Age-specific fluoride exposure in drinking water and osteosarcoma (United States).
Bassin EB, Wypij D, Davis RB, Mittleman MA. Cancer Causes Control. 2006 May;17(4):421-8.
Objective: We explored age-specific and gender-specific effects of fluoride level in drinking water and the incidence of osteosarcoma.
Methods: We used data from a matched case–control study conducted through 11 hospitals in the United States that included a complete residential history for each patient and type of drinking water (public, private well, bottled) used at each address. Our analysis was limited to cases less than 20 years old. We standardized fluoride exposure estimates based on CDC-recommended target levels that take climate into account. We categorized exposure into three groups (< 30%, 30–99%, >99% of target) and used conditional logistic regression to estimate odds ratios.
Results: Analysis is based on 103 cases under the age of 20 and 215 matched controls. For males, the unadjusted odds ratios for higher exposures were greater than 1.0 at each exposure age, reaching a peak of 4.07 (95% CI 1.43, 11.56) at age 7 years for the highest exposure. Adjusting for potential confounders produced similar results with an adjusted odds ratio for males of 5.46 (95% CI 1.50, 19.90) at age 7 years. This association was not apparent among females.
Conclusions: Our exploratory analysis found an association between fluoride exposure in drinking water during childhood and the incidence of osteosarcoma among males but not consistently among females. Further research is required to confirm or refute this observation.
Special risk to young males
“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. Also, osteosarcoma, for the ages we considered, generally originates in the metaphyseal areas of long bones and the pattern of the blood supply to the metaphyses and epiphyses, where growth of long bones takes place, differs from that of the diaphyses because of the special circulation to the epiphyseal growth plate in the young which in turn disappears when growth is complete.
“Lastly, the amount of fluoride present in bone depends on gender and intake, and intake, on average,
is greater for males than females for all ages over 1 year.”
Confirmation of previous fluoride-osteosarcoma studies
“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.”
“Our results are consistent with a pattern seen in the National Toxicology Program (NTP) animal study and two ecological studies. The NTP animal study, which reported ‘‘equivocal evidence’’ for an association between fluoride and osteosarcoma, found a positive association for male rats, but no association for female rats or mice of either gender.
“Using data from the Surveillance, Epidemiology and End Results (SEER), Hoover et al. found an unexplained increase in osteosarcoma in males less than 20 years of age in fluoridated versus non-fluoridated areas.”
“A similar, but smaller study examining osteosarcoma in New Jersey also showed an increase in incidence rates for males less than 20 years old who lived in fluoridated areas compared to those living in non-fluoridated areas.”
Age-specific window of exposure critical to detection of osteosarcoma connection
“The evaluation of age-specific effects distinguishes our study from the other investigations. Rothman  has warned that failure to identify the appropriate time window for exposure may result in misclassification which can adversely affect the ability to detect an association. This might explain why the study by Gelberg et al. did not find an association between fluoride in drinking water and osteosarcoma since age-specific effects were not evaluated.”