Toxicity of 11 metal oxide nanoparticles to three mammalian cell types in vitro

Angela Ivask, Tiina Titma, Meeri Visnapuu, Heiki Vaija, Aleksandr Käkinen, Marliis Sihtmäe, Suman Pokhrel, Lutz Mädler, Margit Heinlaan, Vambola Kisand, Ruth Shimmo, Anne Kahru

Research output: Contribution to journalReview ArticleResearchpeer-review

104 Citations (Scopus)


The knowledge on potential harmful effects of metallic nanomaterials lags behind their increased use in consumer products and therefore, the safety data on various nanomaterials applicable for risk assessment are urgently needed. In this study, 11 metal oxide nanoparticles (MeOx NPs) prepared using flame pyrolysis method were analyzed for their toxicity against human alveolar epithelial cells A549, human epithelial colorectal cells Caco2 and murine fibroblast cell line Balb/c 3T3. The cell lines were exposed for 24 h to suspensions of 3-100 μg/mL MeOx NPs and cellular viability was evaluated using. Neutral Red Uptake (NRU) assay. In parallel to NPs, toxicity of soluble salts of respective metals was analyzed, to reveal the possible cellular effects of metal ions shedding from the NPs. The potency of MeOx to produce reactive oxygen species was evaluated in the cell-free assay. The used three cell lines showed comparable toxicity responses to NPs and their metal ion counterparts in the current test setting. Six MeOx NPs (Al2O3, Fe3O4, MgO, SiO2, TiO2, WO3) did not show toxic effects below 100 μg/mL. For five MeOx NPs, the averaged 24 h IC50 values for the three mammalian cell lines were 16.4 μg/mL for CuO, 22.4 μg/mL for ZnO, 57.3 μg/mL for Sb2O3, 132.3 μg/mL for Mn3O4 and 129 μg/mL for Co3O4. Comparison of the dissolution level of MeOx and the toxicity of soluble salts allowed to conclude that the toxicity of CuO, ZnO and Sb2O3 NPs was driven by release of metal ions. The toxic effects of Mn3O4 and Co3O4 could be attributed to the ROS-inducing ability of these NPs. All the NPs were internalized by the cells according to light microscopy studies but also proven by TEM, and internalization of Co3O4 NPs seemed to be most prominent in this aspect. In conclusion, this work provides valuable toxicological data for a library of 11 MeOx NPs. Combining the knowledge on toxic or non-toxic nature of nanomaterials may be used for safe-by-design approach.

Original languageEnglish
Pages (from-to)1914-1929
Number of pages16
JournalCurrent Topics in Medicinal Chemistry
Issue number18
Publication statusPublished - 1 Jul 2015
Externally publishedYes


  • In vitro toxicity
  • Metals
  • QSAR
  • Reactive oxygen species
  • Risk assessment
  • Safe by design
  • Solubilization

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