In Vivoandin VitroKinetics of Ethylene Oxide Metabolism in Rats and Mice

Abstract

Ethylene oxide (EO) is a direct-acting mutagen and animal carcinogen used as an industrial intermediate and sterilant with a high potential for human exposure. Kinetics of EO metabolism in rodents can be used to develop human EO dosimetry models. This study examined the kinetics of EO metabolismin vivoandin vitroin male and female F-344 rats and B6C3F1 mice.In vivostudies measured blood and tissue EO levels during and 2–20 min following whole-body inhalation exposure (4 hr, 100 or 330 ppm EO). At 100 ppm EO, the half-life of elimination (t1/2) in rats was 13.8 ± 0.3 (mean ± SD) and 10.8 ± 2.4 min for males and females, respectively, compared to at1/2in mice of 3.12 ± 0.2 and 2.4 ± 0.2 min in males and females, respectively. On exposure to 330 ppm EO, thet1/2in mice increased approx twofold, while no change int1/2was observed in rats.In vitrokinetic parameters (VmaxandKM) of EO metabolism were determined using tissue cytosol and microsomes. EO metabolismin vitrooccurred primarily via cytosolic glutathioneS-transferase-mediated EO–GSH conjugation (cGST–EO), with highest activity in the liver. Liver cGST–EO activity (Vmax) was 258 ± 86.9 and 287 ± 49.0 nmol/mg protein/min (mean ± SD) in male and female mice, respectively, compared to 52.7 ± 10.8 and 29.3 ± 4.9 in male and female rats, respectively. In rats, but not mice, there was a statistically significant (p< 0.05) gender difference in theVmaxfor liver cGST. TheKMfor liver cGST–EO was approximately 10 mMin both species. The higherVmaxvalues observed in mice are consistent with the more rapid elimination of EO observed for this speciesin vivocompared to rats.