IARC MONOGRAPHS ON THE EVALUATION OF CARCINOGENIC ...

STYRENE 515
styrene 7,8-oxide. Johanson et al. (2000) have quantified blood levels of styrene 7,8oxide
in human volunteers exposed to styrene.
In all experimental animal species studied, styrene is rapidly metabolized to styrene
7,8-oxide following absorption by oral, dermal or inhalation exposure. Styrene 7,8-oxide
is sufficiently stable to be readily detected in the blood of both rats and mice exposed to
styrene. Systemic styrene 7,8-oxide concentrations do not, however, explain interspecies
differences in the carcinogenic response to styrene. At styrene exposure concentrations
of 1000 ppm [4260 mg/m 3 ] (the highest concentration tested), styrene 7,8-oxide concentrations
in the blood of rats were two orders of magnitude higher than those in the blood
of mice exposed to 20–40 ppm [85–170 mg/m 3 ] styrene (the lowest concentrations
causing tumours), although mice, but not rats, develop lung tumours (Cruzan et al., 1998,
2001).
The enzymatic oxidation of styrene to styrene 7,8-oxide is mediated by several isoforms
of cytochrome P450 (CYP) enzymes including CYP2E1, CYP2B6 and CYP2F1
in humans. In experimental animals, CYP2E1 appears to be the major isoform responsible
for styrene oxidation in the liver, and CYP2F2 is the major form in the mouse lung,
as determined by in-vitro studies (Carlson, 1997a). Interspecies differences exist in the
rates of metabolism of styrene by liver and lung tissue. In particular, human lung tissue
produces less styrene 7,8-oxide than that of rats and considerably less than that of mice
(Nakajima et al., 1994a; Carlson et al., 2000; Filser et al., 2002).
The metabolism of styrene to styrene 7,8-oxide in mouse lung occurs almost exclusively
in the Clara cells and the rate of styrene oxidation in these cells is threefold faster
than in Clara cells of rats (Hynes et al., 1999). The mouse Clara cell may be at greater
risk than the rat Clara cell if locally generated, rather than extrapulmonary, styrene
7,8-oxide is critical for cytotoxic or genotoxic damage.
Metabolism of styrene 7,8-oxide can proceed through hydrolysis of styrene
7,8-oxide by epoxide hydrolase or through conjugation with glutathione mediated by
glutathione S-transferase. Conversion to phenylacetaldehyde and other ring-opened
metabolites provides additional pathways for styrene and styrene 7,8-oxide metabolism
(Sumner & Fennell, 1994; Johanson et al., 2000). Stable products representing each of
these pathways are eliminated in the urine. Interspecies differences exist in the proportion
of styrene 7,8-oxide that is eliminated via each of these pathways, and these differences
may play a role in the species sensitivity towards the toxic and carcinogenic
effects of styrene exposure. For example, the capacity of epoxide hydrolase in human
tissues to detoxify styrene 7,8-oxide exceeds that of rat or mouse tissues. In contrast, the
activity of glutathione S-transferase in human tissues is much lower than in rodent tissues
(summarized in Cohen et al., 2002). Mouse tissues show significantly higher rates of
activation of styrene to DNA-reactive epoxides than do rat or human tissues. While
mouse, rat and human tissues all use epoxide hydrolase to detoxify styrene 7,8-oxide, the
mouse also uses glutathione S-transferase to a significant extent, with less activity in the
rat and very little in humans.