876~120.7 mg/kg 14 days Liver damage [50] Respiratory tract 25 1~10 mg/kg 10 days Lung damage [51] Intraperitoneal 30 200~500 mg/kg 17 days Slight damages in the liver, kidney, and heart [52] Digestive tract 20 to 30 5 g/kg 14 days Liver and kidney toxicity [53] Respiratory tract 10 1,500 mg/m3 7~28 days Increased in pulmonary inflammation [54] Caudal vein 20 to 100 0.1~0.8 mg/ml 5 days Induce DNA damage of the liver and kidney [55] Digestive tract 4 5 g/kg 14 days No change in coefficients of the organs [56] Intraperitoneal 6.9 5~150 mg/kg 14 days Induced kidney toxicity [57] Respiratory

tract 15 1~10 mg/kg 7~days Lung injury, changed the enzyme activities [58] Caudal #Depsipeptide randurls[1|1|,|CHEM1|]# vein 5 0.24 μg/mouse 1~48 h this website Increase content of Ti in the liver, lung, and spleen [59] Respiratory tract 80 – 1 month Distribution of Ti in the neural system [60] Respiratory tract 50 0.5~50 mg/kg 7 days Induced oxidative stress in the liver and kidney [61] Respiratory tract 20~30 3.5~17.5 mg/kg 5 weeks Lung damage, oxidative effects, inflammation [62] Intraperitoneal 62 1~15 mg/kg 21 days Nephrotoxicity and tubular damages [63] Respiratory tract 5 0.8~20 mg/kg 7 days Liver and lung

damage [64] Respiratory tract 5~10 0.4~40 mg/kg 7 days Changed enzyme activities [65] Respiratory tract 25.1 2~50 mg/m3 5 days Enzyme activities and induced lung toxicity [66] Respiratory tract 28.4 5 mg/kg 1 weeks Lung damage [67] Respiratory tract 5 0.8~20 mg/kg 7 days Aggregate in the lung Oxalosuccinic acid and kidney [68] Respiratory tract 5, 21, 50 0.5~50 mg/kg 7 days Pulmonary toxicity [69] Respiratory tract 20 to 30 3.5~17.5 mg/kg 5 weeks Immune system toxicity The toxicity of nano-TiO2 from vitro studies The cultured cells exposed to toxic agents can respond with various mechanisms that differ in the level of cell damage. Nano-TiO2 has been studied mainly with established in vitro toxicity

assays that analyze major cellular parameters such as cytotoxicity, enzyme activities, genotoxicity, and response to various stress factors. Although a variety of cell studies using nano-TiO2 has been published so far, different articles may have no coherent results. In this study, we calculated the percentage of positive studies with several of important endpoints. The overall percentage of positive studies differed very significantly (p < 0.01) from the expected value of positive studies if there is no true effect (less than 5% of studies are expected to show a p value less than 0.05 just by chance), suggesting that we can reject the null hypothesis. According to Tables  3, 4, 5, the total percentage of positive studies was lower for studies on inflammation (25%) than for studies on other endpoints, and the group of genotoxicity had a highest percent positive result that reached 100% but based on small numbers.