ZeroPM prioritization workshop: Physiologically Based Kinetic Modelling (PBK) using QIVIVE to predict the toxicokinetic profiles of triazines and triazoles via oral route of administration

Summary and Results •A simple rat PBK model, parameterized with the measured in vitro ADME values on intrinsic metabolic liver clearance; permeability and fraction unbound, predicted a plasma concentration comparable to values observed in in vivo studies. •The corrected free medium (EC20) concentrations from the NAM test battery are in the same range or lower compared to the unbound plasma concentration derived from the in vivo LOAEL values. The in vitro assays therefore provide a conservative estimate and can be used to rank compounds according to their toxicological properties. •The surface water and ground water derived unbound human plasma concentrations are about 100 – 1000 times smaller than those values derived from the in vitro/in vivo studies. Assess the risk of PM substances using in quantitative vitro to in vivo extrapolation (QIVIVE).Build abottom up PBK model, which uses in vitro ADME data to estimate the bioavailable concentration of PM compounds after oral exposure via drinking water.The concept is illustrated with two compound classes -triazoles and triazines. Aim Methods Acknowledgements Lorem ipsum dolor sit amet, consectetur adipiscing elit, sed do eiusmod tempor incididunt ut labore et dolore magna aliqua. Ut enim ad minim veniam, quis nostrud exercitation ullamco laboris nisi ut aliquip ex ea commodo consequat. Duis aute irure dolor in reprehenderit in voluptate velit esse cillum dolore eu fugiat nulla pariatur. This project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 101036756. Partners Grouping Concepts in Toxicokinetics: Assess the Bioavailability of PM Compounds using PBK Modelling Abishek Laxmanan Ravi Shankar1,*,Jenny Irwan1,Max Spänig1,Anke Londenberg1,Maxim Carlier2,Nicole Zumbülte3,Todd Gouin4, Patrik Lundquist5, Pawel Barenczewski5, Timo Hamers2,Tanja Hansen1,Sylvia E. Escher1 Presenting authors*; 1Fraunhofer ITEM, Germany; 2Vrije Universiteit Amsterdam, Netherlands; 3TZW: DVGW-Technologiezentrum Wasser, Germany, 4TG Environmental Research, United Kingdom;5Department of Pharmacy, Drug delivery, Uppsala University, Sweden Data type Clint PHH = 3.62 [µl/min/million cells] In Vivo Data Ratio C_max [µg/ml] 5.91 4.63 1.27 T_max [h] 7.11 1.53 4.64 AUC [µg/mL * h] 154.5 112.36 1.37 Fig 1 : PBKiT © Fraunhofer ITEM PBK Model Fig 2 : Tebuconazole Data type C_ma x µg/ml T_max h AUC µg/mL * h Fu (ZeroPM) 1.61 1.53 8.49 Fu (CompTox) 1.12 1.39 4.72 In vivo data[4] 1.151 3.06 4.41 Ratio 1.19 1.46 1.92 Fig 3 : Cyromazine Approach: NAM data are derived from several in vitro assays testing mainly endocrine activity (Androgen hormone receptor , Estrogen hormone receptor, thyroid hormone receptor, TTR binding assay and H295R steroidogenisis). In vitro biokinetic modelling[1] is used to convert the EC20 value to the free unbound medium concentration. These values are compared to the human unbound plasma concentrations estimated form exposure and in vivo reference values. Human extrapolation assumptions •Route of exposure is oral via drinking water,administered 4 times a day, modelled for 100h Reference concentrations •Lowest observed adverse effect level (LOAEL) from in vivo rodent studies, scaled allometrically to human. •The maximum water solubility of the chemical illsutrates the worst case input via drinking water •Exposure estimate - modelled concentration in ground water and surface water. •Human unbound plasma concentration (Cmax)from ground water and surface water is compared against LOAEL, maximum solubility and in vitro test assays. Data rich Data poor •Estimate ADME properties like intrinsic hepatic clearance value from „data rich“ to „data poor“. •All the data rich compounds show low intrinsic clearance > Prediction is low clearance for all RAX compounds. Read Across Approach (RAX) Outcome Fig 5 : a) Difenoconazole b) Tebuconazole c) Tetraconazole d) Ametryn e) Atrazine f) Cyromazine c) Tetraconazoleb) Tebuconazole a) Difenoconazole d) Ametryn e) Atrazine f) Cyromazine Assessment of the Kinetic properties of Tebuconazole and Cyromazine using a rat PBK Model Fig 4 : Read Across Approach