IARC MONOGRAPHS ON THE EVALUATION OF CARCINOGENIC ...

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1968; Engström et al., 1978a,b; Ramsey et al., 1980; Wigaeus et al., 1983, 1984;
Pezzagno et al., 1985; Wieczorek & Piotrowski, 1985; Löf et al., 1986a,b). This has been
confirmed by more recent studies (Johanson et al., 2000; Wenker et al., 2001a,b).
Wrangskog et al. (1996) developed a simple one-compartment model for estimation of
styrene uptake based on measurements of urinary excretion of mandelic and phenylglyoxylic
acids.
In human volunteers exposed by placing one hand in liquid styrene for 10–30 min,
absorption was low, averaging 1 μg/cm 2 /min (Berode et al., 1985). Limasset et al. (1999)
carried out a field study comparing urinary excretion of metabolites of styrene in four
groups of workers who performed the same task but wore different protective equipment
(see Section 1.4.1(d)), and concluded that percutaneous absorption of styrene was not an
important contribution to the body burden.
(b) Distribution
Several studies have suggested that styrene accumulates in subcutaneous fat (Wolff
et al., 1977; Engström et al., 1978a,b). However, based on measurement of urinary metabolites,
workers exposed to 37 ppm (160 mg/m 3 ) styrene showed no accumulation during
the working week (Pekari et al., 1993). As noted below, pharmacokinetic analysis of the
disposition of styrene supports this conclusion.
(c) Metabolism
IARC MONOGRAPHS VOLUME 82
The metabolic pathways for styrene are shown in Figure 1. Styrene is primarily metabolized
to styrene 7,8-oxide by cytochrome P450 (CYP) enzymes. The oxide is metabolized
by epoxide hydrolase to phenylethylene glycol and then to mandelic, phenylglyoxylic
and benzoic acids. Additional routes of metabolism include ring hydroxylation, but
this appears to be a minor pathway in humans. Pfäffli et al. (1981) identified small
amounts of 4-vinylphenol in the urine of workers exposed to styrene (less than 1% of the
amount of mandelic acid excreted by these workers). Another pathway is conversion of
styrene to 1- and 2-phenylethanol, which is further metabolized to phenylacetaldehyde,
phenylacetic acid, phenylaceturic acid and hippuric acid. Styrene 7,8-oxide may also be
metabolized by conjugation with glutathione to form mercapturic acids. This appears to
be a minor pathway in humans, amounting to less than 1%. Ghittori et al. (1997)
evaluated urinary excretion in 22 workers in a reinforced-plastics factory (see
Section 1.1.5(b)) and identified racemic mercapturates, i.e., the R- and S-diastereoisomers
of N-acetyl-S-(1-phenyl-2-hydroxyethyl)cysteine and N-acetyl-S-(2-phenyl-2hydroxyethyl)cysteine.
Assuming a styrene uptake of 64%, the conversion to mercapturic
acids was calculated to be between 0.021 and 0.325% of the dose.
Korn et al. (1994) found a linear correlation between concentrations of styrene
7,8-oxide in the blood of workers exposed to styrene (10–73 ppm [43–310 mg/m 3 ]) and
styrene in ambient air and blood. At 20 ppm [85 mg/m 3 ] styrene, the steady-state level of
styrene 7,8-oxide was about 1 μg/L blood.