A PHYSIOLOGICAL PHARMACOKINETIC MODEL FOR STYRENE AND STYRENE-7,8-OXIDE IN MOUSE, RAT AND MAN

Concern about the carcinogenic potential of styrene (ST) is due to its reactive metabolite, styrene-7,8-oxide (SO). To estimate the body bur den of SO resulting from various scenarios, a physiologically based ph armacokinetic (PBPK) model for ST and its metabolite SO was developed. This PBPK model describes the distribution and metabolism of ST and S O in the rat, mouse and man following inhalation, intravenous (i.v.), oral (p.o.) and intraperitoneal (i.p.) administration of ST or i.v., p .o. and i.p. administration of SO. Its structure includes the oxidatio n of ST to SO, the intracellular first-pass hydrolysis of SO catalyzed by epoxide hydrolase and the conjugation of SO with glutathione. This conjugation is described by an ordered sequential ping-pong mechanism between glutathione, SO and glutathione S-transferase. The model was based on a PBPK model constructed previously to describe the pharmacok inetics of butadiene with its metabolite butadiene monoxide. The equat ions of the original model were revised to refer to the actual tissue concentration of chemicals instead of their air equivalents used origi nally. Blood: air and tissue: blood partition coefficients for ST and SO were determined experimentally and have been published previously. Metabolic parameters were taken from in vitro or in vivo measurements. The model was validated using various data sets of different laborato ries describing pharmacokinetics of ST and SO in rodents and man. In a ddition, the influences of the biochemical parameters, alveolar ventil ation and blood: air partition coefficient for ST on the pharmacokinet ics of ST and SO were investigated by sensitivity analysis. The PBPK m odel presented can be used to predict concentration-time curves of ST or SO in blood and different tissues.