Assessing interaction thresholds for trichloroethylene in combination withtetrachloroethylene and 1,1,1-trichloroethane using gas uptake studies andPBPK modeling

The volatile organic solvents trichloroethylene (TCE), tetrachloroethylene (perchloroethylene, PERC), and 1,1,1-trichloroethane (methylchloroform, MC) are widely distributed environmental pollutants and common contaminants of many chemical waste sites. To investigate the mode of pharmacokinetic inte ractions among TCE, PERC, and MC and to calculate defined "interaction thre sholds", gas-uptake experiments were performed using a closed-chamber expos ure system. In each experiment, two rats (Fischer 344, male, 8-9 weeks old) were exposed to different initial concentrations of TCE, PERC, and MC, app lied singly or as a mixture, and their concentration in the gas phase of th e chamber was monitored over a period of 6 h. A physiologically based pharm acokinetic (PBPK) model was developed to test multiple mechanisms of inhibi tory interactions, i.e., competitive, non-competitive, or uncompetitive. Al l mixture exposure data were accurately described by a system of equations in which a PBPK model was provided for each chemical and each was regarded as an inhibitor of the others' metabolism. Sensitivity-analysis techniques were used to investigate the impact of key parameters on model output and o ptimize experimental design. Model simulations indicated that, among these three chemicals, the inhibition was competitive. The PBPK model was extende d to assess occupationally relevant exposures at or below the current thres hold-limit values (TLVs). Based on 10% elevation in TCE blood levels as a c riterion for significant interaction and assuming TCE exposure is set at TL V of 50 ppm, the calculated interaction thresholds for PERC and MC were 25 and 135 ppm, respectively. TLV exposures to binary TCE/PERC mixture were be low the 10% significance level. The interaction threshold for TCE and MC co -exposure would be reached at 50 and 175 ppm, respectively. Such interactiv e PBPK models should be of value in risk assessment of occupational and env ironmental exposure to solvent mixtures.