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ENITRE Thesis Final CORRECTED 1 TECHNISCHE UNIVERSITÄT MÜNCHEN Fachgebiet für Biowissenschaftliche Grundlagen in Kooperation mit der Gemeinsamen Forschungsstelle der Europäischen Kommission (DG JRC) in Ispra (Italien) Physiologically- based toxicokinetic and toxicodynamic modelling of single and repeated dose toxicity Monika Gajewska Vollständiger Abdruck der von der Fakultät Wissenschaftszentrum Weihenstephan für Ernährung, Landnutzung und Umwelt der Technishen Universität München zur Erlangung des akademischen Grades eines Doktors der Naturwissenschaften genehmigten Dissertation. Vorsitzender: Univ.-Prof. Dr. H.-W. Mewes Prüfer der Dissertation: 1. apl. Univ.-Prof. Dr. K.-W. Schramm 2. Univ.-Prof. Dr. H. Briesen Die Dissertation wurde am 28.10.2014 bei der Technischen Universität München eingereicht und durch die Fakultät Wissenschaftszentrum Weihenstephan für Ernährung, Landnutzung und Umwelt am 02.02.2015 angenommen. Abstract To analyse the effects of human exposure to selected chemicals, physiologically-based toxicokinetic (PBTK) and toxicodynamic (PBTD) models for the healthy adult Caucasian population were constructed and parameterised for the following nine case study compounds, which include industrial chemicals and substances found in consumer products and food: coumarin, estragole, hydroquinone, caffeine, ethanol, isopropanol, methyl iodide, styrene and nicotine. Literature quantitative structure-property relationships (QSPRs) for skin permeation, plasma protein binding and blood-to-air partition coefficient were collected and evaluated for these substances. A simple PBTK model structure was first refined in terms of the skin, gastrointestinal and respiratory tracts by introducing sub-compartments to give a better simulation of absorption profiles. Subsequently the PBTK model was applied for the purposes of interspecies (rat-to- human) and route-to-route extrapolations of experimental no-observed adverse effect level (NOAEL) doses, in vitro-to-in vivo correlations of skin permeation and liver clearance, and the prediction of metabolites in blood and urine. Selected case studies for the route-to-route extrapolations showed that the Area under Curve (AUC) in blood was the parameter indicating the lowest dermal thresholds. Under defined exposure conditions, these thresholds were higher than those corresponding to oral NOAEL values (oral NOAEL doses are protective) for coumarin and ethanol but were lower for hydroquinone, caffeine and isopropanol. The simulated skin permeation of caffeine and coumarin using in vitro parameters was found to be lower than the estimated in vivo permeation. On average, the liver clearance (calculated as a sum of Vmax/Km ratios of all formed metabolites) in vitro was found to be higher than the one optimised from in vivo blood data. The application of joint PBTK-TD modelling was illustrated by simulating the effects of nicotine and caffeine on acute heart rate and blood pressure for selected daily exposure scenarios and, in the case of caffeine only, on cell-level changes (HepaRG cell viability). These effects were related to external doses under defined oral and dermal exposure scenarios (for nicotine also following inhalation). A multi-scale modelling approach (PBTK combined with a virtual cell-based assay) revealed almost no effect of caffeine (up to 5.33 mg/kg body weight) on the viability of liver (HepaRG) cells, regardless of the absorption route. Finally, the PBTK model for oral absorption was successfully applied to simulate the concentration–time profiles of ethanol, and its two metabolites, ethyl sulfate and ethyl glucuronide, in blood and urine, following the ingestion of 4 and 8 units of ethanol. In this novel application of PBTK modelling, a Euclidean-based strategy was used to help back extrapolate the time of ethanol consumption. ¡ Table of Contents 1. Background and the aim of the work .............................................................................................. 5 2. Introduction ..................................................................................................................................... 8 2.1 Toxicokinetic and toxicodynamic (PBTK-TD) modelling ..................................................... 8 2.2 Modelling of exposure routes ................................................................................................ 14 2.2.1 Oral absorption .................................................................................................................. 14 2.2.2 Dermal absorption ............................................................................................................. 14 2.2.3 Inhalation........................................................................................................................... 17 2.3 Metabolism ............................................................................................................................ 17 2.4 Route-to-route extrapolation ................................................................................................. 19 2.5 In vitro-to- in vivo extrapolation ........................................................................................... 21 2.6 Available software for PBTK-TD modelling ........................................................................ 24 2.7 Literature applications of PBTK/TD models for case study compounds .............................. 25 2.8 Strengths and limitations of PBTK-TD modelling ............................................................... 27 2.9 Case study compounds .......................................................................................................... 30 2.9.1 Coumarin .......................................................................................................................... 31 2.9.2 Estragole ........................................................................................................................... 33 2.9.3 Hydroquinone ................................................................................................................... 34 2.9.4 Caffeine ............................................................................................................................ 35 2.9.5 Ethanol ............................................................................................................................. 37 2.9.6 Isopropanol ....................................................................................................................... 39 2.9.7 Styrene............................................................................................................................... 40 2.9.8 Methyl iodide ................................................................................................................... 42 2.9.9 Nicotine ............................................................................................................................. 43 2.10 Differences in molecular properties between cosmetic ingredients and drugs ..................... 46 3. Materials and methods .................................................................................................................. 48 3.1 Experimental Data ................................................................................................................. 48 3.1.1 Single and repeated toxicokinetics .................................................................................... 48 3.1.2 Single and repeated toxicodynamics ................................................................................. 56 3.1.3 Cell viability ...................................................................................................................... 57 3.2 PBTK, PBTD and VCBA model structures and equations ................................................... 58 3.2.1 PBTK model ...................................................................................................................... 59 3.2.2 PBTD model ...................................................................................................................... 79 3.2.3 Virtual cell-based assay model .......................................................................................... 81 3.3 Sensitivity Analysis and optimisation ................................................................................... 85 3.4 Quantitative structure-property relationships (QSPRs) ......................................................... 91 3.4.1 QSPRs for skin permeation ............................................................................................... 91 3.4.2 Plasma protein binding ...................................................................................................... 95 £ 3.4.3 Tissue-to-blood partition coefficients ............................................................................... 96 3.4.4 Blood-to-air partition coefficient ...................................................................................... 97 4. Results and Discussion .................................................................................................................. 98 4.1 Quantitative structure-property relationships (QSPRs) ......................................................... 98 4.1.1 QSPRs for skin permeation ............................................................................................... 98 4.1.2 Plasma/ protein binding and blood –to-plasma ratio ...................................................... 102 4.1.3 Blood-to-air partition coefficient ...................................................................................
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