Beyond pharmaceuticals: Fit-for-purpose new approach methodologies for environmental cardiotoxicity testing

Abstract

Environmental factors play a substantial role in determining cardiovascular health, but data informing the risks presented by environmental toxicants is insufficient. In vitro new approach methodologies (NAMs) offer a promising approach with which to address the limitations of traditional in vivo and in vitro assays for assessing cardiotoxicity. Driven largely by the needs of pharmaceutical toxicity testing, considerable progress in developing NAMs for cardiotoxicity analysis has already been made. As the scientific and regulatory interest in NAMs for environmental chemicals continues to grow, a thorough understanding of the unique features of environmental cardiotoxicants and their associated cardiotoxicities is needed. Here, we review the key characteristics of as well as important regulatory and biological considerations for fit-for-purpose NAMs for environmental cardiotoxicity. By emphasizing the challenges and opportunities presented by NAMs for environmental cardiotoxicity we hope to accelerate their development, acceptance, and application.

Keywords: IVIVE; arrhythmia; cardiac tissue engineering; hERG assay; hiPSC-cardiomyocytes.

Fig. 1:. Comparison of the defining features of pharmaceutical compounds and environmental chemicals for cardiotoxicity testing

Fit-for-purpose NAMs should account for critical differences in the chemical properties and exposure profiles of pharmaceutical compounds (left) and environmental chemicals (right). MoA, mechanism of action; NAMs, new approach methodologies; PoTs, pathways of toxicity

Fig. 2:. The chain of translatability for NAMs for environmental cardiotoxicity testing

Effective NAMs should include (left) a biologically relevant assay system, (center) context-appropriate stimuli, and (right) actionable system readout. Underlying general and cardiac-specific criteria for each link in the chain are listed below their respective category (top and bottom, respectively). CVD, cardiovascular disease; hiPSC-CMs, human induced pluripotent stem cell-derived cardiomyocytes; IVIVE, in vitro to in vivo extrapolation; NAMs, new approach methodologies; PAHs, polyaromatic hydrocarbons; PCBs, polychlorinated biphenyls; PM_2.5, fine particulate matter

Fig. 3:. Comparison of traditional target-based and novel phenotypic in vitro assays in detecting known and unknown mechanisms of cardiotoxicity

(Left) Target-based assays (e.g., hERG assay) isolate the effects of a single molecular target, allowing more sensitive detection of compounds with low-dose cardiotoxicity involving that PoT, but with a higher risk of false positives. (Right) Phenotypic assays (e.g., spheroid or microtissue, EHT, or MPS) that better mimic human cardiac physiology can detect toxicity that results from unknown or unanticipated PoTs from environmental cardiotoxicants but can possess reduced sensitivity to specific PoTs compared to target-based assays. EHT, engineered heart tissue; hERG, human ether-a-go-go related gene; MPS, microphysiological system; PoT, pathway of toxicity