Health Risks from Dioxin and Related Compounds
Evaluation of the EPA Reassessment
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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.
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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.
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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.
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
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
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)
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
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.
Acknowledgment of Review Participants
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 National Research Council’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:
Melvin Andersen, CIIT Centers for Health Research
John Doull, University of Kansas Medical Center
David Gaylor, Gaylor & Associates
Michael Holsapple, ILSI Health and Environmental Sciences
Daniel Krewski, University of Ottawa
Philip Landrigan, Mount Sinai School of Medicine
John A. Moore, Hollyhouse, Inc.
Stephen S. Olin, ILSI Research Foundation/Risk Science
Richard Peterson, School of Pharmacy, Harvard School of Public Health
Louise Ryan, Harvard School of Public Health
Steven Safe, Texas A&M University
Glenn Sipes, University of Arizona
Martin Van den Berg, Utrecht University
Noel Weiss, University of Washington
Lauren Zeise, California Environmental Protection Agency
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 William Halperin and John Bailar. Appointed by the National Research Council, 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.
Preface
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), also called dioxin, is among the most toxic anthropogenic substance ever identified. TCDD and a number of similar polychlorinated dioxins, dibenzofurans, and coplanar polychlorinated biphenyls (dioxin-like compounds [DLCs]) have been the subject of intense scientific research and frequently controversial environmental and health policies. Animal studies have demonstrated potent effects of TCDD, other dioxins, and many DLCs on tumor development, birth defects, reproductive abnormalities, immune dysfunction, dermatological disorders, and a plethora of other adverse effects. Because of their persistence in the environment and their bioaccumulative potential, TCDD, other dioxins, and DLCs are now ubiquitous environmental pollutants and are detected at low concentrations in virtually all organisms at higher trophic levels in the food chain, including humans. Inadvertent exposures of humans through industrial accidents, occupational exposures to commercial compounds (primarily phenoxyacid herbicides), and through dietary pathways have led to a wide range of body burdens of TCDD, other dioxins, and DLCs, and numerous epidemiological studies have attempted to relate exposures to a variety of adverse effects in humans.
Because of substantial policy and economic implications associated with the regulation of TCDD, other dioxins, and DLCs in the environment, the U.S. Environmental Protection Agency (EPA) began in the mid-1980s to invest enormous efforts in risk assessment of these compounds. Many scientists in the dioxin research community participated in writing numerous review chapters on various aspects of dioxin toxicology, chemistry, and environmental fate. In September 1992, initial drafts of all background chap-
ters of the EPA assessment underwent extensive peer review, followed by extensive revision and additional review of some chapters. In September 1994, all the chapters, plus the first draft of a summary “risk characterization” chapter, were subjected to more peer review and public comment. In 1997 and 1998, additional modifications of the compiled information led to the development of an “Integrated Summary and Risk Characterization” document. This document, as well as additional information on toxic equivalency of DLCs, was revised and subsequently reviewed by EPA’s Science Advisory Board (SAB) in November 2000. Recognizing the broad policy implications of the dioxin reassessment, an Interagency Working Group (IWG), consisting of representatives of seven federal agencies, was established in 2000 to foster information sharing, develop a common language for dioxin science and science policy across governmental agencies and programs, identify gaps and needs in dioxin risk assessment, and coordinate risk management strategies. The IWG has provided input to EPA on the draft dioxin reassessment and has been coordinating risk management issues on TCDD and other dioxins for the federal government since its inception. After further revisions in response to SAB and other public comments, in December 2003, EPA released a preliminary draft document titled Exposure and Human Health Reassessment of 2,3,7,8-Tetrachlorodibenzo-p-Dioxin (TCDD) and Related Compounds, referred to in this report as the Reassessment.
In the summer of 2004, EPA requested the National Research Council (NRC) to create “an expert committee to review EPA’s draft reassessment of the risks of dioxin and dioxin-like compounds.” In response, the NRC appointed the Committee on EPA’s Exposure and Human Health Reassessment of TCDD and Related Compounds, which was charged, to the extent possible, to review “EPA’s modeling assumptions, including those associated with dose-response curve and points-of-departure dose ranges and associated likelihood estimates for identified human health outcomes; EPA’s quantitative uncertainty analysis; EPA’s selection of studies as a basis for its assessments and gaps in scientific knowledge.” The charge also requested that the committee address two specific points of controversy: (1) the scientific evidence for classifying dioxin as a human carcinogen, and (2) the validity of the nonthreshold linear dose-response model and the cancer slope factor calculated by EPA through the use of this model. The committee was also asked to comment on the usefulness of toxic equivalency factors (TEFs) and the uncertainties associated with their use in risk assessment of complex mixtures. Finally, the committee was also asked to review the uncertainty associated with the Reassessment’s approach to the analysis of food sampling and human dietary intake data.
The entire Reassessment consists of three parts totaling more than 1,800 pages of scientific review. Part I contains several volumes of a previous sci-
entific review of information relating to sources and exposures to TCDD and other dioxins in the environment, and Part II contains detailed reviews of scientific information on the health effects of TCDD, other dioxins, and DLCs. The information in Parts I and II were provided to the committee as background, with the recognition that many chapters in these two volumes have not been updated for several years. The committee was asked to focus its review on Part III of the Reassessment, which represents an “integrated summary and risk characterization for TCDD and related compounds.”
The committee held five meetings between November 22, 2004, and July 7, 2005. The first three meetings provided opportunity for public input. The committee heard from scientists from the IWG, EPA, Food and Drug Administration, Department of Agriculture, Agency for Toxic Substance and Disease Registry, National Center for Health Statistics, and National Toxicology Program and from representatives from academia, environmental organizations, and the regulated community. The committee was provided with written testimony and new scientific papers that have appeared since 2003 (and thus were not available for consideration by EPA in the Reassessment).
It is important to recognize what the committee did not consider to be part of its charge. Although the committee made every effort to consider critical new studies that have appeared since the last revision of Part III of the Reassessment, it did not conduct an exhaustive and detailed review of all scientific information published on TCDD and other dioxins since 2003, and any information that became available to the public after the date of the committee’s last meeting (July 7, 2005) was not considered. The committee did not attempt to “redo” the risk assessment—rather, it tried to provide constructive comments in areas in which the scientific approaches or justifications were thought to need improvement, the expectation being that EPA might need to reconsider and revise its approaches and documentation accordingly.
The final recommendations of the committee are offered to EPA with the recognition and appreciation of the enormous amount of time and effort that has been committed to the execution of this Reassessment for nearly 14 years. Although many of the comments are, not surprisingly, critical of certain aspects or approaches taken by EPA, the committee was impressed overall with the tremendous dedication and hard work that has gone into the creation of the Reassessment. The committee hopes the report will be of value in assisting EPA to make final changes to Part III that will allow the timely release of a scientifically defensible document. The committee further hopes that this review will help to guide all federal agencies in making rational and defensible health and environmental policies that adequately protect human health and the environment from the adverse effects of TCDD, other dioxins, and DLCs in the environment.
The Committee on EPA’s Exposure and Human Health Reassessment of TCDD and Related Compounds was aided immensely by a number of in-
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
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
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
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
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, |
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1-1 |
Benzene ring (a) with conjugated bonds and (b) with inner ring depicting conjugated bonds, |
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1-2 |
Double benzene ring structures of (a) dioxins and (b) furans, |
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1-3 |
Biphenyl ring structure of PCBs, |
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1-4 |
Examples of toxic PCDDs, PCDFs, and PCBs of interest in the Reassessment, |
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2-1 |
Vmax, |
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5-1 |
Possible mechanism for TCDD hepatocarcinogenicity, |
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5-2 |
Range of plausible CSF values: Consideration of parameter confidence intervals only, |
TABLES
1-1 |
TEFs for Humans and Nonhuman Mammals, |
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1-2 |
Summary of North American PCDD, PCDF, and PCB TEQ WHO Concentrations in Environmental Media and Food, |
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2-1 |
Categories of Key Decisions EPA Faced in Characterizing Cancer Risk, |
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2-2 |
Categories of Key Decisions EPA Faced in Characterizing Noncancer Risk, |
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2-3 |
Components of a Systematic Review, |
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5-1 |
Dioxin Cancer Bioassays, |
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5-2 |
TCDD, Other Dioxins, and DLC Cancer Bioassays, |