Critical Reviews in Toxicology For Peer Review Only Workshop Report: Putative Adverse Ou tcome Pathways (AOP) Relevant to Neurotoxicity Journal: Critical Reviews in Toxicology Manuscript ID: Draft Manuscript Type: Review Date Submitted by the Author: n/a Complete List of Authors: Price, Anna; European Commission Joint Research Centre, Institute for Health and Consumer Protection Crofton, Kevin; US Environmental Protection Agency, Sachana, Magdalini; European Commission Joint Research Centre, Institute for Health and Consumer Protection Shafer, Timothy; USEPA, Behl, Mamta; National Institute of Environmental Health Sciences, Forsby, Anna; Department of Neurochemistry, Stockholm University, Hargreaves, Alan; Nottingham Trent University, Nottingham, Landesmann, Brigitte; European Commission Joint Research Centre, Lein, Pamela; School of Veterinary Medicine, University of California Davis, Department of Molecular Biosciences Louisse, Jochem; European Commission Joint Research Centre, Monnet-Tschudi, Florianne; University of Lausanne, Paini, Alicia; European Commission Joint Research Centre, Rolaki, Alexandra; European Commission Joint Research Centre, Schrattenholz, André; ProteoSys AG Mainz, Suñol, Cristina; Institut d’Investigacions Biomèdiques de Barcelona, van Thriel, Christoph; IfADo-Leibniz Research Center for Working Environment and Human Factors, Whelan, Maurice; European Commission Joint Research Centre, Institute for Health and Consumer Protection Fritsche, Ellen; Leibniz Research Institute for Environmental Medicine, Keywords: pathways of neurotoxicity, key events, adverse outcome , in vitro testing, URL: http://mc.manuscriptcentral.com/btxc Email: [email protected] Page 1 of 172 Critical Reviews in Toxicology 1 2 3 4 predictive toxicology 5 6 7 8 9 10 11 12 13 14 For Peer Review Only 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 URL: http://mc.manuscriptcentral.com/btxc Email: [email protected] Critical Reviews in Toxicology Page 2 of 172 1 2 3 Workshop Report: Putative Adverse Outcome Pathways (AOP) Relevant to Neurotoxicity 4 5 6 7 1 2 1 2 3 8 Anna Bal-Price , Kevin M.Crofton , Magdalini Sachana , Timothy J. Shafer , Mamta Behl , 4 5 1 6 1 9 Anna Forsby , Alan Hargreaves , Brigitte Landesmann , Pamela J. Lein , Jochem Louisse , 10 Florianne Monnet-Tschudi 7, Alicia Paini 1, Alexandra Rolaki 1, André Schrattenholz 8, Cristina 11 9 10 1 11 12 Suñol , Christoph van Thriel , Maurice Whelan and Ellen Fritsche 13 14 For Peer Review Only 15 1 16 Joint Research Centre of the European Commission, Institute for Health and Consumer 17 Protection, Ispra, Italy; 2National Center for Computational Toxicology, Office of 18 Research and Development, U.S. Environmental Protection Agency, RTP, NC 27711, 19 3 20 USA; Division of the National Toxicology Program, National Institute of Environmental 21 Health Sciences, Research Triangle Park, NC, USA; 4 Department of Neurochemistry, 22 Stockholm University, Sweden; 5Nottingham Trent University, Nottingham, UK; 23 6 24 Department of Molecular Biosciences, School of Veterinary Medicine, University of 25 California Davis, Davis, California, USA; 7Department of Physiology and SCAHT, 26 8 27 University of Lausanne, Lausanne, Switzerland; ProteoSys AG, Mainz, Germany; 9 28 Institut d’Investigacions Biomèdiques de Barcelona. IIBB-CSIC. IDIBAPS. CIBERESP, 29 Barcelona, Spain; 10IfADo-Leibniz Research Center for Working Environment and 30 11 31 Human Factors, Dortmund, Germany; IUF - Leibniz Research Institute for 32 Environmental Medicine, Düsseldorf, Germany 33 34 35 36 37 38 Corresponding author: 39 40 Dr Anna K. Bal-Price 41 Systems Toxicology Unit 42 EURL- ECVAM 43 44 Institute for Health and Consumer Protection, 45 European Commission, 46 Joint Research Centre, TP 580 47 Via Fermi 1, 21026 Ispra (VA), Italy 48 Tel.: +39 0332 78 6018 49 50 Fax: +39 0332 78 5336 51 Email: [email protected] 52 53 54 55 56 57 58 59 60 1 URL: http://mc.manuscriptcentral.com/btxc Email: [email protected] Page 3 of 172 Critical Reviews in Toxicology 1 2 3 Abstract 4 5 6 The Adverse Outcome Pathway (AOP) framework provides a template that facilitates 7 8 understanding of complex biological systems and the pathways of toxicity that result in adverse 9 10 11 outcomes (AOs). The AOP starts with an molecular initiating event (MIE) in which a chemical 12 13 interacts with a biological target(s), followed by a sequential series of KEs, which are cellular, 14 For Peer Review Only 15 anatomical and/or functional changes in biological processes, that ultimately result in an AO 16 17 18 manifest in individual organisms and populations. It has been developed as a tool for a 19 20 knowledge-based safety assessment that relies on understanding mechanisms of toxicity, rather 21 22 than simply observing its adverse outcome. 23 24 25 A large number of cellular and molecular processes are known to be crucial to proper 26 27 development and function of the central (CNS) and peripheral nervous systems (PNS). However, 28 29 there are relatively few examples of well-documented pathways that include causally linked 30 31 32 MIEs and KEs that result in adverse outcomes in the CNS or PNS. As a first step in applying the 33 34 AOP framework to adverse health outcomes associated with exposure to exogenous neurotoxic 35 36 37 substances, the EU Reference Laboratory for Alternatives to Animal Testing (EURL ECVAM) 38 39 organized a workshop (March 2013, Ispra, Italy) to identify potential AOPs relevant to 40 41 neurotoxic and developmental neurotoxic outcomes. Although the AOPs outlined during the 42 43 44 workshop are not fully described, they could serve as a basis for further, more detailed AOP 45 46 development by further identification of data gaps and application of modified Bradford-Hill 47 48 criteria (Meek et al., 2014) to be useful for human health risk assessment. 49 50 51 52 53 54 55 Key words: pathways of neurotoxicity, molecular initiating event, key events, adverse outcome 56 57 pathway, in vitro testing, predictive toxicology 58 59 60 2 URL: http://mc.manuscriptcentral.com/btxc Email: [email protected] Critical Reviews in Toxicology Page 4 of 172 1 2 3 4 Table of Contents 5 6 7 Introduction to AOP concept ........................................................................................................................ 4 8 9 Challenges for neurotoxicity AOP development .......................................................................................... 7 10 11 Common key events for neurotoxic outcomes .............................................................................................. 9 12 Considering life stage-specific susceptibility in neurotoxicity AOPs ......................................................... 12 13 14 Future directionsFor for development Peer of Neurotoxicity Review AOPs .................................................. Only ...................... 15 15 16 Further development of the outlined AOPs to neurotoxicity ...................................................................... 20 17 18 References ................................................................................................................................................... 23 19 Appendix: Examples of the putative AOPs for neurotoxicity ................................................................... 28 20 21 I. Adverse Outcome Pathway on: Binding of antagonist to an NMDAR during synaptogenesis contributes 22 to impairment of learning and memory abilities ......................................................................................... 28 23 24 II. Adverse Outcome Pathway on: Binding of agonist to NMDA receptor causes excitotoxicity that 25 mediates neuronal cell death, contributing to reduction (or loss) of cognitive, sensory and motor function 26 27 .................................................................................................................................................................... 35 28 III. Adverse Outcome Pathway on: Binding of antagonist to GABA receptor results in hyperexcitability 29 A 30 and convulsions ........................................................................................................................................... 42 31 IV. Adverse Outcome Pathway on: Binding of Pyrethroids to Voltage-gated Sodium Channels induces 32 33 acute neurotoxicity ...................................................................................................................................... 47 34 V. Adverse Outcome Pathway on: Binding of certain organophosphates to NTE results in delayed 35 36 neuropathy .................................................................................................................................................. 56 37 VI. Adverse Outcome Pathway on: Impairment of learning and memory induced by binding of 38 39 electrophilic chemicals to SH(thiol)-group of proteins and non-protein molecules in neuronal and glial 40 cells during development ............................................................................................................................ 63 41 42 VII. Adverse Outcome Pathway on: Binding of inhibitors to the mitochondrial respiration chain complex 43 I, II, III or IV or interaction of uncouplers with oxidative phosphorylation decreases or blocks ATP 44 production resulting in neurodegeneration. ..............................................................................................