Use of the AOP framework to support the ALTERNATIVE platform for cardiotoxicity assessment

For the last 30 years, cardiovascular diseases have been among the top-ranked causes of death in mature and aged populations. The incidence of these diseases continues to rise and environmental exposure to exogenous toxic chemicals has been put forward as one of the possible reasons underlying this increase. At present, cardiotoxicity is not included as a specific endpoint in the safety assessment of chemicals and adequate tools to assess cardiotoxic effects are lacking. Within the H2020 ALTERNATIVE project, an innovative in vitro/in silico platform will be developed to evaluate cardiotoxicity. The platform will consist of a 3D tissue engineered in vitro model mimicking human cardiac tissue, coupled with a reliable, high-throughput monitoring system based on multi-omics analyses, and integrated into a computational risk assessment tool. To facilitate its regulatory use and uptake, the information generated by the ALTERNATIVE platform will be structured according to the AOP framework. As a first step, data related to AOPs for cardiotoxicity will be collected by consulting the AOP-Wiki and performing a systematic literature search. All information will be combined into extended, updated and/or novel AOPs for cardiotoxicity. If needed, different AOPs will also be combined into an AOP network. Afterwards, the information generated with the ALTERNATIVE testing will be used to identify new MIEs and KEs in the AOP. Finally the AOP will be used to structure a guidance on how the ALTERNATIVE platform, either alone or in combination with other methods and data sources, can be used within a regulatory context.