REVIEW OF THE ENVIRONMENTAL PROTECTION
AGENCY’S STATE-OF-THE-SCIENCE EVALUATION OF
NONMONOTONIC
DOSE-RESPONSE
RELATIONSHIPS

AS THEY APPLY TO
ENDOCRINE DISRUPTORS

Committee to Review EPA’s State of the Science Paper
on Nonmonotonic Dose Response

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 to Review EPA’s State o the Scienc Paper t E of ce on Nonmono o otonic Dose R Response Board on Environme n ental Studies and Toxico s ology Division on Earth and Lif Studies D E fe

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COMMITTEE TO REVIEW EPA’S DRAFT STATE OF THE SCIENCE PAPER ON NONMONOTONIC DOSE RESPONSE Members DAVID A. SAVITZ (Chair), Brown University, Providence, RI ANDREA BACCARELLI, Harvard School of Public Health, Boston, MA ROBERT E. CHAPIN, Pfizer, Inc., Groton, CT RICHARD A. CORLEY, Pacific Northwest National Laboratory, Richland, WA GEORGE P. DASTON, Procter and Gamble Company, Mason, OH RUSS B. HAUSER, Harvard School of Public Health, Boston, MA AMY H. HERRING, University of North Carolina, Chapel Hill, NC ANDREAS KORTENKAMP, Brunel University, Uxbridge, United Kingdom HEATHER B. PATISAUL, North Carolina State University, Raleigh, NC ELIZABETH N. PEARCE, Boston University, Boston, MA TRACEY J. WOODRUFF, University of California San Francisco, CA LAUREN ZEISE, California Environmental Protection Agency, Oakland, CA YILIANG ZHU, University of South Florida, Tampa, FL Staff SUSAN N.J. MARTEL, Project Director KERI STOEVER, Research Associate NORMAN GROSSBLATT, Senior Editor MIRSADA KARALIC-LONCAREVIC, Manager, Technical Information Center RADIAH ROSE, Manager, Editorial Projects TAMARA DAWSON, Program Associate Sponsor US Environmental Protection Agency v

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BOARD ON ENVIRONMENTAL STUDIES AND TOXICOLOGY 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, 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 vi

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OTHER REPORTS OF THE BOARD ON ENVIRONMENTAL STUDIES AND TOXICOLOGY Review of EPA’s Integrated Risk Information System (IRIS) Process (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) vii

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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 (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 Potential health effects of endocrine-disrupting chemicals raise an environ- mental health concern about the chemicals’ ability to interfere with normal hor- mone function in humans and wildlife. Some research on endocrine-disrupting chemicals has identified dose–response relationships that have nonmonotonic curves; that is, lower doses are not always associated with smaller responses, nor higher doses with larger responses. Nonmonotonic dose–response (NMDR) curves have been a subject of debate in regulatory toxicology because of their implica- tions for how chemicals should be tested and for how risks posed by such chemi- cals should be assessed. The debate has focused on whether standard toxicity- testing protocols assess relevant health effects for such chemicals, on the degree to which such tests might miss low-dose effects of NMDR relationships (false- negative results), and on the implications of the evidence on NMDR curves for current risk-assessment practices. To help to address those issues, the US Envi- ronmental Protection Agency (EPA) developed a draft State of the Science Eval- uation: Nonmonotonic Dose Responses as They Apply to Estrogen, Androgen, and Thyroid Pathways and EPA Testing and Assessment Procedures. EPA asked the National Research Council to conduct an independent review of its evaluation to ensure that it is scientifically sound and of high quality. In response to EPA’s request, the National Research Council convened the Committee to Review EPA’s Draft State of the Science Paper on Nonmonotonic Dose Response, which prepared this report. The members of the committee were selected for their expertise in reproductive and developmental toxicology, endo- crinology, epidemiology, environmental epigenetics, toxicogenomics, mechanis- tic toxicology, physiologically based pharmacokinetic modeling, risk assess- ment, and biostatistics. Biographic information on the committee members is presented in Appendix A. The committee’s report has been reviewed in draft form by persons chosen for their diverse perspectives and technical expertise in accordance with proce- dures approved by the National Research Council’s Report Review Committee. The purpose of the independent review is to provide candid and critical com- ments 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, ix

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x Preface evidence, and responsiveness to the study charge. The review comments and draft manuscript remain confidential to protect the integrity of the deliberative process. We thank the following for their review of the report: Sandra Baird, Massachusetts Department of Environmental Protection; Niladri Basu, McGill University; Jan-Åke Gustafsson, University of Houston; Sangtae Kim, Purdue University; M. Sue Marty, The Dow Chemical Company; Shyamal Peddada, National Institute of Environmental Health Sciences; Gail Prins, University of Illinois at Chicago; Justin Teeguarden, Pacific Northwest National Laboratory; Rochelle Tyl, RTI International; John Vandenbergh, North Carolina State Uni- versity; and R. Thomas Zoeller, University of Massachusetts Amherst. 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 Linda McCauley, Emory University, and Martin Philbert, University of Michigan. Appointed by the National Re- search Council, 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 content of the report rests entirely with the author committee and the institution. The committee is grateful for the assistance of National Research Council staff in preparing the report. It particularly wishes to acknowledge with deep gratitude the support of Project Director Susan Martel, who coordinated the pro- ject and contributed to the committee’s report. Other staff members who con- tributed to this effort are James Reisa, director of the Board on Environmental Studies and Toxicology; Keri Stoever, research associate; Tamara Dawson, pro- gram associate; Norman Grossblatt, senior editor; and Mirsada Karalic- Loncarevic, manager of the Technical Information Center. Finally, I thank all the members of the committee for their efforts throughout the development of this report. Their varied expertise attests to the complexity of this topic, and the committee’s ability to synthesize that expertise into a clear consensus is much appreciated. David A. Savitz, PhD, Chair Committee to Review EPA’s Draft State of the Science Paper on Nonmonotonic Dose Response

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Contents SUMMARY ...............................................................................................................3 1 INTRODUCTION ...........................................................................................9 Background and History of Endocrine-Disruptor Research, 10 The Committee’s Task and Approach, 13 Organization of This Report, 14 References, 14 2 REVIEW OF THE ENVIRONMENTAL PROTECTION AGENCY’S METHODS FOR EVALUATING EVIDENCE ON NONMONOTONIC DOSE–RESPONSE RELATIONSHIPS ...........16 Introduction, 16 Evaluation of the Environmental Protection Agency’s Approach, 17 Conclusions, 31 Recommendations, 32 References, 34 3 THE ENVIRONMENTAL PROTECTION AGENCY’S EVALUATION OF IMPLICATIONS OF NONMONOTONIC DOSE–RESPONSE RELATIONSHIPS FOR CURRENT TOXICITY-TESTING STRATEGIES AND RISK-ASSESSMENT PRACTICES ..................................................................................................38 The Environmental Protection Agency’s Evaluation of the Adequacy of Toxicity Testing, 38 The Environmental Protection Agency’s Evaluation of the Implications of Nonmonotonic Dose–Response Relationships for Risk-Assessment Practices, 42 Conclusions, 44 Recommendations, 44 References, 45 APPENDIX BIOSKETCHES OF THE COMMITTEE TO REVIEW EPA’S DRAFT STATE OF THE SCIENCE PAPER ON NONMONOTONIC DOSE RESPONSE..............................................................................................................47 xi

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xii Contents FIGURES, TABLES, AND BOXES FIGURES 1-1 Examples of monotonic and nonmonotonic dose–response curves, 10 2-1 Relationship between the statistical power of a toxicologic experiment and the ability to reveal a nonmonotonic dose–response (NMDR) relationship, 28 TABLE 2-1 Comparison of Study-Selection Criteria and Study-Quality Evaluations Used in Different Sections of the SOTS Evaluation, 23 BOXES 1-1 Statement of Task, 13 2-1 Design Elements of a Systematic Review, 17 2-2 Three Central Scientific Questions to Be Addressed in the SOTS Evaluation (EPA 2013a), 19 3-1 Central Scientific Questions EPA Addressed in the SOTS Evaluation (EPA 2013), 39