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Table 1 Inhalation studies investigating the effect of nanomaterial characteristics on lung deposition, clearance, and/or pulmonary inflammation

From: Physicochemical characteristics of nanomaterials that affect pulmonary inflammation

Nanoparticle characteristic studied Reference Chemical composition Primary particle size Agglomerate particle size in air Exposure time and type Lung deposition, clearance, and translocation Lung inflammation
Agglomerate size Ho et al. 2011 [15] Zinc oxide Not reported 35 nm CMD1 6 hours inhalation   Dose-dependent pulmonary inflammation. Exposure concentration: 2.4, 3.7, 12.1 mg/m3 for the 35 nm particles and 7.2, 11.5, 45.2 mg/m3 for the 250 nm particles.
250 nm CMD
Agglomerate size Kreyling et al. 2002 [16] Radio-labelled Iridium Not reported 15 nm CMD 1 hour inhalation: 0.6 μg 15 nm; 6.0 μg 80 nm Larger deposited fraction of 15 nm compared to 80 nm particles. Similar clearance kinetics via gastro-intestinal tract. Translocation very low, but higher for the 15 nm compared to the 80 nm particles.  
80 nm CMD
Agglomerate size Kreyling et al. 2009 [17] Radio-labelled Iridium 2 – 4 nm 20 nm CMD 1 hour inhalation: 0.6 μg 15 nm; 6.0 μg 80 nm Translocation of 20 nm Iridium particles is larger compared to 80 nm Iridium particles  
  80 nm CMD Translocation of Iridium particles is higher compared to similar sized carbon particles.
Chemical composition
Iridium-labelled Carbon 5 – 10 nm 25 nm CMD
Agglomerate size Noël et al. 2012 [18] Titanium dioxide 5 nm 30 and 185 nm agglomerates (2 mg/m3) 31 and 194 nm agglomerates (7 mg/m3) 6 hours inhalation: 2 mg/m3 and 7 mg/m3 Similar lung deposition of small and large agglomerates. Exposure to both small and large agglomerates at 7 mg/m3 resulted in adverse effects. Exposure to the large agglomerates results in a significant increase in neutrophils in the lungs, while the small agglomerates did not.
Agglomerate size Oberdörster et al. 2000 [10] Platinum Not reported 18 nm CMD 6 hours inhalation: 100 μg/m3 platinum and carbon; 40 μg/m3 Teflon Ultra-fine particles all reach interstitial sites after translocation.  
Carbon 26 nm CMD
Teflon 18 nm CMD
Agglomerate size Oberdörster et al. 2000 [10] Teflon Not reported Starting with 18 nm CMD, size increasing over time 6 hours inhalation: ~50 μg/m3   Particles increased in size over time while particle number decreased; only freshly generated fumes (<100 nm) caused inflammation.
Charge and solubility Cho et al. 2012 [19] Silver 91.9 nm Not applicable Intratracheal instillation: 150 cm2/rat   Instillation of aluminum oxide, both cerium dioxides, cobalt oxide, both cupper oxides, nickel oxide, and both zinc oxides induced significant pulmonary inflammation, whereas instillation of the other nanoparticles did not.
Aluminum oxide 6.3 nm
Cerium dioxide 9.7 and 4.4 nm
Cobalt oxide 18.4 nm
Chromium oxide 205 nm
Copper oxide 23.1 and 14.2 nm Regarding the high-solubility nanoparticles, the inflammogenicity of copper oxide and zinc oxide was derived from their soluble ions. Other parameters showed a poor correlation with inflammation potential of nanoparticles.
Magnesium oxide 15 nm
Nickel oxide 5.3 nm
Silicon dioxide 6.2 nm
Titanium dioxide 5.6 and 30.5 nm
Zinc oxide 10.7 and 137 nm
Charge Choi et al. 2010 [20] Quantum dots (Zwitterionic, polar, anionic, cationic) 5 – 38 nm Not applicable Intratracheal instillation A size threshold of ~34 nm determines whether there is rapid translocation of nanoparticles. Below 34 nm, surface charge is a major factor influencing translocation, with zwitterionic, anionic and polar surfaces being permissive and cationic surfaces being restrictive.  
Silica (Polar) 56 – 320 nm
Polystyrene(Zwitterionic, polar, anionic) 7 – 270 nm
Chemical composition Heinrich et al. 1995 [21] Diesel exhaust - 0.25 μm MMAD2 2 year inhalation (rats) Deposition, retention and total lung burden of diesel exhaust particles was highest compared to carbon black and titanium dioxide. Clearance was reduced in all groups; mostly reduced in group exposed to highest concentration of diesel exhaust. Similar effects in all particle groups; carbon black induced the most lung tumours. Exposure concentration: 0.8, 2.5, 4.5, 7 mg/m3 diesel exhaust, 11.6 mg/m3 carbon black and 10 mg/m3 titanium dioxide.
Carbon black 14 nm 0.64 μm MMAD 1 year inhalation (mice)
Titanium dioxide 15 – 40 nm 0.80 μm MMAD
Chemical composition Landsiedel et al. 2010 [22] Titanium dioxide 40 nm (A) - 5 days inhalation: 2, 10, 50 mg/m3 TiO2 (B); 0.5, 2.5, 10 mg/m3 ZrO2, CeO, SiO2, ZnO, CB; 0.1, 0.5, 2.5 mg/m3 MWCNT Similar deposition of the particles. Only exposure to anatase titanium dioxide (B) resulted in particle overload in the lungs. Titanium dioxide, cerium oxide, zinc oxide and MWCNT induced dose-dependent pulmonary inflammation. The effects of MWCNT were most severe and progressive. Zirconium dioxide, silicon dioxide and carbon black did not induce inflammation.
Titanium dioxide 25 nm (B) 0.9 μm MMAD
Zirconium dioxide 40 nm 1.5 μm MMAD
Cerium oxide 40 nm 0.8 μm MMAD
Zinc oxide 60 nm 0.9 μm MMAD
Silicon dioxide 15 nm 1.2 μm MMAD
Carbon black 27 nm 0.8 μm MMAD
MWCNT - 1.5 μm MMAD
Chemical composition Wang et al. 2010 [23] Iron oxide 30 nm Not reported Spraying in the nose, twice daily for 3 days: 8.5 mg/kg bw Fe2O3 and 2.5 mg/kg bw ZnO 12 hours after exposure, zinc was detected in liver; 36 hours after exposure, iron was detected in liver and zinc in the kidneys. Zinc oxide particles caused more severe changes in the liver while iron oxide caused more severe lung lesions.
Zinc oxide 20 nm
Hydrophobicity Arts et al. 2007 [24] Pyrogenic silica Not reported 2 – 3 μm MMAD 5 days inhalation: 1, 5 and 25 mg/m3   Pyrogenic silica induced the most pronounced pulmonary inflammation compared to the other silica types.
Silica gel
Precipitated silica
Hydrophobicity Reuzel et al. 1991 [25] Hydrophilic silica 12 nm 1 – 120 μm MMAD 13 weeks inhalation: 1, 6, and 30 mg/m3 The 12 nm hydrophilic silica particles were more quickly cleared from the lungs compared to the other silica types. Hydrophilic 12 nm (pyrogenic) silica induced more pulmonary inflammation compared to the other silica’s.
Hydrophobic silica 12 nm
Hydrophilic silica 18 nm
Primary particle size Balasubramanian et al. 2013 [26] Gold 7 nm 45.6 CMD 15 days inhalation: 0.086 -0.9 mg/m3 7 nm; 0.053 – 0.57 mg/m3 20 nm 7 nm gold NPs deposited in the brain, blood, small intestine and pancreas at greater mass concentration compared to 20 nm gold NPs. Clearance of the 20 nm particles is more effective compared to the 7 nm particles.  
20 nm 41.7 CMD
Primary particle size Geraets et al. 2012 [27] Cerium oxide 5 – 10 nm 1.02 μm MMAD 28 days inhalation: 11 mg/m3 5–10 nm; 20 mg/m3 40 nm; 55 mg/m3 < 5000 nm Similar deposition in all groups; slow clearance in all groups; even slower clearance in 5 – 10 nm group. Very low translocation to secondary organs.  
40 nm 1.17 μm MMAD
<5000 nm 1.4 μm MMAD
Primary particle size Gosens et al. 2010 [28] Gold 50 nm 200 nm agglomerated Intratracheal instillation: 1.6 mg/kg bw   Mild pulmonary inflammation; more effects for single 250 nm particles than for single 50 nm particles.
250 nm 770 nm agglomerated
Primary particle size Gosens et al. 2013 [29] Cerium oxide 5 – 10 nm 1.02 μm MMAD 28 days inhalation: 11 mg/m3 5–10 nm; 20 mg/m3 40 nm; 55 mg/m3 < 5000 nm   All materials induced dose-dependent pulmonary inflammation to the same extent.
40 nm 1.17 μm MMAD
<5000 nm 1.4 μm MMAD
Primary particle size Horie et al. 2012 [30] Nickel oxide 100 nm Not applicable Intratracheal instillation: 0.2 mg/0.4 ml   Nano-sized nickel particles induced inflammation and oxidative stress, while larger sized particles did not.
600 – 1400 nm
Chemical composition Titanium dioxide 7 nm
Nano-sized nickel particles induced inflammation and oxidative stress, while the titanium dioxide particles did not.
200 nm
Primary particle size Kobayashi et al. 2009 [31] Titanium dioxide 4.9 nm Not applicable Intratracheal instillation: 1.5 mg/kg   Smaller particles induced greater inflammatory response at the same mass dose.
23.4 nm
154.2 nm
Primary particle size Oberdörster et al. 1994 [32] Titanium dioxide 20 nm 0.71 μm MMAD 12 weeks inhalation: 24 mg/m3 20 nm TiO2; 22 mg/m3 250 nm TiO2 Similar deposition in both groups. After deposition, disaggregation into smaller agglomerates. Retention halftime for 20 nm particles is longer compared to 250 nm particles.  
250 nm 0.78 μm MMAD
Primary particle size Oberdörster et al. 2000 [10] Platinum Not reported 13 nm CMD 6 hours inhalation: ~110 μg/m3 Uptake of ultra-fine particles by lung macrophages was lower compared to larger sized particles.  
Primary particle size Oberdörster et al. 2000 [10] Titanium dioxide 20 nm Not applicable Intratracheal instillation Both in rats and mice, 20 nm particles induced inflammation at lower mass dose compared to 250 nm particles. Exposure concentrations for the 20 nm particles: 31, 125, 500 μg in rats and 6, 25, 100 μg in mice. Exposure concentrations for the 250 nm particles: 125, 500, 2000 μg in rats and 25, 100, 400 μg in mice.
250 nm
Primary particle size Pauluhn et al. 2009 [13] Aluminum oxyhydroxide 10 nm 1.7 μm MMAD 4 weeks inhalation: 0.4, 3 and 28 mg/m3 Translocation of 40 nm particles was higher compared to the 10 nm particles. Both particles induced pulmonary inflammation to the same extent.
40 nm 0.6 μm MMAD
Primary particle size Roursgaard et al. 2010 [33] Quarts 100 nm Not applicable Intratracheal instillation: 50 μg   Both particles induced pulmonary inflammation to the same extent.
1.6 μm
Primary particle size Sadauskas et al. 2009 [34] Gold 2 nm (12 μg/ml) Not applicable 5 intratracheal instillations within 3 weeks: 50 μl Gold particles of all sizes detected in alveolar macrophages; translocation very low, but seems higher for 2 nm particles compared to larger sized particles.  
40 nm (58 μg/ml)
100 nm (60 μg/ml)
Primary particle size Sayes et al. 2010 [35] Silica Not reported 37 nm CMD 1 or 3 day inhalation: 1.8 and 86 mg/m3   No induction of pulmonary inflammation.
83 nm CMD
Primary particle size Stoeger et al. 2006 [36] Carbonaceous nanoparticles Six particles ranging from 10 – 50 nm Not applicable Intratracheal instillation: 5, 20 and 50 μg   Dose-dependent pulmonary inflammation; smaller nanoparticles induced more severe effects compared to larger nanoparticles.
Primary particle size Zhu et al. 2008 [37] Ferric oxide 22 nm Not applicable Intratracheal instillation: 0.8 and 20 mg/kg bw   Both particles induced pulmonary inflammation and oxidative stress to the same extent.
280 nm
Shape Porter et al. 2012 [38] Titanium dioxide spheres (anatase) <70 – 200 nm Not applicable Pharyngeal aspiration: 15, 30 μg spheres; 7.5, 15, 30 μg nanobelts of 3 μm; 1.88, 7.5, 15, 30 μg nanobelts of 9 μm Similar deposition for different shaped particles. Lung burden after exposure to nano-spheres was significantly lower compared to exposure to long nano-belts 112 days after exposure: impaired clearance of nano-belts. Dose-dependent pulmonary inflammation in the animals exposed to titanium dioxide nano-belts. The longer nano-belts caused more severe pulmonary inflammation compared to the shorter ones. Shape and length affect pulmonary responses.
Titanium dioxide nano-belts (anatase) Length:3 μm (1 – 5 μm), width: 70 nm (40 – 120 nm) Length: 9 μm (4 – 12 μm), width: 110 nm (60 – 140)
Shape Schinwald et al. 2012 [39] Silver nanowires 3 μm length, 115 nm diameter Pharyngeal aspiration: 10.7, 17.9, 35.7, and 50 μg for 3, 5, 10 and 14 μm fibres, respectively Length dependent restriction of macrophage locomotion. Fibre-length ≥ 5 μm resulted in impaired motility. Length dependent inflammatory response in the lungs with threshold at a fibre length of 14 μm. Shorter fibres elicited no significant inflammation.
5 μm length, 118 nm diameter
10 μm length, 128 nm diameter
14 μm length, 121 nm diameter
28 μm length, 120 nm diameter
Shape Schinwald et al. 2012 [40] Graphene platelets 5.6 μm projected area diameter Pharyngeal aspiration and intrapleural instillation: 50 μg Prolonged retention of graphene platelets in the pleural space. Exposure to graphene nanoplatelets caused pulmonary inflammation, while exposure to carbon black did not.
Carbon black 10 nm
Shape Ma-Hock et al. 2013 [41] Multi-walled carbon nanotubes 15 nm, fiber-shape 0.5 μm CMD 5 days inhalation: 0.1, 0.5, and 2.5 mg/m3 MWCNT, 0.5, 2.5, and 10 mg/m3 graphene, nanoplatelets and CB The lung deposition was calculated to be 0.03 mg/lung MWCNT, 0.3 mg/lung graphene, 0.2 mg/lung graphite nanoplatelets, and 0.4 mg/lung carbon black. Pulmonary inflammation was induced after exposure to multi-walled carbon nanotubes at all concentrations, and exposure to graphene at 10 mg/m3. The other exposures did not induce pulmonary inflammation. The lung burden did not correlate to the observed toxicity.
Graphene Up to 10 μm, flake 0.6 μm CMD
Graphite nanoplatelets Up to 30 μm, flake 0.4 μm CMD
Carbon black 50 – 100 nm 0.4 μm CMD
Solubility Cho et al. 2011 [42] Zinc oxide 10.7 nm 137 nm Not applicable Intratracheal instillation: 50 and 150 cm2/rat   Zinc oxide particles caused severe pulmonary inflammation probably caused by zinc ions released from rapid dissolution of inside phagolysosomes.
Nickel oxide 5.3 nm
Titanium dioxide 30.5 nm
Solubility Cho et al. 2012 [43] Nickel oxide 10 – 20 nm Not applicable Intratracheal instillation: 30, 100, 300 cm2/ml NiO; 3, 10, 30 cm2/ml ZnO and CuO   Pulmonary inflammation is caused by nickel oxide nanoparticles and not the ions, zinc oxide and copper oxide nanoparticles caused particle-specific eosinophil recruitment. In vitro, zinc and copper ions caused the observed adverse effects.
Zinc oxide <10 nm
Copper oxide (and their aqueous extracts) <50 nm
Surface reactivity Van Ravenzwaay et al. 2009 [44] Titanium dioxide (70% anatase, 30% rutile) 20 – 30 nm 1.0 μm MMAD 5 days inhalation: 88 mg/m3 20–30 nm TiO2; 274 mg/m3 200 nm TiO2; 96 mg/m3 Quartz   Both titanium particles induced reversible effects, while the effects caused by quartz remained. Quartz induced the most prominent pulmonary inflammation while the surface area of deposition was the lowest.
Chemical composition
Titanium dioxide (rutile) 200 nm 1.1 μm MMAD
Quartz   1.2 μm MMAD
Surface reactivity Warheit et al. 2007 [11] Nano-titanium Not reported 140 nm Intratracheal instillation: 1 and 5 mg/kw bw   Only the titanium dioxide particles with the highest surface reactivity induced pulmonary inflammation.
Nano-titanium 130 nm
Fine titanium 380 nm (size in water)
Surface reactivity Warheit et al. 2007 [12] Nano-Quartz 50 nm Not applicable Intratracheal instillation: 1 and 5 mg/kg bw   Pulmonary inflammation was not dependent on particle size but correlated well with the haemolytic potential of the particles.
Nano-Quartz 12 nm
Fine Quartz 300 nm
  1. 1CMD: count median diameter.
  2. 2MMAD: mass median aerodynamic diameter.
  3. Studies are listed according to the nanoparticle characteristic studied, in alphabetical order.