Styrene Inhalation Toxicity Studies in Mice: II. Sex Differences in Susceptibility of B6C3F1 Mice

Abstract

Styrene Inhalation Toxicity Studies in Mice. II. Sex Differences in Susceptibility of B6C3F1 Mice. Morgan, D. L., Mahler, J. F., Dill, J. A., Price, H. C., Jr., and Adkins, B., Jr. (1993). Fundam. Appl. Toxicol. 21, 317-325.Styrene is a commercially important chemical used in the production of plastics and resins. In initial short-term styrene inhalation studies, toxicity was significantly greater in male B6C3F1 mice than in females, suggesting that males may metabolize styrene more extensively and/or may be less able to detoxify reactive metabolites. In addition, a nonlinear dose-response was observed where toxicity and mortality were greater in mice exposed to 250 ppm than in those exposed to 500 ppm. These studies were conducted to investigate potential mechanism(s) for sex differences and the nonlinear dose-response in styrene toxicity by evaluating the effects of repeated styrene exposure on styrene oxide production, hepatic GSH availability, and hepatotoxicity in male and female B6C3F1 mice. Mice (36/sex/dose) were exposed to 0, 125, 250, or 500 ppm styrene 6 hr/day for up to 3 days. Styrene exposure caused increased mortality and hepatotoxicity (centrilobular necrosis, increased serum liver enzymes) in males and females after one or two exposures to 250 and 500 ppm. Hepatic GSH levels were decreased in a dose-dependent manner in males and females. After one exposure, GSH levels in males rebounded above controls in all dose groups. After three exposures to 125 or 250 ppm males appeared to maintain GSH levels; GSH was still decreased in the 500 ppm group. GSH levels in females were decreased after each exposure in all dose groups to lower levels than in males, and did not rebound above controls. Male mice had significantly greater blood styrene levels than females after one exposure to 500 ppm; however, there were no significant sex differences in blood styrene after subsequent exposures. Levels of SO in blood were not significantly greater in male mice than females within a dose group, and did not change significantly with repeated styrene exposures for 3 days. Blood styrene and SO levels were significantly higher at 500 ppm than at 250 ppm indicating that styrene uptake and metabolism are greater at 500 ppm than at 250 ppm. The higher incidence of mortality in male mice and the nonlinear dose-response to styrene cannot be explained by gender- or dose-related differences in hepatotoxicity, GSH depletion, or blood styrene or SO levels.