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
Washington, D.C.
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-09-003 between the National Academy of Sciences and the US 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.
International Standard Book Number-13: 978-0-309-29754-7
International Standard Book Number-10: 0-309-29754-0
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
THE NATIONAL ACADEMIES
Advisers to the Nation on Science, Engineering, and Medicine
The National Academ of Sciences is a private, nonprofit, self-perpetuating society of distinguished scholars engaged in scientific and engineering research, dedicated to the furtherance of science and technology and to their use for the general welfare. Upon the authority of the charter granted to it by the Congress in 1863, the Academy has a mandate that requires it to advise the federal government on scientific and technical matters. Dr. Ralph J. Cicerone is president of the National Academy of Sciences.
The National Academy of Engineering was established in 1964, under the charter of the National Academy of Sciences, as a parallel organization of outstanding engineers. It is autonomous in its administration and in the selection of its members, sharing with the National Academy of Sciences the responsibility for advising the federal government. The National Academy of Engineering also sponsors engineering programs aimed at meeting national needs, encourages education and research, and recognizes the superior achieve ents 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 services of eminent members of appropriate professions in the examination of policy matters pertaining to the health of the public. The Institute acts under the responsibility given to the National Academy of Sciences by its congressional charter to be an adviser to the federal government and, upon its own initiative, to identify issues of medical care, research, and education. Dr. Harvey V. Fineberg is president of the Institute of Medicine.
The National Research Council was organized by the National Academy of Sciences in 1916 to associate the broad community of science and technology with the Academy’s purposes of furthering knowledge and advising the federal government. Functioning in accordance with general policies determined by the Academy, the Council has become the principal operating agency of both the National Academy of Sciences and the National Academy of Engineering in providing services to the government, the public, and the scientific and engineering communities. The Council is administered jointly by both Academies and the Institute of Medicine. Dr. Ralph J. Cicerone and Dr. C. D. Mote, Jr., are chair and vice chair, respectively, of the National Research Council.
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
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
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)
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
Preface
Potential health effects of endocrine-disrupting chemicals raise an environmental health concern about the chemicals’ ability to interfere with normal hormone 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 implications for how chemicals should be tested and for how risks posed by such chemicals 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 Environmental Protection Agency (EPA) developed a draft State of the Science Evaluation: 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, endocrinology, epidemiology, environmental epigenetics, toxicogenomics, mechanistic toxicology, physiologically based pharmacokinetic modeling, risk assessment, 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 procedures approved by the National Research Council’s 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 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 University; 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 Research Council, they were responsible for making certain that an independent examination of the report was carried out in accordance with institutional procedures 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 project and contributed to the committee’s report. Other staff members who contributed to this effort are James Reisa, director of the Board on Environmental Studies and Toxicology; Keri Stoever, research associate; Tamara Dawson, program 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
FIGURES, TABLES, AND BOXES
FIGURES
1-1 Examples of monotonic and nonmonotonic dose–response curves
TABLE
BOXES
2-1 Design Elements of a Systematic Review
2-2 Three Central Scientific Questions to Be Addressed in the SOTS Evaluation (EPA 2013a)
3-1 Central Scientific Questions EPA Addressed in the SOTS Evaluation (EPA 2013)