TOXICOKINETICS OF INHALED BENZO[a]PYRENE: Plasma and Lung Bioavailability

Abstract

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.

Organ-specific distribution of 7-chlorinated benz[<i>a</i>]anthracene and regulation of selected cytochrome P450 genes in rats

“…*Statistically significant differences at p < 0.05 vs control. a These data taken from our previous report (Kido et al, 2013). lized in the body, for example by hydroxylation and epoxidation (Ramesh et al, 2001). The physiological metabolism of 7-Cl-BaA requires further investigation.…”

Evaluation of nose-only aerosol inhalation chamber and comparison of experimental results with mathematical simulation of aerosol deposition in mouse lungs

“…The disadvantage with these systems is a large deposition of the aerosolized drug all over the animal's Alternatively, nose-only inhalation chambers were developed to avoid the above problems for small animals like rats and mice. 23,24 Validation of these nose-only inhalation chambers is an important step towards their suitable use in inhalation studies. 25,26 Unfortunately, little data is available in the literature on the fraction of drug that deposits in the mice and their lungs using such chambers.…”

Comparison of the kinetics of various biomarkers of benzo[a]pyrene exposure following different routes of entry in rats

“…For instance, studies indicate that diolBaPs exhibit a rapid elimination in urine like 1-hydroxypyrene but in contrast with 3-OHBaP Viau, 1996, 1997). Other metabolites that may be of potential interest for the biomonitoring of exposure include 8,9, and 3,, but data are very limited in terms of kinetics (Kim et al, 2000;Ramesh et al, 2001a;Wang et al, 2003;Weyand and Bevan, 1986).…”