Table 2.

Summary of major findings from studies characterizing the effect of metal nanomaterials on dermal allergy grouped by metal

Metal	Author/year	Material	Size	Animal or cell type	Model	Exposure route	Dose	Findings
Aluminum	Varlamova et al. 2015	AI2O3	–	M/F BALB/c, CBA/CaLac, out-bred mice and guinea pig	LLNA	Subcutaneous, intramuscular, intravenous, intra-dermal injection		No intensification of anaphylaxis systemic reaction, no inflammatory reaction to ConA, no delayed allergic reaction, no redness or edema at site of application
	Brown et al. 2008	AI2O3	50–120 nm	HaCaT human keratinocytes		In vitro	10–10,000 μg/mL	24 h exposure resulted in IL-8 expression, IL-1α release, indicating potential for irritation or sensitization
Cobalt	Choet al. 2012	Co3O4	18.4±5.0nm	F C57BL/6 mouse	OVA	Subcutaneous injection	25 μg	Balanced Th1/Th2 response when used as adjuvant, causing higher specific lgG2c and IgGI and less IgE
Gold	Ishii et al. 2008	Au	5.2±1.3nm	F Japan White Rabbit		Intradermal injection	1 mg	Azobenzene dye hapten conjugation to AuNP led to high yield of IgG specific to the agent indicating the capacity for AuNP to act as both a carrier and adjuvant
Iron	Shen et al. 2012	Fe₃O₄	58.7 nm	M BALB/c mouse	OVA	Intravenously	0.2–10 mg/kg	Decreased footpad swelling, infiltration of macro-phages and T-cells, and IFN-y, IL-6, TNF-α levels
	Hsiao et al. 2018	Fe₃O₄	58.7 nm	M BALB/c mouse	OVA	Intravenously	1–100 μg	Attenuation in TH17 responses
Silica	Choi et al. 2011	SiO₂	7nm	CBA/N mouse	HSEM LLNA	Dermal	10–1,000 μg	SiO₂NP did not induce phototoxicity or skin sensitization
	Hirai et al. 2015	SiO₂	30 nm	F NC/Nga slc mouse	HDM	Dermal	20 μl @ 12.5mg/mL	Concurrent exposure to allergen and particles resulted in low-level production of allergen-specific IgG subtypes and increased sensitivity to anaphylaxis
	Ostrowski et al. 2014	SiO₂	55±6nm	M SKH1 mouse	Oxazolone	Dermal	–	Functionalized nanoparticles had no impact on allergic response to oxazolone in an ACD model
	Smulders et al. 2015	SiO₂	19nm	M BALB/c mouse	DNCB	Dermal	0.4, 4.0, or 40mg/mL×3d	SiO₂NP exposure prior to sensitization with DNCB did not alter the stimulation index
Silver	Kim et al. 2013	Ag	10nm	M SPF guinea pig	GPMT	Intradermal injection	0.1 mL @ 1:1 (v/v)	No eye or skin irritation or corrosion. 1/20 guinea pigs developed erythema following subcutaneous injection, leading to its classification as a weak skin sensitizer
				M New Zealand White rabbit	–	Occular application	100 mg	No eye irritation effects 1–72 hours after exposure
	Bhol et al. 2005	Ag	<50nm	F BALB/c mouse	DNFB	Dermal	100 mg 1% nanocrystalline	Reductions in ear swelling, erythema, and inflammation were seen after 4 days of treatment with nanopartide-containing cream
	Smulders et al. 2015	Ag	25–85 nm	M BALB/c mouse	DNCB	Dermal	0.4, 4.0, or 40mg/mLx3d	Exposure prior to sensitization with DNCB did not alter the stimulation index
	Zelga et al. 2016	Ag	-	Guinea pig	GPMT	Dermal	2%	AgNP-containing dressings for chronic wounds were tested via GPMT, wherein 2/10 animals developed slight erythema that resolved after 72 hours, leading to classification as a mild sensitizer
	Korani et al. 2011	Ag	<100nm	M Harley Albino guinea pig	-	Dermal	100–10,000 μg/ml	Dose-dependent increase in number of Langerhans cells recruited to skin
Titanium	Parket al. 2011	TiO₂	<25nm	F CBA/N mouse	LLNA	Dermal	10–1000 μg/mL	TiO₂ did not induce skin sensitization
				F Hartley Albino guinea pig	-	Dermal	50 μg	TiO₂ did not induce phototoxicity or acute cutaneous irritation
	Hussain et al. 2012	TiO₂	12±2nm	M BALB/c mouse	DNCB	Subcutaneous Injection	0.004–0.4 mg/mL	TH2 adjuvancy, increased DNCB dermal sensitizer potency
	Auttachoat et al. 2014	TiO₂	<25nm	F BCC3F1 mouse	-	Dermal, Subcutaneous Injection	1.25–250 mg/kg	Dermal exposure did not induce auricular lymph node expansion, despite irritancy response at 5% and 10%, no ear swelling, but lymph node cell proliferation resulted following subcutaneous injection
	Smulders et al. 2015	TiO₂	15nm	M BALB/c mouse	DNCB	Dermal	0.4, 4.0, or 40mg/mL×3d	Exposure to 4.0 mg/mL of TiO₂ prior to sensitiza-tion with DNCB resulted in increased stimulation index
	Piasecka-Zelga et al. 2015	TiO₂		New Zealand albino rabbit	Acute Dermal Irritation	Dermal	0.5 g	5 UV-absorbers containing nano-sized particles were assessed for irritation and sensitization potential. Anatase Ti0₂-containing agent did not induce irritation, but caused mild sensitization
				Dunkin-Hartley guinea pig	GPMT	Dermal	0.1 mL/site
Zinc	Piasecka-Zelga et al. 2015	ZnO	APS 396 nm, containing nanoparticles	New Zealand albino rabbit	Acute Dermal Irritation	Dermal	0.5 g	5 UV-absorbers containing nano-sized particles were assessed for irritation and sensitization potential. Z11 modifier caused minor dermal irritation and mild sensitization
				Dunkin-Hartley guinea pig	GPMT	Dermal	0.1 mL/site
	Kim et al. 2016	ZnO	20–50 nm, 13.1 m²/g	M Sprague-Dawley Rat, M New Zealand White rabbit, M guinea pig	GPMT	Dermal	50%	ZnONP did not induce dermal sensitization, acute dermal toxicity, irritation, or corrosion

Summary of studies investigating metal nanomaterial immune effects in the skin and select in vitro studies using dermal cells, grouped by metal. APS: average particle size, DNCB: dinitrochlorobenzene; GPMT: guinea pig maximization test; HDM: house dust mite; HSEM: Human Skin Equivalent Model; LLNA: Local Lymph Node Assay; OVA: ovalbumin; UV: ultraviolet.