Fluoride Action Network

home // Researchers // The National Toxicology Program // NTP 1990 Cancer Study: Osteosarcoma

The National Toxicology Program

This section is dedicated to the National Toxicology Program’s (NTP) long involvement with the issue of fluoride's toxicity. The NTP is the scientific research arm for U.S. regulatory agencies. It comes under the aegis of the National Institute of Environmental Health Sciences (NIEHS). The NIEHS, in turn, comes under the umbrella of the National Institutes of Health (NIH). -Updated May 2, 2023 (EC).

NTP 1990 Cancer Study: Osteosarcoma

J. William Hirzy, PhD, a senior risk assessor at the U.S Environmental Protection Agency, gave a presentation that outlined the role of Congress and the background of this time period at the Second Citizens’ Conference on Fluoride in 2006. He noted,

… In 1952 and again in 1957 Congress convened hearings on the rapidly developing national program of promoting water fluoridation, noting deficiencies in the research reported by the Public Health Service as part of that agency’s promotional efforts. Thus over a period of 25 years the Congress held four sets of hearings – about one every six years.

In 1977, the U.S. Congress requested that animal studies be conducted to determine if fluoride can cause cancer. The result of the Congressional request was an extensive animal study conducted in the 1980s by the National Toxicology Program (NTP) and published in 1990.

The principal finding of NTP’s study, performed by Battelle Columbus Laboratories, was a dose-dependent increase in osteosarcoma (bone cancer) among the fluoride-treated male rats.

However, despite the fact that

1) the cancer occurred in the target organ (bone) for fluoride accumulation,
2) the increase in bone cancer was statistically-significant,
3) the doses of fluoride were low for an animal cancer study, and
4) NTP acknowledged it is “biologically plausible” that fluoride could induce bone cancer,

the NTP ruled that the study only provided “equivocal evidence” that fluoride was the cause of the cancer.

According to a 1990 report by Bette Hileman in Chemical & Engineering News: “A number of 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.”

In 2000, Dr. J William Hirzy testified before the U.S. Senate’s Subcommittee on Wildlife, Fisheries and Drinking Water on behalf of the EPA’s professional union, NTEU Chapter 280, requesting an independent review of NTP’s cancer bioassay study.

In 2002, the World Health Organization (Fluorides: Environmental Health Criteria 227) advised scientists to take NTP’s finding seriously. According to the WHO: “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.”

In 2005, the Environmental Working Group “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.”

In addition to increased bone cancer, the NTP study also found increases in rare liver cancers, oral cavity cancers and thyroid cancers among the fluoride-treated rats. The NTP ruled, however, that the cancers were not related to the fluoride treatment – despite reaching “statistical significance” in some of NTP’s analyses.

The Dose of Fluoride used by nTP:

“the level of fluoride the low- and mid-dose animals had in their drinking water was within an order of magnitude of what humans are exposed to when drinking water containing the EPA-established maximum level of 4 ppm fluoride. This is almost unheard of in animal bioassays. Usually, animal exposure is four to six orders of magnitude more than what humans receive.”
SOURCE: Hileman B. (1990). Fluoride bioassay study under scrutiny. Chemical & Engineering News September 17.

“it is important to note that the dose range is not, as is sometimes the case, orders of magnitude higher than that encountered in human population, nor is the body burden expressed as concentrations in bone orders of magnitude higher than that found in human populations also ingesting fluoride.”
SOURCE: Silbergeld E. (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. 62-63.

“the difference between the animal study and the human exposures is not nearly as great as typical with synthetic chemicals.”
SOURCE: Gold L. (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. 71.

“I think it’s important to realize that even though the water concentrations were higher than what we see, or what humans are exposed to, the bone concentrations were not.”
SOURCE: Zeise L. (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. 79.

Substance

Daily Dose
(mg/kg/day) 

Maximum Contaminant Level
(mg/L)

Fluoride

7.9

4

Red dye #3

4000

none

Tetrachlorethylene

386

0.005

Chloroform

160

0.100

Benzene

50

0.005

Carbon tetrachloride

47

0.005

Vinyl chloride

1.7

0.002
Data Compiled by Dr. William Marcus, EPA, March 1990.

Osteosarcomas:

Incidence of Osteosarcoma in Fluoride-Treated Male Rats

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).

“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.

Oral Cancers:

“A second potential target site for sodium fluoride when given in drinking water is the upper digestive tract and oral cavity. Squamous cell neoplasms of the oral mucosa (tongue, palate, or gingiva) occurred with marginally increased incidences in dosed males and female rats over the rates in controls. The increased incidences of these neoplasms were not statistically significant when compared with the incidences in concurrent controls; however, the incidences in the high-dose groups were significantly higher than the incidences observed in historical control animals (0.7% male rats; 0.6% female rats).
As with lesions of the bone, a direct comparison with the historical rates for oral cavity neoplasms is not completely accurate because of the increased attention given to the oral cavity and teeth in the sodium fluoride studies compared to previous NTP studies. Rates for oral cavity neoplasms similar to those observed in high-dose male and female rats in the sodium fluoride studies (4%) have been observed twice for males and once for females in the historical control database of 42 dosed feed or water studies. Neoplasms of the oral cavity were observed in control male and female rats in the current studies; one was observed in an age-matched control male rat and one occurred in a control female rat in the main study.
An argument could be made for combining the male and female rat studies for analysis of oral cavity neoplasms because a marginal increase occurred in both groups. An analysis for significance of the combined P values for the logistic regression trend tests for males and female rats resulted in a nonsignificant P value of 0.065.
In contrast to osteosarcomas, for which there are no recognized benign or preneoplastic counterparts (Litvinov and Soloviev, 1973), squamous cell hyperplasias of the oral cavity are considered preneoplastic precursor lesions of squammous cell neoplasms of the oral cavity (Brown and Hardisty, 1990). Squamous cell hyperplasia occurred in no more than one animal in any of the dosed or control groups in the current studies. Thus, based on the absence of statistical significance versus the concurrent controls, the occurrence of these tumors in control animals, and the lack of a dose-related increase in non-neoplastic precursor lesions, it is concluded that there is insufficient evidence to relate tumors of the oral cavity with administration of sodium fluoride to male or female rats. Glattre and Wiese (1979) reported an association between a decrease in human mortality due to oral cavity neoplasia and increasing fluoride content in water over the range of 0 to 0.5 ppm.”
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. 73-74.

Thyroid Cancers:

“Follicular cell neoplasms of the thyroid gland appeared with a marginally increased incidence in high-dose male rats compared with controls. This increase is not statistically significant compared with controls unless control animals from both interim groups (27 and 66 weeks) and the age-matched controls are pooled with the main study control group. If this is done, the logistic regression P value for the trend is 0.027. Thyroid follicular cell neoplasms typically occur with an incidence of 1.2% in historical control animals.Incidences of 6% have previously been observed in untreated control groups for gavage studies. The incidence of these neoplasms in the high-dose groups was 5/90 (5.5%;includes 10 animals from the 66-week interim sacrifice, one of which had a thyroid follicular cell carcinoma). Three of these tumors were adenomas. The incidence of carcinomas did no differ across the dosed groups and the incidence of follicular cell hyperplasia was not increased. No increase in the incidence of these tumors occurred in female rats. Based on these considerations, follicular cell neoplasms of the thyroid are not considered related to sodium fluoride administration.”
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. 74.

Interviews with EPA Scientists About NTP Study:

 

Print Friendly Version of this pagePrint Get a PDF version of this webpagePDF
back to top