Species difference in the disposition of acrylonitrile: quantitative whole-body autoradiographic study in rats and mice

Abstract

Previous studies from this and other laboratories have indicated the role of species difference in acrylonitrile (VCN) toxicity and its metabolism to cyanide. Our recent studies also indicated a more pronounced elimination of VCN following oral as compared to i.v. administration. To further characterize the mechanism of these differences on the distribution of VCN, quantitative whole-body autoradiographic distribution and elimination studies were conducted at various time points (0.08, 8, 24, 48 h) following the administration of an equivalent i.v. dose of 2-[14C]-VCN to male Fischer rats and male CD-1 mice. Whole-body autoradiographs obtained from freeze-dried and acid-extracted sections of rats and mice demonstrated a rapid uptake of 14C in liver, lungs, spleen and bone marrow at early time intervals. Quantitatively, the uptake, retention and covalent interaction of 14C were higher in organs of rats as compared to mice, over 48 h. Mice eliminated 74% of the total administered dose of 2-[14C]-VCN (expired air 4%, urine 16% and feces 54%), while rats eliminated only 26% of the dose (expired air 2%, urine 4% and feces 20%). Species differences in VCN toxicity seem to be correlated with its rate of elimination. The distribution and elimination data demonstrated that mice divest VCN more rapidly than rats. The study also demonstrated that administration of VCN in rats resulted in covalent interactions and retention of 2-[14C]-VCN/metabolites in the tissues thus exerting more chronic toxicity to rats than to mice.