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Re: Fluoride and Cancer

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BillO, 

 

We must consider the fact that there have been over 4000 studies on fluoride alone.  Some studies are peer-reviewed, some studies have been debunked.

 

It is odd isn't it.  When one looks at the discussion presented by the American Cancer Society on water fluoridation, ( https://www.cancer.org/cancer/cancer-causes/water-fluoridation-and-cancer-risk.html ) one would think water fluoridation does not lead to any kind of cancer.  In the studies the ACS presents there is either No Evidence, (For example:  "In 2011, the state of California’s Carcinogen Identification Committee (CIC) reviewed the evidence and concluded that “fluoride and its salts has not been clearly shown to cause cancer.”), or there is No Strong Evidence for any link between the two.  

 

On the other hand, when one looks at your cherry-picked non-peer reviewed studies, one would think that osteosarcoma and other forms of bone cancer are almost a certainty.

 

Considering the fact that there are roughly 400 cases of the bone cancer, osteosarcoma, per year in the U.S., and considering the fact that hundreds of millions of people enjoy the health benefits of optimally fluoridated water on a daily basis, you would think, according to your cherry-picked studies, that hospitals would be over-run with these bone-cancer victims.  But they aren't are they.

 

The American Cancer does not accept funding from unethical alternative health businesses which routinely receive warning letters from the FDA.  Fluoride Alert, & the Fluoride Action Network do.  The sole existence of the American Cancer Society does not depend on the creation of some controversy, where no controversy actually exists.  The existence of Fluoridealert does. 

 

Perhaps that is why we see such different interpretations between the American Cancer Society & Fluoridealert when it comes to water fluoridation and cancer. 

 

Dr. Bill, have you ever had any relationship with the Fluroide Action Network? 

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Re: Fluoride and Cancer

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Procter and Gamble:

Procter & Gamble, releases the findings of its own rat study of fluoride and cancer they conducted between 1981-1983.  While Procter and Gamble’s study finds several bone tumors in the fluoride-treated animals (versus none in the controls), the results do not achieve statistical significance and Proctor & Gamble’s scientists dismiss them as random. According to the published report:

“All bone neoplasms were considered to be incidental and spontaneous and not related to fluoride treatment, because of their low incidence and random distribution”[10]

In 1991, the FDA publishes a review of Procter & Gamble’s rat study. The FDA identifies two additional osteosarcomas in the fluoride-treated rats which were not identified in Procter & Gamble’s published report. The FDA states:

“The adequacy of the gross examination at necropsy was questioned based upon the rat tumors that were not identified by the contract (Procter & Gamble) laboratory” (FDA 1991).

The FDA notes that the incidence of bone tumors in the Procter & Gamble study still do not achieve statistical significance. The FDA thereby concurs with Procter & Gamble that the bone tumors are incidental.

Contributes to Osteomas: Maurer 1993, the FDA also reviews Procter & Gamble’s mouse study.  Among both sexes of the fluoride-treated mice, there is a significant, dosedependent increase in osteomas, although no osteosarcomas. The occurrence of the osteomas is believed to be related to the presence of a virus in the mice; however, the FDA finds:

“Active virus was found in the osteomas but not in animals that did not have osteomas. It is clear, nonetheless, that if [the virus] had a role it was only in the presence of fluoride.”

Known Osteosarcoma Association: Cohn 1992.  The New Jersey Department of

Health conducts a study of osteosarcoma occurrence in Central New Jersey,  “An Epidemiologic Report on Drinking Water and Fluoridation.” The study finds a statistically significant relationship between fluoridation and osteosarcoma among males less than 20 years old: 

“Recently, a national study of drinking water fluoridation at the country level found a significant association with osteosarcoma incidence among males under 20 years of age (Hoover et al., 1991). However, the meaning of the association was questioned by the authors because of the absence of a linear trend of association with the duration of time for which the water supplies were fluoridated… As a follow-up to the study by Hoover et al., a small study of similar design was initiated by the New Jersey Department of Health to compare drinking water fluoridation at the municipal level with the municipal residence of osteosarcoma cases at the time of diagnosis… The study observed an association between fluoridation of water and osteosarcomas among males under 20 years of age in seven Central New Jersey counties.”

 

Known Carcinogenic: Lee[1] 1993 Reported 6.9 times higher osteosarcoma incidence for males aged 10-19 years old when comparing fluoridated and non-fluoridated seven counties in the central New Jersey area.

Known Carcinogenic: Yiamouyiannis, 1993, analyzes the National Cancer Institute’s data in addition to two other databases containing fluoride exposure/ osteosarcoma information. Like NCI’s investigators (Hoover 1991), Yiamouyiannis finds osteosarcoma rates to be higher among young males under 20 in fluoridated versus unfluoridated areas. To quote:

“Recent studies showing substantial increases in the incidence of bone cancer and osteosarcoma in males (but not females) exposed to fluoride gave us the unique opportunity of using females as a control group to determine whether there is a link between fluoridation and bone cancer in males. Using three different data bases, we found that 

  • the bone cancer incidence rate was as much as 0.95 cases a year per 100,000 population higher in males under age 20 living in fluoridated areas;
  • the osteosarcoma incidence rate was 0.85 new cases a year per 100,000 population higher in males under age 20 living in fluoridated areas; and
  • for males of all ages, the bone cancer death rate and bone cancer incidence rate was as much as 0.23 and 0.44 cases higher per 100,000 population, respectively, in fluoridated areas. These findings indicate that fluoridation is linked to an increase in bone cancer and deaths from bone cancer in human populations among males under age 20 and that this increase in bone cancer is probably all due to an increase in osteosarcoma caused by fluoride.”

Genotoxic Mihashi 1996 report fluoride is genotoxic to rat bone. The authors note that the fluoride-induced genotoxicity in bone reinforce the biologic plausibility of a fluorideosteosarcoma connection. The authors used the same type of rat (F344/N) used in NTP’s cancer bioassay.

“Because the origin of osteosarcoma is considered to be osteoblastic/osteogenic cells, the ability of sodium fluoride to induce chromosome aberrations in these cells provides a mechanistic basis for the occurrence of osteosarcomas observed in sodium fluoride treated animals in the NTP study. Ingested fluoride is accumulated in bone, suggesting that osteoblastic/osteogenic cells in the bone microenvironment can be exposed to high levels of fluoride during bone formation. Our data and the NTP findings provide evidence that bone can be an organ for NaF carcinogenesis.”[2]

 

Gandhi (2017)[3] “Oxidative stress is reported to negatively affect osteoblast cells. Present study reports oxidative and inflammatory signatures in fluoride-exposed human osteosarcoma (HOS) cells, and their possible association with the genes involved in osteoblastic differentiation and bone development pathways. HOS cells were challenged with sublethal concentration (8 mg/L) of sodium fluoride for 30 days and analyzed for transcriptomic expression. In total, 2632 transcripts associated with several biological processes were found to be differentially expressed. Specifically, genes involved in oxidative stress, inflammation, osteoblastic differentiation, and bone development pathways were found to be significantly altered. Variation in expression of key genes involved in the abovementioned pathways was validated through qPCR. Expression of serum amyloid A1 protein, a key regulator of stress and inflammatory pathways, was validated through western blot analysis. This study provides evidence that chronic oxidative and inflammatory stress may be associated with the fluoride-induced impediment in osteoblast differentiation and bone development.” 

 Note: Although the 8 mg/L Gandhi used is sublethal, it is much higher than blood concentrations but not out of range for bone fluoride concentrations which can reach higher, over 800 ppm.   Gandhi (2017) appears to dovetail with Wei (2014) below.

Wei (2014)[4] Chronic excessive fluoride intake may cause fluorosis, which chiefly manifests as bone damage (or skeletal fluorosis). However, the molecular mechanism of skeletal fluorosis has not been clarified up to the present. The objective of this study was to analyze the effects of fluoride treatment on two of bone morphogenetic protein family member (BMP-2 and BMP-3) expression and cell viability using human osteosarcoma MG-63 cells as a model. Sodium fluoride (NaF) had pro-proliferation effects at relatively moderate concentration, with 5 × 10(3) μmol/L having the best effects. At 2 × 10(4) μmol/L, NaF inhibits cell proliferation. BMP-2 and BMP-3 expression was significantly induced by 5 × 10(3) μmol/L NaF and, to lesser extent, by 2 × 10(4) μmol/L NaF. Correspondingly, mothers against decapentaplegic homolog 1 (Smad-1) increased at both doses of NaF, which indicated the BMP signaling pathway was activated. Notable increases in secreted alkaline phosphatase (ALP) were observed when cells were treated with 5 × 10(3) μmol/L NaF. A BMP specific inhibitor LDN193189 suppressed cell proliferation induced by 5 × 10(3) μmol/L NaF. Also, 2 × 10(4) μmol/L NaF induced apoptosis but likely through a mechanism unrelated to the BMP pathway. Collectively, data show that NaF had dose-dependent effects on cell proliferation as well as BMP-2 and BMP-3 expression in MG-63 cells and suggested that cell proliferation enhanced by NaF-induced BMP members may be a molecular mechanism underlying skeletal fluorosis.

Note: Wei (2014) reported specific effects at 5 × 10(3) μmol/L NaF, which is 9.5 mg/L (ppm), close to Gandhi’s 8 ppm.  

Sandhu (2011)[5]The present study was planned to analyze serum fluoride, sialic acid, calcium, phosphorus, and alkaline phosphatase levels in 25 patients of osteosarcoma and age- and sex-matched subjects with bone-forming tumours other than osteosarcoma and musculo-skeletal pain (controls, 25 each). . . Mean serum fluoride concentration was found to be significantly higher in patients with osteosarcoma as compared to the other two groups. The mean value of flouride in patients with other bone-forming tumors was approximately 50% of the group of osteosarcoma; however, it was significantly higher when compared with patients of group I. Serum sialic acid concentration was found to be significantly raised in patients with osteosarcoma as well as in the group with other bone-forming tumors as compared to the group of controls. There was, however, no significant difference in the group of patients of osteosarcoma when compared with group of patients with other bone-forming tumors. These results showing higher level of fluoride with osteosarcoma compared to others suggesting a role of fluoride in the disease.”

Huo (2013)[6] [Saos-2 cells are osteosarcoma cells] “We found that fluoride enhanced the proliferation of Saos-2 cells in a dose-dependent manner and 0.2 mM of fluoride resulted in a higher expression of osteoblast marker genes. In addition, immunofluorescence analysis showed that the promotion effects of 0.2 mM of fluoride on Saos-2 cells differentiation were associated with the activation of the BMP/Smad pathway.”

Huo (2013) Figure 1. “Growth curve of fluoride-treated Saos-2 cells. Saos-2 cells were seeded into 96-well plates and cultured with different concentrations of NaF for 24, 48, and 72 h as indicated in the “Materials and Methods.” The WST assay was performed to quantify the cytotoxicity of fluoride to Saos-2 cells. Asterisk indicate the significant differences.”

 

 

 

Huo (2013) Fig. 3

Content of Smad1 and p-Smad1/5 protein in fluoride-treated Saos-2 cells. Laser scanning confocal microscopy was used to detect expression of Smad1 and p-Smad1/5 proteins after exposure to NaF (200×). a, c Control (0 mM NaF) and b, d 0.2 mM NaF groups; a, b Smad1 and c, d p-Smad1/5. Three wells were assayed for each experimental treatment, and three separate experiments were performed

Note:  For comparison, 0.2 mM x 1,000 μmol/mM = 200 μmol X o.oo19 μmol/L NaF = 0.38 mg/L (ppm) sodium fluoride.

 

[1] Lee JR Fluoridation and Bone Cancer, Fluoride, Vol.26. No.2 1993   Accessed 4/25/2015 http://www.fluorideresearch.org/262/files/ FJ1993_v26_n2_p079-164.pdf

[2] (Mihashi M, Tsutsui T. (1996). Clastogenic activity of sodium fluoride to rat vertebral body-derived cells in culture. Mutation Research 368(1):7-13. May.)

[3] Gandhi D, Naoghare PK, Bafana A, Kannan K, Sivanesan S .Biol Trace Elem Res. Fluoride-Induced Oxidative and Inflammatory Stress in Osteosarcoma Cells: Does It Affect Bone Development Pathway?  2017 Jan;175(1):103-111. doi: 10.1007/s12011-016-0756-6. Epub 2016 May 28.

 

[4] Wei Y1, Wu Y, Zeng B, Zhang H.  Effects of sodium fluoride treatment in vitro on cell proliferation, BMP-2 and BMP-3 expression in human osteosarcoma MG-63 cells. Biol Trace Elem Res. 2014 Dec;162(1-3):18-25. doi: 10.1007/s12011-014-0148-8. Epub 2014 Oct 14.

[5] Sandhu R1, Lal H, Kundu ZS, Kharb S.  Serum fluoride and sialic acid levels in osteosarcoma. Biol Trace Elem Res. 2011 Dec;144(1-3):1-5. doi: 10.1007/s12011-009-8382-1. Epub 2009 Apr 24.

 

 

[6] Huo L1, Liu K, Pei J, Yang Y, Ye Y, Liu Y, Sun J, Han H, Xu W, Gao Y. Fluoride promotes viability and differentiation of osteoblast-like Saos-2 cells via BMP/Smads signaling pathway. Biol Trace Elem Res. 2013 Oct;155(1):142-9. doi: 10.1007/s12011-013-9770-0. Epub 2013 Aug 7.

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Re: Fluoride and Cancer

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  1. Concerns with NTP Review of Carcinogenicity of Fluoride

Despite criticism, the NTP maintains their assessment of “equivocal evidence.” In 1991, NTP scientists publish a paper which concludes:

“The current findings are weakly supportive of an association between sodium fluoride administration and the occurrence of osteosarcomas in male rats, but are not conclusive… [I]n view of the widespread exposure of the population to fluorides from a variety of sources it would appear prudent to re-examine previous animal and human epidemiologic studies, and perform further studies as needed to evaluate more fully any possible association between exposure to fluorides and the occurrence of osteosarcomas of bone.”[1]       

            NTP review comments on page 10, include:

  1. “Dr. Ashby, the second principal reviewer, agreed with the conclusions. However, he considered the definition for equivocal evidence of carcinogenic activity to be insufficiently precise for male rates. . . .” He suggested: “Taken together the current findings are inconclusive, but are weakly supportive of an association between sodium fluoride administration and the occurrence of osteosarcomas in male rats.”
  2. Silbergeld, “pointed out that the doses used were not orders of magnitude above human exposure levels. She supported further research on genotoxicity and on mechanisms of sex differences seen.”
  3. Gold noted that this was an unusual study in that there was not a zero control group.”
  4. “There was discussion by Dr. McKnight with Dr. J. Haseman, NIEHS, as to why data from paired (age-matched) controls were not used in primary data tables.
  5. Zeise “reiterated the need expressed by other Panel members for designing another study with higher top doses. Dr. Zeise noted that the fluoride concentrations in high-dose rats were within the range observed in humans and the differences in pharmacokinetics and deposition of fluoride in bone between humans and animals should be studied.”
  6. Yiamouyiannis said, “a dose-dependent relationship between fluoride and the number of male rats with oral squamous cell tumors and a dose-dependent relationship between oral squamous cell metaplasia dn tumors in female rats along with the increased incidence of osteosarcomas in male rats supported a finding of clear evidence of carcinogenic activity of fluoride in rats.”
  7. Those representing dentists and industry objected to the conclusions.

             

When fluoride damages DNA, is the damaged DNA make the offspring more

susceptible to cancer?   With the current research, objection to the NTP study should also be made to the lack of a “life-time” exposure from preconception with parents, throughout life of the offspring.   Starting the rats and mice at 5 and 4 weeks of age in the NTP study, did not demonstrate the effects of the fluoride on sperm, egg, fetus, and during a major growth period of their early lives. 

Downgrading by NTP of non-bone tumors (liver, oral, and thyroid) found with increased incidence among the fluoride-treated animals is controversial.  

Concerns with NTP study:  The journal Chemical & Engineering News reports:

“A number of other government officials who asked not to be identified also have told C&EN that they have concerns about the conclusions of the NTP study. They, too, believe that fluoride should have been placed in the “some evidence” category, in part because osteosarcoma is a very rare form of cancer in rodents.”

Cancer diagnosis upheld:    Battelle’s diagnosis of hepatocholangiocarcinoma was upheld by the scientist (Dr. Melvin Reuber) who first identified hepatocholangiocarcinoma as a distinct cancer. As noted by EPA toxicologist Dr. William Marcus:

“Melvin Reuber, M.D., a board certified pathologist and former consultant to EPA and part time EPA employee, reviewed some of [the] pathology slides and the Batelle report. . . . [Reuber] first published the work that identified hepatochangiocarcinoma as a pathologic entity. . . . Dr. Reuber reviewed the pathology slides and stated that these lesions are indeed hepatocholangiocarcinoma.”[2]

Despite Reuber’s concurrence, the NTP ultimately downgraded the hepatocholangiocarcinoma finding. The NTP did so through a two-step process. First, NTP’s “Quality Assurance” pathogist reclassified them as hepatoblastomas (another form of liver cancer). Then, while conducting their statistical analysis, NTP reclassified the hepatoblastomas as hepatocarcinomas – a more common form of tumor. Because there was no significant increase in hepatocarcinomas among the fluoride-treated animals, the NTP concluded that there was no effect.

            The NTP has issued the following statements about this analysis:

“During the pathology review procedures several of the tumors diagnosed originally as hepatocholangiocarcinomas were considered more apppropriately callled hepatoblastomas.”[3]

“The study pathologist (Battelle) diagnosed hepatocholangiocarcinomas in one special control female, one low dose male, one low dose female, one medium dose male, three high dose males, and three high dose females. The QA (Quality Assurance) pathologist confirmed the presence of these tumors but felt that most of them were more appropriately diagnosed as hepatoblastomas.”[4]

“The incidences of liver neoplasms in all groups of dosed and control male and female mice were higher than incidences previously seen in NTP studies, but did not appear related to chemical treatment. Several hepatoblastomas and hepatocholangiocarcinomas were diagnosed in male and female mice. Hepatoblastoma and hepatocholangiocarcinoma of mice are phenotypic variants of hepatocellular carcinoma with characteristic cell types and morphologic patterns. The hepatoblastomas contained a cell population which resembled embryonal liver cells as well as neoplastic cells characteristic of a typical hepatocellular carcinoma, whereas the hepatocholangiocarcinomas exhibited both hepatocyte and biliary differentiation. As phenotypic variants of hepatocellular carcinoma, the incidences of these neoplasms were combined with the other hepatocellular neoplasms for analysis. The appearance of these phenotypic variants in dosed animals is unusual, and the biologic significance, if any, is unknown.”[5]

Summary of NTP study by LANCET:

“The original study was directed from 1985 to 1987 by Dr John D. Toft II, manager of the pathology section at Battelle Memorial Institute in Columbus, Ohio. The Battelle study’s principal finding was the occurrence of an extremely rare liver cancer, hepatocholangiocarcinoma, in male and female mice. In 1989, the NTP asked Experimental Pathology Laboratories, of Sterling, Virginia, to review Battelle’s data. At this point, the liver cancer finding, along with a diagnosis of metaplastic and precancerous cells in the mouths of rats, was downgraded.

The only effect of fluoride that was left after these reclassifications and still another review by a board of pathologists and others was osteosarcoma. Dr Marcus believes the Battelle diagnosis of liver cancers was sound and should have been included in the NTP report. This, he says, would change “the (NTP) equivocal finding… to at least some evidence or clear evidence of carcinogenicity”.

NTP’s failure to emphasize another finding also figured in Dr Marcus’ critique. Three out of four in-vitro tests, he says, proved fluoride to be mutagenic, “supporting the conclusion that fluoride is a probable human carcinogen”. A careful reader can find this information in the text of the report, but the authors make no mention of these data in their conclusions.”[6]

Summary of NTP study by C&E News: 

“The final report for the study was prepared by the NTP staff, but the testing itself was done by Battelle Columbus Laboratories under contract to NTP. A report prepared by Battelle was audited by a quality assurance contractor, and a separate group of pathologists reviewed the studies. In the process, a number of positive findings in the original Battelle report were downgraded. Slides first diagnosed as showing a rare form of liver cancer called hepatochlolangiocarcinoma were later said to indicate hepatoblastoma, another type of rare malignant lesion, and finally to show the far more common cancer hepatocarcinoma. These hepatocarcinomas were combined with the other hepatocarcinomas found in both treated and control animals, Marcus said. In addition, dose-dependent oral lesions noted in the Battelle report were downgraded from dysplasia and metaplasia to degeneration. Some other liver carcinomas were eventually reclassified as nonmalignant lesions. Because of what he calls systematic downgrading of the slides, Marcus has written a memo to the director of the criteria and standards division in the office of drinking water asking that EPA assemble an independent board of pathologists to review the slides again.[7]

Summary of NTP by Yiamouyiannis: 

“In 1977, Congress instructed the U.S. Public Health Service to conduct animal studies to determine whether or not fluoride causes cancer. As a result, the National Toxicology Program retained the Battelle Memorial Institute in Columbus, Ohio to perform two studies, one on mice, and another on rats.

Doctor John T. Toft, II, manager of the Pathology Section at Battelle, was placed in charge of the NTP mouse study. On October 28, 1988, after a year of analyzing these results, Doctor Toft completed the pathology narrative and final report.

The most significant finding was the occurrence of an extremely rare form of liver cancer, hepatocholangiocarcinoma in fluoride-treated male and female rats — mice, excuse me.

Among male mice, no such cancers were observed among 79 in the control group. At 11 parts per million, the lowest dose used, one was observed among 50 male mice; and 45 parts per million, one was observed among 51 male mice and at seventy-nine parts per million three were observed among 80 male mice.

Using historical controls and doing a binomial analysis of this, the odds of these results occurring by chance are less than one in two million. Normally, we consider it significant one in twenty; this is one in two million.

Making these findings even more convincing are the results with female mice. In the control group, no hepatocholangiocarcinomas were observed among eighty. At 11 parts per million, one was observed among 52. At 45 (ppm), none were observed among 50. And at 79 parts per million, three were observed among 80 female mice — female mice.

Based on these findings, and these findings alone, there was clear evidence of the carcinogenic activity of the fluoride in mice receiving 11, 45, or 79 parts per million in drinking water for two years or less.”[8]

PHS confirms risk:    The Public Health Service and NCI in 1991 report that the incidence of osteosarcoma throughout the U.S. has increased at a greater rate among young males in fluoridated areas vs. unfluoridated areas. The NCI, however, dismisses this result because of an inability to demonstrate a linear-dose relationship between the duration of fluoridation and the increased osteosarcoma incidence in fluoridated areas:

“In summary, analysis of incidence data from the SEER program has revealed some age- and sexspecific increases over time for bone and joint cancers, and for osteosarcomas, which are more prominent in fluoridated than in non-fluoridated areas. However, on further analysis these increases are unrelated to the timing of fluoridation, and thus are not linked to the fluoridation of water supplies.” (Hoover 1991)

Calabrese[9] 1993 was requested by the East Bay Municipal Utility District to conduct an independent appraisal of the 1990 NTP report.  He found the NTP’s choice of the word “equivocal” to be confusing, inappropriate and not consistent with what most people would call equivocal, for the following reasons:

  1. Its own definition of equivocal is in disagreement with the generally accepted definition of equivocal.
  2. The findings with the male rat clearly exceeded marginal increases and are biologically plausible given the capacity for fluoride to both concentrate and be biologically active in bone.
  3. The statistical analysis for trend effects is stronger than pair-wise comparisons since it uses all available data not just data from two comparison groups, yet this point is never acknowledged.
  4. The basic reality is that humans can be exposed in critical target tissues to as much fluoride as the high dose rats while consuming water at the EPA maximum contaminant level of 4 mg/liter.

 

 

[1] Bucher JR, et al. (1991). Results and conclusions of the National Toxicology Programs rodent carcinogenicity studies with sodium fluoride. International Journal of Cancer 48(5):733-7. July 9.

[2] Marcus W. (1990). Memorandum from Dr. William Marcus,to Alan B. Hais, Acting Director Criteria & Standards Division Of... of Drinking Water, US EPA. May 1, 1990.

[3] Bucher J. (1990). Testimony at Board of Scientific Counselors, National Toxicology Program; Peer Review of Draft Techn... Report of Long-Term Toxicology and Carcinogenesis Studies and Toxicity Study, Sodium Fluoride; Research Triangle Park, North Carolina, Thursday, April 26, 1990.

[4] Hamilton BF. (1989). Carcinogenesis bioassay of sodium fluoride with dosed water in B6C3F1 mice: Quality Assessment Narrative. Experimental Pathology Laboratories, Inc. p. 26-27.

[5] Bucher JR, et al. (1991). Results and conclusions of the National Toxicology Programs rodent carcinogenicity studies with sodium fluoride. International Journal of Cancer 48: 733-737.

[6] Sibbison JB. (1990). USA: More About Fluoride. The Lancet 336(8717): 737. Sept 22.

[7] Hileman B. (1990). Fluoride bioassay study under scrutiny. Chemical & Engineering News September 17

[8] Yiamouyiannis J. (1990). Testimony before Board of Scientific Counselors, National Toxicology Program; Peer Review of Draft Technical Report of Long-Term Toxicology and Carcinogenesis Studies and Toxicity Study, Sodium Fluor...; Research Triangle Park, North Carolina, Thursday, April 26, 1990.

[9] Calabrese, EJ, Lee, JR, Evaluation of the National Toxicology Program (NTP) Cancer Bioassay on Sodium Fluoride, Fluoride 26

(1) 1993  Accessed 4/25/15 http://www.fluorideresearch.org/261/files/FJ1993_v26_n1_p001-078.pdf

[10] Maurer JK, et al. 1990. Two-year carcinogenicity study of sodium fluoride in rats. Journal of the National Cancer Institute 82(13): 1118-26. July 4.

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Re: Fluoride and Cancer

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Review of Levy (2012)

Levy 2012.   As evidence of fluoride’s lack of carcinogenicity, PHS 2015 cites at 77, Levy 2012. 

The Levy 2012 study concludes that water fluoridation in the U.S. is not associated with an increased risk of osteosarcoma. Levy 2012 use a notably crude measurement for determining fluoride exposure, the National Cancer Institute’s SEER data, average fluoridation rate of the child’s STATE of residence at the time of diagnosis rather than exposure a decade earlier. 

By contrast, when the NCI conducted its analysis of the SEER data in 1990 (in which NCI found elevated rates of osteosarcoma among young males in fluoridated areas), the NCI considered the fluoridation status on the COUNTY level — a smaller unit which is less prone to classification error.  A study without significance is not proof of safety.  The Levy study thus sheds little light on fluoride’s possible relationship to osteosarcoma.  

Blakey et al (2014) [1]

“The study objective was to examine whether increased risk of primary bone cancer was associated with living in areas with higher concentrations of fluoride in drinking water.” 

This is an ecological study where cases were obtained from cancer registries and fluoride levels in drinking water from regional companies, Drinking Water Inspectorate, and Scottish Water.  The record does not show total fluoride exposure, supplements, blood, bone, urine or any other fluoride concentration measurement, nor whether the cohorts were actually drinking the water or swallowing toothpaste.  “Other sources of fluoride are not taken into consideration.”  

In contrast with Bassin’s 2006 study, cases with Blakey 2014 were divided into three age groups, 0-14, 15-29 and 30-49 years of age at diagnosis.   Bassin’s study used each year of life and contacted each water source to ensure the address while growing up actually received fluoride in the water (10% reporting error) and the subject lived in that location.  Bassin found ingestion of fluoridated water during 6-8 years of age increased cancer several years later.  By including all ages 0-14 in one group and 15-29 in another group, Blakey would have “watered down the evidence” and not account for the high risk growth spurts reported by Bassin.  Blakey assumes fluoride consumption was consistent throughout the study time-frame.

Blakey 2014 reported, “The monitoring data suggests that levels in some AF areas were much lower than 1 ppm.  Indeed, 33% of AF WSZs were below 0.7 ppm. . . and 61% of AF SAUs had such a level.  This suggest that 35% of populations residing in AF areas were being supplied with AF water dosed below the optimal level.”  

Blakely 2014 states, “Furthermore, although the overall results contradict those from Bassin’s study, the use of total accumulated fluoride dose rather than a specific time in life course prevents any direct comparisons being made.”

Osteosarcoma is a rare cancer (Blakely 2.64/million) and unless a study is carefully controlled, the data can be easily diluted, negating significance.  

Blakely’s Table 1 is produced here for the purpose of understanding the importance of age.  In this study, an increase in osteosarcoma is evident during 15-29 years of age and over 49 years of age.  Studies must include age and measured fluoride serum, urine, and bone concentrations.  Perhaps the rate of bone turnover is reduced during middle age.  Fluoride accumulates with time and seniors have higher bone fluoride concentrations perhaps triggering risk.

Age-group (years)

!                                   

Number of osteosarcoma cases

!                                     

Number of Ewing sarcoma cases

Males

Females

Total

Males

Females

Total

0-14

406

411

817

356

303

659

15-29

821

494

1315

516

284

800

30-49

266

168

434

116

75

191

0-49

1493

1073

2566

988

662

1650

  

Gelberg et al (1994)

The PHS 2015 failed to consider Gelberg KH. (1994) reporting, “When fluoride exposure

increases, the following bone responses generally occur: 1) an increase in the number of osteoblasts, 2) an increase in the rate of bone formation, 3) an increase in the serum activity of alkaline phosphatase, and 4) an inhibition of osteoblastic acid phosphatase… The increase in osteoblast proliferation and activity may increase the probability that these cells will undergo malignant transformation.”[2]

The case-control study by Gelberg, published first as a PhD dissertation (Gelberg 1994) and then later in two peer-reviewed journals (Gelberg 1995, 1997), may represent the most substantive study on fluoride/osteosarcoma previous to Bassin’s 2001 analysis.

While Gelberg has errors, such as stating cases were females when they were males, and reversing cases and controls in the “Total Fluoride” and “Toothpaste” categories in Tables 2 and 3,  primary concerns with Gelberg’s work relates to the methods used to analyze her data.

Gelberg uses data from NY Cancer Registry and state rather than county fluoridation rates. Gelberg, like Hoover 1991,[3] never analyzes her data with subjects divided into a simple two-category model: exposed versus unexposed, but rather quartiles.

However, for males the lower “quartile” group shows a borderline statistically significant increased risk OR of 2.8 (95%CI 1.0-8.1). For females the OR is even higher and statistically significant at 10.5 (95%CI 1.2-91). For both males and females in the higher “quartiles” of exposure, the ORs are no longer significant, but the risk for osteosarcoma generally stays above 1.0. If, instead of breaking the data into “quartiles”, it had been broken into just “exposed” and “unexposed”, it is quite possible the exposed group would have a significantly elevated risk for osteosarcoma compared to the unexposed group.

In looking for other possible risk factors for osteosarcoma, Gelberg (1994) found that a history of exposure to dental x-rays was significantly related to the development of osteosarcoma (OR 4.0; 95%CI 1.3-12) . Dental x-rays were, in fact, one of the few variables Gelberg examined that had an effect reaching statistical significance.  

However, increased dental x-rays would indicate possibly more frequent dental visits which indicate  more frequent topical applications of fluoride (22,300 ppm fluoride) in the dental office.  The efficacy of fluoride varnish is mixed, and risks have not been studied. 

Bassin 2006; Cohn 1992; Hoover 1991 are consistent with the National Toxicology Program’s (NTP) cancer bioassay which raised concerns that fluoride-treated male rats had a dose-dependent increase in osteosarcoma. (Bucher 1991). Although a number of studies including PHS 2015 citations have failed to detect an association between fluoride and osteosarcoma, none of these studies have measured the risk of fluoride at specific windows in time, which is the critical question with respect to fluoride and osteosarcoma.

A report by the National Academy of Sciences (NAS), titled “Drinking Water and Health”, expresses concern about a possible connection between water fluoridation and osteosarcoma in young males:

“There was an observation in the Kingston-Newburgh (Ast et al, 1956) study that was considered spurious and has never been followed up. There was a 13.5% incidence of cortical defects in bone in the fluoridated community but only 7.5% in the non-fluoridated community… Caffey (1955) noted that the age, sex, and anatomical distribution of these bone defects are `strikingly’ similar to that of osteogenic sarcoma. While progression of cortical defects to malignancies has not been observed clinically, it would be important to have direct evidence that osteogenic sarcoma rates in males under 30 have not increased with fluoridation.” (NAS 1977)

 

[1] Blakey, K, Feltbower, R et al, Is fluoride a risk factor for bone cancer?  Small area analysis of osteosarcoma and Ewing sarcoma diagnosed among 0-49-year-olds in Great Britain, 1980-2005. Int J Epidemiol. 2014 Feb; 43(1): 224-234.

[2] Gelberg KH. (1994). Case-control study of osteosarcoma. Doctoral Thesis, Yale University. p. 13.

[3] Hoover R.N., Devesa S.S., Cantor K.P., Lubin J.H., Fraumeni J.F. (1991). Time trends for bone and joint cancers and osteosarcomas in the Surveillance, Epidemiology and End R.... National Cancer Institute. In: Review of Fluoride: Benefits and Risks Report of the Ad Hoc Committee on Fluoride of the Committee to Coordinate Environmental Health and Related Programs US Public Health Service.

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What did some reviewers say?

 

Thiessen’s Review of Kim et al. (2011), (Referenced in PHS 2015 as evidence of safety).

“The paper by Kim et al. (2011) is part of the Harvard osteosarcoma study. The paper describes a comparison of bone fluoride levels in cases of osteosarcoma and a set of controls. The authors report no significant difference in bone fluoride levels between cases and controls and no significant association between bone fluoride levels and osteosarcoma risk. 

“To give some context it is important to know that an earlier part of the Harvard osteosarcoma study, namely the work of Bassin et al. (2006; based on a 2001 dissertation by Bassin 2001), reported an association between age-specific fluoride exposure and risk of osteosarcoma, with the highest risks for childhood exposure for young males. Bassin's study involved 103 cases under the age of 20 (median age, 13.7) and 215 matched controls (median age, 14.5; matching based on age, gender, and distance from the hospital) from the orthopedics departments of the same hospitals. Cases were diagnosed between November 1989 and November 1992. Bassin estimated fluoride exposure from drinking water and fluoride supplements or rinses for each participant, for each year of life, based on residential histories. Bassin et al. describe the limitations of their study and point out that additional studies with larger numbers of osteosarcoma patients, with incidence under age 20, that examine age-specific and sex-specific associations are required to confirm or refute the findings of the current study. 

“The NRC report (NRC 2006, pp. 329-330) was published shortly before the Bassin et al. paper appeared, but included an analysis of Bassin's dissertation (2001), which reported essentially the same findings. The NRC also reported a personal communication from C. Douglass of the Harvard School of Dental Medicine, describing a second study involving 189 cases and 289 controls. This study was said to include residence history, detailed interviews about water consumption, and fluoride assays of bone specimens and toenails of all subjects. The NRC committee was told that the preliminary results indicated no statistically significant association with fluoride intakes and that the results were expected to be reported in the summer of 2006. The NRC report describes some concerns about possible bias (in either direction) in the selection of controls and the expectation that the study could have limited statistical power to detect a small increase in osteosarcoma risk due to fluoride exposure. 

“When Bassin's work was published (Bassin et al. 2006), the same issue of the journal contained a letter to the editor by Douglass and Joshipura (2006), both of whom were coauthors on an earlier paper describing Bassin's exposure analysis (Bassin et al. 2004). This letter mentioned that preliminary findings from the second set of cases did not appear to replicate the earlier work (Bassin's study) and indicated that their findings, which were “currently being prepared for publication,” did not suggest an overall association between fluoride and osteosarcoma. It also indicated that both a fluoride intake history and a bone specimen were being obtained for each participant, and that their preliminary analysis indicated that the fluoride content of the bone was not associated with excess risk of osteosarcoma. However, this letter provided no data and therefore constitutes no more than an opinion. 

“The paper by Kim et al. (2011) was submitted to the Journal of Dental Research in January 2011 and published electronically in late July 2011. No mention is made of why it took 5 years from the time Douglass and Joshipura indicated that their findings were “currently being prepared for publication.” Nor is it obvious why the paper was published in a dental journal, when it does not deal directly with anything related to dentistry. Other recent papers that include some of the same coauthors (specifically, C. Douglass and R.N. Hoover) have been published in cancer research journals, (e.g., Savage et al. 2007; Mirabello et al. 2011a,b,c), as was Bassin's work (Bassin et al. 2006). 

“Kim et al. (2011) describe a study involving 137 cases (37 ages 0-14, 72 ages 15-29, 13 ages 30- 44, and 15 ages 45 and older) and 51 controls, with cases diagnosed between 1993 and 2000. 

“Although there is mention of “orthopedic” controls (patients with benign tumors or non- neoplastic conditions), only “tumor” controls were in fact used. The selection of cases and controls was affected in part by the need to obtain bone specimens. The cases had a median age of 17.6 years, the controls, 41.3 years. Kim et al. report no significant difference in the median fluoride concentration in bone between matched osteosarcoma case and tumor control in 32 pairs where age matching was possible. In an unmatched analysis of all cases and controls, the median bone fluoride concentration was significantly higher in controls than in cases. The authors conclude that their study “did not demonstrate an association between fluoride levels in bone and osteosarcoma.” 

“The use of an individual measure of fluoride exposure (bone fluoride concentration) is important to note. However, as the authors themselves point out, “if risk is related to exposures at a specific time in life, rather than total accumulated dose, this metric would not be optimal” (Kim et al. 2011). Bone fluoride concentration is a measure of cumulative fluoride exposure to the time of diagnosis and surgery. Given a “lag time” of at least 5 years between initiation and diagnosis of most cancer types, the bone fluoride concentration at time of diagnosis can be affected by fluoride exposures that occurred after the cancer was initiated. Most importantly, a bone fluoride concentration at time of diagnosis says nothing about fluoride exposure at specific ages, so it does not address the key finding of Bassin et al. (2006). 

“The osteosarcoma cases analyzed by Kim et al. (2011) included 28 individuals aged 30 or older. The actual number of patients under 20 years old is not given, but was said to be too few to provide sufficient statistical power. Thus the cases analyzed by Kim et al. are not fully comparable to the cases analyzed by Bassin et al. While osteosarcoma obviously occurs in adults, the majority of cases occur in children and young adults (Sergi and Zwerschke 2008; Mirabello et al. 2011a,b,c; Savage et al. 2007); Kim et al. (2011) themselves indicate that osteosarcoma is more prevalent in individuals less than 20 years old. Kim et al. have not explained their justification for including older individuals, other than to have large enough numbers to do their statistical analyses. The possibility that different mechanisms are involved in pediatric and geriatric osteosarcoma has not been addressed. 

“As mentioned, the controls were all patients with malignant bone tumors other than osteosarcoma, apparently because bone samples were more readily available for tumor controls than for other controls (Kim et al. 2011). Kim et al. point out that if “fluoride levels were related to bone cancer in general, the current study design would be unable to detect this. There is no published evidence of such an association.” There also is no published evidence clearly demonstrating a lack of such an association. The one small finding that has been published (as part of an appendix to a Public Health Service report) was an excess of Ewing's sarcoma in fluoridated counties as opposed to nonfluoridated counties (Hoover 1991). This was explained as an artifact of the analysis. However, given the distinct lack of adequate analyses of fluoride exposure and other types of bone cancer, the use by Kim et al. (2011) of tumor controls alone obviously has to be regarded with caution. 

“Bassin et al. (2006) limited their analysis to 103 cases diagnosed before the age of 20 (median age 13.7) and used 215 orthopedic controls (median age 14.5). Kim et al. (2011) used a much broader range of ages among cases, together with a relatively small set of controls very different in age from the cases and who were themselves bone cancer patients. While there were apparently limitations in selecting controls who could provide bone samples, nevertheless, the result is that the analysis by Bassin et al. had a much better set of controls than did the analysis of Kim et al. 

“Kim et al. (2011) report a higher median fluoride concentration of controls compared with cases, which they attribute to the older ages of the controls than the cases. Comparison of the distributions of bone fluoride concentrations between cases and controls (Figure, part D) indicates that the ranges are not greatly different. Given that the median age of the controls is more than twice the median age of the cases (41.3 vs. 17.6), the obvious conclusion is not a lack of association between fluoride exposure and osteosarcoma, but considerably higher average exposure (by a factor of 2) in cases and controls, in order to reach similar bone fluoride concentrations. Kim's 2007 dissertation, on which the 2011 paper is based, reports estimates of “median cumulative lifetime water fluoride” of 14.4 ppm year for the cases and 16.5 ppm year for the controls. These cumulative exposures together with the median ages of the two groups again indicate higher average fluoride exposure among cases than controls, by a factor of 2. Rather than refuting the work of Bassin et al., these findings by Kim et al. support an association between fluoride exposure and osteosarcoma. 

“In order to obtain the estimates of median cumulative lifetime water fluoride, Kim had to develop the exposure histories for the individual cases and controls. In addition, her dissertation indicates that the exposure histories were available for the orthopedic (noncancer) controls. Douglass and Joshipura (2006) indicated that exposure histories were being obtained. Any meaningful comparison of Kim's findings with those of Bassin et al. (2011) will require use of the individual exposure histories to look at exposures at various ages, as opposed to just the comparison of bone fluoride concentrations. 

“As an incidental note, the bone fluoride concentrations reported by Kim et al. (2011, Figure) for both osteosarcoma cases and tumor controls, extend into the range reported for skeletal fluorosis (NRC 2006).

Also of note is that Kim et al. (2011) found that a history of broken bones was a significant predictor of osteosarcoma risk. An increased risk of bone fracture has been associated with fluoride exposure in a variety of studies (e.g., NRC 2006; Alarcón-Herrera et al. 2001; Danielson et al. 1992).”[1]

A National Cancer Institute (NCI) report[2] on Kim (2011), failed to appreciate using a different cancer for controls is not “normal” bone fluoride concentration.  

 

The NCI states “they [Kim] measured fluoride concentration in samples of normal bone adjacent to a person’s tumor. . . The analysis showed no difference in bone fluoride levels between people with osteosarcoma and people in a control group who had other malignant bone tumors.” 

 

Thiessen’s Review of Comber et al. (2011) (Comber et al was cited by the PHS 2015 recommendation as evidence fluoride is not carcinogenic and safe.)

“Comber et al. (2011) compare osteosarcoma rates in nonfluoridated Northern Ireland and in partially fluoridated Republic of Ireland, with the latter data divided between fluoridated and nonfluoridated areas. They report no significant differences in either age-specific or age- standardized incidence rates of osteosarcoma between fluoridated and nonfluoridated areas. 

“Comber et al. also describe several limitations of their study, including uncertainty about fluoridation status of particular areas (the possibility of misclassification), the possibility that the place of residence at the time of diagnosis may not be an accurate proxy for lifetime exposure to fluoridated water, and the lack of an accurate measure of total fluoride exposure. Perhaps the most important limitation pointed out by Comber et al. is the relative rarity of the cancer and the correspondingly wide confidence intervals of the relative risk estimates. They estimate that the risk for a fluoridated population would need to be at least 1.7 times that of the nonfluoridated population (a 70% increase) for a statistically significant effect to be detected. In other words, fluoride could cause a 50-60% increase in risk of osteosarcoma, and this study would not be able to detect it. 

“With respect to using the place of residence at the time of diagnosis as a proxy for lifetime exposure to fluoridated water, Comber et al. point out that if fluoride exposure at a specific age is critical to osteosarcoma development (citing Bassin et al. 2006), use of the fluoride estimation at the time of diagnosis is less valuable. In other words, their analysis cannot evaluate the importance of age-specific exposure. 

“With respect to the lack of an accurate measure of total fluoride exposure, the authors mention that at least one-third of fluoride intake is estimated to come from sources other than drinking water, citing tea, fish, and toothpaste as examples. The authors do not discuss the possibility that variability in total fluoride intake within the Irish populations could overwhelm differences between populations in fluoride intakes from drinking water alone. 

“In summary, the paper by Comber et al. does not demonstrate an absence of a relationship between fluoride exposure and osteosarcoma, simply that any effect of fluoridated water (as opposed to total fluoride intake) is not large enough to detect by the methods employed.”[3]

 

[1] Thiessen IBID  Pages 12-14.

[2] Kim FM, Hayes C, Williams PL, et al. An assessment of bone fluoride and osteosarcoma. Journal of Dental Research 2011; 90(10):1171–1176.  https://www.cancer.gov/about-cancer/causes-prevention/risk/myths/fluoridated-water-fact-sheet#q4  Accessed 2/14/2017

 

 

[3] Thiessen IBID p. 12.

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Nothing in science is "settled."  We have theories which must constantly be retested and tested again in light of the new research and understanding.  Nothing in science is written in stone.  There are no absolutes, no "never" and "always."  We scientists must live in a state of discovery.  

 

I have provided some research on the basics and will now go into some of the specific cancers.

 

  1. BONE CANCER:

PHS 2015 notes about 100 unique comments regarding fluoride as a carcinogen.  Of the many references provided to PHS 2015, they include nine references and dismiss carcinogenicity.  Osteosarcoma is the singular cancer listed. PHS 2015 references: 

  1. PHS 2015 lists Bassin 2006[1] as reporting an association between fluoride and osteosarcoma; although PHS 2015 does not go into specifics.   

CHESTER DOUGLASS HISTORY: 

DOUGLASS REPORTS NO ASSOCIATION:  A team of Harvard scientists, led by

Dr. Chester Douglass, publish the preliminary findings of a large case-control analysis of fluoride and osteosarcoma (McGuire et al 1995). In the preliminary analysis the authors report no association between fluoride and osteosarcoma. 

DOUGLASS REPORTS ELEVATED RISK:  To the NIH, Chester Douglass

reports “all” of his analyses which assumed bottled water contains no fluoride found that fluoridated drinking water (>0.7 ppm) is associated with elevated, but not statistically significant, rates of osteosarcoma.  Douglass later expresses concern about the ramifications to water fluoridation from reporting that fluoridation is associated with an elevated, even if not statistically significant, rate of bone cancer:

“Because of the importance of the question at hand, we think the policy implications of reporting that the relative risk maybe higher than 1.5 would have consequences for fluoridation health policies.”

 DOUGLASS REPORTS NO RISK:              In 1995, 1998 & 2002 Douglass states that

the study shows fluoridation has either no effect, or a slightly protective effect, on osteosarcoma rates. 

DOUGLASS KNOWS THERE IS RISK: However, Douglass’s signature is on Bassin’s

2001 thesis using Douglass’s data which found a statistically significant increase in osteosarcomas. 

DOUGLASS REPORTS NO RISK:                In 2004, the National Research Council

(NRC) begins a review of the safety of currently allowable levels of fluoride in drinking water.  Douglass submits a summary of his fluoride/osteosarcoma study to the NRC, claiming no significant association between fluoridation and osteosarcoma.  Douglass even cites Bassin’s study as one of 2 supporting references for this summary of no fluoride osteosarcoma association.  Douglass fails to report that Bassin found a statistically significant, 5-to-7-fold risk of osteosarcoma among boys drinking fluoridated water a decade prior to their diagnosis of cancer.

Bassin et al published some of her thesis data in 2006.  She reports that boys drinking fluoridated water during the ages of 6 to 8 have a five-fold increased risk of developing osteosarcoma during their teenage years:

“We observed that for males diagnosed before the age of 20 years, fluoride level in drinking water during growth was associated with an increased risk of osteosarcoma, demonstrating a peak in the odds ratios from 6 to 8 years of age. All of our models were remarkably robust in showing this effect, which coincides with the mid-childhood growth spurt. For females, no clear association between fluoride in drinking water during growth and osteosarcoma emerged.”[2]

The Bassin study is consistent with other studies.  The fluoride carcinoma risk appears age and cell cycle dependent.   

DOUGLASS ADMITS SOME ASSOCIATION:  Douglass publishes a letter in the

same issue in which he publicly discloses for the first time that he had found some associations between fluoride exposure and osteosarcoma in the (retrospective) dataset that Bassin analyzed. 

DOUGLASS CAUTIONS AND PROMISE: Douglass states that he was unable to

replicate these findings in a new (prospective) dataset, and thus cautions readers from making any conclusions based on Bassin’s findings. Douglass notes, however, that he has yet to conduct an age-specific analysis on the prospective data. He notes though that he is planning on doing so. To quote:

 “A parallel analysis of age-specific exposure to fluoride, especially during growth periods, is also being pursued by our study team in the second set of cases of our study. Accordingly, readers are cautioned not to generalize and over-interpret the results of the Bassin et al. paper and to await the publications from the full study, before making conclusions, and especially before influencing any related policy decisions.”[3]

Note: As of April, 2015 Douglas, to our knowledge, has not published the agespecific analysis on the prospective data.

COMPLAINT AGAINST DOUGLASS:         The Environmental Working Group filed a complaint of scientific misconduct with the National Institute of Health which launched an investigation run by Harvard University; however, EWG is reported to have not been contacted.  

NO INTENT TO MISREPRESENT:  Harvard issued a short, one page press release announcing that Douglass did not “intentionally misrepresent” the research.

 

To be continued:

 

[1] Bassin EB et al, Age-specific fluoride exposure in drinking water and osteosarcoma (United States).  Cancer Causes Control 2006;17:421-8

[2] Bassin EB, et al. 2006. Age-specific fluoride exposure in drinking water and osteosarcoma (United States). Cancer Causes & Control 17(4):421-8. May.)

[3] Douglass CW, and Joshipura K. 2006. Caution needed in fluoride and osteosarcoma study. Cancer Causes & Control 17(4):481-82. May.

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THE DOSE OF FLUORIDE USED BY NTP 2006:

“the level of fluoride the low- and mid-dose animals had in their drinking water was within an order of magnitude of what humans are exposed to when drinking water containing the EPA-established maximum level of 4 ppm fluoride. This is almost unheard of in animal bioassays. Usually, animal exposure is four to six orders of magnitude more than what humans receive.”[1]

“it is important to note that the dose range is not, as is sometimes the case, orders of magnitude higher than that encountered in human population, nor is the body burden expressed as concentrations in bone orders of magnitude higher than that found in human populations also ingesting fluoride.”[2]

“the difference between the animal study and the human exposures is not nearly as great as typical with synthetic chemicals.”[3]

“I think it’s important to realize that even though the water concentrations were higher than what we see, or what humans are exposed to, the bone concentrations were not.”[4]

“a small number of osteosarcomas occurred in mid- and high-dose male rats. These neoplasms occurred with a significant dose response trend, but at a rate wtihin the upper range of incidences previously seen in control male rats in NTP studies. Three of the tumors arose in the vertebra, a site not commonly associated with chemically induced osteosarcomas. Bone is known to accumulate fluoride, and fluoride has been shown to be genotoxic to some mammalian cells in culture. No osteosarcomas were seen in female rats, and several osteosarcomas seen in mice occurred with an incidence that did not suggest a relationship with sodium fluoride exposure.Taken together, the current findings are inconclusive, but are weakly supportive of an association between sodium fluoride administration and the occurrence of osteosarcomas in male rats.”90

20 Large City Comparison:  Burk91 1977, head of cytochemistry section of the USA National Cancer Institute, reported year-by-year average observed cancer death rates of ten large central cities of the United States, which served as the control group and remained un-fluoridated from 1940 through 1968.  These were compared for the years 1940 through 1968 with the year-by-year average observed cancer death rates of ten large central cities of the United States which served as the experimental group and remained unfluoridated from 1940 through 1951, but fluoridated between 1952 and 1956, and remained fluoridated through 1968 and thereafter.92‑    The experiment came to an end in 1968 because fluoridation was introduced in the control cities step-by-step from and after 1969.  The necessary data are available for all years except for 1951 and 1952.  Seven million in ten control cities and eleven million in ten experimental cities over about thirty years.   Cancer rates in the fluoridated cities (CDRo(+F) clearly increased faster compared to the non fluoridated cities at a rate of 31.3 excess cancer deaths per 100,000 persons.

                                1940               1950               1950               1970

     CDRo(+F)                  154.2               181.8             186.3               222.6

     CDRo(- F)                  153.5               181.3              l83.6              188.8   

USPHS responded in defense of their policy that Burk had not adjusted for age, race or sex.  PHS was suspicious the subject cities had all aged faster.  However, Burk had adjusted for demographic variables and he testified to the fact to Congress and to the courts of law.  In response Arthur Upton provided the “Upton Statement” in a 17 page

Dean Burk and J. R. Graham, Lord Jauncey and Justice Flaherty: Opposing Views of the Fluoridation-Cancer Link, 17 FLUORIDE 63

(1984) [hereinafter Burk & Graham]; Pierre Morin et al., Les fluorures versus le cancer et les maladies congentales: l’image globale,

GOURVERNEMENT DU QUEBEC, MINISTERE DES AFFAIRES SOCIALES (The 1984); Pierre Morin et al., Fluorides, Water Fluoridation,

Cancer, and Genetic Diseases, 12 SCI. & PUB. POL’Y 36 (1985); Rudolf Ziegelbecker, Zur Frage eines Zusammenhanges zwischen

Trinkwasserfluordierung, Krebs, und Leberzirrhose, 218 GWF WASSER/ABWASSER 111 (1987); Dean Burk et al., A Current Restatement and Continuing Reappraisal Concerning Demographic Variables in American Time-Trend Studies on Water Fluoridation and Human Cancer, 61 PROC. PA. ACAD. OF SCI. 138 (1988) [hereinafter Burk, Graham, & Morin].

92

See Burk & Yiamouyiannis, supra note 108, at 104; Burk, Graham, & Morin, supra note 108, at 138.

document.[5]  Upton set for an adjustment in weighted averages, suggesting cancer mortality actually grew 1% faster in the unfluoridated cities.  

1950                     1970                  Change

CDRo/CDRe  (+F)             1.23                      1.24                     +.0l

CDRo/CDRe  (-F)              1.15                      1.l7                      +.02

Cities

1940

1950

1960

1970

CDRo (+F)

154.2

181.8

186.3

222.6

CDRe (+F)

128.1

146.9

146.9

174.7

CDRo/CDRe (+F)

1.204

1.238

1.268

1.274

CDRo-CDRe (+F)

26.1

34.9

39.4

47.9

Burk and Yiamouyiannis[6]  demonstrated Upton’s flaw.  Upton had simply used 1950 with 1970 and failed to also consider data reported in-between those two points, and before and after the two points.  

CDRo (-F)

153.5

181.3

183.6

188.8

CDRe (-F)

140.3

155.5

155.5

166.0

CDRo/CDRe (-F)

1.094

1.166

1.181

1.137

CDRo-CDRe (-F)

13.2

25.8

28.1

22.8

The change in CDRo/CDRe = [(1.274-1.137) – (1.268-1.181)] + [(1.204-1.094) – (1.238-1.166)] = +.088.  This coefficient means that, relative to what might be expected in light of the demographic structure of the two populations here in question, adjusted cancer mortality grew about 9% faster in the fluoridated cities.

In terms of CDRo-CDRe, fluoridation is associated with [(47.9-22.8) – (39.4-28.1)] + [(26.1-13.2) – (34.9-25.8)] = 17.6 excess cancer deaths per 100,000 persons exposed after 15-20 years.  

Burk and Yiamouyiannis reported 17.6 additional cancer deaths per 100,000. 

Apparently Black males have a higher cancer rate than White males.  Returning to Burk’s data and correcting for race might show a further increase.  

 

[1] Hileman B. (1990). Fluoride bioassay study under scrutiny. Chemical & Engineering News September 17.

[2] Silbergeld E. (1990). Peer Review of Draft Technical Report of Long-Term Toxicology and Carcinogenesis Studies and Toxicit... Study, Sodium Fluoride; Research Triangle Park, North Carolina, Thursday, April 26, 1990. p. 62-63.

[3] Gold  IBID p. 71.

[4] Zeise L. IBID . p. 79.

[5] National Cancer Program (Part 2), Hearings Before the Subcomm. of the Comm. on Government Operations, 95th Cong. 471 (1977) [hereinafter National Cancer Program].

[6] Dr. John Yiamouyiannis executed an adjustment of the basic data, using weighted averages and US-1950 as the standard population, exactly as stipulated in the Upton Statement.  He adjusted only for the years after 1950, deriving CDRo values for 1950 and 1970, by linear regression analysis of the CDRo data for 1950 and 1953-1969, and showed an association in terms of CDRo/CDRe = +.042, and in terms of CDRo-CDRe = 12.4 cancer deaths per 100,00 persons exposed within after fifteen to twenty years after the introduction of fluoridation in the experimental cities.  See National Cancer Program, supra note 109, at 64-65.  The main objection to this technique came from Dr. David Newell of the Royal Statistical Society in defense of the Upton Statement.  He claimed that, because populations between census years and thus denominators in intercensal CDRs must be estimated by linear interpolation, they are not reliable data, and therefore not suitable for linear regression analysis.  See Aitkenhead v. Borough of West View, No. GD-4585, Trial Transcript, May 8, 1978, at 72, 72A, 73-76 (Allegheny Court of Common Pleas, Pa).  This criticism was exploded by none other than Dr. Guy Newell, Deputy Director of the NCI, who supervised preparation of the Upton Statement and introduced it before Congress.  Later speaking as a professor of epidemiology at the University of Texas, he stated emphatically that use of linear interpolation to derive denominators in intercensal CDRs is “accepted procedure” in modern applied epidemiology, and, therefore, perfectly reliable.  See Safe Water Found. of Texas v. City of Houston, No. 80-52271, Trial Transcript, Jan. 26, 1982, at 1648-54 (151st Jud. Dist., Tex.).  The correctness of undertaking a linear regression analysis of intercensal CDRs in which the denominators were estimated by linear interpolation was further confirmed by Dr. Hubert Arnold, professor of statistics at the University of California, Davis.  See National Cancer Program, supra note 109, at 580. The propriety and necessity of such use of interpolated data, based on fundamental principles of inductive logic, is discussed in Burk & Graham, supra note 108, at 68-69, and Burk, Graham, & Morin, supra note 108, at 143-44.

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Re: Fluoride - Demand AARP Take Action

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There is a big difference between causing cancer and potentiating existing cancer. Bone cancer is so rare that proving fluoride causes it or does not cause it in man is very difficult.

On the other hand, the Yiamouyiannis analyses indicate well that in the 1960's when fluoridation began to spread widely across the U.S. that cancer mortality continued to progressively increase in incidence in those cities that began fluoridation, compared to cities that did not fluoridate where cancer mortality rates slowed over the same time periods. These data were heavliy challenged and analyzed in several court cases which concluded that fluoride potentiates most forms of cancer. The mechanism for this may be fluoride interference with immune sytem protection or other possibilities. 

It has been stated here many times by fluoridation promoters that a key reason why fluoridation still remains and is still recommended by the CDC is because there are no successful litigations for harm caused by fluoridation. And yet the conclusions of several courts mentioned above have had no bearing at all on the continuance of fluoridation anyway.

There is also a huge difference between natural fluoride in water that comes from calcium fluoride contamination, versus artificial fluoridation with industrial, calcium-absent, fluoride-containing chemicals that always also contain significant arsenic and lead which are themselves carcinogenic. that add to existing contaminants in a city water supply. 

The notion that fresh drinking water was somehow created as a deficient substance if it did not also contain fluoride is very relevant to fluoridation. Fluoridation promoters have argued often that  somehow drinking water supplies were not created with a proper amount of fluoride in it, so we as humans need to repair the deficient water by adding fluoride into it that is missing. But the functions of water do not include treating dental caries. The functions are to prevent dehydration, to hydrate tissues so that metabolic processes can exist normally, and to maintain normal volumes of blood, interstitial, and intracellular fluid.. Fluoride is not a mineral nutrient and has no physiologic function of any kind in living things including man. Fluoride is not listed as a normal ingredient of the bloodstream, in any clinhicla or nursing text or other source because fluoride does not belong in blood. Again, fluoride is a contaminant of some fresh water supplies, and in blood is a contaminant as well. Fresh drinking water does not require fluoride to be normal. 

Richard Sauerheber, Ph.D.
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Re: Fluoride and Cancer

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And more research on cancer:

 

Chromosome aberrations: Joseph (2000) “Our results indicate that there is a significant increase in the frequencies of chromosome aberrations and SCE in one of the village populations exposed to a fluoride concentration higher than the permissible limit. The lymphocytes of these residents were also more susceptible to a clastogen such as Mitomycin-C than the other populations and displayed a significant increase in chromosome aberrations.”[1]

Chromosome aberrations Meng (1997)“Our study here provides evidence that the air pollutants at the phosphate fertilizer factory, in which HF and SiF4 are the main chemicals, could induce both CA (chromosomal aberrations) and MN (micronuclei) in human blood lymphocytes in vivo. Our earlier observation on sister-chromatid exchanges (SCE) of peripheral blood lymphocytes from this same population showed that the mean SCEs/cell of the workers was significantly higher than that of the controls (p < 0.01). The results of our studies imply that even if the concentration of the chemical pollutants in the air is low (e.g. F 0.50-0.80 mg/m 3), it may cause damage to genetic material at the chromosomal level… it is suggested that chromosomal abnormalities induced by fluoride could be the results from interaction with the enzymes responsible for DNA synthesis or repair, rather than directly with

DNA.”[2]

Mutagenic Agent: Wu (1950 “The results in this paper showed an obvious increase in the SCE frequency of the patients with fluorosis, indicating that fluorine had some mutagenic effects, and could give rise to DNA damage. The fact that the SCE frequency of the healthy people in the endemic regions was also higher than that of the controls in the non-endemic regions suggests that early harm by fluorine can be cytogenetically detected in the sub-clinical patients with fluorosis who could not be given an early diagnosis clinically. Under normal circumstances, the incidence rate of micronucleus is very low, usually 0-2%. The normal value checked in this paper is 0-2%, which agrees with that reported in the literature. The results show that the mean value of the micronucleus rate of the fluorine-toxic patients was 1.94 + 0.86% (range 1-15%) which is 2-3 times more than that of 0.57 + 0.44% in the controls… To sum up, the rise of SCE and MN in the peripheral blood lymphocytes of the fluorine-intoxicated patients indicates that fluorine is a mutagenic agent which can cause DNA and chromosomal damage.”[3]

Meng (1995) “Our study here provided evidence that the air pollutants at the phosphate fertilizer factory, of which HF and SiF4 are the main chemicals, could induce SCEs in human blood lymphocytes in vivo. These results imply that even if the concentration of the chemical pollutants in the air is low (e.g.F: 0.50 – 0.80 mg/m3), it may cause damage to genetic material at the chromosomal level, although the general health of the workers in the phosphate fertilizer factory was found to be satisfactory.”[4]

Chromosome Aberrations: Sheth (1994)“A number of investigators have utilized the SCE

(Sister Chromatid Exchange) test to study the genotoxicity of fluoride. In the present study, human populations directly exposed to fluoride in drinking water in endemic regions of North Gujarat were investigated to evaluate the possible effect of fluoride on SCE. To the best of our knowledge this is the first report on genotoxic effects following long-term fluoride intake in an endemic area in India… The results of the present investigation suggest that in fluoride-affected persons exposed to 1.95 – 2.2 ppm fluoride in drinking water chromosomal alterations as indicated by SCE frequency and chromosome aberrations were higher than in normal persons exposed to 0.6 – 1.0 ppm drinking water fluoride.”[5]

 DNA Damage and Fluorosis: Li (1991)“With peripheral blood lymphocyte culture, a study of SCE and micronuclei test was done in 24 patients with fluorosis and same number of normal people as control. The results obtained showed that in the patient group the mean value of SCE per cell and the frequency of micronuclei were 10.24±1.67 and 1.42‰ ,respectively, while in the control only 7.62 ± 0.80 and 0.33‰, respectively, were found. And both of the two respective parameters, statistically, were in significant difference. These findings suggested that excess fluorine would cause increases of SCE frequency and micronuclear number in lymphocyte and make DNA damaged.”[6]

SCE Rate Induced: Velazquez-Guadarrama (2005): “The results concerning the SCE rate

induced by sodium fluoride are shown in Table 1. Although no significant increase was observed with the two low doses tested (from 2 to 4 mg/kg), a significant SCE increase was found with the three highest doses. The cumulative frequency of these data reveals about 70% of cells with four SCE in the group treated with the high dose, a value which is twice the level of the negative control.”[7]

Chromosome Damage: Mohamed (1982)“Cytological studies on bone marrow cell chromosomes and spermatocytes showed that 1-200 ppm F (as sodium fluoride) was able to induce chromosomal changes in a dose-dependent manner. The frequency of the induced chromosomal damage was significantly higher in each treatment than in the controls. The observed abnormalities included translocations, dicentrics, ring chromosomes, and bridges plus fragments, or fragments by themselves. There was a significant correlation between the amount of fluoride in the body ash and the frequency of the chromosomal abnormalities.”[8]

Chromosomal aberrations: Gileva (1975)“Cryolite concentrations of 3 mg/m3 as well as a mixture of 0.5 mg/m3 of cryolite and 0.35 mg/m3 of hydrogen fluoride increases 3 1/2 to 4 1/2 times (over controls) the percentage of cells with chromosomal aberrations in the bone marrow of rats. The data indicate the need for further study of the mutagenic features of fluoride compounds in relation to their potential for harmful impact on the mechanism of inheritance in humans.”[9]

Mutagen: Voroshilin (1975) “The mutagenic effect of hydrogen fluoride in concentration 1.0 mg/ m-3 was studied in rats and mice. Prolonged inhalation of this compound increased the frequency of cells with chromosome abnormalities in the bone marrow of albino rats. The mutagenic effect was higher in older animals.”[10]

Acceleration of tumor tissue growth: Taylor (1965) “In 54 tests involving 991 mice bearing transplanted tumors and 58 tests including 1817 tumor-bearing eggs, data were obtained which indicated a statistically significant acceleration of tumor tissue growth in association with comparatively low levels of NaF.”[11]

NTP 1990:   Dose-Dependent increase in Osteosarcoma: NTP (1990)               In

1977, the U.S. Congress requested that animal studies regarding the potential of a fluoride/cancer connection.  NTP and published the study in 1990.

The main finding of NTP’s 1990 study was a dose-dependent increase in osteosarcoma (bone cancer) among the fluoride-treated male rats. However, despite the fact that 1) the cancer occurred in the target organ (bone) for fluoride accumulation, that 2) the increase in bone cancer was statistically-significant, that 3) the doses of fluoride were low for an animal cancer study, and that 4) NTP acknowledged it is “biologically plausible” that fluoride could induce bone cancer, the NTP ruled that the study only provided “equivocal evidence” that fluoride was the cause of the cancer.

          According to a report in Chemical & Engineering News: “A number of government

officials who asked not to be identified also have told C&EN that they have concerns about the conclusions of the NTP study. They, too, believe that fluoride should have been placed in the “some evidence” category, in part because osteosarcoma is a very rare form of cancer in rodents.”

In addition to increased bone cancer, the NTP study also found increases in rare liver cancers, oral...NTP ruled, however, that the cancers were not related to the fluoride treatment despite reaching “statistical significance” in some of NTP’s analyses.

 

[1] Joseph S, Gadhia PK. (2000). Sister chromatid exchange frequency and chromosome aberrations in residents of fluoride endemic regions of South Gujarat. Fluoride 33(4):154-158.

[2] Meng Z, Zhang B. (1997). Chromosomal aberrations and micronuclei in lymphocytes of workers at a phosphate fertilizer factory. Mutation Research 393: 283-288.

[3] Wu DQ, Wu Y. (1995). Micronucleus and Sister Chromatid Exchange Frequency in Endemic Fluorosis. Fluoride 28(3):125-127.

[4] Meng Z, et al. (1995). Sister-chromatid exchanges in lymphocytes of workers at a phosphate fertilizer factory. Mutation Research 334(2):243-6.

[5] Sheth FJ, et al. (1994). Sister chromatid exchanges: A study in fluorotic individuals of North Gujurat. Fluoride 27: 215-219.

[6] Li J, et al. (1991). The influence of high-fluorine on DNA stability in the human body. Chinese Journal of Endemiology.  [Article in

Chinese]

[7] Velazquez-Guadarrama N, Madrigal-Bujaidar E, Molina D, Chamorro G. (2005). Genotoxic evaluation of sodium fluoride and sodium perborate in mouse bone marrow cells. Bulletin of Environmental Contamination and Toxicology 74(3):566-72.

[8] Mohamed AH, Chandler ME. (1982). Cytological effects of sodium fluoride on mice. Fluoride 15(3):110-18.

[9] Gileva EA, et al. (1975). The mutagenic activity of inorganic fluorine compounds. Fluoride 8(1):47-50. [Originally published in Russian; condensed from Gig. Sanit., 37(1):9-12, Jan. 1972.]

[10] Voroshilin SI, et al. (1975). Mutagenic effect of hydrogen fluoride on animals. Tsitol Genet. 9(1): 42-44.

[11] Taylor A, Taylor NC. (1965). Effect of sodium fluoride on tumor growth. Proceedings of the Society for Experimental Biology and Medicine 119:252-255.

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And to continue:

 

Clastogenic: Albonese (1987) “Chromosomal aberrations were recorded for all the concentrations used. . . .The authors conclude that sodium-fluoride may be considered to be clastogenic in these cells.”[1]

Genetic Damage:  Caspary (1987) “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.”[2]

Genotoxic and suggested carcinogenic:   Tsutsui (1984) “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.”[3]

DNA Damage: Tsutsui (1984)            “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.”[4]

DNA Damage:  Tsutsui (1984)           “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.”[5]

Neoplasm:     Greenberg (1982) 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.”[6]

Chromosome damage at artificial fluoridation concentrations:             “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.”[7]

Mutagenic agent: Mohamad (1977)  “These findings indicate that HF in addition to being a mutagenic agent is also able to reduce crossing over in certain chromosome segments.”[8]

Genetic damage: Gerdes (1971) “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.”[9]

Genetic aberrations: Gerdes (1971) “Results indicate that treatment increased the incidence of genetic aberrations as measured by at least two parameters.”[10]

Known mutagen: Mohamed (1970)  “These findings indicate that HF is a mutagenic agent.”[11]

 DNA damage: Wu (1995)“In recent years, SCE analysis has been considered to be a sensitive method for detecting DNA damage. There is a clear relationship between a substance’s ability to induce DNA damage, mutate chromosomes, and cause cancers. The SCE frequency in the human body in peripheral blood lymphocytes is very steady, and does not vary with age or sex. Any increase of the SCE frequency is primarily due to chromosome damage. Thus using a method to detect SCE for exploring the toxicity and harm caused by fluoride is of great importance. The results in this paper showed an obvious increase in the SCE frequency of the patients with fluorosis, indicating that fluorine had some mutagenic effects, and could give rise to DNA damage.”[12]

The Oral Health Research Institute at the Indiana University School of Dentistry has repeatedly failed to find any evidence of genotoxic effects from fluoride exposure, whether in fluoride-exposed humans or animals. (Jackson 1997; Li 1995; Dunipace 1995; Jackson 1994). 

Chromosome aberrations: Joseph (2000) “Our results indicate that there is a significant increase in the frequencies of chromosome aberrations and SCE in one of the village populations exposed to a fluoride concentration higher than the permissible limit. The lymphocytes of these residents were also more susceptible to a clastogen such as Mitomycin-C than the other populations and displayed a significant increase in chromosome aberrations.”[13]

Chromosome aberrations Meng (1997)“Our study here provides evidence that the air pollutants at the phosphate fertilizer factory, in which HF and SiF4 are the main chemicals, could induce both CA (chromosomal aberrations) and MN (micronuclei) in human blood lymphocytes in vivo. Our earlier observation on sister-chromatid exchanges (SCE) of peripheral blood lymphocytes from this same population showed that the mean SCEs/cell of the workers was significantly higher than that of the controls (p < 0.01). The results of our studies imply that even if the concentration of the chemical pollutants in the air is low (e.g. F 0.50-0.80 mg/m 3), it may cause damage to genetic material at the chromosomal level… it is suggested that chromosomal abnormalities induced by fluoride could be the results from interaction with the enzymes responsible for DNA synthesis or repair, rather than directly with

DNA.”[14]

Mutagenic Agent: Wu (1950 “The results in this paper showed an obvious increase in the SCE frequency of the patients with fluorosis, indicating that fluorine had some mutagenic effects, and could give rise to DNA damage. The fact that the SCE frequency of the healthy people in the endemic regions was also higher than that of the controls in the non-endemic regions suggests that early harm by fluorine can be cytogenetically detected in the sub-clinical patients with fluorosis who could not be given an early diagnosis clinically. Under normal circumstances, the incidence rate of micronucleus is very low, usually 0-2%. The normal value checked in this paper is 0-2%, which agrees with that reported in the literature. The results show that the mean value of the micronucleus rate of the fluorine-toxic patients was 1.94 + 0.86% (range 1-15%) which is 2-3 times more than that of 0.57 + 0.44% in the controls… To sum up, the rise of SCE and MN in the peripheral blood lymphocytes of the fluorine-intoxicated patients indicates that fluorine is a mutagenic agent which can cause DNA and chromosomal damage.”[15]

Meng (1995) “Our study here provided evidence that the air pollutants at the phosphate fertilizer factory, of which HF and SiF4 are the main chemicals, could induce SCEs in human blood lymphocytes in vivo. These results imply that even if the concentration of the chemical pollutants in the air is low (e.g.F: 0.50 – 0.80 mg/m3), it may cause damage to genetic material at the chromosomal level, although the general health of the workers in the phosphate fertilizer factory was found to be satisfactory.”[16]

 

[1] Albanese R. (1987). Sodium fluoride and chromosome damage (in vitro human lymphocyte and in vivo micronucleus assays). Mutagenesis 2:497-9.

[2] Caspary WJ, et al (1987). Mutagenic activity of fluorides in mouse lymphoma cells. Mutation Research 187:165-80.

[3] 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 em.... Cancer Research 44:938-41.

[4] 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.

[5] 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.

[6] Greenberg SR. (1982). Leukocyte response in young mice chronically exposed to fluoride. Fluoride 15: 119-123.

[7] achimczak D, Skotarczak B. (1978). The effect of fluorine and lead ions on the chromosomes of human leucocytes in vitro. Genetica Polonica 19: 353-7.

[8] Mohamed AH. (1977). Cytogenetic effects of hydrogen fluoride gas on maize. Fluoride 10: 157-164.

[9] Gerdes RA, et al. (1971). The effects of atmospheric hydrogen fluoride upon Drosophila melanogaster. II. Fecundity, hatchabili... and fertility. Atmospheric Environment 5:117-122.

[10] Gerdes RA. (1971). The influence of atmospheric hydrogen fluoride on the frequency of sex-linked recessive lethals and ... Drosophila Melanogaster. Fluoride 4: 25-29.

[11] Mohamed AH. (1970). Chromosomal changes in maize induced by hydrogen fluoride gas. Canadian Journal of Genetics and Cytology 12: 614-620.

[12] Wu DQ, Wu Y. (1995). Micronucleus and sister chromatid exchange frequency in endemic fluorosis. Fluoride. 28(3):125-127.

[13] Joseph S, Gadhia PK. (2000). Sister chromatid exchange frequency and chromosome aberrations in residents of fluoride endemic regions of South Gujarat. Fluoride 33(4):154-158.

[14] Meng Z, Zhang B. (1997). Chromosomal aberrations and micronuclei in lymphocytes of workers at a phosphate fertilizer factory. Mutation Research 393: 283-288.

[15] Wu DQ, Wu Y. (1995). Micronucleus and Sister Chromatid Exchange Frequency in Endemic Fluorosis. Fluoride 28(3):125-127.

[16] Meng Z, et al. (1995). Sister-chromatid exchanges in lymphocytes of workers at a phosphate fertilizer factory. Mutation Research 334(2):243-6.

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