Complex Mixtures and Multiple Stressors: Evaluating Combined Chemical Exposures and Cumulative Toxicity
The problem of environmental mixtures encompasses biological, analytical, logistical, and regulatory challenges, among others. Components of contaminant mixtures can produce additive effects and less frequently, can interact to produce effects that are greater than or less than those predicted by additivity (synergistic or antagonistic effects, respectively). As has been demonstrated, combinations of low or “no” activity chemicals can act additively or synergistically to elicit significant, measurable effects and/or can modulate the effects of endogenous hormone activity. Biomonitoring studies continue to report routine human exposure to hundreds or thousands of chemicals through the integration of exposomics and metabolomics, underscoring the incredible complexity involved in understanding real world mixture exposures. Such complexity presents practical barriers, as research efforts cannot possibly examine every contaminant mixture, given the unique chemical exposure profile experienced by each individual person. With an estimated >350,000 chemicals and mixtures registered on the global market, the number of unique mixture combinations that could potentially be tested is staggering. Research tends to overlook whole mixtures in toxicological testing, with >80% of mixture studies focusing on small, technically simple mixtures of two or three similar components. These realities have driven the prevalence of and reliance on component-based approaches in the field of mixture risk assessment. While the evaluation of defined chemical mixtures increases our understanding of chemical interactions and generates potentially useful data for mixture assessments, these simple mixtures often lack environmental relevance. To robustly address human exposure to increasingly encountered environmental mixtures like floodwaters, wildfire smoke, or house dust and ultimately reduce the uncertainty associated with mixture risk and hazard estimates, we must advance the state of the science on mixtures research and risk assessment.