Hydrogen fluoride

Carcinogenicity

Description of key information

No studies with HF are available.  High quality NTP studies in the rat and mouse are available for sodium fluoride

Key value for chemical safety assessment

Carcinogenicity: via oral route

Link to relevant study records

Reference

Reference 1

Endpoint:

carcinogenicity: oral

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

7th October 1985 to 27th September 1987

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: NTP study

Qualifier:

according to guideline

Guideline:

other: NTP protocol

Principles of method if other than guideline:

NTP protocol for the assessment of carcinogenicity

GLP compliance:

yes

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Details on test animals or test system and environmental conditions:

Male and female F344/N rats were used, obtained from the National Cancer Institute's Frederick Cancer Research Facility. Rats were 4 weeks old on arrival, and were quarantined for 12 days. Rats were placed on study when they were 6 weeks old. Rats were housed 5 per cage in polycarbonate cages rotated every other week,and identified by toe marks. Specially formulated low fluoride feed (NIH-07 Rat and Mouse Pellets Low Fluoride) and deionised water were available ad libitum. Beta-Chip hardwood chips were provided as bedding as changed twice weekly. Temperature was maintained at 19.4-26.1oC, humidity: 22-76%, fluorescent light was provided 12 hours/day, and there were 10 room air changes per hour.

The study began on 7th October 1985, the 105 week scheduled termination took place on 27th September 1987.

Route of administration:

oral: drinking water

Vehicle:

water

Details on exposure:

Rats were given sodium fluoride in deionised drinking water at 0, 25, 100 or 175 ppm ad libitum for up to 103 weeks.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Dose formulation analyses were conducted utilising a potentiometric method with a fluoride ion electrode. Analyses were conducted weekly on all dose formulations during the first 6 months, then every 8 weeks for the remainder of the study. Analyses indicated that all dose formulations were within ±10% of target concentrations throughout the study. Deionised water had a fluoride concentration of =0.1ppm.

Duration of treatment / exposure:

Fluoridated drinking water was available ad libitum, daily for up to 103 weeks.

Frequency of treatment:

Daily.

Post exposure period:

Rats were sacrificed approximately 1 week after the final dose.

Remarks:

Doses / Concentrations:
0, 25, 100 or 175 ppm
Basis:
nominal in water

No. of animals per sex per dose:

Groups of 100 rats of each sex received 0 or 175ppm sodium fluoride, and groups of 70 rats of each sex received 25 or 100 ppm. An additional group of 50 animals of each sex was included to provide paired age-matched controls, these animals received deionised water.

Control animals:

yes, concurrent vehicle

Details on study design:

Groups of 100 rats of each sex received 0 or 175ppm sodium fluoride, and groups of 70 rats of each sex received 25 or 100 ppm. The doses were based on the lower weight gain of male and female rats given 300ppm in a 6 month study, and the occurrence of potentially life-threatening lesions in the stomach of these rats. Also, an initial 2 year study had been conducted using 100ppm as the top dose, but it was felt that the rats could tolerate higher concentrations, therefore the top dose chosen for the present study was 175ppm. An additional group of 50 animals of each sex was included to provide paired age-matched controls, these animals received deionised water. During every study week that one or more rats from any group receiving sodium fluoride in the water was found dead or killed in a moribund condition, one animal of the same sex was chosen at random from the paired control group and killed. For group assignment, animals were assigned to weight classes, then randomised to test and control groups by partitioning algorithm using Xybion Pathology/Toxicology Data System.

Positive control:

Not required.

Observations and examinations performed and frequency:

Rats were observed twice daily for mortality and morbidity. Initially weights and clinical signs were recorded weekly through to week 13, then monthly thereafter. Every 4 weeks feed and water consumption was recorded for a 7 day consecutive period.

Sacrifice and pathology:

Necropsy was performed on all animals including those found dead. Interim sacrifices were performed at 27 weeks and 66 weeks. Terminal sacrifice was performed at 105 weeks.

Other examinations:

In addition, studies to assess the bioavailability of fluoride in the diet were conducted in male rats at approx. 6, 12 and 18 months on study. Urinalysis, haematology and clinical chemistry were carried out at 27 and 66 weeks. The left humerus of all rats killed at interim sacrifices and of 10 randomly selected rats from each group at terminal sacrifice was evaluated for fluoride concentration. The incisors of designated rats at all scheduled sacrifices were evaluated for attrition and mottling.

Statistics:

Survival analyses: the probability of survival was estimated by the product-limit procedure of Kaplan and Meier. Analyses for possible dose-related effects on survival used Cox's method for testing two groups for equality and Tarone's life table test for dose-related trends.
The incidence of neoplastic or nonneoplastic lesions was given as the ratio of the number of animals bearing such lesions at a specific anatomic site to the number of animals in which that site was examined.
Tumour incidence was analysed by logistic regression, tumour prevalence was modeled as a logisitic function of chemical exposure and time. Also used were the life table test, the Fisher exact test, and the Cochran-Armitage trend test. Tests of significance included pairwise comparisons.
Continuous variables were analysed by comparing dosed groups to the control group using the nonparametric Dunn or Shirley multiple comparison test. Jonckheere's test was also used.

Clinical signs:

effects observed, treatment-related

Mortality:

mortality observed, treatment-related

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

no effects observed

Ophthalmological findings:

not examined

Haematological findings:

no effects observed

Clinical biochemistry findings:

effects observed, treatment-related

Urinalysis findings:

effects observed, treatment-related

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Histopathological findings: neoplastic:

effects observed, treatment-related

Details on results:

CLINICAL SIGNS AND MORTALITY

There was no treatment-related mortality; survival was unaffected by treatment. Clinical signs were limited to the teeth of rats at 100 and 175 ppm (attrition, deformity, discoloration, mottling, malocclusion). Mottling of the teeth was apparent at 25 ppm.

BODY WEIGHT AND WEIGHT GAIN

Bodyweights and weight gain were unaffected by treatment with NaF.

FOOD CONSUMPTION

Food consumption was unaffected by treatment


WATER CONSUMPTION AND COMPOUND INTAKE

Water consumption was unaffected by treatment. The intake of sodium fluoride over the course of the study was estimated to be 1.3, 5.2 and 8.6 mg/kg bw/d in males; 1.3, 5.5 abd 9.5 mg/kg bw/d for females.


HAEMATOLOGY

Parameters were unaffected by treatment.

CLINICAL CHEMISTRY

Parameters were unaffected by treatment.

URINALYSIS

Parameters were unaffected by treatment, with the possible exception of a small increase in calcium concentration in 175 ppm females.


ORGAN WEIGHTS

Organ weights were unaffected by treatment.


HISTOPATHOLOGY: NON-NEOPLASTIC

The incidence of osteosclerosis was increased in females at 175 ppm. Aterations in the teeth (dentine dysplasia, odontoblast and ameloblast degeneration) were seen in the incisors and were more frequent in males than females.


HISTOPATHOLOGY: NEOPLASTIC

Osteocarcoma was seen in one male at 100 ppm(2%) and three males at 175 ppm (4%). Squamous cell tumours of the oral mucosa were seen in control and treated animals and were not considered to be related to treatment. A marginal increase in thyroid follicular cell neoplasms was not considered to be related to treatment. A decreased incidence of uterine stromal polyps was seen in females at 175 ppm.


HISTORICAL CONTROL DATA

Osteosarcoma was reported to occur with a mean incidence of 0.5% in untreated male rats in NTP studies and a maximum incidence of 6%. The incidences in treated males in this study are within the historical range.

OTHER FINDINGS

Plasma fluoride concentration, urine fluoride concentration and bone fluoride concentration were increased in all treated groups.

Relevance of carcinogenic effects / potential:

Based on the results of this study the NTP state that there was 'equivocal evidence of carcinogenic activity' of sodium fluoride in male F344/N rats based on the occurrence of a small number of osteosarcomas in dosed animals (equivocal evidence is a category for uncertain findings defined as studies that are interpreted as showing a marginal increase of neoplasms that may be related to chemical administration). There was no evidence of carcinogenic activity in female F344/N rats receiving sodium fluoride in their drinking water at 25, 100 or 175ppm.

Dose descriptor:

NOAEL

Effect level:

25 ppm (nominal)

Sex:

male

Basis for effect level:

other: Equivoval evidence of carcinogenicity was seen at 100 and 175 ppm

Remarks on result:

other: Effect type: carcinogenicity (migrated information)

Dose descriptor:

NOAEL

Effect level:

175 ppm (nominal)

Sex:

female

Basis for effect level:

other: No evidence of carcinogenicity was seen at any dose level

Remarks on result:

other: Effect type: carcinogenicity (migrated information)

Dose descriptor:

NOAEL

Effect level:

< 25 ppm

Sex:

male/female

Basis for effect level:

other: Dental effects were apparent in all treated groups

Remarks on result:

other: Effect type: toxicity (migrated information)

Survival rates after 2 years were:

males - control 42/80; 25ppm 25/51; 100ppm 23/50; 175ppm 42/80

females - control 59/80; 25ppm 31/50; 100ppm 34/50; 175ppm 42/80.

The pairwise comparison of the incidence of osteosarcomas in the 175 ppm group versus that in the controls was not statistically significant, however osteosarcomas occurred with a statistically significant dose-response trend.

Bone osteosarcomas in male rats

Bone: Osteosarcoma	Control	25ppm	100ppm	175ppm
Overall rates^a	0/80 (0%)	0/51 (0%)	1/50 (2%)	3/80 (4%)^b
Adjusted rates^c	0.0%	0.0%	4.3%	5.3%
Terminal rates^d	0/42 (0%)	0/25 (0%)	1/23 (4%)	1/42 (2%)
First incidence (days)	-	-	729 (T)	388
Logisitic regression tests^e	P=0.027	-^f	P=0.380	P=0.099

(T) Terminal sacrifice

^aNumber of tumour bearing animals/number of animals necropsied.

^bOne extraskeletal osteosarcoma occurred in a high dose male rat.

^cKaplan-Meier estimated tumour incidence at the end of the study after adjustment for intercurrent mortality.

^dObserved incidence at terminal kill.

^eBeneath the control incidence are the P values associated with the trend test. Beneath the dosed group incidence are the P values corresponding to pairwise comparisons between the controls and that dosed group. The logistic regression tests regard these lesions as non fatal.

^fNo tumours in dosed group or control group; statistical test not performed.

Tooth abnormalities (gross observations) in rats

Observation^a	Control	25ppm	100ppm	175ppm
Male
Attrition^b	0 (0%)	0 (0%)	7 (30%)	22 (50%)
Deformity^c	1 (1%)	0 (0%)	12 (17%)	27 (27%)
Discolouration^c	1 (1%)	2 (3%)	15 (21%)	31 (31%)
Malocclusion^c	1 (1%)	1 (1%)	2 (3%)	13 (13%)
Mottling^b	2 (5%)	22 (85%)	22 (96%)	44 (100%)
Female
Attrition	0 (0%)	0 (0%)	1 (3%)	2 (4%)
Deformity	0 (0%)	0 (0%)	1 (1%)	8 (8%)
Discolouration	0 (0%)	2 (3%)	2 (3%)	8 (8%)
Malocclusion	1 (1%)	0 (0%)	0 (0%)	1 (1%)
Mottling	0 (0%)	8 (26%)	32 (94%)	53 (98%)

^aDiscolouration designates an overall effect, while mottling indicates variegated discolouration. The terms are not mutually exclusive.

^bThe incidences for this observation are for the lower incisors of animals observed at week 104 only (males n=43, 26, 23, 44; females n=59, 31, 34, 54).

^cThe incidences for this observation include interim and terminal sacrifice animals (males and females n = 100, 70, 70, 100).

Conclusions:

Based on the results of this study the NTP state that there was 'equivocal evidence of carcinogenic activity' of sodium fluoride in male F344/N rats based on the occurrence of a small number of osteosarcomas in dosed animals (equivocal evidence is a category for uncertain findings defined as studies that are interpreted as showing a marginal increase of neoplasms that may be related to chemical administration). There was no evidence of carcinogenic activity in female F344/N rats receiving sodium fluoride in their drinking water at 25, 100 or 175ppm.

Executive summary:

The potential carcinogenic activity of sodium fluoride was determined in a 2 year drinking water study using male and female F344/N rats. Rats were exposed to concentrations of 0, 25, 100 or 175ppm daily in their drinking water. Survival rates were not affected by sodium fluoride administration. The teeth of the rats showed a dose-dependent whitish discolouration, and males had an increased incidence of tooth deformities and attrition leading on occasion to malocclusion. Osteosclerosis of long bones was increased in female rats given 175ppm, no other significant nonneoplastic lesions appeared related to sodium fluoride administration. A small number of osteosarcomas were seen in male rats given 100 or 175ppm, none were seen in the control or 25ppm groups. Osteosarcomas occurred with a statistically significant dose-response trend, leading to the conclusion that a weak association may exist between

the occurrence of these neoplasms and the administration of sodium fluoride. Therefore, according to the NTP Explanations of Levels of Incidence, the NTP concluded that under the conditions of this study, there was 'equivocal evidence of carcinogenic activity' of sodium fluoride in male F344/N rats based on the occurrence of a small number of osteosarcomas in dosed animals. Equivocal evidence is a category for uncertain findings defined as studies that are interpreted as showing a marginal increase of neoplasms that may be related to chemical administration. There was no evidence of carcinogenic activity in female F344/N rats receiving sodium fluoride in their drinking water at 25, 100 or 175ppm.

Reference 2

Endpoint:

carcinogenicity: oral

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

28th October 1985 to 19th October 1987

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: NTP study.

Qualifier:

according to guideline

Guideline:

other: NTP protocol

Principles of method if other than guideline:

The study was performed according to the NTP carcinogenicity study protocol

GLP compliance:

yes

Species:

mouse

Strain:

B6C3F1

Sex:

male/female

Details on test animals or test system and environmental conditions:

Male and female B6C3F1 mice were used, obtained from the National Cancer Institute's Frederick Cancer Research Facility. Mice were 4 weeks old on arrival, and were quarantined for 13 days. Mice were placed on study when they were 6 weeks old. Mice were housed individually in polycarbonate cages rotated every other week,and identified by toe marks. Specially formulated low fluoride feed (NIH-07 Rat and Mouse Pellets Low Fluoride) and deionised water were available ad libitum. Beta-Chip hardwood chips were provided as bedding as changed twice weekly. Temperature was maintained at 19.4-26.1oC, humidity: 22-76%, fluorescent light was provided 12 hours/day, and there were 10 room air changes per hour. The study began on 28th October 1985, the 105 week scheduled termination took place on 19th October 1987.

Route of administration:

oral: drinking water

Vehicle:

water

Details on exposure:

Mice were given sodium fluoride in deionised drinking water at 0, 25, 100 or 175ppm ad libitum for up to 103 weeks.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Dose formulation analyses were conducted utilising a potentiometric method with a fluoride ion electrode. Analyses were conducted weekly on all dose formulations during the first 6 months, then every 8 weeks for the remainder of the study. Analyses indicated that all dose formulations were within ±10% of target concentrations throughout the study. Deionised water had a fluoride concentration of =0.1ppm.

Duration of treatment / exposure:

Fluoridated drinking water was available ad libitum, daily for up to 103 weeks.

Frequency of treatment:

Daily.

Post exposure period:

Mice were sacrificed approximately 1 week after the final dose.

Remarks:

Doses / Concentrations:
0, 25, 100 or 175 ppm
Basis:
nominal in water

No. of animals per sex per dose:

Groups of 100 mice of each sex received 0 or 175ppm sodium fluoride, and groups of 70 mice of each sex received 25 or 100 ppm. An additional group of 50 animals of each sex was included to provide paired age-matched controls, these animals received deionised water.

Control animals:

yes, concurrent vehicle

Details on study design:

Groups of 100 mice of each sex received 0 or 175 ppm sodium fluoride, and groups of 70 mice of each sex received 25 or 100 ppm.
The doses were based on the lower weight gain of male and female mice given 200 ppm in a 6 month study. Also, an initial 2 year study had been conducted using 100 ppm as the top dose, but it was felt that the mice could tolerate higher concentrations, therefore the top dose chosen for the present study was 175 ppm.

An additional group of 50 animals of each sex was included to provide paired age-matched controls, these animals received deionised water. During every study week that one or more mice from any group receiving sodium fluoride in the water was found dead or killed in a moribund condition, one animal of the same sex was chosen at random from the paired control group and killed.

For group assignment, animals were assigned to weight classes, then randomised to test and control groups by partitioning algorithm using Xybion Pathology/Toxicology Data System.

Positive control:

Not relevant.

Observations and examinations performed and frequency:

Mice were observed twice daily for mortality and morbidity. Initially weights and clinical signs were recorded weekly through to week 13, then monthly thereafter. Every 4 weeks feed and water consumption was recorded for a 7 day consecutive period.

Sacrifice and pathology:

Necropsy was performed on all animals including those found dead. Interim sacrifices were performed at 24 weeks and 66 weeks. Terminal sacrifice was performed at 105 weeks.

Other examinations:

Haematology and clinical chemistry were carried out at 24 and 66 weeks. The left humerus of all mice killed at interim sacrifices and of 10 randomly selected rats from each group at terminal sacrifice was evaluated for fluoride concentration. The incisors of designated mice at all scheduled sacrifices were evaluated for attrition and mottling.

Statistics:

Survival analyses: the probability of survival was estimated by the product-limit procedure of Kaplan and Meier. Analyses for possible dose-related effects on survival used Cox's method for testing two groups for equality and Tarone's life table test for dose-related trends.
The incidence of neoplastic or nonneoplastic lesions was given as the ratio of the number of animals bearing such lesions at a specific anatomic site to the number of animals in which that site was examined.
Tumour incidence was analysed by logistic regression, tumour prevalence was modeled as a logisitic function of chemical exposure and time. Also used were the life table test, the Fisher exact test, and the Cochran-Armitage trend test. Tests of significance included pairwise comparisons.
Continuous variables were analysed by comparing dosed groups to the control group using the nonparametric Dunn or Shirley multiple comparison test. Jonckheere's test was also used.

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

no effects observed

Ophthalmological findings:

not examined

Haematological findings:

no effects observed

Clinical biochemistry findings:

effects observed, treatment-related

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Histopathological findings: neoplastic:

effects observed, treatment-related

Details on results:

CLINICAL SIGNS AND MORTALITY

There was no treatment-related effect on survival or mortality. Clinical signs were limited to white teeth, which were first noted earliest in animals at the top dose level (Day 74), intermediate and low dose levels (Days 81-200) and controls (Day 508). Detailed dental investigation revealed attrition at 175 ppm; discoloration and mottling in all treated groups.

BODY WEIGHT AND WEIGHT GAIN

Bodyweights and weight gains were unaffected by treatment.

FOOD CONSUMPTION

Food consumption was unaffected by treatment.


WATER CONSUMPTION AND COMPOUND INTAKE

Water consumption was unaffected by treatment. The average intake of sodium fluoride was calculated to be 2.4, 9.6 and 16.7 mg/kg bw/d in males; 2.8, 11.3 and 18.8 mg/kg bw in females.


HAEMATOLOGY

There were no effects of treatment.

CLINICAL CHEMISTRY

There were no effects of treatment, with the exception of elevated serum alkaline phosphatase activity in females at 175 ppm.

ORGAN WEIGHTS

Organ weights were unaffected by treatment.


HISTOPATHOLOGY: NON-NEOPLASTIC

Dentine dysplasia was significnalty increased in male mice at 175 ppm.

HISTOPATHOLOGY: NEOPLASTIC

A marginal increase in the incidence of malignant lymphoma was not considered to be treatment-related. A slight numerical increase in hepatoblastoma was not considered to be biologically significant.

Relevance of carcinogenic effects / potential:

There was no evidence of carcinogenic activity of sodium fluoride in male or female mice receicing sodium fluoride at concentrations of 25, 100 or 175ppm in drinking water for 2 years.

Dose descriptor:

NOAEL

Effect level:

175 ppm (nominal)

Sex:

male/female

Basis for effect level:

other: There was no evidence of carcinogencity in this study.

Remarks on result:

other: Effect type: carcinogenicity (migrated information)

Survival rates after 2 years were:

males - control 58/79; 25ppm 39/50; 100ppm 37/51; 175ppm 65/80

females - control 53/80; 25ppm 38/52; 100ppm 34/50; 175ppm 52/80.

Conclusions:

No evidence of carcinogenicity was seen under the conditions of this study.

Executive summary:

The potential carcinogenic activity of sodium fluoride was determined in a 2 year drinking water study using male and female B6C3F1 mice. Mice were exposed to concentrations of 0, 25, 100 or 175ppm daily in their drinking water. Survival rates were not affected by sodium fluoride administration. There was no evidence of carcinogenic activity in male or female B6C3F1 mice receiving sodium fluoride in their drinking water at 25, 100 or 175ppm for 2 years.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

Study duration:

chronic

Species:

rat

Quality of whole database:

Key GLP studies using Sodium Fluoride as a surrogate analogue are Klimisch 1 (NTP, 1990) in rats and (NTP, 1990) study in mice for 103 weeks.
Supporting (surrogate analogue) studies (Maurer et al 1990 and 1993) are of less reliability but as a weight of evidence confirm a lack of carcinogenic potential.

Carcinogenicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Carcinogenicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

No classification is proposed. The EU RAR has reviewed all available data for HF and NaF and concludes that the data are sufficient to suggest that fluoride is not carcinogenic in animals.

Additional information

Justification for read-across from sodium fluoride

There are no carcinogenicity studies available for HF. The effects of chronic HF exposure will be dominated by local effects at the site of contact (irritation/corrosion), therefore performing studies with HF cannot be supported for scientific reasons and also on animal welfare grounds. Once absorbed into the body, HF will dissociate into its constituent ions and systemic toxicity will be due to fluoride. The analagous bevaviour of sodium fluoride (or any other water-soluble fluoride salts) means that read-across from NaF to HF is scientifically justified.

Studies in the rat

The NTP rat study showed evidence of an effect of sodium fluoride administration on the bones and teeth, consistent with the findings of other studies. There was no effect on survival in this study; bodyweights, food and water consumption, haematological and clinical chemistry parameters and organ weights were unaffected by treatment. Serum, urine and bone fluoride concentrations were increased in all treated groups; the urine calcium concentration was also marginally higher in females at the highest dose level. Osteosclerosis was seen in females at the highest dose level. The incidence of osteosarcoma was increased in males at the intermediate dose level (2%) and the high dose level (4%) but was within the historical range (0 -6%; mean 0.5%). The NTP concluded that the study provides 'equivocal evidence' for carcinogenicity in male rats.

An additional carcinogenicity study with NaF in the rat is available (Maurer et al, 1990). No evidence of carcinogenicity was seen in this study, at dose levels sufficient to cause toxicity.

Studies in the mouse

The NTP mouse study showed evidence of an effect of sodium fluoride administration on the teeth, consistent with the findings of other studies. There was no effect on survival in this study; bodyweights, food and water consumption, haematological parameters and organ weights were unaffected by treatment. Clinical chemistry revealed elevated ALP activity in females at the highest dose level. Microscopic findings were limited to dentine dysplasia in male mice at 175 ppm. There was no evidence of carcinogencity in either sex.

An additional carcinogenicity study with NaF is available (Maurer et al, 1993). A high level of osteosarcomas was seen in all (control and treated) groups in this study, a finding which was attributed to infection with a retrovirus. No conclusion on the carcinogenicity of sodium fluoride can be drawn from this study.