Potential extrapulmonary effects of nitrogen dioxide (NO2) on hepatic xenobiotic metabolism were examined. Initial studies were conducted using pentobarbital (PEN) induced sleeping time (S.T.) in mice as an indicator of integrated mechanisms of xenobiotic clearance. A 3 hr. exposure to concentrations as low as 0.47 mg NO2/cu. m. (0.25 ppm) caused a significant increase in PEN-induced S.T. in female mice. When exposures were repeated for several days, the magnitude of the effect diminished. Investigation of sex sensitivity indicated that female mice were affected by acute exposure (3 hr./day, 1 or 2 days), but males were not. It was also observed that a 4 day (3 hr./day) exposure to 1.88 mg NO2/cu. m. (1.0 ppm) induced tolerance to the effects of 9.4 mg NO2/cu. m. (5.0 ppm). Mechanisms for the increase in PEN-induced S.T. were sought by evaluating hepatic cytochrome P-450 levels and the activity of 3 hepatic mixed function oxidases (aniline hydroxylase, aminopyrine N-demethylase and p-nitroanisole O-demethylase) in female mice exposed to concentrations of NO2 causing an increase in PEN-induced S.T. No significant effects were observed. A 3 hr. exposure to 9.4 mg NO2/cu. m. increased cytochrome P-450 levels in the lung, but not the liver, of rabbits.