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Suggested Citation:"Front Matter." National Research Council. 2006. Assessing the Human Health Risks of Trichloroethylene: Key Scientific Issues. Washington, DC: The National Academies Press. doi: 10.17226/11707.
×

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

Suggested Citation:"Front Matter." National Research Council. 2006. Assessing the Human Health Risks of Trichloroethylene: Key Scientific Issues. Washington, DC: The National Academies Press. doi: 10.17226/11707.
×

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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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Suggested Citation:"Front Matter." National Research Council. 2006. Assessing the Human Health Risks of Trichloroethylene: Key Scientific Issues. Washington, DC: The National Academies Press. doi: 10.17226/11707.
×

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.


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Suggested Citation:"Front Matter." National Research Council. 2006. Assessing the Human Health Risks of Trichloroethylene: Key Scientific Issues. Washington, DC: The National Academies Press. doi: 10.17226/11707.
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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

Suggested Citation:"Front Matter." National Research Council. 2006. Assessing the Human Health Risks of Trichloroethylene: Key Scientific Issues. Washington, DC: The National Academies Press. doi: 10.17226/11707.
×

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.

Suggested Citation:"Front Matter." National Research Council. 2006. Assessing the Human Health Risks of Trichloroethylene: Key Scientific Issues. Washington, DC: The National Academies Press. doi: 10.17226/11707.
×

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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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)

Suggested Citation:"Front Matter." National Research Council. 2006. Assessing the Human Health Risks of Trichloroethylene: Key Scientific Issues. Washington, DC: The National Academies Press. doi: 10.17226/11707.
×

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

Suggested Citation:"Front Matter." National Research Council. 2006. Assessing the Human Health Risks of Trichloroethylene: Key Scientific Issues. Washington, DC: The National Academies Press. doi: 10.17226/11707.
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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.

Suggested Citation:"Front Matter." National Research Council. 2006. Assessing the Human Health Risks of Trichloroethylene: Key Scientific Issues. Washington, DC: The National Academies Press. doi: 10.17226/11707.
×

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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Suggested Citation:"Front Matter." National Research Council. 2006. Assessing the Human Health Risks of Trichloroethylene: Key Scientific Issues. Washington, DC: The National Academies Press. doi: 10.17226/11707.
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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

Suggested Citation:"Front Matter." National Research Council. 2006. Assessing the Human Health Risks of Trichloroethylene: Key Scientific Issues. Washington, DC: The National Academies Press. doi: 10.17226/11707.
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Suggested Citation:"Front Matter." National Research Council. 2006. Assessing the Human Health Risks of Trichloroethylene: Key Scientific Issues. Washington, DC: The National Academies Press. doi: 10.17226/11707.
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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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Suggested Citation:"Front Matter." National Research Council. 2006. Assessing the Human Health Risks of Trichloroethylene: Key Scientific Issues. Washington, DC: The National Academies Press. doi: 10.17226/11707.
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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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Suggested Citation:"Front Matter." National Research Council. 2006. Assessing the Human Health Risks of Trichloroethylene: Key Scientific Issues. Washington, DC: The National Academies Press. doi: 10.17226/11707.
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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

Suggested Citation:"Front Matter." National Research Council. 2006. Assessing the Human Health Risks of Trichloroethylene: Key Scientific Issues. Washington, DC: The National Academies Press. doi: 10.17226/11707.
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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

Suggested Citation:"Front Matter." National Research Council. 2006. Assessing the Human Health Risks of Trichloroethylene: Key Scientific Issues. Washington, DC: The National Academies Press. doi: 10.17226/11707.
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ASSESSING THE HUMAN HEALTH RISKS OF TRICHLOROETHYLENE

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Trichloroethylene is a chlorinated solvent widely used as a degreasing agent in industrial and manufacturing settings. It is also used as a chemical intermediate in making other chemicals and is a component of products such as typewriter correction fluid, paint removers, adhesives, and spot removers. In 2001, EPA issued a draft health risk assessment and proposed exposure standards for trichloroethylene. PA's Scientific Advisory Board (SAB) reviewed the draft and it was issued for public comment. A number of scientific issues were raised during the course of these reviews.

Assessing the Human Health Risks of Trichloroethylene identifies and assesses the key scientific issues relevant to analyzing the human health risks of trichloroethylene, considering pertinent toxicologic, epidemiologic, population susceptibility, and other available information, including relevant published scientific literature, EPA's 2001 draft health risk assessment of trichloroethylene, scientific and technical comments received by EPA from public and private sources, and additional relevant information to be provided by the sponsoring agencies. This report highlights issues critical to the development of an objective, realistic, and scientifically balanced trichloroethylene health risk assessment.

Guidance for hazard characterization of trichloroethylene is presented in Chapters 2 through 10. Chapter 2 provides guidance for evaluating large sets of epidemiologic data. In Chapter 3, the committee applies this guidance as an example in its evaluation of the epidemiologic data on trichloroethylene and kidney cancer, and this example should help guide evaluations of other cancer risks. Chapter 3 also assesses new information on the kidney toxicity of trichloroethylene and its metabolites and potential modes of action. Chapters 4, 5, 6, 7, and 8 evaluate the key issues regarding liver toxicity and cancer, reproductive and developmental toxicity, neurotoxicity, respiratory tract toxicity and cancer, and immunotoxicity, respectively. However, the committee's review focused on mode-of-action information to understand how trichloroethylene might affect certain processes differently in different species. Chapter 9 discusses susceptibility to trichloroethylene and its metabolites, and Chapter 10 describes important factors in considering trichloroethylene in mixtures. Physiologically based pharmacokinetic models are evaluated in Chapter 11, and guidance is provided on future directions for model development. Finally, Chapter 12 considers issues related to dose-response assessment and quantitative assessment of risk.

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