Salt-induced matrix effects on PFAS quantification in online SPE–LC–MS/MS analysis

Residual inorganic ions in automated online solid-phase extraction (SPE) workflows can alter electrospray ionization and bias LC–MS/MS quantification of perfluoroalkyl substances (PFAS) in environmental waters. We evaluated the influence of modest salt concentration (10–30 mg/L NaCl or CaCl 2 ) on the PFAS analytical response using an online SPE–LC–MS/MS system in negative ESI-MRM (Electrospray Ionization-Multiple Reaction Monitoring) mode. PFBA (50 ng/L) was non-detectable under salt-free conditions but produced well-defined peaks after salt addition, with detection limits improving to 0.17–0.22 ng/L (LOD) and 0.57–0.74 ng/L (LOQ) at 20–30 mg/L of NaCl and CaCl 2 . The isotopically labeled internal standard remained stable across conditions, but the PFBA/ 13 C 4 -PFBA area ratio increased from 1.67 to 1.89, demonstrating incomplete compensation for salt-dependent response changes by isotope dilution. A matrix effect assessment across the full PFAS target list revealed a wide range from − 74% to + 1005%, with short-chain compounds exhibiting the strongest enhancements (up to tenfold for PFPeA) and longer-chain PFAS showing weaker or negative effects. NaCl amplified chain length-dependent contrast more strongly than CaCl 2 did, producing divergent responses, particularly for C 8 –C 9 compounds. These findings demonstrate that the environmentally relevant salt concentrations substantially alter PFAS response patterns in automated online SPE–LC–MS/MS systems, with implications for method validation and data interpretation. The ionic composition should be explicitly considered when quantifying PFAS in water matrices with varying ionic composition, particularly for short-chain compounds where internal standardization provides incomplete correction.