- Concerns with NTP Review of Carcinogenicity of Fluoride
Despite criticism, the NTP maintains their assessment of “equivocal evidence.” In 1991, NTP scientists publish a paper which concludes:
“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.”[1]
NTP review comments on page 10, include:
- “Dr. Ashby, the second principal reviewer, agreed with the conclusions. However, he considered the definition for equivocal evidence of carcinogenic activity to be insufficiently precise for male rates. . . .” He suggested: “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.”
- Silbergeld, “pointed out that the doses used were not orders of magnitude above human exposure levels. She supported further research on genotoxicity and on mechanisms of sex differences seen.”
- Gold noted that this was an unusual study in that there was not a zero control group.”
- “There was discussion by Dr. McKnight with Dr. J. Haseman, NIEHS, as to why data from paired (age-matched) controls were not used in primary data tables.
- Zeise “reiterated the need expressed by other Panel members for designing another study with higher top doses. Dr. Zeise noted that the fluoride concentrations in high-dose rats were within the range observed in humans and the differences in pharmacokinetics and deposition of fluoride in bone between humans and animals should be studied.”
- Yiamouyiannis said, “a dose-dependent relationship between fluoride and the number of male rats with oral squamous cell tumors and a dose-dependent relationship between oral squamous cell metaplasia dn tumors in female rats along with the increased incidence of osteosarcomas in male rats supported a finding of clear evidence of carcinogenic activity of fluoride in rats.”
- Those representing dentists and industry objected to the conclusions.
When fluoride damages DNA, is the damaged DNA make the offspring more
susceptible to cancer? With the current research, objection to the NTP study should also be made to the lack of a “life-time” exposure from preconception with parents, throughout life of the offspring. Starting the rats and mice at 5 and 4 weeks of age in the NTP study, did not demonstrate the effects of the fluoride on sperm, egg, fetus, and during a major growth period of their early lives.
Downgrading by NTP of non-bone tumors (liver, oral, and thyroid) found with increased incidence among the fluoride-treated animals is controversial.
Concerns with NTP study: 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.”
Cancer diagnosis upheld: Battelle’s diagnosis of hepatocholangiocarcinoma was upheld by the scientist (Dr. Melvin Reuber) who first identified hepatocholangiocarcinoma as a distinct cancer. As noted by EPA toxicologist Dr. William Marcus:
“Melvin Reuber, M.D., a board certified pathologist and former consultant to EPA and part time EPA employee, reviewed some of [the] pathology slides and the Batelle report. . . . [Reuber] first published the work that identified hepatochangiocarcinoma as a pathologic entity. . . . Dr. Reuber reviewed the pathology slides and stated that these lesions are indeed hepatocholangiocarcinoma.”[2]
Despite Reuber’s concurrence, the NTP ultimately downgraded the hepatocholangiocarcinoma finding. The NTP did so through a two-step process. First, NTP’s “Quality Assurance” pathogist reclassified them as hepatoblastomas (another form of liver cancer). Then, while conducting their statistical analysis, NTP reclassified the hepatoblastomas as hepatocarcinomas – a more common form of tumor. Because there was no significant increase in hepatocarcinomas among the fluoride-treated animals, the NTP concluded that there was no effect.
The NTP has issued the following statements about this analysis:
“During the pathology review procedures several of the tumors diagnosed originally as hepatocholangiocarcinomas were considered more apppropriately callled hepatoblastomas.”[3]
“The study pathologist (Battelle) diagnosed hepatocholangiocarcinomas in one special control female, one low dose male, one low dose female, one medium dose male, three high dose males, and three high dose females. The QA (Quality Assurance) pathologist confirmed the presence of these tumors but felt that most of them were more appropriately diagnosed as hepatoblastomas.”[4]
“The incidences of liver neoplasms in all groups of dosed and control male and female mice were higher than incidences previously seen in NTP studies, but did not appear related to chemical treatment. Several hepatoblastomas and hepatocholangiocarcinomas were diagnosed in male and female mice. Hepatoblastoma and hepatocholangiocarcinoma of mice are phenotypic variants of hepatocellular carcinoma with characteristic cell types and morphologic patterns. The hepatoblastomas contained a cell population which resembled embryonal liver cells as well as neoplastic cells characteristic of a typical hepatocellular carcinoma, whereas the hepatocholangiocarcinomas exhibited both hepatocyte and biliary differentiation. As phenotypic variants of hepatocellular carcinoma, the incidences of these neoplasms were combined with the other hepatocellular neoplasms for analysis. The appearance of these phenotypic variants in dosed animals is unusual, and the biologic significance, if any, is unknown.”[5]
Summary of NTP study by LANCET:
“The original study was directed from 1985 to 1987 by Dr John D. Toft II, manager of the pathology section at Battelle Memorial Institute in Columbus, Ohio. The Battelle study’s principal finding was the occurrence of an extremely rare liver cancer, hepatocholangiocarcinoma, in male and female mice. In 1989, the NTP asked Experimental Pathology Laboratories, of Sterling, Virginia, to review Battelle’s data. At this point, the liver cancer finding, along with a diagnosis of metaplastic and precancerous cells in the mouths of rats, was downgraded.
The only effect of fluoride that was left after these reclassifications and still another review by a board of pathologists and others was osteosarcoma. Dr Marcus believes the Battelle diagnosis of liver cancers was sound and should have been included in the NTP report. This, he says, would change “the (NTP) equivocal finding… to at least some evidence or clear evidence of carcinogenicity”.
NTP’s failure to emphasize another finding also figured in Dr Marcus’ critique. Three out of four in-vitro tests, he says, proved fluoride to be mutagenic, “supporting the conclusion that fluoride is a probable human carcinogen”. A careful reader can find this information in the text of the report, but the authors make no mention of these data in their conclusions.”[6]
Summary of NTP study by C&E News:
“The final report for the study was prepared by the NTP staff, but the testing itself was done by Battelle Columbus Laboratories under contract to NTP. A report prepared by Battelle was audited by a quality assurance contractor, and a separate group of pathologists reviewed the studies. In the process, a number of positive findings in the original Battelle report were downgraded. Slides first diagnosed as showing a rare form of liver cancer called hepatochlolangiocarcinoma were later said to indicate hepatoblastoma, another type of rare malignant lesion, and finally to show the far more common cancer hepatocarcinoma. These hepatocarcinomas were combined with the other hepatocarcinomas found in both treated and control animals, Marcus said. In addition, dose-dependent oral lesions noted in the Battelle report were downgraded from dysplasia and metaplasia to degeneration. Some other liver carcinomas were eventually reclassified as nonmalignant lesions. Because of what he calls systematic downgrading of the slides, Marcus has written a memo to the director of the criteria and standards division in the office of drinking water asking that EPA assemble an independent board of pathologists to review the slides again.[7]
Summary of NTP by Yiamouyiannis:
“In 1977, Congress instructed the U.S. Public Health Service to conduct animal studies to determine whether or not fluoride causes cancer. As a result, the National Toxicology Program retained the Battelle Memorial Institute in Columbus, Ohio to perform two studies, one on mice, and another on rats.
Doctor John T. Toft, II, manager of the Pathology Section at Battelle, was placed in charge of the NTP mouse study. On October 28, 1988, after a year of analyzing these results, Doctor Toft completed the pathology narrative and final report.
The most significant finding was the occurrence of an extremely rare form of liver cancer, hepatocholangiocarcinoma in fluoride-treated male and female rats — mice, excuse me.
Among male mice, no such cancers were observed among 79 in the control group. At 11 parts per million, the lowest dose used, one was observed among 50 male mice; and 45 parts per million, one was observed among 51 male mice and at seventy-nine parts per million three were observed among 80 male mice.
Using historical controls and doing a binomial analysis of this, the odds of these results occurring by chance are less than one in two million. Normally, we consider it significant one in twenty; this is one in two million.
Making these findings even more convincing are the results with female mice. In the control group, no hepatocholangiocarcinomas were observed among eighty. At 11 parts per million, one was observed among 52. At 45 (ppm), none were observed among 50. And at 79 parts per million, three were observed among 80 female mice — female mice.
Based on these findings, and these findings alone, there was clear evidence of the carcinogenic activity of the fluoride in mice receiving 11, 45, or 79 parts per million in drinking water for two years or less.”[8]
PHS confirms risk: The Public Health Service and NCI in 1991 report 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:
“In summary, analysis of incidence data from the SEER program has revealed some age- and sexspecific 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)
Calabrese[9] 1993 was requested by the East Bay Municipal Utility District to conduct an independent appraisal of the 1990 NTP report. He found the NTP’s choice of the word “equivocal” to be confusing, inappropriate and not consistent with what most people would call equivocal, for the following reasons:
- Its own definition of equivocal is in disagreement with the generally accepted definition of equivocal.
- The findings with the male rat clearly exceeded marginal increases and are biologically plausible given the capacity for fluoride to both concentrate and be biologically active in bone.
- The statistical analysis for trend effects is stronger than pair-wise comparisons since it uses all available data not just data from two comparison groups, yet this point is never acknowledged.
- The basic reality is that humans can be exposed in critical target tissues to as much fluoride as the high dose rats while consuming water at the EPA maximum contaminant level of 4 mg/liter.
[1] Bucher JR, et al. (1991). Results and conclusions of the National Toxicology Program’s rodent carcinogenicity studies with sodium fluoride. International Journal of Cancer 48(5):733-7. July 9.
[2] Marcus W. (1990). Memorandum from Dr. William Marcus,to Alan B. Hais, Acting Director Criteria & Standards Division Of... of Drinking Water, US EPA. May 1, 1990.
[3] Bucher J. (1990). Testimony at Board of Scientific Counselors, National Toxicology Program; Peer Review of Draft Techn... Report of Long-Term Toxicology and Carcinogenesis Studies and Toxicity Study, Sodium Fluoride; Research Triangle Park, North Carolina, Thursday, April 26, 1990.
[4] Hamilton BF. (1989). Carcinogenesis bioassay of sodium fluoride with dosed water in B6C3F1 mice: Quality Assessment Narrative. Experimental Pathology Laboratories, Inc. p. 26-27.
[5] Bucher JR, et al. (1991). Results and conclusions of the National Toxicology Program’s rodent carcinogenicity studies with sodium fluoride. International Journal of Cancer 48: 733-737.
[6] Sibbison JB. (1990). USA: More About Fluoride. The Lancet 336(8717): 737. Sept 22.
[7] Hileman B. (1990). Fluoride bioassay study under scrutiny. Chemical & Engineering News September 17
[8] Yiamouyiannis J. (1990). Testimony before Board of Scientific Counselors, National Toxicology Program; Peer Review of Draft Technical Report of Long-Term Toxicology and Carcinogenesis Studies and Toxicity Study, Sodium Fluor...; Research Triangle Park, North Carolina, Thursday, April 26, 1990.
[9] Calabrese, EJ, Lee, JR, Evaluation of the National Toxicology Program (NTP) Cancer Bioassay on Sodium Fluoride, Fluoride 26
(1) 1993 Accessed 4/25/15 http://www.fluorideresearch.org/261/files/FJ1993_v26_n1_p001-078.pdf
[10] Maurer JK, et al. 1990. Two-year carcinogenicity study of sodium fluoride in rats. Journal of the National Cancer Institute 82(13): 1118-26. July 4.
