We have characterized the physicochemical properties of nanotalc particles from two different geographical regions and examined their toxicity mechanisms in human lung epithelial (A549) cells. Indigenous nanotalc (IN) of Indian origin and commercial nanotalc (CN) of American origin were used in this study. Physicochemical properties of nanotalc particles were characterized by X-ray diffraction (XRD), transmission electron microscopy (TEM), energy dispersive X-ray spectroscopy (EDS), Brunauer-Emmet-Teller (BET), and dynamic light scattering (DLS). Results showed that both IN and CN particles significantly induce cytotoxicity and alteration in cell cycle phases. Both IN and CN particles were found to induce oxidative stress indicated by induction of reactive oxygen species (ROS), lipid peroxidation, and depletion of antioxidant levels. DNA fragmentation and caspase-3 enzyme activation due to IN and CN particles exposure were also observed. We further showed that after iron chelation, IN and CN particles produce significantly less cytotoxicity, oxidative stress, and genotoxicity to A549 cells as compared with nonchelated particles. In conclusion, this study demonstrated that redox active iron plays significant role in the toxicity of IN and CN particles, which may be mediated through ROS generation and oxidative stress. © 2012 Wiley Periodicals, Inc. Environ Toxicol 29: 394–406, 2014.