DETERMINATION OF BIOKINETIC INTERACTIONS IN CHEMICAL MIXTURES USING REAL-TIME BREATH ANALYSIS AND PHYSIOLOGICALLY BASED PHARMACOKINETIC MODELING

Abstract

Regulatory agencies are challenged to conduct risk assessments on chemical mixtures without full information on toxicological interactions that may occur at real-world, lowdose exposure levels. The present study was undertaken to investigate the pharmacokinetic impact of low-dose coexposures to toluene and trichloroethylene in vivo in male F344 rats using a real-time breath analysis system coupled with physiologically based pharmacokinetic (PBPK) modeling. Rats were exposed to compounds alone or as a binary mixture, at low (5 to 25 mg/kg) or high (240 to 800 mg/kg) dose levels. Exhaled breath from the exposed animals was monitored for the parent compounds and a PBPK model was used to analyze the data. At low doses, exhaled breath kinetics from the binary mixture exposure compared with those obtained during single exposures, thus indicating that no metabolic interaction occurred with these low doses. In contract, at higher doses the binary PBPK model simulating independent metabolism was found to underpredict the exhaled breath concentration, suggesting an inhibition of metabolism. Therefore the binary mixture PBPK model was used to compare the measured exhaled breath levels from high- and low-dose exposures with the predicted levels under various metabolic interaction simulations (competitive, noncompetitive, or uncompetitive inhibition). Of these simulations, the optimized competitive metabolic interaction 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.