Toxicological Study of Human Exposure to Mixtures of Chemicals: Challenges and Approaches

Humans are exposed to highly diverse mixtures of complex and often unknown compositions, which may adversely impact their health. There is a lack of guidance on how to design toxicological studies of chemical mixtures. This paper aims to evaluate the weaknesses and strengths of chemical mixture studies and to propose the practical design of mixture effect studies including chemical selection, dosing considerations, and determination of toxicological mechanisms of mixtures. The design of mixture effect studies should be optimized to yield relevant information on real-life mixture effects (1) by selecting appropriate chemicals based on the association between chemical effects and diseases using information from epidemiological studies and “chemical-disease” associations from toxicological databases and/or animal studies; (2) by testing mixture ratios and concentrations derived from biomonitoring data; (3) by evolving from binary mixtures and those with a low number of components to complex and diverse mixtures with as many components as practically possible; (4) by applying multiomics and high-throughput screening approaches to increase the number of testable individual chemicals and mixture scenarios; and (5) by implementing computational mixture models in the experiment planning phase and to interpret the outcomes to examine the toxicological mechanisms of “multiple exposure-multiple targets”. We urge to move mixture investigation from answering academic questions such as mixture interaction models at high effect and concentration levels to mixture scenarios that are relevant for today’s human exposure, i.e., low concentration, low effect but high complexity mixtures.