Physiologically Based Kinetic Modelling (PBK) using QIVIVE to predict the toxicokinetic profiles of PFAS via oral route of administration

— Physiologically Based Kinetic Modelling (PBK) using QIVIVE to predict the toxicokinetic profiles of PFAS via oral route of administration Abishek Laxmanan Ravi Shankar*, Jenny Irwan, Maxim Carlier, Deepika Deepika, Nicole Zumbülte, Todd Gouin, Timo Hamers, Vikas Kumar, Tanja Hansen, Sylvia E. Escher -internal - Motivation Time Plasma concentration ZeroPM WP6 NAM Approach:Bridges external environmental concentrations to the in vitro assay benchmark concentrations using QIVIVE-based PBK model. PBK PFAS Modeling:Assesses long-term oral exposure and obtains steady-state plasma concentrations. PFOS PFOA Fluorinated tail Functional group -internal - PFAS Compound Selection & Read Across 29.10.20253 READ ACROSS COMPOUNDS PFHxA TFMSA PFPrS TFA PFPrA PFBA GenX PFEtS DATA RICH COMPOUNDS PFOS PFOA PFHxS PFNA PFBS PFOS PFOA PFBS GenX PFBA PFHxA What are the parameters Read acrossed? Fraction unbound Measured tissue – partition coefficients Tmc - Resorption maximum (µg/h) kt – Affinity Constant -internal - PFAS Specific PBK Model (Fabrega F et al., 2014) 29.10.20254 What we obtain from the PBK Model? •Free Blood / Plasma Concentration curve •Toxicokinetics •Tissue specific concentrations •Cmax , Tmax and AUC value Physiological parameters Substance-specific ADME parameters Exposure scenario *<a href="https://www.freevector.com/group-of-people-vector--28523">FreeVector.com</a> Fabrega F 2014 et al. -internal - In Vitro Biokinetics 29.10.20255 Fisher C et al., Virtual in vitro distribution model for the mechanistic prediction of intracellular concentrations of chemicals in in vitro toxicity assays. Toxicol In Vitro. 2019 Aug;58:42-50. doi: 10.1016/j.tiv.2018.12.017. Epub 2018 Dec 29. PMID: 30599189. Carlier MP et al., Profiling the endocrine-disrupting properties of triazines, triazoles, and short-chain PFAS. Toxicol Sci. 2024 Dec 1;202(2):250-264. doi: 10.1093/toxsci/kfae131. PMID: 39365753; PMCID: PMC11589101. In Vitro Test Assays Androgen Receptor (AR) assay Estrogen Receptor (ER) assay Thyroid hormone receptor (TR) assay Human transthyretin (TTR) Binding assay H295R Steroidogenisis HepaRG reactive oxygen species assay Estimates in vitro correction free available concentration in the medium free intracellular concentration percentage bound to plastics / protein -internal - Application of PBK models in QIVIVE process 29.10.20256 In vitro biokinetic PBK Model Plasma concentration curve External concentration -internal - PFAS – Data Rich Compounds 29.10.20257 LOAEL Standard input 1 mg/kg/bw Surface water Ground water LOAEL Standard input 1 mg/kg/bw Surface water •All horizontal lines represent the Cmax free unbound human plasma concentrations •Assay inactivity -internal - PFAS – Read Across Approach to Model Data Poor Compounds 29.10.20258 LOAEL Standard input 1 mg/kg/bw Surface water LOAEL Standard input 1 mg/kg/bw Surface water Ground water -internal - PFAS Comparison 29.10.20259 Mean Cmax values for PFAS as horizontal lines Transthyretin (TTR) protein binding assay is highly sensitive