Innovative non-animal based testing platform to detect chemical-induced cardiotoxicity - A roadmap for regulatory uptake

Accounting for 32% of all global deaths in 2019, cardiovascular diseases (CVDs) are the leading cause of mortality worldwide¹. However, the relationship between environmental chemical exposure and CVD development is poorly understood. With an aging population and chronic exposure to chemical mixtures, particularly in Europe, there is an urgent need to develop robust, non-animal based mechanistic strategies to assess the cardiotoxicity of chemicals.

In this context, the Horizon 2020 project ALTERNATIVE (grant no. 101037090) aims to develop a non-animal test platform to detect the cardiotoxicity of chemicals². The platform includes a 3D in vitro physiological system mimicking healthy and aged human cardiac tissue, as well as multi-omics analyses and an integrated Machine Learning (ML) risk assessment tool.

To facilitate regulatory uptake of the platform, we first reviewed existing regulations for chemicals, pesticides and biocides, and indicated how limitations in their coverage of cardiotoxicity as well as their coverage of the elderly population and chemical mixtures could be overcome using new approach methodologies (NAMs)³. An adverse outcome pathway (AOP) network relevant to cardiotoxicity is being developed based on a comprehensive systematic review. Finally, an AOP-informed integrated approach to testing and assessment (IATA) will be drafted by integrating existing knowledge and other IATA components developed within this project. Subsequently, our IATA will be proposed for common elaboration within the ASPIS cluster, OECD working groups and regulatory stakeholders/policy makers, aiming to integrate our IATA into a larger framework for a NAM based assessment of systemic toxicity. Ultimately, we aim to improve the regulatory acceptance and uptake of NAMs for cardiotoxicity assessment, and contribute to the prevention of exposure to potential cardiotoxic chemicals.

References

1.          Cardiovascular diseases (CVDs). https://www.who.int/news-room/fact-sheets/detail/cardiovascular-diseases-(cvds).

2.          ALTERNATIVE Project. https://alternative-project.eu/.

3.          A, S., S, M., B, M. & M, P. Cardiotoxicity of chemicals: Current regulatory guidelines, knowledge gaps, and needs. ALTEX (2023) doi:10.14573/ALTEX.2301121.