New tobacco products with the potential to reduce the risk associated with smoking are under development and require a careful safety assessment strategy.To investigate the effect of the aerosol generated by Philip Morris’s candidate Modified Risk Tobacco Product, named Tobacco Heating System 2.2 (THS2.2), organotypic tissue cultures derived from human nasal and bronchial primary epithelial cells were chosen as the test model. Tissue cultures were exposed for 28 min, at the air liquid interface, to air (sham control), THS2.2 aerosol or mainstream smoke derived from 3R4F reference cigarettes (obtained from the University of Kentucky). 3R4F smoke and THS2.2 aerosol were diluted with air to match the same nicotine level (Fig. 1). Various endpoints were collected at different time points after exposure to identify and compare the dose- and time-dependent effect of each exposure condition (Fig. 2A).By using systems toxicology-based risk assessment approaches combining computable biological network models and gene expression changes, we compared the molecular perturbations in both 3R4F smoke and THS2.2 aerosol exposure conditions. The overall assessment results reported here highlight a reduced toxicity of THS2.2 aerosol acute exposure on both nasal and bronchial epithelial tissue culture when compared to combustible cigarette smoke.