The genetic toxicity of fluoride has been investigated extensively by various test systems. However, results obtained have been inconsistent. Fluoride has been reported to be non-genotoxic, genotoxic, and synergistic or antagonistic with certain mutagens. To date, there are no published human studies on the genotoxicity of fluoride. The purpose of this investigation was to determine genotoxic risks of long-term exposure to various concentrations of fluoride in drinking water in humans with normal or inadequate nutrition. Six groups of subjects with either normal or inadequate nutritional intakes were selected from areas of approximately 0.2, 1.0, or 4.8 ppm (10.5, 52.6, or 252.6 μmol/L) fluoride in water. The subjects had been continuous residents in the area for at least 35 years. Samples of drinking water, plasma, and urine were analyzed for fluoride content. Blood lymphocytes were examined to determine the frequency of sister chromatid exchange (SCE). Blood chemistry and electrolytes were also analyzed. The results showed that average daily fluoride intake as well as urine and plasma fluoride levels increased with increase in the fluoride content of the drinking water. The blood chemistry and electrolyte values were within the normal range for all populations, but several parameters were significantly different. While the numerical differences were small, the subjects with low fluoride in the water (0.11 and 0.23 ppm or 5.8 and 12.1 umol/L) had significantly higher SCE frequencies than those with higher fluoride exposures. Reasons for the reduced SCE frequency in subjects with higher fluoride exposure are unclear; however, the data demonstrated that long-term exposure to fluoride in the drinking water, even at an elevated level, does not have genotoxic effects in humans.
Aardema MJ, Gibson DP, LeBoeuf RA (1989). Sodium fluoride-induced chromosome aberrations in different stages of the cell cycle: a proposed mechanism. Mutat Res223:191-203.
2.
Auletta A. (1991). Regulatory perspectives: TSCA. In: Genetic toxicology. Li AP, Heflich RH, editors. Boston: CRC Press, pp. 435-454.
3.
Auletta A., Ashby J. (1988). Workshop on the relationship between short-term test information and carcinogenicity. Environ Molec Mutagen11:135-146.
4.
Bender MA, Preston RJ, Leonard RC, Pyatt BE, Gooch PC (1992). On the distribution of spontaneous SCE in human peripheral blood lymphocytes. Mutat Res281:227-232.
5.
Clayson DB, Krewski D. (1986). The concept of negativity in experimental carcinogenesis, ICPEMC working paper No. 3. Mutat Res167:233-240.
6.
Caspary WJ, Myhr B., Bowers L., McGregor D., Riach C., Brown A. (1987). Mutagenic activity of fluorides in mouse lymphoma cells. Mutat Res187:165-180.
7.
Caspary WJ, Langenbach R., Penman BW, Crespi C., Myhr BC, Mitchell AD (1988). The mutagenic activity of selected compounds at the TK locus: rodent vs. human cells. Mutat Res196:61-81.
8.
Centers for Disease Control (1992). Public health focus: fluoridation of community water systems. MMWR41 :372-381.
9.
Crespi CL, Seixas GM, Turner T., Penman BW (1990). Sodium fluoride is a less efficient human cell mutagen at low concentrations. Environ Molec Mutagen15:71-77.
10.
de Serres FJ, Matsushima T. (1987). Meeting report: deployment of short-term assays for environmental mutagens and carcinogens. Mutat Res182:173-184.
11.
Dunipace AJ, Zhang W., Noblitt TW, Li Y., Stookey GK (1989). Genotoxic evaluation of chronic fluoride exposure: micronucleus and mouse sperm morphology studies. J Dent Res68:1525-1528.
12.
Gerdes RA (1971). The influence of atmospheric hydrogen fluoride on the frequency of sex-linked lethals and sterility in Drosophila melanogaster . Fluoride4:25-29.
13.
He W., Liu A., Bao H., Wang Y., Cao W. (1983). Effect of sodium fluoride and fluoroacetamide on sister chromatid exchanges and chromosomal aberrations in cultured Red Muntjac (Muntjacus muntjak) cells. Acta Scientiae
14.
Circumstantiae3:94-100.
15.
Jackson R., Kelly S., Noblitt T., Zhang W., Dunipace A., Li Y., et al. (1994). The effect of fluoride therapy on blood chemistry parameters in osteoporotic females. Bone Min27:13-23. Kishi K., Tonomura A. (1984). Cytogenetic effects of sodium fluoride (abstract). Mutation Res130:367.
16.
Kram D., Schneider EL, Singer L., Martin GR (1978). The effects of high and low fluoride diets on the frequencies of sister chromatid exchanges. Mutat Res57:51-55.
17.
Lambert B., Lundblad A., Nordenskjold M., Werelius B. (1978). Increased frequency of sister chromatid exchanges in cigarette smokers. Hereditas88:147-149.
18.
Latt SA, Allen J., Bloom S., Carrano A., Falke E., Kram D., et al. (1981). Sister chromatid exchanges: a report of the Gene-Tox Program. Mutat Res87:17-62.
19.
Li AP, Heflich RH (1991). Genetic toxicology. Boston: CRC Press. Li Y, Dunipace AJ, Stookey GK (1987a). Absence of mutagenic and antimutagenic activities of fluoride in Ames Salmonella assays. Mutat Res190:229-236.
20.
Li Y., Dunipace AJ, Stookey GK (1987b). Lack of genotoxic effects of fluoride in the mouse bone-marrow micronucleus test. J Dent Res66:1687-1690.
21.
Li Y., Dunipace AJ, Stookey GK (1988). Genotoxic effects of fluoride: a controversial issue. Mutat Res195:127-136.
22.
Li Y., Heerema NA, Dunipace AJ, Stookey GK (1987c). Genotoxic effects of fluoride evaluated by sister-chromatid exchange. Mutat Res192:191-201.
23.
Li Y., Zhang W., Noblitt TW, Dunipace AJ, Stookey GK (1989). Genotoxic evaluation of chronic fluoride exposure: sister chromatid exchange study. Mutat Res227:159-165.
24.
Ma J., Cheng L., Bai W., Wu H. (1986). The effects of sodium fluoride on SCEs of mice and on micronucleus of bone marrow of pregnant mice and fetal liver. Hereditas8:39-41. Marthaler TM (1984). Explanations for changing patterns of disease in the Western world. In: Cariology today. Guggenheim B, editor. New York: S. Karger, pp. 12-23. Martin GR, Brown KS, Matheson DW, Lebowitz H., Singer L., Ophaug R. (1979). Lack of cytogenetic effects in mice or mutations in Salmonella receiving sodium fluoride. Mutat Res66:159-167.
25.
Martin GR, Brown KS, Singer L., Ophaug R., Kram DJ ( 1982). Cytogenetic and mutagenic assays on fluoride. In: Fluorides, effects on vegetation, animals and humans. Shupe JL, editor. Salt Lake City: Paragon Press, Inc., pp. 271-280.
26.
Mohammed AH, Chandler ME (1977). Cytological effects of sodium fluoride on mice . In: Hearings, the National Cancer Program, Part 2-Fluoridation of public drinking water, 9/21 and 10/12, 1977. Washington, DC: US Government Printing Office, pp. 42-60.
27.
Mukherjee RN, Sobels FA (1968). The effects of sodium fluoride and iodoacetamide on mutation induction by x-irradiation in mature spermatozoa of Drosophila . Mutat Res6:217-225. National Research Council (1993). Health effects of ingested
28.
fluoride. Washington, DC: National Academy Press, pp. 91-108.
29.
National Toxicology Program (1990). Technical report 393.
30.
Toxicology and carcinogenesis studies of sodium fluoride in F344/N rats and B6C3F1 mice . NIH Publication No. 90-2848. Washington, DC.
31.
Obe G., Slacik-Erben R. (1973). Suppressive activity by fluoride on the induction of chromosome aberrations in human cells with alkylating agents in vitro. Mutat Res19:369-371.
32.
Perry P., Evans HJ (1975). Cytological detection of mutagen-carcinogen exposure by sister chromatid exchange. Nature258:121-125.
33.
Perry P., Thomson EJ (1984). The methodology of sister chromatid exchanges . In: Handbook of mutagenicity test procedures. 2nd ed. Kilbey BJ, Legator M, Nichols W, Ramel C, editors. Amsterdam: Elsevier, pp. 495-529.
34.
Skare JA, Schrotel KR, Nixon GA (1986). Lack of DNA-strand breaks in rat testicular cells after in vivo treatment with sodium fluoride. Mutat Res170:85-92.
35.
Slacik-Erben R., Obe G. (1976). The effect of sodium fluoride on DNA synthesis, mitotic indices and chromosomal aberrations in human leukocytes treated with Trenimon in vitro. Mutat Res37:253-266.
36.
Slamenova D., Gabelova A., Ruppova K. (1992). Cytotoxicity and genotoxicity testing of sodium fluoride on Chinese hamster V79 cells and human EUE cells. Mutat Res279:109-115. Solomon E., Bobrow M. (1975). Sister chromatid exchanges-a sensitive assay of agents damaging human chromosomes . Mutat Res30:273-278.
37.
Taves DR (1968). Separation of fluoride by rapid diffusion using hexamethyldisiloxane. Talanta15:969-974.
38.
Thomson EJ, Kilanowski FM, Perry PE (1985). The effect of fluoride on chromosome aberration and sister chromatid exchange frequencies in cultured human lymphocytes. Mutat Res144:89-92.
39.
Tong CC, McQueen CA, Ved Brat S., Williams GM (1988). The lack of genotoxicity of sodium fluoride in a battery of cellular tests. Cell Biol Toxicol4:173-186.
40.
Tsutsui T., Ide K., Maizumi H. (1984a). Induction of unscheduled DNA synthesis in cultured human oral keratinocytes by sodium fluoride. Mutat Res140:43-48.
41.
Tsutsui T., Suzuki N., Ohmori M. (1984b). Sodium fluoride-induced morphological and neoplastic transformation, chromosome aberrations, sister chromatid exchanges, and unscheduled DNA synthesis in cultured Syrian hamster embryo cells. Cancer Res44:938-941.
42.
Tsutsui T., Suzuki N., Ohmori M., Maizumi H. (1984c). Cytotoxicity, chromosome aberrations and unscheduled DNA synthesis in cultured human diploid fibroblasts induced by sodium fluoride . Mutat Res139:193-198.
43.
US Public Health Service (1991). Review of fluoride benefits and risks, report of the ad hoc subcommittee on fluoride. Washington, DC: US Government Printing Office, pp. 45-47. Vogel E. (1973). Strong antimutagenic effects of fluoride on mutation induction by Trenimon and 1-phenyl-3,3-dimethyltriazene in Drosophila melanogaster. Mutat Res20:339-352.
44.
World Health Organization (1984). Fluorine and fluorides. Environmental Health Criteria 36. Geneva: WHO.
