Mixture Toxicity in Human Health: Integrating One Health, Exposomics, and Modern Risk Assessment Strategies.

Human and environmental health are critically threatened by combined exposures to multiple chemical toxicants, including industrial chemicals, heavy metals, pesticides, endocrine-disrupting chemicals (EDCs), and per- and polyfluoroalkyl substances (PFAS). These substances interact biologically, producing additive, synergistic, or antagonistic effects that conventional single-substance risk assessments fail to predict. This leads to a systematic underestimation of health risks, particularly for vulnerable populations. Despite robust evidence on mixture toxicity, major regulatory frameworks such as the US Toxic Substances Control Act (TSCA) and the EU's REACH program continue to assess chemicals in isolation. This review synthesizes current science on toxicant interactions and critiques global regulatory shortcomings, underscoring the real-world consequences through case studies on PFAS, heavy metals, and pesticide mixtures. It advocates for a paradigm shift, proposing reforms that integrate emerging tools like exposomics and computational toxicology with holistic frameworks such as One Health. We highlight pioneering regulatory efforts, including Canada's mandate for cumulative risk assessments under CEPA and the EU's development of mixture assessment factors (MAFs), as essential models for progress. Our recommendations include mandating science-based mixture assessments, harmonizing global standards, and implementing equity-driven policies to align regulations with the reality of multichemical exposures.