Decoding the Partitioning Behavior of Poly- and Perfluoroalkyl Substances: Insights from Human Liver and Blood Biomonitoring with Machine Learning.

Perfluoroalkyl substances (PFASs) are known for their tendency to accumulate in the human liver, potentially causing hepatotoxic effects. However, the relationship between PFAS concentrations in the liver and their distribution in whole blood remains unclear. In this study, we analyzed 15 commonly used PFASs in paired normal liver tissue and whole blood samples from patients undergoing liver resection due to liver cancer. Our results revealed that perfluorooctanoate (PFOA; 6.9 ng/mL in blood and 15 ng/g dw in liver), perfluorooctane sulfonate (PFOS; 4.9 ng/mL and 16 ng/g dw), and 6:2 chlorinated polyfluoroalkyl ether sulfonate (6:2 Cl-PFESA; 3.6 ng/mL and 5.1 ng/g dw) were the most abundant in both matrices. Branched isomers of PFOA and PFOS contributed an average of 4.8% and 21% to their total concentrations in the liver. The ratio of perfluoroalkyl carboxylates (PFCAs) in liver to whole blood (RL/B) increased from 0.088 ± 0.039 (perfluorobutanoate, PFBA) to 0.32 ± 0.078 (PFOA) with longer carbon chains, then declined to 0.095 ± 0.065 (perfluorododecanoate, PFDoA). The mean RL/B for 6:2 Cl-PFESA was higher than that for PFOS. Branched isomers of PFOA and PFOS had lower mean RL/B values than their linear forms. Utilizing machine learning models, we identified molecular shape, charge state, and hydrophobicity as critical factors influencing PFAS partitioning between the liver and whole blood. To our knowledge, this study is among the first to comprehensively characterize the relative distribution patterns of multiple PFASs between paired human liver and whole blood samples. By integrating biomonitoring data with interpretable machine learning analysis, this study provides new insights into the physicochemical factors associated with PFAS liver-blood distribution behavior and their potential underlying mechanisms.