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EFFECTS OF INGESTED FLUORIDE ON RENAL, GASTROINTESTESTINAL, AND IMMUNE SYSTEMS EFFECTS ON THE RENAL SYSTEM The kidney is the potential site of acute fluoride toxicity because kidney cells are exposed to relatively high fluoride concentrations. Fluoride concentrations in the kidney show an increasing gradient of concentra- tion, the lowest concentrations occurring in the renal cortex and the highest in the papilla (Whitford, 1990~. Fluoride, after oral administra- tion, is rapidly absorbed into the blood. Peak serum concentrations occur 30-90 minutes after administration and then decline rapidly (Cowell and Taylor, 1981~. Approximately 50% of the daily intake of fluoride is cleared by the kidneys (Whitford, 1990~. Consequently, the kidney is thought to be a target organ for any adverse effects of fluoride because of the bioconcentration and kinetics of fluoride metabolism and excretion patterns. A few experimental studies have examined the effects of fluoride exposure on rodent kidneys. Daston et al. (1985) administered] a single intraperitoneal dose of fluoride at 30 or 40 mg/kg of body weight to 29- day-old rats. They observed transitory (disappearing within 120 hours) renal effects, such as polyuria, increased urinary pH, and proximal tubular cell necrosis. The renal effects in rodents are probably age- dependent because suckling rats have a lower urinary pH than weanling rats do. The lower pH likely results in more selective reabsorption of 85

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86 Health Effects of Ingested Fluoride fluoride, which results in higher tissue concentrations. Studies of wean- ling rats consuming water with high concentrations of sodium fluoride (NaF at 380 mg/L for 6 weeks) have demonstrated necrosis of the proxi- mal and distal renal tubules Tim et al., 1978~. In a study of weanling rats administered drinking water with NaF at 100 mg/L for 6 months, Taylor et al. (1961) reported interstitial nephritis and dilation of the renal tubules at the corticomedulIary junction. No effects were observed at 50 mg/~. Structural changes in the kidneys have also been reported by other investigators following chronic fluoride exposure, although the eventual effects on renal function were not examined (Hodge and Smith, 1977; Greenberg, 1986~. In humans, the potential for health effects of fluoride exposures on renal function is enhanced because of selective absorption by the kidney and the kinetics of fluoride distribution ant} excretion. The healthy kidney removes fluoride from the blooct much more efficiently than it removes the other halogens. Furthermore, the tissue-to-plasma fluoride- concentration ratios for soft tissues were highest in the kidneys (Whi- tford, 19891. Studies of persons receiving the halogenated anesthesia, methoxyflurane, observed renal insufficiency in some patients due to high serum fluoride concentrations (Mazze, 1984~. The effect was transient, and renal function returned to normal once the serum fluoride concentra- tions decreased below 30 micromoles Mold/. Several epidemiological studies have examined the possible association between fluoride exposures and renal effects. Hanhijarvi (1975), in a study of plasma fluoride concentrations in 2,200 hospital patients in Finland (which included 501 persons living in an area with naturally occurring fluoride concentrations at less than 0.2 mg/L of drinking water and 1,083 persons living in an area with fluoride added to drinking water at ~ mg/~), showed that concentrations increased with age and were higher in individuals living in the area with added fluoride in drinking water. Renal clearance of fluoride increased with age in both groups but was approximately twice as high in persons living in the area with acIded fluoride. Decreased renal clearance of fluoride was observed in persons with renal insuf- ficiency or with diabetes mellitus. Other studies have shown decreased fluoride clearance in both adults and children with impaired renal func- tion (Kong et al., 1984; Spak et al., 1985~. Several large community- based epidemiological studies found no increased renal disease associated with long-term exposure to drinking water with fluoride concentrations

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Effects of Fluoride on Renal, Gastrointestinal, arid Immune Systems 87 up to ~ mg/L (Leone et al., 1954; Schlesinger et al., 1956; Geever et al. 1958). In summary, although experimental studies have shown transient and permanent renal effects at concentrations of fluoride over 50-100 mg/L, human epidemiological studies have not observed increased renal disease in populations with long-term exposure to fluoride concentrations up to X mg/L of drinking water. EFFECTS ON THE GASTROINTESTINAL SYSTEM With the exception of monofluorophosphate, all fluoride-releasing compounds form hydrogen fluoride when mixed with hydrochloric acid in the stomach. In the acid environment of the stomach, fluoricie and hydrogen ions form the nonionized molecule hydrogen fluoride, which might be irritating to the stomach mucosa if the concentration is suff~- ciently high. Hydrogen fluoride has been shown to induce structural and functional adverse effects on the gastric mucosa of rats and dogs at concentrations of 190 mg/L. These effects range from loss of the mu- cous layer and scattered desquamation of mucous cells to widespread erosions of the gastric mucosa (Whitford, 1990~. Experimental studies in rodents given extremely high doses of NaF (1,900 mg/L) demonstrated erosive and hemorrhagic injury to the gastric mucosa and disruption of the structure and integrity of the gastric glancis; healing progressed over 7 days (Easmann et al., 1984, 1985; PashIey et al., 19844. In rats, chronic exposure to NaF at 4, 10, or 25 mg/kg in the diet resulted in dose-dependent chronic gastritis and glandular stomach acanthosis (Appendix D in PHS, 1991~. Gross lesions were observed in the mucosa of the glandular stomach of male rats treated for 6 months with NaF at 300 mg/L (NTP, 1990~. The lesions in male and female rats included clifi~use hyperplasia of the mucosal epithelium accompanied by cellular necrosis. Studies of workers occupationally exposed to varying concentrations of fluoride have reported a variety of gastrointestinal effects. These include chronic gastritis with or without accompanying skeletal fluorosis, duodenal ulcers, and erosion of the gastric mucosa (MecIvecleva, 1983; Desai et al., 1986~. Neither of the studies reporteci ambient fluoride

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88 Health Effects of Ingested Fluoride measurements, so the actual exposure concentrations are unknown but are presumed to be high. In summary, high concentrations of fluoride, in the form of hydrogen fluoride, which is due to mixing in We stomach with hydrochloric acid, Carl be irritating to We gastric mucosa, resulting in dose~ependent adverse effects. There are limited data on humans at low exposures, indicating that at optimal concentrations of fluoride, gastrointestinal effects are not a problem. HYPERSENSITnnTY AND IMMUNOLOGICAL EFFECTS Few animal and human data on sodium fluoride-related hyper- sensitivity reactions are found in the literature. In animal studies, ex- cessively high doses, inappropriate routes of administration of fluoride, or both were used Lewis and Wilson, 1985; fain and Susheela, 1987~. Thus, the predictive value of those data, in relation to human exposures at accepted exposure levels, is questionable. Reports of hypersensitivity reactions in humans resulting from exposure to NaF are mostly anecdotal (Arnold et al., 1960; Richmond, 1985; Modly and Burnett, 1987; Razak and Latifah, 1988~. The most common reactions observed included dermatitis, urticaria, inflammation of the oral mucosa, and gastrointestin- al disturbances. Hypersensitivity reactions to fluoride dental preparations were mild to moderately severe and appeared to resolve completely with discontinuation of the product (Adair, 1989~. It was reported that those reactions were caused by NaF or by alcohol, dyes, or flavoring agents in the products. Waldbott (1962) reported that ingestion of fluoride at ~ mg/L of water produced numerous symptoms, which included gastrointestinal distress and joint pains. Those symptoms were also reported in a few patients who received a daily dose of 20 me or more in treatment for bone conditions (Rich et al., 1964; Shambaugh and Sundar, 1969~. However, those symptoms are not believed to be caused by chronic intake of fluoride at any concentration, let alone at the low fluoride concentrations cited by Waldbott. The findings should be disregarded for the following reasons: (~) insufficient clinical and laboratory evidence of allergy or intolerance to fluorides used in the fluoridation of community water, and

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Effects of Fluoride or' Renal, Gastrointestinal, and Immune Systems 89 (2) no evidence of immunologically mediated reactions in a review of the reported allergic reactions (Austen et al., 1971~. Waidbott (1978) proposed Hat the skin lesion Chizzola maculae might be caused by airborne fluorides. Waidbott and Cecilioni (1969) attributed the development of these discrete skin lesions to fluoride exposure in 10 of 32 persons living near fertilizer plants in Ontario, Canada, and Iowa and close to an iron foundry in Michigan. Evidence for Chizzola macu- lae resulting from exposure to fluoride has been reviewed extensively by several investigators (Hodge and Smith, 1977), who concluded that the evidence was circumstantial and unsupported by field surveys. The literature pertaining to immunological and immunomodulation effects of fluoride is limited. Although direct exposure to high con- centrations of NaF in vitro affects a variety of enzymatic activities (AIm, 1983; Mircevova et al., 1984; National Health and Medical Research Council, 1985; Takanaka and O'Brien, 1985; O'Shea et al., 1987; Okada and Brown, 1988; Mizuguchi et al., 19X9), the relevance of the effects in vivo is unclear. Standardized immunotoxicity tests of NaF at relevant concentrations and routes of administration have not been conducted. DISCUSSION The kidney and gastrointestinal system are exposed to varying fluoride concentrations owing to specific characteristics of fluoride kinetics and excretion patterns. The kidney exhibits the highest tissue-to-plasma fluoride concentrations measured for any soft tissue with a concentration gradient existing across the different anatomic sections of the kidney. All the soluble fluoride-releasing compounds except monophosphate form hydrogen fluoride when mixed with hydrochloric acid in the stomach. Hydrogen fluoride is irritating to the stomach mucosa. For the kidney, experimental studies have demonstrated transient renal effects at relative- ly high fluoride concentrations (50-100 mg/L). Human epidemiological studies have not observed increased rates of renal disease in populations exposed to fluoride concentrations up to ~ mg/L of drinking water. Experimental studies of the effects of fluoride on the gastrointestinal tract in several animal species have shown dose-dependent adverse effects, such as chronic gastritis and lesions of the stomach mucosa, at doses as low as 190 mg/L. The limited reports on adverse gastrointestinal effects

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90 Health Effects of Ingested Fluoride in humans are primarily studies of persons occupationally exposed to unknown concentrations of fluoride. One problem in those studies is Hat the workers are exposed to a variety of potentially toxic agents, so the contribution of fluoride exposure to risk of adverse effects on Be gastro- intestinal system is unknown. Because of the lack of documented adverse effects on the renal and gastrointestinal systems et fluoride concentrations below S mg/L of drinking water, no research recommendations are made at this time. The literature pertaining to immunological and immunomodulation effects of fluoride is limited. The weight of evidence shows that fluoride is unlike- ly to produce hypersensitivity and other immunological effects.