Abstract

Recent studies have documented that the Sprague-Dawley rat is markedly more sensitive than the Golden Syrian hamster to 1,3-dinitrobenzene (1,3-DNB)-induced testicular toxicity and methemoglobinemia. The present studies have investigated the possibility that differences in 1,3-DNB metabolism and pharmacokinetics could explain this species difference. [14C]1,3-DNB (25 mg/kg, ip) was administered to both species at a dose known to induce a testicular lesion in the rat and levels of 1,3-DNB and its metabolites were measured in blood and urine. Elimination of 1,3-DNB from the blood was initially rapid, followed by a second, much slower phase. Peak blood levels of 1,3-DNB were very different between the two species, with the hamster reaching levels only one-half those found in the rat (46.3 vs. 99.5 nmol/ml, respectively). Administration of a 50-mg/kg dose to the hamster resulted in 1,3-DNB blood levels which were similar to those found in the rat at 25 mg/kg. Since no obvious testicular toxicity is apparent in the hamster even at the higher dose level, a direct effect of 1,3-DNB on the testes seems unlikely, although it is possible that hamster cells inherently lack sensitivity to toxicity. Other major differences between the two species were a more rapid initial elimination rate and much higher blood levels of nitroaniline in the rat. Analysis of urinary metabolites revealed that the rat excreted more unconjugated metabolites and less phenolic metabolites compared with the hamster. Overall, the data indicate that the capacity to form reductive metabolites may play an important role in susceptibility to toxicity.