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
The International Programme on Chemical Safety (IPCS) is a
joint venture of the United Nations Environment Programme, the
International Labour Organisation, and the World Health
Organization. The main objective of the IPCS is to carry out and
disseminate evaluations of the effects of chemicals on human health
and the quality of the environment. Supporting activities include
the development of epidemiological, experimental laboratory, and
risk-assessment methods that could produce internationally
comparable results, and the development of manpower in the field of
toxicology. Other activities carried out by the IPCS include the
development of know-how for coping with chemical accidents,
coordination of laboratory testing and epidemiological studies, and
promotion of research on the mechanisms of the biological action of
ISBN 92 4 154096 6
The World Health Organization welcomes requests for permission
to reproduce or translate its publications, in part or in full.
Applications and enquiries should be addressed to the Office of
Publications, World Health Organization, Geneva, Switzerland, which
will be glad to provide the latest information on any changes made
to the text, plans for new editions, and reprints and translations
(c) World Health Organization 1984
Publications of the World Health Organization enjoy copyright
protection in accordance with the provisions of Protocol 2 of the
Universal Copyright Convention. All rights reserved.
The designations employed and the presentation of the material
in this publication do not imply the expression of any opinion
whatsoever on the part of the Secretariat of the World Health
Organization concerning the legal status of any country, territory,
city or area or of its authorities, or concerning the delimitation
of its frontiers or boundaries.
The mention of specific companies or of certain manufacturers'
products does not imply that they are endorsed or recommended by the
World Health Organization in preference to others of a similar
nature that are not mentioned. Errors and omissions excepted, the
names of proprietary products are distinguished by initial capital
ENVIRONMENTAL HEALTH CRITERIA FOR FLUORINE AND FLUORIDES
1. SUMMARY AND RECOMMENDATIONS FOR FURTHER RESEARCH
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
2.1.2. 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
126.96.36.199 Soil and rocks
188.8.131.52 Animal tissues
2.2.2. Separation and determination of fluoride
184.108.40.206 Colorimetric methods
220.127.116.11 The fluoride selective electrode
18.104.22.168 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
4.2. Retention and distribution
4.2.1. The fluoride balance
4.2.5. Soft tissues
4.3.6. Transplacental transfer
4.4. Indicator media
5. EFFECTS ON PLANTS AND ANIMALS
5.3. Aquatic animals
5.4.1. Acute effects
5.4.2. Chronic effects
5.5.1. Acute effects
22.214.171.124 Exposure to sodium fluoride
126.96.36.199 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
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
7.6. 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
IPCS TASK GROUP ON ENVIRONMENTAL HEALTH CRITERIA FOR FLUORINE
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)
Professor P. Grandjean, Department of Environmental Medicine,
Odense University, Odense, Denmark (Temporary Adviser)
Dr D.E. Barmes, Oral Health, World Health Organization,
a Invited, but could not attend.
Professor M. Guillemin, Institut de Médecine du Travail et
d'Hygične industrielle, University of Lausanne, Le
Professor F. Valic, International Programme on Chemical
Safety, World, Health Organization, Geneva, Switzerland
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
* * *
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 -
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
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
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
1.1.1. 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
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
1.1.4. Effects of fluoride on plants and animals
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.
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
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.,
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
(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
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.
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,
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-
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
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).
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
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).
188.8.131.52. 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
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
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 184.108.40.206).
220.127.116.11. 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
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.
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.
18.104.22.168. 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.
22.214.171.124. 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,
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
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
The precision and accuracy of the electrode method equal or
even exceed those of the colorimetric techniques for most samples.
126.96.36.199. 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
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
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
Table 1. Fluoride content of foods according to different
Food Before Oelschlager Toth & Sugar Koivistoinen
1956b (1970) Toth et al. (1980)
(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
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
Other 0.1 - 0.6 0.1 - 0.3 0.1 - 0.4 0.1 - 0.3
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)
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
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
Vegetables 0.3 (0.1 - 0.4) 0.8
(canned) (0.6 - 1.1)
Beans and pork 0.3 0.8
Cheese 0.2 - 0.3 1.3 - 2.2 Elgersma & Klomp
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
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
Armstrong & 0.27-0.32 - - Analyses of 3 meals for
Knowlton (1942) hospital staff, no
Machle et al. 0.16 0.30b 0.46 Analyses of one persons
(1942) 0.54 max 0.75 daily intake during 40
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
Danielsen & 0.56-0.57 - - Calculated intake of
Gaarder (1955) persons > 14 years
Cholak (1960) 0.3-0.8 - - Excluding fluoride from
Kramer et al. 0.8-1.0b - - Analyses of general hos-
(1974) pital diets in 4 cities,
3 meals, no food/drink
Osis et al. 0.7-0.9b - - See Kramer et al. (1974)
Singer et al. 0.37 0.54 0.91
Becker & Bruce 0.41 0.20 0.61 Calculated from anal-
(1981) yses of market basket
samples and from food
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
San Filippo & 0.78-0.90 1.3-1.5 2.1-2.4 Analyses of 4 market
Battistone basket samples
Marier & Rose 1.0-2.1 1.0-3.2 1.9-5.0 Calculated from the
(1966) diets of 7 laboratory
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
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
Becker & Bruce 0.41 1.6-1.9 2.0-2.3 Calculated from
(1981) analysies and food
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,
4. CHEMOBIOKINETICS AND METABOLISM
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.,
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.
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
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.
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).
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
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).
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.
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.
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).
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 &
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.
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
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
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
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
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
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-
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).
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.
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
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
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)
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
Mugil cephalus 100 96 h None Hemens & Warwick (1972)
Mugil cephalus 5.5 113 days None Hemens et al. (1975)
Mugil cephalus 52 72 days Increased Hemens & Warwick (1972)
Ambassis safgha 100 96 h None Hemens & Warwick (1972)
Therapon jarbua 100 96 h None Hemens & Warwick (1972)
Penaeus indicus 5.5 113 days None Hemens et al. (1975)
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)
Palaemon pacificus 52 72 days Affected Hemens & Warwick (1972)
Perna perna 7.2 5 days Evidence of Hemens & Warwick (1972)
(brown mussel) toxic effects
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
5.5.1. Acute effects
188.8.131.52. 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
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-
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).
184.108.40.206. Exposure to fluorine, hydrogen fluoride, or silicon
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
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
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
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
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
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
Slight gross periosteal no yes yes yes
Moderate gross periosteal no no yes yes
Significant incidence of no no no yes
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
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
d Metacarpal or metatarsal bone, dry, fat-free basis.
e Based on values taken after 2 - 3 years of exposure; density
Table 8. Dietary fluoride tolerances for domestic animalsa,b
Animal Performancec Pathologyd
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
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,
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
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.
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.
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-
Table 9. Data from studies on the effect on dental caries of
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
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,
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
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
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
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
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.,
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
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
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
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
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
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,
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
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
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
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.
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
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).
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
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".
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
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
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 220.127.116.11), 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 18.104.22.168). 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
Alkaline phosphatase (EC 22.214.171.124) 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
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
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
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.
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.
ACGIH (l980) Documentation of the threshold limit values,
Cincinatti, Ohio, American Conference of Governmental
ACGIH (1983-1984) TLVs - Threshold limit values for chemical
substances in the work environment adopted by the ACGIH for
1983-1984, Cincinnati, Ohio, American Conference of
Governmental Industrial Hygienists, pp. 1-93 (ISBN:
ADLER, P. (195l) [Caries protection in adults by naturally
fluorinated drinking water.] Zahn- Mund- Kieferheilkd., 15:
24-30 (in German).
AL-ALOUSI, W., JACKSON, D., CROMPTON, G., & JENKINS, O.C.
(1975) Enamel mottling in a fluoride and a non-fluoride
community. Br. dent. J., 138: 9-15, 56-60.
ALARY, J., BOURBON, P., BALSA, C., BONTE, J., & BONTE, C.
(1981) A field study of the validity of static paper sampling
in fluoride pollution surveys. Sci. total Environ., 20: 11.
ALCAN SURVEILLANCE COMMITTEE (l979) Environmental effects of
emissions from the Alcan smelter at Kittimat, BC, Province of
British Columbia, Canada, Ministry of the Environment, 151 pp.
ALHAVA, E.M., OLKKONEN, H., KAURANEN, P., & KARI, T. (l980)
The effect of drinking-water fluoridation on the fluoride
content, strength and mineral density of human bone. Acta
orthop. Scand., 5l: 4l3-420.
AMERICAN PUBLIC HEALTH ASSOCIATION, AMERICAN WATER WORKS
ASSOCIATION AND WATER POLLUTION CONTROL FEDERATION (1971)
Standard methods for the examination of water and waste-water,
13th ed., Washington DC, American Public Health Association,
ANASUYA, A. (l982) Role of fluoride in formation of urinary
calculi: Studies in rats. J. Nutr., 112: 1787-1795.
ANDERBERG, U. & MAGNUSSON, B. (1977) [Fluoride content in
tea and some other beverages.] Tandläkartidningen, 69: 346-348
ANDERSEN, A., DAHLBERG, B.E., MAGNUS, K., & WANNAG, A.
(1982) Risk of cancer in the Norwegian aluminium industry.
Int. J. Cancer, 29: 295-298.
ANERMANN, E. (1973) Fluoride uptake in humans. Fluoride, 6:
ANGELOVIC, J.W., SIGLER, W.F., & NEUHOLD, J.M. (1961)
Temperature and fluorosis in rainbow trout. J. water Pollut.
Control, 33: 371-38l.
ARMSTRONG, W.D. & KNOWLTON, M. (1942) Fluorine derived from
food. J. dent. Res., 21: 326.
ARMSTRONG, W.D., SINGER, L., & MAKOWSKI, W.L. (l970)
Placental transfer of fluoride and calcium. Am. J. Obstet.
Gynecol., 107: 432-434.
ARNOLD, F.A. & RUSSELL, A.L. (1962) Fifteenth year of the
Grand Rapids fluoridation study. J. Am. Dent. Assoc., 65:
ARNOLD, F.A., MCCLURE, F.J., & WHITE, C.L. (1960) Sodium
fluoride tablets for children. Dent. Prog., 1: 8-12.
AST, D.B., SMITH, D.J., WACHS, B., & CANTWELL, K.T. (1956)
Newburgh-Kingston caries-fluorine study. XIV. Combined
clinical and roentgenographic dental findings after ten years
of fluoride experience. J. Am. Dent. Assoc., 52: 314-325.
AUSTEN, K.F., DWORETZKY, M., FARR, R.S., LOGAN, G.B., MALKIEL,
S., MIDDLETON, E., Jr, MILLER, M.M., PATTERSON, R., REED,
C.E., SIEGEL, S.C., & VAN ARSDEL, P.P., Jr (1971) A
statement on the question of allergy to fluoride used in the
fluoridation of community water supplies. J. Allergy clin.
Immunol., 47: 347-348.
BACKER DIRKS, O., JONGELING-EIJNDHOVEN, J.M.P.A., FLISSE-
BAALJE, T.D., & GEDALIA, I. (1974) Total and free ionic
fluoride in human and cow's milk as determined by gas-liquid
chromatography and the fluoride electrode. Caries Res., 8:
BALAZOVA, G. & HLUCHAN, E. (1969) The effect of fluoride
emission on animals in the surrounds of an aluminium plant,
air pollution. In: Procedures of the 1st European Congress on
the Influence of Air Pollution on Plants and Animals,
Wageningen, the Netherlands, p. 275.
BALE, S.S. & HART, G.E. (l973a) Studies on the cytogenetic
and genetic effects of fluoride on barley: I. A comparative
study of the effect of sodium fluoride and hydrofluoric acid
on seedling root tips. Can. J. Genet. Cytol., 15: 371-375.
BALE, S.S. & HART, G.E. (l973b) Studies on the cytogenetic
and genetic effects of fluoride on barley: II. The effects of
teatments of seedling coleoptiles with sodium fluoride. Can.
J. Genet. Cytol., 15: 703-712.
BALTAZAR, R.F., MOWER, M.M., REIDER, R., FUNK, M., & SALOMON,
J. (1980) Acute fluoride poisoning leading to fatal
hyperkalemia. Chest, 78: 660-663.
BANKS, R.E. & GOLDWHITE, H. (1966) Fluorine chemistry. In:
Smith, F.A., ed. Handbook of experimental pharmacology, New
York, Springer-Verlag, Vol. 20, Part 1, 608 pp.
BARMES, D.E. (1983) Indicators for oral health and their
implications for developing countries. Int. dent. J., 33(1):
BAUD, C.-A., LAGIER, R., BOIVIN, G., & BOILLAT, M.-A. (1978)
Value of the bone biopsy in the diagnosis of industrial
fluorosis. Virshows Arch. A Pathol. Anat. Histol., 380:
BECKER, W. & BRUCE, A. (1981) [Fluoride intake from food.]
Var föda, 33(Suppl. 3): 198-261 (in Swedish).
BELCHER, R., LEONARD, M.A., & WEST, T.S. (1959)
Submicro-methods for the analysis of organic compounds. Part
X. Determination of fluorine. J. Am. Chem. Soc., 81: 3577.
BELISLE, J. (1981) Organic fluorine in human serum: Natural
versus industrial sources. Science, 212: 1509-1510.
BERGLUND, G., WIKSTRAND, J., WALLENTIN, I., & WILHELMSEN, L.
(1976) Sodium excretion and sympathetic activity in relation
to severity of hypertensive disease. Lancet, i: 324.
BERGLUND, K., ISELIUS, L., LINDSTEN, J., MARSK, L., & RYMAN,
N. (1980) [Incidence of Down's syndrome in Sweden during the
years 1968-1977.] Stockholm, National Swedish Board of Health
and Welfare (Report to the Reference Group for Malformations
and Developmental Disturbances) (in Swedish).
BERMAN, L.B. & TAVES, D. (1973) Fluoride excretion in normal
and uremic humans. Clin. Res., 21: 100.
BERNDT, A.F. & STEARNS, R.I. (1979) Dental fluoride
chemistry, Springfield, Ill., Charles C. Thomas Publ.
BERNSTEIN, D.S., SADOWSKY, N., HEGSTED, D.M., GURI, C.D., &
STARE, F.J. (1966) Prevalence of osteoporosis in high- and
low-fluoride areas in North Dakota. J. Am. Med. Assoc., 198:
BERRY, W.T.C. (1962) Fluoridation. Med. Off., 108: 204-205.
BIERENBAUM, M.L. & FLEISCHMAN, A.I. (1974) Effect of
fluoridated water upon serum lipids, ions and cardiovascular
disease mortality rates. J. Med. Soc. New Jersey, 7l: 663-666.
BIERSTEKER, K., ZIELHUIS, R.L., BACKER DIRKS, O., VAN LEUWEN,
P., & VAN RAY, A. (1977) Fluoride excretion in urine of
school children living close to an aluminium refinery in the
Netherlands. Environ. Res., 13: 129-134.
BINDER, K., DRISCOLL, W.S., & SCHUETZMANNSKY, G. (1978)
Caries-preventive fluoride tablet programs. Caries Res.,
12(Suppl. 1): 22-30.
BIRKELAND, J.M. & TORRELL, P. (1978) Caries-preventive
fluoride mouth viruses. Caries Res., 12(Suppl. 1): 38-51.
BLAYNEY, J.R. & HILL, I.N. (1967) Fluorine and dental
caries. J. Am. Dent. Assoc., 74: 225-303.
BOILLAT, M.A., BAUD, C.A., LAGIER, R., GARCIA, J., REY, P.,
BANG, S., BOIVIN, C., DEMEUNISSE, D., GOESSI, M.,
TOCHON-DANGUY, H.J., VERY, J.M., BURKHARDT, P., VOINER, B.,
DONATH, A., & COURVOISIER, B. (1979) Fluorose industrielle.
Etude multidisciplinaire de 43 ouvriers de l'industrie de
l'aluminium. Schweiz. Med. Wochenschr., 109(Suppl. 8): 5-28.
BOILLAT, M.A., GARCIA, J., & VELEBIT, L. (1981) Radiological
criteria of industrial fluorosis. Skeletal Radiol., 5: 161-165.
BONTE, J. (l982) Effects of air pollutants on flowering and
fruiting. In: Unsworth, M.H. & Ormrod, D.P., ed. Effects of
gaseous air pollution in agriculture and horticulture, London,
Butterworth Scientific, pp. 207-223.
BROWN, W.E. & KONIG, K.G., ed. (1977) Cariostatic mechanism
of fluorides. Caries Res., 11(Suppl. 1): 1-327.
BROWN, H.K. & POPLOVE, M. (1965) Brantford-Sarnia-Stratford
fluoridation study: final survey 1963. J. Can. Dent. Assoc.,
BROWN, H.K., MCLAREN, H.R., JOSIE, G.H., & STEWART, B.J.
(1956) Brantford fluoridation study. 1956 report. J. Can.
Dent. Assoc., 22: 207-216.
BROWN, H.K., MCLAREN, H.R., & POPLOVE, M. (1960) The
Brantford-Sarnia-Stratford fluoridation study - 1959 report.
J. Can. Dent. Assoc., 26: 131-142.
BUCCHI, R. (l977) Induced dominant lethal mutations and
cytotoxic effects in germ cells of Drosophila melanogaster
with Trenimon, PDMT and sodium monofluorophosphate. Genetics,
BURGSTAHLER, A.W. (1965) Dental and medical aspects of
fluoridated drinking-water. Trans. Kansas Acad. Sci., 68: 2.
BURKE, W.J., HOEGG, U.R., & PHILLIPS, R.E. (1973) Systemic
fluoride poisoning resulting from a fluoride skin burn.
J. occup. Med., 15: 39-41.
BURKI, K. & BUCCHI, R. (1975a) Influence of NaF and NaPO3 on
chemically induced aberrations in mature sperm of Drosophila.
Mutat. Res., 31: 315.
BURKI, K. & BUCCHI, R. (1975b) Origin of chromosome
aberrations in mature sperm Drosophila: Influence of sodium
fluoride on treatments with trenimon and 1-phenyl-3,3-
dimethyltriazine. Arch. Genet., 48: 59.
BUTTNER, W. & KARLE, E. (1974) Chronic toxicity and
retention of fluoride in the unilaterally nephrectomized rat.
Caries Res., 8: 359-367.
CAMERON, J.M.R. (l977) Poison plants in Western Australia
and coloniser problem-solving. J. R. Soc. West Aust., 59:
CANADIAN PUBLIC HEALTH ASSOCIATION (1979) Criteria document
in support of a drinking-water standard for fluoride, Ottawa,
Canadian Public Health Association.
CAPAR, S.G. & GOULD, J.H. (1979) Lead, fluoride and other
elements in bone meal supplements. J. Assoc. Off. Anal.
Chem., 62: 1054-1061.
CARLSON, C.H., ARMSTRONG, W.D., & SINGER, L. (1960a)
Distribution and excretion of radiofluoride in the human.
Proc. Soc. Exp. Biol. Med., 104: 235-239.
CARLSON, C.H., ARMSTRONG, W.D., & SINGER, L. (1960b)
Distribution, migration and binding of whole blood fluoride
evaluated with radiofluoride. Am. J. Physiol., 199: 187-189.
CARNOW, B.W. & CONIBEAR, S.A. (1981) Industrial fluorosis.
Fluoride, 14: 172-181.
CARPENTER, R. (1969) Factors controlling the marine
geochemistry of fluorine. Geochim. cosmochim. Acta, 33:
CASS, J.S. (1961) Fluorides: A critical review: IV.
Response of livestock and poultry to absorption of inorganic
fluorides. J. occup. Med., 3: 471-477, 527-543.
CASS, R.M., CROFT, J.D., Jr, PERKINS, P., NYE, W., WATERHOUSE,
C., & TERRY, R. (1966) New bone formation in osteoporosis
following treatment with sodium fluoride. Arch. intern. Med.,
CATE, S.M. TEN (1979) Remineralization of enamel lesions,
Gröningen, Netherlands, Thesis.
CAUSSE, J.R., SHAMBAUGH, G.E., CAUSSE, J.B., & BRETLAU, P.
(1980) Enzymology of otospongiosis and NaF therapy. Am. J.
Otol., 1: 206-213.
CAVAGNA, G. & BOBBIO, G. (1970) Chemical and physical
properties of effluents from an aluminium plant and their
biological effects. Med. lav., 61: 69-101.
CHAN-YEUNG, M., WONG, R., TAN, F., ENARSON, D., SCHULZER, M.,
SUBBARAO, D., KNICKERBOCKER, J., & GRZYBOWSKI, S. (1983)
Epidemiologic health study of workers in an aluminum smelter
in Kitimat, B.C. II. Effects on musculoskeletal and other
systems. Arch. environ. Health, 38: 34-40.
CHAREN, J., TAVES, D.R., STAMM, J.W., & PARKINS, F.M. (1979)
Bone fluoride concentrations associated with fluoridated
drinking-water. Calcif. Tissue Int., 27: 95-99.
CHARKES, N.D., MAKLER, P.T., Jr, & PHILLIPS, C. (1978)
Studies of skeletal tracer kinetics. I. Digital-computer
solution of a five-compartment model of (18F) fluoride
kinetics in humans. J. nucl. Med., 19: 1301-1309.
CHEMICAL MARKETING REPORTER (1978a) Fluorocarbons. Chem.
Mark. Rep., 14(6): 9.
CHEMICAL MARKETING REPORTER (1978b) Hydrofluoric acid.
Chem. Mark. Rep., 14(8): 9.
CHOLAK, J. (1960) Current information on the quantities of
fluoride found in air, food and water. Am. Med. Assoc. Arch.
ind. Health, 21: 312-315.
CHRISTIE, D.P. (1980) The spectrum of radiographic bone
changes in children with fluorosis. Radiology, 136: 85-90.
CHURCHILL, H.V. (1931) Occurrence of fluorides in some water
of the United States. Ind. Eng. Chem., 23: 996-998.
CLARK, R.B., BEARD, A.G., & THOMPSON, D.S. (1979) Renal
functions in newborns and mothers exposed to methoxyflurane
analgesia for labour and delivery. Clin. Rep., 51: 464-467.
COHEN, E.N. & VAN DYKE, R.A. (1977) Metabolism of volatile
anesthetics, Reading, Mass., Addison-Wesley.
COMMITTEE ON RESEARCH INTO FLUORIDATION (1969) The
fluoridation studies in the United Kingdom and the results
achieved after eleven years, London, Her Majesty's Stationery
Office, 43 pp.
COUSINS, M.J. & MAZZE, R.I. (1973) Methoxyflurane
nephrotoxicity. A study of dose response in man. J. Am. Med.
Assoc., 225: 1611-1616.
COUSINS, M.J., MAZZE, R.I., KOSEK, J.C., HITT, B.A., & LOVE,
F.V. (1974) The etiology of methoxyflurane nephrotoxicity.
J. Pharmacol. exper. Ther., 190: 530-541.
CRAIG, G. & POWELL, K. (1980) Blemishes of anterior teeth.
Dent. Outlook, 6: 25.
CROSBY, N.D. & SHEPHERD, P.A. (1957) Studies on patterns of
fluid intake, water balance and fluoride retention. Med. J.
Aust., 10: 341-346.
CUASAY, O.S., RAMAMURTHY, R., SALEM, M.R., SENDAYDIEGO, P.M.,
ELGINDY, L.I., & CABURNAY, F.S. (1977) Inorganic fluoride
levels in parturients and neonatates following methoxyflurane
analgesia during labor and delivery. Anesth. Analg., 56:
DAHLGREN, B.E. (1978) Urinary fluoride concentration in
mothers and neonatates after methoxyflurane-nitrous oxide
analgesia during labour. Acta pharm. Sued., 15: 211-217.
DANIELSEN, M.E. & GAARDER, T. (1955) Fluorine content of
drinking-water and food in western Norway, the Bergen
district. Univ. Bergen, Arbok 1955. Nat. Recke, 15: 1.
DANILOVA, V.V. (1944) [The geochemistry of dispersed
fluorine.] Tr. Biogeochem. Lab. Akad. Nauk., 7: 76-83 (in
DAVIS, R.K. (1961) Fluorides: A critical review, V. Fluoride
intoxication in laboratory animals. J. occup. Med., 3:
DAVISON, A.W. (l982) The effects of fluorides on plant
growth and forage quality. In: Unsworth, M.H. & Ormrod, D.P.,
ed. Effects of gaseous air pollution in agriculture and
horticulture, London, Butterworth Scientific, pp. 267-515.
DAVISON, A.W. (l984) Uptake, transport and accumulation of
soil and airborne fluorides by vegetation, In: Shupe, J.L.,
ed. Fluorides: Effects on vegetation, animals and humans, Salt
Lake City, Utah, Paragon Press, pp. 6l-84.
DAVISON, A.W. & BLAKEMORE, J. (l980) Rate of deposition and
resistance to deposition of fluoride on alkali impregnated
papers. Environ. Pollut., 1(series B): 305-319.
DAVISON, A.W., BLAKEMORE, J., & CRAGGS, C. (1979) The
fluoride content of forage as an environmental quality
standard for the protection of livestock. Environ. Pollut.,
DAY, T.K. & POWELL-JACKSON, P.R. (1972) Fluoride, water
hardness and endemic goitre. Lancet, i: 1135-1138.
DEAN, H.T. (1934) Classification of mottled enamel
diagnosis. J. Am. Dent. Assoc., 21: 1421-1426.
DEAN, H.T. (1938) Endemic fluorosis and its relation to
dental caries. Public Health Rep., 53: 1443-1452.
DEAN, H.T. (1942) The investigation of physiological effects
by the epidemiological method. Am. Assoc. Adv. Sci., 19:
DEAN, H.T. & ELVOVE, E. (1935) Studies on the minimal
threshold of the dental sign of chronic endemic fluorosis
(mottled enamel). Public Health Rep., 50: 1719.
DEAN, H.T. & ELVOVE, E. (1937) Further studies on the
minimal threshold of chronic endemic fluorosis. Public Health
Rep., 52: 1249-1264.
DEAN, H.T., ARNOLD, F.A., & ELVOVE, E. (1941a) Domestic
waters and dental caries. II. Study of 2832 white children
aged 12-14 years, of 8 surburban Chicago communities,
including Laxtobacillus acidophilus counts of 1761 children.
Public Health Rep., 56: 761-792.
DEAN, H.T., ARNOLD, F.A., & ELVOVE, E. (194lb) Domestic
waters and dental caries. V. Additional studies of the
relation of fluoride domestic waters to dental caries
experience in 4425 white children aged 12-14 years of 13
cities in 4 states. Public Health Rep., 57: 1155-1179.
DEATHERAGE, C.F. (1943) A study of fluoride domestic waters
and dental caries experience in 262 white, Illinois selective
servicemen living in fluoride areas following the period of
calcification to the permanent teeth. J. dent. Res., 22: 173.
DEEDS, F. & THOMAS, J.O. (1933-34) Comparative chronic
toxicities of fluorine compounds. Proc. Soc. Exp. Biol. Med.,
DE LOPEZ, O.H., SMITH, F.A., & HODGE, H.C. (1976) Plasma
fluoride concentrations in rats acutely poisoned with sodium
fluoride. Toxicol. appl. Pharmacol., 37: 75-83.
DEMOLE, V. (1970) Toxic effects on the thyroid. In:
Fluorides and human health, Geneva, World Health Organization,
pp. 255-262 (WHO Monograph Series No. 59).
DERRYBERRY, O.M., BARTHOLOMEW, M.D., & FLEMING, R.B.L.
(1963) Fluoride exposure and worker health. Arch. environ.
Health, 6: 503-510.
DE VILLIERS, A.J. & WINDISH, J.P. (1964) Lung cancer in a
fluorspar mining community. Br. J. ind. Med., 21: 94-109.
DINMAN, B.D., BOVARD, W.J., BONNEY, T.B., COHEN, J.M., &
COLWELL, M.O. (1976a) Absorption and excretion of fluoride
immediately after exposure. Part I. J. occup. Med., 18: 7-13.
DINMAN, B.D., ELDER, M.J., BONNEY, T.B., BOWARD, P.G., &
COLWELL, M.O. (1976b) A 15-year retrospective study of
fluoride excretion and boney radiopacity among aluminium
smelter workers. Part 4. J. occup. Med., 18: 2l-23.
DIPASQUALE, L.C. & DAVIS, H.V. (1971) The acute toxicity of
brief exposures to hydrogen fluoride, hydrogen chloride,
nitrogen dioxide, and hydrogen cyanide singly and in
combination with carbon monoxide, Wright Patterson Air Force
Base, Dayton, Ohio, pp. 279-290 (AMRL-TR-71-120, Paper No. 20.)
DIXON, A. St. J. (1983) Non-hormonal treatment of
osteoporosis. Br. med. J., 286: 999-1000.
DOLAN, T., LEGETTE, L., & MONEAL, J. (1978) Determination of
fluoride in deboned meat. J. Off. Anal. Chem., 61: 982-985.
DREISBACK, R.H. (1971) Handbook of poisoning: Diagnosis and
treatment, Los Altos, California, Lange Medical
Publications, 517 pp.
DRISCOLL, W.S. (1974) The use of fluoride tablets for the
prevention of dental caries. In: Forrester, D.J. & Schulz,
E.M., ed. International workshop on fluoride and dental
caries reductions, Maryland, University of Maryland, pp.
DUCHASSAING, D., RIGAT, B., BARBEROUSSE, J.P., & LAISNE, M.J.
(1982) The elimination of inorganic fluoride after enflurane
anesthesia - Transitory action on parathyroid tissue. Int. J.
clin. Pharmacol. Ther. Toxicol., 20: 366-372.
DUCKWORTH, S.C. & DUCKWORTH, R. (1978) The ingestion of
fluoride in tea. Br. dent. J., 145: 368-370.
DURRANT, P.J. & DURRANT, B. (1962) Introduction to advanced
inorganic chemistry, London, Longman Group Limited, 1171 pp.
DUXBURY, A.J., LEACH, F.N., & DUXBURY, J.T. (1982) Acute
fluoride toxicity. Br. dent. J., 153: 64-66.
DYKE, R.A. VAN (l979) Fluoride from anesthetics and its
consequences. In: Johansen, E., Taves, D.R., & Olsen, T.O.,
ed. Continuing evaluation of the use of fluorides, Boulder,
Colorado, Westview, pp. 241-252.
EAGER, J.M. (1901) Chiaie teeth. Public Health Rep., 16:
EAGERS, R. (1969) Toxic properties of inorganic fluorine
compounds, London, Elsevier Publ. Co.
EDWARD, S. (1982) [Treatment of dental fluorosis.]
Tandläkartidningen, 74(17): 1 (in Swedish).
EKSTRAND, J. (1977) Studies on the pharmacokinetics in man,
Stockholm, Karolinska Institute, Thesis.
EKSTRAND, J. & EHRNEBO, M. (1979) Influence of milk products
on fluoride bioavailability in man. Eur. J. clin. Pharmacol.,
EKSTRAND, J., ERICSSON, Y., & ROSELL, S. (1977a) Absence of
protein-bound fluoride from human blood plasma. Arch. oral
Biol., 22: 229-232.
EKSTRAND, J., ALVAN, G., BOREUS, L.O., & NORLIN, A. (1977b)
Pharmacokinetics of fluoride in man after single and multiple
oral doses. Eur. J. clin. Pharmacol., 12: 3ll-3l7.
EKSTRAND, J., EHRNEBO, M., & BOREUS, L.O. (1978) Fluoride
bioavailability after intravenous and oral administration:
importance of renal clearance and urine flow. Clin.
Pharmacol. Ther., 23: 329-371.
EKSTRAND, J., BOREUS, L.O., & DE CHATEAU, P. (1981) No
evidence of transfer of fluoride from plasma to breast milk.
Br. med. J., 283: 761-762.
EKSTRAND, J., SPAK, C.J., & EHRNEBO, M. (1982) Renal
clearance of fluoride in a steady state condition in man:
influence of urinary flow and pH changes by diet. Acta
pharmacol. toxicol., 50: 321-325.
ELEY, A.J., KEMP, F.A., KERLEY, P.J., & BERRY, W.T. (1957)
The incidence of spinal defects in high- and low-fluoride
areas. Lancet, 2: 712.
ELGERSMA, R.H.C. & KLOMP, H. (1975) The effect of
fluoridated tap-water used in the cheese-making process, on
the fluoride content of Gouda cheese. Neth. Milk Dairy J.,
EL-KHOURY, G.Y., MOORE, T.E., ALBRIGHT, J.P., HUANG, H.K., &
MARTIN, A.E. (1982) Sodium fluoride treatment of
osteoporosis. Radiologic findings. J. Roentgenol., 139: 39.
ELLIS, M.M. (1937) Detection and measurement of stream
pollution. Bull. Bur. Fish., XLVIII(22): 429.
ENGLANDER, H.R. & WALLACE, D.A. (1962) Effects of naturally
fluoridated water on dental caries in adults. Public Health
Rep., 77: 887-893.
ERDMANN, W. & KETTNER, H. (1975) [Results of measurements of
fluoride emission near an aluminium plant.] Oeff.
Gesundh.-Wesen, 37: 29-32 (in German).
ERICKSON, J.D. (1978) Mortality in selected cities with
fluoridated and non-fluoridated water supplies. New Engl. J.
Med., 293: 1112-1116.
ERICKSON, J.D. (1980) Down's syndrome, water fluoridation
and maternal age. Teratology, 21: 177.
ERICKSON, J.D., OAKLEY, G.P., FLYNT, J.W., & HAY, S. (1976)
Water fluoridation and congenital malformations: No
association. J. Am. Dent. Assoc., 93: 981-984.
ERICSSON, Y. (1969) Fluoride excretion in human saliva and
milk. Caries Res., 3: 159-166.
ERICSSON, Y., ed. (1978) Progress in caries prevention.
Caries Res., 12(Suppl. 1): 1-112.
ERICSSON, Y. & FORSMAN, B. (1969) Fluoride retained from
mouth rinses and dentifrices in preschool children. Caries
Res., 3: 290-300.
ERICSSON, Y., GYDELL, K., & HAMMARSKIOELD, T. (1973) Blood
plasma fluoride: An indicator of skeletal fluoride content.
J. Int. Res. Commun. Syst., 1: 33.
EVANS, R.J. & PHILLIPS, P.H. (1938) New low fluoride diet
and its effect upon the rat. J. Nutr., 18: 353-358.
FANNING, E.A., CELLIER, K.M., LEADBEATER, M.M., & SOMERVILLE,
C.M. (1975) South Australian kindergarten children. Fluoride
tablet supplements and dental caries. Aust. dent. J., 20: 7-9.
FARLEY, J.R., WERGEDAL, J.E., & BAYLINK, D.J. (1983)
Fluoride directly stimulates proliferation and alkaline
phosphatase activity of bone-forming cells. Science, 222:
FEHR, F.R. VON DER & MOLLER, I.J. (1978) Caries preventive
fluoride dentifrices. Caries Res., 12(Suppl. 1): 31-37.
FEJERSKOV, O., THYLSTRUP, A., & JOOST LARSEN, M. (1977)
Clinical and structural features and possible pathogenic
mechanisms of dental fluorosis. Scand. J. dent. Res., 85:
FEJERSKOV, O., YEAGER, J.A., & THYLSTRUP, A. (1979)
Microradiography of the effect of acute and chronic
administration of fluoride on human and rat dentine and
enamel. Arch. oral Biol., 24: 123-130.
FEJERSKOV, O., THYLSTRUP, A., & JOOST LARSEN, M. (1981)
Rational use of fluorides in caries prevention. Acta odontol.
Scand., 39: 241-249.
FELLENBERG, T. VON (l948) [On the significance of fluoride
for the teeth.] Mitt. Lebensmittelunters. Hyg., 39: 124-182,
386-388 (in German).
FELTMAN, R. (1956) Prenatal and postnatal ingestion of
fluorides: A progress report. Dent. Dig., 62: 353-357.
FELTMAN, R. & KOSEL, G. (1961) Prenatal and postnatal
ingestion of fluorides - fourteen years of investigation -
Final Report. J. dent. Med., 16: 190-199.
FORREST, J.R. (1956) Caries incidence and enamel defects in
areas with different levels of fluoride in the
drinking-water. Br. dent. J., 100: 195-200.
FORREST, J.R. & JAMES, P.M.C. (1965) A blind study of enamel
opacities and dental caries prevalence after 8 years of
fluoridation of water. Br. dent. J., 119: 319-322.
FORREST, J.R., PARFITT, G.J., & BRANSBY, E.R. (1951) The
incidence of dental caries among adults and young children in
three high and three low fluoride areas in England.
Mon. Bull. Minist. Health, 10: 104-111.
FORSMAN, B. (1977) Early supply of fluoride and enamel
fluorosis. Scand. J. dent. Res., 85: 22-30.
FOURNIER, A.E., JOHNSON, W.J., TAVES, D.R., BEABOUT, J.W.,
ARNAUD, C.D., & GOLDSMITH, R.S. (1971) Etiology of
hyperparathyroidism and bone disease during chronic
hemodialysis. I. Association of bone disease with potentially
etiologic factors. J. clin. Invest., 50: 592-598.
FRANKE, J. & ANERMANN, E. (1972) The importance of iliac
crest biopsy with histological and micro-analytical
investigation of the obtained bone material in the diagnosis
of fluorosis. Int. Arch. Arbeitsmed., 29: 85-94.
FRANKE, J., RUNGE, H., FENGLER, F. (1978) Endemic and
industrial fluorosis. In: Courvoisier, B., Donath, A., & Baud,
A., ed. Fluoride and bone, Bern, Hans Huber, pp. 129-143.
FRANT, M.S. & ROSS, J.W., Jr (l966) Electrode for sensing
fluoride ion activity in solution. Science, 154: 1553-1554.
FREIS, E.D. (1976) Salt, volume and the prevention of
hypertension. Circulation, 53: 589-594.
FUCHS, C., DORN, D., FUCHS, C.A., HENNING, H.V., MCINTOSH, C.,
& SCHELER, F. (1975) Fluoride determination in plasma by ion
selective electrodes: a simplified method for the clinical
laboratory. Clin. chim. Acta, 60: 157-167.
GABOVICH, R.D. (1957) [Fluorine and its hygienic
importance.] Kazan, USSR (in Russian).
GABOVICH, R.D. & OVRUTSKIY, C.D. (1969) Fluorine in
stomatology and hygiene, Bethesda, Maryland, US Department of
Health and Welfare, 1028 pp. (DHEW Publication No. (NIH)
GALAGAN, D.J. & VERMILLION, J.R. (1957) Determining optimum
fluoride concentrations. Public Health Rep., 72: 491-493.
GALAGAN, D.J., VERMILLION, J.R., NEVITT, G.A., STADT, Z.M., &
DART, R.E. (1957) Climate and fluoride intake. Public
Health Rep., 72: 484-490.
GALAL, H.E. & ABD-ALLA, S.A. (l976) Chromosomal aberrations
and mitotic inhibition induced by sodium fluoride and dimethyl
amine in root-tip cells of Alluim cepa, A. sativum and Vicia
faba. Egypt. J. Genet. Cytol., 5: 262-280.
GALL, J.F. (1966) Hydrogen fluoride. In: Kirk-Othmer
encyclopedia of chemical technology, 2nd ed., New York, John
Wiley and Sons, Interscience Publishers, Vol. 9, pp. 610-625.
GEDALIA, I. (1970) Distribution in placenta and foetus. In:
Fluorides and human health, Geneva, World Health Organization,
pp. 128-134 (WHO Monograph Series No. 59).
GEEVER, E.F., LEONE, N.C., GEISER, P., & LIEBERMAN, J.E.
(1958) Pathological studies in man after prolonged ingestion
of fluoride in drinking water. Public Health Rep., 73:
GERDES, R.A. (1971) The influence of atmospheric hydrogen
fluoride on the frequency of sex-linked recessive lethals and
sterility in Drosophila melanogaster. Fluoride, 4: 125-129.
GERDES, R.A., SMITH, J.D., & APPLEGATE, H.G. (1971) The
effect of atmospheric hydrogen fluoride upon Drosophila
melanogaster, I. Differential genotypic response. Atmos.
Environ., 5: 113.
GIBBS, G.W. & HOROWITZ, I. (1979) Lung cancer mortality in
aluminium reduction plant workers. J. occup. Med., 21: 347-353.
GLASS, R.L., ed. (1982) The first international conference
on the declining prevalence of dental caries. J. dent. Res.,
GLATTRE, E. & WIESE, H. (1979) Inverse relationship between
fluoride and cancer in mouth and throat. Acta odontol.
Scand., 37: 9-14.
GLENN, F.B., GLENN, W.D., & DUNCAN, R.C. (1982) Fluoride
tablet supplementation during pregnancy for caries immunity: A
study of the offspring produced. Am. J. Obstet. Gynecol., 143:
GOTTLIEB, L. & GRANT, S.G. (1932) Diuretic action of sodium
fluoride. Proc. Soc. Exp. Biol. Med., 29: 1293-1294.
GOWARD, P.E. (1976) Enamel mottling in a non-fluoride
community in England. Commun. Dent. oral Epidemiol., 4:
GRANDJEAN, P. & THOMSEN, G. (1983) Reversibility of skeletal
fluorosis. Br. J. ind. Med., 40: 456-461.
GRENNAN, D.M., PALMER, D.G., MALTHUS, R.S., MATANGI, M.F., &
DE SILVA, R.T.D. (1978) Iatrogenic fluorosis. Aust. N.Z. J.
Med., 8: 528-531.
GRIMBERGEN, G.W. (1974) A double-blind test for
determination of intolerance to fluoridated waters. Cancer
Control J., 5: 91-94.
GUY, W.S., TAVES, D.R., & BREY, W.S., Jr (1976) Organic
fluoro-compounds in human plasma: Prevalence and
characterization. In: Fuller, R., ed. Biochemistry involving
carbon-fluorine bonds, Washington DC, American Chemical
Society, pp. 117-134 (Symposium Series 28.)
HAGAN, T.L.I., PASTERNACK, M., & SCHOLZ, G.C. (1954)
Waterborn fluorides and mortality. Public Health Rep., 69:
HAGOOD, C.O., KLEMMERER, W.T., & JACKSON, B. (1973)
Nephrotoxicity associated with methoxyflurane anesthesia. Am.
J. Surg., 125: 786-788.
HAKEEM, H. & SHEHAB, A. (l970) Morpho-cytological studies on
the effect of sodium fluoride solution on Vicia faba. UAR J.
Bot., 13: 9-27.
HALL, R.J. (1974) The metabolism of ammonium fluoride and
sodium monofluoroacetate by experimental Acacia georginae.
Environ. Pollut., 6: 267-280.
HALL, L.L., SMITH, F.A., DE LOPEZ, O.H., & GARDNER, D.E.
(1972) Direct potentiometric determination of total ionic
fluoride in biological fluids. Clin. Chem., 18: 1455-1458.
HALLETT, G.E.M. & PORTEOUS, J.R. (1970) Observations of the
dental health of young adults in Hartlepool and Newcastle.
Br. dent. J., 128: 171-174.
HAM, M.P. & SMITH, M.D. (1954) Fluorine balance studies on
three women. J. Nutr., 52: 225-232.
HANHIJAERVI, H. (1974) Comparison of free ionized fluoride
concentrations of plasma and renal clearance in patients of
artificially fluoridated and nonfluoridated drinking water
areas. Proc. Finn. Dent. Soc., 70(Suppl. III): 21.
HANSSON, T. & ROOS, B. (1978) Effect of combined therapy
with sodium fluoride, calcium and vitamin D on the lumbar
spine in osteoporosis. Am. J. Roentgenol., 126: 1294-1297.
HARGREAVE, G.A. (l972) Changes in diet and dental health of
children living in the Scottish Island of Lewis. Caries Res.,
HEASMAN, M.A. & MARTIN, A.E. (1962) Mortality in areas
containing natural fluoride in their water supplies. Mon.
Bull. Health Lab. Serv., 21: 150-173.
HEIFETZ, S.B. & HOROWITZ, H.S. (1975) Fluoride dentifrices.
In: Newbrun, E., ed. Fluorides and dental caries, 2nd ed.,
Springfield, Illinois, Charles C. Thomas, pp. 31-45.
HEMENS, J. & WARWICK, R.J. (1972) The effects of fluoride on
estuarine organisms. Water Res., 6: 130l-1308.
HEMENS, J., WARWICK, R.J., & OLIFF, W.D. (1975) Effect of
extended exposure to low fluoride concentration on estuarine
fish and crustacea. Prog. Water Technol., 7: 579-585.
HENDRICKSON, E.R. (1968) Air sampling and quantity
measurement. In: Stern, A.C., ed. Air pollution, Vol. 2,
Analysis, monitoring and surveying, New York, Academic Press,
HENNON, D.K., STOOKEY, G.K., & MUHLER, J.C. (1972)
Prophylaxis of dental caries; Relative effectiveness of
chewable fluoride preparations with and without added
vitamins. J. Pediatr., 80: 1018-1021.
HERBERT, D.W.M. & SHURBEN, D.S. (1964) The toxicity of
fluoride to rainbow trout. Water Waste Treat. J., 10: 141-142.
HIGGINS, B.A., NASSIM, R.J., ALEXANDER, R., & HILB, H. (1965)
Effect of sodium fluoride on calcium, phosphorus and nitrogen
balance in patients with Paget's disease. Br. med. J., 1:
HODGE, H.C. (1969) Fluoride. In: Gleason, M.N., Gosslin,
R.E., Hodge, H.C., & Smith, R.P., ed. Clinical toxilogy of
commercial products. Acute poisoning. Section III: Therapeutics
index, 3rd ed., Baltimore, Williams and Wilkins, pp.
HODGE, H.C. & SMITH, F.A. (1954) Some public health aspects
of water fluoridation. In: Shaw, J.H., ed. Fluoridation as a
public health measure, Washington DC, American Association for
the Advancement of Science.
HODGE, H.C. & SMITH, F.A. (1965) In: Simons, J.H., ed.
Fluorine chemistry, New York, Academic Press, Vol. IV, 786 pp.
HODGE, H.C. & SMITH, F.A. (1970) Minerals: Fluorine and
dental caries. In: Dietary chemicals vs dental caries,
Washington DC, American Chemical Society (Advances in
Chemistry Series 94).
HODGE, H.C. & SMITH, F.A. (1977) Occupational fluoride
exposure. J. occup. Med., 19: 12-39.
HODGE, H.C. & TAVES, D.R. (1970) Chronic toxic effects on
the kidneys. In: Fluorides and human health, World Health
Organization, Geneva, pp. 249-255 (WHO Monograph Series No. 59).
HODGE, H.C., SMITH, F.A., & GEDALIA, I. (1970) Excretion of
fluorides. In: Fluorides and human health, Geneva, World
Health Organization, pp. 141-161 (WHO Monograph Series No. 59).
HORTON, C.A. (1962) Fluorine. In: Kolthoff, J.M. & Elving,
P.J., ed. Treatise of analytical chemistry, New York,
Interscience Publishers, Vol. 7, Part 2, pp. 207-334.
HOSKING, D.J. & CHAMBERLAIN, M.J. (1977) Studies in man with
fluoride. Clin. Sci., 42: 153-161.
IARC (1982) Some aromatic amines, anthraquinones and nitroso
compounds, and inorganic fluorides used in drinking water and
dental preparations, Lyons, International Agency for Research
on Cancer (IARC Monographs on the Evaluation of the
Carcinogenic Risk of Chemicals to Humans, Vol. 27).
ILO (1980) Occupational exposure limits for airborne toxic
substances, 2nd ed., Geneva, International Labour Office
(Occupational Safety and Health Series No. 37.)
INKOVAARA, J., HANHIJAERVI, H., IISALO, E., & JAERVINEN, K.
(1975) Prophylactic treatment and aged bones. Br. med. J.,
IPAI (1981) Environmental legislation survey, London,
England, International Primary Aluminium Institute, 115 pp.
ISAAC, S., BRUDEVOLD, F., SMITH, F.A., & GARDNER, D.E.
(l958) Solubility rate and natural fluoride content of
surface and subsurface enamel. J. dent. Res., 37: 254-263.
ISRAEL, G.W. (1974) Evaluation and comparison of three
atmospheric fluoride monitors under field conditions. Atmos.
Environ., 8: 159-166.
JACKSON, D. (1961) A clinical study of non-endemic mottling
of enamel. Arch. oral Biol., 5: 212-223.
JACKSON, W.P.V. (l962) Further observations on Kenhardt bone
disease and its relation to fluorosis. S. Afr. med. J., 36:
JACKSON, D. & WEIDMANN, S.M. (1958) Fluorine in human bone
related to age and the water supply of different regions.
J. Pathol. Bacteriol., 76: 451-459.
JACKSON, D., MURRAY, J.J., & FAIRPO, C.-G. (1973) Life-long
benefits of fluoride in drinking water. Br. dent. J., 134:
JACOBSON, J.S. & HILL, A.C., ed. (1970) Recognition of air
pollution injury to vegetation: A pictorial atlas, Pittsburgh,
Pennsylvania, Air Pollution Control Association.
JACOBSON, J.S. & WEINSTEIN, L.H. (1977) Sampling and
analysis of fluoride: Methods for ambient air, plant and
animal tissues, water, soil and foods. J. occup. Med., 19:
JAGIELLO, G. & LIN, J.S. (1974) Sodium fluoride as potential
mutagen in mammalian eggs. Arch. environ. Health, 29: 230-235.
JANSEN, I. & THOMSEN, H.M. (1974) Heart deaths and
fluoridation. Fluoride, 7: 62-65.
JARDILLIER, J.C. & DESMET, G. (1973) Etude de fluor sérique
et de ses combinaisons par une technique utilisant une
électrode spécifique. Clin. chim. Acta, 47: 357-360.
JARNBERG, P.O., EKSTRAND, J., IRESTEDT, L., & SANTESSON, J.
(1979) Fluoride kinetics and renal function during enflurane
anaesthesia. Acta anaesthesiol. Scand., 71(Suppl.): 20-23.
JENKINS, G.N. (1967) The mechanism of action of fluoride in
reducing caries incidence. Int. dent. Health, 17: 552-563.
JHA, M. & SUSHEELA, A.K. (l982a) In vivo chondrogenesis and
histochemical appearence of dermatan sulphate in rabbit
cancellous bone. Differentiation, 22: 235.
JHA, M. & SUSHEELA, A.K. (l982b) Characterization of
glycosaminoglycans from normal and fluoride treated rabbit
iliac crest. Biochem. biophys. Res. Commun., 105: 711-716.
JHA, M., SUSHEELA, A.K., KRISHNA, N., RAJYALAKSHMI, K., &
VENKIAH, K. (l983) Excessive ingestion of fluoride and the
significance of sialic acid: glycosaminoglycans in the serum
of rabbit and human subjects. J. Toxicol. clin. Toxicol.,
JOLLY, S.S. (1976) Fluoride balance studies in endemic
fluorosis. Fluoride, 8: 138-147.
JOLLY, S.S., SINGH, B.M., & MATHUR, O.C. (1969) Endemic
fluorosis in Punjab (India). Am. J. Med., 47: 553-563.
JONES, C.M., HARRIS, J.M., & MARTIN, A.E. (1971) Fluorine in
leafy vegetables. J. Sci. Food Agric., 22: 602-605.
JORDAN, W. (1962) The Austin School health study. Dental
health. Am. J. public Health, 52: 301-303.
JOWSEY, J., RIGGS, B.L., KELLY, P.J., & HOFFMAN, L. (1972)
Effect of combined therapy with sodium fluoride, vitamin D and
calcium in osteoporosis. Am. J. Med., 53: 43-49.
JUNCOS, L.I. & DONADIO, J.V. (1972) Renal failure and
fluorosis. J. Am. Med. Assoc., 222: 783-785.
KALTREIDER, N.L., ELDER, M.J., CRALLEY, L.V., & COLWELL, M.O.
(1972) Health survey of aluminium workers with special
reference to fluoride exposure. J. occup. Med., 14: 531-541.
KANISAWA, M. & SCHROEDER, H.A. (l969) Life term studies on
the effect of trace elements on spontaneous tumours in mice
and rats. Cancer Res., 29: 892.
KE, P.J., POWER, H.E., & REGIER, L.W. (1970) Fluoride
content of fish protein concentrate and raw fish. J. Sci.
Food Agric., 21: 108-109.
KEENE, H.J., ROVELSTADT, G.H., & HOFFMAN, S. (1971) Fluoride
availability and the prevalence of caries-free naval recruits,
a preliminary ten year report. Arch. oral Biol., 16: 343-346.
KESTELOOT, H., JOOSENS, J.V., LEE, C.S., PARK, B.C., &
BREMS-HEYNS, E. (1978) A comparative study of blood pressure
and sodium intake in Belgium and Korea. Acta cardiol., 23: 82.
KING, D.R., OLIVER, J.R., & MEAD, R.J. (l978) The adaptation
of some Western Australian mammals to food plants containing
fluoroacetate. Aust. J. Zool., 26: 699-712.
KLEIN, W., KOCSIS, R., & ALTMANN, H. (1974) Biochemical
investigations of the effects of sodium fluoride on mammalian
cells. I. Influence on biosynthesis of nucleic acids and
proteins in mouse spleen cells in vitro. Ber. Oesterr.
Studienges. Atomenerg., 2325: 1-17.
KLEMMER, P.J. & HADLER, N.M. (1978) A consequence of abuse
of an organofluoride anesthetic. Ann. intern. Med., 89:
KNIZVNIKOV, V.A. (1958) [Effect of fluorine in drinking
water on some health indicators of the adult population.]
Gig. i Sanit., 8: 18 (in Russian).
KOIVISTOINEN, P. (1980) Mineral element composition of
Finnish foods. Acta agric. Scand., 22(Suppl.).
KRAM, D., SCHNEIDER, E.L., SINGER, L., & MARTIN, G.R. (1978)
The effects of high and low fluoride diets on the frequencies
of sister chromatid exchanges. Mutat. Res., 57: 51-55.
KRAMER, L., OSIS, D., WIATROWSKI, I., & SPENCER, H. (1974)
Dietary fluoride in different areas of the United States.
Am. J. clin. Nutr., 27: 590-594.
KRISHNAMACHARI, K.A.V.R. & KRISHNASWAMY, K. (1973) Genu
valgum and osteoporosis in an area of endemic fluorosis.
Lancet, 2: 887-889.
KRUGGEL, W.G. & FIELS, R.A. (1977) Fluoride content of
mechanically deboned beef and pork from commercial sources in
different geographical areas. J. food Sci., 42: 190-192.
KUMPULAINEN, J. & KOIVISTOINEN, P. (1977) Fluorine in foods.
Residue Rev., 68: 37-57.
KUNZEL, W. (1980) Effect of an interruption in water
fluoridation on the caries prevalence of primary and secondary
dentition. Caries Res., 14: 304-310.
KUNZEL, W. & SOTO PADRON, F. (1984) [Comparative
effectiveness of collective local application of fluoride
solution with fluoridated drinking-water.] Stomatol. DDR, 34:
(in press) (in German).
KWANT, G.W., HOUWINK, B., BACKER DIRKS, O., GROENEVELD, A., &
POT, T.J. (1973) Artificial fluoridation of drinking-water
in the Netherlands. Neth. dent. J., 80(Suppl. 9): 6-27.
LARGENT, E.J. (1952) Rates of elimination of fluorides
stored in the tissues of man. Arch. ind. Hyg. occup. Med., 5:
LARGENT, E.J. & HEYROTH, E.F. (1949) The absorption and
excretion of fluorides, III. Further observations on
metabolism of fluoride at high levels of intake. J. ind. Hyg.
Toxicol., 3: 134-138.
LARSEN, S. & WIDDOWSON, A.E. (l97l) Soil fluorine. J. soil
Sci., 22: 210-221.
LARSON, R.H. (1977) Animal studies relating to caries
inhibition by fluoride. Caries Res., 11(Suppl. 1): 42-58.
LEE, R.E., CALDWELL, J., AKLAND, G.G., & FRANKHAUSER, R.
(1974) The distribution and transport of airborne particulate
matter and inorganic components in Great Britain. Atmos.
Environ., 8: 1095-1109.
LEMKE, C.W., DOHERTY, J.M., & ARRA, M.C. (1970) Controlled
fluoridation; the dental effects of discontinuation in Antigo,
Wisconsin. J. Am. Dent. Assoc., 8: 782-786.
LEONE, N.C., SHIMKIN, M.B., ARNOLD, F.A., STEVENSON, C.A.,
ZIMMERMAN, E.R., GEISER, P.B., & LIBERMAN, J.E. (1954)
Medical aspects of excessive fluoride in a water supply.
Public Health Rep., 69: 925-936.
LEONE, N.C., STEVENSON, C.A., HILBISH, T.F., & SOSMAN, M.C.
(1955) A roentgenologic study of human population exposed to
high-fluoride domestic water. Am. J. Roentgenol. radium Ther.
nucl. Med., 74: 874-855.
LEONE, N.C., STEVENSON, C.A., BESSE, B., HAWES, L.E., &
DAWBER, T.R. (1960) The effects of the absorption of
fluoride. II. A radiological investigation of five hundred
and forty-six human residents of an area in which the drinking
water contained only a minute trace of fluoride. Arch. ind.
Health, 21: 326-327.
LESS, L.N., MCGREGOR, A., JONES, L.H.P., COWLING, D.W., &
LEAFE, E.L. (1975) Fluorine uptake by grass from aluminium
smelter fume. Int. J. environ. Stud., 7: 153-160.
LEVERETT, D.H. (1982) Fluorides and the changing prevalence
of dental caries. Science, 217: 26-30.
LINKINS, R.C., MCCLURE, F.J., & STEERE, A.C. (1962) Urinary
excretion of fluoride following defluoridation of a water
supply. In: McClure, F.J., ed. Fluoride drinking waters,
Bethesda, Maryland, US Department of Health, Education and
Welfare, Public Health Service, National Institute of Dental
Research, pp. 421-423.
LIVINGSTONE, D.A. (1963) Chemical composition of rivers and
lakes. In: Fleischer, M., ed. Data of geochemistry, 6th ed.,
Washington DC, US Department of the Interior (Geological
survey professional paper 440-G).
LUOMA, H., HELMINEN, S.K.J., RANTA, H., RYTOEMAA, K., &
MEURMAN, J.H. (1973) Relationships between the fluoride and
magnesium concentrations in drinking water and some component
in serum related to cardiovascular diseases in men from four
rural districts in Finland. Scand. J. clin. Lab. Invest., 32:
MACDONALD, A. (1970) Methods of analysis of fluorine. In:
Smith, F., ed. Pharmacology of fluorides, Berlin,
Springer-Verlag, Vol. 20, Part 2, pp. 1-47.
MACDONALD, H.E. & BERKELEY, P.D. (1969) Fluoride in air
pollutant. Fluoride, 2: 4-12.
MACDONALD, D.J. & LUKER, M.A. (1980) Fluoride: Interaction
with chemical mutagens in Drosophila. Mutat. Res., 71: 211-218.
MACHLE, W., SCOTT, E.W., & LARGENT, E.J. (1942) The
absorption and excretion of fluorides. Part I. The normal
fluoride balance. J. ind. Hyg. Toxicol., 24: 199-204.
MACLEAN, D.C. (1982) Air quality standard for fluoride to
protect vegetation. Regional, seasonal, and other
considerations. J. Air Pollut. Control Assoc., 32: 82-84.
MACLEAN, D.C. & SCHNEIDER, R.E. (1971) Fluoride
phytotoxicity: Its alteration by temperature. In: England,
H.M. & Beery, W.T., ed. Proceedings of the Second Clean Air
Congress, New York, Academic Press, pp. 292-295.
MAHESWARI, U.R., MCDONALD, J.T., SCHNEIDER, V.S., BRUNETTI,
A.J., LEYBIN, L., NEWBRUN, E., & HODGE, H.C. (1981) Fluoride
balance studies in ambulatory healthy men with and without
fluoride supplements. Am. J. clin. Nutr., 34: 2679-2684.
MAIER, F.J. (1972) Fluoridation, Cleveland, CRC Press, 53 pp.
MANSON, B. & RAHEMTULLA, F. (1978) [Calcium tablets and bone
meal - a fluoride source.] Tandläkartidningen, 70: 383-385
MARCOVITCH, S. (1928) The relative toxicities of arsenicals
and fluorine compounds to various organisms. J. econ.
Entomol., 21: 108-114.
MARIER, J.R. (1982) Halogenated hydrocarbon environmental
pollution: the special case of halogenated anesthetics.
Environ. Res., 28: 212-239.
MARIER, J.R. & ROSE, D. (1966) The fluoride content of some
foods and beverages - a brief survey using a modified
Zr-SPADNS method. J. food Sci., 31: 941-946.
MARTHALER, T.M. & SCHENARDI, C. (1962) Inhibition of caries
in children after 5-years use of fluoridated table salt.
Helv. odontol. Acta, 6: 1-6.
MARTIN, D.J. (1951) The Evanston dental caries study. VIII.
Fluorine containing waters. J. dent. Res., 30: 676-681.
MARTIN, A.E. & JONES, C.M. (1971) Some medical
considerations regarding atmospheric fluorides. HSMHA health
Rep., 86: 752-758.
MARTIN, G.R., BROWN, K.S., MATHESON, D.W., LEBOWITZ, H.,
SINGER, L., & OPHAUG, R. (1979) Lack of cytogenetic effects
in mice or mutations in Salmonella receiving sodium fluoride.
Mutat. Res., 66: 159-167.
MASON, B.H. (1974) Geochemical distribution of elements.
In: Encyclopedia Britannica, Macropaedia 6, 15th ed., Chicago,
Helen Hemingway Benton.
MASUDA, T.T. (1964) Persistence of fluoride from organic
origins in waste waters. Dev. ind. Microbiol., 5: 33-70.
MAZZE, R.I., CALVERLEY, R.K., & SMITH, N.T. (1977) Inorganic
fluoride nephrotoxicity. Anesthesiology, 46: 265-271.
MCCLURE, F.J. (1944) Fluoride domestic water and systemic
effects I. Relation to bone fracture experience, height and
weight of high school boys and young selectees of the armed
forces of the United States. Public Health Rep., 59:
MCCLURE, F.J. (1946) Nondental physiological effects of
trace quantities of fluorine. In: Moulton, F.R., ed. Dental
caries and fluorine, Washington DC, American Association for
the Advancement of Science.
MCCLURE, F.J. (1949) Fluorine in foods. Public Health Rep.,
MCCLURE, F.J. (1953) Ingestion of fluoride and dental
caries. Quantitative relations based on food and water
requirements of children one to twelve years old. Am. J. Dis.
Child., 66: 362-369.
MCCLURE, F.J. & KINSER, C.A. (1944) Fluoride domestic waters
and systemic effects II. Fluorine content of urine in relation
to fluorine in drinking waters. Public Health Rep., 59:
MCCLURE, F.J. & MITCHELL, H.H. (1931) The effect of calcium
fluoride and phosphate rock on the calcium retention of young
growing pits. J. agric. Res., 42: 363-373.
MCCUNE, D.C. (l969) On the establishment of air quality
criteria with reference to the effects of atmospheric fluorine
on vegetation, New York, American Petroleum Institute, 33 pp
(Air Quality Monographs 69-3).
MCENIERY, T.M. & DAVIES, G.N. (1979) Brisbane dental survey,
1977. A comparative study of caries experience of children in
Brisbane, Australia over a 20-year period. Commun. Dent. oral
Epidemiol., 7: 42-50.
MCKAY, F.S. (1926) Do water supplies cause defects in teeth
enamel? Water Works Eng., 79: 1332.
MCPHAIL, C.W.B. & ZACHERL, W. (1965) Fluid intake and
climate temperature. Relations to fluoridation. J. Can.
Dent. Assoc., 31: 7-16.
MCQUEEN, E.G. (1977) New Zealand Committee on Adverse Drug
Reactions: Twelfth annual report 1977. N.Z. med. J.,
MEJIA, R., ESPINAL, F., VELEZ, H., & AGUIRRE, M. (1976)
[Study on fluoridated salt. VIII Results obtained in the years
1964-1972.] Bol. Ofic. Sanit. Pan-Am., 80: 67 (in Spanish).
MENDELSON, D. (l976) Lack of effect of sodium fluoride on a
maternal repair system in Drosophila oocytes. Mutat. Res.,
MERVI VAN DER, E.H.M., BISCHOFF, J.L., FATTI, L.P., RETIEF,
D.H., BARBAKOW, F.H., & FEIEDMAN, M. (1977) Relationships
between fluoride in enamel, DMFT Index and fluorosis in high
and low-fluoride areas in South Africa. Commun. Dent. oral
Epidemiol., 5: 61-64.
MESSER, H.H., ARMSTRONG, W.D., & SINGER, L. (1972) Fertility
impairment in mice on a low fluoride intake. Science, 177: 893.
MESSER, H.H., ARMSTRONG, W.D., & SINGER, L. (1973) Influence
of fluoride intake on reproduction in mice. J. Nutr., 103:
MILHAM, S. (1979) Mortality in aluminum reduction plant
workers. J. occup. Med., 21: 475-480.
MITCHELL, B. & GERDES, R.A. (1973) Mutagenic effects of
sodium and stannous fluoride upon Drosophila melanogaster.
Fluoride, 6: 113-117.
MOHAMED, A.H. & CHANDLER, M.E. (1977) Cytological effects of
sodium fluoride on mice. Hearings before a subcommittee of a
committee on Government operations. September 21 and
October 12, 1977, Washington DC, US Government Printing Office.
MOLLER, P.F. & GUDJONSSON, S.V. (1933) [Fluorosis massive
ossium et ligamentorum.] Ugeskr. Laeg., 95: 1-9 (in Danish).
MOLLER, I.J. & POULSEN, S. (1975) A study of dental mottling
in children in Khouribga, Morocco. Arch. oral Biol., 20:
MORNSTAD, H. & VAN DIJKEN, J. (1982) Caries preventive doses
of fluoride and cyclic AMP levels in human plasma. Caries
Res., 16: 277-281.
MORRIS, J.B. & SMITH, F.A. (1982) Regional deposition and
absorption of inhaled hydrogen fluoride in the rat. Toxicol.
appl. Pharmacol., 62: 81-89.
MOUFTAH, S.P. & SMITH, J.D. (l97l) Mitotic aberrations in
bean chromosomes induced by sodium fluoride. Texas J. Sci.,
22: 296 (Abstr.).
MUEHLBERGER, C.W. (1930) Toxicity studies of fluorine
insecticides. J. Pharmacol. exp. Ther., 319: 246-248.
MUKHERJEE, R.N. & SOBELS, F.M. (1968) The effects of sodium
fluoride and iodoacetate on mutation induction by
X-irradiation in mature spermatozoa of Drosophila. Mutat.
Res., 6: 217-225.
MURRAY, J.J. (1971a) Adult dental health in fluoride and
nonfluoride areas. Part 1: Mean DMF-values by age. Br. dent.
J., 131: 391-395.
MURRAY, J.J. (1971b) Adult dental health in fluoride and
nonfluoride areas. Part 3. Tooth mortality by age. Br.
dent. J., 131: 487-492.
MURRAY, F. (l982) Fluoride retention by sandy soils. Water
Air Soil Pollut., 20: 361-367.
MURRAY, F. (1983) Fluoride retention by sandy soils. Water
Air Soil Pollut., 20: 361-367.
MURRAY, J.J. & RUGG-GUNN, A.J. (1979) Additional data on
water fluoridation, Poster at XXVI ORCA Congress.
MURRAY, J.J. & SHAW, L. (1979) Classification and prevalence
of enamel opacities in the human deciduous and permanent
dentitions. Arch. oral Biol., 24: 7-14.
MYERS, H.M. (1978) Fluorides and dental fluorosis. In:
Monographs in oral science, Basel, S. Karger, Vol. 7, 76 pp.
NAS-NRC COMMITTEE ON ANESTHESIA (1971) National Academy
National Research Council Committee on Anesthesia 1971.
Statements regarding the role of methoxyflurane in the
production of renal dysfunction. Anesthesiology, 34: 505-509.
NEEDLEMAN, H.L., FUESCHEL, S.M., & ROTHMAN, K.J. (1974)
Fluoridation and the occurrence of Down's syndrome. New Engl.
J. Med., 291: 821-823.
NEUHOLD, J.M. & SIGLER, W.F. (1960) Effects of sodium
fluoride on carp and rainbow trout. Trans. Am. Fish. Soc.,
NEUMAN, W.F. & NEUMAN, M.W. (1958) The chemical dynamics of
bone mineral, Chicago, University of Chicago Press.
NEVITT, G.A., FRANKEL, J.M., & WITTER, D.M. (1963)
Occurrence of non-fluoride opacities and non-fluoride
hypoplasias of enamel of 588 children aged 9-14 years. J. Am.
Dent. Assoc., 66: 79-83.
NEWBRUN, E. (1978) Dietary fluoride supplementation for the
prevention of caries. Pediatrics, 62: 733-737.
NEWESELY, H. (1961) Changes in crystal types of low
solubility calcium phosphates in the presence of accompanying
ions. Arch. oral Biol., 6: 174-180.
NIOSH (l977) Occupational diseases. A guide to their
recognition, Washington DC, US Department of Health, Education
and Welfare, pp. 319 (NIOSH publication no. 77-181).
NOEMMIK, H. (1953) Fluorine in Swedish agricultural
products, soils and drinking water. Acta polytech., 127.
OBE, G. & SLACIK-ERBEN, R. (1973) Suppressive activity by
fluoride on the induction of chromosome aberrations in human
cells with alkylating agents in vitro. Mutat. Res., 19:
OELSCHLAEGER, W. (1970) Fluoride in food. Fluoride, 3: 6-11.
OHNO, S.M., KADOTA, M., & YATAZAWA, M. (1973) Determination
of trace fluorine in biological materials by photonuclear
activation analysis. Michrochim. Acta, 1: 61-68.
OMUETI, J.A.I. & JONES, R.L. (1977) Fluorine content of soil
from Morrow plots over a period of 67 years. Soil Sci. Soc.
Am. J., 41: 1023-1024.
OSIS, D., WIATROWSKI, E., SAMACHSON, J., & SPENCER, H. (1974)
Dietary fluoride in man. J. Nutr., 104: 1313-1318.
PACK, M.R. & SULZBACH, C.W. (l976) Response of plant
fruiting to hydrogen fluoride fumigation. Atmos. Environ., 10:
PAGE, L.B., VANDERVERT, D., NADER, K., LUBIN, N., & PAGE, J.R.
(1978) Blood pressure, diet and body form in traditional
nomads of the Qash Gai Tribe, Southern Iran. Acta cardiol.,
PAHO (1983) Handbook of resolutions of the governing bodies
of the Pan American Health Organization, Vol. 2, 2nd ed.,
Washington DC (PAHO Official Document No. 191).
PANDIT, C.G., RAGHAVACHARI, T.N.S., RAO, D.S., & KRISHNAMURTI,
V. (1940) Endemic fluorosis in South India: a study of the
factors involved in the production of mottled enamel and
severe bone manifestations in adults. Indian J. med. Res.,
PANTCHEK, M.B. (1975) Hygiene evaluation of exposure to
fluoride fume from basic arc-welding electrodes. Ann. occup.
Hyg., 18: 207-212.
PARSONS, S.V., CHOUDHURY, A.A., WASS, J.A.H., & VERNON, A.
(1975) Renal excretion of fluoride in renal failure and after
renal transplantation. Br. med. J., 1: 128-130.
PETRABORG, H.T. (1974) Chronic fluoride intoxication from
drinking water. Fluoride, 7: 47-52.
PLASSCHEART, A.J.M. & KOENIG, K.G. (1973) The effect of
motivation and information and the effect of fluoride tablets
on the incidence of dental caries in school children. Ned.
Tijdschr. Tandheelkd., 80: 21-35.
PLATTS, M.M., GOODE, G.C. & HISLOP, J.S. (1977) Composition
of the domestic water supply and the incidence of fractures
and encephalopathy in patients on home dialysis. Br. med. J.,
POLSON, C.J. & TATTERSALL, R.N. (1979) Hydrofluoric acid and
sodium fluoride. In: Clinical toxicology, Philadelphia,
Pennsylvania, J.B. Lippincott Co., pp. 160-172.
PRICHARD, J.L. (1969) The prenatal and postnatal effects of
fluoride supplements on West Australian school children, aged
6, 7 and 8, Perth 1967. Aust. dent. J., 14: 335-338.
PURVES, M.S. (1962) Some effects of administering sodium
fluoride to patient with Paget's disease. Lancet, 2: 1188.
RABINOWITCH, V.M. (1945) Acute fluoride poisoning. Can. Med.
Assoc. J., 52: 345-349.
RAO, S.R., MURTHY, K.J.R., & MURTHY, T.V.S.D. (1979) Urinary
fluoride excretion in endemic fluorosis. Fluoride q. Rep., 12:
RAPAPORT, I. (1956) Contribution ą l'étude de mongolisme.
Role pathogénique du fluor. Bull. Acad. Natl Méd., 140:
RAPAPORT, I. (1959) Nouvelles recherches sur le mongolisme.
A propos du role pathogénique du fluor. Bull. Acad. Natl
Med., 143: 367-370.
RAPAPORT, I. (1963) Oligophrenie mongolienne et caries
dentaires. Rev. stomato., 46: 207.
REDDY, D.R. (1979) Skeletal fluorosis. In: Viuken, P.J. &
Bruyer, G.W., ed. Handbook of clinical neurology, Vol. 36,
Intoxications of the nervous system, Amsterdam, North-Holland,
Part I, pp. 465-504.
RICH, C. & ENSINCK, J. (1961) Effect of sodium fluoride on
calcium metabolism of human beings. Nature (Lond.), 192:
RICHARDS, L.F., WESTMORELAND, W.W., TASHIRO, M., MCKAY, C.M.,
& MORRISON, T.J. (1967) Determination of optimum fluoride
levels for community water supplies in relation to
temperature. J. Am. Dent. Assoc., 74: 289-397.
RICHARDSON, A.S. (1967) Parental participation on the
administration of fluoride supplements. Can. J. public
Health, 58: 508-513.
RIGGS, B.L., HODGSON, S.F., HOFFMAN, D.L., KELLY, P.J.,
JOHNSON, K.A., & TAVES, D. (1980) Treatment of primary
osteoporosis with fluoride and calcium, clinical tolerance and
fracture occurence. J. Am. Med. Assoc., 243: 446-449.
RIGGS, B.L., SEEMAN, E., HODGSON, M.D., TAVES, D.R., &
O'FALLON, W.M. (1982) Effect of the fluoride/calcium regimen
on vertebral fracture occurrence in postmenopausal
osteoirisus. New Engl. J. Med., 306: 446-450.
RIPPEL, A. (1972) Fluoride intake from food. Fluoride, 5:
RITIEF, D.H., NAVIA, J.M., & LOPEZ, H. (1977) A
microanalytical technique for the estimation of fluoride in
rat molar enamel. Arch. oral Biol., 22: 207-213.
ROBINSON, J.M., GRUBER, G.I., LUSK, W.D., & SANTY, M.J.
(1972) Engineering and cost effectiveness study of fluoride
emissions control, Springfield, Va., Office of Air Programs,
Environmental Protection Agency, Vol. 1 (Final report).
ROCKETTE, H.E. & ARENA, V.C. (1983) Mortality studies of
aluminum reduction plant workers: Potroom and carbon
department. J. occup. Med., 25: 549-557.
ROGOT, E., SHARRETT, A.R., FEINLEB, M., & FABSITZ, R.R.
(1978) Trends in urban mortality in relation to fluoridation
status. Am. J. Epidemiol., 107: 104-112.
ROHOLM, K. (1937) Fluorine intoxication. A clinical-
hygienic study, London, Lewis.
ROSENHOLTZ, M.J., CARSON, T.R., WEEKS, M.H., WILINSKY, F.,
FORD, D.F., & OBERST, F.W. (1963) A toxipathologic study in
animals after brief single exposure to hydrogen fluoride.
Am. Ind. Hyg. Assoc. J., 24: 253-261.
ROYAL COLLEGE OF PHYSICIANS (1976) Fluoride, teeth and
health, Tunbridge Wells, Kent, Pitman Medical, 85 pp.
ROYAL COMMISSION IN ONTARIO (1968) Report of the Committee
appointed to enquire into and report upon the pollution of
air, soil and water in the townships of Dunn, Moulton and
Sherbrooke, Haldimand County, Ontario, Ontario, Canada.
RUSOFF, L.L., KONIKOFF, B.S., FRYE, J.B., Jr, JOHNSTON, J.E.,
& PRYE, W.W. (1962) Fluoride addition to milk and its
effects on dental caries in school children. Am. J. clin.
Nutr., 12: 94-101.
RUSSELL, A.L. (1953) The inhibition of proximal caries in
adults with lifelong fluoride exposure. J. dent. Res., 32:
RUSSELL, A.L. & ELVOVE, E. (1951) Domestic water and dental
caries. VII. A study of the fluoride dental caries
relationship in an adult population. Public Health Rep., 66:
SAN FILIPPO, F.A. & BATTISTONE, G.C. (1971) The fluoride
content of a representative diet of the young adult male.
Clin. chim. Acta, 31: 453-457.
SARIC, M., ZUSKIN, E., & GOMZI, M. (1979) Bronchoconstric-
tion in potroom workers. Br. J. ind. Med., 36: 211-215.
SCHAMSCHULA, R.G. (1981) Fluoride and health; Dental caries,
osteoporosis and cardiovascular disease. Annu. Rev. Nutr., 1:
SCHAMSCHULA, R.G., AGUS, H.M., CHARLTON, G., DUPPENTHALER,
J.L., & UN, P.S.H. (1979) Associations between fluoride
concentration in successive layers of human enamel and
individual dental caries experience. Arch. oral Biol., 24:
SCHAMSCHULA, R.G., SUGAR, E., AGUS, H.M., UN, P.S.H., & TOTH,
K. (1982) The fluoride content of human tooth enamel in
relation to environmental exposure to fluoride. Aust. dent. J.,
SCHIFFL, H.H. & BINSWANGER, U. (1980) Human urinary fluoride
excretion as influenced by renal functional impairment.
Nephron, 26: 69-72.
SCHLESINGER, E.R., OVERTON, D.E., CHASE, H.C., & CANTWELL,
K.T. (1956) Newburgh-Kingston caries-fluorine study XIII.
Pediatric findings after ten years. Am. Dent. Assoc., 52: 296.
SCHMIDT, C.W. (1976a) [Appearence of neighbourhood fluorosis
in the population of a small saxon town.] Dtsch
Gesundheitswes., 31: 1271-1274 (in German).
SCHMIDT, C.W. (1976b) [Neighbourhood fluorosis.] Dtsch
Gesundheitswes., 31: 1700-1703 (in German).
SCHNEIDER, W. (1968) [Long-term studies on the fluoride
situation in a highly industrialized area.] Staub Reinhalt.
Luft, 28: 17-24 (in German).
SCHWARZ, K. & MILNE, D.B. (1972) Fluorine requirement for
growth in rat. Bioinorg. Chem., 1: 331.
SHAMBAUGH, G.E., Jr & CAUSSE, J. (1974) Ten years experience
with fluoride in otosclerotic (otospongiotic) patients. Ann.
Otol., 83: 635-642.
SHEA, J.J., GILLESPIE, S.M., & WALDBOTT, G.L. (1967) Allergy
to fluoride. Ann. Allergy, 25: 388-391.
SHILLER, W.R. & FRIES, R.H. (1980) Control of enamel caries
in young adult male population. AADR abstr., 890.
SHOLTES, R.S., MEADOWS, E.H., Jr, & KOOGLER, J.B. (1973)
Evaluation and modification of fluoride sampling and
analytical methods, Washington, DC, US Environmental
Protection Agency, 84 pp (EPA-650/2-73-007).
SIDDIQUI, A.H. (1955) Fluorosis in the Nalgonda district,
Hyderabad-Deccan. Br. med. J., 2: 1408-1413.
SIMONSSON, B.G., HAEGER ARONSEN, B., SJOEBERG, A., & EKLUNDH,
G. (1977) Bronchial excitability in workers exposed to
aluminum salts. Scand. J. respir. Dis., 58(Suppl. 99): 36-37.
SIMPSON, E., SHANKARA RAO, L.G., EVANS, R.M., WILKIE, W.,
RODGER, J.C., & LAKHANI, A. (1980) Calcium metabolism in a
fatal case of sodium fluoride poisoning. Ann. clin. Biochem.,
SINGER, L. & ARMSTRONG, W.D. (1954) Determination of
fluoride: Procedure based upon diffusion of hydrogen
fluoride. Anal. Chem., 26: 904-906.
SINGER, L. & ARMSTRONG, W.D. (1959) Determination of
fluoride in blood serum. Anal. Chem., 31: 105-108.
SINGER, L. & ARMSTRONG, W.D. (1962) Comparison of fluoride
contents of human dental and skeletal tissues. J. dent. Res.,
SINGER, L. & ARMSTRONG, W.D. (1965) Determination of
fluoride, procedure based upon diffusion of hydrogen
fluoride. Anal. Biochem., 10: 495-500.
SINGER, L. & ARMSTRONG, W.D. (1977) Fluoride in treated
sewage and in rain and snow. Arch. environ. Health, 32: 21-23.
SINGER, L. & OPHAUG, R.H. (1979) Total fluoride intake of
infants. Pediatrics, 63: 460-466.
SINGER, L. & OPHAUG, R.H. (1982) Ionic and nonionic fluoride
in plasma (or serum). CRC Crit. Rev. clin. lab. Sci., 18:
SINGER, L., ARMSTRONG, W.D., & OPHAUG, R.H. (1978) Effects
of acute fluoride intoxication on rats. Proc. Soc. Exp. Biol.
Med., 157: 363-368.
SINGER, L., OPHAUG, R.H., & HARLANDF, B.F. (1980) Fluoride
intake of young male adults in the United States. Am. J.
clin. Nutr., 33: 328-332.
SINGH, A. & JOLLY, S.S. (1970) Chronic toxic effects on the
skeletal system. In: Fluorides and human health, Geneva, World
Health Organization, pp. 239-249 (Monograph Series No. 59).
SINGH, A., JOLLY, S.S., BANSAL, B.C., & MATHUR, C.C. (1961a)
Endemic fluorosis. Epidemiological, clinical and biochemical
study of chronic fluorine intoxication in Panjab (India).
Medicine, 42: 229-246.
SINGH, A., JOLLY, S.S., & BANSAL, B.C. (1961b) Skeletal
fluorosis and its neurological complications. Lancet, I:
SMALL, B.W. & MURRAY, J.J. (1978) Enamel opacities:
prevalence, classifications and etiological considerations.
J. Dent., 6: 33-42.
SMALLEY, J.W. & EMBERY, G. (l980) The influence of fluoride
administration on the structure of proteoglycans in the
developing rat incisor. Biochem. J., 190: 263-272.
SMITH, F.A. & HODGE, H.C. (1959) Fluoride toxicity. In:
Muhler, J.C. & Hine, M.K., ed. Fluorine and dental health,
Bloomington, Indiana University Press, pp. 11-37.
SMITH, F.A. & HODGE, H.C. (1979) Airborne fluorides and man.
Part I. Crit. Rev. environ. Control, 8: 293-371.
SMITH, M.C. & LEVERTON, R.M. (1933) Toxic effects of
fluorine compounds in rats. J. dent. Res., 13: 249.
SMITH, M.C., LANTZ, E.M., & SMITH, H.V. (1931) The cause of
mottled enamel. Science, 74: 244.
SMITH, F.A., GARDNER, D.E., & HODGE, H.C. (1953) Age
increase in fluoride content in human bone. Fed. Proc., 12:
SONNEBORN, M. & MANDELKOW, J. (1981) German studies on
health effects of inorganic drinking water constituents.
Sci. total Environ., 18: 47-60.
SOU (1981) [The use of fluoride in dental caries
prevention. A report by the Swedish fluoride commission,]
Stockholm, Liber Forlag, 294 pp. (Report No. 32) (in Swedish
with English summary).
SPENCER, H., LEWIN, I., FOWLER, J., & SAMACHSON, J. (1969)
Effect of sodium fluoride on calcium absorption and balance in
man. Am. J. clin. Nutr., 22: 381-390.
SPENCER, H., OSIS, D., & WIATROWSKI, E. (1975) Retention of
fluoride with time. Clin. Chem., 21: 613-618.
SPENCER, H., KRAMER, L., OSIS, D., WIATROWSKI, E., NORRIS, C.,
& LENDER, M. (1980) Effect of calcium, phosphorus,
magnesium, and aluminum on fluoride metabolism in man. Ann.
New York Acad. Sci., 355: 181-194.
SPENCER, H., OSIS, D., & LENDER, M. (1981) Studies of
fluoride metabolism in man. A review and report of original
data. Sci. total Environ., 17: 1-12.
SPIRA, L. (1956) Urinary calculi and fluorine. Exp. Med.
Surg., 14: 72-78.
SPOERKE, D.G., BENNETT, D.L., & GULLEKSON, D.J.K. (1980)
Toxicity related to acute low dose sodium fluoride ingestions.
J. fam. Pract., 10: 139-140.
STAMM, J.W. & BANTING, D.W. (1980) Comparison of root caries
prevalence in adults with life-long residence in fluoridated
and non-fluoridated communities. AADR abstr., 552.
STEPHEN, K.W. & CAMPBELL, D. (1980) A four-year double-blind
study with fluoridated school milk. XXVLL ORCA Congr., 17
STEVENSON, C.A. & WATSON, A.R. (1957) Fluoride osteoscler-
osis. Am. J. Roentgenol. radium Ther. nucl. Med., 78: 13-18.
SUKETA, Y. & MIKAMI, E. (1977) Changes in urinary ion
excretion and related renal enzyme activities in fluoride-
treated rats. Toxicol. appl. Pharmacol., 40: 551-559.
SUKETA, Y. & TERUI, M. (1980) Adrenal function and changes
of sodium and potassium in serum and urine in fluoride-
intoxicated rats. Fluoride, 13: 4-9.
SUKETA, Y., MIKAMI, E., & HAYASHI, M. (1977) Changes in
calcium and magnesium in the kidneys of rats intoxicated with
a single large dose of fluoride. Toxicol. appl. Pharmacol.,
SUMMENS, J.L. & KEITZER, W. (1975) Effect of water
fluoridation on urinary tract calculi. Ohio State med. J.,
SUSHEELA, A.K. & SINGH, M. (1982) Adenyl cyclase activity
following fluoride ingestion. Toxicol. Lett., 10: 209-212.
SUTTIE, J.W. (l969) Fluoride content of commercial dairy
concentrates and alfalfa forage. J. agric. food Chem., 17:
SUTTIE, J.W. (1977) Effects of fluoride on livestock.
J. occup. Med., 19: 40-48.
SUTTIE, J.W., CARLSSON, J.R., & FALTIN, E.C. (1972) Effects
of alternating periods of high- and low-fluoride ingestion on
dairy cattle. J. dairy Sci., 55: 790-804.
SZULC, M., SZACZAWINSKI, J., & IWANSKA, M. (1974) [Fluorine
content of tissues of cows from areas subject to industrial
pollution from the viewpoint of public health meat
inspection.] Medycyna, 30: 200-204 (in Polish).
TANNENBAUM, A. & SILVERSTONE, H. (l949) The genesis and
growth of tumors. IV Effects of varying the proportion of
protein (Casein) in the diet. Cancer Res., 9: 162-173.
TASK GROUP ON LUNG DYNAMICS (1966) Deposition and retention
models for internal dosimetry of the human respiratory tract.
Health Phys., 12: 173-207.
TAVES, D.R. (1966) Normal human serum fluoride
concentrations. Nature (Lond.), 211: 192-193.
TAVES, D.R. (1968a) Evidence that there are two forms of
fluoride in human serum. Nature (Lond.), 217: 1050-1051.
TAVES, D.R. (1968b) Determination of submicromolar
concentrations of fluoride in biological samples. Talanta,
TAVES, D.R. (1968c) Electrophoretic mobility of serum
fluoride. Nature (Lond.), 220: 582-583.
TAVES, D.R. (1970) New approach to the treatment of bone
disease with fluoride. Fed. Proc., 29: 1185-1187.
TAVES, D.R. (1978) Fluoridation and mortality due to heart
disease. Nature (Lond.), 272(565): 361-362.
TAVES, D.R. & NEUMAN, W.F. (1964) Factors controlling
calcification in vitro: fluoride and magnesium. Arch.
Biochem. Biophys., 108: 390-397.
TAVES, D.R., TERRY, R., SMITH, F.A., & GARDNER, D.E. (1965)
Use of fluoridated water in long-term analysis. Arch. intern.
Med., 115: 167-172.
TAYLOR, A. (l954) Sodium fluoride in drinking water of mice.
Dent. Dig., 60: 170-172.
TAYLOR, J.M., SCOTT, J.K., MAYNARD, E.A., SMITH, F.A., &
HODGE, H.C. (1961) Toxic effects of fluoride on the rat
kidney. Toxicol. appl. Pharmacol., 3: 278-314.
TEMPLE, P.J. & WEINSTEIN, L.H. (l978) Is hydrogen fluoride
mutagenic to plants? J. Air Pollut. Control Assoc., 28:
TEOTIA, M., TEOTIA, S.P.S., & KUNWAR, K.B. (1971) Endemic
skeletal fluorosis. Arch. Dis. Child., 46: 686-691.
THERIAULT, G., CORDIER, S., & HARVEY, R. (1980) Skin
telangiectases in workers at an aluminum plant. New Engl. J.
Med., 303: 1278-1281.
THOMPSON, R.J., MCMULLEN, T.B. & MORGAN, G.B. (1971)
Fluoride concentrations in the ambient air. J. Air Pollut.
Control Assoc., 21: 484-487.
THYLSTRUP, A. & FEJERSKOV, O. (1978) Clinical appearance and
surface distribution of dental fluorosis in permanent teeth in
relation to histological changes. Commun. Dent. oral
Epidemiol., 6: 329-337.
THYLSTRUP, A., FEJERSKOV, O., BRUUN, C., & KANN, J. (1979)
Enamel changes and dental caries in 7-year old children given
fluoride tablets from shortly after birth. Caries Res., 13:
THYLSTRUP, A., BILLE, J., & BRUUN, C. (1982) Caries
prevalence in Danish children living in areas with low and
optimal levels of natural water fluoride. Caries Res., 16:
TOTH, K. (1976) A study of 8 years domestic salt
fluoridation for prevention of caries. Commun. Dent. oral
Epidemiol., 4: 106-110.
TOTH, K. & SUGAR, E. (1976) Effect of drinking waters of
high fluorine content on the urinary fluoride level. Acta
physiol. Acad. Sci. Hung., 47: 65-72.
TOTH, K. & SUGAR, E. (1978) Fluorine content of foods and
the estimated daily intake from foods. Acta physiol. Acad.
Sci. Hun., 51: 361-369.
TOTH, K., SUGAR, E., BORDOCS, I., KIRALY, L., & PALLER, I.
(1978) Fluorine content of vegetables and fruits. Acta.
physiol. Acad. Sci. Hun., 51: 353-359.
TRUHAUT, R. (1955) Le fluor dans les aliments: Aspects
biologiques et analytiques du problčme. Ann. Fals. Fraud.,
UNDERWOOD, E.J. (1971) Fluorine. In: Trace elements in human
and animal nutrition, 3rd ed., New York, Academic Press, pp.
UNSWORTH, M.H. & ORMROD, D.P. (l982) Effects of gaseous air
pollution in agriculture and horticulture, London, Boston,
Sydney, Wellington, Durban, Toronto, Butterworth Scientific.
US BUREAU OF MINES (1980) Mineral industry surveys.
Fluorspar in 1979, Washington DC, US Department of the
US EPA (1980) Reviews of the environmental effects of
pollutants: IX Fluoride, Cincinnati, US Environmental
Protection Agency, 441 pp (EPA-600/1-78-050).
US NAS (1971) Fluorides, Washington DC, National Academy of
Sciences, 295 pp.
US NAS (1974) Effects of fluorides in animals, Washington
DC, National Academy of Sciences, 70 pp.
US NIH (1972) Misrepresentation of statistics on heart
deaths in Antigo, Wisconsin, National Institute of Health
(reference PPB-47, November 1972).
VALLIN, S. (1968) [Poisonous effect of fluoride on fish.]
Vatten, 1: 51-52 (in Swedish).
VANDEPUTTE, M., DE COCK, J., DRYON, L., VERCRUYSSE, A.,
ALEXANDER, F., & MASSART, D.L. (1977) A contribution to the
study of fluoride excretion. Clin. chim. Acta, 75: 205-212.
VELU, H. & BALOZET, L. (1931) Reproduction experimentale
chez le mouton de la dystrophie dentaire des animaux des zones
phosphates. Bull. Acad. Vét. France, 4: 373-376.
VICTORIA COMMITTEE (1980) Report of the committee of inquiry
into the fluoridation of victorian water supplies, Melbourne,
FD Atkinson, Government Printer, 278 pp.
VINOGRADOV, A.V. (1937) [Fluorine in nature.] Gig. i Sanit.,
3: 11-25 (in Russian).
VOGEL, E. (1973) Strong antimutagenic effects of fluoride on
mutation induction by trenimon and 1-phenyl-3,3-dimethyltriazene
in Drosophila melanogaster. Mutat. Res., 20: 339-352.
VOHRA, P. (1973) Fluoride tolerance of Japanese quail.
Poult. Sci., 52: 391-393.
VOROSILIN, S.I., PLOTKE, E.G., GATIJATULLINA, E.Z., & GILEVA,
E.A. (1973) [Cytogenic effect of inorganic fluorine
compounds on human and animal cells in vivo and in vitro.]
Sov. Genet., 9: 492-496 (in Russian).
WAERN, U. (1977) Findings at a health survey of 60-year-old
men and recorded diseases during their preceeding 10 years of
life, Uppsala, Sweden, Thesis.
WALDBOTT, G.L. (1978) Fluoridation the great dilemma,
Lawrence, Kansas, Coronado Press, Inc.
WALDBOTT, G.L. (1981) Mass intoxication from accidental
overfluoridation of drinking water. Clin. Toxicol., 18:
WALDBOTT, G.L. & CECILIONI, V.A. (1969) "Neighborhood"
fluorosis. Fluoride, 2: 206.
WEATHERELL, J.A. (l966) Fluoride and the skeletal and dental
tissues. In: Eichler, O., Farah, A., Herksen, H., Welch, A.D.,
& Smith, F.A., ed. Handbook of experimental pharmacology, New
York, Springer-Verlag, Vol. 20, part 1, pp. 141-172.
WEATHERELL, J.A., DEUTSCH, D., ROBINSON, C., & HALLSWORTH,
A.S. (1977) Assimilation of fluoride by enamel throughout
the life of the tooth. Caries Res., 11(Suppl. 1): 85-115.
WEIDMANN, S.M. & WEATHERELL, J.A. (1970) Distribution of
fluorides: Distribution in hard tissues. In: Fluorides and
human health, Geneva, World Health Organization, pp. 104-128
(Monograph Series No. 59).
WEIDMANN, S.M., WEATHERELL, J.A., & JACKSON, D. (1963) The
effect of fluoride on bone. Proc. Nutr. Soc., 22: 105-110.
WEINSTEIN, L.H. (1977) Fluoride and plant life. J. occup.
Med., 19: 49-78.
WEINSTEIN, L.H. & ALSCHER-HERMAN, R. (l982) Physiological
responses of plants to fluorine. In: Unsworth, M.H. & Ormrod,
D.P., ed. Effects of gaseous air pollution in agriculture and
horticulture, London, Butterworth Scientific, pp. 139-167.
WHITFORD, G.M., PASHLEY, D.H., & STRINGER, G.I. (1976)
Fluoride renal clearance: a pH-dependent event. Am. J.
Physiol., 230: 527-532.
WHO (1970) Fluorides and human health, Geneva, World Health
Organization, 364 pp. (Monograph Series No. 59).
WHO (1973) Trace elements in human nutrition. A report of a
WHO expert committee, Geneva, World Health Organization (WHO
technical report series No. 532).
WHO (in press) Appropriate uses of fluorides for oral
health, FDI/WHO/Kellogg Foundation Joint Conference on
WILLARD, H.H. & WINTER, O.B. (1933) Volumetric method for
determination of fluorine. Ind. Eng. Chem., 5: 7-10.
WIRTZ, R. (1964) [Milk in Winterthur from 1958-1964.]
Schweiz. Monatschr. Zahnheilk., 74: 767-779 (in German).
WISEMAN, A. (1970) Effect of inorganic fluoride on enzymes.
In: Smith, F.A., ed. Handbook of experimental pharmacology,
Berlin, Springer-Verlag, pp. 48-97.
WOHLSCHLAGEL, J., DIPASQUALE, L.C., & VERNOT, E.H. (1976)
Toxicity of solid rocket motor exhaust - effects of HCl, HF
and alumina on rodents. J. Combust. Toxicol., 3: 61-70.
WOOD, H. (l975) Fluorine. In: Mineral facts and problems,
Washington DC, US Bureau of Mines, US Government Printing
Office, pp. 379-399.
WORL, R.G., VAN ALSTINE, R.E., & SHAWE, D.R. (1973)
Fluorine. In: Brobst, D.A. & Pratt, W.P., ed. United States
mineral resources, Washington DC, US Department of the
Interior (Geological survey professional paper 820).
WRIGHT, D.A. (1977) Toxicity of fluoride to brown trout fry
(Salmo trutta). Environ. Pollut., 12: 57-62.
YU, M.-H., MILLER, G.W., & LOVELACE, C.J. (1971) Gas
chromatographic analysis of fluoroorganic acids in plants and
animal tissue. Proceedings of the 2nd International Clean Air
Congress, pp. 156-158.
ZIEGLER, E. (1956) [Studies on the caries prevention effect
of fluoridated milk.] Mitt. Naturwiss. Ges. Winterthur, 28 (in
ZIMMERMAN, E.R. (1954) Fluoride and non-fluoride opacities.
Public Health Rep., 69: 1115-1120.
ZIPKIN, I., LIKINS, R.C., MCCLURE, F.J., & STEERE, A.C.
(1956) Urinary fluoride levels associated with use of
fluoridated waters. Public Health Rep., 71: 767-772.
ZIPKIN, I., MCCLURE, F.J., LEONE, N.C., & LEE, W.A. (1958)
Fluoride deposition in human bones after prolonged ingestion
of fluoride in drinking water. Public Health Rep., 73: 732-740.
ZIPKIN, I., ZUCAS, S.M., LAVENDER, D.R., FULLMER, H.M.,
SCHIFFMAN, E., & CORCORAN, B.A. (1970) Fluoride and
calcification of rat aorta. Calcif. Tissue Res., 6: 173-182.