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