A systems toxicology approach for identification of disruptions in cholesterol homeostasis after aggregated exposure to mixtures of perfluorinated compounds (PFAS) in humans.

Per- and polyfluoroalkyl substances (PFAS) are used in various household and industrial products. In humans, positive associations were reported between PFAS, including perfluorsulfonic acid and perfluorooctanoic acid, and cholesterol, a cardiometabolic risk factor. Animal studies show the opposite. Human-centered approaches are needed to better understand the effects of PFAS mixtures on cholesterol. Here, a systems toxicology approach is described, using a gene-centered cholesterol biokinetic model. PFAS exposure-gene expression relations from published data were introduced into the model. An existing PFAS physiologically based kinetic model was augmented with lung and dermal compartments and integrated with the cholesterol model to enable exposure-effect modelling. The final model was populated with data reflecting lifetime mixture exposure from: tolerable weekly intake values (TWI); the environment; high occupational exposures (ski waxing, PFAS industry). Results indicate that low level exposures (TWI, environmental), did not change cholesterol. In contrast, occupational exposures clearly resulted in internal PFAS exposure and disruption of cholesterol homeostasis, largely in line with epidemiological observations. Despite model limitations (e.g. dynamic range, directionality), changes in cholesterol homeostasis were predicted for ski waxers, hitherto unknown from epidemiological studies. Here, future studies involving lipid metabolism could improve risk assessment. Impact statement Using a human-centered computational approach, the effects of aggregated lifetime PFAS exposure on cholesterol homeostasis clearly distinguished background exposures versus high occupational exposures, and helped to identify occupational subgroups at potential risk. The approach may help to develop human-based quantitative health risk assessment approaches for PFAS, unlikely to be achieved by animal and epidemiological studies alone.