Genetic toxicity of fluoride

Abstract

F- is not mutagenic in standard bacterial systems, but produces chromosome aberrations and gene mutations in cultured mammalian cells. Although there is disagreement in the literature concerning the ability of F- to induce chromosome aberrations in cultured human and rodent cells, the weight of the evidence leads to the conclusion that F- exposure results in increased chromosome aberrations in these test systems. NaF induced primarily chromatid gaps and chromatid breaks, indicating that the rodent cells are responsive in the G2 stage of the cell cycle. In contrast, studies with synchronized human cells indicated that the S phase was the most sensitive. If F- does have a cell cycle-specific effect, it could be expected that differences in the cell treatment and harvest protocols could lead to conflicting results for the induction of chromosome aberrations. Gene mutations were produced in cultured rodent and human cells in the majority of the studies. Unfortunately, a number of the in vitro and in vivo cytogenetic studies are of questionable utility because of the protocols used, the quality of the responses reported, or the interpretations of the data. The conflicting results in the in vivo cytogenetic studies are difficult to reconcile. There are reports of increased chromosome aberrations in rat bone marrow and testes, but other studies, using similar protocols and dose ranges, have reported no induced chromosome damage. Although some of the studies were performed at toxic levels of F-, other studies, including those that showed positive results, were at F- concentrations (1-5 ppm) equivalent to human exposure levels. In the majority of studies that were reported to be positive, there were high background frequencies, or the investigators reported categories of nuclear or chromosome damage that are difficult to interpret. Interestingly, many of the positive results were obtained when anaphase cells were scored, whereas similar treatment protocols in other laboratories yielded negative results when metaphase cells were the only cell type examined. It is difficult, without additional data, to determine the reasons for finding chromosome breaks in anaphase, but not metaphase, cells. Other reports have presented insufficient information to allow adequate evaluations. Therefore, at this time, the question of whether F- produces chromosome damage in vivo should be considered unresolved.

Evaluation of mutagenic and cytotoxic effects of sodium fluoride on mammalian cells influenced by an acid environment

“…This is not surprising, since overwhelmingly the literature on NaF supports the conclusion that it is primarily clastogenic and not mutagenic. NaF is only readily detected in "mutations" like L5178Y at genetic loci that can tolerate larger deletions, not HGPRT unless very high doses and long incubations such as used by Crespi and colleagues (1990) are employed (Zeiger et al, 1993). Results presented in this paper support the contention that the effects of sodium fluoride in humans probably do not represent any serious mutagenic or carcinogenic threat.…”

“…Carcinogenic effects of NaF were suggested by the results of Tsutsui and co-workers (1984c) and Lasne and co-workers (1988), who demonstrated that NaF causes neoplastic transformation of SHE cells and BALB/3T3 cells in vitro, as well as by results obtained by Jones and co-workers (1988), who found that NaF can promote the frequency of morphologically transformed cell clones previously initiated with either procarcinogens or directacting agents. A summary report on results of genotoxicity testing of fluoride in microbial test systems and in vitro and in vivo mammalian test systems has been published (Zeiger et al, 1993). Crespi and co-workers (1990) suggested that NaF induces gene-locus mutations at the thymidine kinase and hypoxanthineguanine phosphoribosyl transferase (HGPRT) loci in human lymphoblastoid cells treated with toxic concentrations of NaF.…”

“…In all cases where cytotoxic data were reported, the genotoxic effect achieved significance only for sodium fluoride concentrations that resulted in substantial cell death. Moreover, it is generally agreed (Aardema et al, 1989;Zeiger et al, 1993) that fluoride-induced genotoxicity acts via an indirect mechanism involving inhibition of DNA synthesis that leads to clastogenic effects.…”

Genotoxic damage in oral epithelial cells induced by fluoride in drinking-water on students of Tula de Allende, Hidalgo, Mexico

“…Exposure to F -increases the production of superoxide as a consequence of hydrogen peroxide metabolism, inducing peroxinitrate, hydroxyl radicals increasing oxidative stress (Barbier et al, 2010;GarciaMontalvo et al, 2009;Chinoy, 2003), and inducing lypoperoxidation of membranes, apoptosis and DNA damage (Wang et al, 2007). The clinical application of NaF induced genotoxicity on the oral epithelium in acute exposition according to Zeiger et al (1993). Tiwari and Rao (2010) considered F -as a mutagenic agent that even in low concentrations can increase the induction of chromosomal aberrations.…”

Opinion of the Scientific Panel on Dietetic Products, Nutrition and Allergies (NDA) on a request from the Commission related to the Tolerable Upper Intake Level of Fluoride

“…Both negative and positive results on cytogenetic changes -mostly chromosomal aberrationshave been reported with sodium monofluorophosphate in human lymphocytes and leukocytes (Zeiger et al, 1993).…”