Overcoming Matrix Effects in Non-Target Screening: A Novel Strategy for Urban Runoff Analysis.

Matrix effects (MEs) challenge the reliability of target and non-target screening (NTS) in urban runoff analysis, particularly due to sample heterogeneity, which makes pooled samples inadequate for method development, validation, and ME corrections. This study investigated MEs in 21 urban runoff samples from different catchment areas, showing high variability in signal suppression (0-67% median suppression at 50× relative enrichment factor, REF). Runoff collected after prolonged dry periods ("dirty" samples) required enrichment below REF 50 to avoid suppression exceeding 50%. In contrast, "clean" samples had suppression below 30% even at REF 100. To correct residual MEs, a novel Individual Sample-Matched Internal Standard (IS-MIS) strategy consistently outperformed established ME correction methods, achieving <20% RSD for 80% of features through analysis of samples at three REFs as part of the analytical sequence to match features and internal standards. In contrast, internal standard matching with a pooled sample resulted in only 70% of features meeting this threshold (<20% RSD). Although IS-MIS requires additional analysis time (59% more runs for the most cost-effective strategy), it significantly improves accuracy and reliability, making it a viable and cost-effective solution for large-scale urban runoff monitoring. Furthermore, IS-MIS generates valuable data on peak reliability through measurements of signal intensities across multiple REFs, which can be used to remove "false" peaks and improve data preprocessing and method development in NTS.