Toxicological Effects of Titanium Dioxide Nanoparticles: A Review of In Vivo Studies

Table 6

In vivo studies that investigated the adverse effects of TiO₂ NPs on hematopoietic and immunological systems.

Hematopoietic and immunological systems
References	Crystal phase composition (particle size in nm)	Type of exposure	Type and number of animals	Results
Wang et al., 2007 [121]	TiO2 (25, 80, 155)	Intragastric administration: 5 g/kg TiO2 in a minute.	20 male and female CD-1 (ICR) mice per group	Spleen histology: no alterations.
Nemmar et al., 2008 [43]	Rutile TiO2 nanorods (4–6)	Intratracheal instillation: 1, 5 mg/kg TiO2.	6-7 male Wistar rats per group	Blood parameters: increased MONs and GRAs, decreased PLTs.
Chen et al., 2009 [22]	Anatase TiO2 (80–110)	Intraperitoneal injections: 324–2592 mg/kg TiO2.	10 male and female ICR mice.	Spleen histology: severe lesions; NEU infiltration.
Li et al., 2010 [140]	Anatase TiO2 (~6-7)	Intraperitoneal injections: 5–150 mg/kg TiO2 every day for 45 days.	20 female CD-1 (ICR) mice per group	Oxidative stress in spleen: increased ROS and MDA.; Spleen histology: congestion, lymph nodule proliferation, splenocyte apoptosis.; Apoptosis mechanism: TiO2 activated caspase −3 and −9, decreased Bcl-2, increased Bax and cytochromec.
Liang et al., 2009 [30]	TiO2 (5, 21)	Intratracheal instillation: 0.5–50 mg/kg TiO2.	6 male and female Sprague Dawley rats per group	Oxidative stress: decreased SOD activity in plasma.
Duan et al., 2010 [21]	Anatase TiO2 (5)	Intragastric administration: 62.5–250 mg/kg TiO2	20 female CD-1 (ICR) mice per group	Blood parameters: WBC, RBC, Hb, mean corpuscular Hb concentration, thrombocytes, reticulocytes decreased; mean corpuscular volume, mean corpuscular Hb, red cell distribution width, PLTs, HT, mean PLT volume increased.; Immunological parameters: CD3, CD4, CD8, CD4/CD8, B, and NK cells decreased.; Inflammatory action: IL-2 decreased and NO increased by TiO2.
Bu et al., 2010 [129]	Rutile-anatase TiO2 mixture (<50)	Intragastric administration: 0.16–1 g/kg TiO2 once a day for 14 consecutive days.	16 male and female Wistar rats per group	Blood parameters: WBC, LYMs, MONs, EOS increased.; Spleen histology: no alterations.
Rossi et al., 2010 [71]	Silica coated rutile TiO2 (~10×40); Rutile TiO2 (<5 μm)	Inhalation: 10±2 mg/m^3 TiO2 for 2 hr a day, 3 days a wk, for 4 wks.	8 female BALB/c/Sca mice per group	Inflammatory action: TiO2 NPs decreased TNF-α and IL-13 expression in spleen cells.
Nemmar et al., 2011 [79]	Rutile Fe-doped nanorod TiO2 (length: 80; diameter: 7)	Intratracheal instillation: 1, 5 mg/kg TiO2	4 male Wistar rats per group	Blood parameters: WBC, IL-6, SOD, GSH, PLTs increased.
Moon et al., 2011 [116]	TiO2 (<25, <100)	Intraperitoneal injections: once a day for 7 days	Mice	Spleen cells: splenocytes, CD4+, LPS stimulated NK cells CD8+ decreased; B-lymphocyte development and LPS-stimulated spleen cell proliferation were retarded by TiO2.
Wang et al., 2011 [141]	Anatase TiO2	Intragastric administration: 5–150 mg/kg TiO2 for 30 consecutive days.	20 female CD-1 (ICR) mice per group	Spleen histology: congestion, lymph nodule proliferation.; Oxidative stress: O2−, H2O2, MDA levels, and p38, JNK, NF-kB, Nrf-2, and HO-1 expression increased in spleen.

EOS, eosinophil; GRA, granulocyte; GSH, reduced glutathione; Hb; haemoglobin; HT, hematocrit; HO-1, Heme oxygenase-1; IL-, interleukin; JNK, c-Jun N-terminal kinase; LPS, lipopolysaccharide; LYM, lymphocyte; MDA, malondialdehyde; MON, Monocyte; NEU, neutrophil; NF-kB, nucleic factor-kB; NK, natural killer; Nrf-2, nuclear factor-E2-related factor-2; PLT, platelet; RBC, red blood cells; ROS, reactive oxygen species; SOD, superoxide dismutase; TiO₂ NPs, titanium dioxide nanoparticles; TNF-α, tumor necrosis factor-α; WBC, white blood cells.