The signaling pathways by which this agent works are slowly becoming elucidated.

Life-long exposure to fluoride at the MCLG of 4 mg/L may have the potential to induce stage II or stage III skeletal fluorosis and may increase the risk of fracture. These adverse effects are discussed separately below.

The current MCLG was designed to protect against stage III skeletal fluorosis. As discussed above, the committee judges that stage II is also an adverse health effect, as it is associated with chronic joint pain, arthritic symptoms, slight calcification of ligaments, and osteosclerosis of cancellous bones. The committee found that bone fluoride concentrations estimated to be achieved from lifetime exposure to fluoride at 2 mg/L (4,000 to 5,000 mg/kg ash) or 4 mg/L (10,000 to 12,000 mg/kg ash) fall within or exceed the ranges historically associated with stage II and stage III skeletal fluorosis (4,300 to 9,200 mg/kg ash and 4,200 to 12,700 mg/kg ash, respectively). This suggests that fluoride at 2 or 4 mg/L might not protect all individuals from the adverse stages of the condition. However, this comparison alone is not sufficient evidence to conclude that individuals exposed to fluoride at those concentrations are at risk of stage II skeletal fluorosis. There is little information in the epidemiologic literature on the occurrence of stage II skeletal fluorosis in U.S. residents, and stage III skeletal fluorosis appears to be a rare condition in the United States. Therefore, more research is needed to clarify the relationship between fluoride ingestion, fluoride concentrations in bone, and stage of skeletal fluorosis before any firm conclusions can be drawn.

Although a small set of epidemiologic studies were useful for evaluating bone fracture risks from exposure to fluoride at 4 mg/L in drinking water, there was consistency among studies using ecologic exposure measures to suggest the potential for an increased risk. The one study using serum fluoride concentrations found no appreciable relationship to fractures. Because serum fluoride concentrations may not be a good measure of bone fluoride concentrations or long-term exposure, the ability to shown an association might have been diminished. Biochemical and physiological data indicate a biologically plausible mechanism by which fluoride could weaken bone. In this case, the physiological effect of fluoride on bone quality and risk of fracture observed in animal studies is consistent with the observational evidence. Furthermore, the results of the randomized clinical trials were consistent with the observational studies. In addition, a dose-response relationship is indicated. On the basis of this information, all members of the committee agreed that there is scientific evidence that under certain conditions fluoride can weaken bone and increase the risk of fractures. The majority of the committee concluded that lifetime exposure to fluoride at drinking-water concentrations of 4 mg/L or higher is likely to increase fracture rates in the population, compared with exposure at 1 mg/L, particularly in some



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