APPENDIX E
Detailed Information on Endocrine Studies of Fluoride

The tables that follow contain detailed information on the endocrine studies discussed in Chapter 8, including study design, exposure information, and reported effects. Exposure conditions and duration and fluoride concentrations are provided as given in the published articles. Many of the tables include estimates of exposure in units of mg/kg/day to aid in comparing studies. When possible, these estimates were made from information (e.g., intake rate of drinking water, body weight) given in the articles. Where such information was not available in a published article, the assumptions used to make the estimates are listed in footnotes to the tables. Note that for most of the human studies, the exposure estimates (mg/kg/day) are for typical or average values for the groups and do not reflect the full range of likely exposures.



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Fluoride in Drinking Water: A Scientific Review of EPA’S Standards APPENDIX E Detailed Information on Endocrine Studies of Fluoride The tables that follow contain detailed information on the endocrine studies discussed in Chapter 8, including study design, exposure information, and reported effects. Exposure conditions and duration and fluoride concentrations are provided as given in the published articles. Many of the tables include estimates of exposure in units of mg/kg/day to aid in comparing studies. When possible, these estimates were made from information (e.g., intake rate of drinking water, body weight) given in the articles. Where such information was not available in a published article, the assumptions used to make the estimates are listed in footnotes to the tables. Note that for most of the human studies, the exposure estimates (mg/kg/day) are for typical or average values for the groups and do not reflect the full range of likely exposures.

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Fluoride in Drinking Water: A Scientific Review of EPA’S Standards TABLE E-1 Effects of Fluoride on Thyroid Follicular Cell Function in Experimental Animals Species and Strain Exposure Conditions Fluoride Concentration or Dosea Exposure Duration Effects Reference Rats (Hebrew University albino, males; infants at start, 30-32 g) See also Table E-16 Drinking water 0.55, 1, or 10 mg/L (0.055, 0.1, and 1 mg/kg/day)b 9 months No significant differences in basal metabolic ratio, thyroid weight, radioiodine uptake, total blood iodine, protein-bound iodine, or urinary excretion. TSH not measured. Gedalia et al. 1960 Rats (females, 180-230 g) Gastric tube 0.2 or 2.2 µg/day iodine in diet 750 µg/day in 1 mL water (3.3-4.2 mg/kg/day) 2 months No effect of fluoride on body weight, weight of thyroid, total composition of iodinated amino acids, or amount of iodide present in the thyroid. No effect of fluoride on iodine excretion in the higher-iodine group. Decreased protein-bound iodine, T3, and T4 (low-iodine group). Decreased biogenesis of T3 and T4 following administration of131I (low- and high-iodine groups). TSH not measured. Stolc and Podoba 1960 Rats (Wistar, males; initial weight 170-230 g; 13 per group) Drinking water Dietary iodine, 0.45 µg/g feed (0.45 ppm) 0, 0.1, or 1 mg/day (0, 0.43-0.59, or 4.3- 5.9 mg/kg/day) 60 days Decreased plasma T3 and T4, decreased free T4 index, increased T3-resin uptake (all changes statistically significant except for the decrease in T3 for the group receiving 0.1 mg/day)c TSH not measured. Bobek et al. 1976

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Fluoride in Drinking Water: A Scientific Review of EPA’S Standards Cows (Holstein; various states of lactation, 9-13 cows from each of 9 herds) See also Table E-3 Feed supplements 1-22 mg/kg F in feed (estimated) (approximate doses, 0.03-0.7 mg/kg/day)d Chronic Urinary fluoride ≥ 2.9 mg/L (range 1.04-15.7mg/L, average 5.13 mg/L). Decreased T3, T4, cholesterol and increased eosinophils with increasing urinary fluoride (adjusted for stage of lactation); serum calcium correlated with T3 and T4. Fluorosis herds (S1, C4, V3, B2) had lower T4 than herds W, B, M, G (P < 0.05). Feeding of iodinated casein to herd B2 for 3 weeks resulted in 100% increase in milk production, increased hematopoiesis, reduced eosinophils, increased serum calcium, decreased serum phosphorus, and increase in serum T4 from 3.4 to 14.1 µg/dL. TSH not measured. Bone fluoride: mean, 2,400 ppm in ash (range, 850-6,935, 22 specimens from 8 herds). Hillman et al. 1979 Rats (Wistar) See also Table E-16 Drinking water and diet Water: 0, 1, 5, 10, 50, 100, or 200 mg/L Diet: 0.31 or 34.5 ppm (0, 0.1, 0.5, 1, 5, 10, or 20 mg/kg/day from water and 0.025 or 2.8 mg/kg/day from feed)e 54-58 days Elevated T3 and T4 in rats on 1 mg/L in drinking water and low-fluoride diet. Low T3 and normal T4 in rats on 1, 5, or 10 mg/L in drinking water and high-fluoride diet. Decreased TSH and GH in animals receiving 100 or 200 mg/L in drinking water. Full details not available. Hara 1980

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Fluoride in Drinking Water: A Scientific Review of EPA’S Standards Species and Strain Exposure Conditions Fluoride Concentration or Dosea Exposure Duration Effects Reference Rats (Wistar, 3-month-old, 200-400 g) Drinking water Animals were kept 21 days on a diet containing 0.15% PTU to deplete their thyroid glands of iodine and thyro-globulin. For the next 2 days, a low- iodine diet (0.04 µg/g) was fed, but no more PTU. During the next 6 days the rats were given sufficient iodine (1.5 µg of iodide/mL of drinking water, labeled with 0.1 µCi of 125I). Then fluoride was given as indicated. 60 or 200 mg/L (6-20 mg/kg/day)b 6 days Serum fluoride at end of experiment (µg/mL): 0.165 (controls), 0.246 (60 mg/L), and 0.576 (200 mg/L). No significant differences from control values for relative thyroid weight, iodine content of thyroglobulin, thyroidal content of organic iodine, or amounts of monoiodotyrosine, diiodotyrosine, T3, and T4. TSH not measured. Sieben- hüner et al. 1984

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Fluoride in Drinking Water: A Scientific Review of EPA’S Standards Cows (Holstein, females; age 5-6 months at start, 30 animals total) NaF added to feed Iodine intake not stated, presumably adequate 30 or 50 ppm in feed Approx. 0.8 or 1.4 mg/kg/day at 30 weeks of age; approx. 0.5 or 0.8 mg/kg/day at 100 weeks of age Data reported through age 100 weeks Serum fluoride at age 88 weeks (mg/L): 0.06 (controls), 0.20 (30 ppm in feed), and 0.28 (50 ppm in feed). Urinary fluoride at age 88 weeks (mg/L): 1 (controls), 13 (30 ppm in feed), and 20 (50 ppm in feed). Bone fluoride at age 17 months (ppm in tail vertebra, means of groups of 5 animals): 352 and 453 (controls), 2,306 and 2,712 (30 ppm in feed), and 3,539 and 3,946 (50 ppm in feed). No significant differences from control values for T4 concentration and T3 uptake at ages 40, 56, 72, and 88 weeks.f TSH not measured. Clay and Suttie 1987 Rats (Wistar, males and females; 120 ± 19 g at start, 212 animals total) See also Table E-2 Drinking water Low or normal iodine 10 or 30 mg/L in drinking water (1 or 3 mg/kg/day)b 7 months 10 mg/L and normal iodine: no significant effect (some decrease in serum T4 and T3). 30 mg/L and normal iodine: statistically significant decreases in T4, T3, thyroid peroxidase, 131I uptake, [3H]-leucine uptake, and thyroid weight. 10 mg/L and low iodine: abnormalities in thyroid function beyond those attributable to low iodine; reduced thyroid peroxidase; low T4, without compensatory transformation of T4 to T3. TSH not measured. Guan et al. 1988

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Fluoride in Drinking Water: A Scientific Review of EPA’S Standards Species and Strain Exposure Conditions Fluoride Concentration or Dosea Exposure Duration Effects Reference Mice (Kunmin, males; 288 animals in 9 groups of 32 each; 13-15 g at start) Drinking water (NaF) Iodine: low (0 µg/L); normal (20 µg/L); excess 2500 µg/L) Low-iodine, low-fluoride chow fed to all groups. Low, 0 mg/L; normal,0.6 mg/L; excess, 30 mg/L (0, 0.06, and 3 mg/kg/day)b 100 or 150 days For iodine-excess groups, thyroid weight relative to body weight decreased significantly with increasing fluoride intake. For iodine-deficient groups, goiter incidence at 100 days was 18%, 40%, and 66% for low-, normal-, and high-fluoride groups, respectively; at 150 days, goiter incidence was 81-100%. Fluoride-excess groups at 100 days had elevated T4 with all concentrations of iodine intake and elevated T3 for iodine-deficient animals. Fluoride excess significantly inhibited radioiodine uptake in iodine-deficient and iodine-normal groups. Incisor fluorosis occurred only in the fluoride excess groups; severity was greater in the iodine-deficient animals. Bone fluoride in fluoride-excess animals was greater in iodine-deficient (means, 2,560-2,880 ppm ash) or iodine-excess animals (means, 2,140-2,380 ppm ash) than in iodine-normal animals (means, 1,830-2,100 ppm ash). TSH not measured. Zhao et al. 1998

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Fluoride in Drinking Water: A Scientific Review of EPA’S Standards Cattle near aluminum smelter in India Contaminated pasture from smelter emissions No information on iodine intake Not available Notavailable Skeletal and enamel fluorosis (58% of animals within 3 km of plant were affected). Significantly decreased concentrations of T3. Significantly increased concentrations of alkaline phosphatase, inorganic phosphorus, and creatinine. Urinary fluoride averaged 26.5 mg/L close to smelter. Full details not available. Swarup et al. 1998 Cattle, buffaloes, sheep, and goats in 21 villages in India (286 calves, 1,675 adult cattle, 290 adult buffaloes, 780 goats, 564 sheep) Drinking water No information on iodine intake 1.5-4 mg/L in drinking water Native livestock present in relevant area since birth Prevalence of enamel fluorosis up to 75% (adult buffalo), 70% (adult cattle), or 100% (calves), depending on location; prevalence of skeletal fluorosis up to 37.5% (buffalo) or 29% (cattle), depending on location; no evidence of enamel or skeletal fluorosis in goats or sheep. No clinical evidence of goiter in any fluorotic animals. Animals not showing clinical signs of fluorosis were not examined for goiter. No measurements of any thyroid hormone parameters or TSH. Choubisa 1999 Mice (Wistar, adult females; about 30 g at beginning; fluoride was administered during pregnancy and lactation)g Drinking water (Iodine intake 0.720 ± 0.12 µg/g in diet) 500 mg/L in drinking water (50 mg/kg/day to the mothers)b From day 15 of pregnancy to day 14 of lactation Body weight of pups at 14 days old was reduced 35%; 75% decrease in plasma T4 in pups; 17% decrease in cerebral protein in pups; histological changes in cerebellum in pups. TSH not measured. Trabelsiet al. 2001

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Fluoride in Drinking Water: A Scientific Review of EPA’S Standards Species and Strain Exposure Conditions Fluoride Concentration or Dosea Exposure Duration Effects Reference Cows (3 years old with chronic fluorosis, 10 controls without fluorosis, from different regions of Turkey) Drinking water Iodine intakes not specifically stated 5.7-15.2 mg/L in drinking water (approximate doses, 0.7-1.8 mg/kg/day)h Lifelong Mean values of T4, T3, and PBI in fluorotic animals were below the normal ranges and also significantly less than in controls. Low concentrations of bioavailable iodine in fluorosis region might be a factor. TSH not measured. Cinar and Selcuk 2005 aInformation in parentheses was calculated from information given in the papers or as otherwise noted. bBased on water consumption of about 10% of body weight. cATSDR (2003) stated that an intermediate-duration minimal risk level (MRL) derived from this study of thyroid effects in rats would have been lower (more protective) than the chronic-duration MRL derived from a human study of bone effects (0.05 mg/kg/day). dBased on feed consumption of 16 kg/day (dry weight) and body weight of 500 kg. eBased on water consumption of about 10% of body weight and feed consumption of about 8% of body weight. fText says “triiodiothyronine uptake” and table says “thyroxine uptake.” Data for different treatment groups were not given. gIn many mammalian species, maternal fluoride exposures are not well reflected by fluoride concentrations in milk; therefore, the impacts of fetal exposure and of reduced milk production by the mothers must also be considered. hBased on water consumption of 60 L/day and body weight of 500 kg. ABBREVIATIONS: GH, growth hormone; PBI, protein-bound iodine; TSH, thyroid-stimulating hormone.

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Fluoride in Drinking Water: A Scientific Review of EPA’S Standards TABLE E-2 Summary of Effects of Fluoride Exposure for Rats with Different Amounts of Iodine Intake (Means ± SD) Group Body Weight, g Urinary Fluoride, mg/L Urinary Iodine, µg/24 hours 131I Uptake, % at 24 hours Serum T4, µg/dL Serum T3, ng/dL TPO, G.U./100 g of body weight [3H] Leucine Uptake, cpm/10 mg Thyroid Weight, mg/g (control; normal iodine,a normal fluorideb) 293 ± 57 1.23 ± 0.22 1.110 ± 0.226 47.37 ± 5.66 3.64 ± 1.45 70.65 ± 30.29 2.04 ± 0.22 1,808 ± 358 9.97 ± 3.52 (normal iodine,a fluoride, 10 mg/L in drinking water) 294 ± 85 6.65 ± 0.91c 1.215 ± 0.357 44.74 ± 5.14 3.02 ± 1.48 61.96 ± 26.02 1.98 ± 0.51 1,728 ± 790 9.58 ± 2.40 (normal iodine,a fluoride, 30 mg/L in drinking water) 254 ± 68c 8.16 ± 0.89c 1.150 ± 0.87 42.73 ± 4.31c 1.44 ± 0.39c 43.00 ± 11.31c 1.73 ± 0.24c 1,258 ± 293c 7.90 ± 2.37c (low iodine,d normal fluoridef) 289 ± 72 1.23 ± 0.26 0.095 ± 0.029c 58.40 ± 9.54c,e 0.76 ± 0.70c 95.81 ± 25.18c 2.57 ± 0.44c 2,252 ± 683c 19.91 ± 11.23c (low iodine,d fluoride, 10 mg/L indrinking water) 308 ± 63 6.23 ± 0.88c 0.099 ± 0.017c 59.05 ± 7.59c,e 0.65 ± 0.57c 68.05 ± 21.96 1.75 ± 0.21c 1,804 ± 459 20.13 ± 22.10c aNormal iodine: 310 ng/g in diet; 8.2 ng/mL in drinking water. bFluoride: 1.856 ppm in diet; 0.4 mg/L in drinking water. cP < 0.01, compared with group 1 (control). dLow iodine: 20-62.5 ng/g in diet; deionized drinking water. eAlso statistically significant at 2 hours and 6 hours (P < 0.01, compared with group 1). fFluoride: 1.743 ppm in diet; deionized water. ABBREVIATIONS: cpm, counts per minute; G.U., guaiacol unit; TPO, thyroid peroxidase. SOURCE: Guan et al. 1988. Reprinted with permission; copyright 1988, Chinese Medical Association.

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Fluoride in Drinking Water: A Scientific Review of EPA’S Standards TABLE E-3 Summary of Selected Findings for Fluoride-Exposed Dairy Cows Herda Number Observed Urinary Fluoride, mg/Lb Serum T4, µg/dLc Serum T3, ng/dLd Plasma Calcium, mg/dLe W 12 2.92 ± 0.52 4.60 ± 0.34 175 ± 7.2 10.1 ± 0.15 B 12 5.37 ± 0.43 4.83 ± 0.19 168 ± 5.8 9.5 ± 0.11 M 12 6.39 ± 0.92 5.30 ± 0.38 177 ± 8.4 9.6 ± 0.11 G 12 6.33 ± 0.74 4.82 ± 0.28 159 ± 7.7 9.4 ± 0.15 P 12 3.47 ± 0.47 — — 9.3 ± 0.12 S1 12 6.29 ± 1.08 3.59 ± 0.26 126 ± 8.4 9.1 ± 0.17 C4 9 —f 2.21 ± 0.54 — 9.5 ± 0.14 V3 10 — 3.35 ± 0.47 — 9.5 ± 0.13 B2 13 — 3.39 ± 0.42 — 8.9 ± 0.12 aHerd identification as reported by Hillman et al. (1979). Enamel fluorosis and elevated bone fluoride were confirmed in herds S1, C4, V3, and B2. Cows were uniformly distributed throughout lactation in all herds. bW < all others (P < 0.05). cC4 < all others; S1, V3, B2 < W, B, M, G (P < 0.05). dS1 < W, B, M, G (P < 0.05). eB2 < M, W; S1, P, G < W (P < 0.05). f—indicates not measured or not reported. SOURCE: Hillman et al. 1979. Reprinted with permission; copyright 1979, Journal of Dairy Science.

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Fluoride in Drinking Water: A Scientific Review of EPA’S Standards TABLE E-4 Effects of Fluoride in Drinking Water on Thyroid Follicular Cell Function in Humans Study Population(s) and Type Fluoride Concentrationa and Exposure Duration/Conditions Iodine Status and Other Information Effects Reference India, 3 villages, 2,008 persons, all ages Ecologic study; cross-sectional; entire population of each village included 5.4, 6.1, and 10.7 mg/L (means for the villages) Lifelong Iodine in drinking water: 14.4-175.3 µg/L (inverse relationship to fluoride concentration). Iodine from salt: 86 µg/day. Calcium in diet: 480 mg/day. Diet considered deficient in proteins, fats, calcium, vitamins A and C. Transient goiters in persons aged 14-17; associated with increased fluoride in water and with decreased iodine in water. Siddiqui 1960 Israel, 2,685 girls, ages 7-18 Ecologic study; cross-sectional; may have included all eligible subjects, but not specifically stated <0.1-0.9 mg/L Lifelong Iodine in drinking water: <2-100 µg/L. Endemic goiter associated with low iodine content of water, but not with fluoride content of water. Gedalia and Brand 1963 U.S., adults ages 18-60; 106 from Crisfield, Maryland (42% female); 109 from New York City (29% female) Ecologic exposure measure; cross-sectional; no information on subject selection 0.09 mg/L in New York City 3.48 mg/L in Crisfield, Maryland ≥10 years exposure General iodine status not given. Chrisfield: the 3 individuals with the highest PBI concentrations were all on iodine medication for non-thyroidal disease, and one of the individuals with the lowest PBI had had a partial thyroidectomy for a thyroid cyst.b New York City: the individualwith the highest PBI was taking 3 grains of thyroid daily.b No differences in PBI. No gross thyroid abnormalities or gross evidence for thyroid disease. Mild or moderate enamel fluorosis in 75% of individuals from Crisfield. Leone et al. 1964

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Fluoride in Drinking Water: A Scientific Review of EPA’S Standards Species and Strain Exposure Conditions Concentration or Dosea Exposure Duration Rabbits (Dutch-Belted, female, 3 1/2 months old at start, 1.55 kg) See also Table E-11 Drinking water 0 and 100 mg/L [7-10.5 mg/kg/day]g 6 months Rats (Sprague-Dawley, male, 30-40 g weanlings at start, 432 animals total) Drinking water Either calcium-deficient diet or diet deficient in protein, energy, or total nutrients 5, 15, or 50 mg/L [0.5, 1.5, or 5 mg/kg/day]c 16 or 48 weeks Rats (Charles River, Wistar, females, normal and with streptozotocin-induced diabetes, 8 per group) C: normal, no fluoride in water F10: normal, fluoride in water D: diabetic, no fluoride in water DF10: diabetic, fluoride in water FF: normal, with fluoride intake adjusted to match that of DF10 (1.6-3 mg/day per rat) Drinking water and feed (NaF in drinking water) Drinking water: Groups C and D, 0 mg/L Groups F10 and DF10, 10 mg/L Group FF, adjusted to match fluoride intake of DF10 Feed: 13 ppm (all groups) [C: 1.0-1.5 mg/kg/day F10: 2.1-2.9 mg/kg/day D: 2.2-2.5 mg/kg/day DF10: 8.4-18.6 mg/kg/day FF: 8.3-11.8 mg/kg/day]i 3 weeks Horses (6 total, thoroughbreds, average age 5 years, average weight 509 kg, euthanized at end of experiment) Sevoflurane anesthesia Not available Mean, 18.5 hours

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Fluoride in Drinking Water: A Scientific Review of EPA’S Standards Effects Reference Statistically significant (P < 0.05) increase in serum glucose (17%). Increased IGF-1 (40%). Insulin or other regulators of serum glucose were not measured. No effect of fluoride on serum urea, creatinine, phosphorus, total protein, albumin, or bilirubin; serum glutamate oxaloacetate transaminase; or total alkaline phosphatase. Increased serum fluoride (0.728 versus 0.0441 mg/L)h and bone fluoride (6,650-7,890 versus 850-1,150 ppm in ash). Turner et al. 1997 No significant effect on fasting plasma glucose; specific data by fluoride treatment group not reported. Combination of general malnutrition and calcium deficiency was not examined. Dunipace et al. 1998 Normal rats had similar intakes of feed and water regardless of fluoride intake; final body weights were similar. Diabetic rats had 3-5 times higher water intake than normal rats and almost twice the feed intake; final body weights for group D were lower than for normal rats; final body weights for group DF10 were lower than initial body weights. Increase in overall severity of diabetes and higher fasting blood glucose concentrations in fluoride-treated diabetic rats; about 400 mg/dL (22 mM/L) in DF10 versus 250 mg/dL (14 mM/L) in D and 90 mg/dL (5 mmol/L) in C, F10, and FF. Plasma fluoride (approximate, mg/L): C, 0.029; F10, 0.038; D, 0.038; DF10, 0.095; FF, 0.057.j Bone (femoral) fluoride (approximate, ppm in ash): C, 400; F10, 600; D, 400; DF10, 1000; FF, 1900). Fluoride treatment in nondiabetic rats did not cause significant alteration of blood glucose concentrations. Boros et al. 1998 Mean plasma fluoride after 8 hours was 0.7-0.9 mg/L (38-45 µmol/L). Total and ionized calcium decreased over time; ionized calcium remained within normal limits; total calcium below normal values after 2 hours. Serum glucose concentrations increased throughout, exceeding normal concentrations at 6 hours and thereafter, but within the values commonly observed during general inhalation anesthesia in horses; glucosuria also present after 10 hours. Driessen et al. 2002

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Fluoride in Drinking Water: A Scientific Review of EPA’S Standards Species and Strain Exposure Conditions Concentration or Dosea Exposure Duration Rats (Wistar, adult females, 150-170 g at start; fluoride administered during pregnancy and lactation)k NaF orally by feeding tube 40 mg/kg/day NaF (18 mg/kg/ day fluoride to the mothers) Day 6 of gestation through day 21 of lactation Rats (Wistar FL, males, 14 weeks old, 8 treated, 10 controls) Intraperitoneal injection 35 mg/kg NaF (15.8 mg/kg fluoride) in physiological saline Controls, saline only Single dose, sacrificed 90 minutes later aInformation in brackets was calculated from information given in the papers or as otherwise noted. bBased on average of initial and final mean body weights. cBased on water consumption of about 10% of body weight, with no significant differences in body weight with fluoride intake. dBased on water consumption of about 10% of body weight and feed consumption of about 8% of body weight, with no significant differences in body weight with fluoride intake. eBased on final (6-month) mean body weights of 508.8 g for controls and 445.4 g for diabetics, with pretermination (3- and 6-month combined) metabolic data for fluoride intake. fPlasma fluoride (µmol/L) in controls: 0.42-0.54, 0.8-0.9, 1.5, and 3.8-4.3; in diabetics: 0.51-0.65, 1.9-2.4, 5.5-6.1, and 13.6-19.2 gBased on average daily water consumption of 163 mL, mean initial weight of 1.55 kg, and mean final weight of 2.33 kg for the fluoride-treated group. hSerum fluoride: 38.31 versus 2.32 µmol/L. IBased on average daily fluoride intake for days 1-4 with average initial body weight for all groups and average daily intake for days 15-21 with average final body weight for the group. jPlasma fluoride (approximate, µmol/L): C, 1.5; F10, 2; D, 2; DF10, 5; FF, 3. kIn many mammalian species, maternal fluoride exposures are not well reflected by fluoride concentrations in milk; therefore, the impacts of fetal exposure and of reduced milk production by the mothers must also be considered.

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Fluoride in Drinking Water: A Scientific Review of EPA’S Standards Effects Reference Marked hypoglycemia in mothers and offspring, attributed to reduced feed consumption. Reduced serum protein content, significant increases in serum sodium and potassium. Significant recovery on withdrawal of NaF or supplementation with vitamins C, D, and E. Verma and Guna Sherlin 2002a Hyperglycemia (47% increase), accompanied by impairment in renal function, decreased calcium concentrations (13%). Grucka-Mamczar et al. 2005

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Fluoride in Drinking Water: A Scientific Review of EPA’S Standards TABLE E-17 Effects of Fluoride on Other Endocrine Organs in Humans Study Population(s) Exposure Conditions Concentration or Dosea and Exposure Duration 76 male and female inmates of Japanese mental hospital Observational study; summary of cases; cross-sectional Thought to be from pesticide use Not available Chronic 41 Russian males with fluorosis, ages 33-45, 19 controls (no contact with fluorine compounds) Case-control study; cross-sectional; full details not available Occupational exposure Not available >15 years for some Volunteers in Argentina, 6 adults Experimental study; subjects included the authors of the report and members of their laboratory Oral administration to fasting persons 27 mg of fluoride (60 mg of NaF) [0.4 mg/kg]b Single dose 25 young adults (14 males, 11 females) in India with endemic fluorosis (skeletal and enamel), ages 15-30 years (nonobese, nonsmokers, no personal or family history of diabetes mellitus or hypertension) 25 controls with normal fluoride intake (age, sex, and body mass index matched; comparable social and working conditions) Case-control study; cross-sectional for all; longitudinal for subjects initially found to have impaired glucose tolerance; tests were repeated after 6 months on a low-fluoride water source Drinking water 2-13 mg/L in drinking water [0.067-0.43 mg/kg/day]c Controls: < 1 mg/L [< 0.03 mg/kg/day]c Since birth Poland, residents of Skawina (living in the vicinity of an aluminum smelter) and Chorzów (employed in any of 3 industries); approximately 50 individuals per group (approximately 200 total) Ecologic measure of exposure (exposure to environmental fluorides from industrial pollution) Airborne fluorides Skawina: chronic exposure to fluorine compounds Chorzów: chronic exposure to environmental fluorides and other toxic compounds 8-10 times the Maximum Allowable Concentration for fluoride of 1.6 µg/m3 (12.8-16 µg/m3)

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Fluoride in Drinking Water: A Scientific Review of EPA’S Standards Effects Reference Endocrine disturbances including melanosis in 20 of 76 patients; attributed to dysfunction of parathyroids and adrenals, reversed upon treatment for chronic fluorine poisoning. Spira 1962 Elevated follicle-stimulating hormone and decreased testosterone in blood in all men with fluorosis; elevated blood luteinizing hormone in men with long-term exposure (>15 years). Tokar’ and Savchenko 1977 After 1 hour, significant fall of plasma insulin concentrations and increased fluoride; reduced insulin response to glucose challenge. Plasma fluoride: 0.1-0.3 mg/L (5-15 µmol/L). Rigalli et al. 1990 Impaired glucose tolerance (IGT) in 40% (6 males, 4 females); fasting serum fluoride concentrations positively correlated (P < 0.01) with area under glucose curve in those 10; effect appeared to be reversible on provision of drinking water with “acceptable” fluoride concentrations (<1 mg/L). For all 25 endemic fluorosis patients, significant positive correlation between serum fluoride and fasting serum immunoreactive insulin; significant negative correlation between serum fluoride and fasting glucose:insulin ratio. Normal serum calcium, inorganic phosphorus, and vitamin D; elevated serum alkaline phosphatase in patients with endemic fluorosis. Urine fluoride (mg/L): fluorosis patients, 2-8; controls, 0.2-0.5. Serum fluoride (mg/L): patients with IGT, 0.08 ± 0.04; patients with normal glucose tolerance, 0.02 ± 0.01; controls, 0.01 ± 0.009; IGT patients after 6 months on low-fluoride water, 0.02 ± 0.01. Trivedi et al. 1993 Excessive excretion of fluorides in urine (53-100% with urine fluoride > 2.3 mg/L; for Skawina, mean = 5.6 mg/L; SD = 2.5, n = 46), associated with a decrease in urine and erythrocyte magnesium concentrations (36-65% with urine magnesium < 5.4 mg/L); increased blood glucose and lactate concentrations, which were normalized by magnesium supplementation. For Skawina, 74% had blood glucose results above the norm (70-100 mg/dL or 3.89-5.55 mmol/L; n = 42). Kedryna et al. 1993

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Fluoride in Drinking Water: A Scientific Review of EPA’S Standards Study Population(s) Exposure Conditions Concentration or Dosea and Exposure Duration U.S., female osteoporosis patients (patients with previous history of hyperparathyroidism and several other conditions were excluded) Initial recruitment included 203 in-state patients from previous fluoride trials and 95 controls who had not taken fluoride; of these, 40 fluoride patients and 43 controls were scheduled for appointments; 15 fluoride patients were no longer taking fluoride or failed the appointments; 5 controls failed the appointments; final study included 25 fluoride patients and 38 controls (mean ages, 70.1 for fluoride group, 69.5 for controls) Cross-sectional study; fluoride-treated patients and non-fluoride-treated controls recruited from database of osteoporosis patients of one investigator; fasting samples; analyses of drinking water, blood, and urine performed blindly; results reported as means of groups and as number outside the normal range for the parameter; urine and plasma fluoride clearly different between groups; no significant difference in mean water fluoride concentrationsSee also Table E-12 Slow-release sodium monofluorophosphate plus 1,500 mg/day calcium carbonate Most controls (n = 38) had calcium supplementation 23 mg/day (mean dose) [0.33 mg/kg/day]b 1.4-12.6 years (mean, 4.2 years) China, healthy adults (approximately 120 per group, with either normal or inadequate nutritional intakes; mean ages of groups, 44.9-47.7 years) Cross-sectional cohort study; subjects grouped by location (water fluoride concentration) and nutritional status; populations generally similar (e.g., socially and economically); estimated fluoride intakes and measurements of urine and plasma fluoride and other parameters were made for individuals but results reported only for groups; probably overlap between low (<0.3 mg/L) and middle (around 1 mg/L) fluoride exposure groups for each nutritional category; no mention of whether analyses were performed blindly See also Table E-12 Drinking water Normal nutrition defined as > 75 g/day protein and Ca >600 mg/day Inadequate nutrition defined as <60 g/day protein and Ca <400 mg/day 0.23, 1.02, and 5.03 mg/L (normal nutrition) 0.11, 0.90, and 4.75 mg/L (inadequate nutrition) Estimated intakes: 1.70, 3.49, and 14.8 mg/day (normal nutrition); 1.20, 2.64, 15.32 mg/ day (inadequate nutrition) At least 35 years of continuous residency in the study area

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Fluoride in Drinking Water: A Scientific Review of EPA’S Standards Effects Reference Mean fasting blood glucose concentrations 104.7 (SD = 53.0) for fluoride-treated group and 95.2 (SD = 10.3) for controls (difference not considered significant); 3 of 25 fluoride-treated individuals outside normal range (versus 1 of 38 controls). Urine fluoride (mg/L, mean and SD): fluoride group, 9,7 (4.1); controls, 0.8 (0.5); plasma fluoride (mg/L, mean and SD)d: fluoride group, 0.17 (0.068); controls, 0.019 (0.0076). Jackson et al. 1994 No significant differences in mean blood glucose concentrations among groups. Not clear whether samples were fasting or nonfasting. Li et al. 1995

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Fluoride in Drinking Water: A Scientific Review of EPA’S Standards Study Population(s) Exposure Conditions Concentration or Dosea and Exposure Duration 2 postmenopausal women in Argentina Experimental study; subjects were members of the authors’ department who were receiving NaF as treatment for osteoporosis and who volunteered to undergo glucose tolerance tests; tests were administered in the fasting state Treatment for osteoporosis 13.6 mg/day (30 mg/day NaF) [0.23 mg/kg/day]e 9 and 24 months 24 women and 2 men, ages 44-66, former residents of an area of endemic fluorosis in Argentina Ecologic exposure measure; cross-sectional study; fasting blood samples Drinking water Not stated Chronic U.S., 199 adult volunteers (mean ages of groups, 62.3, 58.6, 57.2 years) Ecological study; cross-sectional; subjects grouped by location (water fluoride concentration); subjects not randomly selected; nonfasting samples; urine and plasma fluoride concentrations significantly different for groups; study parameters reported by groups; no information on whether analyses were performed blindly See also Table E-12 Drinking water, natural fluoride Dietary calcium and calcium concentrations in drinking water were not discussed 0.2, 1.0, 4.0 mg/L [0.003, 0.01, 0.06 mg/kg/day]b At least 30 years of continuous residency in their communities 160 males ages 20-50 years, in Mexico Ecologic exposure measure based on occupation; exposure groups overlapped; no information on selection of subjects Drinking water alone for 27 men (low group) Occupational exposure and drinking water for 133 men (high group) 3.0 mg/L in drinking water 2-13 mg/day estimated for low group [0.03-0.19 mg/kg/day]b 3.4-27.4 mg/day estimated for high group [0.05-0.39 mg/kg/day]b Chronic (at least 1 year for occupational exposure) aInformation in brackets was calculated from information given in the papers or as otherwise noted. bBased on 70-kg per person. cBased on consumption of 2 L of drinking water per day by a 60-kg adult. dReported as 9.0 (3.6) µmol/L for the fluoride group and 1.0 (0.4) µmol/L for the controls. eBased on 60-kg per person.

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Fluoride in Drinking Water: A Scientific Review of EPA’S Standards Effects Reference Disturbed glucose homeostasis when given glucose tolerance test. Plasma F: 0.11 and 0.13 mg/L (5.6 and 6.7 µM/L). Rigalli et al. 1995 Inverse relationship between plasma fluoride and area under curve of insulin during a standard glucose tolerance test. Plasma F: 0.01-0.18 mg/L (0.5-9.2 µM/L). Urine F: > 1.1 mg/day. de la Sota et al. 1997 No significant differences among mean glucose concentrations (nonfasting); all mean values were within normal ranges. Jackson et al. 1997 Elevated follicle stimulating hormone; decreased testosterone, inhibin B, and prolactin; apparent reduction in sensitivity of the hypothalamic-pituitary axis to negative feedback action from inhibin B. Fluoride exposures of the two groups overlapped, and occupational exposures included other chemicals besides fluoride. Ortiz-Perez et al. 2003

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