A physiologically based pharmacokinetic model for ethylene oxide in mouse,rat, and human

Ethylene oxide (EO) is widely used as a gaseous sterilant and industrial in termediate and is a direct-acting mutagen and carcinogen. The objective of these studies was to develop physiologically based pharmacokinetic (PB-PK) models for EO to describe the exposure-tissue dose relationship in rodents and humans. We previously reported results describing in vitro and in vivo kinetics of EO metabolism in male and female F344 rats and B6C3F1 mice, The se studies were extended by determining the kinetics of EO metabolism in hu man liver cytosol and microsomes. The results indicate enzymatically cataly zed GSH conjugation via cytosolic glutathione S-transferase (cGST) and hydr olysis via microsomal epoxide hydrolase (mEH) occur in both rodents and hum ans. The in vitro kinetic constants were scaled to account for cytosolic (c GST) and microsomal (mEH) protein content and incorporated into PB-PK descr iptions for mouse, rat, and human. Flow-limited models adequately predicted blood and tissue EO levels, disposition, and elimination kinetics determin ed experimentally in rats and mice, with the exception of testis concentrat ions, which were overestimated. Incorporation of a diffusion-limited descri ption for testis improved the ability of the model to describe testis conce ntrations. The model accounted for nonlinear increases in blood and tissue concentrations that occur in mice on exposure to EO concentrations greater than 200 ppm. Species differences are predicted in the metabolism and expos ure-dose relationship, with a nonlinear relationship observed in the mouse as a result of GSH depletion, These models represent an essential step in d eveloping a mechanistically based EO exposure dose-response description for estimating human risk from exposure to EO. (C) 2001 Academic Press.