A mechanistic effect modeling approach to the prioritization of hidden drivers in chemical cocktails

Exposure to a single chemical does not exist in reality. Mixtures, which are the ecological norm, are often characterized by numerous intrinsic driving factors with unknown combined effects. Interactions between heterogeneous chemicals, or chemical and nonchemical stressors, could alter their toxicity traits relative to single exposure. Hence, revealing the hidden environmental effects affecting multiple stressor interactions is essential to expand our knowledge about uncertainty sources in chemical risk-based decision contexts. Global sensitivity analysis (GSA) techniques involving Morris method sampling and elementary effects (EE) sensitivity analysis was applied to investigate the driving factors underlying the combined effects on Scenedesmus obliquus, and identify the mode of interaction in mixtures at environmentally-relevant concentrations. One hundred mixed-exposure formulas were generated with 9 variables (8 chemicals and temperature) via the Morris method, representing environmental perspective in the field. Subsequently, EE sensitivity analysis combined with quantitative high-throughput screening (q-HTS) was adopted to identify the most critical mixture and its primary drivers. Combined exposure exerted significantly increased effects on S. obliquus compared to the effects of individual exposure. The critical drivers were identified and validated by the control variate method. For the mode of combined action, mixture toxicity did not match the additivity relationship, and a strong interaction existed among chemicals. Collectively, the data provides evidence that a combination of specific pesticides and emerging brominated flame retardants can produce comparable, or even stronger, bionegative effects than pure chemicals due to complicated interactions. The method used offers direct comparison of multifarious factors in a unified standard scale, bridges the actual interaction scenarios in the field to toxicity simulations in the laboratory, and fill a gap in ecotoxicology.