can increase the uptake of aluminum into bone (Ahn et al. 1995) and brain (Varner et al. 1998).

Fluoride concentrations in plasma, extracellular fluid, and intracellular fluid are in approximate equilibrium. The concentrations in the water of most tissues are thought to be 40% to 90% of plasma concentrations, but there are several important exceptions. Tissue fluid/plasma (T/P) ratios exceed one for the kidney because of high concentrations in the renal tubules. T/P ratios can exceed one in tissues with calcium deposits, such as the placenta near the end of pregnancy. The pineal gland, a calcifying organ that lies near the center of the brain but outside the blood-brain barrier, has been found to accumulate fluoride (Luke 2001). Fluoride concentrations in adipose tissue and brain are generally thought to be about 20% of plasma or less (Whitford 1996). The blood-brain barrier is thought to reduce fluoride transfer, at least in short-term experiments (Whitford 1996). It is possible that brain T/P ratios are higher for exposure before development of the blood-brain barrier.

Most tissue measurements are based on short-term exposures of healthy adult animals. Similar T/P ratios have been found for liver and kidney in some chronic animal experiments (Dunipace et al. 1995), but not all organs have been examined. The literature contains some unexplained exceptions to these T/P generalizations (Mullenix et al. 1995; Inkielewicz and Krechniak 2003). Mullenix et al. (1995) reported atypically high, dose-dependent T/P ratios for the rat brain: more than 20 for control animals and about 3 for animals exposed to fluoride at 125 mg/L in drinking water for 20 weeks. Because these T/P ratios for brain are much higher than earlier results, Whitford (1996) speculated that the results of Mullenix et al. were due to analytical error. Additional measurements of fluoride tissue concentrations after chronic dosing are needed.

Fluoride is cleared from plasma through two primary mechanisms: uptake by bone and excretion in urine. Plasma clearance by the two routes is approximately equal in healthy adult humans. (Plasma clearance is the volume of plasma from which fluoride is removed per unit time. The rate of removal equals the clearance times the plasma fluoride concentration. Clearances are additive.) The relative clearance by bone is larger in young animals and children because of their growing skeletal systems. “In contrast to the compact nature of mature bone, the crystallites of developing bone are small in size, large in number and heavily hydrated. Thus, they afford a relatively enormous surface area for reactions involving fluoride” (Whitford 1996, p. 94). Experimental work in growing dogs demonstrates that extrarenal clearance, almost entirely uptake by bone, is inversely related to age. Renal clearance depends on pH and glomerular filtration rate. At low pH, more HF is formed, promoting reabsorption. Excretion of previously absorbed fluoride from the body is almost entirely via urine. Fluoride not absorbed



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