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Health Efiects of ingested Fluoride Subcommittee on Health Effects of Ingested Fluoride Committee on Toxicology Board on Environmental Studies and Toxicology Commission on Life Sciences National Research Council NATIONAL ACADEMY PRESS Washington, D.C. 1993

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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 repast was approved by the Governing Board of the National Research Council, whose members are drawn from Me 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 competencies and with regard for appropriate balance. This report has been reviewed by a group other than the authors according to procedures approved by a Report Review Committee consisting of members of the National Academy of Sciences, the National Academy of Engineering, and the Institute of Medicine. The National Academy of Sciences is a private, non-profit, 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 ~e 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. Frank Press 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. Robert M. White 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 ofthe 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 1. 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. Frank Press and Dr. Robert M. White are chairman and vice chairman, respectively, of the National Research Council. The project was supported by U.S. Environmental Protection Agency Contract CR-819504-01-0. Library of Congress Catalog Card No. 93-85306 International Standard Book No. 0-309-04975-X Additional copies of this report are available from: National Academy Press, 2101 Constitution Avenue, NW, Box 285, Washington, DC 20055. B-186 Copyright 1993 by the National Academy of Sciences. All rights reserved. Printed in the United States of America First Printing, August 1993 Second Printing, March 1995

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SUBCOMMITTEE ON HEALTH EFFECTS OF INGESTED FLUORIDE BERNARD M. WAGNER (Chair), Wagner Associates, Inc., Millburn' N.J. BRIAN A. BURT, University of Michigan, Ann Arbor, Mich. KENNETH P. CANTOR, National Cancer Institute, Rockville, Md. DANIEL ~EWSKI, Health & Welfare Canada, Ottawa, Ontario STEVEN M. LEVY, University of Iowa, Iowa City, Iowa ERNEST EUGENE MCCONNELL, Raleigh, N.C. GARY M. WHITFORD, Medical College of Georgia, Augusta, Ga. Staff RICHARD D. THOMAS, Program Director KULBIR S. BAKSHI, Project Director RllTH E. CROSSGROVE, Editor CATHERINE M. KUBIK, Senior Program Assistant RUTH P. DANOFF, Project Assistant . . . ...

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COMMITTEE ON TOXICOLOGY ROGENE F.HENDERSON (ChairJ, Lovelace Biomedical and Environmental Research Institute, Albuquerque, N.M. BERNARD M. WAGNER (Vice-ChairJ, Wagner Associates, Inc., Millburn, Net. R. HAYS BELL, Eastman Kodak Company, Rochester, N.Y. DEAN E. CARTER, University of Arizona, Tucson, Ariz. CHARLES E. FEIGLEY, University of South Carolina, Columbia. S.C. DONALD E. GARDNER, ManTech Environmental Technology, Inc., Research Triangle Park, N.C. MARY ESTHER GAULDEN, University of Texas Southwestern Medical School, Dallas, Tex. WALDERICO M. GENEROSO, Oak Ridge National Laboratory, Oak Ridge, Tenn. IAN A. GREAVES, University of Minnesota, Minneapolis, Minn. RONALD A. MITES, Indiana University, Bloomington, Ind. CAROLE A. KTMMEL, Environmental Protection Agency, Washington, D.C. RALPH L. KODELL, Food and Drug Administration, National Center for Toxicological Research, Jefferson, Ark. LOREN D. KOLLER, Oregon State University, Corvallis, Oreg. ERNEST EUGENE MCCONNELL, Raleigh, N.C. MICHELE A. MEDINSKY, Chemical Industry Institute of Toxicology, Research Triangle Park, N.C. ROBERT SNYDER, Rutgers University, Piscataway, N.~. BAILUS WALKER, JR., University of Oklahoma, Oklahoma City, Okla. HANSPETER R. WITSCHI, University of California, Davis, Calif. GERALD N. WOGAN, Massachusetts Institute of Technology, Cambridge, Mass. GAROLD S. YOST, University of Utah, Salt LJake City, Utah v

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~f~8 0" ~~ DACHAS D. THOMAS, Program Director IBM S. BAITS Senior Program Officer H=~ A. SC Senior Shag Scientist CROSSBOW Bier CATS M. ~, Senior Program Assistant In P. DANOe, Project Assistant

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BOARD ON EN=RONMENTAL STUDIES AND TOXICOLOGY PAUL G. RISSER fiChair), University of Miami, Oxford, Ohio FREDERICK R. ANDERSON, Cadwalader, Wickersham & Taft, Washington, D.C. JO~ C. BAILAR, m, McGill University School of Medicine, Montreal, Quebec, Canada GARRY D. BREWER, University of Michigan, Ann Arbor, Mich. JO~ CA~NS, JR., Virginia Polytechnic Institute and State University, Blacksburg, Va. EDWIN H. CLARK, Department of Natural Resources and Environmental Control, State of Delaware, Dover, Del. JOHN L. EMERSON, Lilly Research Laboratories, Greenheld, Ind. ROBERT C. FORNEY, Unionville, Pa. ALFRED G. KNUDSON, Fox Chase Cancer Center, Philadelphia, Pa. KAI LEE, Williams College, Williamstown, Mass. GENE E. LIKENS, The New York Botanical Garden, MilIbrook, N.Y. JANE LUBCHENCO, Oregon State University, Corvallis, Oreg. DONALD MATTISON, University of Pittsburgh, Pittsburgh, Pa. HAROLD A. MOONEY. Stanford University, Stanford, Calif. GORDON ORIANS, University of Washington, Seattle, Wash. FRANK L. PARKER, Vanderbilt University, Nashville, Tenn., and Clemson University, Anderson, S.C. GEOFFREY PLACE, Hilton Head, S.C. MARGARET M. SEMINARIO, AFL/CID, Washington, D.C. I. GLENN SIPES, University of Arizona, Tucson, Ariz. BAILUS WALKER, JR., University of Oklahoma, Oklahoma City, Okla. WALTER I. WEBER, JR., University of Michigan, Ann Arbor, Mich. . . Vil

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Staff of Board on Environmental Studies aM Toxicology .lAMES l. REISA, Director DAVID it. POLICANSKY, Associate Director and Program Director for Natural Resources and Applied Ecology RICHARD D. THOMAS, Associate Director and Program Director for Human Toxicology and Risk Assessment LEE R. PAULSON, Program Director for Information Systems and Statistics RAYMOND A. WASSEL, Program Director for Environmental Sciences and Engineering . . . Viz!

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COMMISSION ON LIFE SCIENCES THOMAS D. DOLLAR (Chair), Johns Hopkins Medical School, Baltimore, Md. BRUCE N. AMES, University of California, Berkeley, Calif. I. MICHAEL BISHOP, Hooper Research Foundation, University of California Meclical Center, San Francisco, Calif. DAVID BOTSTEIN, Stanford University School of Medicine, Stanford, Calif. 1\IICHAEL T. CLEGG, University of California, Riverside, Calif. GLENN A. CROSBY, Washington State University, Pullman, Wash. LEROY E. HOOD, University of Washington, Seattle, Wash. MARIAN E. KOSHLAND, Univers ity of C al if o rn i a, B erke] ey, C al if RICHARD E. LENSKI, University of Oxford, Oxford, United Kingclom STEVEN P. PAKES, Southwestern Medical Center, Dallas, Tex. EMIL A. PFITZER, Hoffmann-La Roche Inc., NutIey, N.J. MALCOLM C. PIKE, University of Southern California School of Medicine, Los Angeles, Calif. PAUL G. RISSER, Miami University, Oxford, Ohio JOHNATHAN M. SALT, University of New Mexico School of c Medicine, Albuquerque, N.M. HAROLD M. SCHMECK, JR., Armonk, N.Y. CARLA I. SHATZ, University of California, Berkeley, Calif. SUSAN S. TAYLOR, University of California at San Diego, La JolIa, Calif. P. ROY VAGELOS, Merck anti Company, Inc., Whitehouse Station, N.J. TORSTEN N. WIESEL, Rockefeller University, New York, N.Y. Star PAUL OILMAN, Executive Director

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Other Recent Reports of Abe Bonsai on Environmental Studies and Toxicology 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) Biologic Markers in Immunotoxicology (1992) Dolphins and the Tuna Industry (1992) Environmental Neurotoxicology (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) Tracking Toxic Substances at Inclustrial Facilities (1990) Biologic Markers in Pulmonary Toxicology (1989) Biologic Markers in Reproductive Toxicology (1989) Copies of these reports may be ordered from the National Academy Press (8009 624-6242 (2029 334-3313 Xl i

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PREFACE Fluoridation of public water supplies has aroused considerable discus- sion among scientists and the general public since it began in 1945. Although the majority of scientists support the measure, some take the view that fluoridation can produce not only adverse cosmetic effects from severe dental fluorosis, but also adverse health effects. Scientists have become increasingly aware of the potential for exposure to toxic concentrations of fluoride from water and other sources (e.g., foods, processed beverages, dental products, and fluoride supplements). Thus, accurate information on the potential health effects of fluoride is needed. To address that need, the U.S. Environmental Protection Agen- cy (EPA) requested that the Committee on Toxicology (COT) review the health effects of ingested fluoride and determine whether EPA's maxi- mum contaminant level of 4 milligrams (mg) of fluoride per liter (~) of drinking water is appropriate. In response, COT organized the Subcom- mittee on Health Effects of Ingested Fluoride, which includes! scientists with expertise in toxicology, pathology, medicine, dentistry, epiclemiol- ogy, biostatistics, and risk assessment. The subcommittee reviewed various kinds of toxicity that have been attributed to ingestion of fluoride (dental fluorosis; bone fracture; reproductive, renal, gastrointestinal, and immunological toxicities; genotoxicity; and carcinogenicity) anti assesses! the current EPA drinking-water stand are] for fluoride to determine if it is protective of public health. The report of the subcommittee is intended for use by EPA in deciding whether to maintain or revise its current drinking-water standard for fluoride. . x'''

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XiV Preface The subcommittee gratefully acknowledges He interest and support of Edward Ohanian and Kenneth Bailey of EPA. We also thank other per- sons who provided information or prepared presentations for the sub- committee, including Steven Gordon, National Institutes of Health; Daniel Hoffman, George Washington University; Lent Johnson, John Pletcher, and Michael Slayter, Armed Forces Institute of Pathology; and Frank Young, U.S. Department of Health and Human Services. We are grateful to the anonymous reviewers for their many helpful comments and suggestions that have resulted in improvements in the presentation of the subcommittee's findings. This report could not have been produced without the untiring efforts of the National Research Council staff: Richard D. Thomas, program director; Ruth E. Crossgrove, editor; Ruth Danoff, project assistant; and Catherine Kubik, senior program assistant. Finally, the subcommittee gratefully acknowledges the persistence, patience, and expertise of Kulbir S. Bakshi, project director of the sub- committee, in bringing this report to its final form. Bernard Wagner, Chair Subcommittee on Health Effects of ingested Fluoride Rogene F. Henderson, Chair Committee on Toxicology

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CONTENTS . EXECUTIVE SUMMARY 1 INTRODUCTION 2 DENTAL FLUOROSIS The Fluoride Content of Teeth Fluoride's Action in Preventing Dental Caries Histopathology of Dental Fluorosis Diagnostic Issues in Dental Fluorosis Indexes for Dental Fluorosis Dental Fluorosis and Fluoride Intake Prevalence of Dental Fluorosis Risk Factors in Dental Fluorosis The Relation Between Dental Fluorosis and Caries Conclusions Research Recommendations 3 FLUORIDE EXPOSURE AND RISK OF BONE FRACTURE Bone Fracture in Humans Bone Fracture in Animals 4 REPRODUCTIVE EFFECTS OF FLUORIDE Reproductive Effects in Humans Reproductive Ejects in Animals xv 1 ~ r 19 19 20 22 25 27 29 32 41 45 45 48 51 51 61 73 73 74

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XVi Contents Discussion EFFECTS OF INGESTED FLUORIDE ON RENAL, GASTROINTESTINAL, AND IMMUNE SYSTEMS Effects on the Renal System Effects on the Gastrointestinal System Hypersensitivity and Immunological Effects Discussion 6 GENOTOXICITY OF FLUORIDE In Vitro Genotoxicity Test Systems In Vivo Genotoxicity Test Systems Proposed Mechanisms of Genotoxicity Summary 7 CARCINOGENICITY OF FLUORIDE Fluoride Carcinogenicity in Humans Fluoride Carcinogenicity in Animals Conclusions Recommendations INTAKE, METABOLISM, AND DISPOSITION OF FLUORIDE Fluoride Intake Fluoride Absorption Fluoride in Plasma Tissue Distribution Fluoride Excretion Recommendations REFERENCES APPENDIX 1 APPENDIX 2 APPENDIX 3 82 85 85 87 88 89 91 91 101 107 108 109 109 113 121 122 125 125 128 129 130 131 133 135 167 173 177

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