Effects of dose and route of exposure on dioxin disposition

Abstract

The absorption, distribution, metabolism and excretion of 2,3,7,8-tetrabromodibenzo- p-dioxin (TBDD) was studied in male F344 rats. Oral absorption was dose-dependent. Absorption of 1 nmol/kg by both the oral and intratracheal (itr) routes was 〉80%, whereas only 〉12% was absorbed through the skin. Tissue distribution was dependent on dose, time, and route of exposure. Liver:fat ratios of 3.4, 2.9, 2.0, and 1.5 were observed 3 days after iv, oral, itr, and dermal administration, respectively, of 1 nmol/kg. Liver:fat ratios were 0.2 and 2.6 by 56 days after 1 and 100 nmol/kg iv, respectively. Dose-dependent elimination in urine and feces was observed beginning 3 weeks after iv administration. However, auto-induction of dioxin metabolism did not occur in vivo when evaluated by biliary excretion of [ 3H]TBDD or [ 3H]TCDD in pretreated and naive rats. Dose-response profiles for TBDD induction of hepatic cytochromes CYP1A1 and CYP1A2 indicated the latter to be a more sensitive response. Finally, comparison of the dose-response behavior for TBDD induction of hepatic CYP1A2 with hepatic concentrations of TBDD suggests that induction of CYP1A2 alone does not account for nonlinearities in dioxin disposition exemplified by dose-related increases in the ratio of dioxin concentrations in liver and fat.