Liver 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 Biochemical parameters: ALT and ALT/AST increased. Histology: hydropic degeneration and necrosis. Fabian et al., 2008 [138 ] Anatase-rutile TiO2 mixture (20–30) Intravenous injection: 5 mg/kg3 male Wistar rats per group Biochemical parameters: no alterations in TBIL, ALP, ALT, AST. 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 Biochemical parameters: no changes in TP, ALB, ALT, AST. Oxidative stress: decreased SOD and increased MDA activity. Guo et al., 2009 [131 ] N.A. Intraperitoneal injections : 200 and 500 mg/kg TiO2 every other day for 5 times.15 male ICR mice per group Biochemical parameters: ALT and AST/ALT increased. Chen et al., 2009 [22 ] Anatase TiO2 (80–110) Intraperitoneal injections : 324–2592 mg/kg TiO2 .10 male and female ICR mice. Biochemical parameters: ALT and AST increased. Histology: fibrosis, hydropic degeneration, necrotic, and apoptotic cells, NEUs were detected. Liu et al., 2009; 2010 [122 , 135 ] Anatase TiO2 (5) 2 (10–15 μ m) Intra-abdominal injections : 5–150 mg/kg BW anatase TiO2 and 150 mg/kg bulk TiO2 everyday for 14 days.10 female CD-1 (ICR) mice per group Biochemical parameters: ALT, ALP, ALB, glucose, TG, TCHO, HDL-C levels were increased by both particles; LAP, PChE, TP, were increased and TBIL was reduced by anatase TiO2 . Oxidative stress: induced by anatase TiO2 in liverMa et al., 2009 [132 ] See Liu et al., 2009 [122 ] Biochemical serum parameters: ALT, ALP, AST, LDH, PChE, LAP, TCHO, and HDL-C increased by both particles; ALB, GLB, TG increased and LDL-C decreased by anatase TiO2 . Histology: basophilia, ischemia and vein congestion (both TiO2 ). Apoptosis induced by anatase TiO2 . Inflammatory action: NF-kB, MIF, TNF-α , IL-6, IL-1β , CRP, IL-4, and IL-10 increased by anatase TiO2 . Wu et al., 2009 [115 ] Anatase TiO2 (
1
0
±
1
) 2 (
2
5
±
5
;
6
0
±
1
0
) 2 (~21) 2 (0.3–0.5 μ m) Cutaneous application : 24 mg of 5% TiO2 test formulation on the dorsal interscapular skin6 hairless mice (BALB/c/nu/nu) per group Liver histology: TiO2 penetrated the skin inducing necrosis. Oxidative stress: increased MDA activity in liverWang et al., 2009 [134 ] Anatase TiO2
4
5
.
8
7
±
7
.
7
5
; thickness:10–15) Intraarticular injection : 0.2–20 mg/kg TiO2 in the knee joints every other day for 4 times.10 male Sprague Dawley rats per group Biochemical parameters: ALP decreased; AST/ALT, LDH increased. Histology: fatty degeneration, inflammatory cell infiltration. Duan et al., 2010 [21 ] Anatase TiO2 (5) Intragastric administration : 62.5–250 mg/kg TiO2 for 30 consecutive days.20 female CD-1 (ICR) mice per group Biochemical parameters: ALT, ALP, AST, LDH, ChE, TP, TG, TCHO increased, ALB/GLB, TBIL decreased. Histology: blurred hepatocytes, congested vessels. Cui et al., 2011 [133 ] Anatase TiO2 (5) Intragastric administration : 5, 10, 50 mg/kg TiO2 for 60 consecutive days.20 female CD-1 (ICR) mice per group Biochemical parameters: ALT, AST, ALP, LDH, PChE, LAP increased. Inflammatory action: IkB and IL-2 decreased; IKK1, IKK2, NF-kB, NF-kBP52–65, TNF-α , NIK, TLR-2, and TLR-4 increased. Histology: fatty degeneration, necrosis, apoptosis, inflammation. Cui et al., 2010 [136 ] Anatase TiO2 (6.9) Intragastric administration : 5, 10, 50 mg/kg TiO2 for 60 consecutive days.20 female CD-1 (ICR) mice per group Histology: hepatocyte apoptosis. Oxidative stress :
O
2
−
, H2 O2 , MDA, NO increased. Gene expression: SOD, CAT, GSH-Px, MT, GST, HSP70, P53, TF decreased, CYP1A increased. Bu et al., 2010 [129 ] Rutile-anatase TiO2 mixture (<50) Intragastric administration : 0, 0.16, 0.4, 1 g/kg TiO2 once a day for 14 consecutive days.16 male and female Wistar rats per group 1 α -ketoglutarate, hippurate, histidine, TMAO, taurine, citrulline, acetate, PAG, and citrate levels; decrease in methionine and 3-D-HB levels 1 Histology: no alterations. Li et al., 2010 [137 ] Anatase TiO2 Intra-abdominal injections: 5, 10, 50, 100, 150 mg/kg for 14 consecutive days.10 female CD-1 (ICR) mice per group Ti liver content: dose-dependent increase. Interaction with DNA: TiO2 was bound on DNA, caused changes in DNA conformation, induced DNA cleavage. Tang et al., 2010 [75 ] TiO2 (5) Intratracheal instillation: 0.8, 4, 20 mg/kg TiO2 .8 male Sprague Dawley rats per group Biochemical parameters: ALT increased. 1 Tang et al., 2011 [40 ] Anatase TiO2 (
5
±
1
) Intratracheal instillation: 0.8, 4, 20 mg/kg TiO2 .8 male Sprague Dawley rats per group Biochemical parameters: ALB and GLU increased. 1 TEM analysis: swollen hepatocytes, congested sinusoids. Nemmar et al., 2011 [79 ] Rutile Fe-doped TiO2 (length: 80; diameter: 7) Intratracheal instillation: 1, 5 mg/kg TiO2 4 male Wistar rats per group Biochemical parameters: AST and ALT increased. Histology: inflammatory cell infiltration, mainly LYMs. Yamashita et al., 2011 [100 ] TiO2 (35) Intravenous injection: 0.8 mg TiO2 for 2 consecutive gestational days.Pregnant mice Ti distribution: TiO2 detected in fetal liver
2-OG, 2-Oxoglutarate; 3-D-HB, 3-D-hydroxybutyrate; ALB, albumin; ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CAT, catalase activity; ChE, cholinesterase; CRP, cross-reaction protein; CYP1A, cytochrome p450 1A; DMA, Dimethylamine; GLB, globulin; GLU. Glutamic acid; GSH-Px, glutathione peroxidase; GST, glutathione-S-transferase; HDL-C, high-density lipoprotein cholesterol; HSP70, heat shock protein 70; IL-, interleukin; LDL-C, low-density lipoprotein cholesterol; LAP, leucine acid peptide; LDH, lactate dehydrogenase; LYM, lymphocyte; MDA, malondialdehyde; MIF, migration inhibitory factor; MT, metallothionein; NO, nitric oxide; NEU, neutrophil; NF-kB, nucleic factor-kB; NIK, NF-κ B-inducible kinase; NMR, nuclear magnetic resonance; PAG, phenylacetylglycine; PChE, pseudocolinesterase; SOD, superoxide dismutase; TBIL, total bilirubin; TCHO, total cholesterol; TEM, transmission electron microscopy; TF, transferrin; TG, triglycerides; TLR-, toll-like receptor-; TMAO, trimethylamine-N-oxide; TiO2 NPs, titanium dioxide nanoparticles; TNF-α , tumor necrosis factor-α ; TP, total protein. 