SCIENCE AND DECISIONS

Advancing Risk Assessment

Committee on Improving Risk Analysis Approaches Used by the U.S. EPA

Board on Environmental Studies and Toxicology

Division on Earth and Life Studies

NATIONAL RESEARCH COUNCIL OF THE NATIONAL ACADEMIES

THE NATIONAL ACADEMIES PRESS

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Committee on Improving Risk Analysis Approaches Used by the U.S. EPA 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 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 EP-C-06-056 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 authors and do not necessarily reflect the view of the organizations or agencies that provided support for this project. Library of Congress Cataloging-in-Publication Data National Research Council (U.S.). Committee on Improving Risk Analysis Approaches Used by the U.S. EPA. Science and decisions : advancing risk assessment / Committee on Improving Risk Analysis Approaches Used by the U.S. EPA, Board on Environmental Studies and Toxicology, Division on Earth and Life Studies. p. cm. Includes bibliographical references. ISBN-13: 978-0-309-12046-3 (pbk.) ISBN-10: 0-309-12046-2 (pbk.) ISBN-13: 978-0-309-12047-0 (pdf) ISBN-10: 0-309-12047-0 (pdf) 1. Environmental risk assessment—United States. 2. Technology—Risk assessment—United States. 3. Health risk assessment—United States. I. National Research Council (U.S.). Board on Environmental Studies and Toxicology. II. National Research Council (U.S.). Division on Earth and Life Studies. III. Title. GE150.N37 2009 361.1—dc22 2008055771 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 2009 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 distin- guished 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 au- tonomous 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. Charles M. Vest 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 com- munities. The Council is administered jointly by both Academies and the Institute of Medicine. Dr. Ralph J. Cicerone and Dr. Charles M. Vest are chair and vice chair, respectively, of the National Research Council. www.national-academies.org

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COMMITTEE ON IMPROvINg RISk ANALySIS APPROACHES USED by THE U.S. ENvIRONMENTAL PROTECTION AgENCy Members Thomas a. Burke (Chair), Johns Hopkins Bloomberg School of Public Health, Baltimore, MD a. John Bailer, Miami University, Oxford, OH John m. BalBus, Environmental Defense, Washington, DC Joshua T. Cohen, Tufts Medical Center, Boston, MA adam m. Finkel, University of Medicine and Dentistry of New Jersey, Piscataway, NJ Gary GinsBerG, Connecticut Department of Public Health, Hartford, CT BruCe k. hope, Oregon Department of Environmental Quality, Portland, OR JonaThan i. levy, Harvard School of Public Health, Boston, MA Thomas e. mCkone, University of California, Berkeley, CA GreGory m. paoli, Risk Sciences International, Ottawa, ON, Canada Charles poole, University of North Carolina School of Public Health, Chapel Hill, NC Joseph v. rodriCks, ENVIRON International Corporation, Arlington, VA Bailus Walker, Jr., Howard University Medical Center, Washington, DC Terry F. yosie, World Environment Center, Washington, DC lauren Zeise, California Environmental Protection Agency, Oakland, CA Staff eileen n. aBT, Project Director JenniFer saunders, Associate Program Officer (through December 2007) norman GrossBlaTT, Senior Editor ruTh CrossGrove, Senior Editor mirsada karaliC-lonCareviC, Manager, Technical Information Center radiah a. rose, Editorial Projects Manager morGan r. moTTo, Senior Program Assistant (through February 2008) panola Golson, Senior Program Assistant Sponsor u.s. environmenTal proTeCTion aGenCy 

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bOARD ON ENvIRONMENTAL STUDIES AND TOxICOLOgy1 Members JonaThan m. sameT (Chair), University of Southern California, Los Angeles ramón alvareZ, Environmental Defense Fund, Austin, TX John m. BalBus, Environmental Defense Fund, Washington, DC dallas BurTraW, Resources for the Future, Washington, DC James s. Bus, Dow Chemical Company, Midland, MI ruTh deFries, Columbia University, New York, NY CosTel d. denson, University of Delaware, Newark e. donald ellioTT, Willkie, Farr & Gallagher LLP, Washington, DC mary r. enGlish, University of Tennessee, Knoxville J. paul Gilman, Covanta Energy Corporation, Fairfield, NJ JudiTh a. Graham (Retired), Pittsboro, NC William m. leWis, Jr., University of Colorado, Boulder JudiTh l. meyer, University of Georgia, Athens dennis d. murphy, University of Nevada, Reno 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 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 eileen n. aBT, Senior Program Officer for Risk Analysis susan n.J. marTel, Senior Program Officer for Toxicology kulBir Bakshi, Senior Program Officer ellen k. manTus, Senior Program Officer ruTh e. CrossGrove, Senior Editor 1This study was planned, overseen, and supported by the Board on Environmental Studies and Toxicology. i

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OTHER REPORTS OF THE bOARD ON ENvIRONMENTAL STUDIES AND TOxICOLOgy 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) 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 (seven volumes, 2000-2008) 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) ii

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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 iii

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Preface Risk assessment has become a dominant public-policy tool for informing risk manag- ers and the public about the different policy options for protecting public health and the environment. Risk assessment has been instrumental in fulfilling the missions of the U.S. Environmental Protection Agency (EPA) and other federal and state agencies in evaluating public-health concerns, informing regulatory and technologic decisions, setting priorities for research and funding, and developing approaches for cost-benefit analyses. However, risk assessment is at a crossroads. Despite advances in the field, it faces a num- ber of substantial challenges, including long delays in completing complex risk assessments, some of which take decades to complete; lack of data, which leads to important uncertainty in risk assessments; and the need for risk assessment of many unevaluated chemicals in the marketplace and emerging agents. To address those challenges, EPA asked the National Acad- emies to develop recommendations for improving the agency’s risk-analysis approaches. In this report, the Committee on Improving Risk Analysis Approaches Used by the U.S. EPA conducts a scientific and technical review of EPA’s current risk-analysis concepts and practices and offers recommendations for practical improvements that EPA could make in the near term (2-5 y) and in the longer term (10-20 y). The committee focused on human health risk assessment but considered the implications of its conclusions and recommenda- tions for ecologic risk assessment. This report has been reviewed in draft form by persons chosen for their diverse per- spectives 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 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 wish to thank the following for their review of this report: Lawrence W. Barnthouse, LWB Environmental Services, Inc.; Roger G. Bea, University of California, Berkeley; Allison C. Cullen, University of Washington; William H. Farland, Colorado State University; J. Paul ix

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x PREFACE Gilman, Convanta Energy Corporation; Bernard D. Goldstein, University of Pittsburgh; Lynn R. Goldman, Johns Hopkins University; Dale B. Hattis, Clark University; Carol J. Henry, American Chemistry Council (retired); Daniel Krewski, University of Ottawa; Amy D. Kyle, University of California, Berkeley; Ronald L. Melnick, National Institute of En- vironmental Health Sciences; Gilbert S. Omenn, University of Michigan Medical School; Louise Ryan, Harvard School of Public Health; and Detlof von Winterfeldt, University of Southern California. 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 the report was overseen by the review coordinator, William Glaze, Georgetown, TX and the review monitor, John Ahearne, Sigma Xi. Appointed by the National Research Council, they were responsible for making certain that an independent examination of the report was carried out in accor- dance with institutional procedures and that all review comments were carefully considered. Responsibility for the final content of the report rests entirely with the committee and the institution. The committee gratefully acknowledges the following for making presentations to the committee: Nicholas Ashford, Massachusetts Institute of Technology; Robert Brenner, Michael Callahan, George Gray, Jim Jones, Tina Levine, Robert Kavlock, Al McGartland, Peter Preuss, Michael Shapiro, Glenn Suter, and Harold Zenick, EPA; Douglas Crawford- Brown, University of North Carolina; Kenny Crump, ENVIRON International Corporation; Robert Donkers, Delegation of the European Commission to the United States; William Farland, Colorado State University; James A. Fava, Five Winds International; Penny Fenner- Crisp, International Life Sciences Institute Research Foundation; Dale Hattis, Clark Univer- sity; Amy D. Kyle, University of California, Berkeley; Rebecca Parkin, George Washington University; Chris Portier, National Institute of Environmental Health Sciences; Lorenz Rhomberg, Gradient Corporation; Jennifer Sass, Natural Resources Defense Council; Jay Silkworth, General Electric Company; and Thomas Sinks, Centers for Disease Control and Prevention. The committee is thankful for the useful input of Roger Cooke, Resources for the Future and Dorothy Patton, Environmental Protection Agency (retired) in the early deliberations of this study. The committee is also grateful for the assistance of the National Research Council staff in preparing this report. Staff members who contributed to this effort are Eileen Abt, project director; James Reisa, director of the Board on Environmental Studies and Toxicol- ogy; Jennifer Saunders, associate program officer; Norman Grossblatt and Ruth Crossgrove, senior editors; Mirsada Karalic-Loncarevic, manager of the Technical Information Center; Radiah Rose, editorial projects manager; and Morgan Motto and Panola Golson, senior program assistants. I would especially like to thank the committee members for their efforts throughout the development of this report. Thomas Burke, Chair Committee on Improving Risk Analysis Approaches Used by the U.S. EPA

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Abbreviations ARARs Applicable or Relevant and Appropriate Requirements ATSDR Agency for Toxic Substances and Disease Registry BMD benchmark dose CARE Community Action for a Renewed Environment CASAC Clean Air Scientific Advisory Committee CBPR community-based participatory research CERCLA Comprehensive Environmental Response Compensation and Liability Act CTE central tendency exposure DBP dibutyl phthalate DBPs disinfection byproducts EPA U.S. Environmental Protection Agency EPHT Environmental Public Health Tracking Program FIFRA Federal Insecticide, Fungicide and Rodenticide Act FQPA Food Quality Protection Act GAO Government Accountability Office GIS geographic information systems HAPs hazardous air pollutants HI hazard index IARC International Agency for Research on Cancer IPCS International Program on Chemical Safety IRIS Integrated Risk Information System LNT linear, no-threshold MACT maximum achievable control technology MCL maximum contaminant level xi

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xii ABBREVIATIONS MCLG maximum contaminant level goal MeCl2 methylene chloride MEI maximally exposed individual MOA mode of action MOE margin of exposure MTD maximum tolerated dose NAAQS National Ambient Air Quality Standards NCEA National Center for Environmental Assessment NEJAC National Environmental Justice Advisory Council NER National Exposure Registry NHANES National Health and Nutrition Examination Survey NOAEL no-observed-adverse-effect level NPL National Priorities List NRC National Research Council NTP National Toxicology Program OAR Office of Air and Radiation OP organophosphate OPPTS Office of Prevention, Pesticides and Toxic Substances OSWER Office of Solid Waste and Emergency Response OW Office of Water PBPK physiologically based pharmacokinetic PD pharmacodynamic PDF probability density function PK pharmacokinetic POD point of departure PPDG Pesticide Program Dialogue Group RAGS Risk Assessment Guidance for Superfund Red Book Risk Assessment in the Federal Goernment: Managing the Process RfC reference concentration RfD reference dose RI/FS remedial investigation and feasibility study RME reasonable maximum exposure ROD record of decision RR relative risk RRM relative risk model SDWA Safe Drinking Water Act SEP socioeconomic position TCA 1,1,1-trichloroethane TCE trichloroethylene TSCA Toxic Substances Control Act UF uncertainty factor VOI value-of-information WHO World Health Organization WOE weight-of-evidence

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Contents SUMMARy 3 1 INTRODUCTION 15 Background, 16 Challenges, 17 Traditional and Emerging Views of the Roles of Risk Assessment, 18 Technical Impediments to Risk Assessment, 20 Improving Risk Analysis, 21 The National Research Council Committee, 22 Organization of the Report, 23 References, 24 2 EvOLUTION AND USE OF RISk ASSESSMENT IN THE ENvIRONMENTAL PROTECTION AgENCy: CURRENT PRACTICE AND FUTURE PROSPECTS 26 Overview, 26 Statutory Plan and Regulatory Structure, 27 The Pivotal Role of the Red Book, 29 Current Concepts and Practices, 36 Institutional Arrangements for Managing the Process, 47 Extramural Influences and Participants, 53 Conclusions and Recommendations, 57 References, 59 3 THE DESIgN OF RISk ASSESSMENTS 65 Risk Assessment As a Design Challenge, 65 Design Considerations: Objectives, Constraints, and Tradeoffs, 68 xiii

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xi CONTENTS Environmental Protection Agency’s Current Guidance Related to Risk-Assessment Design, 73 Incorporating Value-of-Information Principles in Formative and Iterative Design, 80 Conclusions, 89 Recommendations, 90 References, 90 4 UNCERTAINTy AND vARIAbILITy: THE RECURRINg AND RECALCITRANT ELEMENTS OF RISk ASSESSMENT 93 Introduction to the Issues and Terminology, 93 Uncertainty in Risk Assessment, 97 Variability and Vulnerability in Risk Assessment, 108 Uncertainty and Variability in Specific Components of Risk Assessment, 113 Principles for Addressing Uncertainty and Variability, 119 Recommendations, 121 References, 122 5 TOWARD A UNIFIED APPROACH TO DOSE-RESPONSE ASSESSMENT 127 The Need for an Improved Dose-Response Framework, 127 A Unified Framework and Approach for Dose-Response Assessment, 135 Case Studies and Possible Modeling Approaches, 151 Implementation, 173 Conclusions and Recommendations, 177 References, 182 6 SELECTION AND USE OF DEFAULTS 188 Current Environmental Protection Agency Policy on Defaults, 189 The Environmental Protection Agency’s System of Defaults, 193 Complications Introduced by Use of Defaults, 195 Enhancements of the Environmental Protection Agency’s Default Approach, 198 Performing Multiple Risk Characterizations for Alternative Models, 205 Conclusions and Recommendations, 207 References, 208 7 IMPLEMENTINg CUMULATIvE RISk ASSESSMENT 213 Introduction and Definitions, 213 History of Cumulative Risk Assessment, 216 Approaches to Cumulative Risk Assessment, 219 Key Concerns and Proposed Modifications, 223 Recommendations, 235 References, 237 8 IMPROvINg THE UTILITy OF RISk ASSESSMENT 240 Beyond the Red Book, 241 A Decision-Making Framework that Maximizes the Utility of Risk Assessment, 242 The Framework: An Overview, 245 Additional Improvements Offered by the Framework, 251 Potential Concerns Raised by the Framework, 253 Conclusions and Recommendations, 255 References, 256

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x CONTENTS 9 TOWARD IMPROvED RISk-bASED DECISION-MAkINg 258 Transition to the Framework for Risk-Based Decision-Making, 259 Institutional Processes, 259 Leadership and Management, 262 Conclusions and Recommendations, 262 References, 271 APPENDIxES A bIOgRAPHIC INFORMATION ON THE COMMITTEE ON IMPROvINg RISk ANALySIS APPROACHES USED by THE ENvIRONMENTAL PROTECTION AgENCy 275 b STATEMENT OF TASk OF THE COMMITTEE ON IMPROvINg RISk ANALySIS APPROACHES USED by THE ENvIRONMENTAL PROTECTION AgENCy 281 C TIMELINE OF SELECTED ENvIRONMENTAL PROTECTION AgENCy RISk-ASSESSMENT ACTIvITIES 283 D ENvIRONMENTAL PROTECTION AgENCy RESPONSE TO RECOMMENDATIONS FROM SELECTED NRC REPORTS: POLICy, ACTIvITy, AND PRACTICE 299 E ENvIRONMENTAL PROTECTION AgENCy PROgRAM AND REgION RESPONSES TO QUESTIONS FROM THE COMMITTEE 367 F CASE STUDIES OF THE FRAMEWORk FOR RISk-bASED DECISION-MAkINg 399 bOxES, FIgURES, AND TAbLES boxes 2-1 Agencywide Risk-Assessment Guidelines, 33 2-2 Science Policy and Defaults, 36 2-3 Agency Guidance on Risk Characterization: Attention to Uncertainty, 39 2-4 Commentary on Risk Characterization for the Dioxin Reassessment, 40 2-5 Guideline Implementation and Risk-Assessment Impacts, 42 2-6 Choices and a Reference Dose Value for Perchlorate, 44 2-7 Impact of New Studies, 47 2-8 Arsenic in Drinking Water: Uncertainties and Standard-Setting, 51 2-9 Risk Assessment Planning: Multiple Participants, 55 2-10 After Peer Review, 56 3-1 Selected Elements of Scope Considered During Planning and Scoping, 74 3-2 Selected Methodologic Considerations in Problem Formulation, 75 3-3 Planning and Scoping: An Example Summary Statement, 77 3-4 Major Elements of an Analysis Plan, 79

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xi CONTENTS 4-1 Terminology Related to Uncertainty and Variability, 96 4-2 Some Reasons Why It Is Important to Quantify Uncertainty and Variability, 98 4-3 Cognitive Tendencies That Affect Expert Judgment, 102 4-4 Levels of Uncertainty Analysis, 103 4-5 Examples of Uncertainties for Comparisons of Discrete and Continuous Possibilities, 106 4-6 Expressing and Distinguishing Model and Parameter Uncertainty, 108 4-7 Recommended Principles for Uncertainty and Variability Analysis, 120 5-1 A Risk-Specific Reference Dose, 140 5-2 Conceptual Model 1: Default Linear Low-Dose Extrapolation for Phosgene, 159 5-3 Calculating a Risk-Specific Dose and Confidence Bound in Conceptual Model 2, 164 6-1 Boron: Use of Data-Derived Uncertainty Factors, 200 8-1 Key Definitions Used in the Framework for Risk-Based Decision-Making, 246 8-2 Phase I of the Framework for Risk-Based Decision-Making (Problem Formulation and Scoping), 247 8-3 Phase II of the Framework for Risk-Based Decision-Making (Planning and Conduct of Risk Assessment), 248 8-4 Other Technical Analyses Necessary for the Framework for Risk-Based Decision- Making, 249 8-5 Elements of Phase III of the Framework for Risk-Based Decision-Making (Risk Management), 250 Figures S-1 A framework for risk-based decision-making that maximizes the utility of risk assessment, 11 2-1 The National Research Council risk-assessment–risk-management paradigm, 31 2-2 The World Health Organization’s framework for integrated health and ecologic risk assessment, 34 2-3 Timeline of major documentary milestones, 37 3-1 Schematic representation of the formative stages of risk-assessment design, 73 3-2 Illustration of the scope of a risk assessment, indicating both pathways considered (bold lines) and pathways not considered, 78 3-3 Schematic of the application of value-of-information analysis to assess the impacts of additional studies in a specific decision context, 83 3-4 Schematic of an analysis of the value of various methodologic opportunities (or “value of methods” analysis) to enhance the risk-assessment process and products, 87 4-1 Illustration of key components evaluated in human health risk assessment, tracking pollutants from environmental release to health effects, 95 4-2 Factors contributing to variability in risk in the population, 110

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xii CONTENTS 5-1 Current approach to noncancer and cancer dose-response assessment, 130 5-2 Value of physiologic parameter for three hypothetical populations, illustrating that population responses depend on a milieu of endogenous and exogenous exposures and on vulnerability of population due to health status and other biologic factors, 131 5-3a New conceptual framework for dose-response assessment, 136 5-3b Risk estimation and description under the new conceptual framework for dose- response assessment, 137 5-4 Linear low-dose response in the population dose-response relationship resulting from background xenobiotic and endogenous exposures and variable susceptibility in the population, 141 5-5 Nonlinear or threshold low-dose response relationships for individuals and populations, 142 5-6 Linear low-dose response models for individuals and population, 142 5-7 Dose-response relationships involving a continuous effect variable, 143 5-8 New unified process for selecting approach and methods for dose-response assessment for cancer and noncancer end points involves evaluation of background exposure and population vulnerability to ascertain potential for linearity in dose-response relationship at low doses and to ascertain vulnerable populations for possible assessment, 144 5-9 Population vulnerability distribution, 147 5-10 Examples of conceptual models to describe individual and population dose- response relationships, 149 5-11 Widely differing sensitivity can create a bimodal distribution of risk, 151 5-12 Three example conceptual models lead to different descriptions of dose-response relationships at individual or population levels, 152 5-13 Baseline airway reactivity as vulnerability factor for allergen-induced respiratory effects expressed as relative risk, 155 5-14 Effect of asthma-related gene polymorphisms on human vulnerability to asthma, 156 5-15 Dose-response relationship for liver spongiosis in 1,4-dioxane-exposed rats, 157 5-16 Steps in derivation of risk estimates for low-dose nonlinear end points, 161 5-17 Steps to derive population and individual risk estimates, with uncertainty in estimates from animal data, 167 5-18 A, AUC for proximate carcinogen in bladder in units of nanograms-minutes simulated for 500 people. B, simulated fraction bound in bladder, presumed to indicate differences in susceptibility due to PK and physiologic parameters, 170 8-1 A framework for risk-based decision-making that maximizes the utility of risk assessment, 243 9-1 A framework for risk-based decision-making that maximizes the utility of risk assessment, 268 E-1 Community involvement activities at NPL sites, 377 E-2 The framework for ecological risk assessment, 388 E-3 Conditions for regulation under SDWA 1996, 389

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xiii CONTENTS Tables 3-1 Transition in EPA Human Health Risk-Assessment Characteristics According to EPA, 69 4-1 Examples of Factors Affecting Susceptibility to Effects of Environmental Toxicants, 109 5-1 Potential Approaches to Establish Defaults to Implement the Unified Framework for Dose-Response Assessment, 175 6-1 Examples of Explicit EPA Default Carcinogen Risk-Assessment Assumptions, 194 6-2 Examples of Explicit EPA Default Noncarcinogen Risk-Assessment Assumptions, 195 6-3 Examples of “Missing” Defaults in EPA “Default” Dose-Response Assessments, 196 7-1 Modified Version of Stressor-Based Cumulative-Risk-Assessment Approach from Menzie et al. (2007) Oriented Around Discriminating among Risk- Management Options, 222 C-1 Timeline of Selected EPA Risk-Assessment Activities, 284 D-1 Environmental Protection Agency Response to National Research Council Recommendations of 1983-2006: Policy, Activity, and Practice, 301 E-1 Nine Evaluation Criteria for Superfund Remedial Alternatives, 378 E-2 Examples of Default Exposure Values with Percentiles, 380