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Health Implications of Perchlorate Ingestion Health Implications of Perchlorate Ingestion Committee to Assess the Health Implications of Perchlorate Ingestion 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. www.nap.edu
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Health Implications of Perchlorate Ingestion 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 68-C-03-081 between the National Academy of Sciences and the U.S. Environmental Protection Agency, U.S. Department of Defense, U.S. Department of Energy, and National Aeronautics and Space Administration. Any opinions, findings, conclusions, or recommendations expressed in this publication are those of the author(s) and do not necessarily reflect the view of the organizations or agencies that provided support for this project. International Standard Book Number 0-309-09568-9 (Book) International Standard Book Number 0-309-54811-X (PDF) Library of Congress Control Number 2005925051 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 2005 by the National Academy of Sciences. All rights reserved. Printed in the United States of America
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Health Implications of Perchlorate Ingestion THE NATIONAL ACADEMIES Advisers to the Nation on Science, Engineering, and Medicine The National Academy of Sciences is a private, nonprofit, self-perpetuating society of distinguished scholars engaged in scientific and engineering research, dedicated to the furtherance of science and technology and to their use for the general welfare. Upon the authority of the charter granted to it by the Congress in 1863, the Academy has a mandate that requires it to advise the federal government on scientific and technical matters. Dr. Bruce M. Alberts 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 achievements of engineers. Dr. Wm. A. Wulf 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. Bruce M. Alberts and Dr. Wm. A. Wulf are chair and vice chair, respectively, of the National Research Council www.national-academies.org
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Health Implications of Perchlorate Ingestion COMMITTEE TO ASSESS THE HEALTH IMPLICATIONS OF PERCHLORATE INGESTION Members RICHARD B. JOHNSTON, JR. (Chair), University of Colorado School of Medicine, Denver STACY BRANCH, Djehuty Biomed Consulting, Clayton, NC GREGORY BRENT, University of California, Los Angeles ROSALIND BROWN, Harvard University School of Medicine and Children’s Hospital in Boston, MA CHARLES C. CAPEN, The Ohio State University, Columbus DAVID COOPER, The Johns Hopkins University; Sinai Hospital of Baltimore, MD RICHARD CORLEY, Pacific Northwest National Laboratory, Richland, WA LINDA COWAN, University of Oklahoma, Oklahoma City JAMES C. LAMB, The Weinberg Group Inc., Washington, DC GEORGE LAMBERT, UMDNJ–Robert Wood Johnson Medical School, Piscataway, NJ R. MICHAEL MCCLAIN, McClain Associates, Randolph, NJ SUSAN SCHANTZ, University of Illinois at Urbana-Champaign, Urbana DALENE STANGL, Duke University, Durham, NC LYNETTE STOKES, Environmental Health Administration, Department of Health, Washington, DC ROBERT UTIGER, Harvard University School of Medicine, Boston, MA Staff ELLEN MANTUS, Project Director ROBERTA WEDGE, Program Director for Risk Assessment MARY FOX, Program Officer NORMAN GROSSBLATT, Senior Editor JENNIFER SAUNDERS, Research Associate ROBERT POLICELLI, Project Assistant LAURA WATERS, Project Assistant Sponsors U.S. ENVIRONMENTAL PROTECTION AGENCY U.S. DEPARTMENT OF DEFENSE U.S. DEPARTMENT OF ENERGY NATIONAL AERONAUTICS AND SPACE ADMINISTRATION
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Health Implications of Perchlorate Ingestion BOARD ON ENVIRONMENTAL STUDIES AND TOXICOLOGY1 Members JONATHAN M. SAMET (Chair), The Johns Hopkins University, Baltimore, MD RAMÓN ALVAREZ, Environmental Defense, Austin, TX THOMAS BURKE, The Johns Hopkins University, Baltimore, MD JUDITH C. CHOW, Desert Research Institute, Reno, NV RORY B. CONOLLY, CIIT Centers for Health Research, Research Triangle Park, NC COSTEL D. DENSON, University of Delaware, Newark E. DONALD ELLIOTT, Willkie Farr & Gallagher LLP, Washington, DC CHRISTOPHER B. FIELD, Carnegie Institution of Washington, Stanford, CA SHERRI W. GOODMAN, Center for Naval Analyses, Alexandria, VA JUDITH A. GRAHAM, American Chemistry Council, Arlington, VA DANIEL S. GREENBAUM, Health Effects Institute, Cambridge, MA ROBERT HUGGETT, Michigan State University, East Lansing BARRY L. JOHNSON, Emory University, Atlanta, GA JAMES H. JOHNSON, Howard University, Washington, DC JUDITH L. MEYER, University of Georgia, Athens PATRICK Y. O’BRIEN, ChevronTexaco Energy Technology Company, Richmond, CA DOROTHY E. PATTON, International Life Sciences Institute, Washington, DC STEWARD T.A. PICKETT, Institute of Ecosystem Studies, Millbrook, NY JOSEPH V. RODRICKS, ENVIRON Corporation, Arlington, VA ARMISTEAD G. RUSSELL, Georgia Institute of Technology, Atlanta MITCHELL J. SMALL, Carnegie Mellon University, Pittsburgh, PA LISA SPEER, Natural Resources Defense Council, New York, NY KIMBERLY M. THOMPSON, Harvard School of Public Health, Boston, MA G. DAVID TILMAN, University of Minnesota, St. Paul CHRIS G. WHIPPLE, ENVIRON Corporation, Emeryville, CA LAUREN A. ZEISE, California Environmental Protection Agency, Oakland Senior Staff JAMES J. REISA, Director DAVID J. POLICANSKY, Scholar RAYMOND A. WASSEL, Senior Program Officer for Environmental Sciences and Engineering KULBIR BAKSHI, Senior Program Officer for Toxicology ROBERTA M. WEDGE, Senior Program Officer for Risk Analysis K. JOHN HOLMES, Senior Program Officer SUSAN N.J. MARTEL, Senior Program Officer SUZANNE VAN DRUNICK, Senior Program Officer EILEEN N. ABT, Senior Program Officer ELLEN K. MANTUS, Senior Program Officer RUTH E. CROSSGROVE, Senior Editor 1 This study was planned, overseen, and supported by the Board on Environmental Studies and Toxicology.
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Health Implications of Perchlorate Ingestion OTHER REPORTS OF THE BOARD ON ENVIRONMENTAL STUDIES AND TOXICOLOGY Air Quality Management in the United States (2004) Endangered and Threatened Species of the Platte River (2004) Atlantic Salmon in Maine (2004) Endangered and Threatened Fishes in the Klamath River Basin (2004) Cumulative Environmental Effects of Alaska North Slope Oil and Gas Development (2003) Estimating the Public Health Benefits of Proposed Air Pollution Regulations (2002) Biosolids Applied to Land: Advancing Standards and Practices (2002) The Airliner Cabin Environment and Health of Passengers and Crew (2002) Arsenic in Drinking Water: 2001 Update (2001) Evaluating Vehicle Emissions Inspection and Maintenance Programs (2001) Compensating for Wetland Losses Under the Clean Water Act (2001) A Risk-Management Strategy for PCB-Contaminated Sediments (2001) Acute Exposure Guideline Levels for Selected Airborne Chemicals (4 volumes, 2000-2004) Toxicological Effects of Methylmercury (2000) Strengthening Science at the U.S. Environmental Protection Agency (2000) Scientific Frontiers in Developmental Toxicology and Risk Assessment (2000) Ecological Indicators for the Nation (2000) Waste Incineration and Public Health (1999) Hormonally Active Agents in the Environment (1999) Research Priorities for Airborne Particulate Matter (4 volumes, 1998-2004) The National Research Council’s Committee on Toxicology: The First 50 Years (1997) Carcinogens and Anticarcinogens in the Human Diet (1996) Upstream: Salmon and Society in the Pacific Northwest (1996) Science and the Endangered Species Act (1995) Wetlands: Characteristics and Boundaries (1995) Biologic Markers (5 volumes, 1989-1995) Review of EPA’s Environmental Monitoring and Assessment Program (3 volumes, 1994-1995) Science and Judgment in Risk Assessment (1994) Pesticides in the Diets of Infants and Children (1993) Dolphins and the Tuna Industry (1992) Science and the National Parks (1992) Human Exposure Assessment for Airborne Pollutants (1991) Rethinking the Ozone Problem in Urban and Regional Air Pollution (1991) Decline of the Sea Turtles (1990) Copies of these reports may be ordered from the National Academies Press (800) 624-6242 or (202) 334-3313 www.nap.edu
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Health Implications of Perchlorate Ingestion Preface In 1985, perchlorate contamination was discovered at Superfund sites in California; however, the extent of perchlorate contamination of water sources nationwide was not revealed until 1997. Today, over 11 million people have perchlorate in their public drinking-water supplies at concentrations of 4 ppb (4 µg/L) or higher. Because of the controversy surrounding the concentration at which perchlorate should be regulated, the Department of Defense (DOD), the Department of Energy (DOE), the National Aeronautics and Space Administration (NASA), and the Environmental Protection Agency (EPA) asked the National Research Council to assess the potential adverse health effects of perchlorate ingestion from clinical, toxicologic, medical, and public-health perspectives. In this report, the Committee to Assess the Health Implications of Perchlorate Ingestion reviews the current state of the science regarding potential adverse health effects of perchlorate exposure. Specifically, the committee evaluated human clinical and epidemiologic studies and animal toxicology studies, and determined the relevance of the animal studies for predicting adverse effects in humans, especially sensitive populations. The committee also assessed perchlorate concentrations at which chronic inhibition of iodide uptake and subsequent changes in thyroid hormone production might lead to adverse health effects in humans. As a final task, the committee reviewed and determined whether EPA’s findings in its 2002 draft risk assessment, Perchlorate Environmental Contamination: Toxicological Review and Risk Characterization, are consistent with current scientific evidence. Recommendations are provided for scientific research that could reduce uncertainty in the understanding of human health effects associated with low-level perchlorate ingestion. This report has been reviewed in draft form by persons chosen for their diverse perspectives and technical expertise in accordance with procedures
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Health Implications of Perchlorate Ingestion 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 perchlorate committee and the Research Council in making the published report as sound as possible and to ensure that the report meets the Research Council’s 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 people for their review of this report: Michael Aschner, Vanderbilt University Medical Center; Gerard Burrow, Yale University School of Medicine; George Daston, Proctor and Gamble Company; Kelly Dix, Lovelace Respiratory Research Institute; Ronald Estabrook, The University of Texas Southwestern Medical Center; Ellen Gold, University of California, Davis; Philip Landrigan, Mount Sinai School of Medicine; Gilbert Omenn, University of Michigan Medical School; Louise Ryan, Harvard School of Public Health; Rudi Schmid, Retired; Jerrold Ward, National Institutes of Health; and E. Dillwyn Williams, University of Cambridge. Although the reviewers listed above have provided many constructive comments and suggestions, they were not asked to endorse the conclusions or recommendations, nor did they see the final draft of the report before its release. The review of this report was overseen by John C. Bailar and Floyd Bloom. 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 committee and the National Research Council. The committee gratefully acknowledges the persons who made presentations at the committee’s public meetings (see Appendix C) and Raymond York, of Argus Laboratories, for providing the committee with original data from selected animal toxicology studies. The committee also thanks the sponsor representatives who responded to data requests and provided background materials: Lisa Matthews, Annie Jarabek, and William Farland, EPA; Daniel Rogers and Jeff Cornell, DOD; Richard Williams and Richard Wickman, NASA; and Patrice Bubar, Karen Guevara, Blaine Rowley, and Mark Frei, DOE. The committee is especially grateful for the consistently strong and knowledgeable assistance of the National Research Council staff in preparing this report, particularly Ellen Mantus, project director, but also James Reisa, director of the Board on Environmental Studies and Toxicology; Roberta Wedge, program director for risk analysis; Mary Fox, program
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Health Implications of Perchlorate Ingestion officer, Jennifer Saunders, research associate, Mirsada Karalic-Loncarevic, research associate; Ruth E. Crossgrove, senior editor; Norman Grossblatt, senior editor; Bryan Shipley, research associate; and Robert Policelli and Laura Waters, project assistants. Finally, I thank the members of the committee for their commitment to the breadth and importance of our task and their dedication to deriving conclusions and recommendations based only on the best available scientific evidence. Richard B. Johnston, Jr. Chair, Committee to Assess the Health Implications of Perchlorate Ingestion
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Health Implications of Perchlorate Ingestion Contents SUMMARY 3 1 INTRODUCTION 19 Regulatory History, 20 Characteristics of Perchlorate, 22 Use and Occurrence of Perchlorate, 23 Sensitive Populations, 26 Scientific Controversies, 27 Committee’s Charge and Approach to Charge, 29 Organization of Report, 31 References, 32 2 THE THYROID AND DISRUPTION OF THYROID FUNCTION IN HUMANS 35 Anatomy, 36 Thyroid Hormone Production, Transport, and Action, 36 Regulation of Thyroid Hormone Production, 43 Iodide Nutrition and Metabolism, 45 Perturbations of Thyroid Hormone Production, 47 Hypothalamic-Pituitary-Thyroid Development and Function in Fetuses and Infants, 52 Perchlorate and the Thyroid, 59 Nonthyroid Effects of Perchlorate, 67 References, 68 3 EPIDEMIOLOGIC STUDIES OF OCCUPATIONAL AND ENVIRONMENTAL EXPOSURES TO PERCHLORATE 75 Studies in Occupational Cohorts and Adults, 77
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Health Implications of Perchlorate Ingestion Studies in Neonates, Children and Pregnant Women, 91 Summary, 108 References, 111 4 ANIMAL STUDIES 115 Comparison of Thyroid Function in Rats and Humans, 115 Thyroid Hormones and Thyroid Histopathology, 118 Brain Morphometry, 126 Neurobehavioral Studies, 135 Thyroid Gland Tumors, 141 PBPK Modeling, 145 Other Effects of Perchlorate, 146 Summary, 152 References, 153 5 RISK CHARACTERIZATION OF PERCHLORATE 164 Mode-of-Action Model, 164 Adverse Effect and Key Event, 165 Point of Departure, 167 Uncertainty Factors, 172 Summary, 177 References, 178 6 RESEARCH RECOMMENDATIONS 182 Overview, 182 Chronic Exposure, 183 Sensitive Populations, 188 Public-Health Implications of Iodide Status, 195 References, 196 APPENDIXES A. Biographical Information on the Committee to Assess the Health Implications of Perchlorate Ingestion 199 B. Glossary 205 C. Participants at Public Sessions 213 D. Sensitivity of Perchlorate-Induced Iodide Uptake Inhibition to Serum Iodide Concentrations 216 E. Physiologically Based Pharmacokinetic Modeling 219
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Health Implications of Perchlorate Ingestion FIGURES S-1. Committee’s suggested mode-of-action model for perchlorate toxicity in humans, 14 1-1. Timeline of perchlorate-related regulatory activities, 21 1-2. EPA’s proposed continuum of possible health effects of perchlorate exposure, 28 2-1. Diagram of thyroid cells and thyroid follicle, showing key steps in thyroxine (T4) and triiodothyronine (T3) synthesis and secretion, 37 2-2. Structures of thyroxine (T4), triiodothyronine (T3), and reverse triiodothyronine (reverse T3), 38 2-3. Diagram of a cell showing pathways of thyroxine (T4) and triiodothyronine (T3) metabolism, 42 2-4. Diagram of hypothalamic-pituitary-thyroid system, 44 4-1. Serum thyroxine (T4), triiodothyronine (T3), and thyroid stimulating hormone (TSH) concentrations in dams treated with ammonium perchlorate at indicated doses in drinking water, 120 4-2. Serum thyroxine (T4), triiodothyronine (T3), and thyroid stimulating hormone (TSH) concentrations in fetus and pups of dams treated with ammonium perchlorate at indicated doses in drinking water, 122 4-3. Changes in serum T4, T3, and TSH in dams, fetuses, and pups presented as percent change from control, 124 4-4. Parallelogram approach for using adult human, adult male rat, and female rat gestation and lactation models to estimate human equivalent exposures for human pregnancy and lactation models, 147 5-1. Committee’s suggested mode-of-action model of perchlorate toxicity in humans, 166 5-2. Committee’s suggested mode-of-action model for perchlorate toxicity in humans indicating first adverse effect in continuum, 167 5-3. EPA’s summary of NOAELs and LOAELs for various health effects in rat studies, 171 TABLES 1-1. EPA Provisional or Proposed Reference Doses (RfDs) and Corresponding Drinking Water Concentrations, 23
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Health Implications of Perchlorate Ingestion 1-2. Perchlorate Drinking-Water Concentrations Based on Monitoring Data from Unregulated Contaminant Monitoring Rule as of May 2004, 25 2-1. 24-Hour Thyroid Radioiodide Uptake in Healthy Subjects before, during, and after Oral Administration of Potassium Perchlorate for 14 Days, 64 3-1. Summary of Epidemiologic Studies, 78 4-1. Thyroid Histopathology in Control Dams and Dams Given Four Doses of Perchlorate, 123 4-2. Thyroid Histopathology in Control and Perchlorate-Exposed Fetuses and Pups, 123 4-3. Summary of Morphometric Findings in Rat Pups Exposed to Perchlorate, 128 6-1. Protocol for Controlled Clinical Study, 185 6-2. Three-Month Dose-Range Finding Toxicity Study in Cynomolgus Monkeys, 186 6-3. One-Year Chronic Toxicity Study in Cynomolgus Monkeys, 187