Review of the metabolic fate of styrene.

Styrene and styrene oxide have been implicated as reproductive toxicants, neurotoxicants, or carcinogens in vivo or in vitro. The use of these chemicals in the manufacture of plastics and polymers and in the boat-building industry has raised concerns related to the risk associated with human exposure. This review describes the literature to date on the metabolic fate of styrene and styrene oxide in laboratory animals and in humans. Many studies have been conducted to assess the metabolic fate of styrene in rats, and investigations on the metabolism of styrene in humans have been of considerable interest. Limited research has been done to assess metabolism in the mouse. The metabolism of styrene to styrene oxide and further conversion to styrene glycol (via epoxide hydrolase), mandelic acid, and phenylglyoxylic acid has been given considerable attention, and is considered to be the major pathway of activation and detoxication for humans. While the hydrolysis of styrene oxide to styrene glycol historically has been the favored pathway for the rat, studies in more recent years have indicated that glutathione conjugation also is a viable and significant pathway for both the rat and the mouse. This pathway has not been established in humans. Mandelic acid and phenylglyoxylic acid have been used as urinary markers of exposure in humans exposed to styrene. Extensive investigations have been conducted on the kinetics of styrene and styrene oxide in rodents. In people, the kinetics of styrene and styrene oxide in the blood of occupationally exposed workers and volunteers have been determined. Pharmacokinetic models developed in the last decade have become increasingly complex, with the most recent physiologically based model describing the kinetics of styrene and styrene oxide. This model shows pronounced species differences in sensitivity coefficients for styrene or styrene oxide between mice, rats, and humans, where mice are the more sensitive species to the Vmax for both epoxide hydrolase and monooxygenase. This result is particularly interesting in light of the recent findings of extensive mortality and hepatotoxicity for mice exposed to relatively low levels of styrene (250 to 500 ppm), while rats and humans exhibit only nasal and eye irritations at exposure concentrations well above 500 ppm.