A novel interaction-based algorithm for predicting biological doses during chronic exposures to 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
A physiologically-based algorithm was developed for predicting the steady-state internal doses of inhaled volatile organic chemicals (VOCs) resulting from chronic exposures to mixtures of VOCs. This algorithm takes into account metabolic interactions of chemicals in mixtures, and was developed as a simplification of the full Physiologically Based Toxicokinetic (PBTK) model by utilizing a set of equations constituting pulmonary uptake and metabolic clearance, including the consideration of dose-dependent change in the free concentration of chemicals at the metabolizing site (liver), and competitive inhibition. The resulting algorithm, 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 affinity constant, inhibition constants, and free concentration of chemical at the metabolizing site) provides predictions of dose metrics (e.g., arterial blood concentration and rate of amount metabolized) identical to those of the corresponding whole-body PBTK models. This algorithm is dose independent, and facilitates the rapid, direct computation of steady-state internal doses for a variety of exposure concentrations and mixture constitution by accounting for the non-linear processes. In data-poor situations, when the statistical distributions for all input parameters in mixture models are not known or available, the application of the steady-state algorithm allows rapid assessment of the impact of interactions. Demonstration case studies are presented for mixtures of different complexities involving benzene, toluene, xylene, etc., covering binary, tertiary, quaternary, and a complex 12 chemical mixture.