This report contains the collective views of an international group of

experts and does not necessarily represent the decisions or the stated policy

of the United Nations Environment Programme, the International Labour

Organization or the World Health Organization.

Environmental Health Criteria 227

FLUORIDES

First draft prepared by Dr R. Liteplo and Ms R. Gomes, Health Canada,

Ottawa, Canada and Mr P. Howe and Mr H. Malcolm, Centre for

Ecology and Hydrology, Cambridgeshire, United Kingdom 

Please note that the pagination and layout of this pdf-file

are not identical to those of the printed EHC

Published under the joint sponsorship of the United Nations

Environment Programme, the International Labour

Organization and the World Health Organization, and

produced within the framework of the Inter-Organization

Programme for the Sound Management of Chemicals.

World Health Organization

Geneva, 2002
The International Programme on Chemical Safety (IPCS), established

in 1980, is a joint venture of the United Nations Environment Programme

(UNEP), the International Labour Organization (ILO) and the World Health

Organization (WHO). The overall objectives of the IPCS are to establish the

scientific basis for assessment of the risk to human health and the environment

from exposure to chemicals, through international peer review processes, as a

prerequisite for the promotion of chemical safety, and to provide technical

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Agriculture Organization of the United Nations, WHO, the United Nations

Industrial Development Organization, the United Nations Institute for Training

and Research and the Organisation for Economic Co-operation and Development

(Participating Organizations), following recommendations made by the 1992 UN

Conference on Environment and Development to strengthen cooperation and

increase coordination in the field of chemical safety. The purpose of the IOMC

is to promote coordination of the policies and activities pursued by the

Participating Organizations, jointly or separately, to achieve the sound management of chemicals in relation to human health and the environment.

WHO Library Cataloguing-in-Publication Data

Fluorides.

(Environmental health criteria ; 227)

1.Fluorides - adverse effects 2.Environmental exposure 3.Occupational

exposure 4.Risk assessment I.International Programme for Chemical Safety

II.Series

ISBN 92 4 157227 2 (NLM classification: QV 282)

ISSN 0250-863X

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CONTENTS

ENVIRONMENTAL HEALTH CRITERIA FOR

FLUORIDES

PREAMBLE ix

ACRONYMS AND ABBREVIATIONS xxi

1. SUMMARY AND CONCLUSIONS 1

1.1 Identity, physical and chemical properties and 

analytical methods 1

1.2 Sources of human and environmental exposure 1

1.3 Environmental transport, distribution and

transformation 2

1.4 Environmental levels and human exposure 3

1.5 Kinetics and metabolism in humans and laboratory animals 7

1.6 Effects on laboratory mammals and in vitro test 

systems 8

1.7 Effects on humans 10

1.8 Effects on other organisms in the laboratory

and field 11

1.9 Evaluation of human health risks and effects on the environment 14

1.10 Conclusions 15

2. IDENTITY, PHYSICAL AND CHEMICAL 

PROPERTIES AND ANALYTICAL METHODS 17
EHC 227: Fluorides

iv

2.1 Identity and physical and chemical properties 17

2.2 Analytical methods 18

3. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE 20

3.1 Natural occurrence 20

3.2 Anthropogenic sources 20

3.2.1 Production and use 20

3.2.1.1 Hydrogen fluoride 20

3.2.1.2 Calcium fluoride 21

3.2.1.3 Sodium fluoride 21

3.2.1.4 Fluorosilicic acid 21

3.2.1.5 Sodium hexafluorosilicate 22

3.2.1.6 Sulfur hexafluoride 22

3.2.1.7 Fluorapatite 22

3.2.1.8 Phosphate fertilizers 22

3.2.2 Emissions 23

4. ENVIRONMENTAL TRANSPORT, DISTRIBUTION

AND TRANSFORMATION 24

4.1 Transport and distribution between media 24

4.1.1 Atmosphere 24

4.1.2 Water and sediment 28

4.1.3 Soil 30

4.2 Speciation and complexation 34

4.2.1 Atmosphere 34

4.2.2 Water 34

4.3 Bioaccumulation 34

5. ENVIRONMENTAL LEVELS AND HUMAN 

EXPOSURE 38

5.1 Environmental levels 38

5.1.1 Surface water 38

5.1.2 Air 41

5.1.3 Soil 41

5.1.4 Biota 43

5.1.4.1 Aquatic organisms 43

5.1.4.2 Terrestrial organisms 48

5.2 General population exposure 53

5.2.1 Drinking-water 53
v

5.2.2 Food 56

5.2.3 Indoor air 61

5.2.4 Consumer products 63

5.2.5 Intake estimates 63

5.3 Occupational exposure 70

6. KINETICS AND METABOLISM IN HUMANS AND

LABORATORY ANIMALS 71

6.1 Absorption 71

6.1.1 Absorption in humans 71

6.1.2 Absorption in laboratory animals 73

6.2 Distribution and retention 74

6.2.1 Fluoride in blood 74

6.2.2 Distribution in soft tissues 76

6.2.3 Distribution to calcified tissues 76

6.2.4 Transplacental transfer 78

6.2.5 Fluoride levels in human tissues and organs 78

6.3 Elimination 80

6.3.1 Renal handling of fluoride 80

6.3.2 Excretion via breast milk 80

6.3.3 Excretion via faeces, sweat and saliva 81

7. EFFECTS ON LABORATORY MAMMALS AND

IN VITRO TEST SYSTEMS 83

7.1 Single exposure 83

7.2 Short- and medium-term exposure 84

7.3 Long-term exposure and carcinogenicity 86

7.4 Mutagenicity and related end-points 92

7.4.1 In vitro genotoxicity 92

7.4.2 In vivo genotoxicity 94

7.5 Reproductive toxicity 95

7.6 Immunotoxicity 97

7.7 Mechanisms of action 97

7.8 Interaction with other substances 97

8. EFFECTS ON HUMANS 100

8.1 General population 100
EHC 227: Fluorides

vi

8.1.1 Acute toxicity 100

8.1.2 Clinical studies 101

8.1.2.1 Skeletal effects 101

8.1.2.2 Haematological, hepatic or renal

effects 102

8.1.3 Epidemiological studies 102
vii

8.1.3.1 Cancer 102

8.1.3.2 Skeletal fluorosis 104

8.1.3.3 Skeletal fracture 111

8.1.3.4 Reproductive effects 116

8.1.3.5 Respiratory effects 116

8.1.3.6 Neurobehavioural effects 117

8.1.3.7 Genotoxic effects 118

8.1.3.8 Dental effects 119

8.1.4 Interactions with other substances 125

8.2 Occupationally exposed workers 126

8.2.1 Case reports 126

8.2.2 Epidemiological studies 126

8.2.2.1 Cancer 126

8.2.2.2 Skeletal effects 127

8.2.2.3 Respiratory effects 128

8.2.2.4 Haematological, hepatic or renal 

effects 128

8.2.2.5 Genotoxic effects 128

9. EFFECTS ON OTHER ORGANISMS IN THE LABORATORY

AND FIELD 130

9.1 Laboratory experiments 130

9.1.1 Microorganisms 130

9.1.1.1 Water 130

9.1.1.2 Soil 132

9.1.2 Aquatic organisms 132

9.1.2.1 Plants 132

9.1.2.2 Invertebrates 133

9.1.2.3 Vertebrates 138

9.1.3 Terrestrial organisms 142

9.1.3.1 Plants 142

9.1.3.2 Invertebrates 148

9.1.3.3 Vertebrates 149

9.2 Field observations 153

9.2.1 Microorganisms 153

9.2.2 Aquatic organisms 153

9.2.3 Terrestrial organisms 154

9.2.3.1 Plants 154

9.2.3.2 Invertebrates 158
EHC 227: Fluorides

viii

9.2.3.3 Vertebrates 158

10. EVALUATION OF HUMAN HEALTH RISKS AND EFFECTS ON

THE ENVIRONMENT 163

10.1 Evaluation of human health risks 163

10.1.1 Exposure 163

10.1.2 Hazard identification 164

10.1.3 Exposure–response analysis for adverse

effects in bone 170

10.2 Evaluation of effects on the environment 172

10.2.1 Exposure 172

10.2.2 Effects 175

10.2.3 Evaluation 176

11. CONCLUSIONS AND RECOMMENDATIONS FOR

PROTECTION OF HUMAN HEALTH AND THE

ENVIRONMENT 179

11.1 Conclusions 179

11.2 Recommendations 180

12. FURTHER RESEARCH 181

12.1 Health effects research 181

12.2 Environmental effects research 182

13. PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES 184

REFERENCES 185

RESUME ET CONCLUSIONS 232

RESUMEN Y CONCLUSIONES 251
ix

NOTE TO READERS OF THE CRITERIA MONOGRAPHS

Every effort has been made to present information in the criteria

monographs as accurately as possible without unduly delaying their

publication. In the interest of all users of the Environmental Health Criteria

monographs, readers are requested to communicate any errors that may have

occurred to the Director of the International Programme on Chemical Safety,

World Health Organization, Geneva, Switzerland, in order that they may be

included in corrigenda.

* * *

A detailed data profile and a legal file can be obtained from the

InternationalRegister of Potentially Toxic Chemicals,Casepostale 356, 1219

Châtelaine, Geneva, Switzerland (telephone no. + 41 22 - 9799111, fax no. +

41 22 - 7973460, E-mail irptc@unep.ch).

* * *

This publication was made possible by grant number 5 U01 ES02617-15

from the National Institute of Environmental Health Sciences, National

Institutes of Health, USA, and by financialsupport from the Federal Ministry

for the Environment, Nature conservation and Nuclear Safety, Germany.
x

Environmental Health Criteria

P R E A M B L E

Objectives

In 1973, the WHO Environmental Health Criteria Programme was

initiated with the following objectives:

(i) to assess information on the relationship between exposure to

environmental pollutants and human health, and to provideguidelinesfor

setting exposure limits;

(ii) to identify new or potential pollutants;

(iii) to identify gapsin knowledge concerningthe healtheffects of pollutants;

(iv) to promote the harmonization of toxicological and epidemiological

methods in order to have internationally comparable results.

The first Environmental HealthCriteria (EHC) monograph, on mercury,

was published in 1976, and since that time an ever-increasing number of

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methodology,e.g.,for genetic, neurotoxic, teratogenic and nephrotoxic effects.

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Since its inauguration, the EHC Programme has widened its scope, and

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increasingly emphasized in the total evaluation of chemicals.

The original impetus for the Programme came from World Health

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of the International Programme on Chemical 

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manner, with the strong support of the new partners, the import ance of
xi

occupational health and environmental effects was fully recognized. The EHC

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Scope

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Preparation ofEnvironmentalHealthCriteria Monographs. PCS/99.9, Geneva,

World Health Organization).

In the evaluation of human health risks, sound human data, whenever

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The EHC monographs are intended to assist national and international

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decisions. They represent a thorough evaluation of risks 
EHC 227: Fluorides

xii

and are not, in any sense, recommendations forregulation orstandard setting.

These latter are the exclusive purview of national and regional governments.

Content

The layout of EHC monographs for chemicals is outlined below. 

• Summary — a review of the salient facts and the risk evaluation of the

chemical

• Identity — physical and chemical properties, analytical methods

• Sources of exposure

• Environmental transport, distribution and transformation

• Environmental levels and human exposure

• Kinetics and metabolism in laboratory animals and humans

• Effects on laboratory mammals and in vitro test systems

• Effects on humans

• Effects on other organisms in the laboratory and field

• Evaluation of human health risks and effects on the environment

• Conclusions and recommendations for protection of human health and

the environment

• Further research

• Previousevaluationsby international bodies, e.g.,IARC,JECFA,JMPR

Selection of chemicals

Since the inception of the EHC Programme, the IPCS has organized

meetings of scientists to establish lists of priority chemicals for subsequent

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Kingdom, 1984; Berlin, Germany,1987; and NorthCarolina, USA, 1995. The

selection of chemicals has been based on the following criteria: the existence

of scientific evidence that the substance presents a hazard to human health

and/ortheenvironment;the possible use, persistence, accumulation ordegradation of the substance shows that there may be significant human or

environmental exposure; the size and nature of populations at risk (both

human and otherspecies) and risksfor the environment; international concern,

i.e., the substance is of majorinterest to several countries;adequatedataon the

hazards are available.

If an EHC monograph is proposed for a chemical not on the priority list,

the IPCS Secretariat consults with the cooperating organizations and all the
xiii

Participating Institutions before embarking on the preparation of the

monograph.

Procedures

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IPCS Focal Points or individualscientists known for their particular expertise.

Generally,some four months are allowed before the comments are considered

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approved by the Director, IPCS, is then distributed to Task Group members,

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Group is dictated by the range of expertise required for the subject of the

meeting and by the need for a balanced geographical distribution.
xiv

Commitment to draft EHC

Document preparation initiated

Draft sent to IPCS Responsible Officer (RO)

EHC PREPARATION FLOW CHART

Revision as

necessary

Possible meeting 

of a few experts 

to resolve 

controversial issues

First Draft First Draft

Responsible Officer, Editor check for coherence of text and 

readability (not language editing)

Responsible Officer, Editor check for coherence of text and 

readability (not language editing)

International circulation to Contact Points (150+)

Comments to IPCS (RO)

Review of comments, reference cross-check;

preparation of Task Group (TG) draft

Task Group meeting

Insertion of TG changes

Post-TG draft; detailed reference cross-check

Editing

Word-processing

Camera-ready copy

Final editing

Approval by Director, IPCS

WHO Publication Office

Printer Proofs Publication

Graphics

Library for

CIP Data

French/Spanish 

translations of Summary

Working group,

if required Editor

routine procedure

optional procedure
xv

The three cooperatingorganizations of the IPCSrecognizethe important

role played by nongovernmental organizations. Representatives from relevant

national and international associations may be invited to join the Task Group

as observers. While observers may provide a valuable contribution to the

process, they can speak only at the invitation of the Chairperson. Observers

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All individuals who as authors, consultants or advisers participatein the

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It is accepted that the following criteria should initiate the updating of

an EHC monograph: new dataare available that would substantially change the

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All Participating Institutions are informed, through the EHC progress

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in ensuring that these rules are followed.
xvi

WHO TASK GROUP ON ENVIRONMENTAL HEALTH

CRITERIA FOR FLUORIDES

Members

Professor Peter Aggett, Lancashire Postgraduate School of Medicine and

Health, University of Central Lancashire, Preston, Lancashire, United

Kingdom

Dr Roberto Belmar, Environmental Health Division, Ministry of Health,

Santiago, Chile (Chairman)

Dr John Bucher, Environmental Toxicology Program, National Institute of

Environmental Health Sciences, National Institutes of Health, Research

Triangle Park, NC, USA

Dr Julio Camargo, Ecology Department, Faculty of Science, University of

Alcalá, Madrid, Spain

Dr Jane Cauley, Department of Epidemiology, University of Pittsburgh,

Pittsburgh, PA, USA

Professor Jan Ekstrand, Department of Basic Oral Sciences, Karolinska

Institute, Stockholm, Sweden

Mr Paul Howe, Centre for Ecology and Hydrology, Monks Wood, Abbots

Ripton, Huntingdon, Cambridgeshire, United Kingdom (CoRapporteur)

Dr Gopalakrishnan Karthikeyan, Department of Chemistry, Gandhigram

Rural Institute, Gandhigram, Tamil Nadu, India

Dr Uwe Kierdorf, Institute of General and Systematic Zoology, JustusLiebig-University of Giessen, Giessen, Germany

Dr Päivi Kurttio, Radiation and Nuclear Safety Authority, Helsinki, Finland
xvii

Dr Robert Liteplo, Existing Substances Division, Bureau of Environmental

Contaminants, Health Canada, Ottawa, Ontario, Canada (CoRapporteur)

Dr Akiyoshi Nishikawa, National Institute of Health Sciences, Tokyo,

Japan

Mr Daryl Stevens, Land and Water, Commonwealth Scientific and

Industrial Research Organisation, Adelaide, Australia

Professor Paolo Vineis, Department of Biomedical Science and Human

Oncology, University of Torino, Torino, Italy

Dr Jin Yinlong, Institute of Environmental Health and Engineering, Chinese

Academy of Preventive Medicine, Beijing, People’s Republic of China

Secretariat

Dr Antero Aitio, International Programme on Chemical Safety, World

Health Organization, Geneva, Switzerland (Secretary)

Dr Bing Heng Chen, Department of Environmental Health, School of Public

Health, Shanghai Medical University, Shanghai, People’s Republic of

China

Mr John Fawell, Director, Environmental Division, Warren Associates,

Devizes, Wiltshire, United Kingdom

Ms Rose Gomes, Existing Substances Division, Bureau of Environmental

Contaminants, Health Canada, Ottawa, Ontario, Canada

Dr Philip Jenkins, International Programme on Chemical Safety, World

Health Organization, Geneva, Switzerland
xviii

ENVIRONMENTAL HEALTH CRITERIA FOR

FLUORIDES

A WHO Task Group on Environmental HealthCriteriaforFluorides met

at the Institute of Environmental Health and Engineering of the Chinese

Academy of Preventive Medicine in Beijing, People’s Republic of China, on

28 May – 1 June 2001. The group reviewed the draft document and the peer

review comments and revised and further updated the draft, including the

evaluation of the risks for human health and the environment from exposure

to fluorides.

The first and second drafts of this monograph were prepared by Dr R.

Liteplo, Health Canada, Canada, and Mr P. Howe, Centre for Ecology and

Hydrology, United Kingdom. The document was sent for peer review to the

IPCS contact points and additional experts on fluoride. The authors, in

collaboration with the IPCS Secretariat, revised the document based on the

comments received. Following an updating at the end of 2000, the document

was sent for review to the Task Group members and further revised based on

these comments. 

Peer review comments were received from the following:

Dr J. Ahlers, Umwelt Bundes Amt, Germany

Dr R. Benson, Region VIII, US Environmental Protection Agency,

USA

Professor G.B. Bliss, N.N. Petrov’s Research Institute of Oncology,

Russian Federation

Dr M. Bolger, US Food and Drug Administration, USA

Dr J. Bucher, National Institute of Environmental Health Sciences,

USA

Dr J. Camargo, University of Alcalá, Spain

Dr S. Cao, Chinese Academy of Preventive Medicine, People’s

Republic of China

Dr F.M. Carpanini, European Centre for Ecotoxicology and

Toxicology of Chemicals, Belgium

Dr J. Cauley, University of Pittsburgh, USA

Dr L.K. Cohen, National Institute of Dental Research, USA
xix

Dr A. Conacher, Health Canada, Canada

Dr P. Dargan, National Poison Information Service, United Kingdom

Professor I. Dési, Albert Szent-Györgyi University, Hungary

Dr J. Donohue, US Environmental Protection Agency, USA

Dr J. Ekstrand, Karolinska Institute, Sweden

Dr L. Friberg, Karolinska Institute, Sweden

Dr R. Hertel, Federal Institute for Health Protection of Consumers

and Veterinary Medicine, Germany

Dr C. Hiremath, National Center for Environmental Assessment, US

Environmental Protection Agency, USA

Dr B.L. Johnson, Agency for Toxic Substances and Disease Registry,

USA

Dr G. Karthikeyan, Gandhigram Rural Institute, India

Dr U. Kierdorf, Justus-Liebig-University of Giessen, Germany

Dr J. Kriz, National Institute of Public Health, Czech Republic

Dr P. Kurttio, Radiation and Nuclear Safety Authority, Finland

Dr P. Lundberg, National Institute for Working Life, Sweden

Dr E. Ohanian, Office of Water, US Environmental Protection

Agency, USA

Dr Y.A. Rakhmanine, Sysin Research Institute of Human Ecology and

Environmental Health, Russian Federation

Dr D. Renshaw, Department of Health, United Kingdom

Dr J.M. Rice, International Agency for Research on Cancer, France

Dr T.G. Rossman, New York University School of Medicine, USA

Dr U. Schlottman, Federal Ministry for the Environment, Nature

Conservation and Nuclear Safety, Germany

Dr P.A. Schulte, National Institute for Occupational Safety and

Health, USA

Dr D. Stevens, Commonwealth Scientific and Industrial Research

Organisation, Australia

Dr G. Ungváry, National Institute of Occupational Health, Hungary

Dr P. Vineis, University of Torino, Italy

Ms J. Walter, Swedish Poisons Information Centre, Sweden

Dr G. Whitford, Medical College of Georgia, USA
EHC 227: Fluorides

xx

Dr A. Aitio of the IPCS central unit was responsible for the scientific

aspects of the monograph, and Ms M. Sheffer, Ottawa, Canada, for the

technical editing.

The efforts of all who helped in the preparation and finalization of the

monograph are gratefully acknowledged. 
xxi

ACRONYMS AND ABBREVIATIONS

ATP adenosine triphosphate

ATPase adenosine triphosphatase

CAS Chemical Abstracts Service

CI confidence interval

DNA deoxyribonucleic acid

EC50 median effective concentration

EHC Environmental Health Criteria monograph

FAO Food and Agriculture Organization of the United

Nations

HMDS hexamethyldisiloxane

IARC International Agency for Research on Cancer

ILO International Labour Organization

IPCS International Programme on Chemical Safety

IQ intelligence quotient

JECFA Joint FAO/WHO Expert Meeting on Food

Additives

JMPR Joint FAO/WHO Meeting on Pesticide Residues

LC50 median lethal concentration

LD50 median lethal dose

LOEC lowest-observed-effect concentration

LOEL lowest-observed-effect level

LT50 median lethal time

MATC maximum acceptable toxicant concentration 

NOEC no-observed-effect concentration

NTP National Toxicology Program (USA)

OR odds ratio

RO Responsible Officer

RR relative risk

SD standard deviation

UN United Nations

UNEP United Nations Environment Programme

WHO World Health Organization
1

1. SUMMARY AND CONCLUSIONS

This document focuses on environmental exposure to fluoride

derived mostly frominorganic sources and its effects on humans, animals and other biota. Data on hydrogen fluoride, calcium fluoride,

sodiumfluoride,sulfur hexafluoride and silicofluorides are covered, as

these compounds are considered to be the most relevant of the inorganic fluorides on the basis of quantities released to the environment,

environmentalconcentrations and toxicologicaleffects on livingorganisms.

1.1 Identity, physical and chemical properties and

analytical methods

Hydrogen fluoride (HF) is a colourless, pungent liquid or gas that

is highly soluble in organic solvents and in water, in which it forms

hydrofluoric acid. Calcium fluoride (CaF2) is a colourless solid that is

relatively insoluble in water and dilute acids and bases. Sodium fluoride (NaF) is a colourless to white solid that is moderately soluble in

water. Sulfurhexafluoride (SF6) is a colourless, odourless, inert gas that

is slightly soluble in water and readily soluble in ethanol and bases.

The most common procedure used to quantify free fluoride anion

is the fluoride ion-selective electrode. Microdiffusion techniques are

considered to be themost accurate methods ofsample preparation (i.e.,

liberation of free ionic fluoride from organic and inorganic complexes).

1.2 Sources of human and environmental exposure

Fluorides are released into the environment naturally through the

weathering and dissolution of minerals, in emissions from volcanoes

and in marine aerosols. Fluorides are also released into the environment via coal combustion and process waters and waste from various

industrial processes, including steel manufacture, primary aluminium,

copper and nickel production, phosphate ore processing, phosphate

fertilizer production and use, glass, brick and ceramic manufacturing,

and glue and adhesive production. The use of fluoride-c ontaining

pesticides as well as the controlled fluoridation of drinking-water

supplies also contribute to the release of fluoride from anthropogenic
EHC 227: Fluorides

2

sources. Based on available data, phosphate ore production and use

as well as aluminium manufacture are the major industrial sources of

fluoride release into the environment. 

Hydrogen fluoride is an important industrial compound that is

used mainly in the production of synthetic cryolite (Na3AlF6), aluminium fluoride (AlF3

), motor gasoline alkylates and chlorofluorocarbons,

with an annual world consumption in excess of 1 million tonnes. It is

also used in etching semic onductor devices, cleaning and etching

glass, cleaning brick and aluminium and tanning leather, as well as in

commercial rust removers. Calcium fluoride is used as a flux in steel,

glass and enamel production, as the raw material for the production of

hydro fluoric acid and anhydrous hydrogen fluoride, and as an

electrolyte in aluminium production. Sodium fluoride is used in the

controlled fluoridation of drinking-water, as a preservative in glues, in

glass and enamel production, as a flux in steel and aluminium

production, as an insecticide and as a wood preservative. Sulfur

hexafluoride is used extensively in various electronic components and

in the production of magnesium and aluminium. Fluorosilicic acid

(H2SiF6) and sodium hexafluorosilicate (Na2SiF6) are used for th e

fluoridation of drinking-water supplies.

1.3 Environmental transport, distribution and

transformation

Fluorides in the atmosphere may be in gaseous orparticulate form.

Atmospheric fluorides can be transported over large distances as a

result of wind or atmospheric turbulence or can be removed from the

atmosphere via wet and dry deposition or hydrolysis. Fluoride compounds, with the exception of sulfur hexafluoride, are not expected to

remain in the troposphere for long periods or to migrate to the stratosphere. Sulfurhexafluoride has an atmospheric residence time ranging

from 500 to several thousand years. 

The transport and transformation of fluoride in water are influenced by pH, water hardness and the presence of ion-exchange materials such as clays. Fluoride is usually transported through the water

cycle complexed with aluminium. 
Summary and Conclusions

3

The transport and transformation offluoride in soil are influenced

by pH and the formation of predominantly aluminium and calcium

complexes. Adsorption to the soil solid phase is stronger at slightly

acidic pH values (5.5–6.5). Fluoride is not readily leached from soils. 

The uptake of fluoride by biota is determined by the route of exposure, the bioavailability of the fluoride and the uptake/excretion

kinetics in the organism. Soluble fluorides are bioaccumulated by some

aquatic and terrestrial biota. However, no information was identified

concerning the biomagnification of fluoride in aquatic or terrestrial

food-chains. 

Terrestrial plants may accumulate fluorides fo llowing airborne

deposition and uptake from soil.

1.4 Environmental levels and human exposure

Fluoride levels in surface waters vary according to location and

proximity to emission sources. Surface water concentrations generally

range from 0.01 to 0.3 mg/litre. Seawater contains more fluoride than

fresh water, with concentrations ranging from1.2 to 1.5 mg/litre.Higher

levels of fluoride have been measured in areas where the natural rock

is rich in fluoride, and elevated inorganic fluoride levels are often seen

in regions where there is geothermal or volcanic activity(e.g., 25–50 mg

fluoride/litre in hot springs and geysers and as much as 2800 mg/litre

in certain East African Rift Valley lakes). Anthropogenic discharges

can also lead to increased levels of fluoride in the environment. 

Airborne fluoride exists in gaseous and particulate forms, which

are emitted from both natural and anthropogenic sources. Fluoride

released as gaseous and particulate matter is deposited in the general

vicinity of an emission source, although some particulates may react

with other atmospheric constituents. The distribution and deposition

of airborne fluoride are dependent upon emission strength,

meteorological conditions, particulate size and chemical reactivity. In

areas not in the direct vicinity of emission sources, the mean

concentrations of fluoride in ambient air are generally less than 0.1

μg/m3. Levels may be slightly higher in urban than in rural locations;

h owever, even in the vicinity of emission sources, the levels of

airborne fluoride usually do not exceed 
EHC 227: Fluorides

4

2–3 μg/m3. In areas of China where fluoride-rich coal is used as a

source of fuel, reported concentrations of fluoride in ambient air have

reached 6 μg/m3. 

Fluoride is a component of most types of soil, with total fluoride

concentrations ranging from 20 to 1000 μg/g in areas without natural

phosphate or fluoridedeposits and up to several thousand micrograms

per gram in mineral soils with deposits of fluoride. Airborne gaseous

and particulate fluorides tend to accumulate within the surface layer of

soils but may be displaced throughout the root zone, even in

calcareous soils. The clay and organic carbon content as well as the

pH ofsoil are primarily responsible forthe retention of fluoride in soils.

Fluoride in soil is primarily associated with the soil colloid or clay

fraction. For all soils, it is the soluble fluoride content that is

biologically important to plants and animals.

Fluorides can be taken up by aquatic organisms directly from the

water or to a lesser extent via food. Fluorides tend to accumulate in the

exoskeleton or bone tissue of aquatic animals.Mean fluoride concentrations of >2000 mg/kg have been measured in the exoskeleton of krill;

mean bone fluoride concentrations in aquatic mammals, such as seals

and whales, ranged from 135 to 18 600 mg/kg dry weight.

Fluoride levels in terrestrial biota are higher in areas with high

fluoride levels fromnatural and anthropogenic sources. Lichens have

been used extensively as biomonitors forfluorides.Mean fluoride concentrations of 150–250 mg/kg were measured in lichens growing within

2–3 kmof fluoride emission sources, comparedwith a background level

of <1 mg fluoride/kg.

Most of the fluoride in the soil is insoluble and, therefore, less

available to plants. However, high soil fluoride concentrations or low

pH, clay and/or organic matter can increase fluoride levels in soil solution, increasing uptake via the plant root. If fluoride is taken up

through the root, its concentrations are often higher in the root than in

the shoot, due to the low mobility of fluoride in the plant. Most

fluorides enter plant tissues as gases through the stomata and

accumulate in leaves. Small amounts ofairborne particulate fluoride can

enter the plant through the epidermis and cuticle.Vegetation has been

widely monitored in the vicinity of anthropogenic fluoride emission

sources. Correlations between fluoride concentrations in vegetation
Summary and Conclusions

5

and annual growth increments, wind pattern, distance from fluoride

source and hydrogen fluoride concentrations in aerial emissions have

been observed.

Fluoride accumulates in the bone tissue of terrestrial vertebrates,

depending on factors such as diet and the proximity of fluoride

emission sources. For example,mean fluoride concentrations of 7000–

8000 mg/kg have been measured in the bones of small mammals in the

vicinity of an aluminium smelter.

Fluoride is ubiquitous in the environment; therefore, sources of

drinking-water are likely to contain at least some small amount of

fluoride. The amount of fluoride present naturally in non-fluoridated

drinking-water (i.e., drinking-water to which fluoride has not been

intentionally added for the preventio n of dental caries) is highly

variable,being dependent upon the individual geological environment

from which the water is obtained. Levels may range up to approximately 2.0 mg/litre; however, in areas of the world in which endemic

fluorosis of the skeleton and/orteeth has been well documented, levels

of fluoride in drinking-water supplies range from 3 to more than

20 mg/litre. In areas in which drinking-wateris fluoridated (i.e., fluoride

is intentionally added for the prevention of dental caries), the

concentration of fluoride in drinking-watergenerally ranges from0.7 to

1.2 mg/litre.

Virtually all foodstuffs contain at least trace amounts of fluoride.

Elevated levels are present in fish. Tea leaves are particularly rich in

fluoride; the amount of fluoride in brewed tea is dependent upon the

concentration ofsoluble fluoride in the tea leaves, the level of fluoride

in the water used in its preparation and the length of the brewing

period. The concentration of fluoride in food products is not significantly increased by the addition of superphosphate fertilizers, which

contain significant concentrations offluoride (1–3%) as impurities, to

agricultural soil, due to the generally low transfer coefficient from soil

to plant material. However, a recent study suggests that, given the

right soil conditions and application of sufficient fluoride as an

impurity in phosphate fertilizers to soils, plant uptake of fluoride can be

increased. The use of water containing relatively low (<3.1 mg/litre)

levels of fluoride forcrop irrigation generally does not increase fluoride

concentrations in foodstuffs. However, this is dependent on plant

species and fluoride concentrations in soil and water. The level of
EHC 227: Fluorides

6

fluoride in foods is significantly affected by the fluoride content ofthe

water used in preparation or processing, most notably in beverages

and dry foodstuffs — for example,powdered baby formula — to which

wateris added priorto consumption.The concentrations of fluoride in

unwashed or unpro cessed foods grown in the vicinity of industrial

sources (emissions) of fluoride may be greater than the levels in the

same foods grown in other non-industrially exposed areas.In commercially available infant formulas sold in the USA, soy-based ready-touse and liquid concentrate formulas contained higher levels of fluoride

than the equivalent milk-based products; however, no significant

difference was observed between soy- and milk-based powdered infant

formulas. Fluoride has been detected in breast milk; reported levels

range from <2 to about 100 μg/litre,with most values being between 5

and 10 μg/litre.

Available data on the concentrations of fluoride in indoor air are

limited. In the Netherlands, concentrations of gaseous fluoride ranged

from <2 to 49 μg/m3 in the indoor air of five homes constructed with

wood treated with a preservative containing 56% fluoride. In China,

concentrations as high as 155 μg/m3have been reported forsamples of

indoor air collected from homes where coal containing high amounts

of fluoride was burned indoors.

Dentifrice products for adults that are commercially available in

many countries generally contain fluoride at concentrations ranging

from 1000 to 1500 μg/g; some products designed for use by children

contain lower levels, ranging from 250 to 500 μg/g. Dental products

such as toothpaste, mouthwash and fluoride supplements have been

identified as significant sources offluoride.Mouth rinses marketed for

daily home use usually contain between 230 and 500 mg fluoride/litre,

whereas mouthwash products intended forweekly or biweekly use may

contain 900–1000 mg fluoride/litre.

A lthough individual exposure to fluoride is likely to be highly

variable, the inhalation of airborne fluoride generally makes a minor

contribution to the total intake of this substance. For adults, the

consumption of foodstuffs and drinking-wateris the principalroute for

the intake of fluoride.In areas of the world in which coalrich in fluoride

is used for heating and food preparation, the inhalation of indoor air

and consumption of foodstuffs containing increased levels of fluoride

also contribute to elevated intakes. Infants fed formula receive
Summary and Conclusions

7

50–100 times more fluoride than exclusively breast-fed infants. The

ingestion of dentifrice by young children makes a significant contribution to their total intake of fluoride. In general, estimated intakes of

fluoride in children and adolescents do not exceed approximately

2 mg/day. Although adults may have a higher absolute daily intake of

fluoride in milligrams,the daily intake of fluoride by children, expressed

on a milligram per kilogram body weight basis, may exceed that of

adults. In certain areas worldwide in which the concentration of

fluoride in the surrounding environment may be exceedingly high and/

or where diets are composed of foodstuffs rich in fluoride, estimated

intakes of fluoride in adults as high as 27 mg/day have been reported,

the principal source being drinking-water obtained from groundwater

sources located in geological areas rich in fluoride. 

Occupational exposure to fluoride via inhalation or dermal contact

likely occurs in individuals involved in the operation of welding equipment or in the processing of aluminium, iron ore or phosphate ore. In

relatively recent studies, reported concentrations of airborne fluoride

in the potrooms of aluminium smelters have been in the order of

1 mg/m3.

1.5 Kinetics and metabolism in humans and laboratory

animals 

In humans and laboratory animals, the absorption of ingested

fluoride into the general circulation occurs primarily in the stomach and

intestine and is dependent upon the relative aqueous solubility of the

form consumed. Soluble fluorides are almost completely absorbed from

the gastrointestinal tract; however, the extent of absorption may be

reduced by complex formation with aluminium, phosphorus, magnesium or calcium. There is partial to complete absorption of gaseous

and particulate fluorides from the respiratory tract, with the extent of

absorption dependent upon solubility and particle size. 

Fluoride is rapidly distributed by the systemic circulation to the

intracellular and extracellularwater oftissues; however, in humans and

laboratory animals, approximately 99% of the total body burden of

fluoride is retained in bones and teeth. In teeth and skeletal tissue,

fluoride becomes incorporated into the crystal lattice.
EHC 227: Fluorides

8

Fluoride crosses the placenta and is transferred from mother to

fetus. Fluoride is eliminated from the body primarily in the urine. In

infants, about 80–90% of a fluoride dose is retained; in adults, the

corresponding figure is approximately 60%. These values can be

altered by alterations in urinary flow and urinary pH. 

Fluoride is present in body organs, tissues and fluids. Concentrations of fluoride in whole blood of individuals residing in a community in the USA receiving fluoridated drinking-water ranged from20

to 60 μg/litre. The mean plasma level in 127 subjects with 5.03 mg

fluoride/litre in their drinking-water was 106 ± 76 (SD) μg/litre. Serum

and plasma contain virtually the same amount of fluoride. Levels of

fluoride in calcified tissues are generally highest in bone, dentine and

enamel. The concentration of fluoride in bone varies with age, sexand

the type and specific part of bone and is believed to reflect an individual’s long-term exposure to fluoride. The concentration of fluoride

in dental enamel decreases exponentially with the distance from the

surface and varies with site, surface attrition, systemic exposure and

exposure to topically applied fluoride. The concentration of fluoride in

soft tissues is reflected by that in blood. Levels of fluoride in the urine

of healthy individuals are related to the intake of fluoride. Increased

levels of urinary fluoride have been measured in individuals following

occupational exposure to airborne fluoride and among those residing

in areas associated with endemic fluorosis.

1.6 Effects on laboratory mammals and in vitro test

systems 

Effects on the skeleton, such as inhibition of bone mineralization

and formation,delayed fracture healing and reductions in bone volume

and collagen synthesis, have been observed in a variety of studies in

which rats received fluoride orally for periods of 3–5weeks.In mediumterm exposure studies, altered bone remodelling, hepatic megalocytosis, nephrosis, mineralization of the myocardium, necrosis and/or

degeneration of the seminiferous tubules in the testis were observed

in mice administered fluoride in drinking-water (>4.5 mg/kg body

weight per day) over a period of 6 months. 

In a comprehensive carcinogenicity bioassay in which groups of

male and female F344/N rats and B6C3F1 mice were administered 
Summary and Conclusions

9

drinking-water containing up to 79 mg fluoride/litre as sodium fluoride

for a period of 2 years, there was no statistically significant increase in

the incidence of any tumour in any single exposed group. There was

a statistically significant trend of an increased incidence of osteosarcomas in male rats with increasing exposure to fluoride. However, the

incidence was within the range of historical controls. 

Another 2-year carcinogenicity bioassay involving SpragueDawley rats exposed to up to 11.3 mg/kg body weight per day in the

diet also found no statistically significant increase in the incidence of

osteosarcoma or other tumours. Another study, which reported an

increased incidence of osteomas in mice receiving up to 11.3 mg/kg

body weight per day, is difficult to interpret, because the animals were

infected with Type C retrovirus.

In general, fluoride is not mutagenic in prokaryotic cells.Although

fluoride has been shown to increase the frequency of mutations at

specific loci in cultured mouse lymphoma and human lymphoblastoid

cells, these mutations are likely due to chromosomal damage rather

than point mutations. Fluoride has been shown to be clastogenic in a

variety of cell types. The mechanism of clastogenicity has been

attributed to the effect of fluoride upon the synthesis of proteins

involved in DNA synthesis and/orrepair, rather than direct interaction

between fluoride and DNA. In most studies in which fluoride was

administered orally to rodents, there was no effect upon sperm morphology or the frequency of chromosomal aberrations, micronuclei,

sister chromatid exchange or DNA strand breaks. However, cytogenetic damage in bone marrow or alterations in sperm cell morphology

were reported when the substance was administered to rodents by

intraperitoneal injection.

Reproductive or developmental effects were not observed in

recent studies in which laboratory animals were administered fluoride

in drinking-water.However, histopathological changes in reproductive

organs have been reported in male rabbits administered (orally) 4.5 mg

fluoride/kg body weight per day for 18–29 months, in male mice administered (orally) $4.5 mg fluoride/kg body weight per day for 30 days

and in female rabbits injected subcutaneously with $10 mg fluoride/kg

body weight per day for 100 days. Adverse effects on reproductive

function have been reported in female mice administered (orally) $5.2

mg fluoride/kg body weight per day on days 6–15 after mating and in
EHC 227: Fluorides

10

male rabbits administered (orally) $9.1 mg fluoride/kg body weight per

day for 30 days.

1.7 Effects on humans 

Epidemiologicalinvestigations on the effects offluorideon human

health have examined occupationally exposed workers employed primarily in the aluminiumsmelting industry and populations consuming

fluoridated drinking-water. In a number of analytical epidemiological

studies of workers occupationally exposed to fluoride, an increased

incidence of lung and bladder cancer and increased mortality due to

cancer of these and other sites have been observed. In general, however, there has been no consistent pattern; in some of these epidemiological studies, the increased morbidity or mortality due to cancer can

be attributed to the workers’ exposure to substances other than fluoride.

The relationship between the consumption of fluoridated

drinking-water and morbidity or mortality due to cancer has been

examined in a large number of epidemiological studies, performed in

many countries. There is no consistent evidence of an association

between the consumption of controlled fluoridated drinking-water and

increased morbidity or mortality due to cancer. 

Fluoride has both beneficial and detrimental effects on tooth

enamel. The prevalence of dental caries is inversely related to the concentration of fluoride in drinking-water. The prevalence of dental

fluorosis is highly associated with the concentration of fluoride, with

a positive dose–response relationship.

Cases of skeletal fluorosis associated with the consumption of

drinking-water containing elevated levels of fluoride continue to be

reported. A number of factors, such as nutritional status and diet,

climate (related to fluid intake), concomitant exposure to other substances and the intake of fluoride from sources other than drinkingwater, are believed to play a significant role in the development of this

disease. Skeletal fluorosis may develop in workers occupationally

exposed to elevated levels of airborne fluoride; however, only limited

new information was identified. 
Summary and Conclusions

11

Evidence fromseveral ecologicalstudies has suggested that there

may be an association between the consumption of fluoridated water

and hip fractures. Other studies, however, including analytical epidemiological investigations, have not supported this finding. In some

cases, a protective effect of fluoride on fracture has been reported. 

Two studies permit an evaluation of fracture risk across a range

of fluoride intakes. In one study, the relative risks of all fractures and

of hip fracture were elevated in groups drinking water with $1.45 mg

fluoride/litre (totalintake $6.5 mg/day); this difference reached statistical significance for the group drinking water containing $4.32 mg

fluoride/litre (total intake 14 mg/day). In the other study, an increased

incidence of fractures was observed in one age group of women

exposed to fluoride in drinking-waterin a non-dose-dependent manner.

Epidemiological studies show no evidence of an association

between the consumption offluoridateddrinking-waterby mothers and

increased risk of spontaneous abortion or congenital malformation.

Other epidemiologicalinvestigations of occupationally exposed workers have provided no reasonable evidence of genotoxic effects orsystemic effects upon the respiratory, haematopoietic, hepatic or renal

systems that may be directly attributable to fluoride exposure per se.

1.8 Effects on other organisms in the laboratory and field

Fluoride did not affectgrowth orchemicaloxygen demand degrading capacity of activated sludge at concentrations of 100 mg/litre. The

EC50 for inhibition of bacterial nitrification was 1218 mg fluoride/litre.

Ninety-six-hour EC5 0s, based on growth, for freshwater and marine

algae were 123 and 81 mg fluoride/litre, respectively.

Forty-eight-hour LC50s for aquatic invertebrates range from53 to

304 mg/litre. The most sensitive freshwater invertebrates were the fingernail clam (Musculium transversum), with statistically significant

mortality (50%) observed at a concentration of 2.8 mg fluoride/litre in

an 8-weekflow-through experiment, and several net-spinning caddisfly

species (freshwater; family: Hydropsychidae), with “safe concentrations” (8760-h EC0.0 1s) ranging from 0.2 to 1.2 mg fluoride/litre. The

brine shrimp (Artemia salina) was the most sensitive marine species 
EHC 227: Fluorides

12

tested. In a 12-day static renewal test, statistically significant growth

impairment occurred at 5.0 mg fluoride/litre.

Ninety-six-hour LC50s for freshwater fish range from 51 mg/litre

(rainbow trout, Oncorhynch us mykiss) to 460 mg/litre (threespine

stickleback, Gasterosteus aculeatus). All of the acute toxicity tests

(96 h) on marine fish gave results greater than 100 mg/litre. Inorganic

fluoride toxicity to freshwater fish appears to be negatively correlated

with water hardness (calciumcarbonate) and positively correlated with

temperature. The symptoms of acute fluorid e intoxication include

lethargy, violent and erratic movement and death. Twenty-day LC50s

for rainbow trout ranged from 2.7 to 4.7 mg fluoride/litre in static

renewal tests. “Safe concentrations” (infinite hours LC0.01s) have been

estimated for rainbow trout and brown trout (Salmo trutta) at 5.1 and

7.5 mg fluoride/litre, respectively. At concentrations of $3.2 (effluent)

or $3.6 (sodium fluoride)mg fluoride/litre,the hatching of catla (Catla

catla) fish eggs was delayed by 1–2 h. 

Behavioural experiments on adult Pacific salmon (Oncorhynchus

sp.) in soft-water rivers indicate that changes in water chemistry

resulting from an increase in the fluoride concentration to 0.5 mg/litre

can adversely affect migration; migrating salmon are extremely sensitive to changes in the water chemistry oftheir river of origin. In laboratory studies,fluoride seems to be toxic formicrobialprocesses at concentrations found in moderately fluoride polluted soils;similarly,in the

field, accumulation of organic matter in the vicinity of smelters has

been attributed to severe inhibition of microbial activity by fluoride.

Signs of inorganic fluoride phytotoxicity (fluorosis), such as

chlorosis,necrosis and decreased growth rates, are most likely to occur

in the young, expanding tissues of broadleaf plants and elongating

needles ofconifers.The induction of fluorosis has been clearly demonstrated in laboratory, greenhouseand controlled field plot experiments.

A large number of the papers published on fluoride toxicity to plants

concern glasshouse fumigation with hydrogen fluoride.Foliarnecrosis

was first observed on grapevines (Vitis vinifera) exposed to 0.17 and

0.27 μg/m3after 99 and 83 days, respectively. The lowest-observedeffect level for leaf necrosis (65% of leaves) in the snow prin cess

gladiolus (Gladiolus grandiflorus) was 0.35 μg fluoride/m3. Airborne

fluoride can also affect plant disease development, although the type
Summary and Conclusions

13

and magnitude of the effects are dependent on the specific plant–

pathogen combination. 

Severalshort-term solution culture studies have identified a toxic

threshold for fluoride ion activity ranging from approximately 50 to

2000 μmol fluoride/litre. Toxicity is specific not only to plant species,

but also to ionic species of fluoride; some aluminium fluoride complexes present in solution culture may be toxic at activities of 22–

357 μmol fluoride/litre, whereas hydrogen fluoride is toxic at activities

of 71–137 μmol fluoride/litre. A few studies have been carried out in

which the fluoride exposures have been via the soil. The type of soil

can greatly affect the uptake and potential toxicity of fluorides. 

In birds, the 24-h LD50 was 50 mg/kg body weight for 1-day-old

European starling (Sturnus vulgaris) chicks and 17 mg/kg body weight

for 16-day-old nestlings.Growth rates were significantly reduced at 13

and 17 mg fluoride/kg body weight (the highest doses at which growth

was monitored). Most of the early work on mammals was carried out on

domesticated ungulates. Fluorosis has been observed in cattle and

sheep. The lowest dietary level observed to cause an effect on wild

ungulates was in a controlled captive study with white-tailed deer

(Odocoileus virginianus) in which a general mottling of the incisors

characteristic of dental fluorosis was noted in the animals at the 35

mg/kg diet dose.

Aluminiumsmelters, brickworks, phosphorus plants and fertilizer

and fibreglass plants have all been shown to be sources of fluoride

that are correlated with damage to local plant communities.Vegetation

in the vicinity of a phosphorus plant revealed that the degree of

damage and fluoride levels in soil humus were inversely related to the

distance fromthe plant.Average levels offluoride in vegetation ranged

from 281 mg/kg in severely damaged areas to 44 mg/kg in lightly

damaged areas; at a control site, the fluoride concentration was

7 mg/kg. Plant communities near an aluminium smelter showed differences in community composition and structure due partly to variations in fluoride tolerance.However, it must be noted that, in the field,

one of the main problems with the identification of fluoride effects is

the presence of confounding variables such as other atmospheric

pollutants. Therefore, care must be taken when interpreting the many

field studies on fluoride pollution.
EHC 227: Fluorides

14

The original findings of fluoride effec ts on mammals were from

studies in the field on domestic animals such as sheep and cattle.

Fluoride can be taken up from vegetation, soil and drinking-water.

Tolerance levels have been identified for domesticated animals, with

the lowest values for dairy cattle at 30 mg/kg feed or 2.5 mg/litre

drinking-water. Incidents involving domesticated animals have originated both from natural fluoride sources, such as volcanic eruptions

and the underlying geology, and fromanthropogenic sources, such as

mineral supplements, fluoride-emitting industries and power stations.

Symptoms of fluoride toxicity include emaciation, stiffness of joints

and abnormal teeth and bones. Other effects include lowered milk

production and detrimental effects on the reproductive capacity of

animals.The lowest dietary concentration of fluoride to causefluorosis

in wild deer was 35 mg/kg. Investigations of the effects of fluoride on

wildlife have focused on impacts on the structural integrity of teeth

and bone. In the vicinity ofsmelters,fluoride-induced effects, such as

lameness, dental disfigurement and tooth damage, have been found.

1.9 Evaluation of human health risks and effects on the

environment

Fluoride has both positive and negative effects on human health,

but there is a narrow range between intakes that are associated with

these effects. Exposure to all sources of fluoride, including drinkingwater and foodstuffs, is important.

There is little information to characterize the dose–response relationships for the different adverse effects. In particular, there are few

data on total exposure, particularly with respect to intake and fluoride

absorption.

The most serious effect is the skeletal accumulation of fluoride

from long-term excessive exposure to fluoride and its effect on nonneoplastic bone disease — specifically, skeletal fluorosis and bone

fractures. There is clear evidence from India and China th at skeletal

fluorosis and an increased risk of bone fractures occur at total intakes

of 14 mg fluoride/day and evidence suggestive of an increased risk of

bone effects at total intakes above about 6 mg fluoride/day.
Summary and Conclusions

15

In the freshwater environment, natural fluoride concentrations are

usually lower than those expected to cause toxicity in aquatic organisms. However, aquatic organisms might be adversely affected in the

vicinityofanthropogenic discharges. Fluoride toxicity is dependent on

water hardness. 

Sensitive plant species growing near anthropogenic sources of

fluoride are at risk. The release of fluoride fromanthropogenic sources

is associated with damage to local terrestrial plant communities, but it

is often difficult to attribute these effects to fluoride alone, due to the

presence of other atmospheric pollutants. Fluoride is generally

strongly adsorbed by soils. Consequently, plant uptake via this

pathway is relatively low, and leaching of fluoride through soil is

minimal. 

Concentrations of fluoride in vegetation in the vicinity of fluoride

emission sources, such as aluminium smelters, can be higher than the

lowest dietary effect concentration reported formammals in laboratory

experiments. Fluorosis in domesticated animals has been reported.

There are stillsome areas reporting fluorosis incidents in livestock due

to uptake of fluoride-rich mineral supplements and drinking-water.

Furthermore, there is a potential risk from fluoride-contaminated pasture and soil ingestion due to the long-term use of phosphate fertilizers

containing fluoride as an impurity. Fluoride-induced effects, such as

lameness and tooth damage, have also been reported in wild mammals

close to anthropogenic sources.

1.10 Conclusions

All organisms are exposed to fluoride fromnatural and/or anthropogenic sources. Very high intakes have been observed in areas worldwide in which the environment is rich in fluoride and where groundwater high in fluoride is consumed by humans. Increased exposure

might occurin the vicinityof point sources. Fluoride in dental products

is an additional source for many people.

Fluoride has both beneficial and detrimental effects on human

health, with a narrowrange between the intakes at which these occur.
EHC 227: Fluorides

16

Effects on the teeth and skeleton may be observed at exposures below

those associated with the development of other organ- or tissuespecific adverse health effects. 

Effects on the bone (e.g., skeletal fluorosis and fracture) are considered the most relevant outcomes in assessing the adverse effects of

long-term exposure of humans to fluoride.

Skeletal fluorosis is a crippling disability that has a major public

health and socioeconomic impact, affecting millions of people in

various regions of Africa, China and India.

Intake of fluoride in water and foodstuffs is the primary causative

factor for endemic skeletalfluorosis.In some regions, the indoor burning of fluoride-rich coal also serves as an important source of fluoride.

There are few data from which to estimate total exposure to and

the bioavailability of fluoride, and there are inconsistencies in reports

on the characterization of its adverse effects.

There is clear evidence fromIndia and China that skeletalfluorosis

and an increased risk of bone fractures occur at a total intake of 14 mg

fluoride/day and evidence suggestive of an increased risk of bone

effects at total intakes above about 6 mg fluoride/day.

Excess exposure to bioavailable fluoride constitutes a risk to

aquatic and terrestrial biota.

Fluoride-sensitive species can be used as sentinels forthe identification of fluoride hazards to the environment.

There is a need to improve knowledge on the accumulation of

fluoride in organisms and on how to monitor and control this. 

The biological effects associated withfluoride exposure should be

better characterized. 
17

2. IDENTITY, PHYSICAL AND CHEMICAL

PROPERTIES AND ANALYTICAL METHODS

This document focuses on environmental exposure to fluoride

derived mostly from inorganic sources and its effects on humans,

animals and other biota. Data on hydrogen fluoride, calcium fluoride,

sodiumfluoride,sulfur hexafluoride and silicofluorides are emphasized,

as these compounds are considered the most relevant of the inorganic

fluorides on the basis of quantities re leased to the environment,

environmental concentrations and toxicological effects on living

organisms.

2.1 Identity and physical and chemical properties

There is one stable isotope of fluorine (F), with an atomic mass of

18.9984. There are also several radioactive isotopes (

17F, 18F, 20F, 21F

and 22F), with 18F having the longest half-life (109.7 min)(Weast, 1986).

 At roomtemperature, hydrogen fluoride (HF) (relative molecular

mass 20.01; density 0.991 g/litre; CAS No. 7664-39-3) is a colourless,

pungent, acrid liquid or gas with a melting point of !83 °C and a boiling point of 19.5 °C. Hydrogen fluoride is highly soluble in many

organic solvents and in water, in which it forms hydrofluoric acid

(Neumüller, 1981; Weast, 1986). 

Calcium fluoride (CaF2) (relative molecular mass 78.08; CAS No.

7789-75-5) is a colourless solid with a melting point of 1403 °C and a

boiling point of 2513 °C. It is relatively insoluble in water — approximately 3000 times less soluble in water than sodium fluoride (McIvor,

1990) — as well as in dilute acids and bases (Neumüller, 1981). Calcium

fluoride is also known as fluorite. Fluorspar is a mineral containing

60–97% calcium fluoride, depending on the grade.

Sodium fluoride (NaF) (relative molecular mass 41.99; CAS No.

7681-49-4) is a colourless to white solid with high melting(988–1012 °C)

and boiling (1695 °C) points. It is moderately soluble in water

(Neumüller, 1981). 
EHC 227: Fluorides

18

Fluorosilicic acid (H2SiF6) (relative molecular mass 144.08; CAS

No. 16961-83-4), which is also known as hexafluorosilicic acid, hydrofluorosilicic acid, fluosilicic acid or fluorosilicic acid, is a colourless

solid that is highly soluble in water. 

Sodium hexafluorosilicate (Na2SiF6) (relative molecular mass

188.05; CAS No. 16893-85-9), also known as disodium hexafluorosilicate orsodium silicofluoride, is a colourless solid that is moderately

soluble in water. 

Sulfur hexafluoride (SF6) (relative molecular mass 146.05; density

6.16 g/litre; CAS No. 2551-62-4) is a colourless, odourless, tasteless,

chemically inert and non-flammable gas. It is slightly soluble in water

but readily soluble in ethanol and bases (Weast, 1986).

2.2 Analytical methods

Methods employed forthe quantification of fluoride in biological

samples and environmental media generally rely on the detection of

fluoride ion (F–). Perhaps the most widely used method of fluoride

quantification has involved potentiometry employing the fluoride ionselective electrode (Neumüller, 1981; Harzdorf et al., 1986; ATSDR,

1993). This method has been used for the quantification of fluoride in

biological tissues and fluids (e.g., urine, serum and plasma, organs,

bone, teeth), foodstuffs and environmentalmedia (e.g., air, water, soil).

Owing to variations in the efficacy of sample preparation procedures,

detection limits using the fluoride ion-selective electrode may range

from 0.1 to 300 ng/m3in air, from 1 to 1000 μg/litre in water and from

0.05 to 20 mg/kg in tissues (Harzdorf et al., 1986; ATSDR, 1993). Other

approaches for the quantification of fluoride have included spectrophotometry, gas chromatography, ion chromatography, capillary electrophoresis,atomic absorption and photon activation (Neumüller,1981;

ATSDR, 1993; Wen et al., 1996).

Appropriate sample preparation is a critical step in the accurate

quantification offluoride, especially where only the free fluoride ion is

measured. For analyses involving biological materials, the most

accurate method is the microdiffusion technique, such as the acidhexamethyldisiloxane (HMDS) diffusion method by Taves (1968),since

methods involving acid or alkali digestion may not convert all complex
Identity, Physical and Chemical Properties, Analytical Methods

19

inorganic and organic fluorides into an ionic form that can be

conveniently measured (Venkateswarlu, 1983). Open ashing methods

may result in the loss of volatile fluoride compounds or of fluoride

itself at temperatures in excess of 550 °C, or they may result in contamination with extraneous fluoride (Venkateswarlu, 1975; Campbell,

1987). 
20

3. SOURCES OF HUMAN AND 

ENVIRONMENTAL EXPOSURE

3.1 Natural occurrence

Fluorides are released into the environment naturally through the

weathering of minerals, in emissions from volcanoes and in marine

aerosols (Symonds et al., 1988; ATSDR, 1993). Estimates of the annual

global release of hydrogen fluoride from volcanic sources through

passive degassing and eruptions range from 60 to 6000 kilotonnes, of

which approximately 10% may be introduced directly into the stratosphere (Symonds et al., 1988). Annually, approximately 20 kilotonnes

of fluoride may be released in marine aerosols (Symonds et al., 1988).

The main naturalsource of inorganic fluorides in soil is the parent

rock (WHO, 1984). During weathering, some fluoride minerals (e.g.,

cryolite, or Na3AlF6) are rapidly broken down, especially under acidic

conditions (Fuge & Andrews, 1988). Other minerals, such as fluorapatite (Ca5

(PO4)3F) and calcium fluoride, are dissolved more slowly

(Kabata-Pendias & Pendias, 1984). Themineralfluorophlogopite (mica;

KMg3(AlSi3O10)F2) is stable in alkaline and calcareous soils (Elrashidi

& Lindsay, 1986). However, its solubility is affected by pH and the

activities of silicic acid (H4SiO4) and aluminium (Al3+), potassium (K+)

and magnesium (Mg2+) ions.

3.2 Anthropogenic sources

3.2.1 Production and use

3.2.1.1 Hydrogen fluoride

Hydrogen fluoride (hydrofluoric acid) is an important industrial

compound, with an estimated annual world consumption in excess of

1 million tonnes (Greenwood & Earnshaw, 1984). Hydrogen fluoride is

manufactured from calcium fluoride and is used mainly in the

prod uction of synthetic cryolite, aluminium fluoride (AlF3), motor

gasoline alkylates and chlorofluorocarbons; however, the demand for

chlorofluorocarbons is decreasing as a result of efforts to restrict their
Sources of Human and Environmental Exposure

21

use. Hydrogen fluoride is also used in the synthesis of uraniumtetrafluoride (UF4

) and uranium hexafluoride (UF6), both of which are used

in the nuclear industry (Neumüller, 1981). It is also used in etching

semiconductor devices, cleaning and etching glass, cleaning brick and

aluminium and tanning leather, as well as in petrochemical manufacturing processes. Hydrogen fluoride may also be found in commercial

rust removers (Upfal & Doyle, 1990). 

3.2.1.2 Calcium fluoride

Industrially, calcium fluoride is the principal fluoride-containing

mineralused (WHO, 1984). Identified production data were confined to

the USA, where the average annual production of calciumfluoride was

estimated to range from 118 000 to 225 000 tonnes during 1972–1978

(ATSDR, 1993). The consumption of calcium fluoride (as fluorspar) in

Canada in 1989 was estimated at 180 000 tonnes (Government of

Canada, 1993); in 1977, the estimated consumption of calciumfluoride

in the USA was 1 063 000 tonnes (ATSDR, 1993). Calcium fluoride is

used as a flux in steel, glass and enamel production and as the raw

material for the production of hydrofluoric acid and anhydrous

hydrogen fluoride (Neumüller, 1981). Calcium fluoride is also used as

a molten electrolyte for the separation of oxygen and alumina in

aluminium production.

3.2.1.3 Sodium fluoride

Data concerning the total annual consumption or production of

s odium fluoride worldwide were not identified. Sodium fluoride is

usually prepared from hydrofluoric acid and sodium carbonate or

sodium hydroxide (Neumüller, 1981); it is used in the controlled

fluoridation of drinking-water, as a preservative in certain glues, in

glass and enamel production, as a flux in steel and aluminium production, as an insecticide and as a wood preservative (Neumüller, 1981).

3.2.1.4 Fluorosilicic acid

Fluorosilicic acid is an aqueous solution that is most commonly

manufactured as a co-product from the manufacture of phosphate

fertilizers. It is used widely for the fluoridation of drinking-water, in

which it hydrolyses to release fluoride ions. When used for the fluoridation of drinking-water, fluorosilicic acid should meet appropriate
EHC 227: Fluorides

22

standards, such as those published by the American Water Works

Association and the European Committee for Standardization or other

approved schemes for drinking-water chemicals. 

3.2.1.5 Sodium hexafluorosilicate

Sodium hexafluorosilicate, like fluorosilicic acid, is used in the

fluoridation of drinking-water. It is normally completely dissolved in

water prior to dosing, when it hydrolyses to give fluoride ions. When

used for drinking-water fluoridation, it too should meet appropriate

standards of purity for drinking-water chemicals.

3.2.1.6 Sulfur hexafluoride

More than 110 tonnes of sulfur hexafluoride are imported into

Canada annually (Government of Canada, 1993). This substance is

used extensively as an insulation and current interruption medium in

electricalswitchgear, such as power circuit breakers,in various components in electrical substations (Government of Canada, 1993) and as a

protective inert gas over molten metals, such as magnesium and

aluminium (Neumüller, 1987). Over 90% of the total amount of sulfur

hexafluoride imported into Canada is used in the production of magnesium; the remainder is used in electrical switchgear (Government of

Canada, 1993).

3.2.1.7 Fluorapatite

Fluorapatite, an important calcium- and fluoride-containing

mineral, is used as a source of phosphates in the fertilizer industry

(Neumüller, 1981).

3.2.1.8 Phosphate fertilizers

Phosphate fertilizers are the major source of fluoride contamination of agricultural soils. They are manufactured from rock phosphates, which generally contain around 3.5% fluorine (Hart et al., 1934).

However, during the manufacture of phosphate fertilizers, part of the

fluoride is lost into the atmosphere during the acidulation process, and

the concentration of fluoride in the final fertilizer is lowered further

through dilution with sulfur (superphospha tes) or ammonium ion

(ammoniated phosphates); the final product commonly contains
Sources of Human and Environmental Exposure

23

between 1.3 and 3.0% fluorine (McLaughlin et al., 1996). In Australia,

an average annual addition of fluoride to soil through fertilization has

been estimated to be 1.1 kg/ha.

3.2.2 Emissions

Available quantitative information concerning the release of

fluoride into the environment (air, water and soil) from industrial

sources is limited.Fluoride is released into the environment via exhaust

fumes, process waters and waste from various industrial processes,

including steel manufacture, primary aluminium, copper and nickel

production, phosphate fertilizer production and use, glass, brick and

ceramic manufacturing, and glue and adhesive production. The use of

fluoride-containing pesticides as well as the fluoridation of drinkingwater supplies also contribute to the release of fluoride from anthropogenic sources. 

The total annual amount of fluoride released to the environment

from industrial sources was estimated to be in excess of 23 500 tonnes

in Canada and 46 600 tonnes in the Netherlands (Sloof et al., 1989;

Government of Canada, 1993). The relative contribution of various

anthropogenic sources to total emissions of fluoride to air, water and

soil in Canada are estimated at 48% for phosphate fertilizerproduction,

20% for chemical production, 19% for aluminium production, 8% for

steel and oil production and 5% for coal burning (Government of

Canada, 1993). In the Netherlands, 93% of total fluoride emissions to

air, water and soil are derived from phosphate ore production and use,

with smaller amounts emitted via mineral processing (2%), the metal

industry (4%) and “other industry” (1%) (Sloof et al., 1989). The total

amounts of hydrogen fluoride released to air, surface water, underground injection and land in the USA during 1999 were 33 000, 7.7, 1800

and 64 tonnes, respectively. Total amounts of fluorine released to air,

surface water and land were 39, 24 and 500 tonnes, respectively (US

EPA, 1999).
24

4. ENVIRONMENTAL TRANSPORT, DISTRIBUTION AND

TRANSFORMATION

4.1 Transport and distribution between media

The cycling of fluoride through the biogeosphere is summarized

in Figure 1 

Fig. 1. Cycling of fluoride through the biogeosphere

4.1.1 Atmosphere

The fate of inorganic fluorides in the atmosphere is primarily influenced by vaporization, aerosol formation, wet and dry deposition and

hydrolysis (Environment Canada, 1994). Non-volatile inorganic fluoride

particulates are removed from the atmosphere via condensation or

nucleation processes.

Rivers, lakes &

 groundwater

Sediments

Oceans

Volcanoes Rocks Dead organic

matter/excreta

Air

Soil

Anthropogenic

 sources

Biota
Environmental Transport, Distribution and Transformation

25

Atmospheric fluorides emitted from both natural and anthropogenic sources may be in gaseous or particulate form (Kirk & Lester,

1986). Gaseous forms include hydrogen fluoride, silicon tetrafluoride

(SiF4), fluorosilicic acid and sulfur hexafluoride. Particulate forms

include sodium aluminium fluoride (cryolite), aluminium fluoride,

calcium fluoride, sodium hexafluorosilicate, lead fluoride (PbF2) and

calcium phosphate fluoride (fluorapatite). Globally, hydrogen fluoride

and inorganic fluoride particulates (sodium and calcium fluoride)

account for approximately 75% and 25%, respectively, of inorganic

fluorides present in the atmosphere (Health Council of the Netherlands,

1990). Fluorine and the silicon fluorides are hydrolysed in the atmosphere to form hydrogen fluoride. Hydrogen fluoride may combine with

water vapour to produce an aerosol or fog of aqueous hydrofluoric

acid.

Fluorides adsorbed on particulate matter in the atmosphere are

generally stable and are not readily hydrolysed, although they may be

degraded by radiation if they persist in the atmosphere (US NAS,

1971).

Hydrofluoric acid is approximately 5 orders of magnitude less

soluble than hydrochloric acid and will therefore be degassed from

marine aerosols more readily than hydrochloric acid. Hydrofluoric acid

is expected to be depleted in aged marine aerosols, and this may be a

significant source of hydrogen fluoride in the troposphere (Brimblecombe & Clegg, 1988).

Schotte (1987) used a dispersion model to predict the formation

and behaviour of the fog formed from the release of hydrogen fluoride

to the atmosphere. Initially, the hydrogen fluoride will cool significantly due to depolymerization. The fog will therefore stay near ground

level, since it is more dense than ambient air. As the fog mixes with

more air, it will begin to warm up and it may rise, depending on the

ambient air temperature and the relative humidity.

Davison et al. (1973) reported that between 60 and 74% of atmospheric fluoride in urban coal-burning areas in the United Kingdom was

in gaseous form. Similarly, approximately 60% of the fluorides in the

atmosphere in the Netherlands are in the gaseous state (Sloof et al.,

1989).
EHC 227: Fluorides

26

Based upon available data, inorganic fluoride compounds, with

the exception of sulfur hexafluoride, are not expected to remain in the

troposphere for long periods or to migrate to the stratosphere. Estimates of the residence time of sulfur hexafluoride in the atmosphere

range from 500 to several thousand years (Ramanathan et al., 1985;

Chu, 1991).

Fluoride in aerosols can be transported over large distances by

wind or as a result of atmospheric turbulence. The distance travelled

is determined by the deposition velocity of both the gaseous hydrogen

fluoride and the fluorides in particulate form. The transportation of

particles with a diameter greater than 10 Fm is determined by the

particle falling speed, and the dispersion of such particles is generally

limited to the immediate vicinity of the source. Smaller particles are less

restricted by the falling speed and can be transported over larger

distances (Sloof et al., 1989).

Atmospheric fluorides may be transported to soils and surface

waters through both wet and dry deposition processes (US NAS,

1971). Seasonal climatic conditions are expected to influence the rate

at which and mode by which atmospheric fluorides are deposited; for

example, in the Tamar Valley, Tasmania, wet deposition dominates

during winter (high precipitation; June to August), and dry deposition

dominates during summer (low precipitation; December to February)

(Low & Bloom, 1988).

Wet deposition of fluoride may occur as washout from plumes

below cloud or rainout of particulates taken up by clouds. The

washout process is of particular importance for the removal of soluble

fractions such as hydrogen fluoride aerosols at short distances from

the source. It is assumed that all irreversibly soluble gases such as

hydrogen fluoride are washed out during showers. The rainout process

is more important for the removal of fluorides distant from the source

when the plume is situated at least partially in the clouds. The

scavenging ratio, the ratio between measured concentrations in

rainwater and the atmosphere, was calculated to be 0.15 × 10 (Sloof et 6

al., 1989). For large-scale dispersion of fluorides, the annual average

wet deposition rate was 1.4% per hour for fluoride aerosol and 5.9% per

hour for gaseous fluorides. These values give an atmospheric

residence time of 12 h for gaseous fluoride and 50 h for particulates.
Environmental Transport, Distribution and Transformation

27

The dry deposition rate for fluoride in the Agra region of India

was highest between December and June, when atmospheric fluoride

concentrations were highest (Saxena et al., 1994). Seasonally averaged

dry deposition rates at the four sites ranged from 0.14 to 0.15 mg/m per 2

day for summer (March to June), from 0.08 to 0.21 mg/m per day for

2

winter (October to February) and from 0.008 to 0.03 mg/m per day for 2

the monsoon season (July to September). Similar patterns of dry

deposition were recorded by Chandrawanshi & Patel (1999) for central

India during 1995; however, higher deposition rates were reported, with

values of up to 1.1 mg/m per day being recorded during the winter

2

months. The overall mean fluoride flux deposited with dust and

rainwater during 1995 in central India was 474 kg/km .

2

Several studies have been conducted to determine whether fluoride in rainwater was derived from anthropogenic emissions or natural

sources such as sea salt cycling. Barnard & Nordstrom (1982) stated

that fluoride should not be regarded as a cyclical sea salt, because the

fluoride concentrations in rain from areas with no local anthropogenic

emissions were not correlated with sea salt availability (as determined

by the sodium concentration). Mass balance considerations suggested

that the majority of fluoride samples in the rainwater were of anthropogenic origin. Similarly, Saether et al. (1995) calculated that more than

90% of fluoride in precipitation samples collected in southern Italy

were of non-marine origin.

The ratio between total fluorine and chloride in rainwater from

Wales was greater than the ratio in seawater (Neal et al., 1990). This

implied enrichment of total fluorine relative to chloride, reflecting

complex fractionation processes in the transport of fluorine from the

sea to the atmosphere and back to land as precipitation. The total

fluorine/chloride ratio in streamwater was higher than it was in rainwater, suggesting a net release of total fluorine from the catchment to

the stream. The source of the release was uncertain, since the total

fluorine concentration in baseflow waters was not significantly higher

than stormflow values.

Mahadevan et al. (1986) reported a strong correlation between

fluoride and sodium concentrations in precipitation samples collected

from marine, coastal and inland sites in India. The authors suggested

that fluoride in precipitation was derived from the cycling of sea salt.
EHC 227: Fluorides

28

The correlation was not as strong in samples from urban areas, where

the majority of fluoride was derived from anthropogenic sources.

The deposition of fluoride emitted from a phosphorus plant was

reported to decrease with increasing distance from the source (Sidhu,

1982). The rate of deposition at 1.4 km from the source was calculated

to be 2.61 g fluoride/ha per millimetre of rain and 3.10 g fluoride/ha per

millimetre of snow water. These data corresponded to an annual

deposition rate of 3.43 kg/ha. Fluoride deposition on soil from leaf litter

also decreased with increasing distance from the source. Fluoride input

to soil ranged from 10 to 720 g/ha per year. Input from precipitation was

5–10 times greater than it was for leaf litter.

Davison & Blakemore (1980) determined the deposition of fluoride

at field sites near areas of industrial and urban sources of fluorides.

The mean total fluoride deposited from wet and dry deposition and

sedimentation was 38.0 Fg/dm per week. Deposition of gaseous fluor- 2

ide was 23.4 Fg/dm per week. 2

The average large-scale deposition velocity for total soluble fluoride in the Netherlands was calculated to be 1.4 cm/s (Sloof et al., 1989).

This figure was based upon 70% of the soluble fluoride being in a

gaseous state and an atmospheric residence time of 14 h for gaseous

fluorides and 12 days for aerosol fluorides. The average deposition

velocity calculated does not apply to the area surrounding a point

source. Under stable atmospheric conditions, a low deposition velocity

will be accompanied by high atmospheric concentrations. The deposition velocity of fluoride depends heavily on atmospheric conditions.

The deposition velocity for hydrogen fluoride can vary by more than

7 orders of magnitude; for particulate fluoride, it varies by less than

10%. The annual average effective deposition velocity varies with

height of the emission source and was calculated to be 1.2 and 2.5 cm/s

for low and high source heights, respectively, in the Netherlands.

4.1.2 Water and sediment

In water, the transport and transformation of inorganic fluorides

are influenced by pH, water hardness and the presence of ionexchange materials such as clays (Environment Canada, 1994). Fluoride

is usually transported through the water cycle complexed with

aluminium (Ares, 1990).
Environmental Transport, Distribution and Transformation

29

In areas of extreme acidity and alkalinity, inorganic fluorides may

leach from fluoride-containing minerals into surface water or groundwater (Cuker & Shilts, 1979). Solubilization of inorganic fluorides from

minerals may also be enhanced by the presence of ion-exchange

materials (e.g., bentonite clays and humic acid) (Pickering et al., 1988).

Once dissolved, inorganic fluorides remain in solution under

conditions of low pH and hardness and in the presence of ionexchange material (Cuker & Shilts, 1979; Sahu & Karim, 1989). Soluble

inorganic fluorides may also form aerosols at the air–water interface or

vaporize into the atmosphere (Brimblecombe & Clegg, 1988), whereas

undissolved species generally undergo sedimentation (Drury et al.,

1980).

Kudo et al. (1987) calculated the fluoride mass balance for the

once severely polluted Maurienne Valley in the French Alps. Fluoride

emission into the valley from aluminium production plants was

500 tonnes per year in 1980. Fluoride output by the river was calculated

to be 680 tonnes per year, of which 665 tonnes were due to water flow

and 15 tonnes to sediment movements.

Chamblee et al. (1984) analysed approximately 100 estuarine water

samples and reported that 10.5% of fluoride originated from fluoride

complexes with trivalent cations such as Fe and Al . The proportion 3+ 3+

of fluoride in the form of magnesium fluoride (MgF2) ranged from 0.4

to 33.7%. Fluoride concentrations were reported to increase with

salinity (within a salinity range of 0.1–16‰).

Fluoride in seawater is divided between the following fractions

(Stumm & Morgan, 1981):

Fraction Proportion (%) Concentration (mol/litre)

F 51 4.1 × 10 – –5

MgF 47 3.7 × 10 + –5

CaF 2 1.6 × 10 + –6

In seawater, fluorides are removed by the formation of complexes

with calcium compounds, principally carbonate and phosphate (Carpenter, 1969). Undissolved fluoride is generally removed from the

aquatic phase by sedimentation (US EPA, 1980). Carpenter (1969)
EHC 227: Fluorides

30

calculated a residence time for fluoride in ocean sediment to be 2–

3 million years.

Fluorosilicic acid and hydrofluoric acid in high aquatic concentrations such as may be found in industrial waste ponds may volatilize,

releasing silicon tetrafluoride and hydrogen fluoride into the atmosphere (US NAS, 1971).

4.1.3 Soil

Factors that influence the mobility of inorganic fluorides in soil

are pH and the formation of aluminium and calcium complexes

(Pickering, 1985; Environment Canada, 1994).

In more acidic soils, concentrations of inorganic fluoride were

considerably higher in the deeper horizons. The low affinity of fluorides for organic material results in leaching from the more acidic surface

horizon and increased retention by clay minerals and silts in the more

alkaline, deeper horizons (Davison, 1983; Kabata-Pendias & Pendias,

1984). This distribution profile is not observed in either alkaline or

saline soils (Gilpin & Johnson, 1980; Davison, 1983). The fate of

inorganic fluorides released to soil also depends on the chemical form,

rate of deposition, soil chemistry and climate (Davison, 1983).

Fluoride in soil is mainly bound in complexes. The maximum

adsorption of fluoride to soil was reported to occur at pH 5.5 (Barrow

& Ellis, 1986). In acidic soils with pH below 6, most of the fluoride is in

complexes with either aluminium or iron (e.g., AlF , AlF , AlF , AlF ,

2+ + 0 –

2 3 4

FeF , FeF , FeF ) (Perrott et al., 1976; Murray, 1984b; Elrashidi &

2+ + 0

2 3

Lindsay, 1986). Fluoride in alkaline soils at pH 6.5 and above is almost

completely fixed in soils as calcium fluoride, if sufficient calcium

carbonate is available (Brewer, 1966).

Fluoride binds to clay by displacing hydroxide from the surface

of the clay (Huang & Jackson, 1965; Bower & Hatcher, 1967;

Meeussen et al., 1996). The adsorption follows Langmuir adsorption

equations and is strongly dependent upon pH and fluoride concentration. It is most significant at pH 3–4, and it decreases above pH 6.5.

Pickering et al. (1988) determined changes in free fluoride ions and

total fluoride levels following equilibration of either poorly soluble
Environmental Transport, Distribution and Transformation

31

fluoride species, such as calcium fluoride and aluminium fluoride, or

wastes from aluminium smelters. The experiments were carried out on

materials that had different cation-exchange capacities, such as

synthetic resins, clay minerals, manganese oxide and a humic acid.

Increased amounts of fluoride were released from fluoride salts and

fluoride-rich wastes when solids capable of exchanging cations were

present. The effect was greatest when there were more exchange sites

available and when the fluoride compound cation had greater affinity

for the exchange material. In a few cases, soluble complex ions were

formed when the released fluoride attacked the substrate, such as illite

or alumina wastes.

Fluoride is extremely immobile in soil, as determined by lysimeter

experiments. MacIntire et al. (1955) reported that 75.8–99.6% of added

fluoride was retained by loam soil for 4 years. Fluoride retention was

correlated with the soil aluminium content. The leaching of fluoride

occurred simultaneously with the leaching of aluminium, iron and

organic material from soil (Polomski et al., 1982). Soil phosphate may

contribute to the mobility of inorganic fluoride (Kabata-Pendias &

Pendias, 1984). Oelschläger (1971) reported that approximately 0.5–

6.0% of the annual addition of fluoride (atmospheric pollution and

artificial fertilizers) to a forest and agricultural areas was leached from

the surface to lower soil horizons. Arnesen & Krogstad (1998) found

that fluoride (added as sodium fluoride) accumulation was high in the

upper 0–10 cm of soil columns, where 50–90% of the accumulated

fluoride was found. The B-horizons sorbed considerably more fluoride

than the Ah-horizons, due to higher content of aluminium oxides/

hydroxides. A study by McLaughlin et al. (2001) involving long-term

application of phosphate fertilizers has shown a large portion of fluoride applied as impurities in the fertilizer to remain in the 0- to 10-cm

depth of the soil profile.

In sandy acidic soils, fluoride tends to be present in water-soluble

forms (Shacklette et al., 1974). Street & Elwali (1983) determined the

activity of the fluoride ion in acid sandy soils that had been limed.

Fluorite was shown to be the solid phase controlling fluoride ion activity in soils between pH 5.5 and 7.0. At pH values below 5.0, the fluoride

ion activity indicated supersaturation with respect to fluorite. These

data indicate that liming of acid soils may precipitate fluorite, with a

subsequent reduction in the concentration of fluoride ion in solution.
EHC 227: Fluorides

32

Murray (1984b) reported that low amounts of fluoride were

leached from a highly disturbed sandy podzol soil of no distinct structure. Even at high fluoride application rates (3.2–80 g per soil column

of diameter 0.1 m with a depth of 2 m), only 2.6–4.6% of the fluoride

applied was leached in the water-soluble form. The pH of the eluate

increased with increasing fluoride application, and this was probably

due to adsorption of fluoride, releasing hydroxide ions from the soil

metal hydroxides. Over time, the concentration of water-soluble fluoride decreased due to increased adsorption on soil particles.

Mean soil concentrations in Pennsylvania, USA, were 377, 0.38

and 21.7 mg/kg for total fluoride, water-soluble fluoride and resinexchangeable fluoride, respectively. The authors suggested that fluoride is relatively immobile in soil, since most of the fluoride was not

readily soluble or exchangeable (Gilpin & Johnson, 1980).

The water-soluble fluoride in sodic surface soil treated with gypsum increased with increasing exchangeable sodium per cent (Chhabra

et al., 1979). The increase in exchangeable sodium per cent also caused

an increase in soil pH, which in turn caused an increase in watersoluble fluoride. Incubation studies revealed that a major portion of the

added fluoride was adsorbed to soil within the first 8 days. Adsorption

to soil followed Langmuir isotherms up to an equilibrium soluble

fluoride concentration (11.4 mg/litre), with precipitation at higher concentrations.

Calcium fluoride was formed in soils irrigated with fluoride solutions. Calcium fluoride is formed when the fluoride adsorption capacity

is exceeded and the fluoride and calcium ion activities exceed the ion

activity product of calcium fluoride (Tracy et al., 1984). Less than 2%

of applied fluoride was measured in the leachate, and between 15 and

20% of added fluoride was precipitated as calcium fluoride. Fluoride

was precipitated in the upper profile, although the authors expected

that once the adsorption mechanisms were exceeded, soluble fluoride

would leach deeper into the soil with continued irrigation.

A large fraction of the fluoride in topsoil sampled at a distance of

0.5–1.0 km from an aluminium smelter was reported to be in watersoluble form (Polomski et al., 1982). The authors concluded that the

fluoride was present as calcium fluoride.
Environmental Transport, Distribution and Transformation

33

Breimer et al. (1989) determined the vertical distribution of fluoride

in the soil profiles sampled near an industrial region. In calcareous

soils, fluoride (as extractable with hydrochloric acid) was restricted to

the top 40–50 cm, probably due to the precipitation of calcium fluoride

in the presence of lime. A slight leaching of fluoride into the Bt and C

horizons was reported in non-calcareous soils. Water-extractable fluoride showed an increase with depth in the A horizons and subsequently

decreased to base levels in the lower subsoil.

The adsorption of fluoride from the water phase may be an important transport characteristic in calcareous soils at low flow rates, but

this exchange may be rate-limited at high flow rates (Flühler et al.,

1982). Dissolved fluoride concentrations may be high around the root

zone in soils with a high fluoride input such as from atmospheric

deposition. The high concentrations exist only for a limited time until

the fluoride is withdrawn from the solution. The adsorption isotherm

was reported to be non-linear between initial concentrations of 10 and

50 mg fluoride/litre. Retention of fluoride in uncontaminated calcareous

soil was higher than retention in calcareous soil from areas with

fluoride contamination. The adsorption and desorption of fluoride in

acidic soil were not related to previous fluoride contamination.

Fluoride-containing solutions increased the mobilization and

leaching of aluminium from soils. Leaching of aluminium was reported

to be greater from soil contaminated from an aluminium smelter than

from uncontaminated soil (Haidouti, 1995). In the uncontaminated soil,

losses of aluminium from the acid soil were higher than those from the

calcareous soil. Arnesen (1998) also found that fluoride can solubilize

aluminium, iron and organic material and can increase soil pH through

exchange with hydroxide ions.

Unlike other soluble salts, fluoride was not leached from naturally

salinized salt-affected soil. It was redistributed within the soil profile

(Lavado et al., 1983). The adsorption of fluoride to soils increased with

decreasing pH within the pH range 8.5–6. Retention of fluoride in the

soil was positively correlated with ammonium acetate extractable iron.
EHC 227: Fluorides

34

4.2 Speciation and complexation

4.2.1 Atmosphere

Molecular fluorine hydrolyses to form hydrogen fluoride, the

most stable form of fluorine in the atmosphere (ATSDR, 1993). Silicon

tetrafluoride reacts with moisture in the atmosphere, forming hydrated

silica and fluorosilicic acid. Uranium hexafluoride, which is used in

nuclear power applications, is hydrolysed to hydrogen fluoride and

uranyl fluoride (UO2F2), which are removed from the atmosphere by

condensation or nucleation processes.

4.2.2 Water 

In dilute solutions at neutral pH, dissolved fluorides are predominantly present as the fluoride ion (Bell et al., 1970). As the pH

decreases below pH 5.5, the proportion of fluoride ions decreases, and

the proportion of non-dissociated hydrogen fluoride increases. However, if sufficient aluminium is present in solution, aluminium–fluoride

complexes (AlF , AlF and AlF ) generally dominate below pH 5.5

2+ +

2 3

until pH 1, where hydrogen fluoride begins to dominate as pH

decreases further (Parker et al., 1995). Aluminium solubility is low

between pH 5.2 and pH 8.8, whereas at higher pH values, aluminium

solubilizes as the aluminate ion (Al(OH) ). 4

–

4.3 Bioaccumulation

Soluble fluorides are bioaccumulated by some aquatic and terrestrial biota. However, no information was identified concerning the

biomagnification of fluoride in aquatic or terrestrial food-chains

(Hemens & Warwick, 1972; Barbaro et al., 1981; ATSDR, 1993).

Inorganic fluorides tend to accumulate preferentially in the skeletal and

dental hard tissues of vertebrates, exoskeletons of invertebrates and

cell walls of plants (Hemens & Warwick, 1972; Davison, 1983; Michel

et al., 1984; Kierdorf et al., 1997; Sands et al., 1998).

Bioconcentration factors greater than 10 (expressed on a wet

weight basis) were reported in both aquatic plants and animals following exposure to solutions of up to 50 mg fluoride/litre (Sloof et al.,

1989). Twenty-four hours after sodium fluoride (22 mg fluoride/litre)

was released into an experimental pond, the concentration of fluoride
Environmental Transport, Distribution and Transformation

35

in aquatic vascular plants was increased 35-fold, and uptake was also

increased in algae (14-fold), molluscs (12-fold) and fish (7-fold) (Kudo

& Garrec, 1983). 

The water hyacinth (Eichhornia crissipes) has been reported to

take up fluoride from water. Plants were exposed to fluoride solutions

of 6–26 mg/litre for 4 weeks, and fluoride uptake was related to exposure, ranging from 0.8 to 5 mg/kg (Rao et al., 1973).

The fluoride concentration in Sydney rock oyster (Saccostrea

commercialis) sprat increased with increasing fluoride exposure. The

sprat were exposed to 0.7–30.7 mg fluoride/litre for 3 weeks and had

whole-body concentrations ranging from 45 to 204 mg/kg dry weight

(Nell & Livanos, 1988).

Following exposure to inorganic fluoride levels of 52 mg/litre for

72 days, prawn (Penaeus indicus), crab (Tylodiplax blephariskios),

shrimp (Palaemon pacificus) and mullet (Mugil cephalus) had wholeanimal (ash) concentrations of 3248, 1414, 3116 and 7743 mg fluoride/kg, respectively (Hemens & Warwick, 1972). The fluoride was

accumulated from the water and not via ingested plant food. No differences in total-body fluoride levels were reported in the same species

when exposed to 5.7 or 5.9 mg/litre for either 68 or 113 days (Hemens

et al., 1975). Fluoride was accumulated mainly in the calcified skeletal

structures of fish and crustaceans, with higher accumulation rates

reported during the early stages of growth in fish and during periods

of deposition of new skeletal material (ecdysis) in crustaceans.

Wright (1977) exposed brown trout (Salmo trutta) fry to inorganic

fluoride (5, 10 or 20 mg/litre) for 200 h (12 EC; pH 6.8; hardness

73 mg/litre). Fry accumulated 10, 18 and 30 mg fluoride/kg at the three

fluoride concentrations, respectively.

Terrestrial plants may accumulate inorganic fluorides following

airborne deposition and uptake from the soil (Davison, 1983). Sloof et

al. (1989) reported that the main route of uptake of fluoride by plants is

from aerial deposition on the plant surface. Plant uptake from soil is

generally low (except for accumulators) unless the fluoride has been

added suddenly, such as following amendment with sludge or phosphate fertilizer. The availability to plants tends to decrease with time

following application of fluoride. The degree of accumulation depends
EHC 227: Fluorides

36

on several factors, including soil type and, most prominently, pH. At

acidic pH (below pH 5.5), fluoride becomes more phytoavailable

through complexation with soluble aluminium fluoride species, which

are themselves taken up by plants or increase the potential for the

fluoride ion to be taken up by the plant (Stevens et al., 1997). Plant

uptake of fluoride from solution culture is dependent on plant species

and positively related to the ionic strength of the growth solution.

Once a threshold fluoride ion activity in nutrient solutions is reached,

fluoride concentrations in plants increase rapidly (Stevens et al.,

1998a).

The uptake of fluoride by ryegrass (Lolium multiflorum) grown

in soil amended with a fluoride-rich sludge increased with increasing

fluoride application (84–672 kg/ha) (Davis, 1980). Fluoride concentrations in the plant tissue exceeded the 30 mg/kg dry matter threshold

of toxicity to cattle in the first cuts of grass exposed to 300 kg sludge/

ha or greater. Concentrations in the second cut of grass exceeded the

threshold value at 672 kg sludge/ha, and the third cut of grass was

below the threshold at all concentrations tested.

The amount of fluoride taken up from soil by sunflower seedlings

(Helianthus annuus) was proportional to the fluoride concentration of

the solution added to the soil (10–100 Fg/ml). Highest concentrations

were found in the roots, with reduced concentrations in successive leaf

ranks (Cooke et al., 1978). Similarly, concentrations of fluoride were

high in roots and low in shoots in tomatoes (Lycopersicon esculentum)

and oats (Avena sativa) grown on fluoride-enriched media (Stevens et

al., 2000).

Reynolds & Laurence (1990) found that exposure of kidney bean

(Phaseolus vulgaris) plants to intermittent high levels of atmospheric

hydrogen fluoride (3 Fg fluoride/m for 5 consecutive days or 5 Fg

3

fluoride/m for 3 consecutive days) caused higher accumulation in

3

leaves than did exposure to a continuous dose at a lower level (1 Fg

fluoride/m for 15 consecutive days), even though the plants received

3

the same total dose. They also noted that the rate of uptake from the

air over a 15-day period, particularly for the highest dose (5 Fg fluoride/m ), was most significant at first exposure and declined during

3

subsequent exposures.
Environmental Transport, Distribution and Transformation

37

Walton (1987a) demonstrated that untreated earthworms (Lumbricus terrestris) from which gut soil had been removed (depurated)

contained only 6% of the amount of fluoride reported in whole worms.

Worms kept in soil were exposed to a sodium fluoride concentration of

1000 mg/litre for 30 days. The fluoride content of the worms was

established either at the end of exposure or following an 8-day starvation period. The fluoride concentration in treated worms with their gut

contents washed out was more than 6 times greater than the fluoride

concentration of untreated worms. Even after an 8-day starvation

period, the concentration in exposed worms was 4 times greater than

the concentration in the unexposed worms. The fluoride concentration

in the worms was always lower than the concentration in the soil.

The deposition of fluoride in the bones of white leghorn (Gallus

gallus) chicks exposed to 252 mg fluoride/kg in the diet from hatching

for 3–10 weeks was 3–7 times greater than for birds fed a basal diet.

Fluoride was deposited in the bones of exposed females following

sexual maturity and was shown to be associated with physiological

factors associated with egg production, since birds with restricted

ovulation had fluoride levels similar to those of males (Michel et al.,

1984).

The bioavailability of fluoride to sheep (Ovis aries) from plants

such as sea aster (Aster tripolium), sand couch (Elymus pycnanthus),

fescue (Festuca rubra) and common salt-marsh grass (Puccinellia

maritima) grown in an industrial area was calculated to range from 65

to 90% (Baars et al., 1987).

Dairy calves (Bos sp.) were fed on continuous (1.5 mg/kg body

weight), periodic (1.5 mg/kg body weight for 6 months; control diet for

6 months) and alternate (3 mg/kg body weight for 4 months; 0.75 mg/kg

body weight for 8 months) diets for 6 years. Vertebral fluoride levels

were 550 mg/kg ash weight for controls and 15 000, 7700 and 14 000

mg/kg for the three treatment groups, respectively (Suttie, 1983).

Suttie et al. (1985) maintained white-tailed deer (Odocoileus

virginianus) on diets containing fluoride at 25 and 50 mg/kg for 1 year.

Fluoride levels in antlers ranged from 3000 to 5800 mg/kg ash weight

and in vertebrae from 4200 to 7400 mg/kg.
38

5. ENVIRONMENTAL LEVELS AND 

HUMAN EXPOSURE

5.1 Environmental levels

5.1.1 Surface water

Fluoride levels in surface waters vary according to geographical

location and proximity to emission sources. Surface water concentrations generally range from0.01 to 0.3 mg/litre (ATSDR, 1993). Ambient

surface water fluoride levels are summarized in Table 1. Seawater

contains more fluoride than fresh water, with concentrations ranging

from 1.2 to 1.5 mg/litre.

Higher levels of fluoride have been measured in areas where the

natural rock is rich in fluoride and near industrial outfalls. Skjelkvåle

(1994a) measured fluoride in Norwegian lakes and found concentrations ranging from <0.005 to 0.56 mg/litre, with a mean value of

0.037 mg/litre. Fluoride content in the bedrock was the most important

factor determining fluoride levels in lake waters. Elevated fluoride concentrations were found in acidified areas compared with otherregions

with similargeology (Skjelkvåle,1994a). Similarly,Hirayama et al. (1996)

reported increased levels of fluoride (up to 1 mg/litre) in some rivers

flowing into Lake Biwa, Japan, because of the local geology.

Elevated inorganic fluoride levels in surface water are often seen

in regions where there is geothermal or volcanic activity, at the foot of

high mountains and in areas with geological deposits of marine origin.

Thus, hot springs and geysers in Yellowstone National Park, USA,

contain 25–50 mg fluoride/litre (Neuhold & Sigler, 1960), whereas the

Firehole and Madison rivers, also in Yellowstone National Park, contain 1–14 mg fluoride/litre. Walker and Pyramid lakes,in Nevada, USA,

contain levels as high as 13 mg fluoride/litre (Sigler & Neuhold, 1972).

The most well documented area of high-fluoride surface water

associated with volcanic activity follows the East African Rift Valley

system fromthe Jordan Valley down through Sudan, Ethiopia,Uganda,

Kenya and Tanzania. Many of the lakes ofthe Rift Valley system have

extremely high fluoride concentrations — for example, 1640 mg/litre
Environmental Levels and Human Exposure

39

Table 1. Concentrations of fluoride in unpolluted water

Location Fluoride

concentration

(mg/litre)a

Reference

Areas with low natural fluoride

Canada 0.05 Environment Canada

(1994)

USA 0.035–0.052b

(<0.001–0.59)

Overton et al. (1986)

USA (Cache la Poudre

River)

(0.3–0.5) Camargo et al. (1992)

Belgium (River

Meuse)

0.13–0.2 Van Craenenbroeck &

Marivoet (1987)

France (rivers) 0.08–0.25 Martin & Salvadori

(1983)

Norway (lakes) 0.037 (<0.005–0.56) Skjelkvåle (1994a)

Spain (Duratón River) 0.1 Camargo (1996a)

United Kingdom

(rivers)

<0.05–0.4 Fuge & Andrews (1988)

Wales, United

Kingdom (streams)

0.02–0.22 Neal (1989)

Nigeria (River Niger) 0.1–0.12 Nriagu (1986)

India (rivers) 0.2–0.25 Zingde & Mandalia

(1988)

India (rivers) 0.038–0.21 Datta et al. (2000)

Tibet, China (rivers) 0.04 Cao et al. (2000)

Areas with high natural fluoride

Hot springs and

geysers, Yellowstone

National Park, USA

(25–50) Neuhold & Sigler

(1960)

Firehole and Madison

rivers, USA

(1–14) Neuhold & Sigler

(1960)

Walker and Pyramid

lakes, Nevada, USA

(up to 13) Sigler & Neuhold

(1972)

Kenya (lakes) (up to 2800) Nair et al. (1984)
EHC 227: Fluorides

40

a Mean and range of fluoride concentrations, unless otherwise stated.

b Range of means from four different regions of the eastern USA.

and 2800 mg/litre, respectively, in the Kenyan lakes Elmentaita and

Nakura (Nair et al., 1984). 

Anthropogenic sources can also lead to increased local levels of

fluoride.Harbo et al. (1974) found increased concentrations of fluoride

in the surface waters of Kitimat Harbour, Canada, in the vicinity of a

large smelter. Fluoride concentrations in the River Meuse, Belgium,

increased froma maximumof 0.2 mg/litre upriver to a mean value of 0.65

mg/litre near the outfall of a phosphate fertilizer plant (Van

Craenenbroeck & Marivoet, 1987). Zingde & Mandalia (1988) found

that fluoride levels were below 0.3 mg/litre in unpolluted surface

waters; however, levels were higher close to a plant manufacturing

fluoride chemicals in India. Surface water concentrations ranged from

0.8 to 2.8 mg fluoride/litre, with a mean value of 1.6 mg fluoride/litre.

Similarly, Somashekar & Ramaswamy (1983) reported a mean level of

2.97 mg fluoride/litre (range 0.34–5.12 mg/litre) in the River Cauvery,

India, near discharges from both fertilizer and paper factories. Mean

fluoride levels had declined to 0.64 mg/litre 8 km downstream of the

factory discharges. Fluoride concentrations in the Uppanar Estuary,

South India, ranged from 0.2 to 23.2 mg/litre in the vicinity of a factory

producing fluoride compounds (Karunagaran & Subramanian, 1992).

Camargo (1996a)monitored the Duratón River, Spain, downstreamfrom

an effluent discharge point. The mean fluoride concentration in the

effluent was 25.3 mg/litre; fluoride concentrations at 0.1, 2.2 and 7.3 km

downstream were 6.8, 2.7 and 1.3 mg/litre, respectively.

Skjelkvåle (1994b) found that streams close to Norwegian aluminium smelters contained 10 times more fluoride than natural background

levels due to 40 years of fluoride emissions. The levels had decreased

to background within 5 km. The author pointed out that despite the

higher levels near the smelters, the fluoride concentrations are still

within the general range of concentrations for Norwegian surface

waters. Similar results were reported by Roy et al. (2000) for an aluminium smelter on the Saguenay River, Quebec, Canada. Mean fluoride

concentrations 300 m downstream of the smelter outfalls ranged from

0.2 to 0.28 mg/litre. Camargo et al. (1992) analysed the fluoride

concentration in the Cache la Poudre River, USA, downstream from a

wastewater treatment plant. The mean fluoride concentration downstream was 1.17 mg/litre, about 4 times the mean fluoride concentration

upstream.
Environmental Levels and Human Exposure

41

5.1.2 Air

Airborne fluoride exists in gaseous and particulate forms emitted

from both natural and anthropogenic sources. The gaseous fluorides

include hydrogen fluoride,carbon tetrafluoride (CF4), hexafluoroethane

(C2F6) and silicon tetrafluoride. Particulate fluorides include cryolite,

chiolite (Na5A l3F14), calcium fluoride, aluminium fluoride and sodium

fluoride.Fluoride released as gaseous and particulate matter is deposited in the general vicinity of an emission source (Sidhu, 1979; Low &

Bloom, 1988), although some particulates may react with other atmospheric constituents. The distribution and deposition of airborne

fluoride are dependent upon emission strength, meteorological

conditions, particulate size and chemical reactivity (Low & Bloo m,

1988).

Levels of gaseous and particulate fluoride in ambient air and in air

near industrialsources are summarized in Tables 2 and 3, respectively.

In areas not in the direct vicinity of emission sources, the mean

concentrations of fluoride in ambient air are generally less than 0.1

μg/m3. Levels may be slightly higher in urban than in rural locations;

however, even in the vicinity of emission sources, the levels of

airborne fluoride usually do not exceed 2–3 μg/m3. In Canada, mean

concentrations of fluoride in samples of outdoor air collected between

1980 and 1991 in the vicinity of industrial emission sources ranged up

to 0.85 μg/m3(Health Canada, 1993). In the Netherlands (Groningen,

Sloe and Sas van Gent), mean concentrations of fluoride in samples of

outdoor air collected during 1985 and 1986 in the vicinity of various

industrial emission sources (brickworks, aluminium plant and a glass

fibre factory) ranged from0.25 to 0.4 μg/m3 (Sloof et al., 1989). Median

concentrations of fluoride in the air surrounding a Norwegian aluminium smelter in the spring and summer of 1994 ranged from 1.3 to

3.8 μg/m3 (Søyseth et al., 1996). In areas of China where fluoride-rich

coal is used as a source of fuel, concentrations of fluoride in ambient

air have reached 6 μg/m3 (Liu, 1995).

5.1.3 Soil

Data on the levels of total and water-soluble fluoride in soil are

presented in Table 4. Fluoride is a component of most types of soil,

with total concentrations ranging from20 to 1000 μg/g in areas without

natural phosphate or fluoride deposits and up to several thousand

micrograms per gram in mineral soils with deposits of fluoride
EHC 227: Fluorides

42

Table 2. Concentration of fluoride in ambient air

Location Detection

limit

(mg/m3)

Number

of

samples

Concentrationa

(mg/m3)

Reference

Arctic, Canada 0.001–0.00

4

nab 0.002–0.007c Barrie &

Hoff (1985)

0.001–0.00

4

na 0.006–0.008c Barrie &

Hoff (1985)

Toronto,

Ontario,

Canada

na na 0.03

(0.01–0.05)

Health

Canada

(1993)

147 nonindustrial

urban

locations, USA

0.05 3687 <0.05

(ndd–1.65)

Thompson

et al.

(1971)

29 rural

locations, USA

0.05 724 <0.05 (nd) Thompson

et al.

(1971)

1 nonindustrial

urban

location,

United

Kingdom

0.1 na <0.1

(<0.1–0.17)

Bennett &

Barratt

(1980)

4 nonindustrial

urban

locations, The

Netherlands

na na 0.07

(0.05–0.08)

Sloof et al.

(1989)

a Mean and range of concentrations of total (gaseous and particulate) fluoride

in ambient air, unless otherwise stated.

b na = not available. 

c Range of means.

d nd = not detectable.

(Davison , 1983). Airborne gaseous and particulate fluorides tend to

accumulate within the surface layer of soils but may be displaced

throughout the root zone, even in calcareous soils (Polomski et al.,

1982). The clay and organic carbon content as well as the pH ofsoil are

primarily responsible forthe origin and/or retention offluoride in soils.

Fluoride in soil is primarily associated with the soil colloid or clay

(Omueti & Jones, 1977). For all soils, it is the soluble fluoride content

that is biologically important to plants and animals. It has also been

reported that in saline soils, the bioavailability of fluoride to plants is

related to the water-soluble component of the fluoride present

(Davison, 1983). 
Environmental Levels and Human Exposure

43

Table 3. Concentration of fluoride in outdoor air near industrial sources

Location Distance from

source (km)

Concentrationa

(μg/m3)

Reference

Cornwall Island,

Ontario, Canada

1.65 0.79–0.85

(ndb–5.54)

Environment

Canada

(1989)

4.0 0.43

(nd–23.08)

Brampton, Ontario,

Canada

<1.0 0.73

(0.28–2.01)

Health

Canada

(1993)

Trail, British

Columbia, Canada

#5.0 0.59

(0.51–0.61)

Environment

Canada

(1994)

Various locations,

Quebec, Canada

0.5–2.0 0.1–0.67

(0.03–2.16)

Environment

Canada

(1994)

South African

Highveld

Various 0.08–0.14c

2.9 (maximum)

Scheifinger &

Held (1997)

Norway 1.3–3.8 Søyseth et al.

(1996)

Groningen, The

Netherlands

1.3 0.4 Sloof et al.

(1989)

Zeeland (Sloe area),

The Netherlands

6.0 0.25 Sloof et al.

(1989)

China 2–6 Liu (1995)

a Mean and range of fluoride concentrations, unless otherwise stated.

b nd = not detectable.

c Range of means.

5.1.4 Biota

Inorganic fluorides have been measured in a wide variety of

organisms; therefore, the data summarized here will be only a representative sample of the available literature.

5.1.4.1 Aquatic organisms

Fluorides can be taken up by aquatic organisms directly from the

water or, to a lesser extent, via food. Uptake of fluorides by biota will

very much depend on the proximity of anthropogenic sources,the local

geology and the physicochemical conditions,which will determine the

bioavailability of fluorides to any given organism.
Table 4. Concentration of fluoride in soil

.

 Location Soil description Soil depth

(cm)

Total fluoride

(mg/kg)a

Water-soluble

fluoride (mg/kg)a

Reference

Canada 3 reference soil samples from the

Canadian Soil Survey Committee

0–15 160 (90–247) nab Schuppli (1985)

Canada 23 reference soil samples from the

Canadian Soil Survey Committee

0–130 309 (63–1003) na Schuppli (1985)

Newfoundland, Canada forest soil na 6 2 (na) Sidhu (1982)

soil humus from various forests 0–3 (6–11) na (0.95–2.72) Sidhu (1979)

0.7 km north-east of an elemental

phosphorus plant

0–3 1138–1915 9.7–60.2 Sidhu (1979)

18.7 km north-east of an elemental

phosphorus plant

0–3 18.7–26.1 0.93–1.9 Sidhu (1979)

Pennsylvania, USA 55 samples of silt and clay 0–10 377 (136–990) 0.38 (<0.05–1.5) Gilpin & Johnson (1980)

Illinois, USA 201 surface soil samples from various

locations

na 271 (70–618) na Omueti & Jones (1977)

Montana, USA forest soil samples from an area exposed to

atmospheric fluoride emissions from an

aluminium smelter

na 330–1747 15.6–704 Polomski et al. (1982)

Ohio, USA silt loam (0–5 cm) collected from 7 sites

located in the vicinity of an aluminium

plant

0.5–4 353–371 na McClenahen (1976)
Table 4 (contd).

 Location Soil description Soil depth

(cm)

Total fluoride

(mg/kg)a

Water-soluble

fluoride (mg/kg)a

Reference

Oklahoma, USA reference site 0–2 121 (117–124) 0.2 Schroder et al. (1999)

petrochemical waste site 0–2 1954

(38.1–5871)

4.8 (1.2–12.6)

Greece 0–4 km from an aluminium plant 0–5 823 (729–910) na Tsiros et al. (1998)

5–15 km from an aluminium plant 0–5 570 (509–658) na

8–15 km from an aluminium plant 0–5 339 (258–480) na

Austria 0.5 km from an aluminium smelter 0–10 – 84–124c Tscherko & Kandeler

(1997)

1 km from an aluminium smelter 0–10 – 48–54c

4 km from an aluminium smelter 0–10 – 21–33c

15 km from an aluminium smelter 0–10 – 9.8–10c

The Netherlands 72 samples of agricultural soil na na (39–679) na (0.5–13) Sloof et al. (1989)

Guangdong Province,

China

19 samples of cultivated, acidic soil (pH

3.8–4.5)

0–20 186–387c 0.76–2.71c Fung et al. (1999) 

Tibet 40 samples of agricultural, forest and

urban soils

na – 0.45 Cao et al. (2000)

a Mean and range of fluoride concentrations, unless otherwise stated.

b na = not available.

c Range of means. 
EHC 227: Fluorides

46

Hocking et al. (1980) indicated that although there was some

accumulation of inorganic fluoride in marine vegetation, the rate of

accumulation was far lower than that of airborne inorganic fluoride by

terrestrial plants. In the vicinity of an aluminium smelter, samples of

seaweed were analysed fortheir inorganic fluoride concentrations. For

the seaweeds Fucus distichus and Ectocarpus sp., inorganic fluoride

concentrations were determined for both low- and mid-tide sites at 150

and 500 m from the outfall. A t the low-tide sites, F. distichus had

values of 62 and 48 mg fluoride/kg at 150 and 500 m, respectively.

Ectocarpus sp. had a level of 143 mg fluoride/kg at 500 m from the

outfall. A t the mid-tide sites at 150 and 500 m, Ectocarpus sp. had

levels of 317 and 140 mg fluoride/kg, respectively, while F. distichus

had a level of 18 mg fluoride/kg at 500 m from the outfall.

Four species of sea grass, a marine higher plant, were sampled in

the Antikyra Gulf, Greece, near an aluminium factory. Mean fluoride

concentrations ranged from 23.4 to 34.4 mg/kg dry weight (Malea,

1995).

Aquatic invertebrates and fish tend to accumulate fluoride in the

exoskeleton and in bone, respectively. Adelung et al. (1987) sampled

two krill species, Euphausia superba and Meganyctiphanes

norvegica, and found mean whole-body fluoride concentrations of

1058 and 2153 mg/kg dry weight,respectively.Most of the fluoride was

concentrated in the exoskeleton, with levels of <6 mg/kg being found

in soft tissues. Similarwhole-body and exoskeleton values were found

by Boone & Manthey (1983) and Christians & Leinemann (1980); however, they found higher levels in soft tissues, which Adelung et al.

(1987) suggested was due to contamination from the exoskeleton during analysis. Sands et al. (1998) monitored a range of Antarctic crustaceans and found that euphausiids accumulated the highest fluoride

concentrations, with levels up to 5477 mg/kg in the exoskeleton of

Euphausia crystallorophias. The mouthparts of E. superba contained

almost 13 000 mg fluoride/kg dry weight. Copepods contained the

lowest fluoride levels (0.87 mg fluoride/kg whole body).

Wright & Davison (1975) studied the accumulation offluoride in

a number of marine and intertidal animals found close to an aluminium

smelter at Lynemouth, United Kingdom. The seawater was found to

contain approximately 3.4 mg fluoride/litre (1.9 mg fluoride/litre

above background levels). The skeletal tissue of both vertebrates and

invertebrates was found to contain elevated fluoride levels.The mean
Environmental Levels and Human Exposure

47

exo skeleton fluoride concentrations for the swimming crab Portunus

depurator, the shrimp Crangon vulgaris and the prawn Leander

serratus were 11.6, 11.5 and 11.3 mg/kg, respectively. Tissue accumulation of fluoride in the Atlantic cod (Gadus morhua) was highest in

the skin (mean 29.6 mg fluoride/kg); in haddock (G. aeglefinus) and

dabs (Pleuronectes limanda), the mean tissue values were highest in

the axial skeleton, 49.3 and 99.7 mg fluoride/kg, respectively.

Fish, predominantly mullet (Mugil auratus, Mugil cephalus and

Mugil labrosus), caught in Gabes Bay, South Tunisia, where fluoriderich effluents were discharged (inorganic fluoride levels in water were

about 2–3 mg/litre), were found to have tissue fluoride levels 4–5 times

higher than fish obtained from the Tunis Bay, which is remote fro m

point sources (fluoride levels in waterwere about 1.4 mg/litre)(Milhaud

et al., 1981). The mullet caught in Gabes Bay had mean inorganic

fluoride values of 320, 9.6 and 14.6 mg/kg wet weight forbone, muscle

and muscle/skin, respectively.Comparatively,the mean levels of fluoride in control fish were 73, 1.8 and 3.8 mg/kg wet weight, respectively.

Similar values to those found in polluted environments were reported

by Gikunju (1992) for fish inhabiting Lake Naivasha, Kenya (water

fluoride concentrations ranged from 2.4 to 2.6 mg/litre). Tilapia (Oreochromis leucostictus) contained fluoride concentrations of 1.97, 4.96,

143.1 and 210.6 mg/kg wet weight for muscle, skin, gills and bone,

respectively.

Adelung et al. (1985) analysed bone and soft tissue fromAntarctic

seals (Weddel seal, Leptochynotus weddelli, and crabeater seal,

Lobodon carcinophagus). Mean bone fluoride concentrations ranged

from 135 to 6380 mg/kg dry weight; soft tissues contained mean concentrations ranging from 2.3 (kidney) to 9.1 (brain) mg fluoride/kg.

Bone samples taken from fin whales (Balaenoptera physalus) in the

North Atlantic contained fluoride concentrations ranging from4300 to

18 600 mg/kg (Landy et al., 1991); fluoride concentrations were positively correlated with age. Mikaelian et al. (1999) found mean bone

fluoride levels of 10 365 mg/kg in beluga whales (Delphinapterus

leucas) from Hudson Bay, Canada, compared with mean levels of

4539 mg fluoride/kg in whales from the St. Lawrence estuary, Canada;

fluoride levels were positively correlated with age only in the latter

population.
EHC 227: Fluorides

48

5.1.4.2 Terrestrial organisms

Fluoride levels in terrestrial biota tend to be increased in areas

with high fluoride levels due to both natural and anthropogenic

sources.

Lichens have been used extensively as biomonitors for fluorides.

Davies & Notcutt (1988)sampled lichens fromthe slopes of the Mount

Etna volcano in 1985 and 1987 and found fluoride levels ranging from

2 to 141 mg/kg (lichen from control sites contained <2 mg fluoride/kg).

Similarly, Davies & Notcutt (1989) found that lichens growing in the

Canary Islands accumulated fluorides from minor volcanic eruptions.

Fluoride levels of up to 23 mg / kg were measured, compared with a

background level of <1 mg/kg.Lichens have also been used to monitor

anthropogenic outputs of fluorides fromboth brickfields (Davies, 1982,

1986) and an aluminium smelter (Perkins et al., 1980; Perkins & Millar,

1987). Levels of fluoride were found to be related to site emissions,

prevailing winds and distance from source. Mean fluoride

concentrations of 150–250 mg/kg were measured in lichens growing

within 2–3 km of the pollution source.

Most of the inorganic fluoride in the soil is insoluble and therefore

less available to plants. The capacity for a plant to absorb inorganic

fluoride from the soil will also depend on the species of plant and, to

some extent, the ionic species of fluoride present in solution (Stevens

et al., 1997, 1998a, 1998b) (see section 4.2). For example, some genera

(e.g., Dichapetalum, Thea, Camellia, Oxylobium, Acacia and

Palicoure) accumulate fluoride and show none of the symptoms of

fluoride toxicity, with fluoride concentrations up to 4000 μg/g dry

weight (Jacobson et al., 1966; Weinstein & Alscher-Herman, 1982). In

samples obtained near a reclaimed fluorspar mining site, the levels of

inorganic fluorides in plants were higher than those in samples

obtained from a control site (Andrews et al., 1982). High total soil

fluoride (10 000 mg/kg) has been measured in the metalliferous

fluorspar tailings and is reflected by elevated concentrations in

vegetation (300–1000 mg/kg) (Andrews et al., 1989). Other genera are

non-accumulators of fluoride and have shown signs of fluoride toxicity

at much lower fluoride concentrations in their tissues. For example,

gladiolus (Gladiolus sp.) plants may become necrotic with 20 μg

fluoride/g dry weight (Jacobson et al., 1966). Normal concentrations of
Environmental Levels and Human Exposure

49

fluoride in plant leaves usually range from 0.1 to 15 μg/g (Cholak, 1959;

Cooke et al., 1976; Hara et al., 1977).

Several plant species have the ability to convert soluble fluorides

taken up from soil into carbon–fluoride compounds, such as monofluoroacetic acid, monofluoro-oleic acid, monofluoropalmitic acid and

monofluoromyristic acid (Marais, 1944; Ward et al., 1964). Two well

known Australian species that synthesize monofluoroacetates are

Gastrolobium spp. (Aplin, 1968) and Georgina gidgee (Acacia

georginae F.M. Bailey) (Oelrichs & McEwan, 1961); other species

include Oxylobium spp. (Australia), Dichapetalum spp. (Africa) and

Palicourea marcgravii (reviewed by Weinstein, 1977). The function

of monofluoroacetate in the plant is unknown. The assumption that its

synthesis by the plant is a response to high concentra tions of

available inorganic fluoride in soil or water (Preuss et al., 1970) is not

supported by the finding that some plants containing

monofluoroacetate grow in soils with lowfluoride concentrations (Hall,

1972).

Most fluorides enter plant tissues as gases through the stomata

and accumulate in leaves. Small amounts of airborne particulate

fluoride can enter the plant through the epidermis and cuticle

(Weinstein, 1977). Vegetation has been widely monitored in the vicinity

of anthropogenic emission sources of fluoride. Rice et al. (1984)

obtained background fluoride concentrations for 17 plant species

indigenous to the Northern Great Plains in the USA. Mean fluoride

concentrations ranged from 1.5 to 3.3 mg /kg. Nine of these species

were also monitored in polluted areas, and mean fluoride

concentrations ranged from 2.8 to 11.3 mg/kg, with Rocky Mountain

juniper (Juniperus scopulorum) accumulating the highest amounts of

fluoride.

Leece et al. (1986) found increased levels of fluoride in basal

leaves of grapevines (Vitus vinifera), 9–25 km downwind of an

aluminium smelter in New South Wales, Australia. Inorganic fluoride

concentrations of 4–42 mg/kg were recorded, with the highest levels

9–11 km from the smelter. Bowen (1988) monitored vegetation around

two aluminium smelters in Hunter Valley, Australia. Foliar concentrations were greater than background levels at distances of up to 3 km

from one smelter and up to 1 km from the other. Close to the smelters,

tree species accumulated more foliarfluoride than shrub species, which

in turn accumulated more foliar fluoride than herb species.
EHC 227: Fluorides

50

Fluoride levels in trees near an aluminium smelter in Kitimat,

British Columbia, Canada, have been measured since 1954. From 1954

to 1973, western hemlock (Tsuga heterophylla) tree foliage from the

vicinity of the smelter contained a mean fluoride concentration of

271 mg/kg; the surrounding area had mean levels of 104 mg/kg.Forthe

5-year period 1974–1979, during which time there was a 64% decline in

smelter emissions, foliage fromthe inner, outer and surrounding zones

contained mean inorganic fluoride levels of 87, 29 and 22 mg /kg,

respectively (Bunce, 1985). Similarly, Amundson et al. (1990) found

significantly higher levels of foliar fluoride in pine species (Pinus sp.)

growing within 0.8 km of a smelter than in those growing at a distance

of 1.8 km. Mean fluoride levels in vegetation in the vicinity of a phosphorus plant ranged from 44 mg/kg in lightly damaged areas to

281 mg/kg in severely damaged areas (Thompson et al., 1979). Horntvedt (1995) monitored pine and spruce (Picea sp.) needles for 15–

25 years on permanent plots around eight aluminium smelters and

found a high correlation between needle fluoride levels and smelter

emissions.

Taylor & Basabe (1984) established correlations between fluoride

concentrations in needles of Douglas-fir (Pseudotsuga menziesii) and

annual growth increments,wind pattern, distance fromfluoride source

(aluminium smelter) and hydrogen fluoride concentrations in aerial

effluents.Mean fluoride concentrations in needles ranged from27.6 to

60.9 mg/kg dry weight for the period 1972–1975, with an overall range

of 2–590 mg/kg. Needles collected from a control site contained mean

fluoride concentrations ranging from 3.2 to 5.8 mg/kg.

Several invertebrate species have been sampled in the vicinity of

fluoride sources such as aluminium smelters. Walton (1986) analysed

earthworms collected at different distances froman aluminiumsmelter.

The mean whole-body fluoride concentration was 112 mg /kg within

1 km of the plant and ranged from 19 to 48 mg/kg at a distance of 3–

15 km. Breimer et al. (1989) found a highly significant correlation

between total fluoride in earthworms (Lumbricussp.) and hydrochloric

acid-extractable fluoride in topsoil. Worm tissue (without gut) contained 6–14 mg/kg at controlsites and up to 135 mg/kg at contaminated

sites (topsoil contained >200 mg fluoride/kg). Vogel & Ottow (1991)

sampled a variety of earthworm species in the vicinity of a chemical

factory. They found a significant difference in fluoride accumulation

between species. Lumbricus terrestris showed the lowest 
Environmental Levels and Human Exposure

51

accumulation; the authors pointed out that this species tends to

migrate to deeper, less contaminated mineral horizons. Those species

that remain in the upper soil horizons tended to accumulate larger

amounts of fluoride.

Buse (1986) monitored a range ofinvertebrates near an aluminium

smelter and found that scavengers, such as millipedes and woodlice,

accumulated the highest concentrations (mean 1100 mg fluoride/kg).

Predatory spiders (Arachnida:Araneae), harvestmen (Arachnida:Opiliones), slugs and snails (Gastropoda: Pulmonata), earthworms (Oligochaeta), beetles (Insecta: Coleoptera) and centipedes (Chilopoda)

contained mean fluoride concentrations of 393, 258, 190, 148, 50 and 48

mg/kg, respectively . The lowest mean fluoride value was found in

grasshoppers, at 20 mg/kg.

Fluoride has been measured in the femurs of 12 species of predatory birds in the British Isles. Mean fluoride concentrations ranged

from 112 mg/kg (common barn-owl, Tyto alba) to 2690 mg/kg (merlin,

Falco columbarius). Raptors that feed predominantly on small birds

accumulated the highest fluoride concentrations (Seel & Thomson,

1984). Henny & Burke (1990) measured fluoride in femurs of blackcrowned night-herons (Nycticorax nycticorax) near a phosphateprocessing complex. Fluoride concentrations ranged from540 to 11 000

mg/kg and increased with age. Vikøren & Stuve (1996a) found that the

mean eggshell fluoride concentration was significantly increased in

mew gull (Larus canus) and herring gull (Larus argentatus) eggs

collected near aluminium smelters (120–212 mg fluoride/kg ash weight)

compared with a control site (83–143 mg fluoride/kg). 

Several authors have monitored bone fluoride concentrations in

small mammals (voles, mice and shrews) in the vicinity of anthropogenic sources of fluoride (Walton, 1988). A t a heavily polluted site near

an aluminium smelter in the United Kingdom, field voles (Microtus

agrestis) contained bone fluoride concentrations ranging from 910 to

11 000 mg/kg (mean 7148 mg/kg), and wood mice (Apodemus

sylvaticus) contained bone fluoride concentrations ranging from 1800

to 17 200 mg/kg (mean 8430 mg/kg) (Walton, 1987b). Small mammals

(field vole, M. agrestis, and common shrew, Sorex araneus) sampled

from metalliferous fluorspar tailings contained mean fluoride concentrations ranging from 120 to 360 mg/kg. Individuals collected from a 
EHC 227: Fluorides

52

controlsite contained mean fluoride concentrations ranging from11 to

85 mg/kg (Andrews et al., 1989).

Thomson (1987)studied the bone fluoride in the prey of common

barn-owls (T. alba), field voles (M. agrestis) and common shrews (S.

araneus). Specimens were collected from owl pellets 0.9 km from an

aluminium smelter and another site 22 km from the plant. Voles were

also trapped at two locations, and shrews were trapped at six sites. A

negative correlation was found between distance from the smelter and

inorganic fluoride levels in the vole, and inorganic fluoride levels did

not widely differbetween trapped specimens and owl pellet specimens.

Fluoride concentrations in bones of the trapped voles ranged from

1581 to 2318 mg/kg at the plant site and from 111 to 257 mg/kg at the

control site. Walton (1985) found a downward trend in bone fluoride

concentrations in mice and voles at increasing distances from the

smelter. Walton (1986) analysed bones from common shrews (S.

araneus) and moles (Talpa europaea) collected at different distances

fromthe emission source.Fluoride concentrations in shrews decreased

with distance fromthe smelter. Mean fluoride concentrations in shrews

were 2093 mg/kg close to the plant and ranged from 770 to 1705 mg/kg

at a distance of 4–15 km. Moles from within 1 km of the plant had a

mean bone fluoride content of 7740 mg/kg; however, moles collected

at distances from 3 to 15 km showed no significant relationship with

distance, with mean concentrations ranging from 935 to 1853 mg

fluoride/kg.Shore (1995) established that it was possible to predict the

bone fluoride content of field voles (M. agrestis), common shrews (S.

araneus) or wood mice (A. sylvaticus) at a particular site based on data

from any one of the other species.

Walton (1984) monitored red foxes (Vulpes vulpes) in the United

Kingdom and found mean bone fluoride concentrations ranging from

283 mg/kg at an unpolluted site to 1650 mg/kg near a smelter. There

was a positive correlation between bone fluoride content and age.

Larger mammals have also been extensively monitored for bone

fluoride accumulation. Kierdorf et al. (1989) found mandibular fluoride

in roe deer (Capreolus capreolus) to be positively correlated with age,

the increase in concentration being higher in younger animals and

declining in older deer.Similarly,positive correlations between age and

bone fluoride content in the same species (Walton & Ackroyd, 1988),

in red deer (Cervus elaphus) (Dabkowska & Machoy, 1989) and in 
Environmental Levels and Human Exposure

53

European elk (Alces alces) (Machoy et al., 1995) have been found.

Several studies have found that bone fluoride is increased in larger

mammals in the vicinity of fluoride emission sources. Newman & Yu

(1976) found that the bones of deer from an area nea r an aluminium

plant in northwest Washington, USA, contained 10–35 times more

fluoride than bones of control deer. The ribs of control deer contained

157 and 465 mg fluoride/kg,whereas the ribs of exposed deer contained

2820 and 6809 mg fluoride/kg. H. Kierdorf & Kierdorf (1999) found a

significant reduction in the bone fluoride content of roe deer (C.

capreolus) near a coal-fired power plant (Germany) when comparing

deer monitored between 1973 and 1986 (mean 1529 mg fluoride/kg dry

weight) with animals monitored between 1987 and 1998 (mean 452 mg

fluoride/kg). Kierdorf & Kierdorf (2000) carried out a historical

biomonitoring study on red deer (C. elaphus) antlers. Antlers collected

prior to 1860 contained fluoride levels ranging from28 to 79 mg/kg ash

weight. The highest fluoride concentrations (up to 1392 mg/kg) were

found during the 1970s, with a pronounced decline during the late

1980s and 1990s to fluoride concentrations ranging from 159 to 367

mg/kg.

5.2 General population exposure

5.2.1 Drinking-water

Fluoride is ubiquitous in the environment, and, therefore,sources

of drinking-water are likely to contain at least some small amount of

fluoride. The amount of fluoride present naturally in non-controlled

fluoridated drinking-water(i.e., drinking-waterto which fluoridehas not

been intentionally added for the prevention of dental caries) is highly

variable, being dependent upon the individual geological environment

fromwhich the wateris obtained. Available data fromnationalsurveys

conducted in a number of countries are summarized in Table 5.

In 1986, approximately 40% of the population of Canada was

served with controlled fluoridated drinking-water (Droste, 1987).

Throughout Canada, there are a number of communities where sources

of drinking-water contain elevated levels of fluoride (as high as

4.3 mg/litre) from natural sources; however, those identified communities represent only a very small proportion (0.8%) of the total population (Droste, 1987). Approximately 62% of the US population that
EHC 227: Fluorides

54

Table 5. National surveys of fluoride in drinking-water

Location Fluoride

concentration

(mg/litre)

Comment References

Canada 0.05–0.21 Range of mean concentrations in

non-fluoridateda samples

collected between 1984 and 1989

from 67 communities in 5

provinces 

Health

Canada

(1993)

0.73–1.25 Range of mean concentrations in

fluoridatedb samples collected

between 1986 and 1989 from 320

communities in 8 provinces

Health

Canada

(1993)

Czech

Republic

0.05–3.0 Range of concentrations in more

than 4000 samples of drinkingwater collected between 1994 and

1996 from 36 districts within the

Czech Republic

NIPH (1996)

Finland <0.1–3.0 Range of concentrations in 5900

groundwater samples

Lahermo et

al. (1990)

<0.1–5.8 Range of concentrations in 1421

well-water samples

KorkkaNiemi et al.

(1993)

<0.1–6.0 Range of concentrations in

groundwater database of

Geological Survey of Finland,

7229 shallow wells

Lahermo &

Backman

(2000)

<0.1–9.3 Range of concentrations in

groundwater database of

Geological Survey of Finland,

571 drilled wells

Lahermo &

Backman

(2000)

Germany 0.02–0.17 Range of concentrations of

drinking-water collected from

various facilities in Germany

between 1975 and 1986

Bergmann

(1995)

The

Netherlands

0.04–0.23 Public drinking-water samples

collected in 1985 from water

treatment plants in 12 provinces

Sloof et al.

(1989)

Poland 0.02–3.0 Range of mean concentrations in

samples of drinking-water

collected from 94 localities in

central and northern Poland

between 1993 and 1995

Czarnowski

et al. (1996)
Environmental Levels and Human Exposure

55

Table 5 (contd).

Location Fluoride

concentration

(mg/litre)

Comment References

USA <0.1–1.0 Fluoride levels in drinkingwater of approximately 62%

of the US population served

by public supplies range from

<0.1 to 1.2 mg/litre; levels of

fluoride in drinking-water of

approximately 14% of the US

population served by public

supplies range from 1 to 2

mg/litre

US EPA

(1985); US

DHHS

(1991)

a Drinking-water in which inorganic fluoride was not intentionally added for the

prevention of dental caries.

b Drinking-waterin which inorganic fluoride was intentionally added forthe prevention of dental caries.

is served by public water systems is supplied with drinking-water

containing fluoride at concentrations at or below 1.2 mg/litre (US EPA,

1985; US DHHS, 1991). Approximately 0.4% of the population in the

USA is supplied with drinking-water (from groundwater sources) containing naturalfluoride that exceeds a concentration of 2.0 mg/litre (US

EPA, 1985; US DHHS, 1991). In other countries, such as Poland,

Finland and the Czech Republic, levels of fluoride in drinking-water as

high as 3 mg/litre have also been reported (Lahermo et al., 1990; Bergmann, 1995; Czarnowski et al., 1996; NIPH, 1996).

In areas of the world in which endemic fluorosis of the skeleton

and/or teeth has been well documented, levels of fluoride in groundwater supplies have been reported to range from 3 to more than

20 mg/litre (WHO, 1984; Krishnamachari, 1987; Kaminsky et al., 1990;

US DHHS, 1991). In Tanzania, 30% of waters used for drinking-water

contained fluoride at concentrations above 1.5 mg/litre, levels in the

Rift Valley being up to 45 mg/litre (Latham & Gretch, 1967). 

Mean concentrations of fluoride ranged from 0.19 to 0.33 mg/litre

in more th an 24 varieties of domestic and imported bottled waters

purchased in the USA in 1989 (Nowak & Nowak, 1989; Stannard et al.,

1990). In a study of 52 varieties of bottled water purchased in the

vicinity of Houston, Texas, USA, between 1989 and 1991, the levels of

fluoride ranged from <0.1 to 0.72 mg/litre (Tate & Chan, 1994). Similar

findings were reported in a study of bottled water sold in Cleveland,

Ohio,USA (Lalumandier & Ayers, 2000). The concentration of fluoride

in 24 samples of mineral water collected in Germany between 1984 and

1989 ranged from 0.017 to 2.70 mg/litre (Bergmann, 1995).
EHC 227: Fluorides

56

5.2.2 Food

Since publication of the first EHC document on fluoride (WHO,

1984), additionalinformation on the levels of fluoride in foodstuffs has

become available.Virtually all foodstuffs contain atleast trace amounts

of fluoride.A summary of various studies in which the levels of fluoride in foods have been assessed is presented in Table 6.

Table 6. Levels of fluoride in foodstuffs

Table 6 (contd).

Food Fluoride

concentration

(mg/kg)a

Comment References

Milk and

milk

products

0.01–0.8 Range of concentrations

in 12 varieties of dairy

products in Canada

Dabeka &

McKenzie

(1995)

0.045–0.51 Range of mean

concentrations in 13

varieties of dairy products

in Hungary

Schamschula

et al. (1988a)

0.019–0.16 Range of concentrations

in milk and milk products

sampled between 1981

and 1989 in Germany

Bergmann

(1995)

Meat and

poultry

0.04–1.2 Range of concentrations

in 17 varieties of (cooked

and raw) meat and poultry

in Canada

Dabeka &

McKenzie

(1995)

0.01–1.7 Range of mean

concentrations in 7

varieties of meat and

poultry in Hungary 

Schamschula

et al. (1988a)

0.29 Mean concentration in

canned meat and sausage

sampled between 1981

and 1989 in Germany

Bergmann

(1995)

Fish 0.21–4.57 Range of concentrations

in 4 varieties of fish

available in Canada

Dabeka &

McKenzie

(1995)
Environmental Levels and Human Exposure

Table 6 (contd).

Food Fluoride

concentration

(mg/kg)a

Comment References

57

Fish

(contd).

0.06–1.7 Range of concentrations

in 6 varieties of fish

available in the USA

Whitford

(1996)

Soups 0.41–0.84 Range of concentrations

in 4 varieties of soup

available in Canada

Dabeka &

McKenzie

(1995)

0.42–0.94 Range of mean

concentrations in 7

varieties of soup available

in Hungary

Schamschula

et al. (1988a)

Baked

goods and

cereals

0.04–1.02 Range of concentrations

in 24 varieties of baked

goods and cereals

available in Canada

Dabeka &

McKenzie

(1995)

1.27–1.85 Range of mean

concentrations in rice

consumed in three

villages in China

Chen et al.

(1996)

0.06–0.49 Range of mean

concentrations in 13

varieties of baked goods

and cereals available in

Hungary

Schamschula

et al. (1988a)

0.05–0.39 Range of concentrations

in bread and grains

sampled between 1981

and 1989 in Germany

Bergmann

(1995)

Vegetable

s

0.01– 0.68 Range of concentrations

in 38 varieties of raw,

cooked and canned

vegetables in Canada

Dabeka &

McKenzie

(1995)

0.28–1.34 Range of mean

concentrations in three

staple vegetables

consumed in three

villages in China

Chen et al.

(1996)

0.01–0.86 Range of mean

concentrations in 24

varieties of vegetables

available in Hungary

Schamschula

et al. (1988a)

0.023 Mean concentration in

some vegetables sampled

between 1981 and 1989

in Germany

Bergmann

(1995)
EHC 227: Fluorides

Table 6 (contd).

Food Fluoride

concentration

(mg/kg)a

Comment References

58

Fruits and

fruit juices

0.01–0.58 Range of concentrations

in 25 varieties of fruit and

fruit juices available in

Canada

Dabeka &

McKenzie

(1995)

0.03–0.19 Range of mean

concentrations in 16

varieties of fruits and fruit

juices available in

Hungary

Schamschula

et al. (1988a)

0.02–2.8 Range of concentrations

in 532 varieties of fruit

juice and juice-flavoured

beverages in the USA

Kiritsy et al.

(1996)

0.027 Mean concentration in

some fruits sampled

between 1981 and 1989

in Germany

Bergmann

(1995)

0.014–0.35 Range of concentrations

in some fruit juices

sampled between 1984

and 1989 in Germany

Bergmann

(1995)

Fats and

oils

0.05–0.13 Range of concentrations

in 3 varieties of fats and

oils available in Canada

Dabeka &

McKenzie

(1995)

Sugars

and

candies

0.01–0.28 Range of concentrations

in 7 varieties of sugarcontaining products available in Canada

Dabeka &

McKenzie

(1995)

0.01–0.31 Range of mean

concentrations in 12

varieties of sugarcontaining foods

available in Hungary

Schamschula

et al. (1988a)

Beverages 0.21–0.96 Range of concentrations

in 6 varieties of beer,

wines, coffee and soft

drinks available in

Canada

Dabeka &

McKenzie

(1995)

0.19–0.78 Range of mean

concentrations in 3

varieties of coffee and soft

drinks available in

Hungary

Schamschula

et al. (1988a)

0.003–0.39 Range of concentrations

in some soft drinks

sampled between 1984

and 1989 in Germany

Bergmann

(1995)
Environmental Levels and Human Exposure

Table 6 (contd).

Food Fluoride

concentration

(mg/kg)a

Comment References

59

Beverages

(contd).

0.02–1.28 Range of concentrations

in 332 samples of soft

drinks sold in Iowa, USA,

between 1995 and 1997

Heilman et

al. (1999)

Tea 4.97 Concentration in tea

available in Canada

Dabeka &

McKenzie

(1995)

90.94–287.9 Range of mean

concentrations of tea

consumed in 3 villages in

China

Chen et al.

(1996)

243.7 Mean concentration in 4

samples of tea leaves

used in Hungary

Schamschula

et al. (1988a)

82–371 Range of concentrations

in samples of 32 tea

leaves purchased in Hong

Kong

Wei et al.

(1989)

0.005–0.174 Range of concentrations

in herbal and children’s

teas sampled between

1984 and 1989 in

Germany

Bergmann

(1995)

0.37–2.07 Range of concentrations

in black tea sampled

between 1984 and 1989

in Germany

Bergmann

(1995)

a For liquid items, concentrations are in mg/litre.

Tea leaves are particularly rich in fluoride (see Table 6). The conc entration of fluoride in brewed tea is dependent upon the concentration of soluble fluoride in the tea leaves, the level of fluoride in the

water used in its preparation and the length of the brewing period

(Smid & Kruger, 1985). Chan & Koh (1996) reported that the mean

concentration of fluoride in 21 brands of caffeinated tea, 11 brands of

decaffeinated tea and 12 brands of herbal tea purchased in the USA

and brewed (with water containing <0.02 mg fluoride/litre) for 5–120

min was approximately 1.5–2.4, 3.2–4.2 and 0.05–0.1 mg/litre, respectively. The levels of fluoride in 40 brands of brewed and instant coffee

purchased in the USA ranged from 0.1 to 0.58 mg/litre, with no significant difference between caffeinated and decaffeinated coffees (Warren

et al., 1996). 
EHC 227: Fluorides

60

The concentration offluoride in food products is usually not significantly increased by the addition of superphosphate fertilizers to

agricultural soil (Oelschläger, 1971), due to the generally low transfer

coefficient from soil to plant material. However, a recent study by

McLaughlin et al. (2001) found significant increases in fluoride concentrations in herbage harvested from plots fertilized with phosphate

fertilizers (537 kg total phosphorus added over 59 years) over a long

period (22 mg fluoride/kg) compared with concentrations in herbage

harvested from unfertilized plots (11 mg fluoride/kg). These data

suggest that, given the right soil conditions and application of

sufficient fluoride as an impurity in phosphate fertilizers to soils, plant

uptake of fluoride can be increased. The use of water containing relatively low (<3.1 mg/litre) levels offluoride for crop irrigation generally

does not increase foodstuff fluoride concentrations (Schamschula et

al., 1988a). However, this is dependent on plant species and fluoride

concentrations in soil and water. For example, Kabasakalis & Tsolaki

(1994)showed that fluoride concentrations in vegetables irrigated with

water containing 10 mg fluoride/litre were increased compared with

fluoride concentrations in vegetables grown with irrigation water containing low fluoride concentrations (0.15 mg/litre). They also commen ted that fluoride has a tendency to accumulate in the vegetable

leaves rather than in the fruits. 

Levels of fluoride in foods are significantly affected by the fluoride content of the water used in preparation or processing, most

notably in beverages and dry foodstuffs to which wateris added prior

to consumption (Kumpulainen & Koivistoinen, 1977; Schamschula et

al., 1988a). In a study conducted in a rural area of China, immersion of

vegetables in hot spring water containing elevated levels of fluoride

(approximately 20.3 mg/litre) reportedly led to a significant increase in

the fluoride content of the food product (Xu et al., 1995). The concentration of fluoride in water used to parboil rice influenced the level

in the final product (Anasuya & Paranjape, 1996). The concentrations

of fluoride in unwashed or unprocessed foods grown in the vicinity of

industrialsources (emissions) of fluoride in Japan (Sakurai et al., 1983;

Tsunoda & Tsunoda, 1986; Muramoto et al., 1991) and the United

Kingdom (Jones et al., 1971) have been up to 100-fold greaterthan the

levels in the same foods grown in othernon-industrially exposed areas.

In commercially available infant formulas sold in the USA, soybased ready-to-use and liquid concentrate formulas contained higher
Environmental Levels and Human Exposure

61

levels of fluoride than the equivalent milk-basedproducts;however, no

significant differencewas observed between soy- and milk-based powdered infant formulas (McKnight-Hanes et al., 1988) (Table 7). The

mean concentrations of fluoride in liquid milk- and soy-based concentrated formulas diluted with water containing 1 mg fluoride/litre were

0.62 and 0.74 mg/litre, respectively. The mean concentrations in powdered milk- and soy-based formulas diluted with water containing 1 mg

fluoride/litre were 0.83 and 0.85mg/litre,respectively (McKnight-Hanes

et al., 1988). For infant formulas available in Australia, the average

concentrations of fluoride in powdered milk- and soy-based formulas

diluted with water containing 1 mg fluoride/litre were 1.2 and 1.34

mg/litre, respectively (Silva & Reynolds, 1996). Studies of fluoride

levels in infant foods available in Germany revealed mean concentrations generally of 0.02–0.3 mg/litre (Bergmann, 1995). In other

studies (see Table 7), levels of fluoride in infant formulas have ranged

from 100 to 1600 μg/litre (Fomon & Ekstrand, 1993). A study of a

variety of infant food products available in the USA indicated concentrations offluoride ranging from0.01 to 8.38 μg/g; the highest concentrations were in products containing chicken (Heilman et al., 1997). In

otherinfant food and beverage products (see Table 7), fluoride levels

ranged from 10 to 6000 μg/litre (Fomon & Ekstrand, 1993). Reported

levels of fluoride in breast milk have ranged from <2 to 100 μg/litre,with

most values being between 5 and 10 μg/litre (Ekstrand, 1981; Esala et

al., 1982; Dabeka et al., 1986; Bergmann, 1995). 

5.2.3 Indoor air

Available data on the concentrations of fluoride in indoor air are

limited. In the Netherlands, concentrations of gaseous fluoride ranged

from <2 to 49 μg/m3 in the indoor air of five homes constructed with

wood treated with a preservative containing 56% fluoride (Sloof et al.,

1989). Gu et al. (1990) reported a mean concentration of fluoride of

approximately 60 μg/m3 for samples of indoor air collected fromhomes

in China where coal containing high amounts of fluoride was burned

indoors. In other studies conducted in China, the levels of fluoride in

the indoor air of homes where fluoride-rich coal was burned have

ranged from 2.1 to 46.1 μg/m3(Liu, 1995) and from 15 to 155 μg/m3

(Zhang & Cao, 1996). (See section 5.1.2 for concentrations of fluoride

in outdoor air.)
EHC 227: Fluorides

62

Table 7. Concentrations of fluoride in infant foodsa

Food item Fluoride

concentration

(μg/litre)b

Reference

Human milk 5–10 Esala et al. (1982);

Spak et al. (1983);

Ekstrand et al. (1984)

Cow’s milk 30–60 J. Ekstrand

(unpublished data)

Formula Johnson & Bawden

(1987); McKnightHanes et al. (1988)

Ready to feed 100–300

Concentrated

liquid

Milk-based 100–300

Isolated

soybean-based

100–400

Powdered

Milk-based 400–1000

Isolated

soybean-based

1000–1600

Most products other than

dry cereals

100–300 Singer & Ophaug

(1979); Dabeka et al.

(1982)

Fruit juices Singer & Ophaug

(1979); Dabeka et al.

(1982)

Produced with

non-fluoridated

water

10–200

Produced with

fluoridated water

100–1700

Dry cereals Singer & Ophaug

(1979); Dabeka et al.

(1982)

Produced with

non-fluoridated

water

90–200

Produced with

fluoridated water

4000–6000

Wet-pack cereal fruit

products

2000–3000 Singer & Ophaug

(1979); Dabeka et al.

(1982)

Poultry-containing

products

100–5000 Singer & Ophaug

(1979); Dabeka et al.

(1982)

a From Fomon & Ekstrand (1993); Fomon et al. (2000).

b Concentration rangeshave been rounded off. Most reported values fall within

the ranges listed in the table.
Environmental Levels and Human Exposure

63

5.2.4 Consumer products

Dentifrice products for adults that are commercially available in

many countries generally contain fluoride at concentrations ranging

from 1000 to 1500 μg/g (Whitford, 1987; Sloof et al., 1989; Newbrun,

1992). Some dentifrices designed for use by children contain lower

levels of fluoride,ranging from250 to 500 μg/g (Newbrun, 1992). Dental

products such as toothpaste, mouthwash and fluoride supplements

have been identified as significant sources of fluoride (Ekstrand, 1987;

Drummond et al., 1990). Topical mouth rinses marketed fordaily home

use may contain between 230 and 500 mg fluoride/litre, while

mouthwash products intended forweekly or biweekly use may contain

900–1000 mg fluoride/litre (Sloof et al., 1989; Grad, 1990; Whitford,

1996).

5.2.5 Intake estimates

Published estimates for the intake of fluoride have been summarized in Table 8. Although individual exposure to fluoride is likely to be

highly variable,the inhalation of airborne fluoride in most cases makes

a minor contribution to the total intake of this element. Infants may

receive small quantities of fluoride from breast milk. For adults, the

consumption of foodstuffs and drinking-wateris the principalroute for

the intake of fluoride. The ingestion of dentifrice by young children

makes a significant contribution to their total intake of fluoride.Studies

have indicated that children between 2 and 5 years of age may ingest

between 0.11 and 0.39 g of dentifrice per brushing (Bruun & Thylstrup,

1988; Simard et al., 1989; Naccache et al., 1990, 1992). In general,

estimated intakes of fluoride in children and adolescents do not exceed

approximately 2 mg/day.

Although adults may have a higher absolute daily intake of fluoride in milligrams, the daily intake of fluoride by children on a milligram

per kilogram body weight basis may exceed that of adults. In certain

areas of the world in which the concentration of fluoride in the

surrounding enviro nment (mainly groundwater) may be exceedingly

high and/or diets are composed of foods rich in fluoride, estimated

intakes of fluoride in adults as high as 27 mg/day have been reported

(Liu, 1995; Anasuya et al., 1996; Cao et al., 1996; Karthikeyan et al.,

1996). In certain areas of China in which coal rich in fluoride is used for

heating and food preparation (e.g., cooking, food drying), the 
Table 8. Estimated intakes of fluoride

Sources of fluoride

exposure

Age group Estimated fluoride

intake, mg/day (mg/kg

body weight per day)a

Comment References

Foodstuffs Adults 0.6 Intakes based upon levels of fluoride and

consumption of major foodstuffs

Varo &

Koivistoinen

(1980)

Foodstuffs and

drinking-water in four

regions of the USA

infants (6 months):

(drinking-water <0.3 mg fluoride/litre)

(drinking-water >0.7 mg fluoride/litre)

children (2 years old):

(drinking-water <0.3 mg fluoride/litre)

(drinking-water >0.7 mg fluoride/litre)

0.226 (0.028)

0.418 (0.052)

0.207 (0.017)

0.621 (0.05)

Intakes based on fluoride levels in market

basket survey of foods and drinking-water

and estimated consumption

Ophaug et

al. (1985)

Foodstuffs (including

infant formulas) and

beverages,

fluoridated or nonfluoridated drinkingwater in North

America

children (up to 6 years of age) 0.05–1.23 (0.01–0.16) Summary of 8 studies published between

1943 and 1988 on the estimated intakes of

fluoride from food and beverages by North

American children

Levy (1994)
Table 8 (contd).

Sources of fluoride

exposure

Age group Estimated fluoride

intake, mg/day (mg/kg

body weight per day)a

Comment References

Ambient air,

foodstuffs (including

infant formula or

breast-fed),

fluoridated or nonfluoridated drinkingwater, soil, dentifrice

in Canada

infants (up to 6 months of age)

children (7 months to 4 years)

adolescents (5–11 years)

adults (20+ years)

<0.01–0.65

(<0.001–0.09) 

0.6–2.1 (0.05–0.16)

0.7–2.1 (0.03–0.08)

2.2–4.1 (0.03–0.06) 

Estimated total intakes by multimedia

exposure analysis based upon ranges of

mean concentrations of fluoride in

ambient air, fluoridated or non-fluoridated

drinking-water and soil; levels of fluoride in

survey of 109 foodstuffs in Canada, breast

milk, infant formula and average level of

fluoride in dentifrice available in Canada,

as well as assigned reference values for

body weight, inhalation of air, and

consumption of water, soil and foodstuffs,

by various age groups of the population of

Canada

Government

of Canada

(1993)

(Infant formula or

breast-fed), cereal,

juices, fluoridated or

non-fluoridated

drinking-water,

dentifrice, fluoride

supplements in the

USA

infants (6 months of age)

children (1 year of age)

children (2–3 years of age)

0.4–1.4 (0.05–0.19)

0.32–0.73 (0.03–0.08)

0.76–1.23 (0.06–0.09)

Estimated intakes based upon

concentrations of fluoride in breast milk or

various infant formulas reconstituted with

fluoridated or non-fluoridated drinkingwater, levels in juices and cereals, as well

as estimated intakes from dentifrice and

fluoride supplements by children in the

USA

Levy et al.

(1995)
Table 8 (contd).

Sources of fluoride

exposure

Age group Estimated fluoride

intake, mg/day (mg/kg

body weight per day)a

Comment References

Various infant

formulas

reconstituted with

fluoridated or nonfluoridated drinkingwater in Australia

infants (6 months of age)

infants (1 year of age)

0.13–1.35 (0.02–0.17)

0.14–1.65 (0.02–0.17)

Estimated intakes based upon levels of

fluoride in various infant formulas

available in Australia reconstituted with

either fluoridated or non-fluoridated

drinking-water

Silva &

Reynolds

(1996)

Ambient air,

drinking-water and

limited variety of

foodstuffs in China

adolescents (7–15 years)

adults (16+ years)

1.16–4.57

1.61–7.51

Estimated intakes based upon levels of

fluoride in ambient air, local supplies of

drinking-water and levels in a limited

variety of locally grown foodstuffs in an

area of China with known elevated levels

of fluoride in local water supplies 

Liu (1995)

Ambient air,

drinking-water and

limited variety of

foodstuffs in China

adolescents (8–15 years)

adults (16+ years)

1.51–10.6

1.79–17.0

Estimated intakes based upon levels of

fluoride in ambient air, indoor air, local

supplies of drinking-water and levels of

fluoride in a limited variety of locally

grown foodstuffs in four areas of China

where fluoride-containing coal is burned

for heating and cooking

Liu (1995)
Table 8 (contd).

Sources of fluoride

exposure

Age group Estimated fluoride

intake, mg/day (mg/kg

body weight per day)a

Comment References

Principal foods

consumed by

Tibetan and Han

peoples residing in

Sichuan province in

China (levels of

fluoride in drinkingwater were low [0.1

mg/litre])

Tibetan

(8–15 years)

(>15 years)

Han

(8–15 years)

(>15 years)

5.49

10.43

1.44

2.54

Increased intake of fluoride by Tibetans

based upon their consumption of a local

type of prepared barley and brick tea;

foodstuffs not consumed by Han residing in

this area; prevalence of dental and

skeletal fluorosis greater among Tibetans

than among Han

Cao et al.

(1996)

Ambient air,

beverages, food and

drinking-water in

Hungary

children with a mean age of 3.9 years

adolescents with a mean age of 14

years

0.22–1.11

0.3–1.49

Estimated intakes based upon levels in

available foodstuffs, beverages, air and

drinking-water containing levels of fluoride

ranging from 0.06 to 3.1 mg/litre

Schamschula

et al. (1988b)

Drinking-water and

food in India

children (age not specified) 1.5–20 Estimated range of mean intakes based

upon levels in foodstuffs and local supplies

of drinking-water that ranged in

concentration from 0.32 to 9.6 mg/litre

Karthikeyan

et al. (1996)
Table 8 (contd).

Sources of fluoride

exposure

Age group Estimated fluoride

intake, mg/day (mg/kg

body weight per day)a

Comment References

Drinking-water and

food in normal or

fluorotic villages in

India

adults (age not specified) 0.84–4.69 (normal)

3.40–27.1 (fluorotic)

Range of intakes based upon consumed

foodstuffs and local supplies of drinkingwater from rural areas in India considered

either normal or fluorotic, based upon the

absence or occurrence of endemic skeletal

fluorosis in these areas, respectively

Anasuya et

al. (1996)

Diet, beverages and

toothpaste in New

Zealand

children (3–4 years of age) 0.17–1.31 (0.01–0.07) Range of intakes based on duplicate-diet

survey of foodstuffs and beverages (nonfluoridated or fluoridated) consumed as

well as calculated intake from toothpaste,

in a study of 66 children

GuhaChowdhury et

al. (1996)

Commercially

available foods and

drinking-water in

Germany

infants 1–12 months of age 0.099–0.205 Estimated intake based upon consumption

of commercially available food and

drinking-water containing 0.13 mg

fluoride/litre

Bergmann

(1995);

Bergmann &

Bergmann

(1995)

Breast milk and

homemade food in

Germany

infants 1–12 months of age 0.002–0.075

(0.0005–0.007)

Estimated intakes by infants receiving

breast milk as well as homemade foods
Table 8 (contd).

Sources of fluoride

exposure

Age group Estimated fluoride

intake, mg/day (mg/kg

body weight per day)a

Comment References

Food, beverages and

drinking-water in

Germany

children 1–15 years of age 0.112–0.264 Estimated intake based upon consumed

foodstuffs, beverages and drinking-water

Bergmann

(1995);

Bergmann &

Bergmann

Foods, beverages (1995)

and drinking-water in

Germany

adolescents (15–18 years of age) 0.523 (males) (0.008)

0.470 (females) (0.009)

Estimated intake based upon consumed

foodstuffs, beverages and drinking-water

Foods, beverages

and drinking-water in

Germany

Adults 0.560 (males) (0.007)

0.442 (females) (0.007)

Estimated intake based upon consumed

foodstuffs, beverages and drinking-water

16- to 40-month-old children

consuming drinking-water containing

0.3 mg fluoride/litre

0.965 (0.073) Estimated intake based upon consumed

foodstuffs, beverages and drinking-water

Foods, beverages

and dentifrice in the

USA

16- to 40-month-old children

consuming drinking-water containing

0.8–1.2 mg fluoride/litre

0.965 (0.07) Estimated intake based upon consumed

foods, beverages and dentifrice

RojasSanchez et

al. (1999)

a Data in parentheses are the estimated intakes of fluoride, expressed as mg/kg body weight per day, when presented in the reference cited.
EHC 227: Fluorides

70

inhalation of indo or air and consumption of foodstuffs containing

increased levels offluoride also contribute to elevated intakes (Zhang

& Cao, 1996; Liang et al., 1997). 

5.3 Occupational exposure

The informatio n presented in this section focuses on data that

have become available since the last EHC document on fluoride was

published (WHO, 1984). Occupational exposure to fluoride via

inhalation or dermal contact likely occurs for individuals involved in

the operation of welding equipment orin the processing of aluminium,

iron ore or phosphate ore (Sloof et al., 1989). In the Netherlands,

concentrations of fluoride in the workroom air ofseven machine shops

and shipyards where welding operations were conducted ranged from

30 to 16 500 μg/m3; levels were highest in areas where welding

activities were conducted in small enclosed spaces (Sloof et al., 1989).

The mean concentration of fluoride in the workroomair of an aluminium

plant in Sweden was 900 μg/m3, with 34% of the fluoride present in the

gaseous form (Sloof et al., 1989). The concentration of total airborne

fluoride in the potroom of an aluminium smelter in British Columbia,

Canada, was approximately 0.48 mg/m3(Chan-Yeung et al., 1983a).

Søyseth et al. (1995) reported that between 1986 and 1988, the average

concentration of total fluoride in the potroom of an aluminium smelter

in western Norway was approximately 0.5 mg/m3. Rønneberg (1995)

indicated that, based upon monitoring studies conducted at a Norwegian aluminiumsmelterin 1962, time-weighted-average concentrations

of airborne fluoride ranged from 1.5 to 2.7 mg/m3. The time-weightedaverage concentrations of either dust-borne fluorideorhydrogen fluoride at two aluminium production facilities in the Netherlands operating

since the mid-1960s were reported to be approximately 0.5 mg/m3(Sorgdrager et al., 1995). The mean level of total airborne fluoride in the

potroom of an Iranian aluminium smelter was reportedly 0.93 mg/m3

(Akbar-Khanzadeh, 1995). During 1987–1988 and 1990–1994, the mean

levels of gaseous fluoride in the air of a hydrofluoric acid production

facility located in Mexico were reportedly 1.78 and 0.21 mg/m3,

respectively (Calderon et al., 1995). Mean levels of hydrogen fluoride

up to 3 mg/m3 were reported for some areas of a phosphate fertilizer

production facility in Poland (Czarnowski & Krechniak, 1990).
71

6. KINETICS AND METABOLISM IN HUMANS AND

LABORATORY ANIMALS

6.1 Absorption

6.1.1 Absorption in humans

In humans, the dominating route of fluoride absorption is via the

gastrointestinal tract. Airborne fluoride may also be inhaled. 

Fluoride ions are released from readily soluble fluoride compounds, such as sodium fluoride, hydrogen fluoride, fluorosilicic acid

and sodium monofluorophosphate (Na2PO3F), and almost completely

absorbed (Ekstrand et al., 1978; Spaket al., 1982). Fluoride compounds

with low solubility, on the other hand, including calcium fluoride,

magnesium fluoride and aluminium fluoride, are poorly absorbed.

Afterintake ofsodiumfluoride as tablets or a solution, fluoride is

rapidly absorbed. Only a few minutes afterintake, there is a rise in the

plasma fluoride concentration, and the plasma peak usually occurs

within 30 min. The height of the plasma peak is proportional to the

fluoride dose ingested (Ekstrand et al., 1977b).

The absorptive process occurs by passive diffusion, and fluoride

is absorbed principally fromboth the stomach and the intestine. There

is no convincing evidence that active transport processes are

involved.The mechanism and the rate of gastric absorption of fluoride

are related to gastric acidity. 

Fluoride is mainly absorbed in the form of hydrogen fluoride,

which has a pKa of 3.45. That is, when ionic fluoride enters the acidic

environment of the stomach lumen,it is largely converted into hydrogen fluoride (Whitford & Pashley, 1984). Most of the fluoride that is

not absorbed from the stomach will be rapidly absorbed from the small

intestine. 

In a bioavailability study in which young volunteers were given

4 mg fluoride as calciumfluoride (a poorly soluble fluoride compound)

and plasma fluoride was followed for 6 h, no increase in the plasma
EHC 227: Fluorides

72

fluoride concentration was detected following intake, indicating no

fluoride absorption (Afseth et al., 1987). 

Fluoride compounds that occur naturally or are added to drinkingwater yield fluoride ions, which are almost completely absorbed from

the gastrointestinal tract. Thus, fluoride in drinking-water is generally

bioavailable.

There is only limited information on the bioavailability of fluoride

from fluoride-containing diets. In a balance study in infants, it was

found that the bioavailability of the fluoride in the infants’ diet was

about 90% (Ekstrand et al., 1994).

The ingestion of fluoride with food retards its absorption and

reduces its bioavailability. When fluoride was ingested as sodium

fluoride tablets on a fasting stomach, the bioavailability of fluoride was

almost 100%. When the same dose was taken together with a glass of

milk, the bioavailability decreased to 70%; when it was taken together

with a calcium-rich breakfast,the bioavailability was furtherreduced to

60% (Ekstrand & Ehrnebo, 1979; Trautner & Einwag, 1989; Shulman &

Vallejo, 1990). The decrease in absorption associated with the

ingestion of milk or food is probably due to binding of fluoride with

certain food constituents, including calcium and other divalent and

trivalent cations. When this occurs, the faecal excretion of fluoride will

increase.The timing of fluoride ingestion in relation to a mealis critical

with respect to fluoride bioavailability. When a few grams of a fluoride

dentifrice are swallowed on a fasting stomach, the plasma peak is

recorded within 30 min; however, when the dentifrice is swallowed 15

min after a meal, the peak does not occur until after 1 h. The fluoride

from most dental products intended for oral application is almost

completely absorbed when swallowed (Ekstrand, 1987).

There is partialto complete absorption of gaseous and particulate

fluorides from the respiratory tract (McIvor, 1990), with the extent of

absorption depe ndent upon solubility and particle size. Particulate

fluorides deposited in the bronchioles and nasopharynx may be swallowed (via ciliary clearance and/or coughing) and reach the gastrointestinal tract, where they are absorbed; relatively insoluble

particulate fluorides deposited deep within the lungs may be absorbed

gradually over time.
Kinetics and Metabolism in Humans and Laboratory Animals

73

Available information on the absorption of fluoride through the

skin is limited to cases of acute dermal exposure to hydrofluoric acid.

Although hydrofluoric acid appears to be rapidly absorbed following

dermal exposure, in view of the extremely corrosive nature of this

compound, absorption into the general circulation could also be a

consequence of damage to the vascular system.

6.1.2 Absorption in laboratory animals

Experimental studies performed in vivo with rats (Sato et al., 1986)

and in vitro with isolated segments of dog jejunum (Messer et al.,

1989) have indicated that fluoride (as sodium fluoride) is rapidly

absorbed from the stomach and intestinal tract in animals. The rate at

which fluoride is absorbed fromthe stomach is inversely related to the

pH of the stomach contents (Whitford, 1990; Messer & Ophaug, 1993).

Although most of the fluoride ingested by laboratory animals is

absorbed through the gastrointestinaltract,smallamounts may also be

absorbed from the oral cavity. In female Fischer F-344 rats intubated

endotracheally (with oesophageal ligation)with 200 μl of a solution of

sodium fluoride (Na18F), approximately 7% of the administered material

was absorbed from the oral cavity within 2.5 h (Patten et al., 1978). The

absorption of fluoride (as sodium fluoride in solution) from the oral

cavity of Syrian hamsters increased with decreasing pH of the solution

(Whitford et al., 1982). 

In laboratory animals, the presence offood (Rao, 1984) and fluoride-binding ions (i.e., aluminium, calcium, magnesium) in the gastrointestinal tract (Spencer et al., 1981) significantly reduces the amount

of fluoride absorbed into the general circulation. The absorption of

ingested fluoride by female Wistar rats was reduced from 76 to 47%

when the level of calcium in their diet was increased from 0.5 to 2%

(Harrison et al., 1984). In male albino rabbits administered drinkingwater containing 25 or 250 mg fluoride/litre (as sodium fluoride) for 4

weeks, the levels of fluoride in the serum (and femoral bone) were

approximate ly 2-fold higher in animals administered a diet low in

calcium (0.4%) than in controls administered a diet containing 1.6%

calcium (Tsuchida et al., 1992). 

Otherthan the observation by Morris & Smith (1982) that gaseous

hydrogen fluoride was almost completely absorbed from the upper
EHC 227: Fluorides

74

respiratory tract following the exposure of rats to concentrations ranging from 30 to 176 mg fluoride/m3

, no additional quantitative data on

the absorption of fluorides following inhalation exposure were identified. 

Quantitative information on the dermal absorption of fluorides in

animals was not identified. 

6.2 Distribution and retention

6.2.1 Fluoride in blood

Fluoride is rapidly distributed by the systemic circulation to the

intracellular and extracellular water of tissues; however, the ion normally accumulates only in calcified tissues, such as bone and teeth.

Fluoride is not bound to any plasma proteins (Taves, 1968; Ekstrand

et al., 1977a). In the blood, the ion is asymmetrically distributed

between plasma and the blood cells, so that the plasma concentration

is approximately twice as high as that associated with the cells (Whitford, 1996).

There is no homeostatic regulation of the fluoride concentration

in the blood. In a short-term human pharmacokinetic study, fluoride

doses ranging from 3 to 10 mg were given orally in the form of tablets.

The data were interpreted using an open three-compartment model, and

the plasma half-life was determined from the final terminal phase,

ranging from 3 to 10 h. The plasma level rose and fell during each dosage interval. That is, the fluctuation of the plasma fluoride concentration depended on the fluoride dose ingested, dose frequency and

the plasma half-life of fluoride (Ekstrand et al., 1977b). 

The literature contains a wide range (0.4–2.4 μmol/litre) for “normal” plasma fluoride concentrations. Some of the results may have

been due to the use of fasting individuals in some studies and nonfasting in others.It is virtually certain also that problems with the analysis of fluoride have been contributory. This is especially the case

when only the fluoride electrode is used for the analysis of samples

with lowconcentrations.The use of preparative methods that concentrate the fluoride in small volumes, such as the acid-HMDS

microdiffusion method, is necessary when such low levels of fluoride

are to be measured.
Kinetics and Metabolism in Humans and Laboratory Animals

75

Understeady conditions of exposure via drinking-water, the concentration of fluoride in plasma collected from fasting subjects is

directly related to the concentration in the drinking-water consumed

(Guy et al., 1976; Ekstrand, 1978). The mean concentration of fluoride

in the blood plasma of 30 residents of communities in the USA served

by drinking-water contain ing low concentrations of fluoride (i.e.,

<0.1mg/litre)was 0.4 μmol/litre,while the mean concentration in plasma

fromindividuals consuming drinking-watercontaining higher amounts

of fluoride (i.e., 0.9–1.0 mg/litre) was reportedly 1 μmol/litre (Guy et al.,

1976). Serum and plasma contain virtually the same amount of fluoride

(Guy et al., 1976; Kono et al., 1986). There is a considerable variation

during the day in plasma fluoride levels in subjects living in an area

with a high fluoride concentration in the drinking-water, particularly in

adults (Ekstrand, 1978). 

In addition to recent fluoride intake and the level of chronic fluoride intake, plasma fluoride levels are influenced by the relative rates of

bone accretion and dissolution and by the renal clearance rate of

fluoride (Waterhouse et al., 1980). In the long term, there is a positive

relationship between the concentration offluoride in plasma and bone.

Also, a positive relationship between plasma fluoride and age has been

reported (Parkins et al., 1974). 

The levels of fluoride in plasma, serumand urine have been considered useful biomarkers for fluoride exposure (Ekstrand & Ehrnebo,

1983; Ekstrand et al., 1983; Ehrnebo & Ekstrand, 1986; Whitford, 1996;

WHO, 1996a; Lund et al., 1997). The concentra tions of fluoride in

parotid saliva have also been used to assess plasma levels of fluoride

(Ekstrand, 1977; Whitford et al., 1999a). There are, however, ethical and

technical limitations of the use of these fluids for large-scale monitoring of the body burden of fluoride in humans. It has been

suggested that the fluoride concentration in nails and hair can be used

as a markerof fluoride exposure (Czarnowski & Krechniak, 1990; Kono

et al., 1990; Whitford et al., 1999b). However, there is only limited

information on the reliability of these methods and the risks of

contamination during exposure in field conditions. Information on

appropriate preparation methods as wellas analyticaltechniques needs

to be further evaluated before these methods can be used on a largescale basis.
EHC 227: Fluorides

76

6.2.2 Distribution in soft tissues

Fluoride is distributed from the plasma to all tissues and organs.

The rates of delivery are generally determined by the blood flow to the

tissues in question. Consequently, steady-state fluoride

concentrations are achieved more rapidly between plasma and well

perfused tissues, such as the heart, lungs and liver, than between

plasma and less well perfused tissues,such as resting skeletal muscle,

skin and adipose tissue. In general, steady-state tissue-to-plasma

fluoride concentration ratios fall between 0.4 and 0.9, regardless of the

rates at which the steady-state levels are achieved (Whitford et al.,

1979). Exceptions to this range include the kidney, pineal gland, brain

and adipose tissue. Fluoride is concentrated to high levels within the

kidney tubules,so this organ has a higher concentration than plasma.

Most information on the levels of fluoride in soft tissues of

humans is derived from a report published by Taves et al. (1983), in

which the amounts in a number of tissues (from autopsies of 13 cases

of sudden death in the USA) were quantified (see Table 9 in section

6.2.5 below).

6.2.3 Distribution to calcified tissues

The rate of clearance of fluoride from plasma by bone is higher

than that of calcium. In humans and laboratory animals, approximately

99% ofthe total body burden of fluoride is retained in bones and teeth

(Kaminsky et al., 1990; Hamilton, 1992), with the remainder distributed

in highly vascularized soft tissues and the blood (McIvor, 1990). The

degree to which fluoride is stored in the skeletal tissue is related to the

turnove r rate of skeletal components and the level of previous

exposure (Caraccio et al., 1983). Levels of fluoride in calcified tissues

are generally highest in bone, dentine and enamel. The concentration

of fluoride in bone varies with age, sex and the type and specific part

of bone and is believed to reflect an individual’s long-term exposure to

fluoride.

During the growth phase of the skeleton, a relatively high portion

of an ingested fluoride dose will be deposited in the skeleton. In

infants and children with skeletal growth or individuals not consuming

fluoridated drinking-water, up to 75% of the daily amount of fluoride

that is absorbed may be incorporated into skeletal tissue (US DHHS,

1991). When a fluoride dose (e.g., a fluoride tablet or an infant formula
Kinetics and Metabolism in Humans and Laboratory Animals

77

diluted with fluoridated drinking-water) is given to infants, the retention will be strongly correlated with the absorbed fluoride dose per

kilogram body weight: the higher the fluoride dose, the higher the

fluoride retention. Retention of fluoride following intake of a fluoride

supplement of 0.25 mg given to infants was shown to be as high as

80–90%. In a study with adults (aged 23–27 years) in which fluoride

was given as a single intravenous injection, about 60% of the injected

dose (3 mg fluoride as sodium fluoride) was retained (Ekstrand et al.,

1978). 

The selective affinity of fluoride for mineralized tissues is, in the

short term, due to uptake on the surfa ce of bone crystallites by the

processes of isoionic and heteroionic exchange.In the long run,fluoride is incorporated into the crystal lattice structure of teeth and skeletal

tissue by replacing some hydroxyl ions within the unit cells of

hydroxyapatite, producin g partially fluoridated hydroxyapatite (i.e.,

fluorapatite or fluorhydroxyapatite) (WHO, 1994).

Fluoride is not irreversibly bound to bone. This has been demonstrated in persons who had lived in an area with a high fluoride

concentration in the drinking-water and then moved to an area with a

low water fluoride level. The urinary fluoride conce ntration in these

individuals fell slowly for long periods, indicating that fluoride was

being mobilized continuously from the skeleton and subsequently

excreted (Hodge et al., 1970). Similar findings have been noted among

workers with chronic occupational exposure to fluoride who were

subsequently employed elsewhere (Boillat et al., 1979). Their plasma

fluoride levels reflectedtheirbone fluoride concentrations (based upon

iliac crest biopsies) for long periods (2–3 years) after the industrial

fluoride exposure had stopped.

The “balance” of fluoride in the body (i.e., the difference between

the amount of fluoride ingested and the amount offluoride excreted in

the urine and the faeces) can be positive or negative. When the

fluoride is derived fromhuman milk or cow’s milk, biologicalfluids with

a low fluoride content, urinary excretion generally exceeds intake (i.e.,

there is a negative fluoride balance). In infants, when fluoride intakes

are low,sufficient fluoride is released frombone to extracellular fluid to

result in urinary excretion being higher than intake (Ekstrand et al.,

1994).
EHC 227: Fluorides

78

Hence, the plasma concentrations and the urinary excretions

mirror a physiological balance that is determined by earlier fluoride

exposure, the degree of accumulation of the ion in bone, the mobilization rate from bone and the efficiency of the kidneys in excreting

fluoride.

6.2.4 Transplacental transfer

Human studies have shown that the placenta is not in any sense

a barrier to the passage of fluoride to the fetus. There is a direct relationship between the serum fluoride concentration of the mother and

that of the fetus; the cord serum concentration is 75% that of the

maternalfluoride concentration. Fromthe fetal blood,fluoride is readily

taken up by the calcifying fetal bones and teeth (Shen & Taves, 1974).

6.2.5 Fluoride levels in human tissues and organs

Information on the levels of fluoride in the tissues and organs of

individuals is summarized in Table 9. The concentration of fluoride in

the plasma of healthy individuals may range from 7.6 to 28.5 μg/litre

(Guy, 1979). The mean plasma level in 127 subjects with 5.03 mg

fluoride/litre in drinking-waterwas 106 ± 76 (SD) μg/litre (Li et al., 1995).

A study of 250 healthy individuals residing in Spain revealed levels of

fluoride in serum ranging from 1 to 47 μg/litre (Torra et al., 1998). 

Table 9. Concentration of fluoride in human tissues and organs

Tissue/organ Number of

samplesa

Concentrationb

(mean [range])

Reference

Whole blood nac na (20–60) μg/litre Kissa (1987)

Serum 1088 14.4 (na) μg/litre Kono et al. (1986)

Serum 250 17.4 (1–47)

μg/litre

Torra et al. (1998)

Plasma 72 14.3 (2.7–79.8)

μg/litre

Guy et al. (1976)

Urine na 780 (na) μg/litre Kono et al. (1986)

Saliva 98 8.74 (na) ng/g Schamschula et al.

(1985)

Tooth

enameld

na na (740 000–

2 100 000) ng/g

Berndt & Stearns

(1979)
Kinetics and Metabolism in Humans and Laboratory Animals

79

Table 9 (contd).

Tissue/organ Number of

samplesa

Concentrationb

(mean [range])

Reference

Iliac crest e 78 720 500

(106 000–

2 360 000) ng/g 

Alhava et al. (1980)

Iliac crestf 10 1 500 000 (na)

ng/g

Zipkin et al. (1960)

Ribf 9 1 600 000 (na)

ng/g

Zipkin et al. (1960)

Vertebraef 10 2 200 000 (na)

ng/g

Zipkin et al. (1960)

Hair 53 2505 (na) ng/g Tagaki et al. (1986)

Braing 7 31.2 (na) ng/g Taves et al. (1983)

Body fatg 5 28.5 (na) ng/g Taves et al. (1983)

Liverg 5 19.6 (na) ng/g Taves et al. (1983)

Muscleg 9 40.3 (na) ng/g Taves et al. (1983)

Lungg 9 71.4 (na) ng/g Taves et al. (1983)

Thymusg 4 9005.2 (na) ng/g Taves et al. (1983)

Aortag 8 4331.6 (na) ng/g Taves et al. (1983)

Kidneyg 9 159.2 (na) ng/g Taves et al. (1983)

Fingernails 22 8800 (na) ng/g Czarnowski &

Krechniak (1990)

Fingernails 6–9 na (1590–7570)

ng/g

Whitford et al.

(1999b)

a Total number of tissue samples analysed. 

b Mean and range of concentrations of fluoride in the tissues and organs of

individuals.

c na = not available.

d Samples of surface tooth enamel from adults 20 years of age. Samples were

taken from individuals consuming drinking-water containing up to 1 mg

fluoride/litre.

e Samples of iliac crest bone from adults (mean age 60 years). Samples were

taken from individuals consuming drinking-wate r containing up to 0.97 mg

fluoride/litre over a period of 14–18 years.

f Samples of bone from adults 26–90 years of age. Samples were taken from

individuals consuming drinking-water containing up to 1 mg fluoride/litre over

a period of 10–87 years.

g Tissues(analysed on a wet weight basis) were obtained from autopsiesof cases

of sudden death in the USA (mean age 29 years). Some tissue samples may

have been prepared with water containing 0.9–1 mg fluoride/litre.

Levels of fluoride in calcified tissues are generally highest in

bone, dentine and enamel, although they are highly variable,owing, at
EHC 227: Fluorides

80

least in part, to the methods of analysis used (Weidmann &

Weatherell, 1970). 

The concentration of fluoride in dental enamel decreases exponentially with the distance from the surface and varies with site, age,

surface attrition, systemic exposure and exposure to topically applied

fluoride (Weatherell et al., 1977; Schamschula et al., 1982). The average

concentration of fluoride in dentine is approximately 2- to 3-fold higher

than that in enamel and, like enamel, is higher in surface regions,

increases with age and is related to the levels of fluoride in the

drinking-water consumed (Weidmann & Weatherell, 1970; US NAS,

1971).

6.3 Elimination

Whitford et al. (1991) examined a number of pharmacokinetic

parameters (i.e., plasma, renal and extrarenal clearances) in mongrel

dogs, Sprague-Dawley rats, cats, rabbits and hamsters intravenously

administered a single dose (0.5 mg fluoride/kg body weight) ofsodium

fluoride and concluded that dogs mostresembled humans with respect

to their elimination of flu oride; plasma clearance rates were approximately 2-fold higher in rats than in dogs. 

6.3.1 Renal handling of fluoride

The majorroute for the removal of fluoride fromthe body is by the

kidneys.

The renal clearance of fluoride in the adult typically ranges from

30 to 50 ml/min, whereas clearance rates of the other halogens (chloride, iodide and bromide) are usually less than 1.0 ml/min. The percentage of the filtered fluoride reabsorbed fromthe renaltubules can range

from about 10 to 90%. The degree of reabsorption depends largely on

the pH of the tubular fluid, urinary flow and renalfunction (Ekstrand et

al., 1980, 1982; Whitford, 1996). The excretion of fluoride in urine is

reduced in individuals with impaired renal function (Schiffl & Binswanger, 1980; Spak et al., 1985; Kono et al., 1986).

6.3.2 Excretion via breast milk

The literature contains a wide range (0.1–5 μmol/litre) forfluoride

levels in breast milk. It is probable that problems with the analysis of

fluoride have been contributory. The concentration of fluoride in

colostrum and mature breast milk is reported to be the same — about
Kinetics and Metabolism in Humans and Laboratory Animals

81

0.4 μmol/litre (Spak et al., 1983). The same investigators found no

significant difference in fluoride concentrations of milk from mothers

living in areas with fluoride concentrations in drinking-water of 1 or 0.2

mg/litre, even though their plasma concentrations reflected this

difference.Further, they found no diurnal variation in the fluoride concentration (Spak et al., 1983). Studies of lactating mothers have shown

that there is a limited transfer of fluoride from plasma to breast milk

(Ekstrand et al., 1981). Dabeka et al. (1986), on the other hand,reported

that the concentration of fluoride in breast milk was related to the

fluoride content of the drinking-water consumed by the women; the

mean concentration of fluoride in breast milk obtained from 32 women

consuming drinking-water containing <0.16 mg fluoride/litre was

0.23 μmol/litre, whereas breast milk obtained from 112 women consuming drinking-water containing 1 mg fluoride/litre reportedly contained 0.48 μmol fluoride/litre. Concentrations of fluoride in samples of

breast milk collected in Finland (Esala et al., 1982) ranged from 0.1 to 2.7

μmol/litre.In the Finnish study, the fluoride in the milk (both ionic and

total fluoride) was measured after ashing the samples. Taves (1983)

showed no difference between inorganic (microdiffusion) and total

(ashing) fluoride in cow’s milk. Obviously, there is some uncer-tainty

as to whether there really is a non-ionic fraction of fluoride in milk or

whether the discrepancy is due to an analytical overestimation. 

The fluoride content of human breast milk represents the natural

daily fluoride intake during the first 6 months of life. This is especially

important when comparing the daily fluoride intake by formula-fed and

breast-fed infants.

6.3.3 Excretion via faeces, sweat and saliva

It is generally accepted that most of the fluoride in the faeces is

not absorbed. Faecalfluoride usually accounts forless than 10% of the

amount ingested each day (Ekstrand et al., 1984).

The quantitative role of sweating in fluoride balance studies has

not been explored using modern analyticalmethods in controlled studies. Based on some preliminary data from Henschler et al. (1975) on

predicted losses in workers whose urinary fluoride levels are about

5 mg/litre and who lose 6 litres of sweat containing 0.2–0.3 mg fluoride

during a shift, the sweat could account for approximately 5% of the

fluoride excreted.In tropical climates, during periods of prolonged and
EHC 227: Fluorides

82

heavy exercise or in occupational exposure to elevated temperatures,

the fluid loss from the body via sweat may approach as much as 4–6

litres a day.

The concentration of fluoride in saliva is about two-thirds of the

plasma fluoride concentration and seems to be independent of flow

rate, in contrast to the situation for most electrolytes (Ekstrand, 1977;

Oliveby et al., 1989; Whitford et al., 1999a). A diurnalfluctuation in the

saliva fluoride concentration is also seen in an area with fluoridated

drinking-water containing 1 mg fluoride/litre (Oliveby et al., 1990). The

levels of fluoride in saliva are important, because this potentially

provides further topical exposure of the teeth to fluoride.
83

7. EFFECTS ON LABORATORY MAMMALS AND

IN VITRO TEST SYSTEMS

7.1 Single exposure

LD50s forthe oral administration ofsodiumfluoride,sodiummonofluorophosphate and stannous fluoride (SnF2

) to rats include values of

31–101 mg fluoride/kg body weight, 75–102 mg fluoride/kg body

weight and 45.7 mg fluoride/kg body weight,respectively (IARC, 1982;

Whitford, 1987, 1990; ATSDR, 1993). LD50s for the oral administration

of sodium fluoride, sodium monofluorophosphate and stannous

fluoride to mice include values of 44.3 and 58 mg fluoride/kg body

weight, 54 and 94 mg fluoride/kg body weight and 25.5 and 31.2 mg

fluoride/kg body weight, respectively (IARC, 1982; Whitford, 1990).

The acute oralexposure of laboratory animals to fluoride produces

salivation, lacrimation, vomiting and diarrhoea, as well as respiratory

arrest and cardiac depression (WHO, 1984). 

Nephrotoxic effects produced in laboratory animals following

acute oral exposure to fluoride have been reviewed (WHO, 1984). Subsequent studies have indicated that the severity of the acute renal

toxicity ofsodiumfluoride in rats appears to be related to the age of the

animal. In a study in which single doses of sodiumfluoride (13.6 or 21.8

mg fluoride/kg body weight)were injected intraperitoneally into 1-, 8-,

15- or 29-day-old male and female Sprague-Dawley rats, proximal

tubular necrosis and marked changes in kidney weight, urine

osmolarity and pH, and chloride excretion were observed in the 29-dayold animals; effects in the younger animals were considered mild and

less severe (Daston et al., 1985).

In laboratory animals, adverse effects within the gastrointestinal

tract have been reported following the ingestion of acutely toxic doses

of fluoride. In a study in which solutions of 1, 10 and 50 mmol fluoride/litre (as sodium fluoride dissolved in 0.1 N HCl) were introduced

into the stomachs of anaesthetized female Wistar rats,

histopathological effects on the gastric mucosa (i.e., desquamation of

surface epithelial cells, cell loss and damage)were observed in animals
EHC 227: Fluorides

84

administered 10 and 50 mmol/litre within 30 min of exposure (Easmann

et al., 1984). Subsequently, Easmann et al. (1985) reported that

following intubation of Holtzman rats with 1.5 ml of 100 mmol sodium

fluoride/litre (approximately 17.8 mg fluoride/kg body weight),

histopathological effects (i.e., haemorrhage, disruption of epithelial

integrity and glandular structure, lysis and loss of epithelial cells)

within the gastric mucosa were observed. After 48 h, there was

recovery of gastric mucosal integrity.

Hydrogen fluoride is acutely toxic when administered via inhalation. LC50s ranging from 4065 to 14 400 mg fluoride/m3

have been

reported for the 5-min exposure of rats to hydrogen fluoride (WHO,

1984; ATSDR, 1993). An LC50 of approximately 1084 mg fluoride/m3has

been reported for the 60-min exposure of rats to hydrogen fluoride

(Rosenholtz et al., 1963). LC50s of approximately 5000 and 280 mg

fluoride/m3 have been reported for the 5- or 60-min exposure of mice to

hydrogen fluoride, respectively (WHO, 1984; ATSDR, 1993).

The inhalation exposure of laboratory animals to levels of hydrogen fluoride near the LC50 produces severe ocular and nasal irritation,

pulmonary congestion, oedema, respiratory distress and erythema of

the exposed skin (ATSDR, 1993). 

Direct exposure of the skin to hydrofluoric acid produced severe

burns and tissue damage,with the severity of these effects dependent

upon the length of the exposure and concentration (Derelanko et al.,

1985). The direct application of sodium fluoride (0.5 and 1.0% in

distilled water) to the abraded skin of rats produced effects ranging

from superficial necrosis to oedema and inflammation (Essman et al.,

1981).

Application of an aqueous solution of 2% sodium fluoride to the

eyes of rabbits caused corneal epithelial defects and necrosis in the

conjunctiva (Grant & Schuman, 1993). 

7.2 Short- and medium-term exposure

In short-term studies, survival was reduced in male and female

F344/N rats and in male, but not female, B6C3F1 mice administered
Effects on Laboratory Mammals and In Vitro Test Systems

85

drinking-water containing 363.2 mg fluoride/litre for a period of 14 days

(NTP, 1990). In other investigations, fluoride-induced effects on the

skeleton included inhibition of trabecular bone mineralization in female

Wistar rats administered drinking-water containing 113.5 or 136.2 mg

fluoride/litre for a period of 5 weeks (Harrison et al., 1984); inhibition of

endosteal bone formation and a reduction in cancellous bone volume

in male Holtzman rats administered drinking-water containing 85.5 mg

fluoride/litre for a period of 21 days (Turner et al., 1989); delayed

fracture healing and a reduction in collagen synthesis in male albino

rats receiving 14 mg fluoride/kg body weight per day for 30 days (Uslu,

1983); an increase in dermatan sulfate and chondroitin-6-sulfate in the

tibia of male Sprague-Dawley rats receiving 17.5 mg fluoride/kg body

weight per day for a period of 1–2 months (Prince & Navia, 1983); and

a 20% increase in bone matrixformation in male C57BL/6 mice receiving

0.8 mg fluoride/kg body weight per day for 4 weeks (Marie & Mott,

1986). Ultrastructural changes were observed in skeletalmuscle of male

Wistarrats administered drinking-watercontaining 100mg fluoride/litre

(as sodium fluoride) for 8 weeks (Pang et al., 1996).

Although male Swissmice administered (orally)5.2 mg fluoride/kg

body weight per day over a period of 35 days reportedly had reduced

red blood cell counts and numbers of lymphocytes (39%) and

increased numbers ofmonocytes, eosinophils and basophils compared

with controls (Pillai et al., 1988), the levels of red blood cells, lymphocytes, neutro p hils, monocytes and eosinophils in male B6C3F1 mice

receiving 8.1 mg fluoride/kg body weight per day (from drinking-water

for 24 weeks) were similar to those in controls receiving 0.6 mg

fluoride/kg body weight per day (NTP, 1990).

In medium-term exposure studies,femoralbone bending strength

was increased (approximately 38%)or decreased (approximately 20%)

in adult rats administered drinking-water containing 16 mg fluoride/litre

or 64–128 mg fluoride/litre, respectively, over a period of 16 weeks

(Turner et al., 1992). Vertebral bone quality (compression resistance

normalized for ash content) was reportedly reduced in female Wistar

rats administered drinking-water containing 100 or 150 mg fluoride/litre

for a period of 90 days (Søgaard et al., 1995). Altered bone remodelling,

based on thickening of the osteoid seams in the tibia and femur, was

observed in male and female B6C3F1 mice administered drinking-water

containing $22.7 and 45.4 mg fluoride/litre, respectively, over a period

of 6 months (NTP, 1990).
EHC 227: Fluorides

86

Compared with unexposed controls, other effects observed in

animals administered drinking-water containing added fluoride for

6 months included hyperplasia of the stomach and pathological effects

(i.e., lymphocytic infiltration, hyperplasia, necrosis) in the glandular

stomach of F344/N rats administered drinking-water containing 45.4

and 136 mg fluoride/litre, respectively (NTP, 1990); and reduced survival (82% and 44% in female and male B6C3F1 mice, respectively),

hepatic megalocytosis, renal nephrosis, mineralization of the myocardium, necrosis and/or degeneration of the seminiferous tubules in the

testis of B6C3F1 mice receiving drinking-water containing 272.4 mg

fluoride/litre (NTP, 1990).

The daily intragastric administration of 22.7 mg fluoride/kg body

weight per day (as sodium fluoride) to rabbits for 136 days interfered

with the maturation and metabolism of collagen (Sharma, 1982a). 

7.3 Long-term exposure and carcinogenicity

In early carcinogenicity bioassays conducted by Tannenbaum &

Silverstone (1949), Taylor(1954) and Kanisawa &Schroeder(1969), the

incidence of tumours in mice administered sodium fluoride (in either

their diet or drinking-water) was, in general, not markedly greater than

that observed in the unexposed controls.However, the documentation

and protocols of these studies were inadequate. Deficiencies in design

included small groups of animals of single sexes or various ages

exposed to single dose levels for short periods of time with inadequate

examination of possible target tissues.

In a comprehensive study of the carcinogenicity ofsodiumfluoride in laboratory animals (NTP, 1990), groups of male and female

F344/N rats were administered drinking-water containing 0, 25, 100 or

175 mg sodium fluoride/litre (0, 11, 45 and 79 mg fluoride/litre) for a

period of 2 years. There were 100 rats in each of the control and

175 mg/litre groups, while 70 rats pergroup were administered drinkingwater containing 25 or 100 mg sodium fluoride/litre. Groups of 10 rats

of each sex at each level of exposure were sacrificed after 27 and 66

weeks.In the high-dose group, 42 males and 54 females survived until

terminalsacrifice.The estimated total intakes of fluoride from food and

drinking-water by the male and female F344/N rats administered

drinking-water containing 0 (control), 25, 100 or 175 mg sodium 
Effects on Laboratory Mammals and In Vitro Test Systems

87

fluoride/litre were approximately 0.2, 0.8, 2.5 and 4.1 mg/kg body weight

per day and 0.2, 0.8, 2.7 and 4.5 mg/kg body weight per day,

respectively. A t the end of the 2-year study, the levels of fluoride in

the humeral bone of the control, low-, mid- and high-dose male and

female rats were approximately 0.44, 0.98, 3.65 and 5.26 μg/mg bone ash

and 0.55, 1.34, 3.72 and 5.55 μg/mg bone ash, respectively (NTP, 1990).

In male F344/N rats receiving 0.2, 0.8, 2.5 or 4.1 mg fluoride/kg

body weight per day, the incidence of osteosarcomas (three tumours

in the vertebra and one in the humerus) was 0/80, 0/51, 1/50 and 3/80,

respectively (NTP, 1990). A pairwisecomparison of the incidence in the

high-dose group versus controls was not statistically significant (P =

0.099); if an extraskeletal osteosarcoma, located in the subcutis of the

flank of one high-dose male rat, was included in the total tumour

incidence in this group of animals, the pairwise comparison with the

control group remained statistically insignificant (P = 0.057). However,

the osteosarcomas occurred with a statistically significant (P = 0.027,

by logistic regression) dose–response trend (NTP, 1990). The incidence of osteosarcoma at any site was within the range of historical

controls; however, the amount of fluoride in the diets in previous

National Toxicology Program (NTP) studies of other chemicals was

uncontrolled and was estimated to be approximately 3.5- to 5.9-fold

higher than in the NTP sodium fluoride study (NTP, 1990). In male

F344/N rats receiving 0.2, 0.8, 2.5 or 4.1 mg fluoride/kg body weight per

day, the incidence of oral cavity lesions (squamous papillomas or

squamous cell carcinomas)was 0/80, 1/51, 2/50 and 3/80, respectively;

the incidence in the fluoride-exposed groups was not significantly

different from the controls and was not considered to be compoundrelated.The incidence of (thyroid gland)follicularcell tumours (adenomas and carcinomas) was 1/80, 1/51, 1/50 and 4/80 in the control, low-,

medium- and high-dosemales,respectively; the incidence in the highdose group was not significantly different from controls and was not

considered to be compound-related. There was no increase in the

incidence of osteosarcomas in female F344/N rats receiving fluoride;

the incidence of oral cavity neoplasms (squamous papillomas or squamous cell carcinomas) was 1/80, 1/50, 1/50 and 3/81 in female F344/N

rats receiving 0.2, 0.8, 2.7 and 4.5 mg/kg body weight per day, respectively; the incidence in the high-dose group was not significantly

different from the controls (NTP, 1990).
EHC 227: Fluorides

88

In the NTP carcinogenicity bioassay with male and female F344/N

rats, no significant compound-related effects upon survival, body

weight or weights of major internal organs were observed, compared

with controls (NTP, 1990); however, the incidence of osteosclerosis in

female rats administered drinking-water containing 175 mg sodium

fluoride/litre (18/81) was significantly (P = 0.04) increased, compared

with controls (6/80) (NTP, 1990). It was concluded (NTP, 1990) that the

osteosarcoma finding was “equivocal evidence of carcinogenic

activity” in male rats, and that there was “no evidence of carcinogenic

activity” in the female rats exposed to fluoride underthese conditions.

In a carcinogenicity bioassay conducted with Sprague-Dawley

rats, groups of 70 animals of each sex were administered diets supplemented with various amounts of sodium fluoride for a period of 95–

99 weeks (Maurer et al., 1990). The estimated total intake of fluoride by

these groups of animals was 0.1, 1.8, 4.5 or 11.3 mg/kg body weight per

day, respectively. After 26 weeks on study, as many as 10 animals of

each sex per group were sacrificed, and after 53 weeks, 10 animals of

each sex per group were sacrificed (Maurer et al., 1990). At terminal

sacrifice (i.e., after 95 and 99 weeks on study for males and females,

respectively), there were 26 males and 12 females remaining in the highdose groups. A t study termination,the concentration of fluoride in the

bone (radius and ulna) of the males and females receiving 0.1, 1.8, 4.5

or 11.3 mg fluoride/kg body weight per day was 0.5, 5.0, 8.8 and 16.7

μg/mg bone ash and 0.5, 4.5, 8.3 and 14.4 μg/mg bone ash, respectively.

In this study, the incidence of bone tumours was 0/70, 0/58, 2/70

(one chordoma and one chondroma) and 1/70 (fibroblastic sarcoma

with areas of osteoid formation) in male rats and 0/70, 2/52 (one

osteosarcoma and one chondroma), 0/70 and 0/70 in female rats

receiving 0.1, 1.8, 4.5 and 11.3 mg fluoride/kg body weight per day,

respectively (Maurer et al., 1990). However, detailed information on the

incidence of tumours in tissues or organs other than the bone and

stomach were not presented, and histologicalexamination of bone from

both mid-dose groups was limited. The cranium, femur, premaxilla,

maxilla, mandible, cervical vertebra, stomach, liver, kidney, incisors,

adrenals, brain, heart, lungs, ovaries, uterus, pancreas, pituitary, prostate, seminal vesicles, spleen, bladder, testes, epididymides, thyroids

and parathyroids obtained at the interim and terminalsacrifices fromall

animals receiving 0.1 or 11.3 mg fluoride/kg body weight per day were
Effects on Laboratory Mammals and In Vitro Test Systems

89

examined microscopically.The stomach, bones and teeth from animals

receiving 4.5 mg fluoride/kg body weight per day and sacrificed after

26 weeks and from animals receiving 1.8 or 4.5 mg fluoride/kg body

weight per day and sacrificed after 53 weeks were also examined

microscopically. Not all of the bones (i.e., cranium, femur, premaxilla,

maxilla,mandible, cervical vertebra) fromeach of the remaining animals

(i.e., those alive after the interim sacrifices) receiving 1.8 or 4.5 mg

fluoride/kg body weight per day were examined microscopically;

however, tissues with gross lesions obtained from dead and moribund

animals were evaluated.

Sprague-Dawley rats receiving 11.3 mg fluoride/kg body weight

per day (administered in the diet) over a period of 95–99 weeks had

reduced weight gain; animals receiving 4.5 or 11.3 mg fluoride/kg body

weight per day had an increased incidence of subperiosteal hyperostosis in the skull and hyperkeratosis and acanthosis in the stomach,

compared with controls receiving 0.1 mg/kg body weight per day

(Maurer et al., 1990).

In the NTP (1990) carcinogenicity bioassay, male and female

B6C3F1 mice were also administered drinking-water containing 0, 25,

100 or 175 mg sodiumfluoride/litre (0, 11, 45 and 79 mg fluoride/litre)for

2 years. There were 100 animals in each of the control and 175 mg/litre

groups, and 70 mice per group were administered drinking-water

c ontaining 25 or 100 mg sodium fluoride/litre; the total intake of

fluoride from water and the diet for the males and females in these

groups was estimated to be approximately 0.6, 1.7, 4.9 and 8.1 mg/kg

body weight per day and 0.6, 1.9, 5.7 and 9.1 mg/kg body weight per

day,respectively.A t the end of the 2-year study (groups of 10 animals

of each sex at each level of exposure were sacrificed after 24 and

66 weeks), the levels of fluoride in the humeral bone of the control, low-

, mid- and high-dose male and female mice were approximately 0.72,

1.61, 3.58 and 5.69 μg/mg bone ash and 0.92, 1.52, 4.37 and 6.24 μg/mg

bone ash, respectively (NTP, 1990).

In male B6C3F1 mice receiving 0.6, 1.7, 4.9 or 8.1 mg fluoride/kg

body weight per day, the incidence of hepatoblastoma was 0/79, 1/50,

1/51 and 3/80, respectively (NTP, 1990). The overall incidence of

hepatic neoplasms (adenoma, carcinoma, hepatoblastoma)was similar

among all groups, and the incidence of liver tumours in all groups

(control and exposed) of male mice(73–78%)was higherthan observed
EHC 227: Fluorides

90

(16–58%) in previous NTP carcinogenicity bioassays (NTP, 1990). In

female B6C3F1 mice receiving 0.6, 1.9, 5.7 or 9.1 mg fluoride/kg body

weight per day, the incidence of hepatoblastoma was 0/80, 1/52, 0/50

and 2/80, respectively. The overall incidence of hepatic neoplasms

(adenoma, carcinoma, hepatoblastoma) was similar among all groups,

and the incidence oflivertumours in all groups (control and exposed)

offemale mice (52–69%)was higherthan observed (3–20%)in previous

NTP carcinogenicity bioassays (NTP, 1990). The incidence of

malignant lymphoma was 11/80, 5/52, 11/50 and 19/80 (P = 0.051),

respectively. The incidence of malignant lymphoma in the control and

low-dose groups was less than the lowest incidence observed in nine

otherinvestigations conducted atthe study laboratory.In addition,the

incidence in the high-dose group was less than the average incidence

observed in historical controls (35%) and within the range of incidence

observed in historical controls (10–74%) (NTP, 1990).

The administration of drinking-water containing 25, 100 or 175 mg

sodium fluoride/litre to male or female B6C3F1 mice over a period of 2

years had no significant compound-related adverse effects upon

survival, body weight or weights of major internal organs, compared

with controls (NTP, 1990). It was concluded (NTP, 1990) that there was

“no evidence of carcinogenic activity” in male and female mice exposed

to fluoride under these conditions.

In a carcinogenicity bioassay in which sodiumfluoride was administered in the diet to groups of 60 male and 60 female CD-1 mice over a

period of 95 and 97 weeks, respectively (10 mice of each sex per group

were sacrificed after 40 weeks), the incidence of osteomas in male and

female controls and mice receiving 1.8, 4.5 or 11.3 mg fluoride/kg body

weight per day was 1/50, 0/42, 2/44 and 13/50 and 2/50, 4/42, 2/44 and

13/50, respectively (no statistical analysis provided) (Maurer et al.,

1993). The incidence of this type of tumour was increased in the highdose groups compared with the controls. These animals were infected

with a Type C retrovirus, and the role of fluoride in the etiology of

these tumours is not clear (Maurer et al., 1993). Moreover, there is

some contro versy concerning whether they should be classified as

neoplasms (US NRC, 1993). The concentration of fluoride in the bone

(radius or ulna) of male controls and mice receiving 1.8, 4.5 or 11.3 mg

fluoride/kg body weight per day was approximately 1.5, 4.4, 7.2 and 13.2

μg/mg bone ash, respectively; the concentration of fluoride in the

(radius or ulna) bone of female controls and mice receiving 1.8, 4.5 or
Effects on Laboratory Mammals and In Vitro Test Systems

91

11.3 mg fluoride/kg body weight per day was approximately 1.0, 3.4, 6.2

and 10.6 μg/mg bone ash, respectively.

In studies on non-neoplastic effects associated with the chronic

toxicity of fluoride, bone mineralization (based on mic roscopic analysis) was inhibited in male and female rats administered drinking-water

containing 22.7 and 36.3 mg fluoride/litre (as sodium fluoride) for a

period of 250 days (Qiu et al., 1987). Femoral bone strength was

reduced in male Sprague-Dawley rats administered drinking-watercontaining 50 mg fluoride/litre for 18 months (Turner et al., 1995). Compared with controls, the oral administration of a single dose of 4.5 mg

fluoride/kg body weight per day (as sodium fluoride) to rabbits for

periods ranging from 6 to 24 months produced slight alterations in

ATPase (sodium and potassium) activity within erythrocytes, the

activity of serum acid and alkaline phosphatase (Jain & Susheela,

1987a), the levels of dermatan sulfate, chondroitin-4-sulfate an d

chondroitin-6-sulfate in cancellous bone (Sharma & Susheela, 1988a),

the number of haematopoietic cells in the blood (Susheela & Jain, 1983)

and the disaccharide content of glycosaminoglycans isolated from

cancellous bone (Sharma & Susheela, 1988b).

Evidence of mineralization of the aorta (Susheela & Kharb, 1990),

morphological changes within the duodenum (Susheela & Das, 1988)

and renal glomerulus (Bhatnagar & Susheela, 1998), and alterations in

skin collagen metabolism (Sharma,1982b)have also been observed in

rabbits administered 4.5 mg fluoride/kg body weight per day for periods ranging from6 to 24 months. Other effects produced following the

long-term exposure of rabbits to this dose of fluoride included alterations in the proportion of erythrocytes with abnormal morphology

(Susheela & Jain, 1986), the level of cortisol and corticosterone in the

plasma (Das & Susheela, 1991), the level of sialic acid and glycosaminoglycans in the serum (Jha et al., 1982) and the amount of

hydroxyproline present in collagen derived from tendons and cortical

bone (Susheela & Sharma, 1982).

Alterations in bone remodelling (based on histomorphometric

analysis) have been observed in pigs (Mosekilde et al., 1987;

Kragstrup et al., 1989) administered (orally) 2 mg fluoride/kg body

weight per day (as sodium fluoride) and dogs (Snow & Anderson,

1986)receiving 0.32 mg fluoride/kg body weight per day (fromdrinkingwater containing sodium fluoride) over a period of 6 months.
EHC 227: Fluorides

92

7.4 Mutagenicity and related end-points

7.4.1 In vitro genotoxicity

The genotoxicity of fluoride has been examined in a large number

of in vitro and in vivo assays, in which a wide range of end-points has

been assessed. Since publication of the firstEHCdocument on fluoride

(WHO, 1984), the results froma number ofstudies have confirmed that,

in general, fluoride is not mutagenic in prokaryotic cells (Li et al., 1987a;

Tong et al., 1988; NTP, 1990; Zeiger et al., 1993); however, Ahn &

Jeffery (1994) reported no significant uptake of fluoride into S.

typhimurium TA98 cells. 

Fluoride has been shown to increase the frequency of mutations

at the thymidine kinase locus in cultured mouse lymphoma and human

lymphoblastoid cells (Cole et al.,1986; Caspary et al., 1987, 1988; Crespi

et al., 1990). In the studies by Cole et al. (1986) and Caspary et al.

(1987), exposure to sodium fluoride produced a preferentialincrease in

the frequency of “small mutant colonies,” a phenomenon generally

associated with chromosomal damage rather than point mutations

(Moore et al., 1985). Indeed, the failure of sodium fluoride to increase

the frequency of cells resistant to ouabain (which is produced only by

a specific point mutation within the Na+, K

+

-ATPase gene locus) (Cole

et al., 1986) is consistent with this result. In human lymphoblastoid

cells, the mutagenic response at the thymidine kinase locus following

a 20-day exposure to sodium fluoride was non-linear and lower than

predicted from extrapolation of the 28-h exposure data, a result

suggested to be indicative of a threshold for the mutagenicity of

(sodium) fluoride at concentrations above 50 mg/litre (Crespi et al.,

1990). Sodium fluoride did not increase the frequency of mutations at

the hypoxanthine–guanine phosphoribosyl transferase locus in rat

liver epithelial cells (Tong et al., 1988), Chinese hamster ovary cells

(Oberly et al., 1990) or Chinese hamster lung cells exposed under

neutral (Slamenova et al., 1992) or acidic (Slamenova et al., 1996)

conditions.

Sodium fluoride was clastogenic in many, but not all, in vitro

cytogenetic assays. The frequency of chromosomal aberrations was

increased (compared with unexposed controls) following exposure of

Chinese hamster lung (Don) cells (Bale & Mathew, 1987), Chinese

hamster ovary cells (Aardema et al., 1989a; NTP, 1990), Syrian hamster
Effects on Laboratory Mammals and In Vitro Test Systems

93

embryo cells (Tsutsui et al., 1984a), rat vertebral body-derived cells

(Mihashi& Tsutsui, 1996), rat bone marrow cells (Khalil, 1995), human

leukocytes (Jachimczak & Skotarczak, 1978), human peripheral blood

lymphocytes (Kishi & Tonomura, 1984; Albanese, 1987), human

fibroblasts (Tsutsui et al., 1984b; Scott, 1986; Scott & Roberts, 1987;

Suzuki & Tsutsui, 1989), human amnion (F1) cells (Aliev et al., 1988),

human and chimpanzee lymphoid cells (Kishi & Ishida, 1993) and

human oral keratinocytes (Tsutsui et al., 1991) to sodiumfluoride. The

chromosomal aberrations induced by sodium fluoride consisted primarily of breaks/deletions and gaps, with very few exchanges. No

significant increase in chromosomal aberrations was observed in

human fibroblasts,Chinese hamster ovary cells or human diploid lung

cells exposed to sodium fluoride at concentra tions at or below

10 mg/litre (Scott, 1986; Scott & Roberts, 1987; Aardema et al., 1989a;

Oguro et al., 1995; Tsutsui et al., 1995) orin Chinese hamsterlung cells

at concentrations at or below 500 mg/litre (Ishidate, 1987). 

Although no increase in the frequency of chromosomal

aberrations was observed in human lymphocytes exposed to fluoride

(Gebhart et al., 1984; Thomson et al., 1985; Gadhia & Joseph, 1997),

these results are likely attributable to a number of variables related to

the methodology used to assess clastogenic activity (i.e., the method

of classifying chromosomal aberrations, phase of the cell cycle during

which the cells were exposed and the concentration of fluoride). The

pattern of induced chromosomal aberrations, the increased formation

of endoreduplicated cells (Aardema et al., 1989a, 1989b), the increased

delay in the cell cycle and the increased sensitivity of cells in the G2

phase to sodium fluoride are all consistent with a mechanism of

clastogenicity involving an inhibition of DNA synthesis and/orrepair,

and it has been suggested that the effect of fluoride is upon the

synthesis of proteins involved in DNA synthesis and/or repair rather

than involving direct interaction between fluoride and DNA.

Although no increase in sister chromatid exchange was reported

following the exposure of human peripheral blood lymphocytes (Kishi

& Tonomura, 1984; Thomson et al., 1985; Tong et al., 1988; Gadhia &

Joseph, 1997) and Chinese hamster ovary cells (Li et al., 1987b; Tong

et al., 1988) or rat bone marrow cells (Khalil and Da’dara, 1994) to

sodium fluoride, increased sister chromatid exchange was observed in

Syrianhamster embryo cells (Tsutsui et al., 1984a)and Chinesehamster

ovary cells (NTP, 1990) exposed to sodium fluoride. Differences in

harvest times used to accommodate cell cycle delay may be, at least in
EHC 227: Fluorides

94

part, responsible forthe inconsistency in the results observed for the

induction of sister chromatid exchange by fluoride.

Although the results ofsome studies have indicated that(sodium)

fluoride increases unscheduled DNA synthesis in Syrian hamster

embryo cells, human foreskin fibroblasts and human keratinocytes

(Tsutsui et al., 1984a, 1984b, 1984c), Skare et al. (1986a)suggested that

these results might be an artefact, possibly due to the formation of

precipitable complexes of magnesium, fluoride and [3H]thymidine

triphosphate.

Sodium fluoride has been reported to induce the morphological

transformation of Syrian hamster embryo cells (Tsutsui et al., 1984a;

Jones et al., 1988a,1988b; Lasne et al., 1988), but not murine BALB/3T3

embryo cells (Lasne et al., 1988).

With sodium monofluorophosphate, both negative and positive

results on cytogenetic change (mostly chromosomal aberrations) in

human lymphocytes and leukocytes have been reported, without a

clear explanation for why some studies were negative and others

positive (Zeiger et al., 1993).

Fluoride induces chromosomal aberrations in several plant

species, including onions (Allium spp.), broadbean (Vicia faba) and

barley (Hordeum vulgare) (Zeiger et al., 1993).

7.4.2 In vivo genotoxicity

Sodiumfluoridewas reported to induce recessive lethalmutations

in the germ cells of male fruitfly (Drosophila melanogaster) (Dominok

& Miller, 1990). The results of studies on the genotoxic potential of

fluoride following its in vivo administration to laboratory animals have

varied, principally depending upon the route of administration.

Sodium fluoride induced cytogenetic damage in bone marrow or

sperm cells (i.e., chromosomal aberrations, micronuclei, alterations in

sperm morphology) when administered to rodents by intraperitoneal

injection (Ma et al., 1986; Pati & Bhunya, 1987); negative results have,

however, also been reported (Hayashi et al., 1988). While some positive

results have been reported (Akhundow et al., 1981; Aliev & Babaev,

1981; Mohammed & Chandler, 1982; M a et al., 1986; Pati & Bhunya,

1987), in most studies in which (sodium) fluoride was administered
Effects on Laboratory Mammals and In Vitro Test Systems

95

orally (either acutely or chronically) to rodents, there was no effect

upon sperm morphology or the frequency of chromosomal aberrations,

micronuclei,sister chromatid exchange or DNA strand breaks (Martin

et al., 1979; Skare et al., 1986b; Albanese, 1987; Li et al., 1987b, 1987c,

1987d, 1989; Pillai et al., 1988; Dunipace et al., 1989, 1998; Lu et al.,

1989; Zeiger et al., 1994).

After administration of sodium monofluorophosphate,

cytogenetic studies have also mostly given negative results

(Voroshilin et al., 1973; Gocke et al., 1981; Albanese, 1987; Li et al.,

1987b, 1989; Hayashi et al., 1988).

7.5 Reproductive toxicity

No evidence of pregnancy or implantation of embryos within the

uterus was observed in female mice administered (orally) $5.2 mg

fluoride/kg body weight per day on days 6–15 after mating (Pillai et al.,

1989), although few experimental details were provided.Reductions in

fertility have been observed in male rabbits administered (orally) $9.1

mg fluoride/kg body weight per day and in male mice given 4.5 mg

fluoride/kg body weight per day for 30 days (Chinoy et al., 1991;

Chinoy & Sharma, 1998). Histopathological changes within the organs

of the reproductive system have been observed in the testes of male

rabbits administered (orally)4.5 mg fluoride/kg body weight per day for

18–29 months (Susheela & Kumar, 1991), in the ovaries of female

rabbits injected subcutaneously with $10 mg fluoride/kg body weight

per day for 100 days (Shashi, 1990) and in the testes of male mice

administered (orally) $4.5 mg fluoride/kg body weight per day for 30

days (Chinoy & Sequeira, 1989a, 1989b). Sperm motility and viability

were reduced in rats and mice administered 4.5 mg fluoride/kg body

weight per day (as sodium fluoride) orally for 30 days (Chinoy et al.,

1995; Chinoy & Sharma, 1998). A single injection of sodium fluoride

(0.05 ml of a solution containing 250 mg sodium fluoride/litre;

equivalent to an injection of approximately 5.6 μg fluoride)directly into

the testes of male Sprague-Dawley rats reportedly had no significant

effect upon the morphology of this organ (Sprando et al., 1996).

Sprando et al. (1997) also reported that spermatogenic effects (e.g.,

sperm count, testes weight, histopathology) and endocrine effects

(serum testosterone, luteinizing hormone and follicle stimulating 
EHC 227: Fluorides

96

hormone) were not observed in rats administered drinking-water containing 0, 25, 100, 175 or 200 mg sodium fluoride/litre for 14 weeks or in

their F1 offspring exposed in utero and after parturition to fluoride. In

a follow-up study, morphometric analysis revealed no changes in the

testes of F1rats exposed in utero and after birth to similar levels of

fluoride in drinking-water (Sprando et al., 1998). 

In an older multigeneration study conducted with female SwissWebster mice administered a low-fluoride diet and drinking-water

containing 0, 50, 100 or 200 mg fluoride/litre, reproductive function

appeared normal in the group receiving drinking-water supplemented

with 50 mg fluoride/litre, based on litter production, infertility proportions, age at delivery of first litter, time interval between litters and

frequency of postpartum conception; maternal toxicity and impaired

reproduction were observed at higher doses (Messer et al., 1973). Tao

& Suttie (1976) reported that various parameters of reproductive

function (i.e., reproduction rate, litter size and weight) were not significantly different in female Webster mice administered diets containing

either <0.5 or approximately 2 or 100 mg fluoride/kg for up to three

generations. In an investigation in which rats were fed dog food containing high fluoride levels (56 or 460 mg fluoride/kg), no adverse

reproductive effects were observed; however, there was uncertainty

about the precise dose of fluoride due to a lack of data on the intake

and bioavailability of fluoride in the diet (Marks et al., 1984). Although

significant bone resorption was observed in breeding female rats

exposed to drinking-water containing 150 mg fluoride/litre (as sodium

fluoride) prior to breeding, during pregnancy and during lactation, no

effects were observed in the bones of weanling pups from these

females (Ream et al., 1983a, 1983b). 

Adverse effects on fetal development were not observed in a

study conducted with Charles Riverrats, in which dams received up to

approximately 25 mg fluoride/kg body weight per day from drinkingwater on days 0–20 of gestation (Collins et al., 1995). Fetal

development was similarin a study in which pregnant CD rats and New

Zealand White rabbits were administered drinking-water containing

sodium fluoride on days 6 through 15 and 6 through 19 of gestation,

respectively, at concentrations up to 300 and 400 mg/litre,respectively

(Heindel et al., 1996). In this study, the total intake of fluoride fromfeed

and drinking-water(and intake of fluoride from feed alone) for the rats
Effects on Laboratory Mammals and In Vitro Test Systems

97

and rabbits in the highest exposure groups was approximately 13.2 (1.0)

and 13.7 (0.7) mg/kg body weight per day, respectively.

7.6 Immunotoxicity

Compared with controls, T-cell mitogenesis was significantly

increased (84%) while B-cell activity (antibody production) was significantly reduced (10%) in female C57BL/6N mice administered (intragastrically) 13.6 mg fluoride/kg body weight per day (as sodium

fluoride dissolved in distilled water) for 10 weeks (Sein, 1988). Antibody production was also inhibited in female rabbits administered

(orally) 4.5 mg fluoride/kg body weight per day over a 6- to 9-month

period (Jain & Susheela, 1987b). Evidence of fluoride’s activity as a gut

and systemic adjuvant was presented by Butler et al. (1990), based

upon the results of a study in which rats were administered (intragastrically) 5 ml of a 100 mmol/litre solution ofsodium fluoride twice a

week for 2–3weeks and given an antigen (ovalbumin)in their drinkingwater.

7.7 Mechanisms of action

Tissue- or organ-specific effects linked with repeated exposure to

fluorides may involve metabolic pathways associated withlipid, carbohydrate, bone and energy metabolism, as well as signal transduction

pathways (Kaminsky et al., 1990). Fluoride influences a number of

enzymatic activities. The results of studies carried out in vitro have

indicated that fluoride inhibits the synthesis of DNA and protein,

inhibits cell proliferation and is cytotoxic in sufficiently high doses

(Gilman, 1987; Elsair & Khelfat, 1988; Godfrey & Watson, 1988;

Kaminsky et al., 1990). Effects produced by the exposure of laboratory

animals and humans to fluoride may be attributable to one or more of

these metabolic and biochemical effects. The stimulatory effect of

fluoride on osteoblast proliferation may proceed, at least in part,

through the inhibition of phosphotyrosyl protein phosphatases

(Thomas et al., 1996; Lau & Baylink, 1998). 

7.8 Interaction with other substances

In a study designed to assess the effects of fluoride on aluminium

distribution and toxicity, Stevens et al. (1987) reported that while the 
EHC 227: Fluorides

98

concurrent administration of 1 mg fluoride/day (as sodium fluoride) to

male Sprague-Dawley rats receiving 0.5 mg aluminium/day (as aluminium chloride) (both compounds administered by subcutaneous injection) ove r a period of 30 days increased the amount of aluminium

deposited in the liver (3.7-fold,P < 0.005),spleen (2-fold,P < 0.005) and

adrenal glands (1.6-fold, P < 0.05) compared with animals receiving

aluminium alone, the co-administration of fluoride had no effect upon

the amount of aluminiumdeposited in the brain. Deficits in some tests

of open field behaviour as well as reductions in body weight gain were

greater in animals co-administered fluoride and aluminium than in

animals administered either alone. 

In a study conducted by Ahn et al. (1995) in which groups of male

New Zealand rabbits were administered drinking-water containing 0–50

mg fluoride/litre (as sodium fluoride), 0–500 mg aluminium/litre (as

aluminium chloride) or both combined for a period of 10 weeks, the

accumulation of aluminiumin the liverwas not significantly affected by

the concurrent consumption of fluoride.However, the accumulation of

aluminium in the tibia (which was not influenced by the addition of

aluminium to the drinking-water) was increased when the drinkingwater contained 50 mg fluoride/litre.The accumulation of fluoride in the

teeth and bone (tibia) was reduced with the concurrent consumption

of aluminium. The aluminium content of the sterna of high-dose and

control rats from the NTP (1990) sodium fluoride study described

above (see sections 7.2 and 7.3) was also measured and found to be

approximately 8-fold higher in rats receiving 79 mg fluoride/litre in

drinking-water than in controls receiving deionized water (Ahn et al.,

1995).

The level of aluminium in the brains of male Long-Evans rats

given laboratory chow and distilled water or distilled water containing

2.1 mg sodium fluoride/litre or 0.5 mg aluminium fluoride/litre for

52 weeks was reported to be approximately 2-fold higherin the sodium

fluoride group and about 2.5 higher in the aluminium fluoride group

than in animals given the same feed and distilled water for drinking.

There was significant mortality in the aluminiumfluoride group. In the

kidney, there was no increased aluminiumin the sodiumfluoride group

but about twice as much in the aluminium fluoride group. Levels in the

liverwere not different between the three groups. Pathology studies of

the brain revealed increased neuronal abnormalities in both fluorideexposed groups in parts of the right and left hemispheres, alterations
Effects on Laboratory Mammals and In Vitro Test Systems

99

in the neuronal density in the left hemisphere and alterations of $-

amyloid, amyloid A and IgM in various parts of the brain (Varner et al.,

1998). In an earlier study, the authors reported greater mortality and

effects at the dose of aluminium fluoride used in this study than at 10-

and 100-fold greater levels of aluminum fluoride.No dose–response in

changes in the brain was apparent (Varner et al., 1993).

In a study on the neurotoxicity ofsodiumfluoride in rats (Mullenix

et al., 1995), changes in behaviour were monitored in groups of

Sprague-Dawley rats after exposure to fluoride at three different experimental stages. A number of behavioural patterns were examined, and

pairs of control and experimental animals were observed at the same

time. Some of the statistical methods were not fully described. In the

first group, dams were administered subcutaneous injections of

0.13 mg sodium fluoride/kg on gestation days 14–18 or 17–19, 2–

3 times daily. Nine weeks after delivery, they were examined, and

measures of time–structure changes were depressed in exposed

animals compared with controls. The second group was exposed to 0,

75, 100, 125 or 175 mg fluoride/litre in their drinking-water for 6 or 20

weeks immediately after weaning. The top group was discontinued

because of mortality and dehydration, and the second top group

showed significant deficits in body weight. Plasma fluoride was

elevated over controls in all groups, and low-level behavioural effects

from noise were correlated with plasma fluoride levels but not dose.

Some specific behavioural changes compared with controls were

reported for 100 and 125 mg/litre females and 125 mg/litre males, but

there was considera ble variation in the controls, and data for some

dose groups were not reported. Plasma fluoride did not show a

dose–response trend. The third group was given 0 or 100 mg

fluoride/litre in drinking-water for 5–6 weeks. Testing after 10 weeks

was reported to show a depression in low-level behavioural effects in

females but not males.It is difficult to interpret the results of this study

without more detailed analysis of the data, some of which are not

presented; consequently, the significance of these data remains

uncertain.
1 Gastrointestinal effects linked to longer-term exposure to fluoride

have been reported in some older studies of occupationally exposed

workers (effects included gastritis, duodenal ulcers, abdominal

distention, nausea) (see US DHHS, 1991; ATSDR, 1993) and observed

100

8. EFFECTS ON HUMANS

8.1 General population

8.1.1 Acute toxicity

Acute oral exposure to fluoride may produce effects including

nausea, vomiting, abdominal pain, diarrhoea, fatigue, drowsiness,

coma, convulsions, cardiac arrest and death (Kaminsky et al., 1990;

Whitford, 1990; Augenstein et al., 1991; ATSDR, 1993). Severe tissue

damage, respiratory effects, cardiac arrest and deaths have been noted

in case reports of individuals exposed accidentally to hydrofluoric acid

through dermal contact (Buckingham, 1988; Upfal & Doyle, 1990;

Bordelon et al., 1993). 

The lethal dose of sodium fluoride to the average adult has been

estimated to be between 5 and 10 g (32–64 mg fluoride/kg body

weight); an acute dose of 5 mg fluoride/kg body weight has been considered to be the minimum that might lead to adverse health effects

(Whitford, 1996). Gessner et al. (1994) reported the case of a death due

to acute fluoride poisoning resulting from improperly fluoridated

drinking-water; the individual was estimated to have ingested approximately 17.9 mg fluoride/kg body weight prior to death. 

The toxicity of fluoride is dependent upon the type or species of

the compound ingested. Generally, the more soluble salts of inorganic

fluorides (e.g., sodium fluoride) are more toxic that those that are either

weakly soluble or insoluble (e.g., calcium fluoride) (WHO, 1984). 

Gastrointestinal effects produced following the acute ingestion of

toxic amounts of fluoride likely arise from the corrosive action of

hydrofluoric acid, which is produced within the acidic environment of

the stomach (Spak et al., 1990; Whitford, 1990; Augenstein et al.,

1991). 1 Damage to the gastric mucosa (e.g., haemorrhage, loss of
Effects on Humans

in some individuals residing in areas of endemic skeletal fluorosis

(effects included dyspepsia, abnormal surface morphology of

gastrointestinal mucosa ) (Gupta et al., 1992; Dasarathy et al., 1996) or

in some patients receiving fluoride for the treatment of osteoporosis

(effects included pain, nausea, vomiting, diarrhoea, histological

changes in gastrointestinal mucosa) (Laroche & Mazières, 1991; Das

et al., 1994).

101

epithelium) has also been observed in human volunteers administered

acidulated phosphate fluoride gels (Spak et al., 1990) or sodium fluoride

solutions (Spak et al., 1989). Some individuals may be unusually

hypersensitive to stannous fluoride, as manifested by ulcerations in

the oral cavity after topical treatment (Razak & Latifah, 1988).

Cardiac arrest following accidental exposure to high levels of

fluoride has been attributed to the development of hypocalcaemia

and/or hyperkalaemia (Cummings & McIvor, 1988; Augenstein et al.,

1991; ATSDR, 1993). The acute effects of fluoride upon the central

nervous system may be due to fluoride-induced hypocalcaemia and the

inhibition of cellular enzymes (Augenstein et al., 1991).

Respiratory effects (e.g., haemorrhage, pulmonary oedema, tracheobronchitis, shortness of breath) have been observed in

individuals following inhalation of hydrogen fluoride (Dayal et al.,

1992; ATSDR, 1993).

8.1.2 Clinical studies

8.1.2.1 Skeletal effects

Since the 1960s, fluoride (usually as sodium fluoride or sodium

monofluorophosphate, in combination with added calcium and, sometimes, vitamin D) has been used for the treatment of age-dependent

osteoporosis at high dose levels (approximately 20–30 mg fluoride/day). While it seems apparent that such treatment increases the

trabecular bone density, it apparently has no similar beneficial effect on

cortical bone. Although such treatment may be protective against vertebral fractures, data on other fractures, including femoral bone, are

very controversial. The assessment of the efficacy of fluoride therapies

for osteoporosis is outside the scope of this document. The most often

encountered side-effects of high-dose fluoride therapy include
EHC 227: Fluorides

102

gastrointestinal pains and painful stress microfractures of feet (Bayley

et al., 1990; Delmas et al., 1990; Gutteridge et al., 1990; Murray et al.,

1990; Orcel et al., 1990; Riggs et al., 1990; Schnitzler et al., 1990; Riggs,

1991; Pak et al., 1994; Rizzoli et al., 1995; Meunier et al., 1998; Reginster

et al., 1998; Alexandersen et al., 1999). Exposure to fluoride during

treatment for osteoporosis may lead to calcium deficiency, owing to the

stimulation of bone growth, even in cases where patients are given

supplemental calcium as part of the therapeutic protocol (Dure-Smith

et al., 1996). 

8.1.2.2 Haematological, hepatic or renal effects

No evidence of significantly adverse haematological, hepatic or

renal effects was reported in a study of osteoporotic patients administered approximately 60 mg sodium fluoride/day (equivalent to a dose

of 389 μg fluoride/kg body weight per day in an adult weighing 70 kg)

over a period of 5 years (Hasling et al., 1987). In a study with elderly

postmenopausal osteoporotic females receiving 23 mg elemental fluoride/day for a mean period of 4.2 years (ranging from 1.4 to 12.6 years)

(equivalent to an intake of 470 μg/kg body weight per day in an individual weighing 58 kg), no clinically adverse alterations in blood and

urine chemistries or in the frequency of sister chromatid exchange in

peripheral blood lymphocytes were observed in the fluoride-exposed

patients (n = 25) compared with controls not administered fluoride

(Jackson et al., 1994).

8.1.3 Epidemiological studies

8.1.3.1 Cancer

The relationship between the consumption of fluoridated

drinking-water and morbidity or mortality due to cancer has been

examined in a large number of epidemiological studies, performed in

many countries. These studies were largely prompted by a report by

Yiamouyiannis & Burk (1977) that found an increase in overall cancer

mortality in two of several broad age groups in 10 US cities following

the implementation of drinking-water fluoridation. Although dismissed

based on a variety of methodological flaws (see Doll & Kinlen, 1977;

Smith, 1980; Kinlen & Doll, 1981; Chilvers, 1982; IARC, 1982, 1987;

Knox, 1985), the Yiamouyiannis & Burk (1977) study stimulated a large

number of other ecological studies, performed in Australia, Canada, 
Effects on Humans

103

China and the Province of Taiwan, England and Wales, New Zealand,

Norway and the USA (Hoover et al., 1976; IARC, 1982, 1987; Knox,

1985; Hrudey et al., 1990; Mahoney et al., 1991; Cohn, 1992; Freni &

Gaylor, 1992; Yang et al., 2000), that found no consistent relationship

between deaths due to any type of cancer and the consumption of

fluoride-containing (fluoridated or with naturally high fluoride content)

drinking-water. Although some age- and sex-related increases in

tumour incidence over time for cancer of the bones and joints and

osteosarcomas were observed in one study (US DHHS, 1991), these

increases were not related to the length of time that the water had been

“fluoridated.” Another report of an age- and sex-related increase in the

rate of osteosarcoma in areas of New Jersey, USA, served with fluoridated drinking-water was based on only 10 and 7 cases in the fluoridated and non-fluoridated areas, respectively (Cohn, 1992).

Although there has been no consistent evidence of an

association between the consumption of fluoridated drinking-water

and increased morbidity or mortality due to cancer, most of these

epidemiological studies were primarily geographic or ecological

correlational investigations. Such studies are characterized by the use

of aggregate units of observation, such as counties, states or

provinces, rather than individuals, and usually involve the comparison

of mortality or morbidity rates between exposed and unexposed areas

or among areas with varying degrees of exposure. Generally, studies of

t his nature are limited, since the movement of individuals in and out of

the exposed and non-exposed groups and other variable factors (e.g.,

industrialization, personal habits, etc.) that have an influence on the

development of adverse health effects are not taken into account, and

the statistical power may be insufficient to reveal small differences in

health-related effects (e.g., increases in the incidence of rare tumours).

Moreover, in such ecological studies, the intake of fluoride from other

sources such as food and dental care products is not taken into

account. Notably, the total intake of fluoride by individuals consuming

fluoridated or non-fluoridated drinking-water may not be markedly

different, due to the intake of significant amounts of fluoride from food

and dental care products (US DHHS, 1991; Burt, 1992). 

However, in a case–control study conducted in New York State

(but excluding New York City), USA, information on the intake of

fluoride from drinking-water and dental care products (e.g., fluoride

tablets, mouth rinses, toothpaste and dental treatments), but not 
EHC 227: Fluorides

104

foodstuffs, was obtained for males and females #24 years of age

having been diagnosed with osteosarcoma between 1978 and 1988

(Gelberg et al., 1995). The analyses were based on 130 cases and as

many controls (matched by years of birth and gender). Interviews on

exposure patterns were made with the subjects themselves and/or with

their parents. No significant risks were observed for any individual

fluoride exposure group, using either the parents’ or the children’s

exposure assessments. Nor was any significant trend observed when

using the parents’ exposure assessments. However, using the

subjects’ exposure estimates, there was a monotonous increase in the

odds ratios (ORs) for osteosarcoma with increasing exposure

estimates: 1, 1.16 (95% confidence interval [CI] = 0.44–3.04), 1.72 (95%

CI = 0.55–5.39) and 1.88 (95% CI = 0.64–5.55) for the exposure

categories of 0–1250, 1251–2338, 2339–3987 and 3988–9291 mg total

fluoride. 

In a case–control study, Moss et al. (1995) found no evidence of

a significantly increased risk of osteosarcoma among males or females

(or both genders combined) residing in Wisconsin, USA, associated

with the consumption of fluoridated drinking-water. Cases of osteosarcoma (and brain and digestive system cancers) and their controls

were studied in relation to their consump tion of fluoridated drinkingwater (i.e., containing >0.7 mg fluoride/litre) between 1979 and 1989.

Controls (approximately four per case) were matched to cases based

upon age, sex and race. Odds ratios (also adjusted by conditional

logistic regression for likely natural exposure to waterborne radiation

and population size) for risk of osteosarcoma with consumption of

fluoridated drinking-water were 1.0 (95% CI = 0.6–1.5; 110 exposed

cases), 0.9 (95% CI = 0.5–1.6; 56 exposed cases) and 1.1 (95% CI =

0.6–1.9; 54 exposed cases) for both genders combined, females and

males, respectively.

In a further hospital-based case–control study on osteosarcoma

(22 cases and 22 matched controls), the odds ratio for “high”

(>0.7 mg/litre) average lifetime or childhood drinking-water fluoride

concentration was 0.33 (McGuire et al., 1991).

8.1.3.2 Skeletal fluorosis

Skeletal fluorosis is a pathological condition that may arise following long-term exposure (either by inhalation or by ingestion) to

elevated levels of fluoride. Although the incorporation of fluoride into
Effects on Humans

105

bone may increase the stability of the crystal lattice and render the

bone less soluble, bone mineralization is delayed or inhibited (Grynpas,

1990), and consequently the bones may become brittle and their tensile

strength may be reduced. The severity of the effects associated with

skeletal fluorosis is relat ed to the amount of fluoride incorporated into

bone. In a preclinical phase, the fluorotic patient may be relatively

asymptomatic, with only a slight increase in bone mass, detected radiographically. Sporadic pain and stiffness of the joints, chronic joint pain,

osteosclerosis of cancellous bone and calcification of ligaments are

associated with the first and second clinical stages of skeletal

fluorosis. Crippling skeletal fluorosis (clinical phase III) may be

associated with limited movement of the joints, skeletal deformities,

intense calcification of ligaments, muscle wasting and neurological

deficits (Krishnamachari, 1987; Kaminsky et al., 1990; US DHHS, 1991).

A consistent finding in cases of chronically elevated fluoride uptake

is an increase in mineralization lag time of bone, which can be

demonstrated by dynamic histomorphometry (Boivin et al., 1989).

Osteomalacia may be observed in fluorotic individuals with a reduced

or suboptimal intake of calcium; secondary hyperparathyroidism may

also be observed in a subset of patients (Krishnamachari, 1987; US

DHHS, 1991). Apparently in combination with nutritional deficiencies,

high intakes of fluoride and the subsequent osteomalacia may also lead

in children to bone deformities such as genu valgum, originally

described as Kenhardt bone disease (Jackson, 1962; Krishnamachari

& Krishnaswamy, 1973; Krishnamachari, 1976; Chakma et al., 2000). In

osteoporotic patients, fluoride can stimulate bone formation to such an

extent that, despite calcium supplementation, calcium deficiency,

secondary hyperparathyroidism and osteomalacia occur (Dure-Smith

et al., 1996).

The concentration of fluoride in the bone of individuals in the preclinical or crippling stages of skeletal fluorosis may be between 3500

and 5500 mg/kg bone or greater than 8400 mg/kg bone, respectively,

compared with the reference values of 500–1000 mg/kg bone ash

weight (US DHHS, 1991). 

A number of factors, such as age, nutritional status, renal function

and calcium intake, in addition to the extent and duration of exposure,

can influence the amount of fluoride deposited in bone and, consequently, the development of skeletal fluorosis (US DHHS, 1991).

Individuals with impaired renal function, such as those with diabetes,

may be more prone to developing fluoride-related toxicological effects
EHC 227: Fluorides

106

(i.e., fluorosis) due to their diminished excretion of fluoride (Kaminsky

et al., 1990; US DHHS, 1991). Skeletal fluorosis may be reversible to

some degree in a manner that is dependent upon the extent of bone

remodelling (Grandjean & Thomsen, 1983). 

Felsenfeld & Roberts (1991) reported the case of a 54-year-old

woman who, after having consumed drinking-water containing approximately 8 mg fluoride/litre over a period of 7 years, had osteosclerosis

and stiffness in her knees and hips. Five cases of crippling skeletal

fluorosis in the USA have been reported over the past 40 years; the

total intake of fluoride by some of these individuals over a 20-year

period was estimated to be approximately 15–20 mg/day (US DHHS,

1991) (equivalent to a daily intake of 230–310 μg fluoride/kg body

weight per day in an adult weighing 64 kg). There have been no systematic studies of the prevalence of this disease in the USA.

The occurrence of endemic skeletal fluorosis has been well documented in case reports and surveys of individuals residing in certain

areas of the world (e.g., India, China, northern, eastern, central and

southern Africa), where the intake of fluoride may be inordinately high

as a result of the often significant consumption of drinking-water containing substantial amounts of naturally occurring fluoride, the indoor

burning of fluoride-rich coal for heating and cooking, the preparation

of foodstuffs in water containing increased fluoride and/or the consumption of specific foodstuffs naturally rich in fluoride (Haimanot et

al., 1987; Krishnamachari, 1987; Pettifor et al., 1989; Kaminsky et al.,

1990; Tobayiwa et al., 1991; Mithal et al., 1993; Wang et al., 1994;

Abdennebi et al., 1995; Liu, 1995; Michael et al., 1996; Zhao et al., 1996;

Teotia et al., 1998). Large numbers of individuals residing in India and

China are afflicted with skeletal fluorosis, which in some cases may be

severely crippling. In addition to an increased intake of fluoride from

foodstuffs and drinking-water with high levels of fluoride, other

factors, such as nutritional status as well as climate and other factors

influencing fluid intake, may possibly play a significant role in the

development of endemic skeletal fluorosis (Krishnamachari, 1987;

Haimanot, 1990; Zang et al., 1996). These issues make it difficult to

characterize the exposure–response relationship in studies of skeletal

fluorosis, such as those outlined below.

In China, endemic fluorosis associated with coal burning has been

identified in epidemiological investigations. Local residents absorb 
Effects on Humans

107

high doses of fluoride through inhalation and/or ingestion, as a consequence of the indoor use of high-fluoride coal in cooking, heating and

drying of food (the average concentrations of fluoride in coal were

200–1500 mg/kg, with the highest up to 3000 mg/kg). In those areas, the

intakes of fluoride via drinking-water were relatively low (range from 0.1

to 0.52 mg/day per person) (Table 10). The number of cases of coalburning-type skeletal fluorosis has been estimated to be 1.5 million

(Hou, 1997; Liang et al., 1997).

Table 10. Daily fluoride intake in different endemic areas in China using

high-fluoride coal for cooking and drying foodstuffs indoors

Endemic area Coal type Daily intake (mg/person)

Food DrinkingwaterAir Total

Sichuan Soft coal 8.86 0.1 0.67 9.63

Hubei Anthracite 4.12 0.45 0.55 6.12

Jiangxi Anthracite 2.54 0.5 0.24 3.28

Hunan Anthracite 1.81 0.52 0.31 2.64

Hubei Anthracite 1.86 0.42 0.15 2.43

Jiangxi

(control)

Firewood 1.14 0.24 0.11 1.49

In a short communication with few details, the relationship

between air, well-water and dietary fluoride and skeletal fluorosis (no

information on diagnostic criteria provided) was studied among

6792 individuals in Inner Mongolia (Xu et al., 1997) (Table 11). The

concentrations of fluoride in air and diet were low, and that in drinkingwater showed a correlation of 0.87 with the prevalence of fluorosis. The

skeletal fluorosis prevalence was #0.21% for fluoride concentrations

of 0.65 mg/litre or lower and reached 19.9% for fluoride concentrations

of 6.9 mg/litre. 

The relationship between fluoride concentrations in drinkingwater and the prevalence of skeletal fluorosis was also reported in

another Chinese study (Liang et al., 1997) (Table 12).

According to an early estimate, the number of persons at risk of

developing skeletal fluorosis was 5 million in Punjab and more in

Andhra Pradesh and Madras, India (Siddiqui, 1970).
EHC 227: Fluorides

108

Table 11. Prevalence of skeletal fluorosis in villages in Inner Mongolia,

Chinaa

Fluoride content of

drinking-water

Skeletal fluorosis

Cases %

0.4 0 0

0.65 2 0.21

1.4 93 7.72

1.6 109 12.3

3.2 101 12.7

3.4 132 15.2

4.7 42 19.6

6.9 166 19.9

a From Xu et al. (1997).

Table 12. Prevalence of skeletal fluorosis in China as a function of drinkingwater fluoride concentrationa

Fluoride concentration

in drinking-water

(mg/litre)

Prevalence of

skeletal fluorosis (%)

among individuals

with normal

nutritionb

Prevalence of skeletal

fluorosis (%) among

individuals with deficient

nutritionc

<0.3 0 0

0.6–1.0 0 0

>4.0 43.8 69.2

a From Liang et al. (1997).

b Normal nutrition = protein >75 g/day, high-quality protein >20% of total

protein, calcium >600 mg/day.

c Deficient nutrition = protein <20 g/day, high-quality protein <10% of total

protein, calcium <400 mg/day.

The frequency of skeletal fluorosis (as identified by the clinical

picture) among children 3–10 years of age was 39% (18/46) in a village

in India, where the fluoride concentrations in the three wells were 0.6,

4.0 and 1.34 mg/litre (Shivashankara et al., 2000). It was not possible to

discern, from the information available, the contribution of each well to

the drinking-water of the residents.

In a clinical survey for fluorosis in a random sample of residents

in five areas in Tamil Nadu, South India, the drinking-water fluoride
Effects on Humans

109

concentration was directly related to the prevalence of dental fluorosis

in children (8–15 years of age) and adults. Among children, no skeletal

fluorosis (no information on diagnostic criteria provided) was

observed; among adults, the prevalence of fluorosis was 34% (157 individuals surveyed) in the area with the highest drinking-water fluoride

concentration (summer month average 6.8 mg/litre, non-summer month

average 5.6 mg/litre) (estimated total daily fluoride intake 20 mg), while

no skeletal fluorosis was observed in the other areas, where the mean

fluoride concentrations were 2.2 (summer months) and 1.8 (non-summer

months) mg/litre or lower, with estimated total daily fluoride intakes

less than 10 mg (Karthikeyan et al., 1996).

A correlation between average water fluoride concentration and

prevalence of skeletal fluorosis (assessed by X-ray) was found among

adults in 15 villages in Dungapur district in Rajasthan, India (Choubisa

et al., 1997) (Table 13). The prevalence ranged from 4.4% at a water

fluoride level of 1.4 mg/litre to 63.0% at the level of 6.0 mg/litre.

Crippling fluorosis was consistently observed in villages with fluoride

concentrations of $3 mg/litre.

In four villages in the Faridabad district, North India, the percentage of people with skeletal fluorosis (assessed by the clinical appearance of impaired mobility) was 57, 43, 18 and 17, while the respective

means (ranges) of the water fluoride contents were 3.2 (0.25–8.0), 3.7

(0.3–7.0), 2.5 (0.3–5.4) and 1.0 (0.7–1.6) mg/litre (Susheela et al., 1993).

A cross-sectional study in Punjab also reported the relationship

between water fluoride and the prevalence of skeletal fluorosis (Jolly

et al., 1968). Skeletal fluorosis was rare (assessed by X-ray) (2.4%) in

a village where the average well-water fluoride concentration was

1.4 mg/litre, but its incidence was 71% in the village with the highest

water fluoride concentration, 9.7 mg/litre. In five villages where the

water fluoride concentration was 3–4 mg/litre, the prevalence of

skeletal fluorosis was 10–42%. It was suggested that lower calcium

concentrations in some water sources were associated with higher

skeletal fluorosis prevalence. 

The dependence of skeletal fluorosis on duration of exposure and

age was studied in a village in Andhra Pradesh, India, where the
EHC 227: Fluorides

110

Table 13. Relationship between drinking-water fluoride concentration and

skeletal fluorosis in Rajasthan, Indiaa

Village Fluoride

concentration

(mg/litre)

Prevalence

of fluorosis

% Crippling

fluorosis

Mean Range

Amaliya

Fala

1.4 0.5–1.8 4/92 4.3 No

Doja 2 1.2–2.0 10/102 9.8 No

Selaj 2 1.5–2.5 4/85 4.7 No

Anturi 2.3 0.3–3.5 16/180 8.9 No

Batikada 2.4 1.3–3.1 16/120 13.3 No

Devsomnath 2.5 0.0–3.1 14/188 7.4 No

Masania 2.6 1.0–2.6 28/176 15.9 No

Dora 3 1.2–3.9 22/96 22.9 Yes

Dolwaniya

Ka Oda

3 2.5–3.5 14/78 17.9 Yes

Palvasi 3.4 2.3–4.2 38/114 33.3 Yes

Jogiwara 3.4 1.0–4.3 27/106 25.5 Yes

Kolkhanda 4.5 4.2–4.7 52/106 49.1 Yes

Banda

Ghanti

5.7 3.8–6.7 61/115 53.0 Yes

Hadmatiya 6 3.9–8.3 118/205 57.6 Yes

Pantali 6 2.4–10.

8

121/192 63.0 Yes

a From Choubisa et al. (1997).

drinking-water was derived from five wells, in which the fluoride concentrations were between 7.2 and 10.7 mg/litre (average 9.0 mg/litre); it

was estimated that the daily water consumption was 4.6 litres, which

would lead to a daily dose of 36–54 mg fluoride (Saralakumari &

Ramakrishna Rao, 1993). Skeletal fluorosis started to appear after

10 years of residence in the village and reached 100% after 20 years.

In a cross-sectional study of 50 randomly selected adults who had

been residents of one of two villages for all their lives in Senegal,

kyphosis was used as an indicator of skeletal fluorosis (and was

radiologically confirmed to be fluorosis in three cases) (Brouwer et al.,

1988). The prevalence of severe kyphosis was 4 out of 55 (7%) in 
Effects on Humans

111

Guinguineo, where the well-water fluoride concentration was 3.9 mg/litre, and 11 out of 42 (26%) in Darou Rahmarie Fall, where the fluoride

concentration was 7.4 mg/litre.

8.1.3.3 Skeletal fracture

Several ecological and cross-sectional studies have been performed to investigate the relationship between fluoride in drinkingwater (from natural sources or from fluoridation) and bone fractures or

bone density (McClure, 1944; Goggin et al., 1965; Bernstein et al., 1966;

Korns, 1969; Madans et al., 1983; Simonen & Laitinen, 1985; Arnala et

al., 1986; Avorn & Nielssen, 1986; Sowers et al., 1986; Danielson et al.,

1992; Jacobsen et al., 1992, 1993; Suarez-Almazor et al., 1993; Kröger

et al., 1994; Jacqmin-Gadda et al., 1995; Lan et al., 1995; Czarnowski et

al., 1999; Fabiani et al., 1999). Limitations in exposure assessment and

study design preclude firm conclusions from being drawn from these

studies. 

Based on an ecological study of the rates of skeletal fracture

among men and women between 65 and 90 years of age in the USA, the

rates of hip fracture were not significantly increased among those

residing in fluoridated areas (i.e., $0.7 mg fluoride/litre) compared with

rates in those residing in non-fluoridated areas (i.e., #0.3 mg

fluoride/litre); however, among males, the relative rates of fracture of

the proximal humerus and distal forearm were significantly increased by

approximately 23% and 16%, respectively (Karagas et al., 1996).

Other studies have reported either no increase or a reduced risk

of hip (or skeletal) fract ure associated with the consumption of

fluoridated drinking-water (Madans et al., 1983; Simonen & Laitinen,

1985; Arnala et al., 1986; Jacobsen et al., 1993; Suarez-Almazor et al.,

1993; Lehmann et al., 1998; Fabiani et al., 1999).

The relative risk of hip, wrist or spinal fracture was 2.2 (95% CI =

1.07–4.69) in women 55–80 years of age residing in an “elevated

fluoride community” (with drinking-water containing 4 mg/litre)

compared with those in a control community, with drinking-water containing 1 mg fluoride/litre (Sowers et al., 1986, 1991). The estimated

mean intake of fluoride (from water-based beverages only) by women

in the “elevated-fluoride community” was approximately 72 μg/kg body

weight per day.
EHC 227: Fluorides

112

In a retrospective cohort study of 144 627 persons who had lived

at least during 1967–1980 in a Finnish village outside the municipal

water system, the relationship between hip fracture in 1981–1994 (from

hospital discharge records) and drinking-water fluoride concentration,

as estimated from a nationwide groundwater survey of 8927 wells, was

studied (Kurttio et al., 1999). The fluoride levels in the wells were

estimated from a national database and were approximately 1.4 times

higher than the actually measured fluoride levels. The median fluoride

concentration in the well-water was 0.1 mg/litre; the maximum value

was 2.4 mg/litre. No association was observed between hip fractures

in either men or women and the well-water fluoride concentration, when

all age groups were considered. However, in women 50–65 years old at

the start of follow-up, age- and area-adjusted relative risks (RR) for hip

fracture increased with increasing well-water concentration in the

categories 0.11–0.3, 0.3–0.5, 0.5–1.0, 1.1–1.5 and >1.5 mg/litre (RR =

1.16, 95% CI = 0.93–1.43; RR = 1.31, 95% CI = 0.86–1.99; RR = 1.53 [P <

0.05], 95% CI = 1.08–2.16; RR = 1.24, 95% CI = 0.77–2.01; RR = 2.09 [P

< 0.05], 95% CI = 1.16–3.76), in comparison with a fluoride

concentration of #0.1 mg/litre.

In a case–control study, Feskanich et al. (1998) assessed the risk

of forearm and hip fracture among a group of female US nurses in

relation to their long-term exposure to fluoride, assessed on the basis

of the levels of fluoride in toenails. Women in the three highest quartiles of fluoride exposure (i.e., levels of fluoride in toenails of 2.00–3.35,

3.36–5.50 and >5.50 mg/kg) had increased and reduced risks (not

statistically significant) of forearm and hip fracture, respectively, compared with women in the lowest quartile of fluoride exposure (i.e., <2.00

mg/kg). 

Bone mineral density was investigated in a random stratified

sample of 3222 perimenopausal women in eastern Finland (Kröger et al.,

1994). Of these women, 969 had used artificially fluoridated drinkingwater (1.0–1.2 mg/litre) for more than 10 years, 2024 had never used it

(drinking-water fluoride concentration <0.3 mg/litre) and 229 had used

fluoridated water for less than 10 years. There was no significant

difference in the 10-year incidence of self-reported bone fractures

between the first group and the second and third groups combined.

Bone mineral densities of the spine and femoral neck, measured by dual

X-ray densitometry and adjusted for age, weight, menopausal status,

calcium intake, physical activity class, deliveries, alcohol consumption
Effects on Humans

113

and oestrogen use, were statistically significantly (approximately 1%)

higher among women who had used fluoridated drinking-water longer

than 10 years than among the rest. 

In a 5-year follow-up study (Jacqmin-Gadda et al., 1998) of

3216 men and women aged 65 years or more, risk factors of fractures of

the hip or elsewhere were studied. The fluoride exposure was estimated

from analyses of fluoride in water in 78 areas and by weighting the

concentrations by duration of water supply use during the last 10

years and the relative contributions of different water sources in the

drinking-water. Fracture rates were assessed from questionnaires and

verified by the doctor of each patient reporting a fracture, when the site

or multiplicity of the fracture was questionable. Logistic regression

analysis was used to assess the influence of different variables on the

fracture risk; the analysis considered age, sex, body mass index, smoking status, alcohol consumption, use of psychotropic drugs and

fluoride exposure. No relationship was observed between fluoride

exposure and fractures other than at the hip. For hip fractures, participants in the two highest drinking-water fluoride quartiles (0.11–

0.25 mg/litre and >0.25 mg/litre) were at a higher risk (OR = 3.25, 95% CI

= 1.66–6.38; and OR = 2.43, 95% CI = 1.11–5.33, respectively) than

those below these levels. However, participants at drinking-water

fluoride levels >0.7 mg/litre were not at a higher risk than those below

this level (OR = 0.77, 95% CI = 0.37–1.62). When divided at the 1

mg/litre level, no increased risk appeared either.

In a multicentre prospective study on the risk factors of osteoporosis in postmenopausal women (n = 7129) (Phipps et al., 2000) (in

which the earlier study, Cauley et al., 1995, is subsumed), the relationship between drinking-water fluoride exposure during the years 1950–

1994 and density of lumbar spine, proximal femur, radius and calcaneus,

plus incident fractures of vertebrae, hip, wrist and humerus in

1971–1990, was investigated. In a multivariate analysis, the results were

adjusted for age, weight, education, muscle strength, surgical

menopause, calcium intake, drinks per week, current oestrogen use,

current thiazide use, non-insulin-dependent diabetes, current thyroid

hormone use, walking for exercise and smoking status. The bone density was 2% higher among women continuously exposed to fluoride in

drinking-water for 20 years in lumbar spine and proximal femur but

lower in distal and proximal radius; for calcaneus, the difference was

not statistically significant. Risk of incident fracture of the hip (RR = 
EHC 227: Fluorides

114

0.69, 95% CI = 0.50–0.99) and spine (RR = 0.73, 95% CI = 0.55–0.97) was

significantly lower among those continuously exposed to fluoride than

among the non-exposed; for fractures of the humerus, the difference

was not significant (RR = 0.85, 95% CI = 0.58–1.23), and for fractures of

the wrist, the risk among those exposed to fluoride was elevated (RR

= 1.32, 95% CI = 1.00–1.71).

In a population-based case–control study on the relationship

between naturally occurring fluoride in drinking-water and fractures of

the hip, lifetime drinking-water fluoride concentration was determined

from residential history and data from water suppliers on 514 cases and

527 sex- and age-matched controls in the United Kingdom (Hillier et al.,

2000). After adjustment for sex and age, body mass index, physical

activity, age at menopause, current alcohol consumption, smoking,

current treatment with oral corticosteroids and dietary calcium, the

odds ratio for lifetime drinking-water containing $0.9 mg fluoride/litre

was 1.0 (95% CI = 0.7–1.5) in comparison with lifetime drinking-water

containing lower fluoride concentrations. No effect of fluoride concentration early or late in life on hip fracture risk was observed either.

However, based on estimated total fluoride intakes in the United Kingdom, the contribution of fluoride in drinking-water was rather small

(probably less than one-third).

The relationship between drinking-wat er fluoride concentration

and hip fracture, as well as all bone fractures since the age of 20 years,

was studied among 8266 Chinese men and women, residents of six

villages with different drinking-water fluoride concentrations (Li et al.,

2001). The studied persons had lived in the same village for no less

than 25 years, most for their whole lives, and were no less than

50 years of age at the time of the study. Altogether, 531 subjects

reported one or more fractures, and for 526 of them the fracture was

confirmed by X-ray; the number of hip fractures was 56. In a multiple

logistic regression analysis, adjusted for age and gender, the odds

ratio for any fracture was 1.50, 1.25, 1.00, 1.17, 1.18 and 1.47 for

drinking-water fluoride concentrations of 0.25–0.34, 0.58–0.73,

1.00–1.06, 1.45–2.19, 2.62–3.56 and 4.32–7.97 mg/litre, respectively

(Table 14). From analysis of the fluoride concentrations in tea and air

and anamnestic information on the use of fluoride-containing

toothpastes or mouth rinses, it was concluded that drinking-water was

the only significant source of fluoride exposure, and the estimated

daily fluoride intake from drinking-water was estimated to be 0.73, 1.62,

3.37, 6.54,
Effects on Humans

115

Table 14. Water fluoride concentration and risk of skeletal fracturea

Water fluoride

concentration

(mg/litre)

Total fluoride

intake 

(mg/day)

Odds ratio for all

fractures 

(P value)

Odds ratio for

hip fracture 

(P value)

0.25–0.34 0.73 1.50 (0.01) 0.99 (0.99)

0.58–0.73 1.62 1.25 (0.17) 1.12 (0.85)

1.00–1.06 3.37 1.00 1.00

1.45–2.19 6.54 1.17 (0.33) 2.13 (0.15)

2.62–3.56 7.85 1.18 (0.35) 1.73 (0.34)

4.32–7.97 14.13 1.47 (0.01) 3.26 (0.02)

a From Li et al. (2001).

7.85 and 14.13 mg in the six exposure categories. The difference

between the group with the lowest odds ratio was significant (P < 0.01)

for the lowest and highest exposure group. The observation remained

qualitatively similar when only fractures after the age of 50 years were

considered, but reached statistical significance only for the high exposure group. For hip fractures, the prevalence was similar for the three

lowest exposure groups, but elevated for the three high exposure

groups (OR = 2.13, 1.73 and 3.26); the difference was significant for the

high exposure group.

In a meta-analysis (Jones et al., 1999) of ecological, crosssectional and cohort studies on water fluoridation and bone fractures

published in 1966–1997, water fluoridation was not observed to have

an effect on fracture incidence (RR = 1.02, 95% CI = 0.96–1.09). Out of

26 studies (published in English), 18 contained information that could

be used in the meta-analysis and were included. The meta-analysis

correctly assigned a qualitative score to the different studies (by which

the studies were weighted) and considered sources of bias such as

publication bias. Although overall no relationship between fluoridation

and fracture risk was observed, there was considerable heterogeneity

between the studies. Four of the studies also reported on the

relationship between water fluoridation and bone mass. A significant

increase in lumbar spine bone mass was observed; for femoral neck,

the change was positive, but statistically not significant, and for distal

radius, it was negative and statistically not significant. 
EHC 227: Fluorides

116

8.1.3.4 Reproductive effects

In case–control studies, no evidence of an association between

the consumption of fluoridated drinking-water by mothers and

increased risk of spontaneous abortion (Aschengrau et al., 1989), late

adverse pregnancy outcome (Aschengrau et al., 1993) or congenital

cardiac disease in children (Zierler et al., 1988) was identified. These

findings confirm previous observations of no apparent relationship

between the rates of Down syndrome or congenital malformation and

the consumption of fluoridated drinking-water (see Berry, 1962;

Needleman et al., 1974; Erickson et al., 1976; Berglund et al., 1980;

Erickson, 1980; all cited previously in WHO, 1984).

Freni (1994) reported evidence suggesting that exposure to fluoride in drinking-water may be associated with reduced fertility rates,

based upon the results of an ecological study that evaluated the “total

fertility rate” (i.e., total age-specific births per 1000 women) between

1970 and 1988 for white women, 10–49 years of age, residing in

30 regions in nine US states. However, this study was based upon

population means, rather than individual data.

8.1.3.5 Respiratory effects

Ernst et al. (1986) examined respiratory function in a group of male

and female adolescents with “high” or “low” exposure to the emissions

from an aluminium plant located near Cornwall, Ontario, Canada, and

reported evidence of respiratory abnormalities (i.e., a 49% increase [P

= 0.05] in the ratio of the closing volume/vital capacity) in males, but

not females, in the “high” exposure group, compared with those with

“low” exposure. Individuals were considered to have “high” and “low”

exposure if they resided more than 60% of their lives within

approximately 4 and 17 km of the plant, respectively. 

Lung X-ray findings were reported in 45 cases with skeletal fluorosis in an area of China contaminated by coal combustion. Chronic

bronchitis with diffuse interstitial fibrosis and pulmonary emphysema

were reported to occur (Liu, 1996). 

Since the residents in both studies were likely exposed to other

airborne contaminants and particulates, it is difficult to attribute the

effects on respiratory function solely to fluorides per se.
Effects on Humans

117

8.1.3.6 Neurobehavioural effects

Two studies in two different regions of China have considered the

potential effects of fluoride from drinking-water on children’s intelligence.

The first study (Li et al., 1995) was conducted on 907 children

(ages 8–13) of the Guizhou province. Intelligence was measured by the

China Rui Wen’s Scaler for Rural Areas. Children lived in four areas

with different degrees of fluorosis prevalence (urinary fluoride ranging

from 1.02 to 2.69 mg/litre). The average IQ was 89.9 in the non-fluorosis

area and 80.3 in the high prevalence area. The trend among the four

areas was statistically significant (P < 0.01).

The second study was carried out in Shanxi (Zhao et al., 1996) and

involved 160 children (ages 7–14) randomly selected from each of two

villages, one with a high level of fluoride contamination of the water

(4.12 mg/litre, with 86% of the population having signs of dental

fluorosis), and one with low contamination (0.91 mg/litre and 14%

dental fluorosis). The “official intelligence quotient (IQ)” was measured. The average IQ in the first village was 97.69, and in the second

it was 105.21 (P < 0.01). (The much higher IQ in comparison with the Li

et al. (1995) study is noteworthy, but it is probably justified by the use

of a different scale [Zhao et al., 1996].)

These two studies deserve similar comments: 

C There is no reference to the reliability of IQ measurement in the

context of rural China.

C There is no evidence that the measurements were blind; in fact,

they were probably not, being conducted in different villages. 

C There is no information on the training of the professional figures

who performed the tests.

C In the second study, an attempt was made to adjust for confounding by only the educational level of the parents, and the

difference between differently contaminated areas persisted.

The significance of these studies remains uncertain, but in a study

of 197 children between the ages of 7 and 11 years in which childhood

behavioural problems were assessed in relation to different levels of 
EHC 227: Fluorides

118

dental fluorosis, there was no association between behavioural problems and dental fluorosis (Morgan et al., 1998).

8.1.3.7 Genotoxic effects

Based on an analysis of the frequency of sister chromatid

exchanges in peripheral blood lymphocytes obtained from groups of

approximately 100 male and female Chinese adults consuming drinkingwater containing from 0.11 to 5.03 mg fluoride/litre, Li et al. (1995)

concluded that fluoride was not genotoxic at these levels of exposure.

The average estimated daily intake of fluoride, based upon levels in

food, water and average body weight, ranged from about 20 to 280

μg/kg body weight per day. The plasma fluoride level in the 5.03

mg/litre area was 5.56 μmol/litre.

Although Jackson et al. (1997) observed a slight (7–15%)

although statistically significant (P < 0.001) increase in the frequency

of sister chromatid exchange in peripheral blood lymphocytes collected

from individuals in the USA (n = 68, males and females) residing in an

area served with drinking-water containing 4.0 mg fluoride/litre (compared with that from individuals in other areas served with water

containing 0.2 and 1.0 mg fluoride/litre [n = 64 and 59, respectively]), a

subsequent comparison among individuals residing in the highfluoride area having consumed either city water (4 mg/litre; n = 30) or

well-water (<0.3 mg/litre; n = 28) revealed no significant difference in

the frequency of sister chromatid exchange in blood lymphocytes

(Jackson et al., 1997).

In a report with scanty details on the selection of persons to be

studied, an increased peripheral lymphocyte micronucleus and sister

chromatid exchange frequency was observed among fluorosis patients

(n = 53), compared with healthy referents (n = 20) from a fluorosisendemic area and non-fluoride exposed referents (n = 30) in Inner

Mongolia, China (Wu & Wu, 1995). In another study with limited

reporting, an increased sister chromatid exchange frequency was

reported among residents of a fluorosis-endemic area in North Gujarat,

India (n = 100), in comparison with referents from a non-endemic area

in Ahmedabad (n = 20) (Sheth et al., 1994). In a further similar study,

sister chromatid exchange frequencies were elevated among residents

of one out of three fluorosis-endemic villages, and chromosomal aberrations were elevated in all three villages, compared with referents from
Effects on Humans

1 This section was based primarily on a review prepared by WHO

(1994).

119

a nearby township in south Gujarat, India (Joseph & Gadhia, 2000). In

all these studies, the interpretation is complicated by the limited details

provided on subject selection and by possible confounding variables.

However, no effect on chromosomal aberrations or micronuclei in

lymphocytes was observed in a randomized double-blind study on

seven non-smoking female osteoporosis patients treated with sodium

fluoride or sodium monofluorophosphate (average dose 29 mg fluoride/

day) for an average of 29 months, in comparison with seven matched

non-treated controls (van Asten et al., 1998).

8.1.3.8 Dental effects1

It has been recognized for over five decades that fluoride may

have both beneficial and potentially harmful effects on dental health.

While the prevalence of dental caries is inversely related to a range of

concentrations of fluoride in drinking-water consumed, the prevalence

of dental fluorosis has been shown to be positively related to fluoride

intake from many sources (Fejerskov et al., 1988, 1996). Public health

programmes seeking to maximize the beneficial effects of fluoride on

dental health through the introduction of fluoridated drinking-water

have, at the same time, strived to minimize its adverse fluorotic effects

on teeth. Based upon the studies conducted by Dean and colleagues

five decades ago, the “optimum” level of fluoride in drinking-water,

associated with the maximum level of dental caries protection and

minimum level of dental fluorosis, was considered to be approximately

1 mg/litre. The effects of fluoride on dental health were examined by a

WHO Expert Committee (WHO, 1994).

1) Dental caries

Since the first reports by Dean and colleagues published in the

1930s, oral fluoride is still considered an effective means of reducing

dental caries. Historically, populations consuming fluoridated drinkingwater had a much lower prevalence of dental caries than did those

consuming non-fluoridated drinking-water. Over time, the difference in
EHC 227: Fluorides

120

caries prevalence among those consuming fluoridated and nonfluoridated drinking-water has narrowed significantly. This apparent

diminution in the cariostatic effectiveness of fluoridated drinking-water

is likely attributable to a “diffusion” in which individuals consuming

non-fluoridated drinking-water may consume significant amounts of

beverages prepared in other locales with fluoridated drinking-water, as

well as exposure to fluoride through the use of dental care products —

mainly fluoridated toothpaste. It has been estimated that whereas

approximately 210 million individuals throughout the world consume

drinking-water containing levels of fluoride considered adequate for

the prevention of dental caries, approximately 500 million people use

fluoridated toothpastes (WHO, 1994).

Historically, it was believed that fluoride needed to become incorporated into the crystal lattice of enamel in order to effectively prevent

the development of dental caries. Fluoride was considered to improve

lattice stability and render the enamel less soluble to acid demineralization. Since the incorporation of fluoride into enamel, as partially

fluoridated hydroxyapatite, was believed to be essential for its action,

fluoride was thought best ingested. There is now, however, an increasing body of evidence to suggest that a substantial part of the

cariostatic activity of fluoride is due to its effects on erupted teeth, and

that the continual presence of fluoride in the saliva and in the fluid

phase of dental plaque is critical to its mechanism of action. There is a

growing consensus that through its interaction with the surface of

enamel, fluoride in saliva and dental plaque inhibits the

demineralization and promotes the remineralization taking place at the

surface of the tooth.

Since the introduction of controlled fluoridated drinking-water,

efforts to reduce dental caries have been extended to include the use

of fluoridated toothpaste, mouth rinses and topically applied dental

treatments (e.g., gels, varnishes, solutions), as well as through the use

of fluoride supplements, fluoridated milk and fluoridated salt. The

effectiveness and factors affecting the implementation of these various

exposure regimens have been reviewed in detail by WHO (1994), and

therefore only a brief summary is presented here.

The controlled fluoridation of community drinking-water to an

optimum level is one of the most cost-effective means of delivering 
Effects on Humans

121

fluoride to large numbers of individuals. This method of fluoride delivery requires a suitable community-wide drinking-water delivery system

along with a reasonable level of technological development (e.g., infrastructure, equipment and appropriately trained support personnel).

Depending upon the annual average maximum daily air temperature,

recommended levels of fluoride in drinking-water considered useful for

the prevention of dental caries have ranged from 0.5 to 1.2 mg/litre.

Some countries have introduced controlled fluoridated salt as a

means of reducing the prevalence of dental caries among their respective populations. Unlike controlled fluoridated drinking-water and

toothpastes, there is little quantitative information on the cariostatic

action of fluoridated salt, although it is considered to act in a manner

like that of fluoridated drinking-water. The optimum concentration of

fluoride in salt needed to reduce the incidence of dental caries must

take into account the level of salt intake and the concentration of

fluoride in drinking-water in individual geographical areas; however,

200 mg fluoride/kg salt has been suggested to be a minimum value

(WHO, 1994).

Formerly, the administration of fluoridated milk to children was

considered to be a suitable means of increasing their intake of fluoride;

however, little quantitative information is available on the efficacy of

this delivery system in the prevention of dental caries. To be effective

as a means of delivering fluoride to children, implementation of a

fluoridated milk programme requires close cooperation with the dairy

industry as well as a widespread system of distribution.

It has been estimated that, worldwide, almost twice as many

people are exposed to fluoride for the prevention of dental caries

through the use of toothpastes as from the consumption of controlled

fluoridated drinking-water. In many countries, fluoridated toothpastes,

which usually contain approximately 1000 mg fluoride/kg, represent

more than 95% of total dentifrice sold. The use of these products is

considered to be one of the major factors responsible for the gradual

decline in the prevalence of dental caries in most industrialized

countries. In areas where the prevention of dental caries through the

widespread use of fluoridated drinking-water, salt or milk may not be

feasible, the use of fluoridated toothpastes remains an effective means

of improving dental health.
EHC 227: Fluorides

122

Fluoride supplements, in the form of tablets, liquid drops or

lozenges, are intended to provide a systemic source of fluoride when

fluoridated drinking-water is not available. Problems associated with

the widespread use of such supplements include poor compliance

among socially and economically disadvantaged groups and the

potentially inappropriate use of these products by those already

consuming drinking-water containing optimal amounts of fluoride.

Moreover, the results of studies suggest that fluoride is most effective

when continually present at low levels in saliva and plaque fluid. In a

number of jurisdictions, the recommended daily dosage of fluoride

supplements is linked to the level of fluoride in the drinking-water as

well as the age of the child. Although fluoride supplements may be

appropriate for use in certain areas where the prevalence of dental

caries is high, available data on the efficacy of this fluoride delivery

system in preventing dental caries are equivocal, and there appears to

be a growing consensus that fluoride supplements have a limited

public health role in improving dental health.

The use of fluoridated mouth rinses has achieved a significant

level of popularity among publicly based health care programmes,

particularly those involving school-aged children. The levels of fluoride in these mouth rinses (0.05 or 0.2%) are related to whether they are

recommended for daily or weekly use. The efficacy of fluoridated

mouth rinses in the prevention of dental caries is related to the frequency of use, the level of compliance and exposure to other sources

of fluoride, most notably in drinking-water. The use of fluoridated

mouth rinses may be recommended for individuals with an elevated risk

of dental caries, although the mouth rinses may not be appropriate for

use by children younger than 6 years of age, due to their propensity to

swallow significant amounts of such material, thereby increasing their

risk of developing dental fluorosis.

Solutions, gels or varnishes usually applied infrequently over the

course of a year by dental care professionals may be most efficacious

in individuals with an elevated risk of dental caries. Owing to the level

of fluoride in these materials (e.g., up to 22 300 mg/kg), health care

professionals must follow protocols that reduce inadvertent ingestion

of significant amounts of these products by younger children, which

could cause acute toxic effects. 
Effects on Humans

123

2) Dental fluorosis

Since the publication of the WHO (1994) assessment on the

quantitative relationship between dental fluorosis and fluoride intake,

a large number of further studies have been published on the matter.

A recent meta-analysis (McDonagh et al., 2000) of such studies is presented in Figures 2 and 3. Proportion of population with fluorosis

Fluoride level – mg/L (log scale)

0.1 0.2 0.4 1.0 2.0 4.0

.1

.2

.3

.4

.5

.6

.7

.8

.9

1

Note: Fluoride level plotted on the log scale because there was anapproximatelylinear association between this

and the log (odds) of fluorosis.

Fig. 2. Proportion of the population with dental fluorosis by water fluoride

level together with the 95% upper and lower confidence limits for the

proportion

[Reproduced with permission from Br Med J (2000) 321: 855–859]

Dental fluorosis is a condition that results from the intake of

excess levels of fluoride during the period of tooth development,

usually from birth to approximately 6–8 years of age. It has been termed

a hypoplasia or hypomineralization of dental enamel and dentine and

is associated with the excessive incorporation of fluoride into these

structures. The severity of this condition, generally characterized as

ranging from very mild to severe, is related to the extent of fluoride

exposure during the period of tooth development. Mild dental fluorosis

is usually typified by the appearance of small white areas in the

enamel; individuals with severe dental fluorosis have teeth that are

stained and pitted (“mottled”) in appearance. In human fluorotic teeth,

the most prominent feature is a hypomineralization of the enamel. In

contrast to many animal species, fluoride-induced enamel hypoplasia

(indicating severe fluoride disturbance of enamel matrix production)

seems to be rare in fluorosed human enamel. The staining and pitting
EHC 227: Fluorides

124

Proportion with fluorosis of a esthetic concern

Fluoride level – mg/L

0 .4 .8 1.2 1.6 2 2.5 3 3.5 4 4.5

.1

.2

.3

.4

.5

.6

.7

.8

.9

1

Note: Fluoride level plotted on the untransformed scale because there was an approximately linear association

between this and the log (odds) of “aesthetic fluorosis.”

Fig. 3. Proportion of the population with fluorosis of aesthetic concern by

water fluoride level [Reproduced with permission from Br Med J (2000) 321:

855–859]

of fluorosed dental enamel are both posteruptive phenomena (i.e.,

acquired after tooth eruption and occur as a consequence of the

enamel hypomineralization). The incorporation of excessive amounts

of fluoride into enamel is believed to interfere with its normal

maturation, as a result of alterations in the rheologic structure of the

enamel matrix and/or effects on cellular metabolic processes associated

with normal enamel development (WHO, 1994; Aoba, 1997; Whitford,

1997). Experimental animal studies suggest that this hypomineralization

results from fluoride disturbance of the process of enamel maturation

(Richards et al., 1986). 

Unlike skeletal fluorosis, which is considered to be a marker of

long-term exposure to fluoride (due to the ongoing process of bone

remodelling), dental fluorosis is considered to be indicative of the level

of exposure to fluoride only during the period of enamel formation.

Exposure to excessive levels of fluoride after tooth development

appears to have little influence on the extent of fluorosis. Re-evaluation

of classical fluorosis data (Dean et al., 1941, 1942; Richards et al., 1967;

Butler et al., 1985) has shown that even at low fluoride intake from

water, a certain level of dental fluorosis will be found (Fejerskov et al.,

1996). A dose–response relationship was also demonstrated. The data

demonstrated an increase of the fluorosis community index by 0.2 for

every dose increase of 0.01 mg fluoride/kg body weight.
Effects on Humans

125

Over the past 30–40 years, there has been an increase in the

prevalence of dental fluorosis among populations consuming either

fluoridated or non-fluoridated drinking-water. Although greater numbers of individuals are now being served by fluoridated drinking-water,

for the most part this increased prevalence in dental fluorosis has been

attributed to the widespread intake of fluoride from sources other than

drinking-water, especially in areas served by non-fluoridated drinkingwater. Unlike the situation in the 1930s, when the primary sources of

exposure to fluoride were limited to drinking-water and foodstuffs, now

there is potential exposure to fluoride from a variety of additional

sources, such as toothpastes, mouth rinses, fluoride supplements and

topically applied dental gels, solutions and varnishes. Exposure to

fluoride may also result from the ingestion of fluoridated salt or fluoridated milk.

The prevalence of dental fluorosis is also elevated in certain areas

of the world where the intake of fluoride may be inordinately high, due

in large part to the elevated fluoride content of the surrounding

geological environment. In China, large numbers of people exhibit

dental fluorosis (Liu, 1995). In addition to the actual consumption of

often large amounts of drinking-water containing naturally occurring

elevated levels of fluoride, the indoor burning of coal rich in fluoride,

the preparation of foodstuffs in water containing increased fluoride

levels and the consumption of specific foodstuffs naturally rich in

fluoride, such as tea, are believed to contribute to the elevated intake

of fluoride, with the resultant development of dental fluorosis (Chen et

al., 1993, 1996; Grimaldo et al., 1995; Han et al., 1995; Liu, 1995; Xu et al.,

1995).

8.1.4 Interactions with other substances

In a cross-over study, six volunteers were exposed to drinkingwater with high fluoride (2.3 mg/litre), high arsenic (0.47 mg/litre) or

high fluoride and high arsenic (4.05 mg fluoride/litre and 0.58 mg

arsenic/litre). All volunteers followed one of these three regimes for

5 days, drank distilled water for 3 days and then were exposed to

another regime. Exposure to this level of arsenic did not influence the

rate of urinary excretion of fluoride of the volunteers (Wu et al., 1998).
EHC 227: Fluorides

126

In the area of Kuitun, Xinjiang, in China, it was found that among

619 wells investigated, 102 wells contained high levels of arsenic and

fluoride. It was found that arsenic dermatosis manifested when the

water arsenic level was at or above 0.12 mg/litre, with no association

with the fluoride level in the water; dental fluorosis developed when

the water fluoride level was at or above 3 mg/litre, regardless of the

water arsenic level (Wang et al., 1997).

8.2 Occupationally exposed workers

The health of workers occupationally exposed to fluorides, particularly those employed in the aluminium smelting industry, has been

examined in a variety of epidemiological studies. Workers in this

industrial setting are also exposed to a number of other substances,

such as ammonia, carbon monoxide, sulfur dioxide, distillation products

of tar, pitch and coal, aluminium oxide (alumina), cyanides, dust and

metals such as nickel, chromium and vanadium (IARC, 1984; Søyseth

& Kongerud, 1992).

8.2.1 Case reports

Severe tissue damage, respiratory effects, cardiac arrest and

deaths have often been noted in case reports of workers exposed

accidentally to hydrofluoric acid through dermal contact (Mayer &

Gross, 1985; Chan et al., 1987; Mullet et al., 1987; Greco et al., 1988;

Upfal & Doyle, 1990; Gubbay & Fitzpatrick, 1997). Following the

exposure of two male workers to breakdown products (sulfur tetrafluoride, thionyl fluoride, hydrogen fluoride) of sulfur hexafluoride, the

men became semicomatose and developed cyanosis and pulmonary

oedema (Pilling & Jones, 1988). Eye and throat irritation, chest tightness, nausea, vomiting, headache and fatigue have also been observed

in electrical workers exposed to the breakdown products of sulfur

hexafluoride (Kraut & Lilis, 1990).

8.2.2 Epidemiological studies

8.2.2.1 Cancer

In a number of analytical epidemiological studies, an increased

incidence of lung and bladder cancer and increased mortality due to

cancer of the lung, liver, bladder, stomach, oesophagus, pancreas, 
Effects on Humans

127

lymphatic–haematopoietic system, prostate or brain (central nervous

system) have been observed in fluoride-exposed workers employed in

the aluminium smelting industry (Giovanazzi & D’Andrea, 1981; Andersen et al., 1982; Rockette & Arena, 1983; Theriault et al., 1984; Gibbs,

1985; Armstrong et al., 1986, 1994; Mur et al., 1987; Siemiatycki et al.,

1991; Spinelli et al., 1991; Rønneberg & Andersen, 1995; Romundstad

et al., 2000). However, in general, there has been no consistent pattern,

and bone cancer was not usually assessed. Although increases in lung

cancer were observed in several studies, it is not possible to attribute

these increases to fluoride exposure per se due to concomitant

exposure to other substances. Indeed, in some of these epidemiological

studies, the increased morbidity or mortality due to cancer was

attributed to the workers’ exposure to aromatic hydrocarbons.

In a cohort study of cryolite mill workers in Denmark, Grandjean

et al. (1992) indicated that a portion of the increase in the incidence of

bladder cancer (17 observed versus 9.2 expected cases) among the

workers may have been attributable to occupational exposure to fluoride; however, the workers were also exposed to other substances, such

as quartz, siderite and small amounts of metal sulfides (Grandjean et al.,

1985).

8.2.2.2 Skeletal effects

Generally, most data on the occurrence of skeletal fluorosis in

occupationally exposed workers have come from older studies. Based

upon a review of older studies involving aluminium smelter workers in

which the number of workers examined was usually small and quantitative data on exposure to airborne fluoride were not always provided,

Hodge & Smith (1977) concluded that the “incidence of detectable

osteosclerosis was often high” when the levels of fluoride in the air

exceeded 2.5 mg/m3and/or levels of fluoride in the urine of these

workers were greater than 9 mg/litre; at airborne concentrations below

2.5 mg/m3(and levels in the urine of below 5 mg/litre), “ years of exposure in potrooms did not produce osteosclerosis.” The development

of skeletal fluorosis in cryolite workers in Copenhagen was attributed

to the intake (from occupational exposure) of between 20 and 80 mg

fluoride/day (Grandjean, 1982). Chan-Yeung et al. (1983a) reported

finding no definitive signs of skeletal fluorosis in potroom workers

employed in an aluminium smelter and exposed to 0.48 mg fluoride/m3.
EHC 227: Fluorides

128

In a more recent study in which skeletal changes in 2258 workers

employed at an aluminium plant in Poland were assessed (clinically and

radiologically), the occurrence of fluorosis (multiple joint pain, initial

ossification, osteosclerosis) was reported to increase with increasing

duration of employment (Czerwinski et al., 1988). The occurrence of

these skeletal changes was related not to quantitative data on the

concentration of airborne fluoride per se, but to a qualitative “exposure

index,” calculated on the basis of the years of employment and the

extent to which the concentration of fluoride in the air in different areas

of the plant exceeded the highest permitted level of 0.5 mg hydrogen

fluoride/m3. The prevalence of skeletal fluorosis reportedly increased

with this “index of exposure-years,” the more severe effects being

observed in older workers.

8.2.2.3 Respiratory effects

Since publication of the first EHC on fluorides (WHO, 1984),

additional studies have reported adverse effects on the respiratory

system (e.g., reduced lung capacity, irritation of the respiratory tract,

asthma, cough, bronchitis, shortness of breath and/or emphysema) in

workers, predominantly those employed in aluminium smelters, occupationally exposed to airborne fluorides (Chan-Yeung et al., 1983b;

Larsson et al., 1989; Søyseth & Kongerud, 1992; Rønneberg, 1995;

Søyseth et al., 1995; Radon et al., 1999; Romundstad et al., 2000).

Owing to the exposure of these workers to other airborne contaminants

and particulates, it may not be possible to attribute the effects on respiratory function solely to fluoride per se.

8.2.2.4 Haematological, hepatic or renal effects

No evidence of haematopoietic, hepatic or renal dysfunction was

observed in potroom workers employed at an aluminium smelter and

exposed to 0.48 mg fluoride/m3 (Chan-Yeung et al., 1983a).

8.2.2.5 Genotoxic effects

The mean frequency of sister chromatid exchange in peripheral

blood lymphocytes obtained from 40 Chinese fertilizer production

workers was significantly (P < 0.01) increased by approximately 50%,

compared with that in a similarly sized group of controls matched for

age, sex and smoking habits (Meng et al., 1995). During the period of
Effects on Humans

129

analysis, workers were exposed to levels of fluoride (mostly hydrofluoric acid and silicon tetrafluoride) ranging from 0.5 to 0.8 mg/m3

, as

well as to phosphate fog, ammonia and sulfur dioxide. Among the

workers, the average frequency of sister chromatid exchange was

approximately 27% higher (P < 0.01) in smokers than in non-smokers.

Information on the total intake of fluoride was not presented.

In a further study, an increased frequency of both chromosomal

aberrations and micronuclei in circulating blood lymphocytes was also

observed among the fertilizer plant workers (n = 40), in comparison with

40 controls working and studying in Shanxi University, situated in the

same city as the factory, matched for sex, age and smoking habits

(Meng & Zhang, 1997); the microscopic analysis was performed on

coded slides.
130

9. EFFECTS ON OTHER ORGANISMS IN THE

LABORATORY AND FIELD

9.1 Laboratory experiments

9.1.1 Microorganisms

9.1.1.1 Water

Fluoride (100 mg/litre) did not affect growth or the chemical

oxygen demand degrading capacity of activated sludge when added

either as a pulse or continuously. Sludge settleability did not change

following a pulse addition of fluoride; however, continuous addition

of fluoride resulted in poor settling, indicated by 100–200% increases

in settled sludge volume.The authors concluded that the poor settling

was probably due to enhanced growth of filamentous organisms

(Singh & Kar, 1989). Beg (1982) found the EC50 fo r inhibition of

bacterial nitrification to be 1218 mg fluoride/litre.

McNulty & Lords (1960) exposed the green alga Chlorella

pyrenoidosa to hydrogen fluoride in 110-min tests. Significant

increases in oxygen consumption and total phosphorylated

nucleotides were observed at fluoride concentrations of 2, 20 and 200

mg/litre (0.105, 1.05 and 10.5 mmol/litre). The authors concluded that,

based on measurements of gas exchange at several pH values, the

stimulation was probably due to the undissociated hydrogen fluoride

in the medium. Smith & Woodson (1965) found that fluoride

concentrations greater than 19 mg/litre (1 mmol/litre) caused growth

inhibition in the same species. However, Nichol et al. (1987) found no

effect of fluoride at concentrations ranging from 5 to 150 mg/litre at a

variety of pH levels (5.9–8.0).

LeBlanc (1984) calculated 96-h EC50s, based on growth, to be 123

and 81 mg fluoride/litre for the fre shwater green alga Selenastrum

capricornutum and the marine alga Skeletonema costatum, respectively.

Rai et al. (1998) calculated 15-day LC50s for the alga Chlorella

vulgaris to be 380 and 266 mg fluoride/litre (14 and 20 mmol/litre) at pH
Effects on Other Organisms in the Laboratory and Field

131

6.8 and pH 6.0, respectively; at pH 4.5, the 3-day LC50 was 133 mg

fluoride/litre (7 mmol/litre). Non-inhibitory concentrations we re 66.5,

28.5 and 9.5 mg fluoride/litre (3.5, 1.5 and 0.5 mmol/litre) at pH 6.8, 6.0

and 4.5, respectively.

Antia & Klut (1981) exposed five euryhaline phytoplankton species to fluoride concentrations ranging from50 to 200 mg/litre (14–15‰

salinity). The growth rate and maximum growth density of the

chlorophyte Duniella tertiolecta and the diatom Thalassiosira weissflogii were unaffected at all exposure concentrations. The growth of

the diatom Chaetoceros gracilis appeared to be stimulated by the

presence of fluoride. The haptophyte Pavlova lutheri was 35–50%

inhibited at fluoride concentrations of$150 mg/litre.The dinoflagellate

Amphidinium carteri was 20–25% inhibited at 150 mg/litre and more

than 90% inhibited at 200 mg/litre. Hekman et al. (1984) studied the

effect of dissolved fluoride concentrations of up to 150 mg/litre on six

phytoplankton species. Growth and photosynthetic oxygen evolution

were unaffected at fluoride concentrations up to 50 mg/litre in all algae

except Synechococcus leopoliensis. S. leopoliensis growth ceased for

a period followed by growth at a reduced rate at 50 mg fluoride/litre;

the threshold for growth effects and inhibition of photosynthesis in

this species was 25 mg/litre.Nichol et al. (1987) found that fluoride concentrations of $100 mg/litre (5.2 mmol/litre) caused a growth lag in S.

leopoliensis at neutral pH. The effect of fluoride on the growth lag was

pH-dependent, with the growth lag increasing with decreasing pH. At

pH 5.9, there was a measurable growth lag at 5 mg fluoride/litre.

Fluoride resistance was induced by prior growth in the medium at noninhibitory levels of sodium fluoride. It was suggested that fluorideresistant cells retain less fluoride (taken up as undissociated hydrogen

fluoride) by developing increased permeability to the fluoride anion.

No effect on growth of 12 species of marine phytoplankton was

observed at fluoride concentrations ranging from 10 to 50 mg/litre. At

the highest concentration (100 mg/litre), no effect on growth was

observed in 9 of the 12 species tested; however, 25–30% inhibition of

growth was found in a diatom (Nitzschia angularis affinis), a dinoflagellate (A. carteri) and a haptophyte (P. lutheri) (Oliveira et al., 1978).

Joy & Balakrishnan (1990) studied the effect of fluoride on the

diatoms Nitzschia palea (freshwater) and Amphora coffeaeformis

(brackish water) during 96-h exposures. Significant enhancement of

growth, compared with controls (no added fluoride), was observed at
EHC 227: Fluorides

132

fluoride concentrations ranging from 30 to 110 mg/litre with N. palea

and at a concentration of 70 mg/litre in A. coffeaeformis. A. coffeaeformis did not show significant growth differences from controls at

fluoride concentrations of 90 and 110 mg/litre.

The marine dinoflagellate Amphidinium carteri was unable to

grow in nutrient-enriched seawater containing 200 mg fluoride/litre.

However, the organism could be adapted to grow under these conditions after repeatedly being cultured with stepwise increases in subinhibitory fluoride concentrations.Electron microscopic investigation

of the adapted dinoflagellate cells revealed abnormal ultrastructural

features in the chloroplast,mitochondria and nucleus. Fluoride adaptation seemed to confer a prolamellar-like configuration on the thylakoids

(extensive membrane system containing the components of

photosynthesis) in the centre ofthe pyrenoid (protein structure associated with formation and storage ofstarch); in organisms that had not

been adapted, fluoride caused extreme disorganization of thylakoid

formation (Klut et al., 1981).

9.1.1.2 Soil

Van Wensem & Adema (1991) studied the effect of potassium

fluoride (32.3–3230 mg fluoride/kg [1.7–170 μmol fluoride/g]) on

Carolina poplar (Populus canadensis) litter. After 4 weeks, total respiration was increased and the phosphate concentration was

decreased at the highest fluoride concentration. Ammonium, nitrate

and phosphate concentrations were decreased by fluoride after 9

weeks. No-observed-effect concentrations (NOECs) for the effect of

fluoride on net mineralizationofammonium,nitrate and phosphate were

323, 100.7 and 1007 mg/kg dry weight (17, 5.3 and 53 μmol/g), respectively.The authors concluded that fluoride seems to be toxic formicrobial processes at concentrations found in moderately fluoride polluted

areas. 

9.1.2 Aquatic organisms

9.1.2.1 Plants

Wang (1986) exposed the common duckweed (Lemna minor) to

fluoride and calculated an EC50, based on a reduction in frond growth,

to be >60 mg fluoride/litre.
Effects on Other Organisms in the Laboratory and Field

133

9.1.2.2 Invertebrates

The acute toxicity of fluoride to aquatic invertebrates is summarized in Table 15. Forty-eight-hour LC50

s/EC50s range from 53 to

304 mg/litre.

Hemens & Warwick (1972) found that fluoride concentrations of

up to 100 mg/litre caused no mortality in prawns exposed for 96 h.

However, the brown mussel(Perna perna) showed up to 30% mortality

at an initial fluoride concentration of 7.2 mg/litre during a 5-day test

(the background fluoride concentration was 1 mg/litre).

LeBlanc (1980) found a 48-h NOEC for Daphnia magna of 50 mg

fluoride/litre, whereas Kühn et al. (1989) reported a no-effect

concentration of 231 mg fluoride/litre (24 h). Camargo & La Point (1995)

calculated “safe concen trations” (8760-h EC0.01s) for the last-instar

larvaeofseveralnet-spinning caddisfly species. “Safe concentrations”

ranged from 0.39 mg fluoride/litre (Hydropsyche pellucidula) to 1.18

(Hydropsyche lobata) and 1.79 mg fluoride/litre (Chimarra marginata).

Further “safe concentrations”were calculated forthe caddisfly species

Hydropsyche bronta, at 0.2 mg fluoride/litre, and H. occidentalis and

Cheumatopsyche pettiti, at 0.7 mg fluoride/litre (Camargo, 1996b).

Pankhurst et al. (1980) performed toxicity tests on the blue mussel

(Mytilus edulis) (160 h), the anemone Anthopleura aureoradiata

(144 h) and the red krill (Munida gregaria) (259 h) using seawater

dilutions of both fluoride-loaded effluent and sodiumfluoride.Effluent

solutions of 50 and 100 mg fluoride/litre produced high mortality,

whereas sodium fluoride at concentrations up to 100 mg fluoride/litre

caused negligible mortality.

Nell & Livanos (1988) found that weight gains in Sydney rock

oysters (Saccostrea commercialis) decreased linearly (P < 0.01) with

increasing fluoride additions from 0 to 30 mg/litre, and there was a 20%

growth depression at the highest fluoride concentration. Th e

b ackground level of fluoride in this study was 0.7 mg/litre. Fluoride

concentrations of up to 11 mg/litre had no significant effect on growth

of prawns (Penaeus indicus) over a 20-day exposure period (McClurg,

1984). Fluoride (5.88 mg/litre) had no effect on the survival of mud

crabs (Tylodiplax blephariskios) or the survival and growth of 
Table 15. Acute toxicity of sodium fluoride to aquatic invertebratesa

Organism Size/age Temperatur

e

(oC)

Hardness

(mg/litre)b

pH Salinit

y

(‰)

Parameterc Concentration

(mg

fluoride/litre)d

Reference

Water flea

(Daphnia magna)

Neonates 20 24-h EC50 205 n Dave (1984)

<24 h 20 8 24-h EC50 352 n Kühn et al. (1989)

<24 h 173 8 24-h LC50 308 n LeBlanc (1980)

<24 h 173 8 48-h LC50 154 n LeBlanc (1980)

Neonates 20 48-h EC50 98 n Dave (1984)

<24 h 15 169.3 8.14 48-h LC50 304 m Fieser et al. (1986)

<24 h 20 169.3 8.14 48-h LC50 251 m Fieser et al. (1986)

<24 h 25 169.3 8.14 48-h LC50 200 m Fieser et al. (1986)

Caddisfly

(Chimarra

marginata)

Last instar 15.2 15.6 7.5 48-h LC50 120 m Camargo (1991)

Last instar 15.2 15.6 7.5 72-h LC50 79.7 m Camargo (1991)

Last instar 15.2 15.6 7.5 96-h LC50 44.9 m Camargo &

Tarazona (1990)

Caddisfly

(Hydropsyche

bulbifera)

Last instar 15.2 15.6 7.5 48-h LC50 79.2 m Camargo (1991)

Last instar 15.2 15.6 7.5 72-h LC50 44.9 m Camargo (1991)

Last instar 15.2 15.6 7.5 96-h LC50 26.3 m Camargo &

Tarazona (1990)
Table 15 (contd).

Organism Size/age Temperatur e(oC)Hardness

(mg/litre)

b

pH Salinit y

(‰)

Parameterc Concentration

(mg

fluoride/litre)

d

Reference

Caddisfly (Hydropsyche

exocellata)

Last instar 15.2 15.6 7.5 48-h LC50 86.6 m Camargo (1991)

Last instar 15.2 15.6 7.5 72-h LC50 43.7 m Camargo (1991)

Last instar 15.2 15.6 7.5 96-h LC50 26.5 m Camargo &

Tarazona (1990)

Caddisfly (Hydropsyche

lobata)

Last instar 15.2 15.6 7.5 72-h LC50 78.2 m Camargo (1991)

Last instar 15.2 15.6 7.5 96-h LC50 48.2 m Camargo &

Tarazona (1990)

Caddisfly (Hydropsyche

pellucidula)

Last instar 15.2 15.6 7.5 48-h LC50 112 m Camargo (1991)

Last instar 15.2 15.6 7.5 72-h LC50 59.1 m Camargo (1991)

Last instar 15.2 15.6 7.5 96-h LC50 38.5 m Camargo &

Tarazona (1990)

Caddisfly (Hydropsyche

bronta)

Last instar 18 40.2 7.8 48-h LC50 52.6 m Camargo et al.

(1992)

Last instar 18 40.2 7.8 72-h LC50 25.8 m Camargo et al.

(1992)

Last instar 18 40.2 7.8 96-h LC50 17 m Camargo et al.

(1992)
Table 15 (contd).

Organism Size/age Temperatur

e

(

oC)

Hardness

(mg/litre)b

pH Salinit

y

(‰)

Parameterc Concentration

(mg

fluoride/litre)d

Reference

Caddisfly

(Hydropsyche

occidentalis)

Last instar 18 40.2 7.8 48-h LC50 102 m Camargo et al.

(1992)

Last instar 18 40.2 7.8 72-h LC50 53.5 m Camargo et al.

(1992)

Last instar 18 40.2 7.8 96-h LC50 34.7 m Camargo et al.

(1992)

Caddisfly

(Cheumatopsyche

pettiti)

Last instar 18 40.2 7.8 48-h LC50 128 m Camargo et al.

(1992)

Camargo (1996b) Last instar 18 40.2 7.8 72-h LC50 73.2 m

Last instar 18 40.2 7.8 96-h LC50 42.5 m

Prawn (Penaeus

indicus)

35 96-h LC50 1118 ne McClurg (1984)

Mysid shrimp

(Mysidopsis

bahia)

96-h LC50 10.5 n LeBlanc (1984)

a All tests were conducted under static conditions (water unchanged for duration of test).

b Hardness expressed as mg calcium carbonate/litre. 

c EC50s based on immobilization. 

d n = based on nominal concentrations; m = based on measured concentrations. 

e Since seawater (35‰) was used in this test, it must be assumed that only approximately 100 mg fluoride/litre was, in fact, dissolved.
Effects on Other Organisms in the Laboratory and Field

137

penaeid shrimps (Penaeus indicus) during 68-day exposures when

compared with controls (0.89 mg fluoride/litre). In a 113-day test,

shrimps gained significantly more weight during exposure to fluoride

(5.5mg/litre)than did controls.The authors attributed this to variations

in the food source within the tanks (Hemens et al., 1975).

The fingernail clam (Musculium transversum) appears to be one

of the most sensitive freshwater species tested. Sparks et al. (1983)

conducted an 8-week flow-through experiment in which statistically

significant mortality (50%) was observed at a concentration of 2.8 mg

fluoride/litre. The brine shrimp (Artemia salina) was the most sensitive

marine species tested. In a 12-day static renewal test using brine

shrimp larvae,statistically significant growth impairment (measured as

body length increase relative to controls) occurred at 5.0 mg

fluoride/litre (Pankhurst et al., 1980). In a flow-through 90-day life cycle

test, the amphipods Grandidierella lutosa and G. lignorum showed

maximum population increase at a mean fluoride concentration of 2.6

mg/litre (background seawater levels ranged from 1.3 to 1.7 mg

fluoride/litre). Population performance was comparable to controls at

5 mg fluoride/litre. A maximum acceptable toxicant concentration

(MATC) was set at between 5.0 and 6.2 mg fluoride/litre. However,

female fecundity appeared to be the most sensitive parameter, and a

mean MATC based on this parameter was 4.2 mg fluoride/litre (Connell

& Airey, 1982).

In a 3-week exposure test, survival and reproduction of Daphnia

magna were studied (Fieser et al., 1986). Impairment of reproduction

was observed at fluoride concentrations greater than 26 mg/litre. A

concentration of 35 mg fluoride/litre reduced the neonate production

to 44% of controls. The average number of live young dropped by

more than 98% at 49 mg fluoride/litre. However, no statistics were

performed in the study. Dave (1984) calculated that the NOEC for

growth in Daphnia magna after 7 and 21 days was between 3.7 and

7.4 mg fluoride/litre. Similarly,for parthenogenic reproduction, the 21-

day NOEC was between 3.7 and 7.4 mg fluoride/litre. The “safe”

concentration, equivalent to the geometric mean of the NOEC or

MATC in hard water, was 4.4 mg fluoride/litre. Kühn et al. (1989)

reported a 21-day NOEC of 14 mg fluoride/litre for Daphnia magna; the

most sensitive parameter was reproduction rate.
EHC 227: Fluorides

138

9.1.2.3 Vertebrates

The acute toxicity of fluoride to fish is summarized in Table 16.

Ninety-six-hourLC50s forfreshwaterfish range from51 mg fluoride/litre

(rainbow trout, Oncorhynchus mykiss) to 460 mg fluoride/litre

(threespine stickleback, Gasterosteus aculeatus). All of the acute toxicity tests (96 h) on marine fish gave results greater than 100 mg

fluoride/litre.

Inorganic fluoride toxicity to freshwater fish appears to be negatively correlated with water hardness (due to the complexation of

fluoride ions with calcium) and positively correlated with temperature

(Angelovic et al., 1961; Pimentel & Bulkley, 1983; Smith et al., 1985).

The 96-h LC50 for rainbow trout exposed to sodium fluoride in soft

water (17 mg calcium carbonate/litre) was 51 mg fluoride/litre.

Increasing the waterhardness to 49 mg calciumcarbonate/litre doubled

the LC50 to 128 mg fluoride/litre; a further increase in water hardness to

182 mg calcium carbonate/litre led to an LC50 of 140 mg fluoride/litre

(Pimentel & Bulkley, 1983). Angelovic et al. (1961) found that

increasing temperature significantly increased the toxicity of fluoride

to rainbow trout at temperatures ranging from 7.2 to 23.9 °C.

Camargo & Tarazona (1991) exposed rainbow trout (O. mykiss)

and brown trout (Salmo trutta) to fluoride in soft water (22 mg calcium

carbonate/litre) during short-termtoxicitytests. Forrainbowtrout, 120-,

144-, 168- and 192-h LC50s were 92.4, 85.1, 73.4 and 64.1 mg

fluoride/litre,respectively; for brown trout, they were 135.6,118.5,105.1

and 97.5 mg fluoride/litre, respectively. The addition of chloride ions

(sodium chloride) decreases the toxicity of fluoride. LC50s (120 h) for

rainbow trout were 6 mg fluoride/litre in the absence of chloride ions

and 22 mg fluoride/litre at a chloride ion concentration of 34 mg/litre

(Neuhold & Sigler, 1962). LT50 values for brown trout exposed to

fluoride at a water hardness of 73 mg calciumcarbonate/litre have been

calculated. LT50 values ranged from ~12 h at 60 mg fluoride/litre to ~80

h at 20 mg/litre; at concentrations of #15 mg/litre, LT50 values were

>240 h (Wright, 1977).

Neuhold & Sigler (1960) reported that 20-day LC50s for rainbow

trout (O. mykiss) (10–20 cm) ranged from 2.7 to 4.7 mg fluoride/litre in

static renewaltests at 13 °C undersoft-water conditions (<3mg calcium

carbonate/litre). The authors noted that there was no further
Table 16. Acute toxicity of fluoride to fisha

Organism Size/age Temperatur

e

(°C)

Hardness

(mg/litre)b

 pH Salinit

y

(‰)

Parameter Concentration

(mg fluoride/

litre)c

Reference

Rainbow trout

(Oncorhynchus

mykiss)

<3 g 15 23–62 7.4–8.0 96-h LC50 200 n Smith et al. (1985)

1.8 g 12 17 7.2 96-h LC50 51 m Pimentel & Bulkley (1983)

1.8 g 12 49 8.3 96-h LC50 128 m Pimentel & Bulkley (1983)

1.8 g 12 182 8.3 96-h LC50 140 m Pimentel & Bulkley (1983)

1.8 g 12 385 8.7 96-h LC50 193 m Pimentel & Bulkley (1983)

fry 15.1–15.5 20.6–24.2 7.5–7.8 96-h LC50 107.5 m Camargo & Tarazona

(1991)

Brown trout (Salmo

trutta)

fry 15.1–15.5 20.6–24.2 7.5–7.8 96-h LC50 164.5 m Camargo & Tarazona

(1991)

Fathead minnow

(Pimephales

promelas)

<1 g 15–19 10–44 7.5–8.0 96-h LC50 315 n Smith et al. (1985)

Threespine 

stickleback

(Gasterosteus

aculeatus)

<1 g 20 78 7.4–7.9 96-h LC50 340 n Smith et al. (1985)

<1 g 20 146 7.4–7.9 96-h LC50 380 n Smith et al. (1985)

<1 g 20 300 7.4–7.9 96-h LC50 460 n Smith et al. (1985)

Bluegill (Lepomis

macrochirus)

96-h LC50 >240 n LeBlanc (1984)
Table 16 (contd).

Organism Size/age Temperatur

e

(°C)

Hardness

(mg/litre)b

 pH Salinit

y

(‰)

Parameter Concentration

(mg fluoride/

litre)c

Reference

Sheepshead minnow

(Cyprinodon

variegatus)

8–15 mm 25–31 10–31 96-h LC50 >225 n Heitmuller et al. (1981)

Ambassid (Ambassis

safgha)

adult 20–21 10–28 96-h LC50 >100 n Hemens & Warwick (1972)

Crescent perch

(Therapon 

jarbua)

adult 20–21 10–28 96-h LC50 >100 n Hemens & Warwick (1972)

Mullet (Mugil

cephalus)

juvenile 20–21 10–28 96-h LC50 >100 n Hemens & Warwick (1972)

a All tests were conducted under static conditions (water unchanged for duration of test).

b Hardness expressed as mg calcium carbonate/litre.

c n = based on nominal concentrations; m = based on measured concentrations.
Effects on Other Organisms in the Laboratory and Field

141

mortality after 10 days. The symptoms of acute fluoride intoxication

included lethargy, violent and erratic movement and death. The

authors postulated that the variation in the response of fish to fluoride

could be due to a chloride–fluoride excretion mechanism over the

epithelial tissues (Sigler& Neuhold, 1972). Camargo (1996a) calculated

“safe concentrations” (infinite hours LC0.01s) for rainbow trout and

brown trout at fluoride concentrations of 5.1 and 7.5 mg fluoride/litre,

respectively.

Hemens et al. (1975) found that fluoride (5.9 or 5.5 mg/litre)had no

effect on survival of mullet (Mugil cephalus) during 68- or 113-day

exposures when comparedwith controls (0.9 mg fluoride/litre). Fluoride

had no significant effect on the growth of larger mullet (50–55 mm);

however, smaller mullet (16–18 mm) showed a significant decrease in

growth during the 68-day test.

The eggs of the freshwater catla (Catla catla) were exposed to

fluoride concentrations ranging from 1.9 to >16 mg/litre from both

effluent and sodium fluoride dilutions. Hatching occurred after 6 h in

both controls and those exposed to 1.9 mg fluoride/litre. A t concentrations of $3.2 mg fluoride/litre for effluent dilutions and $3.6 mg

fluoride/litre for sodium fluoride dilutions, hatching was delayed by

1–2 h. The authors stated that the lowpH (4.1) of the effluent may have

contributed to its toxicity. The weight of eggs exposed to fluoride

decreased with increasing fluoride concentration and exposure time.

Significant decreases in egg protein were observed at fluoride concentrations causing delayed hatching.The toxicity of fluoride to eggs was

more related to the availability of fluoride ions than to total fluoride in

the media (Pillai & Mane, 1984).

Kaplan et al. (1964) found little external evidence of toxicity in

adult leopard frogs (Rana pipiens) exposed to fluoride concentrations

ranging from 5 to 50 mg/litre for 30 days. Total red and white cell

counts were reduced at all fluoride exposure concentrations; however,

no statistical analysis was carried out. A t fluoride concentrations ranging from50 to 300 mg/litre,the survival time decreased with increasing

exposure concentration. All frogs died within 30 days at both 250 and

300 mg fluoride/litre. Kuusisto & Telkkä (1961) exposed frog (Rana

temporaria) larvae to sodium fluoride concentrations of 1, 2 and 10 mg/

litre. All fluoride concentrations caused a delay in metamorphosis and
EHC 227: Fluorides

142

reduced the activity of the thyroids revealed by histological

examination. No statistical analysis of the results was carried out.

9.1.3 Terrestrial organisms

9.1.3.1 Plants

Fluoride toxicity to terrestrialplants has been studied extensively

(Weinstein, 1977). Signs of inorganic fluoride phytotoxicity (fluorosis),

such as chlorosis, necrosis and decreased growth rates, are most likely

to occur in the young, expanding tissues of broadleaf plants and

elongating needles of conifers (Pushnik & Miller, 1990). The induction

of fluorosis has been clearly demonstrated in laboratory, greenhouse

and controlled field plot experiments (Weinstein, 1977; Hill & Pack,

1983; Staniforth & Sidhu, 1984; Doley, 1986, 1989; McCune et al., 1991).

Weinstein & Alscher-Herman (1982) reviewed the physiological

responses of plants to fluoride. They concluded that calcium and

magnesium play a central role in the response of plants to fluoride. A

detoxification mechanism appears to consist of the sequestration and

insolubilization of fluoride by reaction with calcium. The effects of

atmospheric fluoride on a wide variety of terrestrial plant species have

been extensively reviewed (VDI, 1989); the studies that follow have

been chosen to reflect the lowest adverse effect levels cited in the

literature.

A large number of the papers published on fluoride toxicity to

plants concern greenhouse fumigation with hydrogen fluoride.

Wolting (1975) observed leaf necrosis on freesia (Freesia sp.) cultivars

during continuous fumigation at 0.5 μg fluoride/m3 for 5 months and

during intermittent fumigation with 0.3 μg fluoride/m3(6 h/day,

3–4 times/week) for 18 weeks. Leaf tip necrosis was identified in a

variety of tulip (Tulipa sp.) cultivars exposed to fluoride for 6 h/day for

3 days at concentrations ranging from 0.15 to 0.67 μg fluoride/m3

(Wolting, 1978). Hitchcock et al. (1962) reported necrotic leaf tips in

gladiolus (Gladiolus sp.) cultivars exposed to 0.17 μg fluoride/m3for

9 days.In 40-day exposures of gladiolus cultivars to 0.76 μg/m3, Hill et

al. (1959) found 46% necrosis and a significant increase in respiration

(39%). Long-term greenhouse experiments (2–10 growing seasons)

were conducted to determine the effects (necrosis, photosynthesis and

growth) of hydrogen fluoride on 16 varieties offlower, fruit,vegetable

and forage crops (Hill & Pack, 1983). Three identical greenhouses were
Effects on Other Organisms in the Laboratory and Field

143

used to represent a control (filtered ambient air; mean hydrogen

fluoride level was 0.03 μg fluoride/m3), a hydrogen fluoride treatment

(filtered ambient air; mean hydrogen fluoride levels ranged from 0.3 to

1.9μg fluoride/m3, depending on the exposure duration for gladioli) and

an industrialtreatment (unfiltered ambient air; located 1.6kmdownwind

of a steel plant; mean hydrogen fluoride levels ranged from 0.2 to 1.9

μg fluoride/m3). The most sensitive species tested (based on

measurement of necrosis over two growing seasons, following

117 days of hydrogen fluoride exposure) was the snow princess

gladio lus (Gladiolus grandiflorus). The lowest-observed-effect level

(LOEL) for leaf necrosis (65% of leaves) in this plant was 0.35 μg

fluoride/m3. The extent of necrosis was positively correlated with

increased hydrogen fluoride concentration and increased exposure

duration. Less severe necrosis (2%) occurred in the industrial greenhouse chamber. The results from other test species included reduced

growth or necrosis at hydrogen fluoride exposure concentrations of

0.44, 0.54 and 21.3 μg fluoride/m3for apples (Malis domestica borkh),

pole beans (Phaseolus vulgaris) and forage (red clover, Trifolium

pratense, and alfalfa, Medicago sativa), respectively.

Murray (1984a) exposed grapevines (Vitis vinifera) to hydrogen

fluoride concentrations of 0.07 (control), 0.17 and 0.27 μg fluoride/m3

for 189 days. Foliar necrosis was first observed on vines exposed to

0.17 and 0.27 μg fluoride/m3 after 99 and 83 days, respectively.Fluoride

had no significant effect on bunch weight, number of bunches, grape

yield,grape water or potential alcohol content, leaf chlorophyll b or leaf

protein concentration. Both chlorophyll a and total chlorophyll were

significantly reduced by fluoride exposure. Doley (1986) fumigated

three varieties of grapevine with hydrogen fluoride forfoursuccessive

growing seasons (the duration of exposure varied from 54 to 159 days

for each season). Leaf size during the first growth of the season was

not affected by fluoride concentrations of up to 1.5 μg/m3. However,

leafsize was significantly reduced during the middle and latter portion

of the fourth season of fumigation in two of the varieties at 0.64 μg

fluoride/m3.

Suture red spot is a serious physiological disorder of the peach

(Prunus persica) fruit. In open-top field chambers, hydrogen fluoride

levels causing an induction of this disorder were 0.3 μg fluoride/m3 in

continuous exposures of 80 days and 1.0 μg fluoride/m3 in intermittent
EHC 227: Fluorides

144

exposures for three 6-h periods each week for 9 weeks (MacLean et al.,

1984b).

Wheat (Triticum aestivum) and barley (Hordeum vulgare)

exposed to hydrogen fluoride (0.38 μg/m3) for 90 days showed no

effect of treatment on yield.There was, however, a significant increase

in the grain protein concentration of fluoride-exposed barley plants

(Murray & Wilson, 1988c). MacLean & Schneider (1981) found a

significant reduction (20%) in the mean dry mass of wheat plants (T.

aestivum) exposed to 0.9 μg fluoride/m3for 4 days. MacLean et al.

(1984a) exposed wheat (T. aestivum) and two sorg h um (Sorghum sp.)

hybrids to hydrogen fluoride at concentrations ranging from 1.6 to

3.3 μg/m3for three successive 3-day periods. Anthesis (the maturing

of the stamens) was the mostsensitive stage, and this occurred during

the first exposure period in wheat and the third exposure in sorghum.

Hydrogen fluoride-induced foliar damage did not occur in wheat;

however, both sorghumhybrids developed foliardamage in proportion

to the exposure concentration. Pack (1971) found no effect of hydrogen

fluoride on the progeny of bean plants (no species stated) grown at

0.58 μg fluoride/m3. However, the primary leaves of some F1 progeny

of plants grown at $2.1 μg fluoride/m3 were severely stunted and

distorted.MacLean et al. (1977) observed a significant reduction (25%)

in the fresh mass of pods from bean plants (Phaseolus vulgaris)

exposed to 0.6 μg fluoride/m3for 43 days (emergence to harvest) in

open-top field chambers. There was no effect of hydrogen fluoride

exposure (0.6 μg fluoride/m3) on growth or fruiting in tomato (Lycopersicon esculentum) plants.

Madkour & Weinstein (1988) found that hydrogen fluoride at

nominal concentrations of 1, 3 and 5 μg fluoride/m3inhibited the active

loading of [14C]sucrose into the minor veins of soybean (Glycine max)

leaf discs during 8- to 11-day exposures. Similar results were obtained

for both controlled-environment and field conditions.

Several species of eucalypt (Eucalyptus spp.) have shown sensitivity to fluoride. Murray & Wilson (1988b) exposed E. tereticornis to

hydrogen fluoride (0.38 μg fluoride/m3) for 90 days in open-top

chambers. Fluoride significantly reduced leaf surface area and weight

in mature and immature leaves. The same significant effects on immature leaves were noted for marri (E. calophylla), tuart (E. gomphocephala) and jarrah (E. marginata) at 0.39 μg fluoride/m3

for 120 days.
Effects on Other Organisms in the Laboratory and Field

145

However, in mature leaves, leaf surface area and weight were reduced

in tuart, and surface area was reduced in marri. In jarrah,these two endpoints were unaffected (Murray & Wilson, 1988a).

Coniferous trees have also been identified as sensitive plant species. In field exposure chambers, significant dose–response relationships were observed between hydrogen fluoride exposure and

developmen t of needle necrosis in 2-year-old black spruce (Picea

mariana) and 3-year-old white spruce (P. glauca) (McCune et al.,

1991). Four test chambers, one ofwhich served as a control, were used

for different hydrogen fluoride exposure regimens for each coniferous

species. Measurements of tissue necrosis were recorded 10 days

following hydrogen fluoride exposure for 78 h with black spruce and 20

days following hydrogen fluoride exposure for 50 h with white spruce.

Lowest-observed-effect concentrations (LOECs)for necrosis were 4.4

and 13.2 μg fluoride/m3for black spruce and white spruce,respectively.

Airborne fluoride can also affect plant disease development,

although the type and magnitude of the effects are dependent on the

specific plant–pathogen combination (Laurence, 1983). Van Bruggen

& Reynolds (1988) found that exposure of soybean (Glycine max)

plants to hydrogen fluoride (2 μg fluoride/m3) in a controlled chamber

led to significantly larger hypocotyl lesions after inoculation with

either Rhizoctonia solani or Phytophthora megasperma. Plants were

exposed to hydrogen fluoride for 1 week before and after the

infestation.However, Laurence&Reynolds(1984)found no significant

effect of hydrogen fluoride (1 or 3 μg fluoride/m3 for 5 days) on lesion

characteristics of the bacterium Xanthomonas campestris on the leaves

of red kidney bean (Phaseolus vulgaris) plants. Similar findings were

reported by Reynolds & Laurence (1990) during both continuous (1, 3

or 5 μg fluoride/m3 for 15, 5 or 3 days, respectively) and intermittent (3

or 5 μg fluoride/m3 for 15 days) exposures.

Severalstudies on fluoride have been carried out in culture media.

Belandria et al. (1989) studied the effect of sodium fluoride on the

germination of lichen ascospores. They found that 20% of the

Xanthoria parietina spores were able to germinate in the presence of

19 mg fluoride/litre (1000 μmol/litre), and similar results were obtained

for Physconia distorta and Peltigera canina. P. distorta was found to

be 37% inhibited at a concentration of 0.95 mg fluoride/litre

(50 μmol/litre). The most resistant species was Lecanora conizaeoides,
EHC 227: Fluorides

146

which was only weakly inhibited (44% inhibition) at 38 mg fluoride/litre

(2000 μmol/litre). Ballantyne (1984) found that exposure of pea (Pisum

sativum) shoots to solutions containing 19 mg fluoride/litre (1

mmol/litre) for up to 3 days caused significant increases in ATP levels

in the youngest, fully expanded leaves and in entire shoots. These

increases occurred before significant decreases in fresh weight, water

content or water uptake and stem elongation. Neither in vitro exposure

of spinach (Spinacia oleracea) petioles to 38 mg fluoride/litre (2

mmol/litre) for3 h nor in vivo exposure of plants to gaseous hydrogen

fluoride at 5 μg fluoride/m3for 6 days resulted in visible injury.

However, there was evidence from experiments on chlorophyll a

fluorescence of a reduced ability to develop or maintain a transthylakoid proton gradient in chloroplasts containing elevated levels of

fluoride (Boese et al., 1995).

Fluoride at concentrations of 190 mg/litre (10 mmol/litre) significantly reduced the in vitro photosynthetic capacity of azalea (Rhododendron sp.) cultivars (Ballantyne, 1991). 

Stevens et al. (1998a) grew tomato (Lycopersicon esculentum) and

oat (Avena sativa) plants in nutrient solutions (12–13 days) at nominal

sodiumfluoride concentrations ranging from 1 to 128 mg fluoride/litre.

Fluoride ion concentrations greater than 28 mg/litre (1473 μmol/litre)

caused significant decreases in the dry weights of tomato shoots and

roots; oat plants were unaffected at all fluoride exposure

concentrations. Stevens et al. (1998b)found that dry weights of tomato

and oat shoots and roots were significantly decreased as the pH of the

solution culture decreased below 4.3 at hydrogen fluoride

concentrations of 1.4 mg fluoride/litre (71 μmol/litre) and 2.6 mg

fluoride/litre (137 μmol/litre) fortomatos and oats, respectively. Fluoride concentrations in tomato and oat shoots that corresponded with

significant reductions in plant dry weights were 228 and 125 mg/kg,

respectively. Aluminium–fluoride complexation increased fluoride

uptake (see chapter 4) and toxicity in oats relative to the free fluoride

ion; shoot and root dry weights were significantly limited at AlF2+

concentrations of 11–22 μmol/litre and AlF2

+

concentrations of 126–357

μmol/litre (Stevens et al., 1997).

Ratsch & Johndro (1986) calculated EC50s, based on inhibition of

root growth, for lettuce (Lactuca sativa) plants exposed to fluoride.For
Effects on Other Organisms in the Laboratory and Field

147

the 115-h papersubstrate method, an EC50 value of 450 mg fluoride/litre

was found, and for the 5-day solution method, the EC50 was 660 mg

fluoride/litre.

Cooke (1976) studied the effect of fluoride (200 mg/litre) on

common sunflower (Helianthus annus) seeds grown in sand culture.

No effect on total dry weight was observed; however, there were significant reductions in leaf growth. Keller (1980) grew Norway spruce

(Picea abies) cuttings in sand and watered with 100 mg fluoride/litre

during winter until bud break. Watering with sodium fluoride significantly depressed the carbon dioxide uptake of shoots. Although the

previous year’s needles did not show signs of injury, most of the new

needles were killed immediately after flushing with fluoride. Exposure

to fluoride significantly increased the susceptibility of plants to sulfur

dioxide in subsequent fumigation experiments. Zwiazek & Shay (1987)

grew jack pine (Pinus banksiana) seedlings in sand culture at 3 or

15 mg fluoride/kg dry weight. Wilting was the first sign of fluoride

injury and occurred in approximately 50% of plants after 25–26 h at

15 mg fluoride/kg and 2–6 h later in only 7% of plants exposed to

3 mg/kg. Fluoride-induced injuries to mesophyll and guard cells were

similar to those caused by drought and included the appearance of

lipid materialin the cytoplasmduring early stages of injury,suggesting

cell membrane damage. Plants exposed to 3 mg/kg for up to 168 h

showed significant reductions in water content. Respiration was

significantly reduced after 24 h, but not after longer exposure times,

while photosynthetic oxygen release was significantly reduced at 48

and 91 h but had recovered after 168 h (Zwiazek & Shay, 1988a).

Zwiazek & Shay (1988b) reported that 3 mg fluoride/kg significantly

reduced growth (as measured by fresh weight) and acid phosphatase

activity and increased total organic acid content of jack pine (P.

banksiana) seedlings. 

A few studies have been carried out in which the fluoride exposures have been via the soil. However, the type of soil can greatly

a ffect the uptake and subsequent toxicity of fluorides. For example,

Conover& Poole (1971) found that calcined clay prevented the uptake

of water-soluble fluoride, whereas sphagnum peat did not have the

same capability.

In pot experiments, Singh et al. (1979) grew rice (Oryza sativa)

plants in soil (pH >9.4) amended with 25–200 mg fluoride (ad ded as

sodium fluoride); the rice plants were harvested, and the soil was
EHC 227: Fluorides

148

subsequently sown with wheat (Triticum aestivum). The authors

found that the critical water-extractable fluoride concentration in soil

for grain yield in wheat was 22 mg fluoride/kg, which related to a

fluoride content of 35 mg/kg in mature wheat straw. 

There are limited data available to determine the critical value for

fluoride in soil with respect to plant toxicity. The data are also complicated by plant species ranges of sensitivities, heterogeneity of soils,

soil chemical parameters that can influence fluoride availability and

toxicity, and the relative toxicity of ionic species of fluoride found in

the soil solution. However, more controlled solution culture studies

have attempted to define toxic concentrations of fluoride exposed to

the plant roots and are perhaps the best first approximation of toxic

concentrations of fluoride in soil solution.

Elrashidi et al. (1998) found that an application of 100 mg fluoride/kg significantly reduced dry matter yield of barley (Hordeum

vulgare) grown on both acid (pH4.75) and neutral (pH 6.6) soils for 40

days; however, plants growing on alkaline soil (pH 7.5) were unaffected at 1000 mg/kg. The authors found no clear influence of phosphate (50–550 mg/kg soil) on the adverse effect of fluoride on dry

matter yield.

Davis & Barnes (1973) found that an added soil fluoride concentration of 380 mg/kg (20 mmol/litre) significantly reduced the growth of

loblolly pine (Pinus taeda) and red maple (Acer rubrum) seedlings. 

9.1.3.2 Invertebrates

Johansson & Johansson (1972) found that egg production and

survival were adversely affected in flour beetles (Tribolium confusum)

exposed to flour containing 4524 mg fluoride/kg (0.1% sodiumfluoride)

for up to 27 days. However, short-term (1–7 days) exposure to fluoride

concentrations of 452.4 mg/kg (0.01% sodium fluoride) produced

significant stimulation of egg production.

Hughes et al. (1985) fed cabbage looper (Trichoplusia ni) larvae

on a wheat germ diet dosed with sodium fluoride (50 and 187 mg

fluoride/kg dry weight) or potassium fluoride (48 and 235 mg fluoride/kg dry weight) or a diet of hydrogen fluoride-fumigated leaves

(40–187 mg fluoride/kg dry weight). Larvalfeeding, growth and rate of

development were generally reduced on diets containing sodium
Effects on Other Organisms in the Laboratory and Field

149

fluoride and potassium fluoride. The same parameters were generally

greater with or unaffected by diets containing fumigated leaves.

Wang & Bian (1988) exposed silkworms (Bombyx mori) to mulberry (Morus alba) leaves containing fluoride concentrations ranging

from10 to 200 mg/kg.The threshold concentration formortality was 30

mg/kg; 30% mortality was observed at concentrations of 30–50 mg

fluoride/kg, 70% at 50–120 mg fluoride/kg and 95% at 120–200 mg

fluoride/kg. There was a close correlation between cocoon development and the fluoride content of leaves, with >80 mg fluoride/kg

severely inhibiting cocoon production.

Survival of isopods (woodlouse, Porcellio scaber) was not

affected after 4 weeks of exposure to fluoride levels in litter up to

3230 mg/kg (170 μmol/g) (Van Wensem & Adema, 1991).

Davies et al. (1998) found no effect on the reproduction of aphids

(Aphis fabae) feeding on bean (Vicia faba) plants (12 days) that had

been previously exposed to either sodium fluoride in nutrient solution

(15 μg fluoride/cm3) or hydrogen fluoride via fumigation (6.5 μg

fluoride/m3). Plants accumulated more fluoride in the shoots during

fumigation and at levels of up to 200 mg fluoride/kg; aphids accumulated up to 300 mg fluoride/kg from these plants. Similarly, Port et al.

(1998) found no effect of hydrogen fluoride on the growth and survival

of cabbage white caterpillars (Pieris brassicae) at a dietary concentration of 178.3 mg fluoride/kg.

9.1.3.3 Vertebrates

Guenter & Hahn (1986) fed white leghorn hens on a diet containing up to 1300 mg fluoride/kg for 252 days. Concentrations of

$1000 mg/kg resulted in sig nificant depression of feed intake, body

weight gain, feed efficiency and egg quality. In a second experiment,

pullets were fed 1300 mg/kg for 49 days;similarresults were obtained,

but the addition of aluminium (1040 mg/kg) to the diet reduced the

effects. Chan et al. (1973) found no effect on growth in Japanese quail

(Coturnix coturnix japonica) fed diets resulting in average tibial

fluoride concentrations of 13–2223 mg/kg ash weight. 
EHC 227: Fluorides

150

Fleming et al. (1987) dosed nestling European starlings (Sturnus

vulgaris) with daily oral doses of 6–160 mg fluoride/kg body weight.

Dosing began 24–48 h after hatching and continued for 16 days. The

24-h LD50 was 50 mg/kg body weight for 1-day-old chicks and 17 mg/kg

body weight for 16-day-old nestlings. Growth rates were significantly

reduced at 13 and 17 mg fluoride/kg body weight (the highest doses at

which growth was monitored). No histological damage due to fluoride

treatments was found in liver, spleen or kidney.

Carrière et al. (1987) fed nesting American kestrels (Falco sparverius) on a diet containing fluoride levels of 62.4 (background), 4512

or 7690 mg/kg for 10 days. The diet consisted of cockerels (Gallus

gallus) that had been exposed to fluoride. Fluoride levels in femurs and

eggshells of treated kestrels were significantly higher than those in

controls. There were no significant effects of fluoride on per cent

fertility or hatchability of eggs. Clutch sizes tended to be smaller with

increasing fluoride in the diet; however, the difference was not statistically significant. Seven-day-old kestrel chicks were fed on a cockerel

mash diet containing 0, 1120 or 2240 mg/kg for 27 days. Growth of

chicks and weights of internal organs were not significantly affected

by fluoride in the diet. Per cent bone ash was significantly increased,

while bone-breaking strength was significantly decreased by fluoride

(Bird et al., 1992). Bird & Massari (1983) fed kestrels on a diet to which

flourcontaminated with fluoride (10, 50 or 500 mg/kg) had been applied.

The birds receiving the highest fluoride dose died within 6 days.

Fluoride at the lower doses had no effect on clutch size,hatchability or

fledging success but was associated with a higher fertility. Eggs laid

by kestrels at 50 mg/kg had significantly thicker shells. Lower

reproductive success of eastern screech-owls (Otus asio) wa s noted

when birds were fed 90 mg fluoride/kg diet wet weight (as sodium

fluoride), but not when fed 18 mg fluoride/kg diet (Hoffman et al., 1985;

Pattee et al., 1988).

Most of the early work on mammals was carried out on domesticated ungulates (Suttie,1983). Fluorosis has been observed in experimental studies on cattle and sheep exposed to fluoride. Cattle are less

tolerant of fluoride toxicity than are other livestock (Phillips & Suttie,

1960). In long-term experiments with beef cattle, 30 mg/kg of dietary

fluoride caused excessive wear and staining of teeth (Hobbs & Merriman, 1959). In a furtherstudy, beginning with young calves and lasting

7 years, the tolerance for soluble fluoride was also 30 mg/kg dry diet

(Shupe et al., 1963). Suttie et al. (1957) found that lactating cows could
Effects on Other Organisms in the Laboratory and Field

151

tolerate 30 mg/kg, with a rate of 50 mg/kg causing fluorosis within 3–5

years.

Tolerance levels ha ve been identified for domesticated animals

based on clinical signs and lesions.Tolerance levels in feed range from

30–40 mg/kg dry weight in dairy cattle to 150 mg/kg in lambs; in water,

tolerance levels range from 2.5–4.0 mg/litre in dairy cattle to 12–15

mg/litre in lambs (Shupe & Olson, 1983; Cronin et al., 2000). The lowest

dietary level observed to cause an effect on wild ungulates was in a

controlled captive study, where white-tailed deer (Odocoileus

virginianus) were exposed to 10 (control feed), 35 or 60 mg fluoride/kg

wet weight (as sodium fluoride) in their diet for 2 years (Suttie et al.,

1985). A general mottling of the incisors characteristic of dental

fluorosis was noted in the animals at the 35 mg/kg diet dose; those on

the higher dose also experienced minor increased wear of the molars,

as well as mild hyperostoses of the long bones of the leg. No gross

abnormalities of the mandible were observed. The mean fluoride content of the mandibles was approximately 1700 mg/kg ash weight forthe

control, 4550 mg/kg for the low-dose group and 6600 mg/kg for the

high-dose group, the lattertwo levels being similar to those observed

in affected wild deer nearsources of industrial pollution (Karstad,1967;

Kay et al., 1975; Newman & Yu, 1976).

Deer mice (Peromyscus maniculatus) fed diets of 38 (control),

1065, 1355 or 1936 mg fluoride/kg diet dry weight (as sodium fluoride)

for 8 weeks exhibited, at all concentrations above the control, marked

weight loss, mortality, changes in femur size and dental disfigurement

(Newman & Markey, 1976). Bank voles (Clethrionomys glareolus)

showed a reduction in the number of litters per female, an increase in

the number of days from mating to producing the firstlitter, increased

mortality of offspring and a changed sexratio (greater number of males)

in offspring of animals fed 97 mg/kg diet (wet or dry basis not

specified). Animals fed 47 mg/kg diet also showed these effects, but

the differences were not significant fromthe control(Krasowska,1989).

Boulton et al. (1995) exposed short-tailed field voles (Microtus

agrestis), bank voles (Clethrionomys glareolus) and wood mice

(Apodemus sylvaticus) to drinking-water containing 0, 40 or 80 mg

fluoride/litre for up to 84 days. Both fluoride exposures induced 
EHC 227: Fluorides

152

premature mortalities in both vole species. Severe dentallesions were

observed in animals surviving the highest dose. Voles were also fed on

a diet containing 100 mg fluoride/kg (vegetation contaminated by

atmospheric fluorides). Offspring of the vole s fed the contaminated

diet had significantly lower growth rates and body weights during

stages of infancy and early adulthood. The incisors of newly born

young were not significantly different between the contaminated and

control diets; however, incisors of offspring weaned on to the

contaminated diet showed marked morphological changes and severe

dental lesions (Boulton et al., 1994a).

Fluoride was suggested as the cause of reduced milk production

with subsequent mortality of kits in farm-raised red foxes (Vulpes

vulpes) fed a diet containing 98–137 mg fluoride/kg dry weight

(Eckerlin et al., 1986).

Aulerich et al. (1987) fed mink (Mustela vison) diets containing

35–385 mg fluoride/kg for 382 days. No significant differences were

observed in body weight gains or fur quality between dosed and

control mink. No adverse effects of fluoride on breeding, gestation,

whelping or lactation were found. Survival was adversely affected at

385 mg fluoride/kg; some of the surviving mink at this concentration

had weakened frontal, parietal and femoral bones. Fluoride did not

affect haematological parameters orserumcalciumconcentrations, but

serum alkaline phosphatase activity was significantly increased at

fluoride concentrations of $229 mg/kg.

Mink (Mustela vison) kits and adult male mink were fed diets

containing fluoride (as sodiumfluoride)at concentrations ranging from

26 to 287 mg fluoride/kg wet weight for up to 8 months. Gross,

radiographic and microradiographic changes were seen in bones from

animals ingesting the higher levels of fluoride. Chemical analyses for

fluoride generally reflected the levels ingested. After data were evaluated, a tolerance level in the feed of 50 mg fluoride/kg for breeding

stock was recommended (Shupe et al., 1987).
Effects on Other Organisms in the Laboratory and Field

153

9.2 Field observations

9.2.1 Microorganisms

Rao & Pal (1978) found a positive correlation between concentrations of fluoride in soil and soil organic matter content at eight sites

near an aluminium factory in India and inferred that fluoride decreased

the activity ofsoil microorganisms responsible forlitterdecomposition.

Significant increases in the organic matter ofsoils were not found until

total soil fluoride concentrations were greater than approximately

1000 mg/kg.

Tscherko & Kandeler (1997) studied the influence of atmospheric

fluoride deposits on soil microbial biomass and its enzyme activities

near an aluminium smelter at Ranshofen, Upper Austria. Mean waterextractable fluoride concentrations ranged from 10 to 124 mg/kg dry

soil and were inversely correlated with microbial activity. In the most

contaminated soil (up to 189 mg/kg), the microbial activities were only

5–20% of those in unpolluted soil. At a fluoride concentration above

100 mg/kg, microbial biomass and dehydrogenase activity decreased

substantially, whereas arylsulfatase activity was inhibited at only

20 mg/kg. The accumulation of organic matter nearthe smelter (124 mg

fluoride/kg) also indicated severe inhibition of microbial activity by

fluoride.

9.2.2 Aquatic organisms

Kudo & Garrec (1983) simulated the accidental release of ammoniumfluoride into a pond. Mean fluoride concentrationsincreased from

0.2 to 7.3 mg/litre following the release. Fluoride levels returned to

background concentrations within 30 days. No visible toxic effects on

plants, algae,molluscs or fish were observed during the 30-day period.

No details regarding the chemical characteristics of the pond water

were given.

Ares et al. (1983) monitored fluoride concentrations and diatom

populations in seawater near an aluminiumsmelter in southern Argentina. Fluoride concentrations primarily ranged from 1.1 to 1.3 mg/litre.

Anthropogenic emissions accounted for 6–8% of the variance of fluoride levels in the waters. The correlations observed between fluoride 
EHC 227: Fluorides

154

concentrations and some structural characteristics of the diatom community did not show significant effects of the discharged fluoride.

Fluoride-loaded effluent adversely affected the species richness

of a marine encrusting community for up to 400 m from the point of

discharge. Fluoride concentrations greater than 50 mg/litre (the

concentration of fluoride in effluent at which mortality was observed

in the laboratory) seldomextended formore than 20 m from the outfall.

The authors concluded that a sublethal effect of fluoride and/or some

other effluent component appeared to be producing the observed

distribution (Pankhurst et al., 1980).

High mortality and delayed migration were observed in Pacific

salmon (Oncorhynchus sp.) migrating upstream near an aluminium

plant on the Columbia River, USA (Washington/Oregon border).

Fluoride levels in the waterranged between 0.3 and 0.5 mg/litre during

1982. Bioassay experiments on adult salmon suggested that fluoride

concentrations of 0.5 mg/litre would adversely affect migration.

Between 1983 and 1986, discharges from the aluminium plant were

reduced, there was a corresponding drop in fluoride concentrations,

and fish mortality and migration delays were decreased (Damkaer &

Dey, 1989).

Mishra & Mohapatra (1998) monitored toads (Bufo melanosticus)

at a fluoride-contaminated site at Hirakud, India. Mean haemoglobin

content, total red blood cell count and haematocrit in blood samples

were found to be significantly reduced, whereas mean corpuscular

concentration and volume were significantly elevated when compared

with toads at an uncontaminated site. Mean bone fluoride concentrations were 2736 mg/kg at the contaminated site and 241 mg/kg at the

control site.

9.2.3 Terrestrial organisms

9.2.3.1 Plants

Aluminiumsmelters, brickworks, phosphorus plants and fertilizer

and fibreglass plants have all been shown to be sources of fluoride

that are correlated with damage to local plant communities. In 1970,

vegetation in the vicinity of a phosphorus plant in Newfoundland,

Canada, began to show symptoms of damage (tip burn and margin 
Effects on Other Organisms in the Laboratory and Field

155

burn). Samples collected during 1973–1975 revealed that the degree of

damage and fluoride levels in soil humus were inversely related to the

distance fromthe plant.Average levels of fluoride in vegetation ranged

from 281 mg/kg in severely damaged areas to 44 mg/kg in lightly

damaged areas; at a control site, the fluoride concentration was 7

mg/kg (Thompson et al., 1979). Klumpp et al. (1994,1996a)reported that

plants downwind of fertilizer industries in Brazil showed damage

(necrotic bands or tip burn). Bioindicator plants have revealed that

severe damage corresponded to high leaf fluoride concentrations (no

statistical analysis performed). Klumpp et al. (1996b) found a highly

significant linear regression between leaf damage and fluoride

accumulation in Gladiolus plants; the plants developed typical

fluoride-induced leaf lesions. Murray (1981) found that plant communities near an aluminium smelter showed differences in community

composition and structure due partly to variations in fluoride tolerance.

However, it must be noted that in the field, one of the main problems with the identification of fluoride effects is the presence of confounding variables,such as other atmospheric pollutants.McClenahen

(1978) examined stands of vegetation along pollution gradients recording species richness, evenness ofstand,diversity indexand concentrations of three pollutants. Most vegetation characteristics were altered

in areas of high pollution. Statistical analysis showed a significant

positive correlation between fluorides and shrub density; however,

chloride appeared to have the greatest impact on the same parameter.

Therefore, care must be taken when interpreting the many field studies

on fluoride pollution.

Lichens have been used widely as biomonitors of fluoride

pollution. LeBlanc et al. (1971) transplanted epiphytic lichens from an

unpolluted area to various distances from an aluminium factory.

Lichens accumulated 600–900 mg fluoride/kg during periods of 4 or 12

months within 8 km of the factory compared with 70 mg/kg at a control

site. Lichen thalli exposed for 4 months at 1 km from the factory

contained some extractable chlorophyll; however, thoseexposed for 12

months did not. Soredia (viable structures with a potential to develop

into parent lichen thalli under favourable ecological conditions) were

absent in lichens growing within 4 kmof the plant.Davies (1982) found

that visible damage to lichen (Xanthoria parietina) thalli (growing

within a 30-km radius ofthe Bedfordshire brickfields,United Kingdom)
EHC 227: Fluorides

156

was observed when internal fluoride concentrations exceeded 68

mg/kg, and internal damage occurred at >90 mg fluoride/kg.

Gilbert (1985) monitored lichens near an aluminiumsmelter during

its 11-year operational life. Epiphytic lichens were severely damaged

(>50% injury) over a 25-km2area close to the smelter. Fluoride

concentrations in Ramalina farinacea near the smelter increased from

9–11 mg/kg prior to the start of the smelting opera tion to 120–156

mg/kg within 4 months and had reached these higher levels up to 3 km

from the smelter within 3 years.

Perkins & Millar (1987) studied the effect of airborne fluoride

emitted from an aluminium works on previously unpolluted assemblages of saxicolous lichens. Prior to emissions, lichens contained a

mean concentration of 16 mg fluoride/kg.Fruticose (shrubby) lichens,

such as Ramalina species, were the most sensitive to fluoride emissions, with lichens containing >100 mg fluoride/kg showing severe

damage. Some foliose (leaf-like) lichens tolerated >200 mg fluoride/kg,

and crustose (crust-like) lichens were the most tolerant group, with

overall survival at 32% and 70% for the two groups, respec tively,

within 1 km of the works. Damage to lichens was greatest less than

2 km from the works, where 41% of Ramalina thalli showed >50%

chlorosis or necrosis. Loss of lichens decreased with increasing distance fromthe works.The authors reported that lichens containing 300,

100 and 50 mg fluoride/kg dry weight lost 46, 15 and 10% of cover per

year, respectively (Perkins, 1992).

Several studies have been carried out on the effects of fluorides

on a variety of tree species and the subsequent damage to forests.

Infrared aerial photographs offorest near an aluminium plant in northwestern Montana, USA, revealed widespread damage to nearly

75 000 ha of pine (Pinus sp.) trees. The authors identified several

factors that suggest fluoride as the cause, including proximity to the

plant, high fluoride concentrations in conifer leaves and the presence

of typical fluoride-induced leaf lesions (Carlson, 1978). Bunce (1984)

reported that the growth reduction of forest (2800 m3/year) estimated

for the years from the establishment of an aluminium smelter (Kitimat,

British Columbia, Canada) to 1974 declined by 78% for the period

1974–1979. The improvement in growth corresponded to a 79% decline

in fluoride content of foliage and a 64% decline in fluoride emissions.
Effects on Other Organisms in the Laboratory and Field

157

The effects of fluoride emissions from a phosphorus plant (the

plant closed in 1989) in Long Harbour, Newfoundland, Canada, on the

conifers balsam fir (Abies balsamea), black spruce (Picea mariana)

and larch (Larix laricina) were monitored at sites downwind from the

plant during the summer of 1982 (Sidhu & Staniforth, 1986). Mean

fluoride concentrations ranged between 11.4 μg/m3at a distance of

1.4 km from the source and 0.08 μg/m3 18.7 km from the source. At the

closest site, seed production in balsam fir, black spruce and larch was

impaired by 76.4%, 87.4% and 100%, respectively, compared with

controls. At 10.3 km from the source (mean ambient air concentration

0.9μg fluoride/m3), the effects included reduction of 3–10% in seed size

and 23–30% in cone size and a decrease of 17–72% (varied with

species)in the number of cones per tree. A significant negative correlation was observed between atmospheric fluoride levels and seed

production for all three species. A significant negative correlation was

also observed between foliar injury in the three species (chlorosis and

necrosis) and mean atmospheric fluoride levels.Toxic effects of fluoride on these coniferspecies have resulted in their replacement by more

tolerant hardwood species, such as birch (Betula sp.) and alder (Alnus

sp.). Reproductive and vegetative characteristics of raspberry (Rubus

sp.) and blueberry (Vaccinium sp.) were monitored at six sites downwind from the plant. Within 1.4 km of the plant, flower mortality was

89% for blueberry and 78% forraspberry, compared with 27% and 26%,

respectively,for a control site; there were also significant decreases in

size, number and dry weight of fruit.Fluoride concentrations in foliage

were 403 mg/kg for raspberry and 216 mg/kg for blueberry, compared

with 8 and 9 mg/kg, respectively, for the control site (Staniforth &

Sidhu, 1984).

Taylor& Basabe (1984) established correlations between fluoride

concentratio ns in pine needles (Douglas-fir, Pseudotsuga menziesii)

and annual growth increments, wind pattern, distance from fluoride

source (aluminium smelter) and hydrogen fluoride concentrations in

emissions.The authors noted that visible fluoride symptoms and over

40% growth reduction occurred in trees that were accumulating fluorides below established “injury threshold levels.” They suggested that

synergism between hydrogen fluoride and sulfur dioxide may have

given rise to these reduced threshold levels.

Vike & Håbjørg (1995) recorded fluoride content and leafinjury in

a variety of plant species growing in the vicinity of aluminiumsmelters
EHC 227: Fluorides

158

in Norway. Scots pine (Pinus sylvestris) was the most sensitive

species,showing leafinjury symptoms at a leaf fluoride content of less

than 50 mg/kg at the northern-most locality and <100 mg/kg under

sou thern maritime conditions. Broad-leaved species such as downy

birch (Betula pubescens), goat willow (Salix caprea) and European

mountain-ash (Sorbus aucuparia) showed similar symptoms at

concentrations of 100 and 170 mg/kg forthe two sites, respectively. In

a later study, Vike (1999) reported that leaf injury appeared at leaf

fluoride content levels as low as 30 mg/kg, and damage was restricted

to within 2 km of the emission sources.Regression analysis showed a

positive correlation between leaf injury and fluoride content of leaves

within a locality, but great variation between localities. The author

concluded that the establishment of tolerable emission levels must take

into account local dispersal patterns and climatic conditions.

Ivinskis & Murray (1984)found that reductions in photosynthetic

capacity, chlorophyll a and b and leaf area of grey gum (Eucalyptus

punctata) were all significantly correlated with leaf fluoride content,

fluoride in air and distance froman aluminiumsmelter. The authors also

found that dusky-leaved ironbark (Eucalyptus fibrosa), a species

believed to be tolerant of fluoride, showed no significant differences

between sites for any of the variables except leaf area.

9.2.3.2 Invertebrates

Mayer et al. (1988) conducted a 3-year study on honeybees (Apis

mellifera) in Puyallup Valley, Washington, USA, near an aluminium

plant. The mean fluoride content of bees from a site 0.8 km downwind

of the plant ranged from 82 to 261 mg/kg dry weight. No significant

effect of fluoride on brood survival, brood development or honey

production was found.

9.2.3.3 Vertebrates

Van Toledo (1978) found that the number of avian species near

fluoride-emitting aluminium factories in Europe was depressed. They

speculated that the reductions were due to fluoride emissions.Newman

(1977) believed that the nesting density of house martins (Delichon

urbica) was reduced near an aluminium plant with high fluoride

emissions. However, there were many other air pollutants present, and

so it is difficult to establish a causal relationship with fluoride in 
Effects on Other Organisms in the Laboratory and Field

159

particular. Henny & Burke (1990) monitored black-crowned night

herons (Nycticorax nycticorax) living near a phosphate-processing

complex in Idaho, USA. Fluoride in femurs ranged from 540 to

11 000 mg/kg ash weight and increased with age.The authors studied

bone strength, but, because of the strong relationship between age

and fluoride concentrations, it proved difficult to separate the effects

of fluoride from those of age.

The original findings of fluoride effe cts on mammals were from

studies in the field on domestic animals such as sheep (Moule, 1944;

Harvey, 1952; Peirce, 1952) and cattle (Rand & Schmidt, 1952; Neeley

& Harbaugh, 1954; Burns & Allcroft, 1964; Allcroft & Burns, 1968;

Krook& Maylin, 1979), and more recent studies have shown this to be

a n ongoing problem in some areas (Jubb et al., 1993; Fidanci et al.,

1998; Swarup et al., 1998; Choubisa, 1999; Patra et al., 2000). Fluoride

can be taken up from vegetation, soil and drinking-water. Incidents

involving domesticated animals have originated both from natural

fluoride sources, such as volcanic eruptions and the underlying

geology, and from anthropogenic sources, such as mineral supplements, fluoride-emitting industries and power stations. Symptoms of

chronic fluoride toxicity include emaciation, stiffness of joints and

dental and skeletal fluorosis. Other effects include lowered milk

production and detrimental effects on the reproductive capacity of

animals. Guidance is available on fluoride tolerance levels in feed and

water for domesticated animals based on clinical signs and lesions

(Shupe & Olson, 1983; Cronin et al., 2000) (see section 9.1.3.3).

Investigations of the effects of fluoride on wildlife have focused

on impacts on the structural integrity of teeth and bone. Most

observations have involved large herbivores. For example,dental and

skeletal lesions were found in mule deer (Odocoileus hemionus), elk

(Cervus canadensis) and American bison (Bison bison) exposed to

elevated levels (no specific anthropogenic sources identified) of

fluoride in Utah, Idaho, Montana and Wyoming, USA (Shupe et al.,

1984). Black-tailed deer (Odocoileus hemionus columbianus) near an

aluminium smelter in Washington, USA, were found to have dental

disfigurement, with the premolars of one individual deer being worn

down to the gumline. Fluoride levels in ribs ranged from 2800 to

6800 mg/kg on a fat-free basis, compared with control deer, which had

levels ranging from 160 to 460 mg/kg (Newman & Yu, 1976). Lameness

of deer adjacent to an aluminium smelter in Montana, USA,was noted
EHC 227: Fluorides

160

by Kay et al. (1975). They speculated that fluorosis was the cause of

a change in age structure of the mule deer population. Levels in

mandibles of the mule deer and white-tailed deer (Odocoileus

virginianus) ranged from 1100 to 7000 and from 3400 to 9800 mg/kg,

respectively, on a fat-free basis, whereas those of control deer were

less than 200 mg/kg. White-tailed deer inhabiting an area adjacent to

an aluminiumsmelterin South Carolina,USA,exhibited dentalfluorosis

but no osteofluorosis (Suttie et al., 1987). Mean levels in mandibles of

deer olderthan 2.5 years were 286 mg/kg ash weight before opening of

the smelter and 1275 mg/kg 3 years after start-up.

Karstad (1967) found that mandibular bone fluoride contents of

4300–7125 mg/kg in mule deer (Odocoileus hemionus) near an industrial complex were associated with pitting and black discoloration of

teeth, abnormal tooth wear and fractures of teeth and jaw bones. All

red deer (Cervus elaphus) yearlings, sampled near Norwegian aluminium smelters, with mandibular fluoride levels exceeding 2000 mg/kg

were found to have dental fluorosis. Gross osteofluorosis was

observed in deer with mandibularfluoride residues of greaterthan 8000

mg/kg (Vikøren & Stuve, 1996b). Pathological alterations in the teeth

of roe deer (Capreolus capreolus) in Germany were diagnosed as

dental fluorosis. The diagnosis was confirmed by analysis of

mandibles, which contained significant levels of fluoride (Kierdorf,

1988). The dental fluorosis was found to occur mainly in the heavily

industrialized Ruhr area of Germany. H. Kierdorf et al. (1996) and U.

Kierdorf et al. (1996) monitored mandibular bone fluoride

concentrations and frequency and intensity of fluoride-induced dental

lesions in red deer in the Czech Republic and Germany (Figure 4). The

frequency and severity of dental fluorosis were positively correlated

with bone fluoride levels.Detailed macroscopic,microradiographic and

scanning electron microscopic methods have revealed structural

changes in fluorosed dental enamel of both roe and red deer (U.

Kierdorf et al., 1993, 1996). Corresponding changes have also been

described in fluorosed enamel of wild boars (Sus scrofa) from fluoridepolluted areas (H. Kierdorf et al., 2000). Kierdorf & Kierdorf (1997)

concluded that periods of especially elevated plasma fluoride levels in

chronically fluoride-stressed deer can cause a disruption in the

function of secretory ameloblasts similar to that following acute

fluoride dosing in laboratory rodents. Morphological imaging has

revealed a decreased width and an increased porosity of the antler

cortex in deer from highly fluoride polluted areas (U. Kierdorf et al.,

2000). Kierdorf et al. (1997) concluded that increased fluoride exposure
Effects on Other Organisms in the Laboratory and Field

161

of deer leads to reduced mineral content and mineral density of antler

bone and that it is the rapidity of their growth and mineralization that

makes antlers especially susceptible to fluoride action.The occurrence

of osteofluorotic alterations has also been diagnosed in red deer (C.

elaphus) with bone fluoride concentrations greater than 4000 mg/kg

dry weight (Schultz et al., 1998). The authors concluded that in addition

to fluoride-induced dental lesions, the occurrence of marked

periodontal disease and tooth loss is an important factor responsible

for a reduction of life expectancy in severely fluorotic wild red deer. It

has been demonstrated that in the case of regional, long-term fluoride

pollution, dental fluorosis can be used as a sensitive biomarker of

fluoride exposure in deer and thus as an indicator of the level of

environmental contamination by fluorides (U. Kierdorf & Kierdorf,

1999).

Fig. 4. Row of permanent mandibular cheek teeth (from right to left, 2nd, 3rd,

4th premolar, 1st, 2nd, 3rd molar) of a red deer (Cervus elaphus) exhibiting

pronounced dental fluorosis. The premolars and the M3 exhibit enamel

discoloration and increased wear. Note destruction of the tooth crown in the

P3 (asterisk) and dysfunctional crown shape of the M3 (arrow). Due to the

increased wear, the alveolar process has regressed in the region of P3 and P4

(arrowheads).

Exposure of predatory wildlife is often minimal, as fluoride is

largely unavailable to those mammalian and avian predators that do not

digest bone. For example, barn-owls regurgitate pellets that contain

virtually intact skeletons of their prey (Thomson, 1987).
EHC 227: Fluorides

162

Walton (1987c) found that severe dental damage in field voles

(Microtus agrestis) and wood mice (Apodemus sylvaticus) was evident

only within 200–300 m (downwind) of an aluminium smelter. A

significant increase in tooth wearwas noted in moles (Talpa europaea)

at between 4 and 15 kmfromthe smelter. Radiographs of the skeletons

of voles and mice with bone fluoride levels of up to 15 000 mg/kg dry

weight showed no changes when compared with rodents fromcontrol

sites. Paranjpe et al. (1994) identified fluorosis in cotton rats (Sigmodon

hispidus) at a petrochemical waste site. Approximately 80% of the

cotton rats collected by Schroder et al. (1999) at the same site were

found to have dentalfluorosis.Mean bone fluoride and mean soil total

fluoride levels were 1515 and 1954 mg/kg, respectively. Bone fluoride

was found to be an accurate predictor of dental fluorosis when it was

low(<1000 mg fluoride/kg; no fluorosis) or high (>3000 mg fluoride/kg;

fluorosis), but not when it was intermediate (Schroder et al.,2000). Field

voles (M. agrestis) and bank voles (Clethrionomys glareolus) showed

severe dental lesions on incisor and molar teeth near a chemicalworks

(549 mg total fluoride/kg dry weight of vegetation) and an aluminium

smelter (187 mg fluoride/kg vegetation), with less marked damage at a

mine tailings dam(80 mg fluoride/kg vegetation)(Boulton et al., 1994b).

Boulton et al. (1999) reported that the severity of lesions in both incisor

and molar teeth of field voles (M. agrestis) was positively correlated

with the respective tissue fluoride concentrations.
Table 16 (contd).

Organism Size/age Temperatur

e

(°C)

Hardness

(mg/litre)b

 pH Salinit

y

(‰)

Parameter Concentration

(mg fluoride/

litre)c

Reference

Sheepshead minnow

(Cyprinodon

variegatus)

8–15 mm 25–31 10–31 96-h LC50 >225 n Heitmuller et al. (1981)

Ambassid (Ambassis

safgha)

adult 20–21 10–28 96-h LC50 >100 n Hemens & Warwick (1972)

Crescent perch

(Therapon 

jarbua)

adult 20–21 10–28 96-h LC50 >100 n Hemens & Warwick (1972)

Mullet (Mugil

cephalus)

juvenile 20–21 10–28 96-h LC50 >100 n Hemens & Warwick (1972)

a All tests were conducted under static conditions (water unchanged for duration of test).

b Hardness expressed as mg calcium carbonate/litre.

c n = based on nominal concentrations; m = based on measured concentrations.
163

10. EVALUATION OF HUMAN HEALTH RISKS 

AND EFFECTS ON THE ENVIRONMENT

10.1 Evaluation of human health risks

10.1.1 Exposure

Individuals are exposed to some level of fluoride fromnatural and/

or anthropogenic sources. The consumption of foodstuffs, drinkingwater and other beverages is generally the principal route of exposure.

Significant intake may also occur in younger children from the

ingestion offluoridateddentifrice and supplements.Infants can receive

small amounts of fluoride from breast milk. The inhalation offluorides

in air usually makes only a minor contribution to the overall total

intake. High intakes of fluoride have been noted in geographical areas

worldwide where the surrounding environment is rich in naturalfluoride. In these areas, drinking-water, foodstuffs and the inhalation of

indoor air where coalrich in fluoride is used for heating and cooking all

contribute to the overall intake. Exposures might be increased somewhat in the vicinity of certain anthropogen ic sources of fluoride. In

certain occupationalenvironments,the inhalation of workroomair containing fluoride would contribute to higherthan typical ambient exposures.

Estimates of daily fluoride intake by children in Canada range from

<0.01 mg (<1 μg/kg body weight forinfants)to 2.1 mg (160 μg/kg body

weight for children up to 4 years of age and 80 μg/kg body weight for

adolescents aged 5–11 years). For adults, estimates of daily fluoride

intake range from 2.2 to 4.1 mg (approximately 30 to 60 μg/kg body

weight, assuming an average body weight of 64 kg). For individuals

residing in certain geographical areas rich in natural fluoride, daily

intakes as high as 27 mg (420 μg/kg body weight, assuming an average

body weight of 64 kg) have been reported. The estimates of total

fluoride intake usually do not take into account its bioavailability (e.g.,

the degree offluoride absorption fromfluoride-containing food items).

Such information is needed in order to derive accurate estimates of

daily total fluoride intake in individuals living in fluoridated as well as

non-fluoridated areas and in areas of endemic fluorosis.
EHC 227: Fluorides

1 The effects of fluoride on dental health were reviewed in depth by

WHO (1994), and therefore only a brief summary is presented here.

164

10.1.2 Hazard identification1

Fluoride has both positive and negative effects on human health,

similar to essential elements. Compared with many other chemicals,

there is a relatively narrow range between intakes associated with

beneficialeffects and exposures causing adverse effects.The exposure

to lowlevels of fluoride in drinking-water(i.e., approximately 1 mg/litre)

has long been known to have a beneficial effect on the reduction of

dental caries. Clinical use of fluoride in the treatment of osteoporosis

(at doses generally greater than 25 mg/day) has been investigated in

a number of studies.

Based on the available data, it is evident that skeletal and dental

effects related to fluoride exposure in humans occur at doses or intakes

lower than those associated with other potential adverse tissue- or

organ-specific effects.This is likely a consequence of the accumulation

of fluoride almost exclusively in bones and teeth. In children, intakes

of fluoride associated with beneficial effects on dentition overlap with

those that lead to an increas e d prevalence of dental fluorosis. Consequently, public health programmes have sought to maximize the

beneficial effects of fluoride on dental health, while at the same time

minimizing its adverse fluorotic effects on the teeth. 

Effects on the skeleton are the most consistent and best characterized of the toxic responses to fluoride and are considered to have

direct public health relevance. The skeletal changes that have been

observed in a number of animal species (i.e., cattle, sheep, poultry,

rodents) exposed to fluoride are not inconsistent with effects observed

in humans, although data from such studies have not been utilized in

the assessment of human exposure–response.

Case reports or descriptive ecological human studies of skeletal

fluorosis or osteosclerosis or studies on the occurrence of endemic

(crippling)skeletalfluorosis in which the levels of fluoride are naturally

very high provide little quantitative information useful in establishing

an adverse effect level associated with total fluoride intake. In such

studies, nutrition, the intake offluoride (and additional minerals) from
Evaluation of Human Health Risks and Environmental Effects

165

othersources and potentially confounding concomitant exposures, all

of which have been suggested to play a role in the etiology of this

disease (for a re view, see WHO, 1984; US EPA, 1985), were not

adequately documented. There is also limited quantitative information

on exposure to fluoride and the development of skeletal effects

(osteosclerosis or fluorosis) in occupationally exposed workers (see

Hodge & Smith, 1977; Grandjean, 1982; Chan-Yeung et al., 1983a;

Czerwinski et al., 1988). Inconsistent results of inherently limited crosssectional studies of small populations exposed to often unspecifie d

concentrations of fluoride in the vicinity of industrialsources (cited in

Hodge & Smith, 1977) contribute little to an assessme nt of

exposure–response for skeletal effects associated with exposure to

fluoride. Information obtained from clinical studies, in which sodium

fluoride was administered to patients forthe treatment of osteoporosis,

is inadequate, owing to the nature of the protocols, characteristics of

the patients in these studies and inconsistencies in the results.

Moreover, these clinical studies were undertaken to assess the

considered beneficial effects of fluoride (i.e., its capacity to increase

bone mass and decrease vertebral fractures), rather than its potential

to produce adverse effects after long-term exposure.

Estimating a putative effect level for the development of skeletal

fluorosis (or related changes) in humans exposed to fluoride is further

complicated by differences in the radiologicaldiagnosis of early-stage

skeletal fluorosis among health care professionals (Chan-Yeung et al.,

1983a), as well as by the multiplicity of factors that may influence the

amount of fluoride deposited in the bone, and hence the severity of the

disease. In case accounts, the development of crippling skeletalfluorosis was attributed to an intake of approximately 230–310 μg fluoride/kg body weight per day in adults weighing 64 kg (US DHHS, 1991).

Skeletal fluorosis has been observed in cryolite workers having

estimated (occupational) intakes of approximately 310–1250 μg fluoride/kg body weight per day in adults weighing 64 kg (Grandjean,1982).

Evidence from ecological studies suggests that there may be an

association between the consumption of fluoridated drinking-water

and an increased incidence of hip fracture (based on hospitalization

rates), particularly among the elderly. These results should be

interpreted with caution, however, in view of the limitations of

epidemiological investigations of this design. Moreover, owing to the
EHC 227: Fluorides

166

lack of data on individual exposure in such studies, it is difficult to

derive meaningful conclusions concerning the exposure–response

relationship for possible skeletal effects associated with exposure to

fluoride from these studies.

Although the relative risk of hip, wrist or spinal fracture was

increased in some groups of women residing in an elevated-fluoride

community (with drinking-water containing 4 mg/litre, and having an

estimated [mean]intake of approximately 72 μg fluoride/kg body weight

per day) compared with those in a control community (with drinkingwater containing 1 mg fluoride/litre) (Sowers et al., 1986, 1991), the

intake of fluoride by women in the elevated-fluoride community was

likely underestimated (since it was derived solely from the amount of

water-based beverages consumed), and the level of calcium in the

drinking-water from the elevated-fluoride community was

approximately 25% of the level in the control community.

Otherstudies, including analyticalinvestigations,have not identified an increased riskofskeletalfracture associated with the consumption of drinking-water containing elevated levels of fluoride (Madans

et al., 1983; Simonen & Laitinen, 1985; Arnala et al., 1986; Jacobsen et

al., 1993; Suarez-Almazor et al., 1993; Kröger et al., 1994; Cauley et al.,

1995; Lehmann et al., 1998; Hillier et al., 2000). 

Only two analytical studies evaluated the risk of fracture across

a range of fluoride exposures. Among 144 627 Finnish men and women,

no association was observed between hip fractures and the well-water

fluoride concentration,when allage groups were considered.However,

in women 50–65 years of age at the start of follow-up, the relative risk

of hip fracture increased with increasing well-waterfluoride concentrations in the categories <0.1, 0.1–0.3, 0.3–0.5, 0.5–1.0, 1.1–1.5 and >1.5

mg/litre. The respective relative risk of hip fracture was 1.0, 1.16, 1.31,

1.53 (P < 0.05), 1.24 and 2.09 (P < 0.05) (Kurttio et al., 1999).

Among 8266Chinesemen and women, the risk of all fractures and

hip fractures was examined across a range of fluoride exposures (see

Table 14 in chapter 8) (Li et al., 2001). There was an increased risk of

overall fracture and hip fracture that became statistically significant at

drinking-water levels in excess of 4.32 mg fluoride/litre. 

Owing to the widespread controlled addition of fluoride to public

drinking-water supplies, numerous epidemiological and experimental
Evaluation of Human Health Risks and Environmental Effects

167

studies have attempted to address concerns related to the potential

carcinogenicity of this substance. There has been no consistent evidence of an association between the consumption of fluoridated

drinking-water and the incidence of, or mortality due to, cancer in a

large number of ecological studie s performed in many countries.

Although these results do not support the hypothesis of an

association, their considerable limitations preclude firm conclusions

frombeing drawn regarding the carcinogenicity of fluoride in humans.

For example, cancer of the bone was not assessed in the majority of

these human ecological studies. Case–control studies (Gelberg et al.,

1995; Moss et al., 1995) have not identified a relationship between

bone cancer and exposure to fluoride.

The incidence of, or death due to, cancer has also been investigated in a number of historic cohort studies of workers exposed to

fluoride predominantly in the aluminium smelting industry. While

excesses of cancers of different types have been reported in various

studies, the only site forwhich there was excess riskin several investigations is lung cancer; due to confounding by concomitant exposure

to known human carcinogens in analytical studies of occupationally

exposed workers, the observed excesses cannot be attributed to

fluoride exposure per se.Bone cancer was not assessed in the majority

of these studies.

Although the weight of evidence does not support the view that

fluoride causes cancer in humans, the data on bone cancer are

relatively limited.

In early carcinogenicity bioassays conducted by Kanisawa &

Schroeder(1969), Taylor(1954) and Tannenbaum& Silverstone (1949),

the incidence of tumours in miceadministered sodiumfluoride (in either

the diet or drinking-water) was, in general, not markedly greater than

that observed in controls. Owing to inadequate documentation and to

numerous methodologicalshortcomings, however, the results of these

investigations do not contribute meaningfully to an assessment of the

weight of evidence of the carcinogenicity of (sodium) fluoride. 

The administration of drinking-water containing sodium fluoride

(in amounts estimated to provide intakes ranging from 0.6 to 9.1 mg

fluoride/kg body weight per day) to male and female B6C3F1 mice over
EHC 227: Fluorides

168

a period of 2 years produced a marginal (statistically insignificant)

increase in the incidence of hepatoblastoma, compared with the incidence in groups of controls administered drinking-waterwithout added

fluoride;however,this minorincreasewas not considered “biologically

significant,” since the overall incidence of hepatic tumours (adenoma,

carcinoma, hepatoblastoma) was not increased in animals receiving

sodium fluoride, and the incidence of all hepatic tumours in these

groups of mice was higher than that in previous NTP carcinogenicity

bioassays (NTP, 1990). The marginal increase in the incidence of

malignant lymphoma in female B6C3F1 mice administered drinkingwater containing sodiumfluoride was considered not to be compoundrelated,since the incidence in the high-dose group was similar to that

observed in historical controls (NTP, 1990). No other increases in

tumour incidence were observed; however, failure to attain the maximumtolerated dose may have reduced somewhat the sensitivity of this

study in mice.In a less extensive carcinogenicity bioassay in which the

incidence of osteomas in male and female CD-1 mice receiving 11.3 mg

fluoride/kg body weight per day in the diet was increased compared

with controls (Maurer et al., 1993), the specific role of fluoride in the

etiology of the tumours cannot be determined with certainty, owing to

the infection ofthese animals with Type Cretrovirus (US DHHS, 1991;

Maurer et al., 1993; US NRC, 1993).

The administration of drinking-water containing sodium fluoride

(in amounts estimated to provide intakes ranging from 0.2 to 4.5 mg

fluoride/kg body weight per day) to F344/N rats over a period of

2 years produced a marginal (not statistically significant) increase in

the incidence of oral cavity neoplasms (in males and females) and

tumours in the thyroid gland (in males)(NTP, 1990). The squamous cell

tumours of the oral cavity were not considered to be compoundrelated,since the incidence of tumours in the high-dose group was not

significantly different from the controls, the incidence of these neoplasms was within the range observed in historical controls and there

was no supporting evidence of focal hyperplasia of the oral mucosa

(NTP, 1990). The marginal increase in thyroid (follicular cell) tumours

was also considered not to be compound-related, since the incidence

of these tumours in the high-dose group was not significantly different

from the controls, the incidence of these neoplasms was within the

range observed in historical controls and the incidence of follicularcell

hyperplasia was not increased in fluoride-exposed animals (NTP, 1990).

The incidence of osteosarcoma in rats with intakes ranging from 0.8 to
Evaluation of Human Health Risks and Environmental Effects

169

4.5 mg fluoride/kg body weight per day was not significantly increased,

compared with controls receiving approximately 0.2 mg fluoride/kg

body weight per day (NTP, 1990); however, for the male F344/N rats,

it was reported that “the osteosarcomas occurred with a significant

dose response trend (P = 0.027, by logistic regression)” (NTP, 1990).

In a more limited carcinogenicity bioassay conducted by Maurer et al.

(1990), the administration of diets containing sodium fluoride (in

amounts estimated to provide intakes ranging from 1.8 to 11.3 mg

fluoride/kg body weight per day) to male and female Sprague-Dawley

rats over a period of 95–99 weeks produced no significant increase in

the incidence of any types of tumours, compared with groups of

controls receiving approximately 0.1 mg fluoride/kg body weight per

day, although a small number of malignant tumours of the bone were

observed. 

In assessing the evidence for the carcinogenicity of fluoride

derived from studies conducted with laboratory animals, some significance might be attributed to the observation of a dose–response

trend in the occurrence of osteosarcomas in male F344/N rats

administered sodium fluoride in drinking-water (NTP, 1990). Such a

trend associated with the occurrence of a rare tumour in the tissue in

which fluoride is known to accumulate cannot be casually dismissed.

Moreover, the level of fluoride in the bones of the high-dose group of

male rats in the NTP carcinogenicity bioassay, in which a nonsignificant increase in osteosarcomas was observed, is similar to that

measured in humans with a preclinical phase of skeletal fluorosis.

However, the biological significance of this dose–response trend is

tempered by the lack of statistical significance of the observed excess

in the high-dose males in comparison with controls, as well as by the

absence of a comparable statistically significant trend in the incidence

of osteosarcomas in female F344/N rats or male and female B6C3F1 mice

receiving comparable amounts of inorganic fluoride (NTP, 1990).

Indeed, the levels of fluoride in the bone of (male and female) F344/N

rats and B6C3F1 mice administered sodium fluoride in drinking-water

were similar (NTP, 1990). No dose–response trend in the incidence of

osteosarcomas was observed in groups of male and female SpragueDawley rats administered diets containing sodium fluoride (Maurer et

al., 1990), even though the levels of fluoride in the bone in the highdose animals were greaterthan those in the male F344/N rats in which

there was an increase in osteosarcomas in the NTP (1990)

carcinogenicity bioassay; however, there may be variations in 
EHC 227: Fluorides

170

sensitivity of the two strains to the effects of fluoride. There is

controversy concerning whether or not the osteomas in male and

female CD-1 mice observed in the carcinogenicity bioassay conducted

by Maure r et al. (1993) should be classified as neoplasms, and a

retrovirus (in addition to fluoride)has been implicated in their etiology;

however, the significant increases in (the highest-dose) fluorideexposed versus control groups (in animals infected with retrovirus), in

a tissue in which fluoride is known to accumulate, adds some weight,

albeit weak, to the evidence of carcinogenicity. Overall, the evidence

regarding the carcinogenicity of fluoride in laboratory animals is

inconclusive.

There is evidence that fluoride is genotoxic based on the outcome

of in vitro studies. Fluoride is not mutagenic in bacterial cells but is

clastogenic in human and animal cells exposed in vitro. Sodium

fluoride induced recessive lethalmutations in Drosphilamelanogaster

and cytogenetic damage after intraperitoneal injection in rodents.

Generally, however, in studies in which fluoride was administered to

laboratory animals by routes of exposure similar to those by which

humans are normally exposed (i.e., orally), fluoride had no effect upon

the frequency of chromosomal aberrations,micronuclei,sister chromatid exchange, DNA strand breaks or sperm morphology. The mechanism by which fluoride could induce genetic alterations is not known;

however, it is not likely due to an interaction between the fluoride ion

and DNA. Rather, it may be a secondary effect of the actions of

fluoride that result from its inhibition of enzymes involved in DNA

synthesis and/or repair.

10.1.3 Exposure–response analysis for adverse effects in bone

A few investigations on skeletal fluorosis or the risk of fractures

include quantitative estimates of the dose–responserelationship.Studies in China and India report an increased prevalence of skeletal

fluorosis above the level of 1.4 mg fluoride/litre in drinking-water(Jolly

et al., 1968; Choubisa et al., 1997; Xu et al., 1997). However, suc h

studies suffer from limitations: the diagnostic criteria are not always

specified or consist of self-reported symptoms, and only drinkingwateris considered as a source of exposure.The latter problemis likely

to be important, since other studies (Liang et al., 1997; Ando et al.,

1998) estimate that, at least in some regions of China and India , the

contribution from food can greatly exceed that from water. Therefore,

one cannot rule out that high rates of skeletalfluorosis associated with
Evaluation of Human Health Risks and Environmental Effects

171

a level greater than 1.4 mg/litre in drinking-water are due to other

exposures. While there is a clear excess of skeletal fluorosis in these

studies for a total intake of 14 mg/day, the quantitative relationship

between total intake of fluoride from different sources and the risk of

skeletal fluorosis cannot be estimated because of substantial

uncertainties in the prevalence of effects in the range of intakes

between 3 and 14 mg/day.

The studies on fractures are also difficult to interpret, but for

different reasons: 

• Few studies report an interpretable range of exposures to fluoride.

• Results tend to be contradictory, with no clear-cut trend in both

men and women. 

• Total intake of fluoride is not estimated. 

One exception is represented by a study in China (Li et al., 2001) in

which different sources of exposure have been considered and an

estimate of total intake is presented. In this study, there is an upward

trend for the risk of total fractures above an exposure of 1.45 mg

fluoride/litre in drinking-water, but only for the highest level of exposure (i.e., >4.32 mg fluoride/litre in drinking-water) was the relative risk

statistically significant (RR= 1.47; P = 0.01). In the concentration range

of 1.45–2.19 mg fluoride/litre in drinking-water, corresponding to a total

intake of 6.54 mg/day, there was a relative risk for all fractures of 1.17

and for hip fractures of 2.13 (both not statistically significant).

In summary, estimates based on studies from China and India

indicate that:

• for a total intake of 14 mg/day, there is a clear excess ris k of

skeletal adverse effects; and 

• there is suggestive evidence of an increased risk of effects on the

skeleton at total fluoride intakes above about 6 mg/day.
EHC 227: Fluorides

172

10.2 Evaluation of effects on the environment

10.2.1 Exposure

Fluorides are released into the environment naturally through the

weathering and dissolution of minerals, in emissions from volcanoes

and in marine aerosols. Fluorides are also released into the environment via coal combustion and process waters and waste from various

industrial processes, including steel manufacture, primary aluminium,

copper and nickel production, phosphate ore processing, fertilizer

production and use, glass, brick and ceramic manufacturing, and glue

and adhesive production.

Atmospheric fluorides can be transported overlarge distances as

a result of wind or atmospheric turbulence or removed from the

atmosphere via wet or dry deposition or hydrolysis. Fluoride concentrations in groundwater are primarily due to dissolution from local

geologicalsources. The transport of fluorides in wateris influenced by

pH and water hardness and the presence of ion-exchange materials

such as clays, and fluoride is usually complexed with aluminium and

calcium. Fluoride is not readily leached from soils, with adsorption

being strongest at pH 5.5–6.5. Soluble fluorides are bioaccumulated by

some aquatic and terrestrial biota; however, no information was

identifiedconcerning the biomagnificationoffluoride.Terrestrialplants

may accumulate fluorides from airborne deposition and, to a lesser

extent, via uptake from soil, as fluoride adsorbs strongly to soil.

Fluoride accumulates in the exoskeleton of invertebrates and the bone

and dental hard tissues of vertebrates.

Surface freshwaterfluoride concentrationstend to range from0.01

to 0.3 mg/litre,whereas typical marine concentrations range from1.2 to

1.5 mg/litre (Figure 5). Higher concentrations are found in areas where

there is geothermal or volcanic activity. Anthropogenic discharges

lead to increased levels of fluoride in the environment. Airborne

fluoride exists in gaseous and particulate forms,which are emitted from

both naturaland anthropogenic sources. Mean fluoride concentrations

in ambient air are generally less than 0.1 μg/m3. Levels may be slightly

higherin urban than in rurallocations; however, even in the vicinity of

emission sources, the levels of airborne fluoride usually do not exceed

2–3 μg/m3(Figure 6). Fluoride is a component of most types of soil,

with concentrations ranging from 20 to 1000 mg
10-3

10-2

10-1

100

101

102

 Concentration mg F/litre

sea water

freshwater; background

freshwater; geothermal/volcanic

freshwater; local industrial

Figure 5: Reported concentrations of fluoride in surface waters

Evaluation of Human Health Risks and Environmental Effects

10 173 -3

10-2

10-1

100

101

 Concentration ug F/m3

Ambient: remote

Ambient: rural

Ambient: urban

Local industrial

Figure 6 : Reported concentrations of fluoride in air
EHC 227: Fluorides

174

total fluoride/kg in areas without natural phosphate or fluoride

deposits and up to several thousand milligrams per kilogramin mineral

soils with deposits of fluoride (Figure 7). Reported concentrations of

fluoride in vegetation are plotted in Figure 8.

10-2

10-1

100

101

102

103

104

 Concentration mg F/kg

Natural: total

Natural: water soluble

Anthropogenic: total

Anthropogneic: water soluble

Figure 7: Reported concentrations of fluoride in soil

10-1

100

101

102

103

 Concentration mg F/kg

Natural

Natural: lichens

Natural: tree foliage

Local industrial

Local industrial: lichens

Local industrial: tree foliage

Mining

Volcanic: lichens

Figure 8: Reported concentrations of fluoride in vegetation
Evaluation of Human Health Risks and Environmental Effects

175

10.2.2 Effects

The most sensitive aquatic invertebrate species tested were the

freshwater fingernail clam (Musculium transversum), with an 8-week

LC50 of 2.8 mg fluoride/litre, freshwater net-spinning caddisflies

(Hydropyschidae), with estimated “safe concentrations” ranging from

0.2 to 1.2 mg fluoride/litre, and the marine brine shrimp (Artemia

salina), with significant impairment ofgrowth being observed in a 12-

day static test at 5 mg/litre. Fo r fish, 20-day LC50s for rainbow trout

(Oncorhynchus mykiss) ranged from 2.7 to 4.7 mg fluoride/litre; in

another study under different conditions (such as higher water hardness), a “safe concentration” of 5.1 mg/litre was estimated.The hatching of fish eggs (Catla catla) was delayed at fluoride concentrations

greater than or equal to 3.6 mg fluoride/litre. Behavioural experiments

on adult Pacific salmon in soft-water rivers indicate that changes in

water chemistry, due to an increase in the fluoride concentration to

0.5 mg/litre, can adversely affect migration; migrating salmon are

extremely sensitive to changes in the water chemistry of their river of

origin. (Reported toxicity test results for a range of freshwater

organisms are plotted in Figure 9.)

10-1

100

101

102

103

 Concentration mg F/litre

Algae: EC50

Algae: LOEC

Algae: NOEC

Invertebrates: LC50

Invertebrates: LOEC

Invertebrates: NOEC

Invertebrates -"Safe concentration"

Fish: LC50

Fish: LOEC

Fish: NOEC

Fish - "Safe concentration"

* - chronic

Fish behaviour LOEC

Figure 9: Reported toxicity of fluoride to freshwater organisms

*

*

*
EHC 227: Fluorides

176

In laboratory studies, fluoride seems to be toxic for microbial

processes at concentrations found in moderately fluoride-polluted

soils; similarly, in the field, accumulation of organic matter in the

vicinityofsmelters has been attributed to severe inhibition of microbial

activity by fluoride.

The LOELs for leaf necrosis in terrestrial plants were at fluoride

concentrations of 0.2–0.4 μg/m3. On the basis of effect concentrations

and no-effect concentrations forfumigation experiments, a relationship

was derived between the NOEC and the exposure period. If this

relationship is extrapolated to two growing seasons, the derived NOEC

is approximately 0.2 μg fluoride/m3. Severalshort-term solution culture

studies have identified a toxic threshold for fluoride ion activity

ranging from approximately 50 to 2000 μmol fluoride/litre. Toxicity is

specific not only to plant species, but also to ionic species of fluoride,

where some aluminium–fluoride complexes present in solution culture

may be toxic at activities of 22–357 μmol fluoride/litre, whereas

hydrogen fluoride is toxic at activities of 71–137 μmol/litre. Due to the

complexity of fluoride availability in soil and the high concentrations

generally required for plant toxicity, no soil effect range was defined.

The growth rate of young starlings was significantly reduced at

a fluoride concentration of 13 mg/kg body weight. Fluoride has been

shown to cause adverse effects on domesticated animals in both the

laboratory and the field. Recent studies have shown this to be an

ongoing problem. Tolerance levels have been identified for domesticated animals, with the lowest values for dairy cattle at 30 mg/kg feed

or 2.5 mg/litre drinking-water. The lowest dietary concentration of

fluoride to cause fluorosis in white-tailed deer (Odocoileus virginianus) was 35 mg/kg. Field surveys have found that bone fluoride

concentrations of >2000 mg/kg in young deer and >3000 mg/kg in

cotton rats (Sigmodon hispidus) are associated with fluorosis in all

individuals. Osteofluorotic alterations have been diagnosed in deer

with bone fluoride concentrations of >4000 mg/kg.

10.2.3 Evaluation

In the freshwaterenvironment, naturalfluoride concentrations are

usually lower than those expected to cause toxicity in aquatic organisms. However, aquatic organisms might be adversely affected in the
Evaluation of Human Health Risks and Environmental Effects

177

vicinityofanthropogenic discharges. Fluoride toxicity is dependent on

water hardness, with organisms living in soft-water environments at

greater risk than those in hard-water areas. Because of the particular

sensitivity ofsome freshwater invertebrates and Pacific salmon, fluoride concentrations in soft-water ecosystems (low in calcium) should

not be increased by anthropogenic inputs to values exceeding 0.5 mg

fluoride/litre. Aquatic organisms that inhabit areas with high natural

fluoride levels fromgeothermal or volcanic activity would be expected

to be adapted to such conditions.

Comparing the long-term NOEC for plants with air concentrations

reveals that sensitive species growing near anthropogenic sources of

fluoride are at risk. In the field, anthropogenic sources of fluoride have

been shown to be corre lated with damage to local terrestrial plant

communities. However, these adverse effects are often difficult to

attribute to fluoride alone, due to the presence of other atmospheric

pollutants. Fluoride is generally strongly adsorbed by soils. Consequently, plant uptake via this pathway is relatively low, and leaching

of fluoride through soil is minimal. However, high fluoride concentrations in soil fromnatural and anthropogenic sources, combined with

soil properties that minimize fluoride adsorption (below pH 5.5, low

carbon and clay content), can lead to increased plan t availability of

fluoride. Plant availability is also dependent on the ionic species of

fluoride present in the soil solution. Above soil pH 5.5, fluoride in

solution is predominantly the free fluoride ion, CaF+ or MgF+, which is

relatively less available to uptake via the plant root. Below soil pH 5.5,

aluminium–fluoride complexes can become dominant in soil solution,

potentially increasing plant availability of fluoride. However, plant

toxicity from uptake of fluoride from soil is rare.

Concentrations offluoride in vegetation in the vicinity of fluoride

emission sources,such as aluminium smelters, can be higher than the

lowest dietary effect concentration reported formammals in laboratory

experiments. Fluorosis in domesticated animals has been reported.

Incidents have originated both from natural fluoride sources, such as

volcanic eruptions and the underlying geology, and from

anthropogenic sources,such as fluoride-emitting industries and power

stations. Guidance is available on fluoride tolerance levels in feed and

water; however, there are stillsome areas reporting fluorosis incidents

in livestock due to uptake of fluoride-rich mineral supplements and

drinking-water. Furthermore, there is a potential risk from fluoridecontaminated pasture and soil ingestion due to the long-term use of
EHC 227: Fluorides

178

phosphate fertilizers containing fluoride as an impurity. Fluorideinduced effects, such as lameness and tooth damage, have also been

reported in wild ungulates, such as deer, and in small mammals close

to anthropogenic sources of fluoride. Several studies have demonstrated that wild deer and rodents are sensitive bioindicators of

environmental pollution by fluorides and can, therefore, be used as

sentinels for the identification of fluoride hazards to the environment.

Within some areas of Europe, where effective emission control measures have been introduced following clean air legislation, the bone

fluoride levels in deer have fallen by around 70% in the last 15–

20 years. Based on the correlation between bone fluoride levels and

fluorosis,it can be assumed that the prevalence and severity of fluoride-induced effects in the wild deer population in these areas will

probably have fallen at a similar rate. However, it should be noted that

in other regions of Europe, fluoride discharges to the environment

have not shown the same downward trend during this period, and this

is reflected in the bone fluoride levels of mammals from these areas.
179

11. CONCLUSIONS AND RECOMMENDATIONS

FOR PROTECTION OF HUMAN HEALTH AND THE

ENVIRONMENT

11.1 Conclusions

All organisms are exposed to various levels of fluoride from

natural and/or anthropogenic sources. Very high intakes have been

observed in areas worldwide in which the environment is rich in natural

fluoride and where groundwater high in fluoride is consumed. 

Fluoride in dental products may form a source of exposure for

many individuals. Increased exposures might be experienced in the

vicinity of anthropogenic point sources.

Fluoride has both beneficial and detrimental effects on human

health, with a narrow range between the intakes associated with its

beneficial and adverse health effects.

Effects on the teeth and skeleton are observed at exposures below

those associated with the development of other organ- or tissuespecific adverse health effects. Effects on the bone are considered the

most relevant in assessing the adverse effects of long-term exposure

of humans to fluoride. 

Skeletal fluorosis is a crippling disability affecting millions of

people in various regions of Africa, India and China, which has major

public health and socioeconomic impact.Intake of fluoride in the water

and/or foodstuffs is the primary causative factor in the incidence of

endemic skeletal fluorosis. In parts of China, a large number of people

have been shown to be impacted by the indoor burning of coal with a

high fluoride content. There are few data from which to estimate total

exposure to and the bioavailability of fluoride, and there are inconsistencies in the characterization of its adverse effects. 

There is clearevidence fromIndia and China that skeletalfluorosis

and an increased riskof bone fractures occur at a total intake of 14 mg

fluoride/day, and there is evidence suggestive of an increased risk of

bone effects at total intakes above about 6 mg fluoride/day.
EHC 227: Fluorides

180

Excess exposure to bioavailable fluoride constitutes a risk to

aquatic and terrestrial biota.

Fluoride-sensitive species can be used as sentinels forthe identification of fluoride hazards to the environment.

11.2 Recommendations

Consideration should be given to the levels of fluoride and the

means of application required to maximize the beneficial effects of

fluoride while minimizing the potential for adverse effects on the

skeleton and teeth. 

It is recommended that international and national agencies

identify areas in which health effects related to fluoride are found,

identify the primary sources offluoride exposure and take appropriate

action(s) to reduce exposure.

It is recommended that international and national agencies

support research to better characterize total fluoride exposure,

exposure–health relationships and the various factors that modify and

influence these. 

In areas exposed to increased fluoride from anthropogenic

sources, fluoride levels in the environment should be mon itored for

changes using appropriate bioindicators.
181

12. FURTHER RESEARCH

There is a need to improve knowledge on the accumulation of

fluoride in organisms and on how to monitor and control this.

The biological effects associated with fluoride exposure should be

better characterized. 

12.1 Health effects research 

There is a need:

# to determine total dietary fluoride intakes and bioavailability

and elucidate the relative contribution of water and foodstuffs

to fluoride intake; 

# to develop robust markers of fluoride exposure and effects in

animals and humans to further elucidate the mechanisms

(including work on a molecular level) of fluoride’s effects on

bone, and how these might be reversed; 

# to design high-quality studies at population and individual

levels, to characterize the adverse effects of fluoride on bone,

cancer and reproductive outcomes; available data sets should

be exploited to generate sound epidemiologicalobservations —

for example,through a linkage between population registries in

high-exposure areas and cancer or other disease registries; 

# to characterize the potential interactions of fluoride with other

elements — aluminium, copper, lead, arsenic,selenium— in the

environment and their influence on fluoride bioavailability and

mobility; 

# to clarify quantitatively and mechanistically howenvironmental

factors (e.g., atmospheric pollution, coal burning, climate,

rainfall, altitude) and lifestyle (including occupation) influence

fluoride exposure;
EHC 227: Fluorides

182

# to characterize the short- and long-term turnover of fluoride in

the body and how factors such as bone remodelling and renal

function influence this;

# to improve the routine quantitative analysis offluoride in body

fluids; 

# to develop robust biomarkers in animals and humans; 

# to investigate the passage of fluoride through the food-chain

from the geochemical environment to the diet; 

# to determine if fluoride has potential adverse effects on other

systems, including the neurological system; 

# to investigate what factors (age, genetic polymorphisms, diet,

etc.) might make particula r population subgroups more

susceptible to the effects of fluoride; and

# to determine themechanisms associated with the clastogenicity

of fluoride.

Additional research needs include studies on the interactions

of fluoride with nuclear proteins (i.e., histones) and polyamines as well

as on factors influencing the membrane transport of fluoride.

12.2 Environmental effects research

There is a need:

# forthe identification of more fluoride-sensitive species fromdifferent environmental compartments for use as bioindicators;

# to define critical measures of fluoride concentrations in soil to

assess plant fluoride availability (i.e., when plant fluoride concentrations increase significantly from background or, to a lesser

extent, become toxic to plants);

# to determine the bioavailability of fluoride in animals that ingest

significant quantities of soil in their diet (e.g., cattle);
Further Research

183

# forthe standardization of the assessment of the effects of fluoride

on wild animals; and

# to improve the quantitative routine analysis of fluoride in soil and

plants. 
184

13. PREVIOUS EVALUATIONS BY 

INTERNATIONAL BODIES

Fluoride (used in drinking-water) is considered to be “not

classifiable as to its carcinogenicity to humans” (Group 3) in the

classification scheme of the International Agency for Research on

Cancer (IARC, 1987).

The WHO recommended guideline value for fluoride in drinkingwater is 1.5 mg/litre (WHO, 1993, 1996b). It was also noted that “in

setting national standards for fluoride, it is particularly important to

consider climatic conditions, water intake and intake of fluoride from

other sources (e.g., from food and air). In areas with high natural

fluoride levels,it is recognized that the guideline value may be difficult

to achieve in some circumstances, with the treatment technology

available” (WHO, 1996b).

An expert consultation of the WHO on trace elements in human

nutrition and health (WHO, 1996c) categorized fluoride among

“potentially toxic elements, some of which may nevertheless have

some essential functions at low levels.” Fluoride was regarded as

“essential,” since the consultation “considered resistance to dental

caries to be a physiologically important function.” The consultation

indicated that total intakes at 1, 2 and 3 years of age “should, if

possible, be limited to 0.5, 1.0 and 1.5 mg/day, respectively,” with not

more than 75% coming in the form of soluble fluorides from drinkingwater. It was also noted that “adult intakes exceeding 5 mg of fluoride

per day from all sources probably pose a significant risk of skeletal

fluorosis.”
185

REFERENCES

Aardema M, Gibson D, & LeBoeuf R (1989a) Sodium fluoride induced chromosome

aberrations in different stages of the cell cycle: a prop osed mechanism. Mutat Res, 223:

191–203.

Aardema M, Gibson D, & LeBoeuf R (1989b) The kinetics of sodium fluoride-induced endoreduplication in Chinese hamsterovary cells. Environ Mol Mutagen, 14(suppl15): 3 (abstract).

Abdennebi EH, Fandi R, & Lamnaouer D (1995)Human fluorosis in Morocco: analytical and

clinical investigations. Vet Hum Toxicol, 37: 465–468.

Adelung D, Bossmann K, & Rossler D (1985) The distribution of fluoride in some Antarctic

seals. Polar Biol, 5: 31–34. 

Adelung D, Buchholz F, Culik B, & Keck A (1987) Fluoride in tissues of krill Euphausia

superba Dana and Meganyctiphanes norvegica M. Sarsin relation to the moult cycle. Polar

Biol, 7(1): 43–50. 

Afseth J, Ekstrand J, & Hagelid P (1987) Dissolution of calcium fluoride tablets in vitro and

bioavailability in man. Scand J Dent Res, 95: 191–192.

Ahn HW & Jeffery EH (1994) Effect of aluminum on fluoride uptake by Salmonella

typhimurium TA98; implications for the Ames mutagenicity assay. J Toxicol Environ Health,

41: 357–368.

Ahn H, Fulton D, Moxon D, & Jeffery E (1995) Interactive effects of fluoride and aluminum

uptake and accumulation in bonesof rabbitsadministered both agents in their drinking water.

J Toxicol Environ Health, 44: 337–350.

Akbar-Khanzadeh F (1995) Exposure to particulates and fluorides and respiratory health of

workersin an aluminum production potroom with limited control measures. Am Ind Hyg Assoc

J, 56: 1008–1015.

Akhundow WY, Aliew AA, Kulgawin AH, & Sariva TN (1981)[Effect of complex and separate

exogenousadministration of vitamins on the level of chromosome aberrations in ratsinduced

by sodium fluoride in a subacute experiment.] Izv Akad Nauk Az SSR, Ser Biol Nauk, 4: 3–5

(in Russian).

Albanese R (1987) Sodium fluoride and chromosome damage (in vitro human lymphocytes

and in vivo micronucleus assays). Mutagenesis, 2: 497–499.

Alexandersen P, Riis BJ, & Christiansen C (1999) Monofluorophosphate combined with

hormone replacement therapy inducesa synergisticeffect on bone massby dissociating bone

formation and resorption in postmenopausal women: a randomised study. J Clin Endocrinol

Metab, 84: 3013–3020.

Alhava E, Olkkonen H, Kauranen P, & Kari T (1980)The effect of drinking water fluoridation

on the fluoride content, strength and mineral density of human bone. Acta Orthop Scand, 51:

413–420.

Aliev AA & Babaev DA (1981) Cytogenetic activity of vitamins in bone marrow cells of rat

femursunder conditions of induction of mutations by sodium fluoride. Cytol Cytogen (USSR),

15: 15–18.
EHC 227: Fluorides

186

Aliev A, Dzhafarova S, Medzhidov M, & Asadova A (1988)Investigation of the phenomenon

and substantiation of the mechanism of antimutagenesis under conditions of the effect of

sodium fluoride. Cytol Genet, 22: 24–27.

Allcroft R & BurnsKN (1968) Fluorosis in cattle in England and Wales: incidence and sources.

Fluoride, 1: 50–53. 

Amundson RG, Belsky AJ, & Dickie RC (1990) Fluoride deposition via litterfall in a coastalplain pine plantation in South Carolina. Water Air Soil Pollut, 50: 301–310. 

Anasuya A & Paranjape PK (1996) Effect of parboiling on fluoride content of rice. Fluoride,

29: 193–201.

Anasuya A, Bapurao S, & Paranjape PK (1996) Fluoride and silicon intake in normal and

endemic fluorotic areas. J Trace Elem Med Biol, 10: 149–155.

Andersen A, Dahlberg B, Magnus K, & Wannag A (1982) Risk of cancer in the Norwegian

aluminum industry. Int J Cancer, 29: 295–298.

Ando M, Tadano M, Asanuma S, Tamura K, Matsushima S, Watanabe T, Kondo T, Sakurai

S, Ji R, Liang C, & Cao S (1998) Health effects of indoor fluoride pollution from coal burning

in China. Environ Health Perspect, 106: 239–244.

AndrewsS, Cooke J, & Johnson M (1982)Fluoride in small mammalsand their potential food

sources in contaminated grasslands. Fluoride, 15: 56–63. 

Andrews SM, Cooke JA, & Johnson MS (1989) Distribution of trace element pollutants in a

contaminated ecosystem established on metalliferous fluorspartailings. 3: Fluoride. Environ

Pollut, 60: 165–179. 

Angelovic JW, Sigler WF, & Neuhold JM (1961) Temperature and fluorosisin rainbow trout.

J Water Pollut Control Fed, 33(4): 371–381. 

Antia NJ & Klut ME (1981) Fluoride addition effects on euryhaline phytoplankter growth in

nutrient-enriched seawater at an estuarine level of salinity. Bot Mar, 24: 147–152. 

Aoba T (1997) The effect of fluoride on apatite structure and growth. CritRev Oral Biol Med,

8: 136–153.

Aplin TEH (1968)Poison plants of Western Australia. The toxic speciesof the genera Gastrolobiumand Oxylobium heart-leaf poison (Gastrolobium bilobum), river poison (Gastrolobium

forrestii), Stirling Range poison (Gastrolobium velutinumi ). J Dep Agric West Aust, 9(2):

69–74.

Ares J (1990) Fluoride–aluminium water chemistry in forest ecosystems of central Europe.

Chemosphere, 21(4/5): 597–612. 

Ares JO, Villa A, & Gayoso AM (1983) Chemical and biological indicators of fluoride input

in the marine environment near an industrial source (Argentina). Arch Environ Contam

Toxicol, 12: 589–602. 

Armstrong B, Tremblay C, Cyr D, & Thériault G (1986) Estimating the relationship between

exposure to tar volatiles and the incidence of bladder cancer in aluminum smelter workers.

Scand J Work Environ Health, 12: 486–493.
References

187

Armstrong B, Tremblay C, Baris D, & Theriault G (1994) Lung cancer mortality and

polynuclear aromatic hydrocarbons: a case–cohort study of aluminum production workers in

Arvida, Quebec, Canada. Am J Epidemiol, 1: 250–262.

Arnala I, Alhava E, Kivivuoir R, & Kauranen P (1986)Hip fracture not affected by fluoridation.

Acta Orthop Scand, 57: 344–346.

Arnesen AKM (1998)Effect of fluoride pollution on pH and solubility of Al, Fe, Ca, Mg, K and

organic matter in soil from Årdal (western Norway). Water Air Soil Pollut, 103: 375–388.

Arnesen AKM & Krogstad T (1998) Sorption and desorption of fluoride in soil polluted from

the aluminium smelter at Årdal in western Norway. Water Air Soil Pollut, 103: 357–373.

Aschengrau A, Zierler S, & Cohen A (1989) Quality of community drinking water and the

occurrence of spontaneous abortion. Arch Environ Health, 44: 283–290.

Aschengrau A, Zierler S, & Cohen A (1993) Quality of community drinking water and the

occurrence of late adverse pregnancy outcomes. Arch Environ Health, 48: 105–113.

ATSDR (1993) Toxicological profile for fluorides, hydrogen fluoride, and fluorine. Atlanta,

Georgia, US Department of Health and Human Services, Agency for Toxic Substances and

Disease Registry (TP-91/17).

Augenstein W, Spoerke D, Kulig K, Hall A, Hall P, Riggs B, Saadi M, & Rumack B (1991)

Fluoride ingestion in children: A review of 87 cases. Pediatrics, 88: 907–912.

Aulerich RJ, Napolitano AC, & Bursian SJ (1987)Chronic toxicity of dietary fluorine to mink.

J Anim Sci, 65: 1759–1767. 

Avorn J & Nielssen LC (1986) Relationship between long bone fractures and water

fluoridation. Gerodontics, 2: 175–179.

Baars AJ, van Beek H, Spierenburg TJ, de Graf GJ, Beeftink WGJN, Boom J, & Pekelder JJ

(1987) Fluoride pollution in a salt marsh: movement between soil, vegetation, and sheep.

Bull Environ Contam Toxicol, 39: 945–952. 

Bale S & Mathew M (1987) Analysis of chromosomal abnormalities at anaphase–telophase

induced by sodium fluoride in vitro. Cytologia, 52: 889–893.

Ballantyne DJ (1984)ATP and growth in fluoride-treated pea shoots. Environ Exp Bot, 24(3):

277–282. 

Ballantyne DJ (1991) Fluoride and photosynthetic capacity of azalea (Rhododendron)

cultivars. Fluoride Q Rep, 24(1): 11–16. 

Barbaro A, Francescon A, & Polo B (1981)Fluorine accumulation in aquatic organismsin the

lagoon of Venice. Fluoride, 14: 102–107. 

Barnard WR & Nordstrom DK (1982) Fluoride in precipitation. II. Implications for the

geochemical cycling of fluoride. Atmos Environ, 16(1): 105–111. 

Barrie LA & Hoff RM (1985) Five years of air chemistry observations in the Canadian arctic.

Atmos Environ, 19(12): 1995–2010.
EHC 227: Fluorides

188

BarrowNJ & Ellis AS (1986) Testing a mechanisticmodel — III. The effectsof pH on fluoride

retention by a soil. J Soil Sci, 37: 287–293. 

Bayley TA, Harrison JE, Murray TM, Josse RG, Sturtridge W, PritzkerKP, Strauss A, Vieth R,

& Goodwin S (1990) Fluoride-induced fractures: relation to osteogenic effect. J Bone Miner

Res, 5(suppl 1): S217–S222.

Beg SA (1982) Inhibition of nitrification by arsenic, chromium and fluoride. J Water Pollut

Control Fed, 54: 482–488. 

Belandria G, Asta J, & Nurit F (1989) Effects of sulphur dioxide and fluoride on ascospore

germination of several lichens. Lichenologist, 21(1): 79–86. 

Bell ME, Largent EJ, Ludwig TG, Muhler JC, & Stookey GK (1970) The supplyof fluorine to

man. In: Fluoridesand human health. Geneva, World Health Organization, pp 17–74 (WHO

Monograph Series No. 59). 

Bennett A & Barratt R (1980) Some observations on atmospheric fluoride concentrations in

Stoke-on-Trent. J R Soc Health, 100: 84–89.

Berglund LK, IseliusL, Lindsten J, Marks L, & Ryman N (1980)[Incidence of Down’ssyndrome

in Sweden during the years1968–1977.] Stockholm, National Swedish Board of Health and

Welfare (Report to the Reference Group for Malformations and Developmental Disorders) (in

Swedish).

Bergmann KE & Bergmann RL (1995) Salt fluoridation and general health. Adv Dent Res,

9: 138–142.

Bergmann R (1995)Fluorid in derErnährung des Menschen. Biologische Bedeutung fürden

wachsenden Organismus. Habilitationsschrift. Berlin, Virchow-Klinikum der HumboldtUniversität, 133 pp.

Berndt A & Stearns R (1979) Dental fluoride chemistry. Springfield, Illinois, Charles C.

Thomas.

Bernstein D, Sadowskuy N, & Hegsted D (1966) Prevalence of osteoporosis in high- and lowfluoride areas of North Dakota. J Am Med Assoc, 198: 499–504.

Berry WTC (1962) Fluoridation. Med Off, 108: 204–205.

Bhatnagar M & Susheela AK (1998) Chronic fluoride toxicity: an ultrastructural study of the

glomerulus of the rabbit kidney. Environ Sci, 6: 43–54.

Bird DM & Massari C (1983) Effects of dietary sodium fluoride on bone fluoride levels and

reproductive performance of captive American kestrels. Environ Pollut, A31: 67–76.

Bird DM, Carrière D, & Lacombe D (1992) The effect of dietary sodium fluoride on internal

organs, breast muscle, and bones in captive American kestrels (Falco sparverius). Arch

Environ Contam Toxicol, 22: 242–246.

Boese SR, MacLean DC, & El-Mogazi D (1995) Effects of fluoride on chlorophyl l a

fluorescence in spinach. Environ Pollut, 89(2): 203–208. 

Boillat MA, Baud CA, Lagier R, Garcia J, Rey P, Bang S, Boivin G, Demeurisse C, Gossi M,

Tochon-Danguy HJ, Very JM, Burckhardt P, Voinier B, Donath A, & Courvoisier B (1979)
References

189

[Industrial fluorosis. Multidisciplinary study on 43 workmen in the aluminium industry.]

Schweiz Med Wochenschr, Suppl 8: 1–28 (in French).

Boivin G, Chavassieux P, Chapuy MC, Baud CA, & Meunier PJ (1989) Skeletal fluorosis:

histomorphometricanalysisof bone changesand bone fluoride content in 29 patients. Bone,

10: 89–99.

Boone RJ & Manthey M (1983) The anatomical distribution of fluoride within various body

segments and organs of Antarctic krill (Euphausia superba Dana). Arch Fischereiwiss, 34(1):

81–85. 

Bordelon BM, Saffle JR, & Morris SE (1993) Systemic fluoride toxicity in a child with

hydrofluoric acid burns: a case report. J Trauma, 34: 437–439.

Boulton I, Cooke J, & Johnson M (1994a) Age-accumulation of fluoride in an experimental

population of short-tailed field voles (Microtus agrestis L.). Sci Total Environ, 154: 29–37.

Boulton IC, Cooke JA, & Johnson MS (1994b) Fluoride accumulation and toxicity in wild

small mammals. Environ Pollut, 85: 161–167.

Boulton IC, Cooke JA, & Johnson MS (1995) Fluoride accumulation and toxicity in laboratory

populations of wild small mammals and white mice. J Appl Toxicol, 15(6): 423–431.

Boulton IC, Cooke JA, & Johnson MS (1999) Lesion scoring in field vole teeth: Application

to the biological monitoring of environmental fluoride contamination. Environ Monit Assess,

55: 409–422.

Bowen SE (1988)Spatial and temporal patterns in the fluoride content of vegetation around

two aluminium smelters in the Hunter Valley, New South Wales. Sci Total Environ, 68:

97–111. 

Bower CA & Hatcher JT (1967) Adsorption of fluoride by soils and minerals. Soil Sci, 103:

151–154. 

Breimer RF, Vogel J, & Ottow JCG (1989) Fluorine contamination of soils and earthworms

(Lumbricus spp.)near a site of long-term industrial emission in southern Germany. Biol Fertil

Soils, 7(4): 297–302. 

Brewer RF (1966) Fluorine. In: Chapman HD ed. Diagnostic criteria for plants and soils.

Riverside, California, University of California, Division of Agricultural Science, pp 180–195.

Brimblecombe P & Clegg SL (1988)The solubility and behaviour of acid gasesin the marine

aerosol. J Atmos Chem, 7: 1–18. 

Brouwer ID, DeBruin A, BackerDirks O, & Hautvast JGAJ (1988) Unsuitability of World Health

Organisation guidelines for fluoride concentrations in drinking water in Senegal. Lancet, 1:

223–225.

Bruun C & Thylstrup A (1988)Dentifrice usage among Danish children. J Dent Res, 67: 1114–

1117.

Buckingham FM (1988) Surgery: a radical approach to severe hydrofluoric acid burns. J

Occup Med, 30: 873–874.

Bunce HWF (1984)Fluoride emissions and forest survival, growth and regeneration. Environ

Pollut, A35: 169–188. 
EHC 227: Fluorides

190

Bunce HWF (1985) Apparent stimulation of tree growth by low ambient levels of fluoride in

the atmosphere. J Air Pollut Control Assoc, 35(1): 46–48. 

Burns KN & Allcroft R (1964) Fluorosis in cattle. 1. Occurrence and effectsin industrial areas

of England and Wales, 1954–57. London, HMSO. 

Burt B (1992)The changing patterns of systemic fluoride intake. J Dent Res, 71: 1228–1237.

Buse A (1986) Fluoride accumulation in invertebratesnear an aluminium reduction plant in

Wales. Environ Pollut, A41: 199–217. 

Butler JE, Satam M, & Ekstrand J (1990) Fluoride: An adjuvant for mucosal and systemic

immunity. Immunol Lett, 26: 217–220.

Butler WJ, Segreto V, & Collins E (1985) Prevalence of dental mottling in school-aged

lifetime residents of 16 Texas communities. Am J Public Health, 75: 1408–1412.

Calderon J, Romieu I, Gromaldo M, Hernandez H, & Diaz-Barriga F (1995)Endemic fluorosis

in San Luis Potosi, Mexico. II. Identification of risk factors associated with occupational

exposure to fluoride. Fluoride, 4: 203–208.

Camargo JA (1991)Ecotoxicological study of the influence of an industrial effluent on a netspinning caddisfly assemblage in a regulated river. Water Air Soil Pollut, 60: 263–277. 

Camargo JA (1996a) Comparing levels of pollutants in regulated rivers with safe

concentrations of pollutants for fishes: a case study. Chemosphere, 33(1): 81–90.

Camargo JA (1996b) Estimating safe concentrations of fluoride for three speciesof nearctic

freshwater invertebrates: Multifactor probit analysis. Bull Environ Contam Toxicol, 56(4):

643–648. 

Camargo JA & La Point TW (1995)Fluoride toxicity to aquatic life: a proposal of safe concentrations for five species of palearctic freshwater invertebrates. Arch Environ Contam Toxicol,

29: 159–163. 

Camargo JA & Tarazona JV (1990) Acute toxicity to freshwater benthic macroinvertebrates

of fluoride ion (F–) in soft water. Bull Environ Contam Toxicol, 45(6): 883–887. 

Camargo JA & Tarazona JV (1991) Short-term toxicity of fluoride ion (F–) in soft water to

rainbow trout and brown trout. Chemosphere, 22(5/6): 605–611. 

Camargo JA, Ward JV, & Martin KL (1992)The relative sensitivity of competing hydropsychid

species to fluoride toxicity in the Cache la Poudre River (Colorado). Arch Environ Contam

Toxicol, 22: 107–113. 

Campbell A (1987) Determination of fluoride in various matrices. Pure Appl Chem, 59:

695–702.

Cao J, Bai X, Zhao Y, Zhou D, Fang S, Jia M, & Wu J (1996) The relationship of fluorosisand

brick tea drinking in Chinese Tibetans. Environ Health Perspect, 104: 1340–1343.

Cao J, Zhao Y, Liu J, Xirao R, & Danzeng S (2000)Environmental fluoride content in Tibet.

Environ Res, 83(3): 333–337.
References

191

Caraccio T, Greensher J, & Mofenson H (1983) The toxicology of fluoride. In: Haddad L &

Winchester J ed. Clinical management of poisoning and drug overdose. Philadelphia,

Pennsylvania, W.B. Saunders.

Carlson CE (1978) The use of infrared aerial photography in determining fluoride damage

to forest ecosystemsnear an aluminum plant in northwestern Montana, USA. Fluoride, 11(3):

135–141.

Carpenter R (1969) Factors controlling the marine geochemistry of fluorine. Geochim

Cosmochim Acta, 33: 1153–1167.

Carrière D, Bird DM, & Stamm JW (1987) Influence of a diet of fluoride-fed cockerels on

reproductive performance of captive American kestrels. Environ Pollut, 46: 151–159.

Caspary W, Myhr B, Bowers L, McGregor D, Riach C, & Brown A (1987)Mutagenic activity of

fluorides in mouse lymphoma cells. Mutat Res, 187: 165–180.

Caspary W, Langenbach R, Penman B, Crespi C, MyhrB, & Mitchell A (1988)The mutagenic

activity of selected compounds at the TK locus: rodent vs. human cells. Mutat Res, 196:

61–81.

Cauley JA, Murphy PA, Riley TJ, & Buhari AM (1995)Effectsof fluoridated drinking water on

bone mass and fractures: The study of osteoporotic fractures. J Bone Miner Res, 1 0 :

1076–1086.

Chakma T, Vinay Rao P, Singh SB, & Tiwary RS (2000) Endemic genu valgum and other

bone deformities in two villages of Mandla district in Central India. Fluoride, 33: 187–195.

Chamblee JW, Arey FK, & Heckel E (1984) Free fluoride of the Pamlico River in North

Carolina. A new method to localize the discharge of polluted water into an estuary. Water

Res, 18(10): 1225–1233. 

Chan JT & Koh SH (1996) Fluoride content in caffeinated, decaffeinated and herbal teas.

Caries Res, 30: 88–92.

Chan K-M, Svancarek WP, & Creer M (1987) Fatality due to hydrofluoricacid exposure. Clin

Toxicol, 25: 333–339.

Chan MM, Rucker RB, Zeman F, & Riggins RS (1973) Effect of fluoride on bone formation

and strength in Japanese quail. J Nutr, 103: 1431–1440. 

Chandrawanshi CK & Patel KS (1999) Fluoride deposition in central India. Environ Monit

Assess, 55: 251–265.

Chan-Yeung M, Wong R, Earnson D, SchulzerM, Subbarao K, KnickerbockerJ, & Grzybowski

S (1983a) Epidemiological health study of workers in an aluminum smelterin Kitimat, B.C.

II. Effects on musculoskeletal and other systems. Arch Environ Health, 38: 34–40.

Chan-Yeung M, Wong R, MacLean L, Tan F, Schulzer M, Enarson D, Martin A, Dennis R, &

Grzybowski S (1983b)Epidemiologic health study of workersin an aluminum smelterin British

Columbia. Effects of the respiratory system. Am Rev Respir Dis, 127: 465–469.

Chen Y, Lin M, He Z, Xie X, Liu Y, Xiao Y, Zhou J, Fan Y, Xiao X, & Xu F (1993) Air

pollution-type fluorosisin the region of Pingxiang, Jiangxi,People’sRepublic of China. Arch

Environ Health, 48: 246–249. 
EHC 227: Fluorides

192

Chen YX, Lin MQ, He ZL, Chen C, Min D, Liu YQ, & Yu MH (1996) Relationship between

total fluoride intake and dental fluorosis in areas polluted by airborne fluoride. Fluoride, 29:

7–12.

Chhabra R, Singh A, & Abrol IP (1979) Fluorine in sodic soils. Soil Sci Soc Am J, 44: 33–36.

Chilvers C (1982) Cancer mortality by site and fluoridated water supplies. J Epidemiol

Community Health, 36: 237–242.

Chinoy N & Sequeira E (1989a)Effectsof fluoride on the histoarchitecture of the reproductive

organs of the male mouse. Reprod Toxicol, 3: 261–267.

Chinoy N & Sequeira E (1989b) Fluoride induced biochemical changes in reproductive

organs of male mice. Fluoride, 22: 79–85.

Chinoy NJ & Sharma A (1998) Amelioration of fluoride toxicity by vitamins E and D in

reproductive functions of male mice. Fluoride, 31: 203–216.

Chinoy N, Sequeira E, & Narayama M (1991) Effect of vitamin C and calcium on the

reversibility of fluoride-induced alterations in spermatozoa of rabbits. Fluoride, 24: 29–39.

Chinoy NJ, Narayama MV, Dalal V, Rawat M, & Patel D (1995) Amelioration of fluoride

toxicity in some accessory reproductive glandsand spermatozoa of rat. Fluoride, 28: 75–86.

Cholak J (1959) Fluorides: A critical review. I. The occurrence of fluoride in air, food, and

water. J Occup Med, 1: 501–511.

Choubisa SL (1999)Some observationson endemic fluorosisin domesticanimalsin southern

Rajsthan (India). Vet Res Commun, 23: 457–465.

Choubisa SL, Choubisa DK, Joshi SC, & Choubisa L (1997) Fluorosis in some tribal villages

of Dungapur district of Rajasthan, India. Fluoride, 30: 223–228.

Christians O & Leinemann M (1980) [Untersuchungen über Fluor im Krill (E. superba).] Inf

Fischwirtsch Ausl, 6: 254–260. 

Chu F (1991) SF6 and the atmosphere. Toronto, Ontario, Ontario Hydro Research Division,

Electrical Research Department (91-58-K). 

Cohn P (1992) An epidemiologic report on drinking water and fluoridation. Environmental

Health Service, New Jersey Department of Health, November.

Cole J, Muriel W, & Bridges B (1986) The mutagenicity of sodium fluoride to L5178Y [wildtype and TK+/! (3.7.2C)] mouse lymphoma cells. Mutagenesis, 1: 157–167.

CollinsTFX, Sprando RL, Shackelford ME, BlackTN, AmesMJ, Welsh JJ, Balmer MF, Olejnik

N, & Ruggles DI (1995) Developmental toxicity of sodium fluoride in rats. Food Chem

Toxicol, 33: 951–960.

Connell AD & Airey DD (1982) The chronic effects of fluoride on the estuarine amphipods

Grandidierella lutosa and G. lignorum. Water Res, 16: 1313–1317. 

ConoverCA & Poole RT (1971) Influence of fluoride on foliar necrosisof Cordyline terminalis

Cv Baby Doll during propagation. Proc Fla State Hortic Soc, 84: 380–383. 
References

193

Cooke JA (1976) The uptake of sodium monofluoroacetate by plants and its physiological

effects. Fluoride, 9(4): 204–212. 

Cooke JA, Johnson MS, Davison AW, & Bradshaw AD (1976) Fluoride in plant colonizing

fluorspar mine waste in the Peak District and Weardale. Environ Pollut, 11: 10–23.

Cooke JA, Johnson MS, & Davison AV (1978) Uptake and translocation of fluoride in

Helianthus annus L. grown in sand culture. Fluoride, 11: 76–88. 

Crespi C, Seixas G, Turner T, & Penman B (1990)Sodium fluoride is a less efficient human

cell mutagen at low concentrations. Environ Mol Mutagen, 15: 71–77.

Cronin SJ, Manoharan V, Hedley MJ, & Loganathan P (2000) Fluoride — a review of its fate

and hazard potential in grazed pasture systems. N Z J Agric Res, 43: 295–321.

Cuker W & ShiltsW(1979)Lacustrine geochemistry around the north shore of Lake Superior:

Implications for evaluation of the effects of acid precipitation. Current Research Part C,

Geological Survey of Canada (79-1C).

Cummings C & McIvor M (1988)Fluoride-induced hyperkalemia: the role of Ca2+-dependent

K+ channels. Am J Emerg Med, 6: 1–3.

Czarnowski W & Krechniak J (1990) Fluoride in urine, hair and nails of phosphate fertilizer

workers. Br J Ind Med, 47: 349–351.

Czarnowski W, Wrzenioska K, & Krechniak J (1996) Fluoride in drinking water and human

urine in northern and central Poland. Sci Total Environ, 191: 177–184.

Czarnowski W, Krechniak J, Urbanska B, Stolarska K, Taraszewska-Czarnowska M, & MuraszkoKlaudel A (1999) The impact of water-borne fluoride on bone density. Fluoride, 32: 91–95.

Czerwinski E, Nowack J, Dabrowska D, Skolarczyk A, Kita B, & Ksiezyk M (1988) Bone and

joint pathology in fluoride-exposed workers. Arch Environ Health, 43: 340–343.

Dabeka RW & McKenzie AD (1995) Survey of lead, cadmium, fluoride, nickel, and cobalt in

food composites and estimation of dietary intakes of these elements by Canadians in

1986–1988. J Assoc Off Anal Chem Int, 78: 897–909.

Dabeka RW, McKenzie AD, ConacherHBS, & Kirkpatrick BS (1982) Determination of fluoride

in Canadian infant foods and calculation of fluoride intake by infants. Can J Public Health,

73: 188–191.

Dabeka R, Karpinski K, McKenzie A, & Bajdik C (1986)Survey of lead, cadmium and fluoride

in human milk and correlation of levels with environmental and food factors. Food Chem

Toxicol, 24: 913–921.

Dabkowska E & Machoy Z (1989) Effects of fluoride pollution on calcium and magnesium

content of mandibles (lower jaws) of wild game. Fluoride Q Rep, 22(1): 29–32.

Damkaer DM & Dey DB (1989) Evidence for fluoride effectson salmon passage at John Day

Dam, Columbia River, 1982–1986. North Am J Fish Manage, 9: 154–162.

Danielson C, Lyon J, Egger M, & Goode nough G (1992) Hip fracture and fluoridation in

Utah’s elderly population. J Am Med Assoc, 268: 746–748.
EHC 227: Fluorides

194

Das T & Susheela A (1991) Effect of chronic fluoride toxicity on glucocorticoid levels in

plasma and urine. Fluoride, 24: 23–28.

Das TK, Susheela AK, Gupta IP, Dasarathy S, & Tandon RK (1994) Toxic effects of chronic

fluoride ingestion on the upper gastrointestinal tract. J Clin Gastroenterol, 18: 194–199. 

Dasarathy S, Das TK, Gupta IP, Susheela AK, & Tandon RK (1996) Gastroduodenal

manifestations in patients with skeletal fluorosis. J Gastroenterol, 31: 333–337.

Daston G, Rehnberg B, Carver B, & Kavelock B (1985) Toxicity of sodium fluoride to the

postnatally developing rat kidney. Environ Res, 37: 461–474.

Datta DK, Gupta LP, & Subramanian V (2000) Dissolved fluoride in the Lower Ganges–

Brahmaputra–Meghna river system in the Bengal Basin, Bangladesh. Environ Geol, 39(10):

1163–1168.

Dave G (1984) Effects of fluoride on growth, reproduction and survival in Daphnia magna.

Comp Biochem Physiol, 78C(2): 425–431. 

Davies FBM (1982) Accumulation of fluoride by Xanthoria parietina growing in the vicinity

of the Bedfordshire brickfields. Environ Pollut, 29: 189–196. 

DaviesFBM (1986)The long-term changes in fluoride content of Xanthoria parietina growing

in the vicinity of the Bedfordshire brickfields. Environ Pollut, A42: 201–207. 

Davies FBM & Notcutt G (1988) Accumulation of fluoride by lichens in the vicinity of Etna

volcano. Water Air Soil Pollut, 42: 365–371. 

DaviesFBM & Notcutt G (1989) Accumulation of volcanogenic fluorides by lichens. Fluoride

Q Rep, 22(2): 59–65. 

Davies MT, Port GR, & Davison AW (1998) Effects of dietary and gaseous fluoride on the

aphid Aphis fabae. Environ Pollut, 99: 405–409.

Davis JB & Barnes RL (1973) Effects of soil-applied fluoride and lead on growth of loblolly

pine and red maple. Environ Pollut, 5: 35–44. 

Davis RD (1980) Uptake of fluoride by ryegrass grown in soil treated with sewage sludge.

Environ Pollut, B1: 277–284. 

Davison A (1983) Uptake, transport and accumulation of soil and airborne fluorides by

vegetation. In: Shupe J, Peterson H, & Leone N ed. Fluorides: Effectson vegetation, animals

and humans. Salt Lake City, Utah, Paragon Press, pp 61–82. 

Davison AW & Blakemore J (1980) Rate of deposition, and resistance to deposition, of

fluorides on alkali-impregnated papers. Environ Pollut, B1: 305–319. 

Davison AW, Rand AW, & Betts WE (1973) Measurement of atmospheric fluoride

concentrations in urban areas. Environ Pollut, 5: 23–33. 

Dayal HH, BrodwickM, Morris R, Baranowski T, Trieff N, Harrison JA, Lisse JR, & Ansari GAS

(1992) A community-based epidemiological study of health sequela of exposure to

hydrofluoric acid. Ann Epidemiol, 2: 213–220.
References

195

Dean HT, Jay P, Arnold FA, & Elvove E (1941)Domesticwatersand dental caries. II. A study

of 2832 white children ages 12–14 years of eight suburban Chicago communities, including

Lactobacillus acidophilus studies of 1761 children. Public Health Rep, 56: 761–792.

Dean HT, Arnold FA, & Elvove E (1942) Domestic waters and dental caries. V. Additional

studiesof the relation of fluoride domesticwatersto dental cariesin 4425 white children, age

12–14 years, of 13 cities in 4 states. Public Health Rep, 57: 1155–1179.

Delmas PD, Dupuis J, Duboeuf F, Chapuy MC, & MeunierPJ (1990) Treatment of vertebral

osteoporosis with disodium monofluorophosphate: comparison with sodium fluoride. J Bone

Miner Res, 5(suppl 1): S143–S147.

Derelanko M, Gad S, Gavigan F, & Dunn B (1985)Acute dermal toxicity of dilute hydrofluoric

acid. J Toxicol Cutan Ocular Toxicol, 4: 73–85.

Doley D (1986)Experimental analysisof fluoride susceptibility of grapevine (Vitis vinifera L.):

leaf development during four successive seasons of fumigation. New Phytol, 103: 325–340.

Doley D (1989) Fluoride-induced enhancement and inhibition of shoot growth in four taxa

of Pinus. New Phytol, 112: 543–552. 

Doll R & Kinlen L (1977)Fluoridation of water and cancer mortality in the U.S.A. Lancet, 1:

1300–1302.

Dominok B & Miller G (1990) Effects of fluoride on Drosophila melanogaster in relation to

survival and mutagenicity. Fluoride, 23: 83–91.

Droste RL (1987) Fluoridation in Canada as of December 31, 1986. Ottawa, Ontario, Health

and Welfare Canada (IWD-AR WQB-89-154).

Drummond B, Curzon M, & Strong M (1990)Estimation of fluoride absorption from swallowed

fluoride toothpastes. Caries Res, 24: 211–215. 

Drury JS, Ensminger JT, Hammons AS, Holleman JW, Lewis EB, Preston EL, Shriner CR, &

Towill LE (1980)Reviewsof the environmental effects of pollutants. IX. Fluoride. OakRidge,

Tennessee, Oak Ridge National Laboratory (EPA 600/1-78/050).

Dunipace A, Zhang W, Noblitt T, Li Y, & Stookey G (1989) Genotoxic evaluation of chronic

fluoride exposure: micronucleusand sperm morphology studies. J Dent Res, 68: 1525–1528.

Dunipace A, Brizendine E, Wilson M, Zhang W, Wilson C, Katz B, & Kafrawy A (1998)Effect

of chronic fluoride exposure in uremic rats. Nephron, 78: 96–103.

Dure-Smith BA, Farley SM, Linkhart SG, Farley JR, & Baylink DJ (1996)Calcium deficiency

in fluoride-treated osteoporoticpatientsdespite calcium supplementation. J Clin Endocrinol

Metab, 81: 269–275. 

Easmann R, Steflik D, Pashley D, McKinney R, & Whitford G (1984) Surface changes in rat

gastric mucosa induced by sodium fluoride: a scanning electron microscopy study. J Oral

Pathol, 13: 255–264.

Easmann R, Pashley D, Birdsong N, McKinney R, & Whitford G (1985)Recovery of rat gastric

mucosa following single fluoride dosing. J Oral Pathol, 14: 779–792.
EHC 227: Fluorides

196

Eckerlin RH, KrookL, Maylin GA, & Carmichael D (1986) Toxic effects of food-borne fluoride

in silver foxes. Cornell Vet, 76: 395–402. 

Ehrnebo M & Ekstrand J (1986) Occupational fluoride exposure and plasma fluoride levels

in man. Int Arch Environ Health, 58: 179–190. 

Ekstrand J (1977) Fluoride concentrations in saliva after single oral doses and their relation

to plasma fluoride. Scand J Dent Res, 85: 16–17.

Ekstrand J (1978)Relationship between fluoride in the drinking waterand the plasma fluoride

concentration in man. Caries Res, 12: 123–127.

Ekstrand J (1981) No evidence of transfer of fluoride from plasma to breast milk. Br Med J,

283: 761–762.

Ekstrand J (1987) Pharmacokinetic aspects of topical fluorides. J Dent Res, 66: 1061–1065.

Ekstrand J & Ehrnebo M (1979)Influence of milk products on fluoride bioavailability in man.

Eur J Clin Pharmacol, 16: 211–215.

Ekstrand J & Ehrnebo M (1983)The relationship between plasma fluoride, urinary excretion

rate and urine fluoride concentrations in man. J Occup Med, 25: 745–748.

Ekstrand J, Ericsson Y, & Rosell S (1977a) Absence of protein-bound fluoride from human

blood. Arch Oral Biol, 22: 229–232. 

Ekstrand J, Alván G, Boréus L, & Norlin A (1977b)Pharmacokineticsof fluoride in man after

single and multiple oral doses. Eur J Clin Pharmacol, 12: 311–317.

Ekstrand J, Ehrnebo M, & Boreus L (1978) Fluoride bioavailability afterintravenousand oral

administration: importance of renal clearance and urine flow. Clin Pharmacol Ther, 23:

329–371.

Ekstrand J, Ehrnebo M, Whitford GM,& Järnberg PO (1980)Fluoride pharmacokineticsduring

acid–base changes in man. Eur J Clin Pharmacol, 18: 189–194.

Ekstrand J, BoréusLO, & de Chateau P (1981)No evidence of transferof fluoride from plasma

to breast milk. Br Med J, 283: 761–762.

Ekstrand J, Spak C, & Ehrnebo M (1982) Renal clearance of fluoride in a steady state

condition in man: influence of urinary flowand pH changesby diet. Acta Pharmacol Toxicol,

50: 321–325.

Ekstrand J, Odont LDS, & Ehrnebo M (1983) The relationship between plasma fluoride,

urinary excretion rate and urine fluoride concentration in man. J Occup Med, 25: 745–748.

Ekstrand J, Hardell LI, & Spak CJ (1984) Fluoride balance studieson infants in a 1-ppm water

fluoride area. Caries Res, 18: 87–92.

Ekstrand J, Ziegler EE, Nelson SE, & Fomon SJ (1994) Absorption and retention of dietary

and supplemental fluoride by infants. Adv Dent Res, 8 :175–180.
References

197

Elrashidi MA & Lindsay WL (1986) Chemical equilibria of fluorine in soils. A theoretical

development. Soil Sci, 141: 274–280. 

Elrashidi MA, Persaud N, & Baliger VC (1998) Effect of fluoride and phosphate on yield and

mineral composition of barley grown on three soils. Commun Soil Sci Plant Anal, 29(3&4):

269–283.

Elsair J & Khelfat K (1988) Subcellular effects of fluoride. Fluoride, 21: 93–99.

Environment Canada (1989) Ambient airlevelsof fluoride at Cornwall Island, Ontario, April

14–October 12, 1988. Ottawa, Ontario, Environment Canada, Conservation and Protection

Service, Environmental Protection. 

EnvironmentCanada(1994)Inorganic fluorides. Ottawa, Ontario, Environment Canada,Ecosystem Science and Evaluation Directorate, Eco-Health Branch. 

Erickson JD (1980) Down’s syndrome, water fluoridation and maternal age. Teratology, 21:

177.

Erickson JD, Oakley GP, Flynt JW, & Hay S (1976) Water fluoridation and congenital malformations: No association. J Am Dent Assoc, 93: 981–984.

Ernst P, Thomas D, & Becklake M (1986)Respiratory survey of North American Indian children

living in proximity to an aluminum smelter. Am Rev Respir Dis, 133: 307–312.

Esala S, Vuori E, & Helle A (1982) Effect of maternal fluorine intake on breast milk fluorine

content. Br J Nutr, 48: 201–204.

Essman E, Essman W, & Valderrama E (1981)Histaminergicmediation of the response of rat

skin to topical fluorides. Arch Dermatol Res, 271: 325–340.

Fabiani L, Leoni V, & Vitali M (1999)Bone-fracture incidence rate in two Italian regionswith

different fluoride concentration levels in drinking water. J Trace Elem Med Biol, 13:

232–237.

Fejerskov O, Manji F, Baelum V, & Møller IJ (1988) Dental fluorosis— a handbook for health

workers. Copenhagen, Munksgaard, 123 pp.

Fejerskov O, Baelum V, & RichardsA (1996)Dose–response and dental fluorosis. In: Fejerskov

O, Ekstrand J, & Burt BA ed. Fluoride in dentistry, 2nd ed. Copenhagen, Munksgaard, pp

153–166.

Felsenfeld A & Roberts M (1991) A report of fluorosis in the United States secondary to

drinking well water. J Am Med Assoc, 265: 486–488.

Feskanich D, Owusu W, HunterDJ, Willett W, Ascherio A, Spiegelman D, Morris S, Spate VL,

& Colditz G (1998) Use of toenail fluoride levelsasan indicatorforthe risk of hip and forearm

fractures in women. Epidemiology, 9: 412–416. 

Fidanci UR, Salmanoglu B, Marasli S, & Marasli N (1998)[The natural and industrial fluorosis

in the Middle Anatolia and its effects on animal health.] Tr J Vet Anim Sci,22: 537–544 (in

Turkish).

Fieser AH, Sykora JL, Kostalos MS, Wu YC, & Weyel DW (1986)Effect of fluorides on survival

and reproduction of Daphnia magna. J Water Pollut Control Fed, 58(1): 82–86.

Fleming WJ, Grue CE, Schuler CA, & Bunck CM (1987) Effects of oral doses of fluoride on

nestling European starlings. Arch Environ Contam Toxicol, 16: 483–489. 
EHC 227: Fluorides

198

Flühler H, Polomski J, & Blaser P (1982) Retention and movement of fluoride in soils. J

Environ Qual, 11: 461–468. 

Fomon SJ & Ekstrand J (1993) Fluoride. In: Fomon SJ ed. Nutrition of normal infants. St

Louis, Missouri, Mosby, pp 299–310.

Fomon SJ, Ekstrand J, & ZieglerEE (2000)Fluoride intake and prevalence of dental fluorosis:

Trends in fluoride intake with special attention to infants. J Public Health Dent, 60: 131–139.

Freni S (1994) Exposure to high fluoride concentrations in drinking water is associated with

decreased birth rates. J Toxicol Environ Health, 42: 109–121.

Freni S & GaylorD (1992)International trendsin the incidence of bone cancerare not related

to drinking water fluoridation. Cancer, 70: 611–618.

Fuge R & Andrews MJ (1988) Fluorine in the UK environment. Environ Geochem Health,

10(3/4): 96–104. 

Fung KF, Zhang ZQ, Wong JWC, & Wong MH (1999) Fluoride contents in tea and soil from

tea plantations and the release of fluoride into tea liquor during infusion. EnvironPollut, 104:

197–205.

Gadhia PK & Joseph S (1997)Sodium fluoride induced chromosome aberrations and sister

chromatid exchange in cultured human lymphocytes. Fluoride, 30: 153–156.

Gebhart E, Wagner H, & Behnsen H (1984) The action of anticlastogens in human

lymphocyte cultures and its modification by rat liver S9 mix. Studies with AET and sodium

fluoride. Mutat Res, 129: 195–206.

Gelberg KH, Fitzgerald EF, Hwang S, & Dubrow R (1995) Fluoride exposure and childhood

osteosarcoma: A case–control study. Am J Public Health, 85: 1678–1683.

GessnerB, Beller M, Middaugh J, & Whitford G (1994)Acute fluoride poisoning from a public

water system. N Engl J Med, 330: 95–99. 

GibbsG (1985) Mortality of aluminum reduction plant workers, 1950 through 1977. J Occup

Med, 27: 761–770.

Gikunju JK (1992)Fluoride concentration in tilapia fish (Oreochromis leucostictus) from Lake

Naivasha, Kenya. Fluoride Q Rep, 25(1): 37–43. 

Gilbert OL (1985) Environmental effects of airborne fluorides from aluminium smelting at

Invergordon, Scotland, 1971–1983. Environ Pollut, 39: 293–302. 

Gilman A (1987)G proteins: transducers of receptor-generated signals. Annu Rev Biochem,

56: 615–649.

Gilpin L & Johnson A (1980) Fluorine in agricultural soils of southeastern Pennsylvania. Soil

Sci Soc Am J, 44: 255–258. 

Giovanazzi A & D’Andrea F (1981) [Mortality of workers in a primary aluminum plant.] Med

Lav, 4: 277–282 (in Italian).

Gocke E, King M-T, Eckhardt K, & Wild D (1981) Mutagenicity of cosmetics ingredients

licensed by the European Communities. Mutat Res, 90: 91–109.
References

199

Godfrey P & Watson S (1988) Fluoride inhibits agonist-induced formation of inositol

phosphates in rat cortex. Biochem Biophys Res Commun, 155: 664–669.

Goggin JE, Haddon W, Hambly GS, & Hoveland JR (1965) Incidence of femoral fractures in

postmenopausal women. Public Health Rep, 80: 1005–1012.

Government of Canada (1993) Canadian Environmental Protection Act. Priority Substances

List assessment report forinorganic fluorides. Prepared by Health Canada and Environment

Canada. Ottawa, Ontario, Canada Communication Group (ISBN 0-662-21070-9).

Grad H (1990) Fluorides: old and new perspectives. Univ Toronto Dent J, 3: 27–31.

Grandjean P (1982) Occupational fluorosis through 50 years; clinical and epidemiological

experiences. Am J Occup Med, 3: 227–236.

Grandjean P & Thomsen G (1983) Reversibility of skeletal fluorosis. Br J Ind Med, 40:

456–461.

Grandjean P, Juel K, & Moller-Jensen O (1985) Mortality and morbidity after occupational

fluoride exposure. Am J Epidemiol, 121: 57–64.

Grandjean P, Olsen J, Moller-Jensen O, & Juel K (1992) Cancerincidence and mortality in

workers exposed to fluoride. J Natl Cancer Inst, 84: 1903–1909.

Grant MW & Schuman JS (1993)Toxicology of the eye: effects on the eyesand visual system

from chemicals, drugs, metals and minerals, plants, toxins and venoms: also, systemic side

effects from eye medications, 4th ed. Springfield, Illinois, Charles C. Thomas.

Greco RJ, Hartford CE, Haith LR, & Patton ML (1988) Hydrofluoric acid-induced

hypocalcemia. J Trauma, 28: 1593–1596.

Greenwood N & EarnshawA (1984)Chemistry of the elements. Toronto, Ontario, Pergamon

Press. 

Grimaldo M, Borja-Aburto VH, Ramirez AL, Ponce M, Rosas M, & Diaz-Barriga F (1995)

Endemic fluorosis in San Luis Potosi. I. Identification of risk factors associated with human

exposure to fluoride. Environ Res, 68: 25–30. 

Grynpas M (1990) Fluoride effects on bone crystals. J Bone Miner Res, 5: S169–S175.

Gu S, Rongli J, & Shouren C (1990) The physical and chemical characteristics of particles

in indoor air where high fluoride coal burning takesplace. Biomed Environ Sci, 3: 384–390.

Gubbay AD & FitzpatrickRI (1997)Dermal hydrofluoric acid burns resulting in death. Aust N

Z J Surg, 67: 304–306.

GuenterW& Hahn PHB (1986) Fluorine toxicity and laying hen performance. Poult Sci, 65:

769–778. 

Guha-Chowdhury N, Drummond BK, & Smillie AC (1996) Total fluoride intake in children

aged 3 to 4 years — a longitudinal study. J Dent Res, 75: 1451–1457.

Gupta IP, Das TK, Susheela AK, Dasarathy S, & Tandon RK (1992) Fluoride as a possible

aetiological factor in non-ulcer dyspepsia. J Gastroenterol Hepatol, 7: 355–359.
EHC 227: Fluorides

200

Gutteridge DH, Price RI, Kent GN, Prince RL, & Michell PA (1990)Spontaneous hip fractures

in fluoride-treated patients: potential causative factors. J Bone Miner Res, 5(suppl 1):

S205–S215.

Guy W (1979) Inorganic and organic fluorine in human blood. In: Johansen E, Taves D, &

Olsen T ed. Continuing evaluation of the use of fluorides. Boulder, Colorado, WestviewPress

forthe American Association forthe Advancement of Science, pp 125–147 (AAAS Selected

Symposium 11).

Guy W, Taves D, & Brey W (1976) Organic fluorocompounds in human plasma: prevalence

and characterization. Am Chem Soc Symp Ser, 28: 117–134.

Haidouti C (1995)Effectsof fluoride pollution on the mobilization and leaching of aluminum

in soil. Sci Total Environ, 166: 157–160. 

Haimanot R (1990) Neurological complications of endemic skeletal fluorosis, with special

emphasis on radiculo-myelopathy. Paraplegia, 28: 244–251.

Haimanot RT, Fekadu A, & Bushra B (1987) Endemic fluorosis in the Ethiopian Rift Valley.

Trop Geogr Med, 39: 209–217.

Hall RJ (1972) The distribution of organic fluorine in some toxic tropical plants. NewPhytol,

71: 855–871.

Hamilton M (1992) Water fluoridation: a risk assessment perspective. J Environ Health, 54:

27–32.

Han YZ, Zhang JQ, Liu XY, Zhang XH, Yu XH, & Dai JA (1995) High fluoride content and

endemic fluorosis. Fluoride, 28: 201–202.

Hara T, Sonoda Y, & Iwai I (1977) Growth response of cabbage plant to sodium halides under

water culture conditions. Soil Sci Plant Nutr, 23: 77–84.

Harbo RM, Comas FT, & Thompson JAJ (1974) Fluoride concentration in two Pacific coast

inlets — an indication of industrial contamination. J Fish Res Board Can, 31: 1151–1154. 

Harrison J, Hitchman A, Hassany S, Hitchman A, & Tam C (1984) The effect of diet on

fluoride toxicity in growing rats. Can J Physiol Pharmacol, 62: 259–265.

Hart EB, Phillips PH, & Bohstedt G (1934) Relationship of soil fertilisation with

superphosphates and rock phosphate to the fluorine content of plants and drainage waters.

Am J Public Health, 24: 936–940.

Harvey JM (1952) Chronic endemic fluorosis of merino sheep in Queensland. Queensland

J Agric Sci, 9: 47–141. 

Harzdorf C, Kinwel N, Marangoni L, Ogleby J, Ravier J, & Roost F (1986) The determination

of fluoride in environmentally relevant matrices. Anal Chim Acta, 182: 1–16.

Hasling C, Nielsen H, Melsen F, & Mosekilde L (1987) Safety of osteoporosis treatment with

sodium fluoride, calcium phosphate and vitamin D. Miner Electrol Metab, 13: 96–103.

Hayashi M, Kishi M, Sofuni T, & Ishidate MJ (1988) Micronucleus test in mice on 39 food

additives and eight miscellaneous chemicals. Food Chem Toxicol, 26: 487–500.
References

201

Health Canada (1993) Canadian Environmental Protection Act. Priority Substances List

supporting documentation. Health-related sections for inorganic fluorides. Prepared by

Priority Substances Section, Environmental Health Directorate, Health Canada, Ottawa,

Ontario (unpublished).

Health Council of the Netherlands (1990) Fluorides. Assessment of integrated criteria

document. Advisory report submitted to Minister and State Secretary of Health, Welfare and

Cultural Affairsand the Ministerof Housing, Physical Planning and Environment. The Hague,

Health Council of the Netherlands.

Heilman JR, Kiritsy MC, Levy SM, & Wefel JS (1997)Fluoride concentrationsof infant foods.

J Am Dent Assoc, 128: 857–863.

Heilman JR, Kiritsy MC, Levy SM, & Wefel JS (1999)Assessing fluoride levels of carbonated

soft drinks. J Am Dent Assoc, 130: 1593–1599. 

Heindel JJ, Bates HK, Price KJ, Marr MC, Myers CB, & Schwetz BA (1996) Developmental

toxicity evaluation of sodium fluoride administered to rats and rabbits in drinking water.

Fundam Appl Toxicol, 30: 162–177. 

Heitmuller PT, Hollister TA, & Parrish PR (1981) Acute toxicity of 54 industrial chemicals to

sheepshead minnows (Cyprinodon variegatus). Bull Environ Contam Toxicol, 27: 596–604.

Hekman WE, Budd K, Palmer GR, & MacArthur JD (1984) Responses of certain freshwater

planktonic algae to fluoride. J Phycol, 20: 243–249. 

Hemens J & Warwick RJ (1972) The effects of fluoride on estuarine organisms. WaterRes, 6:

1301–1308. 

Hemens J, Warwick RJ, & Oliff WD (1975)Effect of extended exposure to low fluoride concentrations on estuarine fish and crustacea. Prog Water Technol, 7(3/4): 579–585. 

Henny CJ & Burke PM (1990)Fluoride accumulation and bone strength in wild black-crowned

night-herons. Arch Environ Contam Toxicol, 19: 132–137. 

Henschler D, Büttner W, & Patz J (1975) Absorption, distribution in body fluid and

bioavailability of fluoride. In: Kuhlencordt F & Kruse HP ed. Calcium metabolism, bone and

metabolic diseases. Berlin, Springer Verlag, pp 111–121.

Hill A & PackM (1983)Effectsof atmospheric fluoride on plant growth. In: Shupe J, Peterson

H, & Leone N ed. Fluoride effects on vegetation, animals and humans. SaltLake City, Utah,

Paragon Press, pp 105–113. 

Hill AC, Pack MR, Transtrum LG, & Winters WS (1959) Effects of atmospheric fluorides and

various types of injury on the respiration of leaf tissue. Plant Physiol, 34(1): 11–16.

Hillier S, Cooper C, Kellingray S, Russell G, Hughes H, & Coggon D (2000) Fluoride in

drinking water and risk of hip fracture in the UK: a case–control study. Lancet, 355(9200):

265–269. 

Hirayama N, Maruo M, Obata H, Shiota A, Enya T, & Kuwamoto T (1996) Measurement of

fluoride ion in the river-water flowing into Lake Biwa. Water Res, 30(4): 865–868. 

Hitchcock AE, Zimmerman PW, & Coe RR (1962) Results of ten years’ work (1951–1960) on

the effects of fluorides on gladiolus. Contrib Boyce Thompson Inst, 21: 303–344.
EHC 227: Fluorides

202

Hobbs CS & Merriman GM (1959) The effect of eight years continuous feeding of different

levelsof fluorine and alleviators on feed consumption, teeth, bonesand production of cows.

J Anim Sci, 18: 1526–1529.

Hocking MB, Hocking D, & Smyth TA (1980) Fluoride distribution and dispersion processes

about an industrial point source in a forested coastal zone. Water Air Soil Pollut, 14:

133–157. 

Hodge H & Smith F (1977) Occupational fluoride exposure. J Occup Med, 19: 12–39.

Hodge HC, Smith FA, & Gedalia I (1970) Excretion of fluorides. In: Fluorides and human

health. Geneva, World Health Organization, pp 158–159 (WHO Monograph Series No. 59).

Hoffman DJ, Pattee OH, & Wiemeyer SN (1985) Effects of fluoride on screech owl

reproduction: teratological evaluation, growth, and blood chemistry in hatchlings. Toxicol

Lett, 26: 19–24. 

HooverRN, McKay FW, & Fraumeni FJF (1976)Fluoridated drinkingwaterand the occurrence

of cancer. J Natl Cancer Inst, 57: 757–768 [cited in US DHHS, 1991].

Horntvedt R (1995) Fluoride uptake in conifersrelated to emissions from aluminium smelters

in Norway. Sci Total Environ, 163: 35–37. 

Hou P (1997) The control of coal-burning fluorosis in China. Fluoride, 30: 229–232.

Hrudey SE, Soskolne CL, Berkel J, & Fincham S (1990)Drinking waterfluoridation and osteosarcoma. Can J Public Health, 81: 415–416.

Huang PM & Jackson ML (1965)Mechanism of reaction of neutral fluoride solution with layer

silicates and oxides of soils. Proc Soil Sci Soc Am, 29: 661–665. 

Hughes PR, Weinstein LH, Johnson LM, & Braun AR (1985) Fluoride transfer in the

environment: accumulation and effects on cabbage looper Trichoplusia ni of fluoride from

water soluble salts and HF-fumigated leaves. Environ Pollut, A37: 175–192. 

IARC (1982)Some aromatic amines, anthroquinones and nitroso compounds, and inorganic

fluorides used in drinking-water and dental preparations. Lyon, International Agency for

Research on Cancer, pp 237–303 (IARC Monographson the Evaluation of CarcinogenicRisks

of Chemicals to Humans, Volume 27).

IARC (1984) Polynuclear aromatic compounds. Part 3. Industrial exposures in aluminum

production, coal gassification, coke production and ironand steel making. Lyon, International

Agency for Research on Cancer, pp 37–64 (IARC Monographs on the Evaluation of

Carcinogenic Risks of Chemicals to Humans, Volume 34).

IARC (1987) Overall evaluations of carcinogenicity: An updating of IARC monographs,

volumes 1–42. Lyon, International Agency for Research on Cancer, pp 208–210 (IARC

Monographs on the Evaluation of Carcinogenic Risks to Humans, Supplement 7).

Ishidate MJ (1987) Data book on chromosomal aberration test in vitro, rev. ed. Tokyo, L.I.C.

Inc.

IvinskisM & Murray F (1984)Associationsbetween metabolic injury and fluoride susceptibility

in two species of Eucalyptus. Environ Pollut, A34: 207–223. 

JachimczakD & SkotarczakB (1978)The effect of fluorine and lead ions on the chromosomes

of human leucocytes in vitro. Genet Pol, 19: 353–358.
References

203

Jackson R, KellyS, Noblitt T, Zhang W, & Dunipace A (1994) The effect of fluoride therapy

on blood chemistry parameters in osteoporotic females. Bone Miner, 27: 13–23.

Jackson RD, Kelly SA, Noblitt TW, Zhang W, Wilson ME, Dunipace AJ, Li Y, Katz BP,

Brizendine EJ, & Stookey GK (1997) Lack of effect of long-term fluoride ingestion on blood

chemistry and frequency of sister chromatid exchange in human lymphocytes. Environ Mol

Mutagen, 29: 265–271.

Jackson WPU (1962) Further observations on the Kenhardt bone disease and its relation to

fluorosis. S Afr Med J, 36: 932–936.

Jacobsen S, Goldberg J, Cooper C, & Lockwood S (1992) The association between water

fluoridation and hip fracture among white women and men aged 65 years and older. A

national ecologic study. Ann Epidemiol, 2: 617–626.

Jacobsen S, O’Fallon M, & Melton L (1993) Hip fracture incidence before and after

fluoridation of the public water supply, Rochester, Minnesota. Am J Public Health, 83:

743–745.

Jacobson JS, Weinstein LH, McCune DC, & Hitchcock AE (1966) The accumulation of

fluorine by plants. J Air Pollut Control Assoc, 16: 412–417.

Jacqmin-Gadda H, CommengesD, & Dartigues JF (1995) Fluorine concentration in drinking

water and fractures in the elderly. J Am Med Assoc, 273: 775–776.

Jacqmin-Gadda H, Fourrier A, Commenges D, & Dartigues JF (1998)Risk factorsforfractures

in the elderly. Epidemiology, 9: 417–423.

Jain S & Susheela S (1987a)Effect of sodium fluoride on erythrocyte membrane function —

with reference to metal ion transport in rabbits. Chemosphere, 16: 1087–1094.

Jain S & Susheela A (1987b) Effect of sodium fluoride on antibody formation in rabbits.

Environ Res, 44: 117–125.

Jha M, Susheela A, Krishna N, Rajyalakshmi K, & Venkiah K (1982) Excessive ingestion of

fluoride and the significance of sialic acid: Glycosaminoglycans in the serum of rabbit and

human subjects. J Toxicol Clin Toxicol, 19: 1023–1030.

Johansson TSK & Johansson MP (1972) Sublethal doses of sodium fluoride affecting

fecundity of confused flour beetles. J Econ Entomol, 65(2): 356–357. 

Johnson J Jr & Bawden JW (1987) The fluoride content of infant formulasavailable in 1985.

Pediatr Dent, 9: 33–37.

Jolly SS, Singh BM, Mathur OC, & Malhotra KC (1968) Epidemiological, clinical and

biochemical study of endemic dental and skeletal fluorosisin Punjab. Br Med J, 4: 427–429.

Jones C, Harries J, & Martin A (1971) Fluorine in leafy vegetables. J Sci Food Agric, 22:

602–605.

JonesC, Callahan M, & Huberman E (1988a)Sodium fluoride promotesmorphological transformation of Syrian hamster embryo cells. Carcinogenesis, 9: 2279–2284.

Jones C, Huberman E, Callaham M, Tu A, Halloween W, Pallota S, Sivak A, Lubet R, Avery

M, Kouri R, Spalding J, & Tennant R (1988b) An inter-laboratory evaluation of the Syrian

hamster embryo cell transformation assay using fourteen coded chemicals. Toxicol In Vitro,

2: 103–116.
EHC 227: Fluorides

204

Jones G, Riley M, Couper D, & Dwyer T (1999) Water fluoridation, bone mass and fracture:

a quantitative overview of the literature. Aust N Z J Public Health, 23: 34–40.

Joseph S & Gadhia PK (2000) Sister chromatid exchange frequency and chromosome

aberrations in residentsof fluoride endemic regions of south Gujarat. Fluoride, 33: 154–158.

Joy CM & Balakrishnan KP (1990)Effect of fluoride on axenic cultures of diatoms. Water Air

Soil Pollut, 49: 241–249. 

Jubb TF, Annand TE, Main DC, & Murphy GM (1993)Phosphorussupplementsand fluorosis

in cattle — a northern Australian experience. Aust Vet J, 70: 379–383.

Kabasakalis V & Tsolaki A (1994)Fluoride content of vegetables irrigated with watersof high

fluoride levels. Fresenius Environ Bull, 3(6): 377–380. 

Kabata-Pendias A & PendiasH (1984)Fluorine. In: Trace elements in soil and plants. Boca

Raton, Florida, CRC Press, pp 209–215. 

Kaminsky L, Mahoney M, Leach J, Melius J, & Miller M (1990) Fluoride: Benefitsand risks of

exposure. Crit Rev Oral Biol Med, 1: 261–281.

Kanisawa M & Schroeder H (1969) Life term studies on the effect of trace elements on

spontaneous tumours in mice and rats. Cancer Res, 29: 892–895.

Kaplan HM, Yee N, & Glaczenski SS (1964) Toxicity of fluoride for frogs. Lab Anim Care,

14(3): 185–188. 

Karagas MR, Baron JA, Barrett JA, & Jacobsen SJ (1996) Patterns of fracture among United

States elderly: geographic and fluoride effects. Ann Epidemiol, 6: 209–216.

Karstad L (1967) Fluorosis in deer (Odoceileus virginianus). Bull Wildl Dis Assoc, 3: 42–46.

Karthikeyan G, Pius S, & Apparao BV (1996)Contribution of fluoride in waterand food to the

prevalence of fluorosis in areas of Tamil Nadu in south India. Fluoride, 29: 151–155.

Karunagaran VM & Subramanian A (1992) Fluoride pollution in the Uppanar Estuary,

Cuddalore, South India. Mar Pollut Bull, 24(10): 515–517. 

Kay CE, Tourangeau PC, & Gordon CC (1975) Industrial fluorosisin wild mule and whitetail

deer from western Montana. Fluoride, 8(4): 182–191. 

Keller T (1980) The simultaneous effect of soil-borne NaF and air pollutant SO2 on CO2-

uptake and pollutant accumulation. Oecologia, 44: 283–285. 

Khalil A (1995) Chromosome aberrations in cultured rat bone marrow cells treated with

inorganic fluorides. Mutat Res, 343: 67–74.

Khalil AM & Da’dara AA (1994) The genotoxic and cytotoxic activities of inorganic fluoride

in cultured rat bone marrow cells. Arch Environ Contam Toxicol, 26: 60–63.

Kierdorf H & Kierdorf U (1997) Disturbances of the secretory stage of amelogenesis in

fluorosed deer teeth: a scanning electron-microscopic study. Cell Tissue Res, 289: 125–135.
References

205

Kierdorf H & Kierdorf U (1999)Reduction of fluoride deposition in the vicinity of a brown coalfired power plant as indicated by bone fluoride concentrations of roe deer (Capreolus

capreolus). Bull Environ Contam Toxicol, 63: 473–477.

Kierdorf H, Kierdorf U, Sedlacek F, & Erdelen M (1996) Mandibular bone fluoride levelsand

occurrence of fluoride induced dental lesions in populations of wild deer (Cervus elaphus)

from central Europe. Environ Pollut, 93(1): 75–81. 

Kierdorf H, Kierdorf U, Richards A, & Sedlacek F (2000)Disturbed enamel formation in wild

boars (Sus scrofa) from fluoride polluted areas in Central Europe. Anat Rec, 259: 12–24.

Kierdorf U (1988) [A study on chronic fluoride intoxication in roe deer (Capreolus capreolus

L.) caused by emissions.] Z Jagdwiss, 34: 192–204 (in German).

Kierdorf U & Kierdorf H (1999) Dental fluorosis in wild deer: its use as a biomarker of

increased fluoride exposure. Environ Monit Assess, 57: 265–275.

Kierdorf U & Kierdorf H (2000) The fluoride content of antlers as an indicator of fluoride

exposure in reddeer(Cervus elaphus): A historical biomonitoring study. Arch Environ Contam

Toxicol, 38: 121–127.

Kierdorf U, Kierdorf H, Erdelen M, & Korsch JP (1989)Mandibularfluoride concentration and

its relation to age in roe deer (Capreolus capreolus L.). Comp Biochem Physiol, 94A(4):

783–785.

Kierdorf U, Kierdorf H, & Fejerskov O (1993) Fluoride-induced developmental changes in

enamel and dentine of European roe deer (Capreolus capreolus L.) as a result of

environmental pollution. Arch Oral Biol, 38(12): 1071–1081.

Kierdorf U, Kierdorf H, Sedlacek F, & Fejerskov O (1996) Structural changes in fluorosed

dental enamel of red deer (Cervus elaphus L.) from a region with severe environmental

pollution by fluorides. J Anat, 188: 183–195.

Kierdorf U, Richards A, Sedlacek F, & Kierdorf H (1997) Fluoride content and mineralization

of red deer(Cervus elaphus ) antlersand pedicles from fluoride polluted and uncontaminated

regions. Arch Environ Contam Toxicol, 32: 222–227.

Kierdorf U, Kierdorf H, & Boyde A (2000) Structure and mineralisation density of antler and

pedicle bone in red deer (Cervus elaphus L.) exposed to different levels of environmental

fluoride: a quantitative backscattered electron imaging study. J Anat, 196: 71–83.

Kinlen L & Doll R (1981) Fluoridation of water supplies and cancer mortality. III. A reexamination of mortality in cities in the USA. J Epidemiol Community Health, 35: 239–244.

Kiritsy MC, Levy SM, Warren JJ, Guha-chowdhury M, Heilman JR, & Marshall T (1996)

Assessing fluoride concentrationsof juices and juice-flavoureddrinks. J Am Dental Assoc, 127:

895–902.

Kirk PWW & Lester JN (1986) Halogen compounds. In: Harrison RM & Perry R ed. Handbook

of air pollution analysis, 2nd ed. London, Chapman & Hall, pp 425–462. 

Kishi K & Ishida T (1993) Clastogenic activity of sodium fluoride in great ape cells. Mutat

Res, 301: 183–188.

Kishi K & Tonomura A (1984) Cytogenetic effects of sodium fluoride. Mutat Res, 130: 367

(abstract).
EHC 227: Fluorides

206

Kissa E (1987) Determination of inorganic fluoride in blood with a fluoride ion-selective

electrode. Clin Chem, 33: 253–255.

Klumpp A, Klumpp G, & Domingos M (1994) Plants as bioindicators of air pollution at the

Serra do Mar near the industrial complex of Cubatão, Brazil. Environ Pollut, 85: 109–116.

Klumpp A, Klumpp G, Domingos M, & Dias Da Silva M (1996a) Fluoride impact on native

tree speciesof the Atlantic forest near Cubatao, Brazil. WaterAirSoil Pollut, 87(1–4): 57–71.

Klumpp A, Dominos M, & Klumpp G (1996b) Assessment of the vegetation risk by fluoride

emissions from fertiliser industries at Cubatao, Brazil. Sci Total Environ, 192: 219–228.

Klut ME, Bisalputra T, & Antia NJ (1981)Abnormal ultrastructural features of a marine dinoflagellate adapted to grow successfully in the presence of inhibitory fluoride concentration.

J Protozool, 28(4): 406–414. 

Knox E (1985) Fluoridation of water and cancer: A reviewof the epidemiological evidence.

Report of the British Working Party. London, HMSO.

Kono K, Yoshida Y, Yamagata H, Tanimura Y, Takeda Y, Harada A, & Doi K (1986)Fluoride

clearance in the aging kidney. Fluoride Research 1985. Stud Environ Sci, 27: 407–414.

Kono K, Yoshida Y, Watanabe M, Watanabe H, Inoue S, Murao M, & Doi K (1990) Elemental

analysisof hair among hydrofluoricacid exposed workers. Int Arch Occup Environ Health, 62:

85–88.

Korkka-Niemi K, Sipilä A, Hatva T, Hiisvirta L, Lahti K, & Alfthan G (1993) Nation-wide rural

well water survey. The quality of household waterand factorsinfluencing it. Helsinki,National

Board of Waters and the Environment, 225 pp.

Korns R (1969) Relationship of water fluoridation to bone density in two NY towns. Public

Health Rep, 84: 815–825.

Kragstrup J, RichardsA, & Fejerskov O (1989)Effectsof fluoride on cortical bone remodelling

in the growing domestic pig. Bone, 10: 421–424.

Krasowska A (1989) Influence of low-chitin krill meal on reproduction of Clethrionomys

glareolus (Schreber, 1780). Comp Biochem Physiol, 94C(1): 313–320. 

Kra ut A & Lilis R (1990) Pulmonary effects of acute exposure to degradation products of

sulphur hexafluoride during electrical cable work. Br J Ind Med, 47: 828–832.

Krishnamachari KAVR (1976)Furtherobservationson the syndrome of genu valgum of South

India. Ind J Med Res, 64: 284–291.

Krishnamachari K (1987) Fluorine. Trace Elem Hum Anim Nutr, 1: 365–415.

Krishnamachari KAVR & Krishnaswamy K (1973) Genu valgum and osteoporosis in an area

of endemic fluorosis. Lancet, 2: 887–889.

Kröger H, Alhava E, Honkanen R, Tupperainen M, & Saarikoski S (1994) The effect of

fluoridated drinking water on axial bone mineral density — a population-based study. Bone

Miner, 27: 33–41.
References

207

Krook L & Maylin GA (1979) Industrial fluoride pollution. Chronic fluoride poisoning in

Cornwall Island cattle. Cornell Vet, 69(suppl 8): 4–70.

Kudo A & Garrec J-P (1983)Accidental release of fluoride into experimental pond and accumulation in sediments, plants, algae, molluscs and fish. Regul Toxicol Pharmacol, 3 :

189–198. 

Kudo A, Garrec JP, & Plebin R (1987) Fluoride distribution and transport along rivers in the

French Alps. Ecotoxicol Environ Saf, 13(3): 263–273. 

Kühn R, Pattard M, Pernak K-D, & Winter A (1989) Results of the harmful effects of water

pollutants to Daphnia magna in the 21 day reproduction test. Water Res, 23(4): 501–510. 

Kumpulainen J & Koivistoinen P (1977) Fluorine in foods. Residue Rev, 68: 37–57.

Kurttio P, Gustavsson N, Vartiainen T, & Pekkanen J (1999) Exposure to natural fluoride in

well water and hip fracture: a cohort analysis in Finland. Am J Epidemiol, 150: 817–824. 

Kuusisto AN & Telkkä A (1961) The effect of sodium fluoride on the metamorphosis of

tadpoles. Acta Odontol Scand, 19: 121–127. 

Lahermo P & Backman B (2000) The occurrence and geochemistry of fluorides with special

reference to natural watersin Finland. Espoo, Geological Survey ofFinland, 40 pp. (Research

Report 149).

Lahermo P, Ilmasti M, Juntunen R, & Taka M (1990) The geochemical atlasof Finland. Part

1: The hydrogeochemical mapping of Finnish groundwater. Espoo, Geological Survey of

Finland.

Lalumandier JA & Ayers LW (2000) Fluoride and bacterial content of bottled water vs tap

water. Arch Fam Med, 9: 246–250.

Lan CF, Lin IF, & Wang SJ (1995) Fluoride in drinking water and the bone mineral density

of women in Taiwan. Int J Epidemiol, 24: 1182–1187.

Landy RB, Lambertsen RH, Palsson PA, Krook L, Nevius A, & Eckerlin R (1991) Fluoride in

the bone and diet of fin whales, Balaenoptera physalus. Mar Environ Res, 31: 241–247.

Laroche M & Mazières B (1991) Side-effects of fluoride therapy. Baillière’sClin Rheumatol,

5: 61–76.

Larsson K, Eklund A, Arns R, Lowgren H, Nystrom J, Sundstrom G, & Tornling H (1989) Lung

function and bronchialreactivity in aluminum potroom workers. Scand J WorkEnviron Health,

15: 296–301.

Lasne C, Lu Y, & Chouroulinkov I (1988)Transforming activitiesof sodium fluoride in cultured

Syrian hamster embryo and BALB/3T3 cells. Cell Biol Toxicol, 4: 311–324.

Latham MC & Gretch P (1967) The effects of excessive fluoride intake. Am J Public Health,

57: 651–660.

Lau KH & BaylinkDJ (1998)Molecular mechanism of action of fluoride on bone cells. J Bone

Miner Res, 13: 1660–1667.
EHC 227: Fluorides

208

Laurence JA (1983)Effectsof fluoride on plant–pathogen interactions. In: Shupe J, Peterson

H, & Leone N ed. Fluorides: Effectson vegetation, animalsand humans. Salt Lake City, Utah,

Paragon Press, pp 145–149. 

Laurence JA & Reynolds KL (1984) Growth and lesion development of Xanthomonas

campestris pv. phaseoli on leaves of red kidney bean plants exposed to hydrogen fluoride.

Phytopathology, 74: 578–580. 

Lavado RS, Reinaudi NB, & Parodi AA (1983) Fluoride retention and leach possibilities in

Argentine salt-affected soils. Fluoride Q Rep, 16(4): 247–251. 

LeBlanc GA (1980) Acute toxicity of priority pollutants to water flea (Daphnia magna). Bull

Environ Contam Toxicol, 24: 684–691. 

LeBlanc GA (1984) Interspecies relationships in acute toxicity of chemicals to aquatic

organisms. Environ Toxicol Chem, 3: 47–60. 

LeBlanc F, Comeau G, & Rao DN (1971) Fluoride injury symptoms in epiphytic lichens and

mosses. Can J Bot, 49: 1691–1698. 

Leece DR, Scheltema JH, Anttonen T, & Weir RG (1986)Fluoride accumulation and toxicity

in grapevines Vitis vinifera L. in New South Wales. Environ Pollut, A40: 145–172. 

Lehmann R, Wapniarz M, Hofmann B, Pieper B, Haubitz I, & Allolio B (1998) Drinking water

fluoridation: bone mineral density and hip fracture incidence. Bone, 22: 273–278. 

Levy SM (1994) Review of fluoride exposures and ingestion. Community Dent Oral

Epidemiol, 22: 173–180.

Levy SM, Kiritsy MC, & Warren JJ (199 5) Sources of fluoride intake in children. J Public

Health Dent, 55: 39–52.

Li Y, Dunipace A, & Stookey G (1987a) Absence of mutagenic or antimutagenic activitiesof

fluoride in Ames Salmonella assays. Mutat Res, 190: 229–236.

Li Y, Heerema N, Dunipace A, & Stokey G (1987b) Genotoxic effects of fluoride evaluated

by sister-chromatid exchange. Mutat Res, 192: 191–201.

Li Y, Dunipace A, & Stookley G (1987c) Lack of genotoxic effects of fluoride in the mouse

bone-marrow micronucleus test. J Dent Res, 66: 1687–1690.

Li Y, Dunipace A, & Stookey G (1987d) Effects of fluoride on the mouse sperm morphology

test. J Dent Res, 66: 1509–1511.

Li Y, Zhang W, Noblitt T, Dunipace A, & Stokey G (1989) Genotoxic evaluation of chronic

fluoride exposure: sister-chromatid exchange study. Mutat Res, 227: 159–165.

Li Y, Liang CK, Katz BP, Brizendine EJ, & Stookey GK (1995) Long-term exposure to fluoride

in drinking water and sister chromatid exchange frequency in human blood lymphocytes. J

Dent Res, 74: 1468–1474.

Li Y, Liang C, Slemenda CW, Ji R, Sun S, Cao J, Emsley C, Ma F, Wu Y, Ying P, Zhang Y,

Gao S, Zhang W, Katz B, Niu S, Cao S, & Johnston C (2001)Effect of long-term exposure to

fluoride in drinking water on risks of bone fractures. J Bone Miner Res, 16(5): 932–939.
References

209

Liang CK, Ji R, & Cao SR (1997) Epidemiological analysis of endemic fluorosis in China.

Environ Carcinogen Ecotoxicol Rev, C15(2): 123–138.

Liu BK (1996) Lung X-ray changes in skeletal fluorosiscaused by coal combustion. Fluoride,

29: 33–35.

Liu Y ed. (1995) Human exposure assessment of fluoride. An international study within the

WHO/UNEP Human Exposure Assessment Location (HEAL) Programme. Beijing, Chinese

Academy of Preventive Medicine, Institute of Environmental Health Monitoring, Technical

Cooperation Centre of Fluoride/HEAL Programme, 64 pp.

Low PS & Bloom H (1988) Atmospheric deposition of fluoride in the lower Tamar Valley,

Tasmania. Atmos Environ, 22(9): 2049–2056. 

Lu D, Zheng Z, Wang J, & Chen K (1989)[Study of the mutagenic effect of sodium fluoride.]

Yichuan [Hereditas (Beijing)], 11: 23 (in Chinese).

Lund K, Ekstrand J, Boe J, Sostrand P, & Kongerud J (1997) Exposure to hydrogen fluoride:

an experimental study in humans of concentrationsof fluoride in plasma, symptoms, and lung

function. Occup Environ Med, 54: 32–37.

Ma J, Cheng L, Bai W, & Wu H (1986) [The effects of sodium fluoride on SCEs of the mice

and on the micronucleus of the bone marrow of pregnant mice and its fetus liver.] Yichuan

[Hereditas (Beijing)], 8: 39–41 (in Chinese).

Machoy Z, Dabkowska E, Samujlo D, Ogonski T, Raczynski J, & Gebczynska Z (1995)Relationship between fluoride content in bones and the age in European elk(Alces alces L.). Comp

Biochem Physiol, 111C(1): 117–120. 

MacIntire WH, Sterges AJ, & ShawWM (1955)Fate and effects of hydrofluoric acid added to

four Tennessee soils in a four year lysimeter study. J Agric Food Chem, 3(9): 777–782.

MacLean DC & Schneider RE (1981) Effects of gaseous hydrogen fluoride on the yield of

field-grown wheat. Environ Pollut, 24: 39–44.

MacLean DC, Schneider RE, & McCune DC (1977) Effects of chronic exposure to gaseous

fluoride on yield of field-grown bean and tomato plants. J Am Soc Hortic Sci, 102 (3):

297–299.

MacLean DC, McCune DC, & Schneider RE (1984a)Growth and yield of wheat and sorghum

after sequential exposures of hydrogen fluoride. Environ Pollut, A36: 351–365.

MacLean DC, Weinstein LH, McCune DC, & Schneider RE (1984b) Fluoride-induced suture

red spot in “Elberta” peach. Environ Exp Bot, 24(4): 353–367.

Madans J, Kleinman J, & Cornoni-Huntley J (1983)The relationship betweenhip fracture and

water fluoridation: an analysis of national data. Am J Public Health, 73: 296–298.

MadkourS & Weinstein LH (1988)Effectsof fumigation with hydrogen fluoride on the loading

of [14C]sucrose into the phloem of soybean leaves. Environ Toxicol Chem, 7: 317–320.

Mahadevan TN, Meenakshy V, & Mishra UC (1986)Fluoride cycling in nature through precipitation. Atmos Environ, 20: 1745–1749. 
EHC 227: Fluorides

210

Mahoney MC, Nasca PC, Burnett WS, & Melius JM (1991) Bone cancer incidence rates in

New York State: Time trends and fluoridated drinking water. Am J Public Health, 81:

475–479.

Malea P (1995) Fluoride content in three seagrasses of the Antikyra Gulf (Greece) in the

vicinity of an aluminum factory. Sci Total Environ, 166: 11–17. 

Marais JSC (1944)Monofluoracetic acid, the toxic principle of the “Grifblaar” Dichapetabum

cymosum (Hook) Engl Onderstepoort. J Vet Sci Anim Ind, 20(1): 67–73.

Marie P & Mott M (1986) Short-term effects of fluoride and strontium on bone formation and

resorption in the mouse. Metabolism, 35: 547–561.

Marks TA, Schellenberg D, Metzler CM, Oostveen J, & Morey MJ (1984) Effect of dog food

containing 460 ppm fluoride on rat reproduction. J Toxicol Environ Health, 14: 707–714.

Martin GR, Brown KS, Matheson DW, Lebowitz H, Singer L, & Ophaug R (1979) Lack of

cytogenetic effectsin mice or mutations in Salmonella receiving sodium fluoride. Mutat Res,

66: 159–167.

Martin J-M & Salvadori F (1983) Fluoride pollution in French riversand estuaries. Estuarine

Coastal Shelf Sci, 17: 231–242. 

Maurer J, Cheng M, Boysen B, & Anderson R(1990)Two-year carcinogenicity study of sodium

fluoride in rats. J Natl Cancer Inst, 82: 1118–1126.

Maurer J, Cheng M, Boysen B, Squire R, Strandberg J, Weisbrode J, & Anderson R (1993)

Confounded ca rcinogenicity study of sodium fluoride in CD-1 mice. Regul Toxicol

Pharmacol, 18: 154–168.

Mayer DF, Lunden JD, & Weinstein LH (1988) Evaluation of fluoride levels and effects on

honey bees (Apis mellifera L.) (Hymenoptera: Apidae). Fluoride Q Rep, 21(3): 113–120. 

Mayer TG & Gross PL (1985) Fatal systemic fluorosis due to hydrofluoric acid burns. Ann

Emerg Med, 14: 149–153.

McClenahen J (1976)Distribution of soil fluoridesnear an airborne fluoride source. J Environ

Qual, 5: 472–475.

McClenahen JR (1978) Community changes in a deciduous forest exposed to air pollution.

Can J For Res, 8: 432–438.

McClure FJ (1944) Fluoride domestic water and systemic effects. I. Relation to bone fracture

experience, height and weight of high school boys and young selectees of the armed forces

of the United States. Public Health Rep, 59: 1543–1558.

McClurg TP (1984) Effects of fluoride, cadmium and mercury on the estuarine prawn

Penaeus indicus. Water SA, 10(1): 40–45.

McCune DC, Lauver TL, & Hansen KS (1991) Relationship of concentration of gaseous

hydrogen fluoride to incidence and severity of foliar lesions in black spruce and white spruce.

Can J For Res, 21: 756–761. 

McDonagh MS, Whiting PF, Wilson PM, Sutton AJ, Chestnutt I, Cooper J, Misso K, Bradley

M, Treasure E, & Kleijnen J (2000) Systematic review of water fluoridation. Br Med J, 321:

855–859.
References

211

McGuire S, Vanable E, McGuire M, Buckwalter JA, & Douglass CW (1991) Is there a link

between fluoridated water and osteosarcoma? J Am Dent Assoc, 122: 38–45.

McIvor M (1990) Acute fluoride toxicity: pathophysiology and management. Drug Saf, 5:

79–85.

McKnight-Hanes M, Leverett D, Adair S, & Shields C (1988) Fluoride content of infant

formulas: soy-based formulas as a potential factor in dental fluorosis. Pediatr Dent, 10:

189–194.

McLaughlin MJ, Tiller KG, Naidu R, & Stevens DP (1996) Review: the behaviour and

environmental impact of contaminants in fertilizers. Aust J Soil Res, 34: 1–54.

McLaughlin MJ, Stevens DP, Keerthisinghe G, Cayley JWD, & Ridley AM (2001)

Contamination of soil with fluoride by long-term application of superphosphates to pastures

and risks to grazing animals. Aust J Soil Res, 39(3): 627–640.

McNulty IB&LordsJL (1960)Possible explanation of fluoride-induced respiration in Chlorella

pyrenoidosa. Science, 132: 1553–1554. 

Meeussen JCL, Scheidegger A, Hiemstra T, Van Riemsdijk WH, & Borkovec M (1996)

Predicting multicomponent adsorption and transport of fluoride at variable pH in a

goethite–silica sand system. Environ Sci Technol, 30(2): 481–488. 

Meng Z & Zhang B (1997) Chromosomal aberrations and micronuclei in lymphocytes of

workers at a phosphate fertilizer factory. Mutat Res, 393: 283–288.

Meng Z, Meng H, & Cao X (1995)Sister-chromatid exchange in lymphocytes of workers at a

phosphate fertilizer factory. Mutat Res, 334: 243–246.

MesserH & Ophaug R (1993) Influence of gastric acidity on fluoride absorption in rats. J Dent

Res, 72: 619–622.

MesserHH, Armstrong WD, & Singer L (1973) Influence of fluoride intake on reproduction in

mice. J Nutr, 103: 1319–1326.

Messer H, Nopakum J, & Rudney J (1989) Influence of pH on intestinal fluoride transport in

vitro. J Dent Assoc Thailand, 39: 226–232.

Meunier PJ, Severt JL, Reginster JY, Briancon D, Apelboom T, Netter P, Loeb G, Rouillon

A, Barry S, Evreus JC, Avouac B, & Marchandise X (1998) Fluoride salts are no better at

preventing new vertebral fractures than calcium–vitamin D in postmenopausal osteoporosis:

the FAVO Study. Osteoporosis Int, 8: 4–12.

Michael M, Barot VV, & Chinoy NJ (1996) Investigations of soft tissue functions in fluorotic

individuals of North Gujarat. Fluoride, 29: 63–71.

Michel J, Suttie J, & Sunde M (1984) Fluorine deposition in bone as related to physiological

state. Poult Sci, 63: 1407–1411. 

Mihashi M & Tsutsui T (1996) Clastogenic activity of sodium fluoride to rat vertebral bodyderived cells in culture. Mutat Res, 368: 7–13.

Mikaelian I, Qualls CW, De Guise S, Whaley MW, & Martineau D (1999) Bone fluoride

concentrations in beluga whales from Canada. J Wildl Dis, 35(2): 356–360.
EHC 227: Fluorides

212

Milhaud G, El Bahri L, & Dridi A (1981) The effects of fluoride on fish in Gabes Gulf.

Fluoride, 14(4): 161–168. 

Mishra PC & Mohapatra AK (1998)Haematological characteristicsand bone fluoride content

in Bufo melanostictus from an aluminium industrial site. Environ Pollut, 99: 421–423.

Mithal A, Trivedi N, Gupta SK, Kumar S, & Gupta RK (1993) Radiological spectrum of

endemic fluorosis: relationship with calcium intake. Skeletal Radiol, 22: 257–261.

Mohammed A & Chandler M (1982)Cytological effects of sodium fluoride on mice. Fluoride,

15: 110–118.

Moore M, Clive D, Hozier J, Howard B, Batsun A, Turner N, & Sawyer J (1985) Analysis of

trifluorothymidineresistant(TFTr) mutantsof L5178Y/TK± mouse lymphoma cells. Mutat Res,

151: 161–174.

Morgan L, Allred E, Tavares M, Bellinger D, & Needleman H (1998) Investigation of the

possible associations between fluorosis, fluoride exposure, and childhood behaviour

problems. Am Acad Pediatr Dent, 20(4): 244–252.

Morris JB & Smith FA (1982) Regional deposition and absorption of inhaled hydrogen

fluoride in the rat. Toxicol Appl Pharmacol, 62: 81–89.

Mosekilde I, Kragstrup J, & Richards A (1987) Compression strength, ash weight and volume

of vertebral trabecularbone in experimental fluorosis in pigs. CalcifTissue Int, 40: 318–322.

Moss ME, Kanarek MS, Anderson HA, Hanrahan LP, & Remington PL (1995)Osteosarcoma,

seasonality, and environmental factors in Wisconsin, 1979–1989. Arch Environ Health, 50:

235–241.

Moule GR (1944) Fluoride poisoning of livestock. Queensl Agric J, 58: 54–55.

MullenixPJ, Denbesten K, SchuniorA, & Keernan WJ (1995)Neurotoxicity of sodium fluoride

in rats. Neurotoxicol Teratol, 17(2): 169–177.

Mullet T, Zoeller T, Bingham H, Pepine CJ, Prida XE, Castenholz R, & Kirby R (1987)Fatal

hydrofluoric acid cutaneous exposure with refractory ventricular fibrillation. J Burn Care

Rehab, 8: 216–219. 

Mur J, Moulin J, Meyer-Bisch C, Massin N, Coulon J, & Loulergue J (1987) Mortality of

aluminum reduction plant workers in France. Int J Epidemiol, 16: 257–264.

Muramoto S, Nishizaki H, & Aoyama I (1991) Effects of fluorine emissions on agricultural

products surrounding an aluminum factory. J Environ Sci Health, B26: 351–356. 

Murray F (1981) Effects of fluorides on plant communities around an aluminium smelter.

Environ Pollut, A24: 45–56. 

Murray F (1984a) Effect of long term exposure to hydrogen fluoride on grapevines. Environ

Pollut, A36: 337–349.

Murray F (1984b) Fluoride retention in highly leached disturbed soils. Environ Pollut, B7:

83–95.
References

213

Murray F & Wilson S (1988a) Effects of sulphur dioxide, hydrogen fluoride and their

combination on three Eucalyptus species. Environ Pollut, 52: 265–279. 

Murray F & Wilson S (1988b) Joint action of sulfurdioxide and hydrogen fluoride on growth

of Eucalyptus tereticornis. Environ Exp Bot, 28(4): 343–349. 

Murray F & Wilson S (1988c) The joint action of sulphur dioxide and hydrogen fluoride on

the yield and quality of wheat and barley. Environ Pollut, 55: 239–249. 

Murray TM, Harrison JE, Bayley TA, Josse RG, Sturtridge WC, Chow R, Budden F, Laurier L,

Pritzker KP, Kandel R, Vieth R, Strauss A, & Goodwin S (1990) Fluoride treatment of

postmenopausalosteoporosis: age, renal function, and other clinical factorsin the osteogenic

response. J Bone Miner Res, 5(suppl 1): S27–S35. 

Naccache H, Simard P, Trahan L, Demers M, Lapointe C, & Brodeur J (1990) Variability in

the ingestion of toothpaste by preschool children. Caries Res, 24: 359–363.

Naccache H, Simard P, Trahan L, Brodeur JM, Demers M, Lachapelle D, & Bernard PM

(1992)Factorsaffecting the ingestion of fluoride dentifrice by children. J Public Health Dent,

52: 222–226. 

Nair KR, Manji F, & Gitonga JN (1984) The occurrence and distribution of fluoride in

groundwaters in Kenya. East Afr J Med, 61: 503–512.

Neal C (1989) Fluorine variations in Welsh streams and soil waters. Sci Total Environ, 80:

213–223.

Neal C, Smith CJ, Walls J, Billingham P, Hill S, & Neal M (1990) Comments on the

hydrological regulation of the halogen elements in rainfall, stemflow, throughfall and stream

waters at an acidic forested area in mid-Wales. Sci Total Environ, 91: 1–11.

Needleman HL, Fueschel SM, & Rothman KJ (1974) Fluoridation and the occurrence of

Down’s syndrome. N Engl J Med, 291: 821–823.

Neeley KL & Harbaugh FG (1954) Effects of fluoride ingestion on a herd of dairy cattle in the

Lubbock, Texas, area. J Am Vet Med Assoc, 124: 344–350. 

Nell JA & Livanos G (1988) Effects of fluoride concentration in seawater on growth and

fluoride accumulation by Sydney rockoyster(Saccostrea commercialis) and flat oyster(Ostrea

angasi). Spat Water Res, 22(6): 749–753. 

Neuhold JM & Sigler WF (1960) Effects of sodium fluoride on carp and rainbow trout. Trans

Am Fish Soc, 89: 358–370. 

Neuhold JM & Sigler WF (1962) Chlorides affect the toxicity of fluorides to rainbow trout.

Science, 135: 732–733. 

Neumüller O (1981) Römpps Chemie Lexikon, 8th ed. Vol. 2. Stuttgart, Franck’sch Verlagshandlung.

Neumüller O (1987) Römpps Chemie Lexikon, 8th ed. Vol. 5. Stuttgart, Franck’sch Verlagshandlung.

Newbrun E (1992) Current regulations and recommendations concerning waterfluoridation,

fluoride supplements, and topical fluoride agents. J Dent Res, 71: 1255–1265. 
EHC 227: Fluorides

214

Newman JR (1977) Sensitivity of the house martin, Delichon urbica, to fluoride emissions.

Fluoride, 10: 73–76. 

Newman JR & Markey D (1976) Effects of elevated levels of fluoride on deer mice

(Peromyscus maniculatus). Fluoride, 9(1): 47–52. 

Newman JR & Yu M-H (1976) Fluorosis in black-tailed deer. J Wildl Dis, 12: 39–41. 

Nichol BE, Budd K, Palmer GR, & MacArthur JD (1987)The mechanismsof fluoride toxicity

and fluoride resistance in Synechococcus leopoliensi s (Cyanophyceae). J Phycol, 23(4):

535–541. 

NIPH (1996) System of monitoring the environmental impact on population health of the

Czech Republic. Summary report — 1995. Prague, National Institute of Public Health.

Nowak A & Nowak M (1989) Fluoride concentration of bottled and processed waters. Iowa

Dent J, 75: 28.

Nriagu JO (1986) Chemistry of the River Niger. 1. Major ions. Sci Total Environ, 58: 81–88.

NTP (1990) Toxicology and carcinogenesis studies of sodium fluoride (CAS No. 7681-49-4)

in F344/N rats and B6C3F1 mice (drinking water studies). Research Triangle Park, North

Carolina, US Department of Health and Human Services, Public Health Service, National

Institutes of Health, National Toxicology Program (NTP TR 393).

Oberly T, Rexroat M, Bewsey B, Richardson K, & Michalis K (1990) An evaluation of the

CHO/HGPRT mutation assay involving suspension cultures and soft agarcloning: Resultsfor

33 chemicals. Environ Mol Mutagen, 16: 260–271.

Oelrichs RB & McEwan T (1961)Isolation of the toxic principle in Acacia georginae. Nature,

190: 808–809.

Oelschläger W (1971) Fluoride uptake in soil and its depletion. Fluoride, 4: 80–84.

Oguro A, Cervenka J, & Horii K-I (1995) Effect of sodium fluoride on chromosomal ploidy and

breakage in cultured human diploid cells (IMR-90): an evaluation of continuous and shorttime treatment. Pharmacol Toxicol, 76: 292–296.

Oliveby A, Lagerlöf F, Ekstrand J, & Dawes C (1989) Studies on fluoride excretion in human

whole saliva and its relation to flow rate and plasma fluoride levels. Caries Res, 23: 243–246.

Oliveby A, Twetman S, & Ekstrand J (1990)Diurnal fluoride concentration in whole saliva in

children living in a high- and a low-fluoride area. Caries Res, 24: 44–47.

Oliveira L, Antia NJ, & Bisalputra T (1978) Culture studies on the effects from fluoride

pollution on the growth of marine phytoplankters. J Fish Res Board Can, 35: 1500–1504. 

Omueti J & Jones R (1977) Regional distribution of fluorine in Illinoissoils. Soil Sci Soc Am

J, 41: 771–777.

Ophaug RH, Singer L, & Harland BF (1985) Dietary fluoride intake of 6-month and 2-year-old

children in four dietary regions of the United States. Am J Clin Nutr, 42: 701–707.
References

215

Orcel P, de Vernejoul MC, Prier A, Miravet L, Kuntz D, & Kaplan G (1990) Stress fractures of

the lower limbs in osteoporotic patients treated with fluoride. J Bone Miner Res, 5(suppl 1):

S191–S194.

Overton WS, Kanciruk P, Hook LA, Eilers JM, LandersDH, Brakke DF, Blick DJ, Linthurst RA,

De Haan MD, & Omernik JM (1986) Characteristics of lakes in eastern United States. Vol. II.

Washington, DC, US Environmental Protection Agency (EPA/600/4-86/007c). 

PackMR (1971)Effectsof hydrogen fluoride on bean reproduction. J AirPollut Control Assoc,

21: 133–137. 

Pak CYC, Sakhaee K, Piziak V, Peterson RD, Breslau NA, Boyd P, Poindexter JR, Herzog J,

Heard-Sakhaee A, HaynesS, Adams-Huet B, & ReischJS(1994)Slow-release sodium fluoride

in the management of postmenopausal osteoporosis. A randomized controlled trial. Ann

Intern Med, 120: 625–632.

Pang YX, Guo YQ, Fu KW, Sun YF, & Tang RQ (1996)The effectsof fluoride, alone and in

combination with selenium, on the morphology and histochemistry of skeletal muscle.

Fluoride, 29: 59–62.

Pankhurst NW, Boyden CR, & Wilson JB (1980) The effect of a fluoride effluent on marine

organisms. Environ Pollut, A23: 299–312. 

Paranjpe MG, Chandra AMS, Qualls CW, McMurry ST, RohrerMD, Whaley MM, Lochmiller

RL, & McBee K (1994) Fluorosis in a wild cotton rat (Sigmodon hispidus) population

inhabiting a petrochemical waste site. Toxicol Pathol, 22(6): 569–578.

ParkerDR, Norvell WA, & Chaney RL (1995) GEOCHEM-PC: a chemical speciation program

for IBM and compatible personal computers. Madison, Wisconsin, Soil Science Society of

America (Special Publication 42).

ParkinsFM, Tinaoff N, Moutinho M, Anstey MB, & Waziri MH (1974) Relationship of human

plasma fluoride and bone fluoride to age. Calcif Tissue Res, 16: 335–338. 

Pati P & Bhunya S (1987) Genotoxic effect of an environmental pollutant, sodium fluoride,

in mammalian in vivo test system. Caryologia, 40: 79–87.

Patra RC, Dwivedi SK, Bhardwaj B, & Swarup D (2000) Industrial fluorosis in cattle and

buffalo around Udaipur, India. Sci Total Environ, 253: 145–150.

Pattee OH, WiemeyerSN, & Swineford DM (1988) Effects of dietary fluoride on reproduction

in eastern screech-owls. Arch Environ Contam Toxicol, 17: 213–218. 

Patten J, Whitford G, StringerG, & Pashley D (1978) Oral absorption of radioactive fluoride

and iodide in rats. Arch Oral Biol, 23: 215–217.

Peirce AW (1952) Studies on fluorosis of sheep. I. The toxicity of water-borne fluoride for

sheep maintained in pens. Aust J Agric Res, 3(3): 326–340. 

Perkins DF (1992) Relationship between fluoride contents and loss of lichens near an

aluminium works. Water Air Soil Pollut, 64: 503–510. 

PerkinsDF & Millar RO (1987) Effects of airborne fluoride emissionsnear an aluminium works

in Wales: Part 2 — Saxicolous lichens growing on rocks and walls. Environ Pollut, 48:

185–196. 
EHC 227: Fluorides

216

PerkinsDF, Millar RO, & Neep PE (1980)Accumulation of airborne fluoride by lichens in the

vicinity of an aluminium reduction plant. Environ Pollut, 21: 155–168. 

Perrott KW, Smith BFL, & Inkson RHE (1976) The reaction of fluoride with soils and soil

minerals. J Soil Sci, 27: 58–67. 

Pettifor JM, Schnitzler CM, Ross FP, & Moodley GP (1989) Endemic skeletal fluorosis in

children: hypocalcemia and the presence of renal resistance to parathyroid hormone. Bone

Miner, 7: 275–288.

Phillips PH & Suttie JW (1960) The significance of time in intoxication of domestic animals

by fluoride. Arch Ind Health, 21: 343–345.

Phipps K, Orwoll ES, Mason JD, & Cauley JA (2000) Community water fluoridation, bone

mineral density, and fractures: prospective study of effects in older women. Br Med J, 321:

860–864.

Pickering WF (1985) The mobility of soluble fluoride in soils. Environ Pollut, B9: 281–308.

Pickering WF, Slavek J, & Waller P (1988) The effect of ion exchange on the solubility of

fluoride compounds. Water Air Soil Pollut, 39: 323–336. 

Pillai KS & Mane UH (1984) The effect of fluoride on fertilized eggs of a freshwater fish,

Catla catla (Hamilton). Toxicol Lett, 22: 139–144. 

Pillai K, Mathai A, & Deshmuhk P (1988) Effect of subacute dosage of fluoride on male mice.

Toxicol Lett, 44: 21–29.

Pillai K, Mathai A, & DeshmuhkP (1989)Effect of fluoride on reproduction in mice. Fluoride,

22: 165–168.

Pilling K & Jones H (1988) Inhalation of degraded sulphur hexafluoride resulting in

pulmonary oedema. J Soc Occup Med, 38: 82–84.

Pimentel R & Bulkley RV (1983) Influence of water hardness on fluoride toxicity to rainbow

trout. Environ Toxicol Chem, 2: 381–386. 

Polomski J, Fluhler H, & BlaserP (1982)Accumulation of airborne fluoride in soils. J Environ

Qual, 11: 457–461. 

Port GR, Davies MT, & Davison, AW(1998) Fluoride loading of a lepidopteran larva (Pieris

brassicae) fed on treated diets. Environ Pollut, 99: 233–239.

Preuss PW, Colavito L, & Weinstein LH (1970) The synthesis of monofluoracetic acid by a

tissue culture of Acacia georginae. Experientia, 26: 1059–1060.

Prince C & Navia J (1983) Glycosaminoglycan alterations in rat bone due to growth and

fluorosis. J Nutr, 113: 1576–1582.

Pushnik JC & Miller GW (1990) The influences of elevated environmental fluoride on the

physiology and metabolism of higher plants. Fluoride Q Rep, 23(1): 5–19. 

Qiu M, Zhu X, Li S, Sun G, Ni A, Song W-Z, & Zhang J (1987) Bone dynamic changes in

experimental fluorosis of rats. Chinese Med J, 100: 879–885.
References

217

Radon K, NowakD, Heinrich-Ramm R, & Szadkowski D (1999)Respiratory health and fluoride

exposure in different parts of the modern primary aluminum industry. Int Arch Occup Environ

Health, 72: 297–303.

Rai LC, Husaini Y, & Mallick N (1998) pH-altered interaction of aluminium and fluoride on

nutrient uptake, photosynthesis and other variables of Chlorella vulgaris. Aquat Toxicol, 42:

67–84.

Ramanathan V, Cicerone RJ, Singh HB, & Kiehl JT (1985) Trace gas trends and their

potential role in climate change. J Geophys Res, 90(D3): 5547–5566. 

Rand WE & Schmidt HJ (1952) The effect upon cattle of Arizona waters of high fluoride

content. Am J Vet Res, 13: 50–61. 

Rao DN & Pal D (1978)Effect of fluoride pollution on the organic matter content of soil.Plant

Soil, 49: 653–656.

Rao G (1984) Dietary intake and bioavailability of fluoride. Ann Rev Nutr, 4: 115–136.

Rao KV, Khandekar AK, & Vaidyanadham D (1973) Uptake of fluoride by water hyacinth,

Eichhornia crassipes. Ind J Exp Biol, 11: 68–69. 

Ratsch HC & Johndro D (1986)Comparative toxicity of six test chemicals to lettuce using two

root elongation test methods. Environ Monit Assess, 6: 267–276. 

Razak I & Latifah R (1988) Unusual hypersensitivity to stannous fluoride. Ann Dent, 4 7 :

37–39.

Ream L, Hull D, Scott J, & Pendergrass P (1983a) Fluoride ingestion during multiple

pregnanciesand lactations: microscopicobservationson bone of the rat. Virchows Arch [Cell

Pathol], 44: 35–44.

Ream L, Scott J, & Pendergrass P (1983b) Bone morphology of weanling rats from dams

exposed to fluoride. Cell Tissue Res, 233: 689–691.

Reginster JY, Meurmans L, Zegels B, Rovati LC, Minne HW, Giacovelli G, Taquet AN,

Setnikar I, Collette J, & Gosset C (1998) The effect of sodium monofluorophosphate plus

calcium on vertebral fracture rate in postmenopausal women with moderate osteoporosis. A

randomized, controlled trial. Ann Intern Med, 129: 1–8. 

Reynolds KL & Laurence JA (1990) Development of common blight and accumulation of

fluoride in redkidneybean plantsexposed continuouslyorintermittently to hydrogen fluoride.

Phytopathology, 80(2): 211–216. 

Rice PM, Tourangeau PC, Johns C, & Gordon CC (1984) Baseline sulphur and fluoride

concentrations in indigenous plants common in the Northern Great Plains. Environ Pollut,

B7: 233–246.

Richards A, Kragstrup J, Josephsen K, & Fejerskov O (1986) Dental fluorosis developed in

post-secretory enamel. J Dent Res, 65: 1406–1409.

RichardsLF, Westmoreland WW, Tashiro M, McKay CM, & Morrison TJ (1967)Determination

of optimum fluoride levels for community water supplies in relation to temperature. J Am

Dent Assoc, 74: 389–397.

Riggs BL (1991) Treatment of osteoporosiswith sodium fluoride or parathyroid hormone. Am

J Med, 91: 37S–41S.
EHC 227: Fluorides

218

Riggs B, Hodgson S, O’Fallon W, Chao E, Wahner H, Muhs J, Cedel S, & Melton L (1990)

Effect of fluoride treatment on the fracture rate in postmenopausal women with osteoporosis.

N Engl J Med, 322: 802–809.

Rizzoli R, Chevalley T, Slosman DO, & Bonjour JP (1995) Sodium monofluorophosphate

increasesvertebral bone mineral density in patientswith corticosteroid-induced osteoporosis.

Osteoporosis Int, 5: 39–46.

Rockette H & Arena V (1983) Mortality studies of aluminum reduction plant workers: Potroom

and carbon plant. J Occup Med, 25: 549–557. 

Rojas-Sanchez F, Kelly SA, Drake KM , Eckert GJ, Stookey GK, & Dunipace AJ (1999)

Fluoride intake from foods, beverages and dentifrice by young children in communities with

negligibly and optimally fluoridated water: a pilot study. Community Dent Oral Epidemiol,

27: 288–297.

Romundstad P, Haldorsen T, & Andersen A (2000) Cancer incidence and cause specific

mortality among workers in two Norwegian aluminum reduction plants. Am J Ind Med, 37:

175–183.

Rønneberg A (1995)Mortality and cancermorbidity in workersfroman aluminum smelterwith

pre-baked carbon anodes. 1: Exposure assessment. Occup Environ Med, 52: 242–249.

Rønneberg A & Andersen A (1995) Mortality and cancer morbidity in workers from an

aluminum smelter with pre-baked carbon anodes. 2: Cancermorbidity. Occup Environ Med,

52: 250–254. 

Rosenholtz M, Carson T, Weeks M, Wilinski F, Ford D, & Oberst F (1963) A toxicopathologic

study in animals after brief single exposures to hydrogen fluoride. Am Ind Hyg Assoc J, 24:

253–261.

Roy RL, Campbell PGC, Prémont S, & Labrie J (2000) Geochemistry and toxicity of

aluminium in the Saguenay River, Québec, Canada, in relation to discharges from an

aluminium smelter. Environ Toxicol Chem, 19(10): 2457–2466.

Saether OM, Andreassen BT, & Semb A (1995) Amounts and sources of fluoride in

precipitation over southern Norway. Atmos Environ, 29(15): 1785–1793. 

Sahu NK & Karim MA (1989) Fluoride incidence in natural watersin Amreli district, Gujarat.

J Geol Soc Ind, 33: 450–456. 

Sakurai S, Itai K, & Tsunoda H (1983) Effects of airborne fluoride on the fluoride content of

rice and vegetables. Fluoride, 16: 175–180.

Sands M, Nicol S, & McMinn A (1998) Fluoride in Antarctic marine crustaceans. Mar Biol,

132: 591–598.

Saralakumari D & Ramakrishna Rao P (1993) Endemic fluorosis in the village Ralla

Ananthapuram in Andhra Pradesh, an epidemiological study. Fluoride, 26: 177–180.

Sato T, Yoshitake K, & Hitomi G (1986) Mechanisms of fluoride absorption from the gastrointestinal tract in rats. Fluoride Research 1985. Stud Environ Sci, 27: 325–332.

Saxena A, Kulshrestha UC, Kumar N, Kumari KM, & Srivastava SS (1994)Distribution of airborne fluoride: vapour phase, particulate, precipitation and dry deposition. Environ Technol,

15: 51–59. 
References

219

Schamschula R, Sugar E, Agus H, Un P, & Toth K (1982) The fluoride content of human

enamel in relation to environmental exposure to fluoride. Aust Dent J, 27: 243–247.

Schamschula R, SugarE, Un P, Toth K, Barmes D, & AdkinsB (1985)Physiological indicators

of fluoride exposure and utilization: an epidemiological study. Community Dent Oral

Epidemiol, 13: 104–107.

Schamschula R, Duppenthaler J, Sugar E, Toth K, & BarmesD (1988a)Fluoride intake and

utilization by Hungarian children: associations and interrelationships. Acta Physiol Hung, 72:

253–261.

Schamschula R, Un P, Sugar E, & Duppenthaler J (1988b) The fluoride content of selected

foods in relation to the fluoride concentration of water. Acta Physiol Hung, 72: 217–227.

Scheifinger H & Held G (1997) Aerosol behaviour on the South African Highveld. Atmos

Environ, 31(12): 3497–3509.

Schiffl H & Binswanger U (1980) Human urinary fluoride excretion as influenced by renal

functional impairment. Nephron, 26: 69–72.

Schnitzler CM, Wing JR, Mesquita JM, GearAK, Robson HJ, & Smyth AE (1990) Risk factors

forthe development of stress fractures during fluoride therapy forosteoporosis. J Bone Miner

Res, 5(suppl 1): S195–S200.

Schotte W (1987) Fog formation of hydrogen fluoride in air. Ind Eng Chem Res, 26(2):

300–306.

Schroder JL, Basta NT, Rafferty DP, Lochmiller RL, Kim S, QuallsW, & McBee K (1999) Soil

and vegetation fluoride exposure pathways to cotton rats on a petrochemical-contaminated

landfarm. Environ Toxicol Chem, 18(9): 2028–2033.

Schroder JL, Basta NT, Lochmiller RL, Rafferty DP, Payton M, Kim S, & Qualls CW (2000)

Soil contamination and bioaccumulation of inorganics on petrochemical sites. Environ

Toxicol Chem, 19(8): 2066–2072.

Schultz M, Kierdorf U, Sedlacek F, & Kierdorf H (1998) Pathological bone changes in the

mandibles of wild red deer (Cervus elaphus L.) exposed to hig h environmental levels of

fluoride. J Anat, 193: 431–442.

Schuppli P (1985) Total fluorine in CSSC reference soil samples. Can J Soil Sci, 65:

605–607.

Scott D (1986) Cytogenetic effects of sodium fluoride in cultured human fibroblasts.

Mutagenesis, 1: 69 (abstract).

Scott D & Roberts S (1987) Extrapolation from in vitro tests to human risk: experience with

sodium fluoride clastogenicity. Mutat Res, 189: 47–58.

Seel DC & Thomson AG (1984) Bone fluoride in predatory birds in the British Isles. Environ

Pollut, A36: 367–374. 

Sein G (1988) The effects of sodium fluoride on the immunological responsesin mice. Med

Sci Res, 16: 39.
EHC 227: Fluorides

220

Shacklette HT, Boerngen JG, & Keith JRX (1974) Selenium, fluorine and arsenic in

superficial materialsof the conterminous United States. Washington, DC, US Department of

the Interior (Geological Survey Circular 692).

Sharma Y (1982a) Effect of sodium fluoride on collagen cross-link precursors. Toxicol Lett,

10: 97–100.

Sharma Y (1982b) Variations in the metabolism and maturation of collagen after fluoride

ingestion. Biochim Biophys Acta, 715: 137–141.

Sharma K & Susheela A (1988a) Effect of fluoride on molecular weight, charge density and

age related changes in the sulphated isomersof glycosaminoglycansof the rabbit cancellous

bone. Int J Tissue React, 10: 327–334.

Sharma K & Susheela A (1988b) Fluoride ingestion in excess and its effect on the

disaccharide profile of glycosaminoglycans of cancellous bone of the rabbit. Med Sci Res,

16: 349–350.

Shashi A (1990) Histopathological changes in rabbit ovary during experimental fluorosis.

Indian J Pathol Microbiol, 33: 113–117.

Shen YW & Taves DR (1974) Fluoride concentrations in the human placenta and maternal

and cord blood. Am J Obstet Gynecol, 119: 205–207.

Sheth FJ, Multani AS, & Chinoy NJ (1994) Sister chromatid exchanges: A study in fluorotic

individuals in North Gujarat. Fluoride, 27: 215–219.

Shivashankara AR, Shivajara Shankara YM, Hanumanth Rao S, & Gopalakrishna Bhat P

(2000) A clinical and biochemical study of chronic fluoride toxicity in children of Kheru

Thanda of Gulbara district, Karnataka, India. Fluoride, 33: 66–73.

Shore RF (1995) Predicting cadmium, lead and fluoride levels in small mammals from soil

residues and by species–species extrapolation. Environ Pollut, 88: 333–340. 

Shulman E & Vallejo M (1990) Effects of gastric contents on the bioavailability of fluoride

in humans. Pediatr Dent, 12: 237–240.

Shupe JL & Olson AE (1983) Clinical and pathological aspects of fluoride toxicosis in

animals. In: Shupe J, Peterson H, & Leone N ed. Fluorides: Effects on vegetation, animals

and humans. Salt Lake City, Utah, Paragon Press, pp 319–338. 

Shupe JL, Miner ML, Greenwood DA, Harris LE, & Stoddard GE (1963)The effect of fluorine

on dairy cattle. 2. Clinical and pathologic effects. Am J Vet Res, 24: 964–979.

Shupe JL, Olson AE, Peterson HB, & Low JB (1984) Fluoride toxicosis in wild ungulates. J

Am Vet Med Assoc, 185(11): 1295–1300.

Shupe JL, Larsen AE, & Olsen AE (1987)Effectsof diets containing sodium fluoride on mink.

J Wildl Dis, 23: 606–613.

Siddiqui AH (1970) Fluorosis in areas of India with a high natural content of water fluoride.

In: Fluorides and human health. Geneva, World Health Organization, pp 284–294 (WHO

Monograph Series No. 59).

Sidhu S (1979) Fluoride levels in air, vegetation and soil in the vicinity of a phosphorous

plant. J Air Pollut Control Assoc, 29: 1069–1072.
References

221

Sidhu S (1982)Fluoride deposition through precipitation and leaf litter in a boreal forest in

the vicinity of a phosphorous plant. Sci Total Environ, 23: 205–214. 

Sidhu SS & Staniforth RJ (1986) Effects of atmospheric fluorides on foliage, and cone and

seed production in balsam fir, larch spruce, and larch. Can J Bot, 64: 923–931. 

Siemiatycki J, Gerin M, DewarR, Nadon L, Lakhani R, Begin D, & Richardson L (1991) Associations between occupational circumstances and cancer. In: Siemiatycki J ed. Risk factors

for cancer in the workplace. Boca Raton, Florida, CRC Press, pp 141–295.

Sigler WF & Neuhold JM (1972) Fluoride intoxication in fish: a review. J Wildl Dis, 8:

252–254. 

Silva M & Reynolds EC (1996)Fluoride content of infant formulae in Australia. Aust Dent J,

41: 37–42.

Simard P, Lachapelle D, Trahan L, Naccache H, DemersM, & Brodeur J (1989)The ingestion

of fluoride dentifrice by young children. J Dent Child, 56: 177–181.

Simonen O & Laitinen O (1985)Doesfluoridation of drinking-waterprevent bone fragility and

prevent osteoporosis. Lancet, 2: 432–434.

Singer L & Ophaug R (1979) Total fluoride intake of infants. Pediatrics, 63: 460–466.

Singh M & Kar D (1989) Effect of fluoride on the settleability of biomass from an activated

sludge plant treating petrochemical effluent. J Ferment Bioeng, 67(5): 366–368.

Singh A, Chhabra R, & Abrol IP (1979) Effect of fluorine and phosphorus applied to a sodic

soil on their availability and on yield and chemical composition of wheat. Soil Sci, 128(2):

90–97. 

Skare J, Wong T, Evans L, & Cody D (1986a) DNA repair studies with sodium fluoride:

comparative evaluation using density gradient ultracentrifugation and autoradiography.

Mutat Res, 172: 77–87.

Skare J, Schrotel K, & Nixon G (1986b) Lack of DNA strand breaks in rat testicular cells after

in vivo treatment with sodium fluoride. Mutat Res, 170: 85–92.

Skjelkvåle BL (1994a) Factors influencing fluoride concentrations in Norwegian lakes. Water

Air Soil Pollut, 77: 151–167. 

Skjelkvåle BL (1994b) Water chemistry in areas with high deposition of fluoride. Sci Total

Environ, 152: 105–112. 

Slamenova D, Gabelova A, & Ruppova K (1992) Cytotoxic and genotoxic testing of sodium

fluoride on Chinese hamster V79 and human EUE cells. Mutat Res, 279: 109–115.

Slamenova D, Ruppova K, Gabelova A, & Wsolova L (1996) Evaluation of mutagenic and

cytotoxic effects of sodium fluoride on mammalian cells influenced by an acidic

environment. Cell Biol Toxicol, 12: 11–17.

Sloof W, Eerens H, Janus J, & Ros J (1989) Integrated criteria document: Fluorides.

Bilthoven, National Institute of Public Health and Environmental Protection (Report No.

758474010).
EHC 227: Fluorides

222

Smid J & KrugerB (1985)The fluoride content of some teasavailable in Australia. Aust Dent

J, 30: 25–28.

Smith A (1980)An examination of the relationship between fluoridation of waterand cancer

mortality in 20 large US cities. N Z Med J, 91: 413–416.

Smith AO & Woodson BR (1965) The effects of fluoride on the growth of Chlorella

pyrenoidosa. Va J Sci, 16(1): 1–8.

Smith LR, Holsen TM, Ibay NC, Block RM, & De Leon AB (1985)Studieson the acute toxicity

of fluoride ion to stickleback, fathead minnow, and rainbow trout. Chemosphere, 14(9):

1383–1389. 

SnowG & Anderson C (1986) Short-term chronic fluoride administration and trabecularbone

remodelling in beagles: A pilot study. Calcif Tissue Int, 38: 217–221.

Søgaard CH, Mosekilde L, Schwartz W, Leidig G, Minne HW, & Ziegler R (1995) Effects of

fluoride on rat vertebral body biomechanical competence and bone mass. Bone, 16:

163–169.

Somashekar RK & Ramaswamy SN (1983) Fluoride concentration in the water of the river

Cauvery, Karnataka, India. Int J Environ Stud, 21: 325–327. 

Sorgdrager B, Pal TM, de Loof AJA, Dubois AEJ, & de Monchy JGR (1995) Occupational

asthma in aluminum potroom workersrelatedtopre-employment eosinophil count. Eur Respir

J, 8: 1520–1524.

Sowers M, Wallace R, & Lemke J (1986) The relationship of bone mass and fracture history

to fluoride and calcium intake: a study of three communities. Am J Clin Nutr, 44: 889–898.

Sowers M, Clark M, Jannausch M, & Wallace R (1991) A prospective study of bone mineral

content and fracture in communities with differential fluoride content. Am J Epidemiol, 133:

649–660.

Søyseth V & Kongerud J (1992)Prevalenceofrespiratorydisordersamong aluminum potroom

workers in relation to exposure to fluoride. Br J Ind Med, 49: 125–130.

Søyseth V, Kongerud J, Aalen O, Botten G, & Boe J (1995) Bronchial responsiveness

decreasesin relocated aluminum potroom workerscompared with workers who continue their

potroom exposure. Int Arch Occup Environ Health, 67: 53–57. 

Søyseth V, Kongerud J, & Boe J (1996) Allergen sensitization and exposure to irritants in

infancy. Allergy, 51: 719–723.

Spak CJ, Ekstrand J, & Zylberstein D (1982)Bioavailability of fluoride added to baby formula

and milk. Caries Res, 16: 249–256.

Spak CJ, Hardell LI, & de Chateau P (1983) Fluoride in human milk. Acta Paediatr Scand,

72: 699–701.

SpakC, Berg U, & Ekstrand J (1985)Renal clearance of fluoride in children and adolescents.

Pediatrics, 75: 575–579.

Spak C, Sjostedt S, Eleborg L, Veress B, Perbeck L, & Ekstrand J (1989) Tissue response of

gastric mucosa after ingestion of fluoride. Br Med J, 298: 1688–1689.
References

223

Spak C, Sjostedt S, Eleborg L, Veress B, Perbeck L, & Ekstrand J (1990) Studies of human

gastric mucosa after application of 0.042% fluoride gel. J Dent Res, 69: 426–429.

Sparks R, Sandusky M, & Paparo A (1983) Identification of the water quality factors which

prevent fingernail clams from recolonizing the Illino is River Phase III. Urbana, Illinois,

University of Illinois, Water Resources Center. 

Spencer H, Osis D, & Lender M (1981) Studies of fluoride metabolism in man: a reviewand

report of original data. Sci Total Environ, 17: 1–12.

Spinelli J, Band P, Svirchev L, & Gallagher R (1991) Mortality and cancer incidence in

aluminum reduction plant workers. J Occup Med, 33: 1150–1155.

Sprando RL, Black TN, Ames MJ, Rorie JI, & Collins TFX (1996) Effect of intratesticular

injection of sodium fluoride on spermatogenesis. Food Chem Toxicol, 43: 377–384.

Sprando RL, Collins FX, Black TN, Rorie J, Ames MJ, & O’Donnell M (1997) Testing the

potential of sodium fluoride to affect spermatogenesis in the rat. Food Chem Toxicol, 35:

881–890.

Sprando RL, Collins TF, Black T, Olejnik N, & Rorie J (1998)Testing the potential of sodium

fluoride to affect spermatogenesis: a morphometric study. Food Chem Toxicol, 36:

1117–1124.

Staniforth RJ & Sidhu SS (1984) Effects of atmospheric fluorideson foliage, flower, fruit, and

seed production in wild raspberry and blueberry. Can J Bot, 62: 2827–2834. 

Stannard J, Rovero J, Tsamtsouris A, & Gavris V (1990) Fluoride content of some bottled

waters and recommendations for fluoride supplementation. J Pedodontics, 14: 103–107.

Stevens B, Willis G, Humphrey T, & Atkins R (1987) Combined toxicity of aluminum and

fluoride in the rat: possible implications in hemodialysis. Trace Elem Med, 4: 61–66.

Stevens DP, McLaughlin MJ, & Alston AM (1997) Phytotoxicity of the aluminium–fluoride

complexes and their uptake from solution culture by Avena sativa and Lycopersicon

esculentum. Plant Soil, 192: 81–93.

Stevens DP, McLaughlin MJ, & Alston AM (1998a) Phytotoxicity of the fluoride ion and its

uptake from solution culture by Avena sativa and Lycopersicon esculentum. Plant Soil, 200:

119–129.

Stevens DP, McLaughlin MJ, & Alston AM (1998b) Phytotoxicity of hydrogen fluoride and

fluoroborate and their uptake from solution culture by Avena sativa and Lycopersicon

esculentum. Plant Soil, 200: 175–184.

StevensDP, McLaughlin MJ, Randall PJ, & Keerthisinghe G (2000) Effect of fluoride supply

on fluoride concentrations in five pasture species: Levels required to reach phytotoxic or

potentially zootoxic concentrations in plant tissue. Plant Soil, 227: 223–233.

Street JJ & Elwali AMO (1983) Fluorite solubility in limed acid sandy soils. Soil Sci Soc Am

J, 47(3): 483–485. 

Stumm W & Morgan JJ (1981) Aquatic chemistry, 2nd ed. New York, John Wiley & Sons. 

Suarez-Almazor M, Flowerdew G, Saunders D, Soskolne C, & Russel A (1993) The

fluoridation of drinking water and hip fracture hospitalization rates in two Canadian

communities. Am J Public Health, 83: 689–693.
EHC 227: Fluorides

224

Susheela A & Das T (1988) Chronic fluoride toxicity: A scanning electron microscopic study

of duodenal mucosa. Clin Toxicol, 26: 467–476.

Susheela A & Jain S (1983) Fluoride-induced haematological changes in rabbits. Bull

Environ Contam Toxicol, 30: 388–393.

Susheela A & Jain S (1986) Fluoride toxicity: Erythrocyte membrane abnormality and

“echinocyte” formation. Fluoride Research 1985. Stud Environ Sci, 27: 231–239.

Susheela A & Kharb P (1990)Aortic calcification in chronic fluoride poisoning: Biochemical

and electron-microscopic evidence. Exp Mol Pathol, 53: 72–80.

Susheela S & Kumar A (1991) A study of the effect of high concentrationsof fluoride on the

reproductive organsof male rabbits, using light and scanning electron microscopy. J Reprod

Fertil, 92: 353–360.

Susheela A & Sharma Y (1982)Certain facetsof F– action on collagen protein in osseousand

non-osseous tissues. Fluoride, 15: 177–190.

Susheela AK, Kumar A, Bhatnakar M, & Bahadur R (1993)Prevalence of endemic fluorosis

with gastrointestinal manifestations in people living in some North-Indian villages. Fluoride,

26: 97–104.

Suttie JS, Dickie R, Clay AB, Nielsen P, Mahan WE, Baumann DP, & Hamilton RJ (1987)

Effectsof fluoride emissionsfrom a modern primary aluminum smelteron a local population

of white-tailed deer (Odocoileus virginianus). J Wildl Dis, 23(1): 135–143. 

Suttie JW (1983) The influence of nutrition and otherfactorson fluoride tolerance. In: Shupe

J, Peterson H, & Leone N ed. Fluorides: Effects on vegetation, animals and humans. Salt

Lake City, Utah, Paragon Press, pp 291–303. 

Suttie JW, Miller RF, & Phillips PH (1957) Studies of the dietary NaF on dairy cows. I. The

physiological effects and the development of fluorosis. J Nutr, 63: 211–224.

Suttie JW, Hamilton RJ, Clay AC, Tobin ML, & Moore WG (1985)Effectsof fluoride ingestion

on white-tailed deer (Odocoileus virginianus). J Wildl Dis, 21(3): 283–288. 

Suzuki N & Tsutsui T (1989) [Dependence of lethality of chromosome aberrations induced

by treatment of synchronized human diploid fibroblasts with sodium fluoride on different

periods of cell cycle.] Shigaku, 77: 436–447 (in Japanese).

Swarup D, Dwivedi SK, Dey S, & Ray SK (1998) Fluoride intoxication in bovines due to

industrial pollution. Ind J Anim Sci, 68(7): 605–608.

Symonds R, Rose W, & Reed M (1988) Contribution of Cl- and F-bearing gases to the

atmosphere by volcanos. Nature, 334: 415–418. 

Tagaki Y, Ohkubo Y, Asada T, & Matsuda S (1986) An international comparison of trace

amountsof fluoride contained in human hair. Fluoride Research 1985. Stud Environ Sci, 27:

423–429.

Tannenbaum A & Silverstone H (1949) Effect of low environmental temperature,

dinitrophenol, or sodium fluoride on the formation of tumours in mice. Cancer Res, 9:

403–410.
References

225

Tao S & Suttie JW (1976) Evidence for lack of an effect of dietary fluoride level on

reproduction in mice. J Nutr, 106: 1115–1122.

Tate WH & Chan JT (1994)Fluoride concentrations in bottled and filtered waters. Gen Dent,

42: 362–366.

Taves DR (1968) Electrophoretic mobility of serum fluoride. Nature, 220: 582–583.

Taves DR (1983) Dietary intake of fluoride ashed (total fluoride) v. unashed (inorganic

fluoride) analysis of individual foods. Br J Nutr, 49: 295–301. 

TavesD, ForbesN, Silverman D, & Hicks D (1983)Inorganic fluoride concentrations in human

and animal tissues. In: Shupe J, Peterson H, & Leone N ed. Fluorides: Effectson vegetation,

animals and humans. Salt Lake City, Utah, Paragon Press, pp 189–193.

Taylor A (1954) Sodium fluoride in the drinking water of mice. Dent Dig, 60: 170–172.

Taylor RJ & Basabe FA (1984) Patterns of fluoride accumulation and growth reduction

exhibited by Douglas firin the vicinity of an aluminum reduction plant. Environ Pollut, A33:

221–235. 

Teotia M, Teotia SP, & Singh KP (1998) Endemic chronic fluoride toxicity and dietary

calcium deficiency interactionsyndromesof metabolic bone disease and deformities in India:

year 2000. Indian J Pediatr, 65: 371–381.

Theriault G, GingrasS, & Provencher S (1984) Telangiectasia in aluminum workers: a follow

up. Br J Med, 41: 367–372.

ThomasAB, Hashomoto H, BaylinkD, & Lau K-H (1996)Fluoride at mitogenic concentrations

increasesthe steady state phosphotyrosyl phosphorylation level of cellular proteins in human

bone cells. J Clin Endocrinol Metab, 81: 2570–2578.

Thompson LK, Sidhu SS, & RobertsBA (1979)Fluoride accumulations in soil and vegetation

in the vicinity of a phosphorus plant. Environ Pollut, 18: 221–234. 

Thompson R, McMullen T, & Morgan G (1971) Fluoride concentrations in the ambient air.

J Air Pollut Control Assoc, 21: 484–487.

Thomson AG (1987) Fluoride in the prey of barn owls (Tyto alba). Environ Pollut, 44:

177–192. 

Thomson E, Kilanowski F, & Perry P (1985)The effect of fluoride on chromosome aberration

and sisterchromatid exchange frequencies in cultured human lymphocytes. Mutat Res, 144:

89–92. 

Tobayiwa C, Musiyambiri M, Chironga L, Mazorodze O, & Sapahla S (1991)Fluoride levels

and dental fluorosis in two districts in Zimbabwe. Cent Afr J Med, 37: 353–361.

Tong C, McQueen C, Ved Brat S, & Williams G (1988) The lack of genotoxicity of sodium

fluoride in a battery of cellular tests. Cell Biol Toxicol, 4: 173–186.

Torra M, Rodamilans M, & Corbella J (1998) Serum and urine ionic fluoride: normal range

in a nonexposed population. Biol Trace Elem Res, 63: 67–71. 

Tracy PW, RobbinsCW, & Lewis GC (1984)Fluorite precipitation in a calcareous soil irrigated

with high fluoride water. Soil Sci Soc Am J, 48: 1013–1016. 
EHC 227: Fluorides

226

TrautnerK & Einwag J (1989)Influence of milkand food on fluoride bioavailability from NaF

and Na2FPO3 in man. J Dent Res, 68: 72–77.

Tscherko D & Kandeler E (1997) Ecotoxicological effects of fluorine deposits on microbial

biomass and enzyme activity in grassland. Eur J Soil Sci, 48: 329–335.

TsirosJX, Haidouti C, & Chronopoulou A (1998) Airborne fluoride contamination of soilsand

olive trees near an aluminium plant. Measurements and simulations. J Environ Sci Health,

A33(7): 1309–1324.

Tsuchida M, Horiuchi T, & Mineshita S (1992)Metabolic effectsof fluoride with and without

calcium deprivation. Trace Elem Med, 9: 176–182.

Tsunoda H & Tsunoda N (1986) Fluoride absorption and excretion in human subjects

following ingestion of F-contaminated agricultural products. Fluoride Research 1985. Stud

Environ Sci, 27: 107–112.

Tsutsui T, Suzuki N, & Ohmori M (1984a) Sodium fluoride-induced morphological and

neoplastic transformation, chromosome aberrations, sister chromatid exchanges and

unscheduled DNA synthesis in cultured Syrian hamster embryo cells. Cancer Res, 44:

938–941.

Tsutsui T, Suzuki N, Ohmori M, & Maizumi H (1984b) Cytotoxicity, chromosome aberrations

and unscheduled DNA synthesis in cultured human diploid fibroblasts induced by sodium

fluoride. Mutat Res, 139: 193–198.

Tsutsui T, Koichi I, & Maizumi H (1984c) Induction of unscheduled DNA synthesisin cultured

human oral keratinocytes by sodium fluoride. Mutat Res, 140: 43–48.

Tsutsui T, Kawamoto Y, Suzuki N, Gladen B, & Barrett J (1991)Cytotoxicity and chromosome

aberrations in normal human oral keratinocytes induced by chemical carcinogens:

comparison of inter-individual variations. Toxicol In Vitro, 5: 353–361.

Tsutsui T, Tanaka Y, Matsudo Y, Uehama A, Someya T, Hamaguchi F, Yamamoto H, &

Takahashi M (1995) No increases in chromosome aberrations in human diploid fibroblasts

following exposure to low concentrations of sodium fluoride for long times. Mutat Res, 335:

15–20.

Turner C, AkhterM, & Heaney R (1992) The effects of fluoridated water on bone strength. J

Orthop Res, 10: 581–587.

Turner CH, Hasegawa K, Zhang W, Wilson M, Li Y, & Dunipace AJ (1995) Fluoride reduces

bone strength in older rats. J Dent Res, 74: 1475–1481.

Turner R, Francis R, Brown D, Garand J, Hannon K, & Bell N (1989) The effects of fluoride

on bone and implant histomorphometry in growing rats. J Bone Miner Res, 4: 477–484.

Upfal M & Doyle C (1990)Medical management of hydrofluoricacid exposure. J Occup Med,

32: 726–731.

US DHHS (1991) Review of fluoride. Benefits and risks. Report of the Ad Hoc Subcommittee

on Fluoride of the Committee to Coordinate Environmental Health and Related Programs.

Washington, DC, US Department of Health and Human Services, Public Health Service.
References

227

US EPA (1980) Reviews of the environmental effects of pollutants: IX. Fluoride. Cincinnati,

Ohio, US Environmental Protection Agency, Office of Research and Development, Health

Effects Research Laboratory (EPA-600/1-78-050). 

US EPA (1985) Drinking water criteria document on fluoride. Cincinnati, Ohio, US

Environmental Protection Agency, Office of Drinking Water (Contract 68-03-3279).

US EPA (1999) Chemical-specific TRI (Toxic Release Inventory) release and waste

management data 1999. Washington, DC, US Environmental Protection Agency, Office of

Environmental Information (2810).

Uslu B (1983) Effect of fluoride on collagen synthesis in the rat. Res Exp Med, 182: 7–12.

US NAS (1971) Fluorides, biological effects of atmospheric pollutants. Washington, DC, US

National Academy of Sciences.

US NRC (1993) Health effects of ingested fluoride. Subcommittee on Health Effects of

Ingested Fluoride, US National Research Council.Washington, DC, National AcademyPress,

181 pp.

van Asten P, Darroudi F, Natarajan AT, Terpstra IJ, & Duursma SA (1998)Cytogeneticeffects

on lymphocytes in osteoporotic patientson long-term fluoride therapy. Pharm World Sci, 20:

214–218.

Van Bruggen AHC & Reynolds KL (1988) Effects of hydrogen fluoride on susceptibility of

soybeans to Rhizoctonia solani and Phytophthora megasperma f. sp. glycinea. AgricEcosyst

Environ, 24: 443–452.

Van Craenenbroeck W & Marivoet J (1987) A comparison of simple methods for estimating

the mass flow of fluoride discharged into rivers. Water Sci Technol, 19: 729–740. 

Van Toledo B (1978) Fluoride content in eggs of wild birds (Parus major L. and Strix alueo

L.) and the common house hen (Gallus domesticus). Fluoride, 11: 198–207. 

Van Wensem J & Adema T (19 91) Effects of fluoride on soil fauna mediated litter

decomposition. Environ Pollut, 72: 239–251. 

Varner JA, Huie CW, Horvath W, Jensen KF, & Isaacson RL (1993) Chronic AlF3

administration: II. Selected histological observations. Neurosci Res Commun, 13: 99–104.

Varner JA, Jensen KF, Horvath W, & Isaacson RL (1998) Chronicadministration of aluminumfluoride or sodium-fluoride to rats in drinking water: Alterations in neuronal and

cerebrovascular integrity. Brain Res, 784: 284–298.

Varo P & Koivistoinen P (1980)Mineral composition of Finnish foods. XII. General discussion

and nutritional evaluation. Acta Agric Scand, 22(suppl): 165–171.

VDI (1989) Maximum emission values to protect vegetation: maximum emission values for

hydrogen fluoride. Düsseldorf, Verein Duetscher Ingenieure, 48 pp (in German with English

translation).

VenkateswarluP (1975)Determination of total fluorine in serum and other biological material

by oxygen bomb and reverse extraction techniques. Anal Biochem, 68: 512–521.
EHC 227: Fluorides

228

Venkateswarlu P (1983) Overview of analytical methods for fluorine in air, water, soil

vegetation, body fluids and tissues. In: Shupe J, Peterson H, & Leone N ed. Fluorides: Effects

on vegetation, animals and humans. Salt Lake City, Utah, Paragon Press, pp 19–52. 

Vike E (1999) Air-pollutant dispersal patterns and vegetation damage in the vicinity of three

aluminium smelters in Norway. Sci Total Environ, 236: 75–90.

Vike E & Håbjørg A (1995) Variation in fluoride content and leaf injury on plants associated

with three aluminium smelters in Norway. Sci Total Environ, 163: 25–34.

Vikøren T & Stuve G (1996a) Fluoride exposure and selected characteristics of eggs and

bonesof the herring gull (Larus argentatus) and the common gull (Larus canus). J Wildl Dis,

32(2): 190–198.

Vikøren T & Stuve G (1996b) Fluoride exposure in cervids inhabiting areas adjacent to

aluminium smelters in Norway. II. Fluorosis. J Wildl Dis, 32(2): 181–189.

Vogel J & Ottow JCG (1991) Fluoride accumulation in different earthworm species near an

industrial emission source in southern Germany. Bull Environ Contam Toxicol, 47: 515–520.

Voroshilin SI, Plotko EG, Gatiyatullina EZ, & Gileva EA (1973) Cytogenetic effect of

inorganic fluorine compounds on human and animal cells in vivo and in vitro. Sov Genet,

9: 492–496.

Walton KC (1984) Fluoride in fox bone near an aluminium reduction plant in Anglesey,

Wales, and elsewhere in the United Kingdom. Environ Pollut, B7: 273–280. 

Walton KC (1985) Fluoride in bones of small rodents near an aluminium reduction plant.

Water Air Soil Pollut, 26(1): 65–70. 

Walton KC (1986) Fluoride in moles, shrews and earthworms near an aluminium reduction

plant. Environ Pollut, A42: 361–371. 

Walton KC (1987a) Effects of treatment with sodium fluoride and subsequent starvation on

fluoride content of earthworms. Bull Environ Contam Toxicol, 38: 163–170. 

Walton KC (1987b) Fluoride in bones of small rodents living in areaswith different pollution

levels. Water Air Soil Pollut, 32: 113–122. 

Walton KC (1987c) Tooth damage in field voles, wood mice and moles in areas polluted by

fluoride from an aluminium reduction plant. Sci Total Environ, 65: 257–260. 

Walton KC (1988) Environmental fluoride and fluorosis in mammals. Mammal Rev, 18(2):

77–90. 

Walton KC & Ackroyd S (1988) Fluoride in mandibles and antlers of roe and red deer from

different areas of England and Scotland. Environ Pollut, 54: 17–27. 

Wang GQ, Huang YZ, Xiao BY, Qian XC, Yao H, Hu Y, Gu YL, Zhang C, & Liu KT (1997)

Toxicity from water containing arsenic and fluoride in Xinjiang. Fluoride, 30(2): 81–84.

Wang J-X & Bian Y-M (1988) Fluoride effects on the mulberry–silkworm system. Environ

Pollut, 52: 11–18. 

Wang W (1986) Toxicity tests of aquatic pollutants by using com mon duckweed. Environ

Pollut, B11: 1–14. 
References

229

Wang Y, Yin Y, Gilula LA, & Wilson AJ (1994)Endemic fluorosisof the skeleton: radiographic

features in 127 patients. Am J Roentgenol, 162: 93–98.

Ward PFB, Hall RJ, & Peters RA (1964) Fluoro-fatty acids in the seeds of Dichapetabum

toxicarium. Nature, 201: 611–612. 

Warren DP, Henson HA, & Chan JT (1996) Comparison of fluoride content in caffeinated,

decaffeinated and instant coffee. Fluoride, 29: 147–150.

Waterhouse C, Taves D, & Munzer A (1980) Serum inorganic fluoride: changes related to

previous fluoride intake, renal function and bone resorption. Clin Sci (Lond), 58(2): 145–152.

Weast R (1986) CRC handbook of chemistry and physics, 1985–1986. Boca Raton, Florida,

CRC Press.

Weatherell J, Deutsch D, Robinson C, & Hallsworth A (1977) Assimilation of fluoride by

enamel throughout the life of the tooth. Caries Res, 11: 85–115.

Wei SHY, Hattab FN, & Mellberg JR (1989) Concentration of fluoride and other selected

elements in teas. Nutrition, 5: 237–240.

Weidmann S & Weatherell J (1970) Distribution in hard tissues. In: Fluorides and human

health. Geneva, World Health Organization, pp 104–128 (WHO Monograph Series No. 59).

Weinstein L (1977) Fluoride and plant life. J Occup Med, 19: 49–78. 

Weinstein LH & Alscher-Herman R (1982) Physiological responses of plants to fluorine. In:

Unsworth M & Ormrod DP ed. Effectsof gaseousair pollution in agriculture and horticulture.

London, Butterworth Scientific, pp 139–167.

Wen MK, Li QC, & Wang CY (1996) Developments in the analysis of fluoride 1993–1995.

Fluoride, 29: 82–88.

Whitford G (1987) Fluoride in dental products: safety considerations. J Dent Res, 66:

1056–1060.

Whitford G (1990)The physiological and toxicological characteristics of fluoride. J Dent Res,

69: 539–549.

Whitford G (1996) The metabolism and toxicity of fluoride, 2nd rev. ed. Basel, Karger, 156

pp (Monographs in Oral Science, Volume 16).

Whitford GM (1997) Determinants and mechanisms of enamel fluorosis. Ciba Found Symp,

205: 226–245. 

Whitford GM & Pashley DH (1984)Fluoride absorption: the influence of gastricacidity. Calcif

Tissue Int, 36: 302–307.

Whitford G, Pashley D, & Reynolds K (1979) Fluoride tissue distribution: short-term kinetics.

Am J Physiol, 236: F141–F148.

Whitford G, Callan R, & Wang H (1982)Fluoride absorptionthrough the hamster cheekpouch:

a pH-dependent event. J Appl Toxicol, 2: 303–306.
EHC 227: Fluorides

230

Whitford G, BilesE, & Birdsong-Whitford N (1991) A comparative study of fluoride pharmacokinetics in five species. J Dent Res, 70: 948–951. 

Whitford GM, Thomas JE, & AdairSM (1999a)Fluoride in whole saliva, parotid ductal saliva

and plasma in children. Arch Oral Biol, 44: 785–788.

Whitford GM, Sampaio FC, Arneberg P, & von der Fehr FR (1999b) Fingernail fluoride: a

method for monitoring fluoride exposure. Caries Res, 33: 462–467.

WHO (1984) Fluorine and fluorides. Geneva, World Health Organization (Environmental

Health Criteria 36). 

WHO (1993) Guidelines for drinking-water quality, 2nd ed. Vol. 1. Recommendations.

Geneva, World Health Organization.

WHO (1994) Fluorides and oral health. Report of a WHO Expert Committee on Oral Health

Statusand Fluoride Use. Geneva, World Health Organization (WHO Technical Report Series

846). 

WHO (1996a) Biological monitoring of chemical exposure in the workplace. Vol. 1. Geneva,

World Health Organization.

WHO (1996b) Guidelines for drinking-water quality, 2nd ed. Vol. 2. Health criteria and other

supporting information. Geneva, World Health Organization.

WHO (1996c) Trace elements in human nutrition and health. Geneva, World Health

Organization.

Wolting HG (1975) Synergism of hydrogen fluoride and leaf necrosison freesias. Neth J Plant

Pathol, 81: 71–77.

Wolting HG (1978) Gevoeligheid van kastulphen voor chronische inwerking van

fluorhoudende luchtverontreiniging. Bloembollencultur, 31: 728–730.

Wright DA (1977) Toxicity of fluoride to brown trout fry (Salmo trutta). Environ Pollut, 12:

57–62. 

Wright DA & Davison AW (1975) The accumulation of fluoride by marine and intertidal

animals. Environ Pollut, 8: 1–13. 

Wu DQ & Wu Y (1995) Micronucleus and sister chromatid exchange frequency in endemic

fluorosis. Fluoride, 28: 125–127.

Wu JY, Wu L, Liu KT, & Jiang P (1998)Study on absorption and excretion of joint exposure

to fluoride and arsenic. Endemic Dis Bull, 13(2): 5–9.

Xu RH, Yuan HH, & Fan A (1995)Endemic fluorosis in China from ingestion of food immersed

in hot spring water. Bull Environ Contam Toxicol, 54: 337–341.

Xu RQ, Wu DQ, & Xu RY (1997) Relations between environment and endemic fluorosis in

Hohot region, Inner Mongolia. Fluoride, 30: 26–28.

Yang CY, Cheng MF, Tsai SS, & Hung CF (2000) Fluoride in drinking water and cancer

mortality in Taiwan. Environ Res, 82: 189–193.

Yiamouyiannis J & Burk D (1977) Fluoridation and cancer: Age-dependence of cancer

mortality related to artificial fluoridation. Fluoride, 10: 102–125.
References

231

Zang ZY, Fan JY, Yen W, Tian JY, Wang JG, Li XX, & Wang EL (1996)The effect of nutrition

on the development of endemic osteomalacia in patientswith skeletal fluorosis. Fluoride, 29:

20–24.

ZeigerE, Shelby MD, & Witt KL (1993)Genetic toxicity of fluoride. Environ Mol Mutagen, 21:

309–318.

Zeiger E, Gulati D, Kuar P, Mohamed H, Revazova J, & Deaton T (1994) Cytogenic studies

of sodium fluoride in mice. Mutagenesis, 9: 467–471.

Zhang Y & Cao SR (1996) Coal burning induced endemic fluorosis in China. Fluoride, 29:

207–211.

Zhao ZP, Yaun MB, & Liu GF (1996) X-ray analysis of 80 patients with severe endemic

fluorosis caused by coal burning. Fluoride, 29: 79–81.

Zierler S, Theodore M, Cohen A, & Rothman K (1988)Chemical quality of maternal drinking

water and congenital heart disease. Int J Epidemiol, 17: 589–594.

Zingde MD & Mandalia AV (1988) Study of fluoride in polluted and unpolluted estuarine

environments. Estuarine Coastal Shelf Sci, 27: 707–712. 

Zipkin I, McClure F, & Lee W (1960) Relation of the fluoride content of human bone to its

chemical composition. Arch Oral Biol, 2: 190–195. 

Zwiazek JJ & Shay JM (1987) Fluoride- and drought-induced structural alterations of

mesophyll and guard cells in cotyledons of jack pine (Pinus banksiana). Can J Bot, 65(11):

2310–2317. 

Zwiazek JJ & Shay JM (1988a) Sodium fluoride induced metabolic changes in jack pine

seedlings. I. Effect on gas exchange, water content, and carbohydrates. Can J For Res,

18(10): 1305–1310. 

Zwiazek JJ & Shay JM (1988b) Sodium fluoride induced metabolic changes in jack pine

seedlings. II. Effect on growth, acid phosphatase, cytokinins, and pools of soluble proteins,

amino acids, and organic acids. Can J For Res, 18(10): 1311–1317. 
232

RESUME ET CONCLUSIONS

Ce document est consacré à l’exposition environnementale aux

fluorures, minéraux principalement, et à ses effets sur l’Homme, les

animaux et les autres êtres vivants. Les données prises en compte

concernent le fluorure d’hydrogène, le fluorure de calcium, le fluorure

de sodium, l’hexafluorure de soufre et les silicofluorures étant donné

que ce sont les fluorures minéraux les plus importants du point de vue

des quantités libérées et des concentrations dans l’environnement

ainsi que des effets toxicologiques exercés sur les organismes vivants.

1. Identité, propriétés physiques et chimiques et

méthodes d’analyse

Le fluorure d’hydrogène (HF) s e présente sous la forme d’un

liquide ou d’un gaz incolore, à l’odeur âcre, qui est très soluble dans

les solvants organiques et dans l’eau avec laquelle il donne de l’acide

fluorhydrique. Le fluorure de calcium (CaF2) est un solide incolore,

relativement insoluble dans l’eau et les acides ou bases diluées. Le

fluorure de sodium (NaF) est un solide incolore à blanc, modérément

soluble dans l’eau. L’hexafluorure de soufre (SF6) est un gaz incolore

et inodore, chimiquement inerte, qui est légèrement soluble dans l’eau

et facilement soluble dans l’éthanol et les bases.

Le dosage des fluorures libres s’effectue le plus couramment par

voie électrochimique au moyen d’une électrode sélective. On estime

que les techniques de microdiffusion constituent le moyen le plus

fiable pour la préparation des échantillons (c’est-à-dire par libération

de d’anions fluorure libres à partir de complexes organiques ou minéraux).

2. Sources d’exposition humaine et environnementale

Il y a libération naturelle de fluorures dans l’environnement par

suite de l’érosion et de la dissolution des roches et des minéraux, à la

faveur d’émissions par les volcans ou par l’intermédiaire d’aérosols

marins.La combustion du charbon ainsi que les eaux usées provenant

de diverses opérations industrielles, comme la fabrication de l’acier, la

production d’aluminium, de cuivre et de nickel, le traitement des
Résumé et Conclusions

233

minerais de phosphates, la production et l’utilisation d’engrais

phosphatés, la fabrication de verre, de briques et de céramiques ou

encore la production de colles et d’adhésifs.L’épandage de pesticides

fluorés ainsique la fluoration de l’eau destinée à la boisson sont également des sources anthropogéniques de fluor. Les données disponibles

montrent que l’extraction et l’utilisation des phosphates ainsi que la

production de l’aluminium sont les sources industrielles qui rejettent

le plus de fluorures dans l’environnement.

Le fluorure d’hydrogène est un produit industriel important qui

est principalement utilisé pour la production de cryolithe synthétique

(Na3AlF6), de fluorure d’aluminium (AlF3), des alkylates ou isoparaffines qui entrent dans la composition de l’essence automobile et de

chlorofluorocarbures, avec une consommation annuelle mondiale de

plus de 1 million de tonnes. On l’emploie également pour le décapage

d es dispositifs à semi-conducteurs, le décapage, la gravure et le

dépolissage du verre, le décapage de la brique et de l’aluminium, le

tannage du cuir ainsi que pour la préparation des produits antirouille

vendus dans le commerce. Le fluorure de calcium est utilisé comme

fondant dans la production de l’acier, du verre et de l’émail et ilsert de

matière première pour la préparation de l’acide fluorhydrique et du

fluorure d’hydrogène anhydre ou encore d’électrolyte dans la préparation de l’aluminium. Le fluorure de sodium est utilisé pour la fluoration

réglementée de l’eau de boisson, comme conservateur dans les colles,

le verre et l’émail, comme fondant dans la production de l’acier et de

l’aluminium et comme agent conservateur du bois. L’acide fluorosilicique (H2SiF6

) et l’hexafluorosilicate de disodium (Na2SiF6) sont

utilisés pour la fluoration de l’eau.

3. Transport, distribution et transformation dans

l’environnement

Lesfluorures présents dans l’atmosphère peuvent s e trouversous

forme de gaz ou de particules. Ils sont susceptibles d’être transportés

sur de grandes distances par les vents ou par suite des turbulences

atmosphériques ou être éliminés de l’atmosphère par dépôt à sec, par

les précipitations ou encore par hydrolyse. A l’exception de l’hexafluorure de soufre, on estime que les fluorures ne restent vraisemblablement pas très longtemps dans la troposphère et qu’ils me migrent
EHC 227: Fluorides

234

pas vers la stratosphère. La durée de séjour atmosphérique de l’hexafluorure de soufre va de 500 ans à plusieurs milliers d’années.

Le transport et la transformation des fluorures dans l’eau dépendent du pH, de la dureté de l’eau et de la présence de substances échangeuses d’ions comme les argiles.Le transport des fluorures s’effectue

par le cycle de l’eau sous forme de complexes avec l’aluminium. 

Dans le sol, le transport et la transformation des fluorures

dépendent également du pH, mais aussi de la formation de complexes,

notamment avec l’aluminium et le calcium. L’adsorption à la phase

solide du sol est plus forte lorsque le pH est acide (5.5-6.5). Le lessivage des fluorures présents dans le sol ne se fait pas spontanément.

L’absorption des fluorures parles êtres vivants dépend de la voie

d’exposition, de la biodisponibilité des composés et de la cinétique

d’absorption et d’excrétiondansles divers organismes.Certains biotes

aquatiques et terrestres accumulent les fluorures solubles. On ne

possède cependant aucune information sur la bioamplificatio n des

fluorures dans les chaînes alimentaires aquatiques et terrestres.

Les plantes terrestres peuvent accumuler des fluorures aéroportés

qui se sont déposés ou fixer ceux qui étaient déjà présents dans le sol.

4. Concentrations dans l’environnement et exposition

humaine

La teneur des eauxde surface en fluorures peut varier selon le lieu

et la proximité des sources d’émission. Elle va généralement de 0,01 à

0,3 mg/litre. L’eau de mer contient plus de fluorures que l’eau douce,

avec une concentration comprise entre 1,2 et 1,5 mg/litre.Des concentrations plus fortes ont été relevées dans des zones où les roches sont

riches en fluorures et une teneur élevée en fluorure minéral s’observe

généralement dans les région où existe une activité géothermique ou

volcanique (par ex. 25-50 mg/litre dans les sources chaudes et les

geysers et même 2800 mg/litre dans certains lacs de la vallée du Rift, en

Afrique orientale). Les décharges résultant de l’activité humaine

peuvent également entraînerla présence de concentrations élevées de

fluorures dans l’environnement.
Résumé et Conclusions

235

Les fluorures peuvent être présents dans l’airsous forme gazeuse

ou particulaire par suite d’émissions naturelles ou anthropogéniques.

Les fluorures émis sous forme gazeuse ou particulaire se déposent

généralement au voisinage de la source de l’émission, encore que ceux

quisont présents dans certaines particules puissentréagir sur d’autres

constituants atmosphériques.La distribution et le dépôt des fluorures

aéroportés dépend de l’intensité de l’émission, des conditions météorologiques, de la granulométrie des particules et de leur réactivité

chimique. Dans les zones qui ne sont pas situées au voisinage

immédiat des sources d’émissions, la concentration moyenne en

fluorures dans l’air ambiant est généralement inférieure à 0,1 μg/m3. Elle

peut être légèrement plus élevée en ville qu’à la campagne.Toutefois,

même à proximité de sources d’émissions, la teneur de l’air en fluorures

ne dépasse généralement pas 2 à 3 μg/m3. Dans les régions de la Chine

où l’on utilise de la houille riche en fluorures comme combustible, on

fait état de concentrations dans l’air ambiant pouvant atteindre 6

μg/m3.

Les fluorures sont des constituants de presque tous les types de

sols, avec des teneurs totales allant de 20 à 1000 μg/g dans les régions

où il n’y a pas de gisements naturels de phosphates ou de fluorures et

à des concentrations de plusieurs milliers de microgrammes par gramme

dans lessols où existent de tels gisements.Les fluorures présents dans

l’atmosphère à l’état gazeuxou particulaire ont tendance à s’accumuler

dans les couches superficielles du sol, mais peuvent migrer vers la

zone radiculaire, même dans les sols calcaires. La rétention des

fluorures dans le sol dépend essentiellement de la teneur en argile et en

carbone organique ainsi que du pH. Les fluorures présents dans le sol

y sont surtout associés à la fraction colloïdale ou argileuse.Pourtous

les types de sols, c’est la teneur en fluorures solubles qui est

biologiquement importante pour la faune et la flore.

Les organismes aquatiques peuvent absorber des fluorures soit

directement à partir de l’eau, soit, dans une moindre mesure, à partir de

leur nourriture. Les fluorures ont tendance à s’accumuler dans l’exosquelette ou dans les tissus osseux des animaux aquatiques, selon le

cas. Chez le krill, par exemple, on a mesuré des concentrations

moyennes de fluorures supérieures à 2000 mg/kg dans l’exosquelette.

Chez les mammifères marins comme le phoque ou la baleine, la teneur

moyenne des os en fluorures peut aller de 135 à 18 600 mg/kg de poids

sec.
EHC 227: Fluorides

236

Chez les biotes terrestres, la concentration en fluorures est plus

élevée dans les zones où la présence de fluorures d’origine naturelle ou

anthropogénique est plus importante. On utilise beaucoup les lichens

comme bioindicateurs de la présence de fluorures. Dans des lichens

poussant dans un rayon de 2 à 3 km autour de sources d’émission de

fluorures, on a trouvé des concentrations de l’ordre de 150-250 mg/kg,

alors que la concentration de fond est de moins de 1 mg/kg.

La majorité des fluorures présents dans le sol sont insolubles et

par conséquent, peu biodisponibles pour les végétaux. Toutefois, une

forte teneur du sol en fluorures, un pH acide ou la présence d’argile ou

de matières organiques peuvent accroître la teneur de fluorures en

solution, ce qui va en favoriser leur fixation par le système radiculaire

de la plante. Si des fluorures sont captés au niveau de la racine, leur

concentration sera souvent plus élevée dans cette dernière que dans

les pousses en raison de leurfaible mobilité dans la plante. La plupart

des fluorures pénètrent dans les tissus végétaux sous forme gazeuse

au nivau des stomates et ils s’accumulent dans les feuilles.De petites

quantités de particules fluorées peuvent également pénétrer dans la

plante en traversant l’épiderme et la cuticule. Une très large surveillance s’exerce sur la végétation située aux alentours des sources

d’émission anthropogéniques. On a constaté l’existenced’une corrélation entre la concentration de fluorures dans la végétation et la croissance annuelle, le régime des vents, la distance à la source d’émission

de fluorures et la teneur en fluorure d’hydrogène des rejets atmosphériques.

Les fluorures s’accumulent dans les tissus osseux des vertébrés

terrestres en fonction d’un certain nombre de facteurs tels que le

régime alimentaire et la présence d’émissions de fluorures dans le

voisinage. Par exemple,on a trouvé des une concentration moyenne de

fluorures comprise entre 7000 et 8000 mg/kg dans les os de petits

animaux vivant à proximité d’une usine de production d’aluminium.

Les fluorures se retrouvent dans tout l’environnement, aussi les

sources d’eau potable ont-elles des chances d’en contenir au moins

une petite quantité. La teneur de l’eau de boisson non fluorée en

fluorures d’origine naturelle (il s’agit de l’eau à laquelle on n’a pas

ajouté de flurorures pour prévenir les caries) varie dans d’importantes

proportions, en fonction de l’environnement géologique de la source.

La concentration peut atteindre 2,0 mg/litre; toutefois, dans les régions
Résumé et Conclusions

237

du monde où existe une endémie fluorotique osseuse ou dentaire

parfaitement attesté e, la concentration des fluorures dans l’eau de

consommation va de 3 à plus de 20 mg/litre. Là où l’eau de

consommation est fluorée intentionnellement pour prévenir les caries,

la teneur en fluorures est de 0,7 à 1,2 mg/litre.

Presque toutes les denrées alimentaires contiennent au moins des

traces de fluorures. Ils sont présents à forte concentration dans le

poisson et les feuilles de thé en sont particulièrement riches. La

quantité de fluorures dans le thé infusé dépend de la concentration en

fluorures solubles dans les feuilles et de la durée d’infusion. L’utilisation d’engrais à base de superphosphates, qui contiennent une forte

p roportion de fluorures (1 à 3 %) comme impuretés, pour traiter les

terres agricoles, n’accroît pas sensiblement la teneur des produits

alimentaires en fluorures, car le coefficient de transfert du sol à la

plante est généralement faible. Toutefois, selon une étude récente, si

les conditions pédologiques s’y prêtent et que l’on traite les sols avec

des phosphates suffisamment riches en impuretés flurorées,la fixation

de fluorures parla plante peut augmenter. En revanche, l’irrigation des

cultures avec de l’eau relativement pauvre en fluorures (moins de

3,1 mg/litre), n’entraîne généralement pas d’augmentation de la teneur

des produits alimentaires en fluorures. Cela dépend cependant de

l’espèce végétale en cause et de la concentration des fluorures dans le

sol et l’eau. La concentration des fluorures dans les aliments est

sensiblement modifiée par la teneur en fluorures de l’eau utilisée pour

leur préparation ou leur fabrication, notamment dans le cas des boissons et des aliments secs - comme par exemple les aliments pour

nourrissons que l’on dilue dans l’eau avant consommation.La concentration des fluorures dans les cultures vivrières situées à proximité de

sources d’émission industrielles peut être plus élevée, lorsque les

produits ne sont ni lavés ni transformés, que dans des cultures

identiques mais situées dans des zones où il n’y a pas d’exposition

d’origine industrielle. On a constaté que dans des aliments pour

nourrissons vendus auxEtats-Unis et quis e présentaient sous la forme

de produits à base de soja prêts à être consommés ou encore de concentrés liquides, la concentration en fluorures était plus élevée que

dans les produits à base de lait; on n’a cependant constaté au cune

différence entre ces derniers et les aliments pour nourrissons à base de

poudre de soja. La présence de fluorures a été décelée dans le lait

maternel à des concentrations comprises entre <2 à et environ 100

μg/litre, la plupart des valeurs se situant entre 5 et 10 μg/litre.
EHC 227: Fluorides

238

On ne dispose que de données limitées sur la teneur de l’air

intérieur en fluorures. Aux Pays-Bas, on a observé une concentration

en fluorures gazeux qui allait de <2 à 49 μg/m3dans l’air de cinq

habitations construites avec du bois traité par un conservateur

contenant 56 % de fluorure. En Chine, on a trouvé des concentrations

pouvant atteindre 155 μg/m3 dans des échantillons d’air prélevés dans

des maisons où l’on brûlait du charbon à forte teneur en fluorures.

Les produits dentifrices destinés aux adultes qui sont commercialisés dans de nombreux pays contiennent généralement des

fluorures à des concentrations comprises entre 1000 et 1500 μg/g;

certains produits plus spécialement destinés aux enfants ont une

teneur plus faible en fluorures, qui va de 250 à 500 μg/g. Les produits

d’hygiène bucco-dentaire tels que pâtes dentifrices, bains de bouche

et suppléments fluorés, s e révèlent être une source importante de

fluorures. Les bains de bouche destinés à un usage quotidien contiennent généralement de 230 à 500 mg de fluorures parlitre,alors que ceux

quisont destinés à être utilisés toutes les semaines ou tous les 14 jours

peuvent en contenir entre 900 et 1000 mg/litre.

L’exposition individuelle aux fluorures varie probablement beaucoup, mais l’inhalation de fluorures présents dans l’atmosphère ne

contribue en général que faiblement à l’apport total de ces substances.

Chez l’adulte, ce sont les produits alimentaires et l’eau de boisson qui

en constituent la principale voie d’apport. Dans les régions du monde

où l’on utilise du charbon riche en fluor pour se chauffer et faire la

cuisine, l’air intérieur et les aliments, qui contiennent dès lors une

proportion plus importante de fluorures, contribuent également pour

une part importante à l’apport de ces substances. Les nourrissons

alimentés à l’aide de produits formulés reçoivent 50 à 100 fois plus de

fluorures que ceuxquisont nourris exclusivement au sein. L’ingestion

de dentifrice parles jeunes enfants représente une fraction importante

de la dose totale de fluor qu’ils absorbent. On estime en général que

l’absorption de fluorures parles enfants et les adolescents ne dépasse

pas environ 2 mg/jour. Bien que la dose de fluorures absorbée

quotidiennement par un adulte puisse être supérieure en valeur

absolue à celle qui est absorbée par un enfant, cette dernière, exprimée

en mg par kg de poids corporel, peut être plus élevée que pour un

adulte. Dans les régions du monde où la concentration des fluorures

dans l’environnement peut être excessivement élevée et où le régime

alimentaire peut comporter des produits riches en fluor, on estime
Résumé et Conclusions

239

qu’un adulte peut en absorber jusqu’à 27 mg par jour, la principale

source étant l’eau de boisson provenant de sources souterraines

captées dans des couches géologiques riches en fluor.

Les personnes qui utilisent du matériel de soudage ou qui sont

employées au traitement des minerais d’aluminium, de fer ou de

phosphates subissent vraisemblablement une exposition

professionnelle par inhalation ou contact cutané. Selon des études

relativement récentes, la concentration en fluorures dans l’air des halls

d’électrolyse des usines de production d’aluminium est de l’ordre de

1 mg/m3.

5. Cinétique et métabolisme chez l’Homme et les

animaux de laboratoire

Chez l’Homme comme chez les animaux de laboratoire, c’est

principalement au niveau de l’estomac et de l’intestin que les fluorures

ingérés passent dans la circulation générale et cette résorption dépend

de la solubilité aqueuse relative de la substance en cause. Les fluorures

solubles sont presque entièrement résorbés dans les voies digestives,

mais le tauxde résorption peut être réduit parla formation de complexes

avec l’aluminium, le phosphore, le magnésium ou le calcium. Les

fluorures particulaires ou gazeux qui pénètrent dans les voies

respiratoires sont partiellement à totalement résorbés, le tauxde résorption étant fonction de la solubilité et de la granulométrie.

Les fluorures sont rapidement amenés parle courant sanguin dans

l’eau intracellulaire et extracellulaire des différents tissus; cependant

chez l’Homme et les animauxde laboratoire, environ 99 % de la charge

totale de l’organisme en fluorures est retenue par les os et les dents.

Les fluorures sont incorporés dans le réseau cristallin des tissus

dentaire et osseux.

Les fluorures traversent la barrière placentaire et il passent ainsi

de la mère au foetus. Ils sont principalement éliminés par la voie

urinaire.Chez le nourrisson, le fluor est retenu à environ 80-90 %; chez

l’adulte, le chiffre correspondant est d’environ 60 %. Une modification

du débit urinaire ou du pH peut faire varier ces valeurs.

Les fluorures sont prés ents dans tous les organes, tissus et

liquides de l’organisme. Dans une communauté des Etats-Unis
EHC 227: Fluorides

240

alimentée en eau fluorée, on a relevé des concentrations dans le sang

total qui allaient de 20 à 60 mg/litre. Chez 127 sujets dont l’eau de

boisson avait une teneur en fluorures de 5,03 mg/litre, on a trouvé un

tauxplasmatique moyen de 106 ± 76 (F) μg/litre. Le plasma et le sérum

ont pratiquement la même teneur en fluorures. En ce qui concerne les

tissus calcifiés, c’est généralement dans les os, la dentine et l’émail que

la concentration est la plus élevée. Dans les os, cette concentration

varie en fonction de l’âge et du sexe ainsi que de la nature et de la

partie de l’os concernée. On estime qu’elle est le reflet de l’exposition

à long terme du sujet. Dans l’éma il dentaire, la concentration en

fluorures diminue exponentiellement avec la distance à la surface et elle

dépend de la localisation, de l’usure des faces de la dent, de

l’exposition par la voie générale et des applications topiques de

fluorures auxquelles il a pu être procédé. La teneur en fluorures des

tissus mous correspond à la concentration sanguine. Chez un sujet en

bonne santé, la concentration urinaire des fluorures est liée à l’apport

de fluor. Chez des sujets exposés de parleur profession à des fluorures

présents dans l’air ou résidant dans des zones où la fluorose est

endémique, on constate une élévation de la teneur des urines en

fluorures.

6. Effets sur les mammifères de laboratoire et les

systèmes d’épreuve in vitro

Chez des rats recevant des fluorures par voie orale pendant des

périodes allant de 3 à 5 semaines, diverses études ont mis en évidence

des effets au niveau du squelette consistant en une inhibition de la

minéralisation et de la formation du tissus osseux, un retard dans la

guérison des fractures ainsi qu’une réduction du volume osseuxet de

la synthèse du collagène. Des études à moyen terme au cours

desquelles des souris ont reçu pendant 6 mois une eau de boisson

contenant des fluorures à une concentration supérieure à 4,5 mg/kg de

poids corporel,ontrévélé les effets suivants : anomalies du remodelage

osseux, mégalocytose hépatique, néphrose, minéralisation du myocarde, nécrose ou dégénérescence des tubes séminifères du testicule.

Une étude de cancérogénicité très complète au cours de laquelle

des groupes de rats F344/N et des souris B6C3F1 des deux sexes ont

reçu pendant 2 ans une eau de boisson contenant jusqu’à 79 mg/litre

de fluorure de sodium, n’a révélé aucune augmentation significative,

dans l’un et l’autre groupe, de l’incidence des tumeurs, quelles qu’elles
Résumé et Conclusions

241

soient. On a bien observé une tendance statistiquement significative

à l’accroissement des ostéosarcomes chez les mâles lorsqu’on

augmentait l’exposition au fluorure,mais l’incidence restait cependant

dans les mêmes limites que chez les témoins historiques.

Une autre étude de cancérogénicité de 2 ans a été effectuée sur

des rats Sprague-Dawley, qui ont été exposés par voie alimentaire à des

doses quotidiennes de fluorures allant jusqu’à 11,3 mg/kg p.c.; aucune

augmentation statistiquement significative n’a été relevée dans l’incidence des ostéosarcomes ou d’autres tumeurs. Il existe une autre

étude, qui fait état d’un accroissement de l’incidence des ostéosarcomes chez des souris qui avaient reçu des doses quotidienne de

fluorures allant jusqu’à 11,3 mg/kg p.c., mais les résultats sont difficiles

à interpréter car les animaux étaient infectés par un rétrovirus de type

C.

En règle générale, les fluorures n’ont pas d’action mutagène sur

les cellules procaryotes. On a montré qu’ils augmentaient la fréquence

des mutations au niveau de certains locus dans des cellules de

lymphome murin et des cellules lymphoblastoïdes humaines en culture,

mais ces mutations ne semblent pas être des mutations ponctuelles et

sont probablement plutôt dues à des lésions chromosomiques. Les

fluorures ont des effets clastogènes sur divers types de cellules. On

pense que cette activité clastogène s’explique par un effet sur la

synthèse ou la réparation de l’ADN, plutôt que par une interaction

directe avec cette molécule. Dans la plupart des études au cours

desquelles des fluorures ont été administrés par voie orale à des

rongeurs, on n’a relevé aucun effet sur la morphologie des spermatozoïdes, ni sur la fréquence des aberrations chromosomiques, des

micronoyaux, des échanges entre chromatides-soeurs ou des ruptures

des brins de l’ADN. On a toutefois obs ervé des lésions

cytogénétiques au niveau de la moelle osseuse ainsique des anomalies

affectant la morphologie des spermatozoïdes lorsque ces substances

étaient administrées par voie intrapéritonéale à des rongeurs.

Des études récentes au cours desquelles des animaux de

laboratoire ont reçu des fluorures ajoutés à leur eau de boisson, n’ont

pas mis en évidence d’effets sur la reproduction ou le développement.

Des anomalies histopathologiques ont cependant été relevées au

niveau des organes reproducteurs chez des lapins mâles qui avaient

reçu par voie orale pendant 18 à 29 mois une dose quotidienne de 4,5

mg de fluorures par kg de poids corporel, chez des souris mâles
EHC 227: Fluorides

242

soumises quotidiennement pendant 30 jours à une dose orale de

fluorures supérieure ou égale à 4,5 par kg p.c. ainsi que chez des

lapines qui en avaient reçu pendant 100 jours une dose quotidienne

supérieure ou égale à 10 mg/kg p.c. administrée par voie sous-cutanée.

Des effets génésiques indésirables ont également été observés chez

des souris femelles à qui on avait administré par voie orale une dose de

fluorures supérieure ou égale à 5.2 mg/kg p.c. 6 à 15 jours après

l’accouplement ainsi que chez des lapins mâles qui en avaient reçu une

dose quotidienne supérieure ou égale à 9.1 mg/kg p.c. pendant 30

jours.

7. Effets sur l’Homme

Les études épidémiologiques consacrées auxeffets des fluorures

sur la santé humaine concernent l’exposition professionnelle des

travailleurs, notamment ceux qui sont affectés à la production de

l’aluminium, ainsi que l’exposition des populations consommant de

l’eau fluorée. Un certain nombre d’études d’épidémiologie analytique

portan t sur des travailleurs exposés à des fluorures de par leur profession,font ressortir une augmentation de l’incidence des cancers du

poumon et de la vessie ainsi qu’un accroissement de la mortalité due

à ces cancers ou à des tumeurs d’autre localisation. Il n’y a toutefois

généralement pas de tendance cohérente et dans certaines de ces

études l’augmentation constatée de la morbidité et de la mortalité par

cancer peut être attribuée à l’exposition des travailleurs à d’autres

substances que les fluorures.

Un grand nombre d’études épidémiologiques ont été menée dans

de nombreuxpays pour étudierla relation entre la consommation d’eau

fluorée et la morbidité ou la mortalité par cancer. Il n’existe aucune

preuve solide d’un lien entre la consommation d’eau réglementairement

fluorée une augmentation de la morbidité ou de la mortalité dues au

cancer.

Les effets des fluorures sur l’émail dentaire peuvent être bén éfiques mais également nocifs. La prévalence des caries dentaires est

inversement proportionnelle à la teneur de l’eau de boisson en

fluorures. La prévalence de la fluorose dentaire est en rapport étroit

avec cette teneur, avec une relation dose-réponse positive.
Résumé et Conclusions

243

On continue à observer des cas de fluorose osseuse liés à la consommation d’eau à forte teneur en fluorures. Un certain nombre de

facteurs tels que l’état nutritionnel, le régime alimentaire, le climat (qui

influe sur la prise de liquides), une exposition concomitante à d’autres

substances et un apport de fluorures provenant d’autres sources que

l’eau de boisson jouent,semble-t-il, un rôle important dans l’apparition

de cette maladie. Des cas de fluorose osseuse peuvent survenir parmi

les travailleurs que leur profession expose à des concentrations

élevées de fluorures aéroportés, mais on n’a guère obtenu

d’informations nouvelles à ce sujet.

Les résultats d’un certain nombre d’études écologiques incitent

à penser qu’il existe un lien entre la consommation d’eau fluorée et les

fractures du col du fémur. Ces conclusions ne sont pas confirmées par

d’autres travaux notamment par l’analyse épidémiologique du problème. Dans certains cas, on a même constaté un effet protecteur des

fluorures contre ces fractures.

Deuxétudes permettent d’évaluer le risque de fracture pour toute

une gamme d’apports en fluor. La première a montré que le risque relatif

de fractures de toute nature ainsi que de fracture du col du fémur était

élevé dans des groupes consommant de l’eau dont la teneur en

fluorures était $1,45 mg/litre (apport total $6,5 mg/jour); la différence

atteignait le seuil de signification statistique pour le groupe dont l’eau

de boisson avait une teneur en fluorures $4,32 mg/litre (apport total

14 mg/jour). Dans l’autre étude, on a observé un accroissement de

l’incidence des fractures indépendant de la dose dans un groupe d’âge

constitué de femmes exposées auxfluorures parl’eau qu’elles consommaient.

Selon les études épidémiologiques,rien n’indique que la consommation d’eau fluorée par les femmes enceintes augmente le risque

d’avortement spontané ou de malformations congénitales. D’autres

études épidémiologiques portant sur des travailleurs exposés de par

leur professio n n’ont pas décelé de véritable preuve d’effets génotoxiques ou systémiques au niveau du système respiratoire, des

organes hématopoïétiques, du foie ou du rein qui puisse être

directement attribué à l’exposition aux fluorures en tant que telle.
EHC 227: Fluorides

244

8. Effets sur les autres êtres vivants au laboratoire et

dans leur milieu naturel

La présence de fluorures à la concentration de 100 mg/litre n’a pas

affecté la croissance bactérienne ni la capacité de dégradation de

boues activées mesurée par la demande chimique d’oxygène. La CE50

relative à l’inhibition de la nitrification bactérienne a été trouvée égale

à 1218 mg de fluorures/litre. La CE50 à 96 h relative à la croissance des

algues a été trouvée égale à 123 mg/litre pour les algues d’eau douce

et à 81 mg/litre pour les algues marines. 

Les valeurs de la CL50 à 48 h pour les invertébrés aquatiques vont

de 53 à 304 mg/litre. Les invertébrés d’eau douce les plus sensibles

so nt le sphéridé Musculium transversum avec une mortalité

statistiquement significative (50 %) observée à la concentration de

2,8 mg de fluorures par litre lors d’une étude de 8 semaines, ainsi que

plusieurs phryganes (dulçaquicoles; famille : hydropsychidés) pour

lesquelles les valeurs « sans danger » de la concentration (CE0,01 à

8760 h) vont de 0,2 à 1,2 mg/litre. L’artémia (Artemia salina) a été

l’espèce marine la plus sensible observée. Lors d’un test de 12 jours

avec renouvellement statique de l’eau, on a constaté une réduction

statistiquement significative de la croissance à la concentration de

5,0 mg/litre.

Les valeurs de la CL50 à 96 h pour divers poissons d’eau douce

vont de 51 mg/litre (truite arc-en-ciel, Oncorhynchus mykiss) à

460 mg/litre (épinoche à trois épines, Gasterosteus aculeatus). Dans

tous les tests de toxicité aiguë à 96 h, on a trouvé des valeurs

supérieures à 100 mg/litre pour les poissons de mer. Il existe une

corrélation négative entre la toxicité des fluorures minéraux pour les

poissons d’eau douce et la dureté de l’eau (carbonate de calcium) et

une corrélation positive entre cette toxicité et la température. Les

symptômes d’une intoxication aiguë par les fluorures consistent

notamment en léthargie, mouvements violents et erratiques et mort.

Lors de tests de 20 jours avec renouvellement statique de l’eau, on a

trouvé une CE50 de 2,7 à 4,7 mg/litre pour la truite arc-en-ciel. On estime

que la concentration « sans danger » (CL0,01 à durée infinie) est de 5,1

mg/litre pour la truite arc-en-ciel et de 7,5 mg/litre pour la truite brune

(truite d’Europe, Salmo trutta). A des concentrations $3,2 (effluents)
Résumé et Conclusions

245

ou $3,6 (fluorure de sodium) de fluorure par litre, l’éclosion des oeufs

de la carpe indienne Catla catla a été retardée de 1 à 2 h.

Les études éthologiques effectuées en rivière (eau douce)sur des

saumons coho adultes (Oncorhynchussp.) montrent qu’une modification de la composition chimique des eaux consistant à augmenter la

concentration en fluorures pour la faire passer à 0,5 mg/litre peut avoir

un effet négatif sur la migration; les saumons en migration sont

extrêmement sensibles aux variation de composition chimique de leur

rivière d’origine.Au laboratoire,les fluorures semblent avoir des effets

toxiques sur les processus microbiens à des concentrations qui sont

celles des sols dont la pollution fluorée est modérée; de même, l’accumulation de matières organiques dans les zones situées au voisinage

d’usines de production d’aluminiumest attribuée à une forte inhibition

de l’activité microbienne par les fluorures.

C’est au niveau des jeunes tissus en développement des arbres

feuillus et des aiguilles de conifères en phase d’allongement que l’on

a le plus de chances de constater des signes de phytotoxicité fluorotique (fluorose)tels que chlorose, nécrose et réduction du rythme de

croissance. Le déclenchement de la fluorose a été claireme nt mis en

évidence en laboratoire, en serre ainsi que lors d’essais contrôlés sur

des parcelles expérimentales de ple in champ. Une proportion importante des articles publiés au sujet de la toxicité des fluorures pour les

plantes portent sur la fumigation des serres avec du fluorure d’hydrogène. La nécrose foliaire a été observée pour la première fois sur des

plants de vigne (Vitis vinifera) exposés à des concentrations de 0,17

et 0,27 μg/m3, au bout de 99 et 83 jours respectivement.La dose la plus

faible produisant un effet nécrotique observable (65 % des feuilles)sur

le glaïeul à grandes fleurs (Gladiolus grandiflorus) a été trouvée égale

à 0,35 μg de fluorure par m3. Les fluorures aéroportés peuvent également avoir un effet sur l’apparition des maladies végétales, mais la

nature et l’ampleur de cet effet dépendent du couple plante-germe

pathogène en cause.

Plusieurs études de brève durée portant sur des cultures en

solution nutritive ont permis de déterminer le seuil de toxicité de l’ion

fluor, qui s e situerait dans les limites approximatives de 50 à

2000 μmol/litre. La spécificité toxicologique observée n’est pas

uniquement fonction de l’espèce végétale, elle dépend également de la
EHC 227: Fluorides

246

nature des ions fluor en cause; ainsi, certains fluorures complexes

d’aluminiumprésents dans des cultures en solution nutritive peuvent

s e révéler toxiques à des concentration de 22-357 μmol de fluorure par

litre, alors que le fluorure d’hydrogène est toxique auxconcentrations

de 71-137 μmol/litre. Quelques études ont été consacrées à des cas

d’exposition aux fluorures présents dans le sol. Elles ont permis de

déterminer que la fixation et la toxicité potentielle de ces substances

dépendait beaucoup de la nature du sol.

Dans le cas des oiseaux, on a obtenu une valeur de 50 mg/kg de

poids corporel pour la DL50 à 24 h d’étourneaux sansonnets (Sturnus

vulgaris) âgés de 1 jour et de 17 mg/kg p.c. chez des oisillons de

16 jours. Le taux de croissance a été sensiblement réduit aux doses de

13 et de 17 mg de fluorure par kg p.c.(doses les plus fortes auxquelles

ont a mesuré le taux de croissance). La plupart des premiers travaux

consacrés aux mammifères portent sur les ongulés domestiques. On a

ainsi observé des cas de fluorose chez des bovins et des ovins. La

dose alimentaire la plus faible ayant causé un effet sur des ongulé s

sauvages a été déterminée dans le cadre d’une étude contrôlée sur des

cerfs de Virginie en captivité (Odocoileus virginianus); ils’agissait de

l’apparition de tachetures sur l’ensemble des incisives des animaux à

partir de 35 mg/kg de nourriture.

On a montré que les usines de production d’aluminium, de phosphates et d’engrais, les briquetteries, ainsi que les usines de

production de fibres de verre constituaient toutes des sources de

pollution fluorée et qu’il existait une corrélation entre leur présence et

les dommages constatés sur la végétation du voisinage.L’étude de la

végétation située au voisinage d’une usine de production de

phosphore a montré que l’ampleurdes dommages infligés aux plantes

et la concentration en fluorures dans le sol étaient inversement

proportionnelles à la distance de l’installation . La concentration

moyenne des fluorures allait de 281 mg/kg dans les secteurs où la

végétation était très endommagée, à 44 mg/kg dans les zones où les

dommages étaient moindres; sur le site témoin, la concentration des

fluorures était de 7 mg/kg. Dans des communautés végétales situées

à proximité d’une usine de production d’aluminium, on a constaté des

d ifférences de composition et de structure dues en partie à des

variations dans la tolérance au fluor. Il est toutefois à noter que, dans

la nature, l’un des principaux problèmes qui se posent pour

l’identification des effets de la pollution fluorée tient à la présence

d’autres polluants atmosphériques qui jouent de rôle de variables de
Résumé et Conclusions

247

confusion. La prudence doit donc être de règle lors de l’interprétation

des nombreuses études consacrées à la pollution fluorée dans

l’environnement naturel.

Les premières observations d’effets de la pollution fluorée sur des

mammifères ont été faites dans le cadre d’études de terrain consacrées

à des animaux domestiques tels que les bovins et les ovins. Les

fluorures peuvent passer chez l’animalà partir de la végétation, du sol

et de l’eau qu’il boit. Les niveaux de tolérance pour les animaux

domestiques se situent à 30 mg par kg de nourriture ou à 2,5 mg/litre

d’eau de boisson pour les animaux laitiers. Les incidents dont ont été

victimes des animaux domestiques avaient pour origine soit des

sources naturelles comme les éruptions volcaniques ou la nature

géologique du sol, soit des sources anthropogéniques, telles que

l’administration au bétail de suppléments minéraux ou la présence

d’industries responsables d’émissions de fluorures et de centrales

électriques. Les symptômes constatés consistent en émaciation,

raideur des articulations et anomalies des dents et du squelette. Parmi

les autres effets, on peut citer une baisse de la production de lait et des

effets nocifs sur la capacité de reproduction des animaux. La

concentration alimentaire la plus faible ayant causé une fluorose chez

des cervidés sauvages était égale à 35 mg/kg. Les études consacrées

aux effets du fluor sur la faune sauvage concernent son action sur

l’intégrité de la denture et du squelette. Au voisinage des usines de

production d’aluminium, les effets de la pollution fluorée se traduisent

par de la boiterie et une atteinte lésionnelle des dents.

9. Evaluation des risques pour l’Homme et des effets

sur l’environnement

Les effets des fluorures sur la santé humaine peuvent être positifs

ou négatifs avec un faible écart entre les doses correspondantes. Il

existe une exposition importante à l’ensemble des sources de fluor,

parmi lesquelles les aliments et l’eau de consommation.

On possède peu de données qui permettraient de caractériser les

relations dose-réponse concernant le s divers effets indésirables. En

particulier,les données relatives à l’exposition totale auxfluorures sont

peu nombreuses, notamment concernant l’apport et l’absorption.
EHC 227: Fluorides

248

Les effets les plus graves résultent d’une accumulation de fluor

dans le squelette par suite d’une exposition excessive et de longue

durée et ils s e traduisent par une ostéopathie non maligne, en particulierune fluorose osseuse avec tendance aux fractures.Des données

en provenance de Chine et du sous-continent indien montrent à

l’évidence que la fluorose osseuse et l’augmentation du risque de

fractures s e manifestent lorsque la dose totale de fluor atteint

14 mg/jour et on est fondé à penser que pour un apport fluoré

supérieur à environ 6 mg/jour, le risque de fracture est déjà augmenté.

Dans les eaux douces, la concentration naturelle des fluorures est

généralement inférieure au seuil de toxicité pour les organismes aquatiques. Ces derniers peuvent cependant souffrir de la proximité de

décharges anthropogéniques. La toxicité des fluorures dépend de la

dureté de l’eau.

Il existe un risque pour les espèces végétales sensibles qui

poussent à proximité des sources anthropogéniques de fluorures. La

libération de ces substances dans l’environnement à partir de telles

sources cause des dégâts à la végétation terrestre locale, mais il est

difficile de savoir quelle est la part des seuls fluorures dans ces effets,

car d’autres polluants sont également présents dans l’atmosphère.Les

fluorures sont habituellementfortement adsorbés auxparticules du sol.

Il en résulte que les plantes fixent relativement peu de fluorures par

cette voie et que le lessivage est minime.

La concentration en fluorures dans la végétation au voisinage de

diverses sources d’émission comme les usines de production

d’aluminium, peut être supérieure au seuil de toxicité alimentaire pour

les mammifères déterminé par l’expérimentation animale. On observe

des cas de fluorose parmi les animaux domestiques. Il existe des

régions où l’on signale encore des problèmes de fluorose dans le bétail

à qui l’on donne des suppléments minérauxet une eau de boisson riche

en fluor. En outre, l’utilisation prolongée d’engrais phosphatés contenant des impuretés fluorées fait courir un risque d’intoxication aux

animaux qui broutent dans des pâturages contaminés ou ingèrent de

la terre polluée. Des effets due à une intoxication par le fluor, tels que

boiterie et lésions dentaires, s’observent également chez des mammifères sauvages vivant à proximité de sources d’émission anthropogéniques.
Résumé et Conclusions

249

10. Conclusions

Tous les êtres vivants sont exposés aux fluorures provenant de

s ources naturelles ou anthropogéniques. L’apport en fluor est très

important dans les régions du monde où l’environnement estriche en

cet élément et où l’Homme consomme l’eau de sources souterraines à

forte teneur en fluorures.L’exposition peut être encore plus importante

à proximité de sources d’émission ponctuelles. La fluoration des

produits d’hygiène dentaire constitue pour beaucoup de gens une

source supplémentaire d’exposition.

Les effets des fluorures peuvent être bénéfiques ou indésirables

et l’écart entre les doses correspondantes est étroit.

Des effets sur les dents et les os peuvent s’observer à des doses

inférieures à celles qui produisent des effets indésirables spécifiques

sur d’autres organes ou tissus.

Chez l’Homme, les effets surles os (fluorose osseuse et tendance

aux fracture s) sont considérés comme les plus significatifs pour

l’évaluation des effets indésirables d’une exposition prolongée aux

fluorures.

La fluorose osseuse est une maladie invalidante qui touche des

millions de gens dans diverses régions d’Afrique, de Chine et de l’Inde

et dont les conséquences sanitaires et socio-économiques sont très

importantes.

La principale cause de fluorose osseuse endémique est l’absorption de fluorures présents dans l’eau de boisson et les aliments. Dans

certaines régions, l’utilisation de charbon riche en fluor comme

combustible à l’intérieur des habitations est également une source

importante d’exposition.

On ne possède guère de données à partir desquelles estimer

l’exposition totale aux fluorures ou leur biodisponibilité et les documents relatifs à la caractérisation de leurs effets indésirables contiennent un certain nombre d’incohérences. 
EHC 227: Fluorides

250

Il apparaît clairement, à la lumière des données en provenance de

Chine et du sous-continent indien, que la fluorose osseuse et la

tendance auxfractures s e manifestent pour des doses totales de 14 mg

de fluorure/jour et on est incité à penser qu’à partir d’environ

6 mg/jour, le risque d’atteinte osseuse est d’ores et déjà augmenté.

Une exposition excessive aux fluorures biodisponibles constitue

un risque pour la faune et la flore aquatiques et terrestres.

On peut utiliser les espèces fluoro-sensibles comme sentinelles

pour attirer l’attention sur les dangers dus à la présence de fluorures

dans l’environnement.

Une meilleure connaissance de l’accumulation des fluorures par

les êtres vivants est nécessaire et ilfaut également déterminer comment

surveiller et réduire cette accumulation.

Il convient de mieux caractériser les effets biologiques de

l’exposition aux fluorures.
251

RESUMEN Y CONCLUSIONES

Este documento se centra en la exposición en el medio ambiente

a los fluoruros derivados fundamentalmente de fuentes inorgánicas y

sus efectos en las personas, los animales y otra biota. Contiene datos

sobre el fluoruro de hidrógeno, el fluoruro de calcio, el fluoruro de

sodio, el hexafluoruro de azufre y los silicofluoruros, puesto que s e

considera que estos compuestos son los fluoruros inorgánicos más

importantes, teniendo en cuenta el volumen de las emisiones en el

medio ambiente, las concentraciones en éste y los efectos

toxicológicos en los organismos vivos.

1. Identidad, propiedades físicas y químicas y métodos

analíticos

Elfluoruro de hidrógeno (HF) es un líquido o gas incoloro picante

muy soluble en disolventes orgánicos y en agua, con la que forma

ácido fluorhídrico. El fluoruro de calcio (CaF2) es un sólido incoloro

relativamente insoluble en agua y ácidos y bases diluidos. El fluoruro

de sodio (NaF) es un sólido entre incoloro y blanco moderadamente

soluble en agua. El hexafluoruro de azufre (SF6) es un gas inerte

incoloro e inodoro ligeramente soluble en agua y fácilmente soluble en

etanol y en bases.

El procedimiento más común utilizado para cuantificarla concentración de aniones fluoruro libres es el electrodo selectivo de iones

fluoruro.Se considera que las técnicas de microdifusión son los métodos más exactos de preparación de muestras (es decir, la liberación de

fluoruro iónico a partir de complejos orgánicos e inorgánicos).

2. Fuentes de exposición humana y ambiental

Los fluoruros se liberan en el medio ambiente de manera natural

a través de la meteorización y disolución de minerales, las emisiones de

volcanes y los aerosoles marinos. También se liberan a través de la

combustión del carbón y las aguas industriales y los desechos de

diversos procesos industriales, en particularla fabricación de acero, la

producción primaria de aluminio, de cobre y de níquel, la elaboración

de minerales de fosfato,la producción y uso de fertilizantes fosfatados,
EHC 227: Fluorides

252

la fabricación de vidrio, ladrillos y cerámica y la producción de cola y

adhesivos. La utilización de plaguicidas que contienen fluoruros, así

como la fluoración del abastecimiento de agua potable contribuyen a

la emisión de fluoruros a partir de actividades humanas. Según los

datos disponibles, la obtención y uso de minerales de fluoruro, así

como la fabricación de aluminio, son las principales fuentes industriales de emisiones de fluoruros en el medio ambiente.

Elfluoruro de hidrógeno es un producto industrialimportante que

s e utiliza fundamentalmente en la producción de criolita sintética

(Na3AlF6), trifluoruro de aluminio (AlF3) y los alquilatos y los clorofluorocarburos de la gasolina para motores, con un consumo anual

mundial superior a un millón de toneladas. Se utiliza también en el

tratamiento químico de los dispositivos semiconductores, la limpieza

y el tratamiento químico del vidrio, la limpieza de los ladrillos y del

aluminio y el curtido de pieles, así como en los anticorrosivos comerciales. El fluoruro de calcio se utiliza como fundente en la producción

de acero, vidrio y esmalte, como materia prima para la producción de

ácido fluorhídrico y fluoruro de hidrógeno anhidro y como electrolito

en la producción de aluminio.Elfluoruro de sodio se utiliza en la fluoración controlada del agua de bebida, como conservante en la cola, en

la producción de vidrio y esmalte, como fundente en la producción de

acero y aluminio, como insecticida y como conservante de la madera.

El hexafluoruro de azufre se utiliza ampliamente en diversos

componentes electrónicos y en la producción de magnesio y aluminio.

El ácido hexafluorosilícico (H2SiF6) y el hexafluorosilicato disódico

(Na 2SiF6) s e utilizan para la fluoración de los sistemas de abastecimiento de agua potable.

3. Transporte, distribución y transformación en el

medio ambiente

Los fluoruros s e pueden encontrar en la atmósfera en forma gaseosa o particulada. Los fluoruros atmosféricos pueden recorrer largas

distancias transportados por el viento o por turbulencias atmosféricas,

o eliminarse mediante deposición húmeda y seca o hidrólisis. No cabe

esperar de los compuestos de fluoruro, con la excepción del hexafluoruro de azufre, una permanencia prolongada en la troposfera o su

desplazamiento hacia la estratosfera.El hexafluoruro de azufre tiene un
Resumen y Conclusiones

253

tiempo de permanencia en la atmósfera que oscila entre 500 y varios

miles años.

El transporte y la transformación de los fluoruros en el agua

dependen del pH, la dureza del agua y la presencia de materiales intercambiadores de iones, como la arcilla. Los fluoruros s e suelen transportar a través del ciclo hidrológico formando complejos con el aluminio.

El transporte y la transformación de los fluoruros en el suelo

dependen del pH y de la formación de complejos, sobre todo con el

aluminio y el calcio. La adsorción a la fase sólida del suelo es más

fuerte con un pH ligeramente ácido (5,5-6,5). No es fácil su lixiviación

del suelo.

La absorción de los fluoruros por la biota depende de la vía de

exposición, de su biodisponibilidad y de la cinética de absorción/excreción del organismo. Cierta biota acuática y terrestre bioacumula fluoruros solubles. Sin embargo, no se encontró información relativa a la

bioamplificación de los fluoruros en las cadenas alimentarias acuática

o terrestre.

Las plantas terrestres pueden acumular fluoruros a través de la

deposición de partículas suspendidas en el aire y la absorción del

suelo.

4. Niveles ambientales y exposición humana

Los niveles de fluoruros en las aguas superficiales varían en

función del lugar y de la proximidad a fuentes de emisión. Las concentraciones en aguas superficiales generalmente oscilan entre 0,01 y

0,3 mg/l. El agua marina contiene más fluoruros que el agua dulce, con

concentraciones que van de 1,2 a 1,5 mg/l. Se han registrado niveles

más altos de fluoruros en zonas cuyas rocas naturales los contienen en

una elevada proporción, y s e observan con frecuencia niveles altos de

fluoruros inorgánicos en regiones con actividad geotérmica o

volcánica (p. ej., 25-50 mg/l en fuentes termales y géiseres y hasta

2800 mg/l en ciertos lagos del valle del Rift, en la región oriental de

África). Las descargas de origen humano pueden provocar también un

aumento de su concentración en el medio ambiente.
EHC 227: Fluorides

254

Los fluoruros suspendidos en el aire se encuentran en forma

gaseosa y particulada, procedentes de fuentes tanto naturales como

humanas.Estos fluoruros emitidos como materia gaseosa y particulada

s e suelen depositar en las proximidades de la fuente de emisión,

aunque algunas partículas pueden reaccionar con otros componentes

de la atmósfera. La distribución y deposición de los fluoruros

suspendidos en el aire dependen de la intensidad de la emisión, las

condiciones meteorológicas,eltamaño de las partículas y la reactividad

química. En zonas no situadas en las inmediaciones de las fuentes de

emisión, las concentraciones medias de fluoruros en el aire son

generalmente inferiores a 0,1μg/m3.Los niveles pueden ser ligeramente

más altos en las zonas urbanas que en las rurales;sin embargo, incluso

en las proximidades de las fuentes de emisión los niveles de fluoruros

suspendidos en el aire no suelen sersuperiores a 2-3 μg/m3. En algunas

zonas de China donde se utiliza carbón con un contenido elevado de

fluoruros como fuente de combustible, s e han notificado concentraciones de fluoruros en el aire de hasta 6 μg/m3

.

Los fluoruros forman parte de la mayoría de los tipos de suelos,

con concentraciones totales de entre 20 y 1000 μg/g en zonas sin

depósitos naturales de fosfatos o fluoruros y de hasta varios miles de

μg por gramo en suelos minerales con depósitos de fluoruros. Los

fluoruros gaseosos y particulados suspendidos en el aire tienden a

acumularse en la capa superficial del suelo, pero pueden desplazarse

por toda la rizosfera, incluso en suelos calcáreos. La retención de

fluoruros en el suelo depende fundamentalmente del contenido de

arcilla y carbono orgánico, asícomo del pH delsuelo.Los fluoruros del

suelo están asociados fundamentalmente con su fracción coloidal o

arcillosa. En todos los tipos de suelos, los fluoruros biológicamente

importantes para las plantas y los animales son los solubles.

Los organismos acuáticos pueden absorber fluoruros

directamente del agua o en menormedida a través de los alimentos.Los

fluoruros tienden a acumularse en el exoesqueleto o en el tejido óseo

de los animales acuáticos. Se han registrado concentraciones medias

de fluoruros > 2000 mg/kg en el exoesqueleto del krill; las concentraciones medias de fluoruros en los huesos de mamíferos acuáticos,

como focas y ballenas, oscilan entre 135 y 18 600 mg/kg de peso seco.

Las concentraciones de fluoruros en la biota terrestre son superiores en las zonas con niveles de fluoruros más elevados procedentes
Resumen y Conclusiones

255

de fuentes naturales y humanas. Con frecuencia se han utilizado

líquenes como bioindicadores de fluoruros.En los líquenes que crecían

en un radio de 2-3 km de las fuentes de emisión se determinaron

concentraciones medias de fluoruros de 150-250 mg/kg, en

comparación con un nivel de fondo < 1 mg de fluoruros/kg.

La mayor parte de los fluoruros presentes en el suelo son insolubles y, por consiguiente, están menos disponibles para las plantas.

Sin embargo, factores como una concentración alta de fluoruros en el

suelo o un pH bajo y la presencia de arcilla y/o materia orgánica

pueden aumentar sus niveles en solución, aumentando la absorción a

través de las raíces de las plantas. Si se absorben fluoruros a través de

las raíces, sus concentraciones son con frecuencia más altas en éstas

que en los brotes, debido a su baja movilidad en la planta. La mayor

parte de los fluoruros s e introducen en los tejidos de las plantas en

forma de gases por los estomas y s e acumulan en las hojas. Pueden

entrar en la planta pequeñas cantidades de fluoruros particulados

suspendidos en el aire a través de la epidermis y la cutícula. Se ha

vigilado de cerca la vegetación de las proximida des de fuentes de

emisión de fluoruros de origen humano. Se ha observado una correlación entre la concentración de fluoruros en la vegetación y los incrementos del crecimiento anual, las características del viento, la distancia

de la fuente de fluoruros y la concentración de fluoruro de hidrógeno

en las emisiones aéreas.

Los fluoruros se acumulan en el tejido óseo de los vertebrados

terrestres, en función de factores como la alimentación y la proximidad

de las fuentes de emisión. Por ejemplo, s e han registrado conc entraciones medias de fluoruros de 7000-8000 mg/kg en los huesos de

pequeños mamíferos en las cercanías de una fundición de aluminio.

Los fluoruros son ubicuos en el medio ambiente; por ello, es frecuente que las fuentes de agua de bebida los contengan por lo menos

en pequeñas cantidades.La cantidad de fluoruros presentes de manera

natural en el agua potable no fluorada (es decir, agua de bebida a la

cual no se han añadido deliberadamente fluoruros para prevenir la

caries dental) es muy variable, dependiendo del entorno geológico

concreto de procedencia del agua. Los niveles pueden alcanzar hasta

unos 2,0 mg/l; sin embargo, en las zonas del mundo con fluorosis

endémica del esqueleto y/o los dientes bien documentada, las

concentraciones de fluoruros en la red de abastecimiento de agua

potable van de 3 a más de 20 mg/l. En zonas con agua potable fluorada
EHC 227: Fluorides

256

(es decir, con adición deliberada de fluoruros para la prevención de la

caries dental), la concentración de fluoruros en ella generalmente oscila

entre 0,7 y 1,2 mg/l.

Prácticamente todos los productos alimenticios contienen por lo

menos cantidades ínfimas de fluoruros. Se observan concentraciones

elevadas en los peces. Las hojas de té son particularmente ricas en

ellos; la cantidad en el té en infusión depende de la concentración de

fluoruros solubles en las hojas de té, del nivel de fluoruros en el agua

utilizada en su preparación y del tiempo de permanencia de las hojas en

el agua. La concentración de fluoruros en los productos alimenticios

no aumenta de manera significativa por el uso de fertilizantes

superfosfatados, que contienen concentraciones importantes de fluoruros (1%-3%) como impurezas, en las tierras agrícolas, debido a que el

coeficiente de transferencia del suelo al material de las plantas es

generalmente bajo. Sin embargo, un estudio reciente parece indicar

que, en condiciones apropiadas del suelo y con la aplicación de

suficientes fluoruros como impurezas en los fertilizantes fosfatados,

puede aumentar la absorción de fluoruros por las plantas. El uso de

agua de riego con niveles relativamente bajos (< 3,1 mg/l) de fluoruros

en los cultivos no suele aumentar sus concentraciones en los

productos alimenticios.Sin embargo, esto depende de la especie de la

planta y de las concentraciones de fluoruros en el suelo y el agua. El

nivel de fluoruros en los alimentos depende sobre todo del contenido

de fluoruros del agua utilizada en su preparación o elaboración,sobre

todo en las bebidas y los productos alimenticios secos - por ejemplo,

las preparaciones en polvo para lactantes - a los cuales se añade agua

antes del consumo. Las concentraciones de fluoruros en los alimentos

no lavados o no elaborados en las cercanías de fuentes industriales

(emisiones) de fluoruros pueden ser superiores a las de los mismos

alimentos cultivados en otras zonas no industriales. En las preparaciones infantiles disponibles en el comercio en los Estados Unidos, los

concentrados a base de soja listos para el consumo y líquidos

contenían niveles de fluoruros superiores a los de los productos

lácteos equivalentes; sin embargo, no se observó una diferencia

significativa entre las preparaciones infantiles en polvo a base de soja

y de leche.Se han detectado fluoruros en la leche materna, habiéndose

notificado niveles comprendidos entre < 2 y aproximadamente 100 μg/l,

con la mayoría de los valores situados en el intervalo de 5 a 10 μg/l.
Resumen y Conclusiones

257

Los datos disponibles sobre la concentración de fluoruros en el

aire de espacios cerrados son limitados. En los Países Bajos, las

concentraciones de fluoruros gaseosos eran de < 2 a 49 μg/m3en el aire

del interiorde cinco viviendas construidas con madera tratada con un

conservante que contenía un 56% de fluoruros. En China, se han

notificado concentraciones de hasta 155 μg/m3en muestras de aire

recogido en el interior de viviendas donde s e utilizaba como combustible carbón que contenía concentraciones elevadas de fluoruros.

Los productos dentífricos para adultos presentes en el mercado

de muchos países suelen contener fluoruros en concentraciones

de 1000 a 1500 μg/g; algunos productos infantiles contienen niveles

más bajos, de 250 a 500 μg/g. Se han identificado productos dentales,

por ejemplo pasta de dientes, colutorios y suplementos de fluoruros,

como fuentes importantes de éstos. Los enjuagues bucales

comercializados para uso doméstico cotidiano suelen contener

entre 230 y 500 mg de fluoruros/l, mientras que los colutorios

destinados a un uso semanal o quincenalsuelen contener 900-1000 mg

de fluoruros/l.

Aunque es probable que la exposición individual al fluoruro sea

muy variable, la inhalación de fluoruros suspendidos en el aire

generalmente representa una contribución de escasa importancia a la

ingesta total de esta sustancia. En adultos, la vía principal de ingesta

de fluoruros es el consumo de productos alimenticios y agua de

bebida. En las zonas del mundo en las cuales se utiliza carbón con un

alto contenido de fluoruros en la calefacción y la preparación de los

alimentos, la inhalación del aire interno y el consumo de productos

alimenticios con niveles altos de fluoruros también contribuyen a

aumentar la ingesta. Los lactantes alimentados con preparaciones

reciben 50-100 veces más fluoruros que los que se nutren exclusivamente con leche materna. La ingestión de dentífrico por los niños

pequeños representa una contribución importante a su ingesta total.

En general, la ingesta estimada de fluoruros en niños y adolescentes

no sobrepasa los 2 mg/día.Aunque las personas adultas pueden tener

una ingesta diaria absoluta más alta de fluoruros en mg, la ingesta

diaria de fluoruros por los niños, expresada en mg por kg de peso

corporal, puede ser superior a la de los adultos. Se ha notificado que

en ciertas zonas del mundo en las cuales la concentración de fluoruros

en el ambiente circundante puede ser sumamente alta y/o donde el

régimen alimenticio se basa en productos que los contienen en 
EHC 227: Fluorides

258

abundancia, se estimó una ingesta de fluoruros en adultos de hasta

27 mg/día, siendo la fuente principal el agua de bebida obtenida de

fuentes freáticas situadas en zonas geológicas ricas en fluoruros.

Probablemente s e produce exposición ocupacional a los fluoruros

por inhalación o contacto cutáneo en las personas que trabajan con

equipo de soldadura o en la elaboración del aluminio, el mineral de

hierro o el de fosfato. En estudios relativamente recientes se

no tificaron concentraciones de fluoruros suspendidos en el aire del

cuarto de crisoles de las fundiciones de aluminio del orden de 1 mg/m3.

5. Cinética y metabolismo en el ser humano y en

animales de laboratorio 

En las personas y los animales de laboratorio, el paso de los fluoruros ingeridos a la circulación general se produce fundamentalmente

en el estómago y el intestino y depende de la solubilidad acuosa relativa de la forma consumida. Los fluoruros solubles se absorben casi

completamente del tracto gastrointestin al; sin embargo, el grado de

absorción s e puede verreducido por la formación de complejos con el

aluminio, el fósforo, el magnesio o el calcio. En función de la solubilidad y del tamaño de las partículas,la absorción de los fluoruros gaseosos y particulados del tracto respiratorio puede ser parcial o completa.

Los fluoruros s e distribuyen rápidamente por la circulación sistémica al agua intracelulary extracelularde los tejidos; sin embargo, en

las personas y los animales de laboratorio, los huesos y los dientes

retienen alrededor del 99% de la carga corporal total de fluoruros. En

los dientes y el tejido esquelético, los fluoruros se incorporan al

retículo cristalino.

Los fluoruros atraviesan la placenta y pasan de la madre al feto.

Se eliminan del organismo fundamentalmente en la orina. En los

lactantes,s e retiene alrededor del 80%-90% de la dosis de fluoruros; en

los adultos, la cifra correspondiente es de alrededor del 60%. Estos

valores pueden verse modificados por alteraciones delflujo urinario y

el pH de la orina.

Hay fluoruros presentes en los órganos, los tejidos y los fluidos

del cuerpo. Las concentraciones de fluoruros en la sangre entera de 
Resumen y Conclusiones

259

personas residentes en una comunidad de los Estados Unidos que

recibía agua de bebida fluorada eran de 20 a 60 μg/l. La concentración

media en el plasma de 127 personas con 5,03 mg de fluoruros/l en su

agua de bebida era de 106 ± 76 (SD) μg/l. El suero y el plasma

contienen prácticamente la misma cantidad de fluoruros. Las concentraciones más altas de fluoruros en los tejidos calcificados se suelen

dar en el hueso, la dentina y el esmalte. La concentración de fluoruros

en los huesos varía con la edad, el sexo y el tipo y parte específica de

hueso y s e considera que corresponde a una exposición prolongada de

la persona a los fluoruros.La concentración de fluoruros en el esmalte

dental disminuye exponencialmente con la distancia desde la superficie

y varía en función del lugar, el desgaste superficial, la exposición

sistémica y la exposición a los fluoruros de aplicación externa. La

concentración de fluoruros en los tejidos blandos está relacionada con

la de la sangre. Los niveles de fluoruros en la orina de los individuos

sanos dependen de su ingesta. Se han registrado aumentos de la

concentración de fluoruros en la orina en personas tras la exposición

ocupacional a fluoruros suspendidos en el aire y entre los residentes

en zonas asociadas con fluorosis endémica.

6. Efectos en mamíferos de laboratorio y en sistemas

de ensayo in vitro 

En varios estudios con ratas tratadas con fluoruros por vía oral

durante periodos de tres a cinco semanas s e observaron en el

esqueleto efectos como una inhibición de la mineralización y la

formación de los huesos, retraso en la curación de las fracturas y

reducción del volumen de hueso y la síntesis de colágeno.En estudios

de duración media con ratones tratados con fluoruros en el agua de

bebida (> 4,5 mg/kg de peso corporal al día) durante un periodo de seis

meses s e observó una remodelación alterada de los hues os,

megalocitosis hepática, nefrosis y/o degeneración de los túbulos

seminíferos de los testículos.

En una biovaloración amplia de la carcinogenicidad con grupos

de ratas F344/N y ratones B6C3F1 macho y hembra a los que s e administró en el agua de bebida una concentración de hasta 79 mg de fluoruros/l en forma de fluoruro de sodio durante un periodo de dos años

no se observó un aumento estadísticamente significativo de la

incidencia de tumores en ninguno de los grupos expuestos. Se detectó

una tendencia estadísticamente significativa al aumento de la
EHC 227: Fluorides

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incidencia de osteosarcomas en ratas macho con la exposición

creciente al fluoruro. Sin embargo, la incidencia quedaba dentro del

margen de los testigos históricos.

En otra biovaloración de la carcinogenicidad de dos años con

ratas Sprague-Dawley expuestas a concentraciones de hasta

11,3 mg/kg de peso corporal al día con los alimentos tampoco se

observó un aumento estadísticamente significativo de los

osteosarcomas u otros tumores. Otro estudio, en el que s e notificó un

aumento de la incidencia de osteomas en ratones que recibieron hasta

11,3 mg/kg de peso corporal al día, es difícil de interpretar, porque los

animales estaban infectados por un retrovirus de tipo C.

En general, los fluoruros no son mutagénicos en células procarióticas.Aunque s e ha demostrado que en cultivos de células de linfoma

de ratón y linfoblastoides humanas los fluoruros aumentan la frecuencia de mutaciones en loci específicos, estas mutaciones probablemente

s e deben más al daño cromosómico que a mutaciones puntuales. Se ha

demostrado también que los fluoruros son clastogénicos en diversos

tipos de células. El mecanismo de la clastogenicidad se ha atribuido al

efecto de los fluoruros en la formación de proteínas que intervienen en

la síntesis y/o reparación del ADN, más que a la interacción directa

entre los fluoruros y el ADN. En la mayoría de los estudios en los

cuales se administraron fluoruros por vía oral a roedores, no se observaron efectos en la morfología del esperma o en la frecuencia de

aberraciones cromosómicas, micronúcleos, intercambio de cromátidas

hermanas o rotura de la cadena del ADN. Sin embargo, se notificaron

daños citogenéticos en la médula ósea o alteraciones en la morfología

de las células espermáticas cuando se administraba la sustancia a

roedores por inyección intraperitoneal.

En estudios recientes con animales de laboratorio a los que se

administraba fluoruro en el agua de bebida no s e observaron efectos

reproductivos o en el desarrollo. Sin embargo, se han notificado cambios histopatológicos en los órganos reproductivos de conejos macho

tratados (por vía oral) con 4,5 mg de fluoruros/kg de peso corporal al

día durante 18-29 meses, de ratones macho tratados (por vía oral) con

$ 4,5 mg de fluoruros/kg de peso corporal al día durante 30 días y de

conejos a los que se administraron por inyección subcutánea $ 10 mg

de fluoruros/kg de peso corporal al día durante 100 días. Se han

notificado efectos adversos en la función reproductiva de ratones

hembra tratados (por vía oral) con $ 5,2 mg de fluoruros/kg de peso
Resumen y Conclusiones

261

corp oral al día durante los días 6-15 después del apareamiento y de

conejos macho tratados (por vía oral) con $ 9,1 mg de fluoruros/kg de

peso corporal al día durante 30 días.

7. Efectos en el ser humano

En las investigaciones epidemiológicas sobre los efectos de los

fluoruros en la salud humana s e han examinado trabajadores expuestos

en el lugar de trabajo empleados fundamentalmente en la industria de

la fundición del aluminio y poblaciones consumidoras de agua potable

fluorada. En algunos estudios epidemiológicos analíticos de trabajadores expuestos en el lugar de trabajo a fluoruros,s e ha detectado una

mayor incidencia de cáncer de pulmón y de vejiga y un aumento de la

mortalidad debida al cáncer de estos y otros órganos. En general, sin

embargo, no s e ha observado una pauta uniforme; en algunos de estos

estudios epidemiológicos, el aumento de la morbilidad o la mortalidad

debidas al cáncer se puede atribuir a la exposición de los trabajadores

a sustancias distintas de los fluoruros.

Se ha examinado en un gran número de estudios epidemiológicos

realizados en numerosos países la relación entre el consumo de agua

potable fluorada y la morbilidad o la mortalidad por cáncer. No hay

pruebas convincentes de una asociación entre el consumo de agua

potable fluorada controlada y el aumento de la morbilidad o la mortalidad por cáncer.

Los fluoruros tienen efectos tanto beneficiosos como

perjudiciales en el esmalte dental. La prevalencia de la caries dental es

inversamente proporcional a la concentración de fluoruros en el agua

potable. La prevalencia de la fluorosis crónica está muy asociada con

la concentració n de fluoruros, con una relación dosis-respuesta

positiva.

Se siguen notificando casos de fluorosis esquelética asociada con

el consumo de agua potable que contiene niveles elevados de

fluoruros. Se considera que algunos factores, como el estado

nutricional y el régimen alimenticio, el clima (en relación con el

consumo de líquidos), la exposición simultánea a otras sustancias y la

ingesta de fluoruros de fuentes distintas del agua de bebida,

desempeñan una función importante en la aparición de esta

enfermedad. La fluorosis esquelética puede aparecer en trabajadores
EHC 227: Fluorides

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ocupacionalmente expuestos a concentraciones elevadas de fluoruros

suspendidos en el aire; sin embargo, sólo se ha encontrado

información nueva limitada.

Algunas pruebas obtenidas en varios estudio s ecológicos

parecen indicar que podría haber una asociación entre el consumo de

agua fluorada y las fracturas de cadera. Sin embargo, otros estudios,

incluidas algunas investigaciones epidemiológicas, no respaldan esta

conclusión. En algunos casos se ha notificado un efecto protector de

los fluoruros en las fracturas.

Hay dos estudios que permiten evaluar el riesgo de fractura teniendo en cuenta una serie de ingestas de fluoruros. En un estudio, los

riesgos relativos de todas las fracturas y de la fractura de cadera eran

elevados en los grupos que utilizaban agua de bebida con $ 1,45 mg

de fluoruros/l (ingesta total $ 6,5 mg/día); esta diferencia alcanzó

significación estadística para el grupo expuesto al agua de bebida con

$ 4,32 mg de fluoruros/l (ingesta total, 14 mg/día). En el otro estudio s e

observó un aumento no dependiente de la dosis de la incidencia de

fracturas en un grupo de edad de mujeres expuestas a fluoruros en el

agua de bebida.

Según los estudios epidemiológicos, no hay pruebas de una

asociación entre el consumo de agua de bebida fluorada por las madres

y el aumento delriesgo de aborto espontáneo o malformación congénita. Otras investigaciones epidemiológicas de trabajadores expuestos

en el lugar de trabajo no han proporcionado pruebas razonables de

efectos genotóxicos o efectos sistémicos en los sistemas respiratorio,

hematopoyético, hepático o renal que puedan ser directamente atribuibles a la exposición en sí a los fluoruros.

8. Efectos en otros organismos en el laboratorio y en el

medio ambiente

Elfluoruro no afectó al crecimiento o a la capacidad de reducción

de la demanda química de oxígeno de los lodos activados a concentraciones de 100 mg/l. La CE50 para la inhibición de la tasa de nitrificación

bacteriana fue de 1218 mg de fluoruros/l. La CE50 a las 96 horas, basada

en el crecimiento, para algas de agua dulce y marinas fue de 123 y 81

mg de fluoruros/l, respectivamente.
Resumen y Conclusiones

263

La CL50 a las 48 horas para invertebrados acuáticos fue del orden

de 53 a 304 mg/l. Los invertebrados de agua dulce más sensibles fueron

Musculium transversum, habiéndose observ ado una mortalidad

estadísticamente significativa (50%) a una concentración de 2,8 mg de

fluoruros/l en un experimento de flujo continuo de ocho semanas, y

varias especies de insectos de agua dulce de la familia

Hydropsychidae, con «concentraciones inocuas» (CE0,01 a las

8760 horas) del orden de 0,2 a 1,2 mg de fluoruros/l. La especie marina

más sensible sometida a prueba fue la artemia (Artemia salina). En una

prueba estática con renovación de 12 días,s e produjo un trastorno del

crecimiento estadísticamente significativo con 5,0 mg de fluoruros/l.

La CL50 a las 96 horas para los peces de agua dulce osciló entre

51 mg/l(trucha arco iris, Oncorhynchus mykiss) y 460 mg/l (espinoso,

Gasterosteus aculeatus). Todas las pruebas de toxicidad aguda

(96 horas) en peces marinos dieron resultados superiores a 100 mg/l. La

toxicidad del fluoruro inorgánico para los peces de agua dulce parece

tener una correlación negativa con la dureza del agua (carbonato de

calcio)y positiva con la temperatura.Entre los síntomas de intoxicación

aguda por fluoruros cabe mencionar elletargo, elmovimiento violento

e incierto y la muerte.En pruebas estáticas con renovación la CL50 a los

20 días para la trucha arco iris osciló entre 2,7 y 4,7 mg de fluoruros/l.

Se han estimado «concentraciones inocuas» (CL0,01 en un número

indeterminado de horas) para la trucha arco iris y el reo (Salmo trutta)

de 5,1 y 7,5 mg de fluoruros/l, respectivamente. A concentraciones

$ 3,2 (efluente) o $ 3,6 (fluoruro de sodio) mg de fluoruros/l, la

eclosión de los huevos del pez catla (Catla catla)se retrasó 1-2 horas.

Los experimentos sobre comportamiento realizados en el salmón

del Pacífico adulto (Oncorhynchus sp.) en ríos de aguas blandas indican que los cambios en la química del agua, debido a un aumento de la

concentración de fluoruros hasta 0,5mg/l,puede afectar negativamente

a la migració n; durante la migración los salmones son enormemente

sensibles a los cambios de la química del agua de sus ríos de origen.En

estudios de laboratorio, los fluoruros parecen ser tóxicos para los

procesos microbianos a concentraciones presentes en suelos

moderadamente contaminados con fluoruros; análogamente,la acumulación de materia orgánica sobre el terreno en las cercanías de fundiciones s e ha atribuido a una inhibición grave de la actividad microbiana

por esta sustancia.
EHC 227: Fluorides

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Los signos de fitotoxicidad de los fluoruros inorgánicos (fluorosis) como la clorosis, la necrosis y la disminución de la tasa de

crecimiento es más probable que se produzcan en los tejidos jóvenes

en expansión de las plantas latifolias y las agujas en fase de alargamiento de las coníferas. La inducción de fluorosis s e ha demostrado

claramente en experimentosrealizados en laboratorios, en invernaderos

y en parcelas de terreno controladas. Se han publicado numerosos

estudios sobre la toxicidad de los fluoruros para las plantas en relación

con la fumigación de los invernaderos con fluoruro de hidrógeno. Se

observó por primera vez necrosis foliar en vides (Vitis vinifera)

expuestas a 0,17 y 0,27 μg/m3a los 99 y los 83 días, respectivamente. El

nivelmás bajo con efectos observados para la necrosis foliar (65% de

las hojas) en el gladiolo (Gladiolus grandiflorus) fue de 0,35 μg de

fluoruros/m3. Los fluoruros suspendidos en el aire pueden afectar

también al desarrollo de la enfermedad de la planta, aunque eltipo y la

magnitud de los efectos dependen de la combinación específica plantapatógeno.

En varios estudios breves de cultivos en solución s e ha determinado un umbral tóxico para la actividad del ión fluoruro que oscila

entre alrededor de 50 y 2000 μmoles de fluoruro/l. La toxicidad es

específica no sólo para las especies de plantas, sino también para las

especies iónicas de flu oruro; algunos complejos de fluoruro de aluminio presentes en cultivos en solución pueden ser tóxicos con actividades de 22-357 μmoles de fluoruro/l, mientras que el fluoruro de

hidrógeno es tóxico con actividades de 71-137 μmoles de fluoruro/l. Se

ha realizado un pequeño número de estudios sobre la exposición a los

fluoruros a través del suelo. El tipo de suelo puede afectar enormemente a la absorción y la posible toxicidad de los fluoruros. 

En las aves, la DL50 en 24 horas fue de 50 mg/kg de peso corporal

para las crías de un día de estornino (Sturnus vulgaris) y de 17 mg/kg

de peso corporal para los pajaritos de 16 días.Las tasas de crecimiento

registraron una reducción significativa con 13 y 17 mg de fluoruros/kg

de peso corporal (las dosis más altas a las cuales se vigiló el crecimiento). Gran parte del trabajo inicial sobre mamíferos se realizó en

ungulados domesticados. Se ha observado fluorosis en el gana do

bovino y ovino. La concentración más baja con los alimentos con

efecto en los ungulados salvajes se obtuvo en un estudio controlado

en cautividad con el venado de cola blanca (Odocoileus virginianus),

en el cual s e observó un moteado general de los incisivos
Resumen y Conclusiones

265

característico de la fluorosis dental con la dosis de 35 mg/kg de

alimentos.

Se ha demostrado que las fundiciones de aluminio, las fábricas de

ladrillos,las fábricas de fósforo y las instalaciones de fertilizantes y de

fibra de vidrio son fuentes de fluoruros que están en correlación con

el daño a las comunidades de plantas locales. En la vegetación en las

proximidades de una fábrica de fósforo s e observó que el grado del

daño y las concentraciones de fluoruros en el humus del suelo eran

inversamente proporcionales a la distancia de la fábrica.El promedio de

las concentraciones de fluoruros en la vegetación oscilaba entre

281 mg/kg en las zonas gravemente dañadas y 44 mg/kg en las zonas

menos dañadas; en una zona testigo, la concentración de fluoruro fue

de 7 mg/kg. Las comunidades de plantas en las cercanías de una

fundición de aluminio mostraban diferencias en la composición y

estructura de la comunidad debido en parte a variaciones en la

tolerancia a los fluoruros.Sin embargo, hay que señalar que uno de los

principales problemas con la identificación de los efectos de los

fluoruros en la naturaleza es la presencia de variables confundidoras,

como porejemplo otros contaminantes atmosféricos.Por consiguiente,

se ha de actuar con prudencia a la hora de interpretar los numerosos

estudios sobre el terreno relativos a la contaminación por fluoruros.

Las conclusiones iniciales de los efectos de los fluoruros en los

mamíferos procedían de estudios sobre animales domésticos, como el

ganado ovino y bovino. Los fluoruros se pueden recibir de la vegetación, el suelo y el agua de bebida. Se han determinado los niveles de

tolerancia para los animales domesticados, siendo los niveles más

bajos para las vacas lecheras de 30 mg/kg de pienso o 2,5 mg/l de agua

de bebida. Se han producido incidentes que afectaban a animales

domesticados tanto a causa de fuentes naturales de fluoruros, como

las erupciones volcánicas y la geología subyacente, como porfuentes

de origen humano, por ejemplo los suplementos minerales, las

industrias emisoras de fluoruro y las centrales eléctricas. Entre los

síntomas de la toxicidad por fluoruros cabe mencionar la emaciación,

la rigidezde las articulaciones y anomalías en dientes y huesos. Otros

efectos son una reducción de la producción de leche y efectos

negativos en la capacidad reproductiva de los animales. La

c oncentración más baja de fluoruros en los alimentos que provocó

fluorosis en el ciervo salvaje fue de 35 mg/kg. Las investigaciones

acerca de los efectos de los fluoruros en la flora y fauna silvestres se

han concentrado en las repercusiones sobre la integridad estructural
EHC 227: Fluorides

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de los dientes y los huesos. En las proximidades de las fundiciones se

han observado efectos inducidos por los fluoruros, por ejemplo cojera,

afeamiento dental y daños en los dientes.

9. Evaluación del riesgo para la salud humana y de los

efectos en el medio ambiente

Los fluoruros tienen efectos tanto positivos como negativos para

la salud humana, pero elmargen entre las ingestas asociadas con estos

efectos es reducido.Es importante la exposición a todas las fuentes de

fluoruros, en particular el agua de bebida y los productos alimenticios.

Se dispone de poca información para caracterizarla relación dosisrespuesta relativa a los distintos efectos adversos. Son escasos, sobre

todo, los datos acerca de la exposición total, en particular la ingesta y

la absorción de fluoruros.

El efecto más grave es la acumulación esquelética de fluoruros

debida a una exposición excesiva prolongada y sus efectos en las

enfermedades óseas no neoplásicas, en particular la fluorosis esquelética y las fracturas óseas. Hay pruebas claras obtenidas en la India y

en China de que una ingesta total de 14 mg de fluoruros/día provoca

fluorosis esquelética y un aumento del riesgo de fracturas óseas y

otras pruebas hacen pensar en un mayor riesgo de efectos óseos con

una ingesta total superior a unos 6 mg de fluoruros/día.

En el entorno de agua dulce, las concentraciones de fluoruros

naturales suelen ser inferiores a las supuestamente tóxicas para los

organismos acuáticos. Sin embargo, estos organismos podrían verse

afectados negativamente en las proximidades de descargas de origen

humano. La toxicidad de los fluoruros depende de la dureza del agua.

Las especies de plantas sensibles que crecen cerca de fuentes de

fluoruros de origen humano están expuestas a riesgos. La emisión de

fluoruro de fuentes humanas está asociada con daños para las

comunidades de plantas terrestres locales, pero con frecuencia es

difícil atribuir estos efectos exclusivamente a los fluoruros, debido a la

presencia de otros contaminantes atmosféricos. Los suelo s suelen

adsorberfuertemente los fluoruros.En consecuencia, la absorción por
Resumen y Conclusiones

267

las plantas mediante esta vía es relativamente baja y la lixiviación de los

fluoruros a través del suelo mínima.

Las concentraciones de fluoruros en la vegetació n cercana a

fuentes de emisión, como las fundiciones de aluminio, pueden ser

superiores a la concentración más baja con efecto por vía alimentaria

notificada para los mamíferos en experimentos de laboratorio. Se ha

notificado fluorosis en animales domesticados. Todavía hay algunas

zonas que notifican incidentes de fluorosis en el ganado bovino

debido al consumo de suplementos minerales y agua de bebida con un

contenido elevado de fluoruros. Además, existe un posible riesgo de

ingestión de pastos y suelo contaminados por fluoruros debido al uso

prolongado de fertilizantes fosfatados que contienen fluoruros como

impureza.Se han notificado efectos inducidos porlos fluoruros, como

cojera y daños en los dientes, en mamíferos salvajes de las cercanías

de fuentes humanas.

10. Conclusiones

Todos los organismos están expuestos a fluoruros de fuentes

naturales y/o humanas. Se han observado ingestas muy elevadas en

zonas de todo el mundo donde abundan los fluoruros en la naturaleza

y donde las personas utilizan agua freática con un contenido elevado

de fluoruros como agua de bebida. Podría haber una mayor exposición

en las cercanías de fuentes puntuales. Los fluoruros de los productos

dentales son una fuente adicional para muchas personas.

Los fluoruros tienen efectos tanto beneficiosos como

perjudiciales en la salud humana, con un margen de ingesta reducido

entre ambos.

Se pueden observar efectos en los dientes y en el esqueleto con

exposiciones inferiores a las asociadas con la aparición de otros

efectos adversos para la salud específicos de órganos o tejidos.

Se considera que los efectos en los huesos (por ejemplo, la

fluorosis esquelética y las fracturas) son los resultados más

importantes en la evaluación de los efectos adversos de la exposición

prolongada de las personas a los fluoruros.
EHC 227: Fluorides

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La fluorosis esquelética es una discapacidad invalidante que

afecta a millones de personas en diversas regiones de África, China y

la India, con repercusiones importantes para la salud pública y socioeconómicas.

La ingestión de fluoruros con el agua y los productos alimenticios

es el factor causal primordial de la fluorosis esquelética endémica. En

algunas regiones, la combustión en recintos cerrados de carbón con un

contenido elevado de fluoruros puede contribuir asimismo como una

fuente importante.

Hay pocos datos para estimar la exposición total a los fluoruros

y su biodisponibilidad, y s e han detectado contradicciones en los

informes sobre la caracterización de sus efectos adversos.

Hay pruebas convincentes obtenidas en la India y en China de

que una ingesta total de 14 mg de fluoruros/día produce fluorosis

esquelética y un mayor riesgo de fracturas óseas, y pruebas que

parecen indicar un mayorriesgo de efectos óseos con ingestas totales

superiores a unos 6 mg de fluoruros/día.

Una exposición excesiva a fluoruros biodisponibles representa un

riesgo para la biota acuática y terrestre.

Se pueden utilizar especies sensibles a los flu oruros como

indicadores a fin de identificar sus peligros para el medio ambiente.

Es necesario mejorar los conocimientos sobre la acumulación de

fluoruros en los organismos y sobre su vigilancia y control.

Se deben caracterizar mejorlos efectos biológicos asociados con

la exposición a los fluoruros.