IARC MONOGRAPHS ON THE EVALUATION OF CARCINOGENIC ...

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Styrene caused a dose-dependent increase in serum sorbitol dehydrogenase activity, an
indicator of hepatotoxicity. Pretreatment of the animals with pyridine and β-naphthoflavone,
inducers of CYP enzymes, increased the toxicity of styrene, but pretreatment
with phenobarbital had no such effect. Trichloropropene oxide, an inhibitor of epoxide
hydrolase, increased the hepatotoxicity of styrene 7,8-oxide, while buthionine sulfoximine,
a glutathione depletor, did not. When given at the same dose (300 mg/kg bw), the
racemic mixture of styrene 7,8-oxides and R-styrene 7,8-oxide caused a greater hepatotoxic
effect than did S-styrene 7,8-oxide. However, differences in pulmonary toxicity
between the enantiomers were not statistically significant. In a subsequent study to assess
the susceptibility of mouse strains to the effects of styrene and styrene 7,8-oxide, male
mice (A/J, C57BL/6 or CD-1) were given an intraperitoneal injection of 800 mg/kg bw
styrene and killed 24 h later (Carlson, 1997b). Biomarkers of hepatotoxicity and
pneumotoxicity were evaluated as in the study mentioned above (Gadberry et al., 1996).
CD-1 mice were not as sensitive as the other strains to the hepatotoxic or pneumotoxic
effects of styrene, but were equally sensitive to the toxic effects of styrene 7,8-oxide
given by intraperitoneal injection at 300 mg/kg bw.
Hepatotoxicity and cell proliferation induced in male B6C3F 1 mice by a single 6-h
exposure to 500 ppm [2130 mg/m 3 ] styrene was compared with that caused by repeated
exposures to 500 ppm styrene for 6 h per day for up to 14 days (Mahler et al., 1999).
Single or repeated inhalation exposure of mice to styrene caused severe necrosis of
centrilobular hepatocytes followed by regeneration of necrotic zones. Re-exposure to
styrene of mice that had received only a single dose of styrene resulted in hepatocellular
necrosis, indicating that regenerated centrilobular cells were again susceptible to the
cytolethal effect of styrene following a 14-day recovery. In contrast, continuous styrene
exposure induced hepatocellular resistance to the cytolethal effect of styrene. New
hepatocytes were produced with reduced metabolic activity. Centrilobular hepatocytes
were resistant to styrene while they were actively synthesizing DNA and continued
styrene exposure was required for sustained DNA synthesis.
4.3 Reproductive and developmental effects
Reproductive and developmental effects of styrene have been reviewed by IARC
(1994a) and very extensively by Brown et al. (2000). The present evaluation is mainly
based on these reviews and recent studies not included therein.
4.3.1 Humans
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Early human studies suggested an association between occupational exposure to
styrene and congenital central nervous system malformation (Holmberg, 1977, 1979),
but subsequent, more extensive studies by the same and other investigators did not
confirm the association (Brown et al., 2000).