The EFSA Journal (2004) 100, 1-22
Opinion of the Scientific Panel on Contaminants in the Food Chain on a
request from the Commission related to Fluorine as undesirable substance
in animal feed
(Request N° EFSA-Q-2003-034)
Adopted on 22 September 2004
SUMMARY
Fluorine is one of the most abundant elements in the environment. Animals are exposed to the
ionic form of the element (fluoride) which may be present in feed materials and drinking
water. Moreover, ingestions of feed materials contaminated with soil for examples by
ruminants and horses contribute to exposure in geographic areas with high natural fluorine
concentrations, as the average concentration in soils is higher than the average concentration
in plants. Fluorine is considered as an essential element in various animal species as
experimental diets, low in fluorine resulted in growth retardation, impaired fertility and
reduced dental enamel strength in various animal species, and also in humans. Excessive
exposure, which is observed regularly in distinct geographic areas and incidentally in the
proximity of industrial sites with high fluoride emission, is associated with dental and
skeleton abnormalities. Fluoride accumulates in calcifying tissues (including egg shells) and
stimulates calcium deposition in connective (peri-articular) tissues. The limited data available
provided no evidence for toxic fluoride concentrations in natural pastures and mixed feeds in
Europe. Incidental high concentrations in herbage grown in the proximity of industrial areas
can, however, not be excluded. Transmission into edible tissues including milk and eggs is
limited. Hence, the fluoride concentrations in foods from animal origin contribute only
marginally to human exposure.
KEY WORDS
Fluorine, fluoride, animal feed, fluorosis
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Opinion on Fluorine
TABLE OF CONTENTS
SUMMARY ............................................................................................................................... 1
BACKGROUND........................................................................................................................ 3
1.
2.
General background .............................................................................................................................. 3
Specific background .............................................................................................................................. 4
TERMS OF REFERENCE......................................................................................................... 5
ASSESSMENT .......................................................................................................................... 5
1.
2.
3.
4.
5.
6.
7.
Introduction .................................................................................................................... 5
Methods of analysis and current legislation for feed materials...................................... 7
Occurrence of fluorine in feed materials and animal exposure...................................... 9
Adverse effect on livestock .......................................................................................... 11
4.1. Ruminants............................................................................................................. 12
4.2. Pigs ....................................................................................................................... 12
4.3. Horses................................................................................................................... 13
4.4. Rabbits.................................................................................................................. 13
4.5. Poultry .................................................................................................................. 13
4.6. Fish ....................................................................................................................... 13
Toxicokinetics ....................................................................................................................................... 14
5.1. Absorption............................................................................................................ 14
5.2. Tissue Distribution ............................................................................................... 14
5.3. Excretion .............................................................................................................. 15
Carry over and tissue concentrations ............................................................................................. 15
Human dietary exposure .................................................................................................................... 16
CONCLUSIONS...................................................................................................................... 17
REFERENCES......................................................................................................................... 17
SCIENTIFIC PANEL MEMBERS.......................................................................................... 22
ACKNOWLEDGEMENT ....................................................................................................... 22
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Opinion on Fluorine
BACKGROUND
1.
General background
Directive 2002/32/EC of the European Parliament and of the Council of 7 May 2002 on
undesirable substances in animal feed1 replaces since 1 August 2003 Council Directive
1999/29/EC of 22 April 1999 on the undesirable substances and products in animal nutrition2.
The main modifications can be summarised as follows
-
extension of the scope of the Directive to include the possibility of establishing
maximum limits for undesirable substances in feed additives.
-
deletion of the existing possibility to dilute contaminated feed materials instead of
decontamination or destruction (introduction of the principle of non-dilution).
-
deletion of the possibility for derogation of the maximum limits for particular local
reasons.
-
introduction the possibility of the establishment of an action threshold triggering an
investigation to identify the source of contamination (“early warning system”) and to
take measures to reduce or eliminate the contamination (“pro-active approach”).
In particular the introduction of the principle of non-dilution is an important and far- reaching
measure. In order to protect public and animal health, it is important that the overall
contamination of the food and feed chain is reduced to a level as low as reasonably achievable
providing a high level of public health and animal health protection. The deletion of the
possibility of dilution is a powerful mean to stimulate all operators throughout the chain to
apply the necessary prevention measures to avoid contamination as much as possible. The
prohibition of dilution accompanied with the necessary control measures will effectively
contribute to safer feed.
During the discussions in view of the adoption of Directive 2002/32/EC the Commission
made the commitment to review the provisions laid down in Annex I on the basis of updated
scientific risk assessments and taking into account the prohibition of any dilution of
contaminated non-complying products intended for animal feed. The Commission has
therefore requested the Scientific Committee on Animal Nutrition (SCAN) in March 2001 to
provide these updated scientific risk assessments in order to enable the Commission to
finalise this review as soon as possible (Question 121 on undesirable substances in feed)3.
1
OJ L140, 30.5.2002, p. 10
OJ L 115, 4.5.1999, p. 32
3
Summary record of the 135th SCAN Plenary meeting, Brussels, 21-22 March 2001, point 8 – New questions
(http://europa.eu.int/comm/food/fs/sc/scan/out61_en.pdf)
2
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Opinion on Fluorine
It is worthwhile to note that Council Directive 1999/29/EC is a legal consolidation of Council
Directive 74/63/EEC of 17 December 1973 on the undesirable substances in animal nutrition4,
which has been frequently and substantially amended. Consequently, several of the provisions
of the Annex to Directive 2002/32/EC date back from 1973.
The opinion on undesirable substances in feed, adopted by SCAN on 20 February 2003 and
updated on 25 April 20035 provides a comprehensive overview on the possible risks for
animal and public health as the consequence of the presence of undesirable substances in
animal feed.
On the basis of this opinion, some provisional amendments are proposed to the Annex of
Directive 2002/32/EC in order to guarantee the supply of some essential, valuable feed
materials as the level of an undesirable substance in some feed materials, due to normal
background contamination, is in the range of or exceeds the maximum level laid down in the
Annex I of Directive 2002/32/EC. Also some inconsistencies in the provisions of the Annex
have been observed.
It was nevertheless acknowledged by SCAN itself for several undesirable substances and by
the Standing Committee on the Food Chain and Animal Health that additional detailed risks
assessments are necessary to enable a complete review of the provisions in the Annex.
2.
Specific background
SCAN concluded6 that the ions and elements, including fluorine, listed in Council Directive
1999/29/EC are commonly encountered substances with known toxicity. In each case, the
contribution of food products of animal origin to the human exposure is limited and listing of
these elements as undesirable substance in feed, although concomitantly contributing to an
overall reduction of human exposure to toxic forms, is mainly justified by reasons of animal
health.
A detailed risk assessment of the presence of fluorine in animal feed and the possible effects
for animal health and public health is necessary and urgent as it appears that fluorine present
at the maximum levels established in legislation for fluorine may affect the health of poultry,
horse and rabbit as they are higher than their tolerance levels. Consequently a complete
review of the maximum levels for fluorine on the basis of a detailed risk assessment is
urgently necessary.
4
OJ L 38, 11.2.1974, p. 31
Opinion of the Scientific Committee on Animal Nutrition on Undesirable Substances in Feed, adopted on 20
February 2003, updated on 25 April 2003 (http://europa.eu.int/comm/food/fs/sc/scan/out126_bis_en.pdf)
6
Opinion of the Scientific Committee on Animal Nutrition on Undesirable Substances in Feed, point 6.11.
Conclusions and recommendations.
5
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TERMS OF REFERENCE
The European Commission requests the EFSA to provide a detailed scientific opinion on the
presence of fluorine in animal feed.
This detailed scientific opinion should comprise the
-
determination of the toxic exposure levels (daily exposure) of fluorine for the different
animal species of relevance (difference in sensitivity between animal species) above
which
-
signs of toxicity can be observed (animal health/impact on animal health) or
-
the level of transfer/carry over of fluorine from the feed to the products of animal
origin results in unacceptable levels of fluorine in the products of animal origin in
view of providing a high level of public health protection.
-
identification of feed materials which could be considered as sources of contamination
by fluorine and the characterisation, insofar as possible, of the distribution of levels of
contamination.
-
assessment of the contribution of the different identified feed materials as sources of
contamination by fluorine
-
-
to the overall exposure of the different relevant animal species to fluorine.
-
to the impact on animal health.
-
to the contamination of food of animal origin (the impact on public health), taking
into account dietary variations and variable carry over rates (bio-availability)
depending on the nature of the different feed materials.
identification of eventual gaps in the available data which need to be filled in order to
complete the evaluation.
ASSESSMENT
1.
Introduction
Fluorine belongs to the most abundant elements occurring in different chemical forms in the
environment and in living organisms. Under normal conditions, fluorine (F; atomic weight
18.9984) is a gaseous element, with a strong, typical odour. The major source of fluorine is
volcanic activity, resulting in an atmospheric emission of 1 - 9 million tons per year. Volcanic
emissions also release acid smokes that contain hydrofluoric acid. Another natural source is
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Opinion on Fluorine
deep well water. Fluorine almost exclusively occurs in the environment, food, water and
plants in its ionic form (fluoride). However, the amount of fluoride present naturally in water
is highly variable, depending upon the individual geological environment from which the
water is obtained. In geographic areas of for example central Asia and India, in which
endemic fluorosis is well documented, water may contain up to 20 mg fluoride/L (for review
se Merian et al., 2004).
Due to its high electron affinity, fluorine is easily forming salts, and subsequently more than
100 fluoride minerals have been described. The most abundant inorganic fluorides in the
earth’s crust are fluoroapatite (Ca5(PO4)3F), fluorite (CaF2) and cryolite (Na3AlF6)(CEPA,
1993). These inorganic fluorides are much more abundant than organic fluorides.
Fluorine in the form hydrofluoric acid (HF), silicon tetrafluoride (SiF4), and fluoride
derivatives can also be released from industrial sites associated with aluminium or phosphate
processing, as well as steel and glass production (Cronin et al., 2000). These emissions can
contaminate surface water, soil, and plants in the proximity of industrial sites and have
resulted in Europe to unexpected high exposure rates in livestock in certain distinct areas
(Bunce, 1985). Moreover, fluorides are natural components in phosphate and super-phosphate
fertilizers used in agricultural practice. Fluoroapatite (rock phosphate) sources vary widely in
their fluorine content, depending on their geographic origin. Fluoride-bearing rock phosphate
is used in mineral supplements for livestock. High fluoride rock phosphates can be injurious
to livestock when used over long periods, even in the amounts commonly applied to meet the
calcium and phosphorus requirements of the animals. For this reason, rock phosphates should
be (and are now routinely) de-fluorinated.
Uptake of fluorides by plants from the soil occurs via the roots and uptake from air through
the stomata of the leaves. The availability of soil fluoride for plants depends on soil
characteristics (pH, water content, organic matter content, cation and anion exchange
capacities), the chemical form of the fluoride, and the individual plant species (Longanathan
et al., 2001).
The average concentration of fluoride in soils is approximately 300 mg/kg, but may exceed
1000 mg/kg in soils on basic rocks. Fluorides are retained in roots and only poorly translocated to other parts of the plant. The relative accumulation index in herbage varies from
0.0001 to 0.1, according to the concentration of fluorides in soil (Geeson et al., 1998). Soluble
fluorides taken up from the soil are converted into carbon-fluorine compounds, including
monofluoroacetic acid, monofluorooleic acid, monofluoropalmitinic acid and
monofluoromyristic acid, respectively. The significance of this conversion remains unknown.
Since soil usually contains far higher fluoride concentrations than the plant, soil intake may
be a major source of fluorine exposure to animals under certain feeding regimes.
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Soluble fluorides are bio-accumulated by some aquatic and terrestrial biota, however, the
significance of this biomagnification of fluorine in the aquatic or terrestrial food chains
remains to be elucidated.
In mammals, fluorine is considered to be an essential element, as a low fluoride diet causes
growth retardation and impairment of fertility in various animal species (Anke 1998, 2001).
Fluorine deficiency in humans results in early tooth decay and probably in osteoporosis
(Gabovich and Ovrutskiym, 1969, Anke et al., 1990, Avtsyn et al., 1991). Of medical
importance is also the positive effect of fluoride in the prevention of dental caries, as it
strengthens the enamel of teeth. Hence, in geographic regions with low natural fluorine levels,
the drinking water is often supplemented with fluoride, and it is added routinely to health
products for dental care. Moreover, fluoride is added to calcium products, used in the
prevention and treatment of age-related fluorosis.
In contrast, in various regions of central Asia and the Indian subcontinent, fluorosis, mainly
induced by too high concentration of fluoride in well water, is endemic (for review see WHO,
2002). Clinical signs of excessive fluoride intake comprise skeletal fluorosis (chronic joint
pain, osteosclerosis and calcification of ligaments, progressing into skeletal deformities,
intense calcification and muscle wasting), as well as and neurological deficits, reproductive
effects (spontaneous abortion, no apparent malformations, but congenital cardiac diseases in
children) and adverse respiratory effects (for details see WHO, 2002).
Symptoms of acute toxicity of fluorides in laboratory animals are generally non-specific.
Experimentally induced chronic toxicity resulted in skeletal and dental fluorosis, associated
with nephrotoxicity in rodents. Fluoride is genotoxic (clastogenic but not mutagenic) in
human and animal cells in vitro, but do not appear to induce direct mutagenicity in vivo in
laboratory animals. However, high concentrations may alter the response to mutagens. The
evidence regarding the carcinogenicity of fluoride in laboratory animals is inconclusive
(WHO, 2002; EC, 1996). IARC (1987) stated that the limited animal data available are
inadequate for a reliable risk assessment. More recent NIH studies performed in rats and mice
have only shown an increased incidence of osterosarcomas in male rats, and this effect was
evaluated by NIH as equivocal evidence (NIH, 1990, US-NRC, 1993, EC, 1996).
2.
Methods of analysis and current legislation for feed materials
The determination of fluoride in biological materials is carried out by alkali fusion and
fluoride ion-selective electrodes (Malde et al., 2001). Sodium hydroxide is used as an ashing
aid.
Trace levels of fluoride in biological media are determined primarily by potentiometric (ion
selective electrode [ISE]) and gas chromatographic (GC) methods. Colorimetric methods are
available, but are more time consuming and lack the sensitivity of the other methods
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(Kakabadse et al., 1971; Venkateswarlu et al., 1971). Alternative methods that have been
used include fluorometric, enzymatic, and proton activation analysis (Rudolph et al., 1973).
The latter technique is sensitive to trace amounts of sample, and requires minimal sample
preparation. The most accurate method of sample preparation is microdiffusion techniques,
such as the acid-hexamethyldisiloxane (HMDS). These methods allow the liberation of
fluoride from organic or inorganic matrices (WHO 2002). Bone fluoride levels can be
measured using the ISE technique after ashing of the sample (Boivin et al., 1990).
Numerous national regulations for fluorine exist with respect to drinking water, and the
concentrations permitted in health products. As fluoride is also present in virtually all animal
feed materials, currently the following maximum levels have been set in the European Union.
Table 1. Prescribed limits for total fluorine in feedingstuffs, mg/kg, at a moisture content of 12%7
Feed materials with the exception of:
-
feedingstuffs of animal origin with the exception of marine crustaceans
such as marine krill
-
phosphates and marine crustaceans such as marine krill
-
calcium carbonate
350
-
magnesium oxide
600
-
calcareous marine algae
Complete feedingstuffs with the exception of:
-
500
2000
1000
150
complete feedingstuffs for cattle, sheep and goats
in lactation
30
other
50
-
complete feedingstuffs for pigs
100
-
complete feedingstuffs for poultry
350
-
complete feedingstuffs for chicks
250
Mineral mixtures for cattle, sheep and goats
Other complementary feedingstuffs
7
150
2000
125
Directive 2003/100/EC , OJ L 285 , 01.11.2003, p. 33 - 37 amending Annex I to Directive 2002/32/EC of the
European Parliament and of the Council of 7 May 2002 on undesirable substances in animal feed.
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3.
Opinion on Fluorine
Occurrence of fluoride in feed materials and animal exposure
Concentrations of fluoride in soils vary considerably depending on geographic conditions as
well as industrial pollution. In contrast to many heavy metals, mobility of fluorine in soil is
very limited. Furthermore, most plant species have a limited capacity to absorb fluoride from
the soil, even when fluoride-containing fertilisers are applied.
Data of the occurrence of fluoride in feed materials have been made available by a number of
individual EU member states or taken from reports published within the EU. Some of these
data are difficult to evaluate because of limited information on the nature of the samples (e.g.
compound feed without any detailed information on designated species) or inadequate sample
description. The data for feed materials that can reliably be categorised are summarised in
table 2, and for commercially manufactured compounds or complementary feeds in Table 38.
Table 2. Fluoride concentrations (mg/kg dry matter) in certain feed materials, expressed as
fluorine.
Mean
SD
Median
Min
Max
n=
Fish meal
159
57.7
164
109
250
5
Meat and bone meal
180
23.5
178
132
201
7
Palm kernel expeller meal
46
Rapeseed meal
10
0.8
10
8.6
10.3
5
Soya bean meal
11
2.4
12
5
12
7
244
145.3
261
6
588
192
Sugar beet pulp (fresh and dried)
1
With the exception of sugar beet pulp, none of the samples analysed contained fluorine levels
in excess of the maximum permitted level for that category of feed material. Insufficient
numbers of forage analyses were reported to allow any meaningful summary to be made.
Forages from uncontaminated pastures usually contain between 5 and 16 mg fluorine/kg dry
matter (Allcroft et al., 1965), while concentrations in cereals and cereal by-products are
generally < 3 mg/kg dry matter (US-NRC, 1980). Exceptions to this are crops that have been
contaminated by fumes or dust from industrial processes or by irrigation with fluoride-rich
water. Therefore, with the exception of the latter, fluoride in feed materials are unlikely to
exceed maximum permitted levels.
Since it is stored in the bones of animals, it is not surprising that elevated levels of fluoride
have been reported in fishmeal and meat and bone meal.
8
Where data have been reported as being below the level of detection, e.g. < 0.1 mg/kg, a value of half of the
level of detection (in this case (0.05 mg/kg) has been used in calculating the mean and standard deviation
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Exposure of animals to fluoride is a function of the concentration of fluorides in the feed, and
the amount of feed consumed. In order to estimate the intake of, and level of exposure to
fluoride, it is necessary to have estimates of both the likely intake (g or kg of dry matter per
day) of feed material for each class of livestock, and typical concentrations.
In estimating dietary exposure to fluoride, two approaches were considered. The first was to
describe typical inclusion rates for feed materials used in the manufacture of compound feeds,
and to calculate the final fluoride concentrations. However, this approach had to be rejected,
primarily because information on many individual raw materials was scarce or not available.
The alternative approach was to use data for manufactured compound feeds. This is the
approach that was used previously by SCAN in its reviews of zinc and copper, and it has been
adopted in this report. Information on the fluorine concentrations in complete feedingstuffs
and complementary feedingstuffs, obtained as part of routine surveillance in a number of
Member States, are summarised in Table 3. The maximum permitted levels of total fluorine in
these feeds are given in Table 1.
Table 3. Mean concentrations of fluorine (mg/kg dry matter) in commercial compound
feeds for farm livestock and fish (data reported by EU member states) 9, 10
Mean
SD
Median
Min
Max
n=
Poultry - Layers
24
10.7
22
11
42
9
Poultry - Broilers
24
8.9
25
15
39
7
Poultry - unspecified
32
14.1
31
22
42
2
Fish
30
10.8
29
8
88
354
Pigs < 17 weeks
14
13.0
11
2
33
4
Pigs > 16 weeks
23
6.9
24
12
31
7
Pigs - unspecified
16
7.9
11
3
33
37
Ruminants - unspecified
17
12.5
22
2
33
8
On the basis of the data available, it would appear that compound feeds for farm livestock do
not exceed maximum permitted concentrations. However, it should be noted that with the
exception of fish feeds this conclusion is based on very few samples.
For the majority of non-ruminant livestock (pigs and poultry as well as farmed fish) in the
EU, feed is provided as compounded feed, consisting of a mixture of individual feed
components, to which additives and/or mineral supplements are added. Intake of fluorine may
therefore be estimated by multiplying the concentrations given in Table 3 by the estimated
intake of the compound for the particular class of livestock. Estimating fluoride intake by
ruminants is less straightforward. For these animals, the daily ration usually consists of forage
9
10
Data obtained as part of routine surveillance of feed materials, and provided by Member States.
No data on horse or rabbit feeds have been provided.
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(or mixture of forages), either fresh or conserved, to which may be added complementary
feeds or individual feed materials as necessary to achieve the required level of production
(growth rate, milk yield). The proportions of different feed materials in the diet are influenced
by many factors, including their nutritional value and the required level of production.
However, combining data for feed materials (Table 2), compound feeds for ruminants (Table
3), and assuming normal levels of fluoride in forages, suggests that typical dietary
concentrations are well below the maximum permitted level for complete feedingstuffs as
specified in Directive 2003/100/EC.
However, reference has been made to the fact that soils may contain significantly higher
fluoride concentrations than plants growing on them. As a result, consumption of soil during
grazing (or consumption of soil-contaminated feeds) is an additional factor contributing to
total exposure of livestock (Loganathan et al., 2001 and references therein).
4.
Adverse effect on livestock
The pathological results of skeletal fluorosis include dissociation of the normal sequences in
osteogenesis, acceleration of bone remodelling, production of abnormal bone (exostosis,
sclerosis) and in some cases accelerated bone resorption (osteoporosis). Clinical signs
comprise stiffness and lameness and in severe cases animals refuse to stand, moving instead
on their knees. The stiffness and lameness are primarily associated with oesteofluorotic
lesions and calcification of peri-articular structures and tendons preceding skeletal
deformation.
Excess fluoride intake produces dental fluorosis in animals (like in humans) affecting the
teeth during development. Specific ameloblastic and odontoblastic damage may be caused by
high fluoride intake and varies directly with the levels consumed. Faulty materialisation
results when the matrix laid down by damaged ameloblasts and odontoblasts fails to accept
minerals normally. Once a tooth is fully formed, the amenoblasts have lost their constructive
ability and the enamel lesions cannot be repaired. Oxidation of organic material in the teeth
results in brown or black discoloration, which is a prominent sign of in dental fluorosis. This
discoloration may serve as diagnostic parameter in veterinary medicine (Shupe et al., 1992).
Reduced uptake and loss of condition are most likely the consequences of these dental
abnormities. The tolerance of livestock towards fluoride in feeds varies depending on the
form in which they are present, and the presence of calcium and phosphates, but also
aluminium, in the diet, and the general nutritional status of the animal. Moreover, other
sources than feed, including drinking and the intake of soils, have to be considered.
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Ruminants
Cattle is generally described as the most frequently affected animal species, but this might
reflect the relatively high exposure due to the typical feeding pattern of these animals (high
plant, soil water and mineral intake) rather than a specific sensitivity.
In dairy cattle, rations containing more than 150 mg of fluorine/kg of diet for a period of 1
month were associated with reduced feed intake and slightly reduced milk production (Suttie
and Kolstad, 1977). Minor morphological lesions can occur in young cattle receiving as little
as 20 mg of fluorine /kg of diet when teeth are developing rapidly, but the relationship
between these minor lesions and animal performance is unknown.
Fluoride crosses the placental barrier of cows, and fluoride levels in the bones of the offspring
are correlated with the fluoride concentrations of maternal blood (US-NRC, 1980). However,
bone fluoride concentrations of calves delivered from cows consuming as much as 108 mg/kg
dietary fluoride were low (Hobbs and Merriman, 1962), and it appeared that neither placental
fluoride transfer nor milk fluoride concentrations were sufficient to adversely affect the health
of these calves.
In 8 - 12 months old sheep receiving a concentrate mixture containing 25, 50, 75, 100 or 200
mg/kg fluorine, respectively, over a period of 140 days, the growth rate was significantly
reduced only in the animals receiving the highest dose of 200 mg/kg. In animals of the same
age receiving 100 mg/kg feed over a period of 3 years, the weights of ewes and their lambs
remained normal (Hobbs et al., 1954). Experiments on 9 month-old animals given water
containing 30 mg/L fluorine during 25 months resulted in adverse effects on growth after 32
weeks and signs of fluorosis after 72 weeks (Said et al., 1977).
On the basis of observations made on animals coming from polluted areas and showing
fluorosis, Milhaud et al. (1983) claimed that the sensitivity of goats to fluorine is comparable
to that of sheep, whereas lambs proved to be more resistant to fluorine as compared to goat
kittens.
4.2.
Pigs
Pigs seem to tolerate feed concentrations of more than 100 mg fluoride/kg dry matter
(Gueguen and Pointillart, 1986). Previous studies of Spence et al. (1971) described already
that a dose of 1 mg F-/kg bodyweight had no influence of weight gain, feed intake or
reproduction. Typical signs of intoxication at very high doses include irregular calcification of
teeth and jaw bones, constipation and loss of appetite.
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Horses
No controlled studies have been conducted to determine the sensitivity of horses to graded
amounts of dietary fluoride. Early reports from Shupe and Olson (1971) and Spencer et al.
(1971) describe the typical dental lesions induced by fluorine in horses, but provide no data
on the rate of exposure in these cases.
4.4.
Rabbits
Data on the sensitivity of rabbits towards fluoride exposure are scarce. Experimental data
indicated that a concentration of 150 mg F-/L in drinking water given over a period of 6
months, induced no gross pathological symptoms, and failed to alter antioxidant enzyme
activity (Reddy et al., 2003). In contrast, the application of 10 mg NaF/kg body weight daily
for a period of 18 months provokes severe abnormalities of sperm cells, suggesting a role of
fluoride in impaired fertility of the male rabbit (Kumar et al., 1994).
4.5.
Poultry
Sodium fluoride (150, 300 or 600 mg/kg feed) was added to the basal ration of male and
female chickens when they had reached the age of 98 days. No alterations in body weight
gain, total feed consumption, feed conversion and mortality (as measured until the age of 158
days were observed (Mehdi et al., 1983). Subsequently, egg production started on day 157 158 in all groups. The egg production rate over 70 days showed a tendency to decrease as the
level of added fluoride rose. When broilers and laying hens were fed sodium fluoride at a
level of 1000 and 1500 mg/kg feed, respectively, for 3 months, mean egg weight, feed
consumption and body weight gain decreased (Seddek et al., 1977). Feeding studies with
turkeys indicated that levels up to 400 mg F-/kg feed are tolerated over the entire lifespan,
whereas feed consumption was decreased when fluorine was present in a concentration of 800
mg/kg feed (Anderson et al., 1955). In layers, fluoride accumulates not only in skeletal
tissues, but also in the egg shell (Machalinski, 1996, Nogareda et al., 1990).
4.6.
Fish
Although several papers deal with waterborne exposed fish, few studies have been conducted
on the dietary toxicity of fluoride in fish. Rainbow trout tolerated high fluoride concentrations
(more than 2500 mg/kg for 82 days) in their diet (Tiews et al., 1982).
Fluoride concentrations in fresh water are relatively low (about 0.2 mg/L), but are several fold
higher in sea water (approximately 1.3 mg/L). Hence fluoride concentrations are high in
certain marine organisms such as krill (Julshamn et al., 2003), which is a natural feed source
for wild fish (Grønvik and Klemetsen, 1987). The fluoride content in krill meal ranges from
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1000 to 3000 mg/kg, most of the fluoride is associated with the exoskeleton (Julshamn et al.,
2003).
5.
Toxicokinetics
5.1
Absorption
Fluoride compounds with low solubility like calcium, magnesium or aluminium fluorides are
poorly absorbed while fluoride ions released from readily soluble fluoride compounds such as
sodium or hydrogen fluoride, fluorosilicic acid and monofluorophosphate are almost
completely absorbed from the gastrointestinal tract by passive diffusion in monogastric
species. Conditions of high gastric acidity favour absorption, whereas alkalinity decreases
fluoride absorption. Fluoride from various sources may be absorbed at different rates, as
described by Clay and Suttie, 1985):
Source
relative absorption rate
NaF
100 %
Raw rock phosphate
69 %
Dicalcium phosphate
52 %
Defluorinated phosphate
20 %
As far as sodium fluoride or fluoride derivatives present in plants are concerned, the fraction
actually absorbed by ruminants is approximately 75 % (Shupe et al., 1962). However, in
assessing the bioavailability of fluoride contained in soil in sheep, Milhaud et al. (1990) found
that digestive absorption ranged between 4.5 and 23 % of ingested dose. This percentage was
between 30 and 41 % for bovine species (Wöhlbier et al., 1968). In humans, soluble fluorides
are rapidly and extensively absorbed (virtually 100 % of the ingested dose). In the presence of
other ions (calcium, magnesium, phosphorus, aluminium), the rate of absorption may be
altered significantly (ATSDR, 1993).
5.2.
Tissue Distribution
Absorbed fluoride is sequestered in bones and teeth were it interacts with the hydroxyapatite
of calcified tissues (Kaminsky et al., 1992, Hamilton, 1992). The most efficient uptake of
fluoride into bones and teeth occurs in juvenile animals during periods of rapid development.
Thus mature bone takes up fluoride considerably slower than newly forming bone. Higher
concentrations of fluoride are also found in surface layers of mineral structures than in deep
layers, and fluoride released during bone remodelling is largely re-deposited (Guo et al.,
1988). In goats receiving during 3 years 2.5 mg fluorine/kg/day as sodium fluoride orally in
10 mL water, fluorine residues in bone varied between 4400 – 6600 mg/kg. Results of longterm experiments with beef and dairy cattle indicate that after 7.5 years of exposure to 10, 30,
50 and 100 mg/kg dietary fluoride, fluorine concentrations of 1000, 2000, 5000 and 8000
mg/kg were found in rib and mandibule (Puls, 1994). In cattle grazing fluoride-contaminated
pastures, bone ash concentrations may reach 10,000 mg fluoride per kg bone (about 5.5 % of
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the total concentration of phosphorus) (US-NRC, 1980). The concentration of fluoride in
bones varies, however, with age, sex and the type and specific part of the skeleton and is
believed to reflect an individual’s long-term exposure to fluoride. In contrast to chelating
agents, fluoride is not irreversibly bound to bone tissues, and is mobilized continuously from
the skeleton and subsequently excreted (Baars et al., 1987; WHO, 2002).
Only minor concentrations of fluoride are measurable in body fluid and soft tissues/
Concentrations found in brain and kidneys were 7.9 and 2.6 mg/kg respectively, whereas in
muscle, liver and milk the levels remained below 0.5 mg/kg (Milhaud et al., 1983). Placental
transfer of fluoride to the developing foetus has been demonstrated in rats (Theuer et al.,
1971) and humans (Gedalia et al., 1961). Nevertheless, a partial placental barrier may exist at
high maternal fluoride levels (Gedalia et al., 1970).
Pharmacokinetic models for exposure to fluoride have been developed for the growing pig
(Richards et al., 1985) and the ewe (Joseph-Enriquez et al., 1990). A three compartment open
model was selected to describe fluoride disposition. The mean half-life was 0.7 hours in the
pig and 2.6 hours in sheep.
5.3.
Excretion
Ingested fluoride is rapidly eliminated with urine, but only about half of the ingested dose will
be actually excreted, as the remainder accumulates in calcifying tissues, as mentioned above.
Only a minor percentage of the given dose is excreted with the faeces, as demonstrated in
sheep, in which renal excretion accounted for 2.1 – 9.6 % of fluoride dose (Milhaud et al.,
1990). Experimental data indicated that the degree of saturation of skeletal tissue of animals
affect the relative amount of fluoride retention. It has also been found that farm animals that
shifted form high level of fluoride intake to low levels, reduced the urinary excretion of
fluoride and at the same time start to mobilize some fluorine form skeletal tissues,
maintaining a constant blood level (Mitchell et al., 1952).
6.
Carry over and tissue concentrations
Results of experimental studies designed to assess residue formation, confirmed that fluoride
mainly accumulates in bone and teeth (Patra et al., 2000), and skeletal retention of fluoride
was approximately proportional to the concentration of fluoride in the diet. In soft tissues
fluoride levels are very low (generally < 2.5 mg/kg wet weight),) even following high levels
of dietary exposure (Puls, 1994). Only tendon (Armstrong and Singer, 1970), aorta (Ericsson
and Ullberg, 1958) and placenta have higher fluoride concentrations than other soft tissue,
possibly associated with their relatively high levels of calcium and magnesium.
In fresh water fish (rainbow trout, given feed containing high amounts of fluorine (2538
mg/kg feed) for a period of 82 days, residues in muscle tissue were approximately 4.5 mg/kg
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Opinion on Fluorine
wet weight, whereas in the skeleton up to 2450 mg/kg tissue were found (Tiews et al., 1982).
In Atlantic salmon tissues contained fluorine concentrations up to 1.4 mg/kg wet weight in
muscle tissue, and 5.8 – 7.2 mg/kg in the skeleton, respectively, after being fed with a diet
containing graded amount of fluorine varying from 18 – 358 mg/kg feed (Julshamm et al.,
2003).
Milk fluoride concentrations are affected only to a minor extend by dietary fluoride.
Greenwood et al. (1964) found that when Holstein cows were fed 10, 29, 55 and 109 mg/kg
dietary fluoride over the entire life time (3 months to 7.5 years of age), milk fluoride
concentrations were 0.06, 0.10, 0.14 and 0.20 mg/L respectively.
7.
Human dietary exposure
In continental Europe, drinking water concentrations are generally below 3 mg F/L (only in
some Scandinavian countries fluoride levels up to 9 mg/L have been found. In public water
works in most cases the fluoride concentration is even below 1 mg/L. Hence fluoride had
been added to drinking water in certain countries (EC, 1996). In contrast, in many other parts
of the world, fluorosis occurs as an endemic disease condition, due to as high amounts of
fluorine (20 – 45 mg/L) in well-water supplies (WHO, 1984, Kaminsky et al., 1990, USDHHS, 1991, WHO, 2002). Reviewing common foodstuffs, it becomes evident that high
fluorine concentrations may be found in fish (0.06 – 4.57 mg F/kg (Dubeka and McKenzie,
1995), vegetables form distinct regions (0.01 – 1.34 mg F/mg) (Chen et al., 1996), fruits and
fruit juices (0.1 - 2.8 mg F/kg) (Kiritsy et al., 1996), beverages (0.02 - 1.28 mg F/kg)
(Heilman et al., 1999), and tea (Wei et al., 1989, Bergmann, 1995), whereas edible tissues, as
well as milk and eggs from farm animals contain only low amounts of fluoride.
In conclusion, whereas endemic areas of fluorosis have been identified, where an excessive
exposure is related to local drinking water resources, in many industrialized countries with a
complete water cleaning system dietary intake of fluoride might be rather low, implying that
drinking water is sometimes even fortified with fluoride to achieve protection against dental
caries.
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CONCLUSIONS
•
Fluorine (F) is an abundant element in the environment. It may affect human and
animal health following exposure to high levels. Endemic outbreaks of fluorosis have
been observed in certain geographic areas where water from natural wells contains
high levels of fluorides.
•
Fluoride contributes to teeth and dental enamel strength. In some animals, fluorine is
considered to be an essential element, as diets low in fluoride impaired fertility and
development.
•
Adverse effects of fluoride are frequently reported resulting from locally high fluoride
concentration in the soil, pastures and local drinking water supplies. In these cases
Dental abnormalities can be observed, followed by reduced feed intake and
subsequent production losses and ultimately skeletal fluorosis.
•
In Europe, fluoride levels in the environment are generally low, and fluoride uptake by
herbage is limited. Subsequently, exposure of animals to fluoride is generally below
the limit causing detrimental effects. However, in certain industrial areas, fluoride
emission can be high, contaminating surface water and plants, and should be
monitored on a regular base.
•
A detailed assessment of the likely exposure of livestock to fluoride is not possible
due to the very limited amount of data on the fluoride concentrations in feed materials
and compound feeds. Moreover, exposure of animals will also result from fluoride
containing drinking water, and the ingestion of contaminated soils.
•
Fluoride accumulates particularly in calcifying tissues, which are normally not
consumed. In contrast, fluoride levels in edible tissues, including milk and eggs, are
low, and do not contribute significantly to human exposure.
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SCIENTIFIC PANEL MEMBERS
Jan Alexander, Herman Autrup, Denis Bard, Angelo Carere, Lucio Guido Costa; Jean-Pierre
Cravedi, Alessandro Di Domenico, Roberto Fanelli, Johanna Fink-Gremmels, John Gilbert,
Philippe Grandjean, Niklas Johansson, Agneta Oskarsson, Andrew Renwick, Jirí Ruprich,
Josef Schlatter, Greet Schoeters, Dieter Schrenk, Rolaf van Leeuwen, Philippe Verger.
ACKNOWLEDGEMENT
The Scientific Panel on Contaminants in the Food Chain wishes to thank George Bories,
Bruce Cottrill, Wolfgang Dekant, Johanna Fink-Gremmels, Jürgen Gropp, Karl Honikel,
Gerard Keck, Martha Lopez Alonso and Anne-Kathrine Lundebye Haldorsen for the
contributions to the draft opinion.
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