few exposure groups, with, for example, the “high”-fluoride group in one study having lower concentrations of fluoride in drinking water than the “normal”-fluoride group in another study. In general, the human exposures are not well characterized. Nevertheless, there is consistency among the available studies in the types of effects seen in humans and animals and in the concentrations or fluoride exposures associated with the effects in humans.

For all the endocrine effects reported to occur from fluoride exposure, the variability in exposure and response among populations (or strains of an experimental animal) or within a human population requires further attention. For example, correlations between the fluoride intake or the presence or degree of fluorosis and the presence (or prevalence) or severity of other effects generally have not been examined on an individual basis, which could permit identification of individual differences in susceptibility or response. Several reports have identified subgroups within an exposed population or group, in terms of the response observed, even when group means are not statistically different.

Variability in response to fluoride exposures could be due to differences in genetic background, age, sex, nutrient intake (e.g., calcium, iodine, selenium), general dietary status, or other factors. Intake of nutrients such as calcium and iodine often is not reported in studies of fluoride effects. The effects of fluoride on thyroid function, for instance, might depend on whether iodine intake is low, adequate, or high, or whether dietary selenium is adequate. Dietary calcium affects the absorption of fluoride (Chapter 3); in addition, fluoride causes an increase in the dietary requirements for calcium, and insufficient calcium intake increases fluoride toxicity. Available information now indicates a role for aluminum in the interaction of fluoride on the second messenger system; thus, differences in aluminum exposure might explain some of the differences in response to fluoride exposures among individuals and populations.

The clinical significance of fluoride-related endocrine effects requires further attention. For example, most studies have not mentioned the clinical significance for individuals of hormone values out of the normal range, and some studies have been limited to consideration of “healthy” individuals. As discussed in the various sections of this chapter, recent work on borderline hormonal imbalances and endocrine-disrupting chemicals indicates that significant adverse health effects, or an increased risk for development of clearly adverse health outcomes, could be associated with seemingly mild imbalances or perturbations in hormone concentrations (Brucker-Davis et al. 2001). In addition, the different endocrine organs do not function entirely separately: thyroid effects (especially elevated TSH) may be associated with parathyroid effects (Stoffer et al. 1982; Paloyan Walker et al. 1997), and glucose metabolism may be affected by thyroid or parathyroid status

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