Beyond the Single Chemical: A Systems Toxicology Perspective on Water Pollution in the Anthropocene

Water pollution in the Anthropocene is defined by chemical complexity-thousands of contaminants occur as dynamic mixtures, many of which are unregulated, unidentified, or present at concentrations below individual effect thresholds. Despite decades of research, the dominant paradigm for assessing water quality remains anchored in single-chemical, single-species approaches that fail to capture the cumulative, interactive, and context-dependent nature of real-world exposures. This Perspective argues for a fundamental shift toward systems toxicology as the organizing framework for understanding and mitigating water pollution. We critically assess the limitations of current regulatory toxicology, examine how emerging chemical classes and nonchemical stressors such as climate change amplify risks, and identify priority research directions: advancing effect-based monitoring and bioanalytical tools, integrating exposomics with adverse outcome pathway networks, harnessing new approach methodologies and artificial intelligence for mixture risk assessment, and embedding ecological and human health considerations into a One Health framework. We further emphasize that the success of this transition depends on the parallel development of open-access chemical and toxicological databases, international harmonization of effect-based trigger values, and adaptive regulatory frameworks that can accommodate cumulative risk assessments. We contend that the transition from reductionist to systems-level thinking is not merely an academic exercise but an urgent necessity for protecting and mitigating water resources, biodiversity, and public health in an era of accelerating environmental change.