Toxicity Testing for Assessment of Environmental Agents
Interim Report
THE NATIONAL ACADEMIES PRESS
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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 No. 68-C-03-081 between the National Academy of Sciences and the U.S. Environmental Protection Agency. Any opinions, findings, conclusions, or recommendations expressed in this publication are those of the authors and do not necessarily reflect the views of the organizations or agencies that provided support for this project.
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THE NATIONAL ACADEMIES
Advisers to the Nation on Science, Engineering, and Medicine
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. Ralph J. Cicerone is president of the National Academy of Sciences.
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COMMITTEE ON TOXICITY TESTING AND ASSESSMENT OF ENVIRONMENTALAGENTS
Members
DANIEL KREWSKI (Chair),
University of Ottawa, Ottawa, ON
DANIEL ACOSTA, JR.,
University of Cincinnati, Cincinnati, OH
MELVIN ANDERSEN,
CIIT Centers for Health Research, Research Triangle Park, NC
HENRY ANDERSON,
Wisconsin Division of Public Health, Madison
JOHN BAILAR III,
University of Chicago, Chicago, IL
KIM BOEKELHEIDE,
Brown University, Providence, RI
ROBERT BRENT,
Thomas Jefferson University, Wilmington, DE
GAIL CHARNLEY,
HealthRisk Strategies, Washington, DC
VIVIAN CHEUNG,
University of Pennsylvania, Philadelphia
SIDNEY GREEN,
Howard University, Washington, DC
KARL KELSEY,
Harvard University, Boston, MA
NANCY KERKVLIET,
Oregon State University, Corvallis
ABBY LI,
Exponent, Inc., San Francisco, CA
GEORGE LUCIER, Consultant,
Pittsboro, NC
LAWRENCE MCCRAY,
Massachusetts Institute of Technology, Cambridge
OTTO MEYER,
Danish Institute for Food and Veterinary Research, Søborg, Denmark
D. REID PATTERSON,
Reid Patterson Consulting, Inc., Grayslake, IL
WILLIAM PENNIE,
Pfizer, Inc., Groton, CT
ROBERT SCALA,
Exxon Biomedical Sciences (Ret.), Tucson, AZ
GINA SOLOMON,
Natural Resources Defense Council, San Francisco, CA
MARTIN STEPHENS,
The Humane Society of the United States, Washington, DC
JAMES YAGER, JR.,
Johns Hopkins University, Baltimore, MD
LAUREN ZEISE,
California Environmental Protection Agency, Oakland
Staff
ELLEN MANTUS, Study Director
ROBERTA WEDGE, Study Director (through January 2005)
JOANNE ZURLO, Board Director
JENNIFER OBERNIER, Program Officer
NORMAN GROSSBLATT, Senior Editor
JENNIFER D. ROBERTS, Postdoctoral Research Associate
MIRSADA KARALIC-LONCAREVIC, Research Associate
JORDAN CRAGO, Senior Project Assistant
LUCY FUSCO, Senior Project Assistant
ALEXANDRA STUPPLE, Senior Editorial Assistant
Sponsor
U.S. ENVIRONMENTAL PROTECTION AGENCY
BOARD ON ENVIRONMENTAL STUDIES AND TOXICOLOGY
Members
JONATHAN M. SAMET (Chair),
Johns Hopkins University, Baltimore, MD
RAMÓN ALVAREZ,
Environmental Defense, Austin, TX
JOHN M. BALBUS,
Environmental Defense, Washington, DC
THOMAS BURKE,
Johns Hopkins University, Baltimore, MD
DALLAS BURTRAW,
Resources for the Future, Washington, DC
JAMES S. BUS,
Dow Chemical Company, Midland, MI
COSTEL D. DENSON,
University of Delaware, Newark
E. DONALD ELLIOTT,
Willkie Farr & Gallagher LLP, Washington, DC
J. PAUL GILMAN,
Oak Ridge National Laboratory, Oak Ridge, TN
SHERRI W. GOODMAN,
Center for Naval Analyses, Alexandria, VA
JUDITH A. GRAHAM,
American Chemistry Council, Arlington, VA
DANIEL S. GREENBAUM,
Health Effects Institute, Cambridge, MA
WILLIAM P. HORN,
Birch, Horton, Bittner and Cherot, Washington, DC
ROBERT HUGGETT,
Michigan State University (emeritus), East Lansing
JAMES H. JOHNSON, JR.,
Howard University, Washington, DC
JUDITH L. MEYER,
University of Georgia, Athens
PATRICK Y. O’BRIEN,
ChevronTexaco Energy Technology Company, Richmond, CA
DOROTHY E. PATTON,
International Life Sciences Institute, Washington, DC
STEWARD T.A. PICKETT,
Institute of Ecosystem Studies, Millbrook, NY
DANNY D. REIBLE,
University of Texas, Austin
JOSEPH V. RODRICKS,
ENVIRON International Corporation, Arlington, VA
ARMISTEAD G. RUSSELL,
Georgia Institute of Technology, Atlanta
LISA SPEER,
Natural Resources Defense Council, New York, NY
KIMBERLY M. THOMPSON,
Massachusetts Institute of Technology, Cambridge
MONICA G. TURNER,
University of Wisconsin, Madison
MARK J. UTELL,
University of Rochester Medical Center, Rochester, NY
CHRIS G. WHIPPLE,
ENVIRON International Corporation, Emeryville, CA
LAUREN ZEISE,
California Environmental Protection Agency, Oakland
Senior Staff
JAMES J. REISA, Director
DAVID J. POLICANSKY, Scholar
RAYMOND A. WASSEL, Senior Program Officer for Environmental Sciences and Engineering
KULBIR BAKSHI, Senior Program Officer for Toxicology
EILEEN N. ABT, Senior Program Officer for Risk Analysis
K. JOHN HOLMES, Senior Program Officer
SUSAN N.J. MARTEL, Senior Program Officer
SUZANNE VAN DRUNICK, Senior Program Officer
ELLEN K. MANTUS, Senior Program Officer
RUTH E. CROSSGROVE, Senior Editor
INSTITUTE FOR LABORATORY ANIMAL RESEARCH COUNCIL
Members
PETER A. WARD (Chair),
University of Michigan, Ann Arbor
STEPHEN W. BARTHOLD,
University of California, Davis
WILLIAM C. CAMPBELL,
Drew University, Madison, NJ
JEFFREY EVERITT,
GlaxoSmithKline Research & Development, Research Triangle Park, NC
MICHAEL F. FESTING,
Leicestershire, United Kingdom
ESTELLE B. GAUDA,
Johns Hopkins University, Baltimore, MD
JANET C. GONDER,
Pinehurst, NC
COENRAAD F.M. HENDRIKSEN,
National Institute of Public Health and the Environment, Bilthoven, Netherlands
JAY R. KAPLAN,
Wake Forest University School of Medicine, Winston-Salem, NC
HILTON J. KLEIN,
Merck Research Laboratories, West Point, PA
WILLIAM MORTON,
University of Washington, Seattle
RANDALL J. NELSON,
University of Tennessee, Memphis
ABIGAIL SMITH,
University of Pennsylvania, Philadelphia
MICHAEL K. STOSKOPF,
North Carolina State University, Raleigh
PETER THERAN,
Massachusetts Society for the Prevention of Cruelty to Animals, Boston
Staff
JOANNE ZURLO, Director
KATHLEEN BEIL, Administrative Assistant
OTHER REPORTS OF THE BOARD ON ENVIRONMENTAL STUDIES AND TOXICOLOGY
Superfund and Mining Megasites—Lessons from the Coeur d’Alene River Basin (2005)
Health Implications of Perchlorate Ingestion (2005)
Air Quality Management in the United States (2004)
Endangered and Threatened Species of the Platte River (2004)
Atlantic Salmon in Maine (2004)
Endangered and Threatened Fishes in the Klamath River Basin (2004)
Cumulative Environmental Effects of Alaska North Slope Oil and Gas Development (2003)
Estimating the Public Health Benefits of Proposed Air Pollution Regulations (2002)
Biosolids Applied to Land: Advancing Standards and Practices (2002)
The Airliner Cabin Environment and Health of Passengers and Crew (2002)
Arsenic in Drinking Water: 2001 Update (2001)
Evaluating Vehicle Emissions Inspection and Maintenance Programs (2001)
Compensating for Wetland Losses Under the Clean Water Act (2001)
A Risk-Management Strategy for PCB-Contaminated Sediments (2001)
Acute Exposure Guideline Levels for Selected Airborne Chemicals (4 volumes, 2000-2004)
Toxicological Effects of Methylmercury (2000)
Strengthening Science at the U.S. Environmental Protection Agency (2000)
Scientific Frontiers in Developmental Toxicology and Risk Assessment (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 (4 volumes, 1998-2004)
The National Research Council’s Committee on Toxicology: The First 50 Years (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 volumes, 1989-1995)
Review of EPA’s Environmental Monitoring and Assessment Program (3 volumes, 1994-1995)
Science and Judgment in Risk Assessment (1994)
Pesticides in the Diets of Infants and Children (1993)
Dolphins and the Tuna Industry (1992)
Science and the National Parks (1992)
Human Exposure Assessment for Airborne Pollutants (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 Academies Press
(800) 624-6242 or (202) 334-3313
INSTITUTE FOR LABORATORY ANIMAL RESEARCH PUBLICATIONS
Science, Medicine, and Animals: A Circle of Discovery (2004)
The Development of Science-Based Guidelines for Laboratory Animal Care: Proceedings of the November 2003 International Workshop (2004)
National Need and Priorities for Veterinarians in Biomedical Research (2004)
Occupational Health and Safety in the Care and Use of Nonhuman Primates (2003)
International Perspectives—The Future of Nonhuman Primate Resources: Proceedings of the Workshop Held April 17-19, 2002 (2003)
Guidelines for the Care and Use of Mammals in Neuroscience and Behavioral Research (2003)
Principles and Guidelines for the Use of Animals in Precollege Education (2001)
Strategies That Influence Cost Containment in Animal Research (2000)
Definition of Pain and Distress and Reporting Requirements for Laboratory Animals: Proceedings of the Workshop Held June 22, 2000 (2000)
Monoclonal Antibody Production (1999)
Microbial and Phenotypic Definition of Rats and Mice: Proceedings of the 1999 US/Japan Conference (1999)
The Psychological Well-Being of Nonhuman Primates (1998)
Microbial Status and Genetic Evaluation of Mice and Rats: Proceedings of the 1998 US/Japan Conference (1998)
Biomedical Models and Resources: Current Needs and Future Opportunities (1998)
Approaches to Cost Recovery for Animal Research: Implications for Science, Animals, Research Competitiveness, and Regulatory Compliance (1998)
Occupational Health and Safety in the Care and Use of Research Animals (1997)
Chimpanzees in Research: Strategies for Their Ethical Care, Management, and Use (1997)
Guide for the Care and Use of Laboratory Animals, 7th ed. (1996)
Nutrient Requirements of Laboratory Animals, 4th ed. (1995)
Laboratory Animal Management: Dogs (1994)
Recognition and Alleviation of Pain and Distress in Laboratory Animals (1992)
Infectious Diseases of Mice and Rats (1991)
Companion Guide to Infectious Diseases of Mice and Rats (1991)
Laboratory Animal Management: Rodents (1990)
Immunodeficient Rodents: A Guide to Their Immunobiology, Husbandry, and Use (1989)
Use of Laboratory Animals in Biomedical and Behavioral Research (1988)
Copies of these reports may be ordered from the National Academies Press
(800) 624-6242 or (202) 334-3313
Preface
The U.S. Environmental Protection Agency (EPA) has been given authority to regulate a variety of environmental agents that might harm public health or the environment. Toxicity testing in laboratory animals provides much of the information used by EPA to assess the hazards and risks associated with exposure to environmental agents. The number of regulations, initiatives, and directives that require toxicity testing is growing. Therefore, EPA recognized the need for a comprehensive review of established and emerging toxicity-testing methods and strategies and asked the National Research Council (NRC) to conduct such a review and to develop a long-range vision and strategy for toxicity testing.
In this report, the NRC’s Committee on Toxicity Testing and Assessment of Environmental Agents reviews current toxicity-testing methods and selected aspects of several reports by EPA and others on the topic of toxicity testing and assessment. A second report will present the committee’s long-range vision and strategic plan to advance the practices of toxicity testing and human health assessment of environmental contaminants.
This report has been reviewed in draft form by persons 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 of objectivity, evidence, and responsiveness to the study charge. The review comments and draft manuscript remain confidential to protect the integ-
rity of the deliberative process. We wish to thank the following for their review of this report: George Daston (Proctor and Gamble), David Dorman (CIIT Centers for Health Research), Alan Goldberg (Johns Hopkins University), A. Wallace Hayes (Harvard University) George Maldonado (University of Minnesota), Roger McClellan (Albuquerque, New Mexico), John Quackenbush (Harvard University), Lorenz Rhomberg (Gradient Corporation), I. Glen Sipes (University of Arizona), and Errol Zeiger (Consultant).
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 the review coordinator Donald Gardner (Inhalation Toxicology Associates), and the review monitor, Donald Mattison (National Institutes of Health). Appointed by the NRC, they were 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 committee and the institution.
The committee gratefully acknowledges the following for making presentations to the committee: Hugh Barton (Environmental Protection Agency), Alan Boobis (Imperial College of London), and James Lamb (Weinburg Group) who spoke on behalf of the Health and Environmental Sciences Institute’s Technical Committee on Agricultural Chemical Safety Assessment; Nancy Doerrer and Michael Holsapple (Health and Environmental Sciences Institute); Felix Frueh, David Hattan, and John Leighton (Food and Drug Administration); Laura Gribaldo and Thomas Hartung (European Centre for the Validation of Alternative Methods); William Farland, Michael Firestone, Jim Jones, Robert Kavlock, Carol Kimmel, and Hal Zenick (Environmental Protection Agency); Christopher Portier (National Institute of Environmental Health Sciences); and Lorenz Rhomberg (Gradient Corporation).
The committee is also grateful for the assistance of the NRC staff in preparing this report. Staff members who contributed to this effort are Ellen Mantus, project director; Roberta Wedge, project director through January 2005; Joanne Zurlo, director of the Institute for Laboratory Animal Research; James Reisa, director of the Board on Environmental Studies and Toxicology; Jennifer Obernier, program officer; Norman Grossblatt, senior editor; Jennifer Roberts, postdoctoral research associ-
ate; Mirsada Karalic-Loncarevic, research associate; Jordan Crago, senior project assistant; and Lucy Fusco, senior project assistant.
I would especially like to thank all the members of the committee for their efforts throughout the development of this report.
Dan Krewski, Chair
Committee on Toxicity Testing and Assessment of Environmental Agents
Abbreviations
ACD
acute contact dermatitis
ACS
American Cancer Society
ADJ
adjustment factor
ADME
absorption, distribution, metabolism, and excretion
AEGL
acute exposure guideline level
AhR
aryl hydrocarbon receptor
ARNT
AhR nuclear translocator
BBDR
biologically based dose response
BMC
benchmark concentration
BMD
benchmark dose
BT
Buehler test
CDC
Centers for Disease Control and Prevention
CFR
Code of Federal Regulations
CNS
central nervous system
CSA
chemical safety assessment
CYPs
cytochrome P450s
DAF
dosimetric adjustment factor
EC
European Commission
ECVAM
European Centre for the Validation of Alternative Methods
EDSP
Endocrine Disruptor Screening Program
EDSTAC
Endocrine Disruptor Screening and Testing Advisory Committee
EGP
Environmental Genome Project
ELISA
enzyme-linked immunosorbent assay
EPA
Environmental Protection Agency
EPHT
environmental public-health tracking
EU
European Union
FDA
Food and Drug Administration
FEV1
forced expiratory volume in 1 second
FFDCA
Federal Food, Drug, and Cosmetics Act
FIFRA
Federal Insecticide, Fungicide, and Rodenticide Act
FQPA
Food Quality Protection Act
GD
gestational day
GFP
green fluorescent protein
GMPT
guinea pig maximization test
HESI
Health and Environmental Sciences Institute
HPV
high-production volume
HTS
high-throughput screening
HUPO
Human Proteome Organization
IARC
International Agency for Research on Cancer
IC50
inhibition concentrations 50%
ICCVAM
Interagency Coordinating Committee on the Validation of Alternative Methods
ICH
International Conference on Harmonization
IgM
immunoglobulin M
ILSI
International Life Sciences Institute
IOM
Institute of Medicine
IPCS
International Programme on Chemical Safety
LC50
lethal concentration 50%
LD50
lethal dose 50%
LLNA
local lymph node assay
LOAEL
lowest-observed-adverse-effect level
MPCA
microbial pest-control agent
MTS
medium-throughput screening
NAAQS
national ambient air quality standards
NICEATM
NTP Interagency Center for the Evaluation of Alternative Toxicological Methods
NIEHS
National Institute of Environmental Health Sciences
NOAEL
no-observed-adverse-effect level
NRC
National Research Council
NTP
National Toxicology Program
OECD
Organisation for Economic Co-operation and Development
OSHA
Occupational Safety and Health Administration
PAH
polycyclic aromatic hydrocarbon
PBPK
physiologically based pharmacokinetic
PBT
persistence, bioaccumulation, and toxicity
PK
pharmacokinetic
PMN
premanufacturing notice
PND
postnatal day
QSAR
quantitative structure-activity relationship
REACH
Registration, Evaluation and Authorisation of Chemicals
RfC
Reference concentration
RfD
Reference dose
SAR
structure-activity relationship
SIDS
screening information dataset
SNP
single-nucleotide polymorphism
SRBCs
sheep red blood cells
TCDD
2,3,7,8-tetrachlorodibenzo-p-dioxin
TG
testing guideline
TGD
technical guidance document
TSC
the SNP Consortium
TSCA
Toxic Substances Control Act
UDP
up-down procedure
UF
uncertainty factor
UN
United Nations
vPvB
very persistent and very bioaccumulative
WHO
World Health Organization
BOXES
FIGURES
4-1 |
Endocrine-disruptor screening program overview, |
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4-2 |
Developmental-toxicity testing approach, |
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5-1 |
IPCS (1999) subdivision of interspecies and intraspecies uncertainty factors into pharmacokinetic and pharmacodynamic components, |
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6-1 |
The four objectives of toxicity testing, |
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6-2 |
Guideline study designs used to derive the oral reference dose, |
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6-3 |
Expanded chronic-carcinogenicity study, |
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6-4 |
ILSI-HESI draft proposed tiered approach for systemic-toxicity evaluation, |
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6-5 |
ILSI-HESI draft proposed tiered life-stages testing scheme for pesticides, |
TABLES
1-1 |
Some Major U.S. Regulatory Agency Authority, Public-Health Goals, and Risk-Management Approaches, |
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2-1 |
EPA Acute-Toxicity Categories, |
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2-2 |
Representative Genetic Toxicology Tests, |
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2-3 |
Representative Validated In Vitro Methods for Cellular-Toxicity Testing, |
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3-1 |
Examples of Epidemiologic Study Designs, |
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3-2 |
Examples of Risks or Standards Derived from Human Data, |
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4-1 |
Battery of Tests Required by EPA for New Pesticide Chemicals, |
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4-2 |
Toxicity Tests for Microbial Pest-Control Agents, |
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4-3 |
Concern Levels for Direct Food Additives, |
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4-4 |
Testing Required for Direct and Indirect Food Additives, |
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4-5 |
European Union Testing Strategy, |
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4-6 |
Endocrine-Disruptor Screening Tests, |
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4-7 |
OECD Conceptual Framework for Testing Endocrine Disruptors, |
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5-1 |
EPA’s Weight-of-Evidence Approach for Evaluating Degree of Concern for Prenatal and Postnatal Toxicity on the Basis of Human and Animal Data, |
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5-2 |
Level of Evidence in Carcinogen Classification Schemes or Narrative Descriptions, |
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6-1 |
REACH Testing Strategy, |