Scientists worldwide have put significant effort into advancing human risk assessment of chemicals without using laboratory animals. This effort is also reflected in the vision of the ONTOX project, which started on 1 May 2021. On the occasion of ONTOX’s 2nd birthday, we are proud to present the work that has been done.
Work Package 1: Biological domain
WP1’s main focus was on building the biological foundation for the testing strategies to be developed for the project’s target organs: kidney, liver and developing brain. These physiological roadmaps were made accessible, readable, and interoperable to maximise usability.
Work Package 2: Toxicological domain
WP2 developed a database on drug-induced cholestasis using data from human studies, which contains information on 395 patients and around 60 various factors. Initial findings indicate that chemicals group differently, and new connections between clinical variables have been discovered. A collection of fresh-frozen brain samples with neural tube defects was gathered for transcriptomic analysis. Liver samples from nonalcoholic fatty liver disease patients were also processed and sequenced. New miRNA biomarkers related to steatosis and key events are being identified. Furthermore, WP2 created qualitative Adverse Outcome Pathways (AOP) networks and outlined quantitative models for all case studies.
Work Package 3: Chemical domain
WP3 collected experimental data on physicochemical and toxicokinetic properties from the literature. This data helped profile chemicals and select computational tools to fill data gaps. Experimental and predicted data were shared for other project tasks, e.g. for WP4’s PBK model development. WP3 extracted experimental data from public databases (ChEMBL, Tox21, ToxCast) for binding/inhibition of MIE-associated proteins upstream of AOPs of relevant project adversities. This data was used to evaluate existing computational tools and to develop new models to predict protein activities.
Work Package 4: Kinetic domain
WP4 centred on characterising generic in vitro distribution kinetic models and applicability domains; in vitro characterisation was done together with WP7, 8, and 9. A high-throughput physiologically-based kinetic model framework is developed in collaboration with WP3 and WP6.
Work Package 5: Data integration, ontology and AI
WP5 streamlined data extraction from literature using Natural Language Models (NLP) and provided training on the tools. Furthermore, WP5 is exploring using NLP for AOP construction and expanding the number of labels on SysRev. WP5 created BioBricks, a big data platform, and worked on developing ontologies for target endpoints. Members of WP5 authored a paper on probabilistic risk assessment and hosted a workshop on the topic in Ranco, Italy. They expanded the RASAR method by considering both chemical and property similarity.
Work Package 6: Risk assessment and implementation
WP6 completed the data extraction for the “Systematic scoping review of exposure methods” project and began extracting figures using the SysRev tool. This helped identify the best exposure methods for use in ONTOX. WP6 also mapped stakeholders’ positions on NAMs and probabilistic risk assessment to understand the challenges and opportunities. WP6 organised the first ONTOX Stakeholder network meeting in March 2023, with participants from regulatory authorities, industry, NGO, and academia.
Work Package 7: Hepatotoxicity
WP7 updated the AOP networks on chemical-induced liver cholestasis and steatosis, which will be used to develop in vitro test batteries. The team in WP7 also developed a transcriptomic blueprint of chemical-induced cholestasis using machine learning algorithms and identified a fingerprint of 13 genes linked to key events of the AOP network for testing cholestatic compounds. Moreover, young scientists from WP7 won the Best poster award and Travel bursary at the ESTIV Congress in 2022.
Work Package 8: Nephrotoxicity
WP8 developed a tubular necrosis AOP and is developing a nephrotoxicity AOP network. Moreover, WP8 also conducted a literature search for a tubular necrosis case study using SysRev and developed assays to measure endpoints associated with key events in the AOP nephrotoxicity network. Additionally, they started developing in vitro assays for crystallopathy. A team member has been awarded for the ONTOX work at the ESTIV Congress in 2022.
Work Package 9: Developmental neurotoxicity
WP9 characterised the biological applicability domain of seven in vitro assays and uploaded AOPs describing adverse events leading to decreased cognition in children to the AOPwiki. They further optimised a computational model of neural tube closure. WP9 representatives also won conference prizes at the ICT 2022 and ASPIS Open Symposium 2022. Moreover, WP9 described the computational model in a video.
Video on the development of the computational model for neural tube development made by WP9 members.
Work Package 10: Coordination
The greatest achievement of WP10 in the second year was the submission of the 1st periodic ONTOX report, which was approved by the European Commission. The feedback received was positive, and the project is considered to be on track. In addition, WP10 successfully coordinated the amendment process to include the 19th ONTOX partner – Wageningen University Research.
Work Package 11: Data management and quality control
WP11 received and stored data from multiple sources during ONTOX’s second year. This includes ToxTemp from WP9, multiple transcriptomics datasets, and the first version of physiological maps. The frequency of meetings with data generators from WP7-9 was also increased to ensure data safety and the protection of the project’s legacy.
Eliska Kuchovska, a member of the WP9, won the Best poster award at the ASPIS Open Symposium 2023.
Work Package 12: Dissemination
WP12 organised four training and five webinars for the consortium, reaching over 300 people. This team also organised a successful live-streaming video in the “TOXstreams” series with ONTOX scientists, which reached over 350 views, confirming the audience’s interest in ONTOX activities. WP12 continued to create and develop dissemination material for various events, including exclusive music playlists and fun team activities.
ONTOX coordinator Prof. Mathieu Vinken and WP7 members described ONTOX work in the TOXstreams.
Work Package 13: Exploitation
WP13 created ONTOX Hub version 1, which provides access to chemical, toxicological, and safety data from the ONTOX COSMOS platform and in silico toxicity prediction system VEGA. The team in WP13 also analysed the intellectual property of consortium partners’ NAMs and developed a concept for the exploitation and sustainability plan for ONTOX Hub and the marketplace. WP13 conducted a qualitative analysis of the market and potential customers of ONTOX Hub and marketplace, including interviews and meetings with stakeholders from industry, academia, and regulatory bodies, in close collaboration with WP6,10,12 and 14.
Work Package 14: Communication
WP14’s efforts in the second year led to the increasing popularity of all ONTOX communication channels. The website was viewed more than 16 000 times during the second year, social media (Linkedin, Twitter, Facebook) counted for more than 70 000 impressions, and the number of followers and newsletter subscribers is constantly rising, resulting in more than 1500 accounts in total. This demonstrates that the target audience, including the general public, is interested in ONTOX’s vision of a future without animal testing.
As ONTOX is celebrating its second birthday, here is a reminder of the work done during the project’s first year.