Structure-Informed Comprehensive Screening and Risk Prioritization of Organophosphorus Compounds in Human Serum: Revealing the Hidden Burden and Emerging Risks

Organophosphorus compounds (OPCs) are widely distributed environmental contaminants for which there are increasing health concerns, yet human internal exposure beyond a few well-studied organophosphate esters (OPEs) remains poorly understood. In this study, a structure-informed integrated screening and risk prioritization framework was developed to systematically characterize the internal burden and potential risks of OPCs in human serum. The use of machine-learning-predicted retention times and response factors, coupled with a cross-subgroup multidimensional weighted fragment-ion scoring system, enhanced the identification and semiquantification of broad-spectrum OPCs in complex biological matrices. In serum samples from 254 residents, 59 OPCs were identified, including 33 newly detected OPCs in humans, revealing that emerging OPCs (e.g., organophosphonates, phosphine oxides, and organothiophosphate esters) dominate current exposure profiles. Coexposure network analysis indicated that OPCs may occur in humans as highly interconnected mixtures. Risk prioritization integrating computational toxicology with exposure burden demonstrated that several emerging OPCs exhibit greater toxicological potential than typical OPEs and predominate among high-priority chemicals. This study provides a more comprehensive profile of the human internal exposure landscape of OPCs and emphasizes the importance of emerging OPCs in future exposure assessment and risk management.