Fluoride’s Mutagenicity: In vitro Studies
This section on cancer includes:
• INTRODUCTION
Part 1: Fluoride’s Mutagenicity: In vitro Studies
Part 2: Fluoride’s Mutagenicity: In vivo Studies
Part 3: NTP Bioassay on Cancer (1990)
Part 4: Liver Cancers in NTP Bioassay
Part 5: Osteosarcoma: A Timeline
Part 6: Osteosarcoma Link Is Biologically Plausible
Part 7: Critique of Gelberg’s Study on Osteosarcoma
The relevance of the in vitro findings are further amplified by the fact that there are certain “microenvironments” in the body, such as the bones, oral cavity, kidney, bladder, and pineal gland, where the cells can be exposed to fluoride levels orders of magnitude greater than the fluoride levels found in the blood. Bones, for example, regularly accumulate 1,000 to 4,000 parts per million fluoride. Since bone mineral is regularly broken down by osteoclasts as part of the bone remodeling process, the fluoride sequestered in bones may be periodically released, exposing bone cells to sharp spikes in fluoride levels. This might help explain why fluoride has been associated, in both human and animal studies, with osteosarcoma (bone cancer). One in vitro study, for example, found that 10 to 19 ppm fluoride caused mutagenic effects in bone cells after 24 to 48 hours of exposure. (Mihashi 1996). According to the authors:
“Significant increases in the frequencies of
chromosome aberrations were induced in a dose- and treatment
time-dependent fashion when NaF was administered to [rat vertebral bone]
cells at 0.5 and 1.0 mM [=9.5 to 19 ppm] for 24 and 48 h. The results
indicate that NaF is genotoxic to rat vertebrae, providing a possible
mechanism for the vertebrae, as a target organ of NaF carcinogenesis.”
SOURCE: Mihashi M, Tsutsui T. (1996). Clastogenic activity of sodium fluoride to rat vertebral body-derived cells in culture. Mutation Research 368(1):7-13.
Of further interest is the fact that cells from humans and apes have
been found to be more susceptible to fluoride-induced genetic damage
than rodent cells. (Kishi 1993). Accordingly, chromosome breaks occurred
in human and ape cells at fluoride concentrations (19 to 114 ppm) that
had no effects on rodent cells.SOURCE: Mihashi M, Tsutsui T. (1996). Clastogenic activity of sodium fluoride to rat vertebral body-derived cells in culture. Mutation Research 368(1):7-13.
Finally, a number of recent “in vivo” studies, including studies of humans exposed to high levels of fluoride, have also found increased levels of genetic damage. Although the in vivo research is still limited, the weight of evidence from the in vitro and in vivo studies strongly indicate that fluoride is a mutagen, a finding that has significant implications with respect to fluoride’s capacity to induce or promote cancer.
reviews of In-Vitro research on fluoride’s mutagenicity:
“In summary, sodium fluoride is mutagenic in cultured
mammalian cells and produces transformation of Syrian hamster cells in
vitro. The reports of in vivo cytogenetic studies are mixed, but the
preponderance of the evidence indicates that sodium fluoride can induce
chromosome aberrations and sister chromatid exchanges in cultured
mammalian cells. These mutagenic and clastogenic effects in cultured
cells are supported by positive effects in Drosophila germ cell tests
that measure point mutations and chromosome breakage. In vivo tests in
rodents for chromosome aberrations provide mixed results that cannot
readily be resolved because of differences in protocols and insufficient
detail in some study reports to allow a thorough analysis. The
mechanism(s) by which these effects result from exposure to sodium
fluoride is not known.”
SOURCE: National Toxicology Program [NTP] (1990). Toxicology and Carcinogenesis Studies of Sodium Fluoride in F344/N Rats and B6C3f1 Mice. Technical report Series No. 393. NIH Publ. No 91-2848. National Institute of Environmental Health Sciences, Research Triangle Park, N.C.
SOURCE: National Toxicology Program [NTP] (1990). Toxicology and Carcinogenesis Studies of Sodium Fluoride in F344/N Rats and B6C3f1 Mice. Technical report Series No. 393. NIH Publ. No 91-2848. National Institute of Environmental Health Sciences, Research Triangle Park, N.C.
“The effects of fluoride as a mutagen, carcinogen,
and antimutagen are inconsistent, but the preponderance of evidence in
cultured mammalian cells indicate that sodium fluoride can induce
chromosome aberrations and sister chromatid exchanges.”
SOURCE: Bassin EB. (2001). Association Between Fluoride in Drinking Water During Growth and Development and the Incidence of Ostosarcoma for Children and Adolescents. Doctoral Thesis, Harvard School of Dental Medicine. p. 15.
SOURCE: Bassin EB. (2001). Association Between Fluoride in Drinking Water During Growth and Development and the Incidence of Ostosarcoma for Children and Adolescents. Doctoral Thesis, Harvard School of Dental Medicine. p. 15.
“Fluoride (as sodium fluoride) should be considered
capable of inducing chromosomal aberrations, micronuclei, and
sister-chromatid exchanges in vitro in mammalian cells, although the
results from such studies have been inconsistent.”
SOURCE: Environment Canada. (1993). Inorganic Fluorides: Priority Substances List Assessment Report. Government of Canada, Ottawa.
SOURCE: Environment Canada. (1993). Inorganic Fluorides: Priority Substances List Assessment Report. Government of Canada, Ottawa.
“Genotoxicity studies are highly dependent on the
methods used… Despite the apparently contradictory reports appearing in
the published literature, fluoride has not been shown to be mutagenic in
bacteria (Ames test). In some studies fluoride has been reported to
induce gene mutations in both cultured rodent and human cells. Fluoride
has also been reported to transform rodent cells in vitro. Although
there is disagreement in the literature concerning the ability of
fluoride to be a clastogen (induce chromosome aberrations) in cultured
cells, it has been suggested that fluoride can cause chromosome
aberrations in rodent and human cells. Fluoride induced primarily
chromatid gaps and chromatid breaks, indicating that the cells are most
responsive in the G stage of the cell cycle, i.e., after chromosome
duplication in preparation for cell division. Negative results reported
in some cytogenetic studies are likely the effect of inadequate test
protocols…. Although the mechanism(s) by which these cellular effects
result from exposure to fluoride is not known, a number of possible
mechanisms have been proposed to explain the genetic activity observed.
These mechanisms have been based on the observed reactions of fluoride
in solution with divalent cations or necleotides, or the physiological
and biochemical responses of cells treated with fluoride. Sodium
fluoride inhibits both protein and DNA synthesis in cultured mammalian
cells. The inhibition of DNA synthesis may be a secondary effect of the
inhibition protein synthesis, or a result of the direct inhibition of
DNA polymerase. Fluoride can react with divalent cations in the cell so
as to affect enzyme activities that are necessary for DNA or RNA
synthesis, or chromosome metabolism or maintenance; it may react
directly with DNA as part of a complex; or it ca disrupt other cellular
processes such as cell differentiation or energy metabolism.”
SOURCE: Department of Health and Human Services. (1991). Review of fluoride: benefits and risks. Report of the Ad Hoc Subcommittee on Fluoride. Washington, DC. p. 70. (There is also an abbreviated report)
SOURCE: Department of Health and Human Services. (1991). Review of fluoride: benefits and risks. Report of the Ad Hoc Subcommittee on Fluoride. Washington, DC. p. 70. (There is also an abbreviated report)
“Fluoride has displayed mutagenic activity in studies
of vegetation, insects, and mammalian oocytes. There is a high
correlation between carcinogenicity and mutagenicity of pollutants, and
fluoride has been one of the major pollutants in several situations
where a high incidence of respiratory cancer has been observed. For
these reasons, the relation between airborne fluoride and incidence of
lung cancer needs to be investigated.”
SOURCE: Marier J, Rose D. (1977). Environmental Fluoride. National Research Council of Canada. Associate Committe on Scientific Criteria for Environmental Quality. NRCC No. 16081.
SOURCE: Marier J, Rose D. (1977). Environmental Fluoride. National Research Council of Canada. Associate Committe on Scientific Criteria for Environmental Quality. NRCC No. 16081.
Excerpts from In-Vitro Studies:
“Our study has supported the role of As [arsenic] and
F [fluoride] as potent genotoxic agents, since in vitro exposure of
both caused increased chromosomal anomalies along with primary DNA
damage, in human peripheral blood cultures.”
SOURCE: Tiwari H, Rao MV. (2010). Curcumin supplementation protects from genotoxic effects of arsenic and fluoride. Food & Chemical Toxicology 48(5):1234-8.
SOURCE: Tiwari H, Rao MV. (2010). Curcumin supplementation protects from genotoxic effects of arsenic and fluoride. Food & Chemical Toxicology 48(5):1234-8.
“In order to analyze potential carcinogenic and
genotoxic responses caused by exposure to pollutants existing in
environment, a screening method has been established in our laboratory
that uses a stably transfected HepG2 cell lines containing gadd153
promoter regions which drive a luciferase reporter gene. Activation of
the exogenous gadd153 promoter was quantified using the luciferase
activity following drug exposure. Twenty four agents were used to
evaluate this screening assay. We selected the agents, ranging
from DNA alkylating agents, oxidative agent, radiation, DNAcross-linking
agent, nongenotoxic carcinogens, precarcinogenic agents, which included
cadmium chloride, chromium trichloride, mercuric chloride, lead
nitrate, dichloro-diphenyl-trichloroethane, deltamethrin, biphenylamine,
2-aminofluorene, benzo[a]pyrene, 2,3,7,8,-tetracblorodibenzo-p-dioxin,
diethyl-stilbestrol, carbon tetrachloride, mitomycin C,
hydroxycamptothecin, UV, sodium fluoride,
acrylamide, hydrogen peroxide. In addition, two complex genotoxic
agents (water samples) existing in the environment were selected. The
results showed that all 20 tested known carcinogenic and genotoxic
agents were able to induce gadd153-Luc expression at a sublethal dose.
In contrast, four tested non-carcinogens, included
4-acetylaminofluorene, pyrene, benzylpenicillin sodium and vitamin C,
were unable to induce gadd153-Luc expression. In conclusion, this
reportersystem can facilitate in vitro screening
for potential carcinogens. Therefore, the gadd153-Luc test system we
have developed appears to be a useful and complementary system to
existing genotoxic and mutagenic tests.”
SOURCE: Zhang R, et al. (2009). A stable and sensitive testing system for potential carcinogens based on DNA damage-induced gene expression in human HepG2 cell. Toxicology In Vitro. 23(1):158-65.
SOURCE: Zhang R, et al. (2009). A stable and sensitive testing system for potential carcinogens based on DNA damage-induced gene expression in human HepG2 cell. Toxicology In Vitro. 23(1):158-65.
“In this study we concluded that NaF, in 5 and 10
lg/ml NaF concentrations cause genotoxic alterations. So genotoxic,
mutagenic and teratogenic effects of NaF need to be carefully screened
and evaluated together with other long-term effects using in vitro and
in vivo animal test models.”
SOURCE: Erciyas K, Sarikaya R. (2009). Genotoxic evaluation of sodium fluoride in the Somatic Mutation and Recombination Test (SMART). Food & Chemical Toxicology 47(11):2860-2.
SOURCE: Erciyas K, Sarikaya R. (2009). Genotoxic evaluation of sodium fluoride in the Somatic Mutation and Recombination Test (SMART). Food & Chemical Toxicology 47(11):2860-2.
“Some recent studies have suggested that DNA damage
may be a potential neurotoxic mechanism of fluoride. The tail length, as
measured by an ocular micrometer, is increased in fluoride-treated
human embryonic hepatocytes in a previous study carried out to
investigate the geneotic effect of fluoride (Wang et al., 2004). In the
present study, we performed OTM and percentage of DNA in the tail as
indices of DNA damage. OTM, multiplication of the tail length and
percentage of DNA in the tail, objectively and sensitively reflects the
effect of fluoride on DNA damage. Our findings showed that
fluoride-induced DNA damage and OTM was more a sensitive measure than
percentage of DNA in the tail. The correlation analysis showed a
positive correlation between ROS formation and OTM level (r2=0.583, P
< 0.05), which indicated that ROS might play an important role in the
course of DNA damage.”
SOURCE: Zhang M, et al. (2008). Effects of fluoride on DNA damage, S-phase cell-cycle arrest and the expression of NF-kappaB in primary cultured rat hippocampal neurons. Toxicology Letters 179(1):1-5.
SOURCE: Zhang M, et al. (2008). Effects of fluoride on DNA damage, S-phase cell-cycle arrest and the expression of NF-kappaB in primary cultured rat hippocampal neurons. Toxicology Letters 179(1):1-5.
“As cells were exposed to higher doses of fluoride,
the percentage of L-02 cells with DNA damage increased. This result is
consistent with other studies… Therefore, considering previous studies,
we think that fluoride can cause lipid peroxidation, DNA damage and
apoptosis, and that there is a positive relationship among these
changes.”
SOURCE: Wang AG, et al. (2004). Effects of fluoride on lipid peroxidation, DNA damage and apoptosis in human embryo hepatocytes. Biomedical and Environmental Sciences 17: 217-22.
SOURCE: Wang AG, et al. (2004). Effects of fluoride on lipid peroxidation, DNA damage and apoptosis in human embryo hepatocytes. Biomedical and Environmental Sciences 17: 217-22.
“For fluoride concentrations of 2 ppm to 35 ppm, non
vital cells of less than 10% could be shown. After incubation with 71
ppm and 213 ppm Olaflur, there were 15% and 43% of damaged cells,
respectively. Weak genotoxic effects on mucosal cells as well as on
lymphocytes could be demonstrated at all concentrations tested. In
fluoride concentrations of 213 ppm genotoxicity increased to max.”
SOURCE: Kleinsasser NH, et al. (2001). [Cytotoxicity and genotoxicity of fluorides in human mucosa and lymphocytes]. Laryngorhinootologie 80(4):187-90.
SOURCE: Kleinsasser NH, et al. (2001). [Cytotoxicity and genotoxicity of fluorides in human mucosa and lymphocytes]. Laryngorhinootologie 80(4):187-90.
“To investigate the effects of fluoride on DNA damage
as well as the effects of selenium and zinc against fluoride
respectively or jointly in pallium neural cells of rats, single cell gel
electrophoresis was used to detect the DNA damage of neural cells
prepared in vitro. The results showed that the degree of DNA damage in
the fluoride group and the selenium group were significantly greater
than that in control group (P < 0.01). The damage in the fluoride
group was even more serious. The damage in the fluoride + selenium group
and fluoride + zinc group was slighter than that in the fluoride group
but with no significant difference. The extent of DNA damage in the
fluoride + selenium + zinc group was significantly slighter than that in
the fluoride group(P < 0.05). It suggested that fluoride and
selenium could induce DNA damage in pallium neural cells of rats
respectively.”
SOURCE: Chen J, et al. (2000). [Effects of selenium and zinc on the DNA damage caused by fluoride in pallium neural cells of rats]. Wei Sheng Yan Jiu. 29(4):216-7.
SOURCE: Chen J, et al. (2000). [Effects of selenium and zinc on the DNA damage caused by fluoride in pallium neural cells of rats]. Wei Sheng Yan Jiu. 29(4):216-7.
“”In the present work, 13 compounds [chlordane,
Arochlor 1260, di(2-ethylhexyl)phthalate, 1,1,1-trichloro-2,
2-bis(4-chlorophenyl)ethane, limonene, sodium fluoride,
ethionine, o-anisidine, benzoyl peroxide, o-vanadate, phenobarbital,
12-O-tetradecanoylphorbol 13-acetate and clofibrate] have been tested
for their ability to induce morphological transformation and affect
intercellular communication in Syrian hamster embryo (SHE) cells… In
vitro morphological transformation of SHE cells is now one of the most
frequently used cell transformation systems. Around 500 chemicals have
been tested in this system, and a good correlation has been obtained
with the ability of compounds from different chemical groups to cause
tumours in animals and humans. The SHE cell transformation assay also
responds to tumour promoters and carcinogens not detected by tests for
genotoxicity… [N]ine of the 13 tested substances (TPA, o-vanadate, DEPH,
phenobarbital, Arochlor 1260, clofibrate, o-anisidine, limonene and NaF) are considered positive for induction of morphological transformation.”
SOURCE: Rivedal E, et al. (2000). Morphological transformation and effect on gap junction intercellular communication in Syrian hamster embryo cells as screening tests for carcinogens devoid of mutagenic activity. Toxicology In Vitro 14(2):185-92.
SOURCE: Rivedal E, et al. (2000). Morphological transformation and effect on gap junction intercellular communication in Syrian hamster embryo cells as screening tests for carcinogens devoid of mutagenic activity. Toxicology In Vitro 14(2):185-92.
“Significant increases in the frequencies of
chromosome aberrations were induced in a dose- and treatment
time-dependent fashion when NaF was administered to [rat vertebral bone]
cells at 0.5 and 1.0 mM for 24 and 48 h. The results indicate that NaF
is genotoxic to rat vertebrae, providing a possible mechanism for the
vertebrae, as a target organ of NaF carcinogenesis.”
SOURCE: Mihashi M, Tsutsui T. (1996). Clastogenic activity of sodium fluoride to rat vertebral body-derived cells in culture. Mutation Research 368:7-13.
SOURCE: Mihashi M, Tsutsui T. (1996). Clastogenic activity of sodium fluoride to rat vertebral body-derived cells in culture. Mutation Research 368:7-13.
“The genotoxic effects of inorganic fluorides were
investigated by treating cultured rat bone marrow cells with varying
concentrations (0.1-100 microM) of potassium fluoride (KF) and sodium
fluoride (NaF) for different durations (12, 24 and 36 h) and measuring
the incidence of cells with aberrations and number of breaks per cell.
Both forms of fluoride were found to be weak mutagens relative to the
positive control N-methyl-N-nitro-N-nitrosoguanidine (MNNG). A
specificity of fluoride ion in inducing chromosome aberrations (CA) was
indicated by the observation that both NaF and KF behaved almost
equivalently in this study and at significantly higher variations from
the results with potassium chloride (KCl) and sodium chloride (NaCl).”
SOURCE: Khalil AM. (1995). Chromosome aberrations in cultured rat bone marrow cells treated with inorganic fluorides. Mutation Research 343:67-74.
SOURCE: Khalil AM. (1995). Chromosome aberrations in cultured rat bone marrow cells treated with inorganic fluorides. Mutation Research 343:67-74.
“The testing of hydrogen fluoride (HF) for its
mutagenic activity by fumigation of barley seedlings showed that the
mutation rate was linear with dose. It was found that the cytogenic
effects of gaseous fluoride on grain crops was correlated with the
fluoride content in plant tissue.”
SOURCE: Gritsan, NP. (1993). Cytogenetic effects of gaseous fluorides on grain crops. Fluoride 26: 23-32.
SOURCE: Gritsan, NP. (1993). Cytogenetic effects of gaseous fluorides on grain crops. Fluoride 26: 23-32.
“A significant increase in the incidence of
chromosome aberrations was observed only in cultures treated with NaF
during early and/or middle S phases of cell cycle. These results suggest
that cytotoxicity and clastogenicity of NaF to cultured human diploid
fibroblasts are cell cycle dependent, and that the cells in early and
middle S phases are more sensitive to the effects.”
SOURCE: Hayashi N, Tsutsui T. (1993). Cell cycle dependence of cytotoxicity and clastogenicity induced by treatment of synchronized human diploid fibroblasts with sodium fluoride. Mutation Research 290: 293-302.
SOURCE: Hayashi N, Tsutsui T. (1993). Cell cycle dependence of cytotoxicity and clastogenicity induced by treatment of synchronized human diploid fibroblasts with sodium fluoride. Mutation Research 290: 293-302.
“Conflicting evidence has been reported concerning
the mutagenicity of sodium fluoride (NaF), especially clastogenicity at
concentrations of more than 1 mM. NaF is known to induce chromosome
aberrations at these concentrations in human cells, but not in most
rodent cells. We considered that such species-specific difference in
chromosomal sensitivity would be derived from the phylogenetic distance
between rodents and man. To clarify the role of interspecies
differences, we investigated the chromosomal sensitivity to NaF in cell
lines from various primates, which diverged into many species, including
rodent-like prosimians and human-like great apes. The results showed
that the clastogenicity of NaF was limited to human and great ape cells.
. . . The mechanism of NaF clastogenicity is still unknown, but the
same profile of chromosomal aberrations in man and chimpanzees suggests
that its action on these cells and the response of the cells will be
consistent. The different response to NaF among non-human primates might
give us a clue to clarify the mechanism of NaF clastogenicity.”
SOURCE: Kishi K, Ishida T. (1993). Clastogenic activity of sodium fluoride in great ape cells. Mutation Research 301:183-8.
SOURCE: Kishi K, Ishida T. (1993). Clastogenic activity of sodium fluoride in great ape cells. Mutation Research 301:183-8.
“We tested the induction of mutagenic effects by in
vivo and in vitro bone marrow micronucleus tests. A significant increase
in micronucleated polychromatic erythrocytes was observed 24 H after
intraperitoneal injection of sodium fluoride at a dose of 30 mg/kg body
weight. In the in vitro micronucleus test, the frequency of
micronucleated polychromatic erythrocytes was increased significantly at
concentrations of 2 and 4 mM. These results indicate that the
micronucleus test may be useful in evaluating the cancer risk of sodium
fluoride.”
SOURCE: Suzuki Y, Li J, Shimizu H. (1991). Induction of micronuclei by sodium fluoride. Mutation Research 253:278.
SOURCE: Suzuki Y, Li J, Shimizu H. (1991). Induction of micronuclei by sodium fluoride. Mutation Research 253:278.
“Sodium fluoride was found to induce gene-locus
mutations at the thymidine kinase (tk) and hypoxanthine guanine
phosphoribosyl transferase (hgprt) loci in human lymphoblastoid cells.”
SOURCE: Crespi CL, et al. (1990). Sodium fluoride is a less efficient human cell mutagen at low concentrations. Environmental Molecular Mutagenesis 15:71-7.
SOURCE: Crespi CL, et al. (1990). Sodium fluoride is a less efficient human cell mutagen at low concentrations. Environmental Molecular Mutagenesis 15:71-7.
“Based on these results and those previously reported
for NaF and APC, it is proposed that NaF-induced aberrations may occur
by an indirect mechanism involving the inhibition of DNA
synthesis/repair.”
SOURCE: Aardema MJ, et al (1989). Sodium fluoride-induced chromosome aberrations in different stages of the cell cycle: a proposed mechanism. Mutation Research 223:191-203.
SOURCE: Aardema MJ, et al (1989). Sodium fluoride-induced chromosome aberrations in different stages of the cell cycle: a proposed mechanism. Mutation Research 223:191-203.
“Inducibility of chromosome aberrations of the cells
following treatment with sodium fluoride was also dependent upon the
phase of cell cycle. Significant increase in the incidence of chromosome
aberrations was observed only in cultures treated during early and/or
middle S phases of the cell cycle. These results indicate that
cytotoxicity and clastogenicity of sodium fluoride to cultured human
diploid fibroblasts are cell phase dependent, and that the cells in
early and middle S phases are more sensitive to these effects.”
SOURCE: Suzuki N, Tsutsui T. (1989). [Dependence of lethality and incidence of chromosome aberrations induced by treatment of synchronized human diploid fibroblasts with sodium fluoride on different periods of the cell cycle]. [Article in Japanese] Shigaku. 77(2): 436-47.
SOURCE: Suzuki N, Tsutsui T. (1989). [Dependence of lethality and incidence of chromosome aberrations induced by treatment of synchronized human diploid fibroblasts with sodium fluoride on different periods of the cell cycle]. [Article in Japanese] Shigaku. 77(2): 436-47.
“Sequential treatment of Syrian hamster embryo (SHE)
cells with a chemical carcinogen followed by sodium fluoride (NaF)
resulted in a higher yield of morphologically transformed cell colonies
than treatment of the cells with carcinogen alone… This
enhancement/promotion of cell transformation by NaF was only expressed
after the cells had been pretreated with either direct-acting
carcinogens or procarcinogens. Pretreatment of the cells with
noncarcinogens or weakly-acting carcinogens or administration of NaF
prior to treatment with the carcinogen failed to enhance the yield of
transformation. Transformation was enhanced even when the NaF treatment
was delayed for several days after the carcinogen treatment. However,
the continued presence of NaF was necessary for maintenance of the
increased level of transformation. Removal of NaF prior to termination
of the assay resulted in a reversal of the transformed clonal
morphologies to a normal phenotype such that the final yield of
transformants was decreased, but was still greater than that observed
after carcinogen treatment alone.”
SOURCE: Jones CA, et al. (1988). Sodium fluoride promotes morphological transformation of Syrian hamster embryo cells. Carcinogenesis 9: 2279-84.
SOURCE: Jones CA, et al. (1988). Sodium fluoride promotes morphological transformation of Syrian hamster embryo cells. Carcinogenesis 9: 2279-84.
“Sodium fluoride was found to induce morphological
transformation of SHE cells seeded on a feeder layer of X-irradiated
cells at high concentrations (75-125 micrograms/ml). When the cells were
seeded in the absence of a feeder-layer, the transformation frequencies
increased in a dose-dependent manner with the concentrations of sodium
fluoride ranging from 0 to the highly toxic concentration of 200
micrograms/ml. In the BALB/3T3 cell system, sodium fluoride was negative
in the standard Kakunaga procedure, while through the experiment
designed by table L8 (2(7] of the orthogonal method, an initiating-like
effect and a weak promoting activity were detected within the
concentrations ranging from a 25 micrograms/ml to a 50 micrograms/ml
concentration which is highly toxic for BALB/3T3 cells. From these
results, it is suggested that, besides a genetic mode of action, sodium
fluoride could possibly act through a non-genotoxic mechanism.”
SOURCE: Lasne C, et al. (1988). Transforming activities of sodium fluoride in cultured Syrian hamster embryo and BALB/3T3 cells. Cell Biology and Toxicology 4:311-24
SOURCE: Lasne C, et al. (1988). Transforming activities of sodium fluoride in cultured Syrian hamster embryo and BALB/3T3 cells. Cell Biology and Toxicology 4:311-24
“Chromosomal aberrations were recorded for all the
concentrations used. Maximum effect at all concentrations was observed
after 24 hours of treatment. Several kinds of abnormalities were
revealed with the main ones being bridges, double bridges, sidearm
bridges, bridges with fragments, tripolar and multipolar anaphases with
and without bridges, fragments, and laggards. “Y” and “X” configurations
were also noted at metaphase… The authors conclude that sodium-fluoride
may be considered to be clastogenic in these cells.”
SOURCE: Albanese R. (1987). Sodium fluoride and chromosome damage (in vitro human lymphocyte and in vivo micronucleus assays). Mutagenesis 2:497-9.
SOURCE: Albanese R. (1987). Sodium fluoride and chromosome damage (in vitro human lymphocyte and in vivo micronucleus assays). Mutagenesis 2:497-9.
“While the results in this paper demonstrate the
ability (of fluoride) to induce genetic damage in cultured mammalian
cells, the potential risks to animals or man are not addressed.”
SOURCE: Caspary WJ, et al (1987). Mutagenic activity of fluorides in mouse lymphoma cells. Mutation Research 187:165-80.
SOURCE: Caspary WJ, et al (1987). Mutagenic activity of fluorides in mouse lymphoma cells. Mutation Research 187:165-80.
“The results are used to illustrate the problems
associated with quantitative extrapolation from in vitro tests to human
risk, as follows. (1) There appears to be a threshold response
(clastogenicity vs. dose) with NaF at around 10 micrograms/ml (48 h
exposure) but a more definitive conclusion must await elucidation of the
mechanisms of clastogenicity. (2) NaCl is weakly clastogenic at 1000
times the threshold dose for NaF. The mechanisms are unlikely to be
similar. (3) No clastogenicity was detected with NaF below about 30%
mitotic inhibition but the relationship between clastogenicity and
mitotic inhibition was similar for NaF and MMC. (4) There was no obvious
threshold in the relationship between clastogenicity and cell killing
with NaF. MMC was less clastogenic than NaF at equitotoxic doses.
Observations 3 and 4 preclude the possibility of regarding the
clastogenicity of NaF as a false positive by virtue of associated
cytotoxicity.”
SOURCE: Scott D, Roberts SA. (1987). Extrapolation from in vitro tests to human risk: experience with sodium fluoride clastogenicity. Mutation Research 189(1): 47-58.
SOURCE: Scott D, Roberts SA. (1987). Extrapolation from in vitro tests to human risk: experience with sodium fluoride clastogenicity. Mutation Research 189(1): 47-58.
“These observations, and an analysis of the colony
size of trifluorothymidine-resistant mutants in TK+/- cells, suggest
that sodium fluoride is clastogenic to dividing cultured mammalian cells
at high, toxic concentrations. Further work is desirable to investigate
the mechanism by which chromosomes are damaged at high concentrations
of fluoride, since without such a mechanistic understanding,
extrapolation of our data to the human situation must be insecure.”
SOURCE: Cole J, et al. (1986). The mutagenicity of sodium fluoride to L5178Y [wild-type and TK+/- (3.7.2c)] mouse lymphoma cells. Mutagenesis 1:157-67.
SOURCE: Cole J, et al. (1986). The mutagenicity of sodium fluoride to L5178Y [wild-type and TK+/- (3.7.2c)] mouse lymphoma cells. Mutagenesis 1:157-67.
“The clastogenic effect of NaF has been tested by the
use of several cytogenetic assay systems, but the findings on its
genotoxicity are not consistent. In this study, the effects of NaF on
chromosomes, unscheduled DNA synthesis (UDS) and sister-chromatid
exchanges (SCEs) were investigated using cultured human lymphocytes. For
clastogenicity testing, cells were treated for 24 h in various
concentrations of NaF. At least two donors were tested for each
concentration and more than 10,000 cells were totally observed… Sodium
fluoride treatment had remarkable effects on the induction of
isochromatid gaps and chromosome breaks (NUpds).”
SOURCE: Kishi K, Tonomura A. (1984). Cytogenetic effects of sodium fluoride. Mutation Research 130: 367.
SOURCE: Kishi K, Tonomura A. (1984). Cytogenetic effects of sodium fluoride. Mutation Research 130: 367.
“Mass cultures of cells treated with NaF (75 or 100
micrograms/ml) for 24 hr, followed by continuous cultivation for 35 to
50 passages, developed the ability to grow in soft agar and to produce
anaplastic fibrosarcomas when injected into newborn hamsters. In
contrast, no morphological and neoplastic transformation was observed in
untreated cells. Furthermore, a significant increase in chromosome
aberrations at the chromatid level, sister chromatid exchanges, and
unscheduled DNA synthesis was induced by NaF in a dose- and
time-dependent manner. These results indicate that NaF is genotoxic and
capable of inducing neoplastic transformation of Syrian hamster embryo
cells in culture. A potential for carcinogenicity of this chemical,
which is widely used by humans, is suggested. However, the carcinogenic
risk of this chemical to humans may be reduced by factors regulating in
vivo dose levels.”
SOURCE: Tsutsui T, Suzuki N, Ohmori M. (1984) Sodium fluoride-induced morphological and neoplastic transformation, chromosome aberrations, sister chromatid exchanges, and unscheduled DNA synthesis in cultured syrian hamster embryo cells. Cancer Research 44:938-41.
SOURCE: Tsutsui T, Suzuki N, Ohmori M. (1984) Sodium fluoride-induced morphological and neoplastic transformation, chromosome aberrations, sister chromatid exchanges, and unscheduled DNA synthesis in cultured syrian hamster embryo cells. Cancer Research 44:938-41.
“A significant increase in the frequency of
chromosome aberrations at the chromatid level was observed in treated
cells in a dose-dependent manner… These results suggest that NaF causes
DNA damage in human diploid fibroblasts in culture.”
SOURCE: Tsutsui T, Suzuki N, Ohmori M, Maizumi H. (1984). Cytotoxicity, chromosome aberrations and unscheduled DNA synthesis in cultured human diploid fibroblasts induced by sodium fluoride. Mutation Research 139:193-8.
SOURCE: Tsutsui T, Suzuki N, Ohmori M, Maizumi H. (1984). Cytotoxicity, chromosome aberrations and unscheduled DNA synthesis in cultured human diploid fibroblasts induced by sodium fluoride. Mutation Research 139:193-8.
“The effect of treatment of cultured human oral
keratinocytes with sodium fluoride (NaF) has been investigated with
respect to induction of unscheduled DNA synthesis (UDS)… Significant
levels of UDS were induced in a dose-related fashion by NaF treatment.
The results suggest that NaF causes DNA damage in cultured human oral
keratinocytes.”
SOURCE: Tsutsui T, Ide K, Maizumi H. (1984). Induction of unscheduled DNA synthesis in cultured human oral keratinocytes by sodium fluoride. Mutation Research 140(1): 43-8.
SOURCE: Tsutsui T, Ide K, Maizumi H. (1984). Induction of unscheduled DNA synthesis in cultured human oral keratinocytes by sodium fluoride. Mutation Research 140(1): 43-8.
“The study, by light and fluorescent microscopy, of
sternal and femoral bone marrow taken from young Swiss mice exposed for
period up to 280 days to elevated levels of sodium fluoride in drinking
water, has revealed morphologic abnormalities in cell structure and
mitotic figure formation in immature leukocytes. Alterations in the
content and distribution of RNA and DNA also appear after several weeks
of exposure… The results of this investigation indicate that young
leukocytes chronically exposed to elevated fluoride levels have the
potential for an irreversible shift toward the formation of neoplasm.”
SOURCE: Greenberg SR. (1982). Leukocyte response in young mice chronically exposed to fluoride. Fluoride 15: 119-123.
SOURCE: Greenberg SR. (1982). Leukocyte response in young mice chronically exposed to fluoride. Fluoride 15: 119-123.
“Human leucocytes in the cultures in vitro were
exposed to the action of lead and fluorine ions… Both factors caused
structural and quantitative aberrations in the chromosome set, which
seems to indicate their mutagenic character. It is noteworthy that the
smallest of the applied concentrations of fluorine ions (3.15 x 10-5M)
is equal to the concentration of these ions in the running water of
Szczecin, given for the prevention of caries.”
SOURCE: Jachimczak D, Skotarczak B. (1978). The effect of fluorine and lead ions on the chromosomes of human leucocytes in vitro. Genetica Polonica 19: 353-7.
SOURCE: Jachimczak D, Skotarczak B. (1978). The effect of fluorine and lead ions on the chromosomes of human leucocytes in vitro. Genetica Polonica 19: 353-7.
“These findings indicate that HF in addition to being
a mutagenic agent is also able to reduce crossing over in certain
chromosome segments.”
SOURCE: Mohamed AH. (1977). Cytogenetic effects of hydrogen fluoride gas on maize. Fluoride 10: 157-164.
SOURCE: Mohamed AH. (1977). Cytogenetic effects of hydrogen fluoride gas on maize. Fluoride 10: 157-164.
“while NaF can be a potent meiotic mutagen in the
particular in vitro experimental situations reported here, the variation
of in vitro sensitivity between the mouse (which nevertheless showed
some oocyte abnormality when tested in vivo) and the higher forms (cow
and ewe) would suggest an assessment of abnormal progeny from the latter
species for chromosomal abnormalities in NaF-contaminated areas, as a
reasonable next step for ascertaining the probability of the
mutagenicity of this compound.”
SOURCE: Jagiello G, Lin JS. (1974). Sodium fluoride as potential mutagen in mammalian eggs. Archives of Environmental Health 29:230-5.
SOURCE: Jagiello G, Lin JS. (1974). Sodium fluoride as potential mutagen in mammalian eggs. Archives of Environmental Health 29:230-5.
“Two strains of Drosophila melanogaster were treated
with sub-lethal levels of gaseous hydrogen fluoride for six weeks. Egg
samples were collected at various times for hatchability determinations.
Adults reared from these samples were evaluated for fecundity and
fertility. Treatment with HF caused a marked reduction in hatchability
and fecundity in the more sensitive strain. Male fertility was depressed
but female fertility remained stable over the test period. The
reduction of these parameters in the offspring of populations subjected
to low levels of atmospheric HF contamination for prolonged periods
suggests that HF causes genetic damage.”
SOURCE: Gerdes RA, et al. (1971). The effects of atmospheric hydrogen fluoride upon Drosophila melanogaster. II. Fecundity, hatchability and fertility. Atmospheric Environment 5:117-122.
SOURCE: Gerdes RA, et al. (1971). The effects of atmospheric hydrogen fluoride upon Drosophila melanogaster. II. Fecundity, hatchability and fertility. Atmospheric Environment 5:117-122.
“Genetic differences were observed in the response of
the progeny of treated flies. The maintenance of a population at
sub-lethal concentrations of HF revealed an apparent accumulation of of
physiological abberations resuting in sterility in the treated flies.
Results indicate that treatment increased the incidence of genetic
abberations as measured by at least two parameters.”
SOURCE: Gerdes RA. (1971). The influence of atmospheric hydrogen fluoride on the frequency of sex-linked recessive lethals and sterility in Drosophila Melanogaster. Fluoride 4: 25-29.
SOURCE: Gerdes RA. (1971). The influence of atmospheric hydrogen fluoride on the frequency of sex-linked recessive lethals and sterility in Drosophila Melanogaster. Fluoride 4: 25-29.
“Maize seedlings of the genotype A1A2C1Wx were
fumigated in growth chambers with hydrogen fluoride (HF) at a
concentration of about 3 ug/m3. The experiment was run for 10 days, with
the first group of treated plants removed from the chambers after 4
days and then at intervals of 2 days. Microsporocyte smears from the
treated plants revealed chromosomal aberations that included asynaptic
regions, translocations, inversions, and bridges plus fragments or
fragments by themselves. It is believed that these abnormalities were
due to the physiological effect of HF causing the chromosomes to become
sticky and/or to the occurrence of chromatid breakage followed by
reunion to form structural changes. These findings indicate that HF is a
mutagenic agent.”
SOURCE: Mohamed AH. (1970). Chromosomal changes in maize induced by hydrogen fluoride gas. Canadian Journal of Genetics and Cytology 12: 614-620.
SOURCE: Mohamed AH. (1970). Chromosomal changes in maize induced by hydrogen fluoride gas. Canadian Journal of Genetics and Cytology 12: 614-620.
“Studies on the effects of HF on meiotic chromosomes
of tomatoes indicated a trend toward a higher frequency of chromosomal
aberrations with an increase in the fumigation period. It was indicated
that HF was capable of inducing paracentric inversions with the
possibility of the induction of deficiencies, duplications or even
translocations. The progeny obtained from the treated plants produced a
number of abnormal phenotypes, the same as, or similar to, known
mutations. Further studies in maize microsporocytes for plants treated
with HF confirmed the cytological results obtained in tomatoes with
clear evidence of the occurrence of inversions, translocations and
deficiencies. These results suggest that HF seems to affect primarily
the DNA molecule by blocking its replication, probably through its
action on the enzymatic system.”
SOURCE: Mohamed AH. (1969). Cytogenetic effects of hydrogen fluoride on plants. Fluoride 2(2): 76-84.
SOURCE: Mohamed AH. (1969). Cytogenetic effects of hydrogen fluoride on plants. Fluoride 2(2): 76-84.
“From the results, it is clear that NaF, not being
mutagenic by itselft, interacts with the mechanism of mutation induction
by X-irradiation in fully mature spermatozoa. In fact, the enhancing
effect has been observed in 21 out of 23 experiments where pre-treatment
with NaF was compared to that with saline.”
SOURCE: Mukerjee RN, Sobels FH. (1968). The effects of sodium fluoride and idoacetamide on mutation induction by X-irradiation in mature spermatozoa of drosophila. Mutation Research 6(2): 217- 25.
SOURCE: Mukerjee RN, Sobels FH. (1968). The effects of sodium fluoride and idoacetamide on mutation induction by X-irradiation in mature spermatozoa of drosophila. Mutation Research 6(2): 217- 25.
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