Uptake of styrene in the upper respiratory tract of the CD mouse and Sprague-Dawley rat

Inspired styrene is an olfactory toxicant in the mouse and rat. To provide nasal dosimetric information, upper respiratory tract (URT) uptake efficien cy (UE) of styrene was measured in the surgically isolated URT of the ureth ane-anesthetized CD mouse and Sprague Dawley rat throughout a 45-min exposu re. 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, an d 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 naive and metyrapone (150 mg/kg sc) pretreated animals. In the rat, steady state UE decreased with increasing exposure concentrati on, averaging between 24 and 10% efficiency at 5 to 200 ppm (p < 0.0001). M etyrapone pretreatment resulted in statistically significant reductions in UE with steady-state UE averaging 10-14% at 5-200 ppm. Metyrapone pretreatm ent abolished the concentration dependence. In naive mice, styrene UE did n ot maintain a steady state, but steadily declined during exposure. The mech anisms of the non-steady state behavior are not known, but they appear to b e due to a styrene metabolite, as evidenced by the fact that steady-state U E was observed in metyrapone-pretreated mice; In the mouse, UE averaged bet ween 42 and 10% efficiency at 5 to 200 ppm (p < 0.0001). Metyrapone pretrea tment resulted in statistically significant reductions in UE, with steady s tate UE averaging 20-10% at 5-200 ppm. As in the rat, metyrapone pretreatme nt abolished the concentration dependence. In tote, these data provide stro ng evidence that inspired styrene is metabolized in nasal tissues in the ra t and mouse and that a metabolic basis exists for the observed inspired con centration dependence of UE.