Industrial Hygienists
ADI acceptable daily intake
AIHA American Industrial Hygiene Association
ATSDR Agency for Toxic Substances and Disease Registry
AUC area under the curve
BMD benchmark dose
CAS Chemical Abstract Service
CDC Centers for Disease Control and Prevention
Cmax peak threshold concentration
DART developmental and reproductive toxicology
EC European Commission
ECETOC European Centre for Ecotoxicology and Toxicology of Chemicals
EPA U.S. Environmental Protection Agency
ETICBACK Environmental Teratology Information Center Backfile
F1 first filial generation
FDA U.S. Food and Drug Administration
HEC human equivalent concentration
HFC 134a 1,1,1,2-tetrafluoroethane
HSDB Hazardous Substance Data Base
IARC International Agency for Research on Cancer
ILO International Labor Organization
IPCS International Programme on Chemical Safety
IRIS Integrated Risk Information System (Administered by the U.S. Environmental Protection Agency)
JP-8 jet propellant-8
LC50 lethal concentration for 50% of the test animals
LD50 lethal dose for 50% of the test animals
LHRH luteinizing hormone releasing hormone
LOAEL lowest-observed-adverse-effect level
MDI metered dose inhaler
MeSH medical subject headings
MOE margin of exposure
MTD maximum tolerated dose
NCEA National Center for Environmental Assessment
NIEHS National Institute of Environmental Health Sciences
NIH National Institutes of Health
NIOSH National Institute for Occupational Safety and Health
NOAEL No-observed-adverse-effect level
NRC National Research Council
NTIS National Technical Information Service
NTP National Toxicology Program
OECD Organization for Economic Cooperation and Development
OR odds ratio
ORD Office of Research and Development
P generation parental animals
PEL permissible exposure limit
RACB reproductive assessment of continuous breeding
RfD reference dose
RR relative risk
RTECS Registry of Toxic Effects of Chemical Substances
SIDS screening information data set
SOP standard operating procedure
STEL Short-Term Exposure Limit