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Recent investigations on mechanism of carcinogenesis have demonstrated important quantitative relationships between the induction of neoplasia, the molecular dose of promutagenic DNA adducts and their efficiency for causing base-pair mismatch, and the extent of cell proliferation in target organ. These factors are involved in the multistage process of(More)
Hepatocyte initiation, as indexed by growth-selected gamma-glutamyl transferase-positive foci, was measured during continuous exposure to diethylnitrosamine (DEN) at concentrations used in previous DEN bioassay, DNA adduct, and cell replication studies. Hepatocyte initiation increased in a dose- and lobe-specific manner. The efficiency of DEN as an(More)
The concentration of DNA adducts in specific hepatic cell types has been determined in F344 rats fed 0.02% 2-acetylaminofluorene (AAF) for 28 days followed by control diet for an additional 28 days. In animals killed at 28 days of AAF feeding, the major DNA adduct, N-(deoxyguanosin-8-yl)-2-aminofluorene, was present in each cell type in the order:(More)
Chronic exposure to the hepatocellular carcinogen diethylnitrosamine (DEN) causes a dose-dependent accumulation of the promutagenic DNA adduct O4-ethyldeoxythymidine in hepatocytes and increases in the number of initiated hepatocytes as indicated by gamma-glutamyl transpeptidase positive foci. Initiation is thought to be dependent on the quantity of(More)
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(More)
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