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Over the past decades, there have been increasing demands from both society and the scientific community for a paradigm shift towards chemical safety and risk assessment without the use of animal testing. In addition to ethical concerns around the use of animals for these purposes, there is a fundamental need to consider all potential health effects of chemicals that are specifically relevant to humans.

“Moreover, the limited efficiency of animal testing (low throughput, high costs, and insufficient laboratory capacity) will not be able to keep up with the sheer number of chemicals requiring safety evaluation to ensure the required protection of European citizens,” says Professor Marcel Leist, co-director of CAAT-Europe and professor of in vitro toxicology and biomedicine at the University of Konstanz.

The University of Konstanz is a core component of two new projects – RISK-HUNT3R and TOX-Free – funded under the EU's “Horizon 2020” Programme for Research and Innovation. The overarching goal of the two projects is to develop animal-free strategies and tools for chemical risk and safety assessment to protect the health of citizens. The total funding by the EU for the projects is 27 million euros.

Project RISK-HUNT3R

The first of the two projects, RISK-HUNT3R, started in June 2021. During its 5-year duration, RISK-HUNT3R will investigate animal-free "Next Generation Risk Assessment" (NGRA) and demonstrate that NGRA can be put into practice. The project unites 37 partners – including academic researchers, regulatory authorities, and safety scientists from key industry sectors – and is receiving a budget of 23 million euros from the EU.

The consortium is working on a risk assessment framework that combines in vitro ("in the test tube") hazard assessments, animal-free new approach methods (NAM)-based toxicological tests, and human exposure scenarios, which means facts, assumptions, and conclusions about how exposure occurs. Integrative computational ("in-silico") approaches and final decisions based on the weighted evidence of the pooled information are expected to put NGRA on the road to success.

"We will bundle, under one roof, different innovative test systems and cutting-edge computational and prediction models for hazard identification and integrate these with systematic evaluation of human exposure scenarios," Professor Marcel Leist summarizes the approach.

University of Konstanz plays a crucial role
The group of Professor Marcel Leist and CAAT-Europe will cover a key role in the consortium: On the one hand, they will coordinate the development of targeted testing in advanced model systems. On the other hand, they will coordinate the dissemination of the project results and training activities on the topic.

The ultimate goal of the RISK-HUNT3R project to better protect citizens against hazardous chemicals through animal-free methods while enabling the development of safe and sustainable alternatives is in line with toxic-free environment goal of the European Commission’s Green Deal and the goals of the second new Horizon 2020 project involving Prof. Marcel Leist's group and CAAT-Europe, TOX-Free.

Project TOX-Free
In particular, the harmful effects on our cardiovascular and nervous systems caused by pollutants including pesticides and industrial chemicals, are difficult to assess using currently available testing approaches. Reasons for this include the low sensitivity of existing methods, a lack of relevance of the model systems for humans, and a low suitability of the methods for non-invasive long-term recordings.

The four project partners of TOX-Free are tackling these problems in a unique venture and with a total funding budget of 3 million euros, bringing together novel approaches from physics, materials science, engineering, biology and industrial processes. "In this project, we will develop a revolutionary and fully non-invasive technology to record electrical signals from human neuronal and cardiac cells in vitro," Leist reports.

The VICE biosensor
The new technology, called the VICE biosensor, combines high spatial resolution with parallel recording of electrical signals from thousands of neurons or cardiac muscle cells, enabling the assessment and quantification of subtle disturbances caused by toxicants from the drugs, pesticides, and industrial chemicals sectors. With its joint expertise, the consortium will continuously refine the VICE biosensor, equip it with innovative functionalities, and thoroughly test it in toxicological and pharmacological experiments. "This will not only lead to a revolutionary approach to monitoring the function of heart and brain cells, but also ensure the direct applicability to relevant issues in safety science and pharmacology," explains Dr Giorgia Pallocca, deputy director and coordinator of CAAT-Europe.

The involved researchers from the University of Konstanz will contribute their strong expertise on the bio-molecular chemistry of membrane ion channels and on neuronal cellular models that can accurately replicate toxicity on the human body. In particular, Prof. Leist's group will investigate the capabilities of VICE biosensor technology to read out dynamic neuronal processes using 2D and 3D cell models and develop tailored acute and chronic neurotoxicity tests using the technology.

Innovation and sustainability
Both projects, RISK-HUNT3R and TOX-Free, will also push the commercial use of the validated safety assessment approaches, thereby ensuring the sustainability of the project outcomes and fortifying the innovation capacity of the industry sectors involved. "A key expectation is that our approaches will find broad application in different regulatory contexts, across industry sectors, and in protecting different population groups at all stages of life, including the most vulnerable, such as children, pregnant women, and the elderly," Pallocca concludes.

Key facts:

• The Konstanz-based research group of Professor Marcel Leist and the "Center for Alternatives to Animal Testing in Europe" (CAAT-Europe) started two new Horizon 2020 projects – RISK-HUNT3R and TOX-Free
• Overarching goal: Development of animal-free strategies and tools for chemical risk and safety assessment to protect the health of citizens
• Total EU funding for the projects: 27 million euros
• RISK-HUNT3R: Bundling different innovative test systems and cutting-edge computational and prediction models for hazard identification and integrating them with systematic evaluation of human exposure scenarios (official press release)
• TOX-Free: Development of a fully non-invasive technology to record electrical signals from human neuronal and cardiac cells in vitro