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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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