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    INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY 


    ENVIRONMENTAL HEALTH CRITERIA 36






    FLUORINE AND FLUORIDES











    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 Organisation, or the World Health Organization.

    Published under the joint sponsorship of
    the United Nations Environment Programme,
    the International Labour Organisation,
    and the World Health Organization

    World Health Orgnization
    Geneva, 1984


         The International Programme on Chemical Safety (IPCS) is a
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CONTENTS

ENVIRONMENTAL HEALTH CRITERIA FOR FLUORINE AND FLUORIDES

PREFACE

1. SUMMARY AND RECOMMENDATIONS FOR FURTHER RESEARCH

    1.1. Summary
         1.1.1. Analytical methods
         1.1.2. Sources and magnitude of exposure
         1.1.3. Chemobiokinetics and metabolism
         1.1.4. Effect of fluoride on plants and animals
         1.1.5. Beneficial effects on human beings
         1.1.6. Toxic effects on human beings
    1.2. Recommendations for further research

2. PROPERTIES AND ANALYTICAL METHODS

    2.1. Chemical and physical properties of fluorine
         and its compounds
         2.1.1. Fluorine
         2.1.2. Hydrogen fluoride
         2.1.3. Sodium fluoride and other alkali fluorides
         2.1.4. Fluorspar, cryolite, and fluorapatite
         2.1.5. Silicon tetrafluoride, fluorosilicic
                  acid, and fluorosilicates
         2.1.6. Sodium monoflurophosphate
         2.1.7. Organic fluorides
    2.2. Determination of fluorine
         2.2.1. Sampling and sample preparation
                2.2.1.1  Air
                2.2.1.2  Soil and rocks
                2.2.1.3  Water
                2.2.1.4  Animal tissues
                2.2.1.5  Plants
         2.2.2. Separation and determination of fluoride
                2.2.2.1  Colorimetric methods
                2.2.2.2  The fluoride selective electrode
                2.2.2.3  Other methods

3. FLUORIDE IN THE HUMAN ENVIRONMENT

    3.1. Fluoride in rocks and soil
    3.2. Fluoride in water
    3.3. Airborne fluoride
    3.4. Fluoride in food and beverages
    3.5. Total human intake of fluoride

4. CHEMOBIOKINETICS AND METABOLISM

    4.1. Absorption
    4.2. Retention and distribution
         4.2.1. The fluoride balance
         4.2.2. Blood
         4.2.3. Bone
         4.2.4. Teeth
         4.2.5. Soft tissues
    4.3. Excretion
         4.3.1. Urine
         4.3.2. Faeces
         4.3.3. Sweat
         4.3.4. Saliva
         4.3.5. Milk
         4.3.6. Transplacental transfer
    4.4. Indicator media

5. EFFECTS ON PLANTS AND ANIMALS

    5.1. Plants
    5.2. Insects
    5.3. Aquatic animals
    5.4. Birds
         5.4.1. Acute effects
         5.4.2. Chronic effects
    5.5. Mammals
         5.5.1. Acute effects
                5.5.1.1  Exposure to sodium fluoride
                5.5.1.2  Exposure to fluorine, hydrogen
                         fluoride, or silicon tetrafluoride
         5.5.2. Chronic effects on small laboratory  animals
         5.5.3. Chronic effects on livestock
    5.6. Genotoxicity and carcinogenicity
         5.6.1. Genetic effects and other related end
                points in short-term tests
         5.6.2. Carcinogenicity in experimental
                animals
    5.7. Experimental caries
    5.8. Possible essential functions of fluorides

6. BENEFICIAL EFFECTS ON HUMAN BEINGS

    6.1. Effects of fluoride in drinking-water
    6.2. Cariostatic mechanisms
    6.3. Fluoride in caries prevention
         6.3.1. Fluoridated salt (NaCl)
         6.3.2. Fluoridated milk
         6.3.3. Fluoride tablets
         6.3.4. Topical application of fluorides
    6.4. Treatment of osteoporosis

7. TOXIC EFFECTS ON HUMAN BEINGS

    7.1. Acute toxic effects of fluoride salts
    7.2. Caustic effects of fluorine and hydrogen fluoride
    7.3. Chronic toxicity
         7.3.1. Occupational skeletal fluorosis
         7.3.2. Endemic skeletal fluorosis
         7.3.3. Dental fluorosis
         7.3.4. Effects on kidneys
    7.4. Carcinogenicity
    7.5. Teratogenicity
    7.6. Effects on mortality patterns
    7.7. Allergy, hypersensitivity, and dermatological reactions
    7.8. Biochemical effects

8. EVALUATION OF SIGNIFICANCE OF FLUORIDES IN THE ENVIRONMENT

    8.1. Relative contribution from air, food, and
         water to total human intake
    8.2. Doses necessary for beneficial effects in man
    8.3. Toxic effects in man in relation to exposure
         8.3.1. Dental fluorosis
         8.3.2. Skeletal fluorosis
         8.3.3. Other effects
    8.4. Effects on plants and animals
         8.4.1. Plants
         8.4.2. Animals

REFERENCES

IPCS TASK GROUP ON ENVIRONMENTAL HEALTH CRITERIA FOR FLUORINE
AND FLUORIDES

 Members

Dr F. Berglund, Department of Medical Research, KabiVitrum
   Pharmaceuticals, Stockholm, Sweden

Dr A.W. Davison, Department of Plant Biology, The University,
   Newcastle-Upon-Tyne, United Kingdom  (Rapporteur)

Professor C.O. Enwonwu, National Institute for Medical
   Research, Yaba, Lagos, Nigeria

Professor W. Künzel, Stomatology Section, Erfurt Academy of
   Medicine, Democratic Republic of Germany

Mr F. Murray, Department of Biological Sciences, University of
   Newcastle, New South Wales, Australia

Professor M.H. Noweir, Occupational Health Department, High
   Institute of Public Health, Alexandria, Egypt  (Chairman)

Dr P. Phantumvanit, Faculty of Dentistry, Chulalongkorn
   University, Bangkok, Thailand

Dr R.G. Schamschula, WHO Collaborative Unit for Caries and
   Periodontal Disease Research, Institute of Dental
   Research, Sydney, Australia

Professor Dr Ch. Schlatter, Swiss Federal Institute of
   Technology and University of Zurich, Institute of
   Toxicology, Schwerzenbach, Switzerland

Dr D.R. Taves, Department of Radiation Biology and
   Biophysics, University of Rochester School of Medicine,
   Rochester, New York, USAa

 Representatives of Non-Governmental Organization             
                                                             
Professor M. Lob, Permanent Commission and International     
   Organization on Occupational Health (PCIAOH)              
                                                             
 Secretariat                                                  
                                                             
Professor P. Grandjean, Department of Environmental Medicine,
   Odense University, Odense, Denmark  (Temporary Adviser)    
                                                             
Dr D.E. Barmes, Oral Health, World Health Organization,      
   Geneva, Switzerland                                       
                                                             
---------------------------------------------------------------------------
a  Invited, but could not attend.

 Secretariat (contd.)
                                                             
Professor M. Guillemin, Institut de Médecine du Travail et   
   d'Hygične industrielle, University of Lausanne, Le        
   Mont-sur-Lausanne, Switzerland                            

Professor F. Valic, International Programme on Chemical
   Safety, World, Health Organization, Geneva, Switzerland
    (Secretary)


NOTE TO READERS OF THE CRITERIA DOCUMENTS                     
                                                              
    While every effort has been made to present information in the 
criteria documents as accurately as possible without unduly 
delaying their publication, mistakes might have occurred and are 
likely to occur in the future.  In the interest of all users of the 
environmental health criteria documents, readers are kindly 
requested to communicate any errors found to the Manager of the 
International Programme on Chemical Safety, World Health 
Organization, Geneva, Switzerland, in order that they may be 
included in corrigenda, which will appear in subsequent volumes.
                                                              
    In addition, experts in any particular field dealt with in the 
criteria documents are kindly requested to make available to the 
WHO Secretariat any important published information that may have 
inadvertently been omitted and which may change the evaluation of 
health risks from exposure to the environmental agent under 
examination, so that the information may be considered in the event 
of updating and re-evaluation of the conclusions contained in the 
criteria documents.       

                        *  *  *

     A detailed data profile and a legal file can be obtained from 
the International Register of Potentially Toxic Chemicals, Palais
des nations, 1211 Geneva 10, Switzerland (Telephone no. 988400 -
985850).

ENVIRONMENTAL HEALTH CRITERIA FOR FLUORINE AND FLUORIDES

    Further to the recommendations of the Stockholm United Nations 
Conference on the Human Environment in 1972, and in response to a 
number of World Health Assembly resolutions (WHA 23.60, WHA 24.47, 
WHA 25.58, WHA 26.68) and the recommendation of the Governing 
Council of the United Nations Environment Programme (UNEP/GC/10, 
July 3 1973), a programme on the integrated assessment of the 
health effects of environmental pollution was initiated in 1973.  
The programme, known as the WHO Environmental Health Criteria 
Programme, has been implemented with the support of the Environment 
Fund of the United Nations Environment Programme.  In 1980, the 
Environmental Health Criteria Programme was incorporated into the 
International Programme on Chemical Safety (IPCS).  The result of 
the Environmental Health Criteria Programme is a series of criteria 
documents. 

    The first, second, and final drafts of the Environmental Health 
Criteria Document on Fluorine and Fluorides were prepared by Dr 
B.D. Dinman of the USA, Dr P. Torell of Sweden, and Professor R. 
Lauwerys of Belgium. 

    The Task Group for the Environmental Health Criteria for 
Fluorine and Fluorides met in Geneva from 28 February to 5 March, 
1984.  The meeting was opened by Dr M. Mercier, Manager, 
International Programme on Chemical Safety, who welcomed the 
participants on behalf of the three co-sponsoring organizations of 
the IPCS (UNEP/ILO/WHO).  The Task Group reviewed and revised the 
final draft criteria document and made an evaluation of the health 
risks of exposure to fluorine and fluorides. 

    The efforts of all who helped in the preparation and the 
finalization of the document are gratefully acknowledged. 


                        * * *


    Partial financial support for the publication of this criteria 
document was kindly provided by the United States Department of 
Health and Human Services, through a contract from the National 
Institute of Environmental Health Sciences, Research Triangle Park, 
North Carolina, USA - a WHO Collaborating Centre for Environmental 
Health Effects. 


PREFACE

    In contrast with most compounds treated earlier in this series, 
fluorine and fluorides encompass both beneficial and toxic effects, 
each of which have extremely important public health implications. 

    Fluoride illustrates strikingly the classical medical concept 
that the effect of a substance depends on the dose.  As Paracelsus 
said, "All substances are poisons; there is none  which is not a 
poison.  The right dose differentiates a poison and remedy".  While 
a continuous daily intake of milligrams per day of fluoride has 
been found to be beneficial in the prevention of caries, long-term 
exposure to higher quantities may have deleterious effects on 
enamel and bone, and single, gram doses cause acute toxic effects 
or may even be lethal. 


1.  SUMMARY AND RECOMMENDATIONS FOR FURTHER RESEARCH

1.1.  Summary

1.1.1.  Analytical methods

    The measurement of fluoride in inorganic and organic materials 
includes sample collection, preparation, and determination.  
Preparation usually involves one or more of the following stages: 
washing, drying, ashing, fusion, acid extraction, distillation, or 
diffusion.  Ashing and fusion may be necessary to oxidize organic 
matrices and to release fluoride from refractory compounds, 
respectively.  Separation is used to avoid interference or as a 
means of concentration. Many methods are available for the 
determination of fluoride in suitably prepared samples.  The most 
widely used involve colorimetry or the fluoride specific ion 
electrode; several methods have specialized application.  The ion 
electrode method is more popular than other methods because it 
offers speed and relative freedom from interference; in some 
circumstances, separation may not be necessary.  Variation in 
reported concentrations of fluoride in the same media, and the 
results of inter-laboratory collaborative trials involving all 
methods of determination indicate that frequently accuracy and 
precision are limited by poor quality control rather than by the 
method. 

1.1.2.  Sources and magnitude of exposure

    Because it is so reactive, fluorine rarely, if ever, occurs 
naturally in the elementary state, existing instead in the ionic 
form or as a variety of inorganic and organic fluorides.  Rocks, 
soil, water, air, plants, and animals all contain fluoride in 
widely-varying concentrations.  As a result of this variation, the 
sources and their relative importance for human beings also vary.  
Fluoride enters the body by ingestion and inhalation, and, in 
extreme cases of acute exposure, through the skin.  Not all of the 
fluoride that is ingested or inhaled is absorbed, and a proportion 
is excreted by various means.  Intake is lowest in rural 
communities in which there are no fluoride-rich soils or waters, 
and no exposure to industrial, agricultural, dental, or medical 
sources.  Fluoridation of water for the prevention of caries may 
result in this being the largest source, if there is no exposure to 
other man-made sources, such as industrial emissions.  Consumption 
of high-fluoride foods such as tea or some fish dishes may increase 
intake significantly.  The use of fluorides or fluoride-containing 
materials in industry leads not only to an increase in occupational 
exposure but also, in some cases, to increased general population 
exposure.  Significant occupational exposure occurs where control 
technology is old or outmoded.  However, more significant than the 
preceding sources are deposits of high-fluoride rocks that in some 
areas cause a large increase in the fluoride content of water or 
food.  There are many parts of the world where this exposure to 
fluoride is sufficiently high to cause endemic fluorosis. 

1.1.3.  Chemobiokinetics and metabolism

    A large proportion of the ingested and inhaled fluorides is 
rapidly absorbed through the gastrointestinal tract and through the 
lungs, respectively.  Absorbed fluoride is carried by the blood and 
is excreted via the renal system or taken up by the calcified 
tissues.  Most of the fluoride bound in the skeleton and teeth has 
a biological half-life of several years.  The concentration of 
fluoride in the calcified tissues is a function of exposure and 
age.  No significant accumulation occurs in the soft tissues.  
Renal excretion appears to be based on glomerular filtration 
followed by a variable tubular reabsorption, which is higher at low 
pH and low urinary flow rates.  Fluoride passes through the 
placenta and occurs in low concentrations in saliva, sweat, and 
milk. 

1.1.4.  Effects of fluoride on plants and animals

    (a)  Plants

    Uptake of fluoride in plants mainly occurs through the roots 
from the soil, and through the leaves from the air.  Fluoride may 
induce changes in metabolism, decreased growth and yield, leaf 
chlorosis or necrosis, and in extreme cases, plant death.  
Considerable differences exist in plant sensitivity to atmospheric 
fluoride, but little or no injury will occur when the most 
sensitive species are exposed to about 0.2 µg/m3 air, and many 
species tolerate concentrations many times higher than this. 

    (b)  Animals

    Plants are a source of dietary fluoride for animals and human 
beings.  Thus, elevation of plant fluoride many lead to a 
significant increase in animal exposure.  Chronic toxicity has been 
studied in livestock, which usually develop skeletal and dental 
fluorosis.  Experimentally-induced chronic toxicity in rodents is 
also associated with nephrotoxicity.  Symptoms of acute toxicity 
are generally non-specific.  Fluoride does not appear to induce 
direct mutagenic effects, but at high concentrations it may alter 
the response to mutagens. 

1.1.5.  Beneficial effects on human beings

    With exposure to optimal levels of fluoride in the drinking-
water (0.7 - 1.2 mg/litre, depending on climatic conditions), there 
is a clearly demonstrated cariostatic effect.  The extent of caries 
reduction by various methods is influenced by the initial caries 
prevalence and the standard of health care in the community. 

    Fluoride has been used in the treatment of osteoporosis for two 
decades and, though beneficial effects have been reported, the 
dose-response relationships and efficacy need further clarification. 

1.1.6.  Toxic effects on human beings

    The most important toxic effect of fluoride on human beings is 
skeletal fluorosis, which is endemic in areas with soils and water 
containing high fluoride concentrations.  The sources of fluoride 
that contribute to the total human intake vary geographically 
between endemic fluorosis areas, but the symptoms are generally 
similar.  They range from skeletal histological changes, through 
increases in bone density, bone morphometric changes, and exostoses 
to crippling skeletal fluorosis.  This condition is usually 
restricted to tropical and subtropical areas, and is frequently 
complicated by factors such as calcium deficiency or malnutrition. 

    In non-endemic areas, skeletal fluorosis has occurred as a 
result of industrial exposure.  This condition, whether of endemic 
or industrial origin, is normally reversible by reducing fluoride 
intake. 

    In endemic fluorosis areas, developing teeth exhibit changes 
ranging from superficial enamel mottling to severe hypoplasia of 
the enamel and dentine. 

    Patients with kidney dysfunction may be particularly 
susceptible to fluoride toxicity. 

    Acute toxicity usually occurs as a result of accidental or 
suicidal ingestion of fluoride, and it results in gastrointestinal 
effects, severe hypocalcaemia, nephrotoxicity, and shock.  
Inhalation of high concentrations of fluorine, hydrogen fluoride, 
and other gaseous fluorides may result in severe respiratory 
irritation and delayed pulmonary oedema.  Exposure of the skin to 
gaseous fluorine results in thermal burns, while hydrogen fluoride 
causes burns and deep necrosis. 

    A special case of acute toxicity is the reversible water-losing 
nephritis caused by metabolic liberation of fluoride ions from 
fluoride-containing anaesthetic gases. 

1.2.  Recommendations for Further Research

(a)  Because of the large number of people affected and the
     severity of the symptoms, the most important adverse effect of
     fluoride on human beings is endemic skeletal fluorosis.  The
     problem needs a multi-disciplinary approach and good
     communication among the scientists in the different areas at a
     global level.  The most important recommendation is that there
     should be an assessment of the magnitude of the problem and
     research carried out on the following:

       (i) the sources of fluoride in the diet, especially
           water, in different areas;

      (ii) dose-response relations, and the influence of other
           factors, notably malnutrition; and

     (iii) the means of prevention and cure (e.g.,
           defluorination).

    Assessment of the problem could best be accomplished by means 
of a workshop under the auspices of the WHO. 

(b)  Mapping of the fluoride concentrations in household water
     should be carried out to determine, on the one hand, where
     there might be unrecorded excessive exposure to fluoride
     conducive of fluorosis, and on the other hand, where there
     might be concentrations of fluoride sub-optimal for caries
     prevention.

(c)  Balance studies are required, especially in relation to
     variation in the availability and retention of different
     chemical forms of fluoride.  Data are also needed on the rate
     and control of release of fluoride from calcified tissues.

(d)  The etiology and pathology of early skeletal fluorosis
     should be further studied, particularly in relation to the
     biochemistry of bone mineralization.

2.  PROPERTIES AND ANALYTICAL METHODS

2.1.  Chemical and Physical Properties of Fluorine and its Compounds

    The terms "fluorine" and "fluoride" are used interchangeably in 
the literature as generic terms.  In this document, the terminology 
suggested by US NAS (1971) is followed: 

    "This document, rather than following common usage, uses the 
term "fluoride" as a general term everywhere, where exact 
differentiation between ionic and molecular forms or between 
gaseous and particulate forms is uncertain or unnecessary.  The 
term covers all combined forms of the element, regardless of 
chemical form, unless there is a specific reason to stress the 
gaseous elemental form F2, in which case the term "fluorine" is 
used." 

    Fluorine and fluorides occur ubiquitously in the environment, 
and because of their wide and growing use in industrial processes, 
their environmental importance is increasing.  The use of fluorides 
in dental health care products is also growing. 

    Compounds dealt with in this document, besides fluorine, 
include hydrogen fluoride, alkali fluorides, fluorspar, cryolite, 
fluoroapatite, other inorganic fluoride compounds, and certain 
organic fluorides that release fluoride when metabolized. 

2.1.1.  Fluorine

    Fluorine has a relative atomic mass of 19; at room temperature 
it is a pale, yellow-green gas.  It is the most electronegative and 
reactive of all elements and thus, in nature, is rarely found in 
its elemental state.  Fluorine combines directly at ordinary or 
elevated temperatures with all elements other than oxygen and 
nitrogen (Banks & Goldwhite, 1966) and therefore reacts vigorously 
with most organic compounds.  Fluoride ions have a strong tendency 
to form complexes with heavy metal ions in aqueous solutions, e.g., 
FeF63-, AlF63-, MnF52-, MnF3-, ZrF62-, and ThF62-.  The toxic 
potential of inorganic fluorides is mainly associated with this 
behaviour and the formation of insoluble fluorides. 

    Fluorine reacts with metallic elements to form compounds that 
are usually ionic, both in the crystalline state and in solution.  
Most of these fluorides are readily soluble in water; however, 
lithium, aluminium, strontium, barium, lead, magnesium, calcium, 
and manganese fluorides are insoluble or sparingly soluble.  Some 
high-melting fluorides such as aluminium fluoride (AlF3) are not 
completely decomposed, even by boiling sulfuric acid. 

    Fluorine and hydrogen fluoride react with nonmetallic elements 
to form covalent compounds, e.g., fluorine monoxide, silicon 
tetrafluoride, sulfur hexafluoride, organic compounds containing 
fluorine, and complex anionic forms.  Covalent compounds of 
fluorine tend to have low melting points and high volatility 
(Durrant & Durrant, 1962). 

2.1.2.  Hydrogen fluoride

    At room temperature, hydrogen fluoride is a colourless liquid 
or gas with a pungent odour.  Its freezing point is -83°C and its 
boiling point is +19.5°C.  It fumes in air; below +20°C, it is 
completely soluble in water.  Anhydrous hydrogen fluoride is one of 
the most acidic substances known (Horton, 1962).  It readily 
protonates and dissolves even nonbasic compounds such as alcohols, 
ketones, and mineral acids.  It is a strong dehydrating agent; wood 
and paper are charred on contact and aldehydes undergo condensation 
by elimination of water (Gall, 1966). 

    In the industrial production of hydrogen fluoride, the mineral 
fluorspar is treated with concentrated sulfuric acid.  The volatile 
hydrogen fluoride formed is then condensed and purified by 
distillation.  On the basis of the quantity produced, hydrogen 
fluoride is the most important fluoride manufactured.  About 292 
000 tonnes were produced in the USA in 1977 (Chemical Marketing 
Reporter, 1978b).  Approximately 40% of this amount was used in the 
manufacture of aluminium while 37% was converted into fluorocarbon 
compounds and other products. 

    Because of its extensive industrial use, hydrogen fluoride is 
probably the greatest single atmospheric fluoride contaminant.  
However, owing to its great reactivity, it is unlikely to remain in 
its original form for very long. 

2.1.3.  Sodium fluoride and other alkali fluorides

    The alkali fluorides are typical salts.  They have high melting 
and boiling points and are fairly to highly soluble in water.  All 
alkali fluorides, with the exception of the lithium salt, absorb 
hydrogen fluoride to form acid fluorides of the type MHF2, where M 
is the alkali metal (Banks & Goldwhite, 1966). 

    Sodium fluoride is the most important of the alkali fluorides.  
It is a white, free-flowing crystalline powder that is usually 
prepared by neutralizing aqueous solutions of hydrofluoric acid 
with sodium carbonate or sodium hydroxide.  Sodium fluoride is 
widely used in fluxes and has been proposed for the removal of 
hydrogen fluoride from exhaust gases.  Sodium fluoride was the 
first fluoride compound used in the fluoridation of drinking-water 
in the USA in 1950. 

    There are more reports of accidental intoxications caused by 
sodium fluoride than by any other fluorine compound.  This is 
chiefly because of the confusion of edible materials with sodium 
fluoride preparations domestically used for the extermination of 
insects, fungi, rodents, etc. 

2.1.4.  Fluorspar, cryolite, and fluorapatite

    From an industrial point of view, fluorspar (CaF2) is the 
principal fluorine-containing mineral; the theoretical fluorine 
content is 48.5%.  It is mined in many countries.  The world 
production of fluorspar in 1979 was estimated to be 4 866 000 
tonnes (US Bureau of Mines, 1980). 

    Cryolite (3NaF x AlF3) is a relatively rare mineral that is an 
essential raw material in the aluminium industry; it has a 
theoretical fluorine content of 545 g/kg.  The formerly important 
cryolite deposits of Greenland are now almost exhausted; today most 
supplies have to be prepared synthetically (US NAS, 1971). 

    Fluorapatite [CaF2 x 3Ca3(PO4)3], a constituent of rock 
phosphate, has a theoretical fluoride content of only 38 g/kg.  
Thus, rock phosphate is unimportant as a commercial source of 
fluorine.  However, it is of great environmental significance as it 
is the source of fluoride in some areas of endemic fluorosis and 
because vast quantities are mined and consumed in the production of 
elemental phosphorus, phosphoric acid, and phosphate fertilizers.  
The fluorine content of the rock phosphate mined annually in the 
USA has been estimated to be 729 000 tonnes (Wood, 1975) and the 
total amount of fluoride emitted into the atmosphere from 
industrial sources to be more than 16 300 tonnes in 1969 (US NAS, 
1971). 

2.1.5.  Silicon tetrafluoride, fluorosilicic acid, and fluorosilicates

    Silicon tetrafluoride (SiF4) is a colourless, very toxic gas 
with a pungent odour.  Its boiling point is -86°C and its melting 
point is -90°C.  When bubbled into water, hydrolysis results in 
the formation of the hexafluorosilicate ion (SiF62-), which is very 
toxic.  Most of the fluorosilicates are soluble in water. 

    Silicon tetrafluoride is of important environmental 
significance as it is formed in large quantities during the 
combustion of coal and in the manufacture of superphosphate 
fertilizers, elemental phosphorus, wet-process phosphoric acid, 
aluminium, and brick and tile products.  In plants, where off-gases 
are scrubbed with water, most of the silicon tetrafluoride is 
removed as fluorosilicic acid. 

    Fluorosilicic acid is a colourless flowing liquid that is 
increasingly used to fluoridate drinking-water, as it is simple to 
transport and store and easily provides the ideal fluoride level 
for drinking-water.  Sodium fluorosilicate is suitable for dry-
dosage fluoridation equipment as it is obtained as a dry, free-
flowing powder. 

2.1.6.  Sodium monofluorophosphate

    Sodium monofluorophosphate (Na2FPO3) is another form of 
synthetic fluoride that is widely used in the fluoride dentifrice 
industry, since it is compatible with most abrasives used in 
dentifrices. 

2.1.7.  Organic fluorides

    Covalently-bound fluorine so closely resembles hydrogen that it 
is possible, in principle, to synthesize fluoride analogues for 
almost all of the hydrocarbons known at present and their 
derivatives; already several thousand fluorine-containing compounds 
have been prepared (Banks & Goldwhite, 1966). 

(a)  Fluorocarbons

    Fluorination of organic compounds producing chiefly 
fluorocarbons constituted the greatest single use of hydrogen 
fluoride in the USA in 1977.  About 108 000 tonnes were used 
resulting in the production of 386 000 tonnes of fluorocarbons 
(Chemical Marketing Reporter, 1978a,b).  The fluorocarbons were 
used in aerosol propellants (24%), refrigerants (39%), solvents 
(11%), and blowing agents (12%).  Owing to the banning of non-
essential uses of fluorocarbon propellants in 1978 by the US 
Environmental Protection Agency, the propellant segment of the 
fluorocarbon market in the USA, for example, shrank to about 2% of 
its former value. 

    Although most of the saturated compounds of fluorine and carbon 
are neither toxic nor narcotic, many of the higher unsaturated 
compounds of carbon, hydrogen, fluorine, and other halogens are 
very toxic (ACGIH, 1980). 

(b)  Methoxyflurane (2,2-dichloro-1,1-difluoro-1-methoxyethane) (Penthrane)

    Methoxy-flurane (CH3-O-CF2-CCl2H), enflurane (CHF2-O-CF2-CClFH), 
and isoflurane (CHF2-O-CHCl-CF3), are organofluorine anaesthetics 
that release fluoride when metabolized in the body (Cousins & 
Mazze, 1973; Cousins et al., 1974; Marier, 1982). 

(c)  Natural organic fluorides

    Natural organic fluorides are rare.  Only a few such compounds 
have been described, the most well-known being fluoroacetic acid 
and fluoro-oleic acid.  These have been reported to occur in over 
20 tropical or arid-zone plants; in some species to such an extent 
that their leaves are poisonous to animals (Cameron, 1977; 
Weinstein, 1977; King et al., 1979). 

    Conflicting evidence has been published concerning the possible 
presence of fluoroacetate and fluorocitrate in common crop plants 
exposed to fluorides.  The very high concentrations reported in 
some papers were found to be in error, because of contamination 
with inorganic fluorides (Yu et al., 1971).  From recent 
literature, there does not seem to be any reason to modify the 
opinion expressed by Hall (1974):  "... it seems unlikely that the 
levels of toxic compounds in pastures arising from the sources of 
industrial contaminants mentioned earlier, if they are formed at 
all, constitute a serious hazard."  However, organic fluorides have 
been identified in human plasma, but the significance of this 
finding is still unknown (section 4.2.2). 

2.2.  Determination of Fluorine

    The determination of elementary fluorine is difficult, chiefly 
because of the great reactivity of this element.  Many methods and 
modifications have been proposed for the liberation of fluoride 
from samples of various origins as well as for the subsequent 
determination of the separated fluoride.  This section deals with 
the most commonly used methods.  Other techniques are discussed by 
Jacobson & Weinstein (1977). 

2.2.1.  Sampling and sample preparation

    In investigations of fluoride-containing compounds present in 
the environment, due care must be taken in collecting and handling 
the samples in order to obtain a representative sample and to avoid 
contamination with outside fluoride and loss of fluoride after the 
sampling.  It must be recognized that determination of fluoride is 
one step in a series of operations, all of which may affect the 
accuracy or validity of the final data.  Errors introduced in 
sampling or handling may be much greater than those due to lack of 
accuracy or reliability in the analytical technique.  The media to 
be monitored are many and varied; each situation should be assessed 
and a scheme devised for the collection, preparation, and analysis 
of samples. 

2.2.1.1.  Air

    Sampling for airborne fluorides is complicated by the very low 
concentrations of these compounds generally found in the ambient 
air and by the occurrence of both gaseous and particulate forms.  
For instance, gaseous fluoride compounds such as hydrogen fluoride 
and silicon tetrafluoride are more toxic to vegetation than most 
particulate fluoride compounds (Less et al., 1975; Weinstein, 
1977).  Thus, it is important to use a method for collection in 
which it is possible to separate the two forms, when potential 
injury to vegetation is concerned (Jacobson & Weinstein, 1977). 

    Much equipment has been designed for the collection of air 
samples.  Particulate fluorides are usually collected on acid-
treated filters.  Gaseous fluorides are trapped:  (a) on sodium 
bicarbonate in tubes or on beads; (b) in bubblers containing water 
or a solution of sodium hydroxide, potassium hydroxide, or alkali 
carbonates; or (c) on alkali-treated filters.  Automated equipment 
for determining gaseous fluorides in the air is available.  
However, it is expensive, may need skilled technical attention, and 
is of limited value for measuring low concentrations. 

    Once trapped, determination of fluorides does not present any 
difficulties.  Particulate fluorides, however, usually require 
fusing with alkali to convert refractory fluorides into soluble 
forms.  Details of these methods are given in surveys by 
Hendrickson (1968), MacDonald (1970), the American Industrial 
Hygiene Association (1972), Israel (1974), Jacobson & Weinstein 
(1977), and US EPA (1980). 

    An alternative or adjunct to the above method for the 
determination of gaseous fluoride concentrations in air is to 
measure flux to alkali impregnated surfaces (Davison & Blakemore, 
1980; Alary et al., 1981). 

2.2.1.2.  Soil and rocks

    Mixing soils of different types and horizons to provide a 
single composite sample can mask important information and lead to 
larger errors than separate analysis of each soil type and horizon 
(Jacobson & Weinstein, 1977).  Similar problems may arise in the 
sampling of rocks, because wide variations in the fluoride contents 
of rocks may occur.  Soil samples are usually pulverized and 
homogenized in ball or hammer mills.  Organic matter present in the 
samples is removed by ashing, generally with fluoride-free calcium 
oxide as a fixative (Horton, 1962). 

    Determination of fluoride in soil is preceded by operations to 
convert the fluoride compounds into readily soluble compounds.  
Usually fusion is necessary as soils may often yield refractory 
fluorine combinations of iron, aluminium, and silicon. 

    In many circumstances, the labile (Larsen & Widdowson, 1971) 
fraction is of greater significance than total soil fluoride, as 
this fraction is more available for plant and animal uptake 
(Murray, 1982).  A review of the methods is given in Davison 
(1984). 

2.2.1.3.  Water

    Samples from reservoirs, lakes, rivers, and seas must be 
representative, and repeated collection of samples from several 
sampling stations is often necessary.  Sampling from different 
depths is sometimes advisable, especially when studying industrial 
fluoride discharged into a water recipient. 

    Usually, the fluoride content of the water in deep wells is 
fairly constant, while water from shallow wells can present 
fluctuating values.  For example, values may be high during dry 
periods or periods when the ground is frozen compared with 
those obtained during rainy periods.  The fluoride levels in 
relatively shallow wells, therefore, should be assessed by repeated 
determinations. 

    The fluoride content of samples stored in polyethylene 
containers does not change significantly (Sholtes et al., 1973). 

    Although fluoride usually occurs in water in the ionic form, 
direct quantitative determination of fluoride ions is possible only 
in samples of fresh water with a low mineral content.  In other 
cases, a preceding step of acid distillation is recommended if a 
colorimetric method is to be used, otherwise polyvalent cations 
such as A13+, Fe3+, Si4+, as well as anions such as C1-, SO42-, and 
PO43- may interfere.  When using the ion selective electrode, no 
distillation is normally required, provided the fluoride is in a 

free ionic form.  This may be achieved by using a buffer to 
maintain a suitable total ionic strength, pH, and to avoid complex 
ion formation (section 2.2.2.2). 

2.2.1.4.  Animal tissues

    Preparation of samples usually includes mineralization before 
separation of the fluoride ion.  Fusing to decompose refractory 
fluorides is seldom necessary as animal tissues contain little 
silicon or aluminium. 

    Bone samples are usually collected and prepared for subsequent 
analysis using the fluoride selective electrode.  The samples can 
be prepared in different ways.  For instance, samples freed of 
flesh are simply dissolved in acids (chiefly perchloric acid 
HC104); ashed and dissolved in HC104 or hydrochloric acid (HC1); or 
defatted, ashed, and dissolved in HC104 or HC1.  Charen et al. 
(1979) compared results obtained using the fluoride selective 
electrode, and different methods of preparation of bone samples.  
They did not find any significant systematic differences in the 
results obtained between methods with or without ashing or, with or 
without defatting. 

    Before the fluoride selective electrode became available, body 
fluids (e.g., blood, serum, saliva, and urine) were generally 
gently evaporated to dryness and ashed before the separation of 
fluoride (US NAS, 1971).  Since ashing frequently results in 
refractory fluorides, the solubility of the residue is ensured by 
fusing with alkali carbonate or hydroxide.  Following fusion, the 
melt is dissolved and the fluoride separated for determination. 

2.2.1.5.  Plants

    Representative sampling requires thorough planning as the 
fluoride content of plants varies with time, the type of soil, 
meteorological conditions, the physiological condition and age of 
the plant, and the nature of the fluoride emission (Jacobson & 
Weinstein, 1977; US EPA, 1980).  The fluoride contents of different 
parts of the canopy and different organs also vary considerably. 

    Whether or not fluoride compounds superficially adhering to 
leaves and stems of plants should be removed by washing depends on 
the use of the analytical results.  Washing is used when an 
indication of the internal fluoride content of the plant is 
required.  It is not used when the purpose is to estimate the 
fluoride intake of cattle from grass, forage, etc. 

2.2.2.  Separation and determination of fluoride

    It may be necessary to separate fluoride from other 
constituents of the sample to be analysed.  Most frequently, the 
separation is obtained by distillation or diffusion.  Ion exchange 
has also been proposed.  Pyrohydrolysis and precipitation 
techniques are used in more specialized cases. 

    Distillation was formerly the separation technique most 
commonly used in fluorine determination.  The basic Willard & 
Winter (1933) method included the volatilizaton of 
hexafluorosilicic acid with vapour from perchloric or sulfuric acid 
at 135°C, in the presence of glass beads or glass powder.  It is 
still widely used and is the method used for comparing other 
methods for fluoride determination. 

    Diffusion methods for the separation of fluoride have been 
widely used for determinations in microsamples and have found many 
applications in clinical and biochemical work.  With the diffusion 
method developed by Singer & Armstrong (1954, 1959, 1965), hydrogen 
fluoride liberated by perchloric or sulfuric acid is trapped by an 
alkali layer in a closed vessel. 

2.2.2.1.  Colorimetric methods

    With certain multivalent ions, fluoride ions form stable 
colourless complexes such as (A1F6)3-, (FeF6)3-, (ZrF6)2-, and 
(ThF6)2-.  Most of the colorimetric methods for the indirect 
determination of fluoride ions are based on such complex formation, 
i.e., on the bleaching resulting from reactions of fluoride ions 
with coloured complexes of these metals and organic dyes.  The 
degree of colour change can be assessed by comparison with a 
standard either by visual titration or, as in most cases, by 
spectrophotometry.  Commonly used reagents are zirconyl-alizarin 
for visual titration and zirconyl-SPADNS or zirconium-eriochrome 
cyanine R for spectrophotometry. 

    The alizarin fluoride blue method (Belcher et al., 1959) has 
been widely applied for direct spectrophotometric determination of 
fluoride.  The basic reaction is that a red cerium complex with 
alizarin complexone turns blue on the addition of fluoride ions. 

    Colorimetric methods for fluoride determination have been used 
for plant and animal tissues and fluids, water, soils, foods and 
beverages, and air (Jacobson & Weinstein, 1977).  A semi-automated 
analyser using colorimetric technique is commercially available. 

2.2.2.2.  The fluoride selective electrode

    The fluoride selective electrode was introduced by Frant & Ross 
(1966).  Because of its excellent performance, speed, and general 
convenience, it has become an important method for determining 
fluoride in a wide variety of environmental and industrial samples 
(Jacobson & Weinstein, 1977; US EPA, 1980; Victorian Committee, 
1980). 

    The selectivity of the electrode is based on the properties of 
a membrane of sparingly soluble single crystals of lanthanum, 
praseodynium or neodynium fluoride.  It gives an electrochemical 
response that is proportional to the fluoride ion activity in the 
sample. 

    The fluoride selective electrode is used for the determination 
of fluorides in drinking-water, in industrial effluents, sea water, 
air, and aerosols, flue gases, soils and minerals, urine, serum, 
plasma, plants, and other biological materials (Jacobson & 
Weinstein, 1977).  Micromethods have been developed in which 
determinations can be made in volumes as small as 10 µlitres or 
less (Ritief et al., 1977).  Instruments are available for the 
automated monitoring of fluoride levels using the fluoride 
selective electrode. 

    The precision and accuracy of the electrode method equal or 
even exceed those of the colorimetric techniques for most samples. 

2.2.2.3.  Other methods

    Ion chromatography has recently been introduced for the 
determination of fluoride in a variety of media. 

    The remaining methods for determining fluoride are mostly 
specialized procedures that are appropriate for selected samples or 
that involve specialized facilities; they seem unlikely to find 
widespread, general application (US EPA, 1980). 

3.  FLUORIDE IN THE HUMAN ENVIRONMENT

    Fluorine ranks 13th among the elements in the order of 
abundance in the Earth's crust.  However, despite the prevalence of 
the fluoride ion, gaseous fluorine rarely, if ever, occurs 
naturally. 

3.1.  Fluoride in Rocks and Soil

    The mean fluoride content of rocks lies between 0.1 and 1.0 g/kg.  
The main primary fluoride-containing minerals are fluorspar (CaF2), 
cryolite (3NaF x AlF3), and apatite (3Ca3(PO4)2 x Ca(F,OH,Cl)2), 
but in most soils it is associated with micas and other clay 
minerals (Davison, in press). Sodium fluoride and magnesium 
fluoride are also found as natural minerals. 

    The mean fluoride content of mineral soils is 0.2 - 0.3 g/kg 
(US NAS, 1971), whereas that of organic soils is usually lower.  
However, in soils which have developed from  fluoride-containing 
minerals it may range from 7 (Smith & Hodge, 1979) to 38 g/kg 
(Vinogradov, 1937; Danilova, 1944). 

    The fluoride content of top soil may be increased by the 
addition of fluoride-containing phosphate fertilizers, pesticides, 
irrigation water, or by deposition of gaseous and particulate 
emissions.  In a recent review, Davison (in press) calculated that 
phosphate fertilizers typically add between 0.005 and 0.028 mg F/kg 
per year to soil.  A concentration of 1 µg F/m3 in air similarly 
adds about 0.004 - 0.018 g/kg per year.  Soils have a capacity to 
fix fluoride, so depletion by leaching and removal by crops is very 
slow.  In the USA, one estimate of the annual loss was 0.0025 g/kg 
per year (Omueti & Jones, 1977).  Much research by MacIntire and 
his colleagues showed that addition of fluoride did not 
significantly increase uptake by plants, though there was evidence 
that this might be the case in saline soils (Davison, 1984). 

3.2.  Fluoride in Water

    Some fluoride compounds in the Earth's upper crust are fairly 
soluble in water.  Thus, fluoride is present in both surface- and 
ground-water.  The natural concentration of fluoride in ground-
water depends on such factors as the geological, chemical, and 
physical characteristics of the water-supplying area, the 
consistency of the soil, the porosity of rocks, the pH and 
temperature, the complexing action of other elements, and the depth 
of wells (Livingstone, 1963; Worl et al., 1973).  Owing to these 
factors, fluoride concentrations in ground-water fluctuate within 
wide limits, e.g., from < 1 to 25 mg or more per litre.  In some 
areas of the world, e.g., India, Kenya, and South Africa, levels 
can be much higher than 25 mg/litre (WHO, l970).  In surface fresh 
waters, less influenced by fluoride-containing rocks, the fluoride 
content is usually low, 0.01 - 0.3 mg/litre (Gabovic, 1957).  
Fluoride concentrations are higher in sea than in fresh water, 
averaging 1.3 mg/litre (Mason, 1974).  Most of the fluoride in sea 
water has come from rivers.  At the present rate of delivery of 

fluoride from rivers to seas, it would take about one million years 
to double the average concentration in sea water.  However, it 
appears that a steady-state equilibrium has almost been reached as 
the seas lose fluoride in the form of aerosols to the atmosphere, 
by precipitation as insoluble fluorides, and by incorporation in 
the carbonate- or phosphate-containing tissues of living organisms 
(Carpenter, 1969). 

    Data on the fluoride contents of natural waters and drinking-
water are available from many parts of the world (WHO, 1970).  
However, sufficiently detailed information is still lacking.  
Supplementation of drinking-water with fluoride has been carried 
out since 1945.  Today more than 260 million individuals receive 
fluoridated drinking-water throughout the world.  In addition, 
about as many individuals are supplied with drinking-water with a 
natural fluoride content of 1 mg/litre or more.  A procedure such 
as adding fluoride to drinking-water occasionally carries with it a 
risk of overexposure.  A few instances of control system breakdown 
have resulted in acute intoxications of population subgroups but 
the effects lasted only a short time (Waldbott, 1981). 

    About 50% of sewage fluoride is removed by biological treatment 
(Masuda, 1964), and considerable amounts of fluoride will be 
precipitated by aluminium, iron, or calcium salts during chemical 
treatment.  Thus, effluents from areas with fluoridation will have 
a limited influence on the final fluoride level in the fresh-water 
recipient (Singer & Armstrong, 1977). 

3.3.  Airborne Fluoride

    Traces of fluoride in the air of rural communities and cities, 
arise from both natural sources and human activities.  The natural 
dispersal of fluoride into the air has long been recognized in 
regions of volcanic activity.  The contribution of this source to 
the Earth's atmosphere is 1 - 7 x 106 tonnes per year (US EPA, 
1980).  Other natural sources of fluoride in the air are the dust 
from soils, and sea-water droplets, carried up into the atmosphere 
by winds.  However, most of the airborne fluoride found in the 
vicinity of urbanized areas is generated through human activities.  
It has been estimated that, in 1968, more than 155 000 tonnes of 
fluoride were discharged into the atmosphere from power production 
and major industrial sources in the USA (Smith & Hodge, 1979).  The 
aluminium industry was responsible for about 10% of this fluoride 
emission.  Other industrial sources include steel production 
plants, superphosphate plants, and ceramic factories, coal-burning 
power plants, brickworks, glassworks, and oil refineries.  In many 
of these industries, occupational exposures of the order of 
magnitude of 1 mg/m3 may occur. 

    The amount of airborne fluoride increases with increasing 
urbanization, because of the burning of fluoride-containing fuels 
(coal, wood, oil, and peat) and because of pollution from 
industrial sources.  Individual types of coal contain fluoride 
levels ranging from 4 to 30 g/kg (MacDonald & Berkeley, 1969; 
Robinson et al., 1972).  Increased burning of fuel during the 

winter months results in increased concentrations of airborne 
fluoride.  However, in densely-populated areas, the fluoride 
concentrations will only occasionally reach a level of 2 µg/m3.  
In a 3-year study, Thompson et al. (1971) found that in only 
0.2% of urban samples did the fluoride concentration exceed 1 
µg/m3.  The maximum value was 1.89 µg/m3.  A survey of fluoride 
in the atmosphere of some communities in the USA showed that 
concentrations varied between 0.02 and 2.0 µg/m3 (US EPA, 1980).  
The American data are in accordance with the European findings of 
Lee et al. (1974).  Near heavily industrialized Duisburg in the 
Federal Republic of Germany, Schneider (1968) found a mean 
concentration of 1.3 µg/m3, the 90% range being 0.5 - 3.8 µg/m3.  
In the immediate vicinity of factories producing fluorides or 
processing fluoride-containing raw materials, the amount of 
fluoride in the ambient air may be much higher for short periods.  
More recently reported values for fluoride concentrations in 
ambient air near fluoride-emitting factories are usually lower 
than the older values, because of improved control technology. 

    Fluorides emitted into the air exist in both gaseous and 
particulate forms.  Particulate fluorides in the air around 
aluminium smelters vary in size from 0.1 mm to around 10 mm (Less 
et al., 1975; Davison, in press). 

3.4.  Fluoride in Food and Beverages

    Several thorough reviews concerning the fluoride content of 
foods have been presented, e.g., McClure (1949), Truhaut (1955), 
Kumpulainen & Koivistonen (1977), and Becker & Bruce (1981).  
Comprehensive determinations of fluoride in foods have been 
reported from Finland (Koivistonen, 1980), the Federal Republic of 
Germany (Oelschläger, 1970) and Hungary (Toth & Sugar, 1978; Toth 
et al., 1978).  Becker & Bruce (1981) compiled data from studies 
before 1956 and data from the two last decades (Table 1).  With the 
exception of values for fish, more recent data tend to be slightly 
lower; values for meat and grain products are sometimes 
considerably lower. There are other notable differences between 
values given in some of the papers. 

    Various values for fluoride concentrations in vegetables have 
been reported.  Occasional values in the range of 1 - 7 mg/kg fresh 
weight have been reported for spinach, cabbage, lettuce, and 
parsley, while values for other vegetables have seldom exceeded 0.2 
- 0.3 mg/kg.  Probably, in some cases, the high fluoride values 
have been caused by contamination from air, soil, pesticides, etc.  
It also seems probable that some kind of contamination is 
responsible for the very high values of 10.7 mg/kg and 11 mg/kg, 
respectively, for polished rice given by Oelschläger (1970) and 
Ohno et al. (1973)  since more recent confirmation of the results 
is lacking. 

Table 1.  Fluoride content of foods according to different 
investigationsa
----------------------------------------------------------------
Food          Before     Oelschlager  Toth & Sugar Koivistoinen
              1956b      (1970)       Toth et al.  (1980)
                                      (1978)

                           (mg/kg fresh weight)
----------------------------------------------------------------
Egg products  0.3 - 1.4  -            -            0.3 - 1.7

Wheat, whole  0.1 - 3.1  0.1 - 0.2    0.1 - 0.4    0.2 - 1.4

Wheat, white  0.2 - 0.9  -            -            0.1 - 0.9

Other cereal  0.1 - 4.7  (rice 0.2 -  -            0.1 - 2.5
products                 10.7)

Pulses        0.1 - 1.3  0.1 - 14.1c  0.1 - 0.2    0.1 - 1.3

Roots         0.1 - 1.2  0.1 - 0.2    0.1 - 0.5    0.1 - 0.2

Leafy         0.1 - 2.0  0.1 - 1.1    0.1 - 1.0    0.1 - 0.8
vegetables

Other         0.1 - 0.6  0.1 - 0.3    0.1 - 0.4    0.1 - 0.3
vegetables

Fruit         0.1 - 1.3  0.1 - 0.7    0.1 - 0.4    0.1 - 0.5

Margarine     0.1        -            -            -

Milk          0.1 - 0.1  < 0.1        0.1          0.1

Butter        1.5        -            -            -

Cheese        0.1 - 1.3  0.3          -            0.3 - 0.9

Pork, fresh   0.2 - 1.2  0.3          0.2 - 0.3    0.1 - 0.3

Pork, salted  1.1 - 3.3  -            0.1 - 0.2    -

Beef          0.2 - 2.0  0.2          0.2 - 0.3    0.1 - 0.3

Other meats   0.1 - 1.2  -            0.2 - 0.7    0.1 - 0.2

Offal         0.1 - 2.6  0.3 - 0.5    0.2 - 0.6    0.1 - 0.3
                                                                        
Blood         < 0.1      -            -            < 0.2 
                                                                        
Sausages      1.7         0.3         0.1 - 0.6    0.1 - 0.4
                                                                        
Fish fillets  0.2 - 1.5   1.3 - 5.2   1.3 - 2.5    0.2 - 3.0
----------------------------------------------------------------

Table 1.  (contd.)
-------------------------------------------------------------------
Food          Before       Oelschlager    Toth & Sugar Koivistoinen
              1956b        (1970)         Toth et al.  (1980)
                                          (1978)

                               mg/kg fresh weight)
-------------------------------------------------------------------
Fish, canned  4.0 - 16.1   -              3.8 - 9.4    0.9 - 8.0

Shellfish     0.9 - 2.0    -              -            0.3 - 1.5

Eggs          0.1 - 1.2    < 0.1         0.1 - 0.2    0.3

Tea, leaves   3.2 - 178.8  100.8 - 143.6  -            -

Tea, beverage 1.2          1.6 - 1.8      -            0.5
-------------------------------------------------------------------
a  From: Becker & Bruce (1981).
b  Danielsen & Gaarder (1955); Nömmik (1953); Truhaut (1955); von
   Fellenberg (1948).
c  Product dried.

    According to McClure (1949), the fluoride contents of fresh 
pork and fresh beef varied within the range of 0.2 - 2 mg/kg and  
the  range for  salted beef was 1.3 - 3.3 mg/kg wet weight.  For 
healthy animals, none of the more recent studies have reported 
values higher than 0.6 mg/kg wet weight.  However, Szulc et al. 
(1974) found 0.9 mg of fluoride/kg wet weight in beef from cattle 
with symptoms of fluorosis.  Incomplete deboning could have 
contributed to certain high values reported for pork, beef, and 
chicken.  Kruggel & Fiels (1977) and Dolan et al. (1978) have shown 
that bone fragments left in meat can increase considerably the 
fluoride content of, e.g., frankfurters.  Bone contains high 
amounts of fluoride; 376 - 540 mg fluoride/kg bone meal was 
reported by Manson & Rahemtulla (1978) and 260 - 920 mg/kg by Capar 
& Gould (1979).  However, the availability of fluoride in ingested 
bone fragments is lower than in meat. 

    Fluoride values given for fish fillets vary appreciably, from 
0.1 - 5 mg/kg wet weight.  However, as fishbone contains 
considerable amounts of fluoride, incomplete gutting could have 
contributed to the high fluoride values reported.  It is most 
likely that bone fluoride contributed to the high fluoride values 
for fish protein concentrate, e.g., 21 - 761 mg/kg dry weight, 
reported by Ke et al. (1970).  Canned fish contains fairly large 
amounts of fluoride, mainly originating from the skeleton.  In 
studies by Koivistonen (1980), there were no major differences 
between the amounts of fluoride in the fillets of fish from fresh 
water and those of fish from marine water. 

    The fluoride content of water used in industrial food 
production and home cooking affects the fluoride content of ready-
to-eat products.  Some examples are presented in Table 2.  Martin 
(1951) observed that the uptake by vegetables of fluoride from 

cooking water was proportional to the fluoride content of the water 
over a concentration range of 1 - 5 mg/litre.  The fluoride content 
of vegetables cooked in fluoridated water was about 0.7 mg/kg  
higher than the  content of vegetables cooked in water containing a 
negligible amount of fluoride (Martin, 1951).  In general, the 
fluoride content of processed foods and beverages prepared with 
water  containing a fluoride level of 1 mg/litre will contain 
about 0.5 mg/kg more fluoride than those prepared with non-
fluoridated water (Marier & Rose, 1966; Auermann, 1973; Becker & 
Bruce, 1981).  Thus, foodstuffs processed with fluoridated water 
may contain a fluoride concentration of 0.6 - 1.0 mg/kg rather than 
the normal 0.2 - 0.3 mg/kg (US EPA, 1980). 

Table 2.  Influence of the fluoride content of process water on
fluoride levels in processed food
------------------------------------------------------------------
                    Content in process water      
                 0 - 0.2 mg/litre  1.0 mg/litre
Food                  (mg/kg fresh weight)       Reference
------------------------------------------------------------------
Bakery products  0.3 - 0.6         0.8 - 1.7     Auermann (1973)

Margarine        0.4               1.0 - 1.2

Sausage          0.4 - 1.8         0.7 - 3.3

Beer             0.3               0.7           Marier & Rose 
                                                 (1966)

Vegetables       0.3 (0.1 - 0.4)   0.8            
(canned)                           (0.6 - 1.1)

Beans and pork   0.3               0.8
(canned)

Cheese           0.2 - 0.3         1.3 - 2.2     Elgersma & Klomp
                                                 (1975)
------------------------------------------------------------------

    Generally, substitutes for human milk have a relatively high 
fluoride content compared with that of human milk.  Infant 
formulae, infant gruel, syrups, and juices prepared with 
fluoridated water contain 0.9 - 1.3 mg fluoride/litre compared with 
0.2 - 0.5 mg/litre if prepared with low fluoride water, i.e., water 
containing < 0.2 mg/litre (Becker & Bruce, 1981).  Similar results 
were obtained by Singer & Ophaug (1979) who also compared fluoride 
levels in fruit juices made from concentrates by the addition of 
fluoridated or non-fluoridated water. 

    Tea leaves are usually very rich in fluoride, and levels 
ranging from 3.2 - 400 mg/kg dry weight have been reported 
(Canadian Public Health Association, 1979).  About 40 - 90% of the 
fluoride in tea leaves is eluted by brewing.  The mean fluoride 
concentration of tea brewed with water containing fluoride at 0.1 
mg/litre was found to be 0.85 mg/litre, the upper level being 3.4 

mg/litre (Anderberg & Magnusson, 1977).  Duckworth & Duckworth 
(1978) reported that the fluoride concentrations in tea infusions, 
prepared from 12 different brands of tea, varied from 0.4 to 2.8 
mg/litre.  The authors estimated that the ingestion of fluoride by 
tea drinkers of all ages in the United Kingdom ranged from 0.04 to 
2.7 mg per day. 

    Other beverages are usually low in fluoride.  However, mineral 
waters may contain fluorine levels higher than 1 mg/litre.  It is 
desirable that the fluorine concentration of mineral waters be 
declared on the container. 

3.5.  Total Human Intake of Fluoride

    The fluoride contents of air, water, and food determine the 
human intake of fluoride.  As discussed above, there are 
considerable variations in fluoride levels, and a significant 
variability in human fluoride intake would therefore be expected. 

    The average respiration rate in an adult person is about 20 m3 
per day.  Thus, even if the fluoride concentration in urban air 
occasionally rose to 2 µg/m3, the amount of fluoride inhaled would 
only be 0.04 mg/day.  Martin & Jones (1971) estimated that a person 
living in central London inhaled 0.001 - 0.004 mg of fluoride per 
day.  They stated that this amount might be increased by a factor 
of five or ten on an exceptionally foggy day.  In heavily 
industrialized English cities, the authors considered that the 
maximal amount of fluoride inhaled daily would be of the order of 
0.01 - 0.04 mg.  In the close vicinity of an aluminium plant in the 
Federal Republic of Germany, fluoride intake by inhalation was 
calculated to be 0.025 mg/day (Erdmann & Kettner, 1975).  Biersteker 
et al. (1977) estimated that persons living near two industrial 
sources of fluoride could inhale 0.06 mg fluoride during a day of 
maximal pollution.  Similar values have been reported from 
fluoride-emitting industries in Sweden (SOU, 1981).  As only a 
proportion of inhaled fluoride is retained, actual uptake will be 
less than the above estimate. 

    Occupational exposure may add considerably to the total intake 
of fluoride.  Such exposures occur in the mining and processing of 
fluorspar, cryolite, and apatite (in sedimentary phosphate rock).  
According to NIOSH (1977), fluorides are used in industry as a flux 
in metal smelting; catalysts for organic reactions; fermentation 
inhibitors; wood preservatives; fluoridating agents for drinking-
water; bleaching agents; anaesthetics; and in pesticides, 
dentifrices, and other materials.  They are also used or released 
in the manufacture of steel, iron, glass, ceramics, pottery, and 
enamels; in the coagulation of latex; in the coating of welding 
rods; and in the cleaning of graphite, metals, windows, and 
glassware.  Assuming a total respiration rate of 10 m3 during a 
working day, the daily amount of fluoride inhaled could be as high 
as 10 - 25 mg, when the air concentration is at the most frequent 
exposure limits of 1 -2.5 mg/m3 (ILO, 1980).  Depending on hygiene 
conditions, dust contamination in the industrial setting could also 
add to the oral intake of fluoride. 

    Water requirements increase in hot climates.  Based on the mean 
maximum temperature, Galagan & Vermillion (1957) presented the 
following widely-used formula for the calculation of the "optimum" 
fluoride concentration in drinking-water in different climatic 
regions:  "optimum" level of fluoride in mg/litre = 0.34/(-0.038 + 
0.0062 times the mean maximum temperature in degrees Fahrenheit).  
In temperate areas, the "optimum" level has been established to be 
about 1 mg/litre (section 6.1). 

    When estimating the fluoride intake during the first 6 months 
of life, whether the infant is bottle- or breast-fed should be 
taken into account because of the very low fluoride concentration 
in breast milk.  Different methods of preparing substitutes for 
breast milk will result in different fluoride concentrations in the 
formulae.  In the USA, the mean daily fluoride intake of bottle-fed 
infants during the first 6 months of life has been estimated to be 
0.09 - 0.13 mg/kg body weight in fluoridated areas and a minimum of 
0.01 - 0.02 mg/kg in areas without water fluoridation (Singer & 
Ophaug, 1979).  The corresponding estimate for areas with optimal 
fluoride content in the drinking-water in Sweden is 0.13 - 0.20 
mg/kg body weight and 0.05 - 0.06 mg/kg in low-fluoride areas 
(Becker & Bruce, 1981).  In contrast, the breast-fed infant will 
only receive 0.003 - 0.004 mg fluoride/kg body weight, assuming a 
fluoride level of 0.025 mg/litre in human milk (Ericsson, 1969).  
The fluoride content of human milk is practically the same in low-
fluoride and fluoridated areas (Backer Dirks et al., 1974). 

    Between 6 and 12 months of age, the fluoride intake will be 
determined mainly by the proportion of tap-water used for the 
preparation of infant food.  Between 1 and 12 years of age, about 
half of the necessary quantity of fluids may be ingested in the 
form of cow's milk with a fluoride concentration of 0.10 mg/litre 
(Backer Dirks et al., 1974) or slightly more. 

    The intake of drinking-water in a temperate climate by direct 
consumption and by addition to food, has been estimated to be 0.5 - 
1.1 litre per day for children aged 1 - 12 years (McClure, 1953).  
McPhail & Zacherl (1965) calculated the total amount of water 
necessary for children aged 1 - 10 years to be 0.7 - 1.1 litre per 
day. 

    The fluoride intake of adults from food and drinking-water has 
been estimated in several studies.  Table 3 includes data from low-
fluoride areas with drinking-water containing < 0.4 mg of fluoride 
per litre.  These data indicate that the daily fluoride intake does 
not exceed 1.0 mg.  However, certain national consumption habits, 
for instance, the ingestion of tea in Asia, and seafood in some 
other parts of the world, can be of significance.  The various 
estimates have differed significantly, possibly as a consequence of 
the analytical method used.  Differences can also be related to the 
calculations of weight or the contribution from different 
components in a characteristic diet.  The total diet in communities 
where the water is fluoridated may contain a mean of 2.7 mg 
fluoride/day, compared with 0.9 mg/day where the water is not 
fluoridated (Kumpulainen & Koivistoinen, 1977).  Estimates of the 

daily fluoride intake in fluoridated areas in several studies have 
ranged from 1.0 to 5.4 mg (Table 4).  These figures correspond to 
data given in a number of papers from the USSR (Gabovich & 
Ovrutskiy, 1969).  With the different fluoride levels in various 
food items, considerable variations in individual fluoride intake 
may occur.  Thus, subgroups with very low or very high fluoride 
exposures through the diet may exist. 

    Close to a fluoride-emitting industry, limited contamination of 
leafy vegetables may increase the total fluoride intake of local 
residents by about 1.7% or 1.0% in non-fluoridated and fluoridated 
localities, respectively (Jones et al., 1971).  The fluoride intake 
from animal products is practically unaffected by industrial air 
pollution (US NAS, 1971; US EPA, 1980).  Thus, no increase in 
fluoride concentrations in soft tissues could be found in cattle 
with a high fluoride intake, severe dental fluorosis, and a very 
high level of bone fluoride (US EPA, 1980).  Backer Dirks et al. 
(1974) reported that the normal fluoride concentration in cow's 
milk was 0.10 mg/litre compared with 0.28 mg/litre in milk from 
cows feeding close to an aluminium plant.  Poultry eggs were found 
not to be affected by industrial fluoride pollution (Balazowa & 
Hluchan, 1969; Rippel, 1972). 

Table 3.  Daily fluoride intake of adults in areas with a low 
fluoride content in the drinking-water (< 0.4 mg/litre)a
--------------------------------------------------------------------------
Reference        Fluoride   Fluoride  Total      Comments
                 in food    in liquid intake
                            (mg/day)
--------------------------------------------------------------------------
Armstrong &      0.27-0.32  -         -          Analyses of 3 meals for
Knowlton (1942)                                  hospital staff, no
                                                 water

Machle et al.    0.16       0.30b     0.46       Analyses of one persons
(1942)           0.54 max   0.75                 daily intake during 40
                                                 weeks

McClure et al.   0.3-0.5                         Analyses of normal
(1944)                                           diets for young men

Ham & Smith      0.43-0.76  0.0-0.03  0.43-0.79  Analyses of diets of 3
(1954b)                                          young women avoiding
                                                 high fluoride foods
                                                 (tea, fish)

Danielsen &      0.56-0.57  -         -          Calculated intake of
Gaarder (1955)                                   persons > 14 years
                                                 of age

Cholak (1960)    0.3-0.8    -         -          Excluding fluoride from
                                                 drinking-water

Kramer et al.    0.8-1.0b   -         -          Analyses of general hos-
(1974)                                           pital diets in 4 cities,
                                                 3 meals, no food/drink
                                                 between meals

Osis et al.      0.7-0.9b   -         -          See Kramer et al. (1974)
(1974)

Singer et al.    0.37       0.54      0.91
(1980)

Becker & Bruce   0.41       0.20      0.61       Calculated from anal-
(1981)                                           yses of market basket
                                                 samples and from food
                                                 consumption data
--------------------------------------------------------------------------
a  From: Becker & Bruce (1981).
b  Includes tea/coffee.

Table 4.  Daily fluoride intakes of adults in areas with fluoridated
drinking-water (ca 1 mg/litre)
-------------------------------------------------------------------------
Reference       Fluoride   Fluoride   Total     Comments
                in food    in liquid  intake

                           (mg/day)
-------------------------------------------------------------------------
San Filippo &   0.78-0.90  1.3-1.5    2.1-2.4   Analyses of 4 market
Battistone                                      basket samples
(1971)

Marier & Rose   1.0-2.1    1.0-3.2    1.9-5.0   Calculated from the
(1966)                                          diets of 7 laboratory
                                                workers

Spencer et al.  1.2-2.7    1.6-3.2    3.6-5.4   Analyses of diets de-
(1969)                                          signed for low calcium
                                                content for 9 patients

Kramer et al.   1.7-3.4a                        Analyses of hospital
(1974)                                          diets in 12 cities, 3
                                                meals per day, no food/
                                                drink between meals

Osis et al.     2.0a                            Analyses of hospital
(1974)                                          diets in 4 cities, 3
                                                meals, no food/drink
                                                between meals

Osis et al.     1.6-1.8a                        Analyses of a metabolic
(1974)                                          diet, 3 meals, no food/
                                                drink between meals

Singer et al.   0.33-0.59  0.61-1.1   0.99-1.7  Calculated from analyses
(1980)                                          of market basket samples
                                                and from food
                                                consumption data

Koivistoinen    0.56b
(1980)

Becker & Bruce  0.41       1.6-1.9    2.0-2.3   Calculated from
(1981)                                          analysies and food
                                                consumption data
-------------------------------------------------------------------------
a  Includes tea/coffee.
b  Includes liquid except drinking-water.

    Health hazards have been associated with fluoride pollution 
near industrial sources.  Neighbourhood fluorosis in cattle has 
been described since 1912.  Results of case-finding studies in the 
vicinity of facilities producing fluoride-pollution in the German 
Democratic Republic revealed several cases of human skeletal 
fluorosis.  The total number of cases mentioned was about 50, 
mostly slight cases of osteosclerosis and periosteal thickening, 
but detailed clinical examination was only carried out on a few 
patients (Schmidt, 1976a,b; Franke et al., 1978).  Most of the 
German patients had resided within 2 km of the source for at least 
20 years.  A few additional cases were reviewed by Smith & Hodge 
(1979).  Moller & Poulsen (1975) identified dust pollution from a 
phosphate mine as the cause of extensive dental fluorosis in 
several hundred children living within 1 - 1.5 km of the mine.  
Thus, several cases of skeletal abnormalities have been identified 
in a few case-finding studies in the vicinity of fluoride-emitting 
production facilities.  In all these cases, the emission control 
technology was old or outmoded. 

    The human intake of fluoride may also include iatrogenic 
sources.  A frequent assumption is that the use of fluoridated 
dentifrices and mouthrinses results in a daily fluoride uptake of 
about 0.25 mg (Ericsson & Forsman, 1969), although individual 
fluoride intake could conceivably be higher.  Accidental intake of 
sodium fluoride tablets has only occasionally lead to intoxication 
in children (Spoerke et al., 1980; Duxbury et al., 1982).  Adverse 
effects have been attributed to daily ingestion of considerable 
amounts of fluoride as a remedy for osteoporosis (Grennan et al., 
1978). Several anaesthetic gases contain fluoride.  After 
inhalation of these compounds, fluoride ions may be released, 
resulting in considerable internal exposure to fluoride (Marier, 
1982). 

4.  CHEMOBIOKINETICS AND METABOLISM

4.1.  Absorption

    Absorption of fluoride entering the gastrointestinal tract is 
affected by a number of factors such as the chemical and physical 
nature of the ingested fluoride and the characteristics and amount 
of other components of the ingesta (US NAS, 1971).  Solutions of 
fluoride salts are rapidly and almost completely absorbed from the 
gastrointestinal tract, probably by simple diffusion (Carlson et 
al., 1960a).  Fluoride from insoluble or sparingly soluble 
substances, such as calcium fluoride and cryolite, is less 
efficiently absorbed.  However, some fluorides may be more easily 
dissolved in the stomach because of the low pH, and hydrogen 
fluoride will then be formed.  This compound may easily penetrate 
biological membranes, and its chemical reactivity is the probable 
cause of the resulting gastrointestinal symptoms when large amounts 
have been ingested.  Recent balance studies have shown that less 
than 10% of the ingested fluoride is excreted in the faeces, but 
the proportion varies with circumstances (US EPA, 1980) (section 
4.3.2).  The simultaneous presence of strongly fluoride-binding 
ions, especially calcium ions, will reduce the absorption of 
fluoride (Ekstrand & Ehrnebo, 1979).  In comparison with calcium, 
phosphate, and magnesium, aluminium is much more effective in 
reducing fluoride absorption.  Thus, in patients ingesting 
aluminium-containing antacids, fluoride absorption decreased to 
about 40%, and the retention decreased to nil (Spencer et al., 
1980). 

    In the industrial environment, the respiratory tract is the 
major route of absorption of both gaseous and particulate fluoride.  
Hydrogen fluoride being highly soluble in water is rapidly taken up 
in the upper respiratory tract (Dinman et al., 1976a).  Depending 
on their aerodynamic characteristics, fluoride-containing particles 
will be deposited in the nasopharynx, the tracheo-bronchial tree 
and the alveoli (Task Group on Lung Dynamics, 1966). 

    Dermal absorption of fluoride has only been reported in the 
case of burns resulting from exposure to hydrofluoric acid (Burke 
et al., 1973). 

4.2.  Retention and Distribution

4.2.1.  The fluoride balance

    The fluoride absorbed by the human body will circulate in the 
body and then be retained in the tissues, predominantly the 
skeleton, or excreted, mainly in the urine.  Both uptake in 
calcified tissues and urinary excretion appear to be rapid 
processes (Charkes et al., 1978).  The previously retained fluoride 
may be slowly released from the skeleton, and this fluoride may add 
to the levels in blood and urine.  If this factor is taken into 
account, the results of recent balance studies (Maheswari et al., 
1981; Spencer et al., 1981) in a number of subjects over several 
weeks of observation suggest that retention may be 35 - 48%.  Thus, 

these results have, in general, confirmed the early findings of 
Largent & Heyroth (1949) that daily retention of increased amounts 
of fluoride intake approximates 50%.  Additional metabolic studies 
have been conducted using radioactive fluoride (F-18) in healthy 
subjects and in patients (Charkes et al., 1978).  Using published 
data, these authors conducted a computer simulation of a 
compartmental model for fluoride kinetics.  The results suggested 
that bone retains about 60% of intravenously-injected fluoride and 
that the half-time for this uptake is only about 13 min; both blood 
and extracellular fluid levels therefore decrease rapidly.  After 
ingestion of sodium fluoride, plasma fluoride levels show a much 
slower change with a half-life of about 3 h (Ekstrand et al., 
1977a).  This protracted course may be caused by a longer 
absorption time.  Approximately 99% of the fluoride in the body is 
localized in the skeleton.  The rest is distributed between the 
blood and soft tissues. 

4.2.2.  Blood

    The blood acts as a transport medium for fluoride.  About 75% 
of the blood fluoride is present in the plasma; the rest is mainly 
in or on the red blood cells (Carlson et al., 1960b; Hosking & 
Chamberlain, 1977).  The levels of total plasma fluoride reported 
in the literature before 1965 differ by several orders of magnitude 
from more recently reported levels.  Differences in analytical 
performance may explain these discrepancies.  It is now generally 
accepted that fluoride in human serum exists in both ionic and 
nonionic forms.  This conclusion was orginally derived from the 
observation by Taves (1968a) that the total fluoride content of 
serum determined with the fluoride-ion selective electrode after 
ashing was greater than the values obtained with procedures that 
measure ionic fluoride and do not involve ashing of the specimen.  
The nonionic fraction of serum fluorine was found by Taves 
(1968a,b) to be nonexchangeable with radioactive fluoride, and not 
ultrafilterable from human serum.  Electrophoresis of human plasma 
at pH 9.0 resulted in a clear separation of inorganic fluoride from 
the nonionic fluorine which migrated with albumin (Taves, 1968c).  
Guy et al. (1976) isolated and characterized the compounds that 
comprise the major portion of the nonionic fluorine fraction of 
human serum and found them to be predominantly perfluoro-fatty acid 
derivatives containing six to eight carbons.  They indicated that 
human serum also contains much smaller quantities of other 
uncharacterized organic fluorocarbons.  In human serum, the 
nonionic fluorine normally constitutes at least 50% of the total 
fluorine.  However, when fluoride intake is high, the ionic form 
may predominate (Guy et al., 1976).  In a group of rural Chinese, 
organic fluoride constituted about 17% of the serum fluoride 
(Belisle, 1981).  The origin of nonionic fluorine in the serum is 
still unknown (Singer & Ophaug, 1982). 

    For the general population under steady-state conditions of 
exposure, the concentration of fluoride ions in plasma is directly 
related to the fluoride content of the drinking-water.  This close 
relationship has been clearly demonstrated by several authors (Guy 
et al., 1976; Ekstrand et al., 1978; Singer & Ophaug, 1979).  The 
half-time of fluoride in plasma has been found to increase with 
dose, ranging from 2 to 9 h (Ekstrand, 1977; Ekstrand et al., 
1977b), perhaps related to a delayed uptake of higher doses.  For 
the same intake, the plasma fluoride ion concentration increases 
significantly with age (Carlson et al., 1960a; Ekstrand, 1977; 
Singer & Ophaug, 1979).  A possible explanation of this phenomenon 
in children is that uptake is faster in young bone, which is less 
saturated with fluoride (Wheatherell, 1966).  In addition, because 
of the accumulation of fluoride in the skeleton, increased amounts 
may be released from bone remodelling processes to the plasma in 
older individuals. 

    Several studies on plasma or serum fluoride levels have been 
performed, and a few should be mentioned to illustrate the 
magnitude of fluoride concentrations.  In 16 non-fasting young 
adults from an area in which the water was fluoridated, Taves 
(1966) found an average serum fluoride concentration of 13 
mg/litre.  In 20 adults from an area with a fluoride content of 
0.18 mg/  litre in the drinking-water, Fuchs et al. (1975) found a 
mean plasma fluoride ion concentration of 10.4 µg/litre.  Schiffl & 
Binswanger (1980) found a mean serum fluoride ion concentration of 
9.8 µg/litre in 8 healthy persons living in an area with a fluoride 
level of 0.06 mg/litre drinking-water.  Five subjects living in an 
area with a fluoride level in the drinking-water of 0.15 mg/litre 
had plasma fluoride ion concentrations ranging from 27 to 99 
µg/litre, whereas the plasma fluoride level in 7 subjects living in 
an area where the fluoride in drinking-water might reach a value of 
3.8 mg/litre ranged from 57 to 277 µg/litre (Jardillier & Desmet, 
1973) .  Ekstrand (1977) measured plasma fluoride concentrations in 
13 fluoride-exposed workers.  The concentrations were elevated 
compared with a normal range of 10 - 15 µg/litre and exceeded 50 
µg/litre in several workers.  The maximum concentration was 91 
µg/litre, 2 h after the end of exposure.  These marked variations 
found in different studies stress the importance of future 
investigations on blood levels of fluoride, and inter-laboratory 
analytical comparison programmes. 

4.2.3.  Bone

    Fluoride ions are taken up rapidly by bone by replacing 
hydroxyl ions in bone apatite.  It has been suggested that fluoride 
in extracellular fluid enters the apatite crystal by a three-stage 
ion exchange process:  the hydroxyapatite of bone mineral exists as 
extremely small crystals surrounded by a hydration shell; fluoride 
first enters the hydration shell, in which the ions are in 
equilibrium with those of the surrounding tissue fluids and those 
of the apatite crystal surface; the second stage reaction 
constitutes an exchange between the fluoride of the hydration shell 
and the hydroxyl group at the crystal surface; once it has entered 
the surface of the crystal, fluoride is more firmly bound; in the 

third stage, some of the fluoride may migrate deeper into the 
crystal as a result of recrystallization.  The consensus is that 
absorbed fluoride is incorporated into the hard tissues largely by 
a process of exchange and by incorporation into the apatite lattice 
during mineralization (Neuman & Neuman, 1958; US NAS, 1971). 

    The amount of fluoride present in bone depends on a number of 
factors including fluoride intake, age, sex, bone type, and the 
specific part of the bone.  About half of the absorbed fluoride is 
deposited in the skeleton (section 4.2.1) where it accumulates 
because of the long biological half-life of fluoride in bone.  
Young animals store more of the daily intake than older ones, this 
is perhaps related to the skeletal growth; this observation may 
partly explain the faster removal of fluoride ion from the plasma 
of young individuals and their lower fluoride ion concentrations in 
plasma.  The concentration of fluoride in bone increases with age 
(Smith et al., 1953; Jackson & Weidmann, 1958).  For example, in 
cortical bone from midshaft diaphysis of human femora from areas 
supplied with drinking-water containing less than 0.5 mg/litre, 
Weatherell (1966) found fluoride concentrations ranging from 200 to 
800 mg/kg (ash) in the age group 20 - 30 years and from 1000 to 
2500 mg/kg (ash) in the age group 70 - 80 years, respectively.  
Trabecular bone contains more fluoride than compact bone, and the 
biologically active surfaces of bone take up fluoride more readily 
than the interior (Armstrong et al., 1970).  Fluoride can be 
released from bone, as is evidenced by its continuous appearance in 
the urine in increased amounts after exposure has ceased.  Hodge & 
Smith (1970) have suggested, on the basis of published data, that 
such removal takes place in two phases:  a rapid process taking 
weeks and probably involving an ionic exchange in the hydration 
shell, and a slower phase with an average half-life of about 8 
years owing to osteoclastic resorption of bone.  Human data have 
suggested that 2 - 8% of fluoride retained is excreted during 18 
days following the initial retention (Spencer et al., 1975, 1981).  
Because of slower remodelling process, fluoride would be released 
even more slowly from compact than from trabecular bone.  Limited 
information on 43 cases of skeletal fluorosis suggests that the 
fluoride content from iliac crest biopsies may be reduced by one-
half, 20 years after cessation of exposure (Baud et al., 1978). 

4.2.4.  Teeth

    The factors controlling the incorporation of fluoride into 
dental structures have been reviewed by Weidemann & Weatherell 
(1970); they are essentially the same as those pertaining to bone. 

    Cementum is more akin to bone than to enamel and dentin, but 
its fluoride concentration has been found to be higher than that of 
bone (Singer & Armstrong, 1962).  Cementum exposed to oral fluids 
by recession of the gingiva may accumulate considerable amounts of 
fluoride. 

    Once formed, enamel and dentin differ from bone in that they do 
not undergo continuous remodelling.  The fluoride content of enamel 
is acquired partly during development and partly from the oral 
environment after eruption.  While the concentration of enamel 
fluoride decreases exponentially with distance from the surface, 
the actual values also vary with site, age, surface attrition, and 
increases with systemic and topical exposure to fluoride 
(Weatherell et al., 1977; Schamschula et al., 1982).  In adult 
teeth, the fluoride content of the surface layer of enamel 
(thickness 10 mm) is reported to be 900-1 000 mg/kg in areas with 
low fluoride levels in the water, about 1 500 mg/kg in fluoridated 
areas, and about 2 700 mg/kg in areas with fluoride concentration in 
the drinking-water of 3 mg/litre (Berndt & Sterns, 1979).  High 
fluoride content of enamel is associated with decreased solubility 
(Isaac et al., 1958) and probably with increased resistance to 
caries (Schamschula et al., 1979). 

    The average concentration of fluoride in dentine is 2 - 3 times 
that in enamel and is affected by growth and mineralization.  As 
with bone and enamel, dentin fluoride levels are higher in the 
surface (circumpulpal) regions than in the interior (US NAS, 1971). 

4.2.5.  Soft tissues

    The concentrations of fluoride in human soft tissues reported 
by different authors vary greatly.  It is generally agreed, 
however, that the normal soft tissue fluoride concentration in 
human beings is low, usually less than 1 mg/kg wet weight (US EPA, 
1980).  Fluoride has a relatively short biological half-life in 
these organs, and the soft tissue fluoride concentration is 
therefore practically in equilibrium with that in the plasma.  
Unlike fluoride in bone, the concentration does not increase with 
age or duration of exposure (Underwood, 1971).  However, ectopic 
calcification loci may accumulate fluoride in certain tissues, e.g. 
aorta, tendons, cartilage, and placenta (Hodge & Smith, 1970). 

4.3.  Excretion

    The principal route of fluoride excretion is via the urine.  
Some excretion takes place through sweat and faeces, and fluoride 
also appears in saliva.  Fluoride crosses the placenta; it rarely 
seems to be excreted in milk to any significant extent. 

4.3.1.  Urine 

    In adults, approximately half of the absorbed fluoride is 
excreted via the urine (section 4.2.1).  Renal fluoride ion 
excretion involves glomerular filtration followed by pH-dependent 
tubular reabsorption.  Fluoride clearance is less than that of 
creatinine (typically about 0.15 l/h per kg body weight, according 
to Ekstrand et al. (1977b)).  Fluoride appears rapidly in the urine 
after absorption.  Following a single oral dose of a soluble 
fluoride compound, the maximal rate of excretion is observed 2 - 4 h
after fluoride intake; the half-time for the fast compartment after 
gastrointestinal absorption averages about 3 h (Ekstrand et al., 

1977b), but injected fluoride is excreted even more rapidly 
(Charkes et al., 1978).  Several factors may influence the urinary 
excretion of fluoride, such as total current intake, previous 
exposure to fluoride, age, urinary flow, urine pH, and kidney 
status (Whitford et al., 1976; Ekstrand et al., 1978, 1982; Schiffl 
& Binswanger, 1980).  In urine, fluoride exists both as the ion (F-) 
and to a small extent as HF.  The equilibrium between F- and HF is
pH-dependent.  The tubular reabsorption of fluoride occurs mainly 
as HF and is therefore greater in acid urine (Whitford et al., 
1976).  Fluoride excretion can therefore be increased by 
maintaining alkalosis in a poisoned patient.  In a study where 
alkaline urine was produced by a vegetarian diet and acid urine by 
a protein-rich diet, renal fluoride clearance was significantly 
related to urinary pH and also to urinary flow (Ekstrand et al., 
1982). In practice, exposure is the most important factor and 
urinary fluoride concentration is recognized as one of the best 
indices of fluoride intake. 

    On a group basis, the correlation between the fluoride 
concentration in urine and that in drinking-water is excellent.  
This finding implies that, during periods of relatively constant 
fluoride supply, there exists an almost steady-state relationship 
between absorbed fluoride and fluoride excreted in the urine.  
However, some of the fluoride excreted originates from fluoride 
release during bone remodelling.  Thus, excretion rates may 
increase slightly with age, but no sex difference in fluoride 
excretion has been found (Vandeputte et al., 1977; Toth & Sugar, 
1976).  In patients with skeletal fluorosis from an area where this 
disease occurs endemically, the urinary excretion of fluoride was 
related to the severity of the disease and, to some degree, to the 
length of exposure (Rao et al., 1979).  Excess excretion rates may 
continue for years after the cessation of high exposure (Linkins et 
al., 1962; Grandjean & Thomsen, 1983). 

    Younger persons who are actively forming bone minerals excrete 
less fluoride, i.e., a lower proportion of the absorbed dose, than 
adults.  Zipkin et al. (1956) examined the urinary fluoride 
concentrations of children and adults before and after the start of 
fluoridation of the drinking-water supply.  Already after one week, 
the urinary fluoride levels of adults had reached 1 mg/litre.  In 
contrast, it took several years for the urinary fluoride of the 
children to reach the same concentration.  In chronic renal 
failure, the urinary excretion of fluoride is diminished when 
creatinine clearance values drop below 25 ml/min (Schiffl & 
Binswager, 1980).  In such cases, the impairment of urinary 
fluoride excretion is also reflected by an increase in the fluoride 
content of bone (Parsons et al., 1975).  The health significance of 
fluoride in dialysis fluids is discussed in section 7.3.4.  In 
situations with extremely high plasma levels of fluoride, e.g., 
following anaesthesia with methoxyflurane, acute kidney dysfunction 
may ensue with decreased clearance of fluoride. 

4.3.2.  Faeces

    The proportion of ingested fluoride that is eliminated in the 
faeces varies depending on circumstances (US EPA, 1980; Maheshwari 
et al., 1981; Spencer et al., 1981).  Fluoride present in faeces 
results from two sources:  the ingested fluoride that is not 
absorbed and the absorbed fluoride that is reexcreted into the 
gastrointestinal tract.  In persons not occupationally exposed to 
fluoride and not using fluoridated water, the faecal elimination of 
fluoride is usually less than 0.2 mg/day (US NAS, 1971). 

4.3.3.  Sweat

    Usually, only a few percent of the fluoride intake is excreted 
in the sweat.  However, under excessive sweating as much as 50% of 
the total fluoride excreted may be lost via perspiration (Crosby & 
Shepherd 1957). 

4.3.4.  Saliva

    Less than 1% of absorbed fluoride is reported to appear in the 
saliva (Carlson et al., 1960a; Ericsson, 1969).  Saliva fluoride 
levels were found to be about 65% of plasma levels (Ekstrand et 
al., 1977a).  In fact, saliva does not represent true excretion, 
because most of the fluoride will be recycled in the body.  
However, the fluoride content of the saliva is of major importance 
for maintaining a fluoride level in the oral cavity. 

4.3.5.  Milk

    The concentration of fluoride in human milk is quite similar to 
that in plasma (Ekstrand et al., 1981b), and significant exposure 
to fluoride through human milk is therefore very unlikely.  In 
fact, fluoride levels in human milk are lower than those in milk 
substitutes (Backer Dirks et al., 1974). 

4.3.6.  Transplacental transfer

    Fluoride crosses the placenta.  A study by Armstrong et al. 
(1970) measured fluoride from maternal uterine vessels and the 
umbilical vein and artery at caesarean section in human patients 
and did not find any significant gradient between maternal and 
fetal blood levels.  At higher fluoride levels, a partial barrier 
may exist (Gedalia, 1970).  The fluoride content of the fetal 
skeleton and teeth increases with the age of the fetus and with the 
fluoride concentration of the drinking-water used by the mother 
(Gedalia, 1970). 

4.4.  Indicator Media

    Under steady-state conditions of exposure, the plasma fluoride 
concentration is a reflection of the balance between fluoride 
absorption, excretion, and transfer to, and release from, storage 
depots.  Several authors have found a relationship between fluoride 
ion levels in plasma and fluoride intake (sections 4.2.1 and 

4.2.2).  Previous methods for fluoride determination needed an 
intravenous blood sample, but micro-methods using the fluoride ion 
selective electrode have now made capillary blood sampling 
feasible, if contamination from the skin surface can be excluded.  
Thus, plasma (or serum) may become a useful indicator medium in the 
future. 

    Urinary fluoride has usually been used to estimate the absorbed 
amount (Kaltreider et al., 1972; Pantchek, 1975; Dinman et al., 
1976a,b).  In persons not occupationally exposed to fluoride, the 
fluoride level in urine is almost the same as the fluoride 
concentration in the drinking-water.  In occupational fluoride 
exposure, the results of a retrospective study by Dinman et al. 
(1976a) suggest that group post-shift urinary fluoride 
concentrations averaging less than 8 mg/litre over a long period 
were not associated with enhanced risk of skeletal fluorosis and 
the same result appears to apply if preshift urinary fluoride 
concentrations are less than 4 mg/litre.  However, the presence of 
skeletal fluorosis in 43 aluminium potroom workers, of whom 37 had 
a urinary fluoride excretion  below 4 mg/24 h during an exposure-
free period (Boillat et al., 1979), may cast some doubt on the 
validity of this limit, since the exposure causing the disease was 
probably much higher several years previously.  With exposure 
mainly by the respiratory route, an average urinary fluoride 
concentration in postshift samples of 8 mg/litre in aluminium 
workers was found to correspond to an exposure of 2 mg/m3 (Dinman 
et al., 1976b).  However, because of the rapid excretion process, 
the timing of urine sampling is crucial.  Since it is usual for 
only spot urine samples to be available, correction of the widely 
varying urine volumes per time unit is advisable.  Correction to a 
standard density, to a defined amount of creatinine or to 
osmolality is used.  Furthermore, a postshift level below a certain 
limit on one day does not exclude that this limit may be exceeded 
on other days, if exposure conditions are somewhat variable.  Also, 
since a number of factors, including urinary flow and pH, may 
influence the fluoride concentration in the urine, it is not 
possible to make an accurate assessment of individual fluoride 
status on the basis of the urinary fluoride level in a single 
sample. 

    In addition, nails and hair may be useful indicators of long-
term fluoride exposures, under conditions where external 
contamination can be excluded. 

5.  EFFECTS ON PLANTS AND ANIMALS

5.1.  Plants

    Plants are exposed to fluoride in the soil, and in the air as a 
result of volcanic activity, natural fires, wind-blown dusts, 
pesticides, or as emissions from processes in which fluorine-
containing materials are burned, manufactured, handled, or used (US 
NAS, 1971).  The main route of entry of fluoride into animals is by 
ingestion, so plants are important vectors of the element in all 
ecosystems. 

    Fluoride is taken up from the soil by passive diffusion, then 
it is carried to the shoot by transpiration.  In temperate 
climates, and in most soils, the amount accumulated in this way is 
small so the average content of leaves in a non-polluted atmosphere 
is usually less than 10 mg F/kg dry weight.  Where soils are saline 
or enriched by fluoride-containing minerals or the atmosphere 
contains elevated fluoride concentrations, the concentration may be 
much higher.  In such areas, there may be sufficient plant uptake 
of fluoride to contribute significantly to the human or animal 
diet.  This factor should be considered in areas with endemic 
fluorosis.  A number of species accumulate high concentrations, 
even when grown on low-fluoride soils, perhaps as a result of 
complex formation with aluminium (Davison, 1984).  The tea family, 
Theaceae, is the best known of these accumulators, but there are 
several others that warrant further investigations (Davison, 1984). 

    Gaseous and particulate fluorides in the air are deposited on 
exposed plant surfaces, whilst gaseous fluoride enters leaves 
through stomatal pores.  Fluoride is also constantly lost from 
plants by a variety of little-understood processes (Davison, 1982, 
1984).  Superficial deposits may be tenaciously held and may 
account for over 60% of the total fluoride content of the leaf.  
Though such deposits are of negligible toxicity to the plant, they 
may present a hazard for grazing animals.  Fluoride that penetrates 
the internal tissue of leaves or that is deposited on active 
surfaces such as stigmata may affect a variety of metabolic 
processes and result in effects on appearance, growth, or 
reproduction.  Recent reviews of the metabolic effects of fluoride 
have been reported by Bonte (1982) and by Weinstein & Alscher-
Herman (1982). 

    The visible effects of toxic concentrations of fluoride on 
plants are well documented (Jacobson & Hill, 1970; Weinstein, 
1977).  They may include chlorosis, peripheral necrosis, leaf 
distortion, and malformation or abnormal fruit development.  None 
of these symptoms are specific to fluoride, and the effects of many 
other stresses may appear very similar.  The diagnosis of fluoride 
injury normally involves both visual and chemical evidence, and 
comparison of a number of species of known tolerance growing around 
the source.  Factors relating to the frequency of exposure have 
also to be taken into account. 

    The susceptibility of different plant species to excessive 
atmospheric fluoride varies considerably (Jacobson & Hill, 1970; US 
NAS, 1971).  Many conifers are very susceptible during the short 
period of needle growth, but they then become much more resistant.  
Some monocotyledons, such as gladiolus and tulip, are similarly 
susceptible, though there is great varietal variation.  In some 
species, there is a great difference in susceptibility between 
leaves and fruits.  For example, peach fruit are extremely 
sensitive to very low concentrations of fluoride, but leaves are at 
least an order of magnitude more resistant. 

    Available evidence (Weinstein, 1977; Davison, 1982) indicates 
that visible injury and effects on growth or yield are to a large 
extent independent.  Many cases have been reported where there was 
visible foliar injury but no associated growth effects.  Equally, 
there have been instances where visible symptoms were combined with 
stimulation of some parameters of growth, probably by alteration of 
resource allocation.  Most significant, however, are reports that 
there may be economically significant reductions in yield with no 
visible symptoms on the leaves (MacLean & Schneider, 1971; Pack & 
Sulzbach, 1976; Unsworth & Ormrod, 1982).  This last aspect of 
effects on plants needs clarification. 

    Attempts have been made to devise air quality criteria for the 
protection of plants, notably by McCune (1969), who produced dose-
response curves for a number of species.  Generally, there is a 
non-linear, negative relationship between concentration and the 
length of exposure necessary to cause an effect, so air quality 
criteria must be stated in terms of time-related concentration.  
Tissue concentrations are a useful adjunct to diagnosis and to 
quality criteria, but superficial fluoride deposits and 
compartmentation within the leaf make interpretation difficult.  A 
useful summary of air quality criteria adopted by different 
organisations for plant protection is given in IPAI (1981).  Such 
criteria can be adjusted from place to place and from time to time 
to take account into:  (a) the dissimilarity of vegetation and its 
consequent sensitivity in different areas; (b) changes in 
susceptibility of vegetation to fluoride during the year; and (c) 
the intended use of the vegetation (MacLean, 1982). 

    Generally, little or no injury will occur when the most 
sensitive species are exposed to a fluoride level of about 0.2 
mg/m3.  Most species tolerate concentrations many times higher than 
this.  It is difficult to define the minimum tissue fluoride 
concentration associated with injury; however, there are reports of 
some species showing effects with concentrations as low as 20 mg/kg 
dry weight (Weinstein, 1977). 

    Fluoride taken up by plants from soil or air is transferred to 
animals by ingestion of plant cellular fluids, nectar, pollen, 
tissues, or whole organs.  Because the concentration of fluoride 
varies greatly in different parts of plants, the amount ingested by 
an animal depends on its feeding strategy.  For example, animals 
that consume whole shoots will ingest much greater quantities of 
fluoride than phloem-sucking invertebrates.  Food preparation 

reduces the amount of fluoride ingested from contaminated 
vegetables by human beings, because the outer leaves are removed 
and the material is washed before eating. 

    Because of the potential economic importance of fluoride 
accumulation in livestock and the role of plants in fluoride 
transfer to animals, air quality criteria designed to protect 
livestock from fluoride injury are usually based on the fluoride 
content of forage, although the role of fluoride in dietary 
supplements must also be considered (section 5.5.3). 

5.2.  Insects

    Both inorganic and organic fluoride compounds have been used as 
insecticides for many years.  In sub-lethal doses, the former have 
been shown to reduce growth and reproduction in many species of 
invertebrates (US EPA, 1980).  It has been suggested that fluoride-
insect interactions have been responsible for extensive insect 
damage to forests around aluminium smelters, although the mechanism 
of this interaction is not clear (Weinstein, 1977; Alcan 
Surveillance Committee, 1979). 

    Honey bees are known to be susceptible to fluoride, and 
apiarists have suffered significant economic damage in areas around 
some sources of fluoride emission. 

    Insects collected from fluoride-polluted areas show higher 
concentrations of this element than those from non-polluted areas, 
and it has been suggested that this is partly due to food chain 
accumulation (US EPA, 1980).  However, firm evidence concerning 
biomagnification is lacking. 

    Genotoxic effects are discussed in section 5.6. 

5.3.  Aquatic Animals

    Reactions to fluoride have been examined in several studies on 
aquatic animals , chiefly on fish, to provide a basis for 
regulations on the permissible amount of fluoride in waste water 
discharged into the sea or fresh water recipients. 

    Fish exposed to poisonous amounts of sodium fluoride (Tables 5, 
6) become apathetic, lose weight, have periods of violent movement, 
and wander aimlessly.  Finally, there is a loss of equilibrium 
accompanied by tetany and death.  Mucous secretion increases, 
accompanied by proliferation of mucous-producing cells in the 
respiratory and integumentary epithelium (Neuhold & Sigler, 1960). 

    Studies on the effects of fluoride on aquatic animals (some 
results are given in Tables 5 & 6) show that sensitivity and lethal 
doses are influenced by many factors, e.g., size of fish, density 
of fish per m3 of aquarium, water temperature, calcium and chloride 
concentrations in the water, and proper maintenance of streaming 
water.  Crustaceans may be more tolerant to fluorides than fish (US 
EPA, 1980).  However, the studies give only scattered information 

concerning the effects of fluoride on the fish under various living 
conditions.  New and more systematic and detailed studies 
concerning the long-term influence of fluorides on aquatic animals 
are therefore necessary. 

5.4.  Birds

    The bones of birds collected near emission sources show 
elevated fluoride levels, but there are no reports of any other 
effects.  Most reports on the effects on birds pertain to domestic 
species such as chickens, turkeys, quails, etc.  The paucity of 
reports on wild birds may be the consequence of their lower 
economic value.  In addition, the  mobility of birds makes it 
difficult to define the exposure to fluoride.  High fluoride 
ingestion by birds can result in reduced growth rate, leg weakness, 
and bone lesions.  Tolerance to fluorides varies among bird species 
and among individuals of the same species (US NAS, 1971, 1974; US 
EPA, 1980). 

5.4.1.  Acute effects

    Typical symptoms of acute toxicity are reduction or loss of 
appetite, local or general congestion, and sub-mucosal haemorrhages 
of the gastrointestinal tract (Cass, 1961; US EPA, 1980).  Such 
acute responses were recognized when chickens were fed for 10 days 
on a diet containing 6786 mg F- per kg (as sodium fluoride).  
Roosters receiving sodium fluoride at 200 mg/kg body weight, twice 
in 24 h, developed gastro-enteritis with oedema of the mucosa of 
the stomach and upper bowels, subcutaneous oedema, hepatomegaly, 
and atrophy of the pancreas. 

5.4.2.  Chronic effects                           
                                                                    
    Chronic fluorosis in birds can be difficult to diagnose, partly 
because birds do not have teeth, which are important aids to        
diagnosis in other animals (US NAS, 1974).  It is necessary to      
establish the presence of characteristic lesions, a history of      
exposure at the proper time to levels of fluoride known to be       
toxic, and analytical evidence that bone contains fluoride          
concentrations consistently associated with the lesions of chronic  
fluorosis, before a definite diagnosis can be made (Cass, 1961).    

    In birds, chronic fluoride toxicosis develops slowly and       
primarily involves gross and microscopic changes in bone.  If      
elevated fluoride intake persists, the general health of the       
animals deteriorates progressively.  Growth rate decreases,        
lameness may develop, and usually there is loss of appetite (US    
EPA, 1980).  Levels of fluoride in the ration that can be tolerated
have been given as 300 mg/kg for growing chicks and 400 mg/kg for  
laying hens and turkeys (US NAS, 1974).                            

    The body weight, tibia weight in Japanese quail, and the bone 
ash, and eggshell thickness were not affected by a sodium fluoride
concentration in the drinking-water of 50 mg/litre (Vohra, 1973). 


Table 5.  Effect of excessive fluoride on fresh water fish
---------------------------------------------------------------------------------
Species            Fluoride   Exposure    Effect        Reference
                   (mg/litre) time
---------------------------------------------------------------------------------
Goldfish           1000       60 h        No survival   Ellis (1937)

Carp               75 - 91    480 h       50% survival  Neuhold & Sigler (1960)

Red-eye fry        < 25      5 - 6 days  None          Vallin (1968)

Red-eye roe        < 25      7 days      None          Vallin (1968)

Juvenile salmon    100        5 days      Survival      Vallin (1968)

Juvenile trout     200        5 days      Survival      Vallin (1968)
                   (brackish       
                   water)

Brown trout fry    15         240 h       50% survival  Wright (1977)

Brown trout fry    2.0        240 days    uncertain     Wright (1977)

Brown trout fry    0.9        240 days    None          Wright (1977)

Rainbow trout      2 - 4      10 days     uncertain     Angelovic et al. (1961)

Rainbow trout      5.9 - 7.5  10 days     50% survival  Angelovic et al. (1961)

Rainbow trout      8.5        504 h       95% survival  Herbert & Shurben (1964)

Rainbow trout      4.0        504 h       50% survival  Herbert & Shurben (1964)

Rainbow trout egg  222 - 273  424 h       50% survival  Neuhold & Sigler (1960)

Rainbow trout fry  61 - 85    825 h       50% survival  Neuhold & Sigler (1960)
---------------------------------------------------------------------------------

Table 6.  Effect of excessive fluoride on marine animals
-----------------------------------------------------------------------------------
Species             Fluoride   Exposure  Effect           Reference
                    (mg/litre) time
-----------------------------------------------------------------------------------
 Mugil cephalus      100        96 h      None             Hemens & Warwick (1972)
(mullet)

 Mugil cephalus      5.5        113 days  None             Hemens et al. (1975)

 Mugil cephalus      52         72 days   Increased        Hemens & Warwick (1972)
                                         mortality

 Ambassis safgha     100        96 h      None             Hemens & Warwick (1972)
(small fish)

 Therapon jarbua     100        96 h      None             Hemens & Warwick (1972)
(small fish)

 Penaeus indicus     5.5        113 days  None             Hemens et al. (1975)
(prawn)

 Penaeus indicus     100        96 h      None             Hemens & Warwick (1972)

 Penaeus monodon     100        96 h      None             Hemens & Warwick (1972)

 Tylodiplax bleph-   52         72 days   Increased        Hemens & Warwick (1972)
 ariskios (crab)                          mortality

 Tylodiplax bleph-   100        96 h      None             Hemens et al. (1975)
 ariskios

 Palaemon pacificus  52         72 days   Affected         Hemens & Warwick (1972)
                                         reproducibility

 Perna perna         7.2        5 days    Evidence of      Hemens & Warwick (1972)
(brown mussel)                           toxic effects
-----------------------------------------------------------------------------------

                                                                   
5.5.  Mammals

    The toxicity of various fluorides has been studied mainly in 
two categories of animals, i.e., laboratory animals (rats, mice, 
guinea-pigs, rabbits, dogs, and cats) and live-stock.  The acute 
and chronic effects have usually been examined in studies on 
laboratory animals, especially rats.  The chronic effects have been 
extensively studied in large and long-term studies on domestic 
mammals. 

5.5.1.  Acute effects

5.5.1.1.  Exposure to sodium fluoride

    For laboratory animals, the single lethal dose of F-, when 
administered orally as easily soluble fluorides, is in the range of 
20 - 100 mg/kg body weight (Davis 1961; Eagers, 1969).  The lethal 
dose for intravenous, intraperitoneal, and subcutaneous injection 
of sodium fluoride is half of the oral lethal dose (Muehlburger, 
1930).  Fatal acute intoxication may occur in laboratory animals 
following repeated oral administration of sublethal doses of 
soluble fluorides. 

    Signs of acute systemic fluoride intoxication are increased 
salivation, lacrimation, vomiting, diarrhoea, muscular 
fibrillation, and respiratory, cardiac, and general depression.  
The rapidity of onset and the progression of the intoxication 
varies directly with the magnitude of the initial dose (Davis, 
1961).  The anatomical lesions of fatal acute intoxication are non-
specific, but the gastro-enteric irritation is more general and 
more intense than that usually found in most other forms of gastro-
enteritis. 

    Several authors have determined the levels of ionic fluoride in 
the plasma of laboratory animals, that are sufficiently high to 
result in acute fluoride poisoning and ultimately death.  De Lopez 
et al. (1976) determined the LD50 for female rats, weighing 80, 
150, or 200 g, when given sodium fluoride by stomach intubation.  
The LD50 for 80 g rats and 150 g rats was practically the same (54 
and 52 mg/kg body weight, respectively), but this value was 
decidedly higher than that for 200 g rats (31 mg/kg body weight).  
The low LD50 observed in the oldest (heaviest) rats was ascribed to 
a higher degree of fluoride saturation in their skeletons.  The 
plasma ionic fluoride concentration associated with the LD50s 
ranged from 8 - 10 mg/litre and spontaneous death occurred in all 
three groups at these levels.  The maximum fluoride levels were 
reached within 15 min of administration, and levels of at least 4 
mg/litre persisted for 4 h or more. 

    Singer et al. (1978) studied the ionic fluoride levels in 
plasma following intraperitoneal administration of 15, 20, or 25 mg 
of fluoride per kg body weight to 200 g rats.  In animals given 25 
mg/kg, the mean ionic fluoride level in plasma was 38 mg/litre 
after 10 min and the animals invariably died within 1 h.  All 
animals receiving 15 or 20 mg/kg survived, despite mean ionic 

fluoride levels in plasma of 22.9 and 29.2 mg/litre, respectively.  
These levels are considerably higher than the levels that resulted 
in death in the previously mentioned study by De Lopez et al. 
(1976).  Singer & Ophaug (1982) explained this seeming disagreement 
in the following way:  "Administration of the fluoride by stomach 
intubation results in slower absorption of the fluoride and lower 
peak plasma fluoride levels that persist for a longer period.  It 
appears, based upon these investigations, that plasma fluoride 
levels of 4 - 10 ppm for a protracted period is more toxic than 
considerably higher levels for a shorter period of time". 

    Ionic fluoride levels in plasma of 12 - 41 mg/litre were 
observed in rabbits by Hall et al. (1972b), 1 h after the 
administration by stomach intubation of 100 - 140 mg sodium 
fluoride per kg body weight.  The authors reported that plasma 
concentrations of over 28 mg/litre, 1 h after dosing, were lethal.  
Rabbits with a 1-h plasma fluoride level of 24 mg/litre or less 
survived at least 24 h. 

    The nephrotoxic potential has been studied in detail.  Fluoride 
doses (5 - 20 mg/kg body weight) administered intravenously to dogs 
caused an increase in urine volume and a decrease in urea excretion 
(Gottlieb & Grant, 1932).  Sodium fluoride (50 mg/kg body weight) 
administered orally to rats caused increased urinary excretion of 
inorganic phosphate, calcium, magnesium, potassium, and sodium 
associated with polyuria (Suketa & Mikami, 1977).  Similar effects 
have been observed in man following anaesthesia with fluorine-
containing agents (section 7.3.4).  A decrease in renal (Na+ + K+)-
ATPase activity was associated with an increase in urine volume and 
urinary sodium excretion, and with a concomitant decrease in serum 
sodium concentration (Suketa & Mikami, 1977; Suketa & Terui, 1980).  
After intraperitoneal administration of a single large dose of 
fluoride (NaF, 35 mg/kg body weight), the calcium contents of the 
renal cortex and medulla of fluoride-intoxicated rats were 
increased by 33 and 10 times, respectively (Suketa et al., 1977). 

5.5.1.2.  Exposure to fluorine, hydrogen fluoride, or silicon 
tetrafluoride

    Acute intoxication may also result from single or repeated 
episodes of respiratory exposure to elemental fluorine and gaseous 
hydrogen fluoride and silicon tetrafluoride.  These gases primarily 
act as severe respiratory irritants.  Fluorine reacts vigorously 
with almost every element or material, thereby severely injuring 
the respiratory tract.  Hydrogen fluoride and silicon tetrafluoride 
also induce respiratory tract damage.  If the respiratory damage is 
not in itself lethal, systemic intoxication may follow. 

    DiPasquale & Davis (1971) reported the median lethal concentration 
for a 5-min exposure (5 min LC50) to hydrogen fluoride for rat and 
mouse to be 14 400 and 5 000 mg F/m3, respectively.  The 60-min LC50 
values for rat and mouse were reported to be 1 100 and 270 mg F/m3, 
respectively (Wohlschlager et al., 1976). 

    When rats were exposed through inhalation to hydrogen fluoride 
for 5, 15, 30, or 60 min, the LC50s were 4060, 2200, 1670, and 1070 
mg/m3, respectively; the LC50 for guinea-pigs with an exposure of 
15 min was 3540 mg/m3.  Irritation of the mucous membranes of the 
eyes and nose, weakness, and a decrease in body weight were 
observed in the poisoned animals.  Acute inflammation and focal 
necrosis of the nasal mucosa, irritation of the skin, necrosis of 
the renal tubular epithelium, congestion of the liver and 
vacuolation of its cells, and myeloid hyperplasia of the bone 
marrow were found histologically.  When rats, dogs, and rabbits 
were exposed to hydrogen fluoride at a concentration of 6 - 50% of 
the LC50 for rats, the animals developed tracheobronchitis and 
irritation of conjunctiva and the nasal mucosa, which lasted about 
4 days (Rosenholtz et al., 1963). 

    A recent study by Morris & Smith (1982) sheds some light on the 
question of why large doses of a reactive gas such as hydrogen 
fluoride are required to induce pulmonary damage in certain 
species.  After surgically isolating the upper respiratory tract 
from the lower in rats, the authors found that 99.8% of the 
hydrogen fluoride was absorbed in the upper respiratory tract at 
concentrations ranging from 30 - 176 mg F/m3.  Plasma fluoride 
concentrations were significantly elevated by upper respiratory 
tract exposure to hydrogen fluoride and were highly correlated with 
airborne concentrations of hydrogen fluoride. 
                                  
5.5.2.  Chronic effects on small laboratory animals

    The first visible sign of chronic fluoride intoxication in 
laboratory animals is dental fluorosis.  No general threshold value 
can be given.  However, a loss of the orange-brown pigmentation of 
the incisors is seen in rats maintained on a low-fluoride diet (0.1 
- 0.3 mg/kg dry weight) and drinking-water containing 25 mg/litre 
of fluoride (Taylor et al., 1961).  When the fluoride concentration 
of the drinking-water was increased to 50 - 100 mg/litre, the 
incisors became white and chalk-like with tips that fractured 
easily. 

    Accumulation of fluoride in the bones of laboratory animals has 
been examined in many studies (reviews Davis, 1961; Singer & 
Ophaug, 1982).  In rats on a low-fluoride diet (0.1 - 0.3 mg/kg), 
accumulation was chemically detectable at a fluoride level in the 
drinking-water of 1 mg/litre and radiologically visible after 6 
months at a water concentration of 50 mg/litre (Taylor et al., 
1961).  At higher levels of fluoride intake, there is generally an 
enlargement of the flat bones and subsequent interference with the 
functioning of the joints (Davis, 1961).  However, no threshold 
values seem to have been given in the literature for the appearance 
of such clinical osteofluorotic signs in laboratory animals. 

    A toxic effect of fluoride in the form of retarded growth was 
reported for mice kept for 8 weeks on a low-fluoride diet with a 
fluoride content in the drinking-water of 100 mg/litre (Messer et 
al., 1973).  The same conditions of fluoride intake over a period 
of 6 months did not result in growth depression in rats (Taylor et 

al., 1961).  However, growth retardation was registered in rats 
maintained for 6 months on a diet containing a fluoride 
concentration of 3 mg/kg and drinking-water with a fluoride content 
of 100 mg/litre (Büttner & Karle, 1974). 

    A fluoride level of 100 mg/litre in the drinking-water impaired 
reproduction in mice (Messer et al., 1973). 

    Rats on a low-fluoride diet (0.1 - 0.3 mg/kg) tolerated 
drinking-water containing 50 mg/litre for 6 months without the 
appearance of histological alterations or effects on the renal 
function (Taylor et al., 1961).  At a fluoride level in the 
drinking-water of 100 mg/litre, dilation of the renal tubules 
appeared in some of the rats.  This pathological change was 
accompanied by increased urine output and increased water 
consumption in the affected animals.  Evidence was presented by 
Spira (1956), that fluoride may induce the formation of urinary 
calculi.  Results of more recent studies on rats suggest that 
fluoride at high dose levels (23 mg/kg diet) is one of several 
factors that determine the likelihood of calculus formation, 
crystalluria, and urolithiasis (Anasuya, 1982). 

5.5.3.  Chronic effects on livestock

    US EPA (1980) lists the most commonly encountered sources of 
excessive fluoride for livestock as follows: 

    (a)  forage crops, usually the major source of an animal's
         diet, which have been contaminated by fluoride
         emissions, or wind-blown or rain-splashed soil with a
         high fluoride content;

    (b)  water with a high fluoride content;

    (c)  feed supplements and mineral mixtures that have not
         been properly defluorinated; and

    (d)  forage crops grown in soils with a high fluoride
         content.

    The effects and dietary tolerance of animals to long-term 
exposure to levels of fluoride were reviewed in US NAS (1974), 
Suttie (1977), and US EPA (1980). 

    Chronic manifestations of excess fluoride in cattle are very 
similar to those found in man, i.e., dental fluorosis and 
osteofluorosis.  Animals with moderate to severe osteofluorosis 
sometimes exhibit an intermittent, non-specific, atypical lameness 
or stiffness that may be associated with calcification of 
periarticular structures and tendon insertions.  This lameness or 
stiffness is often transitory in nature, and limits feeding or 
grazing time, thereby impairing animal performance.  Other general 
non-specific signs or symptoms sometimes associated with chronic 
fluoride toxicosis include thickened, dry unpliable skin and poor 
performance. 

    Studies on the effects of fluoride in the diet on livestock, 
critically assessed in US NAS (1974), are given in Table 7.  
Symptoms or signs develop progressively at total fluoride dietary 
concentrations exceeding 20 - 30 mg/kg. 

    The tolerance of many common domestic animals, shown in Table 
8, indicates that dairy heifers are the least and poultry the most 
tolerant. 

    Diagnosis of fluorosis is based on determination of fluoride in 
the total diet, clinical observations, especially on the teeth, 
biopsy of tail bones and, where appropriate, post-mortem 
examination. 

    Prevention of fluoride injury in domestic animals can be 
achieved by:  (a) control of fluoride emissions; (b) regular 
monitoring of the total diet; (c) use of properly defluorinated 
mineral supplements; and (d) regular examination by a veterinarian. 

Table 7.  Relationship between fluoride levels in the diet and the
development of various changes in cattlea
----------------------------------------------------------------
Change                        Total fluorine in diet (mg/kg)b
                              ----------------------------------
                              20 - 30  30 - 40  40 - 50  > 50
----------------------------------------------------------------
Discernible dental mottlingc  yes      yes      yes      yes

Enamel hypoplasia (score      no       no       yes      yes
number 4)c

Slight gross periosteal       no       yes      yes      yes
hyperostosis

Moderate gross periosteal     no       no       yes      yes
hyperostosis

Significant incidence of      no       no       no       yes
lameness

Decreased milk production     no       no       no       yes

Skeletal fluoride equivalent  no       no       no       yes
to 5000 mg/kg at 5 yearsd

Urine fluoride of 25          no       no       yes      yes
mg/litree 
----------------------------------------------------------------
a  From: US NAS (1974).
b  The statements "yes" or "no" indicate if the symptom would 
   be reproducibly seen at this level.
c  Only if fluoride is present during formative period of the 
   tooth.
d  Metacarpal or metatarsal bone, dry, fat-free basis.
e  Based on values taken after 2 - 3 years of exposure; density 
   = 1.04.


   
Table 8.  Dietary fluoride tolerances for domestic animalsa,b
------------------------------------------------------------------
Animal                             Performancec       Pathologyd
                                   (mg/kg)            (mg/kg)
------------------------------------------------------------------
Beef or dairy heifers              40                 30

Mature beef or dairy cattlee       50                 40

Finishing cattle                   100                NAf

Feeder lambs                       150                IDg

Breeding ewes                      60                 ID

Horses                             60                 40

Finishing pigs                     150                NA

Breeding sows                      150                100

Growing or broiler chickens        300                ID

Laying or breeding hens            400                ID

Turkeysh                           400                ID

Growing dogs                       100                50
------------------------------------------------------------------
a  From:  US NAS (1974).
b  The values are presented as mg/kg F in dietary dry matter and 
   assume the ingestion of a soluble fluoride, such as NaF.  When 
   the fluoride in the ration is present as some form of 
   defluorinated rock phosphate,    these tolerances may be 
   increased by 50%.
c  Levels that, on the basis of published data for this species, 
   could be fed without clinical interference with normal 
   performance.
d  At this level of fluoride intake, pathologic changes occur.  
   The effects of these changes on performance are not fully known.
e  Cattle first exposed to this level at 3 years of age or older.
f  NA = non applicable.
g  ID = insufficient data.
h  This level has been shown to be safe for growing female turkeys.
   Very limited data suggest that the tolerance for growing male 
   turkeys may be lower.

    Limits for the fluoride content of the diet, proposed as 
standards for the prevention of fluorosis by Suttie (1969), have 
been adopted by many regulatory organisations (IPAI, 1981).  
Because monitoring of the diet of livestock is difficult, it is 
essential that a protocol such as that suggested by Suttie (1969) 
and Davison et al. (1979) should be followed. 

5.6.  Genotoxicity and Carcinogenicity

5.6.1.  Genetic effects and other related end points in short-term tests

    Sodium fluoride did not induce reverse mutations in  Salmonella 
 typhimurium either in the absence or presence of a metabolic 
activation system from Aroclor-induced rats.  In the same study, it 
did not induce gene conversion in  Saccharomyces cerevisiae (Martin 
et al., 1979). 

    A fluoride level of 0.4 - 1.0 mg/litre inhibited DNA repair 
after irradiation of mouse spleen cells  in vitro (Klein et al., 
1974).  Sodium fluoride was not mutagenic in cell cultures of human 
leukocytes at concentrations of 18 and 54 mg/litre (Voroshilin et 
al., 1973) and 18 mg/litre (Obe & Slacik-Erben, 1973).  Little or 
no effect was noted on chromosomes when mouse oocytes were exposed 
 in vitro to a fluoride concentration of 200 mg/litre in media for 
up to 14 h.  Sheep and cow oocytes were unaffected by a 
concentration of 100 mg/litre in media for 24 h (Jagiello & Lin, 
1974). 

    Sodium fluoride, hydrogen fluoride, and stannous fluoride were 
reported to increase the frequency of sex-linked recessive lethals 
in  Drosophila melanogaster following feeding or inhalation exposure 
of adults (Gerdes, 1971; Gerdes et al., 1971; Mitchell & Gerdes, 
1973).  In other studies (Mukherjee & Sobels, 1968; Mendelson, 
1976), no sex-linked recessive lethals were induced in  Drosophila  
following either injection or feeding of sodium fluoride.  Sodium 
monofluorophosphate did not induce dominant lethals in mature sperm 
or oocytes of  Drosophila (Bucchi, 1977).  Mohamed & Chandler 
(1977) reported that the number of cells from bone marrow or 
spermatocytes with chromosomal abnormalities increased in mice with 
a fluoride dose in drinking-water of 1 mg/litre or more.  Owing to 
various inconsistencies and lack of proper double-blind procedures, 
the results of Mohamed & Chandler (1977) have been questioned 
(Victoria Committee, 1980).  Martin et al. (1979) using the same 
experimental design, could not reproduce the effects, even when 
fluoride levels were as high as 100 mg/litre drinking-water. 

    Feeding of sodium fluoride to mice at concentrations of up to 
50 mg/kg diet for seven generations did not induce chromosomal 
aberrations or sister chromatid exchanges in the bone marrow (Kram 
et al., 1978).  No cytogenetic changes occurred in the oocytes of 
mice given single or repeated treatments of sodium fluoride 
(Jagiello & Lin, 1974). 

    Sodium fluoride has been reported to inhibit or potentiate the 
mutagenic effects of irradation or chemicals in  Drosophila 
 melanogaster (Mukherjee & Sobels, 1968; Vogel, 1973; Burki & 
Bucchi, 1975a,b).  The inhibiting effects may be due to decreased 
uptake of the mutagen (MacDonald & Luker, 1980), whereas 
potentiation of the mutagenic effects due to radiation may result 
from the action of fluoride on enzymes involved in DNA repair 
(Mukherjee & Sobels, 1968). 

    Non-specific cytogenetic effects, including anaphase lagging, 
bridges, tetraploidy, multipolar anaphases, and increase in the 
frequency of abnormal mitotic figures, have been induced in several 
plant species by sodium fluoride (Hakeem & Shehab, 1970; Mouftah & 
Smith, 1971; Bale & Hart, 1973a,b; Galal & Abd-Alla, 1976).  In 
contrast, Temple & Weinstein (1978) did not find any chromosomal 
aberrations in plants treated with hydrogen fluoride or sodium 
fluoride. 

5.6.2.  Carcinogenicity in experimental animals

    No adequate long-term carcinogenicity studies on fluoride 
compounds are available.  Two long-term studies in which sodium 
fluoride in the drinking-water is being administered to mice and 
rats are in progress (IARC, 1982). 

    IARC (1982) reviewed the available data from three studies in 
which sodium fluoride in the drinking-water or diet had been 
administered to mice (Tannenbaum & Silverstone, 1949; Taylor, 1954; 
Kanisawa & Schroeder, 1969) and concluded that the available data 
were insufficient to make an evaluation of the carcinogenicity of 
sodium fluoride for experimental animals. 

5.7.  Experimental Caries

    In several hundred studies, caries has been induced in animals, 
especially in rats and hamsters, by sucrose-containing diets (for 
reviews, see Larson, 1977).  Addition of fluoride, usually sodium 
fluoride, to the diet and/or the drinking-water has been found to 
substantially reduce the incidence of experimentally-induced 
carious lesions.  A reduction in caries incidence has also been 
obtained experimentally by the topical application of fluoride. 

5.8.  Possible Essential Functions of Fluorides

    Because of the presence of fluoride in measurable amounts in 
all human and animal tissues and fluids, and because of the extreme 
reactivity of fluorides, studies have been designed to test whether 
fluorides are essential for animal life.  The difficulty of such 
studies is that it is virtually impossible to eliminate all 
fluoride from the diet given to the animals tested. 

    The results of recent studies with diets low in fluoride 
demonstrate that fluoride promotes growth in rats (Schwarz & Milne, 
1972), and increases fertility, and alleviates anaemia in mice 
under the stress of pregnancy on a diet marginally adequate in iron 
(Messer et al., 1972, 1973).  Fluoride may thus play a secondary 
role, by promoting a more efficient utilization of dietary levels 
of iron and possibly other trace elements. 

    Based on crystallographic data, Newesely (1961) suggested that 
fluoride is essential for nucleation of the precipitation and 
crystallization of bone apatite. 

    A WHO expert committee (WHO, 1973) considered fluorine to be 
one of the 14 elements that are essential for animal life. 

6.  BENEFICIAL EFFECTS ON HUMAN BEINGS

    The caries-inhibiting capacity of fluoride ions was discovered 
in the 1930s and has given rise to extensive community and clinical 
trials, documented comprehensively in the scientific literature.  
There has also been extensive implementation of fluoride preventive 
programmes at community and individual levels.  More recently, the 
possible beneficial effects of fluorides on osteoporosis have been 
studied.  The possible essentiality has been examined in laboratory 
animals (section 5.8). 

6.1.  Effects of Fluoride in Drinking-Water

    It was reported in early studies that the prevalence of dental 
caries was negatively correlated with the fluoride concentration in 
the drinking-water.  People using a water supply with a fluoride 
content of 1 mg/litre or more were found to have about 50% less 
dental caries than those with a supply containing 0.1 - 0.3 mg 
fluoride per litre (Dean et al., 1941a,b; Dean, 1942).  No 
"objectionable" dental fluorosis was observed at a water fluoride 
level of 1 mg/litre (Dean, 1938,1942; McClure, 1944; McClure & 
Kinser, 1944), a level that was called the "optimal" level, as it 
was also connected with a low prevalence of caries.  As a 
consequence of these findings, it was suggested that the water-
works should add fluorides to fluoride-poor waters thus raising the 
fluoride level to an "optimal" level.  In areas with a hot climate, 
the "optimal" fluoride concentration is below 1 mg/litre while in 
cold climates it may be up to 1.2 mg/litre (Galagan & Vermillion, 
1957) (section 3.5).  The technical details of fluoride addition do 
not imply any major difficulties (Maier, 1972). 

    In 1945-47, four controlled studies on the effects of 
fluoridation of low fluoride drinking-water were carried out, in 
Brantford, Canada; Evanston, Newburgh, and Grand Rapids, USA.  
These studies gave the expected results, a caries reduction of 50% 
or more, i.e., the same low caries prevalence as in areas naturally 
fluoridated to optimal levels (Ast et al., 1956; Brown et al., 
1956,1960; Blayney & Hill, 1967; Arnold & Russell, 1962; Brown & 
Poplove, 1965).  The results of the Brantford study are illustrated 
in Fig. 1. 

    A compilation of 120 fluoridation studies from all continents 
(Murray & Rugg-Gunn, 1979) showed a reduction in caries in the 
range of 50 - 75% for permanent teeth and about 50% for primary 
teeth, in children, 5 - 15 years of age, following life-long 
consumption of fluoridated water.  In general, water fluoridation 
studies have indicated that maximal caries reduction and delay in 
the progression of carious lesions is achieved in people living in 
a fluoridated area from an early age.  The increasing effect over 
time of fluoridation is illustrated in Fig. 2.  If the fluoridation 
of drinking-water in an area is discontinued, much of the caries 
protection acquired by the residents will gradually disappear 
(Jordan, 1962; Committee on Research into Fluoridation, 1969; Lemke 
et al., 1970; Künzel, 1980).  It is important to realize that these 
large reductions in caries prevalence and progression were achieved 

in the virtual absence of other methods of fluoride use and for 
populations with high or very high caries prevalence.  The same 
reductions should not be expected for populations with a low but 
increasing prevalence; for this type of population, the effect 
would be mainly to halt the increase.  This is also true for 
countries, mainly industrialized, where reductions in caries 
prevalence have been experienced through the widespread use of 
other fluoride preventive methods (Glass., 1982; Leverett, 1982; 
Thylstrup et al., 1982) (Fig. 3).  While addition of water or salt 
fluoridation could be expected to have added preventive effects, 
the percentage reduction would not be great as that in populations 
where other fluoride preventive methods have not been used. 

FIGURE 1

    Usually, the effect of fluoridated drinking-water has been 
studied in children or young adults.  However, several papers show 
conclusively that continued exposure to fluoride ions has a caries-
protecting capacity in adults (Deatherage, 1943; Adler, 1951; 
Forrest et al., 1951; Russell & Elvove, 1951; Russell, 1953; 
Englander & Wallace, 1962; Gabovich & Ovrutskiy, 1969; Hallett & 
Porteous, 1970; Keene et al., 1971; Murray, 1971a,b; Jackson et 
al., 1973; Shiller & Fries, 1980).  In addition to the reduction in 
enamel caries, fluoride ions will also significantly reduce the 
prevalence of cemental caries (Stamm & Banting, 1980).  This fact 

is of importance for middle-aged and old people whose root-surfaces 
are often exposed by gingival recession. 

FIGURE 2

FIGURE 3

    Reports based on epidemiological studies in the USA (Bernstein 
et al., 1966; Taves, 1978) and in Finland (Luoma et al., 1973) 
suggest that the prevalence of heart disease may be lower in 
populations exposed to fluoridated water than in low fluoride 
communities.  However, in two of the three studies, the influence 
of other chemicals could not be excluded.  Further studies in this 
field should be encouraged. 

6.2.  Cariostatic Mechanisms

    A large number of clinical studies and basic research have 
revealed information on the mechanisms involved in caries reduction 
by fluoride.  Compilations of this material have given the 
following concept of the mechanisms (Jenkins, 1967; Brown & König, 
1977; Cate ten, 1979; Ericsson, 1978): 

    In general terms, it is thought that fluoride reduces caries 
through influencing the morphology of teeth by reducing the 
solubility of the enamel and promoting remineralization, and 
through its effect on plaque bacteria.  A carious lesion can be 
regarded as the result of a local imbalance between, on the one 
hand, demineralizing, apatite-dissolving factors and, on the other 
hand, remineralizing, apatite-precipitating factors.  Demineralization 
is effected by acids produced from carbohydrates, especially 
sucrose, by microorganisms in the bacterial (dental) plaques on the 
tooth surfaces.  Remineralization occurs during relatively neutral 
periods being promoted by fluoride ions present in the bio-system 
constituted by dental plaque, saliva, and the enamel surface.  An 
increase in fluoride in this system will facilitate apatite 
formation and consequently stabilize already precipitated crystals, 
thereby counteracting dissolution processes that lead to carious 
cavities.  In addition to influencing the formation of apatite, 
fluoride has also been reported to influence the composition and 
retard the growth of bacterial plaques and the enzymatically 
conducted production of acids and polysaccharides in the plaques.  
More recently, it has been suggested that the most important 
mechanism is the fluoride-facilitated precipitation of calcium 
phosphate at the enamel surface (Fejerskov et al., 1981). 

6.3.  Fluoride in Caries Prevention

    Fluoride is recognized to be the most effective caries-
preventive agent.  Some 260 million people receive fluoridated 
drinking-water.  Systemic alternatives to water fluoridation are 
being used in some areas without collective distribution of 
drinking-water or where water fluoridation is not feasible or 
allowed.  The commonly employed alternatives are fluoridated food 
ingredients, especially table salt and milk, and fluoride tablets. 

6.3.1.  Fluoridated salt (NaCl)

    Fluoridated salt (NaCl) has been tested in Switzerland since 
1955 (Marthaler & Schenardi, 1962), in Hungary since 1966 (Toth, 
1976), and in Colombia since about 1965 (Mejia et al., 1976).  The 
results are reported in Table 9.  The production of fluoridated 

salt is inexpensive and, technically, relatively simple.  Salt 
fluoridation has been recommended as a temporary alternative to 
complement water fluoridation programmes by the Pan American 
Health Organization (PAHO, 1983).  However, the considerable 
variation in individual intake of table salt precludes the 
administration of equal amounts of fluoride to every individual.  
Because of the possible hypertension-inducing effect of table salt 
and its possible significance in cardiovascular diseases, these 
individual variations are expected to become even more pronounced 
in the future (Berglund et al., 1976; Freis, 1976; Waern, 1977; 
Kesteloot et al., 1978; Page et al., 1978).  Such developments may 
influence future indications for the caries-preventive fluoride 
enrichment of salt.  They will affect also the levels of fluoride 
to be added to table salt. 

6.3.2.  Fluoridated milk

    Fluoridated milk has been reported to reduce caries (Ziegler,  
1956; Rusoff  et al., 1962; Wirtz,  1964;  Stephen & Campbell, 
1980).  It may be of value in special cases, for instance, as an 
ingredient in school luncheons.  However, as the consumption of 
milk varies considerably in different age groups and geographical 
areas, fluoridated milk cannot become the general source of caries-
preventive intake. 

Table 9.  Data from studies on the effect on dental caries of 
fluoridated salta
-------------------------------------------------------------------
Country      Fluoride  Time of     Age in the  Caries     Caries
             in salt   experiment  groups      quantity   reduction
             (mg/kg)   (years)     (years)     parameter  (%)
-------------------------------------------------------------------
Colombia     200       8           6 - 14      DMFT       60 - 65

Hungary      250       8           2 - 6       deft       41

Hungary      250       8           7 - 11      DMFT       58

Hungary      250       8           12 - 14     DMFT       36

Switzerland  90        5 1/2       8 - 9       DMFT       18 - 22
-------------------------------------------------------------------
a  From: Marthaler & Schenardi (1962); Toth (1976); and Mejia et 
   al.    (1976).
DMFT = permanent teeth with caries experience.
deft = temporary teeth with caries experience.

6.3.3.  Fluoride tablets

    These tablets are prescribed to give a daily dose of fluoride 
corresponding to the amount of fluoride received by drinking water 
containing the optimal fluoride concentration.  Fluoride tablets 
properly taken seem to give the same caries reduction as 
fluoridated drinking-water, as reviewed by Driscoll (1974) and 
Binder et al. (1978).  However, in general, fluoride tablets cannot 

efficiently replace water fluoridation, as only few families are 
able to maintain a regular tablet intake, day after day, year after 
year (Arnold et al., 1960; Richardson, 1967; Prichard, 1969; Hennon 
et al., 1972; Plasschaert & König, 1973; Fanning et al., 1975; 
Newbrun, 1978; McEniery & Davies, 1979; Thylstrup et al., 1979). 

6.3.4.  Topical application of fluorides

    In areas lacking caries-preventive fluoride concentrations in 
the drinking-water, topical application of fluoride preparations on 
tooth surfaces has been recommended by WHO (1979a, resolution 
WHA31.50).  Hundreds of studies, mostly in children of school age, 
have demonstrated a definite caries-reducing effect of topical 
application.  The most commonly used self-applied fluoride 
preparations are fluoride-containing dentifrices and mouth rinses.  
With daily use of fluoride dentifrices, containing about 1 g F-/kg, 
a 20 - 30% reduction in caries has been reported (Heifetz & 
Horowitz, 1975;  Fehr, von der & Moller, 1978).  Clinical trials 
with mouth rinses, usually containing 0.2 - 1 g F-/litre, have been 
carried out in at least 15 countries.  Frequency of rinsing ranged
from daily to once a week or fortnight.  A caries reduction of
20 - 35% has been reported (Birkeland & Torrell, 1978; WHO, in 
press).  In other studies, a caries-inhibiting effect was 
demonstrated by the professional application of a fluoride varnish 
or fluoride-containing gels. 

    Topical application does not reduce caries to the same extent 
as water fluoridation (Künzel & Soto Padron, 1984).  The combination 
of topical methods and water fluoridation has increased the caries-
preventive effect of the latter, but the ensuing benefit is less 
than the sum of the effects of the individual methods. 

    It has even been claimed that the combination of school-based 
mouth rinsing with additional topical application of 2% sodium 
fluoride in children with high caries activity could reduce the 
caries rate close to that reached in areas with fluoride in the 
drinking-water (Thylstrup et al., 1982) (Fig. 3).  However, in this 
study, the fluoride-treated children were also exposed to fluoride 
levels in the drinking-water of 0.3 - 0.6 mg/litre, which in itself 
would have a substantial, though not optimal, caries-reducing 
effect.  It should also be noted that the caries rate in a town 
with 0.9 - 1.6 F-/litre in the drinking-water was higher than that 
reported from other communities with similar fluoride levels (WHO, 
in press). 

6.4.  Treatment of Osteoporosis

    Osteoporosis may be defined as the loss of bone accelerated 
beyond the normal "physiological" rates (Dixon, 1983).  The 
condition is common either in an idiopathic form or as a 
complication of other diseases.  Early diagnosis is difficult 
because osteoporosis is asymptomatic until it has advanced far 

---------------------------------------------------------------------------
a   Handbook of resolutions and decisions of the World Health
 Assembly and the Executive Board,  Volume II 1973-78, p. 108.

enough to cause structural failure of bone.  Most adults lose 
minerals from bone steadily throughout their life.  In women, this 
bone loss is accelerated for a year or two after the menopause, 
after which the decline slows to the previous rate, so that bone 
mass may ultimately be less than half of that in young adults.  In 
males, a corresponding acceleration may appear at 60 - 65 years of 
age.  Severe clinical manifestations of osteoporosis are:  loss of 
cortical bone, which leads to fracture of long bones, and loss of 
trabecular bone, which may cause fractures in the spine.  An 
excessive intake of fluoride from water and food or from industrial 
dust has been found to increase bone mass.  This fact may be 
related to the observation that indications of osteoporosis were 
less frequently found in areas with drinking-water containing 
fluoride levels of 4 - 8 mg/litre than in low-fluoride areas (Leone 
et al., 1960; Bernstein et al., 1966). 

    Sodium fluoride was first used in the treatment of osteoporosis 
by Rich & Ensinck (1961).  It improved the mineralization of bone 
but did not reduce the number of bone improvements, adverse 
effects, or unaltered clinical picture (Purves, 1962; Higgins et 
al., 1965; Cass et al., 1966; Inkovaara et al., 1975).  In later 
studies, it was realized that it was necessary to combine the 
fluoride therapy with a supplementation of calcium to counteract 
fluoride-related induction of osteomalacia.  Such combinations with 
or without vitamin D have given beneficial effects (Jowsey et al., 
1972; Hansson & Roos, 1978; Riggs et al., 1980,1982), though the 
contribution by fluoride may still be somewhat doubtful, because 
few of the requirements for a controlled clinical trial have been 
followed.  Different combinations containing fluoride were tested 
in the therapy of osteoporosis by Riggs et al. (1982).  Most 
effective in the therapy of post-menopausal osteoporosis appeared a 
combination of calcium, fluoride, vitamin D, and oestrogens.  It 
was noted that the greatest beneficial effect was achieved during 
the second year of treatment.  This finding could perhaps be 
related to the observation that it takes about a year of fluoride 
treatment to achieve radiological evidence of increased bone 
density (El-Khoury et al., 1982).  Most of the fluoride-treated 
patients had been given high doses (40 -100 mg) of sodium fluoride 
per day.  Adverse reactions had been noted in some patients as a 
result of these doses, in particular rheumatic and gastrointestinal 
symptoms (Riggs et al., 1982; Dixon, 1983).  To avoid gastric 
troubles, enteric-coated tablets have been developed.  The 
minimal, active dose has recently been stated to be 30 mg sodium 
fluoride a day when given in conjunction with 1 g calcium a day 
(Dixon, 1983). 

    Skeletal fluorosis has been reported (Grennan et al., 1978).  
In one fatal case, high-dose sodium fluoride therapy (44 mg/day) 
was given for osteoporosis in an elderly woman with impaired renal 
function.  Dehydration and renal failure developed with initiation 
of the sodium fluoride treatment.  She died, in spite of intensive 
treatment to restore fluid balance (McQueen, 1977).  It is 
impossible to assess the significance of individual reports of this 
kind. 

    Sodium fluoride has also been used in the treatment of 
otospongiosis.  Shambaugh & Causse (1974) prescribed 40 - 60 mg of 
fluoride a day for up to 8 years.  The authors considered this 
treatment very effective, and side effects were only reported in a 
few cases (Causse et al., 1980). 

    The possible beneficial effects on osteoporosis of optimally 
fluoridated drinking-water has been examined in a few studies.  The 
results have not given a conclusive answer (Royal College of 
Physicians, 1976).  However, the duration of fluoridation in some 
of the studies might have been too short for an adequate 
assessment.  After 20 years of fluoridation in Kuopio, Finland, 
cancellous bone strength measured by a strain transducer in women 
with chronic immobilizing disease, was statistically significantly 
higher compared with that in a corresponding group from a low-
fluoride area (Alhava et al., 1980).  Although a beneficial effect 
of fluoride seems likely, additional research is needed to 
elucidate the dose ranges that are effective. 

7.  TOXIC EFFECTS IN HUMAN BEINGS

7.1.  Acute Toxic Effects of Fluoride Salts

    Most cases of acute poisoning in human beings described in the 
literature have been associated with the suicidal or accidental 
ingestion of fluoride-containing insecticides and other products 
used in the home.  Poisoning has most frequently been with sodium 
fluoride, sodium fluorosilicate, or hydrofluoric or fluorosilicic 
acid. 

    Acute fluoride poisoning in man has been described by several 
authors.  The most detailed survey, 1211 cases from 1873 to 1935, 
was given by Roholm (1937).  Of these, 60 terminated fatally.  In 
acute fluoride poisoning, practically all the organs and systems 
are affected.  The manifestations include vomiting (sometimes 
blood-stained), diffuse abdominal pain of spasmodic type, 
diarrhoea, cyanosis, severe weakness, dyspnoea, muscle spasms, 
pareses and paralyses, cardiovascular disorders, convulsions, and 
coma.  Hodge & Smith (1965) summarized the acute effects of 
fluoride.  Hodge (1969) grouped most of the acute fluoride effects 
into four categories of major functional derangements: (a) enzyme 
inhibition, (b) calcium complex formation, (c) shock, and (d) 
specific organ injury. 

    In acute poisoning, fluoride kills by blocking normal cellular 
metabolism.  Fluoride inhibits enzymes, in particular metalloenzymes 
involved in essential processes, causing vital functions such as 
the initiation and transmission of nerve impulses, to cease.  
Interference with necessary bodily functions controlled by calcium 
may be even more important.  The strong affinity for calcium 
results in hypocalcaemia, perhaps due to precipitation of 
fluorapatite (Simpson et al., 1980).  The most severe case of 
hypocalcaemia ever reported in a human being was in a patient with 
fluoride poisoning (Rabinowitch, 1945).  Other metal ions may be 
bound to fluoride as well, thereby blocking various biochemical 
mechanisms.  In addition, hyperkaliaemia may ensue with ventricular 
fibrillation of the heart associated with peaking of the T waves in 
the electro-cardiogram (Baltazar et al., 1980).  Massive impairment 
of the functioning of vital organs results in cell damage and 
necrosis.  Terminally, there is a characteristic shock-like 
syndrome. 

    From data in the literature, Hodge & Smith (1965) estimated 
that the first manifestations of poisoning (nausea, vomiting, and 
other gastrointestinal symptoms) appear with the ingestion of 140 - 
210 mg of fluoride (F-) per 70 kg body weight.  In 1- to 3-year-old 
children, the ingestion of 5 mg/kg body weight may lead to toxic 
manifestations (Spoerke et al., 1980).  Hodge & Smith (1965) fixed 
the lethal dose of sodium fluoride for a 70-kg man at 5 - 10 g, 
which means 2.2 -4.5 g of F- (or 32 - 64 mg F- per kg body weight). 

    Fluoride poisoning has no specific signs but resembles 
poisoning from ingestion of other gastrointestinal irritants, 
notably arsenic, mercury, barium, and oxalic acid (Polson & 
Tattersall, 1979).  Without knowledge of the preparation ingested, 
it may therefore be difficult to identify a case of fluoride 
poisoning immediately.  The rapid onset of symptoms from the 
stomach may be related to the formation of hydrogen fluoride at low 
pH conditions.  In the home, incidents of fluoride poisoning 
usually occur from the swallowing of insecticides or rodenticides 
containing highly soluble fluorides.  Sodium fluoride, e.g., for 
cockroach control, may be mistaken for flour or sugar, and in many 
countries such preparations are either banned or required to be 
coloured to avoid confusion.  Although fluoride supplement tablets 
are sometimes stored at home in large numbers, few cases of 
poisoning (nausea, vomiting, diarrhoea) have been reported in 
children after ingestion of fluoride tablets (Spoerke et al., 
1980). 

    All inorganic compounds of fluorine are not equally toxic.  The 
toxicity depends on the mode of entry into the body and the 
physical and chemical properties of the compound.  Of special 
significance is the solubility:  highly soluble compounds are more 
toxic after oral intake than sparingly-soluble or insoluble ones.  
The readily-soluble fluorides, e.g., NaF, KF, Na2SiF6, and BaSiF6 
induce similar toxic effects (Muehlberger, 1930).  To obtain the 
same effect, readily-soluble fluorides need to be given in doses of 
only one-third of cryolite (Deeds & Thomas, 1933-1934; Evans & 
Phillips, 1938), and one-sixth of the dose of calcium fluoride 
(Smith & Leverton, 1933).  A comparative study of the degree of 
toxicity of NaF, Na2SiF6, CaF2, CaSiF6, MgF2, ZnF2, AlF3, and CuF2 
showed that calcium and aluminium fluorides were less toxic than 
the other fluorides and that CuF2 occupied an intermediate position 
(Marcovitch, 1928; McClure & Mitchell, 1931). 

    There is no specific treatment in fluoride poisoning except for 
the administration of calcium salts.  Vomiting is usually 
spontaneous.  If not, an emetic should be given.  Milk or calcium 
chloride should also be given.  Gastric lavage with lime water is 
effective.  A soluble calcium salt, usually calcium gluconate, can 
be given intravenously.  Potassium should be restricted.  Unless 
nephrotoxic effects are present, efficient excretion takes place, 
and the excretion rate may be further enhanced under alkalosis 
conditions.  If a patient survives the first hours of poisoning, 
the chances of survival are good.  Surviving patients recover 
without known sequelae.  This is generally the case in recovery from 
poisoning through the oral intake of fluoride.  On the other hand, 
irreversible necrosis and burns may be caused by gaseous fluorides 
(section 7.2). 

7.2.  Caustic Effects of Fluorine and Hydrogen Fluoride

    Gaseous fluorides can cause considerable damage to the skin and 
respiratory tract.  Largent (1952) listed the increasing intensity 
of acute effects with increasing concentrations of gaseous 
fluorides on the basis of controlled exposures of volunteers (1 ppm 
= 0.7 mg/m3 for HF) as follows: 

    2.1 mg/m3 (3 ppm): no local immediate systemic effects;

    7 mg/m3 (10 ppm): many subjects experienced discomfort;
    21 mg/m3 (30 ppm): all subjects complained and objected
    seriously to staying in the environment;

    42 mg/m3 (60 ppm): at brief exposures, definite irritation
    of conjunctiva, nasal passages, tickling and discomfort of
    pharynx and trachea; and

    84 mg/m3 (120 ppm): the highest concentration tolerated
    (less than 1 min by 2 male subjects), smarting of skin as
    well as above effects were noted.

The permissible occupational levels in the USA for hydrogen 
fluoride and fluorine are 2.5 mg/m3 and 2.0 mg/m3, respectively 
(ACGIH, 1983-84). 

    Pulmonary exposure to either elemental fluorine or hydrogen 
fluoride may occur independently or simultaneously with skin 
exposure.  Continued inhalation of hydrogen fluoride or fluorine at 
high levels results in coughing, choking, and chills, lasting 1 - 2 h
after exposure; in the next one or two days, fever,  coughing, 
chest tightness, rales, and cyanosis may develop, indicating 
delayed pulmonary oedema (Dreisbach, 1971).  The signs and symptoms 
progress for a day or two and then regress slowly over a period of 
a few weeks.  At higher exposures, the violent reaction of gaseous 
fluorine with the skin induces a thermal burn; in contrast, 
solutions of hydrogen fluoride induce deep slow-healing burns that 
develop into abscesses.  The delicate tissues of the lung may be 
intensely and even fatally irritated by high concentrations of 
fluorine or hydrogen fluoride. 

    Gaseous compounds of fluorine attack tissues much more 
vigorously than fluoride salts.  The toxicity of some gaseous 
inorganic compounds of fluorine decreases in the following order: 
F20, F2, HF, BF3, and H2SiF6. 

7.3.  Chronic Toxicity

7.3.1.  Occupational skeletal fluorosis

    Elevated intake of fluoride over prolonged periods of time may 
result in skeletal fluorosis, i.e., an accumulation of fluoride in 
the skeletal tissues associated with pathological bone formation.  
This disease was first discovered in Copenhagen in 1931 during a 
routine examination of cryolite workers (Moller & Gudjonsson, 1933).

The disease was described in detail in a later in-depth study 
reported by Roholm (1937). 

    Skeletal fluorosis has been reported mainly from aluminium 
production, magnesium foundries, fluorspar processing, and 
superphosphate manufacture (Hodge & Smith, 1977). 

    The first stage of osteofluorosis is sometimes asymptomatic 
and can be visualized radiologically as an increase in the 
density of various bones, particularly the vertebrae and the 
pelvis.  In cryolite workers, such changes were seen after about 
four years of daily absorption of 20 - 80 mg of fluoride (Roholm, 
1937).  According to more recent reports, such osteosclerotic 
changes appear at a fluoride content of 5 000 - 6 000 mg/kg of 
dry, fat-free bone (Smith & Hodge, 1959; Weidmann et al., 1963; 
Zipkin et al., 1958).  Franke & Anermann (1972) found pathological 
changes at fluoride levels of about 4000 mg/kg, and a more recent, 
very thorough study on bone biopsies revealed histological changes 
at fluoride levels down to about 2000 mg/kg (Baud et al., 1978; 
Boillat et al., 1979).  These histological effects associated with 
what appear to be very low bone fluoride concentrations may have 
been due to examination coupled with de-fluorination in the post-
exposure period.  It is possible that as fluoride concentrations 
vary greatly within bone, so histological effects may be associated 
with locally high concentrations.  Thus, relatively high levels may 
be accumulated under constant, long-term exposures to low levels of 
fluoride, without discernible effects.  With increasing fluoride 
accumulation, the following picture is noted radiologically:  bone 
density increases, bone contours and trabeculae become uneven and 
blurred, the bones of the extremeties show thickening of the compact 
bone and irregular periosteal growth (exostoses and osteophytes), 
and there is increasing evidence of calcification in ligaments, 
tendons, and muscle insertions (Roholm, 1937). 

    Bone density changes may be difficult to recognize, particularly 
in the early stages of skeletal fluorosis.  Furthermore, such 
changes could be caused by other diseases, such as Paget's disease 
or osteoblastic metastases.  Similarly, arthrosis of the joints may 
be produced not only by fluoride, but many other conditions.  
Studies on Swiss aluminium potroom workers have suggested that 
calcification of ligaments, tendons, and muscle insertions, in 
particular, calcaneal spears on the heel bone, may be more useful 
diagnostic markers (Boillat et al., 1981).  A bone biopsy is often 
necessary, and characteristic changes include:  linear formation 
defects, mottled periosteocytic lacunae, porosity of cortical bone, 
increased trabecular bone volume, and the presence of newly-formed 
periosteal bone (Baud et al., 1978; Boillat et al., 1979).  In the 
early stages, polyarthralgia is a characteristic complaint (Boillat 
et al., 1979).  With increased radiological density, clinical signs 
and symptoms may become more severe, especially pain in joints of 
hands, feet, knees, and spine.  With increasing severity, the pain 
increases and movement of the vertebral column and lower limbs 
becomes limited (Roholm, 1937).  Finally ossification of the 
ligaments and outgrowths or bony spurs in joints may result in 

fusion of the spine ("poker back") and contractures of the hips and 
knees.  This severe stage, called crippling fluorosis, has been 
reported from temperate climate areas in connection with heavy 
industrial fluoride exposure (Roholm, 1937). 

    In a study of 1242 employees in an aluminium smelter using the 
Soderburg process, Carnow & Conibear (1981) reported that clinical 
musculoskeletal effects could occur before skeletal fluorosis 
becomes apparent radiologically.  Questionnaire answers suggested 
an increased incidence of musculoskeletal diseases with increasing 
total fluoride exposure during employment.  On the other hand, 
X-rays of chest and lumbar spine failed to indicate any differences 
related to the exposure index.  As recognized by the authors of 
this paper, this group of workers was heterogeneous, chemical 
exposures were mixed, and ergonomic problems might have occurred. 
Unfortunately, the fluoride levels and the lengths of exposure 
were not reported, thus making a possible dose-response relationship 
impossible to determine.  The employees of the same smelter were 
examined four years later by Chan-Yeung et al. (1983).  The 
exposure levels were determined, and two control groups were 
examined.  The exposure level in the potroom was about 0.5 mg/m3 
for the subgroup with the highest exposure.  The authors were not 
able to confirm the findings of Carnow & Conibear (1981) that 
clinical musculoskeletal effects could occur before skeletal 
fluorosis becomes apparent radiologically. 

    It has been suggested that no discernible radiological 
or clinical signs of osteosclerosis will appear if the air 
concentrations of inorganic fluoride in the work-place remain 
below 2.5 mg/m3 and the urine-fluoride concentration of workers 
does not exceed 4 mg/litre pre-shift (collected at least 48 h after 
previous occupational exposure) and 8 mg/litre post-shift over long 
periods of time (Dinman et al., 1976b; Hodge & Smith, 1977).  
American recommendations for the TLV of air-fluoride limits have 
been established on the basis of these data (NIOSH, 1977).  However, 
some countries recommend lower values.  The USSR recommends 1.0 
mg/m3 as the threshold limit value for air-fluoride concentrations 
expressed as HF (Gabovich & Ovrutskiy, 1969; ILO, 1980; US EPA, 
1980).  The correlation between fluoride levels in the ambient air 
and in the urine and the development of skeletal changes need 
further documentation. 

7.3.2.  Endemic skeletal fluorosis

    Skeletal fluorosis with severe radiological and clinical 
manifestations connected with drinking-water containing fluoride in 
excess of 10 mg/litre was reported in 1937 from Madras in India by 
Pandit et al. (1940).  Corresponding observations were soon 
reported from other tropical areas of India, and from China, South 
Africa, and other countries with a hot climate and high water-
fluoride concentrations (Singh & Jolly, 1970).  On the basis of an 
extensive epidemiological survey, Singh & Jolly (1970) stated that 
crippling fluorosis was the result of continuous daily intake of 20 
- 80 mg fluoride for 10 - 20 years.  In some studies in tropical 
countries reviewed by the Royal College of Physicians (1976) 

(Pandit et al., 1940; Singh et al., 1961b; Jolly et al., 1969), 
relatively marked osteofluorotic symptoms were connected with 
fluoride levels as low as 1 - 3 mg/litre drinking-water.  However, 
the Royal College of Physicians stated that, in these studies, 
fluoride intake from sources other than drinking-water, including 
sediments in wells, food, the use of fluoride-containing stones for 
grinding food, and brackish water of unknown fluoride content for 
cooking, etc., was not taken into account.  On the basis of more 
recent balance studies on patients with endemic fluorosis, which 
showed an average daily fluoride intake of 9.88 mg, Jolly (1976) 
suggested that a daily intake exceeding 8 mg in adults would be 
harmful. 

    In tropical areas with endemic fluorosis, high fluoride levels 
in the drinking-water seem to constitute an important factor in a 
multifactorial causation (Reddy, 1979).  Thus, poor nutrition, 
including calcium deficiency, and hard manual labour seem to play 
an additional role (Siddiqui, 1955; Singh et al., 1961a).  Calcium 
deficiency may result in a secondary hyperparathyroidism.  In 
addition, protein deficiency may increase individual susceptibility 
to fluorosis. 

    Neurological sequelae, usually in the form of cervical 
radiculomyelopathy, result from the mechanical compression of the 
spinal cord and nerve roots due to osteophyte formation and 
subperiosteal growths (Singh et al., 1961b).  These complications 
occur at a late stage of the disease, in one area in about 10% of 
the cases, following 30 - 40 years of exposure to water-fluoride 
levels of 2 - 10 mg/litre (Reddy, 1979). 

    In non-tropical countries, no cases of skeletal fluorosis with 
clinical signs and symptoms have been detected in relation to 
drinking-water containing fluoride levels of less than 4 mg/litre 
(Victoria Committee, 1980).  In Bartlett, Texas, with a (previous) 
water-fluoride level of 8 mg/litre, radiological evidence of 
fluorosis in the form of osteosclerosis was recorded in 10 - 15% of 
the people (Leone et al., 1955).  X-ray changes were also noted in 
a few people living in Oklahoma and Texas where the drinking-water 
contained a fluoride level of 4 - 8 mg/litre (Stevenson & Watson, 
1957).  In other studies, no signs or symptoms of osteofluorosis 
were detected in areas with fluoride levels of up to 6 mg/litre in 
water supplies (McClure, 1946; Eley et al., 1957; Knishnikov, 
1958). 

    Marked skeletal fluorosis may also occur in children exposed to 
high fluoride levels in the drinking-water.  Thus, in a community 
of Tanzanians who moved to an area where a bore-hole water level of 
fluoride of 21 mg/litre was measured, crippling deformities 
developed among the children during the subsequent years:  of 251 
individuals below 16 years of age, 58 had knock-knees, 43 had 
bowlegs, and 30 had sabre shins (Christie, 1980).  On radiographic 
examination of 15 patients, Christie (1980) found several severe 
abnormalities including increased acclivity and height of the 
posterior ribs, increased anteroposterior diameter of the chest, 
vertebral bodies with increased width and decreased height, 

considerable exaggeration of the normal serrations along the iliac 
crest, abnormal shape of pelvis, joint deformities, and lateral 
bowing of the femora.  While typical patterns of sclerosis and 
skeletal fluorosis were seen, these changes did not necessary 
progress into the characteristic adult pattern of the disease.  
Although hyperparathyroidism was not taken into account, and 
dietary deficiencies may have played a role, heavy fluoride 
exposure appears to be the major causal factor.  In the past, 
severe genu valgum in South African children became known as 
Kenhardt bone disease from a village where it was prevalent, and 
similar cases in children with life-long fluoride exposures were 
reported from India (Teotia et al., 1971; Krishnamachari & 
Krishnaswamy, 1973).  In these situtations, signs of both 
osteosclerosis and osteomalacia were observed.  The results of 
these studies suggest that the developing skeleton may be more 
sensitive to fluoride toxicity than the mature one. 

7.3.3.  Dental fluorosis

    During the first part of this century, the etiology of a 
specific type of mottled teeth was discussed.  The mottling was 
endemic in certain geographically well-defined areas.  Eager (1901) 
described a "strange condition in the teeth of people living in a 
small village near Naples".  He characterized its mildest form as 
"very slight, opaque, whitish areas on some posterior teeth.  
Becoming more severe, the defect is more widespread and changes in 
colour from white to shades of grey and brown to almost black.  In 
areas of marked severity, the surfaces of the teeth may in addition 
be marked by discrete or confluent pitting."  He attributed the 
cause of the dental defects to volcanic fumes either fouling the 
atmosphere or forming a solution in the drinking-water.  In other 
areas when mottled teeth occurred, the drinking-water was more 
directly suspected (McKay, 1926) and the interest was focused on 
the presence of fluoride (Churchill, 1931).  Fluoride was definitely 
identified as the causative agent when mottled teeth developed in 
rats and sheep given fluoride in the food (Smith et al., 1931; Velu 
& Balozet, 1931).  Thereafter, this type of mottled teeth was 
designated dental fluorosis or enamel fluorosis. 

    In extensive studies, Dean and co-workers (Dean & Elvove, 1935, 
1937; Dean, 1942) related the appearance and severity of dental 
fluorosis to different fluoride levels in the drinking-water with 
the aid of a special classification and weighing of the severity of 
the lesions (Dean 1934, 1942) (Table 10).  A graphical 
representation of their results is given in Fig. 4. 

Table 10.  Classification of dental fluorosisa                             
---------------------------------------------------------------
Type          Weight  Description                                          
---------------------------------------------------------------
Normal        0       The enamel presents the usual                        
enamel                translucent semi-vitriform type of                   
                      structure.  The surface is smooth,                   
                      glossy, and usually of a pale, creamy                
                      white color.                                         
                                                                           
Questionable  0.5     Slight aberrations from the                          
fluorosis             translucency of normal enamel seen,                  
                      ranging from a few white flecks to                   
                      occasional white spots.  This                        
                      classification is used in instances                  
                      where a definite diagnosis of the                    
                      mildest form of fluorosis is not                     
                      warranted and a classification of                    
                      "normal" not justified.                              
                                                                           
Very mild     1       Small opaque, paper-white areas                       
fluorosis             scatterred irregularly over the tooth   
                      but not involving as much as            
                      approximately 25% of the tooth          
                      surface.  Frequently included in this   
                      classification are teeth showing no     
                      more than about 1 - 2 mm of white       
                      opacity at the tip of the summit of the 
                      cusps of the bicuspids or second molars.
                                                                          
Mild          2       The white opaque areas in the enamel of               
fluorosis             the teeth are more extensive, but do    
                      not involve as much as 50% of the tooth.
                                                                          
Moderate      3       All enamel surfaces of the teeth are                  
fluorosis             affected and surfaces subject to        
                      attrition show marked wear.  Brown      
                      stain is frequently a disfiguring       
                      feature.                                
                                                                           
Severe        4       All enamel surfaces are affected and                  
fluorosis             hypoplasia is so marked that the        
                      general form of tooth may be affected.  
                      The major diagnosis of this             
                      classification is the discrete or       
                      confluent pitting.  Brown stains are    
                      widespread, and teeth often present a   
                      corroded-like appearance.               
---------------------------------------------------------------
a  From: Dean (1942).                                                      

    The "questionable" changes occur with increasing frequency at 
higher fluoride exposure levels.  Their relationship to fluoride 
exposure in population studies is therefore not questionable, 
although the aesthetic significance may be.  Thus, being an effect 
of fluoride on the enamel, the "questionable" changes may more 
properly be given more statistical weight than 0.5, when assessing 
the community index of enamel changes according to Dean's method.  
Several revisions of the scoring system have been proposed, for 
example, those of Jackson (1962), Thylstrup & Fejerskov (1978), and 
Murray & Shaw (1979).  Thylstrup & Fejerskov (1978) developed a 
system where the earliest changes are given a score of 1, and more 
severe abnormalities are given higher scores.  This classification 
system is designed to characterize the macroscopic degree of dental 
fluorosis in relation to the histological abnormalities. 

    Very mild fluorosis is only detectable by close examination of 
dried teeth and in good light.  Mild fluorosis is more easily 
recognized by the trained examiner.  In general, both very mild and 
mild fluorosis remain undetected by the layman. 

    Dental fluorosis is a disturbance affecting the enamel during 
formation, hence all damage occurs before the eruption of the 
teeth.  The brownish-black discoloration of the more severe 
fluorotic defects is, however, a secondary phenomenon due to the 
deposition of stains from the oral cavity into the spongy surface 
of severely mottled areas.  Mild discoloration can be eliminated by 
treatment with a weak solution of phosphoric acid, followed by 
painting with a sodium fluoride solution to facilitate a 
precipitation of apatite in the spongy areas with the aid of 
salivary calcium and phosphate ions (Craig & Powell, 1980; Edward, 
1982).  The level of fluoride-induced changes that would be 
considered aesthetically objectionable is debatable. 

FIGURE 4

    Several concepts may be relevant to the etiological mechanism 
of dental fluorosis:  the enamel-forming cells, the ameloblasts, are 
affected, the maturation of the enamel is delayed, and the general 
mineralization processes may be inhibited, perhaps through 
interference with nucleation and crystal growth.  In addition, 
calcium homeostatic mechanisms may be affected.  Histological 
changes are found in the enamel, but, in severe fluorosis, also in 
dentin (Fejerskov et al., 1977, 1979).  The minimal daily fluoride 
intake in infants that may cause very mild or mild fluorosis in 
human beings has been estimated to be about 0.1 mg per kg body 
weight (Forsman, 1977).  This figure was derived from examination 
of 1094 children from areas with water-fluoride concentrations of 
0.2 - 2.75 mg/litre.  It is in agreement with the reported 0.1 - 
0.3 mg per kg body weight necessary to initiate fluorosis in cows 
(Suttie et al., 1972). 

    The results published by Dean and co-workers have been 
confirmed by many studies in various temperate parts of the world, 
as reviewed by Myers (1978), i.e., fluorosis is of a very mild or 
mild character in areas with drinking-water naturally containing 
fluoride levels of up to 1.5 - 2 mg/litre, severe fluorotic defects 
with disfiguring appearance are to be found at higher fluoride 
levels.  The results have also been confirmed in the pioneer water 
fluoridation studies and the many subsequent fluoridation reports. 

    It is sometimes difficult or almost impossible to discriminate 
between fluorosis and other enamel disturbances (Jackson, 1961; 
Forrest & James, 1965; Goward, 1976; Mervi, van der et al., 1977; 
Small & Murray, 1978; Murray & Shaw, 1979).  Opacities similar to 
fluorotic opacities are also seen in low-fluoride areas and many 
etiological factors other than fluoride have been implicated (Small 
& Murray, 1978).  Proposals of differential diagnosis aimed at 
distinguishing between fluorotic and non-fluorotic effects are 
usually based on the fact that fluorosis presents generalized 
symmetrical defects and therefore can be distinguished from 
localized non-symmetrical lesions (e.g. Zimmerman, 1954; Jackson, 
1961; Nevitt et al., 1963; Hargreave, 1972; Small & Murray, 1978; 
Murray & Shaw, 1979).  However, generalized symmetrical mottling 
presents certain difficulties as symmetrical defects of non-
fluorotic origin may appear independently of the fluoride content 
of the drinking-water.  Small & Murray (1978) concluded:  "Although 
a high concentration of fluoride in drinking-water is one factor, 
it is extremely difficult to decide just how many cases of "enamel 
fluorosis" occur in endemic areas and how many defects are due to 
other etiological factors". 

    Localized enamel defects are reported to be more frequent in 
low-fluoride areas than in areas with optimal water fluoridation 
(Zimmerman, 1954; Ast et al., 1956; Forrest, 1956; Forrest & James, 
1965; Al-Alousi et al., 1975; Forsman, 1977).  One of the 
explanations offered is that part of the difference could be due to 
the greater amount of caries-induced inflammation in temporary 
teeth in low-fluoride areas, as such conditions have been found to 
disturb the mineralization of underlying permanent teeth.  It has 
also been suggested that a certain amount of fluoride is necessary 
for the proper organization and crystallization of enamel. 

    As a consequence of higher water consumption, the frequency and 
severity of dental fluorosis increases with increasing mean maximum 
temperature (Galagan et al., 1957; Richards et al., 1967; Gabovich 
& Ovrutskiy, 1969).  In hot climates, therefore, the values for the 
optimal fluoride concentration in drinking-water have been reduced, 
e.g., to 0.6 - 0.8 mg/litre, usually according to the formula 
developed by Galagan & Vermillion (1957) (section 3.5). 

    As the community index of fluorosis increases, caries 
prevalence decreases until the destructive forms of fluorosis, 
scores of 4 and 5 on Dean's index, become prevalent.  Under the 
latter conditions, an increase in caries may occur, associated with 
loss of integrity of enamel and exposure of underlying dentine.  
However, in these situations, the lesions usually progess slowly 
and frequently become arrested (Barmes, 1983). 

7.3.4.  Effects on kidneys

    In cryolite workers, Roholm (1937) found only insignificant 
haematuria and no albuminuria.  A possible relationship between 
albuminuria and fluoride exposure was suggested by Derryberry et 
al. (1963), but Kaltreider et al. (1972) were unable to show any 
chronic effects on the kidney.  No renal disorder has been related 
to fluoride in areas of endemic fluorosis (Jolly et al., 1969) or 
to cases of industrial fluoride exposure (Dinman et al., 1976b; 
Smith & Hodge, 1979).  No cases of renal signs or symptoms are 
mentioned in connection with prolonged intake of fluoride in the 
treatment of osteoporosis and otospongiosis (Causse et al, 1980; 
Schamschula, 1981; Dixon, 1983), although a thorough examination of 
kidney function may not have been carried out.  No indications of 
increased frequency of kidney diseases or disturbed kidney 
functions have been recognized in areas with water fluoride 
concentrations of 8 mg/litre (Leone et al., 1954, 1955), 2.0 - 5.6 
mg/litre (McClure, 1946; Geever et al., 1958) and 1.0 mg/litre 
(Summens & Keitzer, 1975). 

    Although there are no reports of fluoride-induced chronic renal 
disorders in healthy individuals, several studies have dealt with 
the possible influence of fluoride on people with manifest kidney 
diseases.  In patients with kidney failure, fluoride excretion is 
decreased, and the ionic plasma fluoride concentration is higher 
than the normal (Juncos & Donadio, 1972; Berman & Taves, 1973; 
Hanhijärvi, 1974).  The capacity of the skeleton to store fluoride 
may provide a sufficient safety margin (Hodge & Smith, 1954; Hodge 
& Taves, 1970).  On the other hand, it seems also plausible that an 
increased plasma fluoride concentration may result from fluoride 
liberation from the bone resorption processes involved in certain 
kidney diseases.  Patients with diabetes insipidus may absorb 
excess amounts of fluoride because of the large quantities of 
fluids ingested. 

    Patients with chronic renal failure who are dialysed with 
fluoridated water receive an additional load of fluoride from the 
dialysate.  In comparison with the average gastrointestinal uptake, 
the fluoride absorption increases by 20 - 30-fold during a single 
pass of dialysis.  Thus, raised ionic fluoride levels in plasma 
have been reported (Taves et al., 1965; Fournier et al., 1971).  
However, aluminium is currently viewed as the major causative 
factor associated with both encephalopathy and bone disease in 
dialysed kidney patients (Platts et al., 1977).  The entire subject 
of water suitable for dialysis was considered by a joint working 
party set up in 1979 by the Australasian Society of Nephrology and 
the Australian Kidney Foundation Dialysis and Transplant Committee.  
Its report suggested a maximum limit of 0.2 mg fluoride/litre in 
the dialysate (Victoria Committee, 1980). 

    Modern-day anaesthetic agents include several that contain 
fluorine.  Methoxyflurane has a high lipid solubility and a high 
potency as an anaesthetic agent.  Six years after its introduction 
in 1960, nephrotoxicity was discovered as a side-effect related to 
the metabolites of methoxyflurane (Hagood et al., 1973).  As a 
result of the metabolism of methoxyflurane, enflurane, and 
isoflurane, fluoride is released; halothane may release fluoride as 
well if reductive conditions prevail (Dyke, van 1979; Marier, 
1982).  Peak serum fluoride concentrations may exceed 50 µmol/litre 
(1.0 mg/litre) following methoxyflurane anaesthesia (NAS-NRC 
Committee of Anaesthesia, 1971; Cousins & Mazze, 1973), while less 
than half as much is seen after enflurane anaesthesia and even 
lower levels are associated with other anaesthetic gases (Cohen & 
van Dyke, 1977).  Kidney damage is related to the high serum levels 
of fluoride and may show up days after anaesthesia (Hagood et al., 
1973).  The nephrogenic diabetes insipidus (polyuria, serum 
hyperosmolality, polydipsia) is unresponsive to fluid restriction 
or antidiuretic hormone administration.  The response is aggravated 
by obesity, pre-existing kidney disease, and exposure to 
phenobarbital (Marier, 1982).  In milder cases, kidney function 
recovers when fluoride levels normalize.  Nephrotoxicity has also 
been observed in relation to enflurane anaesthesia (Mazze et al., 
1977).  Although peak fluoride levels associated with acute 
nephrotoxic effects have frequently been higher than 50 µmol/litre, 
the total dose may be of more importance (Marier, 1982).  Changes 
in kidney function have been reported at lower fluoride levels 
(Järnberg et al., 1979).  At serum levels of fluoride averaging 
about 6 mmol/litre after enflurane anaesthesia, no nephrotoxic 
effects were seen, but blood and urine levels of phosphorus changed 
considerably (Duchassaing et al., 1982).  Both methoxyflurane and 
enflurane have been widely used as analgesics and anaesthetics 
during delivery (Cuasay et al., 1977; Dahlgren, 1978; Clark et al., 
1979; Marier, 1982); maternal plasma-fluoride values of 20 - 25 
µmol/litre (0.3 - 0.4 mg/litre), registered 2 h after delivery, 
declined slowly during the first 48 h.  At delivery, plasma-
fluoride values in the neonate were about 10 - 15 µmol/litre (0.18 
- 0.25 mg/litre) compared with 2.1 µmol/litre in control groups. 

    One case of skeletal fluorosis has been reported in a young 
nurse who intermittently abused methoxyflurane and who showed 
decreasing creatinine clearance and a serum fluoride level of 180 
µmol/litre (Klemmer & Hadler, 1978). 

7.4.  Carcinogenicity

    Excess cancer rates have been documented in various 
occupational groups exposed to fluorides.  Thus, fluorspar miners 
(de Villiers & Windish, 1964) and aluminium production workers 
(Gibbs & Horowitz, 1979; Milham, 1979; Andersen et al., 1982) have 
been subject to lung cancer more frequently than expected.  Results 
of a cohort study on more than 20 000 workers who had been employed 
for more than five years in an aluminium reduction plant did not 
confirm an excess pulmonary cancer rate, but slight excesses were 
seen in pancreatic, lymphohaematopoietic, and genitourinary cancers 
(Rockette & Arena, 1983).  However, the miners were exposed to 
radon and the aluminium workers to polycyclic aromatic 
hydrocarbons.  Because most occupational exposures that include 
fluoride are mixed exposures, only limited evidence from such 
studies bears specific relevance to the wider concept of the 
possible carcinogenic effects of long-term fluoride exposures on 
human beings. 

    Cancer mortality rates in areas with different amounts of 
fluoride naturally present in the  drinking-water have been 
compared in a considerable number of epidemiological studies.  
These studies have been carefully reviewed and evaluated by IARC 
(1982) with the following conclusions:  "When proper account was 
taken of the differences among population units in demographic 
composition, and in some cases also in their degree of 
industrialization and other social factors, none of the studies 
provided any evidence that an increased level of fluoride in water 
was associated with an increase in cancer mortality."  Thus, 
"variations geographically and in time in the fluoride content of 
water supplies provide no evidence of an association between 
fluoride ingestion and mortality from cancer in humans". 

7.5.  Teratogenicity

    The results of a recent study suggest that fluoride may indeed 
exert effects on fetal growth:  babies, whose mothers had received 
fluoride tablets during pregnancy, were somewhat heavier and 
slightly longer at birth, and prematurity was much less frequent, 
compared with control groups (Glenn et al., 1982). 

    Rapaport (1956, 1959, 1963) reported an augmented frequency of 
Down's syndrome with increasing water fluoride concentrations.  In 
the first study (Rapaport, 1956), data were examined in relation to 
the place of birth, not to the place of residence of the mother.  
Subsequent papers (Rapaport, 1959, 1963) gave frequency figures for 
Down's syndrome of only 0.24 - 0.40 per 1 000 births in low-fluoride 
areas and 0.70 - 0.80 in high-fluoride areas.  His study comprised 
cases of Down's syndrome registered in specialist institutions in 

four American states and on birth and death certificates in a fifth 
state.  Information was gathered for the years 1950-56.  Many cases 
may not have been detected, because they were cared for at home. 

    Berry (1962) examined Down's syndrome in certain English cities 
and did not find any differences between areas with low (< 0.2 
mg/litre) and high (0.8 - 2.6 mg/litre) fluoride levels in the 
drinking-water.  The rates were 1.58 and 1.42 cases per 1 000 
births, respectively.  The English custom of tea-drinking was not 
taken into account, and the data were not presented in age-specific 
groups.  Needleman et al. (1974) recorded all children born alive 
with Down's syndrome among Massachusetts residents during the 
period 1950-66.  The number found was 1.5 per 1 000 births in both 
low-fluoride and fluoridated areas, but age-specific rates were not 
given.  Erickson et al. (1976) and Erickson (1980) did not find any 
difference in the incidence of Down's syndrome between fluoridated 
and low-fluoride areas, on the basis of birth certificates. 
However, the considerable material gathered in this way may only 
have covered about a half of the real number of children born with 
Down's syndrome.  Berglund et al. (1980) related the incidence in 
Sweden during 1968-77 to the mean water fluoride content of the 
areas where the mothers were living.  Virtually all cases of Down's 
syndrome were probably recognized and the incidence rates per 1000 
births during the period were found to range from 1.32 to 1.46.  
The material was divided into groups according to the maternal age 
below or above 35 years of age.  No influence of fluoride on the 
incidence of Down's syndrome was seen. 

7.6.  Effects on Mortality Patterns

    Limited evidence is available concerning the possible effects 
of occupational fluoride exposures on mortality patterns.  Some of 
the relevant studies are reviewed in section 7.4.  A large cohort 
study (Rockette & Arena, 1983) concerned the causes of death and 
showed indications of an excess rate of respiratory disease, while 
the number of deaths from other non-malignant causes were 
inconspicuous. 

    A report stated that the mortality rate from heart diseases had 
nearly doubled from 1950 to 1970 following the introduction in 1949 
of fluoridation of the drinking-water in Antigo, Wisconsin, a 
little town with only 9 000 inhabitants (Jansen & Thomsen, 1974).  
The report did not adjust for the fact that the number of people 
aged 75 years or more had also doubled in this period.  
Subsequently, epidemiologists from the American National Heart and 
Lung Institute did not find any correlation between deaths due to 
heart diseases and water fluoridation in Antigo (US NIH, 1972). 

    Several epidemiological studies, some of them very large, have 
not revealed any indications that fluoride in drinking-water 
increases the mortality rate from heart diseases (Hagan et al., 
1954; Schlesinger et al., 1956; Heasman & Martin, 1962; Luoma et 
al., 1973; Bierenbaum & Fleischman, 1974, Erickson, 1978; Rogot et 
al., 1978; Taves, 1978).  In fact, some of these studies point to 
the beneficial effects of fluoride on heart diseases (Heasman & 

Martin, 1962; Luoma et al., 1973; Taves, 1978).  Considering 
reports indicating that fluoride may reduce soft tissue 
calcification, such as atherosclerosis (Leone et al., 1954, 1955; 
Heasman & Martin, 1962; Taves & Neuman, 1964; Bernstein et al., 
1966; Zipkin et al., 1970), it seems of value to encourage further 
research on the relationship between fluoride and cardiovascular 
diseases. 

7.7.  Allergy, Hypersensitivity, and Dermatological Reactions

    In 1971, the American Academy of Allergy examined the 
literature on alleged allergic reactions to fluoride:  (Feltman, 
1956; Feltman & Kosel, 1961; Burgstahler, 1965; Waldbott, 1965; 
Shea et al., 1967).  The conclusions of the Executive Committee 
were (Austen et al., 1971):  "The review of the reported allergic 
reactions showed no evidence that immunologically mediated reaction 
of the types I-IV had been presented.  Secondly, the review of the 
cases reported demonstrated that there was insufficient clinical 
and laboratory evidence to state that true syndromes of fluoride 
allergy or intolerance exist."  As a result of this review, the 
members of the Executive Committee of the American Academy of 
Allergy adopted unanimously the following statement:  "There is no 
evidence of allergy or intolerance to fluorides as used in the 
fluoridation of community water supplies." 

    Since 1971, only in a few reports in the allergy literature 
have allergic reactions been suspected to be connected with 
fluoride exposure.  Petraborg (1974) described seven patients with 
various symptoms appearing a week after the introduction of water 
fluoridation.  Grimbergen (1974) using a double blind provocation 
test reported on a patient showing allergic reactions to 
fluoridated water.  Waldbott (1978) reviewed previous reports. 

    However, no animal or laboratory studies have indicated the 
existence of fluoride allergy or fluoride intolerance, and no 
plausible mechanism for such allergic reactions has been suggested.  
Thus, the allergenic effects of fluoride remain unproven. 

    In some occupational environments, aluminium potroom workers 
frequently complain about dyspnoea, chest tightness, and wheezing.  
The asthmatic response could be potentiated by beta-blockade with 
propranolol, and abolished by atropine (Saric et al., 1979).  
Increased bronchial excitability, as shown by the metacholine 
inhalation test, can be induced by aluminium compounds including 
aluminium fluoride (Simonsson et al., 1977).  These studies 
therefore suggest that respiratory exposure to irritants in the 
potroom atmosphere, including fluorides, may cause a non-specific 
hypersensitivity reaction that resembles bronchial asthma. 

    Skin telangiectases were found in an increased number on the 
upper chest, back, and shoulders in 40% of aluminium reduction 
workers in a comprehensive, cross-sectional study (Theriault et 
al., 1980).  These skin changes were not related to any excess of 
associated diseases, but the occurrence of large telangiectases was 
                                                                  

closely related to the length of exposure, and almost all workers 
with high exposures for more than ten years had telangiectases.  
However, the role of fluorides alone cannot be evaluated. 

    Allegations have been made through the years, and most recently 
by Waldbott (1978), that a specific skin manifestation called 
Chizzola maculae could be caused by air-borne fluorides.  Chizzola 
maculae were first reported in the vicinity of an aluminium smelter 
in the village of Chizzola, Trentino, Italy.  The smelter began 
operating in 1929; within two years the area suffered fluoride 
damage to trees and vines as well as livestock, followed in 1932-33 
by an epidemic of skin lesions resembling ecchymosis or erythema 
nodosum.  The condition gradually diminished, though lesions were 
occasionally seen until 1937.  No cases were reported from 1937 to 
1965.  In 1967, a new epidemic occurred in Chizzola and the 
surrounding area, prompting a survey by a Health Commission of the 
Ministry of Health in 1967.  The Commission found that 49% of the 
Chizzola children were affected and that 36 - 52% of comparison 
children examined had similar lesions although not exposed to 
effluents (Cavagna & Bobbio, 1970).  In addition, urinary-fluoride 
levels of children living near the plant were no different from 
those of children from an uncontaminated area. 

    In 1969, Waldbott & Cecilioni reported Chizzola maculae on the 
skin of 10 out of 32 individuals living near fertilizer plants in 
Ontario and in Iowa, and an iron foundry in Michigan.  They 
attributed the spots to fluoride exposure.  A Royal Commission in 
Ontario (1968) conducted a thorough environmental and medical 
survey on residents in the neighbourhood of the fertilizer factory, 
including some of the residents diagnosed by Waldbott & Cecilioni 
as suffering from fluoride poisoning on the basis of a group of 
symptoms including Chizzola maculae.  The Commission did not find 
any evidence of fluoride poisoning in any of the people examined. 

    Finally, lesions similar to the Chizzola maculae have never 
been reported either in areas where fluorosis is endemic, because 
of elevated levels of fluoride in the drinking-water, or among 
workers with significant occupational exposure.  At present, it 
appears that the evidence associating Chizzola maculae with 
fluoride exposure is circumstantial and unsupported by the results 
of field surveys. 

7.8.  Biochemical Effects

    The literature on the influence of fluoride on enzyme systems 
is overwhelming.  Both activating and inhibiting effects of the 
fluoride ions on enzymes are described.  The fluoride ions may 
exert a direct action on enzymes but, more frequently, the effect 
is indirect by complexing with metals of enzymes.  Reviews of the 
literature (Hodge & Smith, 1965; Taves, 1970; Wiseman, 1970; US 
EPA, 1980; SOU, 1981) suggest that low concentrations (about 10 
µmol/litre, i.e., 0.18 mg/litre) of fluoride in serum will 
stabilize and activate several isolated as well as membrane-bound 
enzyme systems.  At higher concentrations (at least 0.3 mg/litre), 
fluoride in serum will inhibit many enzymes.  Pyrophosphatase 

(EC 3.6.1.1), for instance, is inhibited by about 50% at 0.4 
mg/litre, a level that is higher than that found in plasma of an 
individual with a skeletal flouride content of 6000 mg/kg and 
exposure to drinking-water levels of 19 mg/litre (Ericsson et al., 
1973).  However, plasma fluoride concentrations of this magnitude 
have been maintained for years in patients treated with large daily 
doses of fluoride for osteoporosis.  Of particular interest is 
fluoride as an activator for adenyl cyclase (EC 4.6.1.1).  Studies 
in human beings have shown minimal increases in urinary cyclic 
adenosine monophosphate excretion and unchanged plasma levels 
following an oral intake of about 7 mg fluoride, which resulted in 
peak plasma fluoride levels of about 0.3 mg/litre (Mörnstad & van 
Dijken, 1982). 

    Alkaline phosphatase (EC 3.1.3.1) activity may be increased by 
fluoride (Farley et al., 1983), but changes in serum activity 
levels of this enzyme, and in serum calcium and phosphate, have 
been found to be minimal in potroom workers with skeletal fluorosis 
(Boillat et al., 1979). 

    In the mineralization of bones and teeth, the proteoglycans and 
their constituent glycosaminoglycans may play an important role, 
and they form an integral part of the organic matrix of these 
tissues.  Fluoride-induced changes in the formation of these 
compounds could be part of a common mechanism for the skeletal and 
dental effects of fluoride.  Studies on rats have shown that the 
proteoglycans undergo molecular changes, particularly in terms of 
decreased size, during the development of dental fluorosis (Smalley 
& Embery, 1980).  In rabbits, the glycosaminoglycans show major 
changes with the novel appearance of dermatan sulfate, an 
iduroglycosaminoglycan in fluorotic bone (Jha & Susheela, 1982a,b).  
These data, from experimental animal studies using very high 
fluoride exposures, are consistent with limited observations in 
human beings.  A recent study showed that the serum of patients 
with endemic fluorosis (both skeletal and dental) contained 
decreased concentrations of sialic acid and increased levels of 
glycosaminoglycans, compared with control levels; parallel findings 
were obtained in rabbits that had received sodium fluoride at 10 
mg/kg body weight, daily, for 8 months (Jha et al., 1983). 

    Because of the chemical similarities between the halogens, 
iodine and fluorine, there has been much interest in the possible 
effects of fluoride on thyroid function.  A century ago, fluoride 
was even used in the treatment of exophthalmic goitre.  However, 
the therapeutic action was found to be uncertain and such 
medication is now obsolete.  On the basis of a review of the 
literature, Demole (1970) suggested the following conclusions 
concerning the relationship between fluoride and the thyroid gland:  
"the problem of the toxic effects of fluorine in relation to the 
thyroid may be regarded as settled; a specific toxicity of fluorine 
for the thyroid gland does not exist.  The main facts behind this 
statement are:  (a) fluorine does not accumulate in the thyroid; (b) 
fluorine does not affect the uptake of iodine by the thyroid 
tissue; (c) there is no increased frequency in pathological changes 
in the thyroid in regions where the water is fluoridated, either 

naturally or artificially; (d) the administration of fluorine does 
not interfere with the prophylactic action of iodine on endemic 
goitre; and (e) the beneficial effect of iodine in threshold dosage 
to experimental animals is not inhibited by administration of 
fluorine even in an excessive dose". 

    Since then, Day & Powell-Jackson (1972) have reported a lower 
prevalence of goitre in Himalayan villages with a low fluoride 
content (< 0.1 - 0.19 mg/litre) in the drinking-water than in 
villages with a higher content (0.23 - 0.36 mg/litre).  Unfortunately, 
the fluoride values were based on determinations of only one water 
sample from each of the soil wells, and the fluoride content of 
soil wells could vary considerably over time.  Furthermore, the 
Himalayans are heavy tea-drinkers, and differences in this habit 
could elimate the difference in daily fluoride intake from water. 

    The Royal College of Physicians (1976) did not find any 
evidence that fluoride was responsible for any disorder of the 
thyroid.  In addition, in a recent German study, no relationship 
was detected between goitre and the fluoride content of drinking-
water (Sonneborn & Mandelkow, 1981). 

8.  EVALUATION OF SIGNIFICANCE OF FLUORIDES IN THE ENVIRONMENT

8.1.  Relative Contribution from Air, Food, and Water to Total Human 
Intake

    Except under occupational exposure conditions, respirable 
intake of fluoride is almost negligible.  Total fluoride intake 
will generally depend on fluoride levels in food and beverages, and 
on composition of the diet and fluid intake of the individual.  
Fluoride in water adds considerably to fluoride levels in prepared 
food.  Additional intentional fluoride intake may occur through the 
ingestion of fluoride tablets, and the use of fluoride-containing 
therapeutic agents and topical fluoride preparations. 

8.2.  Doses Necessary for Beneficial Effects in Man

    The quantity of fluoride needed for mineralization processes is 
small, and because of the ubiquitous distribution of fluoride, true 
deficiency is unlikely to occur in human beings.  Other essential 
functions have not been studied in detail. 

    Most important in a public health perspective is the 
cariostatic effect of fluoride.  This action depends partly on the 
incorporation of fluoride in developing teeth and partly on post-
eruptive exposure of enamel to adequate levels of fluoride in the 
oral environment.  Both requirements can be satisfied by an optimal 
fluoride concentration in the household drinking-water (0.7 - 1.2 
mg/litre, depending on climatic conditions) or by fluoride 
supplementation of food, e.g., table salt, milk.  Judicious 
administration of fluoride tablets is an alternative means of 
systemic application.  Topical fluoride applications such as 
fluoride dentifrices, rinses, or professionally applied 
preparations confer additional protection and are indicated as a 
primary preventative measure where systemic administration is not 
feasible.  The extent of caries reduction obtained by either or a 
combination of these methods is influenced by the initial caries 
prevalence, the amount of fluoride in the diet, and the level of 
oral health care within the community. 

    Fluoride preparations alone or in combination with other agents 
have been used for the treatment of osteoporosis in numerous 
instances.  Doses have ranged from a few milligrams to about 100 
milligrams per day.  Although this treatment has been used for two 
decades, and beneficial effects have been reported, the dose-
response relationships and efficacy need further clarification. 

8.3.  Toxic Effects in Man in Relation to Exposure

8.3.1.  Dental fluorosis

    Excessive fluoride exposure during the period of tooth 
development may result in defective tooth formation.  The earliest 
changes may resemble or be identical to abnormalities caused by 
other factors and this makes differential diagnosis difficult.  
The changes are rarely considered aesthetically objectionable.  
Depending on the fluoride intake from other sources, and the amount 

of drinking-water consumed, even these early changes occur in only 
a small proportion of a population that is using optimal levels of 
water fluoridation (section 8.2). 

    However, with increasing fluoride exposure, dental fluorosis 
becomes more prevalent and severe and may pose a public health 
problem. 

8.3.2.  Skeletal fluorosis

    The earliest reports of skeletal fluorosis in developed 
countries came from industries where exposure of workers to an 
intake of 40 - 80 mg per day for periods exceeding 4 years resulted 
in severe skeletal changes.  Such occupational fluorosis has been 
reported from industries with old or outmoded control technology.  
Simultaneously with the reports from industry, skeletal fluorosis 
was diagnosed in several areas where there was excessive fluoride 
in soil, water, dust, or vegetable matter. 

    Where industrial exposure is concerned, variability of 
occupational exposure and the difficulty of assessing the amount of 
fluoride absorbed and retained, has made it difficult to establish 
satisfactory dose-response relationships.  In addition to 
monitoring air concentrations, urinary fluoride concentrations are 
used as a means of indicating individual exposure.  Fluorosis is 
unlikely to develop when pre-shift (section 7.3.1) urine fluoride 
concentrations are consistently below about 4 mg/litre. 

    Endemic fluorosis involving severe debilitation of a 
substantial proportion of the population remains a serious problem 
in areas of several developing countries.  It is difficult to 
define the exposure that results in these effects, because the 
sources of the fluoride vary greatly and the severity is 
complicated by other factors such as malnutrition.  The disease is 
slowly reversible with treatment that includes reduction of 
fluoride intake and improvement in diet. 

8.3.3.  Other effects

    Considerable evidence has been presented indicating that 
fluoride exposure does not represent any carcinogenic or 
teratogenic hazard, and no effect on mortality patterns has been 
detected.  However, exposures to high levels of fluoride occur in 
connection with the use of fluorine-containing anaesthetic agents, 
in particular methoxyflurane.  These exposures have given rise to 
water-losing nephritis.  A number of other toxic effects and 
specific health problems have been suggested and studied during 
recent years (section 7).  However, the claim that fluoride played 
any role in these problems has never been substantiated. 

8.4.  Effects on Plants and Animals

8.4.1.  Plants

    Under most circumstances, little fluoride is taken up by roots 

from the soil so the concentration in the shoots of plants in non-
polluted atmospheres is usually less than 10 mg F per kg dry 
weight.  However, there are exceptions, such as when plants grow on 
soils that contain high-fluoride minerals or plants of unusual 
physiology that accumulate high concentrations from low-fluoride 
soils.  Exposure of plants to airborne fluorides leads to 
deposition of fluoride on the outer surfaces and uptake into the 
tissues.  The resultant concentrations in shoots depend on many 
factors, notably the concentration of fluoride in the air and the 
duration of exposure.  Fluoride in vegetation contributes to that 
in the human and animal diet.  The importance of this contribution 
depends on the relative and absolute amounts coming from other 
sources; in some areas where fluorosis is endemic, the importance 
of fluoride in food is not clear.  Toxic concentrations 
accumulated in plants cause visible symptoms that vary in 
significance from being trivial and unimportant to those of great 
economic importance (e.g., suture red spot of peach).  Plant 
species vary greatly in sensitivity to gaseous fluoride, the most 
sensitive being injured by long-term exposure to concentrations in 
excess of 0.2 µg/m3.  Air quality criteria to protect plants have 
been widely adopted. 

8.4.2.  Animals

    The most important effect of fluoride on animals is related to 
wild and domestic animals that are exposed for long periods to 
excess fluoride from sources such as industrial emissions.  Effects 
and dietary tolerances of domestic animals are well documented, but 
comparatively little is known about wild animals. 

    The major route of fluoride uptake by domestic animals is 
through ingestion.  Chronic manifestations of excess fluoride 
exposure are similar to those found in man, i.e., severe dental 
fluorosis and lameness; this limits feeding and therefore impairs 
performance.  Symptoms in livestock develop progressively at total 
dietary fluoride concentrations above 20 - 30 mg/kg dry matter.  
Prevention of fluorosis is based on the control of fluoride 
emissions, monitoring of the total diet (particularly forage), the 
use of properly defluorinated mineral supplements, and regular 
examination of the animals by a veterinarian. 

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    See Also:
       Toxicological Abbreviations