Periodic Reporting for period 1 - ONTOX (Ontology-driven and artificial intelligence-based repeated dose toxicity testing of chemicals for next generation risk assessment)
Reporting period: 2021-05-01 to 2022-10-31
The overall goal of ONTOX is to deliver a generic strategy to create innovative New Approach Methodologies (NAMs) to predict systemic repeated dose toxicity effects of chemicals that, upon combination with tailored exposure assessment, will enable human risk assessment. For proof-of-concept purposes, focus will be put on 3 organs, each with 2 specific types of adversity, namely the liver (steatosis and cholestasis), the kidneys (tubular necrosis and crystallopathy) and the developing brain (neural tube closure and cognitive function defects). This will result in 6 NAMs in total. Chemicals from different application domains will be considered, including from, but not limited to, the pharmaceutical, cosmetics, food and biocide sectors. The 6 NAMs will each consist of a computational system based on advanced Artificial Intelligence (AI), and will be primarily fed by available biological, toxicological, chemical and kinetic data. These data will be consecutively integrated in physiological maps, quantitative Adverse Outcome Pathway (qAOP) networks and ontology frameworks. Data gaps, as identified by the AI system, will be filled by targeted in vitro (cell culture) and in silico (computational) testing. The impact of ONTOX is, however, de facto much broader, as the underlying ontology-driven and AI-based strategy can as such be applied to any type of chemical and systemic repeated dose toxicity effect. ONTOX will thus provide a fully functional and sustainable solution for advancing human risk assessment of chemicals leading to better protection of European citizens without the use of animals.
Highlights of the first reporting period include:
1. Systematic review of scientific literature to collect biological, toxicological, physico-chemical and kinetic data to populate ontologies.
2. Establishment of physiological maps mechanistically describing relevant homeostatic functions in the liver, kidneys and brain.
3. Development and optimization of AOP networks focused on selected adversities in the liver, kidneys and brain.
4. Selection of chemicals to set up in vitro test batteries to predict toxic effects of chemicals in the liver, kidneys and brain.
5. Establishment of a group of stakeholders with industrial and regulatory background to create confidence and end-user acceptance regarding the ONTOX tools and methods.
6. Training of the consortium regarding various aspects critical for the project.
7. Creation of various dissemination and communication tools to maximize visibility of the project and to reach the target audience.
8. Establishment of solid collaboration with PrecisionTox and RISK-HUNT3R as part of the ASPIS cluster in order to leverage impact.
1. Systematic review of scientific literature to collect biological, toxicological, physico-chemical and kinetic data to populate ontologies.
2. Establishment of physiological maps mechanistically describing relevant homeostatic functions in the liver, kidneys and brain.
3. Development and optimization of AOP networks focused on selected adversities in the liver, kidneys and brain.
4. Selection of chemicals to set up in vitro test batteries to predict toxic effects of chemicals in the liver, kidneys and brain.
5. Establishment of a group of stakeholders with industrial and regulatory background to create confidence and end-user acceptance regarding the ONTOX tools and methods.
6. Training of the consortium regarding various aspects critical for the project.
7. Creation of various dissemination and communication tools to maximize visibility of the project and to reach the target audience.
8. Establishment of solid collaboration with PrecisionTox and RISK-HUNT3R as part of the ASPIS cluster in order to leverage impact.
Original and innovative aspects of ONTOX presented against the current state-of-the-art include:
1. State-of-the-art: focus on individual critical aspects of systemic repeated dose toxicity and full risk assessment for development of NAMs mainly in separate projects.
Innovation in ONTOX: ontology-driven and AI-based integration of all critical aspects of systemic repeated dose toxicity (biology, toxicology, chemistry and kinetics) and risk assessment (hazard identification, hazard characterisation and exposure assessment) in a single
collaborative project and resulting in 1 NAM per type of adversity.
2. State-of-the-art: frequent insufficient data for the development of AI systems to predict chemical hazard.
Innovation in ONTOX: generation of an advanced AI system for reliable chemical hazard identification fed by data-rich ontologies and read-across structure-activity relationships, which allows inclusion of heterogeneous big data.
3. State-of-the-art: traditional bottom-up approach for hazard identification in animals using high doses of chemicals starting from the apical toxicological outcome at the organism level.
Innovation in ONTOX: top-down approach for hazard identification and next generation risk assessment in human-based NAMs using physiologically relevant doses starting from basic biology at the molecular level.
4. State-of-the-art: 1-to-1 replacement of animal studies for toxicity testing with single non-animal methods.
Innovation in ONTOX: replacement of animal studies for toxicity testing by batteries of in vitro assays and in silico tools encompassing the full biological spectrum and reflecting the in vivo complexity of adverse effects.
The ambition of ONTOX is to strengthen Europe’s world-leading position regarding the development, exploitation, regulation and application of NAMs for human risk assessment of chemicals by empowering:
1. Scientific excellence: to move beyond the state-of-the-art by delivering an unprecedented set of NAMs.
2. Industrial innovation: to generate new value creation opportunities and market potential.
3. Regulatory pioneering: to introduce a paradigm shift in the validation and use of non-animal methods.
4. Societal prioritisation: to increase human chemical safety while fully replacing the use of animals.
1. State-of-the-art: focus on individual critical aspects of systemic repeated dose toxicity and full risk assessment for development of NAMs mainly in separate projects.
Innovation in ONTOX: ontology-driven and AI-based integration of all critical aspects of systemic repeated dose toxicity (biology, toxicology, chemistry and kinetics) and risk assessment (hazard identification, hazard characterisation and exposure assessment) in a single
collaborative project and resulting in 1 NAM per type of adversity.
2. State-of-the-art: frequent insufficient data for the development of AI systems to predict chemical hazard.
Innovation in ONTOX: generation of an advanced AI system for reliable chemical hazard identification fed by data-rich ontologies and read-across structure-activity relationships, which allows inclusion of heterogeneous big data.
3. State-of-the-art: traditional bottom-up approach for hazard identification in animals using high doses of chemicals starting from the apical toxicological outcome at the organism level.
Innovation in ONTOX: top-down approach for hazard identification and next generation risk assessment in human-based NAMs using physiologically relevant doses starting from basic biology at the molecular level.
4. State-of-the-art: 1-to-1 replacement of animal studies for toxicity testing with single non-animal methods.
Innovation in ONTOX: replacement of animal studies for toxicity testing by batteries of in vitro assays and in silico tools encompassing the full biological spectrum and reflecting the in vivo complexity of adverse effects.
The ambition of ONTOX is to strengthen Europe’s world-leading position regarding the development, exploitation, regulation and application of NAMs for human risk assessment of chemicals by empowering:
1. Scientific excellence: to move beyond the state-of-the-art by delivering an unprecedented set of NAMs.
2. Industrial innovation: to generate new value creation opportunities and market potential.
3. Regulatory pioneering: to introduce a paradigm shift in the validation and use of non-animal methods.
4. Societal prioritisation: to increase human chemical safety while fully replacing the use of animals.