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Health Risks from Dioxin and Related Compounds: Evaluation of the EPA Reassessment Health Risks from Dioxin and Related Compounds Evaluation of the EPA Reassessment Committee on EPA’s Exposure and Human Health Reassessment of TCDD and Related Compounds Board on Environmental Studies and Toxicology Division on Earth and Life Studies NATIONAL RESEARCH COUNCIL OF THE NATIONAL ACADEMIES THE NATIONAL ACADEMIES PRESS Washington, DC www.nap.edu

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Health Risks from Dioxin and Related Compounds: Evaluation of the EPA Reassessment THE NATIONAL ACADEMIES PRESS 500 Fifth Street, N.W. 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. 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 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: 0-309-10258-8 (Book) International Standard Book Number-13: 978-0-309-10258-2 (Book) International Standard Book Number-10: 0-309-66273-7 (PDF) International Standard Book Number-13: 978-0-309-66273-4 (PDF) Library of Congress Control Number 2006933608 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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Health Risks from Dioxin and Related Compounds: Evaluation of the EPA Reassessment 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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Health Risks from Dioxin and Related Compounds: Evaluation of the EPA Reassessment COMMITTEE ON EPA’S EXPOSURE AND HUMAN HEALTH REASSESSMENT OF TCDD AND RELATED COMPOUNDS Members David L. Eaton (Chair), University of Washington, Seattle Dennis M. Bier, Baylor College of Medicine, Houston, TX Joshua T. Cohen, Tufts New England Medical Center, Boston, MA Michael S. Denison, University of California, Davis Richard T. Di Giulio, Duke University, Durham, NC Norbert E. Kaminski, Michigan State University, East Lansing Nancy K. Kim, New York State Department of Health, Troy Antoine Keng Djien Liem, European Food Safety Authority, Parma, Italy Thomas E. McKone, Lawrence Berkeley National Laboratory and School of Public Health, University of California, Berkeley Malcolm C. Pike, University of Southern California, Los Angeles Alvaro Puga, University of Cincinnati Medical Center, Cincinnati, OH Andrew G. Renwick, University of Southampton (emeritus), Southampton, UK David A. Savitz, Mount Sinai School of Medicine, New York, NY Allen E. Silverstone, SUNY–Upstate Medical University, Syracuse, NY Paul F. Terranova, University of Kansas Medical Center, Kansas City Kimberly M. Thompson, Massachusetts Institute of Technology, Cambridge Gary M. Williams, New York Medical College, Valhalla Yiliang Zhu, University of South Florida, Tampa Staff Suzanne van Drunick, Project Director Kulbir Bakshi, Senior Program Officer for Toxicology Ruth Crossgrove, Senior Editor Jean Hampton, Senior Fellow Cay Butler, Editor Mirsada Karalic-Loncarevic, Research Associate Bryan P. Shipley, Research Associate Liza R. Hamilton, Senior Program Assistant Alexandra Stupple, Senior Editorial Assistant Sammy Bardley, Librarian Sponsors U.S. Environmental Protection Agency U.S. Department of Agriculture U.S. Department of Health and Human Services

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Health Risks from Dioxin and Related Compounds: Evaluation of the EPA Reassessment 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 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

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Health Risks from Dioxin and Related Compounds: Evaluation of the EPA Reassessment 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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Health Risks from Dioxin and Related Compounds: Evaluation of the EPA Reassessment OTHER REPORTS OF THE BOARD ON ENVIRONMENTAL STUDIES AND TOXICOLOGY Assessing the Human Health Risks of Trichloroethylene: Key Scientific Issues (2006) New Source Review for Stationary Sources of Air Pollution (2006) Human Biomonitoring for Environmental Chemicals (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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Health Risks from Dioxin and Related Compounds: Evaluation of the EPA Reassessment 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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Health Risks from Dioxin and Related Compounds: Evaluation of the EPA Reassessment Acknowledgments We are appreciative of the generous support provided by the U.S. Environmental Protection Agency and are especially grateful for the outstanding assistance provided by Dr. William Farland. We are also grateful to Lisa Matthews, EPA’s program manager, and for Dr. Richard Canady’s assistance in facilitating invited speakers from the federal agencies. Many people assisted the committee and National Research Council staff in creating this report. We are grateful for the information and support provided by the following: Lesa L. Aylward, Summit Toxicology, L.L.P. P. Michael Bolger, U.S. Food and Drug Administration Gail Charnley, HealthRisk Strategies (on behalf of the Food Industry Dioxin Working Group) Richard W. Clapp, Boston University School of Public Health Edmund A. C. Crouch, Cambridge Environmental Inc. Christopher T. De Rosa, Agency for Toxic Substances and Disease Registry Michael J. DeVito, U.S. Environmental Protection Agency David W. Gaylor, Gaylor and Associates, LLC David P. Goldman, U.S. Department of Agriculture C.T. ‘Kip’ Howlett, Consultant Russell E. Keenan, AMEC Earth & Environmental Inc. Larry L. Needham, Centers for Disease Control and Prevention Christopher J. Portier, National Institute of Environmental Health Sciences Susan Schober, Centers for Disease Control and Prevention Jay B. Silkworth, General Electric Company Nigel Walker, National Institute of Environmental Health Sciences The committee’s work also benefited from written and oral testimony submitted by the public, whose participation is much appreciated.

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Health Risks from Dioxin and Related Compounds: Evaluation of the EPA Reassessment dividuals. The committee, and especially the chair, would like to thank the NRC study director Suzanne van Drunick for her tireless effort and good humor in directing this project under substantial time constraints. We also appreciate the organizational skills of Liza Hamilton for ensuring that our meetings and travel arrangements went smoothly, and other NRC staff, including Bryan Shipley for his technical assistance, Ruth Crossgrove and Cay Butler for their editorial assistance, Mirsada Karalic-Loncarevic for her reference assistance, and Alexandra Stupple for her production assistance. The committee is also grateful to Kulbir Bakshi, senior program officer; James Reisa, director of the Board on Environmental Studies and Toxicology; and Thomas Burke, professor and associate chair, Johns Hopkins University, for their oversight of the study; and to Ann Yaktine, Food and Nutrition Board, Institute of Medicine, for her contribution. I would like to thank all the committee members for their hard work and their dedication to ensuring that the report stands up to the basic charge that we “ensure that the risk estimates … are scientifically robust.” I, the NRC staff, and the committee are indebted to a number of individuals who presented background information, both orally and in writing, that made the committee’s understanding of the issues more complete. Thanks especially to Richard Canady, IWG on dioxin, for his assistance in helping to locate speakers and important background documents and to William Farland for his outstanding assistance. David L. Eaton, Chair Committee on EPA’s Exposure and Human Health Reassessment of TCDD and Related Compounds

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Health Risks from Dioxin and Related Compounds: Evaluation of the EPA Reassessment Abbreviations 2-AAF: 2-acetylaminofluorene AHF: altered hepatocelluar foci AHR: aromatic hydrocarbon receptor Ahr-/-: AHR null AIC: Akaike’s information criterion Anti-SRBC: anti-sheep red blood cell ARNT: AHR nuclear translocator protein ATSDR: Agency for Toxic Substances and Disease Registry AUC: area under the curve BMD: benchmark dose BMDL: benchmark dose low BMR: benchmark response CB: chlorobiphenyl CI: confidence intervals CL: volume of blood cleared per unit time CLB: cumulative lipid burden COX: cyclooxygenase COX-2: cyclooxygenase-2 CSF: cancer slope factor CYP1A: cytochrome P450A1 protein CYP1A1: cytochrome P4501A1 protein CYP1A2: cytochrome P4501A2 protein CYP1B1: cytochrome P4501B1 protein DHHS: U.S. Department of Health and Human Services DIM: diindolymethane

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Health Risks from Dioxin and Related Compounds: Evaluation of the EPA Reassessment DLCs: dioxin-like compounds DOD: U.S Department of Defense DF: dioxins and furons DFP: dioxins, furons, and PCBs ED: effective dose EGFR: epidermal growth factor receptor EPA: U.S. Environmental Protection Agency ER: estrogen receptor FAO: Food and Agriculture Organization of the United Nations FDA: U.S. Food and Drug Administration FSH: follicle-stimulating hormone GGT: γ-glutamyl transpeptidase GnRH: gonadotropin-releasing hormone HAH: halogenated aromatic hydrocarbon hCG: human chorionic gonadotropin HpCDD: heptachlorodibenzo-p-dioxin HepCB: heptachlorobiphenyl HxCDD: hexachlorodibenzo-p-dioxin HxCDF: hexachlorodibenzofuran I3C: indole-3-carbinol IARC: International Agency for Research on Cancer ICZ: indolo-[3,2b]-carbazole IOM: Institute of Medicine IPCS: International Program of Chemical Safety IWG: Interagency Working Group JECFA: Joint Expert Committee on Food Additives LABB: lifetime average body burden LD: lethal dose LED: lowest effective dose LH: lutenizing hormone LOAEL: lowest-observed-adverse-effect level LOD: limit of detection 6-MCDF: 6-methyl-1,3,8-trichlorodibenzofuran MOE: margin of exposure mRNA: messenger ribonucleic acid NAS: National Academy of Sciences NCEA: National Center for Environmental Assessment NIEHS: National Institute of Environmental Health Sciences NIH: National Institutes of Health NIOSH: National Institute for Occupational Safety and Health NOAEL: no-observed-adverse-effect level NOEL: no-observed-effect level NRC: National Research Council

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Health Risks from Dioxin and Related Compounds: Evaluation of the EPA Reassessment NTP: National Toxicology Program OCDF: octachlorodibenzofuran OCDD: octachlorodibenzo-p-dioxin PA: plasminogen activator PAH: polycyclic aromatic hydrocarbon PAI-1: plasminogen activator inhibitor-1 PBDD: polybrominated dibenzo-p-dioxin PBDF: polybrominated dibenzofuran PBPK: physiologically based pharmacokinetics PCB: polychlorinated biphenyl PCDD: polychlorinated dibenzo-p-dioxin PCDF: polychlorinated dibenzofuran PeCB: pentachlorobiphenyl PeCDD: pentachlorodibenzo-p-dioxin PeCDF: pentachlorodibenzofuran PK: pharmacokinetics POD: point of departure PPAR: peroxisome proliferator activated receptor ppt: parts per trillion PR: progesterone receptor QF: quality of fit REP: relative potency RfD: reference dose RR: rate ratio SAB: Science Advisory Board SCF: Scientific Committee on Food SD: standard deviation SE: standard error SMR: standardized mortality (morbidity) ratio T3: triiodothyronine T4: thyroxine TCB: 2,2′,5,5′-tetrachlorobiphenyl TCDD: 2,3,7,8-tetrachlorodibenzo-p-dioxin TCDF: 2,3,7,8-tetrachlorodibenzo furon TEF: toxic equivalency factor TEQ: toxic equivalent quotient tPA: tissue plasminogen activator 2,4,5-T: 2,4,5-trichlorophenoxyacetic acid TSH: thyroid-stimulating hormone UED: upper effective dose USDA: U.S. Department of Agriculture WHO: World Health Organization

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Health Risks from Dioxin and Related Compounds: Evaluation of the EPA Reassessment Contents     PUBLIC SUMMARY   1     SUMMARY   11 1   INTRODUCTION   28      TCDD, Other Dioxins, and DLCs,   30      Toxic Equivalency Factors,   33      Exposure Characterization,   34      Health Effects,   38      Committee Charge and Response,   39 2   GENERAL CONSIDERATIONS OF UNCERTAINTY AND VARIABILITY, SELECTION OF DOSE METRIC, AND DOSE-RESPONSE MODELING   45      Hazard Classification,   47      Exposure Assessment,   48      Assessment of Other Dioxins and DLCs,   50      General Issues Related to Variability and Uncertainty Associated with Selection of Dose Metric and Dose-Response Modeling,   51      General Issues Related to Risk Characterization,   55      Selection of Dose Metric,   57      Dose-Response Modeling,   63      Conclusions and Recommendations,   73

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Health Risks from Dioxin and Related Compounds: Evaluation of the EPA Reassessment            3   TOXIC EQUIVALENCY FACTORS   75      Dioxin-like Compounds,   75      Major Issues, Assumptions, and Uncertainties,   76      Key Studies and Publications to Be Included,   85      Conclusions and Recommendations,   86 4   EXPOSURE ASSESSMENT   90      Assessment Procedures,   90      Overview and Commentary on EPA’s Exposure Characterization,   91      Committee Findings,   99      Conclusions and Recommendations,   105 5   CANCER   108      Qualitative Evaluation of Carcinogenicity,   108      Quantitative Considerations in Assessing TCDD, Other Dioxins, and DLC Carcinogenicity,   121      Conclusions and Recommendations,   140 6   NONCANCER END POINTS   144      Immune Function,   144      Conclusions and Recommendations on the Immunotoxicity of TCDD, Other Dioxins, and DLCs,   153      Reproduction and Development,   154      Other Noncancer End Points,   169      Conclusions and Recommendations on the Reproductive, Developmental, and Other Noncancer End Points of TCDD, Other Dioxins, and DLCs,   173 7   REVIEW OF RISK CHARACTERIZATION   175      Review,   175      Conclusions and Recommendations,   186 8   CONCLUSIONS AND RECOMMENDATIONS   188      Classification of TCDD as Carcinogenic to Humans,   188      Use of Low-Dose Linear Versus Threshold (Nonlinear) Extrapolation Models for Quantitative Cancer Risk Estimations,   190      Use of the 1% Response Level As a Point of Departure for Low-Dose Risk Estimation,   190      Characterization of Uncertainty for Risk Estimates,   192      Use of Toxic Equivalency Factors for Risk Estimation of DLCs and Mixture of DLCs,   193      Use of Body Burden As the Primary Dose Metric for Cross-Species Extrapolation,   193

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Health Risks from Dioxin and Related Compounds: Evaluation of the EPA Reassessment                 EPA’s Exposure Assessment for TCDD, Other Dioxins, and DLCs in the United States,   194      EPA’s Evaluation of Immunotoxicity of TCDD, Other Dioxins, and DLCs,   194      EPA’s Evaluation of Reproductive and Developmental Toxicity of TCDD, Other Dioxins, and DLCs,   195      EPA’s Evaluation of Other Toxic End Points,   195      EPA’s Overall Approach to Risk Characterization,   196     REFERENCES   199     APPENDIXES          A  Biographical Information on Committee Members,   227      B  EPA’s 2005 Guidelines for Carcinogen Risk Assessment,   236 FIGURES S-1   Conceptual illustration of the effect of the selection of the point of departure and of the mathematical model used to extrapolate below the point of departure on the risk estimate,   5,15 1-1   Benzene ring (a) with conjugated bonds and (b) with inner ring depicting conjugated bonds,   31 1-2   Double benzene ring structures of (a) dioxins and (b) furans,   31 1-3   Biphenyl ring structure of PCBs,   31 1-4   Examples of toxic PCDDs, PCDFs, and PCBs of interest in the Reassessment,   32 2-1   Vmax,   69 5-1   Possible mechanism for TCDD hepatocarcinogenicity,   118 5-2   Range of plausible CSF values: Consideration of parameter confidence intervals only,   140 TABLES 1-1   TEFs for Humans and Nonhuman Mammals,   35 1-2   Summary of North American PCDD, PCDF, and PCB TEQ WHO Concentrations in Environmental Media and Food,   40 2-1   Categories of Key Decisions EPA Faced in Characterizing Cancer Risk,   52 2-2   Categories of Key Decisions EPA Faced in Characterizing Noncancer Risk,   53 2-3   Components of a Systematic Review,   57 5-1   Dioxin Cancer Bioassays,   114 5-2   TCDD, Other Dioxins, and DLC Cancer Bioassays,   116

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Health Risks from Dioxin and Related Compounds: Evaluation of the EPA Reassessment     5-3   Dioxin Rat Bioassays,   119 5-4   Hepatic Toxicity in TCDD Rat Bioassays,   126 5-5   EPA Inputs to CSF Estimates Using Epidemiological Data,   133 5-6   ED01, LED01, and UED01 Values,   135 BOXES S-1   Statement of Task,   13 1-1   Statement of Task,   43

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Health Risks from Dioxin and Related Compounds: Evaluation of the EPA Reassessment Health Risks from Dioxin and Related Compounds Evaluation of the EPA Reassessment

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