Review of EPA’s
Integrated Risk
Information System
(IRIS) Process

Committee to Review the IRIS Process

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.

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Committee to Review the IRIS Process Board on Environmental Studies and Toxicology Division on Earth and Life Studies

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THE NATIONAL ACADEMIES PRESS 500 Fifth Street, NW Washington, DC 20001 NOTICE: The project that is the subject of this report was approved by the Governing Board of the Nation- al 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 re- sponsible for the report were chosen for their special competences and with regard for appropriate balance. This project was supported by Contract EP-C-09-003 between the National Academy of Sciences and the U.S. Environmental Protection Agency. Any opinions, findings, conclusions, or recommendations ex- pressed in this publication are those of the authors and do not necessarily reflect the view of the organiza- tions or agencies that provided support for this project. International Standard Book Number-13: 978-0-309-30414-6 International Standard Book Number-10: 0-309-30414-8 Additional copies of this report are available for sale from the National Academies Press, 500 Fifth Street, NW, Keck 360, Washington, DC 20001; (800) 624-6242 or (202) 334-3313; http://www.nap.edu/. Copyright 2014 by the National Academy of Sciences. All rights reserved. Printed in the United States of America

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The National Academy of Sciences is a private, nonprofit, self-perpetuating society of distinguished schol- ars 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 tech- nical 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 Acade- my 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 pro- grams aimed at meeting national needs, encourages education and research, and recognizes the superior achievements of engineers. Dr. C. D. Mote, Jr., 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 ser- vices 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 iden- tify 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 Acad- emy, 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. C. D. Mote, Jr., are chair and vice chair, respectively, of the Na- tional Research Council. www.national-academies.org

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COMMITTEE TO REVIEW THE IRIS PROCESS Members JONATHAN M. SAMET (Chair), University of Southern California SCOTT BARTELL, University of California, Irvine LISA BERO, University of California, San Francisco ANN BOSTROM, University of Washington KAY DICKERSIN, Johns Hopkins School of Public Health, MD DAVID C. DORMAN, North Carolina State University DAVID L. EATON, University of Washington JOE G. GARCIA, University of Arizona MIGUEL HERNÁN, Harvard School of Public Health, MA JAMES S. HOUSE, University of Michigan MARGARET M. MACDONELL, Argonne National Laboratory, IL RICHARD P. SCHEINES, Carnegie Mellon University, PA LEONARD M. SIEGEL, Center for Public Environmental Oversight, CA ROBERT B. WALLACE, University of Iowa College of Public Health YILIANG ZHU, University of South Florida Staff ELLEN K. MANTUS, Project Director KERI STOEVER, Research Associate NORMAN GROSSBLATT, Senior Editor MIRSADA KARALIC-LONCAREVIC, Manager, Technical Information Center RADIAH ROSE, Manager, Editorial Projects IVORY CLARKE, Senior Program Assistant Sponsors U.S. ENVIRONMENTAL PROTECTION AGENCY v

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BOARD ON ENVIRONMENTAL STUDIES AND TOXICOLOGY1 Members ROGENE F. HENDERSON (Chair), Lovelace Respiratory Research Institute, Albuquerque, NM PRAVEEN AMAR, Clean Air Task Force, Boston, MA RICHARD A. BECKER, American Chemistry Council, Washington, DC MICHAEL J. BRADLEY, M.J. Bradley & Associates, Concord, MA JONATHAN Z. CANNON, University of Virginia, Charlottesville, VA GAIL CHARNLEY, HealthRisk Strategies, Washington, DC DOMINIC M. DI TORRO, University of Delaware, Newark, DE DAVID C. DORMAN, North Carolina State University, Raleigh, NC CHARLES T. DRISCOLL, JR., Syracuse University, Syracuse, NY WILLIAM H. FARLAND, Colorado State University, Fort Collins, CO LYNN R. GOLDMAN, George Washington University, Washington, DC LINDA E. GREER, Natural Resources Defense Council, Washington, DC WILLIAM E. HALPERIN, Rutgers University, Newark, NJ STEVEN P. HAMBURG, Environmental Defense Fund, New York, NY ROBERT A. HIATT, University of California, San Francisco, CA PHILIP K. HOPKE, Clarkson University, Potsdam, NY SAMUEL KACEW, University of Ottawa, Ontario, ON, Canada H. SCOTT MATTHEWS, Carnegie Mellon University, Pittsburgh, PA THOMAS E. MCKONE, University of California, Berkeley, CA TERRY L. MEDLEY, E.I. du Pont de Nemours & Company, Wilmington, DE JANA MILFORD, University of Colorado, Boulder, CO MARK A. RATNER, Northwestern University, Evanston, IL JOAN B. ROSE, Michigan State University, East Lansing, MI GINA M. SOLOMON, California Environmental Protection Agency, Sacramento, CA PETER S. THORNE, University of Iowa, Iowa City, IA JOYCE S. TSUJI, Exponent Environmental Group, Bellevue, WA Senior Staff JAMES J. REISA, Director DAVID J. POLICANSKY, Scholar RAYMOND A. WASSEL, Senior Program Officer for Environmental Studies ELLEN K. MANTUS, Senior Program Officer for Risk Analysis SUSAN N.J. MARTEL, Senior Program Officer for Toxicology MIRSADA KARALIC-LONCAREVIC, Manager, Technical Information Center RADIAH ROSE, Manager, Editorial Projects 1 This study was planned, overseen, and supported by the Board on Environmental Studies and Toxicology. vi

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OTHER REPORTS OF THE BOARD ON ENVIRONMENTAL STUDIES AND TOXICOLOGY Review of the Environmental Protection Agency’s State-of-the-Science Evaluation of Nonmonotonic Dose–Response Relationships as They Apply to Endocrine Disruptors (2014) Assessing Risks to Endangered and Threatened Species from Pesticides (2013) Science for Environmental Protection: The Road Ahead (2012) Exposure Science in the 21st Century: A Vision and A Strategy (2012) A Research Strategy for Environmental, Health, and Safety Aspects of Engineered Nanomaterials (2012) Macondo Well–Deepwater Horizon Blowout: Lessons for Improving Offshore Drilling Safety (2012) Feasibility of Using Mycoherbicides for Controlling Illicit Drug Crops (2011) Improving Health in the United States: The Role of Health Impact Assessment (2011) A Risk-Characterization Framework for Decision-Making at the Food and Drug Administration (2011) Review of the Environmental Protection Agency’s Draft IRIS Assessment of Formaldehyde (2011) Toxicity-Pathway-Based Risk Assessment: Preparing for Paradigm Change (2010) The Use of Title 42 Authority at the U.S. Environmental Protection Agency (2010) Review of the Environmental Protection Agency’s Draft IRIS Assessment of Tetrachloroethylene (2010) Hidden Costs of Energy: Unpriced Consequences of Energy Production and Use (2009) Contaminated Water Supplies at Camp Lejeune—Assessing Potential Health Effects (2009) Review of the Federal Strategy for Nanotechnology-Related Environmental, Health, and Safety Research (2009) Science and Decisions: Advancing Risk Assessment (2009) Phthalates and Cumulative Risk Assessment: The Tasks Ahead (2008) Estimating Mortality Risk Reduction and Economic Benefits from Controlling Ozone Air Pollution (2008) Respiratory Diseases Research at NIOSH (2008) Evaluating Research Efficiency in the U.S. Environmental Protection Agency (2008) Hydrology, Ecology, and Fishes of the Klamath River Basin (2008) Applications of Toxicogenomic Technologies to Predictive Toxicology and Risk Assessment (2007) Models in Environmental Regulatory Decision Making (2007) Toxicity Testing in the Twenty-first Century: A Vision and a Strategy (2007) Sediment Dredging at Superfund Megasites: Assessing the Effectiveness (2007) Environmental Impacts of Wind-Energy Projects (2007) Scientific Review of the Proposed Risk Assessment Bulletin from the Office of Management and Budget (2007) 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) 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) vii

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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 (seventeen volumes, 2000-2014) 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 (2000) 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) Upstream: Salmon and Society in the Pacific Northwest (1996) Science and the Endangered Species Act (1995) Wetlands: Characteristics and Boundaries (1995) Biologic Markers (five volumes, 1989-1995) 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 viii

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Preface In 2011, the National Research Council (NRC) released a report that reviewed the draft health assessment on formaldehyde produced by the US Environmental Protection (EPA) for its Integrated Risk Information System (IRIS). The report recommended improvements in the for- maldehyde assessment and in the program responsible for producing the assessment. Congress directed EPA to implement the report’s recommendations and then asked the NRC to review the changes that EPA was making (or proposing to make) in response to the recommendations. In the present report, the Committee to Review the IRIS Process first provides an overview of some general issues associated with IRIS assessments. It then addresses evidence identifica- tion and evaluation for IRIS assessments and discusses evidence integration for hazard evalua- tion and methods for calculating reference values and unit risks. It concludes with some overall recommendations and considerations for future directions. This report has been reviewed in draft form by persons chosen for their diverse perspec- tives and technical expertise in accordance with procedures approved by the NRC 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 in- tegrity of the deliberative process. We thank the following for their review of this report: Gary Ginsberg, Connecticut Department of Public Health; William Griffith, University of Washing- ton; Thomas Hartung, Johns Hopkins Bloomberg School of Public Health; Gunnar Johanson, Karolinska Institute; Roderick Little, University of Michigan; Malcolm Macleod, University of Edinburgh; Peter McClure, SRC Environmental Science Center; Ana Navas-Acien, Johns Hop- kins Bloomberg School of Public Health; Joseph Rodricks, ENVIRON; Ivan Rusyn, University of North Carolina at Chapel Hill; Christopher Schmid, Brown University; Kurt Straif, Interna- tional Agency for Research on Cancer; and Joyce Tsuji, Exponent Environmental Group, Inc. Although the reviewers listed above have provided many constructive comments and sug- gestions, 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 re- view coordinator, Danny Reible, Texas Tech University, and the review monitor, Mark Cullen, Stanford University. Appointed by the NRC, they were responsible for making certain that an independent examination of the report was carried out in accordance with institutional proce- dures and that all review comments were carefully considered. Responsibility for the final con- tent of the report rests entirely with the committee and the institution. The committee gratefully acknowledges the following for their presentations to the com- mittee during open sessions: Richard Atkinson, St. George’s University of London; David Budescu, Fordham University; Weihsueh Chiu, Vincent Cogliano, Glinda Cooper, Lynn Flow- ers, Samantha Jones, and Kenneth Olden, EPA; Chris Frey, North Carolina State University; Steve Goodman, Stanford University; Thomas Hartung and Karen Robinson, Johns Hopkins University; Jay Kadane, Carnegie Mellon University; Tim Lash, Emory University; George Lei- kauf, University of Pittsburgh; Malcolm MacLeod, University of Edinburgh; Lorenz Rhomberg, ix

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x Preface Gradient Corporation; Joe Rodricks, ENVIRON; David Schwartz, University of Colorado; Kris- tina Thayer, NTP; Duncan Thomas, University of Southern California; Rusty Thomas, The Hamner Institutes for Health Sciences; Thomas Wallsten, University of Maryland; Tracey Woodruff, University of California, San Francisco; and Lauren Zeise, California EPA. The committee members also thank the staff of EPA for being so helpful in answering their numerous questions throughout the study process. The committee is grateful for the assistance of the National Research Council staff in pre- paring this report. Staff members who contributed to the effort are Ellen Mantus, project director; Keri Stoever, research associate; James Reisa, director of the Board on Environmental Studies and Toxicology; Norman Grossblatt, senior editor; Mirsada Karalic-Loncarevic, manager of the Technical Information Center; Radiah Rose, manager of editorial projects; and Ivory Clarke, senior program assistant. I especially thank the members of the committee for their efforts throughout the develop- ment of this report. Jonathan M. Samet, Chair Committee to Review the IRIS Process

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Abbreviations ADH1 Alcohol Dehydrogenase ADME Absorption, Distribution, Metabolism, and Excretion BEIR Biological Effects of Ionizing Radiation BMD Benchmark Dose BMDL Benchmark Dose Lower-Confidence Limit BMDS Benchmark Dose Software BUGS Bayesian Inference Using Gibbs Sampling CAAC Chemical Assessment Advisory Committee CAST Chemical Assessment Support Team CCRIS Chemical Carcinogenesis Research Information System CNS Central Nervous System CONSORT Consolidated Standards of Reporting Trials DNA Deoxyribonucleic Acid ECVAM European Centre for the Validation of Alternative Methods ED Effective Dose ELISA Enzyme-Linked Immunosorbent Assay EPA US Environmental Protection Agency FDA US Food and Drug Administration GENETOX Genetic Toxicology GLP Good Laboratory Practice GMP Good Manufacturing Practice GRADE Grading of Recommendations Assessment, Development and Evaluation HERO Health & Environmental Research Online HIV Human Immunodeficiency Virus HSDB Hazardous Substances Data Bank IARC International Agency for Research on Cancer ICCVAM Interagency Coordinating Committee on the Validation of Alternative Methods IHAD Integrated Hazard Assessment Database IOM Institute of Medicine IRIS Integrated Risk Information System LED Lower Effective Dose LOAEL Lowest Observed-Adverse-Effect Level MNP Netherlands Environmental Assessment Agency NOAEL No-Observed-Adverse-Effect Level NRC National Research Council NTP National Toxicology Program OHAT Office of Hazard Assessment and Toxicology OPP Office of Pesticide Programs PBPK Physiologically Based Pharmacokinetic POD Point of Departure PRISM Planning Tool for Resource Integration, Synchronization, and Management QC Quality Control RIVM Netherlands National Institute for Public Health and the Environment RfC Reference Concentration xi

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xii Abbreviations RfD Reference Dose RTECS Registry of Toxic Effects of Chemical Substances SES Socioeconomic Status TSCA Toxic Substance Control Act TSCATS Toxic Substance Control Act Test Submissions UF Uncertainty Factor WOE Weight of Evidence

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Contents SUMMARY ........................................................................................................................................... 3 1 INTRODUCTION .................................................................................................................... 10 The Integrated Risk Information System and the 2011 Formaldehyde Report, 10 Improvements in the Integrated Risk Information System, 11 Systematic Review, 13 The Committee, Its Task, and Its Approach, 14 Organization of Report, 15 References, 15 2 GENERAL PROCESS ISSUES............................................................................................... 17 General Recommendations in the 2011 National Research Council Formaldeyde Report, 17 Response to the National Research Council Formaldehyde Report, 17 Increasing Efficiency in the IRIS Process, 24 Using Expert Judgment in the IRIS Process, 25 Findings and Recommendations, 26 References, 28 3 PROBLEM FORMULATION AND PROTOCOL DEVELOPMENT ............................... 30 Problem Formulation, 30 Protocol Development, 36 Findings and Recommendations, 37 References, 37 4 EVIDENCE IDENTIFICATION ............................................................................................ 40 Consideration of Bias in Evidence Identification, 40 Recommendations on Evidence Identification in the National Research Council Formaldeyde Report, 41 Evaluation of Environmental Protection Agency Response to the National Research Council Formaldehyde Report, 42 Comments on Best Practices for Evidence Identification, 58 Findings and Recommendations, 58 References, 60 5 EVIDENCE EVALUATION ................................................................................................... 63 Recommendations on Evidence Evaluation from the National Research Council Formaldeyde Report, 63 Evaluation of Environmental Protection Agency Response to the National Research Council Formaldehyde Report, 64 Best Practices for Evaluating Evidence From Individual Studies, 66 Evaluating Evidence from Individual Studies, 76 Findings and Recommendations, 77 References, 80 xiii

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xiv Contents 6 EVIDENCE INTEGRATION FOR HAZARD IDENTIFICATION ................................... 85 Terminology, 86 Evaluating Strengths and Weakness of Evidence, 87 Organizing Principles for Integrating Evidence, 87 The Bradford Hill Guidelines, 91 Current Environmental Protection Agency Approach to Integrating Evidence: The Agency’s Response to Recommendations in the National Research Council Formaldehyde Report, 92 Options for Moving Forward, 96 Findings and Recommendations, 105 References, 106 7 DERIVATION OF TOXICITY VALUES ............................................................................ 110 Recommendations on Calculation of Toxicity Values in the National Research Council Formaldeyde Report, 113 Evaluation of Environmental Protection Agency Response to the National Research Council Formaldehyde Report, 113 Relevant Methodologic Issues, 118 Findings and Recommendations, 129 References, 130 8 FUTURE DIRECTIONS ........................................................................................................ 135 Overall Evaluation, 135 Specific Recommendations, 136 Lessons Learned, 136 Looking Forward, 139 References, 139 APPENDIXES A BIOGRAPHIC INFORMATION ON THE COMMITTEE TO REVIEW THE IRIS PROCESS .............................................................................................................. 140 B WORKSHOP AGENDA ........................................................................................................ 144 C PRIMER ON BAYESIAN METHOD................................................................................... 150 BOXES, FIGURES, AND TABLES BOXES 1-1 Statement of Task, 15 2-1 General Recommendations on the IRIS Process in the 2011 National Research Council Formaldehyde Report, 18 3-1 Systematic-Review Protocol Elements, 37 4-1 Recommendations on Evidence Identification in the 2011 National Research Council Formaldehyde Report, 42 5-1 Recommendations from the National Research Council Formaldehyde Report on Evidence Evaluation, 64 5-2 Aspects to Consider in Evaluating Study Quality as Listed in the Preamble for IRIS Assessments, 65 5-3 Considerations for a Template for Evaluating an Epidemiologic Study, 69 6-1 Recommendations on Evidence Integration from 2011 National Research Council Formaldehyde Report, 92

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Contents xv 7-1 Recommendations on Calculation of Toxicity Values in the 2011 National Research Council Formaldehyde Report, 114 7-2 Considerations in Deriving Toxicity Values, 115 7-3 Standard Descriptors to Characterize Level of Confidence, 118 8-1 Recommendations Directly Relevant to Current Revisions, 137 FIGURES S-1 Systematic review in the context of the IRIS process, 4 1-1 Timeline of events since release of the NRC report, Review of the Environmental Protection Agency’s Draft IRIS Assessment of Formaldehyde, 12 1-2 Systematic review in the context of the IRIS process, 14 3-1 The IRIS process; problem formulation and protocol development are highlighted, 31 3-2 The risk-assessment, risk-management paradigm, 31 4-1 The IRIS process; the evidence-identification step is highlighted, 40 5-1 The IRIS process; the evidence-evaluation step is highlighted, 63 5-2 Sample graphic display of risk-of-bias evaluations, 77 5-3 Truncated graph of the risk-of-bias summary that shows review authors’ judgments about each risk-of-bias item for each included study, 78 6-1 The IRIS process; the hazard-identification process is highlighted, 85 6-2 Bayesian estimate of 1, 103 7-1 The IRIS process; the step for dose-response assessment and derivation of toxicity values is highlighted, 110 7-2 Derivation of toxicity values, 112 7-3 Simple Bayesian framework for estimating human toxicity from results of an animal study, 120 7-4 Bayesian framework for combining studies of different types, 122 7-5 Characterization of overarching uncertainty requires vertical and horizontal integration of uncertainties in every stage of the assessment process, 126 7-6 Cumulative distribution of reference concentrations (RfCs) derived from multiple neurotoxicity end points from a collection of epidemiologic studies and laboratory experiments on humans or animals, 127 TABLES 1-1 Materials Received from the US Environmental Protection Agency, 13 3-1 Outcomes for Consideration in Problem Formulation, 35 4-1 Comparison of EPA Draft Materials with IOM Systematic-Review Standards for Evidence Identification, 43 5-1 Types of Biases and Their Sources, 68 6-1 Common Strengths and Weaknesses of Human Epidemiologic (HE), Experimental Animal (EA), and Mechanistic (MECH) Studies for Hazard Identification, 88 6-2 Categories of Carcinogenicity, 94 6-3 Categories of Evidential Weight for Causality, 94 6-4 Comparison of Hill, GRADE, Navigation Guide, and NTP Criteria for Evaluating and Integrating Evidence, 99 6-5 Example Conversion of Quantitative Output to Qualitative Categorical Judgments, 101 7-1 Definitions of Terms Related to Derivation of Toxicity Values, 111 7-2 Conversion of Traditional EPA Uncertainty Factors to Bayesian Prior Standard Deviations on a Natural Log Scale Using 1-Sided or 2-Sided Confidence Intervals, 120 7-3 Summary of Results of the Two-Stage Bayesian Example, 124

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