Table 7.

Metal nanomaterials and corresponding physicochemical properties shown to influence immunological processes involved in the development and augmentation of asthma.

AOP step	Metal nanomaterial effect	Metal	Properties implicated	Source
Sensitization Bioavailability	Increased potential for inhalation	many	dustiness	Evans et al. 2003
	Evasion of uptake by pulmonary macrophages	Si	size, crg, mod	Oh et al. 2010
	Evasion of entrapment by pulmonary mucus	ND	size, crg	Murgia et al. 2016
	Prolonged retention in airways	Al	spec, mor	Park et al. 2017
	Direct translocation across lung epithelial tissue to lymphatics	Au	size, crg	Kreyling et al. 2014
Molecular initating event	Increased potential for metal antigen formation	Ti	size	Vamanu et al. 2008
	Increased protease activity of protein allergens	Au	–	Radauer-Preiml et al. 2016
Cellular response	Adsorption of LPS to nanomaterial surface	Au	size, hyd, mod	Li et al. 2017
	Increased recruitment of DC to lung	Al	mod	Li et al. 2010
	Direct activation of DC	Ti	size, cry	Winter et al. 2011
	Release of DAMPs from immune cells > activation of DC	Zn	size, mor, SA	Hsaio et al. 2011
	Release of DAMPs from epithelial cells > activation of DC	Ag	size, mod, SA, sol	Hamilton et al. 2014
Organ response	Increased CD4þ T-cell presentation efficiency	Ti	size, mor, cry	Schanen et al. 2009
	Increased polarization of CD4þ T-cells to TH2 phenotype	Si	size, mod, SA	Vallhov et al. 2012
	Increased number of B-cells	Ti	–	Park et al. 2009
	Alteration in B-cell expansion/maturation	Au	size	Lee et al. 2014
	Increased production of total IgE	Pt	–	Park et al. 2010b
	Increased production of allergen-specific IgE	Zn	size, sol, cry	Horie et al. 2015
Elicitation
Organism response-early phase reaction	Increased IgE-dependent mast cell degranulation	Au	size, mod	Huang et al. 2009
	Increased IgE-independent mast cell degranulation	many	size, SA, crg	Johnson et al. 2017
	Increased number of lung mast cells	Ce	–	Meldrum et al. 2018
	Altered mast cell exocytic function and granule release	Si	SA	Maurer-Jones et al. 2010
	Altered expression of Fc receptors on immune cells	Ti	size	Liu et al. 2010
Organism response- late phase reaction	Increased endothelial adhesion molecule expression	Al	–	Oesterling et al. 2008
	Increased neutrophil recruitment	Ag	size, sol	Arai et al. 2015
	Increased eosinophil recruitment	Co	sol	Jeong et al. 2015
	Increased lymphocyte recruitment	Zr	mod	Vennemann et al. 2017
	Increased AHR	Ag	size, mod	Seiffert et al. 2015
	Increased airway smooth muscle contractility	Co/Fe	–	Kapilevich et al. 2012
	Mucus cell metaplasia/muus hyeprsecretion	Ti	–	Chen et al. 2011
Chronic effects	Epithelial cell proliferation	Zn	sol	Cho et al. 2011
	Increased fibroblast MMP activity extracellular matrix remodeling	Ti	size, cry, mor	Armand et al. 2012
	Myofibroblast accumulation	Cu	–	Lai et al. 2018

Adverse Outcome Pathway (AOP) steps involved in the sensitization and elicitation phases of asthma, metal nanomaterials shown to impact individual steps, and physicochemical properties associated with effects are shown. Physicochemical properties of interest include size, metal speciation (spec), agglomeration (agg), surface modification (mod), surface area (SA), solubility (sol), surface charge (crg), morphology (mor), crystallinity (cry), and hydrophobicity (hyd). ND (not determined) notation in metal column indicates a study demonstrating a critical role for a specific nanomaterial physicochemical property on the cellular event, but was demonstrated using nonmetal nanomaterials. Findings may be applicable to metals, but have not been demonstrated with individual metal nanomaterials.