Biochemical effects and early lesions in regard to dose-response studies

Trans-4-dimethylaminostilbene is metabolically activated independent of dose after single doses ranging from 5 x 10(-10) up to the LD50 = 2.5 x 10(-4) mol/kg. This is based on the dose related increase of covalent binding to macromolecules in liver, blood and kidney 24 h after oral administration to female Wistar rats. Deviations from proportionality at high doses are related to the rate rather than to the extent of formation of altered cell constituents. It is concluded that the early biochemical lesions critical to tumor formation are also independent of dose. A pharmacokinetic threshold with subcarcinogenic doses cannot be demonstrated down to exposures equivalent to 25 ng per animal or 2 microgram/kg diet.