AROMATIC AMINE DNA ADDUCT FORMATION IN CHRONICALLY-EXPOSED MICE - CONSIDERATIONS FOR HUMAN COMPARISON

Lifetime chronic exposure of mice to the aromatic amines 4-aminobiphen yl (ABP) and 2-acetylaminofluorene (AAF) produces liver and urinary bl adder tumors. In parallel experiments, DNA adduct levels in target tis sues reach a steady-state (a balance between adduct formation and remo val) after about four weeks of either AAF or ABP ingestion. For these and other carcinogens, steady-state DNA adduct levels most frequently increase linearly with dose, but the formation of tumors also depends upon a variety of factors, including the proliferative capacity of the target tissue, the sex of the animal, genotoxic properties of the spe cific adducts formed, and other unknown events. Chronic dosing experim ents in animal models are of interest for human risk assessment becaus e human exposure is typically intermittent, involving repeated exposur es. However, it is to be expected that in a genetically-diverse human population, where the lifetime averages > 70 years, the relationship b etween tumorigenesis and DNA adduct formation will be relatively more complex than that observed in mice. From our studies of chronic ABP ex posure in male mice, we have obtained the daily dose of ABP and the st eady-state level of N-(deoxyguanosin-8-yl)-4-aminobiphenyl (dG-C8-ABP) adduct associated with a 50% mouse bladder tumor incidence. Our attem pt at a human extrapolation for adducts and urinary bladder cancer in smoking males (20-40 cigarettes/day) is based on the ABP dose per ciga rette, values for the dG-C8-ABP adduct in bladder biopsies of lifetime heavy smokers at age similar to 70, and the smoking-related bladder t umor incidence (absolute lifetime risk) for Caucasian males in the Uni ted States aged 65-84 years. The extrapolation has produced two major predictions, one related to adduct formation and the other related to tumorigenesis. First, the observed level of smoking-related dG-C8-ABP in DNA of human bladder epithelium, expressed as a function of daily A BP intake, is about 3500-times higher than similar data for mice, whic h suggests that humans may perform the biotransformation of ABP more e fficiently than mice. Second, at a similar bladder tumor incidence, mo use bladder contained adduct concentrations that were much higher than those observed in human bladder; for example, at a 2.6% tumor inciden ce, mouse bladder contained an average of 55.5 fmol dG-C8-ABP/mu g DNA (1850 adducts/10(8) nucleotides), while bladders from Caucasian male smokers contained an average of 0.036 fmol dG-C8-ABP/mu g DNA (1.2 add ucts/10(8) nucleotides). This suggests that factors other than ABP-DNA adducts, such as adducts of other carcinogens, the influence of promo ters, and synergistic effects of all of these factors contribute subst antially to smoking-related bladder cancer in humans.