Molecular dosimetry of O4-ethyldeoxythymidine in rats continuously exposed to diethylnitrosamine

There is considerable interest in incorporating mechanistically based biological data into the process of quantitative risk assessment. Presently, no adequate data bases for internal dosimeters, such as DNA adducts, exist for humans or experimental animals. Therefore, the major promutagenic ethyl adduct, O4-ethyldeoxythymidine (O4-EtdT), has been quantitated in liver DNA after continuous exposure of rats to drinking water containing 0.4, 1, 4, 10, 40, or 100 ppm diethylnitrosamine (DEN) for 1, 4, 7, 14, 28, 49, or 70 days. The rate of O4-EtdT accumulation was modeled as the difference between a DEN-dependent rate of formation and an O4-EtdT concentration-dependent rate of loss. In general, O4-EtdT concentrations increased rapidly during the first 7 days of exposure and by 7-28 days O4-EtdT had accumulated to apparent steady-state concentrations that were DEN concentration-dependent over the entire dose range. The concentration of the adduct increased with DEN concentration over the entire dose range for exposures of 28 days or less and for doses of 0.4 to 40 ppm DEN the adduct level increased with DEN concentration for exposures of 70 days or less. Although the dose response of O4-EtdT was relatively linear, with increasing DEN concentration a trend toward a less than linear relationship was observed. This suggests that there was a lower efficiency of formation and/or greater loss of O4-EtdT during high-dose exposures. This study provides a data base that can be used to qualitatively and quantitatively examine the relationship between external dose and O4-EtdT over a DEN dose range covering several orders of magnitude.