Table 3.

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

Property investigated	Author/year	Metal	Study design	Property variations	Findings
Size			Kang H et al. 2017	Ag	RBL-2H3 mast cells F NC/Nga mouse, HDM AD: 40 ng	5, 100 nm AgNP	5 nm AgNP induced increases in ROS levels, intracellular calcium, and granule release in mast cells in vitro and earlier and more severe lesions in an AD model in vivo
			Nabeshi et al. 2010	Si	XS52 mouse epidermal Langerhans cell, 0.1–1000 ug/mL	70, 300, 1000 nm SiNP	Cellular uptake and cytotoxicity increased with reductions in particle size
			Yoshida et al. 2010	Si	XS52 mouse epidermal Langerhans cell, 0–100 μg/mL	70, 300, 1000 nm SiNP	ROS generation by LC was higher following exposure to the smaller amorphous SiNP
			Hirai et al. 2012b	Si	M NC/Nga mouse HDM ACD Intradermal injection: 250 μg	1136nm SiO2NP: 33.2 mV, 264 nm SiO2NP: 25.8 mV, 106 nm SiO2NP: 24.3 mV, 76 nm SiO2NP: 19.5 mV, 39 nm SiO2NP: 14.0mV	Reduction in size of SiO2NPs caused enhanced IL-18 and TSLP production, leading to an enhanced systemic Th2 response and aggravation of skin lesions following challenge with house dust mite
			Kang S et al. 2017b	Au	Mouse footpad injection OVA	7, 14, 28 nm AuNP	Size-dependent increase in cellular uptake by DC, T-cell cross-priming, and activation.after injection into footpad, higher delivery efficiency to lymph nodes was associated larger NPs
			Yanagisawa et al. 2009	Ti	M NC/Nga mouse HDM Intradermal injection: 20 μg	15 nm TiO2NP-110 m2/g 50 nm TiO2NP-20–25 m2/g 100 nm TiO2NP-10–15 m2/g	TiO2NP aggravated AD skin lesions, caused increased IL-4 production, IgE levels, and histamine levels, but decreased IFN-γ expression. Effects were not dependent on size
			lives et al. 2014	Zn	F BALB/c mice, OVA ACD Dermal application: 16.67 mg/mL	20, 240 nm ZnONP	Smaller sized ZnONPs were able to penetrate the skin, whereas larger particles were not. Both particles diminished local skin inflammation, but ZnONPs exhibited higher suppressive effects and increased IgE production
	CRG
			Jang et al. 2012	Zn	CBA/N Mouse LLNA: 25, 50, or 100 μg/mL ZnONP HSEM EpiDerm skin irritation Draize skin irritation: 50 μg/mL	20 nm, 29 mV or 40 mV ZnONP 100 nm, 24 mV or 29 mV ZnONP	ZnO are not dermal sensitizers and do not induce skin irritation irrespective of size and zeta potential, but may induce phototoxicity
			Jatana et al 2017b	Si	M/F hairless C57BL6 mouse DNFB ACD Dermal application	32.7 nm SiO2 nanosphere: 25.4 mV 66.5 nm SiO2 nanosphere: 45.7 mV 69.3 nm SiO2 nanosphere: 17.7mV 184.9 SiO2 nanosphere: 33.5 mV 440.0 nm SiO2 nanosphere: 66.0 mV	Small negative and neutral-charged nanoparticles exhibited an immunosuppressive effect, whereas positively-charged particles did not. Positively-charged nanoparticles penetrated skin to a lesser extent. Studies also included lOOnm TiO2NP, 20 nm AgNP, and 20 nm AuNP
			Schaeublin et al. 2010	Au	HaCaT human keratinocyte cells 10 μg/mL–25 μg/mL	1.5 nm AuNP Positive, neutral, or negatively-charged	Cell morphology was disrupted by AuNPs of all 3 charges in a dose-dependent manner. Charged AuNPs caused dose-dependent cytotoxicity and mitochondrial stress
	CRY	SA	Lee et al. 2011	Si	J774A.1 mouse macrophages: 0–1,000 ug/mL, 1 or 3 d LLNA: F BALB/c, 1 mg/ ear × 3 tx	100 nm spherical: mesoporous SiO2 1150 m2/g colloidal SiO2-40 m2/g	Higher surface area caused decreased cytotoxic and poptotic cell death. Similarly, higher surface area induced lower expression of pro-inflammatory cytokines. Lower surface area Si particles acted as an immunogenic sensitizer in the LLNA
Size			Maquieira et al. 2012	Al	Mice and rabbits Intradermal injection	40, 3000 nm amorphous AI2O3, 300 nm crystalline AI2O3	AINP served as both carrier and adjuvant leading to hapten-specific antibody production dependent on size and crystallinity
			Braydich-Stolle et al. 2009	Ti	HEL-30 mouse keratinocytes 0–150 μg/mL 24 h exposure	100% anatase TiO2: 6.3, 10, 40, 50, 100 nm 61% anatase, 39% rutile TiO2: 39 nm 40% anatase, 60% rutile TiO2: 39 nm 75% anatase, 25% rutile TiO2: 26 nm Amorphous TiO2: 40 nm 100% rutile TiO2: 51 nm	Both size and crystal structure contributed to toxicity in vitro. Smaller size and less agglomeration increased cytotoxicity. 100% anatase TiO2 particles, regardless of size, induced cell necrosis, whereas the rutile TiO2 nanoparticles initiated apop-tosis through formation of ROS
		MOD	Orlowski et al. 2013	Ag	291.03C mouse keratinocyte 1–10 μg/mL 24 h exposure	Tannic acid-modified AgNP: 13, 33, and 46 nm Unmodified AgNP: 10 −65 nm	Unmodified, but not modified, AgNP increased production of MCP-1 by keratinocytes and upregulation of TNF-α, attributable to increased ROS production
			Li et al. 2016	Si	F C57BL/6 mouse 5mg injection	Unmodified mesoporous SiNP PEG, PEG-RGD, PEG-RDG- modified SiNP	PEG modification significantly enhanced DC activation in vitro and innate immune cell infiltration in vivo. PEG-modification resulted in less recruitment of DC to area of injection

Summary of study design and major findings from studies comparing the effects of various physicochemical properties of metal nanomaterials on dermal allergy grouped by study property of interest. Properties of interest: size, CRY (crystallinity), CRG (surface charge), SA (surface area), and MOD (surface modification). Reported particle size (nm), specific surface area (m2/g), zeta potential (mV), pore volume (cm3/g), in vitro dose concentration (mg/mL). DC: dendritic cell; DNFB: dinitrofluorobenzene; HDM: house dust mite; LC: Langerhans cell; LLNA: Local Lymph Node Assay; HSEM: Human Skin Equivalent Model; OVA: ovalbumin; PEG: poly(ethyleneglycol) modification, PEG-RDG/RGD; ROS: reactive oxygen species; TSLP: thymic stromal lymphopoietin.