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The field of chemical toxicity testing is undergoing a transition to overcome the limitations of in vivo experiments. This evolution involves implementing innovative non-animal approaches to improve predictability and provide a more precise understanding of toxicity mechanisms. Adverse outcome pathway (AOP) networks are pivotal in organizing existing mechanistic knowledge related to toxicological processes. However, these AOP networks are dynamic and require regular updates to incorporate the latest data. Regulatory challenges also persist due to concerns about the reliability of the information they offer. This study introduces a generic Weight-of-Evidence (WoE) scoring method, aligned with the tailored Bradford-Hill criteria, to quantitatively assess the confidence levels in key event relationships (KERs) within AOP networks. We use the previously published AOP network on chemical-induced liver steatosis, a prevalent form of human liver injury, as a case study. Initially, the existing AOP network is optimized with the latest scientific information extracted from PubMed using the free SysRev platform for artificial intelligence (AI)-based abstract inclusion and standardized data collection. The resulting optimized AOP network, constructed using Cytoscape, visually represents confidence levels through node size (key event, KE) and edge thickness (KERs). Additionally, a Shiny application is developed to facilitate user interaction with the dataset, promoting future updates. Our analysis of 173 research papers yielded 100 unique KEs and 221 KERs among which 72 KEs and 170 KERs, respectively, have not been previously documented in the prior AOP network or AOP-wiki. Notably, modifications in de novo lipogenesis, fatty acid uptake and mitochondrial beta-oxidation, leading to lipid accumulation and liver steatosis, garnered the highest KER confidence scores. In conclusion, our study delivers a generic methodology for developing and assessing AOP networks. The quantitative WoE scoring method facilitates in determining the level of support for KERs within the optimized AOP network, offering valuable insights into its utility in both scientific research and regulatory contexts. KERs supported by robust evidence represent promising candidates for inclusion in an in vitro test battery for reliably predicting chemical-induced liver steatosis within regulatory frameworks., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Mathieu Vinken reports financial support was provided by the Horizon2020 Research and Innovation Framework program. Mathieu Vinken reports financial support was provided by the Flemish government (Methusalem program). Mathieu Vinken reports financial support was provided by the Research Foundation Flanders. Mathieu Vinken reports financial support was provided by the Scientific Fund Willy Gepts. Mathieu Vinken reports financial support was provided by the Center for Alternatives to Animal Testing. Mathieu Vinken reports financial support was provided by the Alternatives Research and Development Foundation. Tamara Vanhaecke reports financial support was provided by the Colgate-Palmolive Grant (Society of Toxicology). Tamara Vanhaecke reports financial support was provided by Onderzoeksraad Vrije Universiteit Brussel. Tamara Vanhaecke reports financial support was provided by Brussels Environment of the Brussels-Capital Region. Tamara Vanhaecke reports financial support was provided by the Research Chair Mireille Aerens for the development of Alternatives to Animal Testing. Mathieu Vinken, editor-in-chief of Toxicology, acts as co-author of this submission. He will not be involved in the handling and evaluation of the manuscript. Furthermore, this submission will be blinded for Mathieu Vinken in the online Editorial Manager system in order to avoid conflict of interest issues If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Allergic contact dermatitis (ACD) often associated with the topical use of perfumed products, remains one of the most common chronic skin disorders in Western countries. Since labelling of scented menstrual hygiene products (MHPs) is not mandatory, women might be unknowingly exposed to allergens. Given that vaginal mucosae lack the vital barrier function of the skin, skin allergens can easily penetrate and become systemically available and hence women may experience adverse effects in the anogenital region. The aim of this study was therefore to investigate whether women using scented MHPs are at risk of sensitization and hence developing ACD. Hereto, a Quantitative Risk Assessment (QRA) is performed on four well-known skin sensitizing chemicals (α-isomethyl ionone, benzyl salicylate, hexyl cinnamaldehyde and heliotropine) that were previously found leaching from five different scented MHPs including tampons and sanitary pads. The amounts of heliotropine, leached by one of the investigated tampons, exceeded acceptable exposure levels determined with the QRA and could induce sensitization. In addition, although no sensitization is expected for the other three compounds, an allergenic reaction might be provoked in women who are already sensitized. Labelling of allergens on scented MHPs would therefore help consumers to prevent adverse effects linked to ACD., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Quinten Marcelis reports financial support was provided by Research Chair Mireille Aerens for alternative animal-free research methods. Quinten Marcelis reports article publishing charges was provided by Research council VUB., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)