A modeling approach to account for toxicokinetic interactions in the calculation of biological hazard index for chemical mixtures

Biological hazard index (BHI) is defined as biological level tolerable for exposure to mixture, and is calculated by an equation similar to the conven tional hazard index. The BHI calculation, at the present time, is advocated for use in situations where toxicokinetic interactions do not occur among mixture constituents. The objective of this study was to develop an approac h for calculating interactions-based BHI for chemical mixtures. The approac h consisted of simulating the concentration of exposure indicator in the bi ological matrix of choice (e.g. venous blood) for each component of the mix ture to which workers are exposed and then comparing these to the establish ed BEI values, for calculating the BHI. The simulation of biomarker concent rations was performed using a physiologically-based toxicokinetic (PBTK) mo del which accounted for the mechanism of interactions among all mixture com ponents (e.g. competitive inhibition). The usefulness of the present approa ch is illustrated by calculating BHI for varying ambient concentrations of a mixture of three chemicals (toluene (5-40 ppm), m-xylene (10-50 ppm), and ethylbenzene (10-50 ppm)). The results show that the interactions-based BH I can be greater or smaller than that calculated on the basis of additivity principle, particularly at high exposure concentrations. At lower exposure concentrations (e.g. 20 ppm each of toluene, m-xylene and ethylbenzene), t he BHI values obtained using the conventional methodology are similar to th e interactions-based methodology, confirming that the consequences of compe titive inhibition are negligible at lower concentrations. The advantage of the PBTK model-based methodology developed in this study relates to the fac t that, the concentrations of individual chemicals in mixtures that will no t result in a significant increase in the BHI (i.e. > 1) can be determined by iterative simulation. (C) 1999 Elsevier Science Ireland Ltd. All rights reserved.