Cardiotoxicity Hazard and Risk Characterization of ToxCast Chemicals Using Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes from Multiple Donors.

Abstract

Heart disease remains a significant human health burden worldwide with a significant fraction of morbidity attributable to environmental exposures. However, the extent to which the thousands of chemicals in commerce and the environment may contribute to heart disease morbidity is largely unknown, because in contrast to pharmaceuticals, environmental chemicals are seldom tested for potential cardiotoxicity. Human induced pluripotent stem cell (iPSC)-derived cardiomyocytes have become an informative in vitro model for cardiotoxicity testing of drugs with the availability of cells from multiple individuals allowing in vitro testing of population variability. In this study, we hypothesized that a panel of iPSC-derived cardiomyocytes from healthy human donors can be used to screen for the potential cardiotoxicity hazard and risk of environmental chemicals. We conducted concentration-response testing of 1029 chemicals (drugs, pesticides, flame retardants, polycyclic aromatic hydrocarbons (PAHs), plasticizers, industrial chemicals, food/flavor/fragrance agents, etc.) in iPSC-derived cardiomyocytes from 5 donors. We used kinetic calcium flux and high-content imaging to derive quantitative measures as inputs into Bayesian population concentration-response modeling of the effects of each chemical. We found that many environmental chemicals pose a hazard to human cardiomyocytes in vitro with more than half of all chemicals eliciting positive or negative chronotropic or arrhythmogenic effects. However, most of the tested environmental chemicals for which human exposure and high-throughput toxicokinetics data were available had wide margins of exposure and, thus, do not appear to pose a significant human health risk in a general population. Still, relatively narrow margins of exposure (<100) were estimated for some perfuoroalkyl substances and phthalates, raising concerns that cumulative exposures may pose a cardiotoxicity risk. Collectively, this study demonstrated the value of using a population-based human in vitro model for rapid, high-throughput hazard and risk characterization of chemicals for which little to no cardiotoxicity data are available from guideline studies in animals.