Review of the Metabolic Fate of Styrene

Abstract

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.

Subchronic Inhalation Studies of Styrene in CD Rats and CD-1 Mice

“…The exposure (Miller et al, 1994), toxicologic (McConnell and Swenberg, 1994;Phillips and Farmer, 1994;Scott and Preston, 1994), metabolic (Sumner and Fennell, 1994), and epidemiologic (Rebert and Hall, 1994;Coggon, 1994) data on styrene were recently reviewed. Several chronic toxicity/carcinogenicity studies of styrene in laboratory animals were performed in the 1970s, but most are deficient for use in human health hazard assessments due to problems in study design, conduct, or reporting (McConnell and Swenberg, 1994); problems included exceeding the Maximum-tolerated-dose, intercurrent disease, and minimal descriptions of the conduct and detailed results of the studies.…”

Detection of Phenolic Metabolites of Styrene in Mouse Liver and Lung Microsomal Incubations

“…These metabolites were also detected in urine of workers in reinforced plastic plants (Pfäffli et al, 1981;Manini et al, 2003). 2-Vinylphenol (2-VP) and 3-vinylphenol (3-VP) have been proposed as aromatic hydroxylation products of styrene (Sumner and Fennell, 1994), but they have never been identified either in experimental animals or in humans exposed to styrene. Most recently, Linhart et al (2010) reported urinary 3-VP, 4-VP, and possible 2-VP in mice exposed to airborne styrene.…”

“…Lung microsomal incubations with styrene afforded a similar metabolite profile except for vinyl-1,4-hydroquinone and 4-hydroxystyrene glycol. The observation of the glycols infers the formation of the corresponding epoxides (Bond, 1989;Sumner and Fennell, 1994). The observed vinyl-1,4-hydroquinone may be spontaneously oxidized to vinyl-1,4-benzoquinone (Scheme 2) (Shen et al, 1997).…”

“…Aromatic hydroxylation of styrene has been reported, and it is considered to be a minor metabolism pathway of styrene (Bond, 1989;Sumner and Fennell, 1994;Vodicka et al, 2006). Urinary 4-vinylphenol (4-VP) and its glucuronide and sulfate conjugates were detected in urine of rats treated with styrene (Bakke and Scheline, 1970;Pantarotto et al, 1978).…”

“…The metabolism of styrene has been extensively investigated. Epoxidation of the vinyl group is the primary oxidation reaction by which styrene is metabolized to styrene-7,8-oxide (SO, 2) (Scheme 1) (Bond, 1989;Sumner and Fennell, 1994). The oxidative metabolite has been reported to be mutagenic and carcinogenic (IARC, 1994;Gadberry et al, 1996).…”