Comparative metabolism, bioavailability, and toxicokinetics of benzo[a]pyrene in rats after acute oral, inhalation, and intravenous administration

The metabolic fate of high doses of BaP is not fully established. To fill this important data need, a comprehensive metabolism, bioavailability, and toxicokinetic study has been undertaken to track the fate of BaP subsequent to single acute exposures. Doses of 100 mg/kg body weight, 0.1 mg/m(3) (equivalent to 19 mg/kg oral dose), and 4.5 mug/kg BaP were administered to 8-week-old male F-344 rats via oral, inhalation (nose only), and intravenous routes, respectively. Rats were sacrificed at 0, 0.5, 1, 2, 4, 6,24, 48, and 72 hr postexposure. Blood, liver, lung, brain, reproductive tissues, urine, and feces samples were analyzed for parent BaP and metabolites by HPLC with fluorescence detection. Most of the administered BaP was metabolized 4, 6, and 72 hr postexposure for inhalation, intravenous, and oral routes, respectively, The following metabolites were detected: 4,5-dihydrodiol, 7,8-dihydrodiol, 9,10-dihydrodiol, 3,6-dione, 3-hydroxy, and 9-hydroxy BaP (organic fraction), glucuronides, sulfates, and glutathione conjugates (aqueous fraction).Toxicokinetic data revealed a high mean residence time, and low clearance values for BaP metabolites in lung, liver, and brain relative to plasma. Findings of this study establish the relationship between bioavailability and the acute toxic effects of BaP observed in our laboratory at these high doses.