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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 the U.S. Department of Defense; (DAMD 17-89-C9086 and DAMD 17-99-C9049), the U.S. Department of Health and Human Services; (PR-470644, PR-470645, 273-MH-901198, 273-MH-913119, P-0158-00-6-00, 0009554547, and 263-MD-635973), the U.S. Environmental Protection Agency; (CR-823615, R-827241-01), the U.S. Department of Veterans Affairs; (V101 P-1578), and the American Industrial Health Council. All contracts and awards were between the sponsoring agency or organization and the National Academy of Sciences. 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.
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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.
Committee on Developmental Toxicology
Elaine M. Faustman (Chair),
University of Washington, Seattle, Washington
John C. Gerhart (Vice Chair),
University of California, Berkeley, California
Nigel A. Brown,
St. George’s Hospital Medical School, London, United Kingdom
George P. Daston,
The Procter & Gamble Company, Cincinnati, Ohio
Mark C. Fishman,
Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
Joseph F. Holson,
WIL Research Laboratories, Inc., Ashland, Ohio
Herman B.W.M. Koëter,
Organisation for Economic Cooperation and Development, Paris, France
Anthony P. Mahowald,
University of Chicago, Chicago, Illinois
Jeanne M. Manson,
University of Pennsylvania, Phildelphia, Pennsylvania
Richard K. Miller,
University of Rochester, Rochester, New York
Philip E. Mirkes,
University of Washington, Seattle, Washington
Daniel W. Nebert,
University of Cincinnati Medical Center, Cincinnati, Ohio
Drew M. Noden,
Cornell University, Ithaca, New York
Virginia E. Papaioannou,
Columbia University College of Physicians and Surgeons, New York, New York
Gary C. Schoenwolf,
University of Utah, Salt Lake City, Utah
Frank Welsch,
Chemical Industry Institute of Toxicology, Research Triangle Park, North Carolina
William B. Wood,
University of Colorado, Boulder, Colorado
Consultant
Paul W.J. Peters,
University of Utrecht, The Netherlands
Staff
Abigail E. Stack, Project Director
Ruth E. Crossgrove, Editor
Mirsada Karalic-Loncarevic, Information Specialist
Leah L. Probst, Senior Project Assistant
Emily L. Smail, Project Assistant
Sponsors
AMERICAN INDUSTRIAL HEALTH COUNCIL
CENTERS FOR DISEASE CONTROL AND PREVENTION
U.S. DEPARTMENT OF DEFENSE
U.S. ENVIRONMENTAL PROTECTION AGENCY
U.S. DEPARTMENT OF VETERANS AFFAIRS
NATIONAL CENTER FOR TOXICOLOGICAL RESEARCH
NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
NATIONAL INSTITUTE FOR OCCUPATIONAL SAFETY AND HEALTH
Board on Environmental Studies and Toxicology
Gordon Orians (Chair),
University of Washington, Seattle, Washington
Donald Mattison (Vice Chair),
March of Dimes, White Plains, New York
David Allen,
University of Texas, Austin, Texas
Ingrid C. Burke,
Colorado State University, Fort Collins, Colorado
William L. Chameides,
Georgia Institute of Technology, Atlanta, Georgia
John Doull,
The University of Kansas Medical Center, Kansas City, Kansas
Christopher B. Field,
Carnegie Institute of Washington, Stanford, California
John Gerhart,
University of California, Berkeley, California
J. Paul Gilman,
Celera Genomics, Rockville, Maryland
Bruce D. Hammock,
University of California, Davis, California
Mark Harwell,
University of Miami, Miami, Florida
Rogene Henderson,
Lovelace Respiratory Research Institute, Albuquerque, New Mexico
Carol Henry,
American Chemical Council, Arlington, Virginia
Barbara Hulka,
University of North Carolina, Chapel Hill, North Carolina
James F. Kitchell,
University of Wisconsin, Madison, Wisconsin
Daniel Krewski,
University of Ottawa, Ottawa, Ontario
James A. MacMahon,
Utah State University, Logan, Utah
Mario J. Molina,
Massachusetts Institute of Technology, Cambridge, Massachusetts
Charles O’Melia,
Johns Hopkins University, Baltimore, Maryland
Willem F. Passchier,
Health Council of the Netherlands, The Hague
Kirk Smith,
University of California, Berkeley, California
Margaret Strand,
Oppenheimer Wolff Donnelly & Bayh, LLP, Washington, D.C.
Terry F. Yosie,
American Chemical Council, Arlington, Virginia
Senior Staff
James J. Reisa, Director
David J. Policansky, Associate Director and Senior Program Director for Applied Ecology
Carol A. Maczka, Senior Program Director for Toxicology and Risk Assessment
Raymond A. Wassel, Senior Program Director for Environmental Sciences and Engineering
Kulbir S. Bakshi, Program Director for Toxicology
Lee R. Paulson, Program Director for Resource Management
Roberta Wedge, Program Director for Risk Analysis
Commission on Life Sciences
Michael T. Clegg (Chair),
University of California, Riverside, California
Paul Berg (Vice Chair),
Stanford University, Stanford, California
Frederick R. Anderson,
Cadwalader, Wickersham & Taft, Washington, D.C.
Joanna Burger,
Rutgers University, Piscataway, New Jersey
James E. Cleaver,
University of California, San Francisco, California
David Eisenberg,
University of California, Los Angeles, California
John Emmerson,
Fishers, Indiana
Neal First,
University of Wisconsin, Madison, Wisconsin
David J. Galas,
Keck Graduate Institute of Applied Life Science, Claremont, California
David V. Goeddel,
Tularik, Inc., South San Francisco, California
Arturo Gomez-Pompa,
University of California, Riverside, California
Corey S. Goodman,
University of California, Berkeley, California
Jon W. Gordon,
Mount Sinai School of Medicine, New York, New York
David G. Hoel,
Medical University of South Carolina, Charleston, South Carolina
Barbara S. Hulka,
University of North Carolina, Chapel Hill, North Carolina
Cynthia Kenyon,
University of California, San Francisco, California
Bruce R. Levin,
Emory University, Atlanta, Georgia
David Livingston,
Dana-Farber Cancer Institute, Boston, Massachusetts
Donald R. Mattison,
March of Dimes, White Plains, New York
Elliot M. Meyerowitz,
California Institute of Technology, Pasadena, California
Robert T. Paine,
University of Washington, Seattle, Washington
Ronald R. Sederoff,
North Carolina State University, Raleigh, North Carolina
Robert R. Sokal,
State University of New York, Stony Brook, New York
Charles F. Stevens,
The Salk Institute, La Jolla, California
Shirley M. Tilghman,
Princeton University, Princeton, New Jersey
Raymond L. White,
University of Utah, Salt Lake City, Utah
Staff
Warren R. Muir, Executive Director
Jacqueline K. Prince, Financial Officer
Barbara B. Smith, Administrative Associate
Laura Holliday, Senior Project Assistant
Other Reports of the Board on Environmental Studies and Toxicology
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 (3 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
(800) 624-6242
(202) 334-3313
Preface
Developmental defects are a significant human-health problem. Approximately 3% of human developmental defects are attributed to exposure to toxic chemicals (e.g., lead and mercury) and physical agents (e.g., radiation), including agents found in the environment. Twenty-five percent of developmental defects might be due to a combination of genetic and environmental factors, where those factors are defined broadly to include physical, chemical, and biological agents and conditions, such as infections, nutritional deficiencies and excesses, life-style factors (e.g., alcohol), hyperthermia, ultraviolet radiation, X-rays, and the myriad of manufactured chemicals (e.g., pharmaceuticals, synthetic chemicals, solvents, pesticides, fungicides, herbicides, cosmetics, and food additives) and natural materials (e.g., plant and animal toxins and products). Because of human-health concerns about the developmental toxicity of environmental agents, scientists and regulators have focused efforts on understanding and protecting against the potential hazards of these agents to developing embryos, fetuses, and children.
Recent advances in the fields of developmental biology and genomics provide opportunities to further understand the role of environmental agents in human developmental defects and, therefore, the National Research Council (NRC) undertook a project to explore the opportunities in this area. The first phase of the project consisted of a symposium entitled “New Approaches for Assessing the Etiology and Risks of Developmental Abnormalities from Chemical Exposure.” The symposium was held December 11-12, 1995, in Washington, D.C. In the second phase, a multidisciplinary committee with expertise in developmental biology and developmental toxicology was convened by the NRC to prepare this consensus report.
In this report, the Committee on Developmental Toxicology evaluates current approaches used to assess risk for developmental defects and identifies key
areas of uncertainty in those approaches. It also evaluates current understanding of the mechanisms of action of chemicals that result in developmental defects. The committee examines recent advances in developmental biology and genomics to highlight how new scientific information can be used to improve risk assessment for developmental toxicants and to elucidate the mechanisms by which toxicants induce developmental defects. Finally, the committee evaluates how the new information and technologies can be integrated into an overall risk-assessment framework.
The number of new discoveries made between late 1995, when the NRC symposium was held, and the beginning of 2000, when this report was completed, is staggering—especially in genomics, human genetics, transgenic mouse studies, and elucidation of signal transduction pathways of central importance to developmental biology and, by extrapolation, to developmental toxicology. The amount of additional information expected in the next 4 years likely will be even more explosive. Hence, it should be emphasized that this report represents a “snapshot in time” during a time of monumental advances in molecular biology and genetic research.
We would like to express our thanks and appreciation to Carole Kimmel, U.S. Environmental Protection Agency, who was instrumental in helping the NRC to initiate this project. The committee was generously assisted by the following people who presented valuable background information during the committee’s public sessions: Carole Kimmel; Lewis Holmes, Harvard Medical School; Daniel Krewski, University of Ottawa; Andrew Olshan, University of North Carolina, Chapel Hill; James Ostell, National Center for Biotechnology Information; Allan Spradling, Carnegie Institute of Washington; and Robert Strausberg, National Cancer Institute. We gratefully acknowledge Barbara Abbott, U.S. Environmental Protection Agency, and Patricia Rodier, University of Rochester, who, at the committee’s request, contributed information on the mechanism of action of 2,3,7,8-tetrachlorodibenzo-p-dioxin and on chemicals that may induce autism, respectively.
We also gratefully acknowledge Paul Peters from the University of Utrecht. Dr. Peters served as a consultant to the committee and provided valuable information on research being done in European countries to improve risk assessment for developmental defects.
The committee wishes to thank the American Industrial Health Council, the Centers for Disease Control and Prevention, the U.S. Department of Defense, the U.S. Environmental Protection Agency, the U.S. Department of Veterans Affairs, the National Center for Toxicological Research, the National Institute of Environmental Health Sciences, the National Institute of Child Health and Human Development, and the National Institute for Occupational Safety and Health for their interest and support of this project.
This report has been reviewed in draft form by individuals chosen for their diverse perspectives and technical expertise in accordance with procedures ap-
proved by the NRC’s Report Review Committee for reviewing NRC and Institute of Medicine reports. The purpose of this independent review is to provide candid and critical comments that will assist the NRC in making the 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 manuscripts remain confidential to protect the integrity of the deliberative process. We wish to thank the following individuals, who are neither officials nor employees of the NRC, for their participation in the review of this report: John DeSesso, Mitretek Systems; Barbara Hales, McGill University; Lewis Holmes, Harvard Medical School; John Moore, National Toxicology Program Center for the Evaluation of Risks to Human Reproduction; Gary Shaw, California Birth Defects Monitoring Program; Allan Spradling, Carnegie Institution of Washington; and Patrick Wier, Smithkline Beecham Pharmaceuticals. Donald Mattison, March of Dimes Birth Defects Foundation, served as review coordinator.
The individuals listed above have provided many constructive comments and suggestions. It must be emphasized, however, that responsibility for the final content of this report rests entirely with the authoring committee and the NRC.
We are grateful for the assistance of the NRC staff in the preparation of the report. Staff members who contributed to this effort are Warren Muir, executive director of the Commission on Life Sciences; James Reisa, director of the Board on Environmental Studies and Toxicology; Carol Maczka, director of BEST’s Toxicology and Risk Assessment Program; Ruth Crossgrove, editor; Mirsada Karalic-Loncarevic, information specialist; Leah Probst, senior project assistant; and Emily Smail, project assistant. We are especially indebted to Abigail Stack, who served as project director. In this role, Dr. Stack served tirelessly, both with scientific and administrative support, maintaining the integrity of the report yet gently insisting on timely responses. We thank her for her excellent service in this challenging role.
Finally, we would like to thank all the members of the committee for their dedicated efforts throughout the development of this report.
We hope this report reflects the exciting deliberations of the committee that led to its genesis.
Elaine Faustman, Ph.D.
Chair, Committee on Developmental Toxicology
John Gerhart, Ph.D.
Vice Chair, Committee on Developmental Toxicology
List of Abbreviations
ACE
angiotensin-converting enzyme
ADH
alcohol dehydrogenase
ADI
acceptable daily intake
ADME
absorption, distribution, metabolism, and excretion
AER
apical ectodermal ridge
AHH
aryl hydrocarbon hydroxylase
AHR
aryl hydrocarbon receptor
ALDH
acetylaldehyde dehydrogenase
ARNT
aryl hydrocarbon receptor nuclear translocator
ASD
autism spectrum disorders
ATP
adenosine triphosphate
AUC
area under the curve
BLAST
Basic Local Alignment Search Tool
BMD
benchmark dose
CDC
Centers for Disease Control and Prevention
cDNA
complementary deoxyribonucleic acid
CGAP
Cancer Genome Anatomy Project
CHEST
chick embryotoxicity test
Cmax
peak threshold concentration
CNS
central nervous system
DBCP
1,2-dibromo-3-chloropropane
DDBJ
DNA Data Bank of Japan
DDT
dichlorodiphenyltrichloroethane
DES
diethylstilbesterol
Δ7-DHC
Δ7-dehydrocholesterol
DME
drug-metabolizing enzyme
DNA
deoxyribonucleic acid
DOE
U.S. Department of Energy
DPH
diphenylhydantoin
EBI
European Bioinformatics Institute
EBV
Epstein-Barr virus
ED05
best estimate of a dose at a 5% level of response
EDSP
Endocrine Disruptor Screening Program
EGEE
ethylene glycol monoethylether
EGF
epidermal growth factor
EGME
ethylene glycol monomethyl ether
EGP
Environmental Genome Project
ELSI
ethical, legal, and social implications
EM
extensive metabolizers
EMBL
European Molecular Biology Library
EPA
U.S. Environmental Protection Agency
ER
endoplasmic reticulum
ES
cell embryonic stem cell
EST
expressed sequence tag
EtO
ethylene oxide
F1
first filial generation
FAE
fetal alcohol effects
FAK
focal adhesion kinases
FAS
fetal alcohol syndrome
FDA
U.S. Food and Drug Administration
FETAX
frog embryo teratogenesis assay-Xenopus
FGF
fibroblast growth factor
FOB
functional observational battery
FQPA
Food Quality Protection Act
GFP
green fluorescent protein
GMS
genomic mismatch scanning
GR
glucocorticoid receptor
GRE
glucocorticoid response element
GSDB
Genome Sequence Database
hCMV
human cytomegalovirus
HEPM
human embryonic palatal mesenchymal
HGP
Human Genome Project
HOX
homeobox
Hsp
heat-shock promoter
HSV-1
herpes simplex virus type 1
ICBD
International Clearinghouse for Birth Defects
IPCS
International Programme on Chemical Safety
IRIS
Integrated Risk Information System
JNK
c-Jun terminal kinase
LANL
Los Alamos National Laboratory
LCR-MT
locus control regions of the metallothionein gene
LOAEL
lowest-observed-adverse-effect level
Mb
megabases
MeHg
methylmercury
mm
millimeter
MMTV LTR
mouse mammary tumor virus long-terminal repeat
MOE
margin of exposure
MOT
mouse ovarian tumor
MRI
magnetic resonance imaging
mRNA
messenger RNA
MTD
maximum tolerated dose
NAREP
North American Registry for Epilepsy and Pregnancy
NCBI
National Center for Biotechnology Information
NCGR
National Center for Genome Resources
NCI
National Cancer Institute
NCTR
National Center for Toxicological Research
NHGRI
National Human Genome Research Institute
NIEHS
National Institute of Environmental Health Sciences
NIGMS
National Institute of General Medical Sciences
NIH
National Institutes of Health
NMDA
n-methyl-D-aspartate
NOAEL
no-observed-adverse-effect level
NRC
National Research Council
OECD
Organization for Economic Cooperation and Development
ORF
open reading frame
PAH
polycyclic aromatic hydrocarbon
PARP
poly(ADP-ribose)polymerase
PCR
polymerase chain reaction
PUBS
percutaneous umbilical blood sampling
PZ
progress zone
RA
retinoic acid
Raldh2
retinaldehyde dehydrogenase-2
RAR
retinoic acid receptor
RAREs
retinoic acid response elements
RfC
reference concentration
RfD
reference dose
RNA
ribonucleic acid
RNAi
RNA-mediated gene interference
RT
reverse transcription
RT-PCR
reverse transcription polymerase chain reaction
RTECS
Registry of Toxic Effects of Chemical Substances
RTK
receptor tyrosine kinase
SAR
structure-activity relationship
SHH
Sonic Hedgehog
SNP
single-nucleotide polymorphism
SOT
Society of Toxicology
SV40
simian virus 40
2,4,5-T
2,4,5-trichlorophenoxyacetic acid
TCDD
2,3,7,8-tetrachlorodibenzo-p-dioxin
TEF
toxicity equivalency factor
TGF
transforming growth factor
Tk
thymidine kinase
TSCA
Toxic Substances Control Act
UM
ultra-metabolizers
VPA
valproic acid
Wnt
Wingless-Int
YPLL
years of potential life lost
ZPA
zone of polarizing activity