Toxicokinetics of inhaled benzo[a]pyrene: plasma and lung bioavailability

Bioavailability and toxicokinetic studies are essential in order to establish dose-response relationships of widely distributed environmental toxicants such as benzo[a]pyrene (BaP), a polycyclic aromatic hydrocarbon. Fischer 344 rats were exposed for 4 h (via nose-only inhalation) to aerosol exposure concentrations of 0.1, 1.0, and 2.5 mg/m(3) of BaP absorbed onto carbon black particles using a state-of-the-art model aerosol generation system. Nominal and chamber concentrations of the particulate aerosol were determined gravimetrically with a seven-stage cascade impactor. The average aerosol for the 3 exposure concentrations used in this study exhibited a trimodal distribution with 93% cumulative mass less than 15.85 microm, 89% cumulative mass less than 10 microm, 55.3% cumulative mass less than 2.5 microm, and 38% less than 1 microm. Fifty-five percent of the aerosol had a cumulative mass less than PM(2.5) and the mass median aerodynamic diameter (MMAD) -/+ geometric standard deviation (GSD) for this mode was 1.7 -/+ 0.085 microm. Plasma and lung samples were collected at 30, 60, 120, and 240 min postexposure. The concentrations of BaP parent compound and metabolites were determined by high-performance liquid chromatography. The toxicokinetic parameters were computed from the time course of plasma BaP concentration. The bioavailability of BaP increased as a function of exposure concentration, and toxicokinetic analysis indicates first-order pharmacokinetics for BaP. However, some toxicokinetic parameters such as clearance and volume of distribution remained constant throughout the duration of the postexposure period. BaP and its metabolite concentrations in plasma peaked at 1 h postexposure. At 240 min postexposure, only trace levels of BaP remained in the plasma. The BaP metabolites in the lung showed an identical trend where no parent compound was detected. Among the metabolites detected, BaP 4,5-, 7,8-, and 9,10-dihydrodiols, 3-OH-BaP, and 9-OH-BaP were predominant.