Fluoride Action Network

Fluoride/Osteosarcoma Link Is Biologically Plausible

Fluoride Action Network | by Michael Connett | Updated April 2015

The “biological plausiblility” of a fluoride-osteosarcoma link is widely acknowledged in the scientific literature. When the connection between a chemical and a cancer is biologically plausible, studies that detect an association between the two are taken more seriously, as the association is less likely to be a random fluke.

As discussed below, the three lines of evidence supporting the plausibility of a fluoride/osteosarcoma connection are:

  1. The preponderance of laboratory evidence indicates fluoride is mutagenic when present at sufficient concentrations. Most mutagens are also carcinogens.
  2. The bone is the principal site for fluoride accumulation in the body, and the rate of accumulation is increased during periods of bone development. Thus, the cells in the bone 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 caused by an abnormal proliferation of the osteoblasts.

In short, 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. The following are some supporting quotes from the literature for each of these three mechanisms:

1) Fluoride Is Mutagenic:

“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.

“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.

2) Bone is the Principal Site of Fluoride Accumulation:

“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 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.

3) Fluoride Increases bone cell division:

“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.

“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.

“[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.