Periodic Reporting for period 1 - GenoQSAR (Genotoxicity prediction by means of QSAR methods for regulatory purposes)
Berichtszeitraum: 2021-10-01 bis 2023-09-30
The EU's regulatory framework for chemical substances has undergone significant revisions due to growing concerns about safeguarding human health and the environment. The European Chemicals Agency (ECHA) is implementing the Registration, Evaluation, Authorization, and Restriction of Chemicals (REACH) legislation. This legislation mandates the chemical industry to assess the toxicity of substances in use, even if they have not undergone prior regulatory testing. However, the REACH regulation has faced criticism from both societal and industrial sectors, primarily due to ethical and economic concerns. The evaluation of chemical toxicity traditionally involves expensive, time-consuming, and ethically contentious animal experiments. As a response, the REACH regulation actively promotes the adoption of alternative methods, emphasizing that animal testing should be a last resort, only employed when no other scientifically reliable methods are available to assess the impact on humans or the environment.
Non-testing methods, particularly computational (in silico) tools, have become increasingly prominent. Among these tools, Quantitative Structure-Activity Relationships (QSAR) modelling stands out as a well-established approach in drug design, toxicology, industrial, and environmental chemistry. Importantly, these methods hold regulatory recognition for hazard and risk assessment, as well as for classification and labelling.
These have been the objectives of the project:
- Development of novel QSAR models to predict different in vitro and in vivo endpoints for human toxicity. An attempt has been made to develop some specific models for nanomaterials. All the models fit the regulatory principles of the OECD.
- Development of a decisional workflow, using models for different endpoints, to obtain a “consensus” score for the prediction of genotoxicity. This workflow follows the guidelines delivered by REACH for the genotoxicity assessment.
- Implementation of the human toxicology models, as well as the decisional workflow, in a computational platform allowing fast and cheap evaluation of the toxicological properties by the end-users.
Non-testing methods, particularly computational (in silico) tools, have become increasingly prominent. Among these tools, Quantitative Structure-Activity Relationships (QSAR) modelling stands out as a well-established approach in drug design, toxicology, industrial, and environmental chemistry. Importantly, these methods hold regulatory recognition for hazard and risk assessment, as well as for classification and labelling.
These have been the objectives of the project:
- Development of novel QSAR models to predict different in vitro and in vivo endpoints for human toxicity. An attempt has been made to develop some specific models for nanomaterials. All the models fit the regulatory principles of the OECD.
- Development of a decisional workflow, using models for different endpoints, to obtain a “consensus” score for the prediction of genotoxicity. This workflow follows the guidelines delivered by REACH for the genotoxicity assessment.
- Implementation of the human toxicology models, as well as the decisional workflow, in a computational platform allowing fast and cheap evaluation of the toxicological properties by the end-users.
- Ten QSAR models have been developed (9 for organic molecules and 1 for NMs), in order to predict human toxicology effects. Moreover, a decisional workflow for the prediction of genotoxicity has been also implemented using five of the aforementioned models (Ames test, in vitro chromosomal aberration, Hprt assay, in vivo micronuclei and comet assay).
- An external validation has been performed for the Ames test model. With this step we ensure a little bit more the robustness of the model.
- The GenoQSAR models have been implemented in a computational platform allowing for the fast and cheap evaluation of the human toxicological properties for regulatory purposes. The decisional workflow has been implemented as a new module in the platform, called GenoITS.
Exploitation and dissemination actions:
- A webpage has been created in the company’s website specific for the GenoQSAR project (https://protoqsar.com/en/genoqsar-en/(öffnet in neuem Fenster)) with information about the details of the project and updates of its evolution. Furthermore, a specific module for the decisional workflow for genotoxicity assessment, named GenoITS, is included in the website of ProtoPRED (https://protopred.protoqsar.com/GenoITS_info/(öffnet in neuem Fenster)).
- Two videos developed by the researcher about different topics related with the research project has been incorporated to the corporate YouTube channel of ProtoQSAR (https://www.youtube.com/@protoqsar3075(öffnet in neuem Fenster)) as part of the action.
- The presentation of the project in different scientific and outreach events.
- Scientific manuscript: José Luis Vallés-Pardo, Eva Serrano-Candelas, Addel Goya-Jorge, Salvador Moncho, Mar Crespo, Donna S. Macmillan and Rafael Gozalbes. “GenoITS: Implementation of an Integrated Testing Strategy workflow for genotoxicity using QSAR-based tools.” This manuscript has been sent for publicacion to the journal "Toxics" (Open access)
- An external validation has been performed for the Ames test model. With this step we ensure a little bit more the robustness of the model.
- The GenoQSAR models have been implemented in a computational platform allowing for the fast and cheap evaluation of the human toxicological properties for regulatory purposes. The decisional workflow has been implemented as a new module in the platform, called GenoITS.
Exploitation and dissemination actions:
- A webpage has been created in the company’s website specific for the GenoQSAR project (https://protoqsar.com/en/genoqsar-en/(öffnet in neuem Fenster)) with information about the details of the project and updates of its evolution. Furthermore, a specific module for the decisional workflow for genotoxicity assessment, named GenoITS, is included in the website of ProtoPRED (https://protopred.protoqsar.com/GenoITS_info/(öffnet in neuem Fenster)).
- Two videos developed by the researcher about different topics related with the research project has been incorporated to the corporate YouTube channel of ProtoQSAR (https://www.youtube.com/@protoqsar3075(öffnet in neuem Fenster)) as part of the action.
- The presentation of the project in different scientific and outreach events.
- Scientific manuscript: José Luis Vallés-Pardo, Eva Serrano-Candelas, Addel Goya-Jorge, Salvador Moncho, Mar Crespo, Donna S. Macmillan and Rafael Gozalbes. “GenoITS: Implementation of an Integrated Testing Strategy workflow for genotoxicity using QSAR-based tools.” This manuscript has been sent for publicacion to the journal "Toxics" (Open access)
There are platforms in the market for the prediction of human toxicological properties of small molecules for regulatory purposes, such as QSAR ToolBox, VEGA, DEREK, TOPKAT and ToxCast, but usually these platforms don’t bring together all the necessary models. For this reason, the goal is to have all the possible human toxicity endpoints in the same platform. In the same direction, we want to have all these models not only with the best metrics possible, but also supplying a complete documentation for regulatory purposes, having a very competitive QMRFs attach to each model. Moreover, the inclusion of a module able to perform predictions based on ITS workflows gives the platform an extra value against other existing tools.
The expected results are: The development of QSAR models to predict human toxicity effects of organic compounds, mainly related to genotoxicity endpoints; The generation of a consensus model for genotoxicity following the rules supplied in the REACH documentation; And the implementation of all the generated models, including the ITS workflow, allowing the fast and cheap evaluation of the toxicological profiles of chemical compounds for regulatory purposes, in a user-friendly web-platform.
To enhance the scientific and technological foundations of the EU and contribute to the European Research Area (ERA), the GenoQSAR project holds the promise of significant scientific impact. From one side, the project has allowed to reinforce the computing systems through the development of GenoQSAR models in the field of human toxicology. On the other side, GenoQSAR project has expanded the scope of the toxicological IATAs, being capable of a complete computational translation of the REACH rules for the genotoxicity ITS and allowing to mix in an effective way experimental and predicted data to deliver a global genotoxicity prediction.
GenoQSAR project will have also a potential societal impact, as it would improve the quality of life of citizens, given that the project has helped to obtain some promising results in some endpoints less studied from the QSAR side, as the neurotoxicity one. Moreover, the application of computational methods contributes to the reduction of animal testing in traditional laboratory assays, aligning with the principles of the 3Rs: refinement, reduction, and replacement.
Finally, the GenoQSAR project will have significant economic and technological influence, enhancing Europe's innovation capacity and competitiveness by providing novel computational insights into human toxicology endpoints for REACH. The utilization of computational models supports adherence to the European directives related to the registration and labelling of compounds, such as REACH, BPR, CLP, among others. These international regulations advocate for the use of computational techniques as alternative methods, aligning with the principles set by the OECD. Furthermore, the GenoQSAR project has played a role in augmenting efficiency, reducing costs, and increasing profits by enabling work in a virtual environment.
The expected results are: The development of QSAR models to predict human toxicity effects of organic compounds, mainly related to genotoxicity endpoints; The generation of a consensus model for genotoxicity following the rules supplied in the REACH documentation; And the implementation of all the generated models, including the ITS workflow, allowing the fast and cheap evaluation of the toxicological profiles of chemical compounds for regulatory purposes, in a user-friendly web-platform.
To enhance the scientific and technological foundations of the EU and contribute to the European Research Area (ERA), the GenoQSAR project holds the promise of significant scientific impact. From one side, the project has allowed to reinforce the computing systems through the development of GenoQSAR models in the field of human toxicology. On the other side, GenoQSAR project has expanded the scope of the toxicological IATAs, being capable of a complete computational translation of the REACH rules for the genotoxicity ITS and allowing to mix in an effective way experimental and predicted data to deliver a global genotoxicity prediction.
GenoQSAR project will have also a potential societal impact, as it would improve the quality of life of citizens, given that the project has helped to obtain some promising results in some endpoints less studied from the QSAR side, as the neurotoxicity one. Moreover, the application of computational methods contributes to the reduction of animal testing in traditional laboratory assays, aligning with the principles of the 3Rs: refinement, reduction, and replacement.
Finally, the GenoQSAR project will have significant economic and technological influence, enhancing Europe's innovation capacity and competitiveness by providing novel computational insights into human toxicology endpoints for REACH. The utilization of computational models supports adherence to the European directives related to the registration and labelling of compounds, such as REACH, BPR, CLP, among others. These international regulations advocate for the use of computational techniques as alternative methods, aligning with the principles set by the OECD. Furthermore, the GenoQSAR project has played a role in augmenting efficiency, reducing costs, and increasing profits by enabling work in a virtual environment.