Physiologically based pharmacokinetic model development and simulations for ethylene dichloride (1,2-dichloroethane) in rats

Abstract

1,2-Dichloroethane (ethylene dichloride, EDC, CAS No. 107-06-2) is a chemical intermediate used in the production of vinyl chloride, trichloroethylene, vinylidene chloride, and trichloroethane. EDC is listed as a Hazardous Air Pollutant (HAP). As such, a need has been identified for a quantitative understanding of the hazards of EDC exposure by the inhalation route. Use of physiologically based pharmacokinetic (PBPK) modeling for route-to-route extrapolation of existing and a future toxicity studies conducted by the oral route may facilitate the quantitative evaluation of potential hazards posed by inhalation of EDC. PBPK models for the disposition of EDC by rats have been previously described, but a need to update the model structure and parameter values was identified based on the current understanding of kinetics of conjugation reactions mediated by glutathione- S-transferases (GSTs) and lack of fit to kinetic data that were not part of the development of previous models. Model structure updates included the addition of extrahepatic metabolism by unspecified enzymes (most likely GSTs or cytochrome P450 enzymes). Chemical-specific disposition parameters were recalibrated and provided good simulations for the majority of the large pharmacokinetic database for single or repeated exposure to EDC via inhalation, gavage, or iv injection in four strains of rats.