Abstract
Ethylene (ET) is the largest volume organic chemical. Mammals metabolize the olefin to ethylene oxide (EO), another important industrial chemical. The epoxide alkylates macromolecules and has mutagenic and carcinogenic properties. In order to estimate the EO burden in mice, rats, and humans resulting from inhalation exposure to gaseous ET or EO, a physiological toxicokinetic model was developed. It consists of the compartments lung, richly perfused tissues, kidneys, muscle, fat, arterial blood, venous blood, and liver containing the sub-compartment endoplasmic reticulum. Modeled ET metabolism is mediated by hepatic cytochrome P450 2E1, EO metabolism by hepatic microsomal epoxide hydrolase or cytosolic glutathione S-transferase in various tissues. EO is also spontaneously hydrolyzed or conjugated with glutathione. The model was validated on experimental data collected in mice, rats, and humans. Modeled were uptake by inhalation, wash-in–wash-out effect in the upper respiratory airways, distribution into tissues and organs, elimination via exhalation and metabolism, and formation of 2-hydroxyethyl adducts with hemoglobin and DNA. Simulated concentration-time courses of ET or EO in inhaled (gas uptake studies) or exhaled air, and of EO in blood during exposures to ET or EO agreed excellently with measured data. Predicted levels of adducts with DNA and hemoglobin, induced by ET or EO, agreed with reported levels. Exposures to 10000 ppm ET were predicted to induce the same adduct levels as EO exposures to 3.95 (mice), 5.67 (rats), or 0.313 ppm (humans). The model is concluded to be applicable for assessing health risks from inhalation exposure to ET or EO.
Highlights
The colorless gas ethylene (ET, Cas No 74-85-1) is the largest volume organic chemical the global demand of which was estimated at 143 million metric tons in 2015
The picture results from the dosedependent manner of the CYP 2E1 (CYP2E1) catalyzed ET metabolism and the ET-induced suicide inhibition of CYP2E1, from the rate of the resynthesis of CYP2E1, and from the kinetic behavior of the ethylene oxide (EO) metabolizing enzymes
The present physiologically based toxicokinetic (PBT) model is of high quality with respect to the AUCs of EO in venous blood of mice and rats resulting from exposures to ET of up to 10000 ppm as evidenced by the comparison of the AUCs obtained from measured and model-simulated curves
Summary
The colorless gas ethylene (ET, Cas No 74-85-1) is the largest volume organic chemical the global demand of which was estimated at 143 million metric tons in 2015. The model was tested on closed-chamber data monitored during EO-exposures of rats and on concentrations of EO measured in blood and various tissues of rats, in blood of mice, and in blood of humans. Csanády et al (2000) described the metabolic elimination of EO by means of a clearance The authors calibrated their PBT model for EO on EO concentrations measured in blood of EO-exposed rats. The model was verified for EO by comparing model-simulated EO concentrations with data measured in blood of EO-exposed mice and humans, in closed chamber studies with rats, and in exhaled air of EOexposed humans. The objectives of the present work were to extend the PBT model of Csanády et al (2000) on the basis of the novel information by incorporating additional compartments with metabolic competence, CYP2E1-mediated metabolism of the suicide substrate ET as well as EH- and GSTmediated and non-enzymatic transformation of EO, in order to enable a more realistic and accurate description of the physiological and biochemical processes involved in the fate of ET and EO in mouse, rat, and human;
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
