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INTAKE, litE:TABOLISM, AND DISPOSITION OF HORDE FLUORIDE INTAKE The literature contains several reviews of the sources and amounts of fluoride intake by age, water fluoride concentration, and geographic region in the United States that may be consulted for detailed discussions (McClure, 1943; Parkas and Parkas, 1974; Myers, 1978; Ophaug et al., 19SOa,b, 19X5; Whitford, 1989; Burt, 1992~. This discussion will sum- marize our current understanding of the main points covered in those reports. The major sources of fluoride intake are water, beverages, food, and fluoride-containing dental products. Fluoride exposure from the atmo- sphere generally accounts for a small fraction (about 0.01 mg per day) of the intake of fluoride (Hodge and Smith, 1977~. The fluoride con- centrations in groundwater range from less than 0. ~ mg/L to more than 100 mg/L and depend mainly on the concentration and solubility of fluoride compounds in the soil. The fluoride concentrations in foods also depend on the fluoride concentrations in soil but can be increased or decreased according to the fluoride concentrations in water used for preparation. The fluoride concentrations in most dental products avail- able in the United States range from 230 ppm (0.05% sodium fluoride mouth rinse) to over 12,000 ppm (~.23% acidulated phosphate fluoride gel). 125

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126 Health Effects of Ingested Fluoride The average intake of dietary fluoride by young children who drink water containing fluoride at 0.7-~.2 mg/L is approximately 0.5 mg per day or 0.04-0.07 mg/kg of body weight per day, although substantial variation occurs among individuals (McClure, 1943; Ophaug et al., 198Oa,b, 1985~. The classical epidemiological studies done in the 1930s and 1940s on the relation between water fluoride concentrations and dental caries and dental fluorosis determined that 0.7-~.2 mg/L was optimal because it provided a high degree of protection against dental caries and a low prevalence of milder forms of dental fluorosis. Thus, Me associated amount of intake by children (0.04-0.07 mg/kg per day) has generally been accepted as optimal, or as Burt (1992) has said, as "a useful upper limit for fluoride intake by children." Fluoride intake by nursing infants depends mainly on whether breast milk or formula is fed. Human breast milk contains only a trace of fluoride (about 0.5 ,umol/L, depending on fluoride intake) and provides less than 0.01 mg of fluoride per day (Ekstrand et al., 19X41. Ready-to- feed formulas generally contain fluoride at less than 004 mg/L (Johnson and Bawden, 1987; McKnight-Hanes et al., 1988), and formulas reconsti- tuted with fluoridated water (0.7-~.2 mg/~) contain fluoride at 0.7 mg/L or more. Thus, fluoride intake from formula might range from less than 0.4 to over I.0 mg per day. It is evident that that range includes amounts that exceed the optimal range of 0.7-~.2 mg/L and, therefore, might be thought to increase the risk of dental fluorosis. Recent evi- dence, however, indicates that the transitional or early-maturation stage of enamel development is when the tissue is most susceptible to fluoride- induced changes (Evans, 1989; Pendrys and Stamm, 1990; Evans and Stamm, 1991a). The early-maturation stage occurs during the third or fourth year of life for the permanent anterior teeth when the amount of dietary fluoride intake in a community with fluoridated water is generally within 0.04~.07 mg/kg per day. Ophaug et al. (19XOa,b) determined dietary fluoride intake by young children in four regions of the United States. Mean intake by 6-month- old infants was 0.21-0.54 mg per day, and that by 2-year-old children was 0.32-0.61 mg per day. The mean intake by the 2-year-old children (but not the 6-month-old group) was directly related to the fluoride concentration in the drinking water. Those data are in close agreement with the findings of Dabeka et al. (1982) and Featherstone and Shields (1988~. Dietary fluoride intake by adults living in areas served with water fluoridated at about i.0 mg/L has been estimated at I.2 mg per day

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Intake, Metabolism, arid Disposition of Fluoride 127 (Singer et al., 1980), I.8 mg per day Waves, 1983), and 2.2 mg per day (San Filippo and Battistone, 1971~. Intake by some people, such as outdoor laborers in warm climates or those with high urine output dis- orders (Klein, 1975), would be substantially higher. Fluoride-containing dental products intended for topical application of fluoride to teeth (especially toothpastes because of their widespread use) are an important source of ingested fluoride for both children and adults. Dowell (1981) reported that nearly 50% of his sample had started brush- ing by the age of 12 months. At 18 months, 75% were brushing with fluoride toothpaste. The average amount of toothpaste used in one brushing is I.0 g (ranging from 0.! to 2.0 g), which, for a product at 1,000 ppm, contains ~ .0 mg of fluoride. The results from several studies indicate that an average of 25% (ranging from 10% to 100%) of fluoride introduced into the mouth with toothpaste or mouth rinse is ingested, but the percentage is higher for young children who do not have good control of the swallowing reflex (HelIstrom, ~ 960; Ericsson and Forsman, ~ 969; Hargreaves et al., 1972; Parkins, 1972; Barnhart et al., 1974; Baxter, 1980; Dowell, 1981; Wei and Kanellis, 1983; Bell et al., 198S; Bruun and ThyIstrup, 1988~. It has been calculated that the amount of fluoride ingested with toothpaste (or mouth rinse) by children who live in a community with optimally fluoridated water, who have good control of swallowing, and who brush (or rinse) twice a day is approximately equal to the daily intake of fluoride with food, water, and beverages (Whitford et al., 1987~. In the case of younger children or those who, for any other reason, have poor control of swallowing, the daily intake of fluo- ride from dental products couIc] exceed dietary intake. For several reasons, differences in fluoride intake in communities with different water fluoride concentrations are likely to be smaller today than in the 1940s, when the epidemiological studies of dental caries and fluorosis studies by H.T. Dean ant! his associates were done. The use of fluoride-containing dental products, especially toothpastes, is wicle- spread, and dietary fluoride supplements are prescribed for children from birth to teenage years more frequently in areas without water fluorida- tion. The dosage schedule for fluoride supplementation currently recom- mended by the American Dental Association and the American Academy of Pediatrics is shown in Table X-~. Furthermore, most urban areas in many states have controlled water fluoride concentrations (about I.0 mug/. In general, the so-called "halo effect" occurs in those areas where foods and beverages are processes! and packaged for distribution

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128 Health Elects of Ingested Fluoride TABLE 8-1 Dietary Fluoride Supplementation Schedule Recommended by the American Dental Association and the American Academy of Pediatrics Age Group, yr Drinking-Water Fluoride Concentration, mg/L <0.3 0.3-0.7 o >0.7 Recommended amounts from birth to 2 Recommended amount from 2 to 3 Recommended amount from 3 to 13 0.25 0.50 1.0 o o o aValues are given in milligrams of fluoride per day (2.2 mg of NaF and 1.0 mg of fluoride). to other communities, including those without fluoridated water supplies. At the expense of tap-water consumption, soft-cirink consumption in the United States and Canada has increased sharply in recent years in both fluoridated and nonfluoridated areas (Bears et al., 19XI; Chao et al., 1984; Ismai! et al., 1984; Clovis and Hargreaves, 19X8~. Fluoride intake from soft drinks and other beverages prepared with fluoridated water amounts to 0.3-0.5 mg per 12 ounces, which makes such products quantitatively important sources of fluoride. Those considerations and others, such as use of certain home-water purification systems that might remove fluoride and consumption of bottled water that might have fluoride concentrations above or below the optimal range, lead to the conclusion that reasonably accurate estimates of total daily fluoride intake are no longer as simple and straightforward as they were when the only important source of fluoride was water. Investigators seeking to examine the possible relation between fluoride intake and health outcomes, such as dental caries, fluorosis, or quality of bone, need to be aware of the complex situation that exists today. It is no longer feasible to estimate with reasonable accuracy the level of fluoride exposure simply on the basis of concentration in drinking water supply. FLUORIDE ABSORPTION Approximately 75-90% of the fluoride ingested each day is absorbed from the alimentary tract. The half-time for absorption is approximately

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Intake, Metabolism, and Disposition of Fluoride 129 30 minutes, so peak plasma concentrations usually occur within 30~0 minutes. Absorption across the oral mucosa is limited and probably accounts for less than I% of the daily intake. Absorption from the stomach occurs readily and is inversely related to the pH of the gastric contents (Whitford and Pashiey, 1984~. Most of the fluoride that enters the intestine will be absorbed rapidly. It was generally believed that fluoride excreted in the feces was never absorbed, although several studies with rats (G.M. Whitford, Medical College of Georgia, Augusta, unpublished data, 1992) indicate that a diet high in calcium or parenteral administration of fluoride can result in fecal fluoride excretion rates that exceed fluoride intake. High concentrations of dietary calcium and other cations that form insoluble complexes with fluoride can reduce fluoride absorption from the gastrointestinal tract. The mechanism of fluoride absorption has received considerable research attention and has led to the conclusion that diffusion is the underlying process. Absorption across the oral and gastric mucosae is strongly pH-dependent. That finding is consistent with the hypothesis that hydrofluoric acid (pKa = 3.4) is the permeating moiety. Results from studies with rats indicate that fluoride absorption across the in- testinal mucosa is not pH-dependent (Nopakun and Messer, 1989~. FLUORIDE IN PLASMA There are two general forms of fluoride in human plasma. The ionic form is the one of interest in dentistry, medicine, and public health. Tonic fluoride is detectable by the ion-specific electrode. It is not bound to proteins or other components of plasma or to soft tissues. The other form consists of several fat-soluble organic fluorocompounds. These can be contaminants derived from food processing and packaging. Perfluoro- octanoic acid (octanoic acid fully substituted with fluoride) has been identified as one of the fluorocompounds (Guy, 1979~. The biological fate and importance of the organic fluorocompounds remains largely unknown. The extent to which the fluorine in these compounds is ex- changeable with the ionic fluoride pool has not been determined. The concentration of ionic fluoride in soft and hard tissues is directly related to the amount of ionic fluoride intake, but that of the fluorocompounds is not. Neither form is homeostatically controlled (Guy, 1979; Whitford and Williams, 1986~.

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130 Health Effects of Ingested Fluoride Provided that water is the major source of fluoride intake, fasting plasma fluoride concentrations of healthy young or middIe-aged adults expressed as micromoles per liter are roughly equal to the fluoride concentrations in drinking water expressed as milligrams per liter. Plasma fluoride concentrations, however, tend to increase slowly over the years until the sixth or seventh decade of life when they, like fluoride concentrations in bone, tend to increase more rapidly. The reason for that change is uncertain but might be due to declining renal function or increasing resorption of bone crystals with low fluoride concentrations (leaving an increased density of crystals with high fluoride concentra- tions). Cord-blood plasma concentrations are 75-80% as high as mater- nal plasma concentrations, indicating that fluoride freely crosses the placenta (Shen and Taves, 1974~. The balance of fluoride in the neonate can be positive or negative during the early months of life, depending on whether intake is sufficient to maintain the plasma concentration that existed at the time of birth (Ekstranct et al., 1984~. TISSUE DISTRIBUTION As indicated by the results of short-term OFF isotope studies with rats, a steady-state distribution exists between the fluoride concentrations in plasma or extracellular fluid and the intracellular fluid of most soft tissues (Whitford et al., 1979~. Intracellular fluoride concentrations are lower, but they change proportionately and simultaneously with those of plasma. With the exception of the kidney, which concentrates fluoride within We renal tubules, tissue-to-plasma (T/P) fluoride ratios are less than I.0. In those cases in which the T/P ratio exceeds unity, as might occur in the aorta or the placenta near term, ectopic calcification should be suspected. Most of the published data on soft-tissue concentrations in humans were obtained with analytical methods that were insensitive and nonspecific or that hac} excessively high blanks. Further work is needed using modern analytical techniques, such as the ion-specific electrode after isolation of fluoride with the hexamethyIdisiloxane-facilitated dif- fusion method of Taves (1968) and modified by Whitford (19891. VenkateswarIu (1990) described and compared the merits of a variety of analytical methods for the determination of fluoride. The fluoride concentrations of several of the specializeci body fluids, including gingival crevicular fluid, ductal saliva, bile, and urine, are also

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Stake, Metabolism, and Disposition of Fluoride 131 related to those of plasma in a steady-state manner. The fluoride con- centrations of breast milk and cerebrospinal fluid tend to be related to those of plasma, but they respond slowly to changes in plasma fluoride concentrations (Spak et al., 19X3~. The mechanism underlying the transmembrane migration of fluoride appears to be the diffusion equilibrium of hydrogen fluoride (Whitford, 1989~. Thus, factors that change the magnitude of transmembrane or transepithelial pH gradients will affect the tissue distribution of fluoride accordingly. In general, epithelia ant! cell membranes of most tissues appear to be essentially impermeable to the fluoride ion, which is charger] and has a large hydrated radius. Approximately 99% of the body burden of fluoride is associated with calcif~ect tissues. Of the fluoride absorber! by the young or middle-aged adult each day, approximately 50% will be associated with calcifies! tissues within 24 hours and the remainder will be excreted in urine. This 50:50 distribution is shifted strongly in favor of greater retention in the very young. Increased retention is due to the large surface area provided by numerous and loosely organized developing bone crystallites, which increase the clearance rate of fluoride from plasma by the skeleton (Whitford, 1989~. Accordingly, the peak plasma fluoride concentrations and the areas uncler the time-plasma concentration curves are directly related to age during the period of skeletal development. Due to de- creased accretion and increased resorption of bone, the 50:50 distribution is probably shifted in favor of greater excretion in the later years of life, but less is known about that. Fluoride is strongly but not irreversibly bound to apatite and other calcium phosphate compounds that might be present in calcified tissues. In the short term, fluoride might be mobilized from the hydration shells and the surfaces of bone crystallites (and presumably dentin ant! develop- ing enamel crystallites) by isotonic or heteroionic exchange. In the long term, the ion is mobilized by the normal process of bone remodeling. Waterhouse et al. (1980) reported that human serum fluoride concentra- tions were increased following administration of Parathormone and decreased by administration of calcitonin. FLUORIDE EXCRETION Elimination of absorbed fluoride from the body occurs almost ex

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132 Health Effects of Ingested Fluoride c~usively via the kidneys. As noted above, about 10-25% of the daily intake of fluoride is not absorbed and remains to be excreted in feces. Data from the 1940s indicated that the amount of fluoride excreted in sweat could nearly equal urinary fluoride excretion under hot moist conditions (McClure et al., 1945~. More recent data obtained with modern analytical techniques (G.M. Whitford, Medical College of Georgia, Augusta, unpublished data, 1992), however, indicate that sweat fluoride concentrations are very low and similar to those of plasma (about I-3 mom/. Therefore, sweat is probably a quantitatively minor route for fluoride excretion under even extreme environmental conditions. The clearance rate of fluoride from plasma is essentially equal to the sum of the clearances by calcified tissues and kidneys. The renal clear- ances of chloride, iodide, and bromide in healthy young or middIe-aged adults are typically less than I.0 mL per minute, but the renal clearance of fluoride is approximately 35 mL per minute (Waterhouse et al., 1980; Cowell and Taylor, 1981; SchiM and Binswanger, 19X2~. Little is known about the renal handling of fluoride by infants, young children, and the elderly. A 600-day longitudinal study of fluoride pharmaco- kinetics Mat began with weanling dogs, however, indicated that the renal clearance of fluoride factored by body weight (milliliter per minute per kilogram) was independent of age (Whitford, 19891. In patients with compromised renal function where the glomerular filtration rate fails to 30% of normal on a chronic basis, fluoride excretion might decline sufficiently to result in increased soft- and hard-tissue fluoride concentra- tions (Schiffl and Binswanger, 19801. Renal handling, tissue concentra- tions, and effects of fluoride in renal patients are subjects in need of further research. Fluoride is freely filtered through the giomerular capillaries and undergoes tubular reabsorption in varying degrees. There is no evidence for net tubular secretion or a tubular transport maximum of the ion. The renal clearance of fluoride is directly related to urinary pH (VVhitford et al., 1976) and, under some conditions, to urinary flow rate (Chen et al., 19561. Recent data from stop-flow studies with dogs indicate that fluo- ride reabsorption is greatest from the distal nephron, the site where the tubular fluid is acidified (Whitford and Pashiey, 19911. As in the cases of gastric absorption and transmembrane migration, the mechanism for the tubular reabsorption of fluoride appears to be He diffusion of hydro- gen fluoride. Thus, factors that affect urinary pH such as diet, drugs, metabolic or respiratory disorders, and altitude of residence, have been

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Stake, Metabolism, arid Disposition of Fluoride 133 shown or can be expected to affect the extent to which absorbed fluoride is retained in the body (Whitford, 1989~. RECOMMENDATIONS Further research is needed in the following areas: Determine and compare the intake of fluoride from all sources, including fluoride-containing dental products, in fluoridated and non- fluoridated communities. That information would improve our under- standing of trends in dental caries, dental fluorosis, and possibly other disorders or diseases. Determine the effects of factors that affect human acid-base balance and urinary pH on the metabolic characteristics, balance, and tissue concentrations of fluoride. Determine the metabolic characteristics of fluoride in infants, young children, and the elderly. Determine prospectively the metabolic characteristics of fluoride in patients with progressive renal disease. Using preparative and analytical methods now available, determine soft-tissue fluoride concentrations and their relation to plasma fluoride concentrations. Consider the relation of tissue concentrations to variables of interest, including past fluoride exposure and age. Identify the compounds that compose the "organic fluoride pool" in human plasma and determine their sources, metabolic characteristics, fate, and biological importance.

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