A physiological toxicokinetic model for exogenous and endogenous ethylene and ethylene oxide in rat, mouse, and human: Formation of 2-hydroxyethyl adducts with hemoglobin and DNA

Ethylene (ET) is a gaseous olefin of considerable industrial importance. It is also ubiquitous in the environment and is produced in plants, mammals, and humans. Uptake of exogenous ET occurs via inhalation. ET is biotransfor med to ethylene oxide (EO), which is also an important volatile industrial chemical. This epoxide forms hydroxyethyl adducts with macromolecules such as hemoglobin and DNA and is mutagenic in vivo and in vitro and carcinogeni c in experimental animals. It is metabolically eliminated by epoxide hydrol ase and glutathione S-transferase and a small fraction is exhaled unchanged . To estimate the body burden of EO in rodents and human resulting from exp osures to EO and ET, we developed a physiological toxicokinetic model. It d escribes uptake of ET and EO following inhalation and intraperitoneal admin istration, endogenous production of ET, enzyme-mediated oxidation of ET to EO, bioavailability of EO, EO metabolism, and formation of 2-hydroxyethyl a dducts of hemoglobin and DNA. The model includes compartments representing arterial, venous, and pulmonary blood, liver, muscle, fat, and richly perfu sed tissues. Partition coefficients and metabolic parameters were derived f rom experimental data or published values. Model simulations were compared with a series of data collected in rodents or humans. The model describes w ell the uptake, elimination, and endogenous production of ET in all three s pecies. Simulations of EO concentrations in blood and exhaled air of rodent s and humans exposed to EO or ET were in good agreement with measured data. Using published rate constants for the formation of 2-hydroxyethyl adducts with hemoglobin and DNA, adduct levels were predicted and compared with va lues reported. In humans, predicted hemoglobin adducts resulting from expos ure to EO or ET are in agreement with measured values. In rodents, simulate d and measured DNA adduct levels agreed generally well, but hemoglobin addu cts were underpredicted by a factor of 2 to 3. Obviously, there are inconsi stencies between measured DNA and hemoglobin adduct levels. (C) 2000 Academ ic Press.