Exploring Route-SpecificPharmacokineticsofPFASinMicebyCoupling in Vivo Tests Andphysiologicallybasedtoxicokineticmodels

BACKGROUND: Oral ingestion, inhalation, andskincontactareimportantexposureroutesforhumanstouptakeper- andpolyfluoroalkyl substances (PFAS). However, nasalanddermalexposuretoPFASremainsunclear, andaccuratelypredictinginternalbodyburdenofPFASinhumansviamultiple exposurepathwaysisurgentlyrequired. OBJECTIVES: We aimedtodevelopmultiplephysiologicallybasedtoxicokinetic(PBTK) modelstounveiltheroute-specific pharmacokineticsandbioavailability ofPFASviarespectiveoral, nasal, anddermalexposurepathwaysusingamousemodelandsoughttopredicttheinternalconcentrations in varioustissuesthroughmultipleexposureroutesandextrapolateittohumans. METHODS: Mice wereadministeredthemixedsolutionofperfluorohexane sulfonate, perfluorooctane sulfonate, andperfluorooctanoic acidthrough oral, nasal, anddermalexposureseparatelyorjointly. Thetime-dependentconcentrationsofPFASinplasmaandtissuesweredeterminedtocalibrate and validatetheindividualandcombinedPBTKmodels, whichwereappliedinsingle- andrepeated-dosescenarios. RESULTS: Thedevelopedroute- specific PBTKmodelssuccessfullysimulatedthetissueconcentrationsofPFASinmicefollowingsingleorjoint exposureroutesaswellaslong- termrepeateddosescenarios. ThetimetopeakconcentrationofPFASinplasmaviadermalexposurewasmuch longer(34.1-83.0h) thanthatvianasalexposure(0.960h). ThebioavailabilityofPFASviaoralexposurewasthehighest(73.2%-98.0%), followedbynasal(33.9%- 66.8%) anddermalexposure(4.59%-7.80%). Thismodelwasextrapolatedtopredictinternallevelsinhumanunderreal environment. DISCUSSION: Based onthesedata, wepredictthefollowing: PFASwereabsorbedquicklyvianasalexposure, whereasadistincthysteresiseffect was observed fordermalexposure. AlmostallthePFAStowhichmicewereexposedviagastrointestinalroutewereabsorbedintoplasma, whichexhibited thehighestbioavailability. ExhalationclearancegreatlydepressedthebioavailabilityofPFASvianasalexposure, whereasthelowestbioavailability indermalexposurewasbecauseoftheinterceptionofPFASwithintheskinlayers. https://doi.org/10.1289/EHP11969