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Arsenic in Drinking Water Subcommittee on Arsenic in Drinking Water Committee on Toxicology Board on Environmental Studies and Toxicology Commission on Life Sciences National Research Council NATIONAL ACADEMY PRESS Washington, DC
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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.
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 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.
This project was supported by Cooperative Agreement No. CX825107-01-0 between the National Academy of Sciences and the U.S. 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 Catalog Card Number 99-62141 International Standard Book Number 0-309-06333-7
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 1999 by the National Academy of Sciences. All rights reserved.
Printed in the United States of America
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Subcommittee on Arsenic in Drinking Water
ROBERT A. GOYER, Chair, (emeritus) University of Western Ontario, London, Ont., Canada
H. VASKEN APOSHIAN, University of Arizona, Tucson, Ariz.
KENNETH G. BROWN, Kenneth G. Brown, Inc., Chapel Hill, N.C.
KENNETH P. CANTOR, National Cancer Institute, Bethesda, Md.
GARY P. CARLSON, Purdue University, West Lafayette, Ind.
WILLIAM R. CULLEN, University of British Columbia, Vancouver, B.C., Canada
GEORGE P. DASTON, The Procter & Gamble Company, Cincinnati, Ohio
BRUCE A. FOWLER, University of Maryland Medical School, Baltimore, Md.
CURTIS D. KLAASSEN, University of Kansas Medical Center, Kansas City, Kans.
MICHAEL J. KOSNETT, University of Colorado Health Sciences Center, Denver, Colo.
WALTER MERTZ, (retired) Director of Beltsville Human Nutrition Research Center, Rockville, Md.
R. JULIAN PRESTON, Chemical Industry Institute of Toxicology, Research Triangle Park, N.C.
LOUISE M. RYAN, Harvard School of Public Health and Dana Farber Cancer Institute, Boston, Mass.
ALLAN H. SMITH, University of California, Berkeley, Calif.
MARIE E. VAHTER, Karolinska Institute, Stockholm, Sweden
JOHN K. WIENCKE, University of California, San Francisco,Calif.
Staff
CAROL A. MACZKA, Director, Toxicology and Risk Assessment Program
KULBIR S. BAKSHI, Program Director for the Committee on Toxicology
MARGARET E. MCVEY, Project Director (prior to January 1998)
RUTH E. CROSSGROVE, Editor
MIRSADA KARALIC-LONCAREVIC, Information Specialist
CATHERINE M. KUBIK, Senior Program Assistant
LUCY V. FUSCO, Project Assistant
Sponsor: U.S. Environmental Protection Agency
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Committee on Toxicology
BAILUS WALKER, JR., Chair, Howard University Medical Center, Washington, D.C.
MELVIN E. ANDERSEN, Colorado State University, Denver, Colo.
GERMAINE M. BUCK, State University of New York at Buffalo, Buffalo, N.Y.
GARY P. CARLSON, Purdue University, West Lafayette, Ind.
JACK H. DEAN, Sanofi Pharmaceuticals, Inc., Malverne, Pa.
ROBERT E. FORSTER II, University of Pennsylvania, Philadelphia, Pa.
PAUL M.D. FOSTER, Chemical Industry Institute of Toxicology, Research Triangle Park, N.C.
DAVID W. GAYLOR, U.S. Food and Drug Administration, Jefferson, Ark.
JUDITH A. GRAHAM, U.S. Environmental Protection Agency, Research Triangle Park, N.C.
SIDNEY GREEN, Howard University, Washington, D.C.
WILLIAM E. HALPERIN, National Institute for Occupational Safety and Health, Cincinnati, Ohio
CHARLES H. HOBBS, Lovelace Respiratory Research Institute and Lovelace Biomedical and Environmental Research Institute, Albuquerque, N.M.
FLORENCE K. KINOSHITA, Hercules Incorporated, Wilmington, Del.
MICHAEL J. KOSNETT, University of Colorado Health Sciences Center, Denver, Colo.
MORTON LIPPMANN, New York University School of Medicine, Tuxedo, N.Y.
THOMAS E. MCKONE, University of California, Berkeley, Calif.
ERNEST E. MCCONNELL, ToxPath, Inc., Raleigh, N.C.
DAVID H. MOORE, Battelle Memorial Institute, Bel Air, Md.
GUNTER OBERDÖRSTER, University of Rochester, Rochester, N.Y.
JOHN L. O'DONOGHUE, Eastman Kodak Company, Rochester, N.Y.
GEORGE M. RUSCH, AlliedSignal, Inc., Morristown, N.J.
MARY E. VORE, University of Kentucky, Lexington, Ky.
ANNETTA P. WATSON, Oak Ridge National Laboratory, Oak Ridge, Tenn.
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Staff
CAROL A. MACZKA, Senior Program Director
KULBIR S. BAKSHI, Program Director
ABIGAIL STACK, Project Director
SUSAN N.J. PANG, Research Associate
RUTH E. CROSSGROVE, Publications Manager
KATHRINE J. IVERSON, Manager, Toxicology Information Center
CATHERINE M. KUBIK, Senior Program Assistant
LINDA V. LEONARD, Senior Program Assistant
LUCY V. Fusco, Project Assistant
CHRISTINE E. PHILLIPS, Project Assistant
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Board on Environmental Studies and Toxicology
GORDON ORIANS, Chair, University of Washington, Seattle, Wash.
DONALD MATTISON, Vice Chair, March of Dimes, White Plains, N.Y.
DAVID ALLEN, University of Texas, Austin, Tex.
MAY R. BERENBAUM, University of Illinois, Urbana, Ill.
EULA BINGHAM, University of Cincinnati, Ohio
PAUL BUSCH, Malcolm Pirnie, Inc., White Plains, N.Y.
PETER L. DEFUR, Virginia Commonwealth University, Richmond, Va.
DAVID L. EATON, University of Washington, Seattle, Wash.
ROBERT A. FROSCH, Harvard University, Cambridge, Mass.
JOHN GERHART, University of California, Berkeley, Calif.
MARK HARWELL, University of Miami, Fla.
ROGENE HENDERSON, Lovelace Respiratory Research Institute, Albuquerque, N.M.
CAROL HENRY, American Petroleum Institute, Washington, D.C.
BARBARA HULKA, University of North Carolina, Chapel Hill, N.C.
DANIEL KREWSKI, Health Canada and University of Ottawa, Ont., Canada
JAMES A. MACMAHON, Utah State University, Logan, Utah
MARIO J. MOLINA, Massachusetts Institute of Technology, Cambridge, Mass.
WARREN MUIR, Hampshire Research Institute, Alexandria, Va.
CHARLES O'MELIA, Johns Hopkins University, Baltimore, Md.
KIRK SMITH, University of California, Berkeley, Calif.
MARGARET STRAND, Oppenheimer Wolff Donnelly & Bayh, LLP, Washington, D.C.
TERRY F. YOSIE, Ruder Finn Inc., Washington, D.C.
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
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Commission on Life Sciences
MICHAEL T. CLEGG, Chair, University of California, Riverside, Calif.
PAUL BERG, Vice Chair, Stanford University, Stanford, Calif.
FREDERICK R. ANDERSON, Cadwalader, Wickersham & Taft, Washington, D.C.
JOHN C. BAILAR III, University of Chicago, Chicago, Ill.
JOANNA BURGER, Rutgers University, Piscataway, N.J.
SHARON L. DUNWOODY, University of Wisconsin, Madison, Wis.
DAVID EISENBERG, University of California, Los Angeles, Calif.
JOHN EMMERSON, Portland, Ore.
NEAL FIRST, University of Wisconsin, Madison, Wis.
DAVID J. GALAS, Chiroscience R&D Inc., Bothell, Wash.
DAVID V. GOEDDEL, Tularik, Inc., South San Francisco, Calif.
ARTURO GOMEZ-POMPA, University of California, Riverside, Calif.
COREY S. GOODMAN, University of California, Berkeley, Calif.
HENRY HEIKKINEN, University of Northern Colorado, Greeley, Colo.
BARBARA S. HULKA, University of North Carolina, Chapel Hill, N.C.
HANS J. KENDE, Michigan State University, East Lansing, Mich.
CYNTHIA KENYON, University of California, San Francisco, Calif.
MARGARET G. KIDWELL, University of Arizona, Tucson, Ariz.
BRUCE R. LEVIN, Emory University, Atlanta, Ga.
OLGA F. LINARES, Smithsonian Tropical Research Institute, Miami, Fla.
DAVID LIVINGSTON, Dana-Farber Cancer Institute, Boston, Mass.
DONALD R. MATTISON, March of Dimes, White Plains, N.Y.
ELLIOT M. MEYEROWITZ, California Institute of Technology, Pasadena, Calif.
ROBERT T. PAINE, University of Washington, Seattle, Wash.
RONALD R. SEDEROFF, North Carolina State University, Raleigh, N.C.
ROBERT R. SOKAL, State University of New York, Stony Brook, N.Y.
CHARLES F. STEVENS, The Salk Institute, La Jolla, Calif.
SHIRLEY M. TILGHMAN, Princeton University, Princeton, N.J.
JOHN L. VANDEBERG, Southwest Foundation for Biomedical Research, San Antonio, Tex.
RAYMOND L. WHITE, University of Utah, Salt Lake City, Utah
MYRON F. UMAN, Acting Executive Director
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Other Reports of the Board on Environmental Studies and Toxicology
Research Priorities for Airborne Particulate Matter: I. Immediate Priorities and a Long-Range Research Portfolio (1998)
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 [Urinary Toxicology (1995), Immunotoxicology (1992), Neurotoxicology (1992), Pulmonary Toxicology (1989), Reproductive Toxicology (1989)]
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)
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 http://www.nap.edu
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Preface IN 1976 under the Safe Drinking Water Act, the U.S. Environmental Protection Agency (EPA) proposed an interim maximum contaminant level (MCL) for arsenic in drinking water of 50 micrograms per liter (µg/L) as part of the National Interim Primary Drinking Water Standards. That standard will apply until EPA adopts a new MCL. As part of a periodic review process, EPA has been reviewing data on arsenic exposure and toxicity to determine the adequacy of the 50-µg/L MCL for protecting public health. To ensure a solid and unbiased scientific basis for its arsenic standard for drinking water and surface waters, EPA requested that the National Research Council (NRC) review and comment on the arsenic toxicity data base and evaluate the scientific validity of EPA's 1988 risk assessment for arsenic in drinking water.
For this report, the Subcommittee on Arsenic in Drinking Water of the NRC's Committee on Toxicology reviewed EPA's characterization of existing human health risks from ingestion of arsenic found in drinking water and food; determined the adequacy of the current EPA MCL for protecting human health in the context of stated EPA policy; and identified priorities for research to fill data gaps. The subcommittee evaluated the Taiwanese epidemiological data for carcinogenic and noncarcinogenic health effects of arsenic exposure; compared effects of arsenic exposure demonstrated in other countries, including the United States, with those documented for Taiwanese populations; and reviewed data on toxicokinetics, metabolism, and mechanism and mode of action of arsenic to ascertain how these data could assist in assessing human health risks from arsenic exposures. In areas where the subcommittee concluded that EPA could improve the toxicity analysis and risk characterization, specific changes are recommended, and the implications of the changes for EPA's current MCL for arsenic are described in this report.
This report has been reviewed in draft form by individuals chosen for their diverse perspectives and technical expertise in accordance with procedures
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Preface
IN 1976 under the Safe Drinking Water Act, the U.S. Environmental Protec-
tion Agency (EPA) proposed an interim maximum contaminant {eve! (MCL)
for arsenic in drinking water of 50 micrograms per liter Age) as part of the
National Interim Primary Drinking Water Standards. That standard will apply
until EPA adopts a new MCL. As part of a periodic review process, EPA has
been reviewing data on arsenic exposure and toxicity to determine the ade-
quacy of the 50-,ug/L MCL for protecting public health. To ensure a solid
and unbiased scientific basis for its arsenic standard for drinking water and
surface waters, EPA requested that the National Research Council (NRC)
review and comment on the arsenic toxicity data base and evaluate the scien-
tific validity of EPA's 1988 risk assessment for arsenic in drinking water.
For this report, the Subcommittee on Arsenic in Drinking Water of the
NRC's Committee on Toxicology reviewed EPA's characterization of existing
human health risks from ingestion of arsenic found in drinking water and
food; determined the adequacy of the current EPA MCL for protecting human
health in the context of stated EPA policy; and identified priorities for re-
search to fill data gaps. The subcommittee evaluated the Taiwanese epidemio-
logical data for carcinogenic and noncarcinogenic health effects of arsenic
exposure; compared effects of arsenic exposure demonstrated in other coun-
tries, including the United States, with those documented for Taiwanese
populations; and reviewed data ontoxicokinetics, metabolism, end mechanism
and mode of action of arsenic to ascertain how these data could assist in
assessing human health risks from arsenic exposures. In areas where the
subcommittee concluded that EPA could improve the toxicity analysis and risk
characterization, specific changes are recommended, and the implications of
the changes for EPA's current MCL for arsenic are described in this report.
This report has been reviewed in draft form by individuals chosen for their
diverse perspectives and technical expertise in accordance with procedures
Xl
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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 manuscript remain confidential to protect the integrity of the deliberative process. We wish to thank the following individuals, who are neither officials nor employees of the NRC, for their participation in the review of this report: Dean E. Carter, University of Arizona; Gerald F. Combs, Cornell University; K.S. Crump, Jr., Fred Hutchinson Cancer Research Center; John L. Emmerson of Portland, Oregon; Janet L. Greger, University of Wisconsin-Madison; Edward Harris, Texas A&M University; Ronald D. Hood, The University of Alabama; David A. Kalman, University of Washington; Karl T. Kelsey, Harvard School of Public Health; Harold H. Sandstead, University of Texas Medical Branch; Joyce S. Tsuji, Exponent; John E. Vanderveen of Rockville, Maryland; and Michael P. Waalkes, National Institute of Environmental Health Sciences.
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 subcommittee and the NRC.
The subcommittee gratefully acknowledges Charles Abernathy, Jeanette Wiltse, Herman Gibb, Denise Lewis, and David Thomas, all of the U.S. Environmental Protection Agency; Michael Bolger, U.S. Food and Drug Administration; Ruth Hund, American Water Works Association Research Foundation; Erik Olson and David Wallinga, Natural Resources Defense Council; Robert Fensterheim, Environmental Arsenic Council; Janice Yager, Electric Power Research Institute; Warner North, Decision Focus, Inc.; Raymond Grissom, Agency for Toxic Substances and Disease Registry; and Chien-Jen Chen, National Taiwan University; for providing background information or for making presentations to the subcommittee. In addition, Chris Le, University of Alberta, at the request of the subcommittee, contributed information on the collection and storage of urine samples for arsenic speciation. That information became an integral section of the report.
We are grateful for the assistance of the NRC staff for preparing the report. Staff members who contributed to this effort are Paul Gilman, former executive director of the Commission on Life Sciences; James J. Reisa, director of the Board on Environmental Studies and Toxicology; Carol A. Maczka, the project director, who coordinated and contributed to the preparation of the subcommittee's report; Margaret M. McVey, former project
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director; Ruth E. Crossgrove, editor; Mirsada Karalic-Loncarevic, information specialist; Lucy V. Fusco, project assistant; and Catherine M. Kubik, senior program assistant.
Finally, I would like to thank all the members of the subcommittee for their dedicated efforts throughout the development of this report.
ROBERT A. GOYER, M.D. Chair, Subcommittee on Arsenic in Drinking Water
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Contents
Executive Summary
1
1 Introduction
10
Background,
11
Scientific Controversies
12
Organization of this Report
13
References
14
2 The U.S. Environmental Protection
Agency's 1988 Risk Assessment for Arsenic
16
Overview of the EPA 1988 Special
Report
16
EPA's 1988 Risk Assessment: 10 Years
Later
21
Summary
24
References
25
3 Chemistry and Analysis of Arsenic
Species in Water and Biological Materials
27
Summary of Arsenic Compounds in Water
and Food
27
Relevant Chemical Considerations
30
Analysis of Arsenic Compounds
35
Arsenic in Water
41
Arsenic in Food
46
Arsenic in Urine, Blood, Hair, and
Nails
56
Summary and Conclusions
66
Recommendations
68
References
68
4 Health Effects of Arsenic
83
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Contents Executive Summary
1
1 Introduction
10
Background,
11
Scientific Controversies
12
Organization of this Report
13
References
14
2 The U.S. Environmental Protection Agency's 1988 Risk Assessment for Arsenic
16
Overview of the EPA 1988 Special Report
16
EPA's 1988 Risk Assessment: 10 Years Later
21
Summary
24
References
25
3 Chemistry and Analysis of Arsenic Species in Water and Biological Materials
27
Summary of Arsenic Compounds in Water and Food
27
Relevant Chemical Considerations
30
Analysis of Arsenic Compounds
35
Arsenic in Water
41
Arsenic in Food
46
Arsenic in Urine, Blood, Hair, and Nails
56
Summary and Conclusions
66
Recommendations
68
References
68
4 Health Effects of Arsenic
83
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Cancer Effects
83
Noncancer Effects
101
Summary and Conclusions
130
Recommendations
133
References
133
5 Disposition of Inorganic Arsenic
150
Absorption
150
Biotransformation
151
Transportation, Distribution, and Elimination
159
Kinetic Model
164
Summary and Conclusions
165
Recommendations
167
References
167
6 Biomarkers of Arsenic Exposure
177
Arsenic in Urine
177
Arsenic in Blood
180
Arsenic in Hair and Nails
182
Summary and Conclusions
184
Recommendations
185
References
186
7 Mechanisms of Toxicity
193
Cancer Effects
193
Noncancer Effects
207
Summary and Conclusions
213
Recommendations
214
References
215
8 Variation in Human Sensitivity
229
Variation in Arsenic Metabolism
229
Nutritional Status
235
Summary and Conclusions
243
Recommendations
244
Reference
244
9 Essentiality and Therapeutic Uses
251
Definition of Essentiality
251
Evidence for Essentiality
252
Therapeutic Uses of Arsenic
257
Summary and Conclusions
259
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Recommendations
260
Reference
260
10 Statistical Issues
264
A Review of Dose-Response Modeling and Risk Assessment
265
The EPA 1988 Analysis
267
Problems with Risk Assessment Based on Ecological Data
269
Internal-Cancer Data from Taiwan
273
Other Issues
284
Discussion
290
Summary and Conclusions
293
Recommendations
295
References
296
11 Risk Characterization
299
References
301
Addendum to Chapter 9
302
Addendum to Chapter 10
307
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Arsenic in Drinking Water
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· e
Arsenic in Drinking Water
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