Investigation of the mechanism(s) of styrene hepatotoxicity were continued. Recently completed studies suggest that development of resistance to styrene hepatotoxicity is associated with sustained cell proliferation. Increased numbers of centrilobular S-phase cells with continuous styrene exposure appear to be due to perturbations in the cell cycle as suggested by preferential BrdU labeling of hepatocytes with enlarged and polyplid nuclei. Resistance does not appear to be caused by changes in metabolic activity. Further studies are in progress to determine possible relationships between cell cycle events and resistance to toxicity. Unlike styrene, inhalation of -methylstyrene (AMS) did not cause hepatotoxicity in mice at similar (and higher) exposure concentrations. In addition, AMS caused hyaline droplet nephropathy in male rats, whereas this lesion was not caused by styrene. Further characterization of this lesion is in progress. In preparation for inhalation studies of divinylbenzene (DVB), generation and monitoring systems have been developed and validated. Results of an initial DVB inhlation study suggests that the liver is the target organ for DVB in mice and that DVB is more hepatotoxic than styrene. Inhalation studies are in progress to investigate and compare mechanisms of DVB hepatotoxicity with styrene. The genotoxicity of DVB is being studied in collaboration with the USEPA. Pharmacokinetic studies are being conducted to evaluate and compare the uptake, distribution, and metabolism of styrene, AMS, and DVB in mice and rats during nose-only inhalation exposure. These data are being used to develop a PBPK model.
