Extrapolation of Carcinogenicity Data to Low Doses with a Dose-Response Study of the Binding of Benzo(a)pyrene to Rat Liver DNA

Abstract

The binding of tritiated benzo(a)pyrene (BP) to liver DNA of 25 adult male rats (SIV 50) has been determined 50 h after a single intraperitoneal injection of doses between 40 ug/kg and 4 mg/kg. The dose-response relationship is linear up to 1 mg/kg, shows a sigmoid step towards 2 mg/kg and a shallow linear slope above that value. The observed binding ranges from 1.7 to 180 nmoles BP per mole DNA phosphate. The non-linearity between 1 and 2 mg/kg could be explained on the basis of an induction of metabolizing enzymes.

A purely mathematical extrapolation of the tumour incidence from a carcinogenic dose (1 × 40 mg/kg for a 20% hepatoma incidence in newborn mice) to human exposure levels (about 0.1 ug/kg per day) would never have followed a step like the one found in our experiments. Our dose-effect study therefore shows how carcinogenicity data could be extrapolated in a biologically founded way to low doses.