L06 Adverse Outcome Pathways (AOPs) PDF

05/06/2024 L06: Adverse Outcome Pathways (AOPs) Nora Bouftas [email protected] Department Environmental Health & Toxicology Previously presented by Lisa Baumann 1 2...

05/06/2024 L06: Adverse Outcome Pathways (AOPs) Nora Bouftas [email protected] Department Environmental Health & Toxicology Previously presented by Lisa Baumann 1 2 1  05/06/2024 Adverse outcome pathways First publication by Gerald Ankley in 2010 3 Adverse outcome pathways Definition: An AOP is a conceptual construct that portrays existing knowledge concerning the linkage between a direct molecular initiating event (e.g. a molecular interaction between a xenobiotic and a specific biomolecule) and an adverse outcome at a biological level or organization relevant to risk assessment (Ankley et al., 2010). 4 2  05/06/2024 Adverse outcome pathways 5 Increased level of biological organization Molecular Cellular Organ/tissue Organism Population 6 3  05/06/2024 Different terms https://www-oecd-org/chemicalsafety/testing/49963576.pdf 7 AOP structure AO KER1 KER2 KER3 KERn Adverse MIE KE1 KE2 KEn Outcome 8 4  05/06/2024 AOP structure AO KER1 KER2 KER3 KERn Adverse MIE KE1 KE2 KEn Outcome MIE: Molecular Initiating Event KE: Key Event KER: Key Event Relationship AO: Adverse Outcome 9 AOP structure AO KER1 KER2 KER3 KERn Adverse MIE KE1 KE2 KEn Outcome MIE: Molecular Initiating Event KE: Key Event KER: Key Event Relationship AO: Adverse Outcome MIE and AO are “specialized” KEs 10 5  05/06/2024 AOP structure MIE: Molecular initiating event A specialized type of key event that represents the initial point of chemical/stressor interaction at the molecular level. KE: Key event A change in biological or physiological state that is both measurable and essential to the progression of a defined biological perturbation leading to an adverse outcome. KER: Key event relationship Defines a causal and predictive relationship between the upstream and downstream event. AO: Adverse outcome A specialized type of key event that is generally accepted as being of regulatory significance on the basis of correspondence to an established protection goal or equivalence to an apical endpoint in an accepted regulatory guideline toxicity test. 11 Scientific relevance of AOPs 12 6  05/06/2024 Five Principles of AOP development 1. AOPs are NOT chemical-specific 2. AOPs are MODULAR 3. AOPs are a pragmatic functional unit of development and evaluation 4. AOP networks are the functional unit of prediction 5. AOPs are living documents 13 1. AOPs are NOT chemical-specific Thyroxine Thyroxine Hippocampal TH (T4) in Hippocampal Hippocampal Cognitive Thyroperoxidase (t4) in Gene Synthesis, Neuronal Anatomy, Function, Function, inhibition Serum, Expression, decreased Tissue, Altered Decreased Decreased Decreased Altered Decreased https://aopwiki.org/aops/42 14 7  05/06/2024 1. AOPs are NOT chemical-specific Thyroxine Thyroxine Hippocampal TH (T4) in Hippocampal Hippocampal Cognitive Thyroperoxidase (t4) in Gene Synthesis, Neuronal Anatomy, Function, Function, inhibition Serum, Expression, decreased Tissue, Altered Decreased Decreased Decreased Altered Decreased Methimazole AOPs do not describe what a single chemical genistein Methimazole does, but what ANY chemical can do that amitrole sulfametazine triggers the MIE. nonylphenol amitrole resorcinol Benzothiazolethi Development: no chemical information needed one Propylthiouracil Application: understanding chemical hazard https://aopwiki.org/aops/42 15 2-AOPs are Modular MIE KE1 KE2 KEn AO 2 Building blocks: Key Events and Key Event Relationships MIE and AO are specialised KEs 16 8  05/06/2024 2-AOPs are Modular MIE KE1 KE2 KEn AO 2 Building blocks: Key Events and Key Event Relationships MIE and AO are specialised KEs A Key Event (KE) is a change in the state of a biological process that we can measure Functional unit of observation or verification Key events are not isolated events, they are essential for an adverse outcome to occur 17 Key Event Relationships A Key Event Relationship (KER) is the causal (directed) relationship between two KEs Supported by biological plausibility and evidence, based on knowledge and measurements Female Adult KE1 Brain KE1 KE1 MIE MIE MIE KE2 KE2 Liver KE2 Male Developing organism 18 9  05/06/2024 Key Event Relationships Non-Adjacent KER AO Adjacent KER1 KER2 KER3 KER4 Adverse MIE KE1 KE2 KE3 Outcome Non-Adjacent KER 19 3- AOPs are a pragmatic functional unit of development and evaluation Individual AOPs are linear, non-branching constructs AOPs are a pragmatic simplification of complex biology. It helps you to focus on a specific aspect of toxicology, for development and evaluation. AO KER1 KER2 KER3 KERn Adverse MIE KE1 KE2 KEn Outcome 20 10  05/06/2024 4- AOP networks are the functional unit of prediction Multiple linked AOPs, better representative of biological complexity and functional unit of prediction of what happens in the real world. MIE KE KE KE AO AO KE KEs or KERs shared by multiple AOPs MIE KE KE AO MIE KE KE KE KE AO MIEs leading to various AOs - can be organism dependent, but does KE AO not have to be MIE KE KE 21 5- AOPs are living documents AOPs are a way of organising existing knowlegde methods evolve, new insights are created The objective is never to make a complete AOP It is ready to use when it is fit-for-purpose 22 11  05/06/2024 AOPwiki 23 AOPwiki 24 12  05/06/2024 AOPwiki 25 AOPwiki 26 13  05/06/2024 AOPwiki 27 AOPwiki 28 14  05/06/2024 AOPwiki - Status Different stages of “readiness”: Endorsed, Approved, Under Review Under Development, (…) 29 Weight of Evidence Evaluation Element of WoE evaluation Considerations Essentiality of KEs Effects reversible if stressor removed? Is downstream pathway prevented if KE is blocked? Biological plausibility of KERs Are KEs and KERs consistent with current biological understanding? Empirical support for KERs Dose-response relationships Temporality (cause before effect) Consistency within applicability domain Quantitative understanding of KERs Extent to which downstream KE can be quantitatively predicted based on upstream KE 30 15  05/06/2024 AOPs – What are the good for? repository clear presentation MIE KE ? ? ? AO alternative tests understanding } biomarker mixtures further research terminology Slide from JRC – Brigitte Landesmann 31 Example of an AOP – Androgen signaling in females https://aopwiki.org/aops/345 32 16  05/06/2024 Example of an AOP – Androgen signaling in females In order to make it feasible- can be divided into KER blocks https://aopwiki.org/aops/345 33 Example of an AOP – Androgen signaling in females 34 17  05/06/2024 Example of an AOP – Androgen signaling in females 35 Example of an AOP – Androgen signaling in females 36 18  05/06/2024 Example of an AOP – Androgen signaling in females 37 Example of an AOP – Androgen signaling in females 38 19  05/06/2024 Example of an AOP – Androgen signaling in females 39 Example of an AOP – Androgen signaling in females 40 20  05/06/2024 Example of an AOP – Androgen signaling in females 41 Example of an AOP – Thyroid axis disruption 42 21  05/06/2024 AOP network for thyroid axis disruption during development – Cross-class AOP IYD inhibition TH in neural Hippocampal Cognitive Hippocampal tissues, function, function, anatomy, altered decreased decreased decreased Iodide in NIS inhibition thyroid, decreased TH T4 in serum, T4 in tissue, Metamorphosis, TPO inhibition synthesis, Survival, reduced decreased decreased impaired decreased T3 in tissue, DIO1 inhibition decreased Anterior SB Hearing, inflation, reduced impaired DIO2 inhibition Population y.o.y survival, trajectory, reduced decreased Posterior SB Swimming inflation, performance, impaired reduced Courtesy of Dan Villeneuve, US EPA 43 Example of an AOP – Thyroid axis disruption ! HPT axis conserved across taxonomic groups  Potential for cross-species extrapolation Knapen et al. Environ. Sci. Technol. 2020, 54, 8491−8499 44 22  05/06/2024 AOP network example Network of 14 AOPs Decreased serum T4 Adverse outcomes in vertebrate development Slide: courtesy of Dan Villeneuve, US EPA 45 AOPs – What are the good for? repository clear presentation MIE KE ? ? ? AO alternative tests understanding } biomarker mixtures further research terminology Slide from JRC – Brigitte Landesmann 46 23  05/06/2024 [email protected] Questions? 47 24