in test animals and in vitro test systems. For example, a few studies suggest that fluoride might be associated with kidney stone formation, while other studies suggest that it might inhibit stone formation. Some effects on liver enzymes have been observed in studies of osteoporosis patients treated with fluoride, but the available data are not sufficient to draw any conclusions about potential risks from low-level long-term exposures. Little data is available on immunologic parameters in human subjects exposed to fluoride from drinking water or osteoporosis therapy, but in vitro and animal data suggest the need for more research in this area.
As noted earlier in Chapters 2 and 3, several subpopulations are likely to be susceptible to the effects of fluoride from exposure and pharmacokinetic standpoints. With regard to the end points covered in this chapter, it is important to consider subpopulations that accumulate large concentrations of fluoride in their bones (e.g., renal patients). When bone turnover occurs, the potential exists for immune system cells and stem cells to be exposed to concentrations of fluoride in the interstitial fluids of bone that are higher than would be found in serum. From an immunologic standpoint, individuals who are immunocompromised (e.g., AIDS, transplant, and bone-marrow-replacement patients) could be at greater risk of the immunologic effects of fluoride.
Studies are needed to evaluate gastric responses to fluoride from natural sources at concentrations up to 4 mg/L and from artificial sources. Data on both types of exposures would help to distinguish between the effects of water fluoridation chemicals and natural fluoride. Consideration should be given to identifying groups that might be more susceptible to the gastric effects of fluoride.
The influence of fluoride and other minerals, such as calcium and magnesium, present in water sources containing natural concentrations of fluoride up to 4 mg/L on gastric responses should be carefully measured.
Rigorous epidemiologic studies should be carried out in North America to determine whether fluoride in drinking water at 4 mg/L is associated with an increased incidence of kidney stones. There is a particular need to study patients with renal impairments.
Additional studies should be carried out to determine the incidence, prevalence, and severity of renal osteodystrophy in patients with renal im-