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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.
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Additional copies of this report are available from:
National Academy Press
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Copyright 2000 by the National Academy of Sciences. All rights reserved.
Printed in the United States of America
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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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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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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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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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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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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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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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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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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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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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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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