Periodic Reporting for period 1 - RISK-HUNT3R (RISK assessment of chemicals integrating HUman centric Next generation Testing strategies promoting the 3Rs)
Berichtszeitraum: 2021-06-01 bis 2022-11-30
Science and society have increasingly started demanding a paradigm shift towards chemical risk assessment without using animals. In addition to growing ethical concerns around the use of animals, there is a fundamental need to address all potential adverse effects on human health. Animals may not be the best model to predict all human adversities. Furthermore, the limited throughput of animal-based testing in European laboratories (high costs, insufficient laboratory and personnel capacity) currently prevents the comprehensive evaluation of all chemicals that require safety assessment.
Scientific advances in in-silico and in-vitro testing, via so-called new approach methodologies (NAMs), have greatly increased the opportunities for application of NAMs in chemical safety testing.
The RISK-HUNT3R vision is that animal-free next generation risk assessment (NGRA) can be implemented through the combination of human exposure scenarios, in-vitro hazard assessment, and NAM-based toxicokinetic and toxicodynamic testing. These will be integrated in a risk assessment framework using computational approaches and final decisions based on weight of evidence. To achieve this, the project hosts world-leading experts from many different disciplines aiming to develop a novel and modular framework for NGRA. Furthermore, RISK-HUNT3R closely works with regulators including European regulatory agencies to enable the translation of research findings to be applied in risk assessment practice.
The aim of the RISK-HUNT3R project is to better protect citizens against hazardous chemicals, while enabling the development of safe and sustainable non-animal approaches. This is in line with the toxic-free environment goal of Europe’s Green Deal and with the need to provide an expertise and testing hub for European industries. RISK-HUNT3R will help achieve this by establishing NAMs required for protection of the human population, not just from acute adversities, but also from multifactorial diseases and chronic effects.
Scientific advances in in-silico and in-vitro testing, via so-called new approach methodologies (NAMs), have greatly increased the opportunities for application of NAMs in chemical safety testing.
The RISK-HUNT3R vision is that animal-free next generation risk assessment (NGRA) can be implemented through the combination of human exposure scenarios, in-vitro hazard assessment, and NAM-based toxicokinetic and toxicodynamic testing. These will be integrated in a risk assessment framework using computational approaches and final decisions based on weight of evidence. To achieve this, the project hosts world-leading experts from many different disciplines aiming to develop a novel and modular framework for NGRA. Furthermore, RISK-HUNT3R closely works with regulators including European regulatory agencies to enable the translation of research findings to be applied in risk assessment practice.
The aim of the RISK-HUNT3R project is to better protect citizens against hazardous chemicals, while enabling the development of safe and sustainable non-animal approaches. This is in line with the toxic-free environment goal of Europe’s Green Deal and with the need to provide an expertise and testing hub for European industries. RISK-HUNT3R will help achieve this by establishing NAMs required for protection of the human population, not just from acute adversities, but also from multifactorial diseases and chronic effects.
From the start of the project, we have been cementing our three main pillars: setting up our science and technology, making sure that our solutions can work in a regulatory context, and recruiting and engaging the people that share our vision and make it a reality.
Ultimately, we want to be able to answer the question whether or not a certain compound is safe by using a safety testing pipeline that works for humans and that does not rely on test animals. To this end, we started to construct our NGRA workflow that is modular in nature, meaning that it is flexible and future-proof. Synergy on these activities has been achieved by common working groups within the ASPIS (Animal-free Safety assessment of chemicals: Project cluster for Implementation of novel Strategies) cluster.
During the first project period, we have set up and tested the different modules in exploratory studies. To test whether a chemical will enter the human body upon exposure, we have established and tested in-vitro test systems for uptake via the lung and for uptake via the gut. We developed a computer simulator for predicting the kinetic behaviour of chemicals upon entering the human body, and we can now perform these simulations for large numbers of chemicals. This includes metabolites that are likely to arise in real-world situations. Moreover, we have tested modules for predicting toxicological hazards that might occur when chemicals are taken up by the body. Based on the chemical structure of compounds we can predict to which targets they may bind. We already did this for liver cells and for developing nerve cells. We generated a panel of pluripotent stem cells with stress response reporters that can be used for high-throughput screening for potential hazards in different cell and tissue types of interest. The key technology of transcriptomics, which can show changes in all cellular processes at the same time, has been applied to many models. A comprehensive and novel toxicogenomics prediction platform was completed for kidney cells and primary human liver cells in 2D. This is currently in progress for a stem cell-based model of liver and kidney, containing multiple different cell types that can live for weeks, as well as a new model of mature peripheral neurons. Finally, we also carried out an extensive state-of-the-art transcriptome and metabolome study to determine whether cells reach a point-of-no-return in their survival.
To assure that all the testing modules can align and interact, we put in place a data management plan and a knowledge-sharing infrastructure, which include the use of data templates as well as compound and methods databases.
For all NAMs that we are deploying we performed self-assessment of their readiness levels for relevant applications, which is required for their success and commercial prospects.
To ensure the uptake of our NGRA workflow, we have engaged with European regulators to map the regulatory needs for the assessment of chronic systemic health effects. We have also launched the development of a new risk assessment algorithm, ASPA, for regulators to operate on the NGRA workflow in a stepwise and transparent manner.
RISK-HUNT3R has established a strong internet presence. Key project publications and events can be found at the project website, in newsletters, and social media.
Lastly, the above-described progress builds on the work of the new generation of safety scientists. RISK-HUNT3R has provided them with an additional training program on NGRA, as well as the practical context of linking lab research and regulatory reality.
Ultimately, we want to be able to answer the question whether or not a certain compound is safe by using a safety testing pipeline that works for humans and that does not rely on test animals. To this end, we started to construct our NGRA workflow that is modular in nature, meaning that it is flexible and future-proof. Synergy on these activities has been achieved by common working groups within the ASPIS (Animal-free Safety assessment of chemicals: Project cluster for Implementation of novel Strategies) cluster.
During the first project period, we have set up and tested the different modules in exploratory studies. To test whether a chemical will enter the human body upon exposure, we have established and tested in-vitro test systems for uptake via the lung and for uptake via the gut. We developed a computer simulator for predicting the kinetic behaviour of chemicals upon entering the human body, and we can now perform these simulations for large numbers of chemicals. This includes metabolites that are likely to arise in real-world situations. Moreover, we have tested modules for predicting toxicological hazards that might occur when chemicals are taken up by the body. Based on the chemical structure of compounds we can predict to which targets they may bind. We already did this for liver cells and for developing nerve cells. We generated a panel of pluripotent stem cells with stress response reporters that can be used for high-throughput screening for potential hazards in different cell and tissue types of interest. The key technology of transcriptomics, which can show changes in all cellular processes at the same time, has been applied to many models. A comprehensive and novel toxicogenomics prediction platform was completed for kidney cells and primary human liver cells in 2D. This is currently in progress for a stem cell-based model of liver and kidney, containing multiple different cell types that can live for weeks, as well as a new model of mature peripheral neurons. Finally, we also carried out an extensive state-of-the-art transcriptome and metabolome study to determine whether cells reach a point-of-no-return in their survival.
To assure that all the testing modules can align and interact, we put in place a data management plan and a knowledge-sharing infrastructure, which include the use of data templates as well as compound and methods databases.
For all NAMs that we are deploying we performed self-assessment of their readiness levels for relevant applications, which is required for their success and commercial prospects.
To ensure the uptake of our NGRA workflow, we have engaged with European regulators to map the regulatory needs for the assessment of chronic systemic health effects. We have also launched the development of a new risk assessment algorithm, ASPA, for regulators to operate on the NGRA workflow in a stepwise and transparent manner.
RISK-HUNT3R has established a strong internet presence. Key project publications and events can be found at the project website, in newsletters, and social media.
Lastly, the above-described progress builds on the work of the new generation of safety scientists. RISK-HUNT3R has provided them with an additional training program on NGRA, as well as the practical context of linking lab research and regulatory reality.
The combination of human stem cell-derived tissue models with modern toxicogenomics platforms developed in the project will transform hazard assessment. Combination of this approach, within quantitative systems toxicology models (QSTM), with our methods to convert exposure information to expected concentration levels in all parts of the body, will be the basis for future NGRA. Uncertainty measures provided by QSTMs are key to making our output useful for regulatory decision-making.
RISK-HUNT3R is one of three projects constituting the research cluster ASPIS (with the projects ONTOX and PrecisionTox). Together, we work towards the sustainable, animal-free and reliable chemical risk assessment of tomorrow. Our joint focus is to fulfil regulatory needs whilst allowing for uptake of innovations that promote non-animal safety testing for more reliable human risk assessment. We anticipate that ASPIS, with RISK-HUNT3R as a major driver and contributor, will help to solve problems in multiple regulatory contexts, across industry sectors. To achieve the goal of protecting different population groups (including the most vulnerable, such as children and elderly), ASPIS will work closely together with PARC. Important technology will be transferred to this initiative for even further refinement and implementation.
The major socio-economic impact will be that predictions from our NGRA approach will enable the regulatory definition of acceptable exposure levels, which is required to safeguard public health. As a result, RISK-HUNT3R will have a tangible impact on the development, production and marketing of safer chemical compounds in all sectors by accelerating the toxicity testing process.
RISK-HUNT3R is one of three projects constituting the research cluster ASPIS (with the projects ONTOX and PrecisionTox). Together, we work towards the sustainable, animal-free and reliable chemical risk assessment of tomorrow. Our joint focus is to fulfil regulatory needs whilst allowing for uptake of innovations that promote non-animal safety testing for more reliable human risk assessment. We anticipate that ASPIS, with RISK-HUNT3R as a major driver and contributor, will help to solve problems in multiple regulatory contexts, across industry sectors. To achieve the goal of protecting different population groups (including the most vulnerable, such as children and elderly), ASPIS will work closely together with PARC. Important technology will be transferred to this initiative for even further refinement and implementation.
The major socio-economic impact will be that predictions from our NGRA approach will enable the regulatory definition of acceptable exposure levels, which is required to safeguard public health. As a result, RISK-HUNT3R will have a tangible impact on the development, production and marketing of safer chemical compounds in all sectors by accelerating the toxicity testing process.