Molecular dosimetry of DNA alkylation during chronic exposure to carcinogens

Incorporation of the molecular dosimetry of DNA adducts is being proposed as a means for placing quantitative risk assessment on a stronger scientific basis. While this is likely to be an improvement over straight mathematical extrapolation, we believe that a more holistic approach that incorporates even more biology is needed. Therefore, we have begun to quantify the dose-response relationships for N-nitrosodiethylamine (NDEA)-induced hepatocarcinogenesis by characterizing the major promutagenic DNA adduct, O4-ethyldeoxythymidine (O4-etdT); hepatocyte proliferation; and hepatocyte initiation in rats continually exposed to drinking-water containing NDEA. The results show that O4-etdT accumulates to apparent steady-state concentrations that are proportional to dose at all but the highest exposures, at which less than linear amounts are found. This appears to be due to excessive cytotoxicity, since hepatocyte proliferation is markedly increased at high but not at low exposures. Hepatocyte initiation, as determined by the presence of gamma-glutamyl transferase-positive foci, appears to have limitations in sensitivity that preclude investigations at low exposures. These methods may provide valuable insight into mechanisms of hepatocarcinogenesis at moderate exposures. Collecting these data should help to identify endpoints that may be relevant for human risk assessment.