Effect of exposure concentration, exposure rate, and route of administration on metabolism of benzene by F344 rats and B6C3F 1 mice

Abstract

To determine the effect of exposure concentration and the route of administration on benzene metabolism, male F344 N rats and B6C3F 1 mice were orally exposed to 1, 10, and 200 mg benzene/kg, and by inhalation for 6 hr to 5, 50, and 600 ppm benzene vapor. The effect of different exposure rates on the metabolism of benzene was determined by exposing rodents over different time intervals to the same total amount of benzene [constant concentration × time factor ( C × T) = 300 ppm × hr]. Water-soluble metabolites constituted > 90% of the metabolite dose to the tissues and were used as a measure of the metabolism of benzene via different pathways. Water-soluble metabolites were measured in the blood, urine, liver, lung, and bone marrow from animals killed following oral exposures and during and following inhalation exposures. The total “dose” to the tissue of individual metabolites was determined by the area under the curve (AUC). The results indicated a shift in metabolism from putative toxification pathways to detoxification pathways as the exposure concentration or oral dose increased. In mice, hydroquinone glucuronide and muconic acid (markers of toxification metabolic pathways) represented a greater percentage of the administered dose at low doses than at high doses. At high doses, phenylglucuronide and prephenylmercapturic acid (detoxification products) increased as a percentage of the administered dose. This same metabolic shift was observed in rats, except that hydroquinone glucuronide was a minor metabolite of benzene at all concentrations. The AUC of phenylsulfate (detoxification pathway) was proportional to the exposure concentration in both species. Within the range of C × T factors studied, the rate of the inhalation exposure to benzene did not affect the AUC of metabolites in tissues of rats; however, a high dose rate (600 ppm 0.5 hr) in mice caused a shift in metabolism to phenyl conjugates. The comparison of oral and 6-hr inhalation exposures indicated that, in terms of metabolite dose to tissues, there is no simple relationship between these two routes of administration. An oral dose and an inhalation exposure concentration which produce an equal dose of one metabolite produce very different doses of another metabolite. These studies demonstrated a species difference in benzene metabolism, as well as a metabolic shift in benzene metabolic pathways as the exposure concentration was increased. The shift toward greater relative formation of putatively less toxic metabolites at higher inhalation exposure concentrations or oral doses might result in underestimating the toxicity of low exposure concentrations of benzene when extrapolating from rodent studies conducted with high level dosing regimens.