The closed chamber technique--uptake, endogenous production, excretion, steady-state kinetics and rates of metabolism of gases and vapors.

The "closed chamber technique" (CCT) is presented. It allows investigation of pharmacokinetics of volatile substances in vivo in animals and in man and in vitro using tissue fractions. During the exposure period only the atmospheric concentrations of the substance are measured. The concentration-time data obtained are pharmacokinetically analyzed by a two compartment model describing uptake, endogenous production and excretion of the unchanged substance and its metabolic elimination. Using this model, pharmacokinetics of ethylene have been determined in rats and man. For both species, the results compared well with an estimation based on an allometric species scaling. Furthermore, the applicability of CCT is demonstrated in vivo on several other gases and vapors of solvents, e.g. trichloroethylene and 1,1,1-trichloroethane, and in vitro on 1,2-epoxybutene-3

A physiologically based toxicokinetic model for inhaled ethylene and ethylene oxide in mouse, rat, and human.

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