Derivation, characterisation and analysis of an adverse outcome pathway network for human hepatotoxicity

Arnesdotter, Emma; Spînu, Nicoleta; Firman, James W.; Ebbrell, David J.; Cronin, Mark T.D.; Vanhaecke, Tamara; Vinken, Mathieu

doi:10.1016/j.tox.2021.152856

Cited by 31 publications

(21 citation statements)

References 57 publications

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“…While creating a new KE can be meaningful in many cases (e.g., the same biological process taking place in a distinct organ or a tissue), unnecessary redundancy can lead to challenges in the application of the AOP-based knowledge. This is especially true when modelling AOPs as a network and using such representation to identify hidden connections and to perform read across analysis (10,(46)(47)(48)(49)(50)(51).…”

Section: Our Annotation Enables Grouping Of Kes Resulting In Improved...mentioning

confidence: 99%

Molecular annotation of AOPs guides the development of the next generation mechanistic chemical safety assessment and new approach methods

Saarimäki

Morikka

Pavel

et al. 2022

Preprint

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Mechanistic toxicology has emerged as a powerful framework to inform on the safety of chemicals and guide the development of new safe-by-design compounds. Although toxicogenomics provides support towards mechanistic evaluation of chemical exposures, the implementation of toxicogenomics-based evidence in the regulatory setting is still hindered by uncertainties related to the analysis and interpretation of such data. Adverse Outcome Pathways (AOPs) are multi-scale models that link chemical exposures to adverse outcomes through causal cascades of key events (KEs). The use of mechanistic evidence through the AOP framework is actively promoted for the development of new approach methods (NAMs) and to reduce animal experimentation. However, in order to unleash the full potential of AOPs and build confidence into toxicogenomics, robust and unified associations between KEs and patterns of molecular alteration need to be established. Here, we hypothesised that systematic curation of molecular events associated with KEs would enable the modelling of AOPs through gene-level data, creating the much-needed link between toxicogenomics and the systemic mechanisms depicted by the AOPs. This, in turn, introduces novel ways of benefitting from the AOP concept, including predictive models, read-across, and targeted assays, while also reducing the need for multiple testing strategies. Hence, we developed a multi-step strategy to annotate the AOPs relevant to human health risk assessment. We show that our framework successfully highlights relevant adverse outcomes for chemical exposures with strong in vitro and in vivo convergence, supporting chemical grouping and other data-driven approaches. Finally, we defined and experimentally validated a panel of robust AOP-derived in vitro biomarkers for pulmonary fibrosis.

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Section: Our Annotation Enables Grouping Of Kes Resulting In Improved...mentioning

confidence: 99%

Molecular annotation of AOPs guides the development of the next generation mechanistic chemical safety assessment and new approach methods

Saarimäki

Morikka

Pavel

et al. 2022

Preprint

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“…He also described the ONTOX (ontology-driven and artificial intelligence-based repeated dose toxicity testing of chemicals for next generation risk management) project, which aims to develop a strategy for the reliable prediction of chemical-induced toxicity. [24][25][26][27] Implementing the 3Rs and related key aspects…”

Section: Developing a 3-d Bioprinted Human Vascular Lung Model To Ide...mentioning

confidence: 99%

Advances in Animal Models and Cutting-Edge Research in Alternatives: Proceedings of the Second International Conference on 3Rs Research and Progress, Hyderabad, 2021

et al. 2022

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The fact that animal models fail to replicate human disease faithfully is now being widely accepted by researchers across the globe. As a result, they are exploring the use of alternatives to animal models. The time has come to refine our experimental practices, reduce the numbers and eventually replace the animals used in research with human-derived and human-relevant 3-D disease models. Oncoseek Bio-Acasta Health, which is an innovative biotechnology start-up company based in Hyderabad and Vishakhapatnam, India, organises an annual International Conference on 3Rs Research and Progress. In 2021, this conference was on ‘Advances in Research Animal Models and Cutting-Edge Research in Alternatives’. This annual conference is a platform that brings together eminent scientists and researchers from various parts of the world, to share recent advances from their research in the field of alternatives to animals including new approach methodologies, and to promote practices to help refine animal experiments where alternatives are not available. This report presents the proceedings of the conference, which was held in hybrid mode (i.e. virtual and in-person) in November 2021.

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“…However, many of these to a large extent still remain in development, limited by biological understanding and supporting evidence, and in some cases, a single AOP may not be sufficient to explain an AO and a network approach may be needed to explain or predict the final AO. A few examples are those of human hepatotoxicity, human neurotoxicity, swim bladder inflation in fishes, and male rat reproductive tract abnormalities, each of which are outlined by several distinct AOPs ( Villeneuve et al, 2014 ; Spinu et al, 2019 ; Arnesdotter et al, 2021 ). Therefore, while the AOPs are very useful in development of NAMs, such an approach for even more complex outcomes like DART, especially in cases where the MoA of a chemical is unknown, is particularly challenging.…”

Section: Introductionmentioning

confidence: 99%

Beyond AOPs: A Mechanistic Evaluation of NAMs in DART Testing

et al. 2022

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New Approach Methodologies (NAMs) promise to offer a unique opportunity to enable human-relevant safety decisions to be made without the need for animal testing in the context of exposure-driven Next Generation Risk Assessment (NGRA). Protecting human health against the potential effects a chemical may have on embryo-foetal development and/or aspects of reproductive biology using NGRA is particularly challenging. These are not single endpoint or health effects and risk assessments have traditionally relied on data from Developmental and Reproductive Toxicity (DART) tests in animals. There are numerous Adverse Outcome Pathways (AOPs) that can lead to DART, which means defining and developing strict testing strategies for every AOP, to predict apical outcomes, is neither a tenable goal nor a necessity to ensure NAM-based safety assessments are fit-for-purpose. Instead, a pragmatic approach is needed that uses the available knowledge and data to ensure NAM-based exposure-led safety assessments are sufficiently protective. To this end, the mechanistic and biological coverage of existing NAMs for DART were assessed and gaps to be addressed were identified, allowing the development of an approach that relies on generating data relevant to the overall mechanisms involved in human reproduction and embryo-foetal development. Using the knowledge of cellular processes and signalling pathways underlying the key stages in reproduction and development, we have developed a broad outline of endpoints informative of DART. When the existing NAMs were compared against this outline to determine whether they provide comprehensive coverage when integrated in a framework, we found them to generally cover the reproductive and developmental processes underlying the traditionally evaluated apical endpoint studies. The application of this safety assessment framework is illustrated using an exposure-led case study.

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Derivation, characterisation and analysis of an adverse outcome pathway network for human hepatotoxicity

Cited by 31 publications

References 57 publications

Molecular annotation of AOPs guides the development of the next generation mechanistic chemical safety assessment and new approach methods

Molecular annotation of AOPs guides the development of the next generation mechanistic chemical safety assessment and new approach methods

Advances in Animal Models and Cutting-Edge Research in Alternatives: Proceedings of the Second International Conference on 3Rs Research and Progress, Hyderabad, 2021

Beyond AOPs: A Mechanistic Evaluation of NAMs in DART Testing

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