Physiologically-Based Kinetics and Mechanistic Models to Assess Exposure to Chemicals Julia Pletz A thesis submitted in partial fulfilment of the requirements of Liverpool John Moores University for the degree of Doctor of Philosophy January 2020 Acknowledgements First and foremost, I would like to thank my Director of Studies, Prof. Mark Cronin, for supporting me to obtain the studentship from Liverpool John Moores University, his continuous support and guidance throughout the course of my doctoral studies and for facilitating my attendance at the Lorentz@Snellius Center workshop on e- Resources to Revolutionise Toxicology: Linking Data to Decisions in October 2019. I would also like to express my deep gratitude to my supervisor Dr. Steven Webb for his generous academic guidance and dedicated support in mathematical modelling, for connecting me to his group of researchers (Webb Lab UK) and facilitating my meeting and fruitful discussion with to Drs. Iain Gardner and Sibylle Neuhoff at Certara. In addition, I would like to extend my sincere gratitude to my supervisor Dr. Judith Madden for her invaluable input on my research and research communication materials. Nothing escapes her eagle eye. I would also like to thank Mark and Judith for their encouragement to do a traineeship at the European Commission Joint Research Centre (JRC) in Ispra (Italy), Drs. Stephanie Bopp, Alicia Paini, Nikolaos Parissis and Andrew Worth for their supervision and guidance at the JRC as well as Samantha Blakeman for working with me on the study presented in Chapter 2. My time at the JRC was very inspiring! In the context of this work, we thank the Norwegian Institute for Public Health (especially Catherine Thomsen and Amrit Kaur Sakhi) and the Danish Rigshospitalet, Department of Growth and Reproduction (especially Anna-Maria Andersson; Hanne Frederiksen; Tina Kold Jensen; Katharina Main) for providing the Human Biomonitoring Data used in this study; and Lara Lamon (European Commission Joint Research Centre) for helping to harvest the information on the EDI and TDI in an early stage of this work. Finally, with much appreciation, we would like to thank John F. Wambaugh (US EPA) for providing the Httk model and introducing the model characteristics. I would also like to thank all of my colleagues at the Chemoinformatics Research Group at Liverpool John Moores University, in particular Drs. David Ebbrell, James Firman and Steve Enoch for helping me to clarify chemistry-related questions, and Dr. Maria Sapounidou, Nicoleta Spinu, Sam Belfield, Antiopi Politi and Michele Assante for the fun and personal enrichment. I greatly appreciate the studentship provided by Liverpool John Moores University without which this research would not have been possible. Final thanks go to Drs. Henk Tennekes and Ester Lovšin Barle for encouraging and guiding me in my early years as a toxicologist, my family, capoeira family and friends for their continuous love and positivity. ii Abbreviations 3Rs Replacement, Reduction and Refinement AABS Amount Absorbed from an ACAT Model Compartment (e.g. AABS(ST) representing the amount absorbed from the stomach lumen compartment) ADEG Amount Degraded in an ACAT Model Compartment (e.g. ADEG(ST) representing the amount degraded in the stomach lumen compartment) ADIS Amount Dissolved in an ACAT Model Compartment (e.g. ADIS(ST) representing the amount dissolved in the stomach lumen compartment) AUND Amount Undissolved in an ACAT Model Compartment (e.g. AUND(ST) representing the amount undissolved in the stomach lumen compartment) ACAT Advanced Compartmental Absorption and Transit ACE Angiotensin-Converting Enzyme ACO Ascending Colon Lumen AD Adipose Tissue ADI Acceptable Daily Intake ADME Absorption, Distribution, Metabolism, Excretion AKI Acute Kidney Injury AO Adverse Outcome AOP Adverse Outcome Pathway AOP-KB AOP Knowledge Base AR Arterial Blood ARB Angiotensin Receptor Blocker ASA Aspirin ATP Adenosine Triphosphate BBzP Butylbenzyl Phthalate BCL B-Cell Lymphoma BE Biomonitoring Equivalent BEEDI Biomonitoring Equivalent based on the EDI BERfD Biomonitoring Equivalent based on the RfD BETDI Biomonitoring Equivalent based on the TDI BEI Biological Exposure Index iii BL Bladder BMA Bayesian Model Averaging BMD Benchmark Dose BMI Body Mass Index BP-3 Benzophenone-3 BPA Bisphenol A BPA-glu Bisphenol A Glucuronide BR Brain BW Body Weight CT Concentration in Compartment T (e.g. C in the lung translates to CLU or C of the arterial blood to CAR) CAE Caecum Lumen CD Collecting Duct (divided into two sections, CD1-2) CDB Collecting Duct Blood (divided into two compartments, CDB1-2) CDC Collecting Duct Cells (divided into two compartments, CDC1-2) CDL Collecting Duct Lumen (divided into two compartments, CDL1-2) CEFIC European Chemical Industry Council CKD Chronic Kidney Disease CLhep Hepatic Clearance Cmax Maximum Concentration COX Cyclooxygenase CP Constant representing Conversion from a Metabolite back to Parent D Diffusion Coefficient DDI Drug-Drug Interactions DEG Degraded Amount in an ACAT Compartment (see ADEG) DextCC External Diameter of the Cellular Compartment (PTC1, PTC2, PTC3, DTC, CDC1, CDC2) DIS Dissolved Amount in an ACAT Compartment (see ADIS) DLC Diameter of luminal compartment of the Henle’s loop DnBP Di-n-Butyl Phthalate DUO Duodenum Lumen DT Distal Tubule iv DTB Distal Tubular Blood DTC Distal Tubular Cells DTL Distal Tubular Lumen ECVAM European Centre for the Validation of Alternative Methods EDI Estimated Daily Intake EFSA European Food Safety Authority EHR Enterohepatic Recirculation EMA European Medicines Agency ER Endoplasmic Reticulum EtP Ethyl Paraben EURL European Union Reference Laboratory FAO Food and Agriculture Organisation of the United Nations FFPT Fluid Flow Leaving the Glomerular Space and Proximal Tubules FFHL Fluid Flow Leaving the Loop of Henle FFDT Fluid Flow Leaving the Distal Tubules and Collecting Ducts FQT Fractional Tissue Blood Flow in Compartment T (e.g. FQ in the lung translates to FQLU) fu(p) Fraction Unbound in Plasma G Glomerulus GB Glomerular Blood GER Gastric Emptying Rate GFR Glomerular Filtration Rate GIT Gastrointestinal Tract Glucs Glucuronides GS Glomerular Space GSH Glutathione GU Gut HA Hepatic Artery HBM Human Biomonitoring Hcc Height of Cells in the Cellular Compartment (PTC1, PTC2, PTC3, DTC, CDC1, CDC2) HE Heart v HI Hazard Index (for an individual i, i.e. HI(i)) HL Henle’s Loop HLB Henle’s Loop Blood HLC Henle’s Loop Cells HLL Henle’s Loop Lumen hOAT Human Organic Anion Transporter Httk High-Throughput Toxicokinetics ICF IndusChemFate ICH International Conference on Harmonisation IL Interleukin IL1/IL2/IL3 Ileum 1 Lumen / Ileum 2 Lumen / Ileum 3 Lumen IPCS International Programme of Chemical Safety IV Intravenous IVIVE In Vitro to In Vivo Extrapolation JE1/JE2 Jejunum 1 Lumen / Jejunum 2 Lumen Jmax Maximum Rate of Transport or Flux via a Transporter Protein ka Absorption Rate Constant, with Specific Rates in Stomach (ka(ST)) and Gut (ka(GU)) ka ACAT Absorption Rate Constant Considering the Paracellular Absorption Rate Constant (ka,p) in a specific ACAT compartment ka,p Paracellular Absorption Rate Constant in an ACAT compartment (e.g. ka,p in the stomach lumen is represented by ka,p,STL) kAT(T) Rate of Active Transport via Transporter Protein T kbil Biliary Elimination Rate Constant KD Dissolution Rate Constant KE Key Event ke(r) Renal Elimination Rate Constant kil Intestinal Loss Rate Constant KI Kidney KIM Kidney Injury Molecule Km Michaelis-Menten Constant kMET(M,i) Rate of Metabolism Forming Metabolite M in Compartment i vi Kp Tissue Partition Coefficient kPT Rate of Passive Diffusion Kp,u(T) Unbound Tissue Partition Coefficient in a Tissue T KS Solubility Coefficient corresponding to an ACAT compartment (e.g. KS in the stomach lumen is represented by KS(STL)) Kt Transit Rate in Small Intestine (Kt(GU)) and Colon (Kt(CO)) Lc Length of the Cylinder LCC Length of Cellular Compartment (PTC1, PTC2, PTC3, DTC, CDC1, CDC2) LCN-2 Lipocalin 2 LI Liver LRI Long Range Research Initiative LU Lung MBzP Monobenzyl Phthalate MeP Methyl Paraben MIE Molecular Initiating Event MnBP Mono-n-Butyl Phthalate MoA Mode of Action MPPGK Microsomal Protein Per Gram of Human Kidney MPT Mitochondrial Permeability Transition MRA Mixture Risk Assessment MSE Mean Squared Error MU Muscle MW Molecular Weight n-BuP n-Butyl Paraben n-PrP n-Propyl Paraben NGAL Lipocalin 2 NHANES National Health and Nutrition Examination Survey NO Nitric Oxide NSAID Nonsteroidal Anti-Inflammatory Drug OAT Organic Anion Transporter OCT Organic Cation Transporter vii ODE Ordinary Differential Equation OECD Organisation for Economic Co-operation and Development OEL Occupational Exposure Limit Oxy Oxybenzone p Particle Density PA Pancreas Papp Apparent Permeability PBBK Physiologically-Based Biokinetic PBK Physiologically-Based Kinetic PBPK Physiologically-Based Pharmacokinetic PBTK Physiologically-Based Toxicokinetic Pdiff,u Unbound Passive Diffusion Clearance Peff Effective Permeability PK/PD Pharmacokinetic-Pharmacodynamic POD Point of Departure PT Proximal Tubules (divided into three sections, PT1-3) PTB Proximal Tubular Blood (divided into three compartments, PTB1-3) PTC Proximal Tubular Cells (divided into three compartments, PTC1-3) PTCPGK Proximal Tubular Cells Per Gram of Kidney PTL Proximal Tubular Lumen (divided into three compartments, PTL1-3) QT Blood Flow in Compartment T (e.g. Q in the lung translates to QLU) QHL-CD2 Blood Flow in Loop of Henle and Collecting Ducts QC Cardiac Output QSAR Quantitative Structure-Activity