From Nontargeted Analysis to Toxicity: Revealing the Disinfection Byproduct Exposome

Abstract Chemical disinfection is essential for ensuring the microbiological safety of drinking water, but it inevitably generates disinfection byproducts (DBPs), introducing a complex and largely unresolved chemical burden. Trihalomethanes (THMs) and haloacetic acids (HAAs) have long underpinned DBP regulation, shaping monitoring and treatment strategies. However, recent analytical advances have fundamentally reshaped our understanding of DBPs. In this perspective, we examine how high-resolution mass spectrometry (HRMS)-based nontargeted analysis (NTA) has expanded the detectable DBP chemical space, while revealing key limitations that hinder translation from detection to identification. We then highlight emerging mass spectrometry and computational approaches as key pathways toward scalable DBP discovery and identification. We further examine the disconnect between rapid DBP discovery and limited toxicological understanding, highlighting key limitations of current toxicity assessments, including high-dose testing paradigms, fragmented end points, and overlooked mixture effects. To address these challenges, we propose an exposome-oriented framework as a conceptual model that integrates comprehensive chemical characterization with toxicity assessment, highlighting the need for future computational tools and prioritization strategies. Bridging chemical diversity to health relevance will be critical for prioritizing DBPs of concern and supporting risk-informed water quality management and public health protection.