Fluoride & Osteosarcoma: A Timeline
As acknowledged by the NTP and most other observers, a fluoride/osteosarcoma connection is biologically plausible. The biological plausibility centers around three facts: 1) Bone is the principal site of fluoride accumulation, particularly during the growth spurts of childhood; 2) Fluoride is a mutagen when present at sufficient concentrations, and 3) Fluoride stimulates the proliferation of bone-forming cells (osteoblasts), which may “increase the risk for some of the dividing cells to become malignant.” (NRC 2006).
A number of studies have failed to detect an association between fluoride and osteosarcoma. None of these studies, however, have looked at the risk of fluoride during specific ages in life. This is important because, in 2001, an age-specific analysis of a national case-control study that previously reported no association between lifelong exposure to fluoridated water and osteosarcoma (Douglass 1995) found that boys consuming fluoridated water during their 6th, 7th, and 8th years of life (the mid childhood growth spurt) had a statistically significant, “remarkably robust,” risk of developing osteosarcoma during their teenage years. (Bassin 2001). Initially published as a PhD dissertation at Harvard, the study was later published in 2006 in the journal Cancer, Causes, and Control. (Bassin 2006).
Although a study in 2011 purported to refute the findings that fluoride causes osteosarcoma (Kim 2011), the study’s methods — by the authors’ own admission — were incapable of assessing the age-specific risk during the critical window period (ages 6 to 8 ) that Bassin identified as the critical risk period from fluoride exposure.
Timeline of Fluoride/Osteosarcoma Research:
1977:
“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:
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:
A) NTP Study
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 fluoride-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.”
“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).
B) NCI Study
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 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. 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 1991)
C) Proctor & Gamble Study
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 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” (Maurer 1990).
“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:
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:
Following NCI’s analysis of national data, the New Jersey Department of Health conducts a study
of osteosarcoma occurrence in Central New Jersey. (Cohn 1992). 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 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.”
1993:
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
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 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.”
1995:
A) New York Study (Gelberg)
A study on a population in New York State reports that
fluoride exposure is not correlated with osteosarcoma. Although
published in the American Journal of Public Health, the study contains a number of surprisingly glaring errors,
uses a questionable method for calculating fluoride exposure from
toothpaste, and fails to address the fact that its own data, when
limited to fluoride exposure from water, shows an elevated risk of
osteosarcoma when comparing those with some exposure to fluoridated
water versus those with no exposure. Although this risk is not
duration-dependent, this doesn’t necessarily mean that the effect is not
real.
B) Harvard Study (Douglass)
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. In a Progress Report
to the NIH, however, Chester Douglass notes that “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. In subsequent correspondence,
Douglass 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.”
Consistent with Douglass’s concern, he never publishes
any of his analyses that found elevated rates of osteosarcoma from
fluoride exposure. Indeed, in all three of Douglass’s public summaries
of his data (in 1995, 1998 & 2002), he states that the study shows fluoridation has either no effect, or a slightly protective effect, on osteosarcoma rates.
1996:
A team of Japanese researchers publish results showing that fluoride is genotoxic to
rat bone. (Mihashi 1996). 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.”
2001:
A doctoral student, Elise Bassin, working with Dr. Chester Douglass
receives her doctorate from the Harvard School of Dental Medicine for a PhD dissertation
that analyzes Douglass’s fluoride/osteosarcoma data (a large,
NIH-funded case control study). 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:
“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.”
2004:
The National Research Council (NRC) begins a review of the safety of
currently allowable levels of fluoride in drinking water. Chester
Douglass submits a summary
of his fluoride/osteosarcoma study to the NRC. In his summary,
Douglass states that his study found no significant association between
fluoridation and osteosarcoma. Although he cites Bassin’s study as one
of 2 supporting references for this summary, Douglass makes no mention
of the fact that Bassin found a statistically significant, 5-to-7-fold
risk of osteosarcoma among boys drinking fluoridated water.
2005:
The Fluoride Action Network (FAN) obtains a copy of Elise Bassin’s
PhD thesis and Douglass’s submission to the NRC. FAN provides these
documents to the Environmental Working Group (EWG) which files a
complaint of scientific misconduct with the National Institute of Health
(NIH). In response to EWG’s complaint, the NIH launches an
investigation. 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.”
The investigation is managed and run by Harvard
University. No one from EWG is contacted during the course of the
investigation, and Chester Douglass is given a draft copy of the
report’s findings several months prior to Harvard issuing a short, one
page press release announcing that Douglass did not “intentionally misrepresent” the research.
2006:
In the wake of allegations that Chester Douglass was suppressing data
suggesting a link between fluoride and osteosarcoma, Dr. Elise Bassin
and several other Harvard scientists publish the findings of Bassin’s
PhD dissertation. As with Bassin’s dissertation (which had been
completed in 2001), the published study 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.”
In the same issue that Bassin publishes this study, Chester Douglass
publishes a letter 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 analysed.
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.”
2011:
Nineteen years after receiving his grant from the NIH to study
fluoride/osteosarcoma, Chester Douglass publishes his first paper on his
fluoride findings. Although Douglass indicated in his 2006 letter that
he would be conducting an age-specific analysis, the published paper
does not do so. Instead, the paper focuses exclusively on the
relationship between bone fluoride content and osteosarcoma — an
analysis incapable of determining age-specific risk. Although the paper
concludes that there is no relationship between bone fluoride content
and osteosarcoma, there are several notable shortcomings in the study’s methods. These shortcomings include:- Douglass’s study was much smaller and weaker than Bassin’s: It had only 20 control subjects under age 30, a fifth the size of Bassin’s sample. For this key age group, Douglass’ study was so small it could provide no reliable conclusions. Even Douglass admitted this serious limitation.
- The controls were much older than the cases: Controls were much older (average = 41 years) than the cases (average = 18 yrs). Since fluoride builds up in bone with age, it is obvious that a 41-year-old will have higher bone-fluoride levels than an 18-year-old. The fact therefore that Douglass did not find higher bone fluoride levels in 18-year-old osteosarcoma patients than 41-year-old non-osteosarcoma patients can hardly be deemed surprising or significant. It is unlikely that Douglass could have adequately compensated for this gross mismatch in age.
2012:
Canadian researchers publish an analysis of water
fluoridation and osteosarcoma rates in children in the United States.
(Levy 2012). The study concludes that water fluoridation in the U.S. is
not associated with an increased risk of osteosarcoma. The authors use a
notably crude measurement for determining fluoride exposure.
Specifically, the authors used the National Cancer Institute’s SEER
data, and limited their analysis to the average fluoridation rate of the
child’s STATE of residence at the time of diagnosis.
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. Also, by focusing on the child’s residence at the
time of diagnosis, the study is incapable of determining the effect of
fluoride intake at the relevant moment in time: namely, the age at which
the osteosarcoma was induced. The study thus sheds little light on
fluoride’s possible relationship to osteosarcoma.
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. [See study]
- 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. [See study]
- 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. [See study]
- Kim FM, et al. (2011). An assessment of bone fluoride and osteosarcoma. Journal of Dental Research 90:1171-76.
- Levy M, Leclerc BS. (2012). Fluoride in drinking water and osteosarcoma incidence rates in the continental United States among children and adolescents. Cancer Epidemiology 36(2):e83-8.
- 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.
- 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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