Genotoxicity assessment of intravenously injected titanium dioxide nanoparticles in gpt delta transgenic mice

Titanium dioxide (TiO2) nanoparticles are increasingly manufactured in large amounts for use in industrial applications such as cosmetics, pigments, foods, and as photo-catalysts. Many in vitro studies have examined the genotoxicity of TiO2 nanomaterials; some of these studies suggest that TiO2 nanoparticles (NPs) are genotoxic. Several in vivo studies have also been reported recently, but the results are inconsistent. In this study, we investigated, using several genotoxicity endpoints, the effects of dispersed TiO2 suspensions following multiple intravenous injections in mice. Male gpt Delta C57BL/6J mice were administered TiO2 NPs at doses of 2, 10 or 50mg/kg body weight per week for 4 consecutive weeks. Genotoxic effects were then analyzed by the Pig-a gene mutation assay and the micronucleus assay on peripheral blood, and by the alkaline comet, gpt mutation, and Spi(-) mutation assays on the liver. We also assessed the localization of TiO2 NPs in the liver, by transmission electron microscopy. Administration of TiO2 NPs did not significantly increase any of the following endpoints: frequency of Pig-a mutants (erythrocytes); frequency of micronuclei (reticulocytes); level of DNA damage (liver); frequencies of gpt and Spi(-) mutants (liver). Most TiO2 NPs in the liver were found in the sinuses and inside Kupffer cells, although some were occasionally observed in liver parenchymal cells. These results indicate that TiO2 NPs do not have genotoxic effects on mouse liver or bone marrow.