IARC MONOGRAPHS ON THE EVALUATION OF CARCINOGENIC ...

STYRENE 483
a maximum and averaged 6.7 nM. There was no evidence of glutathione conjugation or
ring epoxidation.
Individual differences in the metabolic response to styrene were studied in 20 male
volunteers exposed on separate occasions to 104 and 360 mg/m 3 styrene for 1 h while
performing 50-W exercise. Urinary mandelic and phenylglyoxylic acids were measured
to make correlations with individual metabolic capacities determined with enzymespecific
substrates for CYP2E1, CYP1A2 and CYP2D6. No correlation was found
among individuals between the blood clearance of styrene and the metabolic capacity.
Based on the high apparent blood clearance of styrene (1.4 L/min), one explanation
proposed by the authors is that styrene metabolism is limited by the blood flow to the
liver, which has a similar value (Wenker et al., 2001b). Symanski et al. (2001) examined
inter- and intra-individual differences in urinary concentrations of mandelic and phenylglyoxylic
acids based on 1714 measurements in 331 workers over the period 1985–99.
Interindividual differences were greater for post-shift urine samples than for pre-shift
samples.
Hallier et al. (1995) measured R- and S-mandelic acids in the urine of 20 male
workers exposed to 29–41 ppm styrene [124–175 mg/m 3 ]. The ratio of the R- to S-enantiomers
of mandelic acid ranged from 0.7 to 2.2. This variation could not be explained
by differences in exposure levels and was attributed to interindividual differences in
styrene metabolism, probably related to enzyme polymorphisms.
The role of specific CYP isozymes in the metabolism of styrene has been examined.
Nakajima et al. (1994a), using 12 different purified human isozymes, determined that
CYP2B6 and CYP2E1 were the most active in human liver microsomes in forming
styrene glycol, and CYP2F1 was the most active in lung microsomes. Guengerich et al.
(1991) also demonstrated the significance of CYP2E1 in styrene metabolism, using
diethyldithiocarbamate as a specific inhibitor of CYP2E1 and correlations with chlorzoxazone
6-hydroxylation — an indicator of CYP2E1 activity — in human liver microsomes.
Using antibodies against specific human CYP isozymes and by comparing rates
of styrene glycol formation by microsomes isolated from human livers, Kim et al. (1997)
identified CYP2E1 and CYP2C8 as being the most important metabolic enzymes at low
styrene concentration (0.085 mM), while CYP2B6 and CYP2C8 were most prominent at
a high concentration of styrene (1.8 mM).
Wenker et al. (2000) examined the stereospecificity and interindividual variation in
microsomal epoxide hydrolase activity in 20 human liver samples. V max, K m and V max/K m
values for the substrates R- and S-styrene 7,8-oxides varied three- to five-fold between
livers. The rate of hydrolysis of S-styrene 7,8-oxide was approximately five times slower
than that of R-styrene 7,8-oxide, although the K m was six times higher for S-styrene
7,8-oxide. In a further report (Wenker et al., 2001c), an eightfold variation in V max was
found for styrene metabolism by 20 human liver samples (0.39–3.2 nmol/mg protein/
min), and, although CYP2E1 was found to be the most important cytochrome P450 isoform,
there was no correlation between the enzymic activity (V max or K m) and genetic
polymorphisms of this enzyme.