of tooth development, is probably the most important exposure measure to consider when assessing the risk of fluorosis (DenBesten 1999).

Dental enamel is formed by matrix-mediated biomineralization. Crystallites of hydroxyapatite (Ca₁₀(PO₄)₆(OH)₂) form a complex protein matrix that serves as a nucleation site (Newbrun 1986). The matrix consists primarily of amelogenin, proteins synthesized by secretory ameloblasts that have a functional role in establishing and maintaining the spacing between enamel crystallites. Full mineralization of enamel occurs when amelogenin fragments are removed from the extracellular space. The improper mineralization that occurs with enamel fluorosis is thought to be due to inhibition of the matrix proteinases responsible for removing amelogenin fragments. The delay in removal impairs crystal growth and makes the enamel more porous (Bronckers et al. 2002). DenBesten et al. (2002) showed that rats exposed to fluoride in drinking water at 50 or 100 mg/L had lower total proteinase activity per unit of protein than control rats. Fluoride apparently interferes with protease activities by decreasing free Ca²⁺ concentrations in the mineralizing milieu (Aoba and Fejerskov 2002).

Matsuo et al. (1998) investigated the mechanism of enamel fluorosis in rats administered sodium fluoride (NaF) at 20 mg/kg by subcutaneous injections for 4 days or at 240 mg/L in drinking water for 4 weeks. They found that fluoride alters intracellular transport in the secretory ameloblasts and suggested that G proteins play a role in the transport disturbance. They found different immunoblotting-and-pertussis-toxin-sensitive G proteins on the rough endoplasmic reticulum and Golgi membranes of the germ cells of rats’ incisor teeth.

Whether to consider enamel fluorosis, particularly the moderate to severe forms, an adverse cosmetic effect or an adverse health effect has been the subject of debate for decades. Some early literature suggests that the clinical course of caries could be compromised by untreated severe enamel fluorosis. Smith and Smith (1940, pp.1050-1051) observed, “There is ample evidence that mottled teeth, though they be somewhat more resistant to the onset of decay, are structurally weak, and that unfortunately when decay does set in, the result is often disastrous. Caries once started evidently spreads rapidly. Steps taken to repair the cavities in many cases were unsuccessful, the tooth breaking away when attempts were made to anchor the fillings, so that extraction was the only course.” Gruebbel (1952, p.153) expressed a similar viewpoint: “Severe mottling is as destructive to teeth as