Dose-Response Relationship in the Primary Lesion of Strong Electrophilic Carcinogens

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Abstract
The carcinogen trans-4-dimethylaminostilbene was administered orally to female Wistar rats in doses ranging from 5 x 10(-10) to 1.8 x 10(-4) M/kg and covalent binding in liver, blood, kidney and stomach determined after 24 h as a measure for the availability of reactive metabolites. Total binding to proteins in all these tissues and binding to rRNA and DNA in liver and kidney increased linearly with dose over the entire dose range up to 3.5 x 10(-5) M/kg. The increase deviated from linearity only at the highest dose (1.8 x 10(-4) M/kg). In this case it was less than proportional. The result provides experimental evidence for the notion that first order kinetics prevail down to extremely small doses, in the present experiment 25 ng per animal. It is concluded that metabolic activation, distribution of reactive metabolites and their reaction with cellular macromolecules is independent of dose at low doses. This implies that the production of primary lesions is also independent of dose and that a pharmacokinetically determined threshold does not exist for trans-4-dimethylaminostilbene down to nanogramdoses.