Fluoride

Classification and Assessment

The existing epidemiological studies do not support an association between cancer morbidity or mortality and the consumption of fluoridated drinking water. However, as virtually all of these studies are of the ecological or geographical correlation type, their limitations preclude them from providing conclusive evidence for or against an exposure-response relationship. At the same time, ecological studies can be useful for testing the feasibility of hypotheses, and several reviews have noted that the consistency of these studies in not showing a positive association between exposure to fluoridated drinking water and cancer morbidity or mortality can impart a degree of confidence in their findings.

A comprehensive bioassay sponsored by the NTP⁸⁸ provided limited evidence for the carcinogenicity of fluoride based on the observation of a significant dose-response trend for the occurrence of osteosarcomas in male F344/N rats consuming drinking water containing 25-175 ppm NaF. However, a pairwise comparison of osteosarcoma incidence in the high-dose versus control males was not significant, and no dose-response trend for the occurrence of osteosarcoma was observed in fe- male rats or male and female B6C3F₁mice exposed to the same concentrations of fluoride in drinking water. A carcinogenicity bioassay in which male and female Sprague-Dawley rats and CD-1 mice were administered NaF at doses of 4-25 mg/kg bw per day in the diet found no statistically significant dose-response relationship for osteosarcomas in either sex of both species.^89,90 However, recent reviews have noted several limitations of this second bioassay, including high levels of minerals, ions and vitamins in the diet and drinking water; poor survival rate, leading to an early termination of the study; and infection of the mice with a retrovirus.

NaF is capable of inducing clastogenic effects in mammalian cells in vitro, mutations in D. melanogaster in vivo and clastogenicity and other genotoxic effects when administered by intraperitoneal injection to rodents. However, fluoride generally did not increase chromosomal aberrations, micronuclei formation, sister chromatid exchange or DNA strand breaks when administered orally to rodents. It has been suggested that fluoride-induced genotoxicity involves an inhibition of the synthesis of proteins essential for DNA synthesis/ repair rather than a direct interaction between fluoride and DNA.

Following a comprehensive review of the available data on the carcinogenicity and genotoxicity of inorganic fluoride, the Canadian Environmental Protection Act (CEPA) Priority Substances assessment of inorganic fluoride concluded that "although there is some evidence for the carcinogenicity of inorganic fluoride, available data [i.e., laboratory and epidemiological data] are inconclusive."³⁹ Based on this conclusion and a consideration of the principles and approaches for the derivation of maximum acceptable concentrations (MACs) for chemicals in Canadian drinking water, it was determined that a tolerable daily intake (TDI) for fluoride should be derived by division of a NOAEL, lowest-observed-adverse-effect level (LOAEL) or other suitable effect level for a significant non-neoplastic effect by an appropriate uncertainty factor.

Because of the availability of data from human studies and interspecies differences (especially rats) in the response to fluoride exposures, the CEPA assessment emphasized human studies in the development of a daily intake level above which non-neoplastic adverse effects are expected to occur.⁴ The conclusion of the CEPA assessment regarding the health effects data for inorganic fluoride was that "potentially adverse effects associated with skeletal fluorosis are likely to be observed at intakes greater than approximately 200 µg/kg bw per day fluoride."³⁹ Some of the evidence supporting this intake

level included a small number of case reports of crippling skeletal fluorosis following fluoride intakes of approximately 215-285 µg/kg bw per day and the observation of stage I skeletal fluorosis in osteoporosis patients treated with fluoride at doses of 260-389 µg/kg bw per day. Osteoporosis patients were also reported to have small increases in hip fracture incidence following treatment with doses of fluoride greater than or equal to approximately 260 µg/kg bw per day. Also, the 200 µg/kg bw per day effect level is within the range of daily intakes predicted (i.e., based on modelling) to result in bone fluoride concentrations associated with adverse skeletal effects in humans.⁴ An Advisory Review Panel of dental researchers recently reviewed the available data on the relationship between daily fluoride intake in childhood and the occurrence of dental fluorosis. Based on the conclusions of this review¹⁸⁸ and data on the period of greatest risk for dental fluorosis in the anterior permanent teeth, it was estimated that a daily fluoride intake less than or equal to 122 µg/kg bw per day for children 22-26 months old (i.e., period of greatest risk) is unlikely to result in moderate to severe dental fluorosis in the anterior permanent teeth.

The TDI for fluoride is considered to be 122 µg/kg bw per day (0.122 mg/kg bw per day), the daily fluoride intake that is unlikely to produce moderate to severe dental fluorosis in children 22-26 months old. No uncertainty factor was applied in the derivation of the TDI, because the daily intake level was based on studies of the most susceptible age group in the human population. Although there is some controversy as to whether the more severe forms of dental fluorosis represent an aesthetic or a health effect, a limited number of surveys have shown that lay people can detect dental fluorosis, and both clinicians and lay people view the more severe forms as socially embarrassing to the children afflicted.^200-202 As the TDI is 40% less than the 200 µg/kg bw per day effect level for skeletal fluorosis, daily fluoride intakes less than or equal to the TDI are unlikely to produce adverse effects associated with skeletal fluorosis.

Rationale

A MAC for fluoride could be derived from the TDI as follows:

MAC = 0.122 mg/kg bw per day × 13 kg bw × 0.50 / 0.8 L d ≈ 1.0 mg/L

where:

• 0.122 mg/kg bw per day is the TDI, as described above
  
• 13 kg bw is the average body weight for a child in the 7 month to 4 year age group (age group from the CEPA assessment encompassing the period of greatest risk for dental fluorosis)⁴⁰

• 0.50 is the average proportion of total daily fluoride intake allocated to drinking water for children in the 7 month to 4 year age group residing in fluoridated communities in Canada (Table 1)
  
• 0.8 L/d is the average daily water consumption for a child in the 7 month to 4 year age group.⁴⁰
  

After reviewing the proposed drinking water guideline, the Federal-Provincial Subcommittee on Drinking Water concurred with the approaches used for the derivation of both the TDI and the proposed MAC. However, the subcommittee members had two major concerns regarding the proposed MAC: the age of the studies used to estimate daily fluoride intakes from various sources, and the apparent absence of a tangible health benefit associated with reducing the MAC to 1.0 mg/L from the current level of 1.5 mg/L.* Because most of the studies used to estimate daily fluoride intake were conducted between 1970 and 1990, the subcommittee questioned whether these studies reflect current trends in fluoride intake for Canadian children. This is especially the case for intakes from sources other than drinking water (e.g., toothpaste ingestion). In the early 1990s, dental researchers began to advocate measures to reduce children's fluoride intake from tooth-paste ingestion, such as adult supervision of tooth brushing, use of a pea-sized amount of toothpaste, discouraging the swallowing of toothpaste, etc.³⁶ These recommendations may have already reduced the daily intake of fluoride for many Canadian children below the estimated levels used in the derivation of the proposed MAC.

A reduction in the MAC from 1.5 mg/L to 1.0 mg/L would not be expected to significantly decrease the risk of fluoride-induced health effects. Even for communities where the concentration of fluoride in drinking water is 1.5 mg/L, the total daily fluoride intake is estimated to be below the 200 µg/kg bw per day effect level for skeletal fluorosis. In the absence of a significant reduction in health risk, the subcommittee concluded that the increased water treatment costs that would have to be incurred by those communities and private wells that exceed a lowered guideline would be excessive.

Consequently, the subcommittee recommended that the MAC for fluoride be maintained at 1.5 mg/L. The subcommittee also encouraged efforts to control fluoride intake from sources such as toothpaste ingestion and efforts to obtain more up-to-date estimates of daily fluoride intake in Canada. Although drinking water supplies containing fluoride at concentrations above the MAC do not necessarily represent a risk to human health, a risk of moderate to severe dental fluorosis could seriously affect the acceptance of drinking water supplies by consumers and should be avoided.

Although elucidated over 50 years ago, the caries preventative effects of fluoridated drinking water are still evident in modern studies of fluoridated versus non-fluoridated communities. The caries preventative effects arise primarily through a post-eruptive mechanism and have been demonstrated not only in children, but in adults as well. Although the effectiveness of water fluoridation may have decreased over time, this has been attributed to other sources of fluoride (e.g., toothpaste and other fluoridated dental products) that have become available in both fluoridated and non-fluoridated communities since the time of the original research on water fluoridation. Numerous dental and public health associations and dental researchers consider water fluoridation to be a cornerstone method for caries prevention available to all those on public water supplies, regardless of socio-economic status or level of dental care.

If it is desired that water supplies be fluoridated as a public health measure for the prevention of dental caries, an optimal fluoride concentration of 0.8-1.0 mg/L should be maintained. The consumption of drinking water containing 0.8-1.0 mg/L fluoride combined with average daily fluoride intakes from other sources to which Canadian consumers are commonly exposed should convey the beneficial dental effects of fluoride to all age groups. This optimal concentration range was selected by the subcommittee based on a careful consideration of both the MAC and the Advisory Review Panel's recommendations regarding optimal fluoride concentrations.

It is apparent from the data in Table 1 that some children who consume drinking water containing 0.8-1.0 mg/L fluoride may have total daily fluoride intakes that exceed the TDI. However, in recommending this optimal concentration range, the subcommittee recognized concerns similar to those that led to the rejection of the proposed MAC -- i.e., available estimates of total daily fluoride intake by Canadian children may not reflect current intake patterns because of recent initiatives to control fluoride intake from toothpaste ingestion, and the selection of a lower optimal concentration range would not significantly reduce the risk of fluoride-induced health effects, but would reduce the beneficial effects of fluoridated drinking water.

The daily intake of drinking water containing fluoride at or below the MAC combined with average daily intakes of fluoride from air, soil, food and toothpaste should not result in adverse effects associated with skeletal fluorosis. However, the CEPA assessment compared the "estimated daily intakes with those to which it is believed that a person can be exposed daily over a lifetime without developing deleterious non-neoplastic effects" and found that "these average daily intakes are at least 20% less than the level at which adverse effects upon the skeleton ... are anticipated."⁴ In view of this small difference, the CEPA assessment recommended "that exposure of the population of Canada to inorganic fluorides continue to be closely monitored."⁴ If the reference values for the 20+ year age group (i.e., body weight, proportional allocation of drinking water to daily fluoride intake, daily water consumption)** are applied to the 200 µg/kg bw per day effect level for skeletal fluorosis, a reference concentration of 3.7 mg/L can be derived. This reference concentration should under no circumstances supersede or replace the MAC, but it could serve as a useful guide for addressing possible concerns over the relationship between fluoride intake from drinking water and the occurrence of skeletal fluorosis.