Styrene Inhalation Toxicity Studies in Mice: III. Strain Differences in Susceptibility

Abstract

Styrene Inhalation Toxicity Studies in Mice. III. Strain Differences in Susceptibility. Morgan, D. L., Mahler, J. F., Dill, J. A., Price, H. C., Jr., O'Connor, R. W., and Adkins, B., Jr. (1993). Fundam. Appl. Toxicol. 21, 326-333.Inhalation toxicity studies were conducted to evaluate mouse strain differences in the susceptibility to styrene vapors. Male and female B6C3F1, C57BL/6, Swiss, and DBA/2 mice (8 weeks old) were exposed to 0, 125, 250, or 500 ppm styrene 6 hr/day, for 4 days (20/sex/dose). Histopathological changes and changes in liver weights were evaluated as a measure of hepatotoxicity. Styrene uptake and styrene-7,8-oxide (SO) formation were estimated by measuring levels of styrene and SO in blood. An estimate of SO detoxification by conjugation with GSH was obtained by measuring hepatic GSH depletion. In general, mortality, increased liver weights, and hepatocellular necrosis were observed in the 250 and 500 ppm dose groups for all strains and both sexes. Considerable sex and strain differences were observed. Mortality, increased liver weights, and hepatocellular necrosis were greatest in B6C3F1 and C57BL/6 mice in the 250 ppm dose group and in males; hepatotoxicity was similar in both strains. Swiss mice exhibited dose-dependent increases in mortality, liver weights, and in hepatocellular necrosis, with only slight sex differences at early time points. Hepatotoxicity in DBA/2, B6C3F1, and C57BL/6 strains was greater at 250 than 500 ppm; however, toxicity was less severe in DBA/2 than in other strains based on absence of mortality in either sex and less extensive liver necrosis at both 250 and 500 ppm. Blood styrene and SO levels did not correlate well with strain differences in toxicity. The relative toxicity (mortality and hepatotoxicity) was B6C3F1 > Swiss > DBA/2; however, relative blood styrene and SO levels were B6C3F1 ⩾ DBA/2 > Swiss. Hepatic GSH depletion, (B6C3F1 ⩾ DBA/2 > Swiss) correlated with blood SO levels as expected. These results demonstrate significant biologic variability in the susceptibility of mouse strains to styrene toxicity. These differences are presumably due to strain and sex differences in metabolism; however, toxicity did not correlate well with blood SO levels, suggesting that other reactive metabolites may contribute to styrene toxicity in mice.