A Systematic Review on Pollutant Induced Cardiotoxicity: Providing a Toxicological Foundation for NAM Development and Regulatory Acceptance

Cardiovascular disease (CVD) is the leading cause of mortality worldwide, and CVD incidence is expected to rise with the aging population. Lifetime exposure to environmental pollutants is suspected to contribute to the development and severity of CVD. The EU-Horizon 2020 ALTERNATIVE project aims to develop an animal free test platform for improved regulatory cardiotoxicity assessment of chemicals. Systematic reviews (SRs) can provide a foundation for regulatory action and for the development of such non-animal methods by providing a transparent and robust overview of the available toxicological evidence, highlighting the need for alternative test methods that can efficiently assess chemical safety. This toxicological SR therefore aims to characterize pollutant induced cardiotoxicity while supporting regulation with a transparent and actionable overview of current knowledge and concerns. Using the NTP Health Assessment and Translation (HAT) approach for conducting toxicological SRs, we included 360 references with in vitro (17%), in vivo (67%), and combined (16%) study setups for 129 potential cardiotoxic environmental pollutants, including heavy metals (29%), air pollutants (16%), pesticides (27%), and other chemicals (28%). Evidence maps and interactive knowledge graphs will illustrate evidence streams, cardiotoxic effects and associated quality of evidence for pollutants, helping researchers and regulators to efficiently identify pollutants of interest. These results demonstrate toxicological evidence for pollutant-induced cardiotoxicity and highlight the importance of updating regulatory frameworks for human cardiotoxicity assessment. Furthermore, this SR substantiates the need for adequate chemical cardiotoxicity characterization and supports the development of the animal-free ALTERNATIVE test platform.