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 incidenceis expected to rise with the aging population. Lifetime exposure to environmental pollutantsis suspected to contribute to the development and severity of CVD. The EU-Horizon 2020ALTERNATIVE project aims to develop an animal free test platform for improved regulatorycardiotoxicity assessment of chemicals. Systematic reviews (SRs) can provide a foundationfor regulatory action and for the development of such non-animal methods by providing atransparent and robust overview of the available toxicological evidence, highlighting theneed for alternative test methods that can efficiently assess chemical safety. Thistoxicological SR therefore aims to characterize pollutant induced cardiotoxicity whilesupporting regulation with a transparent and actionable overview of current knowledge andconcerns. Using the NTP Health Assessment and Translation (HAT) approach for conductingtoxicological SRs, we included 360 references with in vitro (17%), in vivo (67%), andcombined (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 andregulators to efficiently identify pollutants of interest. These results demonstratetoxicological evidence for pollutant-induced cardiotoxicity and highlight the importance ofupdating regulatory frameworks for human cardiotoxicity assessment. Furthermore, this SRsubstantiates the need for adequate chemical cardiotoxicity characterization and supportsthe development of the animal-free ALTERNATIVE test platform.