Humans are continuously exposed to a wide variety of potentially toxic chemicals including per- and polyfluoroalkyl substances (PFAS) [1]. Several adverse health outcomes, including the increasing occurrence of cardiovascular diseases (CVD), have been linked with environmental exposure to exogenous toxic chemicals [2]. However, cardiotoxic effects of environmental pollutants and their co-exposures with drugs in the vulnerable population (such as older people) are not well understood. Furthermore, cardiotoxicity is still not addressed as a separate endpoint in current risk assessment strategies although many chemicals have been shown to manifest cardiotoxic properties [3],[4]. In this context, the project ALTERNATIVE has been initiated.

Within the Horizon 2020 project ALTERNATIVE (grant no. 101037090), a novel platform will be developed to detect the cardiotoxicity of chemical mixtures [5]. The platform will consist of a 3D in vitro model mimicking the healthy and aged human cardiac tissue, coupled with high-throughput multi-omics analyses, and integrated into a Machine Learning (ML) risk assessment tool. One of the key objectives of the ALTERNATIVE project is to stimulate the regulatory acceptance of this novel platform to provide a more robust basis for decision-making.

Integrated Approaches to Testing and Assessment (IATAs) have been proposed as science-based methodologies for chemical hazard characterization. They usually start with an integrated analysis of all existing toxicological information, such as data from computational models, traditional in vivo, ex vivo and in vitro testing. The outcome of this analysis defines if and which new approach methodologies (NAMs) shall be applied as a second step to complement available data for supporting regulatory decision making [6]. Today, NAMs are not yet widely and consistently used for regulatory decision-making due to the limited insights in the mechanisms understanding toxicity. The Adverse Outcome Pathway (AOP) framework can be applied to characterize mechanistic relevance of NAMs in predicting an adverse outcome. Thus, AOPs can be used as a framework to develop IATAs [7].

In this work, we first identified the current regulatory data requirements for cardiotoxicity outlined in the European Commission (EC) regulations and guidance for industrial chemicals, pharmaceuticals, pesticides, and biocides. Furthermore, the available epidemiological and toxicological evidence forcardiotoxic chemicals and environmental pollutants was reviewed. Currently, mechanistic insights in cardiotoxicity induced by environmental pollutants and chemicals are collected by using the AOP framework. In a next step, an IATA for cardiotoxicity will be drafted based on the developed AOPs according to the international accepted paradigm [8]. The outcome is expected to provide the outline of a potential practical regulatory approach to assess the cardiotoxic potential of chemicals and environmental pollutants, taking into account existing data sources, models, and NAMs for cardiotoxicity.
References

[1] E. M. Sunderland, X. C. Hu, C. Dassuncao, A. K. Tokranov, C. C. Wagner, and J. G. Allen, “A Review of the Pathways of Human Exposure to Poly-and Perfluoroalkyl Substances (PFASs) and Present Understanding of Health Effects HHS Public Access,” J Expo Sci Environ Epidemiol, vol. 29, no. 2, pp. 131–147, 2019, doi: 10.1038/s41370-018-0094-1.

[2] A. Bhatnagar, “Environmental Determinants of Cardiovascular Disease,” Circ Res, vol. 121, no. 2, pp. 162–180, Jul. 2017, doi: 10.1161/CIRCRESAHA.117.306458.

[3] R. Gear, J. A. Kendziorski, and S. M. Belcher, “Effects of bisphenol A on incidence and severity of cardiac lesions in the NCTR-Sprague-Dawley rat: A CLARITY-BPA study,” Toxicol Lett, vol. 275, pp. 123–135, Jun. 2017, doi: 10.1016/J.TOXLET.2017.05.011.

[4] N. Lv et al., “Perfluorooctanoic acid-induced toxicities in chicken embryo primary cardiomyocytes: Roles of PPAR alpha and Wnt5a/Frizzled2,” Toxicol Appl Pharmacol, vol. 381, Oct. 2019, doi: 10.1016/J.TAAP.2019.114716.

[5] “ALTERNATIVE Project.” https://alternative-project.eu/ (accessed Oct. 27, 2022).

[6] “Integrated Approaches to Testing and Assessment (IATA) - OECD.” https://www.oecd.org/chemicalsafety/risk-assessment/iata-integrated-approaches-to-testing-and-assessment.htm.

[7] OECD 2016. Series on Testing & Assessment No. 260. GUIDANCE DOCUMENT FOR THE USE OF ADVERSE OUTCOME PATHWAYS IN DEVELOPING INTEGRATED APPROACHES TO TESTING AND ASSESSMENT (IATA); https://www.oecd.org/chemicalsafety/testing/series-testing-assessment-publications-number.htm.

[8] OECD 2020, Series on Testing and Assessment 329, Overview of Concepts and Available Guidance related to Integrated Approaches to Testing and Assessment (IATA); https://www.oecd.org/chemicalsafety/testing/series-testing-assessment-publications-number.htm