IARC MONOGRAPHS ON THE EVALUATION OF CARCINOGENIC ...

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IARC MONOGRAPHS VOLUME 82
(1.07 nmol/mg protein/min) to human (0.73 nmol/mg protein/min), whereas at a high
styrene concentration (1.85 mM), the rates were in the order of rat (4.21 nmol/mg
protein/min) to mouse (2.72 nmol/mg protein/min) to human (1.91 nmol/mg protein/
min). Activity in pulmonary microsomes from 38 individuals was much lower (0.006–
0.0125 nmol/mg protein/min) than in liver. Carlson et al. (2000) also observed low activity
for styrene metabolism in microsomal preparations from six human lungs. Styrene
7,8-oxide formation was detectable in only one human sample (0.088 nmol/mg protein/
min). [The Working Group noted that enzyme activity measurements based upon
analysis of whole organ homogenates do not reflect the substantial differences that exist
between cell types, as has been demonstrated by immunohistochemical methods for
CYP2E1 and CYP2F2 in lung (Buckpitt et al., 1995; Green et al., 1997).]
A few studies have described the formation of the ring-hydroxylated product 4-vinylphenol
after exposure of rodents to styrene. Bakke and Scheline (1970) reported finding
4-vinylphenol in amounts up to 0.1% of the dose in enzymatically hydrolysed urine of
male rats [strain unspecified] dosed orally with styrene (100 mg/kg bw). Similarly,
Pantarotto et al. (1978) identified small amounts of 4-vinylphenol, 4-hydroxymandelic
acid, 4-hydroxybenzoic acid and 4-hydroxyhippuric acid in the urine of male Sprague-
Dawley rats administered styrene intraperitoneally. More recently, when rats and mice
were exposed by inhalation to [ring-U- 14 C]styrene, Boogaard et al. (2000a) reported
finding 14 CO 2, suggesting that ring hydroxylation may occur followed by ring opening.
The fraction of the dose eliminated as 14 CO 2 varied from 6.4–8.0% of the retained dose
of styrene in mice to 2% of the retained dose in rats. Watabe et al. (1984) demonstrated
the formation of 4-vinylphenol using 14 C-labelled styrene and a rat hepatic microsomal
preparation fortified with NADPH after addition of a large amount of unlabelled 4-vinylphenol
as a trapping agent. They suggested that 4-vinylphenol was formed via the
3,4-oxide but very rapidly metabolized to 4-hydroxystyrene-7,8-glycol. Carlson et al.
(2001) were unable to confirm 4-vinylphenol formation when styrene was incubated with
hepatic and pulmonary microsomal preparations from CD-1 mice and Sprague-Dawley
rats. However, considerable 4-vinylphenol-metabolizing activity, as determined by the
loss of 4-vinylphenol, was observed in both mouse and rat liver and lung microsomal
preparations. This activity was three times higher in mouse liver microsomes than in rat
liver microsomes and eight times higher in mouse lung microsomes than in rat lung
microsomes, and it was completely absent in the absence of NADPH. Studies with cytochrome
P450 inhibitors indicated the involvement of CYP2E1 and CYP2F2.
Several studies have focused on the pharmacokinetics of styrene and some species
comparisons. Ramsey and Young (1978) exposed Sprague-Dawley rats to styrene by
inhalation at concentrations of 80, 200, 600 and 1200 ppm [341, 852, 2560 and
5110 mg/m 3 ] for up to 24 h. The increase in styrene concentration in blood with increased
exposure concentration was non-linear, indicating saturation of metabolism after about
6 h of exposure. Filser et al. (1993) compared male Sprague-Dawley rats and B6C3F 1
mice exposed to styrene by inhalation in a closed chamber (550–5000 ppm
[2340–21 300 mg/m 3 ]), by intraperitoneal injection (20–340 mg/kg bw) or by oral