EVALUATION OF THE METABOLISM AND HEPATOTOXICITY OF STYRENE IN F344 RATS, B6C3F1 MICE, AND CD-1 MICE FOLLOWING SINGLE AND REPEATED INHALATION EXPOSURES

Styrene is used for the manufacture of plastics and polymers. The meta bolism and hepatotoxicity (mice only) of styrene was compared in male B6C3F1 mice, CD-1 mice, and F344 rats to evaluate biochemical mechanis ms of toxicity. Rats and mice were exposed to 250 ppm styrene for 6 h/ day for 1 to 5 days, and liver (mice only) and blood were collected fo llowing each day of exposure. Mortality and increased serum alanine am inotransferase (ALT) activity were observed in mice but not in rats. H epatotoxicity in B6C3F1 mice was characterized by severe centrilobular congestion after one exposure followed by acute centrilobular necrosi s. Hepatotoxicity was delayed by 1 day in CD-1 mice, and the increase in ALT and degree of necrosis was less than observed for B6C3F1 mice. Following exposure to unlabeled styrene for 0, 2, or 4 days, rats and mice were exposed to [7-C-14]-styrene (60 mu Ci/mmol) for 6 h. Urine, feces, and expired air were collected for up to 48 h. Most styrene-der ived radioactivity was excreted in urine. The time-course of urinary e xcretion indicates that rats and CD-1 mice eliminated radioactivity at a faster rate than B6C3F1 mice following a single 250 ppm exposure, c onsistent with a greater extent of liver injury for B6C3F1 mice. The e limination rate following 3 or 5 days of exposure was similar for rats and both mouse strains. Following three exposures, the total radioact ivity eliminated in excreta was elevated over that measured for one ex posure for both mouse strains. An increased excretion of metabolites o n multiple exposure is consistent with the absence of ongoing acute ne crosis following 4 to 5 daily exposures. These data indicate that an i nduction in styrene metabolism occurs after multiple exposures, result ing in an increased uptake and/or clearance for styrene. (C) 1997 Else vier Science Ireland Ltd.