Abstract
Due to difficulties in conducting epidemiological studies, most estimates of cancer risk are based on data from animal bioassays. Extrapolation of cancer risk estimates in animals to humans requires an assumption of equal potency across species based on the average daily dose. The purpose of this paper is to examine the ability to predict tumor incidence across species from DNA adduct concentrations resulting from exposure to carcinogens. A 100-fold range of structurally diverse adduct concentrations corresponding to the same tumor incidence raises questions about quantitative predictability across chemical classes and across species. Differences in adduct structure, mutagenic efficiency, adduct repair rates, and cellular proliferation could account for some of the differences. For specific carcinogen-DNA adducts, the steady-state levels associated with a 50% tumor incidence appear to vary over a narrower range. An equal incidence of liver tumors was obtained at equal concentrations of aflatoxin B1-DNA adducts for rats and trout. A 2- to 3-fold range of 4-aminobiphenyl-DNA adduct concentrations between mice and dogs appears to be associated with nearly equal bladder tumor incidence, on the basis of limited data. In humans, a 5-fold higher concentration of a 4-aminobiphenyl-DNA adduct in bladders of smokers than of nonsmokers is compatible with the relative risk of bladder cancer due to smoking. DNA adduct concentrations certainly can be used to improve quantification of chemical exposures for epidemiological studies. Although promising, more data are needed to judge the usefulness of DNA adduct concentrations to predict cancer incidence across species.
Full text
PDF
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Bechtel D. H. Molecular dosimetry of hepatic aflatoxin B1-DNA adducts: linear correlation with hepatic cancer risk. Regul Toxicol Pharmacol. 1989 Aug;10(1):74–81. doi: 10.1016/0273-2300(89)90014-7. [DOI] [PubMed] [Google Scholar]
- Block N. L., Sigel M. M., Lynne C. M., Ng A. B., Grosberg R. A. The initiation, progress, and diagnosis of dog bladder cancer induced by 4-aminobiphenyl. Invest Urol. 1978 Jul;16(1):50–54. [PubMed] [Google Scholar]
- Cohen S. M., Ellwein L. B. Proliferative and genotoxic cellular effects in 2-acetylaminofluorene bladder and liver carcinogenesis: biological modeling of the ED01 study. Toxicol Appl Pharmacol. 1990 Jun 1;104(1):79–93. doi: 10.1016/0041-008x(90)90284-2. [DOI] [PubMed] [Google Scholar]
- Mommsen S., Aagaard J. Tobacco as a risk factor in bladder cancer. Carcinogenesis. 1983;4(3):335–338. doi: 10.1093/carcin/4.3.335. [DOI] [PubMed] [Google Scholar]
- Moolgavkar S. H., Knudson A. G., Jr Mutation and cancer: a model for human carcinogenesis. J Natl Cancer Inst. 1981 Jun;66(6):1037–1052. doi: 10.1093/jnci/66.6.1037. [DOI] [PubMed] [Google Scholar]
- Poirier M. C., Fullerton N. F., Kinouchi T., Smith B. A., Beland F. A. Comparison between DNA adduct formation and tumorigenesis in livers and bladders of mice chronically fed 2-acetylaminofluorene. Carcinogenesis. 1991 May;12(5):895–900. doi: 10.1093/carcin/12.5.895. [DOI] [PubMed] [Google Scholar]
- Talaska G., Dooley K. L., Kadlubar F. F. Detection and characterization of carcinogen-DNA adducts in exfoliated urothelial cells from 4-aminobiphenyl-treated dogs by 32P-postlabelling and subsequent thin-layer and high-pressure liquid chromatography. Carcinogenesis. 1990 Apr;11(4):639–646. doi: 10.1093/carcin/11.4.639. [DOI] [PubMed] [Google Scholar]
- Talaska G., al-Juburi A. Z., Kadlubar F. F. Smoking related carcinogen-DNA adducts in biopsy samples of human urinary bladder: identification of N-(deoxyguanosin-8-yl)-4-aminobiphenyl as a major adduct. Proc Natl Acad Sci U S A. 1991 Jun 15;88(12):5350–5354. doi: 10.1073/pnas.88.12.5350. [DOI] [PMC free article] [PubMed] [Google Scholar]