Review of the Environmental Protection Agency’s Draft IRIS Assessment of Tetrachloroethylene
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COMMITTEE TO REVIEW EPA’S TOXICOLOGICAL ASSESSMENT OF TETRACHLOROETHYLENE
Members
SAM KACEW (Chair),
University of Ottawa, Ontario, Canada
BRUCE H. ALEXANDER,
University of Minnesota School of Public Health, Minneapolis
MARGIT L. BLEECKER,
Center for Occupational and Environmental Neurology, Baltimore, MD
GARY P. CARLSON,
Purdue University, West Lafayette, IN
LINDA D. COWAN,
University of Oklahoma Health Sciences Center, Oklahoma City
MARY E. DAVIS,
West Virginia University, Morgantown
H. CHRISTOPHER FREY,
North Carolina State University, Raleigh
JOSEPH R. LANDOLPH,
University of Southern California, Los Angeles
M.E. (BETTE) MEEK,
University of Ottawa, Ontario, Canada
DAVID C. MCMILLAN,
University of Nebraska Medical Center, Omaha
M. CHRISTOPHER NEWLAND,
Auburn University, Auburn, AL
JULIA QUINT,
California Department of Public Health (retired), Berkeley
GARY L. ROSNER,
University of Texas M.D. Anderson Cancer Center, Houston
IVAN RUSYN,
University of North Carolina, Chapel Hill
ROLF SCHULTE-HERMANN,
Medical University of Vienna, Austria
IRVIN R. SCHULTZ,
Battelle Pacific Northwest Division, Sequim, WA
ROBERT SNYDER,
Rutgers, the State University of New Jersey, Piscataway
ROBERTA F. WHITE,
Boston University School of Public Health, Boston, MA
LUOPING ZHANG,
University of California, Berkeley
YILIANG ZHU,
University of South Florida, Tampa
Staff
SUSAN N. J. MARTEL, Project Director
NORMAN GROSSBLATT, Senior Editor
MIRSADA KARALIC-LONCAREVIC, Manager,
Technical Information Center
KEEGAN SAWYER, Associate Program Officer
TAMARA DAWSON, Program Associate
RADIAH ROSE, Editorial Project Manager
Sponsor
U.S. ENVIRONMENTAL PROTECTION AGENCY
BOARD ON ENVIRONMENTAL STUDIES AND TOXICOLOGY
Members
ROGENE F. HENDERSON (Chair),
Lovelace Respiratory Research Institute, Albuquerque, NM
RAMÓN ALVAREZ,
Environmental Defense Fund, Austin, TX
TINA BAHADORI,
American Chemistry Council, Arlington, VA
MICHAEL J. BRADLEY,
M.J. Bradley & Associates, Concord, MA
DALLAS BURTRAW,
Resources for the Future, Washington, DC
JAMES S. BUS,
Dow Chemical Company, Midland, MI
JONATHAN Z. CANNON,
University of Virginia, Charlottesville
GAIL CHARNLEY,
HealthRisk Strategies, Washington, DC
RUTH DEFRIES,
Columbia University, New York, NY
RICHARD A. DENISON,
Environmental Defense Fund, Washington, DC
H. CHRISTOPHER FREY,
North Carolina State University, Raleigh
J. PAUL GILMAN,
Covanta Energy Corporation, Fairfield, NJ
RICHARD M. GOLD,
Holland & Knight, LLP, Washington, DC
LYNN R. GOLDMAN,
Johns Hopkins University, Baltimore, MD
JUDITH A. GRAHAM (retired),
Pittsboro, NC
HOWARD HU,
University of Michigan, Ann Harbor
ROGER E. KASPERSON,
Clark University, Worcester, MA
TERRY L. MEDLEY,
E. I. du Pont de Nemours & Company, Wilmington, DE
JANA MILFORD,
University of Colorado at Boulder, Boulder
DANNY D. REIBLE,
University of Texas, Austin
JOSEPH V. RODRICKS,
ENVIRON International Corporation, Arlington, VA
ROBERT F. SAWYER,
University of California, Berkeley
KIMBERLY M. THOMPSON,
Harvard School of Public Health, Boston, MA
MARK J. UTELL,
University of Rochester Medical Center, Rochester, NY
Senior Staff
JAMES J. REISA, Director
DAVID J. POLICANSKY, Scholar
RAYMOND A. WASSEL, Senior Program Officer for Environmental Studies
SUSAN N.J. MARTEL, Senior Program Officer for Toxicology
ELLEN K. MANTUS, Senior Program Officer for Risk Analysis
EILEEN N. ABT, Senior Program Officer
RUTH E. CROSSGROVE, Senior Editor
MIRSADA KARALIC-LONCAREVIC, Manager,
Technical Information Center
RADIAH ROSE, Manager,
Editorial Projects
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Hormonally Active Agents in the Environment (1999)
Research Priorities for Airborne Particulate Matter (four volumes, 1998-2004)
The National Research Council’s Committee on Toxicology: The First 50 Years (1997)
Carcinogens and Anticarcinogens in the Human Diet (1996)
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Biologic Markers (five volumes, 1989-1995)
Science and Judgment in Risk Assessment (1994)
Pesticides in the Diets of Infants and Children (1993)
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Decline of the Sea Turtles (1990)
Copies of these reports may be ordered from the National Academies Press
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Preface
In June 2008, the U.S. Environmental Protection Agency (EPA) released its draft Toxicological Review of Tetrachloroethylene (Perchloroethylene) (CAS No. 127-18-4) in Support of Summary Information on the Integrated Risk Information System (IRIS). The assessment provided estimates of cancer and noncancer effects, which will be used to establish air and water quality standards to protect public health and set cleanup standards for hazardous-waste sites. EPA requested that the National Research Council review the scientific evidence on the adverse health effect of tetrachloroethylene and the agency’s application of such data in quantifying human health risks. The review was sought to ensure that the draft IRIS assessment was consistent with current EPA guidance on conducting risk assessments and that it reflected sound scientific analysis and judgment.
In response to EPA’s request, the National Research Council convened the Committee to Review EPA’s Toxicological Assessment of Tetrachloroethylene, which prepared this report. The members of the committee were selected for their expertise in pharmacokinetics, liver toxicology, kidney toxicology, neurotoxicology, hematopoietic toxicology, reproductive toxicology, developmental toxicology, genotoxicity, carcinogenesis, epidemiology, physiologically based pharmacokinetic modeling, biostatistics, and risk assessment. Biographic information on the committee members is provided in Appendix A.
To help the committee in its review, public meetings were held in November 2008 and January and April 2009 to gather information from EPA, academic and industry researchers, state public-health departments, and the general public. The committee is grateful to those who gave presentations on research related to tetrachloroethylene or on topics relevant to the committee’s task, including Judith Schreiber, Office of the New York State Attorney General; Philip Bushnell, EPA; Thomas Burke, Johns Hopkins Bloomberg School of Public Health; Andy Salmon, California Environmental Protection Agency; and Harvey Clewell III, Hamner Institutes for Health Sciences. The committee also thanks Peter Preuss, Kathryn Guyton, and Karen Hogan for providing background information and responding to questions throughout the study.
One committee member, Rolf Schulte-Hermann, disagreed with the committee’s support of EPA’s conclusion that the mode of action of tetrachloroethylene in inducing liver cancer in rodents is unknown. He judges that the induction of liver cancer in mice can be fully explained by a mode of action that involves the activation of the peroxisome proliferator-activated receptor-alpha. The basis of his judg-
ment and of his dissent from the committee’s position is detailed in Appendix B, where it is followed by the committee’s rebuttal.
This report and the dissenting statement have been reviewed in draft form by persons chosen for their diverse perspectives and technical expertise in accordance with procedures approved by the National Research Council’s Report Review Committee. The purpose of the 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 integrity of the deliberative process. We thank the following for their review of this report: A. John Bailer, Miami University; Lucio Costa, University of Washington; Scott E. Bowen, Wayne State University; Wolfgang Dekant, University of Würzburg; Adnan Elfarra, University of Wisconsin; Jeffrey Fisher, University of Georgia; David H. Garabrant, University of Michigan; Bernard D. Goldstein, University of Pittsburgh; David G. Hoel, Medical University of South Carolina; Ronald Melnick, National Institute of Environmental Health Sciences; Dorothy Patton, Environmental Protection Agency (retired); David Richardson, University of North Carolina School of Public Health; and Lauren Zeise, California Environmental Protection Agency.
Although the reviewers listed above 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 the report was overseen by the review coordinator, David Eaton, University of Washington, and review monitor, Mark Cullen, Yale University. Appointed by the National Research Council, they were responsible for making certain that an independent examination of the report was carried out in accordance with institutional procedures and that all review comments were carefully considered. Responsibility for the final content of the report rests entirely with the author committee and the institution.
The committee is grateful for the assistance of National Research Council staff in preparing the report, in particular Susan Martel, who served as project director and contributed to the report. Other staff members who contributed are James Reisa, director of the Board on Environmental Studies and Toxicology; Keegan Sawyer, associate program officer; Norman Grossblatt, senior editor; Mirsada Karalic-Loncarevic, manager of the Technical Information Center; Radiah Rose, editorial projects manager; and Tamara Dawson, program associate.
Finally, I thank all the members of the committee for their time and efforts throughout the development of this report.
Sam Kacew, Chair
Committee to Review EPA’s Toxicological Assessment of Tetrachloroethylene
Abbreviations
AUC area under the curve
BMC benchmark concentration
BMCL benchmark concentration with its lower confidence limit
BMD benchmark dose
BuChE butyrylcholinesterase
CCI color-confusion index
CFU colony-forming unit
CHO Chinese hamster ovary
CI confidence interval
CNS central nervous system
CYP cytochrome P-450
DCA dichloroacetic acid
DEHP diethylhexylphthalate
EBV Epstein Barr virus
8-OHdG 8-hydroxydeoxyguanosine
EPA U.S. Environmental Protection Agency
FDA Food and Drug Administration
FMO flavin-containing monooxygenase
GJIC gap junctional intercellular communication
GSH glutathione
GST glutathione S-transferase
HD Hodgkin disease
IARC International Agency for Research on Cancer
IRIS Integrated Risk Information System
JEM job-exposure matrix
JISA Japan Industrial Safety Association
JTEM job-task exposure matrix
LGLL large granular lymphocytic leukemia
LOAEL lowest observed-adverse-effect level
MCL mononuclear-cell leukemia
MOA mode of action
N-Ac-TCVCS N-acetyl-S-(1,2,2-trichlorovinyl)-L-cysteine
NCI National Cancer Institute
NES Neurobehavioral Evaluation System
NHL non-Hodgkin lymphoma
NK natural-killer
NOAEL no-observed-adverse-effect level
NRC National Research Council
NTP National Toxicology Program
OECD Organisation for Economic Co-operation and Development
OR odds ratio
PBPK physiologically based pharmacokinetic modeling
PCO palmitoyl-CoA oxidation
POD point of departure
PPARα peroxisome proliferator-activated receptor-alpha
RCC renal-cell carcinoma
RfC reference concentration
RfD reference dose
RfV reference value
SAB Science Advisory Board
SCE sister-chromatid exchange
SIR standardized incidence ratio
SMR standardized mortality ratio
TCA trichloroacetic acid
TCVC S-(1,2,2-trichlorovinyl)-L-cysteine
TCVCS S-(1,2,2-trichlorovinyl)-L-cysteine sulfoxide
TCVG S-(1,2,2-trichlorovinyl) glutathione
TWA time-weighted average
VCS visual-contrast sensitivity
VEP visual evoked potential
WHO World Health Organization
BOXES, FIGURES, AND TABLES
BOXES
11-1 |
EPA Cancer Guidance for Concluding a Chemical is Likely to be Carcinogenic to Humans (EPA 2005), |
FIGURES
S-1 |
Distribution of sample reference values, |
|||
2-1 |
Simplified illustration of the metabolic pathways of tetrachloroethylene, |
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10-1 |
Distribution of sample reference values, |
TABLES