Correlation of DNA adduct levels with tumor incidence: carcinogenic potency of DNA adducts

The quantitative relationship between DNA adducts and tumor incidence is ev aluated in this review. All available data on DNA adduct levels determined after repeated administration of a carcinogen to rats or mice have been com piled. The list comprised 27 chemicals, of all major structural classes of carcinogens. For the correlation with tumor incidence, the DNA adduct level s measured at the given dose were normalized to the dose which resulted in a 50% tumor incidence under the conditions of a 2-year bioassay (TD50 dose) . In rat liver, the calculated adduct concentration 'responsible' for a 50% hepatocellular tumor incidence spanned from 53 to 2083 adducts per 10(8) n ucleotides, for aflatoxin B1, tamoxifen, IQ, MeIQx, 2,4-diaminotoluene, and dimethylnitrosamine tin this order). In mouse liver, the respective figure s were 812 to 5543 adducts per 108 nucleotides, for ethylene oxide, dimethy lnitrosamine, 4-aminobiphenyl, and 2-acetylaminofluorene. The observed span (40-fold in rats, 7-fold in mice) reflects differences between the various DNA adducts to lead to critical mutations. If additional carcinogens fit i n with this astonishingly narrow range, the measurement of DNA adduct level s in target tissue has the potential to be not only an exposure marker but an individual cancer risk marker. For toremifen and styrene, low levels of DNA adducts were detected in rat liver at the end of a negative long-term b ioassay. This shows that the limit of detection of DNA adducts can be well below the limit of detection of an increased tumor incidence. For a cancer risk assessment at low levels of DNA damage, treatment-related adducts must be discussed in relation to the background DNA damage and its inter- and i ntraindividual variability. (C) 1999 Elsevier Science B.V. All rights reser ved.