Determination of biokinetic interactions in chemical mixtures using real-time breath analysis and physiologically based pharmacokinetic modeling

Regulatory agencies are challenged to conduct risk assessments on chemical mixtures without full information on toxicological interactions that may oc cur at real-world, low-dose exposure levels. The present study was. underta ken to investigate the pharmacokinetic impact of low-dose coexposures to to luene and trichloroethylene in vivo in male F344 rats using a real-time bre ath analysis system coupled with physiologically based pharmacokinetic (PBP K) modeling. Rats were exposed to compounds alone or as a binary mixture, a t low (5 to 25 mg/kg) or high (240 to 800 mg/kg) dose levels. Exhaled breat h from the exposed animals was monitored for the parent compounds and a PBP K model was used to analyze the data. At low doses, exhaled breath kinetics from the binary mixture exposure compared with those obtained during singl e exposures, thus indicating that no metabolic interaction occurred with th ese low doses. In contract, at higher doses the binary PBPK model simulatin g independent metabolism was found to underpredict the exhaled breath conce ntration, suggesting an inhibition of metabolism. Therefore the binary mixt ure PBPK model was used to compare the measured exhaled breath levels from high- and low-dose exposures with the predicted levels under various metabo lic interaction simulations (competitive, noncompetitive, or uncompetitive inhibition). Of these simulations, the optimized competitive metabolic inte raction description yielded a K-i value closest to the K-m of the inhibitor solvent, indicating that competitive inhibition is the most plausible type of metabolic interaction between these two solvents.