Table 1.

Lung toxicity in animal models induced by different TiO₂ particles.

Structural Feature	Animals	Dose	Exposure Route	Toxicity Effect	Reference
Ultrafine TiO2 (~20 nm), Fine TiO2 particles (~250 nm)	Rats	23.5 and 22.3 mg/m3	Intratracheal instillation for 6 h per day, 5 day per week for 12 weeks	Ultrafine particles at equivalent masses access the pulmonary interstitium to a larger extent than fine particles; pulmonary clearance of ultrafine particles was slower (t½ = 501 days) than of larger particles (t½ = 174 days); a similar mass deposition of the two particle types in the lower respiratory tract; ultrafine particles elicited a persistently high inflammatory reaction compared to the larger-sized particles; this correlated well with their greater surface area per mass.	[10,34]
Ultrafine TiO2 (~20 nm), larger TiO2 particles (less than 200 nm)	Rats		Intratracheal instillation	Ultrafine particles highly access the pulmonary interstitium; PMNs influx into the alveolar space; The acute inflammatory reaction including an increased percentage of neutrophils, γ-glutamyl transpeptidase concentration (a measure of cell damage), protein concentration (a measure of epithelium permeability), and lactate dehydrogenase (LDH) in BALF were induced.	[20]
Rutile nano-TiO2 (21 nm)	Mice	0.1, and 0.5 mg	Intratracheal instillation for one time	Pulmonary emphysema, extensive disruption of alveolar septa, type II pneumocyte hyperplasia, epithelial cell apoptosis, and accumulation of particle-laden macrophages were induced.	[36]
Fine TiO2 (250 nm mean diameter)	Mice		Intratracheal instillation for 4, 24, or 72 h	Inflammatory cells or expression of inflammatory cytokines were not detected in the lung tissue.	[37]
Ultrafine TiO2 particles (1.4 μm)	Mice, Rats, Hamster	10, 50, and 250 mg/m3	Inhalation for 6 h per day, 5 day per week for 12 weeks	Species differences in pulmonary responses: rats developed a more severe and persistent pulmonary inflammatory response than either mice and hamsters; hamsters are better able to clear TiO2 NPs than similarly exposed mice and rats.	[17,18]
Anatase TiO2 nanospheres, short belts (1–5 μm), long nanobelts (4–12 μm)	Mice	0–30 μg	Pharyngeal aspiration	Both nanospheres and long nanobelts resulted in the lung deposition of 135 μg TiO2. At 112 day after exposure, the lung burden was significantly lower in nanosphere-exposed mice than in nanobelt-exposed mice.	[39]
Rutile TiO2 nanorods	Wistar Rats	1, and 5 mg/kg	Intratracheal instillation for 24 h	Inflammation responses were examined in BALF (significantly increased neutrophilic inflammation) and whole blood (significantly reduced platelets and elevated numbers of monocytes and granulocytes) at doses of 1 or 5 mg/kg.	[40]
Nanoscale TiO2 rods (anatase = 200 nm × 35 nm), nanoscale TiO2 dots (anatase = similar to 10 nm)	Rats	1 and 5 mg/kg	Intratracheal instillation	Produced transient lung inflammation and cell injury in rats at 24 h post-exposure, which is similar to the pulmonary effects of rutile TiO2 NPs (300 nm).	[41]
Anatase/rutile spheres (TiO2-P25), anatase spheres (TiO2-A), anatase nanobelts (TiO2-NBs)	Mice and Rats	20, 70, and 200 μg	Intratracheal instillation	TiO2-A, TiO2-P25, and TiO2-NB caused significant neutrophilia in mice at 1 day in three of four labs, and this effect was resolved by day 7; TiO2-P25 and TiO2-A had no significant effect in rats in any of the labs; Only TiO2 nanobelts caused significant neutrophilia in rats at 1 day after intratracheal instillation in two or three of four labs.	[42,43]
Base TiO2 particles, TiO2 particles coated with aluminum oxide (0%–6%) and/or silica (0%–11%)	Rats	2 and 10 mg/kg; 1130–1300 mg/m3 (high dose)	Intratracheal inhalation and instillation for 4 weeks	Surface-coated TiO2 produced higher pulmonary inflammation (PMNs in BALF) than the uncoated TiO2 at 24 h in SD rats, but this effect was only a short-term, transient lung inflammatory response and was reversible at one week post-exposure; Surface treatments influenced the toxicity of TiO2 particles.	[44]
In situ-produced TiO2 (~21 nm), rutile (<5 μm), nanosized rutile/anatase (~30 nm), nanosized anatase (<25 nm), silica-coated nanosized needle-like rutile (~10 × 40 nm)	Mice	10 mg/m3	Inhalation for 2 h, 4 consecutive days, 4 weeks	Only SiO2-coated rutile commercial TiO2 NPs elicited clear-cut pulmonary neutrophilia, increased expression of tumor necrosis factor (TNF)-α and neutrophil-attracting chemokines; The level of lung inflammation could not be explained by the surface area of the particles, their primary or agglomerate particle size, or free radical formation capacity but was rather explained by the surface coating.	[45]
Hydrophobic and silanized ultrafine TiO2	Rats	250 and 500 μg	Intratracheal instillation	Silanized TiO2 did not show toxicity, but a much lower pulmonary inflammation was induced in comparison to the hydrophilic uncoated TiO2 in rat lung; Surface properties (surface chemistry) appeared to play an important role in ultrafine particle toxicity.	[46]
Pristine TiO2 NPs, TiO2 NPs embedded in paints	Mice	20 μg	Oropharyngeally aspiration once a week for 5 weeks	The paint containing TiO2 ENPs did not modify macrophage and neutrophil counts, but mildly induced KC and IL-1β; The incorporation of TiO2 NPs in aged paint matrix blocked most of the particle-induced lung and systemic blood toxicity.	[47]
Rutile TiO2 NPs coated with alumina (uf-1), rutile TiO2 NPs coated silica/alumina (uf-2), uncoated anatase/rutile TiO2 (uf-3)	Rats	1 or 5 mg/kg	Intratracheal instillation	uf-1 and uf-2 produced transient lung inflammation, and uf-3 produced pulmonary inflammation, cytotoxicity and adverse lung effects, and aggregated macrophages in the alveolar regions of the lung; uf-3 particles showed more chemical reactivity than both uf-1 and uf-2 particles.	[48]
Surface-coated rutile TiO2 (~20.6 nm) (coating content: silicon, aluminum, zirconium and polyalcohol)	Mice	18, 54, and 162 μg	Intratracheal instillation for one time	Nano-TiO2 deposited in the lung; 3000 genes were altered in the pulmonary system; At low doses, surface-coated rutile TiO2 potentially down-regulated several gene expression associated with ion homeostasis and muscle function in the absence of inflammation.	[27]
Commercially TiO2 P25 untreated with hydrophilic surface, TiO2 T805 silanized with hydrophobic surface	Rats	0.15, 0.3, 0.6 and 1.2 mg	Instillation for one time	There was no inflammation or persistent DNA damage in the lung of rats exposed to two types of commercial TiO2 at low doses administered.	[49]
Fine (180 nm) and ultrafine (20–30 nm) TiO2 particles (hydrophilic), surface modified with methylation (hydrophobic)	Rats	1 and 6 mg	Intratracheal instillation for 16 h	A lesser inflammatory response (influx of neutrophils, activated PMNs and total cell number) was induced in rats in comparison to the untreated TiO2; the impact of surface methylation on TiO2 toxicity was negligible; surface area rather than hydrophobic surface determined the pulmonary inflammation.	[50]