IARC MONOGRAPHS ON THE EVALUATION OF CARCINOGENIC ...

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IARC MONOGRAPHS VOLUME 82
according to a two-compartment linear pharmacokinetic model that was similar to that
for rats. The model predicted that there would be no accumulation of styrene at this exposure
concentration and upon repeated administration. Ramsey and Andersen (1984)
developed a physiologically based pharmacokinetic model, which indicated that there
was saturation of styrene metabolism at inhaled doses above 200 ppm [852 mg/m 3 ] in
mice, rats and humans. At lower levels of exposure, the ratio of styrene concentration in
blood to that in inhaled air is controlled by perfusion-limited metabolism.
Another physiologically based pharmacokinetic model was based on data collected
by Mandrala et al. (1993) to predict concentration–time curves for styrene and styrene
7,8-oxide in blood and tissues (Csanády et al., 1994). At low concentrations, styrene is
rapidly removed from blood and the rate of metabolism is limited by the blood flow
through the liver.
Cohen et al. (2002) developed a pharmacokinetic model viewing the lung as two
compartments, the alveolar tract and the capillary bed. This model included both pulmonary
and hepatic metabolism and predicted tissue or organ concentrations of styrene and
styrene 7,8-oxide (both the S- and R-enantiomers, separately), under specified conditions.
It was based on the Csanády et al. (1994) model, which only accounted for styrene
metabolism by the liver. The authors indicated that the model has a substantial degree of
uncertainty, however, because of inconsistencies between studies in reporting styrene
7,8-oxide levels in blood, which complicated the validation of the model.
Filser et al. (2002) compared the modelled concentrations of styrene 7,8-oxide in the
lungs of the mouse, rat and human over a range of styrene concentrations assuming 6- or
8-h exposures. The highest concentrations of styrene 7,8-oxide were predicted for the
mouse followed by the rat, with humans having by far the lowest concentration. These
differences reflected the species differences in the pulmonary metabolism of styrene to
styrene 7,8-oxide and subsequent detoxification of the oxide.
The most comprehensive modelling for styrene metabolism and styrene 7,8-oxide
dosimetry comparing rodents and humans was undertaken by Sarangapani et al. (2002).
It expanded upon the Csanády et al. (1994) model by incorporating information on the
metabolic production of styrene 7,8-oxide and its decrease in the respiratory tract and
was used to predict the concentrations of styrene and styrene 7,8-oxide in blood, liver and
respiratory tract. This model predicts a ten-fold lower styrene 7,8-oxide concentration in
the terminal bronchioles of rats than in mice exposed to identical concentrations of
styrene. The model suggests that styrene 7,8-oxide concentrations in human bronchioles
would be 100-fold lower than for the mouse.
Tornero-Velez and Rappaport (2001) modified the physiologically based pharmacokinetic
model of Csanády et al. (1994) to compare the predicted contribution of styrene
7,8-oxide resulting from metabolism with that from direct exposure in the workplace.
They tested their model against air and blood concentrations of styrene and styrene
7,8-oxide in 252 workers in the reinforced plastics industry. Due to efficient detoxification
of the oxide formed in the liver, direct exposure via inhalation appeared to be a
more important source of styrene 7,8-oxide than the bioactivation of inhaled styrene. The