Toxicokinetics of inhaled and endogenous isoprene in mice, rats, and humans

Isoprene (IP) is ubiquitous in the environment and is used for the producti on of polymers. It is metabolized in vivo to reactive epoxides, which might cause the tumors observed in IP exposed rodents. Detailed knowledge of the body and tissue burden of inhaled IP and its intermediate epoxides can be gained using a physiological toxicokinetic (PT) model. For this purpose, a PT-model was developed for IP in mouse. rat, and human. Experimentally dete rmined partition coefficients were taken from the literature. Metabolic par ameters were obtained from gas-uptake experiments. The measured data could be described by introducing hepatic and extrahepatic metabolism into the mo del. At exposure concentrations up to 50 ppm, the rate of metabolism at ste ady-state is 14 times faster in mice and about 8 times faster in rats than in humans (2.5 mu mol/h/kg at 50 ppm IP in air). IP does accumulate only ba rely due to its fast metabolism and its low thermodynamic partition coeffic ient whole body:air. IP is produced endogenously. This production is neglig ible in rodents compared to that in humans (0.34 mu mol/h/kg). About 90% of IP produced endogenously in humans is metabolized and 10% is exhaled uncha nged. The blood concentration of IP in non-exposed humans is predicted to b e 9.5 nmol/l. The area under the blood concentration - time curve (AUC) fol lowing exposure over 8 h to 10 ppm IP is about 4 times higher than the AUC resulting from the unavoidable endogenous IP over 24 h. A comparison of suc h AUCs can be used for establishing workplace exposure limits. For estimati on of the absolute risk, knowledge of the body burden of the epoxide interm ediates of IP is required. Unfortunately, such data are not yet available. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.