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AOP 42: Inhibition of Thyroperoxidase and Subsequent Adverse Neurodevelopmental Outcomes in Mammals

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AOP 42: Inhibition of Thyroperoxidase and Subsequent Adverse Neurodevelopmental Outcomes in Mammals Organisation for Economic Co-operation and Development DOCUMENT CODE For Official Use English - Or. English 1 January 1990 AOP 42: Inhibition of Thyroperoxidase and Subsequent Adverse Neurodevelopmental Outcomes in Mammals Short Title: TPO Inhibition and Altered Neurodevelopment This document was approved by the Extended Advisory Group on Molecular Screening and Toxicogenomics in June 2018. The Working Group of the National Coordinators of the Test Guidelines Programme and the Working Party on Hazard Assessment are invited to review and endorse the AOP by 29 March 2019. Magdalini Sachana, Administrator, Hazard Assessment, [email protected], +(33- 1) 85 55 64 23 Nathalie Delrue, Administrator, Test Guidelines, [email protected], +(33-1) 45 24 98 44 This document, as well as any data and map included herein, are without prejudice to the status of or sovereignty over any territory, to the delimitation of international frontiers and boundaries and to the name of any territory, city or area. 2 │ Foreword This Adverse Outcome Pathway (AOP) on Inhibition of Thyroperoxidase and Subsequent Adverse Neurodevelopmental Outcomes in Mammals, has been developed under the auspices of the OECD AOP Development Programme, overseen by the Extended Advisory Group on Molecular Screening and Toxicogenomics (EAGMST), which is an advisory group under the Working Group of the National Coordinators for the Test Guidelines Programme (WNT). The AOP has been reviewed internally by the EAGMST, externally by experts nominated by the WNT, and has been endorsed by the WNT and the Working Party on Hazard Assessment (WPHA) in xxx. Through endorsement of this AOP, the WNT and the WPHA express confidence in the scientific review process that the AOP has undergone and accept the recommendation of the EAGMST that the AOP be disseminated publicly. Endorsement does not necessarily indicate that the AOP is now considered a tool for direct regulatory application. The Joint Meeting of the Chemicals Committee and the Working Party on Chemicals, Pesticides and Biotechnology agreed to declassification of this AOP on xxxx. This document is being published under the responsibility of the Joint Meeting of the Chemicals Committee and the Working Party on Chemicals, Pesticides and Biotechnology. The outcome of the internal and external reviews are publicly available respectively in the AOP Wiki and the eAOP Portal of the AOP Knowledge Base at the following links: [internal review] [external review]. │ 3 Table of contents Foreword ................................................................................................................................................ 2 Adverse Outcome Pathway on Inhibition of Thyroperoxidase and Subsequent Adverse Neurodevelopmental Outcomes in Mammals ..................................................................................... 5 Short Title: TPO Inhibition and Altered Neurodevelopment ............................................................... 5 Authors ............................................................................................................................................. 5 Abstract .................................................................................................................................................. 6 Background ............................................................................................................................................ 7 Graphical Representation ..................................................................................................................... 7 Summary of the AOP ............................................................................................................................ 8 Molecular Initiating Events (MIE), Key Events (KE), Adverse Outcomes (AO) ............................... 8 Key Event Relationships ...................................................................................................................... 8 Stressors ............................................................................................................................................... 9 Overall Assessment of the AOP ............................................................................................................ 9 Domain of Applicability .................................................................................................................... 10 Life Stage Applicability ................................................................................................................. 10 Taxonomic Applicability ................................................................................................................ 10 Sex Applicability ............................................................................................................................ 10 Essentiality of the Key Events ............................................................................................................ 11 Weight of Evidence Summary ............................................................................................................ 12 Biological plausibility: ....................................................................................................................... 12 Concordance of dose-response relationships: .................................................................................... 13 Temporal concordance among the key events and adverse effect: .................................................... 14 Consistency: ....................................................................................................................................... 14 Uncertainties, inconsistencies, and data gaps: ................................................................................... 15 Quantitative Consideration ................................................................................................................ 16 References ............................................................................................................................................ 17 Appendix 1 ........................................................................................................................................... 21 List of MIEs in this AOP ................................................................................................................... 21 Event: 279: Thyroperoxidase, Inhibition........................................................................................ 21 List of Key Events in the AOP .......................................................................................................... 27 Event: 277: Thyroid hormone synthesis, Decreased ...................................................................... 27 Event: 281: Thyroxine (T4) in serum, Decreased .......................................................................... 33 Event: 280: Thyroxine (T4) in neuronal tissue, Decreased ............................................................ 39 Event: 756: Hippocampal gene expression, Altered ...................................................................... 45 Event: 757: Hippocampal anatomy, Altered .................................................................................. 49 Event: 758: Hippocampal Physiology, Altered .............................................................................. 53 List of Adverse Outcomes in this AOP .............................................................................................. 58 Appendix 2 ........................................................................................................................................... 64 4 │ List of Adjacent Key Event Relationships in the AOP ...................................................................... 64 Relationship: 309: Thyroperoxidase, Inhibition leads to TH synthesis, Decreased ....................... 64 Relationship: 305: TH synthesis, Decreased leads to T4 in serum, Decreased .............................. 68 Relationship: 312: T4 in serum, Decreased leads to T4 in neuronal tissue, Decreased ................. 72 Relationship: 746: T4 in neuronal tissue, Decreased leads to Hippocampal gene expression, Altered ............................................................................................................................................ 78 Relationship: 747: Hippocampal gene expression, Altered leads to Hippocampal anatomy, Altered ............................................................................................................................................ 82 Relationship: 749: Hippocampal anatomy, Altered leads to Hippocampal Physiology, Altered ... 87 Relationship: 748: Hippocampal Physiology, Altered leads to Cognitive Function, Decreased ... 93 List of Non Adjacent Key Event Relationships in this AOP ............................................................. 98 Relationship: 366: Thyroperoxidase, Inhibition leads to T4 in serum, Decreased ......................... 98 Relationship: 1388: T4 in serum, Decreased leads to Hippocampal anatomy, Altered ............... 111 Relationship: 1389: T4 in serum, Decreased leads to Hippocampal Physiology, Altered ........... 116 Relationship: 403: T4 in serum, Decreased leads to Cognitive Function, Decreased .................. 121 │ 5 Adverse Outcome Pathway on Inhibition of Thyroperoxidase and Subsequent Adverse Neurodevelopmental Outcomes in Mammals Short Title: TPO Inhibition and Altered Neurodevelopment Authors
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