Abstract
The lack of adequate toxicity data for the vast majority of chemicals in the environment has spurred the development of new approach methodologies (NAMs). This study aimed to develop a practical high-throughput in vitro model for rapidly evaluating potential hazards of chemicals using a small number of human cells. Forty-two compounds were tested using human induced pluripotent stem cell (iPSC)-derived cells (hepatocytes, neurons, cardiomyocytes and endothelial cells), and a primary endothelial cell line. Both functional and cytotoxicity endpoints were evaluated using high-content imaging. Concentration-response was used to derive points-of-departure (POD). PODs were integrated with ToxPi and used as surrogate NAM-based PODs for risk characterization. We found chemical class-specific similarity among the chemicals tested; metal salts exhibited the highest overall bioactivity. We also observed cell type-specific patterns among classes of chemicals, indicating the ability of the proposed in vitro model to recognize effects on different cell types. Compared to available NAM datasets, such as ToxCast/Tox21 and chemical structure-based descriptors, we found that the data from the five-cell-type model was as good or even better in assigning compounds to chemical classes. Additionally, the PODs from this model performed well as a conservative surrogate for regulatory in vivo PODs and were less likely to underestimate in vivo potency and potential risk compared to other NAM-based PODs. In summary, we demonstrate the potential of this in vitro screening model to inform rapid risk-based decision-making through ranking, clustering, and assessment of both hazard and risks of diverse environmental chemicals.