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HEALTH EFFECTS:
Fluoride & Osteosarcoma (Bone Cancer)
DIRECTORY: FAN
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Cancer >
Osteosarcoma
Summation
- Fluoride
& Osteosarcoma (Bone Cancer):
Taken together as a whole, the evidence - laboratory,
animal, and human
- suggests that fluoride could either directly initiate, or
contribute to, the development of osteosarcoma in boys under
the age of 20.
Fluoride
& Osteosarcoma
- Biological
Plausibility: (back
to top)
The "biological plausiblility" of
a fluoride-osteosarcoma link is acknowledged in the scientific
literature. The 3 key, acknowledged mechanisms supporting the
plausibility of a fluoride/osteosarcoma connection are:
1) The preponderance of laboratory evidence indicates that
fluoride can be mutagenic when
present at sufficient concentrations. Most mutagens are also
carcinogens.
2) The bone is the principal site for fluoride accumulation
within the body, and the rate of accumulation is increased
during periods of bone development. Thus, the cells in the
bone, particularly during the growth spurts, may be exposed
to some of the highest fluoride concentrations in the body.
3) Fluoride is a 'mitogen' - meaning it can stimulate the proliferation
of bone-forming cells (osteoblasts). Osteosarcoma is a cancer
caued by an abnormal proliferation of the osteoblasts.
Hence, fluoride's ability to induce mutagenic
damage in fluoride-rich environments coupled wtih its ability
to stimulate proliferation of osteoblasts provides a compelling
biological basis by which fluoride could cause, or contribute
to, osteosarcoma.
Here are some supporting quotes from the literature:
“Osteosarcoma presents the greatest
a priori plausibility as a potential cancer target site because
of fluoride’s deposition in bone, the NTP animal study
findings of borderline increased osteosarcomas in male rats,
and the known mitogenic effect of fluoride on bone cells in
culture. Principles of cell biology indicate that stimuli
for rapid cell division increase the risks for some of the
dividing cells to become malignant, either by inducing random
transforming events or by unmasking malignant cells that previously
were in nondividing states.”
SOURCE: National Research Council.
(2006). Fluoride
in Drinking Water: A Scientific Review of EPA's Standards.
National Academies Press, Washington D.C. p 275.
" It is biologically plausible that
fluoride affects the incidence rate of osteosarcoma, and that
this effect would be strongest during periods of growth, particularly
in males. First, approximately 99% of fluoride in the
human body is contained in the skeleton with about 50% of
the daily ingested fluoride being deposited directly into
calcified tissue (bone or dentition). Second, fluoride acts
as a mitogen, increasing the proliferation of osteoblasts
and its uptake in bone increases during periods of rapid skeletal
growth. In the young, the hydroxyapatite structure of bone
mineral exists as many extremely small crystals each surrounded
by an ion-rich hydration shell, providing a greater surface
area for fluoride exchange to occur."
SOURCE: 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.
"if fluoride were to exert a neoplastic effect, it is
reasonable to expect that this might be expressed in a tissue
that accumulates fluoride. This would include bone, and,
therefore, there is biological plausibility
for an association between sodium fluoride administration
and the development of bone osteosarcomas."
SOURCE: National Toxicology Program [NTP] (1990). Toxicology
and Carcinogenesis Studies of Sodium Fluoride in F344/N Rats
and B6C3f1 Mice. Technical
report Series No. 393. NIH Publ. No 91-2848. National Institute
of Environmental Health Sciences, Research Triangle Park,
N.C.
"it would appear
that sodium fluoride is genotoxic
in a number of genetic toxicity assays, through as
yet undetermined mechanisms. So, a neoplastic
effect in a tissue that accumulates fluoride would appear
possible."
SOURCE: Bucher J. (1990). Peer
Review of Draft Technical Report of Long-Term Toxicology and
Carcinogenesis Studies and Toxicity Study, Sodium Fluoride;
Research Triangle Park, North Carolina, Thursday, April 26,
1990. p. 30-31.
"[T]he carcinogenicity of fluoride is consistent with
growth stimulation of osteoblasts, unscheduled DNA synthesis
by human fibroblasts, and transformation of embryonal hamster
fibroblasts into transplantable sarcoma cells. Osteoblasts are
differentiated fibroblasts, and fluoride is accumulated in the
skeleton. Therefore, osteosarcoma would be
the natural target effect to look for in a cancer bioassay of
fluoride, and an excess of osteosarcoma in rats exposed to fluoride
in drinking water clearly confirms an a priori hypothesis."
SOURCE: 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.
"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."
SOURCE: Gelberg KH. (1994). Case-control
study of osteosarcoma. Doctoral
Thesis, Yale University. p. 13.
“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."
SOURCE: Mihashi M, Tsutsui T. (1996). Clastogenic
activity of sodium fluoride to rat vertebral body-derived
cells in culture. Mutation
Research 368:7-13.
Fluoride &
Osteosarcoma
- National
Toxicology Program
(1990) : (back
to top)
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) |
0/80 |
0% |
| Low Dose Group
(11 ppm) |
0/51 |
0% |
| Mid Dose Group
(45 ppm) |
1/50 |
2% |
High Dose Group
(79 ppm) |
3/80
(4/80)* |
4%
(5%)* |
| * 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). |
"Osteosarcomas of the bone were observed
in 3/80 (4%) high-dose and in 1/50 (2%) mid-dose male rats.
An additional osteosarcoma, which was determined to be of
subcutaneous origin, was observed in a fourth high-dose rat.
No osteosarcomas were seen in controls or in male rats receiving
25 ppm. The neoplasms were clearly malignant (one metastasized
to the lung) and there was complete agreement concerning
the diagnoses at both the Quality Assessment and the Pathology
Working Group stages of histopathology review...
Osteosarcomas (in bone or extraskeletal)
are not commonly observed in control male rats in NTP studies.
The historical incidence in control male rats from dosed feed
or water studies is 10/2,106 (0.47%)...
The four osteosarcomas of bone (one in
the mid-dose and three in the high-dose groups) in the current
studies occurred with a statistically significant dose-response
trend by the logistic regression test (P=0.027); the
pairwise comparison of the incidence in the high-dose group
versus that in controls was no statistically significant (P=0.099).
The statistical significance of the trend
test is increased (P=0.010) when the subcutaneous osteosarcoma
in the fourth high-dose rat is included in the incidence,
but the pairwise comparison remains not significant (P=0.057).
The incidence of bone osteosarcomas
of 3/80 and the incidence of all osteosarcomas of 4/80 in
the high-dose male rats are both significantly greater than
the rate of 0.6% for osteosarcomas and osteomas at all sites
in control male rats in the historical database...
To summarize these considerations,
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."
SOURCE: National Toxicology Program
[NTP] (1990). Toxicology and Carcinogenesis Studies of Sodium
Fluoride in F344/N Rats and B6C3f1 Mice. Technical report
Series No. 393. NIH Publ. No 91-2848. National Institute of
Environmental Health Sciences, Research Triangle Park, N.C.
p. 71-73.
World Health Organization
Review of NTP's Findings-
Fluoride & Osteosarcoma: (back
to top)
"Such a (dose-dependent) trend associated
with the occurrence of a rare tumour in the tissue in which
fluoride is known to accumulate cannot be casually dismissed."
SOURCE: World Health Organization.
(2002). Environmental Health Criteria 227: FLUORIDES. World
Health Organization, Geneva.
Fluoride
& Osteosarcoma
- National
Cancer Institute
(Hoover 1990) : (back
to top)
"At the request of the Committee, we
have enclosed a brief description of the
time trends for bone and joint
cancers and for osteosarcomas in the Surveillance, Epidemiology
and End Results (SEER) Program of the National Cancer Institute
(NCI), and the relationship of these trends to fluoridation
of drinking water supplies. The SEER Program,
begun in 1973, is a group of population-based cancer registries
that covers approximately 10% of the U.S. population...
Table 1 presents the data for the entire SEER program split
into 2 time periods (1973-80 and 1981-87). The incidence of
all bone and joint cancers over all ages increased slightly
between these two periods. When examined by age, the only
increase occurred for the rates among those under age 20,
where an 18% rise occurred for the sexes combined, reflecting
a 23% rise in males and a 13% rise in females. When osteosarcomas
are considered separately, there was essentially no change
in the incidence rate over time for the sexes combined, reflecting
the averaging of an 18% rise for males and an 11% decline
among females. Among males, the upward trend resulted mainly
from the experience of those under age 20, whose rates rose
from 0.36 to 0.55 (53%).
It was possible to evaluate these same trends for groupings
of counties within the SEER areas that were "non-fluoridated"
as well as for those undergoing abrupt fluoridation at some
time before the establishment of the SEER program... As shown
in Table 2, the pattern for the entire SEER
program of a rising rate of bone and joint cancers at all ages
combined, due mainly to trends under age 20, was seen in the
"fluoridated" counties but not in the "non-fluoridated"
counties. Tables 3 and 4 are restricted to the patterns
among males. Once again, the larger increase
in males under age 20 seen in the aggregate data for all bone
and joint cancers is seen only in the "fluoridated"
counties. For osteosarcomas among males, increases were seen
for those under age 20 in both the "fluoridated" and
"non-fluoridated" areas, although more prominently
in the "fluoridated" counties.
Based on these data, one could conclude that summarized over
all ages and both sexes, there were no meaningful time trendsd
in incidence of these tumors. However, for bone and joint
cancers, temporal increases were seen among those under age
20 in both sexes. For osteosarcomas, there
were some increases, but only among young males. In
addition, these patterns were associated
with the fluoridation status of the counties for which these
trends were assessed...
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."
SOURCE: Hoover RN, et al. (1990). Time
trends for bone and joint cancers and osteosarcomas in the
Surveillance, Epidemiology and End
Results (SEER) Program. National
Cancer Institute. In: DHHS (1991). Review of Fluoride Benefits
and Risks. US Public Health Service. pp. F1-F7. (***See
pdf file of full report***)
Fluoride &
Osteosarcoma
- New Jersey
Department of Health Study (Cohn 1992):
(back to
top)
"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."
SOURCE: Cohn PD. (1992). A
Brief Report On The Association Of Drinking Water Fluoridation
And The Incidence of Osteosarcoma Among Young Males.
New Jersey Department of Health: Environmental Health Service:
1- 17. (***See pdf file of full report***)
Fluoride
& Osteosarcoma
- Analysis
of National Cancer
Instiute's National Data & New Jersey Health Department's
Data (Yiamouyiannis 1993): (back
to top)
"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."
SOURCE: Yiamouyiannis JA. (1993). Fluoridation and cancer:
The biology and epidemiology of bone and oral cancer related
to fluoridation. Fluoride
26:83-96
Fluoride
& Osteosarcoma
- Analysis
of National Cancer
Data from U.S. during the years 1978-1992 (Takahashi 2001):
(back
to top)
"Age-specific and age-standardized rates
(ASR) of registered cancers for nine communities in the U.S.A.
(21.8 million inhabitants, mainly white) were obtained from
IARC data (1978-82, 1983-87, 1988-92)... The
incidence rate of bone cancer as the mean of three five-years
ASRs was significantly correlated with FD (fluoridated water)
only in males, with CIR-100 of 1.22, whereas in 1978-82 it showed
a high CIR-100 of 2.53
SOURCE: 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 11:170-9.
Fluoride &
Osteosarcoma
- Report
from Japanese Research Team (Mihashi 1996):
(back to
top)
"Significant
increases in the frequencies of chromosome
aberrations were induced in a dose- and treatment
time-dependent fashion when NaF was administered to [rat
vertebral bone] cells at 0.5 and
1.0 mM for 24 and 48 h. The results
indicate that NaF is genotoxic to rat vertebrae, providing
a possible mechanism for the vertebrae, as a target organ
of NaF carcinogenesis."
SOURCE: Mihashi M, Tsutsui
T. (1996). Clastogenic activity of sodium fluoride to
rat vertebral body-derived cells in culture. Mutation
Research 368:7-13.
Fluoride
& Osteosarcoma
- Harvard
Case-Control Study (2006):
(back
to top)
"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."
SOURCE: 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.
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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