Metabolomics in environmental analysis: Applications, advances, and emerging challenges

The growing complexity and ubiquity of environmental contaminants demands sensitive, mechanistically informative tools for exposure science. Metabolomics, capturing system-wide metabolic perturbations from chemical exposures, offers a transformative platform for linking molecular disruptions to organismal and population-level outcomes. This review highlights recent advances in environmental metabolomics, focusing on three key domains: (1) ecological biomonitoring, enhancing early biological effect detection and causality assessment with effect-directed analysis (EDA); (2) mechanistic toxicology, informing Adverse Outcome Pathway (AOP) and quantitative AOP development by bridging multi-scale models from in vivo and in vitro studies; and (3) environmental epidemiology, driving biomarker discovery and pathway inference via metabolome-wide association studies (MWAS), meet-in-the-middle (MITM) frameworks, and advanced statistical, AI computational approaches. By synthesizing methodologies and innovations, this review positions metabolomics as a cornerstone of next-generation environmental health research, advancing predictive, mechanistic chemical risk assessments aligned with New Approach Methodologies (NAMs) in complex scenarios.