Role of Physiologically Based Kinetic modelling in addressing environmental chemical mixtures – A review

The role of Physiologically Based Kinetic (PBK) modelling in assessing mixture toxicology has been growing for the last three decades. It has been widely used to investigate and address interactions in mixtures. This review describes the current state-of-the-art of PBK models for chemical mixtures and to evaluate the applications of PBK modelling for mixtures with emphasis on their role in chemical risk assessment. A total of 35 mixture PBK models were included after searching web resources (Scopus, PubMed, Web of Science, and Google Scholar), screening for duplicates, and excluding articles based on eligibility criteria. Binary mixtures and volatile organic compounds accounted for two-thirds of the chemical mixtures identified. The most common exposure route and modelled system were found to be inhalation and rats respectively. Twenty two (22) models were for binary mixtures, 5 for ternary mixtures, 3 for quaternary mixtures, and 5 for complex mixtures. Both bottom-up and top-down PBK modelling approaches are described. Whereas bottom-up approaches are based on a series of binary interactions, top-down approaches are based on the lumping of mixture components. Competitive inhibition is the most common type of interaction among the various types of mixtures, and usually becomes a concern at concentrations higher than environmental exposure levels. It leads to reduced biotransformation that either means a decrease in the amount of toxic metabolite formation or an increase in toxic parent chemical accumulation. The consequence is either lower or higher toxicity compared to that estimated for the mixture based on the additivity principle. Therefore, PBK modelling can play a central role in predicting interactions in chemical mixture risk assessment.