SIGNIFICANCE OF DNA ADDUCT STUDIES IN ANIMAL-MODELS FOR CANCER MOLECULAR DOSIMETRY AND RISK ASSESSMENT

To elucidate the relationship between DNA adduct formation and tumorig enesis, a number of experiments have been conducted to measure DNA add ucts in target tissues from experimental animals during continuous exp osure to carcinogens. With aflatoxins, aromatic amines, and polycyclic aromatic hydrocarbons, tumor induction appears to be associated with the major DNA adduct detected, whereas with N-nitrosamines the respons e is normally correlated with minor forms of DNA damage. During contin uous carcinogen administration, steady-state adduct concentrations are generally obtained in the target tissues, and there is often a linear correlation between the carcinogen concentration and the steady-state DNA adduct level. Exceptions exist when the mechanism of activation c hanges or with the onset of significant toxicity. Steady-state DNA add uct levels are often linearly related to the tumorigenic response. Car cinogen-induced cell proliferation occurs when significant deviations from linearity are observed. Because DNA adducts detected in humans ar e chemically identical to those found in experimental animals, DNA add uct data in animals may contribute to our understanding of human cance r risk.