Carcinogenicity Bioassay of Bisphenol A

Ian C. Munro1, Lois A. Haighton1, Jason J. Hlywka1, Barry S. Lynch1, John Doull2 and Robert Kroes3

1 CANTOX Health Sciences International 2233 Argentia Road, Suite 308 Mississauga, Ontario, Canada L5N 2X7 2 Department of Pharmacology, Toxicology and Therapeutics University of Kansas Medical Center Kansas City, Kansas, USA 66160-7417 3 Institute of Risk Assessment Sciences (IRAS)-Utrecht University Faculty of Veterinary Medicine PO Box 80176, 3508 TD Utrecht, The Netherlands

To the Editor:

In response to the letter by Huff (2001) published in the December issue of Toxicological Sciences, we would like to clarify issues regarding the NTP study of Bisphenol A (BPA). Huff (2001) states that "it appears that BPA exposure via the diet for two years should be considered associated with tumors of the hematopoietic system in rats and mice, and of the testes and of the mammary glands in male rats." We contend that the original conclusion of the NTP (1982), that "under the conditions of this bioassay, there was no convincing evidence that Bisphenol A was carcinogenic for F344 rats or B6C3F1 mice of either sex," remains valid for the following reasons.

First, the incidence of leukemias in high-dose male rats (13/50, 12/50, 23/50 for control, low- and high-dose, respectively), although statistically significant by the Cochran-Armitage test, was not found to be statistically significant when assessed using a life table analysis, which adjusts for inter-group differences in intercurrent mortality. The survival of treated male rats was slightly, although not significantly, greater than controls (23/50, 30/50, 27/50 for control, low- and high-dose, respectively). Furthermore, the values for leukemia incidence were well within the range of historical control data for this strain (10 to 74%) (Haseman et al., 1990Go; 1998). The combined incidences of lymphomas and leukemias in male mice (2/49, 4% for controls; 9/50, 18% for low-dose; 5/50, 10% for high-dose) also were within the range of historical control data for malignant lymphoma in this strain and species (2 to 20%; Haseman et al., 1998Go), and there was no dose-response relationship.

The nonsignificant, but greater, survival among treated male rats compared to controls also likely influenced the incidence rate for interstitial-cell tumors in rats since this tumor type develops relatively late in the life of the F344 rat (incidence rate of 35/49, 48/50, and 46/49 for control, low and high dose, respectively). Thus, given the difference in survival, and the very high spontaneous incidence of this tumor (>90% in the male F344 rat) (Haseman and Elwell, 1996Go), it is our opinion that the NTP was correct in concluding that this response was not treatment related.

Finally, the incidence of fibroadenomas of the mammary gland in the high-dose male rats (0/50, in the controls; 0/50 in the low-dose; and 4/50 in the high-dose group) was not statistically significant compared to the control group using the Fisher exact tests. Furthermore, the incidence was within the historical range of this tumor type in male rats, which was reported to be 4.3% (mean) with a range of 0-12% (Haseman et al., 1998Go).

The NTP conclusion is further supported by the results of a recent comprehensive scientific evaluation of the carcinogenic potential of BPA, that included consideration of epidemiology, experimental animal carcinogenicity/toxicity, metabolism, genotoxicity, and other mechanistic studies, which indicated that BPA is not a carcinogenic risk to humans (Haighton et al.Go, in press). In summary, there is no convincing evidence that BPA is carcinogenic to F344 rats or B6C3F1 mice.

REFERENCES

Haighton, L. A., Hlywka, J. J., Doull, J., Kroes, R., Lynch, B. S., and Munro, I. C. (in press). An evaluation of the possible carcinogenicity of bisphenol A to humans. Regul. Toxicol. Pharmacol.

Haseman, J. K., and Elwell, M. R. (1996). Evaluation of false positive and false negative outcomes in NTP long-term rodent carcinogenicity studies. Risk Anal. 16, 813–820.[ISI][Medline]

Haseman, J. K., Eustis, S. L., and Arnold, J. (1990). Tumor incidences in Fischer 344 rats: NTP historical data. In Pathology of the Fischer RatReference and Atlas (G. A. Boorman, S. L. Eustis, M. R. Elwell, C. A. Montgomery, Jr., and W. F. MacKenzie, Eds.), Chapter 35, pp. 555–564. Academic Press, Inc., San Diego.

Haseman, J. K., Hailey, J. R., and Morris, R. W. (1998). Spontaneous neoplasm incidences in Fischer 344 rats and B6C3F1 mice in two-year carcinogenicity studies: A National Toxicology Program update. Toxicol. Pathol. 26, 428–441.[ISI][Medline]

Huff, J. (2001). >Carcinogenicity bioassays of bisphenol A, 4-vinylcyclohexene diepoxide, and 4-vinylcyclohexene. Toxicol. Sci. 64, 282–284.[Free Full Text]

NTP (1982). NTP Technical Report on the Carcinogenesis Bioassay of Bisphenol A (CAS No. 80–05–7) in F344 rats and B6C3F1 Mice (Feed Study). Tech. Rept. No. TR-215. National Toxicology Program, Research Triangle Park, NC.