trations between men and women (e.g., Torra et al. 1998), others found greater rates of increase with age in females (Husdan et al. 1976; Hanhijärvi et al. 1981). Enhanced release of fluoride in postmenopausal women is one possible explanation. Similar to our regression results of the Zipkin data, some studies have found a tendency toward elevated bone fluoride concentrations in women (Arnala et al. 1985; Richards et al. 1994). A Finnish study reported that bone fluoride concentrations increased more rapidly with age in women than in men (Alhava et al. 1980). This variability might be due to several factors, including individual differences in water consumption and pharmacokinetics.

In sum, although the data are sparse, severe renal insufficiency appears to increase bone fluoride concentrations, perhaps as much as twofold. The elderly are at increased risk of high bone fluoride concentrations due to accumulation over time; although less clear, decreased renal function and gender may be important.

• Bone fluoride concentrations increase with both magnitude and length of exposure. Empirical data suggest substantial variations in bone fluoride concentrations at any given water concentration.

• On the basis of pharmacokinetic modeling, the current best estimate for bone fluoride concentrations after 70 years of exposure to fluoride at 4 mg/L in water is 10,000 to 12,000 mg/kg in bone ash. Higher values would be predicted for people consuming large amounts of water (>2 L/day) or for those with additional sources of exposure. Less information was available for estimating bone concentrations from lifetime exposure to fluoride in water at 2 mg/L. The committee estimates average bone concentrations of 4,000 to 5,000 mg/kg ash.

• Groups likely to have increased bone fluoride concentrations include the elderly and people with severe renal insufficiency.

• Pharmacokinetics should be taken into account when comparing effects of fluoride in different species. Limited evidence suggests that rats require higher chronic exposures than humans to achieve the same plasma and bone concentrations.

• Additional research is needed on fluoride concentrations in human bone as a function of magnitude and duration of exposure, age, gender, and health status. Such studies would be greatly aided by noninvasive means of measuring bone fluoride. As discussed in other chapters of this report, some soft tissue effects may be associated with fluoride exposure. Most measure-