ASSESSING THE HUMAN HEALTH RISKS OF TRICHLOROETHYLENE

Key Scientific Issues

Committee on Human Health Risks of Trichloroethylene

Board on Environmental Studies and Toxicology

Division on Earth and Life Studies

NATIONAL RESEARCH COUNCIL OF THE NATIONAL ACADEMIES

THE NATIONAL ACADEMIES PRESS

Washington, D.C.
www.nap.edu



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Assessing the Human Health Risks of Trichloroethylene: Key Scientific Issues ASSESSING THE HUMAN HEALTH RISKS OF TRICHLOROETHYLENE Key Scientific Issues Committee on Human Health Risks of Trichloroethylene Board on Environmental Studies and Toxicology Division on Earth and Life Studies NATIONAL RESEARCH COUNCIL OF THE NATIONAL ACADEMIES THE NATIONAL ACADEMIES PRESS Washington, D.C. www.nap.edu

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Assessing the Human Health Risks of Trichloroethylene: Key Scientific Issues THE NATIONAL ACADEMIES PRESS 500 Fifth Street, NW Washington, DC 20001 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. International Standard Book Number-10: 0-309-10283-9 (Book) International Standard Book Number-10: 0-309-66360-1 (PDF) International Standard Book Number-13: 978-0-309-10283-4 (Book) International Standard Book Number-13: 978-0-309-66360-1 (PDF) Additional copies of this report are available from The National Academies Press 500 Fifth Street, NW Box 285 Washington, DC 20055 800-624-6242 202-334-3313 (in the Washington metropolitan area) http://www.nap.edu Copyright 2006 by the National Academy of Sciences. All rights reserved. Printed in the United States of America

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Assessing the Human Health Risks of Trichloroethylene: Key Scientific Issues 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. 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. Wm. 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. Harvey V. Fineberg 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. Ralph J. Cicerone and Dr. Wm. A. Wulf are chair and vice chair, respectively, of the National Research Council. www.national-academies.org

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Assessing the Human Health Risks of Trichloroethylene: Key Scientific Issues 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

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Assessing the Human Health Risks of Trichloroethylene: Key Scientific Issues 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 1 This study was planned, overseen, and supported by the Board on Environmental Studies and Toxicology.

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Assessing the Human Health Risks of Trichloroethylene: Key Scientific Issues 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

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Assessing the Human Health Risks of Trichloroethylene: Key Scientific Issues 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)

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Assessing the Human Health Risks of Trichloroethylene: Key Scientific Issues 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 www.nap.edu

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Assessing the Human Health Risks of Trichloroethylene: Key Scientific Issues 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.

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Assessing the Human Health Risks of Trichloroethylene: Key Scientific Issues 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

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Assessing the Human Health Risks of Trichloroethylene: Key Scientific Issues 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

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Assessing the Human Health Risks of Trichloroethylene: Key Scientific Issues Contents     SUMMARY   1 1.   INTRODUCTION   15      Statement of Task,   16      Committee’s Approach,   16      Overview of Pharmacokinetics,   17      Exposure Considerations,   18      Organization of the Report,   22 2.   METHODOLOGICAL CONSIDERATIONS IN EVALUATING EPIDEMIOLOGIC LITERATURE ON CANCER AND EXPOSURE TO TRICHLOROETHYLENE   25      Health Outcomes,   25      Designs of Epidemiologic Studies,   28      Exposure Assessment,   31      Combining and Evaluating Epidemiologic Data,   44      Findings and Recommendations,   55 3.   KIDNEY TOXICITY AND CANCER   58      Role of Metabolism in Renal Effects,   58      Noncancer Toxicity,   65      Kidney Cancer,   77      Findings,   134      Research Recommendations,   135

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Assessing the Human Health Risks of Trichloroethylene: Key Scientific Issues 4.   LIVER TOXICITY AND CANCER   137      Hepatotoxicity,   137      Liver Cancer,   148      Findings and Recommendations,   172 5.   REPRODUCTIVE AND DEVELOPMENTAL TOXICITY   182      Animal Studies of Reproductive Toxicity,   182      Animal Studies of Developmental Toxicity,   188      Human Studies of Reproductive and Developmental Effects,   197      Findings and Recommendations,   209 6.   NEUROTOXICITY   213      Background,   213      Animal Toxicity,   214      Human Toxicity,   220      Mode of Action,   224      Issues,   225      Findings and Recommendations,   229 7.   RESPIRATORY TRACT TOXICITY AND CANCER   233      Respiratory Tract Toxicity,   233      Respiratory Tract Cancer,   237      Issues,   243      Findings and Recommendations,   245 8.   IMMUNOTOXICITY   246      Background,   246      Animal Studies,   247      Human Studies,   249      Issues for Immunotoxicity Risk Assessment,   250      Findings and Recommendations,   251 9.   SPECIAL POPULATIONS AND SUSCEPTIBILITY   253      Childhood Cancer,   254      Developmental Issues,   255      Genetic Susceptibility,   267      Acquired States with Possible Altered Susceptibility,   269      Gender,   270      Human Variability and the Use of Uncertainty Factors,   270      Findings and Recommendations,   274 10.   MIXTURES   277      Toxicology of Mixtures Containing Trichloroethylene,   278

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Assessing the Human Health Risks of Trichloroethylene: Key Scientific Issues      Potential Mechanisms of Interaction,   291      Effects of Altered or Special Physiologic States,   292      Coexposure Predictions Using PBPK Models,   293      Findings and Recommendations,   295 11.   PHARMACOKINETIC MODELING   297      Overview of Pharmacokinetic Models,   298      Trichloroethylene Pharmacokinetic Models and Risk Assessment,   303      Findings and Recommendations,   312 12.   ISSUES IN THE ASSESSMENT OF DOSE RESPONSE   315      Point of Departure Determination,   315      Linear Extrapolation from the Point of Departure to Zero Dose,   318      Alternative Dose-Response Functions,   323      Other Issues,   324      Uncertainty Analysis,   325      Findings and Recommendations,   326     REFERENCES   329     APPENDIXES     A   Biographic Information on the Committee on Human Health Risks of Trichloroethylene   381 B   Participants at Public Sessions   388 C   Trichloroethylene Metabolism   390 D   Exposure Anaylsis of Selected Studies   406 E   Peroxisome Proliferators and Liver Cancer   418 FIGURES 1-1   Metabolism of trichloroethylene,   19 2-1   Exposure intensity classification approaches,   32 3-1   Composite figure of metabolic pathways relevant to renal toxicity demonstrated in mammalian tissue,   59 4-1   Proposed mode of action for liver tumor formation by peroxisome proliferators,   165 7-1   Proposed scheme of trichloroethylene metabolism,   235 9-1   Overall framework to describe assessment of the effects of a toxicant on development,   256 12-1   Classic “hockey-stick” dose-response shape,   321 12-2   Sigmoidal population dose-response curve with no threshold,   322

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Assessing the Human Health Risks of Trichloroethylene: Key Scientific Issues     TABLES 1-1   Concentrations of Trichloroethylene in Ambient Air,   20 1-2   Example Concentrations of Trichloroethylene in Indoor Air,   21 1-3   Concentrations of Trichloroethylene in Water,   21 1-4   Preliminary Intake Estimates of Trichloroethylene and Related Chemicals,   23 2-1   Years of Solvent Use in Industrial Degreasing and Cleaning Operations,   35 2-2   Methods for Measuring Trichloroethylene,   36 2-3   Plausible Exposure Metrics,   38 3-1   Summary of Renal Toxicity and Tumor Findings in Gavage Studies of Trichloroethylene by NTP,   69 3-2   Summary of Toxicity and Tumor Findings in Gavage Studies of Trichloroethylene by NTP,   70 3-3   Summary of Toxicity and Tumor Findings in Inhalation Studies of Trichloroethylene by Maltoni et al.,   71 3-4   Selected Cohort Studies that Present Associations between Cancer and Exposure to Trichloroethylene,   79 3-5   Selected Results from Cohort Studies of Kidney Cancer and Occupational Exposure to Trichloroethylene,   88 3-6   Average Annual Incidence (per 100,000) of Kidney and Renal Pelvis Cancer in the United States,   92 3-7   Characteristics of the Assessment of Exposure to Trichloroethylene in Selected Cohort Studies,   95 3-8   Description of Case-Control Studies that Present Associations between Kidney Cancer and Possible Exposure to Trichloroethylene,   105 3-9   Selected Results from Case-Control Studies of Kidney Cancer and Occupational Exposure to Trichloroethylene,   115 3-10   Characteristics of the Assessment of Exposure to Trichloroethylene in Selected Case-Control Studies,   118 3-11   Prenarcotic Symptoms and Exposure Duration and Intensity Associated with Rated Exposure Levels in the Vamvakas et al. Study,   120 3-12   Trichloroethylene Exposure Summary for the Arnsberg Area Studies,   123 3-13   Number of Exposed and Unexposed Patients with VHL Gene Mutations,   125 3-14   Mutation Spectra Indicative of Environmental Exposures and DNA Damage,   131 3-15   VHL Mutations in Sporadic Renal Cell Carcinomas,   132 4-1   Hepatotoxicity of Trichloroethylene and Metabolites in Animal Studies,   138

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Assessing the Human Health Risks of Trichloroethylene: Key Scientific Issues 4-2   Hepatotoxicity of Trichloroethylene and Metabolites in Human Studies,   143 4-3   Hepatocarcinogenic Effects of Trichloroacetic Acid in Drinking Water Studies with Mice and Rats,   150 4-4   Hepatocarcinogenic Effects of Dichloroacetic Acid in Drinking Water Studies with Mice and Rats,   152 4-5   Hepatocarcinogenic Effects of Chloral Hydrate in Mice,   155 4-6   Selected Epidemiologic Data on Liver Cancer or Hepatobiliary Cancers and Exposure to Trichloroethylene,   159 4-7   Trichloroethylene and PPARα Mode of Action,   167 4-8   Trichloroacetic Acid and PPARα Mode of Action,   169 4-9   Dichloroacetic Acid and PPARα Mode of Action,   170 4-10   Chloral Hydrate and PPARα Mode of Action,   171 4-11   Strength of the Weight of Evidence for PPARα Mode of Action for Trichloroethylene and Its Metabolites,   172 4-12   PPARα Mode-of-Action Dose-Response Relationships,   173 7-1   Animal Carcinogenicity Studies of Trichloroethylene,   238 7-2   Epidemiologic Data on Lung Cancer and Exposure to Trichloroethylene,   241 9-1   Approximate Uncertainty Analysis Based on Log-Normal Error,   273

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Assessing the Human Health Risks of Trichloroethylene: Key Scientific Issues ASSESSING THE HUMAN HEALTH RISKS OF TRICHLOROETHYLENE

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