Toxicological Effects of Methylmercury

Committee on the Toxicological Effects of Methylmercury

Board on Environmental Studies and Toxicology

Commission on Life Sciences

National Research Council

NATIONAL ACADEMY PRESS
Washington, DC



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Toxicological Effects of Methylmercury Toxicological Effects of Methylmercury Committee on the Toxicological Effects of Methylmercury Board on Environmental Studies and Toxicology Commission on Life Sciences National Research Council NATIONAL ACADEMY PRESS Washington, DC

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Toxicological Effects of Methylmercury NATIONAL ACADEMY PRESS 2101 Constitution Ave., N.W. Washington, D.C.20418 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 Grant Agreement No. X 827238-01 between the National Academy of Sciences and the Environmental Protection Agency. 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. Library of Congress Card Number 00-108382 International Standard Book Number 0-309-07140-2 Additional copies of this report are available from: National Academy Press 2101 Constitution Ave., NW Box 285 Washington, DC 20055 800-624-6242 202-334-3313 (in the Washington metropolitan area) http://www.nap.edu Copyright 2000 by the National Academy of Sciences. All rights reserved. Printed in the United States of America

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Toxicological Effects of Methylmercury THE NATIONAL ACADEMIES National Academy of Sciences National Academy of Engineering Institute of Medicine National Research Council 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. William 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. Kenneth I. Shine 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. William A. Wulf are chairman and vice chairman, respectively, of the National Research Council.

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Toxicological Effects of Methylmercury COMMITTEE ON THE TOXICOLOGICAL EFFECTS OF METHYLMERCURY ROBERT A. GOYER (Chair), University of Western Ontario (Professor, Emeritus), Chapel Hill, North Carolina H. VASKEN APOSHIAN, University of Arizona, Tucson, Arizona LENORE ARAB, University of North Carolina, Chapel Hill, North Carolina DAVID C. BELLINGER, Harvard Medical School, Boston, Massachusetts THOMAS M. BURBACHER, University of Washington, Seattle, Washington THOMAS A. BURKE, The Johns Hopkins University, Baltimore, Maryland JOSEPH L. JACOBSON, Wayne State University, Detroit, Michigan LYNDA M. KNOBELOCH, State of Wisconsin Bureau of Environmental Health, Madison, Wisconsin LOUISE M. RYAN, Dana-Farber Cancer Institute, Boston, Massachusetts ALAN H. STERN, New Jersey Department of Environmental Protection, Trenton, New Jersey Staff CAROL A. MACZKA, Director, Toxicology and Risk Assessment Program MICHELLE C. CATLIN, Research Associate RUTH E. CROSSGROVE, Editor MIRSADA KARALIC-LONCAREVIC, Information Specialist JUDITH L. ESTEP, Senior Program Assistant LAURA T. HOLLIDAY, Senior Program Assistant STEPHANIE K. PARKER, Graphics and Layout Sponsor U.S. ENVIRONMENTAL PROTECTION AGENCY

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Toxicological Effects of Methylmercury BOARD ON ENVIRONMENTAL STUDIES AND TOXICOLOGY GORDON ORIANS (Chair), University of Washington, Seattle, Washington DONALD MATTISON (Vice Chair), March of Dimes, White Plains, New York DAVID ALLEN, University of Texas, Austin, Texas INGRID C. BURKE, Colorado State University, Fort Collins, Colorado WILLIAM L. CHAMEIDES, Georgia Institute of Technology, Atlanta, Georgia JOHN DOULL, The University of Kansas Medical Center, Kansas City, Kansas CHRISTOPHER B. FIELD, Carnegie Institute of Washington, Stanford, California JOHN GERHART, University of California, Berkeley, California J. PAUL GILMAN, Celera Genomics, Rockville, Maryland BRUCE D. HAMMOCK, University of California, Davis, California MARK HARWELL, University of Miami, Miami, Florida ROGENE HENDERSON, Lovelace Respiratory Research Institute, Albuquerque, New Mexico CAROL HENRY, Chemical Manufacturers Association, Arlington, Virginia BARBARA HULKA, University of North Carolina, Chapel Hill, North Carolina JAMES F. KITCHELL, University of Wisconsin, Madison, Wisconsin DANIEL KREWSKI, University of Ottawa, Ottawa, Ontario JAMES A. MACMAHON, Utah State University, Logan, Utah MARIO J. MOLINA, Massachusetts Institute of Technology, Cambridge, Massachusetts CHARLES O'MELIA, Johns Hopkins University, Baltimore, Maryland WILLEM F. PASSCHIER, Health Council of the Netherlands KIRK SMITH, University of California, Berkeley, California MARGARET STRAND, Oppenheimer Wolff Donnelly & Bayh, LLP, Washington, D.C. TERRY F. YOSIE, Chemical Manufacturers Association, Arlington, Virginia Senior Staff JAMES J. REISA, Director DAVID J. POLICANSKY, Associate Director and Senior Program Director for Applied Ecology CAROL A. MACZKA, Senior Program Director for Toxicology and Risk Assessment RAYMOND A. WASSEL, Senior Program Director for Environmental Sciences and Engineering KULBIR BAKSHI, Program Director for the Committee on Toxicology LEE R. PAULSON, Program Director for Resource Management ROBERTA M. WEDGE, Program Director for Risk Analysis

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Toxicological Effects of Methylmercury COMMISSION ON LIFE SCIENCES MICHAEL T. CLEGG (Chair), University of California, Riverside, California PAUL BERG (Vice Chair), Stanford University, Stanford, California FREDERICK R. ANDERSON, Cadwalader, Wickersham & Taft, Washington, D.C. JOANNA BURGER, Rutgers University, Piscataway, New Jersey JAMES E. CLEAVER, University of California, San Francisco, California DAVID EISENBERG, University of California, Los Angeles, California JOHN EMMERSON, Fishers, Indiana NEAL FIRST, University of Wisconsin, Madison, Wisconsin DAVID J. GALAS, Keck Graduate Institute of Applied Life Science, Claremont, California DAVID V. GOEDDEL, Tularik, Inc., South San Francisco, California ARTURO GOMEZ-POMPA, University of California, Riverside, California COREY S. GOODMAN, University of California, Berkeley, California JON W. GORDON, Mount Sinai School of Medicine, New York, New York DAVID G. HOEL, Medical University of South Carolina, Charleston, South Carolina BARBARA S. HULKA, University of North Carolina, Chapel Hill, North Carolina CYNTHIA KENYON, University of California, San Francisco, California BRUCE R. LEVIN, Emory University, Atlanta, Georgia DAVID LIVINGSTON, Dana-Farber Cancer Institute, Boston, Massachusetts DONALD R. MATTISON, March of Dimes, White Plains, New York ELLIOT M. MEYEROWITZ, California Institute of Technology, Pasadena, California ROBERT T. PAINE, University of Washington, Seattle, Washington RONALD R. SEDEROFF, North Carolina State University, Raleigh, North Carolina ROBERT R. SOKAL, State University of New York, Stony Brook, New York CHARLES F. STEVENS, The Salk Institute, La Jolla, California SHIRLEY M. TILGHMAN, Princeton University, Princeton, New Jersey RAYMOND L. WHITE, University of Utah, Salt Lake City, Utah Staff WARREN R. MUIR, Executive Director JACQUELINE K. PRINCE, Financial Officer BARBARA B. SMITH, Administrative Associate LAURA T. HOLLIDAY, Senior Project Assistant

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Toxicological Effects of Methylmercury OTHER REPORTS OF THE BOARD ON ENVIRONMENTAL STUDIES AND TOXICOLOGY Strengthening Science at the U.S. Environmental Protection Agency: Research Management and Peer Review Practices (2000) Scientific Frontiers in Developmental Toxicology and Risk Assessment (2000) Modeling Mobile-Source Emissions (2000) Copper in Drinking Water (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: I. Immediate Priorities and a Long-Range Research Portfolio (1998); II. Evaluating Research Progress and Updating the Portfolio (1999) Ozone-Forming Potential of Reformulated Gasoline (1999) Risk-Based Waste Classification in California (1999) Arsenic in Drinking Water (1999) Brucellosis in the Greater Yellowstone Area (1998) The National Research Council's Committee on Toxicology: The First 50 Years (1997) Toxicologic Assessment of the Army's Zinc Cadmium Sulfide Dispersion Tests (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 reports, 1989-1995) Review of EPA's Environmental Monitoring and Assessment Program (3 reports, 1994-1995) Science and Judgment in Risk Assessment (1994) Ranking Hazardous Waste Sites for Remedial Action (1994) Pesticides in the Diets of Infants and Children (1993) Issues in Risk Assessment (1993) Setting Priorities for Land Conservation (1993) Protecting Visibility in National Parks and Wilderness Areas (1993) Dolphins and the Tuna Industry (1992) Hazardous Materials on the Public Lands (1992) Science and the National Parks (1992) Animals as Sentinels of Environmental Health Hazards (1991) Assessment of the U.S. Outer Continental Shelf Environmental Studies Program, Volumes I-IV (1991-1993) Human Exposure Assessment for Airborne Pollutants (1991) Monitoring Human Tissues for Toxic Substances (1991)

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Toxicological Effects of Methylmercury 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 Academy Press (800) 624-6242 (202) 334-3313 www.nap.edu

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Toxicological Effects of Methylmercury PREFACE IN 1997, the U.S. Environmental Protection Agency (EPA) issued two reports to the U.S. Congress on mercury (Hg) and its effects on public health. The first of these reports, the Mercury Study Report to Congress, assessed the source and amount of Hg emissions in the United States, the detrimental effects of Hg on humans and wildlife, and the feasibility of control technologies. The second report, the Utility Hazardous Air Pollutant Report to Congress, looked specifically at emissions from utility companies and cited Hg as a major contaminant, especially in emissions from coal-fired power plants. Once in the environment, Hg can be converted to methylmercury (MeHg), which bioaccumulates up the food chain. Such bioaccummulation can lead to high concentrations of MeHg in predatory fish. Because of concerns about MeHg exposure levels in the United States from the consumption of contaminated fish, particularly among sensitive populations, questions have arisen among federal agencies over what is an acceptable level of exposure to MeHg. Because of gaps in the scientific data regarding Hg toxicity, particularly MeHg, the potentially widespread implications for human health, and the high financial costs and feasibility problems associated with further regulating Hg emissions, Congress directed EPA in the House Appropriations Report for EPA's Fiscal 1999 funding to contract with the National Research Council (NRC) to prepare recommendations on the appropriate reference dose for Hg exposure. In this report, the Committee on the Toxicological Effects of Methylmercury of the NRC independently reviewed the reference dose

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Toxicological Effects of Methylmercury for MeHg. The committee reviewed the available toxicological, epidemiological, and exposure data (from food and water) and determined the appropriateness of the critical study, end points of toxicity, and uncertainty factors used by EPA in the derivation of the reference dose for MeHg. The committee was also asked to identify data gaps and make recommendations for future research. This report has been reviewed in draft form by individuals chosen for their diverse perspectives and technical expertise in accordance with procedures approved by the NRC's Report Review Committee for reviewing NRC and Institute of Medicine reports. The purpose of this independent review is to provide candid and critical comments that will assist the NRC in making the published report as sound as possible and to ensure that the report meets institutional standards for objectivity, evidence, and responsiveness to the study charge. The review comments and draft manuscripts remain confidential to protect the integrity of the deliberative process. The committee wishes to thank the following individuals, who are neither officials nor employees of the NRC, for their participation in the review of this report: Melvin Andersen, Colorado State University; Michael Aschner, Wake Forest University; Kenny Crump, ICF Consulting; Kim Dietrich, University of Cincinnati; Johanna Dwyer, New England Medical Center; John Emmerson, Eli Lilly (retired); Susan Miller, University of California at San Francisco; Charles Poole, University of North Carolina; Jonathan Samet, Johns Hopkins University; Ellen Silbergeld, University of Maryland; Christopher Whipple, Environ International Corporation; James Woods, University of Washington. The individuals listed above have provided many constructive comments and suggestions. It must be emphasized, however, that responsibility for the final content of this report rests entirely with the authoring committee and the NRC. The committee gratefully acknowledges the following individuals for providing background information and for making presentations to the committee: Richard Duffy of the office of Senator Patrick Leahy (Vermont); Lee Alman of the office of Congressman Alan Mollohan (West Virginia); George Lucier, National Institute of Environmental Health Sciences; William Farland, EPA; Michael Bolger, Food and Drug Administration; Christopher DeRosa, Agency for Toxic Substances and Disease Registry; E. Spencer Garrett, National Oceanic and Atmospheric Administration, Fran Sharples, Office of Science and Technology; Michael Bender, Mercury Policy Project; Jane Williams, California

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Toxicological Effects of Methylmercury Communities Against Toxics; Eric Uram, Sierra Club-Great Lakes Program; Greg Schaefer, Arch Coal, Inc.; Leonard Levin, Electric Power Research Institute; and David Michaud, Wisconsin Electric Power Company. The committee also heard from a number of researchers actively investigating issues related to MeHg exposure. Those researchers are Tord Kjellstrom, University of Auckland, New Zealand; Donna Mergler, University of Quebec at Montreal; Kenny Crump, ICF Kaiser; Ellen Silbergeld, University of Maryland; Philippe Grandjean, University of Southern Denmark; Neils Keiding and Esben Budtz-Jøergensen, both from the University of Copenhagen; and Thomas Clarkson, Christopher Cox, Gary Myers, Philip Davidson, and Mark Moss, all from the University of Rochester. In addition, the committee wants to give special thanks to individuals and groups who provided further analyses and information at the request of the committee. Those are Wayne Rosamond, University of North Carolina; Philippe Grandjean; Neils Keiding; Esben Budtz-Jørgensen; Thomas Clarkson; Christopher Cox; Tord Kjellstrom; Harvey Clewell III; Jeffrey Swartout; Cynthia Van Landingham; and Kenny Crump. The committee also gratefully acknowledges input from individuals representing the Environmental Working Group, the Dental Amalgam Mercury Syndrome (DAMS) organization and the Mercury Free Press. The committee is grateful for the assistance of the NRC staff in preparing the report. Staff members who contributed to this effort are Carol A. Maczka, senior program director for the Toxicology and Risk Assessment Program; Michelle Catlin, research associate; Ruth E. Crossgrove, editor; Laura Holliday and Judy Estep, senior project assistants; and Mirsada Karalic-Loncarevic, information specialist. Finally, I would like to thank all the members of the committee for their dedicated efforts throughout the development of this report. Robert A. Goyer Chair, Committee on the Toxicological Effects of Methylmercury

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Toxicological Effects of Methylmercury CONTENTS     EXECUTIVE SUMMARY   1  1   INTRODUCTION   13      Sources of Hg,   15      Fate and Transport,   16      Health Effects,   16      Exposure Events and Studies,   18      Summary of Risk Assessments for MeHg,   21      Scientific Controversies and Sources of Uncertainty,   26      Organization of the Report,   26      References,   27  2   CHEMISTRY, EXPOSURE, TOXICOKINETICS, AND TOXICODYNAMICS   31      Physical and Chemical Properties,   31      Methods of Chemical Analysis,   37      Exposures to MeHg in the U.S. Population,   38      Toxicokinetics,   42      Mobilization of Body Hg,   51      Chemical Forms of Hg in Toxicity,   52      Toxic Effects and Target Organs,   53      Biochemical Mechanisms of Toxicity,   54      Summary and Conclusions,   58      Recommendations,   60      References,   60

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Toxicological Effects of Methylmercury  3   BIOLOGICAL VARIABILITY   72      Age-Related Susceptibility,   72      Gender Differences,   73      Genetics,   74      Mechanisms of Nutritional Influence on MeHg Health Effects,   75      Toxicokinetic Variability,   83      Conclusions,   95      Recommendations,   96      References,   98  4   DOSE ESTIMATION   105      Dietary Assessment,   105      Biomarkers of Exposure,   111      Analytical Error in Biomarker Measurements,   127      Exposure and Dose Assessment in the Seychelles, Faroe Islands, and New Zealand Studies,   129      Summary and Conclusions,   136      Recommendations,   139      References,   140  5   HEALTH EFFECTS OF METHYLMERCURY   147      Carcinogenicity,   149      Genotoxicity,   154      Immunotoxicity,   156      Reproductive Effects,   161      Renal Toxicity,   164      Cardiovascular Effects,   168      Hematological Effects,   173      Developing Central-Nervous-System Toxicity,   174      Adult Central-Nervous-System Toxicity,   221      Conclusions,   228      Recommendations,   231      References,   232  6   COMPARISON OF STUDIES FOR USE IN RISK ASSESSMENT   250      Assessment of Prenatal Hg Exposure: Cord Blood Versus Maternal Hair and Timing of Exposure,   252      Differences in the Neurobehavioral End Points Assessed and the Children 's Ages at Assessment,   255      Stable Versus Episodic Pattern of Exposure,   258

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Toxicological Effects of Methylmercury      Study Differences in Control for Confounders,   259      Population Differences in Vulnerability,   264      Random Variation in the Detectability of Effects at Low Exposures,   266      Conclusions,   267      Recommendations,   269      References,   269  7   DOSE-RESPONSE ASSESSMENT   271      Risk Assessment for Non-Cancer End Points,   271      Benchmark-Dose Calculations for Continuous Outcomes,   273      Some Specific Considerations for MeHg,   277      Comparing Benchmark Doses,   281      Choosing a Critical Dose for a Point of Departure,   283      An Integrative Analysis,   289      Model Choice Issues,   293      Summary and Conclusions,   298      Recommendations,   300      References,   301  8   RISK CHARACTERIZATION AND PUBLIC HEALTH IMPLICATIONS   304      The Current EPA Reference Dose,   305      Evaluating the RfD–End Points of MeHg Toxicity,   307      Selection of the End Point for the RfD,   311      Examination of Critical Studies for the RfD,   311      BMD Considerations: Selecting a Point of Departure,   314      Selection of the Critical Study and Point of Departure for the Revised RfD,   317      Sources of Uncertainty: Consideration for Uncertainty Factors,   318      Implications for Public Health and Risk Management,   322      Committee Findings and Recommendations,   326      References,   329     APPENDIX TO CHAPTER 7   333     GLOSSARY   337

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