A novel algorithm for computing interaction-based hazard index for the health risk assessment of chemical mixtures
S.S. Isukapalli1, A.F. Sasso1, P.G. Georgopoulos1, K. Krishnan2
1Environmental and Occupational Health Sciences Institute, Piscataway, NJ
2University of Montreal, Canada
Health risk assessment of chemical mixtures is frequently conducted on the basis of exposure and toxicity information for individual components. Routine application of physiologically-based toxicokinetic (PBTK) and toxicodynamic (PBTD) models in mixture risk assessment is limited by the number of parameters that need to be specified for the full model for mixtures. Since human exposures to environmental chemicals frequently lead to steady-state conditions, it is pragmatic to develop a tool that provides the steady-state solutions of full PBTK models of mixtures by accounting for the nature and magnitude of interactions. A steady-state solution was developed for computing dose metrics (i.e., blood concentration and metabolism rate) during mixture exposures and applied for computing interaction-based hazard index for mixtures. The algorithm is based on critical determinants of the internal dose during chronic exposure to VOCs (i.e., alveolar ventilation rate, blood flow rate to liver, blood:air partition coefficient, maximal velocity of metabolism, Michaelis constant, inhibition constants, and free concentration of chemical at the site of interaction and metabolism). This algorithm, developed as a spreadsheet program, is an iterative procedure for estimating an intermediate term representing sum of ratios of liver concentrations of individual components to the Michaelis parameter (or inhibition constant). Case studies demonstrating the application of this tool were conducted for human inhalation exposure to toluene, xylene, ethylbenzene, carbon tetrachloride and tetrachloroethylene. The results demonstrate that the algorithm appropriately accounts for the saturable metabolism and competitive inhibition among the chemicals in mixtures, as a function of exposure concentration. This risk assessment tool should be of use in establishing interaction thresholds for environmental contaminants, as well as for conducting interaction-based risk assessment for populations exposed to chemical mixtures.