"CONCLUSION: The feeding of sodium fluoride to B6C3F1 mice in their drinking water for 104 weeks at the stated doses resulted in the formation of an infrequently encountered hepatic neoplasm which, for purposes of this study, was diagnosed as hepatocholangiocarcinoma. Two basic morphologic forms were identified; well differentiated and poorly differentiated. Although the total number (10) of these neoplasms was small compared to the more commonly seen hepatocellular carcinomas and adenomas, the fact that only one neoplasm occurred in a control animal, and that six of the ten were found in the high dose animals (equally distributed by sex) suggests a possible dose relationship. No positive dose-relationship, however, was noted among other hepatic neoplasms (adenomas or carcinomas), or among non-neoplastic hepatic changes."
SOURCE: J.D. Toft, II, D.V.M., M.S., Manager, Pathology Section, Battelle Columbus Laboratories. Final Report to National Toxicology Program, October 28, 1988.

"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. Dr. Reuber has had his pathologic diagnoses questioned several times in the past. When an independent board together with Dr. Reuber went over the slides his opinion was always upheld. He first published the work that identified hepatochangiocarcinoma as a pathologic entity. The [NTP] report changed Batelle's board certified veterinary pathologists diagnoses from hepatocholangiocarcinoma to hepatoblastoma and finally to hepatocarcinoma. Dr. Reuber reviewed the pathology slides and stated that these lesions are indeed hepatocholangiocarcinoma. Because Dr. Reuber first identified and published his findings on this tumor, I trust his opinion on the matter. These tumors are rare. Dr. Reuber's diagnoses would make the liver cancers significant because of their rarity. This changes the equivocal finding of the [NTP] board to at least some evidence or clear evidence of carcinogenicity."
SOURCE: Marcus W. (1990). Memorandum from Dr. William Marcus,to Alan B. Hais, Acting Director Criteria & Standards Division ODW, US EPA. May 1, 1990.

"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."
SOURCE: Sibbison JB. (1990). More on fluoride. The Lancet 336: 737.

"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."
SOURCE: 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 Fluoride; Research Triangle Park, North Carolina, Thursday, April 26, 1990.

"During the pathology review procedures several of the tumors diagnosed originally as hepatocholangiocarcinomas were considered more apppropriately callled hepatoblastomas."
SOURCE: Bucher J. (1990). Testimony at Board of Scientific Counselors, National Toxicology Program; 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.

"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... The QA pathologist diagnosed a cholangiocarcinoma in one high dose female instead of hepatocholangiocarcinoma since the tumor was composed predominately of ductular structures in contrast to the other neoplasms already described."
SOURCE: Hamilton BF. (1989). Carcinogenesis bioassay of sodium fluoride with dosed water in B6C3F1 mice: Quality Assessment Narrative. Experimental Pathology Laboratories, Inc. p. 26-27.

"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."
SOURCE: 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.