FLUORIDES

a From Li et al. (2001).

In a meta-analysis (Jones et al., 1999) of ecological, cross-sectional and cohort studies on water fluoridation and bone fractures published in 1966–1997, water fluoridation was not observed to have an effect on fracture incidence (RR = 1.02, 95% CI = 0.96–1.09). Out of 26 studies (published in English), 18 contained information that could be used in the meta-analysis and were included. The meta-analysis correctly assigned a qualitative score to the different studies (by which the studies were weighted) and considered sources of bias such as publication bias. Although overall no relationship between fluoridation and fracture risk was observed, there was considerable heterogeneity between the studies. Four of the studies also reported on the relationship between water fluoridation and bone mass. A significant increase in lumbar spine bone mass was observed; for femoral neck, the change was positive, but statistically not significant, and for distal radius, it was negative and statistically not significant.

8.1.3.4 Reproductive effects

In case–control studies, no evidence of an association between the consumption of fluoridated drinking-water by mothers and increased risk of spontaneous abortion (Aschengrau et al., 1989), late adverse pregnancy outcome (Aschengrau et al., 1993) or congenital cardiac disease in children (Zierler et al., 1988) was identified. These findings confirm previous observations of no apparent relationship between the rates of Down syndrome or congenital malformation and the consumption of fluoridated drinking-water (see Berry, 1962; Needleman et al., 1974; Erickson et al., 1976; Berglund et al., 1980; Erickson, 1980; all cited previously in WHO, 1984).

Freni (1994) reported evidence suggesting that exposure to fluoride in drinking-water may be associated with reduced fertility rates, based upon the results of an ecological study that evaluated the "total fertility rate" (i.e., total age-specific births per 1000 women) between 1970 and 1988 for white women, 10–49 years of age, residing in 30 regions in nine US states. However, this study was based upon population means, rather than individual data.

8.1.3.5 Respiratory effects

Ernst et al. (1986) examined respiratory function in a group of male and female adolescents with "high" or "low" exposure to the emissions from an aluminium plant located near Cornwall, Ontario, Canada, and reported evidence of respiratory abnormalities (i.e., a 49% increase [P = 0.05] in the ratio of the closing volume/vital capacity) in males, but not females, in the "high" exposure group, compared with those with "low" exposure. Individuals were considered to have "high" and "low" exposure if they resided more than 60% of their lives within approximately 4 and 17 km of the plant, respectively.

Lung X-ray findings were reported in 45 cases with skeletal fluorosis in an area of China contaminated by coal combustion. Chronic bronchitis with diffuse interstitial fibrosis and pulmonary emphysema were reported to occur (Liu, 1996).

Since the residents in both studies were likely exposed to other airborne contaminants and particulates, it is difficult to attribute the effects on respiratory function solely to fluorides per se.

8.1.3.6 Neurobehavioural effects

Two studies in two different regions of China have considered the potential effects of fluoride from drinking-water on children’s intelligence.

The first study (Li et al., 1995) was conducted on 907 children (ages 8–13) of the Guizhou province. Intelligence was measured by the China Rui Wen’s Scaler for Rural Areas. Children lived in four areas with different degrees of fluorosis prevalence (urinary fluoride ranging from 1.02 to 2.69 mg/litre). The average IQ was 89.9 in the non-fluorosis area and 80.3 in the high prevalence area. The trend among the four areas was statistically significant (P < 0.01).

The second study was carried out in Shanxi (Zhao et al., 1996) and involved 160 children (ages 7–14) randomly selected from each of two villages, one with a high level of fluoride contamination of the water (4.12 mg/litre, with 86% of the population having signs of dental fluorosis), and one with low contamination (0.91 mg/litre and 14% dental fluorosis). The "official intelligence quotient (IQ)" was measured. The average IQ in the first village was 97.69, and in the second it was 105.21 (P < 0.01). (The much higher IQ in comparison with the Li et al. (1995) study is noteworthy, but it is probably justified by the use of a different scale [Zhao et al., 1996].)

These two studies deserve similar comments:

• There is no reference to the reliability of IQ measurement in the context of rural China.
• There is no evidence that the measurements were blind; in fact, they were probably not, being conducted in different villages.
• There is no information on the training of the professional figures who performed the tests.
• In the second study, an attempt was made to adjust for confounding by only the educational level of the parents, and the difference between differently contaminated areas persisted.

The significance of these studies remains uncertain, but in a study of 197 children between the ages of 7 and 11 years in which childhood behavioural problems were assessed in relation to different levels of dental fluorosis, there was no association between behavioural problems and dental fluorosis (Morgan et al., 1998).

8.1.3.7 Genotoxic effects

Based on an analysis of the frequency of sister chromatid exchanges in peripheral blood lymphocytes obtained from groups of approximately 100 male and female Chinese adults consuming drinking-water containing from 0.11 to 5.03 mg fluoride/litre, Li et al. (1995) concluded that fluoride was not genotoxic at these levels of exposure. The average estimated daily intake of fluoride, based upon levels in food, water and average body weight, ranged from about 20 to 280 µg/kg body weight per day. The plasma fluoride level in the 5.03 mg/litre area was 5.56 µmol/litre.

Although Jackson et al. (1997) observed a slight (7–15%) although statistically significant (P < 0.001) increase in the frequency of sister chromatid exchange in peripheral blood lymphocytes collected from individuals in the USA (n = 68, males and females) residing in an area served with drinking-water containing 4.0 mg fluoride/litre (compared with that from individuals in other areas served with water containing 0.2 and 1.0 mg fluoride/litre [n = 64 and 59, respectively]), a subsequent comparison among individuals residing in the high-fluoride area having consumed either city water (4 mg/litre; n = 30) or well-water (<0.3 mg/litre; n = 28) revealed no significant difference in the frequency of sister chromatid exchange in blood lymphocytes (Jackson et al., 1997).

In a report with scanty details on the selection of persons to be studied, an increased peripheral lymphocyte micronucleus and sister chromatid exchange frequency was observed among fluorosis patients (n = 53), compared with healthy referents (n = 20) from a fluorosis-endemic area and non-fluoride exposed referents (n = 30) in Inner Mongolia, China (Wu & Wu, 1995). In another study with limited reporting, an increased sister chromatid exchange frequency was reported among residents of a fluorosis-endemic area in North Gujarat, India (n = 100), in comparison with referents from a non-endemic area in Ahmedabad (n = 20) (Sheth et al., 1994). In a further similar study, sister chromatid exchange frequencies were elevated among residents of one out of three fluorosis-endemic villages, and chromosomal aberrations were elevated in all three villages, compared with referents from a nearby township in south Gujarat, India (Joseph & Gadhia, 2000). In all these studies, the interpretation is complicated by the limited details provided on subject selection and by possible confounding variables.

However, no effect on chromosomal aberrations or micronuclei in lymphocytes was observed in a randomized double-blind study on seven non-smoking female osteoporosis patients treated with sodium fluoride or sodium monofluorophosphate (average dose 29 mg fluoride/day) for an average of 29 months, in comparison with seven matched non-treated controls (van Asten et al., 1998).

8.1.3.8 Dental effects²

It has been recognized for over five decades that fluoride may have both beneficial and potentially harmful effects on dental health. While the prevalence of dental caries is inversely related to a range of concentrations of fluoride in drinking-water consumed, the prevalence of dental fluorosis has been shown to be positively related to fluoride intake from many sources (Fejerskov et al., 1988, 1996). Public health programmes seeking to maximize the beneficial effects of fluoride on dental health through the introduction of fluoridated drinking-water have, at the same time, strived to minimize its adverse fluorotic effects on teeth. Based upon the studies conducted by Dean and colleagues five decades ago, the "optimum" level of fluoride in drinking-water, associated with the maximum level of dental caries protection and minimum level of dental fluorosis, was considered to be approximately 1 mg/litre. The effects of fluoride on dental health were examined by a WHO Expert Committee (WHO, 1994).

1) Dental caries

Since the first reports by Dean and colleagues published in the 1930s, oral fluoride is still considered an effective means of reducing dental caries. Historically, populations consuming fluoridated drinking-water had a much lower prevalence of dental caries than did those consuming non-fluoridated drinking-water. Over time, the difference in caries prevalence among those consuming fluoridated and non-fluoridated drinking-water has narrowed significantly. This apparent diminution in the cariostatic effectiveness of fluoridated drinking-water is likely attributable to a "diffusion" in which individuals consuming non-fluoridated drinking-water may consume significant amounts of beverages prepared in other locales with fluoridated drinking-water, as well as exposure to fluoride through the use of dental care products — mainly fluoridated toothpaste. It has been estimated that whereas approximately 210 million individuals throughout the world consume drinking-water containing levels of fluoride considered adequate for the prevention of dental caries, approximately 500 million people use fluoridated toothpastes (WHO, 1994).

Historically, it was believed that fluoride needed to become incorporated into the crystal lattice of enamel in order to effectively prevent the development of dental caries. Fluoride was considered to improve lattice stability and render the enamel less soluble to acid demineralization. Since the incorporation of fluoride into enamel, as partially fluoridated hydroxyapatite, was believed to be essential for its action, fluoride was thought best ingested. There is now, however, an increasing body of evidence to suggest that a substantial part of the cariostatic activity of fluoride is due to its effects on erupted teeth, and that the continual presence of fluoride in the saliva and in the fluid phase of dental plaque is critical to its mechanism of action. There is a growing consensus that through its interaction with the surface of enamel, fluoride in saliva and dental plaque inhibits the demineralization and promotes the remineralization taking place at the surface of the tooth.

Since the introduction of controlled fluoridated drinking-water, efforts to reduce dental caries have been extended to include the use of fluoridated toothpaste, mouth rinses and topically applied dental treatments (e.g., gels, varnishes, solutions), as well as through the use of fluoride supplements, fluoridated milk and fluoridated salt. The effectiveness and factors affecting the implementation of these various exposure regimens have been reviewed in detail by WHO (1994), and therefore only a brief summary is presented here.

The controlled fluoridation of community drinking-water to an optimum level is one of the most cost-effective means of delivering fluoride to large numbers of individuals. This method of fluoride delivery requires a suitable community-wide drinking-water delivery system along with a reasonable level of technological development (e.g., infrastructure, equipment and appropriately trained support personnel). Depending upon the annual average maximum daily air temperature, recommended levels of fluoride in drinking-water considered useful for the prevention of dental caries have ranged from 0.5 to 1.2 mg/litre.

Some countries have introduced controlled fluoridated salt as a means of reducing the prevalence of dental caries among their respective populations. Unlike controlled fluoridated drinking-water and toothpastes, there is little quantitative information on the cariostatic action of fluoridated salt, although it is considered to act in a manner like that of fluoridated drinking-water. The optimum concentration of fluoride in salt needed to reduce the incidence of dental caries must take into account the level of salt intake and the concentration of fluoride in drinking-water in individual geographical areas; however, 200 mg fluoride/kg salt has been suggested to be a minimum value (WHO, 1994).

Formerly, the administration of fluoridated milk to children was considered to be a suitable means of increasing their intake of fluoride; however, little quantitative information is available on the efficacy of this delivery system in the prevention of dental caries. To be effective as a means of delivering fluoride to children, implementation of a fluoridated milk programme requires close cooperation with the dairy industry as well as a widespread system of distribution.

It has been estimated that, worldwide, almost twice as many people are exposed to fluoride for the prevention of dental caries through the use of toothpastes as from the consumption of controlled fluoridated drinking-water. In many countries, fluoridated toothpastes, which usually contain approximately 1000 mg fluoride/kg, represent more than 95% of total dentifrice sold. The use of these products is considered to be one of the major factors responsible for the gradual decline in the prevalence of dental caries in most industrialized countries. In areas where the prevention of dental caries through the widespread use of fluoridated drinking-water, salt or milk may not be feasible, the use of fluoridated toothpastes remains an effective means of improving dental health.

Fluoride supplements, in the form of tablets, liquid drops or lozenges, are intended to provide a systemic source of fluoride when fluoridated drinking-water is not available. Problems associated with the widespread use of such supplements include poor compliance among socially and economically disadvantaged groups and the potentially inappropriate use of these products by those already consuming drinking-water containing optimal amounts of fluoride. Moreover, the results of studies suggest that fluoride is most effective when continually present at low levels in saliva and plaque fluid. In a number of jurisdictions, the recommended daily dosage of fluoride supplements is linked to the level of fluoride in the drinking-water as well as the age of the child. Although fluoride supplements may be appropriate for use in certain areas where the prevalence of dental caries is high, available data on the efficacy of this fluoride delivery system in preventing dental caries are equivocal, and there appears to be a growing consensus that fluoride supplements have a limited public health role in improving dental health.

The use of fluoridated mouth rinses has achieved a significant level of popularity among publicly based health care programmes, particularly those involving school-aged children. The levels of fluoride in these mouth rinses (0.05 or 0.2%) are related to whether they are recommended for daily or weekly use. The efficacy of fluoridated mouth rinses in the prevention of dental caries is related to the frequency of use, the level of compliance and exposure to other sources of fluoride, most notably in drinking-water. The use of fluoridated mouth rinses may be recommended for individuals with an elevated risk of dental caries, although the mouth rinses may not be appropriate for use by children younger than 6 years of age, due to their propensity to swallow significant amounts of such material, thereby increasing their risk of developing dental fluorosis.

Solutions, gels or varnishes usually applied infrequently over the course of a year by dental care professionals may be most efficacious in individuals with an elevated risk of dental caries. Owing to the level of fluoride in these materials (e.g., up to 22 300 mg/kg), health care professionals must follow protocols that reduce inadvertent ingestion of significant amounts of these products by younger children, which could cause acute toxic effects.

2) Dental fluorosis

Since the publication of the WHO (1994) assessment on the quantitative relationship between dental fluorosis and fluoride intake, a large number of further studies have been published on the matter. A recent meta-analysis (McDonagh et al., 2000) of such studies is presented in Figures 2 and 3.

Dental fluorosis is a condition that results from the intake of excess levels of fluoride during the period of tooth development, usually from birth to approximately 6–8 years of age. It has been termed a hypoplasia or hypomineralization of dental enamel and dentine and is associated with the excessive incorporation of fluoride into these structures. The severity of this condition, generally characterized as ranging from very mild to severe, is related to the extent of fluoride exposure during the period of tooth development. Mild dental fluorosis is usually typified by the appearance of small white areas in the enamel; individuals with severe dental fluorosis have teeth that are stained and pitted ("mottled") in appearance. In human fluorotic teeth, the most prominent feature is a hypomineralization of the enamel. In contrast to many animal species, fluoride-induced enamel hypoplasia (indicating severe fluoride disturbance of enamel matrix production) seems to be rare in fluorosed human enamel. The staining and pitting of fluorosed dental enamel are both posteruptive phenomena (i.e., acquired after tooth eruption and occur as a consequence of the enamel hypomineralization). The incorporation of excessive amounts of fluoride into enamel is believed to interfere with its normal maturation, as a result of alterations in the rheologic structure of the enamel matrix and/or effects on cellular metabolic processes associated with normal enamel development (WHO, 1994; Aoba, 1997; Whitford, 1997). Experimental animal studies suggest that this hypomineralization results from fluoride disturbance of the process of enamel maturation (Richards et al., 1986).

Unlike skeletal fluorosis, which is considered to be a marker of long-term exposure to fluoride (due to the ongoing process of bone remodelling), dental fluorosis is considered to be indicative of the level of exposure to fluoride only during the period of enamel formation. Exposure to excessive levels of fluoride after tooth development appears to have little influence on the extent of fluorosis. Re-evaluation of classical fluorosis data (Dean et al., 1941, 1942; Richards et al., 1967; Butler et al., 1985) has shown that even at low fluoride intake from water, a certain level of dental fluorosis will be found (Fejerskov et al., 1996). A dose–response relationship was also demonstrated. The data demonstrated an increase of the fluorosis community index by 0.2 for every dose increase of 0.01 mg fluoride/kg body weight.

Over the past 30–40 years, there has been an increase in the prevalence of dental fluorosis among populations consuming either fluoridated or non-fluoridated drinking-water. Although greater numbers of individuals are now being served by fluoridated drinking-water, for the most part this increased prevalence in dental fluorosis has been attributed to the widespread intake of fluoride from sources other than drinking-water, especially in areas served by non-fluoridated drinking-water. Unlike the situation in the 1930s, when the primary sources of exposure to fluoride were limited to drinking-water and foodstuffs, now there is potential exposure to fluoride from a variety of additional sources, such as toothpastes, mouth rinses, fluoride supplements and topically applied dental gels, solutions and varnishes. Exposure to fluoride may also result from the ingestion of fluoridated salt or fluoridated milk.

The prevalence of dental fluorosis is also elevated in certain areas of the world where the intake of fluoride may be inordinately high, due in large part to the elevated fluoride content of the surrounding geological environment. In China, large numbers of people exhibit dental fluorosis (Liu, 1995). In addition to the actual consumption of often large amounts of drinking-water containing naturally occurring elevated levels of fluoride, the indoor burning of coal rich in fluoride, the preparation of foodstuffs in water containing increased fluoride levels and the consumption of specific foodstuffs naturally rich in fluoride, such as tea, are believed to contribute to the elevated intake of fluoride, with the resultant development of dental fluorosis (Chen et al., 1993, 1996; Grimaldo et al., 1995; Han et al., 1995; Liu, 1995; Xu et al., 1995).

8.1.4 Interactions with other substances

In a cross-over study, six volunteers were exposed to drinking-water with high fluoride (2.3 mg/litre), high arsenic (0.47 mg/litre) or high fluoride and high arsenic (4.05 mg fluoride/litre and 0.58 mg arsenic/litre). All volunteers followed one of these three regimes for 5 days, drank distilled water for 3 days and then were exposed to another regime. Exposure to this level of arsenic did not influence the rate of urinary excretion of fluoride of the volunteers (Wu et al., 1998).

In the area of Kuitun, Xinjiang, in China, it was found that among 619 wells investigated, 102 wells contained high levels of arsenic and fluoride. It was found that arsenic dermatosis manifested when the water arsenic level was at or above 0.12 mg/litre, with no association with the fluoride level in the water; dental fluorosis developed when the water fluoride level was at or above 3 mg/litre, regardless of the water arsenic level (Wang et al., 1997).

The health of workers occupationally exposed to fluorides, particularly those employed in the aluminium smelting industry, has been examined in a variety of epidemiological studies. Workers in this industrial setting are also exposed to a number of other substances, such as ammonia, carbon monoxide, sulfur dioxide, distillation products of tar, pitch and coal, aluminium oxide (alumina), cyanides, dust and metals such as nickel, chromium and vanadium (IARC, 1984; Sr yseth & Kongerud, 1992).

8.2.1 Case reports

Severe tissue damage, respiratory effects, cardiac arrest and deaths have often been noted in case reports of workers exposed accidentally to hydrofluoric acid through dermal contact (Mayer & Gross, 1985; Chan et al., 1987; Mullet et al., 1987; Greco et al., 1988; Upfal & Doyle, 1990; Gubbay & Fitzpatrick, 1997). Following the exposure of two male workers to breakdown products (sulfur tetrafluoride, thionyl fluoride, hydrogen fluoride) of sulfur hexafluoride, the men became semicomatose and developed cyanosis and pulmonary oedema (Pilling & Jones, 1988). Eye and throat irritation, chest tightness, nausea, vomiting, headache and fatigue have also been observed in electrical workers exposed to the breakdown products of sulfur hexafluoride (Kraut & Lilis, 1990).

8.2.2 Epidemiological studies

8.2.2.1 Cancer

In a number of analytical epidemiological studies, an increased incidence of lung and bladder cancer and increased mortality due to cancer of the lung, liver, bladder, stomach, oesophagus, pancreas, lymphatic–haematopoietic system, prostate or brain (central nervous system) have been observed in fluoride-exposed workers employed in the aluminium smelting industry (Giovanazzi & D’Andrea, 1981; Andersen et al., 1982; Rockette & Arena, 1983; Theriault et al., 1984; Gibbs, 1985; Armstrong et al., 1986, 1994; Mur et al., 1987; Siemiatycki et al., 1991; Spinelli et al., 1991; Rr nneberg & Andersen, 1995; Romundstad et al., 2000). However, in general, there has been no consistent pattern, and bone cancer was not usually assessed. Although increases in lung cancer were observed in several studies, it is not possible to attribute these increases to fluoride exposure per se due to concomitant exposure to other substances. Indeed, in some of these epidemiological studies, the increased morbidity or mortality due to cancer was attributed to the workers’ exposure to aromatic hydrocarbons.

In a cohort study of cryolite mill workers in Denmark, Grandjean et al. (1992) indicated that a portion of the increase in the incidence of bladder cancer (17 observed versus 9.2 expected cases) among the workers may have been attributable to occupational exposure to fluoride; however, the workers were also exposed to other substances, such as quartz, siderite and small amounts of metal sulfides (Grandjean et al., 1985).

8.2.2.2 Skeletal effects

Generally, most data on the occurrence of skeletal fluorosis in occupationally exposed workers have come from older studies. Based upon a review of older studies involving aluminium smelter workers in which the number of workers examined was usually small and quantitative data on exposure to airborne fluoride were not always provided, Hodge & Smith (1977) concluded that the "incidence of detectable osteosclerosis was often high" when the levels of fluoride in the air exceeded 2.5 mg/m³ and/or levels of fluoride in the urine of these workers were greater than 9 mg/litre; at airborne concentrations below 2.5 mg/m³ (and levels in the urine of below 5 mg/litre), " years of exposure in potrooms did not produce osteosclerosis." The development of skeletal fluorosis in cryolite workers in Copenhagen was attributed to the intake (from occupational exposure) of between 20 and 80 mg fluoride/day (Grandjean, 1982). Chan-Yeung et al. (1983a) reported finding no definitive signs of skeletal fluorosis in potroom workers employed in an aluminium smelter and exposed to 0.48 mg fluoride/m³.

In a more recent study in which skeletal changes in 2258 workers employed at an aluminium plant in Poland were assessed (clinically and radiologically), the occurrence of fluorosis (multiple joint pain, initial ossification, osteosclerosis) was reported to increase with increasing duration of employment (Czerwinski et al., 1988). The occurrence of these skeletal changes was related not to quantitative data on the concentration of airborne fluoride per se, but to a qualitative "exposure index," calculated on the basis of the years of employment and the extent to which the concentration of fluoride in the air in different areas of the plant exceeded the highest permitted level of 0.5 mg hydrogen fluoride/m³. The prevalence of skeletal fluorosis reportedly increased with this "index of exposure-years," the more severe effects being observed in older workers.

8.2.2.3 Respiratory effects

Since publication of the first EHC on fluorides (WHO, 1984), additional studies have reported adverse effects on the respiratory system (e.g., reduced lung capacity, irritation of the respiratory tract, asthma, cough, bronchitis, shortness of breath and/or emphysema) in workers, predominantly those employed in aluminium smelters, occupationally exposed to airborne fluorides (Chan-Yeung et al., 1983b; Larsson et al., 1989; Sr yseth & Kongerud, 1992; Rr nneberg, 1995; Sr yseth et al., 1995; Radon et al., 1999; Romundstad et al., 2000). Owing to the exposure of these workers to other airborne contaminants and particulates, it may not be possible to attribute the effects on respiratory function solely to fluoride per se.

8.2.2.4 Haematological, hepatic or renal effects

No evidence of haematopoietic, hepatic or renal dysfunction was observed in potroom workers employed at an aluminium smelter and exposed to 0.48 mg fluoride/m³ (Chan-Yeung et al., 1983a).

8.2.2.5 Genotoxic effects

The mean frequency of sister chromatid exchange in peripheral blood lymphocytes obtained from 40 Chinese fertilizer production workers was significantly (P < 0.01) increased by approximately 50%, compared with that in a similarly sized group of controls matched for age, sex and smoking habits (Meng et al., 1995). During the period of analysis, workers were exposed to levels of fluoride (mostly hydrofluoric acid and silicon tetrafluoride) ranging from 0.5 to 0.8 mg/m³, as well as to phosphate fog, ammonia and sulfur dioxide. Among the workers, the average frequency of sister chromatid exchange was approximately 27% higher (P < 0.01) in smokers than in non-smokers. Information on the total intake of fluoride was not presented.

In a further study, an increased frequency of both chromosomal aberrations and micronuclei in circulating blood lymphocytes was also observed among the fertilizer plant workers (n = 40), in comparison with 40 controls working and studying in Shanxi University, situated in the same city as the factory, matched for sex, age and smoking habits (Meng & Zhang, 1997); the microscopic analysis was performed on coded slides.

9.1.1 Microorganisms

9.1.1.1 Water

Fluoride (100 mg/litre) did not affect growth or the chemical oxygen demand degrading capacity of activated sludge when added either as a pulse or continuously. Sludge settleability did not change following a pulse addition of fluoride; however, continuous addition of fluoride resulted in poor settling, indicated by 100–200% increases in settled sludge volume. The authors concluded that the poor settling was probably due to enhanced growth of filamentous organisms (Singh & Kar, 1989). Beg (1982) found the EC₅₀ for inhibition of bacterial nitrification to be 1218 mg fluoride/litre.

McNulty & Lords (1960) exposed the green alga Chlorella pyrenoidosa to hydrogen fluoride in 110-min tests. Significant increases in oxygen consumption and total phosphorylated nucleotides were observed at fluoride concentrations of 2, 20 and 200 mg/litre (0.105, 1.05 and 10.5 mmol/litre). The authors concluded that, based on measurements of gas exchange at several pH values, the stimulation was probably due to the undissociated hydrogen fluoride in the medium. Smith & Woodson (1965) found that fluoride concentrations greater than 19 mg/litre (1 mmol/litre) caused growth inhibition in the same species. However, Nichol et al. (1987) found no effect of fluoride at concentrations ranging from 5 to 150 mg/litre at a variety of pH levels (5.9–8.0).

LeBlanc (1984) calculated 96-h EC₅₀s, based on growth, to be 123 and 81 mg fluoride/litre for the freshwater green alga Selenastrum capricornutum and the marine alga Skeletonema costatum, respectively.

Rai et al. (1998) calculated 15-day LC₅₀s for the alga Chlorella vulgaris to be 380 and 266 mg fluoride/litre (14 and 20 mmol/litre) at pH 6.8 and pH 6.0, respectively; at pH 4.5, the 3-day LC₅₀ was 133 mg fluoride/litre (7 mmol/litre). Non-inhibitory concentrations were 66.5, 28.5 and 9.5 mg fluoride/litre (3.5, 1.5 and 0.5 mmol/litre) at pH 6.8, 6.0 and 4.5, respectively.

Antia & Klut (1981) exposed five euryhaline phytoplankton species to fluoride concentrations ranging from 50 to 200 mg/litre (14–15% salinity). The growth rate and maximum growth density of the chlorophyte Duniella tertiolecta and the diatom Thalassiosira weissflogii were unaffected at all exposure concentrations. The growth of the diatom Chaetoceros gracilis appeared to be stimulated by the presence of fluoride. The haptophyte Pavlova lutheri was 35–50% inhibited at fluoride concentrations of >150 mg/litre. The dinoflagellate Amphidinium carteri was 20–25% inhibited at 150 mg/litre and more than 90% inhibited at 200 mg/litre. Hekman et al. (1984) studied the effect of dissolved fluoride concentrations of up to 150 mg/litre on six phytoplankton species. Growth and photosynthetic oxygen evolution were unaffected at fluoride concentrations up to 50 mg/litre in all algae except Synechococcus leopoliensis. S. leopoliensis growth ceased for a period followed by growth at a reduced rate at 50 mg fluoride/litre; the threshold for growth effects and inhibition of photosynthesis in this species was 25 mg/litre. Nichol et al. (1987) found that fluoride concentrations of >100 mg/litre (5.2 mmol/litre) caused a growth lag in S. leopoliensis at neutral pH. The effect of fluoride on the growth lag was pH-dependent, with the growth lag increasing with decreasing pH. At pH 5.9, there was a measurable growth lag at 5 mg fluoride/litre. Fluoride resistance was induced by prior growth in the medium at non-inhibitory levels of sodium fluoride. It was suggested that fluoride-resistant cells retain less fluoride (taken up as undissociated hydrogen fluoride) by developing increased permeability to the fluoride anion. No effect on growth of 12 species of marine phytoplankton was observed at fluoride concentrations ranging from 10 to 50 mg/litre. At the highest concentration (100 mg/litre), no effect on growth was observed in 9 of the 12 species tested; however, 25–30% inhibition of growth was found in a diatom (Nitzschia angularis affinis), a dinoflagellate (A. carteri) and a haptophyte (P. lutheri) (Oliveira et al., 1978).

Joy & Balakrishnan (1990) studied the effect of fluoride on the diatoms Nitzschia palea (freshwater) and Amphora coffeaeformis (brackish water) during 96-h exposures. Significant enhancement of growth, compared with controls (no added fluoride), was observed at fluoride concentrations ranging from 30 to 110 mg/litre with N. palea and at a concentration of 70 mg/litre in A. coffeaeformis. A. coffeaeformis did not show significant growth differences from controls at fluoride concentrations of 90 and 110 mg/litre.

The marine dinoflagellate Amphidinium carteri was unable to grow in nutrient-enriched seawater containing 200 mg fluoride/litre. However, the organism could be adapted to grow under these conditions after repeatedly being cultured with stepwise increases in subinhibitory fluoride concentrations. Electron microscopic investigation of the adapted dinoflagellate cells revealed abnormal ultrastructural features in the chloroplast, mitochondria and nucleus. Fluoride adaptation seemed to confer a prolamellar-like configuration on the thylakoids (extensive membrane system containing the components of photosynthesis) in the centre of the pyrenoid (protein structure associated with formation and storage of starch); in organisms that had not been adapted, fluoride caused extreme disorganization of thylakoid formation (Klut et al., 1981).

9.1.1.2 Soil

Van Wensem & Adema (1991) studied the effect of potassium fluoride (32.3–3230 mg fluoride/kg [1.7–170 µmol fluoride/g]) on Carolina poplar (Populus canadensis) litter. After 4 weeks, total respiration was increased and the phosphate concentration was decreased at the highest fluoride concentration. Ammonium, nitrate and phosphate concentrations were decreased by fluoride after 9 weeks. No-observed-effect concentrations (NOECs) for the effect of fluoride on net mineralization of ammonium, nitrate and phosphate were 323, 100.7 and 1007 mg/kg dry weight (17, 5.3 and 53 µmol/g), respectively. The authors concluded that fluoride seems to be toxic for microbial processes at concentrations found in moderately fluoride polluted areas.

9.1.2 Aquatic organisms

9.1.2.1 Plants

Wang (1986) exposed the common duckweed (Lemna minor) to fluoride and calculated an EC₅₀, based on a reduction in frond growth, to be >60 mg fluoride/litre.

9.1.2.2 Invertebrates

The acute toxicity of fluoride to aquatic invertebrates is summarized in Table 15. Forty-eight-hour LC₅₀s/EC₅₀s range from 53 to 304 mg/litre.

Hemens & Warwick (1972) found that fluoride concentrations of up to 100 mg/litre caused no mortality in prawns exposed for 96 h. However, the brown mussel (Perna perna) showed up to 30% mortality at an initial fluoride concentration of 7.2 mg/litre during a 5-day test (the background fluoride concentration was 1 mg/litre).

LeBlanc (1980) found a 48-h NOEC for Daphnia magna of 50 mg fluoride/litre, whereas Kühn et al. (1989) reported a no-effect concentration of 231 mg fluoride/litre (24 h). Camargo & La Point (1995) calculated "safe concentrations" (8760-h EC_0.01s) for the last-instar larvae of several net-spinning caddisfly species. "Safe concentrations" ranged from 0.39 mg fluoride/litre (Hydropsyche pellucidula) to 1.18 (Hydropsyche lobata) and 1.79 mg fluoride/litre (Chimarra marginata). Further "safe concentrations" were calculated for the caddisfly species Hydropsyche bronta, at 0.2 mg fluoride/litre, and H. occidentalis and Cheumatopsyche pettiti, at 0.7 mg fluoride/litre (Camargo, 1996b).

Pankhurst et al. (1980) performed toxicity tests on the blue mussel (Mytilus edulis) (160 h), the anemone Anthopleura aureoradiata (144 h) and the red krill (Munida gregaria) (259 h) using seawater dilutions of both fluoride-loaded effluent and sodium fluoride. Effluent solutions of 50 and 100 mg fluoride/litre produced high mortality, whereas sodium fluoride at concentrations up to 100 mg fluoride/litre caused negligible mortality.

Nell & Livanos (1988) found that weight gains in Sydney rock oysters (Saccostrea commercialis) decreased linearly (P < 0.01) with increasing fluoride additions from 0 to 30 mg/litre, and there was a 20% growth depression at the highest fluoride concentration. The background level of fluoride in this study was 0.7 mg/litre. Fluoride concentrations of up to 11 mg/litre had no significant effect on growth of prawns (Penaeus indicus) over a 20-day exposure period (McClurg, 1984). Fluoride (5.88 mg/litre) had no effect on the survival of mud crabs (Tylodiplax blephariskios) or the survival and growth of penaeid shrimps (Penaeus indicus) during 68-day exposures when compared with controls (0.89 mg fluoride/litre). In a 113-day test, shrimps gained significantly more weight during exposure to fluoride (5.5 mg/litre) than did controls. The authors attributed this to variations in the food source within the tanks (Hemens et al., 1975).

The fingernail clam (Musculium transversum) appears to be one of the most sensitive freshwater species tested. Sparks et al. (1983) conducted an 8-week flow-through experiment in which statistically significant mortality (50%) was observed at a concentration of 2.8 mg fluoride/litre. The brine shrimp (Artemia salina) was the most sensitive marine species tested. In a 12-day static renewal test using brine shrimp larvae, statistically significant growth impairment (measured as body length increase relative to controls) occurred at 5.0 mg fluoride/litre (Pankhurst et al., 1980). In a flow-through 90-day life cycle test, the amphipods Grandidierella lutosa and G. lignorum showed maximum population increase at a mean fluoride concentration of 2.6 mg/litre (background seawater levels ranged from 1.3 to 1.7 mg fluoride/litre). Population performance was comparable to controls at 5 mg fluoride/litre. A maximum acceptable toxicant concentration (MATC) was set at between 5.0 and 6.2 mg fluoride/litre. However, female fecundity appeared to be the most sensitive parameter, and a mean MATC based on this parameter was 4.2 mg fluoride/litre (Connell & Airey, 1982).

In a 3-week exposure test, survival and reproduction of Daphnia magna were studied (Fieser et al., 1986). Impairment of reproduction was observed at fluoride concentrations greater than 26 mg/litre. A concentration of 35 mg fluoride/litre reduced the neonate production to 44% of controls. The average number of live young dropped by more than 98% at 49 mg fluoride/litre. However, no statistics were performed in the study. Dave (1984) calculated that the NOEC for growth in Daphnia magna after 7 and 21 days was between 3.7 and 7.4 mg fluoride/litre. Similarly, for parthenogenic reproduction, the 21-day NOEC was between 3.7 and 7.4 mg fluoride/litre. The "safe" concentration, equivalent to the geometric mean of the NOEC or MATC in hard water, was 4.4 mg fluoride/litre. Kühn et al. (1989) reported a 21-day NOEC of 14 mg fluoride/litre for Daphnia magna; the most sensitive parameter was reproduction rate.

9.1.2.3 Vertebrates

The acute toxicity of fluoride to fish is summarized in Table 16. Ninety-six-hour LC₅₀s for freshwater fish range from 51 mg fluoride/litre (rainbow trout, Oncorhynchus mykiss) to 460 mg fluoride/litre (threespine stickleback, Gasterosteus aculeatus). All of the acute toxicity tests (96 h) on marine fish gave results greater than 100 mg fluoride/litre.

Inorganic fluoride toxicity to freshwater fish appears to be negatively correlated with water hardness (due to the complexation of fluoride ions with calcium) and positively correlated with temperature (Angelovic et al., 1961; Pimentel & Bulkley, 1983; Smith et al., 1985). The 96-h LC₅₀ for rainbow trout exposed to sodium fluoride in soft water (17 mg calcium carbonate/litre) was 51 mg fluoride/litre. Increasing the water hardness to 49 mg calcium carbonate/litre doubled the LC₅₀ to 128 mg fluoride/litre; a further increase in water hardness to 182 mg calcium carbonate/litre led to an LC₅₀ of 140 mg fluoride/litre (Pimentel & Bulkley, 1983). Angelovic et al. (1961) found that increasing temperature significantly increased the toxicity of fluoride to rainbow trout at temperatures ranging from 7.2 to 23.9 °C.

Camargo & Tarazona (1991) exposed rainbow trout (O. mykiss) and brown trout (Salmo trutta) to fluoride in soft water (22 mg calcium carbonate/litre) during short-term toxicity tests. For rainbow trout, 120-, 144-, 168- and 192-h LC₅₀s were 92.4, 85.1, 73.4 and 64.1 mg fluoride/litre, respectively; for brown trout, they were 135.6, 118.5, 105.1 and 97.5 mg fluoride/litre, respectively. The addition of chloride ions (sodium chloride) decreases the toxicity of fluoride. LC₅₀s (120 h) for rainbow trout were 6 mg fluoride/litre in the absence of chloride ions and 22 mg fluoride/litre at a chloride ion concentration of 34 mg/litre (Neuhold & Sigler, 1962). LT₅₀ values for brown trout exposed to fluoride at a water hardness of 73 mg calcium carbonate/litre have been calculated. LT₅₀ values ranged from ~12 h at 60 mg fluoride/litre to ~80 h at 20 mg/litre; at concentrations of <15 mg/litre, LT₅₀ values were >240 h (Wright, 1977).

Neuhold & Sigler (1960) reported that 20-day LC₅₀s for rainbow trout (O. mykiss) (10–20 cm) ranged from 2.7 to 4.7 mg fluoride/litre in static renewal tests at 13 °C under soft-water conditions (<3 mg calcium carbonate/litre). The authors noted that there was no further mortality after 10 days. The symptoms of acute fluoride intoxication included lethargy, violent and erratic movement and death. The authors postulated that the variation in the response of fish to fluoride could be due to a chloride–fluoride excretion mechanism over the epithelial tissues (Sigler & Neuhold, 1972). Camargo (1996a) calculated "safe concentrations" (infinite hours LC_0.01s) for rainbow trout and brown trout at fluoride concentrations of 5.1 and 7.5 mg fluoride/litre, respectively.

Hemens et al. (1975) found that fluoride (5.9 or 5.5 mg/litre) had no effect on survival of mullet (Mugil cephalus) during 68- or 113-day exposures when compared with controls (0.9 mg fluoride/litre). Fluoride had no significant effect on the growth of larger mullet (50–55 mm); however, smaller mullet (16–18 mm) showed a significant decrease in growth during the 68-day test.

The eggs of the freshwater catla (Catla catla) were exposed to fluoride concentrations ranging from 1.9 to >16 mg/litre from both effluent and sodium fluoride dilutions. Hatching occurred after 6 h in both controls and those exposed to 1.9 mg fluoride/litre. At concentrations of >3.2 mg fluoride/litre for effluent dilutions and >3.6 mg fluoride/litre for sodium fluoride dilutions, hatching was delayed by 1–2 h. The authors stated that the low pH (4.1) of the effluent may have contributed to its toxicity. The weight of eggs exposed to fluoride decreased with increasing fluoride concentration and exposure time. Significant decreases in egg protein were observed at fluoride concentrations causing delayed hatching. The toxicity of fluoride to eggs was more related to the availability of fluoride ions than to total fluoride in the media (Pillai & Mane, 1984).

Kaplan et al. (1964) found little external evidence of toxicity in adult leopard frogs (Rana pipiens) exposed to fluoride concentrations ranging from 5 to 50 mg/litre for 30 days. Total red and white cell counts were reduced at all fluoride exposure concentrations; however, no statistical analysis was carried out. At fluoride concentrations ranging from 50 to 300 mg/litre, the survival time decreased with increasing exposure concentration. All frogs died within 30 days at both 250 and 300 mg fluoride/litre. Kuusisto & Telkkä (1961) exposed frog (Rana temporaria) larvae to sodium fluoride concentrations of 1, 2 and 10 mg/litre. All fluoride concentrations caused a delay in metamorphosis and reduced the activity of the thyroids revealed by histological examination. No statistical analysis of the results was carried out.

9.1.3 Terrestrial organisms

9.1.3.1 Plants

Fluoride toxicity to terrestrial plants has been studied extensively (Weinstein, 1977). Signs of inorganic fluoride phytotoxicity (fluorosis), such as chlorosis, necrosis and decreased growth rates, are most likely to occur in the young, expanding tissues of broadleaf plants and elongating needles of conifers (Pushnik & Miller, 1990). The induction of fluorosis has been clearly demonstrated in laboratory, greenhouse and controlled field plot experiments (Weinstein, 1977; Hill & Pack, 1983; Staniforth & Sidhu, 1984; Doley, 1986, 1989; McCune et al., 1991). Weinstein & Alscher-Herman (1982) reviewed the physiological responses of plants to fluoride. They concluded that calcium and magnesium play a central role in the response of plants to fluoride. A detoxification mechanism appears to consist of the sequestration and insolubilization of fluoride by reaction with calcium. The effects of atmospheric fluoride on a wide variety of terrestrial plant species have been extensively reviewed (VDI, 1989); the studies that follow have been chosen to reflect the lowest adverse effect levels cited in the literature.

A large number of the papers published on fluoride toxicity to plants concern greenhouse fumigation with hydrogen fluoride. Wolting (1975) observed leaf necrosis on freesia (Freesia sp.) cultivars during continuous fumigation at 0.5 µg fluoride/m³ for 5 months and during intermittent fumigation with 0.3 µg fluoride/m³ (6 h/day, 3–4 times/week) for 18 weeks. Leaf tip necrosis was identified in a variety of tulip (Tulipa sp.) cultivars exposed to fluoride for 6 h/day for 3 days at concentrations ranging from 0.15 to 0.67 µg fluoride/m³ (Wolting, 1978). Hitchcock et al. (1962) reported necrotic leaf tips in gladiolus (Gladiolus sp.) cultivars exposed to 0.17 µg fluoride/m³ for 9 days. In 40-day exposures of gladiolus cultivars to 0.76 µg/m³, Hill et al. (1959) found 46% necrosis and a significant increase in respiration (39%). Long-term greenhouse experiments (2–10 growing seasons) were conducted to determine the effects (necrosis, photosynthesis and growth) of hydrogen fluoride on 16 varieties of flower, fruit, vegetable and forage crops (Hill & Pack, 1983). Three identical greenhouses were used to represent a control (filtered ambient air; mean hydrogen fluoride level was 0.03 µg fluoride/m³), a hydrogen fluoride treatment (filtered ambient air; mean hydrogen fluoride levels ranged from 0.3 to 1.9 µg fluoride/m³, depending on the exposure duration for gladioli) and an industrial treatment (unfiltered ambient air; located 1.6 km downwind of a steel plant; mean hydrogen fluoride levels ranged from 0.2 to 1.9 µg fluoride/m³). The most sensitive species tested (based on measurement of necrosis over two growing seasons, following 117 days of hydrogen fluoride exposure) was the snow princess gladiolus (Gladiolus grandiflorus). The lowest-observed-effect level (LOEL) for leaf necrosis (65% of leaves) in this plant was 0.35 µg fluoride/m³. The extent of necrosis was positively correlated with increased hydrogen fluoride concentration and increased exposure duration. Less severe necrosis (2%) occurred in the industrial greenhouse chamber. The results from other test species included reduced growth or necrosis at hydrogen fluoride exposure concentrations of 0.44, 0.54 and 21.3 µg fluoride/m³ for apples (Malis domestica borkh), pole beans (Phaseolus vulgaris) and forage (red clover, Trifolium pratense, and alfalfa, Medicago sativa), respectively.

Murray (1984a) exposed grapevines (Vitis vinifera) to hydrogen fluoride concentrations of 0.07 (control), 0.17 and 0.27 µg fluoride/m³ for 189 days. Foliar necrosis was first observed on vines exposed to 0.17 and 0.27 µg fluoride/m³ after 99 and 83 days, respectively. Fluoride had no significant effect on bunch weight, number of bunches, grape yield, grape water or potential alcohol content, leaf chlorophyll b or leaf protein concentration. Both chlorophyll a and total chlorophyll were significantly reduced by fluoride exposure. Doley (1986) fumigated three varieties of grapevine with hydrogen fluoride for four successive growing seasons (the duration of exposure varied from 54 to 159 days for each season). Leaf size during the first growth of the season was not affected by fluoride concentrations of up to 1.5 µg/m³. However, leaf size was significantly reduced during the middle and latter portion of the fourth season of fumigation in two of the varieties at 0.64 µg fluoride/m³.

Suture red spot is a serious physiological disorder of the peach (Prunus persica) fruit. In open-top field chambers, hydrogen fluoride levels causing an induction of this disorder were 0.3 µg fluoride/m³ in continuous exposures of 80 days and 1.0 µg fluoride/m³ in intermittent exposures for three 6-h periods each week for 9 weeks (MacLean et al., 1984b).

Wheat (Triticum aestivum) and barley (Hordeum vulgare) exposed to hydrogen fluoride (0.38 µg/m³) for 90 days showed no effect of treatment on yield. There was, however, a significant increase in the grain protein concentration of fluoride-exposed barley plants (Murray & Wilson, 1988c). MacLean & Schneider (1981) found a significant reduction (20%) in the mean dry mass of wheat plants (T. aestivum) exposed to 0.9 µg fluoride/m³ for 4 days. MacLean et al. (1984a) exposed wheat (T. aestivum) and two sorghum (Sorghum sp.) hybrids to hydrogen fluoride at concentrations ranging from 1.6 to 3.3 µg/m³ for three successive 3-day periods. Anthesis (the maturing of the stamens) was the most sensitive stage, and this occurred during the first exposure period in wheat and the third exposure in sorghum. Hydrogen fluoride-induced foliar damage did not occur in wheat; however, both sorghum hybrids developed foliar damage in proportion to the exposure concentration. Pack (1971) found no effect of hydrogen fluoride on the progeny of bean plants (no species stated) grown at 0.58 µg fluoride/m³. However, the primary leaves of some F₁ progeny of plants grown at >2.1 µg fluoride/m³ were severely stunted and distorted. MacLean et al. (1977) observed a significant reduction (25%) in the fresh mass of pods from bean plants (Phaseolus vulgaris) exposed to 0.6 µg fluoride/m³ for 43 days (emergence to harvest) in open-top field chambers. There was no effect of hydrogen fluoride exposure (0.6 µg fluoride/m³) on growth or fruiting in tomato (Lycopersicon esculentum) plants.

Madkour & Weinstein (1988) found that hydrogen fluoride at nominal concentrations of 1, 3 and 5 µg fluoride/m³ inhibited the active loading of [¹⁴C]sucrose into the minor veins of soybean (Glycine max) leaf discs during 8- to 11-day exposures. Similar results were obtained for both controlled-environment and field conditions.

Several species of eucalypt (Eucalyptus spp.) have shown sensitivity to fluoride. Murray & Wilson (1988b) exposed E. tereticornis to hydrogen fluoride (0.38 µg fluoride/m³) for 90 days in open-top chambers. Fluoride significantly reduced leaf surface area and weight in mature and immature leaves. The same significant effects on immature leaves were noted for marri (E. calophylla), tuart (E. gomphocephala) and jarrah (E. marginata) at 0.39 µg fluoride/m³ for 120 days. However, in mature leaves, leaf surface area and weight were reduced in tuart, and surface area was reduced in marri. In jarrah, these two end-points were unaffected (Murray & Wilson, 1988a).

Coniferous trees have also been identified as sensitive plant species. In field exposure chambers, significant dose–response relationships were observed between hydrogen fluoride exposure and development of needle necrosis in 2-year-old black spruce (Picea mariana) and 3-year-old white spruce (P. glauca) (McCune et al., 1991). Four test chambers, one of which served as a control, were used for different hydrogen fluoride exposure regimens for each coniferous species. Measurements of tissue necrosis were recorded 10 days following hydrogen fluoride exposure for 78 h with black spruce and 20 days following hydrogen fluoride exposure for 50 h with white spruce. Lowest-observed-effect concentrations (LOECs) for necrosis were 4.4 and 13.2 µg fluoride/m³ for black spruce and white spruce, respectively.

Airborne fluoride can also affect plant disease development, although the type and magnitude of the effects are dependent on the specific plant–pathogen combination (Laurence, 1983). Van Bruggen & Reynolds (1988) found that exposure of soybean (Glycine max) plants to hydrogen fluoride (2 µg fluoride/m³) in a controlled chamber led to significantly larger hypocotyl lesions after inoculation with either Rhizoctonia solani or Phytophthora megasperma. Plants were exposed to hydrogen fluoride for 1 week before and after the infestation. However, Laurence & Reynolds (1984) found no significant effect of hydrogen fluoride (1 or 3 µg fluoride/m³ for 5 days) on lesion characteristics of the bacterium Xanthomonas campestris on the leaves of red kidney bean (Phaseolus vulgaris) plants. Similar findings were reported by Reynolds & Laurence (1990) during both continuous (1, 3 or 5 µg fluoride/m³ for 15, 5 or 3 days, respectively) and intermittent (3 or 5 µg fluoride/m³ for 15 days) exposures.

Several studies on fluoride have been carried out in culture media. Belandria et al. (1989) studied the effect of sodium fluoride on the germination of lichen ascospores. They found that 20% of the Xanthoria parietina spores were able to germinate in the presence of 19 mg fluoride/litre (1000 µmol/litre), and similar results were obtained for Physconia distorta and Peltigera canina. P. distorta was found to be 37% inhibited at a concentration of 0.95 mg fluoride/litre (50 µmol/litre). The most resistant species was Lecanora conizaeoides, which was only weakly inhibited (44% inhibition) at 38 mg fluoride/litre (2000 µmol/litre). Ballantyne (1984) found that exposure of pea (Pisum sativum) shoots to solutions containing 19 mg fluoride/litre (1 mmol/litre) for up to 3 days caused significant increases in ATP levels in the youngest, fully expanded leaves and in entire shoots. These increases occurred before significant decreases in fresh weight, water content or water uptake and stem elongation. Neither in vitro exposure of spinach (Spinacia oleracea) petioles to 38 mg fluoride/litre (2 mmol/litre) for 3 h nor in vivo exposure of plants to gaseous hydrogen fluoride at 5 µg fluoride/m³ for 6 days resulted in visible injury. However, there was evidence from experiments on chlorophyll a fluorescence of a reduced ability to develop or maintain a trans-thylakoid proton gradient in chloroplasts containing elevated levels of fluoride (Boese et al., 1995).

Fluoride at concentrations of 190 mg/litre (10 mmol/litre) significantly reduced the in vitro photosynthetic capacity of azalea (Rhododendron sp.) cultivars (Ballantyne, 1991).

Stevens et al. (1998a) grew tomato (Lycopersicon esculentum) and oat (Avena sativa) plants in nutrient solutions (12–13 days) at nominal sodium fluoride concentrations ranging from 1 to 128 mg fluoride/litre. Fluoride ion concentrations greater than 28 mg/litre (1473 µmol/litre) caused significant decreases in the dry weights of tomato shoots and roots; oat plants were unaffected at all fluoride exposure concentrations. Stevens et al. (1998b) found that dry weights of tomato and oat shoots and roots were significantly decreased as the pH of the solution culture decreased below 4.3 at hydrogen fluoride concentrations of 1.4 mg fluoride/litre (71 µmol/litre) and 2.6 mg fluoride/litre (137 µmol/litre) for tomatos and oats, respectively. Fluoride concentrations in tomato and oat shoots that corresponded with significant reductions in plant dry weights were 228 and 125 mg/kg, respectively. Aluminium–fluoride complexation increased fluoride uptake (see chapter 4) and toxicity in oats relative to the free fluoride ion; shoot and root dry weights were significantly limited at AlF²⁺ concentrations of 11–22 µmol/litre and AlF₂⁺ concentrations of 126–357 µmol/litre (Stevens et al., 1997).

Ratsch & Johndro (1986) calculated EC₅₀s, based on inhibition of root growth, for lettuce (Lactuca sativa) plants exposed to fluoride. For the 115-h paper substrate method, an EC₅₀ value of 450 mg fluoride/litre was found, and for the 5-day solution method, the EC₅₀ was 660 mg fluoride/litre.

Cooke (1976) studied the effect of fluoride (200 mg/litre) on common sunflower (Helianthus annus) seeds grown in sand culture. No effect on total dry weight was observed; however, there were significant reductions in leaf growth. Keller (1980) grew Norway spruce (Picea abies) cuttings in sand and watered with 100 mg fluoride/litre during winter until bud break. Watering with sodium fluoride significantly depressed the carbon dioxide uptake of shoots. Although the previous year’s needles did not show signs of injury, most of the new needles were killed immediately after flushing with fluoride. Exposure to fluoride significantly increased the susceptibility of plants to sulfur dioxide in subsequent fumigation experiments. Zwiazek & Shay (1987) grew jack pine (Pinus banksiana) seedlings in sand culture at 3 or 15 mg fluoride/kg dry weight. Wilting was the first sign of fluoride injury and occurred in approximately 50% of plants after 25–26 h at 15 mg fluoride/kg and 2–6 h later in only 7% of plants exposed to 3 mg/kg. Fluoride-induced injuries to mesophyll and guard cells were similar to those caused by drought and included the appearance of lipid material in the cytoplasm during early stages of injury, suggesting cell membrane damage. Plants exposed to 3 mg/kg for up to 168 h showed significant reductions in water content. Respiration was significantly reduced after 24 h, but not after longer exposure times, while photosynthetic oxygen release was significantly reduced at 48 and 91 h but had recovered after 168 h (Zwiazek & Shay, 1988a). Zwiazek & Shay (1988b) reported that 3 mg fluoride/kg significantly reduced growth (as measured by fresh weight) and acid phosphatase activity and increased total organic acid content of jack pine (P. banksiana) seedlings.

A few studies have been carried out in which the fluoride exposures have been via the soil. However, the type of soil can greatly affect the uptake and subsequent toxicity of fluorides. For example, Conover & Poole (1971) found that calcined clay prevented the uptake of water-soluble fluoride, whereas sphagnum peat did not have the same capability.

In pot experiments, Singh et al. (1979) grew rice (Oryza sativa) plants in soil (pH >9.4) amended with 25–200 mg fluoride (added as sodium fluoride); the rice plants were harvested, and the soil was subsequently sown with wheat (Triticum aestivum). The authors found that the critical water-extractable fluoride concentration in soil for grain yield in wheat was 22 mg fluoride/kg, which related to a fluoride content of 35 mg/kg in mature wheat straw.

There are limited data available to determine the critical value for fluoride in soil with respect to plant toxicity. The data are also complicated by plant species ranges of sensitivities, heterogeneity of soils, soil chemical parameters that can influence fluoride availability and toxicity, and the relative toxicity of ionic species of fluoride found in the soil solution. However, more controlled solution culture studies have attempted to define toxic concentrations of fluoride exposed to the plant roots and are perhaps the best first approximation of toxic concentrations of fluoride in soil solution.

Elrashidi et al. (1998) found that an application of 100 mg fluoride/kg significantly reduced dry matter yield of barley (Hordeum vulgare) grown on both acid (pH 4.75) and neutral (pH 6.6) soils for 40 days; however, plants growing on alkaline soil (pH 7.5) were unaffected at 1000 mg/kg. The authors found no clear influence of phosphate (50–550 mg/kg soil) on the adverse effect of fluoride on dry matter yield.

Davis & Barnes (1973) found that an added soil fluoride concentration of 380 mg/kg (20 mmol/litre) significantly reduced the growth of loblolly pine (Pinus taeda) and red maple (Acer rubrum) seedlings.

9.1.3.2 Invertebrates

Johansson & Johansson (1972) found that egg production and survival were adversely affected in flour beetles (Tribolium confusum) exposed to flour containing 4524 mg fluoride/kg (0.1% sodium fluoride) for up to 27 days. However, short-term (1–7 days) exposure to fluoride concentrations of 452.4 mg/kg (0.01% sodium fluoride) produced significant stimulation of egg production.

Hughes et al. (1985) fed cabbage looper (Trichoplusia ni) larvae on a wheat germ diet dosed with sodium fluoride (50 and 187 mg fluoride/kg dry weight) or potassium fluoride (48 and 235 mg fluoride/kg dry weight) or a diet of hydrogen fluoride-fumigated leaves (40–187 mg fluoride/kg dry weight). Larval feeding, growth and rate of development were generally reduced on diets containing sodium fluoride and potassium fluoride. The same parameters were generally greater with or unaffected by diets containing fumigated leaves.

Wang & Bian (1988) exposed silkworms (Bombyx mori) to mulberry (Morus alba) leaves containing fluoride concentrations ranging from 10 to 200 mg/kg. The threshold concentration for mortality was 30 mg/kg; 30% mortality was observed at concentrations of 30–50 mg fluoride/kg, 70% at 50–120 mg fluoride/kg and 95% at 120–200 mg fluoride/kg. There was a close correlation between cocoon development and the fluoride content of leaves, with >80 mg fluoride/kg severely inhibiting cocoon production.

Survival of isopods (woodlouse, Porcellio scaber) was not affected after 4 weeks of exposure to fluoride levels in litter up to 3230 mg/kg (170 µmol/g) (Van Wensem & Adema, 1991).

Davies et al. (1998) found no effect on the reproduction of aphids (Aphis fabae) feeding on bean (Vicia faba) plants (12 days) that had been previously exposed to either sodium fluoride in nutrient solution (15 µg fluoride/cm³) or hydrogen fluoride via fumigation (6.5 µg fluoride/m³). Plants accumulated more fluoride in the shoots during fumigation and at levels of up to 200 mg fluoride/kg; aphids accumulated up to 300 mg fluoride/kg from these plants. Similarly, Port et al. (1998) found no effect of hydrogen fluoride on the growth and survival of cabbage white caterpillars (Pieris brassicae) at a dietary concentration of 178.3 mg fluoride/kg.

9.1.3.3 Vertebrates

Guenter & Hahn (1986) fed white leghorn hens on a diet containing up to 1300 mg fluoride/kg for 252 days. Concentrations of >1000 mg/kg resulted in significant depression of feed intake, body weight gain, feed efficiency and egg quality. In a second experiment, pullets were fed 1300 mg/kg for 49 days; similar results were obtained, but the addition of aluminium (1040 mg/kg) to the diet reduced the effects. Chan et al. (1973) found no effect on growth in Japanese quail (Coturnix coturnix japonica) fed diets resulting in average tibial fluoride concentrations of 13–2223 mg/kg ash weight.

Fleming et al. (1987) dosed nestling European starlings (Sturnus vulgaris) with daily oral doses of 6–160 mg fluoride/kg body weight. Dosing began 24–48 h after hatching and continued for 16 days. The 24-h LD₅₀ was 50 mg/kg body weight for 1-day-old chicks and 17 mg/kg body weight for 16-day-old nestlings. Growth rates were significantly reduced at 13 and 17 mg fluoride/kg body weight (the highest doses at which growth was monitored). No histological damage due to fluoride treatments was found in liver, spleen or kidney.

Carrière et al. (1987) fed nesting American kestrels (Falco sparverius) on a diet containing fluoride levels of 62.4 (background), 4512 or 7690 mg/kg for 10 days. The diet consisted of cockerels (Gallus gallus) that had been exposed to fluoride. Fluoride levels in femurs and eggshells of treated kestrels were significantly higher than those in controls. There were no significant effects of fluoride on per cent fertility or hatchability of eggs. Clutch sizes tended to be smaller with increasing fluoride in the diet; however, the difference was not statistically significant. Seven-day-old kestrel chicks were fed on a cockerel mash diet containing 0, 1120 or 2240 mg/kg for 27 days. Growth of chicks and weights of internal organs were not significantly affected by fluoride in the diet. Per cent bone ash was significantly increased, while bone-breaking strength was significantly decreased by fluoride (Bird et al., 1992). Bird & Massari (1983) fed kestrels on a diet to which flour contaminated with fluoride (10, 50 or 500 mg/kg) had been applied. The birds receiving the highest fluoride dose died within 6 days. Fluoride at the lower doses had no effect on clutch size, hatchability or fledging success but was associated with a higher fertility. Eggs laid by kestrels at 50 mg/kg had significantly thicker shells. Lower reproductive success of eastern screech-owls (Otus asio) was noted when birds were fed 90 mg fluoride/kg diet wet weight (as sodium fluoride), but not when fed 18 mg fluoride/kg diet (Hoffman et al., 1985; Pattee et al., 1988).

Most of the early work on mammals was carried out on domesticated ungulates (Suttie, 1983). Fluorosis has been observed in experimental studies on cattle and sheep exposed to fluoride. Cattle are less tolerant of fluoride toxicity than are other livestock (Phillips & Suttie, 1960). In long-term experiments with beef cattle, 30 mg/kg of dietary fluoride caused excessive wear and staining of teeth (Hobbs & Merriman, 1959). In a further study, beginning with young calves and lasting 7 years, the tolerance for soluble fluoride was also 30 mg/kg dry diet (Shupe et al., 1963). Suttie et al. (1957) found that lactating cows could tolerate 30 mg/kg, with a rate of 50 mg/kg causing fluorosis within 3–5 years.

Tolerance levels have been identified for domesticated animals based on clinical signs and lesions. Tolerance levels in feed range from 30–40 mg/kg dry weight in dairy cattle to 150 mg/kg in lambs; in water, tolerance levels range from 2.5–4.0 mg/litre in dairy cattle to 12–15 mg/litre in lambs (Shupe & Olson, 1983; Cronin et al., 2000). The lowest dietary level observed to cause an effect on wild ungulates was in a controlled captive study, where white-tailed deer (Odocoileus virginianus) were exposed to 10 (control feed), 35 or 60 mg fluoride/kg wet weight (as sodium fluoride) in their diet for 2 years (Suttie et al., 1985). A general mottling of the incisors characteristic of dental fluorosis was noted in the animals at the 35 mg/kg diet dose; those on the higher dose also experienced minor increased wear of the molars, as well as mild hyperostoses of the long bones of the leg. No gross abnormalities of the mandible were observed. The mean fluoride content of the mandibles was approximately 1700 mg/kg ash weight for the control, 4550 mg/kg for the low-dose group and 6600 mg/kg for the high-dose group, the latter two levels being similar to those observed in affected wild deer near sources of industrial pollution (Karstad, 1967; Kay et al., 1975; Newman & Yu, 1976).

Deer mice (Peromyscus maniculatus) fed diets of 38 (control), 1065, 1355 or 1936 mg fluoride/kg diet dry weight (as sodium fluoride) for 8 weeks exhibited, at all concentrations above the control, marked weight loss, mortality, changes in femur size and dental disfigurement (Newman & Markey, 1976). Bank voles (Clethrionomys glareolus) showed a reduction in the number of litters per female, an increase in the number of days from mating to producing the first litter, increased mortality of offspring and a changed sex ratio (greater number of males) in offspring of animals fed 97 mg/kg diet (wet or dry basis not specified). Animals fed 47 mg/kg diet also showed these effects, but the differences were not significant from the control (Krasowska, 1989).

Boulton et al. (1995) exposed short-tailed field voles (Microtus agrestis), bank voles (Clethrionomys glareolus) and wood mice (Apodemus sylvaticus) to drinking-water containing 0, 40 or 80 mg fluoride/litre for up to 84 days. Both fluoride exposures induced premature mortalities in both vole species. Severe dental lesions were observed in animals surviving the highest dose. Voles were also fed on a diet containing 100 mg fluoride/kg (vegetation contaminated by atmospheric fluorides). Offspring of the voles fed the contaminated diet had significantly lower growth rates and body weights during stages of infancy and early adulthood. The incisors of newly born young were not significantly different between the contaminated and control diets; however, incisors of offspring weaned on to the contaminated diet showed marked morphological changes and severe dental lesions (Boulton et al., 1994a).

Fluoride was suggested as the cause of reduced milk production with subsequent mortality of kits in farm-raised red foxes (Vulpes vulpes) fed a diet containing 98–137 mg fluoride/kg dry weight (Eckerlin et al., 1986).

Aulerich et al. (1987) fed mink (Mustela vison) diets containing 35–385 mg fluoride/kg for 382 days. No significant differences were observed in body weight gains or fur quality between dosed and control mink. No adverse effects of fluoride on breeding, gestation, whelping or lactation were found. Survival was adversely affected at 385 mg fluoride/kg; some of the surviving mink at this concentration had weakened frontal, parietal and femoral bones. Fluoride did not affect haematological parameters or serum calcium concentrations, but serum alkaline phosphatase activity was significantly increased at fluoride concentrations of >229 mg/kg.

Mink (Mustela vison) kits and adult male mink were fed diets containing fluoride (as sodium fluoride) at concentrations ranging from 26 to 287 mg fluoride/kg wet weight for up to 8 months. Gross, radiographic and microradiographic changes were seen in bones from animals ingesting the higher levels of fluoride. Chemical analyses for fluoride generally reflected the levels ingested. After data were evaluated, a tolerance level in the feed of 50 mg fluoride/kg for breeding stock was recommended (Shupe et al., 1987).

9.2.1 Microorganisms

Rao & Pal (1978) found a positive correlation between concentrations of fluoride in soil and soil organic matter content at eight sites near an aluminium factory in India and inferred that fluoride decreased the activity of soil microorganisms responsible for litter decomposition. Significant increases in the organic matter of soils were not found until total soil fluoride concentrations were greater than approximately 1000 mg/kg.

Tscherko & Kandeler (1997) studied the influence of atmospheric fluoride deposits on soil microbial biomass and its enzyme activities near an aluminium smelter at Ranshofen, Upper Austria. Mean water-extractable fluoride concentrations ranged from 10 to 124 mg/kg dry soil and were inversely correlated with microbial activity. In the most contaminated soil (up to 189 mg/kg), the microbial activities were only 5–20% of those in unpolluted soil. At a fluoride concentration above 100 mg/kg, microbial biomass and dehydrogenase activity decreased substantially, whereas arylsulfatase activity was inhibited at only 20 mg/kg. The accumulation of organic matter near the smelter (124 mg fluoride/kg) also indicated severe inhibition of microbial activity by fluoride.

9.2.2 Aquatic organisms

Kudo & Garrec (1983) simulated the accidental release of ammonium fluoride into a pond. Mean fluoride concentrations increased from 0.2 to 7.3 mg/litre following the release. Fluoride levels returned to background concentrations within 30 days. No visible toxic effects on plants, algae, molluscs or fish were observed during the 30-day period. No details regarding the chemical characteristics of the pond water were given.

Ares et al. (1983) monitored fluoride concentrations and diatom populations in seawater near an aluminium smelter in southern Argentina. Fluoride concentrations primarily ranged from 1.1 to 1.3 mg/litre. Anthropogenic emissions accounted for 6–8% of the variance of fluoride levels in the waters. The correlations observed between fluoride concentrations and some structural characteristics of the diatom community did not show significant effects of the discharged fluoride.

Fluoride-loaded effluent adversely affected the species richness of a marine encrusting community for up to 400 m from the point of discharge. Fluoride concentrations greater than 50 mg/litre (the concentration of fluoride in effluent at which mortality was observed in the laboratory) seldom extended for more than 20 m from the outfall. The authors concluded that a sublethal effect of fluoride and/or some other effluent component appeared to be producing the observed distribution (Pankhurst et al., 1980).

High mortality and delayed migration were observed in Pacific salmon (Oncorhynchus sp.) migrating upstream near an aluminium plant on the Columbia River, USA (Washington/Oregon border). Fluoride levels in the water ranged between 0.3 and 0.5 mg/litre during 1982. Bioassay experiments on adult salmon suggested that fluoride concentrations of 0.5 mg/litre would adversely affect migration. Between 1983 and 1986, discharges from the aluminium plant were reduced, there was a corresponding drop in fluoride concentrations, and fish mortality and migration delays were decreased (Damkaer & Dey, 1989).

Mishra & Mohapatra (1998) monitored toads (Bufo melanosticus) at a fluoride-contaminated site at Hirakud, India. Mean haemoglobin content, total red blood cell count and haematocrit in blood samples were found to be significantly reduced, whereas mean corpuscular concentration and volume were significantly elevated when compared with toads at an uncontaminated site. Mean bone fluoride concentrations were 2736 mg/kg at the contaminated site and 241 mg/kg at the control site.

9.2.3 Terrestrial organisms

9.2.3.1 Plants

Aluminium smelters, brickworks, phosphorus plants and fertilizer and fibreglass plants have all been shown to be sources of fluoride that are correlated with damage to local plant communities. In 1970, vegetation in the vicinity of a phosphorus plant in Newfoundland, Canada, began to show symptoms of damage (tip burn and margin burn). Samples collected during 1973–1975 revealed that the degree of damage and fluoride levels in soil humus were inversely related to the distance from the plant. Average levels of fluoride in vegetation ranged from 281 mg/kg in severely damaged areas to 44 mg/kg in lightly damaged areas; at a control site, the fluoride concentration was 7 mg/kg (Thompson et al., 1979). Klumpp et al. (1994, 1996a) reported that plants downwind of fertilizer industries in Brazil showed damage (necrotic bands or tip burn). Bioindicator plants have revealed that severe damage corresponded to high leaf fluoride concentrations (no statistical analysis performed). Klumpp et al. (1996b) found a highly significant linear regression between leaf damage and fluoride accumulation in Gladiolus plants; the plants developed typical fluoride-induced leaf lesions. Murray (1981) found that plant communities near an aluminium smelter showed differences in community composition and structure due partly to variations in fluoride tolerance.

However, it must be noted that in the field, one of the main problems with the identification of fluoride effects is the presence of confounding variables, such as other atmospheric pollutants. McClenahen (1978) examined stands of vegetation along pollution gradients recording species richness, evenness of stand, diversity index and concentrations of three pollutants. Most vegetation characteristics were altered in areas of high pollution. Statistical analysis showed a significant positive correlation between fluorides and shrub density; however, chloride appeared to have the greatest impact on the same parameter. Therefore, care must be taken when interpreting the many field studies on fluoride pollution.

Lichens have been used widely as biomonitors of fluoride pollution. LeBlanc et al. (1971) transplanted epiphytic lichens from an unpolluted area to various distances from an aluminium factory. Lichens accumulated 600–900 mg fluoride/kg during periods of 4 or 12 months within 8 km of the factory compared with 70 mg/kg at a control site. Lichen thalli exposed for 4 months at 1 km from the factory contained some extractable chlorophyll; however, those exposed for 12 months did not. Soredia (viable structures with a potential to develop into parent lichen thalli under favourable ecological conditions) were absent in lichens growing within 4 km of the plant. Davies (1982) found that visible damage to lichen (Xanthoria parietina) thalli (growing within a 30-km radius of the Bedfordshire brickfields, United Kingdom) was observed when internal fluoride concentrations exceeded 68 mg/kg, and internal damage occurred at >90 mg fluoride/kg.

Gilbert (1985) monitored lichens near an aluminium smelter during its 11-year operational life. Epiphytic lichens were severely damaged (>50% injury) over a 25-km² area close to the smelter. Fluoride concentrations in Ramalina farinacea near the smelter increased from 9–11 mg/kg prior to the start of the smelting operation to 120–156 mg/kg within 4 months and had reached these higher levels up to 3 km from the smelter within 3 years.

Perkins & Millar (1987) studied the effect of airborne fluoride emitted from an aluminium works on previously unpolluted assemblages of saxicolous lichens. Prior to emissions, lichens contained a mean concentration of 16 mg fluoride/kg. Fruticose (shrubby) lichens, such as Ramalina species, were the most sensitive to fluoride emissions, with lichens containing >100 mg fluoride/kg showing severe damage. Some foliose (leaf-like) lichens tolerated >200 mg fluoride/kg, and crustose (crust-like) lichens were the most tolerant group, with overall survival at 32% and 70% for the two groups, respectively, within 1 km of the works. Damage to lichens was greatest less than 2 km from the works, where 41% of Ramalina thalli showed >50% chlorosis or necrosis. Loss of lichens decreased with increasing distance from the works. The authors reported that lichens containing 300, 100 and 50 mg fluoride/kg dry weight lost 46, 15 and 10% of cover per year, respectively (Perkins, 1992).

Several studies have been carried out on the effects of fluorides on a variety of tree species and the subsequent damage to forests. Infrared aerial photographs of forest near an aluminium plant in northwestern Montana, USA, revealed widespread damage to nearly 75 000 ha of pine (Pinus sp.) trees. The authors identified several factors that suggest fluoride as the cause, including proximity to the plant, high fluoride concentrations in conifer leaves and the presence of typical fluoride-induced leaf lesions (Carlson, 1978). Bunce (1984) reported that the growth reduction of forest (2800 m³/year) estimated for the years from the establishment of an aluminium smelter (Kitimat, British Columbia, Canada) to 1974 declined by 78% for the period 1974–1979. The improvement in growth corresponded to a 79% decline in fluoride content of foliage and a 64% decline in fluoride emissions.

The effects of fluoride emissions from a phosphorus plant (the plant closed in 1989) in Long Harbour, Newfoundland, Canada, on the conifers balsam fir (Abies balsamea), black spruce (Picea mariana) and larch (Larix laricina) were monitored at sites downwind from the plant during the summer of 1982 (Sidhu & Staniforth, 1986). Mean fluoride concentrations ranged between 11.4 µg/m³ at a distance of 1.4 km from the source and 0.08 µg/m³ 18.7 km from the source. At the closest site, seed production in balsam fir, black spruce and larch was impaired by 76.4%, 87.4% and 100%, respectively, compared with controls. At 10.3 km from the source (mean ambient air concentration 0.9 µg fluoride/m³), the effects included reduction of 3–10% in seed size and 23–30% in cone size and a decrease of 17–72% (varied with species) in the number of cones per tree. A significant negative correlation was observed between atmospheric fluoride levels and seed production for all three species. A significant negative correlation was also observed between foliar injury in the three species (chlorosis and necrosis) and mean atmospheric fluoride levels. Toxic effects of fluoride on these conifer species have resulted in their replacement by more tolerant hardwood species, such as birch (Betula sp.) and alder (Alnus sp.). Reproductive and vegetative characteristics of raspberry (Rubus sp.) and blueberry (Vaccinium sp.) were monitored at six sites downwind from the plant. Within 1.4 km of the plant, flower mortality was 89% for blueberry and 78% for raspberry, compared with 27% and 26%, respectively, for a control site; there were also significant decreases in size, number and dry weight of fruit. Fluoride concentrations in foliage were 403 mg/kg for raspberry and 216 mg/kg for blueberry, compared with 8 and 9 mg/kg, respectively, for the control site (Staniforth & Sidhu, 1984).

Taylor & Basabe (1984) established correlations between fluoride concentrations in pine needles (Douglas-fir, Pseudotsuga menziesii) and annual growth increments, wind pattern, distance from fluoride source (aluminium smelter) and hydrogen fluoride concentrations in emissions. The authors noted that visible fluoride symptoms and over 40% growth reduction occurred in trees that were accumulating fluorides below established "injury threshold levels." They suggested that synergism between hydrogen fluoride and sulfur dioxide may have given rise to these reduced threshold levels.

Vike & Håbjr rg (1995) recorded fluoride content and leaf injury in a variety of plant species growing in the vicinity of aluminium smelters in Norway. Scots pine (Pinus sylvestris) was the most sensitive species, showing leaf injury symptoms at a leaf fluoride content of less than 50 mg/kg at the northern-most locality and <100 mg/kg under southern maritime conditions. Broad-leaved species such as downy birch (Betula pubescens), goat willow (Salix caprea) and European mountain-ash (Sorbus aucuparia) showed similar symptoms at concentrations of 100 and 170 mg/kg for the two sites, respectively. In a later study, Vike (1999) reported that leaf injury appeared at leaf fluoride content levels as low as 30 mg/kg, and damage was restricted to within 2 km of the emission sources. Regression analysis showed a positive correlation between leaf injury and fluoride content of leaves within a locality, but great variation between localities. The author concluded that the establishment of tolerable emission levels must take into account local dispersal patterns and climatic conditions.

Ivinskis & Murray (1984) found that reductions in photosynthetic capacity, chlorophyll a and b and leaf area of grey gum (Eucalyptus punctata) were all significantly correlated with leaf fluoride content, fluoride in air and distance from an aluminium smelter. The authors also found that dusky-leaved ironbark (Eucalyptus fibrosa), a species believed to be tolerant of fluoride, showed no significant differences between sites for any of the variables except leaf area.

9.2.3.2 Invertebrates

Mayer et al. (1988) conducted a 3-year study on honeybees (Apis mellifera) in Puyallup Valley, Washington, USA, near an aluminium plant. The mean fluoride content of bees from a site 0.8 km downwind of the plant ranged from 82 to 261 mg/kg dry weight. No significant effect of fluoride on brood survival, brood development or honey production was found.

9.2.3.3 Vertebrates

Van Toledo (1978) found that the number of avian species near fluoride-emitting aluminium factories in Europe was depressed. They speculated that the reductions were due to fluoride emissions. Newman (1977) believed that the nesting density of house martins (Delichon urbica) was reduced near an aluminium plant with high fluoride emissions. However, there were many other air pollutants present, and so it is difficult to establish a causal relationship with fluoride in particular. Henny & Burke (1990) monitored black-crowned night herons (Nycticorax nycticorax) living near a phosphate-processing complex in Idaho, USA. Fluoride in femurs ranged from 540 to 11 000 mg/kg ash weight and increased with age. The authors studied bone strength, but, because of the strong relationship between age and fluoride concentrations, it proved difficult to separate the effects of fluoride from those of age.

The original findings of fluoride effects on mammals were from studies in the field on domestic animals such as sheep (Moule, 1944; Harvey, 1952; Peirce, 1952) and cattle (Rand & Schmidt, 1952; Neeley & Harbaugh, 1954; Burns & Allcroft, 1964; Allcroft & Burns, 1968; Krook & Maylin, 1979), and more recent studies have shown this to be an ongoing problem in some areas (Jubb et al., 1993; Fidanci et al., 1998; Swarup et al., 1998; Choubisa, 1999; Patra et al., 2000). Fluoride can be taken up from vegetation, soil and drinking-water. Incidents involving domesticated animals have originated both from natural fluoride sources, such as volcanic eruptions and the underlying geology, and from anthropogenic sources, such as mineral supplements, fluoride-emitting industries and power stations. Symptoms of chronic fluoride toxicity include emaciation, stiffness of joints and dental and skeletal fluorosis. Other effects include lowered milk production and detrimental effects on the reproductive capacity of animals. Guidance is available on fluoride tolerance levels in feed and water for domesticated animals based on clinical signs and lesions (Shupe & Olson, 1983; Cronin et al., 2000) (see section 9.1.3.3).

Investigations of the effects of fluoride on wildlife have focused on impacts on the structural integrity of teeth and bone. Most observations have involved large herbivores. For example, dental and skeletal lesions were found in mule deer (Odocoileus hemionus), elk (Cervus canadensis) and American bison (Bison bison) exposed to elevated levels (no specific anthropogenic sources identified) of fluoride in Utah, Idaho, Montana and Wyoming, USA (Shupe et al., 1984). Black-tailed deer (Odocoileus hemionus columbianus) near an aluminium smelter in Washington, USA, were found to have dental disfigurement, with the premolars of one individual deer being worn down to the gumline. Fluoride levels in ribs ranged from 2800 to 6800 mg/kg on a fat-free basis, compared with control deer, which had levels ranging from 160 to 460 mg/kg (Newman & Yu, 1976). Lameness of deer adjacent to an aluminium smelter in Montana, USA, was noted by Kay et al. (1975). They speculated that fluorosis was the cause of a change in age structure of the mule deer population. Levels in mandibles of the mule deer and white-tailed deer (Odocoileus virginianus) ranged from 1100 to 7000 and from 3400 to 9800 mg/kg, respectively, on a fat-free basis, whereas those of control deer were less than 200 mg/kg. White-tailed deer inhabiting an area adjacent to an aluminium smelter in South Carolina, USA, exhibited dental fluorosis but no osteofluorosis (Suttie et al., 1987). Mean levels in mandibles of deer older than 2.5 years were 286 mg/kg ash weight before opening of the smelter and 1275 mg/kg 3 years after start-up.

Karstad (1967) found that mandibular bone fluoride contents of 4300–7125 mg/kg in mule deer (Odocoileus hemionus) near an industrial complex were associated with pitting and black discoloration of teeth, abnormal tooth wear and fractures of teeth and jaw bones. All red deer (Cervus elaphus) yearlings, sampled near Norwegian aluminium smelters, with mandibular fluoride levels exceeding 2000 mg/kg were found to have dental fluorosis. Gross osteofluorosis was observed in deer with mandibular fluoride residues of greater than 8000 mg/kg (Vikr ren & Stuve, 1996b). Pathological alterations in the teeth of roe deer (Capreolus capreolus) in Germany were diagnosed as dental fluorosis. The diagnosis was confirmed by analysis of mandibles, which contained significant levels of fluoride (Kierdorf, 1988). The dental fluorosis was found to occur mainly in the heavily industrialized Ruhr area of Germany. H. Kierdorf et al. (1996) and U. Kierdorf et al. (1996) monitored mandibular bone fluoride concentrations and frequency and intensity of fluoride-induced dental lesions in red deer in the Czech Republic and Germany (Figure 4). The frequency and severity of dental fluorosis were positively correlated with bone fluoride levels. Detailed macroscopic, microradiographic and scanning electron microscopic methods have revealed structural changes in fluorosed dental enamel of both roe and red deer (U. Kierdorf et al., 1993, 1996). Corresponding changes have also been described in fluorosed enamel of wild boars (Sus scrofa) from fluoride-polluted areas (H. Kierdorf et al., 2000). Kierdorf & Kierdorf (1997) concluded that periods of especially elevated plasma fluoride levels in chronically fluoride-stressed deer can cause a disruption in the function of secretory ameloblasts similar to that following acute fluoride dosing in laboratory rodents. Morphological imaging has revealed a decreased width and an increased porosity of the antler cortex in deer from highly fluoride polluted areas (U. Kierdorf et al., 2000). Kierdorf et al. (1997) concluded that increased fluoride exposure of deer leads to reduced mineral content and mineral density of antler bone and that it is the rapidity of their growth and mineralization that makes antlers especially susceptible to fluoride action. The occurrence of osteofluorotic alterations has also been diagnosed in red deer (C. elaphus) with bone fluoride concentrations greater than 4000 mg/kg dry weight (Schultz et al., 1998). The authors concluded that in addition to fluoride-induced dental lesions, the occurrence of marked periodontal disease and tooth loss is an important factor responsible for a reduction of life expectancy in severely fluorotic wild red deer. It has been demonstrated that in the case of regional, long-term fluoride pollution, dental fluorosis can be used as a sensitive biomarker of fluoride exposure in deer and thus as an indicator of the level of environmental contamination by fluorides (U. Kierdorf & Kierdorf, 1999).

Exposure of predatory wildlife is often minimal, as fluoride is largely unavailable to those mammalian and avian predators that do not digest bone. For example, barn-owls regurgitate pellets that contain virtually intact skeletons of their prey (Thomson, 1987).

Walton (1987c) found that severe dental damage in field voles (Microtus agrestis) and wood mice (Apodemus sylvaticus) was evident only within 200–300 m (downwind) of an aluminium smelter. A significant increase in tooth wear was noted in moles (Talpa europaea) at between 4 and 15 km from the smelter. Radiographs of the skeletons of voles and mice with bone fluoride levels of up to 15 000 mg/kg dry weight showed no changes when compared with rodents from control sites. Paranjpe et al. (1994) identified fluorosis in cotton rats (Sigmodon hispidus) at a petrochemical waste site. Approximately 80% of the cotton rats collected by Schroder et al. (1999) at the same site were found to have dental fluorosis. Mean bone fluoride and mean soil total fluoride levels were 1515 and 1954 mg/kg, respectively. Bone fluoride was found to be an accurate predictor of dental fluorosis when it was low (<1000 mg fluoride/kg; no fluorosis) or high (>3000 mg fluoride/kg; fluorosis), but not when it was intermediate (Schroder et al., 2000). Field voles (M. agrestis) and bank voles (Clethrionomys glareolus) showed severe dental lesions on incisor and molar teeth near a chemical works (549 mg total fluoride/kg dry weight of vegetation) and an aluminium smelter (187 mg fluoride/kg vegetation), with less marked damage at a mine tailings dam (80 mg fluoride/kg vegetation) (Boulton et al., 1994b). Boulton et al. (1999) reported that the severity of lesions in both incisor and molar teeth of field voles (M. agrestis) was positively correlated with the respective tissue fluoride concentrations.

10.1.1 Exposure

Individuals are exposed to some level of fluoride from natural and/or anthropogenic sources. The consumption of foodstuffs, drinking-water and other beverages is generally the principal route of exposure. Significant intake may also occur in younger children from the ingestion of fluoridated dentifrice and supplements. Infants can receive small amounts of fluoride from breast milk. The inhalation of fluorides in air usually makes only a minor contribution to the overall total intake. High intakes of fluoride have been noted in geographical areas worldwide where the surrounding environment is rich in natural fluoride. In these areas, drinking-water, foodstuffs and the inhalation of indoor air where coal rich in fluoride is used for heating and cooking all contribute to the overall intake. Exposures might be increased somewhat in the vicinity of certain anthropogenic sources of fluoride. In certain occupational environments, the inhalation of workroom air containing fluoride would contribute to higher than typical ambient exposures.

Estimates of daily fluoride intake by children in Canada range from <0.01 mg (<1 µg/kg body weight for infants) to 2.1 mg (160 µg/kg body weight for children up to 4 years of age and 80 µg/kg body weight for adolescents aged 5–11 years). For adults, estimates of daily fluoride intake range from 2.2 to 4.1 mg (approximately 30 to 60 µg/kg body weight, assuming an average body weight of 64 kg). For individuals residing in certain geographical areas rich in natural fluoride, daily intakes as high as 27 mg (420 µg/kg body weight, assuming an average body weight of 64 kg) have been reported. The estimates of total fluoride intake usually do not take into account its bioavailability (e.g., the degree of fluoride absorption from fluoride-containing food items). Such information is needed in order to derive accurate estimates of daily total fluoride intake in individuals living in fluoridated as well as non-fluoridated areas and in areas of endemic fluorosis.

10.1.2 Hazard identification¹

10.1.3 Exposure–response analysis for adverse effects in bone

A few investigations on skeletal fluorosis or the risk of fractures include quantitative estimates of the dose–response relationship. Studies in China and India report an increased prevalence of skeletal fluorosis above the level of 1.4 mg fluoride/litre in drinking-water (Jolly et al., 1968; Choubisa et al., 1997; Xu et al., 1997). However, such studies suffer from limitations: the diagnostic criteria are not always specified or consist of self-reported symptoms, and only drinking-water is considered as a source of exposure. The latter problem is likely to be important, since other studies (Liang et al., 1997; Ando et al., 1998) estimate that, at least in some regions of China and India, the contribution from food can greatly exceed that from water. Therefore, one cannot rule out that high rates of skeletal fluorosis associated with a level greater than 1.4 mg/litre in drinking-water are due to other exposures. While there is a clear excess of skeletal fluorosis in these studies for a total intake of 14 mg/day, the quantitative relationship between total intake of fluoride from different sources and the risk of skeletal fluorosis cannot be estimated because of substantial uncertainties in the prevalence of effects in the range of intakes between 3 and 14 mg/day.

The studies on fractures are also difficult to interpret, but for different reasons:

• Few studies report an interpretable range of exposures to fluoride.
• Results tend to be contradictory, with no clear-cut trend in both men and women.
• Total intake of fluoride is not estimated.

One exception is represented by a study in China (Li et al., 2001) in which different sources of exposure have been considered and an estimate of total intake is presented. In this study, there is an upward trend for the risk of total fractures above an exposure of 1.45 mg fluoride/litre in drinking-water, but only for the highest level of exposure (i.e., >4.32 mg fluoride/litre in drinking-water) was the relative risk statistically significant (RR = 1.47; P = 0.01). In the concentration range of 1.45–2.19 mg fluoride/litre in drinking-water, corresponding to a total intake of 6.54 mg/day, there was a relative risk for all fractures of 1.17 and for hip fractures of 2.13 (both not statistically significant).

In summary, estimates based on studies from China and India indicate that:

• for a total intake of 14 mg/day, there is a clear excess risk of skeletal adverse effects; and
• there is suggestive evidence of an increased risk of effects on the skeleton at total fluoride intakes above about 6 mg/day.

10.2.1 Exposure

Fluorides are released into the environment naturally through the weathering and dissolution of minerals, in emissions from volcanoes and in marine aerosols. Fluorides are also released into the environment via coal combustion and process waters and waste from various industrial processes, including steel manufacture, primary aluminium, copper and nickel production, phosphate ore processing, fertilizer production and use, glass, brick and ceramic manufacturing, and glue and adhesive production.

Atmospheric fluorides can be transported over large distances as a result of wind or atmospheric turbulence or removed from the atmosphere via wet or dry deposition or hydrolysis. Fluoride concentrations in groundwater are primarily due to dissolution from local geological sources. The transport of fluorides in water is influenced by pH and water hardness and the presence of ion-exchange materials such as clays, and fluoride is usually complexed with aluminium and calcium. Fluoride is not readily leached from soils, with adsorption being strongest at pH 5.5–6.5. Soluble fluorides are bioaccumulated by some aquatic and terrestrial biota; however, no information was identified concerning the biomagnification of fluoride. Terrestrial plants may accumulate fluorides from airborne deposition and, to a lesser extent, via uptake from soil, as fluoride adsorbs strongly to soil. Fluoride accumulates in the exoskeleton of invertebrates and the bone and dental hard tissues of vertebrates.

Surface freshwater fluoride concentrations tend to range from 0.01 to 0.3 mg/litre, whereas typical marine concentrations range from 1.2 to 1.5 mg/litre (Figure 5). Higher concentrations are found in areas where there is geothermal or volcanic activity. Anthropogenic discharges lead to increased levels of fluoride in the environment. Airborne fluoride exists in gaseous and particulate forms, which are emitted from both natural and anthropogenic sources. Mean fluoride concentrations in ambient air are generally less than 0.1 µg/m³. Levels may be slightly higher in urban than in rural locations; however, even in the vicinity of emission sources, the levels of airborne fluoride usually do not exceed 2–3 µg/m³ (Figure 6). Fluoride is a component of most types of soil, with concentrations ranging from 20 to 1000 mg total fluoride/kg in areas without natural phosphate or fluoride deposits and up to several thousand milligrams per kilogram in mineral soils with deposits of fluoride (Figure 7). Reported concentrations of fluoride in vegetation are plotted in Figure 8.

10.2.2 Effects

The most sensitive aquatic invertebrate species tested were the freshwater fingernail clam (Musculium transversum), with an 8-week LC₅₀ of 2.8 mg fluoride/litre, freshwater net-spinning caddisflies (Hydropyschidae), with estimated "safe concentrations" ranging from 0.2 to 1.2 mg fluoride/litre, and the marine brine shrimp (Artemia salina), with significant impairment of growth being observed in a 12-day static test at 5 mg/litre. For fish, 20-day LC₅₀s for rainbow trout (Oncorhynchus mykiss) ranged from 2.7 to 4.7 mg fluoride/litre; in another study under different conditions (such as higher water hardness), a "safe concentration" of 5.1 mg/litre was estimated. The hatching of fish eggs (Catla catla) was delayed at fluoride concentrations greater than or equal to 3.6 mg fluoride/litre. Behavioural experiments on adult Pacific salmon in soft-water rivers indicate that changes in water chemistry, due to an increase in the fluoride concentration to 0.5 mg/litre, can adversely affect migration; migrating salmon are extremely sensitive to changes in the water chemistry of their river of origin. (Reported toxicity test results for a range of freshwater organisms are plotted in Figure 9.)

In laboratory studies, fluoride seems to be toxic for microbial processes at concentrations found in moderately fluoride-polluted soils; similarly, in the field, accumulation of organic matter in the vicinity of smelters has been attributed to severe inhibition of microbial activity by fluoride.

The LOELs for leaf necrosis in terrestrial plants were at fluoride concentrations of 0.2–0.4 µg/m³. On the basis of effect concentrations and no-effect concentrations for fumigation experiments, a relationship was derived between the NOEC and the exposure period. If this relationship is extrapolated to two growing seasons, the derived NOEC is approximately 0.2 µg fluoride/m³. Several short-term solution culture studies have identified a toxic threshold for fluoride ion activity ranging from approximately 50 to 2000 µmol fluoride/litre. Toxicity is specific not only to plant species, but also to ionic species of fluoride, where some aluminium–fluoride complexes present in solution culture may be toxic at activities of 22–357 µmol fluoride/litre, whereas hydrogen fluoride is toxic at activities of 71–137 µmol/litre. Due to the complexity of fluoride availability in soil and the high concentrations generally required for plant toxicity, no soil effect range was defined.

The growth rate of young starlings was significantly reduced at a fluoride concentration of 13 mg/kg body weight. Fluoride has been shown to cause adverse effects on domesticated animals in both the laboratory and the field. Recent studies have shown this to be an ongoing problem. Tolerance levels have been identified for domesticated animals, with the lowest values for dairy cattle at 30 mg/kg feed or 2.5 mg/litre drinking-water. The lowest dietary concentration of fluoride to cause fluorosis in white-tailed deer (Odocoileus virginianus) was 35 mg/kg. Field surveys have found that bone fluoride concentrations of >2000 mg/kg in young deer and >3000 mg/kg in cotton rats (Sigmodon hispidus) are associated with fluorosis in all individuals. Osteofluorotic alterations have been diagnosed in deer with bone fluoride concentrations of >4000 mg/kg.

10.2.3 Evaluation

In the freshwater environment, natural fluoride concentrations are usually lower than those expected to cause toxicity in aquatic organisms. However, aquatic organisms might be adversely affected in the vicinity of anthropogenic discharges. Fluoride toxicity is dependent on water hardness, with organisms living in soft-water environments at greater risk than those in hard-water areas. Because of the particular sensitivity of some freshwater invertebrates and Pacific salmon, fluoride concentrations in soft-water ecosystems (low in calcium) should not be increased by anthropogenic inputs to values exceeding 0.5 mg fluoride/litre. Aquatic organisms that inhabit areas with high natural fluoride levels from geothermal or volcanic activity would be expected to be adapted to such conditions.

Comparing the long-term NOEC for plants with air concentrations reveals that sensitive species growing near anthropogenic sources of fluoride are at risk. In the field, anthropogenic sources of fluoride have been shown to be correlated with damage to local terrestrial plant communities. However, these adverse effects are often difficult to attribute to fluoride alone, due to the presence of other atmospheric pollutants. Fluoride is generally strongly adsorbed by soils. Consequently, plant uptake via this pathway is relatively low, and leaching of fluoride through soil is minimal. However, high fluoride concentrations in soil from natural and anthropogenic sources, combined with soil properties that minimize fluoride adsorption (below pH 5.5, low carbon and clay content), can lead to increased plant availability of fluoride. Plant availability is also dependent on the ionic species of fluoride present in the soil solution. Above soil pH 5.5, fluoride in solution is predominantly the free fluoride ion, CaF⁺ or MgF⁺, which is relatively less available to uptake via the plant root. Below soil pH 5.5, aluminium–fluoride complexes can become dominant in soil solution, potentially increasing plant availability of fluoride. However, plant toxicity from uptake of fluoride from soil is rare.

Concentrations of fluoride in vegetation in the vicinity of fluoride emission sources, such as aluminium smelters, can be higher than the lowest dietary effect concentration reported for mammals in laboratory experiments. Fluorosis in domesticated animals has been reported. Incidents have originated both from natural fluoride sources, such as volcanic eruptions and the underlying geology, and from anthropogenic sources, such as fluoride-emitting industries and power stations. Guidance is available on fluoride tolerance levels in feed and water; however, there are still some areas reporting fluorosis incidents in livestock due to uptake of fluoride-rich mineral supplements and drinking-water. Furthermore, there is a potential risk from fluoride-contaminated pasture and soil ingestion due to the long-term use of phosphate fertilizers containing fluoride as an impurity. Fluoride-induced effects, such as lameness and tooth damage, have also been reported in wild ungulates, such as deer, and in small mammals close to anthropogenic sources of fluoride. Several studies have demonstrated that wild deer and rodents are sensitive bioindicators of environmental pollution by fluorides and can, therefore, be used as sentinels for the identification of fluoride hazards to the environment. Within some areas of Europe, where effective emission control measures have been introduced following clean air legislation, the bone fluoride levels in deer have fallen by around 70% in the last 15–20 years. Based on the correlation between bone fluoride levels and fluorosis, it can be assumed that the prevalence and severity of fluoride-induced effects in the wild deer population in these areas will probably have fallen at a similar rate. However, it should be noted that in other regions of Europe, fluoride discharges to the environment have not shown the same downward trend during this period, and this is reflected in the bone fluoride levels of mammals from these areas.

All organisms are exposed to various levels of fluoride from natural and/or anthropogenic sources. Very high intakes have been observed in areas worldwide in which the environment is rich in natural fluoride and where groundwater high in fluoride is consumed.

Fluoride in dental products may form a source of exposure for many individuals. Increased exposures might be experienced in the vicinity of anthropogenic point sources.

Fluoride has both beneficial and detrimental effects on human health, with a narrow range between the intakes associated with its beneficial and adverse health effects.

Effects on the teeth and skeleton are observed at exposures below those associated with the development of other organ- or tissue-specific adverse health effects. Effects on the bone are considered the most relevant to assessing the adverse effects of long-term exposure of humans to fluoride.

Skeletal fluorosis is a crippling disability affecting millions of people in various regions of Africa, India and China, which has major public health and socioeconomic impact. Intake of fluoride in the water and/or foodstuffs is the primary causative factor in the incidence of endemic skeletal fluorosis. In parts of China, a large number of people have been shown to be impacted by the indoor burning of coal with a high fluoride content. There are few data from which to estimate total exposure to and the bioavailability of fluoride, and there are inconsistencies in the characterization of its adverse effects.

There is clear evidence from India and China that skeletal fluorosis and an increased risk of bone fractures occur at a total intake of 14 mg fluoride/day, and there is evidence suggestive of an increased risk of bone effects at total intakes above about 6 mg fluoride/day.

Excess exposure to bioavailable fluoride constitute a risk to aquatic and terrestrial biota.

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

Considerations should be given to the levels of fluoride and the means of application required to maximize the beneficial effects of fluoride while minimizing the potential for adverse effects on the skeleton and teeth.

It is recommended that international and national agencies identify areas in which health effects related to fluoride are found, identify the primary sources of fluoride exposure and take appropriate action(s) to reduce exposure.

It is recommended that international and national agencies support research to better characterize total fluoride exposure, exposure-health relationships and the various factors that modify and influence these.

In areas exposed to increased fluoride from anthropogenic sources, fluoride levels in the environment should be monitored for changes using appropriate bioindicators.

There is a need to improve knowledge on the accumulation of fluoride in organisms and on how to monitor and control this.

The biological effects associated with fluoride exposure should be better characterized.

There is a need:

• to determine total dietary fluoride intakes and bioavailability and elucidate the relative contribution of water and foodstuffs to fluoride intake;
• to develop robust markers of fluoride exposure and effects in animals and humans to further elucidate the mechanisms (including work on a molecular level) of fluoride’s effects on bone, and how these might be reversed;
• to design high-quality studies at population and individual levels, to characterize the adverse effects of fluoride on bone, cancer and reproductive outcomes; available data sets should be exploited to generate sound epidemiological observations — for example, through a linkage between population registries in high-exposure areas and cancer or other disease registries;
• to characterize the potential interactions of fluoride with other elements — aluminium, copper, lead, arsenic, selenium — in the environment and their influence on fluoride bioavailability and mobility;
• to clarify quantitatively and mechanistically how environmental factors (e.g., atmospheric pollution, coal burning, climate, rainfall, altitude) and lifestyle (including occupation) influence fluoride exposure;
• to characterize the short- and long-term turnover of fluoride in the body and how factors such as bone remodelling and renal function influence this;
• to improve the routine quantitative analysis of fluoride in body fluids;
• to develop robust biomarkers in animals and humans;
• to investigate the passage of fluoride through the food-chain from the geochemical environment to the diet;
• to determine if fluoride has potential adverse effects on other systems, including the neurological system;
• to investigate what factors (age, genetic polymorphisms, diet, etc.) might make particular population subgroups more susceptible to the effects of fluoride; and
• to determine the mechanisms associated with the clastogenicity of fluoride.

Additional research needs include studies on the interactions of fluoride with nuclear proteins (i.e., histones) and polyamines as well as on factors influencing the membrane transport of fluoride.

There is a need:

• for the identification of more fluoride-sensitive species from different environmental compartments for use as bioindicators;
• to define critical measures of fluoride concentrations in soil to assess plant fluoride availability (i.e., when plant fluoride concentrations increase significantly from background or, to a lesser extent, become toxic to plants);
• to determine the bioavailability of fluoride in animals that ingest significant quantities of soil in their diet (e.g., cattle);
• for the standardization of the assessment of the effects of fluoride on wild animals; and
• to improve the quantitative routine analysis of fluoride in soil and plants.

Fluoride (used in drinking-water) is considered to be "not classifiable as to its carcinogenicity to humans" (Group 3) in the classification scheme of the International Agency for Research on Cancer (IARC, 1987).

The WHO recommended guideline value for fluoride in drinking-water is 1.5 mg/litre (WHO, 1993, 1996b). It was also noted that "in setting national standards for fluoride, it is particularly important to consider climatic conditions, water intake and intake of fluoride from other sources (e.g., from food and air). In areas with high natural fluoride levels, it is recognized that the guideline value may be difficult to achieve in some circumstances, with the treatment technology available" (WHO, 1996b).

An expert consultation of the WHO on trace elements in human nutrition and health (WHO, 1996c) categorized fluoride among "potentially toxic elements, some of which may nevertheless have some essential functions at low levels." Fluoride was regarded as "essential," since the consultation "considered resistance to dental caries to be a physiologically important function." The consultation indicated that total intakes at 1, 2 and 3 years of age "should, if possible, be limited to 0.5, 1.0 and 1.5 mg/day, respectively," with not more than 75% coming in the form of soluble fluorides from drinking-water. It was also noted that "adult intakes exceeding 5 mg of fluoride per day from all sources probably pose a significant risk of skeletal fluorosis."

Aardema M, Gibson D, & LeBoeuf R (1989a) Sodium fluoride induced chromosome aberrations in different stages of the cell cycle: a proposed mechanism. Mutat Res, 223: 191–203.

Aardema M, Gibson D, & LeBoeuf R (1989b) The kinetics of sodium fluoride-induced endoreduplication in Chinese hamster ovary cells. Environ Mol Mutagen, 14(suppl 15): 3 (abstract).

Abdennebi EH, Fandi R, & Lamnaouer D (1995) Human fluorosis in Morocco: analytical and clinical investigations. Vet Hum Toxicol, 37: 465–468.

Adelung D, Bossmann K, & Rossler D (1985) The distribution of fluoride in some Antarctic seals. Polar Biol, 5: 31–34.

Adelung D, Buchholz F, Culik B, & Keck A (1987) Fluoride in tissues of krill Euphausia superba Dana and Meganyctiphanes norvegica M. Sars in relation to the moult cycle. Polar Biol, 7(1): 43–50.

Afseth J, Ekstrand J, & Hagelid P (1987) Dissolution of calcium fluoride tablets in vitro and bioavailability in man. Scand J Dent Res, 95: 191–192.

Ahn HW & Jeffery EH (1994) Effect of aluminum on fluoride uptake by Salmonella typhimurium TA98; implications for the Ames mutagenicity assay. J Toxicol Environ Health, 41: 357–368.

Ahn H, Fulton D, Moxon D, & Jeffery E (1995) Interactive effects of fluoride and aluminum uptake and accumulation in bones of rabbits administered both agents in their drinking water. J Toxicol Environ Health, 44: 337–350.

Akbar-Khanzadeh F (1995) Exposure to particulates and fluorides and respiratory health of workers in an aluminum production potroom with limited control measures. Am Ind Hyg Assoc J, 56: 1008–1015.

Akhundow WY, Aliew AA, Kulgawin AH, & Sariva TN (1981) [Effect of complex and separate exogenous administration of vitamins on the level of chromosome aberrations in rats induced by sodium fluoride in a subacute experiment.] Izv Akad Nauk Az SSR, Ser Biol Nauk, 4: 3–5 (in Russian).

Albanese R (1987) Sodium fluoride and chromosome damage (in vitro human lymphocytes and in vivo micronucleus assays). Mutagenesis, 2: 497–499.

Alexandersen P, Riis BJ, & Christiansen C (1999) Monofluorophosphate combined with hormone replacement therapy induces a synergistic effect on bone mass by dissociating bone formation and resorption in postmenopausal women: a randomised study. J Clin Endocrinol Metab, 84: 3013–3020.

Alhava E, Olkkonen H, Kauranen P, & Kari T (1980) The effect of drinking water fluoridation on the fluoride content, strength and mineral density of human bone. Acta Orthop Scand, 51: 413–420.

Aliev AA & Babaev DA (1981) Cytogenetic activity of vitamins in bone marrow cells of rat femurs under conditions of induction of mutations by sodium fluoride. Cytol Cytogen (USSR), 15: 15–18.

Aliev A, Dzhafarova S, Medzhidov M, & Asadova A (1988) Investigation of the phenomenon and substantiation of the mechanism of antimutagenesis under conditions of the effect of sodium fluoride. Cytol Genet, 22: 24–27.

Allcroft R & Burns KN (1968) Fluorosis in cattle in England and Wales: incidence and sources. Fluoride, 1: 50–53.

Amundson RG, Belsky AJ, & Dickie RC (1990) Fluoride deposition via litterfall in a coastal-plain pine plantation in South Carolina. Water Air Soil Pollut, 50: 301–310.

Anasuya A & Paranjape PK (1996) Effect of parboiling on fluoride content of rice. Fluoride, 29: 193–201.

Anasuya A, Bapurao S, & Paranjape PK (1996) Fluoride and silicon intake in normal and endemic fluorotic areas. J Trace Elem Med Biol, 10: 149–155.

Andersen A, Dahlberg B, Magnus K, & Wannag A (1982) Risk of cancer in the Norwegian aluminum industry. Int J Cancer, 29: 295–298.

Ando M, Tadano M, Asanuma S, Tamura K, Matsushima S, Watanabe T, Kondo T, Sakurai S, Ji R, Liang C, & Cao S (1998) Health effects of indoor fluoride pollution from coal burning in China. Environ Health Perspect, 106: 239–244.

Andrews S, Cooke J, & Johnson M (1982) Fluoride in small mammals and their potential food sources in contaminated grasslands. Fluoride, 15: 56–63.

Andrews SM, Cooke JA, & Johnson MS (1989) Distribution of trace element pollutants in a contaminated ecosystem established on metalliferous fluorspar tailings. 3: Fluoride. Environ Pollut, 60: 165–179.

Angelovic JW, Sigler WF, & Neuhold JM (1961) Temperature and fluorosis in rainbow trout. J Water Pollut Control Fed, 33(4): 371–381.

Antia NJ & Klut ME (1981) Fluoride addition effects on euryhaline phytoplankter growth in nutrient-enriched seawater at an estuarine level of salinity. Bot Mar, 24: 147–152.

Aoba T (1997) The effect of fluoride on apatite structure and growth. Crit Rev Oral Biol Med, 8: 136–153.

Aplin TEH (1968) Poison plants of Western Australia. The toxic species of the genera Gastrolobium and Oxylobium heart-leaf poison (Gastrolobium bilobum), river poison (Gastrolobium forrestii), Stirling Range poison (Gastrolobium velutinumi). J Dep Agric West Aust, 9(2): 69–74.

Ares J (1990) Fluoride–aluminium water chemistry in forest ecosystems of central Europe. Chemosphere, 21(4/5): 597–612.

Ares JO, Villa A, & Gayoso AM (1983) Chemical and biological indicators of fluoride input in the marine environment near an industrial source (Argentina). Arch Environ Contam Toxicol, 12: 589–602.

Armstrong B, Tremblay C, Cyr D, & Thériault G (1986) Estimating the relationship between exposure to tar volatiles and the incidence of bladder cancer in aluminum smelter workers. Scand J Work Environ Health, 12: 486–493.

Armstrong B, Tremblay C, Baris D, & Theriault G (1994) Lung cancer mortality and polynuclear aromatic hydrocarbons: a case–cohort study of aluminum production workers in Arvida, Quebec, Canada. Am J Epidemiol, 1: 250–262.

Arnala I, Alhava E, Kivivuoir R, & Kauranen P (1986) Hip fracture not affected by fluoridation. Acta Orthop Scand, 57: 344–346.

Arnesen AKM (1998) Effect of fluoride pollution on pH and solubility of Al, Fe, Ca, Mg, K and organic matter in soil from Årdal (western Norway). Water Air Soil Pollut, 103: 375–388.

Arnesen AKM & Krogstad T (1998) Sorption and desorption of fluoride in soil polluted from the aluminium smelter at Årdal in western Norway. Water Air Soil Pollut, 103: 357–373.

Aschengrau A, Zierler S, & Cohen A (1989) Quality of community drinking water and the occurrence of spontaneous abortion. Arch Environ Health, 44: 283–290.

Aschengrau A, Zierler S, & Cohen A (1993) Quality of community drinking water and the occurrence of late adverse pregnancy outcomes. Arch Environ Health, 48: 105–113.

ATSDR (1993) Toxicological profile for fluorides, hydrogen fluoride, and fluorine. Atlanta, Georgia, US Department of Health and Human Services, Agency for Toxic Substances and Disease Registry (TP-91/17).

Augenstein W, Spoerke D, Kulig K, Hall A, Hall P, Riggs B, Saadi M, & Rumack B (1991) Fluoride ingestion in children: A review of 87 cases. Pediatrics, 88: 907–912.

Aulerich RJ, Napolitano AC, & Bursian SJ (1987) Chronic toxicity of dietary fluorine to mink. J Anim Sci, 65: 1759–1767.

Avorn J & Nielssen LC (1986) Relationship between long bone fractures and water fluoridation. Gerodontics, 2: 175–179.

Baars AJ, van Beek H, Spierenburg TJ, de Graf GJ, Beeftink WGJN, Boom J, & Pekelder JJ (1987) Fluoride pollution in a salt marsh: movement between soil, vegetation, and sheep. Bull Environ Contam Toxicol, 39: 945–952.

Bale S & Mathew M (1987) Analysis of chromosomal abnormalities at anaphase–telophase induced by sodium fluoride in vitro. Cytologia, 52: 889–893.

Ballantyne DJ (1984) ATP and growth in fluoride-treated pea shoots. Environ Exp Bot, 24(3): 277–282.

Ballantyne DJ (1991) Fluoride and photosynthetic capacity of azalea (Rhododendron) cultivars. Fluoride Q Rep, 24(1): 11–16.

Barbaro A, Francescon A, & Polo B (1981) Fluorine accumulation in aquatic organisms in the lagoon of Venice. Fluoride, 14: 102–107.

Barnard WR & Nordstrom DK (1982) Fluoride in precipitation. II. Implications for the geochemical cycling of fluoride. Atmos Environ, 16(1): 105–111.

Barrie LA & Hoff RM (1985) Five years of air chemistry observations in the Canadian arctic. Atmos Environ, 19(12): 1995–2010.

Barrow NJ & Ellis AS (1986) Testing a mechanistic model — III. The effects of pH on fluoride retention by a soil. J Soil Sci, 37: 287–293.

Bayley TA, Harrison JE, Murray TM, Josse RG, Sturtridge W, Pritzker KP, Strauss A, Vieth R, & Goodwin S (1990) Fluoride-induced fractures: relation to osteogenic effect. J Bone Miner Res, 5(suppl 1): S217–S222.

Beg SA (1982) Inhibition of nitrification by arsenic, chromium and fluoride. J Water Pollut Control Fed, 54: 482–488.

Belandria G, Asta J, & Nurit F (1989) Effects of sulphur dioxide and fluoride on ascospore germination of several lichens. Lichenologist, 21(1): 79–86.

Bell ME, Largent EJ, Ludwig TG, Muhler JC, & Stookey GK (1970) The supply of fluorine to man. In: Fluorides and human health. Geneva, World Health Organization, pp 17–74 (WHO Monograph Series No. 59).

Bennett A & Barratt R (1980) Some observations on atmospheric fluoride concentrations in Stoke-on-Trent. J R Soc Health, 100: 84–89.

Berglund LK, Iselius L, Lindsten J, Marks 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 Disorders) (in Swedish).

Bergmann KE & Bergmann RL (1995) Salt fluoridation and general health. Adv Dent Res, 9: 138–142.

Bergmann R (1995) Fluorid in der Ernährung des Menschen. Biologische Bedeutung für den wachsenden Organismus. Habilitationsschrift. Berlin, Virchow-Klinikum der Humboldt-Universität, 133 pp.

Berndt A & Stearns R (1979) Dental fluoride chemistry. Springfield, Illinois, Charles C. Thomas.

Bernstein D, Sadowskuy N, & Hegsted D (1966) Prevalence of osteoporosis in high- and low-fluoride areas of North Dakota. J Am Med Assoc, 198: 499–504.

Berry WTC (1962) Fluoridation. Med Off, 108: 204–205.

Bhatnagar M & Susheela AK (1998) Chronic fluoride toxicity: an ultrastructural study of the glomerulus of the rabbit kidney. Environ Sci, 6: 43–54.

Bird DM & Massari C (1983) Effects of dietary sodium fluoride on bone fluoride levels and reproductive performance of captive American kestrels. Environ Pollut, A31: 67–76.

Bird DM, Carrière D, & Lacombe D (1992) The effect of dietary sodium fluoride on internal organs, breast muscle, and bones in captive American kestrels (Falco sparverius). Arch Environ Contam Toxicol, 22: 242–246.

Boese SR, MacLean DC, & El-Mogazi D (1995) Effects of fluoride on chlorophyll a fluorescence in spinach. Environ Pollut, 89(2): 203–208.

Boillat MA, Baud CA, Lagier R, Garcia J, Rey P, Bang S, Boivin G, Demeurisse C, Gossi M, Tochon-Danguy HJ, Very JM, Burckhardt P, Voinier B, Donath A, & Courvoisier B (1979) [Industrial fluorosis. Multidisciplinary study on 43 workmen in the aluminium industry.] Schweiz Med Wochenschr, Suppl 8: 1–28 (in French).

Boivin G, Chavassieux P, Chapuy MC, Baud CA, & Meunier PJ (1989) Skeletal fluorosis: histomorphometric analysis of bone changes and bone fluoride content in 29 patients. Bone, 10: 89–99.

Boone RJ & Manthey M (1983) The anatomical distribution of fluoride within various body segments and organs of Antarctic krill (Euphausia superba Dana). Arch Fischereiwiss, 34(1): 81–85.

Bordelon BM, Saffle JR, & Morris SE (1993) Systemic fluoride toxicity in a child with hydrofluoric acid burns: a case report. J Trauma, 34: 437–439.

Boulton I, Cooke J, & Johnson M (1994a) Age-accumulation of fluoride in an experimental population of short-tailed field voles (Microtus agrestis L.). Sci Total Environ, 154: 29–37.

Boulton IC, Cooke JA, & Johnson MS (1994b) Fluoride accumulation and toxicity in wild small mammals. Environ Pollut, 85: 161–167.

Boulton IC, Cooke JA, & Johnson MS (1995) Fluoride accumulation and toxicity in laboratory populations of wild small mammals and white mice. J Appl Toxicol, 15(6): 423–431.

Boulton IC, Cooke JA, & Johnson MS (1999) Lesion scoring in field vole teeth: Application to the biological monitoring of environmental fluoride contamination. Environ Monit Assess, 55: 409–422.

Bowen SE (1988) Spatial and temporal patterns in the fluoride content of vegetation around two aluminium smelters in the Hunter Valley, New South Wales. Sci Total Environ, 68: 97–111.

Bower CA & Hatcher JT (1967) Adsorption of fluoride by soils and minerals. Soil Sci, 103: 151–154.

Breimer RF, Vogel J, & Ottow JCG (1989) Fluorine contamination of soils and earthworms (Lumbricus spp.) near a site of long-term industrial emission in southern Germany. Biol Fertil Soils, 7(4): 297–302.

Brewer RF (1966) Fluorine. In: Chapman HD ed. Diagnostic criteria for plants and soils. Riverside, California, University of California, Division of Agricultural Science, pp 180–195.

Brimblecombe P & Clegg SL (1988) The solubility and behaviour of acid gases in the marine aerosol. J Atmos Chem, 7: 1–18.

Brouwer ID, DeBruin A, Backer Dirks O, & Hautvast JGAJ (1988) Unsuitability of World Health Organisation guidelines for fluoride concentrations in drinking water in Senegal. Lancet, 1: 223–225.

Bruun C & Thylstrup A (1988) Dentifrice usage among Danish children. J Dent Res, 67: 1114–1117.

Buckingham FM (1988) Surgery: a radical approach to severe hydrofluoric acid burns. J Occup Med, 30: 873–874.

Bunce HWF (1984) Fluoride emissions and forest survival, growth and regeneration. Environ Pollut, A35: 169–188.

Bunce HWF (1985) Apparent stimulation of tree growth by low ambient levels of fluoride in the atmosphere. J Air Pollut Control Assoc, 35(1): 46–48.

Burns KN & Allcroft R (1964) Fluorosis in cattle. 1. Occurrence and effects in industrial areas of England and Wales, 1954–57. London, HMSO.

Burt B (1992) The changing patterns of systemic fluoride intake. J Dent Res, 71: 1228–1237.

Buse A (1986) Fluoride accumulation in invertebrates near an aluminium reduction plant in Wales. Environ Pollut, A41: 199–217.

Butler JE, Satam M, & Ekstrand J (1990) Fluoride: An adjuvant for mucosal and systemic immunity. Immunol Lett, 26: 217–220.

Butler WJ, Segreto V, & Collins E (1985) Prevalence of dental mottling in school-aged lifetime residents of 16 Texas communities. Am J Public Health, 75: 1408–1412.

Calderon J, Romieu I, Gromaldo M, Hernandez H, & Diaz-Barriga F (1995) Endemic fluorosis in San Luis Potosi, Mexico. II. Identification of risk factors associated with occupational exposure to fluoride. Fluoride, 4: 203–208.

Camargo JA (1991) Ecotoxicological study of the influence of an industrial effluent on a net-spinning caddisfly assemblage in a regulated river. Water Air Soil Pollut, 60: 263–277.

Camargo JA (1996a) Comparing levels of pollutants in regulated rivers with safe concentrations of pollutants for fishes: a case study. Chemosphere, 33(1): 81–90.

Camargo JA (1996b) Estimating safe concentrations of fluoride for three species of nearctic freshwater invertebrates: Multifactor probit analysis. Bull Environ Contam Toxicol, 56(4): 643–648.

Camargo JA & La Point TW (1995) Fluoride toxicity to aquatic life: a proposal of safe concentrations for five species of palearctic freshwater invertebrates. Arch Environ Contam Toxicol, 29: 159–163.

Camargo JA & Tarazona JV (1990) Acute toxicity to freshwater benthic macroinvertebrates of fluoride ion (F^–) in soft water. Bull Environ Contam Toxicol, 45(6): 883–887.

Camargo JA & Tarazona JV (1991) Short-term toxicity of fluoride ion (F^–) in soft water to rainbow trout and brown trout. Chemosphere, 22(5/6): 605–611.

Camargo JA, Ward JV, & Martin KL (1992) The relative sensitivity of competing hydropsychid species to fluoride toxicity in the Cache la Poudre River (Colorado). Arch Environ Contam Toxicol, 22: 107–113.

Campbell A (1987) Determination of fluoride in various matrices. Pure Appl Chem, 59: 695–702.

Cao J, Bai X, Zhao Y, Zhou D, Fang S, Jia M, & Wu J (1996) The relationship of fluorosis and brick tea drinking in Chinese Tibetans. Environ Health Perspect, 104: 1340–1343.

Cao J, Zhao Y, Liu J, Xirao R, & Danzeng S (2000) Environmental fluoride content in Tibet. Environ Res, 83(3): 333–337.

Caraccio T, Greensher J, & Mofenson H (1983) The toxicology of fluoride. In: Haddad L & Winchester J ed. Clinical management of poisoning and drug overdose. Philadelphia, Pennsylvania, W.B. Saunders.

Carlson CE (1978) The use of infrared aerial photography in determining fluoride damage to forest ecosystems near an aluminum plant in northwestern Montana, USA. Fluoride, 11(3): 135–141.

Carpenter R (1969) Factors controlling the marine geochemistry of fluorine. Geochim Cosmochim Acta, 33: 1153–1167.

Carrière D, Bird DM, & Stamm JW (1987) Influence of a diet of fluoride-fed cockerels on reproductive performance of captive American kestrels. Environ Pollut, 46: 151–159.

Caspary W, Myhr B, Bowers L, McGregor D, Riach C, & Brown A (1987) Mutagenic activity of fluorides in mouse lymphoma cells. Mutat Res, 187: 165–180.

Caspary W, Langenbach R, Penman B, Crespi C, Myhr B, & Mitchell A (1988) The mutagenic activity of selected compounds at the TK locus: rodent vs. human cells. Mutat Res, 196: 61–81.

Cauley JA, Murphy PA, Riley TJ, & Buhari AM (1995) Effects of fluoridated drinking water on bone mass and fractures: The study of osteoporotic fractures. J Bone Miner Res, 10: 1076–1086.

Chakma T, Vinay Rao P, Singh SB, & Tiwary RS (2000) Endemic genu valgum and other bone deformities in two villages of Mandla district in Central India. Fluoride, 33: 187–195.

Chamblee JW, Arey FK, & Heckel E (1984) Free fluoride of the Pamlico River in North Carolina. A new method to localize the discharge of polluted water into an estuary. Water Res, 18(10): 1225–1233.

Chan JT & Koh SH (1996) Fluoride content in caffeinated, decaffeinated and herbal teas. Caries Res, 30: 88–92.

Chan K-M, Svancarek WP, & Creer M (1987) Fatality due to hydrofluoric acid exposure. Clin Toxicol, 25: 333–339.

Chan MM, Rucker RB, Zeman F, & Riggins RS (1973) Effect of fluoride on bone formation and strength in Japanese quail. J Nutr, 103: 1431–1440.

Chandrawanshi CK & Patel KS (1999) Fluoride deposition in central India. Environ Monit Assess, 55: 251–265.

Chan-Yeung M, Wong R, Earnson D, Schulzer M, Subbarao K, Knickerbocker J, & Grzybowski S (1983a) Epidemiological 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.

Chan-Yeung M, Wong R, MacLean L, Tan F, Schulzer M, Enarson D, Martin A, Dennis R, & Grzybowski S (1983b) Epidemiologic health study of workers in an aluminum smelter in British Columbia. Effects of the respiratory system. Am Rev Respir Dis, 127: 465–469.

Chen Y, Lin M, He Z, Xie X, Liu Y, Xiao Y, Zhou J, Fan Y, Xiao X, & Xu F (1993) Air pollution-type fluorosis in the region of Pingxiang, Jiangxi, People’s Republic of China. Arch Environ Health, 48: 246–249.

Chen YX, Lin MQ, He ZL, Chen C, Min D, Liu YQ, & Yu MH (1996) Relationship between total fluoride intake and dental fluorosis in areas polluted by airborne fluoride. Fluoride, 29: 7–12.

Chhabra R, Singh A, & Abrol IP (1979) Fluorine in sodic soils. Soil Sci Soc Am J, 44: 33–36.

Chilvers C (1982) Cancer mortality by site and fluoridated water supplies. J Epidemiol Community Health, 36: 237–242.

Chinoy N & Sequeira E (1989a) Effects of fluoride on the histoarchitecture of the reproductive organs of the male mouse. Reprod Toxicol, 3: 261–267.

Chinoy N & Sequeira E (1989b) Fluoride induced biochemical changes in reproductive organs of male mice. Fluoride, 22: 79–85.

Chinoy NJ & Sharma A (1998) Amelioration of fluoride toxicity by vitamins E and D in reproductive functions of male mice. Fluoride, 31: 203–216.

Chinoy N, Sequeira E, & Narayama M (1991) Effect of vitamin C and calcium on the reversibility of fluoride-induced alterations in spermatozoa of rabbits. Fluoride, 24: 29–39.

Chinoy NJ, Narayama MV, Dalal V, Rawat M, & Patel D (1995) Amelioration of fluoride toxicity in some accessory reproductive glands and spermatozoa of rat. Fluoride, 28: 75–86.

Cholak J (1959) Fluorides: A critical review. I. The occurrence of fluoride in air, food, and water. J Occup Med, 1: 501–511.

Choubisa SL (1999) Some observations on endemic fluorosis in domestic animals in southern Rajsthan (India). Vet Res Commun, 23: 457–465.

Choubisa SL, Choubisa DK, Joshi SC, & Choubisa L (1997) Fluorosis in some tribal villages of Dungapur district of Rajasthan, India. Fluoride, 30: 223–228.

Christians O & Leinemann M (1980) [Untersuchungen über Fluor im Krill (E. superba).] Inf Fischwirtsch Ausl, 6: 254–260.

Chu F (1991) SF₆ and the atmosphere. Toronto, Ontario, Ontario Hydro Research Division, Electrical Research Department (91-58-K).

Cohn P (1992) An epidemiologic report on drinking water and fluoridation. Environmental Health Service, New Jersey Department of Health, November.

Cole J, Muriel W, & Bridges B (1986) The mutagenicity of sodium fluoride to L5178Y [wild-type and TK+/- (3.7.2C)] mouse lymphoma cells. Mutagenesis, 1: 157–167.

Collins TFX, Sprando RL, Shackelford ME, Black TN, Ames MJ, Welsh JJ, Balmer MF, Olejnik N, & Ruggles DI (1995) Developmental toxicity of sodium fluoride in rats. Food Chem Toxicol, 33: 951–960.

Connell AD & Airey DD (1982) The chronic effects of fluoride on the estuarine amphipods Grandidierella lutosa and G. lignorum. Water Res, 16: 1313–1317.

Conover CA & Poole RT (1971) Influence of fluoride on foliar necrosis of Cordyline terminalis Cv Baby Doll during propagation. Proc Fla State Hortic Soc, 84: 380–383.

Cooke JA (1976) The uptake of sodium monofluoroacetate by plants and its physiological effects. Fluoride, 9(4): 204–212.

Cooke JA, Johnson MS, Davison AW, & Bradshaw AD (1976) Fluoride in plant colonizing fluorspar mine waste in the Peak District and Weardale. Environ Pollut, 11: 10–23.

Cooke JA, Johnson MS, & Davison AV (1978) Uptake and translocation of fluoride in Helianthus annus L. grown in sand culture. Fluoride, 11: 76–88.

Crespi C, Seixas G, Turner T, & Penman B (1990) Sodium fluoride is a less efficient human cell mutagen at low concentrations. Environ Mol Mutagen, 15: 71–77.

Cronin SJ, Manoharan V, Hedley MJ, & Loganathan P (2000) Fluoride — a review of its fate and hazard potential in grazed pasture systems. N Z J Agric Res, 43: 295–321.

Cuker W & Shilts W (1979) Lacustrine geochemistry around the north shore of Lake Superior: Implications for evaluation of the effects of acid precipitation. Current Research Part C, Geological Survey of Canada (79-1C).

Cummings C & McIvor M (1988) Fluoride-induced hyperkalemia: the role of Ca²⁺-dependent K⁺ channels. Am J Emerg Med, 6: 1–3.

Czarnowski W & Krechniak J (1990) Fluoride in urine, hair and nails of phosphate fertilizer workers. Br J Ind Med, 47: 349–351.

Czarnowski W, Wrzenioska K, & Krechniak J (1996) Fluoride in drinking water and human urine in northern and central Poland. Sci Total Environ, 191: 177–184.

Czarnowski W, Krechniak J, Urbanska B, Stolarska K, Taraszewska-Czarnowska M, & Muraszko-Klaudel A (1999) The impact of water-borne fluoride on bone density. Fluoride, 32: 91–95.

Czerwinski E, Nowack J, Dabrowska D, Skolarczyk A, Kita B, & Ksiezyk M (1988) Bone and joint pathology in fluoride-exposed workers. Arch Environ Health, 43: 340–343.

Dabeka RW & McKenzie AD (1995) Survey of lead, cadmium, fluoride, nickel, and cobalt in food composites and estimation of dietary intakes of these elements by Canadians in 1986–1988. J Assoc Off Anal Chem Int, 78: 897–909.

Dabeka RW, McKenzie AD, Conacher HBS, & Kirkpatrick BS (1982) Determination of fluoride in Canadian infant foods and calculation of fluoride intake by infants. Can J Public Health, 73: 188–191.

Dabeka R, Karpinski K, McKenzie A, & Bajdik C (1986) Survey of lead, cadmium and fluoride in human milk and correlation of levels with environmental and food factors. Food Chem Toxicol, 24: 913–921.

Dabkowska E & Machoy Z (1989) Effects of fluoride pollution on calcium and magnesium content of mandibles (lower jaws) of wild game. Fluoride Q Rep, 22(1): 29–32.

Damkaer DM & Dey DB (1989) Evidence for fluoride effects on salmon passage at John Day Dam, Columbia River, 1982–1986. North Am J Fish Manage, 9: 154–162.

Danielson C, Lyon J, Egger M, & Goodenough G (1992) Hip fracture and fluoridation in Utah’s elderly population. J Am Med Assoc, 268: 746–748.

Das T & Susheela A (1991) Effect of chronic fluoride toxicity on glucocorticoid levels in plasma and urine. Fluoride, 24: 23–28.

Das TK, Susheela AK, Gupta IP, Dasarathy S, & Tandon RK (1994) Toxic effects of chronic fluoride ingestion on the upper gastrointestinal tract. J Clin Gastroenterol, 18: 194–199.

Dasarathy S, Das TK, Gupta IP, Susheela AK, & Tandon RK (1996) Gastroduodenal manifestations in patients with skeletal fluorosis. J Gastroenterol, 31: 333–337.

Daston G, Rehnberg B, Carver B, & Kavelock B (1985) Toxicity of sodium fluoride to the postnatally developing rat kidney. Environ Res, 37: 461–474.

Datta DK, Gupta LP, & Subramanian V (2000) Dissolved fluoride in the Lower Ganges–Brahmaputra–Meghna river system in the Bengal Basin, Bangladesh. Environ Geol, 39(10): 1163–1168.

Dave G (1984) Effects of fluoride on growth, reproduction and survival in Daphnia magna. Comp Biochem Physiol, 78C(2): 425–431.

Davies FBM (1982) Accumulation of fluoride by Xanthoria parietina growing in the vicinity of the Bedfordshire brickfields. Environ Pollut, 29: 189–196.

Davies FBM (1986) The long-term changes in fluoride content of Xanthoria parietina growing in the vicinity of the Bedfordshire brickfields. Environ Pollut, A42: 201–207.

Davies FBM & Notcutt G (1988) Accumulation of fluoride by lichens in the vicinity of Etna volcano. Water Air Soil Pollut, 42: 365–371.

Davies FBM & Notcutt G (1989) Accumulation of volcanogenic fluorides by lichens. Fluoride Q Rep, 22(2): 59–65.

Davies MT, Port GR, & Davison AW (1998) Effects of dietary and gaseous fluoride on the aphid Aphis fabae. Environ Pollut, 99: 405–409.

Davis JB & Barnes RL (1973) Effects of soil-applied fluoride and lead on growth of loblolly pine and red maple. Environ Pollut, 5: 35–44.

Davis RD (1980) Uptake of fluoride by ryegrass grown in soil treated with sewage sludge. Environ Pollut, B1: 277–284.

Davison A (1983) Uptake, transport and accumulation of soil and airborne fluorides by vegetation. In: Shupe J, Peterson H, & Leone N ed. Fluorides: Effects on vegetation, animals and humans. Salt Lake City, Utah, Paragon Press, pp 61–82.

Davison AW & Blakemore J (1980) Rate of deposition, and resistance to deposition, of fluorides on alkali-impregnated papers. Environ Pollut, B1: 305–319.

Davison AW, Rand AW, & Betts WE (1973) Measurement of atmospheric fluoride concentrations in urban areas. Environ Pollut, 5: 23–33.

Dayal HH, Brodwick M, Morris R, Baranowski T, Trieff N, Harrison JA, Lisse JR, & Ansari GAS (1992) A community-based epidemiological study of health sequela of exposure to hydrofluoric acid. Ann Epidemiol, 2: 213–220.

Dean HT, Jay P, Arnold FA, & Elvove E (1941) Domestic waters and dental caries. II. A study of 2832 white children ages 12–14 years of eight suburban Chicago communities, including Lactobacillus acidophilus studies of 1761 children. Public Health Rep, 56: 761–792.

Dean HT, Arnold FA, & Elvove E (1942) Domestic waters and dental caries. V. Additional studies of the relation of fluoride domestic waters to dental caries in 4425 white children, age 12–14 years, of 13 cities in 4 states. Public Health Rep, 57: 1155–1179.

Delmas PD, Dupuis J, Duboeuf F, Chapuy MC, & Meunier PJ (1990) Treatment of vertebral osteoporosis with disodium monofluorophosphate: comparison with sodium fluoride. J Bone Miner Res, 5(suppl 1): S143–S147.

Derelanko M, Gad S, Gavigan F, & Dunn B (1985) Acute dermal toxicity of dilute hydrofluoric acid. J Toxicol Cutan Ocular Toxicol, 4: 73–85.

Doley D (1986) Experimental analysis of fluoride susceptibility of grapevine (Vitis vinifera L.): leaf development during four successive seasons of fumigation. New Phytol, 103: 325–340.

Doley D (1989) Fluoride-induced enhancement and inhibition of shoot growth in four taxa of Pinus. New Phytol, 112: 543–552.

Doll R & Kinlen L (1977) Fluoridation of water and cancer mortality in the U.S.A. Lancet, 1: 1300–1302.

Dominok B & Miller G (1990) Effects of fluoride on Drosophila melanogaster in relation to survival and mutagenicity. Fluoride, 23: 83–91.

Droste RL (1987) Fluoridation in Canada as of December 31, 1986. Ottawa, Ontario, Health and Welfare Canada (IWD-AR WQB-89-154).

Drummond B, Curzon M, & Strong M (1990) Estimation of fluoride absorption from swallowed fluoride toothpastes. Caries Res, 24: 211–215.

Drury JS, Ensminger JT, Hammons AS, Holleman JW, Lewis EB, Preston EL, Shriner CR, & Towill LE (1980) Reviews of the environmental effects of pollutants. IX. Fluoride. Oak Ridge, Tennessee, Oak Ridge National Laboratory (EPA 600/1-78/050).

Dunipace A, Zhang W, Noblitt T, Li Y, & Stookey G (1989) Genotoxic evaluation of chronic fluoride exposure: micronucleus and sperm morphology studies. J Dent Res, 68: 1525–1528.

Dunipace A, Brizendine E, Wilson M, Zhang W, Wilson C, Katz B, & Kafrawy A (1998) Effect of chronic fluoride exposure in uremic rats. Nephron, 78: 96–103.

Dure-Smith BA, Farley SM, Linkhart SG, Farley JR, & Baylink DJ (1996) Calcium deficiency in fluoride-treated osteoporotic patients despite calcium supplementation. J Clin Endocrinol Metab, 81: 269–275.

Easmann R, Steflik D, Pashley D, McKinney R, & Whitford G (1984) Surface changes in rat gastric mucosa induced by sodium fluoride: a scanning electron microscopy study. J Oral Pathol, 13: 255–264.

Easmann R, Pashley D, Birdsong N, McKinney R, & Whitford G (1985) Recovery of rat gastric mucosa following single fluoride dosing. J Oral Pathol, 14: 779–792.

Eckerlin RH, Krook L, Maylin GA, & Carmichael D (1986) Toxic effects of food-borne fluoride in silver foxes. Cornell Vet, 76: 395–402.

Ehrnebo M & Ekstrand J (1986) Occupational fluoride exposure and plasma fluoride levels in man. Int Arch Environ Health, 58: 179–190.

Ekstrand J (1977) Fluoride concentrations in saliva after single oral doses and their relation to plasma fluoride. Scand J Dent Res, 85: 16–17.

Ekstrand J (1978) Relationship between fluoride in the drinking water and the plasma fluoride concentration in man. Caries Res, 12: 123–127.

Ekstrand J (1981) No evidence of transfer of fluoride from plasma to breast milk. Br Med J, 283: 761–762.

Ekstrand J (1987) Pharmacokinetic aspects of topical fluorides. J Dent Res, 66: 1061–1065.

Ekstrand J & Ehrnebo M (1979) Influence of milk products on fluoride bioavailability in man. Eur J Clin Pharmacol, 16: 211–215.

Ekstrand J & Ehrnebo M (1983) The relationship between plasma fluoride, urinary excretion rate and urine fluoride concentrations in man. J Occup Med, 25: 745–748.

Ekstrand J, Ericsson Y, & Rosell S (1977a) Absence of protein-bound fluoride from human blood. Arch Oral Biol, 22: 229–232.

Ekstrand J, Alván G, Boréus L, & Norlin A (1977b) Pharmacokinetics of fluoride in man after single and multiple oral doses. Eur J Clin Pharmacol, 12: 311–317.

Ekstrand J, Ehrnebo M, & Boreus L (1978) Fluoride bioavailability after intravenous and oral administration: importance of renal clearance and urine flow. Clin Pharmacol Ther, 23: 329–371.

Ekstrand J, Ehrnebo M, Whitford GM, & Järnberg PO (1980) Fluoride pharmacokinetics during acid–base changes in man. Eur J Clin Pharmacol, 18: 189–194.

Ekstrand J, Boréus LO, & 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, & 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.

Ekstrand J, Odont LDS, & Ehrnebo M (1983) The relationship between plasma fluoride, urinary excretion rate and urine fluoride concentration in man. J Occup Med, 25: 745–748.

Ekstrand J, Hardell LI, & Spak CJ (1984) Fluoride balance studies on infants in a 1-ppm water fluoride area. Caries Res, 18: 87–92.

Ekstrand J, Ziegler EE, Nelson SE, & Fomon SJ (1994) Absorption and retention of dietary and supplemental fluoride by infants. Adv Dent Res, 8 :175–180.

Elrashidi MA & Lindsay WL (1986) Chemical equilibria of fluorine in soils. A theoretical development. Soil Sci, 141: 274–280.

Elrashidi MA, Persaud N, & Baliger VC (1998) Effect of fluoride and phosphate on yield and mineral composition of barley grown on three soils. Commun Soil Sci Plant Anal, 29(3&4): 269–283.

Elsair J & Khelfat K (1988) Subcellular effects of fluoride. Fluoride, 21: 93–99.

Environment Canada (1989) Ambient air levels of fluoride at Cornwall Island, Ontario, April 14–October 12, 1988. Ottawa, Ontario, Environment Canada, Conservation and Protection Service, Environmental Protection.

Environment Canada (1994) Inorganic fluorides. Ottawa, Ontario, Environment Canada, Ecosystem Science and Evaluation Directorate, Eco-Health Branch.

Erickson JD (1980) Down’s syndrome, water fluoridation and maternal age. Teratology, 21: 177.

Erickson JD, Oakley GP, Flynt JW, & Hay S (1976) Water fluoridation and congenital malformations: No association. J Am Dent Assoc, 93: 981–984.

Ernst P, Thomas D, & Becklake M (1986) Respiratory survey of North American Indian children living in proximity to an aluminum smelter. Am Rev Respir Dis, 133: 307–312.

Esala S, Vuori E, & Helle A (1982) Effect of maternal fluorine intake on breast milk fluorine content. Br J Nutr, 48: 201–204.

Essman E, Essman W, & Valderrama E (1981) Histaminergic mediation of the response of rat skin to topical fluorides. Arch Dermatol Res, 271: 325–340.

Fabiani L, Leoni V, & Vitali M (1999) Bone-fracture incidence rate in two Italian regions with different fluoride concentration levels in drinking water. J Trace Elem Med Biol, 13: 232–237.

Fejerskov O, Manji F, Baelum V, & Mr ller IJ (1988) Dental fluorosis — a handbook for health workers. Copenhagen, Munksgaard, 123 pp.

Fejerskov O, Baelum V, & Richards A (1996) Dose–response and dental fluorosis. In: Fejerskov O, Ekstrand J, & Burt BA ed. Fluoride in dentistry, 2nd ed. Copenhagen, Munksgaard, pp 153–166.

Felsenfeld A & Roberts M (1991) A report of fluorosis in the United States secondary to drinking well water. J Am Med Assoc, 265: 486–488.

Feskanich D, Owusu W, Hunter DJ, Willett W, Ascherio A, Spiegelman D, Morris S, Spate VL, & Colditz G (1998) Use of toenail fluoride levels as an indicator for the risk of hip and forearm fractures in women. Epidemiology, 9: 412–416.

Fidanci UR, Salmanoglu B, Marasli S, & Marasli N (1998) [The natural and industrial fluorosis in the Middle Anatolia and its effects on animal health.] Tr J Vet Anim Sci, 22: 537–544 (in Turkish).

Fieser AH, Sykora JL, Kostalos MS, Wu YC, & Weyel DW (1986) Effect of fluorides on survival and reproduction of Daphnia magna. J Water Pollut Control Fed, 58(1): 82–86.

Fleming WJ, Grue CE, Schuler CA, & Bunck CM (1987) Effects of oral doses of fluoride on nestling European starlings. Arch Environ Contam Toxicol, 16: 483–489.

Flühler H, Polomski J, & Blaser P (1982) Retention and movement of fluoride in soils. J Environ Qual, 11: 461–468.

Fomon SJ & Ekstrand J (1993) Fluoride. In: Fomon SJ ed. Nutrition of normal infants. St Louis, Missouri, Mosby, pp 299–310.

Fomon SJ, Ekstrand J, & Ziegler EE (2000) Fluoride intake and prevalence of dental fluorosis: Trends in fluoride intake with special attention to infants. J Public Health Dent, 60: 131–139.

Freni S (1994) Exposure to high fluoride concentrations in drinking water is associated with decreased birth rates. J Toxicol Environ Health, 42: 109–121.

Freni S & Gaylor D (1992) International trends in the incidence of bone cancer are not related to drinking water fluoridation. Cancer, 70: 611–618.

Fuge R & Andrews MJ (1988) Fluorine in the UK environment. Environ Geochem Health, 10(3/4): 96–104.

Fung KF, Zhang ZQ, Wong JWC, & Wong MH (1999) Fluoride contents in tea and soil from tea plantations and the release of fluoride into tea liquor during infusion. Environ Pollut, 104: 197–205.

Gadhia PK & Joseph S (1997) Sodium fluoride induced chromosome aberrations and sister chromatid exchange in cultured human lymphocytes. Fluoride, 30: 153–156.

Gebhart E, Wagner H, & Behnsen H (1984) The action of anticlastogens in human lymphocyte cultures and its modification by rat liver S9 mix. Studies with AET and sodium fluoride. Mutat Res, 129: 195–206.

Gelberg KH, Fitzgerald EF, Hwang S, & Dubrow R (1995) Fluoride exposure and childhood osteosarcoma: A case–control study. Am J Public Health, 85: 1678–1683.

Gessner B, Beller M, Middaugh J, & Whitford G (1994) Acute fluoride poisoning from a public water system. N Engl J Med, 330: 95–99.

Gibbs G (1985) Mortality of aluminum reduction plant workers, 1950 through 1977. J Occup Med, 27: 761–770.

Gikunju JK (1992) Fluoride concentration in tilapia fish (Oreochromis leucostictus) from Lake Naivasha, Kenya. Fluoride Q Rep, 25(1): 37–43.

Gilbert OL (1985) Environmental effects of airborne fluorides from aluminium smelting at Invergordon, Scotland, 1971–1983. Environ Pollut, 39: 293–302.

Gilman A (1987) G proteins: transducers of receptor-generated signals. Annu Rev Biochem, 56: 615–649.

Gilpin L & Johnson A (1980) Fluorine in agricultural soils of southeastern Pennsylvania. Soil Sci Soc Am J, 44: 255–258.

Giovanazzi A & D’Andrea F (1981) [Mortality of workers in a primary aluminum plant.] Med Lav, 4: 277–282 (in Italian).

Gocke E, King M-T, Eckhardt K, & Wild D (1981) Mutagenicity of cosmetics ingredients licensed by the European Communities. Mutat Res, 90: 91–109.

Godfrey P & Watson S (1988) Fluoride inhibits agonist-induced formation of inositol phosphates in rat cortex. Biochem Biophys Res Commun, 155: 664–669.

Goggin JE, Haddon W, Hambly GS, & Hoveland JR (1965) Incidence of femoral fractures in postmenopausal women. Public Health Rep, 80: 1005–1012.

Government of Canada (1993) Canadian Environmental Protection Act. Priority Substances List assessment report for inorganic fluorides. Prepared by Health Canada and Environment Canada. Ottawa, Ontario, Canada Communication Group (ISBN 0-662-21070-9).

Grad H (1990) Fluorides: old and new perspectives. Univ Toronto Dent J, 3: 27–31.

Grandjean P (1982) Occupational fluorosis through 50 years; clinical and epidemiological experiences. Am J Occup Med, 3: 227–236.

Grandjean P & Thomsen G (1983) Reversibility of skeletal fluorosis. Br J Ind Med, 40: 456–461.

Grandjean P, Juel K, & Moller-Jensen O (1985) Mortality and morbidity after occupational fluoride exposure. Am J Epidemiol, 121: 57–64.

Grandjean P, Olsen J, Moller-Jensen O, & Juel K (1992) Cancer incidence and mortality in workers exposed to fluoride. J Natl Cancer Inst, 84: 1903–1909.

Grant MW & Schuman JS (1993) Toxicology of the eye: effects on the eyes and visual system from chemicals, drugs, metals and minerals, plants, toxins and venoms: also, systemic side effects from eye medications, 4th ed. Springfield, Illinois, Charles C. Thomas.

Greco RJ, Hartford CE, Haith LR, & Patton ML (1988) Hydrofluoric acid-induced hypocalcemia. J Trauma, 28: 1593–1596.

Greenwood N & Earnshaw A (1984) Chemistry of the elements. Toronto, Ontario, Pergamon Press.

Grimaldo M, Borja-Aburto VH, Ramirez AL, Ponce M, Rosas M, & Diaz-Barriga F (1995) Endemic fluorosis in San Luis Potosi. I. Identification of risk factors associated with human exposure to fluoride. Environ Res, 68: 25–30.

Grynpas M (1990) Fluoride effects on bone crystals. J Bone Miner Res, 5: S169–S175.

Gu S, Rongli J, & Shouren C (1990) The physical and chemical characteristics of particles in indoor air where high fluoride coal burning takes place. Biomed Environ Sci, 3: 384–390.

Gubbay AD & Fitzpatrick RI (1997) Dermal hydrofluoric acid burns resulting in death. Aust N Z J Surg, 67: 304–306.

Guenter W & Hahn PHB (1986) Fluorine toxicity and laying hen performance. Poult Sci, 65: 769–778.

Guha-Chowdhury N, Drummond BK, & Smillie AC (1996) Total fluoride intake in children aged 3 to 4 years — a longitudinal study. J Dent Res, 75: 1451–1457.

Gupta IP, Das TK, Susheela AK, Dasarathy S, & Tandon RK (1992) Fluoride as a possible aetiological factor in non-ulcer dyspepsia. J Gastroenterol Hepatol, 7: 355–359.

Gutteridge DH, Price RI, Kent GN, Prince RL, & Michell PA (1990) Spontaneous hip fractures in fluoride-treated patients: potential causative factors. J Bone Miner Res, 5(suppl 1): S205–S215.

Guy W (1979) Inorganic and organic fluorine in human blood. In: Johansen E, Taves D, & Olsen T ed. Continuing evaluation of the use of fluorides. Boulder, Colorado, Westview Press for the American Association for the Advancement of Science, pp 125–147 (AAAS Selected Symposium 11).

Guy W, Taves D, & Brey W (1976) Organic fluorocompounds in human plasma: prevalence and characterization. Am Chem Soc Symp Ser, 28: 117–134.

Haidouti C (1995) Effects of fluoride pollution on the mobilization and leaching of aluminum in soil. Sci Total Environ, 166: 157–160.

Haimanot R (1990) Neurological complications of endemic skeletal fluorosis, with special emphasis on radiculo-myelopathy. Paraplegia, 28: 244–251.

Haimanot RT, Fekadu A, & Bushra B (1987) Endemic fluorosis in the Ethiopian Rift Valley. Trop Geogr Med, 39: 209–217.

Hall RJ (1972) The distribution of organic fluorine in some toxic tropical plants. New Phytol, 71: 855–871.

Hamilton M (1992) Water fluoridation: a risk assessment perspective. J Environ Health, 54: 27–32.

Han YZ, Zhang JQ, Liu XY, Zhang XH, Yu XH, & Dai JA (1995) High fluoride content and endemic fluorosis. Fluoride, 28: 201–202.

Hara T, Sonoda Y, & Iwai I (1977) Growth response of cabbage plant to sodium halides under water culture conditions. Soil Sci Plant Nutr, 23: 77–84.

Harbo RM, Comas FT, & Thompson JAJ (1974) Fluoride concentration in two Pacific coast inlets — an indication of industrial contamination. J Fish Res Board Can, 31: 1151–1154.

Harrison J, Hitchman A, Hassany S, Hitchman A, & Tam C (1984) The effect of diet on fluoride toxicity in growing rats. Can J Physiol Pharmacol, 62: 259–265.

Hart EB, Phillips PH, & Bohstedt G (1934) Relationship of soil fertilisation with superphosphates and rock phosphate to the fluorine content of plants and drainage waters. Am J Public Health, 24: 936–940.

Harvey JM (1952) Chronic endemic fluorosis of merino sheep in Queensland. Queensland J Agric Sci, 9: 47–141.

Harzdorf C, Kinwel N, Marangoni L, Ogleby J, Ravier J, & Roost F (1986) The determination of fluoride in environmentally relevant matrices. Anal Chim Acta, 182: 1–16.

Hasling C, Nielsen H, Melsen F, & Mosekilde L (1987) Safety of osteoporosis treatment with sodium fluoride, calcium phosphate and vitamin D. Miner Electrol Metab, 13: 96–103.

Hayashi M, Kishi M, Sofuni T, & Ishidate MJ (1988) Micronucleus test in mice on 39 food additives and eight miscellaneous chemicals. Food Chem Toxicol, 26: 487–500.

Health Canada (1993) Canadian Environmental Protection Act. Priority Substances List supporting documentation. Health-related sections for inorganic fluorides. Prepared by Priority Substances Section, Environmental Health Directorate, Health Canada, Ottawa, Ontario (unpublished).

Health Council of the Netherlands (1990) Fluorides. Assessment of integrated criteria document. Advisory report submitted to Minister and State Secretary of Health, Welfare and Cultural Affairs and the Minister of Housing, Physical Planning and Environment. The Hague, Health Council of the Netherlands.

Heilman JR, Kiritsy MC, Levy SM, & Wefel JS (1997) Fluoride concentrations of infant foods. J Am Dent Assoc, 128: 857–863.

Heilman JR, Kiritsy MC, Levy SM, & Wefel JS (1999) Assessing fluoride levels of carbonated soft drinks. J Am Dent Assoc, 130: 1593–1599.

Heindel JJ, Bates HK, Price KJ, Marr MC, Myers CB, & Schwetz BA (1996) Developmental toxicity evaluation of sodium fluoride administered to rats and rabbits in drinking water. Fundam Appl Toxicol, 30: 162–177.

Heitmuller PT, Hollister TA, & Parrish PR (1981) Acute toxicity of 54 industrial chemicals to sheepshead minnows (Cyprinodon variegatus). Bull Environ Contam Toxicol, 27: 596–604.

Hekman WE, Budd K, Palmer GR, & MacArthur JD (1984) Responses of certain freshwater planktonic algae to fluoride. J Phycol, 20: 243–249.

Hemens J & Warwick RJ (1972) The effects of fluoride on estuarine organisms. Water Res, 6: 1301–1308.

Hemens J, Warwick RJ, & Oliff WD (1975) Effect of extended exposure to low fluoride concentrations on estuarine fish and crustacea. Prog Water Technol, 7(3/4): 579–585.

Henny CJ & Burke PM (1990) Fluoride accumulation and bone strength in wild black-crowned night-herons. Arch Environ Contam Toxicol, 19: 132–137.

Henschler D, Büttner W, & Patz J (1975) Absorption, distribution in body fluid and bioavailability of fluoride. In: Kuhlencordt F & Kruse HP ed. Calcium metabolism, bone and metabolic diseases. Berlin, Springer Verlag, pp 111–121.

Hill A & Pack M (1983) Effects of atmospheric fluoride on plant growth. In: Shupe J, Peterson H, & Leone N ed. Fluoride effects on vegetation, animals and humans. Salt Lake City, Utah, Paragon Press, pp 105–113.

Hill AC, Pack MR, Transtrum LG, & Winters WS (1959) Effects of atmospheric fluorides and various types of injury on the respiration of leaf tissue. Plant Physiol, 34(1): 11–16.

Hillier S, Cooper C, Kellingray S, Russell G, Hughes H, & Coggon D (2000) Fluoride in drinking water and risk of hip fracture in the UK: a case–control study. Lancet, 355(9200): 265–269.

Hirayama N, Maruo M, Obata H, Shiota A, Enya T, & Kuwamoto T (1996) Measurement of fluoride ion in the river-water flowing into Lake Biwa. Water Res, 30(4): 865–868.

Hitchcock AE, Zimmerman PW, & Coe RR (1962) Results of ten years’ work (1951–1960) on the effects of fluorides on gladiolus. Contrib Boyce Thompson Inst, 21: 303–344.

Hobbs CS & Merriman GM (1959) The effect of eight years continuous feeding of different levels of fluorine and alleviators on feed consumption, teeth, bones and production of cows. J Anim Sci, 18: 1526–1529.

Hocking MB, Hocking D, & Smyth TA (1980) Fluoride distribution and dispersion processes about an industrial point source in a forested coastal zone. Water Air Soil Pollut, 14: 133–157.

Hodge H & Smith F (1977) Occupational fluoride exposure. J Occup Med, 19: 12–39.

Hodge HC, Smith FA, & Gedalia I (1970) Excretion of fluorides. In: Fluorides and human health. Geneva, World Health Organization, pp 158–159 (WHO Monograph Series No. 59).

Hoffman DJ, Pattee OH, & Wiemeyer SN (1985) Effects of fluoride on screech owl reproduction: teratological evaluation, growth, and blood chemistry in hatchlings. Toxicol Lett, 26: 19–24.

Hoover RN, McKay FW, & Fraumeni FJF (1976) Fluoridated drinking water and the occurrence of cancer. J Natl Cancer Inst, 57: 757–768 [cited in US DHHS, 1991].

Horntvedt R (1995) Fluoride uptake in conifers related to emissions from aluminium smelters in Norway. Sci Total Environ, 163: 35–37.

Hou P (1997) The control of coal-burning fluorosis in China. Fluoride, 30: 229–232.

Hrudey SE, Soskolne CL, Berkel J, & Fincham S (1990) Drinking water fluoridation and osteosarcoma. Can J Public Health, 81: 415–416.

Huang PM & Jackson ML (1965) Mechanism of reaction of neutral fluoride solution with layer silicates and oxides of soils. Proc Soil Sci Soc Am, 29: 661–665.

Hughes PR, Weinstein LH, Johnson LM, & Braun AR (1985) Fluoride transfer in the environment: accumulation and effects on cabbage looper Trichoplusia ni of fluoride from water soluble salts and HF-fumigated leaves. Environ Pollut, A37: 175–192.

IARC (1982) Some aromatic amines, anthroquinones and nitroso compounds, and inorganic fluorides used in drinking-water and dental preparations. Lyon, International Agency for Research on Cancer, pp 237–303 (IARC Monographs on the Evaluation of Carcinogenic Risks of Chemicals to Humans, Volume 27).

IARC (1984) Polynuclear aromatic compounds. Part 3. Industrial exposures in aluminum production, coal gassification, coke production and iron and steel making. Lyon, International Agency for Research on Cancer, pp 37–64 (IARC Monographs on the Evaluation of Carcinogenic Risks of Chemicals to Humans, Volume 34).

IARC (1987) Overall evaluations of carcinogenicity: An updating of IARC monographs, volumes 1–42. Lyon, International Agency for Research on Cancer, pp 208–210 (IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, Supplement 7).

Ishidate MJ (1987) Data book on chromosomal aberration test in vitro, rev. ed. Tokyo, L.I.C. Inc.

Ivinskis M & Murray F (1984) Associations between metabolic injury and fluoride susceptibility in two species of Eucalyptus. Environ Pollut, A34: 207–223.

Jachimczak D & Skotarczak B (1978) The effect of fluorine and lead ions on the chromosomes of human leucocytes in vitro. Genet Pol, 19: 353–358.

Jackson R, Kelly S, Noblitt T, Zhang W, & Dunipace A (1994) The effect of fluoride therapy on blood chemistry parameters in osteoporotic females. Bone Miner, 27: 13–23.

Jackson RD, Kelly SA, Noblitt TW, Zhang W, Wilson ME, Dunipace AJ, Li Y, Katz BP, Brizendine EJ, & Stookey GK (1997) Lack of effect of long-term fluoride ingestion on blood chemistry and frequency of sister chromatid exchange in human lymphocytes. Environ Mol Mutagen, 29: 265–271.

Jackson WPU (1962) Further observations on the Kenhardt bone disease and its relation to fluorosis. S Afr Med J, 36: 932–936.

Jacobsen S, Goldberg J, Cooper C, & Lockwood S (1992) The association between water fluoridation and hip fracture among white women and men aged 65 years and older. A national ecologic study. Ann Epidemiol, 2: 617–626.

Jacobsen S, O’Fallon M, & Melton L (1993) Hip fracture incidence before and after fluoridation of the public water supply, Rochester, Minnesota. Am J Public Health, 83: 743–745.

Jacobson JS, Weinstein LH, McCune DC, & Hitchcock AE (1966) The accumulation of fluorine by plants. J Air Pollut Control Assoc, 16: 412–417.

Jacqmin-Gadda H, Commenges D, & Dartigues JF (1995) Fluorine concentration in drinking water and fractures in the elderly. J Am Med Assoc, 273: 775–776.

Jacqmin-Gadda H, Fourrier A, Commenges D, & Dartigues JF (1998) Risk factors for fractures in the elderly. Epidemiology, 9: 417–423.

Jain S & Susheela S (1987a) Effect of sodium fluoride on erythrocyte membrane function — with reference to metal ion transport in rabbits. Chemosphere, 16: 1087–1094.

Jain S & Susheela A (1987b) Effect of sodium fluoride on antibody formation in rabbits. Environ Res, 44: 117–125.

Jha M, Susheela A, Krishna N, Rajyalakshmi K, & Venkiah K (1982) Excessive ingestion of fluoride and the significance of sialic acid: Glycosaminoglycans in the serum of rabbit and human subjects. J Toxicol Clin Toxicol, 19: 1023–1030.

Johansson TSK & Johansson MP (1972) Sublethal doses of sodium fluoride affecting fecundity of confused flour beetles. J Econ Entomol, 65(2): 356–357.

Johnson J Jr & Bawden JW (1987) The fluoride content of infant formulas available in 1985. Pediatr Dent, 9: 33–37.

Jolly SS, Singh BM, Mathur OC, & Malhotra KC (1968) Epidemiological, clinical and biochemical study of endemic dental and skeletal fluorosis in Punjab. Br Med J, 4: 427–429.

Jones C, Harries J, & Martin A (1971) Fluorine in leafy vegetables. J Sci Food Agric, 22: 602–605.

Jones C, Callahan M, & Huberman E (1988a) Sodium fluoride promotes morphological transformation of Syrian hamster embryo cells. Carcinogenesis, 9: 2279–2284.

Jones C, Huberman E, Callaham M, Tu A, Halloween W, Pallota S, Sivak A, Lubet R, Avery M, Kouri R, Spalding J, & Tennant R (1988b) An inter-laboratory evaluation of the Syrian hamster embryo cell transformation assay using fourteen coded chemicals. Toxicol In Vitro, 2: 103–116.

Jones G, Riley M, Couper D, & Dwyer T (1999) Water fluoridation, bone mass and fracture: a quantitative overview of the literature. Aust N Z J Public Health, 23: 34–40.

Joseph S & Gadhia PK (2000) Sister chromatid exchange frequency and chromosome aberrations in residents of fluoride endemic regions of south Gujarat. Fluoride, 33: 154–158.

Joy CM & Balakrishnan KP (1990) Effect of fluoride on axenic cultures of diatoms. Water Air Soil Pollut, 49: 241–249.

Jubb TF, Annand TE, Main DC, & Murphy GM (1993) Phosphorus supplements and fluorosis in cattle — a northern Australian experience. Aust Vet J, 70: 379–383.

Kabasakalis V & Tsolaki A (1994) Fluoride content of vegetables irrigated with waters of high fluoride levels. Fresenius Environ Bull, 3(6): 377–380.

Kabata-Pendias A & Pendias H (1984) Fluorine. In: Trace elements in soil and plants. Boca Raton, Florida, CRC Press, pp 209–215.

Kaminsky L, Mahoney M, Leach J, Melius J, & Miller M (1990) Fluoride: Benefits and risks of exposure. Crit Rev Oral Biol Med, 1: 261–281.

Kanisawa M & Schroeder H (1969) Life term studies on the effect of trace elements on spontaneous tumours in mice and rats. Cancer Res, 29: 892–895.

Kaplan HM, Yee N, & Glaczenski SS (1964) Toxicity of fluoride for frogs. Lab Anim Care, 14(3): 185–188.

Karagas MR, Baron JA, Barrett JA, & Jacobsen SJ (1996) Patterns of fracture among United States elderly: geographic and fluoride effects. Ann Epidemiol, 6: 209–216.

Karstad L (1967) Fluorosis in deer (Odoceileus virginianus). Bull Wildl Dis Assoc, 3: 42–46.

Karthikeyan G, Pius S, & Apparao BV (1996) Contribution of fluoride in water and food to the prevalence of fluorosis in areas of Tamil Nadu in south India. Fluoride, 29: 151–155.

Karunagaran VM & Subramanian A (1992) Fluoride pollution in the Uppanar Estuary, Cuddalore, South India. Mar Pollut Bull, 24(10): 515–517.

Kay CE, Tourangeau PC, & Gordon CC (1975) Industrial fluorosis in wild mule and whitetail deer from western Montana. Fluoride, 8(4): 182–191.

Keller T (1980) The simultaneous effect of soil-borne NaF and air pollutant SO₂ on CO₂-uptake and pollutant accumulation. Oecologia, 44: 283–285.

Khalil A (1995) Chromosome aberrations in cultured rat bone marrow cells treated with inorganic fluorides. Mutat Res, 343: 67–74.

Khalil AM & Da’dara AA (1994) The genotoxic and cytotoxic activities of inorganic fluoride in cultured rat bone marrow cells. Arch Environ Contam Toxicol, 26: 60–63.

Kierdorf H & Kierdorf U (1997) Disturbances of the secretory stage of amelogenesis in fluorosed deer teeth: a scanning electron-microscopic study. Cell Tissue Res, 289: 125–135.

Kierdorf H & Kierdorf U (1999) Reduction of fluoride deposition in the vicinity of a brown coal-fired power plant as indicated by bone fluoride concentrations of roe deer (Capreolus capreolus). Bull Environ Contam Toxicol, 63: 473–477.

Kierdorf H, Kierdorf U, Sedlacek F, & Erdelen M (1996) Mandibular bone fluoride levels and occurrence of fluoride induced dental lesions in populations of wild deer (Cervus elaphus) from central Europe. Environ Pollut, 93(1): 75–81.

Kierdorf H, Kierdorf U, Richards A, & Sedlacek F (2000) Disturbed enamel formation in wild boars (Sus scrofa) from fluoride polluted areas in Central Europe. Anat Rec, 259: 12–24.

Kierdorf U (1988) [A study on chronic fluoride intoxication in roe deer (Capreolus capreolus L.) caused by emissions.] Z Jagdwiss, 34: 192–204 (in German).

Kierdorf U & Kierdorf H (1999) Dental fluorosis in wild deer: its use as a biomarker of increased fluoride exposure. Environ Monit Assess, 57: 265–275.

Kierdorf U & Kierdorf H (2000) The fluoride content of antlers as an indicator of fluoride exposure in red deer (Cervus elaphus): A historical biomonitoring study. Arch Environ Contam Toxicol, 38: 121–127.

Kierdorf U, Kierdorf H, Erdelen M, & Korsch JP (1989) Mandibular fluoride concentration and its relation to age in roe deer (Capreolus capreolus L.). Comp Biochem Physiol, 94A(4): 783–785.

Kierdorf U, Kierdorf H, & Fejerskov O (1993) Fluoride-induced developmental changes in enamel and dentine of European roe deer (Capreolus capreolus L.) as a result of environmental pollution. Arch Oral Biol, 38(12): 1071–1081.

Kierdorf U, Kierdorf H, Sedlacek F, & Fejerskov O (1996) Structural changes in fluorosed dental enamel of red deer (Cervus elaphus L.) from a region with severe environmental pollution by fluorides. J Anat, 188: 183–195.

Kierdorf U, Richards A, Sedlacek F, & Kierdorf H (1997) Fluoride content and mineralization of red deer (Cervus elaphus ) antlers and pedicles from fluoride polluted and uncontaminated regions. Arch Environ Contam Toxicol, 32: 222–227.

Kierdorf U, Kierdorf H, & Boyde A (2000) Structure and mineralisation density of antler and pedicle bone in red deer (Cervus elaphus L.) exposed to different levels of environmental fluoride: a quantitative backscattered electron imaging study. J Anat, 196: 71–83.

Kinlen L & Doll R (1981) Fluoridation of water supplies and cancer mortality. III. A re-examination of mortality in cities in the USA. J Epidemiol Community Health, 35: 239–244.

Kiritsy MC, Levy SM, Warren JJ, Guha-chowdhury M, Heilman JR, & Marshall T (1996) Assessing fluoride concentrations of juices and juice-flavoured drinks. J Am Dental Assoc, 127: 895–902.

Kirk PWW & Lester JN (1986) Halogen compounds. In: Harrison RM & Perry R ed. Handbook of air pollution analysis, 2nd ed. London, Chapman & Hall, pp 425–462.

Kishi K & Ishida T (1993) Clastogenic activity of sodium fluoride in great ape cells. Mutat Res, 301: 183–188.

Kishi K & Tonomura A (1984) Cytogenetic effects of sodium fluoride. Mutat Res, 130: 367 (abstract).

Kissa E (1987) Determination of inorganic fluoride in blood with a fluoride ion-selective electrode. Clin Chem, 33: 253–255.

Klumpp A, Klumpp G, & Domingos M (1994) Plants as bioindicators of air pollution at the Serra do Mar near the industrial complex of Cubatao, Brazil. Environ Pollut, 85: 109–116.

Klumpp A, Klumpp G, Domingos M, & Dias Da Silva M (1996a) Fluoride impact on native tree species of the Atlantic forest near Cubatao, Brazil. Water Air Soil Pollut, 87(1–4): 57–71.

Klumpp A, Dominos M, & Klumpp G (1996b) Assessment of the vegetation risk by fluoride emissions from fertiliser industries at Cubatao, Brazil. Sci Total Environ, 192: 219–228.

Klut ME, Bisalputra T, & Antia NJ (1981) Abnormal ultrastructural features of a marine dinoflagellate adapted to grow successfully in the presence of inhibitory fluoride concentration. J Protozool, 28(4): 406–414.

Knox E (1985) Fluoridation of water and cancer: A review of the epidemiological evidence. Report of the British Working Party. London, HMSO.

Kono K, Yoshida Y, Yamagata H, Tanimura Y, Takeda Y, Harada A, & Doi K (1986) Fluoride clearance in the aging kidney. Fluoride Research 1985. Stud Environ Sci, 27: 407–414.

Kono K, Yoshida Y, Watanabe M, Watanabe H, Inoue S, Murao M, & Doi K (1990) Elemental analysis of hair among hydrofluoric acid exposed workers. Int Arch Occup Environ Health, 62: 85–88.

Korkka-Niemi K, Sipilä A, Hatva T, Hiisvirta L, Lahti K, & Alfthan G (1993) Nation-wide rural well water survey. The quality of household water and factors influencing it. Helsinki, National Board of Waters and the Environment, 225 pp.

Korns R (1969) Relationship of water fluoridation to bone density in two NY towns. Public Health Rep, 84: 815–825.

Kragstrup J, Richards A, & Fejerskov O (1989) Effects of fluoride on cortical bone remodelling in the growing domestic pig. Bone, 10: 421–424.

Krasowska A (1989) Influence of low-chitin krill meal on reproduction of Clethrionomys glareolus (Schreber, 1780). Comp Biochem Physiol, 94C(1): 313–320.

Kraut A & Lilis R (1990) Pulmonary effects of acute exposure to degradation products of sulphur hexafluoride during electrical cable work. Br J Ind Med, 47: 828–832.

Krishnamachari KAVR (1976) Further observations on the syndrome of genu valgum of South India. Ind J Med Res, 64: 284–291.

Krishnamachari K (1987) Fluorine. Trace Elem Hum Anim Nutr, 1: 365–415.

Krishnamachari KAVR & Krishnaswamy K (1973) Genu valgum and osteoporosis in an area of endemic fluorosis. Lancet, 2: 887–889.

Kröger H, Alhava E, Honkanen R, Tupperainen M, & Saarikoski S (1994) The effect of fluoridated drinking water on axial bone mineral density — a population-based study. Bone Miner, 27: 33–41.

Krook L & Maylin GA (1979) Industrial fluoride pollution. Chronic fluoride poisoning in Cornwall Island cattle. Cornell Vet, 69(suppl 8): 4–70.

Kudo A & Garrec J-P (1983) Accidental release of fluoride into experimental pond and accumulation in sediments, plants, algae, molluscs and fish. Regul Toxicol Pharmacol, 3: 189–198.

Kudo A, Garrec JP, & Plebin R (1987) Fluoride distribution and transport along rivers in the French Alps. Ecotoxicol Environ Saf, 13(3): 263–273.

Kühn R, Pattard M, Pernak K-D, & Winter A (1989) Results of the harmful effects of water pollutants to Daphnia magna in the 21 day reproduction test. Water Res, 23(4): 501–510.

Kumpulainen J & Koivistoinen P (1977) Fluorine in foods. Residue Rev, 68: 37–57.

Kurttio P, Gustavsson N, Vartiainen T, & Pekkanen J (1999) Exposure to natural fluoride in well water and hip fracture: a cohort analysis in Finland. Am J Epidemiol, 150: 817–824.

Kuusisto AN & Telkkä A (1961) The effect of sodium fluoride on the metamorphosis of tadpoles. Acta Odontol Scand, 19: 121–127.

Lahermo P & Backman B (2000) The occurrence and geochemistry of fluorides with special reference to natural waters in Finland. Espoo, Geological Survey of Finland, 40 pp. (Research Report 149).

Lahermo P, Ilmasti M, Juntunen R, & Taka M (1990) The geochemical atlas of Finland. Part 1: The hydrogeochemical mapping of Finnish groundwater. Espoo, Geological Survey of Finland.

Lalumandier JA & Ayers LW (2000) Fluoride and bacterial content of bottled water vs tap water. Arch Fam Med, 9: 246–250.

Lan CF, Lin IF, & Wang SJ (1995) Fluoride in drinking water and the bone mineral density of women in Taiwan. Int J Epidemiol, 24: 1182–1187.

Landy RB, Lambertsen RH, Palsson PA, Krook L, Nevius A, & Eckerlin R (1991) Fluoride in the bone and diet of fin whales, Balaenoptera physalus. Mar Environ Res, 31: 241–247.

Laroche M & Mazières B (1991) Side-effects of fluoride therapy. Baillière’s Clin Rheumatol, 5: 61–76.

Larsson K, Eklund A, Arns R, Lowgren H, Nystrom J, Sundstrom G, & Tornling H (1989) Lung function and bronchial reactivity in aluminum potroom workers. Scand J Work Environ Health, 15: 296–301.

Lasne C, Lu Y, & Chouroulinkov I (1988) Transforming activities of sodium fluoride in cultured Syrian hamster embryo and BALB/3T3 cells. Cell Biol Toxicol, 4: 311–324.

Latham MC & Gretch P (1967) The effects of excessive fluoride intake. Am J Public Health, 57: 651–660.

Lau KH & Baylink DJ (1998) Molecular mechanism of action of fluoride on bone cells. J Bone Miner Res, 13: 1660–1667.

Laurence JA (1983) Effects of fluoride on plant–pathogen interactions. In: Shupe J, Peterson H, & Leone N ed. Fluorides: Effects on vegetation, animals and humans. Salt Lake City, Utah, Paragon Press, pp 145–149.

Laurence JA & Reynolds KL (1984) Growth and lesion development of Xanthomonas campestris pv. phaseoli on leaves of red kidney bean plants exposed to hydrogen fluoride. Phytopathology, 74: 578–580.

Lavado RS, Reinaudi NB, & Parodi AA (1983) Fluoride retention and leach possibilities in Argentine salt-affected soils. Fluoride Q Rep, 16(4): 247–251.

LeBlanc GA (1980) Acute toxicity of priority pollutants to water flea (Daphnia magna). Bull Environ Contam Toxicol, 24: 684–691.

LeBlanc GA (1984) Interspecies relationships in acute toxicity of chemicals to aquatic organisms. Environ Toxicol Chem, 3: 47–60.

LeBlanc F, Comeau G, & Rao DN (1971) Fluoride injury symptoms in epiphytic lichens and mosses. Can J Bot, 49: 1691–1698.

Leece DR, Scheltema JH, Anttonen T, & Weir RG (1986) Fluoride accumulation and toxicity in grapevines Vitis vinifera L. in New South Wales. Environ Pollut, A40: 145–172.

Lehmann R, Wapniarz M, Hofmann B, Pieper B, Haubitz I, & Allolio B (1998) Drinking water fluoridation: bone mineral density and hip fracture incidence. Bone, 22: 273–278.

Levy SM (1994) Review of fluoride exposures and ingestion. Community Dent Oral Epidemiol, 22: 173–180.

Levy SM, Kiritsy MC, & Warren JJ (1995) Sources of fluoride intake in children. J Public Health Dent, 55: 39–52.

Li Y, Dunipace A, & Stookey G (1987a) Absence of mutagenic or antimutagenic activities of fluoride in Ames Salmonella assays. Mutat Res, 190: 229–236.

Li Y, Heerema N, Dunipace A, & Stokey G (1987b) Genotoxic effects of fluoride evaluated by sister-chromatid exchange. Mutat Res, 192: 191–201.

Li Y, Dunipace A, & Stookley G (1987c) Lack of genotoxic effects of fluoride in the mouse bone-marrow micronucleus test. J Dent Res, 66: 1687–1690.

Li Y, Dunipace A, & Stookey G (1987d) Effects of fluoride on the mouse sperm morphology test. J Dent Res, 66: 1509–1511.

Li Y, Zhang W, Noblitt T, Dunipace A, & Stokey G (1989) Genotoxic evaluation of chronic fluoride exposure: sister-chromatid exchange study. Mutat Res, 227: 159–165.

Li Y, Liang CK, Katz BP, Brizendine EJ, & Stookey GK (1995) Long-term exposure to fluoride in drinking water and sister chromatid exchange frequency in human blood lymphocytes. J Dent Res, 74: 1468–1474.

Li Y, Liang C, Slemenda CW, Ji R, Sun S, Cao J, Emsley C, Ma F, Wu Y, Ying P, Zhang Y, Gao S, Zhang W, Katz B, Niu S, Cao S, & Johnston C (2001) Effect of long-term exposure to fluoride in drinking water on risks of bone fractures. J Bone Miner Res, 16(5): 932–939.

Liang CK, Ji R, & Cao SR (1997) Epidemiological analysis of endemic fluorosis in China. Environ Carcinogen Ecotoxicol Rev, C15(2): 123–138.

Liu BK (1996) Lung X-ray changes in skeletal fluorosis caused by coal combustion. Fluoride, 29: 33–35.

Liu Y ed. (1995) Human exposure assessment of fluoride. An international study within the WHO/UNEP Human Exposure Assessment Location (HEAL) Programme. Beijing, Chinese Academy of Preventive Medicine, Institute of Environmental Health Monitoring, Technical Cooperation Centre of Fluoride/HEAL Programme, 64 pp.

Low PS & Bloom H (1988) Atmospheric deposition of fluoride in the lower Tamar Valley, Tasmania. Atmos Environ, 22(9): 2049–2056.

Lu D, Zheng Z, Wang J, & Chen K (1989) [Study of the mutagenic effect of sodium fluoride.] Yichuan [Hereditas (Beijing)], 11: 23 (in Chinese).

Lund K, Ekstrand J, Boe J, Sostrand P, & Kongerud J (1997) Exposure to hydrogen fluoride: an experimental study in humans of concentrations of fluoride in plasma, symptoms, and lung function. Occup Environ Med, 54: 32–37.

Ma J, Cheng L, Bai W, & Wu H (1986) [The effects of sodium fluoride on SCEs of the mice and on the micronucleus of the bone marrow of pregnant mice and its fetus liver.] Yichuan [Hereditas (Beijing)], 8: 39–41 (in Chinese).

Machoy Z, Dabkowska E, Samujlo D, Ogonski T, Raczynski J, & Gebczynska Z (1995) Relationship between fluoride content in bones and the age in European elk (Alces alces L.). Comp Biochem Physiol, 111C(1): 117–120.

MacIntire WH, Sterges AJ, & Shaw WM (1955) Fate and effects of hydrofluoric acid added to four Tennessee soils in a four year lysimeter study. J Agric Food Chem, 3(9): 777–782.

MacLean DC & Schneider RE (1981) Effects of gaseous hydrogen fluoride on the yield of field-grown wheat. Environ Pollut, 24: 39–44.

MacLean DC, Schneider RE, & McCune DC (1977) Effects of chronic exposure to gaseous fluoride on yield of field-grown bean and tomato plants. J Am Soc Hortic Sci, 102(3): 297–299.

MacLean DC, McCune DC, & Schneider RE (1984a) Growth and yield of wheat and sorghum after sequential exposures of hydrogen fluoride. Environ Pollut, A36: 351–365.

MacLean DC, Weinstein LH, McCune DC, & Schneider RE (1984b) Fluoride-induced suture red spot in "Elberta" peach. Environ Exp Bot, 24(4): 353–367.

Madans J, Kleinman J, & Cornoni-Huntley J (1983) The relationship between hip fracture and water fluoridation: an analysis of national data. Am J Public Health, 73: 296–298.

Madkour S & Weinstein LH (1988) Effects of fumigation with hydrogen fluoride on the loading of [¹⁴C]sucrose into the phloem of soybean leaves. Environ Toxicol Chem, 7: 317–320.

Mahadevan TN, Meenakshy V, & Mishra UC (1986) Fluoride cycling in nature through precipitation. Atmos Environ, 20: 1745–1749.

Mahoney MC, Nasca PC, Burnett WS, & Melius JM (1991) Bone cancer incidence rates in New York State: Time trends and fluoridated drinking water. Am J Public Health, 81: 475–479.

Malea P (1995) Fluoride content in three seagrasses of the Antikyra Gulf (Greece) in the vicinity of an aluminum factory. Sci Total Environ, 166: 11–17.

Marais JSC (1944) Monofluoracetic acid, the toxic principle of the "Grifblaar" Dichapetabum cymosum (Hook) Engl Onderstepoort. J Vet Sci Anim Ind, 20(1): 67–73.

Marie P & Mott M (1986) Short-term effects of fluoride and strontium on bone formation and resorption in the mouse. Metabolism, 35: 547–561.

Marks TA, Schellenberg D, Metzler CM, Oostveen J, & Morey MJ (1984) Effect of dog food containing 460 ppm fluoride on rat reproduction. J Toxicol Environ Health, 14: 707–714.

Martin GR, Brown KS, Matheson DW, Lebowitz H, Singer L, & Ophaug R (1979) Lack of cytogenetic effects in mice or mutations in Salmonella receiving sodium fluoride. Mutat Res, 66: 159–167.

Martin J-M & Salvadori F (1983) Fluoride pollution in French rivers and estuaries. Estuarine Coastal Shelf Sci, 17: 231–242.

Maurer J, Cheng M, Boysen B, & Anderson R (1990) Two-year carcinogenicity study of sodium fluoride in rats. J Natl Cancer Inst, 82: 1118–1126.

Maurer J, Cheng M, Boysen B, Squire R, Strandberg J, Weisbrode J, & Anderson R (1993) Confounded carcinogenicity study of sodium fluoride in CD-1 mice. Regul Toxicol Pharmacol, 18: 154–168.

Mayer DF, Lunden JD, & Weinstein LH (1988) Evaluation of fluoride levels and effects on honey bees (Apis mellifera L.) (Hymenoptera: Apidae). Fluoride Q Rep, 21(3): 113–120.

Mayer TG & Gross PL (1985) Fatal systemic fluorosis due to hydrofluoric acid burns. Ann Emerg Med, 14: 149–153.

McClenahen J (1976) Distribution of soil fluorides near an airborne fluoride source. J Environ Qual, 5: 472–475.

McClenahen JR (1978) Community changes in a deciduous forest exposed to air pollution. Can J For Res, 8: 432–438.

McClure FJ (1944) Fluoride domestic water and systemic effects. I. Relation to bone fracture experience, height and weight of high school boys and young selectees of the armed forces of the United States. Public Health Rep, 59: 1543–1558.

McClurg TP (1984) Effects of fluoride, cadmium and mercury on the estuarine prawn Penaeus indicus. Water SA, 10(1): 40–45.

McCune DC, Lauver TL, & Hansen KS (1991) Relationship of concentration of gaseous hydrogen fluoride to incidence and severity of foliar lesions in black spruce and white spruce. Can J For Res, 21: 756–761.

McDonagh MS, Whiting PF, Wilson PM, Sutton AJ, Chestnutt I, Cooper J, Misso K, Bradley M, Treasure E, & Kleijnen J (2000) Systematic review of water fluoridation. Br Med J, 321: 855–859.

McGuire S, Vanable E, McGuire M, Buckwalter JA, & Douglass CW (1991) Is there a link between fluoridated water and osteosarcoma? J Am Dent Assoc, 122: 38–45.

McIvor M (1990) Acute fluoride toxicity: pathophysiology and management. Drug Saf, 5: 79–85.

McKnight-Hanes M, Leverett D, Adair S, & Shields C (1988) Fluoride content of infant formulas: soy-based formulas as a potential factor in dental fluorosis. Pediatr Dent, 10: 189–194.

McLaughlin MJ, Tiller KG, Naidu R, & Stevens DP (1996) Review: the behaviour and environmental impact of contaminants in fertilizers. Aust J Soil Res, 34: 1–54.

McLaughlin MJ, Stevens DP, Keerthisinghe G, Cayley JWD, & Ridley AM (2001) Contamination of soil with fluoride by long-term application of superphosphates to pastures and risks to grazing animals. Aust J Soil Res, 39(3): 627–640.

McNulty IB & Lords JL (1960) Possible explanation of fluoride-induced respiration in Chlorella pyrenoidosa. Science, 132: 1553–1554.

Meeussen JCL, Scheidegger A, Hiemstra T, Van Riemsdijk WH, & Borkovec M (1996) Predicting multicomponent adsorption and transport of fluoride at variable pH in a goethite–silica sand system. Environ Sci Technol, 30(2): 481–488.

Meng Z & Zhang B (1997) Chromosomal aberrations and micronuclei in lymphocytes of workers at a phosphate fertilizer factory. Mutat Res, 393: 283–288.

Meng Z, Meng H, & Cao X (1995) Sister-chromatid exchange in lymphocytes of workers at a phosphate fertilizer factory. Mutat Res, 334: 243–246.

Messer H & Ophaug R (1993) Influence of gastric acidity on fluoride absorption in rats. J Dent Res, 72: 619–622.

Messer HH, Armstrong WD, & Singer L (1973) Influence of fluoride intake on reproduction in mice. J Nutr, 103: 1319–1326.

Messer H, Nopakum J, & Rudney J (1989) Influence of pH on intestinal fluoride transport in vitro. J Dent Assoc Thailand, 39: 226–232.

Meunier PJ, Severt JL, Reginster JY, Briancon D, Apelboom T, Netter P, Loeb G, Rouillon A, Barry S, Evreus JC, Avouac B, & Marchandise X (1998) Fluoride salts are no better at preventing new vertebral fractures than calcium–vitamin D in postmenopausal osteoporosis: the FAVO Study. Osteoporosis Int, 8: 4–12.

Michael M, Barot VV, & Chinoy NJ (1996) Investigations of soft tissue functions in fluorotic individuals of North Gujarat. Fluoride, 29: 63–71.

Michel J, Suttie J, & Sunde M (1984) Fluorine deposition in bone as related to physiological state. Poult Sci, 63: 1407–1411.

Mihashi M & Tsutsui T (1996) Clastogenic activity of sodium fluoride to rat vertebral body-derived cells in culture. Mutat Res, 368: 7–13.

Mikaelian I, Qualls CW, De Guise S, Whaley MW, & Martineau D (1999) Bone fluoride concentrations in beluga whales from Canada. J Wildl Dis, 35(2): 356–360.

Milhaud G, El Bahri L, & Dridi A (1981) The effects of fluoride on fish in Gabes Gulf. Fluoride, 14(4): 161–168.

Mishra PC & Mohapatra AK (1998) Haematological characteristics and bone fluoride content in Bufo melanostictus from an aluminium industrial site. Environ Pollut, 99: 421–423.

Mithal A, Trivedi N, Gupta SK, Kumar S, & Gupta RK (1993) Radiological spectrum of endemic fluorosis: relationship with calcium intake. Skeletal Radiol, 22: 257–261.

Mohammed A & Chandler M (1982) Cytological effects of sodium fluoride on mice. Fluoride, 15: 110–118.

Moore M, Clive D, Hozier J, Howard B, Batsun A, Turner N, & Sawyer J (1985) Analysis of trifluorothymidine resistant (TFT^r) mutants of L5178Y/TK± mouse lymphoma cells. Mutat Res, 151: 161–174.

Morgan L, Allred E, Tavares M, Bellinger D, & Needleman H (1998) Investigation of the possible associations between fluorosis, fluoride exposure, and childhood behaviour problems. Am Acad Pediatr Dent, 20(4): 244–252.

Morris JB & Smith FA (1982) Regional deposition and absorption of inhaled hydrogen fluoride in the rat. Toxicol Appl Pharmacol, 62: 81–89.

Mosekilde I, Kragstrup J, & Richards A (1987) Compression strength, ash weight and volume of vertebral trabecular bone in experimental fluorosis in pigs. Calcif Tissue Int, 40: 318–322.

Moss ME, Kanarek MS, Anderson HA, Hanrahan LP, & Remington PL (1995) Osteosarcoma, seasonality, and environmental factors in Wisconsin, 1979–1989. Arch Environ Health, 50: 235–241.

Moule GR (1944) Fluoride poisoning of livestock. Queensl Agric J, 58: 54–55.

Mullenix PJ, Denbesten K, Schunior A, & Keernan WJ (1995) Neurotoxicity of sodium fluoride in rats. Neurotoxicol Teratol, 17(2): 169–177.

Mullet T, Zoeller T, Bingham H, Pepine CJ, Prida XE, Castenholz R, & Kirby R (1987) Fatal hydrofluoric acid cutaneous exposure with refractory ventricular fibrillation. J Burn Care Rehab, 8: 216–219.

Mur J, Moulin J, Meyer-Bisch C, Massin N, Coulon J, & Loulergue J (1987) Mortality of aluminum reduction plant workers in France. Int J Epidemiol, 16: 257–264.

Muramoto S, Nishizaki H, & Aoyama I (1991) Effects of fluorine emissions on agricultural products surrounding an aluminum factory. J Environ Sci Health, B26: 351–356.

Murray F (1981) Effects of fluorides on plant communities around an aluminium smelter. Environ Pollut, A24: 45–56.

Murray F (1984a) Effect of long term exposure to hydrogen fluoride on grapevines. Environ Pollut, A36: 337–349.

Murray F (1984b) Fluoride retention in highly leached disturbed soils. Environ Pollut, B7: 83–95.

Murray F & Wilson S (1988a) Effects of sulphur dioxide, hydrogen fluoride and their combination on three Eucalyptus species. Environ Pollut, 52: 265–279.

Murray F & Wilson S (1988b) Joint action of sulfur dioxide and hydrogen fluoride on growth of Eucalyptus tereticornis. Environ Exp Bot, 28(4): 343–349.

Murray F & Wilson S (1988c) The joint action of sulphur dioxide and hydrogen fluoride on the yield and quality of wheat and barley. Environ Pollut, 55: 239–249.

Murray TM, Harrison JE, Bayley TA, Josse RG, Sturtridge WC, Chow R, Budden F, Laurier L, Pritzker KP, Kandel R, Vieth R, Strauss A, & Goodwin S (1990) Fluoride treatment of postmenopausal osteoporosis: age, renal function, and other clinical factors in the osteogenic response. J Bone Miner Res, 5(suppl 1): S27–S35.

Naccache H, Simard P, Trahan L, Demers M, Lapointe C, & Brodeur J (1990) Variability in the ingestion of toothpaste by preschool children. Caries Res, 24: 359–363.

Naccache H, Simard P, Trahan L, Brodeur JM, Demers M, Lachapelle D, & Bernard PM (1992) Factors affecting the ingestion of fluoride dentifrice by children. J Public Health Dent, 52: 222–226.