IARC MONOGRAPHS ON THE EVALUATION OF CARCINOGENIC ...

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IARC MONOGRAPHS VOLUME 82
pancreatic lobules, inflammatory reactions around pancreatic islets (in mice only), and
altered serum insulin levels but no change in blood glucose levels.
Early studies reported morphological changes in the kidney of Sprague-Dawley rats
after intraperitoneal injections of styrene (2.9 and 5.8 mmol/kg bw on five days per week
for six weeks) (Chakrabarti et al., 1987) and in the respiratory mucosa of SD rats exposed
to styrene by inhalation (150 or 1000 ppm [639–4260 mg/m 3 ], 4 h per day, five days per
week, three weeks) (Ohashi et al., 1986). Effects in kidney and lung are associated with
depletion of glutathione (Chakrabarti & Tuchweber, 1987; Elovaara et al., 1990) and
possibly with direct toxicity of glutathione conjugates to the kidney, as was shown in
experiments with a synthetic glutathione–styrene conjugate (Chakrabarti & Malick,
1991). Viau et al. (1987) reported that Sprague-Dawley rats given intraperitoneal injections
of styrene (1 g/kg bw, which is one-fifth the oral LD 50) daily for 10 days showed
only mild tubular damage. In female Sprague-Dawley rats exposed to styrene (300 ppm
[1280 mg/m 3 ], 6 h per day, five days per week, for 12 weeks), a small increase was
observed in the urinary excretion of plasma proteins, with minor changes in kidney histopathology
consisting of interstitial fibrosis, cystic dilatations and hyaline tubules (Mutti
et al., 1999).
Early studies reported that styrene caused hepatotoxicity in rats concomitantly with
a depletion of glutathione, which may be either a direct effect of styrene or mediated by
lipid peroxidation (Srivastava et al., 1983; Katoh et al., 1989). Male albino rats [strain
not stated] were dosed orally with 200 or 400 mg/kg bw styrene on six days per week for
100 days (Srivastava et al., 1982). Liver changes were observed only after the high dose
and were characterized by tiny areas of focal necrosis composed of a small number of
degenerated hepatocytes and inflammatory cells.
Exposure of B6C3F 1 mice to 0, 125, 250 or 500 ppm [0, 530, 1060 or 2130 mg/m 3 ]
styrene for 6 h per day for 14 days caused severe centrilobular hepatic necrosis and death
after one 6-h exposure to 500 ppm or two 6-h exposures to 250 ppm styrene (Morgan
et al., 1993a). Mortality was higher in male than in female mice and, after 14 days of
exposure, the incidence and severity of liver lesions were also greater in male mice. In a
subsequent study, the greater sensitivity of male mice to styrene exposure compared with
females could not be explained by differences in glutathione depletion or styrene or
styrene 7,8-oxide concentrations in blood (Morgan et al., 1993b). Further investigation
of the role of metabolism in the toxicity of styrene in mice revealed that styrene and
styrene 7,8-oxide concentrations in blood did not correlate well with strain differences in
sensitivity (Morgan et al., 1993c). Mortality and hepatotoxicity induced by exposure to
styrene were greater in B6C3F 1 and C57BL/6 mice than in Swiss mice, while DBA/2
mice were the least sensitive. Styrene and styrene 7,8-oxide concentrations in blood as
well as glutathione depletion were similar in B6C3F 1 and DBA/2 mice but greater than
those in Swiss mice. Although strain and gender differences in sensitivity to styrene toxicity
have been suggested to be due to differences in metabolism, styrene 7,8-oxide
concentrations in blood did not correlate with toxicity in these studies. Morgan et al.
(1995) further investigated strain and gender differences in styrene toxicity at inhalation