Benzo[a]pyrene metabolism in mice exposed to diesel exhaust: I. Uptake and distribution

Male Fisher-344 rats were exposed by inhalation to low levels of diesel exhaust and coal dust, alone or in combination, or to filtered air, 7 h/d, 5 d/wk for 24 mo. Cytochrome P-450-associated benzo[a]pyrene hydroxylase and 7-ethoxycoumarin deethylase activities were assayed in lung and liver microsomes after 3, 6, and 24 mo. Age-related changes in enzyme activities were observed, but they were not altered by the exposures. When the data were adjusted for age, only one difference was observed. Lung benzo[a]pyrene hydroxylase activity in rats exposed to diesel exhaust and coal dust in combination was lower than that in animals exposed to coal dust alone (2.8 versus 4.4 pmol/min X mg protein). Neither value, however, differed significantly from the filtered-air controls, and no differences were observed in the other lung and liver activities. The data suggest exposure of the rats to diesel exhaust and/or coal dust had little or no effect on the selected lung and liver cytochrome P-450 activities under the conditions of the experiment.

Section: Discussionmentioning

confidence: 97%

Chronic inhalation of diesel exhaust and coal dust: Effect of age and exposure on selected enzyme activities associated with microsomal cytochrome p‐450 in rat lung and liver

Rabovsky

Petersen

Lewis

et al. 1984

Pharmacokinetics and bioavailability of pyrene in the rat

Withey

Law

Endrényi

1991

Groups of 6 male Wistar rats, of about 400 g body weight, were dosed with 14C-labeled pyrene, dissolved in an Emulphor/water solvent vehicle, at 5 different dose levels by the intravenous or oral routes. Appropriate mathematical models were fitted to blood concentration-time data for [14C]pyrene and pyrene per se and dose-trend analyses were carried out. Areas under these curves were used to assess the bioavailability of the orally administered doses. Tissue concentrations, measured at the termination of the blood sampling period, gave a quantitative measure of the distribution of the administered dose. Attempts to repeat these studies with similar doses of tritium-labeled benzo[a]pyrene were frustrated by the lack of meaningful blood-level data. Dose trends for the derived pharmacokinetic parameters for pyrene revealed that the kinetics were nonlinear and strongly suggestive of enterohepatic recycling. Biliary excretion, measured in a separate experiment, gave support to this hypothesis. The bioavailability of the orally administered doses was between 50 and 60%. Over a 6-d period postdosing, some 45 and 40% of the administered dose was excreted via the urine and feces, respectively, irrespective of the route of administration. Distribution to the tissues of the 14C-label was highest in the perirenal fat, intermediate in the liver, kidneys, and lungs, and lowest in the heart, testes, spleen, and brain.

Percutaneous uptake, distribution, and excretion of pyrene in rats

Withey

Law

Endrényi

1993

Groups of 12 male Wistar rats, of about 400 g body weight, were dosed with 2, 6, or 15 mg/kg of 14C-labeled pyrene, dissolved in acetone, applied to 4 cm2 of a shaved area of the mid back. Three animals in each dose group were killed at 1, 2, 4, and 6 d post-dosing, and their principal organs were removed and analyzed for pyrene and [14C]pyrene equivalents. Urine and feces, as well as the area of skin to which the dose was applied, were also analyzed for [14C]pyrene equivalents. The rate of uptake from the skin was rapid (t1/2 0.5-0.8 d) relative to rate processes for the other organs, and about 50% of the applied dose was excreted over the 6 d of the study. The significant decrease in the fraction of the dose excreted and in the normalized amounts distributed to the various organs and tissues, as the dose increased for all chemical species measured, was strongly suggestive of nonlinear kinetics, as has been observed in previous studies. Levels of pyrene were highest in the liver, kidneys, and fat. Levels of metabolites were also high in the lung. It was evident that the dermal route of uptake was not insignificant for this model polycyclic aromatic hydrocarbon and may represent a significant exposure route for exposed humans.