IARC MONOGRAPHS ON THE EVALUATION OF CARCINOGENIC ...

STYRENE 489
gavage (100–350 mg/kg bw). In both species, the rate of metabolism of the inhaled
styrene was concentration-dependent. At exposure concentrations above 300 ppm
[1280 mg/m 3 ], metabolism was progressively limited by metabolic capacity and was
saturated at concentrations of approximately 700 ppm [2980 mg/m 3 ] in rats and 800 ppm
[3410 mg/m 3 ] in mice. Little accumulation occurred at exposures below 300 ppm
[1280 mg/m 3 ] since uptake was rate-limiting. In rats and mice, intraperitoneal injection
of styrene followed by analysis of exhaled styrene in the closed chamber resulted in
concentration–time curves in agreement with the applied pharmacokinetic model. After
oral administration of styrene, the concentration–time curves showed considerable interanimal
variability.
In a chronic inhalation study in Sprague-Dawley rats exposed (whole-body) to
styrene vapour at 0, 50, 200, 500 or 1000 ppm [0, 213, 852, 2130 or 4260 mg/m 3 ] for 6 h
per day, five days per week for 104 weeks, blood levels of styrene and styrene 7,8-oxide
were measured at the end of a 6-h exposure period during week 95. Styrene 7,8-oxide in
blood was undetectable in males or females at 0 or 50 ppm. While the styrene 7,8-oxide
concentration in blood continued to increase with higher styrene exposure concentration,
some saturation of metabolism was observed (Cruzan et al., 1998). In CD-1 mice
exposed to styrene vapour at 0, 20, 40, 80 or 160 ppm [0, 85, 170, 341 or 682 mg/m 3 ]
for 98 weeks (females) or 104 weeks (males), blood levels of styrene and styrene
7,8-oxide were measured at the end of a 6-h exposure period during week 74. Styrene
7,8-oxide in blood was undetectable in males and females at 0 and 20 ppm. At higher
exposure doses, concentration-dependent increases were observed for styrene and
styrene 7,8-oxide in blood, with no evidence for saturation of metabolism (Cruzan et al.,
2001). Comparing the two studies, blood styrene concentrations in male and female rats
reached 2780 ng/mL and 1950 ng/mL at 200 ppm styrene exposure and blood styrene
7,8-oxide concentrations reached 66 ng/mL and 28 ng/mL at this exposure level, respectively,
whereas for mice the corresponding values at the highest dose (160 ppm) were
1461 ng/mL and 1743 ng/mL for styrene and 33.5 ng/mL and 20.1 ng/mL for styrene
7,8-oxide in males and females, respectively.
The effect of antibodies to CYP2C11/6, CYP2B1/2, CYP1A1/2 and CYP2E1 on the
rates of styrene metabolism was studied in male Wistar rat lung and liver microsomal
preparations. All four antibodies decreased styrene metabolism in microsomes from rat
liver, with anti-CYP2C11/6 having the strongest effect, but only anti-CYP2B1/2 affected
the metabolism in lung microsomes. This indicates that the major CYP isoform responsible
for metabolism of styrene is different in these two tissues (Nakajima et al., 1994b).
Studies with human cytochromes P450 ectopically expressed in cultured hepatoma G2
cells indicate that CYP2B6 and CYP2F1 may also be involved in styrene metabolism
(Nakajima et al., 1994a). The potential contributions of various cytochromes P450 to
styrene metabolism have also been examined by use of chemical inhibitors of specific
isozymes in hepatic and pulmonary microsomal preparations of male CD-1 mice.
Diethyldithiocarbamate inhibited the formation of both enantiomers of styrene 7,8-oxide
in lung and liver, supporting the importance of CYP2E1. 5-Phenyl-1-pentyne showed a