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Table 1 The pulmonary toxicity exhibited by TiO2

From: Identification of the mechanisms that drive the toxicity of TiO2 particulates: the contribution of physicochemical characteristics

Paper

Particle

Model

Endpoints

Findings

Ahn et al., [14]

TiO2 (0.29 μm)

Intratracheal Instillation (4-72 hour exposure)

-rats

BALF cell infiltration

Number of goblet cells

Muc5ac expression (indicative of mucus secretion)

IL-13 production

Histology (for lung tissue morphology)

Increased neutrophils, eosinophils & goblet cells

Increased Muc5ac expression

Increased IL-13

Renwick et al., [6]

TiO2 (29 & 250 nm)

Intratracheal Instillation (24 hour exposure)

-rats

Inflammation (BALF analysis)

Epithelial cell damage

Lung permeability (BALF protein)

Cytotoxicity (BALF LDH)

Macrophage phagocytic ability (determining the uptake of fluorescent polystyrene particles)

Macrophage chemotaxis (ability to migrate towards C5a)

NPs induce a neutrophil infiltration

NPs damage epithelial cells

Increased Lung permeability

Increased Cytotoxicity

NPs impair macrophage phagocytosis

NP treated macrophages increased chemotaxis

Chen et al., [12]

TiO2 (18-21 & 180-250 nm)

Intratracheal Instillation (3 day to 2 week exposure)

-mice

Morphological analysis (included investigation of enlarged alveoli, disrupted septa, thickened alveoli)

Apoptosis in lung tissue (TUNEL assay)

Immunohistochemical staining (antiPCNA)

cDNA microarray analysis

rtPCR & Western Blot (for placenta growth factor (P1GF))

Morphology of lung injury was emphysema-like for NPs.

Observed macrophage infiltration that were particle laden

Increased apoptosis in lung tissue

Gene expression (chemokines & complement) changes indicative of an inflammatory response

P1GF (a cytokine inducer) expression anticipated to be central to the inflammatory response

• No pathology observed for fine particles

Warheit et al., [11]

TiO2 (in various crystal forms)

Intratracheal instillation (24 hours to 3 month exposure)

-rats

Inflammation (BALF cells & cytokines)

Lung permeability (BALF protein)

Cytotoxicity (BALF LDH)

Epithelial cell secretory activity (alkaline phosphatase)

Lung histopathology

Neutrophil infiltration

No cytotoxicity, protein, alkaline phosphatase and lung morphology changes

Macrophage accumulation but normal

• Crystallinity of sample impacts on pulmonary toxicity (greater toxicity for anatase containing particles)

Bermudez et al., [8]

TiO2 (1.40 μm)

Inhalation (13 week exposure)

-mice, rats, hamsters

Inflammation (BALF & Histology)

Lung particle burden

Cytotoxicity (LDH) & permeability (protein)

High concentrations of particles administered impaired their clearance from the lung. However, hamsters were able to most efficiently clear particles.

Inflammatory response evident in all species, but was most severe and persistent in rats.

Increased LDH & protein (least severe in hamsters)

Species differences, and dose dependent effects observed

Bermudez et al., [7]

TiO2 (21 nm)

Inhalation (13 week exposure)

-mice, rats, hamsters

Inflammation (BALF & Histology)

Lung particle burden

Cytotoxicity (LDH) & permeability (protein)

Retained particle burden decreased with (post-exposure) time & particles contained in macrophages

Increased cellular infiltration (macrophages and neutrophils) dependent on species

Increased LDH & protein (not hamsters)

• Findings dependent on species (rats>mice>hamsters) and particle concentration

Heinrich et al., [13]

TiO2

(also diesel soot and ufCB treatment groups)

Inhalation (2 year exposure (with satalite groups at 3, 6, 12 & 18 months), with or without subsequent clean air exposure for 6 months post particle exposure)

-rats and mice

Histology (to assess Carcinogenicity)

DNA adducts

Lung particle burden

Alveolar lung clearance

BALF cytology and biochemical (including LDH, protein) analysis

Increased mortality with TiO2 (although mortality was also high in the control group)

Alveolar lung clearance compromised by TiO2

Increased protein, LDH in BALF

Increased lung tumours

Ferin et al., [3]

TiO2 (12, 21, 230 & 250 nm)

Intratracheal instillation (24 hour exposure)

Inhalation (12 week exposure)

-rats

Inflammation (BALF neutrophil infiltration & histology)

Lung burden & particle clearance

Neutrophil infiltration (greater for smaller particles)

Particles internalised by alveolar macrophages

Particle clearance slower for smaller particles, and access the pulmonary interstitium to a larger extent than fine particles

Grassian et al., [10]

TiO2 (5 & 21 nm)

Inhalation (4 hour exposure will observations made immediately or 24 hours post exposure)

Nasal instillation (24 hour exposure)

-mice

Inflammation (BALF cells & cytokines)

Cytotoxicity (BALF LDH)

Lung Permeability (BALF protein)

Lung histopathology (inflammation, lung injury, and abnormalities in pulmonary architecture)

Inhalation: macrophage infiltration, no changes in protein, LDH & histopathology

Nasal instillation: neutrophil infiltration, increased IL-1β, IL-6, protein and LDH for 21 nm NPs only

• 21 nm NPs more toxic than 5 nm NPs (due to agglomeration differences)

Warheit et al., [9]

6 samples of TiO2 (of various surface coatings, size up to 440 nm)

Inhalation (4 week exposure, with observations made at 2 weeks to 1 year post exposure)

Intratracheal instillation (24 hours to 3 month exposure)

-rats

Inflammation (BALF)

Lung permeability (BALF protein)

Cytotoxicity (BALF LDH)

Histopathology

Inhalation: particle containing macrophage accumulation, epithelial cell hyperplasia, fibrotic response (collagen deposition)

Intratracheal: neutrophil infiltration, particle laden macrophages, increased lung permeability, ncreased cytotoxicity

• Surface treatment paramount to toxicity: aluminia and silica coatings increase toxic potency

• The pulmonary toxicity of the particle panel overall was low & was similar in inhalation and instillation set ups