Table 6.

Summary of major findings from studies comparing the effects of various physicochemical properties of metal nanomaterials on respiratory allergy grouped by property of interest.

Property investigated		Author/year		Metal		Study design	Property variations			Findings
Size		de Haar et al. 2006		Ti		F BALB/cANNCrl mouse	Fine TiO2: 250 nm, 6.6 m2/g			Exposure to equal mass doses of fine and ultrafine TiO2 resulted in
						Ovalbumin, 200 μg intranasal	Ultrafine TiO2: 29.0 nm, 49.8 m2/g			increased TH2 cytokines and serum OVA-specific IgE and IgGI only
										in animals exposed to ultrafine TiO2
		Yoshida et al. 2011		Si		F BALB/c mouse, Ovalbumin	Amorphous silica			Smaller particles induced higher levels of OVA-specific IgE, IgG, and
						Intranasal: 10, 50, or 250 μg/ mouse x3	30, 70, 300, or 1000 nm			IgG1. Splenocytes from mice exposed to the smallest particle pro-
										duced higher levels of TH2 cytokines than other groups.
		Liu et al. 2010		Ti		Rats, Intratracheal instillation	5 or 200 nm TiO2			Decreased chemotactic ability, expression of Fc receptors/MHC II by
						0.5, 5, or 50 μg/mL				alveolar macrophages. Phagocytic function was increased at low
										doses and decreased at high doses
		Chang et al. 2014		Ti		M Sprague Dawley rat	21 nm TiO2NP: 80% anatase, 20% rutile,			Increased macrophage accumulation and alteration of TH1/TH2 status
						Intratracheal instillation: x2, x4 w	1–2 μm TiO2: anatase
						0.5, 4, 32 mg/kg
		Ban et al. 2013		Fe		F BALB/c mouse, Ovalbumin	Submicron Fe2O3: 147±48nm, 6 m2/g			High and medium doses of both Fe particles caused decreases in
						Intratracheal instillation:	Fe2O3NP: 35±14nm, 39 m2/g			eosinophil influx and OVA-specific IgE levels. However, at the low
						4x (100, 250, or 500 μg/mouse)				dose, submicron particles had no effect on allergy, whereas nano-
										particles had an adjuvant effect on the TH2 response to OVA
SA		Rossi et al. 2010		Ti		F BALB/c/Sca mouse, Ovalbumin	Rutile TiO2NP: <5 μm, 2 m2/g			Allergic pulmonary inflammation was dramatically suppressed in asth-
						Inhalation: 10±2mg/m3 × 12	Rutile TiO2NP: 10 × 40 nm, 132 m2/g			matic mice exposed to either size TiO2. Leukocyte number, cyto-
										kines, chemokines, and antibodies were significantly decreased.
		Parketal. 2015		Si		F BALB/c mouse, Ovalbumin	Spherical SiNP: 12.7 m2/g			Acute SiNP exposure induced significant airway inflammation and
						Intranasal inoculation	Mesoporous SiNP: 70.6 m2/g			AHR. Spherical SiNPs induced the greatest degree of exacerbation
							PEGylated SiNP: 12.7 m2/g			of allergic effects in the OVA model
		Han et al. 2016		Si		F BALB/c mouse	Spherical SiNP: 12.7 m2/g, 119.6nm			Sensitized mice exposed to S-SiNP and M-SiNP exhibited elevated
						Ovalbumin	Mesoporous SiNP: 70.6 m2/g, 100.5 nm			AHR over controls. M-SiNPs induced the greatest degree adjuvan-
						Intranasal inoculation: 10 mg/kg 6x	PEGylated SiNP: 12.7 m2/g, 439.1 nm			ticity, whereas PEG-SiNP caused the least toxic effects
MOD		CRG Seydoux et al. 2016		Au		F BALB/c mouse	90 nm AuNP:			APCs preferentially took up cationic AuNPs, causing upregulation of
						AuNP intranasal instillation: 10 μg	NH2-PVA, 7.2 mV			co-stimulatory molecules. Positive AuNPs enhanced OVA-specific
							COOH-PVA 8.2 mV			CD4+ T-cell stimulation in the lung draining lymph nodes
		Marzaioli et al. 2014		Si		F BALB/c mouse, Ovalbumin	Amorphous SiO2NP 15 nm:			Uncoated SiO2NPs induced proinflammatory and immunomodulatory
						Intratracheal instillation: 50 μg	Uncoated 38 mV, PEGylated 26 mV,			effects with increases in lung inflammatory cells, TH2 cytokines.
							Phosphate-coated 43 mV, Amino-coated 0 mV			Amino and phosphate surface modifications mitigated these
										effects, whereas PEG coating did not.
		Omlor et al. 2017		Au		F BALB/c mouse, Ovalbumin	5 nm AuNP, PEGylated or citrated			Asthmatic condition increased nanoparticle uptake. Systemic uptake is
						Intranasal instillation				higher for PEGylated AuNP compared to citrated AuNPs, but both
										inhibited inflammatory infiltrates and AHR, wherein inhibition was
										more significant following exposure to citrated AuNPS
		Vennemann		Zr		F Wistar rat	APTS, TODS, PGA, or acrylic acid coated			Surface coating had minimal effects on inflammation in the lungs of
		et al. 2017				Intratracheal instillation	9–1 Onm ZrO2NPs			rats, but had significant effects on allergic response.
Size MOD		Alessandrini		Ag		F BALB/c mice, Ovalbumin	PVP-coated AgNP: 97 nm, 6.2 m2/g, 7mV			Ag50-PVP significantly reduced OVA-induced inflammatory infiltrate in
		et al. 2017				Intratracheal instillation: 1–50 μg	PVP-coated AgNP: 134nm, 4.5 m2/g, 7mV			sensitized mice. Lung microbiome was altered dependent
							Citrate-AgNP: 20 nm, 30 m2/g, 45 mV			on coating.
		Seiffert et al. 2015		Ag		Brown Norway and Sprague-Dawley rats	PVP-coated AgNP: 20 or iiOnm			Smaller AgNPs increased AHR on d 1, which persisted to d 7 for the
						Intratracheal instillation: 0.1 mg/kg	Citrate-capped AgNP: 20 or iiOnm			citrate AgNPs only. 20 nm AgNP was more pro-inflammatory but
										little difference between different surface coatings
		CRY Horie et al. 2015		Zn		F C57BL/6N mouse, Ovalbumin	Rutile TiO2, AI(OH)3 surf: 30–50 nm 37.1 m2/g			Serum total and OVA IgE, IgG1 increased in mice treated with the
				Ti		Pharyngeal aspiration: 50 μg	ZnO: 21 nm, 49.6 m2/g			uncoated ZnO particle. However, ZnCI2 did not produce similar
				Si			ZnO, SiO2 Surface: 25 nm, unknown SA, ZnCI2			exacerbations. TiO2 and SiO2 did not affect OVA-lgE or IgG levels.
							Amorphous SiO2: 7nm 300 m2/g, 34 nm 80 m2/g
SA	Sandberg		Si		LPS-primed RAW264.7 mouse macrophages, pri-			64 nm Si, 650cm2/mg	Non-crystalline SiO2 particles in both nano and micron size ranges
	et al. 2012				mary rat lung macrophages			369 nm Si, 90 cm2/mg	induced IL-1β release from LPS-primed macrophages following
					0, 50, 100, 250, 500 μg/mL, 6h			~20nm Fumed Si (aerosol), 1880cm2/mg 500nm-10 μm Fused Si (suprasil), 23cm2/mg	uptake, phagosomal leakage, and activation of the NALP3 inflam-
									masome. Particle surface area, reactivity, and uptake all influenced
									the degree of mediator release by cells
	Vandebriel		Ti		F BALB/c mouse, Ovalbumin			Uncoated TiO2NP:	Rutile TiO2NP caused the greatest increase in OVA-specific serum IgE
	et al. 2018				Intranasal exposure: 120 μg TiO2			10–30 nm rutile or 10–25 nm anatase	and IgGI. Neutrophils recruited by rutile, but not anatase
	SOL Jeong et al. 2015		Co		F Rat, Intratracheal Instillation			CoO: 65.4± 2.8 nm, 92.65% solubility	Soluble CoNP induced eosinophilic inflammation, whereas insoluble
					80, 200, 800 μg/mL @ 0.5 mL			Co3O4: 20.2 ± 0.4 nm, 11.46% solubility	CoONP induced neutrophilic inflammation
	Cho et al. 2011		Zn		F Wistar rat			10.7±0.7nm ZnONP 50 or 150cm2/rat	ZnONP induced eosinophilia, proliferation of airway epithelial cells,
					Intratracheal instillation			Zn2+ ions 92.5 μg/rat	goblet cell hyperplasia, and increased IgE levels, and decreased
									IgA- findings which were also seen following instillation of Zn ions

Summary of study design and major findings from studies comparing the effects of various physicochemical properties of metal nanomaterials on respiratory allergy grouped by study property of interest. Properties of interest: size, CRY (crystallinity), MOR (morphology), MOD (surface modification), CRG (surface charge), and SA (surface area), and SOL (solubility). Reported particle size (nm), specific surface area (m2/g), zeta potential (mV), pore volume (cm3/g), in vitro dose concentration (mg/mL). AHR: airway hyperreactivity; APC: antigen-presenting cell; APTS: aminopropylsilane modification; DC-SIGN: dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin; MDDC: monocyte-derived dendritic cell; MHC: major histocompatibility complex; OVA: ovalbumin; PDI: polydispersity index; PEG: poly(ethylene glycol) modification; PGA: poly(lactic-coglycolicacid) modification; PVA: PVP polyvinylpyrrolidone modification; ROS: reactive oxygen species; TODS: tetraoxidecanoic acid modification