A toxicokinetic model for styrene and its metabolite styrene-7,8-oxide in mouse, rat and human with special emphasis on the lung.
Styrene (ST) occurs ubiquitously in the environment and it is an important industrial chemical. After its uptake by the exposed mammalian organism, ST is oxidized to styrene-7,8-oxide (SO) by cytochrome P450 dependent monooxygenases. This reactive intermediate is further metabolized by epoxide hydrolase (EH) and glutathione S-transferase (GST). In long-term animal studies, ST induced lung tumors in mice but not in rats. Considering the lung to be the relevant target organ for ST induced carcinogenicity in mice, we extended a previously developed physiological toxicokinetic model in order to simulate the lung burden with ST and SO in the ST exposed mouse, rat and human. The new model describes oral and pulmonary uptake of ST, its distribution into various tissues, its exhalation and its metabolism to SO in lung and liver. It also simulates the distribution of the produced SO into the tissues and its EH and GST mediated metabolism in liver and in lung. In both organs the ST induced GSH consumption is described together with the formation of adducts to hemoglobin and to DNA of lymphocytes in ST exposed mice, rats and humans. The model includes compartments for arterial, venous and pulmonary blood, liver, muscle, fat, richly perfused tissues and lung. The latter organ is represented by two compartments, namely by the conducting and the alveolar zone. The physiological description of the pulmonary compartments relies on measured alveolar retentions, literature values of surface area of capillary endothelium, of the thickness of the tissue 'air-to-plasma', of the partition coefficient lung:blood and of metabolic parameters of ST and SO measured in pulmonary cell fractions of rodents and humans. Simulations of average pulmonary GSH levels in ST exposed rodents agree with measured data. The model predicts a significant GSH depletion (40%) in the conducting zone of mice exposed for 6 h to a ST concentration of only 20 ppm. In the conducting zone of rats, exposure to 200 ppm ST results in a loss of GSH of about 15% only. In humans, a pulmonary GSH reduction does not occur. The highest average pulmonary SO concentrations are predicted for mice, somewhat lower values for rats and by far the lowest ones for humans. Following steady state exposure to 20 ppm ST, the average SO concentration in mouse lungs is expected to be only three times higher than in rats. This difference diminishes to a factor of less than two at 70 ppm. In humans exposed to 20 ppm ST for 8 h, the average pulmonary SO burden of 0.016 micromol/kg is predicted to be about 17 and 50 times smaller than the corresponding values for rat and mouse. In agreement with reported values, pulmonary DNA adduct levels in rodents exposed to 160 ppm ST were simulated to be similar in rats and mice. In summary, there was no dramatic difference in the calculated average pulmonary SO burden between both animal species. However, pulmonary GSH loss was by far more expressed in ST exposed mice than rats. Since the model was validated on all available ST/SO data in mice, rats and humans, we consider it to be useful for estimating the risk resulting from exposure to ST.
Csanády
Gy A
GA
GSF-Institute of Toxicology, Ingolstädter Landstrasse 1; D-85764 Neuherberg, Germany.
Kessler
W
W
Hoffmann
H D
HD
Filser
J G
JG
D000280:Administration, Inhalation; D000818:Animals; D002273:Carcinogens / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity*; D018736:DNA Adducts / Q000032:analysis; D004852:Epoxy Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity*; D006454:Hemoglobins / Q000378:metabolism; D006801:Humans; D008168:Lung / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D051381:Rats; D013045:Species Specificity; D020058:Styrene / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity*
D002273:Carcinogens; D018736:DNA Adducts; D004852:Epoxy Compounds; D006454:Hemoglobins; D020058:Styrene; C013690:styrene oxide