(e.g., McCarty and Thomas 2003; Procopio and Borretta 2003; Cettour-Rose et al. 2005). Adverse effects in individuals might occur when hormone concentrations are still in the normal ranges for a population but are low or high for that individual (Brucker-Davis et al. 2001; Belchetz and Hammond 2003). Some investigators suggest that endocrine-disrupting chemicals could be associated with nonmonotonic dose-response curves (e.g., U-shaped or inverted-U-shaped curves resulting from the superimposition of multiple dose-response curves) and that a threshold for effects cannot be assumed (Bigsby et al. 1999; Brucker-Davis et al. 2001).
In summary, evidence of several types indicates that fluoride affects normal endocrine function or response; the effects of the fluoride-induced changes vary in degree and kind in different individuals. Fluoride is therefore an endocrine disruptor in the broad sense of altering normal endocrine function or response, although probably not in the sense of mimicking a normal hormone. The mechanisms of action remain to be worked out and appear to include both direct and indirect mechanisms, for example, direct stimulation or inhibition of hormone secretion by interference with second messenger function, indirect stimulation or inhibition of hormone secretion by effects on things such as calcium balance, and inhibition of peripheral enzymes that are necessary for activation of the normal hormone.
Further effort is necessary to characterize the direct and indirect mechanisms of fluoride’s action on the endocrine system and the factors that determine the response, if any, in a given individual. Such studies would address the following:
the in vivo effects of fluoride on second messenger function
the in vivo effects of fluoride on various enzymes
the integration of the endocrine system (both internally and with other systems such as the neurological system)
identification of those factors, endogenous (e.g., age, sex, genetic factors, or preexisting disease) or exogenous (e.g., dietary calcium or iodine concentrations, malnutrition), associated with increased likelihood of effects of fluoride exposures in individuals
consideration of the impact of multiple contaminants (e.g., fluoride and perchlorate) that affect the same endocrine system or mechanism
examination of effects at several time points in the same individuals to identify any transient, reversible, or adaptive responses to fluoride exposure.
Better characterization of exposure to fluoride is needed in epidemiology studies investigating potential endocrine effects of fluoride. Important exposure aspects of such studies would include the following: