Machine learning-derived dose-response relationships considering interactions in mixtures: Applications to the...

Conventional environmental health research is primarily focused on isolated chemical exposures, neglecting the complex interactions between multiple pollutants that may synergistically or antagonistically influence toxicity, thereby posing unexpected health risks. In this study, we address this knowledge gap by introducing an explainable machine learning (ML) approach with Feature Localized Intercept Transformed-Shapley Additive Explanations (FLIT-SHAP) designed to extract the dose-response relationships of specific pollutants in mixtures. In contrast to traditional SHAP, FLIT-SHAP can localize the global intercept to elucidate mixture effects, which is crucial for understanding the oxidative potential (OP) of ambient particulate matter (PM). Assessing multi-pollutant OP using FLIT-SHAP revealed both synergistic (55-63 %) and antagonistic (25-42 %) effects in laboratory-controlled OP data, but an antagonistic (33-66 %; lower OP) effect in ambient PM. Notably, the FLIT-SHAP approach demonstrated higher prediction accuracy (R² = 0.99) compared to the additive model (R² = 0.89) when evaluated against real-world PM samples. Quinones, such as phenanthrenequinone, play a more significant role in PM_2.5 than previously recognized. Through this study, we highlighted the potential of FLIT-SHAP to enhance toxicity predictions and aid decision-making in the field of environmental health.