Effect of dose on the absorption and excretion of [14C]benzene administered orally or by inhalation in rats and mice

Abstract

The effect of dose on the absorption and excretion of [14C]benzene was studied using 13-week old male F344/N rats, Sprague-Dawley rats, and B6C3F1 mice. Gastrointestinal absorption of benzene administered by gavage was greater than 97% in these species for doses between 0.5 and 150 mg benzene/kg body wt. At oral doses below 15 mg/kg, greater than 90% of the 14C excreted was in the urine as nonethylacetate extractable material. Above 15 mg/kg, in both rats and mice, an increasing percentage of the administered benzene was exhaled unmetabolized, suggesting saturation of metabolic pathways. Above 50 mg/kg, total metabolites (as determined by 14C in the urine, feces, and carcass after 2 days) were not linearly related to administered dose. Total metabolites per unit body weight was equal in F344/N rats and B6C3F1 mice at gavage doses up to 50 mg/kg; however, total metabolites in mice did not increase at higher doses. For inhalation exposures, the percentage of inhaled benzene that was absorbed and retained during a 6-hr exposure decreased from 33 +/- 6% (mean +/- standard deviation) to 15 +/- 9% in rats, and from 50 +/- 15 to 10 +/- 2% in mice as the exposure concentration was increased from approximately 26 to 2600 micrograms/liter (10 to 1000 ppm at 615 Torr, 23 degrees C). Total metabolite formation was exponentially related to the benzene exposure concentration with one-half the maximal amount of metabolite formation occurring at 220 micrograms/liter (84 ppm) for B6C3F1 mice and 650 micrograms/liter (250 ppm) for F344/N rats. Total metabolites were higher in mice than in rats at any of the vapor concentrations used due mainly to the higher amount inhaled by mice. Saturation of overall metabolism in mice but not in rats at high doses by both routes of administration indicates species differences in metabolism of benzene.