Comparison of untargeted and targeted perfluoroalkyl acids measured in adolescent girls

Quantitative biomonitoring (e.g., targeted analysis) has served as the gold standard for environmental exposure biomonitoring for several decades. Recent advancements to broaden exposomic research brought new semi-quantitative untargeted assays that capture a wide range of endogenous metabolites and exogenous exposures in a single assay for discovery, though usually at the expense of absolute quantitation. The high-resolution mass spectrometers (HRMS) typically used in untargeted workflows are sensitive and robust, but there do not yet exist comprehensive comparisons between environmental chemicals at population exposure levels measured using targeted and untargeted assays. Using liquid chromatography (LC)-HRMS, we measured per- and polyfluoroalkyl substances (PFAS) including perfluorohexane sulfonate (PFHxS), n-perfluorooctanoic acid (PFOA), n-perfluorooctanesulfonic acid (PFOS), and perfluorononanoic acid (PFNA) in plasma of 180 girls from New York City, and compared them to previously obtained targeted measures using correlation and rank order methods. We showed high agreement between the methods with Spearman Rhos ranging from 0.69 to 0.92 and weighted Kappa's from 0.62 to 0.82 for tertiles among the PFAS. This finding demonstrates that semi-quantitative data from untargeted assays designed for exposomics can be reliably used to estimate environmental exposures occurring in the general population, providing an economic alternative to targeted assays. We also describe an approach that can be used to compare relative quantitation measurements from an untargeted assay to traditional targeted measures to establish fit-for-purpose usability and validation. These results suggest that environmental exposure measures from untargeted assays can serve as reliable inputs into statistical analysis for discovery and for determining their resultant biological impacts. Future efforts to develop new statistical approaches for standardization and merging with targeted measures-toward harmonization-will further enhance the utility of untargeted assays in environmental epidemiology.