ASSESSING THE HUMAN HEALTH RISKS OF TRICHLOROETHYLENE
Key Scientific Issues
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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. DE-AM01-04PI45013 between the National Academy of Sciences and the U.S. Department of Energy. 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
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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 HUMAN HEALTH RISKS OF TRICHLOROETHYLENE
Members
ROGENE F. HENDERSON (Chair),
Lovelace Respiratory Research Institute, Albuquerque, NM
SCOTT BARTELL,
Emory University, Atlanta, GA
SCOTT W. BURCHIEL,
University of New Mexico, Albuquerque
DEBORAH A. CORY-SLECHTA,
University of Medicine and Dentistry of New Jersey, Piscataway
MARY E. DAVIS,
West Virginia University Health Sciences Center, Morgantown
KELLY J. DIX,
Lovelace Respiratory Research Institute, Albuquerque, NM
MARK S. GOLDBERG,
McGill University, Montreal, Quebec, CANADA
EVAN KHARASCH,
Washington University in St. Louis, St. Louis, MO
SERRINE S. LAU,
University of Arizona, Tucson
JOSÉ MANAUTOU,
University of Connecticut, Storrs
D. GAIL MCCARVER,
Medical College of Wisconsin, Milwaukee
HARIHARA MEHENDALE,
University of Louisiana, Monroe
PETER MUELLER,
University of Texas, Houston
JOHN M. PETERS,
University of Southern California, Los Angeles
THOMAS J. SMITH,
Harvard School of Public Health, Boston, MA
LESLIE STAYNER,
University of Illinois, Chicago
ROCHELLE W. TYL,
RTI International, Research Triangle Park, NC
JACK P. VANDEN HEUVEL,
Penn State University, University Park, PA
JANICE W. YAGER,
Electric Power Research Institute, Palo Alto, CA
Staff
SUSAN N. J. MARTEL, Project Director
KARL GUSTAVSON, Senior Program Officer
CAY BUTLER, Editor
MIRSADA KARALIC-LONCAREVIC, Research Associate
TAMARA DAWSON, Senior Program Assistant
Sponsors
U.S. DEPARTMENT OF DEFENSE
U.S. DEPARTMENT OF ENERGY
U.S. ENVIRONMENTAL PROTECTION AGENCY
NATIONAL AERONAUTICS AND SPACE ADMINISTRATION
BOARD ON ENVIRONMENTAL STUDIES AND TOXICOLOGY1
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
ROBERT F. SAWYER,
University of California, Berkeley
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
KARL E. GUSTAVSON, Senior Program Officer
K. JOHN HOLMES, Senior Program Officer
ELLEN K. MANTUS, Senior Program Officer
SUSAN N.J. MARTEL, Senior Program Officer
SUZANNE VAN DRUNICK, Senior Program Officer
RUTH E. CROSSGROVE, Senior Editor
OTHER REPORTS OF THE BOARD ON ENVIRONMENTAL STUDIES AND TOXICOLOGY
New Source Review for Stationary Sources of Air Pollution (2006)
Human Biomonitoring for Environmental Chemicals (2006)
Health Risks from Dioxin and Related Compounds: Evaluation of the EPA Reassessment (2006)
Fluoride in Drinking Water: A Scientific Review of EPA’s Standards (2006)
State and Federal Standards for Mobile-Source Emissions (2006)
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
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Preface
Trichloroethylene, an environmental contaminant, is widespread because of its extensive use as a degreasing agent, because of its use as a chemical intermediate in a variety of industries, and because of disposal practices. To help protect the public from potential health effects caused by exposure to trichloroethylene, government and state agencies perform risk assessments to develop guidelines intended to restrict the public’s contact with the chemical. Such risk assessments require consideration of a wealth of scientific information on trichloroethylene. Government agencies and the scientific community have engaged in much debate over the quality of some data and how to assess the information. Because several government agencies share responsibility for cleaning up contaminated sites, an interagency group composed of the U.S. Department of Defense, the Department of Energy, the Environmental Protection Agency, and the National Aeronautics and Space Administration requested a study by the National Research Council (NRC) to provide independent guidance on scientific issues to support an objective and scientifically balanced health risk assessment for trichloroethylene.
In response to the agencies’ request, the NRC convened the Committee on Human Health Risks of Trichloroethylene, which prepared this report. The members of the committee were selected for their expertise in pharmacokinetics, kidney toxicology, liver toxicology, reproductive and developmental toxicology, neurotoxicology, inhalation toxicology, immunotoxicology, carcinogenesis, epidemiology, physiologically based pharmacokinetic modeling, biostatistics, and risk assessment. Biographical information on the committee members is provided in Appendix A.
This report presents the committee’s assessment of the critical scientific issues that should be addressed in any health risk assessment of trichloroethylene. The guidance is intended to help agencies characterize the hazards from trichloroethylene. The committee also provides guidance on the development of physiologically based pharmacokinetic modeling, dose-response assessments, and other factors to consider in performing quantitative risk assessments of cancer and noncancer risks from trichloroethylene.
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: Adnan Elfarra, University of Wisconsin at Madison; Jeffrey Fisher, University of Georgia; Poh-Gek Forkert, Queen’s University; James Gnarra, Louisiana State University School of Medicine; David Hoel, Medical University of South Carolina; James Klaunig, Indiana University School of Medicine; Jeffrey Larson, Tanox, Inc.; Richard Miller, University of Rochester; K. Michael Pollard, The Scripps Research Institute; Martha Sandy, California Environmental Protection Agency; and William Valentine, Vanderbilt University.
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 Sam Kacew, University of Ottawa, and John C. Bailar, University of Chicago. 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 authoring committee and the institution.
The committee gratefully acknowledges the individuals who made presentations to the committee at its public meetings. A list of those individuals is provided in Appendix B. The committee also thanks Richard Canady, who was with the U.S. Office of Science and Technology Policy during the first half of the study, for coordinating the committee’s interactions with the interagency sponsors, facilitating responses to data requests, and providing background information.
The committee is grateful for the assistance of NRC staff in preparing the report. It particularly wishes to acknowledge the outstanding support
from project director Susan Martel, who coordinated the project and contributed to the committee’s report. Other staff members who contributed to this effort are James Reisa, director of the Board on Environmental Studies and Toxicology; Karl Gustavson, senior program officer; Mirsada Karalic-Loncarevic, research associate; and Tamara Dawson, senior program assistant.
Finally, I would like to thank all the members of the committee for their efforts throughout the development of this report.
Rogene Henderson, Ph.D.
Chair, Committee on Human Health Risks of Trichloroethylene
FIGURES
1-1 |
Metabolism of trichloroethylene, |
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2-1 |
Exposure intensity classification approaches, |
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3-1 |
Composite figure of metabolic pathways relevant to renal toxicity demonstrated in mammalian tissue, |
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4-1 |
Proposed mode of action for liver tumor formation by peroxisome proliferators, |
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7-1 |
Proposed scheme of trichloroethylene metabolism, |
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9-1 |
Overall framework to describe assessment of the effects of a toxicant on development, |
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12-1 |
Classic “hockey-stick” dose-response shape, |
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12-2 |
Sigmoidal population dose-response curve with no threshold, |
TABLES
1-1 |
Concentrations of Trichloroethylene in Ambient Air, |
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1-2 |
Example Concentrations of Trichloroethylene in Indoor Air, |
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1-3 |
Concentrations of Trichloroethylene in Water, |
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1-4 |
Preliminary Intake Estimates of Trichloroethylene and Related Chemicals, |
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2-1 |
Years of Solvent Use in Industrial Degreasing and Cleaning Operations, |
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2-2 |
Methods for Measuring Trichloroethylene, |
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2-3 |
Plausible Exposure Metrics, |
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3-1 |
Summary of Renal Toxicity and Tumor Findings in Gavage Studies of Trichloroethylene by NTP, |
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3-2 |
Summary of Toxicity and Tumor Findings in Gavage Studies of Trichloroethylene by NTP, |
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3-3 |
Summary of Toxicity and Tumor Findings in Inhalation Studies of Trichloroethylene by Maltoni et al., |
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3-4 |
Selected Cohort Studies that Present Associations between Cancer and Exposure to Trichloroethylene, |
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3-5 |
Selected Results from Cohort Studies of Kidney Cancer and Occupational Exposure to Trichloroethylene, |
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3-6 |
Average Annual Incidence (per 100,000) of Kidney and Renal Pelvis Cancer in the United States, |
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3-7 |
Characteristics of the Assessment of Exposure to Trichloroethylene in Selected Cohort Studies, |
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3-8 |
Description of Case-Control Studies that Present Associations between Kidney Cancer and Possible Exposure to Trichloroethylene, |
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3-9 |
Selected Results from Case-Control Studies of Kidney Cancer and Occupational Exposure to Trichloroethylene, |
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3-10 |
Characteristics of the Assessment of Exposure to Trichloroethylene in Selected Case-Control Studies, |
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3-11 |
Prenarcotic Symptoms and Exposure Duration and Intensity Associated with Rated Exposure Levels in the Vamvakas et al. Study, |
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3-12 |
Trichloroethylene Exposure Summary for the Arnsberg Area Studies, |
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3-13 |
Number of Exposed and Unexposed Patients with VHL Gene Mutations, |
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3-14 |
Mutation Spectra Indicative of Environmental Exposures and DNA Damage, |
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3-15 |
VHL Mutations in Sporadic Renal Cell Carcinomas, |
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4-1 |
Hepatotoxicity of Trichloroethylene and Metabolites in Animal Studies, |
4-2 |
Hepatotoxicity of Trichloroethylene and Metabolites in Human Studies, |
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4-3 |
Hepatocarcinogenic Effects of Trichloroacetic Acid in Drinking Water Studies with Mice and Rats, |
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4-4 |
Hepatocarcinogenic Effects of Dichloroacetic Acid in Drinking Water Studies with Mice and Rats, |
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4-5 |
Hepatocarcinogenic Effects of Chloral Hydrate in Mice, |
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4-6 |
Selected Epidemiologic Data on Liver Cancer or Hepatobiliary Cancers and Exposure to Trichloroethylene, |
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4-7 |
Trichloroethylene and PPARα Mode of Action, |
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4-8 |
Trichloroacetic Acid and PPARα Mode of Action, |
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4-9 |
Dichloroacetic Acid and PPARα Mode of Action, |
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4-10 |
Chloral Hydrate and PPARα Mode of Action, |
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4-11 |
Strength of the Weight of Evidence for PPARα Mode of Action for Trichloroethylene and Its Metabolites, |
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4-12 |
PPARα Mode-of-Action Dose-Response Relationships, |
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7-1 |
Animal Carcinogenicity Studies of Trichloroethylene, |
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7-2 |
Epidemiologic Data on Lung Cancer and Exposure to Trichloroethylene, |
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9-1 |
Approximate Uncertainty Analysis Based on Log-Normal Error, |