TIMELINE: Fluoride & Osteosarcoma (Bone Cancer)

DIRECTORY: FAN > Health > Cancer > Osteosarcoma

TIMELINE - Fluoride & Osteosarcoma:

1977: US Congress requests National Toxicology Program (NTP) to conduct animal study to determine if fluoride causes cancer.

1977: National Academy of Sciences expresses concern about possible link between water fluoridation and osteosarcoma in young males.

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. To quote:
"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)

1989: NTP informs EPA that a preliminary review of the long-awaited government study on fluoride/cancer, indicates an increase in bone cancer among fluoride-treated male rats.

In December of 1989, the MEDICAL TRIBUNE reveals that a preliminary review of NTP's cancer bioassay indicates an increase in bone cancer among the fluoride-treated rats. According to John Sullivan, a representative for the American Water Works Association, "If fluoride turns out to be a carcinogen, it will be the environmental story of the century."

1990: NTP confirms dose-dependent increase in osteosarcoma among male rats.
While controversy begins to surface about a "systematic downgrading" by NTP of non-bone tumors (liver, oral, and thyroid) found with increased incidence among the treated animals, the NTP upholds and confirms the dose-dependent increase in osteosarcoma among male rats.

However, the NTP rules that the statistically-significant, dose-dependent increase of cancer in the target organ (bone) for fluoride accumulation, only provides "equivocal evidence" - versus "some evidence" or "clear evidence" - that fluoride is a carcinogen. According to NTP, "Equivocal evidence of carcinogenic activity is demonstrated by studies that are interpreted as showing a marginal increase of neoplasms that may be chemically related."

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."

Despite criticism, the NTP maintains their assessment of "equivocal evidence." In 1991, NTP scientists publish a paper on the study's findings. They state:

"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." (Bucher 1991).

Incidence of Osteosarcoma in Fluoride-Treated Male Rats
- NTP 1990 -

Group of Rats (ppm F in water)

No. of Rats with Osteosarcoma
% of Rats wtih Osteosarcoma
Control Group
(0 ppm)
Low Dose Group
(11 ppm)
Mid Dose Group
(45 ppm)
High Dose Group
(79 ppm)
* Osteosarcoma incidence (in parantheses) in high-dose group indicates the number of osteosarcomas when including the extraskeletal "subcutaneous" osteosarcoma. With and without the extraskeletal osteosarcoma, the dose response trend is statistically significant. P value = 0.027 (without extraskeletal osteosarcoma) and 0.01 (with extraskeletal osteosarcoma).

1990: National Cancer Institute finds osteosarcoma rates in young males to be higher in fluoridated vs unfluoridated areas.

In light of the concern raised by NTP's animal study, the National Cancer Institute (NCI) looks through its National Cancer Registry data to determine if osteosarcoma rates are higher in fluoridated communities. In a report released by the Public Health Service in 1991, the NCI reveals that the incidence of osteosarcoma throughout the U.S. has increased at a greater rate among young boys in fluoridated areas vs. unfluoridated areas. The NCI's analysis covers the years 1973-1987. (See study)

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. To quote:
"In summary, analysis of incidence data from the SEER program has revealed some age- and sex-specific 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 1990)

1990: In response to NTP's findings, Procter & Gamble publishes rat study on fluoride and cancer.

In the spring of 1990, with the NTP's findings attracting media attention, Procter & Gamble, a manufacturer of fluoridated toothpaste, releases the findings of its own rat study of fluoride and cancer (which the company 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 were thereby dismissed as random. According to Procter & Gamble's 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" (Maurer 1990).

Later, in 1991, the FDA publishes an independent review of Procter & Gamble's rat study.

In their analysis, the FDA identify 2 additional osteosarcomas in the fluoride-treated rats which were not identified in Procter & Gamble's published report. According to the FDA:
"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).
However, even with the newly identified osteosarcomas, 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.

1991: FDA reviews Procter & Gamble's mouse study and reports increase in benign bone tumors among fluoride-treated mice.

In addition to reviewing Procter & Gamble's rat study (see above), the FDA also reviews Procter & Gamble's mouse study (Maurer 1993).

The FDA notes that, among both sexes of the fluoride-treated mice, there is a very significant, dose-dependent increase in benign bone tumors (osteomas), although no occurrence of osteosarcomas. While the occurrence of the osteomas is believed to be related to the presence of a virus in the mice, the FDA makes it clear that if the virus played a role, it did so in conjunction with the fluoride. To quote:
"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."
Nevertheless, the FDA rules that Procter & Gamble's mouse study - in light of the absence of malignant tumors - "do not add to the concerns raised by the NTP rat study."

1992: New Jersey Department of Health study shows osteosarcoma rates are higher among young males in fluoridated vs unfluoridated regions of Central New Jersey.

Following NCI's analysis of national data, the New Jersey Department of Health conducts a study of osteosarcoma occurrence in Central New Jersey. The study finds a statistically significant relationship between fluoridation and osteosarcoma among males less than 20 years old (See study).

"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 fluoridatiuon at the municipal level with the municpal 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." (Cohn 1992)

1993: Independent analysis of National Cancer Institute's cancer data confirms fluoridation/osteosarcoma link in males.

Dr. John Yiamouyiannis, the biochemist whose research on fluoridation/cancer in the 1970s led to Congress' request for animal studies on fluoride/cancer, analyzes the National Cancer Institute's data in addition to two other databases containing fluoride exposure/osteosarcoma information. Like NCI's investigators (Hoover 1990), 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 1) 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; 2) 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 3) 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." (Yiamouyiannis 1993).

1995: Preliminary analysis of national case control study published.

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. However, in a follow-up, age-specific analysis of this data, a very strong, statistically significant relationship is found between water fluoridation and osteosarcoma in young males. (See 2001 and 2006).

1996: Japanese researchers report that fluoride is genotoxic to rat bone.

A team of Japanese researchers publish results showing that fluoride is genotoxic to rat bone. The authors note that the fluoride-induced genotoxicity in bone reinforce the biologic plausibility of a fluoride-osteosarcoma connectioin. (Many compounds that cause genotoxicity also cause cancer). 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" (Mihashi 1996).

2001: Harvard Case-Control Study Finds Strong Correlation between Fluoridation and Osteosarcoma in Boys:

A PhD Dissertation from the Harvard School of Dental Medicine analyzes data from a large case control study of fluoride and osteosarcoma (Bassin 2001). The author, Elise Bassin, finds a very strong, statistically-significant relationship (OR = 7.2) between consumption of fluoridated water during the mid-childhood growth spurt (ages 6-8) and osteosarcoma among boys less than 20 years old. To quote:

"Among males, exposure to fluoride at or above the target level was associated with an increased risk of developing osteosarcoma. The association was most apparent between ages 5-10 with a peak at six to eight years of age.. [T]he results continue to demonstrate an effect after adjusting by zipcode, county population, ever use of bottled or well water, age, and any use of self-administered fluoride products. For males, the odds ratio for the high exposure group was 7.20 at 7 years of age with a 95 percent confidence interval of 1.73 to 30.01... All of our models are remarkably robust in showing this effect during the mid-childhood growth spurt, which, for boys, occurs at ages seven and eight years. For females, no clear association between fluoride in drinking water during growth and osteosarcoma is shown in this study... Our results are consistent with findings from the National Toxicology Program animal study which found 'equivocal evidence' for an association between fluoride and osteosarcoma for male, but not female, rats and from two ecological studies that found an association for males less than twenty years old (Hoover et al., 1991; Cohn 1992)."

2005: ENVIRONMENTAL WORKING GROUP Petitions NTP to Re-evaluate Fluoride's Cancer-Causing Potential:

'Citing a strong body of peer-reviewed evidence, the Environmental Working Group (EWG) asked the National Toxicology Program (NTP) of the National Institutes of Health (NIH) to list fluoride in tap water in its authoritative Report on Carcinogens, based on its ability to cause a rare form of childhood bone cancer, osteosarcoma, in boys. The Report on Carcinogens lists only substances that are known or reasonably anticipated to cause cancer in humans.' Read more...

2005: Harvard Dental Professor Charged with Scientific Misconduct for Misrepresenting Findings on Fluoride/Osteosarcoma:

According to the Washington Post (7/13/05):

"Federal investigators and Harvard University officials are probing whether a Harvard professor buried research suggesting a link between fluoridated tap water and bone cancer in adolescent boys.

The National Institute of Environmental Health Sciences (NIEHS), which funded Chester Douglass's $1.3 million study, and the university are investigating why the Harvard School of Dental Medicine epidemiologist told federal officials he found no significant correlation between fluoridated water and osteosarcoma, a rare form of bone cancer. Douglass, who serves as editor in chief for the industry-funded Colgate Oral Care Report, supervised research for a 2001 doctoral thesis that concluded boys exposed to fluoridated water at a young age were more likely to get the cancer.

The Environmental Working Group, an advocacy organization, urged federal officials late last month to explore whether Douglass had skewed his 2004 report to the institute to play down possible risks associated with fluoridation.

2006: Harvard Case-Control Study Published:

A team of Harvard University scientists, led by Dr. Elise Bassin, publish a study which reports a five-fold increased risk of developing osteosarcoma among teenage boys exposed to fluoridated water at ages 6, 7, and 8. The study is an extension of an analysis first completed by Bassin as a Harvard PhD thesis in 2001. However, her thesis adviser, Dr. Chester Douglass (a consultant to Colgate), was charged in 2005 by the Environmental Working Group of withholding and misrepresenting these findings to the public and scientific community.

According to Bassin:

"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." (Bassin 2006)

References - Timeline:

Bassin EB, Wypij D, Davis RB, Mittleman MA. (2006). Age-specific Fluoride Exposure in Drinking Water and Osteosarcoma (United States). Cancer Causes and Control 17: 421-8.

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.

Bucher J.R., Heitmancik M.R., Toft J., Persing R.L. Eustis S.L. Haseman J.K. (1991). Results and conclusions of the National Toxicology Program's rodent carcinogenicity studies with sodium fluoride. International Journal of Cancer 48(5):733-7.

Cohn P.D. (1992). A Brief Report On The Association Of Drinking Water Fluoridation And The Incidence of Osteosarcoma Among Young Males. New Jersey Department of Health and Environmental Health Services.

Food & Drug Administration (FDA). (1991). Dose determination and carcinogenicity studies of sodium fluoride in Crl:CD-1 Mice and Crl:CD (Sprague Dawley)BR Rats. In: Department of Health & Human Services. (U.S. DHHS) (1991). Review of Fluoride: Benefits and Risks. Report of the Ad Hoc Committee on Fluoride, Committee to Coordinate Environmental Health and Related Programs. Department of Health and Human Services, USA. pp. D1-D7.

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 Results (SEER) Program. 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. Appendix E and Appendix F.

Maurer JK, Cheng MC, Boysen BG, Anderson RL. (1990). Two-year carcinogenicity study of sodium fluoride in rats. Journal of the National Cancer Institute 82: 1118-26.

Maurer JK, et al. (1993). Confounded carcinogenicity study of sodium fluoride in CD-1 mice. Regulatory Toxicology and Pharmacology 18:154-68.

McGuire S.M., Douglass C.W., Joshi A., Hunter D., DaSilva J. (1995). Fluoride exposure and osteosarcoma. [Abstract] Journal of Dental Research 74:98.

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

National Academy of Sciences (1977). Drinking Water and Health. National Academy Press, Washington, DC. pp. 388-389.

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.

Takahashi K., Akiniwa K., Narita K. (2001). Regression analysis of cancer incidence rates and water fluoride in the U.S.A. based on IACR/IARC (WHO) data (1978-1992). International Agency for Research on Cancer. Journal of Epidemiology 11(4):170-9.

World Health Organization (2002). Environmental Health Criteria 227: FLUORIDES. World Health Organization, Geneva.

Yiamouyiannis J. (1993). Fluoridation and Cancer: The Biology and Epidemiology of Bone and Oral Cancer Related to Fluoridation. Fluoride 26: 83-96.

References: Studies Reporting No Relationship between Fluoride & Osteosarcoma:

For a review and critique of the following studies, click here

Freni S.C., Gaylor, D.W. (1992). International trends in the incidence of bone cancer are not related to drinking water fluoridation. Cancer 70: 611-8.

Gelberg K.H., Fitzgerald E.F., Hwang S., Dubrow R. (1995). Fluoride exposure and childhood osteosarcoma: a case-control study. American Journal of Public Health 85:1678-83.

Hrudey S.E., Soskolne C.L., Berkel J., Fincham S. (1990). Drinking water fluoridation and osteosarcoma. Canadian Journal of Public Health 81(6):415-6.

Mahoney M.C., Nasca P.C., Burnett W.S., Meius J.M. (1991). Bone cancer incidence rates in New York State: time trends and fluoridated drinking water. American Journal of Public Health 81: 475-9.

McGuire S.M., Vanable E.D., McGuire M.H., Buckwalter J.A., Douglass C.W. (1991). Is there a link between fluoridated water and osteosarcoma? Journal of the American Dental Association 122:38-45.

Moss M.E., Kanarek M.S., Anderson H.A., Hanrahan L.P., Remington P.L. (1995). Osteosarcoma, seasonality, and environmental factors in Wisconsin, 1979-1989. Archives of Environmental Health 50:235-41.

Operskalski E.A., et al. (1987). A case-control study of osteosarcoma in young persons. American Journal of Epidemiology 126:118-26.











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