COMPARISON OF STYRENE HEPATOTOXICITY IN B6C3F1 AND SWISS MICE

Inhalation exposure to styrene at concentrations that cause metabolic saturation results in significantly greater hepatotoxicity in B6C3F1 mice than in Swiss mice; females of both strains are more susceptible than males. These studies were conducted to investigate the mouse strain and gender differences in susceptibility to hepatotoxicity caused by repeated exposure to styrene at concentrations that do not cause metabolic saturation. Male and female B6C3F1 and Swiss mice (8 weeks old) were exposed to 0, 150, or 200 ppm styrene for 6 hr/day, 5 days/week, for up to 2 weeks. Changes in body and liver weights, serum alanine aminotransferase (ALT) and sorbitol dehydrogenase (SDH) levels, liver histopathology, and total liver glutathione (GSH) were evaluated after 2, 3, 5, and 10 exposures (six mice/sex/strain/time point/concentration). Blood levels of styrene and styrene-7,8-oxide (SO) were measured in mice exposed to 200 ppm styrene for 2, 3, or 5 days (six mice/sex/strain/time point/concentration). Serum ALT and SDH levels were significantly elevated only in female B6C3F1 mice after 3 exposures to 200 ppm styrene; enzyme levels had returned to control levels when measured after 5 and 10 exposures. Degeneration and coagulative necrosis of centrilobular hepatocytes were observed in female B6C3F1 mice exposed 2, 3, and 5 days to 150 or 200 ppm styrene; incidences of these lesions were greater in the 200 ppm than in the 150 ppm dose group. After 10 days of exposure to 150 or 200 ppm styrene, hepatocellular lesions had resolved, although a residual chronic inflammation was present in livers of most female B6C3F1 mice. Degeneration of centrilobular hepatocytes was observed in one male B6C3F1 mouse after 3 exposures to 200 ppm, and no significant lesions were observed in livers of exposed Swiss mice. Significant dose-related decreases in hepatic GSH were observed in both sexes of both strains throughout the 2-week exposure. In general, hepatic GSH depletion was greatest in female B6C3F1 mice. Exposure to 200 ppm caused 60-70% GSH depletion in female B6C3F1 mice at each time point. GSH depletion generally decreased in B6C3F1 mice and increased in Swiss mice with continued exposure to 150 ppm styrene. With continued exposure to 200 ppm, GSH depletion generally decreased in all mice. Blood styrene and SO levels increased in all groups with the number of exposures. Styrene levels were significantly higher in B6C3F1 mice than in Swiss mice; however, within each strain gender differences were not significant. These data suggest that the transient hepatotoxicity in female B6C3F1 mice was related to greater hepatic GSH depletion and/or slower GSH regeneration in these animals. (C) 1995 Society of Toxicology