Science and Education Publishing American Journal of Nanomaterials 2372-3122 3 2 2015 11 3 An integrated in Vitro and in Vivo Testing Approach to Assess Pulmonary Toxicity of Engineered Cadmium-Doped Silica Nanoparticles 40 56 EN Uliana De Simone Elisa Roda Cinzia Signorini Teresa Coccini Laboratory of Clinical and Experimental Toxicology, Toxicology Division, IRCCS Salvatore Maugeri Foundation, Scientific Institute of Pavia Medical Centre, Pavia, Italy AJN2015321 10.12691/ajn-3-2-1 2015 6 22 2015 9 6 2015 11 1 An in vitro and in vivo testing strategy for assessing the pulmonary effects was used to investigate the safety characteristics of silica nanoparticles doped with cadmium (Cd-SiNPs). In A549 cells, Cd-SiNPs (0.5-100 μg/ml) caused (i) mitochondrial dysfunction and apoptosis at 1 ̦g/ml, (ii) GSH depletion at 10̦g/ml, (iii) membrane alterations at 25 ̦g/ml, after 1-day, and (iv) cell growth and proliferation inhibition at 0.05 ̦g/ml after prolonged exposure. Cd-SiNP effects were more pronounced compared to CdCl2. SiNPs affected GSH content only. In vivo results revealed early (1 day) and persistent (until 1 month) rat lung damage after intratracheal instillation of Cd-SiNPs (1mg/rat) in terms of enhanced apoptotic phenomena and altered lung parenchyma morphology. Cd-SiNPs and CdCl2 caused a delayed occurrence of oxidative stress by increasing SOD1, iNOS, and F2-IsoPs. The latter was preceded by marked increase of F2-IsoPs levels in plasma. SiNPs did not cause oxidative stress. Cd-SiNPs showed a higher reactivity than CdCl2 and SiNPs. In vitro and in vivo data on Cd-SiNP toxicity suggest that the lung is a susceptible target tissue. These findings support the concept that multiple assays and an integrated testing strategy should be recommended to characterize toxicological response to NPs.