Reply

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 L5N 2X7, Canada 2 Department of Pharmacology, Toxicology, and Therapeutics University of Kansas Medical Center Kansas City, Kansas 66160–7417 3 Institute of Risk Assessment Sciences (IRAS)-Utrecht University Faculty of Veterinary Medicine P.O. Box 80176 Utrecht 3508 TD, The Netherlands

To the Editor:

The issue of carcinogenicity of bisphenol A was discussed in previous letters to the editor (Huff, 2001Go; Munro et al., 2002Go). In his letter revisiting the subject, we note that Huff (2002)Go does not present any new information that was not previously addressed. As we have already commented on the NTP findings in our earlier letter (Munro et al., 2002Go), we have chosen to present additional information in support of our findings with regard to the lack of carcinogenic potential of bisphenol A. However, we would first like to indicate that our original response (Munro et al., 2002Go) was not meant to personally challenge Huff (2001)Go but merely to point out the final concluding statement of the NTP (1982)Go report on BPA that specifies 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." The discussion of the NTP report does state, as indicated by Huff (2001Go, 2002)Go:

When the marginally significant increase of leukemias in male rats and the combined incidence of lymphomas and leukemias in male mice are considered along with the increase in leukemia incidence (not significant) in female rats, the evidence is suggestive of a carcinogenic effect on the hematopoietic system.

However, the NTP (1982)Go prefaces that statement with the following:

Leukemias in male rats occurred at an incidence that showed a statistically significant positive association with the dose of bisphenol A. Although the incidence in high-dose male rats appeared to be statistically significant (p = 0.030), it did not meet the Bonferroni inequality criterion of p = 0.025 for comparing the dosed groups with a common control. The incidence of leukemias was also increased in female rats, but the observed increases were not statistically significant. Life table analyses, adjusted for intercurrent mortality, were also carried out for the leukemia data. It was found that, for male rats, neither the high-dose effect nor the dose-response trend was statistically significant (p = 0.141 and p = 0.074). The female rats likewise showed no significant effects. The increased incidence of leukemia in rats was therefore not considered to be convincing evidence of carcinogenicity in rats.

Consistent with our own review (Haighton et al., 2002Go) and earlier response (Munro et al., 2002Go), we would like to point out the concurring opinion of the European Commission’s Scientific Committee on Food concerning bisphenol A with regard to carcinogenicity and genotoxicity, which was recently made public (SCF, 2002Go). The SCF states that "there was no evidence of substance-related carcinogenicity in 2-year rat and mouse bioassays using dietary administration (NTP, 1982Go). A similar conclusion was reached in other recent reviews" (the SCF cites the German Chemical Society, 1997Go; Dutch Expert Committee on Occupational Standards, 1996Go; Veenstra and Webb, 1999Go; and EU, 2001Go). The SCF (2002)Go also states that:

BPA has been tested extensively for genotoxicity, both in vitro and in vivo. The majority of in vitro studies, which included tests for gene mutations in bacteria, chromosomal aberrations in cultured mammalian cells and gene mutations in cultured mammalian cells, were clearly negative, with a few producing equivocal results that were not replicated in other studies using the same test system. In vivo studies, including a mouse micronucleus test conducted to modern standards and a rat dominant lethal study, were negative. Low levels of DNA adduct formation were observed in vitro and in vivo but the covalent binding index was only 0.01. In vitro tests for aneuploidy were positive at doses close to or causing cytotoxicity, but the absence of micronuclei in the in vivo mouse micronucleus test provides some reassurance that the aneugenic potential observed in vitro is not expressed in vivo. Recent extensive reviews have all concluded that BPA is non-genotoxic in vivo (German Chemical Society, 1997Go; Dutch Expert Committee on Occupational Standards, 1996Go; Veenstra and Webb, 1999Go; EU, 2001Go).

Likewise, the Scientific Committee on Toxicology, Ecotoxicology and the Environment (CSTEE, 2002Go), a group of distinguished scientists that provides an independent evaluation of risk assessments completed by the European Commission Rapporteur, "agrees with the overall conclusion that bisphenol A has no significant mutagenic potential in vivo" and "that bisphenol A does not have a significant carcinogenic potential."

In addition, we wish to reiterate that human exposure to BPA is considerably lower than the exposure experienced in the NTP cancer bioassays. Based on UK food survey data, the SCF identified a mean BPA level in foods of about 20 micrograms/kg food or approximately 0.02 ppm. In the NTP (1982)Go study, rats were fed diets containing 1000 or 2000 ppm BPA, male mice were fed diets containing 1000 or 5000 ppm BPA, and female mice were fed diets containing 5000 or 10,000 ppm. On a body weight basis, 0.02 ppm in food corresponds to approximately 0.00037 mg/kg body weight/day for 60-kg adults and 0.00085 mg/kg body weight/day for 8.8-kg infants (based on 97.5 percentile consumers of canned foods [SCF, 2002Go]). The consumption estimate is representative of a worst-case scenario. On a weight basis, the intake from the NTP (1982)Go study is approximately the following: 74 or 148 mg/kg body weight/day (male rats); 74 or 135 mg/kg body weight/day (female rats); 120 or 600 mg/kg body weight/day (male mice); and, 650 or 1300 mg/kg body weight/day (female mice). The doses used in the toxicology studies are between 87,000 and 1,500,000 times greater than the estimated BPA intake for infants at the 97.5 percentile consumption level. This vast magnitude of difference and the lack of convincing evidence of carcinogenic effects in rats and mice, support de minimis risk for humans.

The lack of convincing evidence of carcinogenicity in the rodent bioassays, combined with the lack of genotoxicity/mutagenicity activity, and the fact that metabolism data indicate that BPA is rapidly glucuronidated and excreted, in addition to the trivial exposure for humans, supports our conclusion, and those of EU scientific committees, that BPA is not a carcinogenic risk to humans.

REFERENCES

CSTEE. (2002). Opinion on the results of the Risk Assessment of Bisphenol A Human Health Part. Scientific Committee on Toxicology, Ecotoxicology and the Environment. Opinion expressed at the 31th CSTEE plenary meeting. Brussels, 22 May 2002.

Dutch Expert Committee on Occupational Standards. (1996). Bisphenol A and its digylcidylether: Health based recommended occupational exposure limits. No. 1996/02WGD. Rijswijk, The Netherlands, 12 September 1996. (Cited in SCF, 2002.)

EU. (2001). Risk Assessment of 2,2-bis(4-hydroxyphenyl)propane (Bisphenol A): Human Health Effects. Document prepared by the UK Health and Safety Executive on behalf of the European Union under the Existing Substances Regulation (Council Regulation EEC/793/93). Draft report, July 2001. (Cited in SCF, 2002.)

German Chemical Society. (1997). Bisphenol A (2,2-Bis-(4-hydroxyphenyl) propane). Edited by the GDCh-Advisory Committee on Existing Chemicals of Environmental Relevance. BUA Report 203, December 1995. S Hirzel, Wissenschaftliche Verlagsgesellschaft, Stuttgart. (Cited in SCF, 2002.)

Haighton, L. A., Hlywka, J. J., Doull, J., Kroes, R., Lynch, B. S., and Munro, I. C. (2002). An evaluation of the possible carcinogenicity of bisphenol A to humans. Regul. Toxicol. Pharmacol. 35, 238–254.[ISI][Medline]

Huff, J. (2001). Carcinogenicity bioassays of bisphenol A, 4-vinylcyclohexene diepoxide, and 4-vinylcyclohexene. Toxicol. Sci. 64, 282–283.[Free Full Text]

Huff, J. (2002). Carcinogenicity of bisphenol A Revisited. Toxicol. Sci. 70, 281–283.[Free Full Text]

Munro, I. C., Haighton, L. A., Hlywka, J. J., Lynch, B. S., Doull, J., and Kroes, R. (2002). Carcinogenicity bioassay of bisphenol A. Toxicol. Sci. 66, 356.[Free Full Text]

NTP (1982). Carcinogenesis Bioassay of Bisphenol A (CAS No. 80–05–7) in F344 Rats and B6C3F1 Mice (Feed Study). Technical Report No. TR-215. National Toxicology Progam, U.S. Department of Health and Human Services, Public Health Service. National Institute of Health, Research Triangle Park, NC.

SCF (2002). Opinion of the Scientific Committee on Food on Bisphenol A. European Commission Health and Consumer Protection Directorate-General. SCF/CS/PM/3936, 3 May 2002.

Veenstra, G. E., and Webb, C. M. C. (1999). Shell International Chemicals Limited Review of Toxicity of Bisphenol A. Toxicology Review No. 99.1417. Shell International Chemicals Limited, London. (Cited in SCF, 2002.)





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