Toxicological Sciences 54, 222-228 (2000)
Copyright © 2000 by the Society of Toxicology
Uptake of Styrene in the Upper Respiratory Tract of the CD Mouse and Sprague-Dawley Rat
Department of Pharmaceutical Sciences, School of Pharmacy, Box U-92, Storrs, Connecticut 06269
Inspired styrene is an olfactory toxicant in the mouse and rat. To provide nasal dosimetric information, upper respiratory tract (URT) uptake efficiency (UE) of styrene was measured in the surgically isolated URT of the urethane-anesthetized CD mouse and Sprague Dawley rat throughout a 45-min exposure. In the first studies, the effect of inspiratory flow rate on styrene UE was examined. At flows of 12-, 24-, or 70-ml/min average UE of 17, 9.8, and 4.1%, respectively, were observed in the mouse. For the rat, UE averaged 14, 9.1 and 5.7% at flow rates of 70, 150, and 400 ml/min, respectively. In the second study, UE was measured at inspired concentrations of 5, 10, 25, 50, 100, or 200 ppm at a flow rate of 12 ml/min in the mouse and 70 ml/min in the rat in both naïve and metyrapone (150 mg/kg sc) pretreated animals. In the rat, steady state UE decreased with increasing exposure concentration, averaging between 24 and 10% efficiency at 5 to 200 ppm (p < 0.0001). Metyrapone pretreatment resulted in statistically significant reductions in UE with steady-state UE averaging 10–14% at 5–200 ppm. Metyrapone pretreatment abolished the concentration dependence. In naïve mice, styrene UE did not maintain a steady state, but steadily declined during exposure. The mechanisms of the non-steady state behavior are not known, but they appear to be due to a styrene metabolite, as evidenced by the fact that steady-state UE was observed in metyrapone-pretreated mice. In the mouse, UE averaged between 42 and 10% efficiency at 5 to 200 ppm (p < 0.0001). Metyrapone pretreatment resulted in statistically significant reductions in UE, with steady state UE averaging 20–10% at 5–200 ppm. As in the rat, metyrapone pretreatment abolished the concentration dependence. In toto, these data provide strong evidence that inspired styrene is metabolized in nasal tissues in the rat and mouse and that a metabolic basis exists for the observed inspired concentration dependence of UE.
Key Words: metyrapone pretreatment; uptake efficiency (UE); concentration dependence; styrene metabolism.
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