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Metal nanomaterials: Immune effects and implications of physicochemical properties on sensitization, elicitation, and exacerbation of allergic disease

Identifieur interne : 000852 ( Pmc/Curation ); précédent : 000851; suivant : 000853

Metal nanomaterials: Immune effects and implications of physicochemical properties on sensitization, elicitation, and exacerbation of allergic disease

Auteurs : Katherine A. Roach [États-Unis] ; Aleksandr B. Stefaniak [États-Unis] ; Jenny R. Roberts [États-Unis]

Source :

RBID : PMC:6649684

Abstract

The recent surge in incorporation of metallic and metal oxide nanomaterials into consumer products and their corresponding use in occupational settings have raised concerns over the potential for metals to induce size-specific adverse toxicological effects. Although nano-metals have been shown to induce greater lung injury and inflammation than their larger metal counterparts, their size-related effects on the immune system and allergic disease remain largely unknown. This knowledge gap is particularly concerning since metals are historically recognized as common inducers of allergic contact dermatitis, occupational asthma, and allergic adjuvancy. The investigation into the potential for adverse immune effects following exposure to metal nanomaterials is becoming an area of scientific interest since these characteristically lightweight materials are easily aerosolized and inhaled, and their small size may allow for penetration of the skin, which may promote unique size-specific immune effects with implications for allergic disease. Additionally, alterations in physicochemical properties of metals in the nano-scale greatly influence their interactions with components of biological systems, potentially leading to implications for inducing or exacerbating allergic disease. Although some research has been directed toward addressing these concerns, many aspects of metal nanomaterial-induced immune effects remain unclear. Overall, more scientific knowledge exists in regards to the potential for metal nanomaterials to exacerbate allergic disease than to their potential to induce allergic disease. Furthermore, effects of metal nanomaterial exposure on respiratory allergy have been more thoroughly-characterized than their potential influence on dermal allergy. Current knowledge regarding metal nanomaterials and their potential to induce/ exacerbate dermal and respiratory allergy are summarized in this review. In addition, an examination of several remaining knowledge gaps and considerations for future studies is provided.


Url:
DOI: 10.1080/1547691X.2019.1605553
PubMed: 31195861
PubMed Central: 6649684

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PMC:6649684

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<p id="P2">The recent surge in incorporation of metallic and metal oxide nanomaterials into consumer products and their corresponding use in occupational settings have raised concerns over the potential for metals to induce size-specific adverse toxicological effects. Although nano-metals have been shown to induce greater lung injury and inflammation than their larger metal counterparts, their size-related effects on the immune system and allergic disease remain largely unknown. This knowledge gap is particularly concerning since metals are historically recognized as common inducers of allergic contact dermatitis, occupational asthma, and allergic adjuvancy. The investigation into the potential for adverse immune effects following exposure to metal nanomaterials is becoming an area of scientific interest since these characteristically lightweight materials are easily aerosolized and inhaled, and their small size may allow for penetration of the skin, which may promote unique size-specific immune effects with implications for allergic disease. Additionally, alterations in physicochemical properties of metals in the nano-scale greatly influence their interactions with components of biological systems, potentially leading to implications for inducing or exacerbating allergic disease. Although some research has been directed toward addressing these concerns, many aspects of metal nanomaterial-induced immune effects remain unclear. Overall, more scientific knowledge exists in regards to the potential for metal nanomaterials to exacerbate allergic disease than to their potential to induce allergic disease. Furthermore, effects of metal nanomaterial exposure on respiratory allergy have been more thoroughly-characterized than their potential influence on dermal allergy. Current knowledge regarding metal nanomaterials and their potential to induce/ exacerbate dermal and respiratory allergy are summarized in this review. In addition, an examination of several remaining knowledge gaps and considerations for future studies is provided.</p>
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<pmc article-type="research-article">
<pmc-dir>properties open_access</pmc-dir>
<pmc-dir>properties manuscript</pmc-dir>
<front>
<journal-meta>
<journal-id journal-id-type="nlm-journal-id">101201960</journal-id>
<journal-id journal-id-type="pubmed-jr-id">34216</journal-id>
<journal-id journal-id-type="nlm-ta">J Immunotoxicol</journal-id>
<journal-id journal-id-type="iso-abbrev">J Immunotoxicol</journal-id>
<journal-title-group>
<journal-title>Journal of immunotoxicology</journal-title>
</journal-title-group>
<issn pub-type="ppub">1547-691X</issn>
<issn pub-type="epub">1547-6901</issn>
</journal-meta>
<article-meta>
<article-id pub-id-type="pmid">31195861</article-id>
<article-id pub-id-type="pmc">6649684</article-id>
<article-id pub-id-type="doi">10.1080/1547691X.2019.1605553</article-id>
<article-id pub-id-type="manuscript">HHSPA1037798</article-id>
<article-categories>
<subj-group subj-group-type="heading">
<subject>Article</subject>
</subj-group>
</article-categories>
<title-group>
<article-title>Metal nanomaterials: Immune effects and implications of physicochemical properties on sensitization, elicitation, and exacerbation of allergic disease</article-title>
</title-group>
<contrib-group>
<contrib contrib-type="author">
<name>
<surname>Roach</surname>
<given-names>Katherine A.</given-names>
</name>
<xref ref-type="aff" rid="A1">a</xref>
<xref ref-type="aff" rid="A2">b</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Stefaniak</surname>
<given-names>Aleksandr B.</given-names>
</name>
<xref ref-type="aff" rid="A3">c</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Roberts</surname>
<given-names>Jenny R.</given-names>
</name>
<xref ref-type="aff" rid="A1">a</xref>
</contrib>
</contrib-group>
<aff id="A1">
<label>a</label>
Allergy and Clinical Immunology Branch (ACIB), National Institute of Occupational Safety and Health (NIOSH), Morgantown, WV, USA;</aff>
<aff id="A2">
<label>b</label>
School of Pharmacy, West Virginia University, Morgantown, WV, USA;</aff>
<aff id="A3">
<label>c</label>
Respiratory Health Division (RHD), National Institute of Occupational Safety and Health (NIOSH), Morgantown, WV, USA</aff>
<author-notes>
<fn fn-type="other" id="FN1">
<p id="P1">This work was authored as part of the Contributor’s official duties as an Employee of the United States Government and is therefore a work of the United States Government. In accordance with 17 U.S.C. 105, no copyright protection is available for such works under U.S. Law.</p>
</fn>
<corresp id="CR1">CONTACT Katherine Roach
<email>WVQ1@cdc.gov</email>
National Institute of Occupational Safety and Health (NIOSH), 1095 Willowdale Drive, Morgantown, WV 26505, USA</corresp>
</author-notes>
<pub-date pub-type="nihms-submitted">
<day>8</day>
<month>7</month>
<year>2019</year>
</pub-date>
<pub-date pub-type="ppub">
<month>12</month>
<year>2019</year>
</pub-date>
<pub-date pub-type="pmc-release">
<day>01</day>
<month>12</month>
<year>2019</year>
</pub-date>
<volume>16</volume>
<issue>1</issue>
<fpage>87</fpage>
<lpage>124</lpage>
<pmc-comment>elocation-id from pubmed: 10.1080/1547691X.2019.1605553</pmc-comment>
<permissions>
<license license-type="open-access">
<license-p>This is an Open Access article distributed under the terms of the Creative Commons Attribution License (
<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">http://creativecommons.org/licenses/by/4.0/</ext-link>
), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.</license-p>
</license>
</permissions>
<abstract id="ABS1">
<p id="P2">The recent surge in incorporation of metallic and metal oxide nanomaterials into consumer products and their corresponding use in occupational settings have raised concerns over the potential for metals to induce size-specific adverse toxicological effects. Although nano-metals have been shown to induce greater lung injury and inflammation than their larger metal counterparts, their size-related effects on the immune system and allergic disease remain largely unknown. This knowledge gap is particularly concerning since metals are historically recognized as common inducers of allergic contact dermatitis, occupational asthma, and allergic adjuvancy. The investigation into the potential for adverse immune effects following exposure to metal nanomaterials is becoming an area of scientific interest since these characteristically lightweight materials are easily aerosolized and inhaled, and their small size may allow for penetration of the skin, which may promote unique size-specific immune effects with implications for allergic disease. Additionally, alterations in physicochemical properties of metals in the nano-scale greatly influence their interactions with components of biological systems, potentially leading to implications for inducing or exacerbating allergic disease. Although some research has been directed toward addressing these concerns, many aspects of metal nanomaterial-induced immune effects remain unclear. Overall, more scientific knowledge exists in regards to the potential for metal nanomaterials to exacerbate allergic disease than to their potential to induce allergic disease. Furthermore, effects of metal nanomaterial exposure on respiratory allergy have been more thoroughly-characterized than their potential influence on dermal allergy. Current knowledge regarding metal nanomaterials and their potential to induce/ exacerbate dermal and respiratory allergy are summarized in this review. In addition, an examination of several remaining knowledge gaps and considerations for future studies is provided.</p>
</abstract>
<kwd-group>
<kwd>Nanotoxicology</kwd>
<kwd>allergy</kwd>
<kwd>metal nanoparticles</kwd>
<kwd>lung function</kwd>
<kwd>immune response</kwd>
</kwd-group>
</article-meta>
</front>
<floats-group>
<fig id="F1" orientation="portrait" position="float">
<label>Figure 1.</label>
<caption>
<p id="P127">Different morphologies of nanomaterials are shown: (a) graphene sheets, (b) silver nanoparticles, (c) silver nanowires, (d) gold nanorods, (e) gold nanoparticles, (f) nickel oxide nanoparticles, and (g) copper oxide nanoparticles.</p>
</caption>
<graphic xlink:href="nihms-1037798-f0001"></graphic>
</fig>
<fig id="F2" orientation="portrait" position="float">
<label>Figure 2.</label>
<caption>
<p id="P128">Steps of the Adverse Outcome Pathway (AOP) for dermal sensitization adapted from the Organization for Economic Cooperation and Development (OECD).</p>
</caption>
<graphic xlink:href="nihms-1037798-f0002"></graphic>
</fig>
<fig id="F3" orientation="portrait" position="float">
<label>Figure 3.</label>
<caption>
<p id="P129">Potential adverse outcomes with respect to the sensitization and elicitation phases of allergy following exposure to immunotoxic agents. Adjuvant effects resulting from exposure prior to allergen sensitization can manifest as increased susceptibility to sensitization. Exposure concurrent to sensitization may lower the threshold of allergen exposure required to induce sensitization. Following sensitization to allergen, exposure to an immunotoxic agent either in the absence or presence of allergen may result in a lower threshold of exposure required to induce elicitation reactions or increased severity of elicitation symptoms. These effects may further increase susceptibility to elicitation reactions as result of physiological alterations such as compromised skin barrier integrity. Furthermore, isolated exposure to immunotoxic agents or concurrent to allergens in established allergic disease conditions may also contribute to the progression of chronic effects, such as airway remodeling, which can also further contribute to elicitation reactions.</p>
</caption>
<graphic xlink:href="nihms-1037798-f0003"></graphic>
</fig>
<table-wrap id="T1" position="float" orientation="landscape">
<label>Table 1.</label>
<caption>
<p id="P130">Metal nanomaterial production rates and corresponding applications.</p>
</caption>
<table frame="hsides" rules="groups">
<colgroup span="1">
<col align="left" valign="middle" span="1"></col>
<col align="left" valign="middle" span="1"></col>
<col align="left" valign="middle" span="1"></col>
</colgroup>
<thead>
<tr>
<th align="left" valign="middle" rowspan="1" colspan="1">Nanomaterial</th>
<th align="left" valign="middle" rowspan="1" colspan="1">Global production volume (tons)</th>
<th align="center" valign="middle" rowspan="1" colspan="1">Applications</th>
</tr>
</thead>
<tbody>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1">Silicon dioxide</td>
<td align="center" valign="middle" rowspan="1" colspan="1">185,000–1,400,000</td>
<td align="left" valign="top" rowspan="1" colspan="1">Nanocomposite filler, cement additive, drug delivery, cosmetics</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1">Titanium dioxide</td>
<td align="center" valign="middle" rowspan="1" colspan="1">60,000–150,000</td>
<td align="left" valign="top" rowspan="1" colspan="1">Ceramics, sunscreens, construction, energy, cosmetics</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1">Zinc oxide</td>
<td align="center" valign="middle" rowspan="1" colspan="1">32,000–36,000</td>
<td align="left" valign="top" rowspan="1" colspan="1">Sunscreen, LED and LCD displays, antimicrobial, water filtration</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1">Aluminum oxide</td>
<td align="center" valign="middle" rowspan="1" colspan="1">5000–10,100</td>
<td align="left" valign="top" rowspan="1" colspan="1">Drilling equipment, energetic fuels, and additives, filtration</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1">Cerium oxide</td>
<td align="center" valign="middle" rowspan="1" colspan="1">880–1400</td>
<td align="left" valign="top" rowspan="1" colspan="1">Catalysts, slurry polishing, UV absorption, anti-corrosion additive</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1">Copper oxide</td>
<td align="center" valign="middle" rowspan="1" colspan="1">290–570</td>
<td align="left" valign="top" rowspan="1" colspan="1">Heat transfer, batteries, antimicrobials, sensors, semiconduction</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1">Silver</td>
<td align="center" valign="middle" rowspan="1" colspan="1">135–420</td>
<td align="left" valign="top" rowspan="1" colspan="1">Biomedicine, antimicrobial textiles, cosmetics, conductive inks</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1">Antimony tin oxide</td>
<td align="center" valign="middle" rowspan="1" colspan="1">120–225</td>
<td align="left" valign="top" rowspan="1" colspan="1">Electronics, composites, coatings, research</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1">Zirconium oxide</td>
<td align="center" valign="middle" rowspan="1" colspan="1">80–300</td>
<td align="left" valign="top" rowspan="1" colspan="1">Heat-resistant coatings, ceramics, catalysts, dental composites</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1">Iron oxide</td>
<td align="center" valign="middle" rowspan="1" colspan="1">9–45</td>
<td align="left" valign="top" rowspan="1" colspan="1">Ground and wastewater cleanup, color imaging, drug delivery</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1">Nickel</td>
<td align="center" valign="middle" rowspan="1" colspan="1">5–20</td>
<td align="left" valign="top" rowspan="1" colspan="1">Ceramic additive, catalyst, energy absorption, electronics</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1">Cobalt oxide</td>
<td align="center" valign="middle" rowspan="1" colspan="1">5–10</td>
<td align="left" valign="top" rowspan="1" colspan="1">Electronics, catalysts, drug delivery, solar energy absorption</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1">Quantum dots</td>
<td align="center" valign="middle" rowspan="1" colspan="1">4.5–9</td>
<td align="left" valign="top" rowspan="1" colspan="1">Photovoltaic devices, photodetecting devices, electronics</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1">Manganese oxide</td>
<td align="center" valign="middle" rowspan="1" colspan="1">2–3.5</td>
<td align="left" valign="top" rowspan="1" colspan="1">Bleaching agent, biomedical diagnostics, plastics additive</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1">Gold</td>
<td align="center" valign="middle" rowspan="1" colspan="1">1–3</td>
<td align="left" valign="top" rowspan="1" colspan="1">Data storage, gene therapy, biosensors, fuel cell additive</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1">Palladium</td>
<td align="center" valign="middle" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">Hydrogen sensor, antimicrobial activity, catalysts</td>
</tr>
</tbody>
</table>
<table-wrap-foot>
<fn id="TFN1">
<p id="P131">Metal nanomaterials, various applications, and reported global production volume for 2014, reported in tons. Adapted from Metal and Metal Oxide Nanomaterials Future Markets Report,
<xref rid="T1" ref-type="table">Table 1</xref>
(Nanomaterials Future Markets 2015).</p>
</fn>
</table-wrap-foot>
</table-wrap>
<table-wrap id="T2" position="float" orientation="landscape">
<label>Table 2.</label>
<caption>
<p id="P132">Summary of major findings from studies characterizing the effect of metal nanomaterials on dermal allergy grouped by metal</p>
</caption>
<table frame="hsides" rules="groups">
<colgroup span="1">
<col align="left" valign="middle" span="1"></col>
<col align="left" valign="middle" span="1"></col>
<col align="left" valign="middle" span="1"></col>
<col align="left" valign="middle" span="1"></col>
<col align="left" valign="middle" span="1"></col>
<col align="left" valign="middle" span="1"></col>
<col align="left" valign="middle" span="1"></col>
<col align="left" valign="middle" span="1"></col>
<col align="left" valign="middle" span="1"></col>
</colgroup>
<thead>
<tr>
<th align="left" valign="top" rowspan="1" colspan="1">Metal</th>
<th align="center" valign="middle" rowspan="1" colspan="1">Author/year</th>
<th align="center" valign="middle" rowspan="1" colspan="1">Material</th>
<th align="center" valign="middle" rowspan="1" colspan="1">Size</th>
<th align="center" valign="middle" rowspan="1" colspan="1">Animal or cell type</th>
<th align="center" valign="middle" rowspan="1" colspan="1">Model</th>
<th align="center" valign="middle" rowspan="1" colspan="1">Exposure route</th>
<th align="center" valign="middle" rowspan="1" colspan="1">Dose</th>
<th align="center" valign="middle" rowspan="1" colspan="1">Findings</th>
</tr>
</thead>
<tbody>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1">Aluminum</td>
<td align="left" valign="top" rowspan="1" colspan="1">Varlamova et al. 2015</td>
<td align="center" valign="top" rowspan="1" colspan="1">AI2O3</td>
<td align="center" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">M/F BALB/c, CBA/CaLac, out-bred mice and guinea pig</td>
<td align="center" valign="top" rowspan="1" colspan="1">LLNA</td>
<td align="left" valign="top" rowspan="1" colspan="1">Subcutaneous, intramuscular, intravenous, intra-dermal injection</td>
<td align="center" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">No intensification of anaphylaxis systemic reaction, no inflammatory reaction to ConA, no delayed allergic reaction, no redness or edema at site of application</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">Brown et al. 2008</td>
<td align="center" valign="top" rowspan="1" colspan="1">AI2O3</td>
<td align="center" valign="top" rowspan="1" colspan="1">50–120 nm</td>
<td align="left" valign="top" rowspan="1" colspan="1">HaCaT human keratinocytes</td>
<td align="center" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">In vitro</td>
<td align="center" valign="top" rowspan="1" colspan="1">10–10,000 μg/mL</td>
<td align="left" valign="top" rowspan="1" colspan="1">24 h exposure resulted in IL-8 expression, IL-1α release, indicating potential for irritation or sensitization</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1">Cobalt</td>
<td align="left" valign="top" rowspan="1" colspan="1">Choet al. 2012</td>
<td align="center" valign="top" rowspan="1" colspan="1">Co3O4</td>
<td align="center" valign="top" rowspan="1" colspan="1">18.4±5.0nm</td>
<td align="left" valign="top" rowspan="1" colspan="1">F C57BL/6 mouse</td>
<td align="center" valign="top" rowspan="1" colspan="1">OVA</td>
<td align="left" valign="top" rowspan="1" colspan="1">Subcutaneous injection</td>
<td align="center" valign="top" rowspan="1" colspan="1">25 μg</td>
<td align="left" valign="top" rowspan="1" colspan="1">Balanced Th1/Th2 response when used as adjuvant, causing higher specific lgG2c and IgGI and less IgE</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1">Gold</td>
<td align="left" valign="top" rowspan="1" colspan="1">
<xref rid="R178" ref-type="bibr">Ishii et al. 2008</xref>
</td>
<td align="center" valign="top" rowspan="1" colspan="1">Au</td>
<td align="center" valign="top" rowspan="1" colspan="1">5.2±1.3nm</td>
<td align="left" valign="top" rowspan="1" colspan="1">F Japan White Rabbit</td>
<td align="center" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">Intradermal injection</td>
<td align="center" valign="top" rowspan="1" colspan="1">1 mg</td>
<td align="left" valign="top" rowspan="1" colspan="1">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</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1">Iron</td>
<td align="left" valign="top" rowspan="1" colspan="1">
<xref rid="R446" ref-type="bibr">Shen et al. 2012</xref>
</td>
<td align="center" valign="top" rowspan="1" colspan="1">Fe
<sub>3</sub>
O
<sub>4</sub>
</td>
<td align="center" valign="top" rowspan="1" colspan="1">58.7 nm</td>
<td align="left" valign="top" rowspan="1" colspan="1">M BALB/c mouse</td>
<td align="center" valign="top" rowspan="1" colspan="1">OVA</td>
<td align="left" valign="top" rowspan="1" colspan="1">Intravenously</td>
<td align="center" valign="top" rowspan="1" colspan="1">0.2–10 mg/kg</td>
<td align="left" valign="top" rowspan="1" colspan="1">Decreased footpad swelling, infiltration of macro-phages and T-cells, and IFN-y, IL-6, TNF-α levels</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">
<xref rid="R167" ref-type="bibr">Hsiao et al. 2018</xref>
</td>
<td align="center" valign="top" rowspan="1" colspan="1">Fe
<sub>3</sub>
O
<sub>4</sub>
</td>
<td align="center" valign="top" rowspan="1" colspan="1">58.7 nm</td>
<td align="left" valign="top" rowspan="1" colspan="1">M BALB/c mouse</td>
<td align="center" valign="top" rowspan="1" colspan="1">OVA</td>
<td align="left" valign="top" rowspan="1" colspan="1">Intravenously</td>
<td align="center" valign="top" rowspan="1" colspan="1">1–100 μg</td>
<td align="left" valign="top" rowspan="1" colspan="1">Attenuation in TH17 responses</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1">Silica</td>
<td align="left" valign="top" rowspan="1" colspan="1">
<xref rid="R66" ref-type="bibr">Choi et al. 2011</xref>
</td>
<td align="center" valign="top" rowspan="1" colspan="1">SiO
<sub>2</sub>
</td>
<td align="center" valign="top" rowspan="1" colspan="1">7nm</td>
<td align="left" valign="top" rowspan="1" colspan="1">CBA/N mouse</td>
<td align="center" valign="top" rowspan="1" colspan="1">HSEM LLNA</td>
<td align="left" valign="top" rowspan="1" colspan="1">Dermal</td>
<td align="center" valign="top" rowspan="1" colspan="1">10–1,000 μg</td>
<td align="left" valign="top" rowspan="1" colspan="1">SiO
<sub>2</sub>
NP did not induce phototoxicity or skin sensitization</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">
<xref rid="R152" ref-type="bibr">Hirai et al. 2015</xref>
</td>
<td align="center" valign="top" rowspan="1" colspan="1">SiO
<sub>2</sub>
</td>
<td align="center" valign="top" rowspan="1" colspan="1">30 nm</td>
<td align="left" valign="top" rowspan="1" colspan="1">F NC/Nga slc mouse</td>
<td align="center" valign="top" rowspan="1" colspan="1">HDM</td>
<td align="left" valign="top" rowspan="1" colspan="1">Dermal</td>
<td align="center" valign="top" rowspan="1" colspan="1">20 μl @ 12.5mg/mL</td>
<td align="left" valign="top" rowspan="1" colspan="1">Concurrent exposure to allergen and particles resulted in low-level production of allergen-specific IgG subtypes and increased sensitivity to anaphylaxis</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">
<xref rid="R345" ref-type="bibr">Ostrowski et al. 2014</xref>
</td>
<td align="center" valign="top" rowspan="1" colspan="1">SiO
<sub>2</sub>
</td>
<td align="center" valign="top" rowspan="1" colspan="1">55±6nm</td>
<td align="left" valign="top" rowspan="1" colspan="1">M SKH1 mouse</td>
<td align="center" valign="top" rowspan="1" colspan="1">Oxazolone</td>
<td align="left" valign="top" rowspan="1" colspan="1">Dermal</td>
<td align="center" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">Functionalized nanoparticles had no impact on allergic response to oxazolone in an ACD model</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">
<xref rid="R462" ref-type="bibr">Smulders et al. 2015</xref>
</td>
<td align="center" valign="top" rowspan="1" colspan="1">SiO
<sub>2</sub>
</td>
<td align="center" valign="top" rowspan="1" colspan="1">19nm</td>
<td align="left" valign="top" rowspan="1" colspan="1">M BALB/c mouse</td>
<td align="center" valign="top" rowspan="1" colspan="1">DNCB</td>
<td align="left" valign="top" rowspan="1" colspan="1">Dermal</td>
<td align="center" valign="top" rowspan="1" colspan="1">0.4, 4.0, or 40mg/mL×3d</td>
<td align="left" valign="top" rowspan="1" colspan="1">SiO
<sub>2</sub>
NP exposure prior to sensitization with DNCB did not alter the stimulation index</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1">Silver</td>
<td align="left" valign="top" rowspan="1" colspan="1">
<xref rid="R212" ref-type="bibr">Kim et al. 2013</xref>
</td>
<td align="center" valign="top" rowspan="1" colspan="1">Ag</td>
<td align="center" valign="top" rowspan="1" colspan="1">10nm</td>
<td align="left" valign="top" rowspan="1" colspan="1">M SPF guinea pig</td>
<td align="center" valign="top" rowspan="1" colspan="1">GPMT</td>
<td align="left" valign="top" rowspan="1" colspan="1">Intradermal injection</td>
<td align="center" valign="top" rowspan="1" colspan="1">0.1 mL @ 1:1 (v/v)</td>
<td align="left" valign="top" rowspan="1" colspan="1">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</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="center" valign="top" rowspan="1" colspan="1"></td>
<td align="center" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">M New Zealand White rabbit</td>
<td align="center" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">Occular application</td>
<td align="center" valign="top" rowspan="1" colspan="1">100 mg</td>
<td align="left" valign="top" rowspan="1" colspan="1">No eye irritation effects 1–72 hours after exposure</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">Bhol et al. 2005</td>
<td align="center" valign="top" rowspan="1" colspan="1">Ag</td>
<td align="center" valign="top" rowspan="1" colspan="1"><50nm</td>
<td align="left" valign="top" rowspan="1" colspan="1">F BALB/c mouse</td>
<td align="center" valign="top" rowspan="1" colspan="1">DNFB</td>
<td align="left" valign="top" rowspan="1" colspan="1">Dermal</td>
<td align="center" valign="top" rowspan="1" colspan="1">100 mg 1% nanocrystalline</td>
<td align="left" valign="top" rowspan="1" colspan="1">Reductions in ear swelling, erythema, and inflammation were seen after 4 days of treatment with nanopartide-containing cream</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">
<xref rid="R462" ref-type="bibr">Smulders et al. 2015</xref>
</td>
<td align="center" valign="top" rowspan="1" colspan="1">Ag</td>
<td align="center" valign="top" rowspan="1" colspan="1">25–85 nm</td>
<td align="left" valign="top" rowspan="1" colspan="1">M BALB/c mouse</td>
<td align="center" valign="top" rowspan="1" colspan="1">DNCB</td>
<td align="left" valign="top" rowspan="1" colspan="1">Dermal</td>
<td align="center" valign="top" rowspan="1" colspan="1">0.4, 4.0, or 40mg/mLx3d</td>
<td align="left" valign="top" rowspan="1" colspan="1">Exposure prior to sensitization with DNCB did not alter the stimulation index</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">Zelga et al. 2016</td>
<td align="center" valign="top" rowspan="1" colspan="1">Ag</td>
<td align="center" valign="top" rowspan="1" colspan="1">-</td>
<td align="left" valign="top" rowspan="1" colspan="1">Guinea pig</td>
<td align="center" valign="top" rowspan="1" colspan="1">GPMT</td>
<td align="left" valign="top" rowspan="1" colspan="1">Dermal</td>
<td align="center" valign="top" rowspan="1" colspan="1">2%</td>
<td align="left" valign="top" rowspan="1" colspan="1">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</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">
<xref rid="R218" ref-type="bibr">Korani et al. 2011</xref>
</td>
<td align="center" valign="top" rowspan="1" colspan="1">Ag</td>
<td align="center" valign="top" rowspan="1" colspan="1"><100nm</td>
<td align="left" valign="top" rowspan="1" colspan="1">M Harley Albino guinea pig</td>
<td align="center" valign="top" rowspan="1" colspan="1">-</td>
<td align="left" valign="top" rowspan="1" colspan="1">Dermal</td>
<td align="center" valign="top" rowspan="1" colspan="1">100–10,000 μg/ml</td>
<td align="left" valign="top" rowspan="1" colspan="1">Dose-dependent increase in number of Langerhans cells recruited to skin</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1">Titanium</td>
<td align="left" valign="top" rowspan="1" colspan="1">Parket al. 2011</td>
<td align="center" valign="top" rowspan="1" colspan="1">TiO
<sub>2</sub>
</td>
<td align="center" valign="top" rowspan="1" colspan="1"><25nm</td>
<td align="left" valign="top" rowspan="1" colspan="1">F CBA/N mouse</td>
<td align="center" valign="top" rowspan="1" colspan="1">LLNA</td>
<td align="left" valign="top" rowspan="1" colspan="1">Dermal</td>
<td align="center" valign="top" rowspan="1" colspan="1">10–1000 μg/mL</td>
<td align="left" valign="top" rowspan="1" colspan="1">TiO
<sub>2</sub>
did not induce skin sensitization</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="center" valign="top" rowspan="1" colspan="1"></td>
<td align="center" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">F Hartley Albino guinea pig</td>
<td align="center" valign="top" rowspan="1" colspan="1">-</td>
<td align="left" valign="top" rowspan="1" colspan="1">Dermal</td>
<td align="center" valign="top" rowspan="1" colspan="1">50 μg</td>
<td align="left" valign="top" rowspan="1" colspan="1">TiO
<sub>2</sub>
did not induce phototoxicity or acute cutaneous irritation</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">
<xref rid="R173" ref-type="bibr">Hussain et al. 2012</xref>
</td>
<td align="center" valign="top" rowspan="1" colspan="1">TiO
<sub>2</sub>
</td>
<td align="center" valign="top" rowspan="1" colspan="1">12±2nm</td>
<td align="left" valign="top" rowspan="1" colspan="1">M BALB/c mouse</td>
<td align="center" valign="top" rowspan="1" colspan="1">DNCB</td>
<td align="left" valign="top" rowspan="1" colspan="1">Subcutaneous Injection</td>
<td align="center" valign="top" rowspan="1" colspan="1">0.004–0.4 mg/mL</td>
<td align="left" valign="top" rowspan="1" colspan="1">TH2 adjuvancy, increased DNCB dermal sensitizer potency</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">
<xref rid="R22" ref-type="bibr">Auttachoat et al. 2014</xref>
</td>
<td align="center" valign="top" rowspan="1" colspan="1">TiO
<sub>2</sub>
</td>
<td align="center" valign="top" rowspan="1" colspan="1"><25nm</td>
<td align="left" valign="top" rowspan="1" colspan="1">F BCC3F1 mouse</td>
<td align="center" valign="top" rowspan="1" colspan="1">-</td>
<td align="left" valign="top" rowspan="1" colspan="1">Dermal, Subcutaneous Injection</td>
<td align="center" valign="top" rowspan="1" colspan="1">1.25–250 mg/kg</td>
<td align="left" valign="top" rowspan="1" colspan="1">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</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">
<xref rid="R462" ref-type="bibr">Smulders et al. 2015</xref>
</td>
<td align="center" valign="top" rowspan="1" colspan="1">TiO
<sub>2</sub>
</td>
<td align="center" valign="top" rowspan="1" colspan="1">15nm</td>
<td align="left" valign="top" rowspan="1" colspan="1">M BALB/c mouse</td>
<td align="center" valign="top" rowspan="1" colspan="1">DNCB</td>
<td align="left" valign="top" rowspan="1" colspan="1">Dermal</td>
<td align="center" valign="top" rowspan="1" colspan="1">0.4, 4.0, or 40mg/mL×3d</td>
<td align="left" valign="top" rowspan="1" colspan="1">Exposure to 4.0 mg/mL of TiO
<sub>2</sub>
prior to sensitiza-tion with DNCB resulted in increased stimulation index</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">
<xref rid="R375" ref-type="bibr">Piasecka-Zelga et al. 2015</xref>
</td>
<td align="center" valign="top" rowspan="1" colspan="1">TiO
<sub>2</sub>
</td>
<td align="center" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">New Zealand albino rabbit</td>
<td align="center" valign="top" rowspan="1" colspan="1">Acute Dermal Irritation</td>
<td align="left" valign="top" rowspan="1" colspan="1">Dermal</td>
<td align="center" valign="top" rowspan="1" colspan="1">0.5 g</td>
<td align="left" valign="top" rowspan="1" colspan="1">5 UV-absorbers containing nano-sized particles were assessed for irritation and sensitization potential. Anatase Ti0
<sub>2</sub>
-containing agent did not induce irritation, but caused mild sensitization</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="center" valign="top" rowspan="1" colspan="1"></td>
<td align="center" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">Dunkin-Hartley guinea pig</td>
<td align="center" valign="top" rowspan="1" colspan="1">GPMT</td>
<td align="left" valign="top" rowspan="1" colspan="1">Dermal</td>
<td align="center" valign="top" rowspan="1" colspan="1">0.1 mL/site</td>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1">Zinc</td>
<td align="left" valign="top" rowspan="1" colspan="1">
<xref rid="R375" ref-type="bibr">Piasecka-Zelga et al. 2015</xref>
</td>
<td align="center" valign="top" rowspan="1" colspan="1">ZnO</td>
<td align="center" valign="top" rowspan="1" colspan="1">APS 396 nm, containing nanoparticles</td>
<td align="left" valign="top" rowspan="1" colspan="1">New Zealand albino rabbit</td>
<td align="center" valign="top" rowspan="1" colspan="1">Acute Dermal Irritation</td>
<td align="left" valign="top" rowspan="1" colspan="1">Dermal</td>
<td align="center" valign="top" rowspan="1" colspan="1">0.5 g</td>
<td align="left" valign="top" rowspan="1" colspan="1">5 UV-absorbers containing nano-sized particles were assessed for irritation and sensitization potential. Z11 modifier caused minor dermal irritation and mild sensitization</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="center" valign="top" rowspan="1" colspan="1"></td>
<td align="center" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">Dunkin-Hartley guinea pig</td>
<td align="center" valign="top" rowspan="1" colspan="1">GPMT</td>
<td align="left" valign="top" rowspan="1" colspan="1">Dermal</td>
<td align="center" valign="top" rowspan="1" colspan="1">0.1 mL/site</td>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">
<xref rid="R208" ref-type="bibr">Kim et al. 2016</xref>
</td>
<td align="center" valign="top" rowspan="1" colspan="1">ZnO</td>
<td align="center" valign="top" rowspan="1" colspan="1">20–50 nm, 13.1 m
<sup>2</sup>
/g</td>
<td align="left" valign="top" rowspan="1" colspan="1">M Sprague-Dawley Rat, M New Zealand White rabbit, M guinea pig</td>
<td align="center" valign="top" rowspan="1" colspan="1">GPMT</td>
<td align="left" valign="top" rowspan="1" colspan="1">Dermal</td>
<td align="center" valign="top" rowspan="1" colspan="1">50%</td>
<td align="left" valign="top" rowspan="1" colspan="1">ZnONP did not induce dermal sensitization, acute dermal toxicity, irritation, or corrosion</td>
</tr>
</tbody>
</table>
<table-wrap-foot>
<fn id="TFN2">
<p id="P133">Summary of studies investigating metal nanomaterial immune effects in the skin and select
<italic>in vitro</italic>
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.</p>
</fn>
</table-wrap-foot>
</table-wrap>
<table-wrap id="T3" position="float" orientation="landscape">
<label>Table 3.</label>
<caption>
<p id="P134">Summary of major findings from studies comparing the effects of various physicochemical properties of metal nanomaterials on dermal allergy grouped by property of interest.</p>
</caption>
<table frame="hsides" rules="groups">
<colgroup span="1">
<col align="left" valign="middle" span="1"></col>
<col align="left" valign="middle" span="1"></col>
<col align="left" valign="middle" span="1"></col>
<col align="left" valign="middle" span="1"></col>
<col align="left" valign="middle" span="1"></col>
<col align="left" valign="middle" span="1"></col>
</colgroup>
<thead>
<tr>
<th align="left" valign="middle" rowspan="1" colspan="1">Property investigated</th>
<th align="center" valign="middle" rowspan="1" colspan="1">Author/year</th>
<th align="center" valign="middle" rowspan="1" colspan="1">Metal</th>
<th align="center" valign="middle" rowspan="1" colspan="1">Study design</th>
<th align="center" valign="middle" rowspan="1" colspan="1">Property variations</th>
<th align="center" valign="middle" rowspan="1" colspan="1">Findings</th>
</tr>
</thead>
<tbody>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1">Size</td>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">
<xref rid="R199" ref-type="bibr">Kang H et al. 2017</xref>
</td>
<td align="left" valign="top" rowspan="1" colspan="1">Ag</td>
<td align="left" valign="top" rowspan="1" colspan="1">RBL-2H3 mast cells F NC/Nga mouse, HDM AD: 40 ng</td>
<td align="left" valign="top" rowspan="1" colspan="1">5, 100 nm AgNP</td>
<td align="left" valign="top" rowspan="1" colspan="1">5 nm AgNP induced increases in ROS levels, intracellular calcium, and granule release in mast cells
<italic>in vitro</italic>
and earlier and more severe lesions in an AD model
<italic>in vivo</italic>
</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">
<xref rid="R319" ref-type="bibr">Nabeshi et al. 2010</xref>
</td>
<td align="left" valign="top" rowspan="1" colspan="1">Si</td>
<td align="left" valign="top" rowspan="1" colspan="1">XS52 mouse epidermal Langerhans cell, 0.1–1000 ug/mL</td>
<td align="left" valign="top" rowspan="1" colspan="1">70, 300, 1000 nm SiNP</td>
<td align="left" valign="top" rowspan="1" colspan="1">Cellular uptake and cytotoxicity increased with reductions in particle size</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">Yoshida et al. 2010</td>
<td align="left" valign="top" rowspan="1" colspan="1">Si</td>
<td align="left" valign="top" rowspan="1" colspan="1">XS52 mouse epidermal Langerhans cell, 0–100 μg/mL</td>
<td align="left" valign="top" rowspan="1" colspan="1">70, 300, 1000 nm SiNP</td>
<td align="left" valign="top" rowspan="1" colspan="1">ROS generation by LC was higher following exposure to the smaller amorphous SiNP</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">
<xref rid="R150" ref-type="bibr">Hirai et al. 2012b</xref>
</td>
<td align="left" valign="top" rowspan="1" colspan="1">Si</td>
<td align="left" valign="top" rowspan="1" colspan="1">M NC/Nga mouse HDM ACD Intradermal injection: 250 μg</td>
<td align="left" valign="top" rowspan="1" colspan="1">1136nm SiO
<sub>2</sub>
NP: 33.2 mV, 264 nm SiO
<sub>2</sub>
NP: 25.8 mV, 106 nm SiO
<sub>2</sub>
NP: 24.3 mV, 76 nm SiO
<sub>2</sub>
NP: 19.5 mV, 39 nm SiO
<sub>2</sub>
NP: 14.0mV</td>
<td align="left" valign="top" rowspan="1" colspan="1">Reduction in size of SiO
<sub>2</sub>
NPs 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</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">
<xref rid="R197" ref-type="bibr">Kang S et al. 2017b</xref>
</td>
<td align="left" valign="top" rowspan="1" colspan="1">Au</td>
<td align="left" valign="top" rowspan="1" colspan="1">Mouse footpad injection OVA</td>
<td align="left" valign="top" rowspan="1" colspan="1">7, 14, 28 nm AuNP</td>
<td align="left" valign="top" rowspan="1" colspan="1">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</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">
<xref rid="R522" ref-type="bibr">Yanagisawa et al. 2009</xref>
</td>
<td align="left" valign="top" rowspan="1" colspan="1">Ti</td>
<td align="left" valign="top" rowspan="1" colspan="1">M NC/Nga mouse HDM Intradermal injection: 20 μg</td>
<td align="left" valign="top" rowspan="1" colspan="1">15 nm TiO
<sub>2</sub>
NP-110 m
<sup>2</sup>
/g 50 nm TiO
<sub>2</sub>
NP-20–25 m
<sup>2</sup>
/g 100 nm TiO
<sub>2</sub>
NP-10–15 m
<sup>2</sup>
/g</td>
<td align="left" valign="top" rowspan="1" colspan="1">TiO
<sub>2</sub>
NP 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</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">lives et al. 2014</td>
<td align="left" valign="top" rowspan="1" colspan="1">Zn</td>
<td align="left" valign="top" rowspan="1" colspan="1">F BALB/c mice, OVA ACD Dermal application: 16.67 mg/mL</td>
<td align="left" valign="top" rowspan="1" colspan="1">20, 240 nm ZnONP</td>
<td align="left" valign="top" rowspan="1" colspan="1">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</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">CRG</td>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">
<xref rid="R181" ref-type="bibr">Jang et al. 2012</xref>
</td>
<td align="left" valign="top" rowspan="1" colspan="1">Zn</td>
<td align="left" valign="top" rowspan="1" colspan="1">CBA/N Mouse LLNA: 25, 50, or 100 μg/mL ZnONP HSEM EpiDerm skin irritation Draize skin irritation: 50 μg/mL</td>
<td align="left" valign="top" rowspan="1" colspan="1">20 nm, 29 mV or 40 mV ZnONP 100 nm, 24 mV or 29 mV ZnONP</td>
<td align="left" valign="top" rowspan="1" colspan="1">ZnO are not dermal sensitizers and do not induce skin irritation irrespective of size and zeta potential, but may induce phototoxicity</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">
<xref rid="R184" ref-type="bibr">Jatana et al 2017b</xref>
</td>
<td align="left" valign="top" rowspan="1" colspan="1">Si</td>
<td align="left" valign="top" rowspan="1" colspan="1">M/F hairless C57BL6 mouse DNFB ACD Dermal application</td>
<td align="left" valign="top" rowspan="1" colspan="1">32.7 nm SiO
<sub>2</sub>
nanosphere: 25.4 mV 66.5 nm SiO
<sub>2</sub>
nanosphere: 45.7 mV 69.3 nm SiO
<sub>2</sub>
nanosphere: 17.7mV 184.9 SiO
<sub>2</sub>
nanosphere: 33.5 mV 440.0 nm SiO
<sub>2</sub>
nanosphere: 66.0 mV</td>
<td align="left" valign="top" rowspan="1" colspan="1">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 TiO
<sub>2</sub>
NP, 20 nm AgNP, and 20 nm AuNP</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">Schaeub
<xref rid="R252" ref-type="bibr">lin et al. 2010</xref>
</td>
<td align="left" valign="top" rowspan="1" colspan="1">Au</td>
<td align="left" valign="top" rowspan="1" colspan="1">HaCaT human keratinocyte cells 10 μg/mL–25 μg/mL</td>
<td align="left" valign="top" rowspan="1" colspan="1">1.5 nm AuNP Positive, neutral, or negatively-charged</td>
<td align="left" valign="top" rowspan="1" colspan="1">Cell morphology was disrupted by AuNPs of all 3 charges in a dose-dependent manner. Charged AuNPs caused dose-dependent cytotoxicity and mitochondrial stress</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">CRY</td>
<td align="left" valign="top" rowspan="1" colspan="1">SA</td>
<td align="left" valign="top" rowspan="1" colspan="1">
<xref rid="R242" ref-type="bibr">Lee et al. 2011</xref>
</td>
<td align="left" valign="top" rowspan="1" colspan="1">Si</td>
<td align="left" valign="top" rowspan="1" colspan="1">J774A.1 mouse macrophages: 0–1,000 ug/mL, 1 or 3 d LLNA: F BALB/c, 1 mg/ ear × 3 tx</td>
<td align="left" valign="top" rowspan="1" colspan="1">100 nm spherical: mesoporous SiO
<sub>2</sub>
1150 m
<sup>2</sup>
/g colloidal SiO
<sub>2</sub>
-40 m
<sup>2</sup>
/g</td>
<td align="left" valign="top" rowspan="1" colspan="1">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</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1">Size</td>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">
<xref rid="R281" ref-type="bibr">Maquieira et al. 2012</xref>
</td>
<td align="left" valign="top" rowspan="1" colspan="1">Al</td>
<td align="left" valign="top" rowspan="1" colspan="1">Mice and rabbits Intradermal injection</td>
<td align="left" valign="top" rowspan="1" colspan="1">40, 3000 nm amorphous AI
<sub>2</sub>
O
<sub>3</sub>
, 300 nm crystalline AI
<sub>2</sub>
O
<sub>3</sub>
</td>
<td align="left" valign="top" rowspan="1" colspan="1">AINP served as both carrier and adjuvant leading to hapten-specific antibody production dependent on size and crystallinity</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">
<xref rid="R47" ref-type="bibr">Braydich-Stolle et al. 2009</xref>
</td>
<td align="left" valign="top" rowspan="1" colspan="1">Ti</td>
<td align="left" valign="top" rowspan="1" colspan="1">HEL-30 mouse keratinocytes 0–150 μg/mL 24 h exposure</td>
<td align="left" valign="top" rowspan="1" colspan="1">100% anatase TiO
<sub>2</sub>
: 6.3, 10, 40, 50, 100 nm 61% anatase, 39% rutile TiO
<sub>2</sub>
: 39 nm 40% anatase, 60% rutile TiO
<sub>2</sub>
: 39 nm 75% anatase, 25% rutile TiO
<sub>2</sub>
: 26 nm Amorphous TiO
<sub>2</sub>
: 40 nm 100% rutile TiO
<sub>2</sub>
: 51 nm</td>
<td align="left" valign="top" rowspan="1" colspan="1">Both size and crystal structure contributed to toxicity in vitro. Smaller size and less agglomeration increased cytotoxicity. 100% anatase TiO
<sub>2</sub>
particles, regardless of size, induced cell necrosis, whereas the rutile TiO
<sub>2</sub>
nanoparticles initiated apop-tosis through formation of ROS</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">MOD</td>
<td align="left" valign="top" rowspan="1" colspan="1">Orlowski et al. 2013</td>
<td align="left" valign="top" rowspan="1" colspan="1">Ag</td>
<td align="left" valign="top" rowspan="1" colspan="1">291.03C mouse keratinocyte 1–10 μg/mL 24 h exposure</td>
<td align="left" valign="top" rowspan="1" colspan="1">Tannic acid-modified AgNP: 13, 33, and 46 nm Unmodified AgNP: 10 −65 nm</td>
<td align="left" valign="top" rowspan="1" colspan="1">Unmodified, but not modified, AgNP increased production of MCP-1 by keratinocytes and upregulation of TNF-α, attributable to increased ROS production</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">Li et al. 2016</td>
<td align="left" valign="top" rowspan="1" colspan="1">Si</td>
<td align="left" valign="top" rowspan="1" colspan="1">F C57BL/6 mouse 5mg injection</td>
<td align="left" valign="top" rowspan="1" colspan="1">Unmodified mesoporous SiNP PEG, PEG-RGD, PEG-RDG- modified SiNP</td>
<td align="left" valign="top" rowspan="1" colspan="1">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</td>
</tr>
</tbody>
</table>
<table-wrap-foot>
<fn id="TFN3">
<p id="P135">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.</p>
</fn>
</table-wrap-foot>
</table-wrap>
<table-wrap id="T4" position="float" orientation="landscape">
<label>Table 4.</label>
<caption>
<p id="P136">Metal nanomaterials and corresponding physicochemical properties shown to influence immunological processes involved in the development and augmentation of ACD.</p>
</caption>
<table frame="hsides" rules="groups">
<colgroup span="1">
<col align="left" valign="middle" span="1"></col>
<col align="left" valign="middle" span="1"></col>
<col align="left" valign="middle" span="1"></col>
<col align="left" valign="middle" span="1"></col>
<col align="left" valign="middle" span="1"></col>
</colgroup>
<thead>
<tr>
<th align="left" valign="bottom" rowspan="1" colspan="1">AOP Step</th>
<th align="left" valign="bottom" rowspan="1" colspan="1">Metal nanomaterial effect</th>
<th align="left" valign="bottom" rowspan="1" colspan="1">Metal</th>
<th align="left" valign="bottom" rowspan="1" colspan="1">Properties implicated</th>
<th align="left" valign="bottom" rowspan="1" colspan="1">Source</th>
</tr>
</thead>
<tbody>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1">Sensitization Bioavailability</td>
<td align="left" valign="top" rowspan="1" colspan="1">Increased potential for nanomaterial penetration of intact skin</td>
<td align="left" valign="top" rowspan="1" colspan="1">Au</td>
<td align="left" valign="top" rowspan="1" colspan="1">size, crg</td>
<td align="left" valign="top" rowspan="1" colspan="1">
<xref rid="R224" ref-type="bibr">Labouta et al. 2011</xref>
</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">Increased potential for nanomaterial penetration of damaged skin</td>
<td align="left" valign="top" rowspan="1" colspan="1">Ti</td>
<td align="left" valign="top" rowspan="1" colspan="1">size, cry</td>
<td align="left" valign="top" rowspan="1" colspan="1">
<xref rid="R306" ref-type="bibr">Monteiro-Riviere et al. 2011</xref>
</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">Increased release of ions from parent nanomaterials</td>
<td align="left" valign="top" rowspan="1" colspan="1">Pd</td>
<td align="left" valign="top" rowspan="1" colspan="1">size</td>
<td align="left" valign="top" rowspan="1" colspan="1">
<xref rid="R114" ref-type="bibr">Filon et al. 2016</xref>
</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">Accumulation of nanomaterial in follicles and skin folds</td>
<td align="left" valign="top" rowspan="1" colspan="1">Zn</td>
<td align="left" valign="top" rowspan="1" colspan="1">mod</td>
<td align="left" valign="top" rowspan="1" colspan="1">
<xref rid="R244" ref-type="bibr">Leite-Silva et al. 2013</xref>
</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1">Molecular initating event</td>
<td align="left" valign="top" rowspan="1" colspan="1">Increased potential for metal antigen formation</td>
<td align="left" valign="top" rowspan="1" colspan="1">Ti</td>
<td align="left" valign="top" rowspan="1" colspan="1">size</td>
<td align="left" valign="top" rowspan="1" colspan="1">
<xref rid="R492" ref-type="bibr">Vamanu et al. 2008</xref>
</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">Adsorbed protein conformational changes</td>
<td align="left" valign="top" rowspan="1" colspan="1">Au</td>
<td align="left" valign="top" rowspan="1" colspan="1">size</td>
<td align="left" valign="top" rowspan="1" colspan="1">Bastus et al. 2009</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1">Cellular response</td>
<td align="left" valign="top" rowspan="1" colspan="1">Selective uptake by LC</td>
<td align="left" valign="top" rowspan="1" colspan="1">Si</td>
<td align="left" valign="top" rowspan="1" colspan="1">size</td>
<td align="left" valign="top" rowspan="1" colspan="1">
<xref rid="R319" ref-type="bibr">Nabeshi et al. 2010</xref>
</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">Direct activation of DC</td>
<td align="left" valign="top" rowspan="1" colspan="1">Ti</td>
<td align="left" valign="top" rowspan="1" colspan="1">size, cry, mor</td>
<td align="left" valign="top" rowspan="1" colspan="1">Schanen et al. 2009</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">Release of DAMPs from skin epithelial cells > activation of DC</td>
<td align="left" valign="top" rowspan="1" colspan="1">Fe</td>
<td align="left" valign="top" rowspan="1" colspan="1">size</td>
<td align="left" valign="top" rowspan="1" colspan="1">
<xref rid="R317" ref-type="bibr">Murray et al. 2013</xref>
</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">Release of DAMPs from dermal immune cells > activation of DC</td>
<td align="left" valign="top" rowspan="1" colspan="1">Si</td>
<td align="left" valign="top" rowspan="1" colspan="1">size, SA</td>
<td align="left" valign="top" rowspan="1" colspan="1">
<xref rid="R242" ref-type="bibr">Lee et al. 2011</xref>
</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">Altered immunogenicity from adsorption of LPS to surface</td>
<td align="left" valign="top" rowspan="1" colspan="1">Au</td>
<td align="left" valign="top" rowspan="1" colspan="1">size, mod, hyd</td>
<td align="left" valign="top" rowspan="1" colspan="1">
<xref rid="R248" ref-type="bibr">Li et al. 2017</xref>
</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1">Organ response</td>
<td align="left" valign="top" rowspan="1" colspan="1">Depot formation > altered delivery kinetics</td>
<td align="left" valign="top" rowspan="1" colspan="1">Si</td>
<td align="left" valign="top" rowspan="1" colspan="1">agg</td>
<td align="left" valign="top" rowspan="1" colspan="1">
<xref rid="R152" ref-type="bibr">Hirai et al. 2015</xref>
</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">Nanomaterial antigen vehicle > altered delivery kinetics</td>
<td align="left" valign="top" rowspan="1" colspan="1">Ti</td>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">
<xref rid="R462" ref-type="bibr">Smulders et al. 2015</xref>
</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">Accumulation in DC endocytic compartments > interference with antigen processing</td>
<td align="left" valign="top" rowspan="1" colspan="1">Si</td>
<td align="left" valign="top" rowspan="1" colspan="1">mod, crg</td>
<td align="left" valign="top" rowspan="1" colspan="1">
<xref rid="R436" ref-type="bibr">Shahbazi et al. 2014</xref>
</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">Enhanced capacity for cross-presentation to CD8+ T-cells</td>
<td align="left" valign="top" rowspan="1" colspan="1">Fe</td>
<td align="left" valign="top" rowspan="1" colspan="1">crg</td>
<td align="left" valign="top" rowspan="1" colspan="1">
<xref rid="R311" ref-type="bibr">Mou et al. 2017</xref>
</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">Increased TH1 signaling</td>
<td align="left" valign="top" rowspan="1" colspan="1">Co</td>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">Cho et al. 2012</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1">Elicitation Organism response</td>
<td align="left" valign="top" rowspan="1" colspan="1">Increased permeability of endothelial cells</td>
<td align="left" valign="top" rowspan="1" colspan="1">Al</td>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">Oesterling et al. 2008</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">Increased effector T-cell recruitment</td>
<td align="left" valign="top" rowspan="1" colspan="1">many</td>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">Lozano-Fernandez et al. 2014</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">Increased number of DC for T-cell activation</td>
<td align="left" valign="top" rowspan="1" colspan="1">Si</td>
<td align="left" valign="top" rowspan="1" colspan="1">mod</td>
<td align="left" valign="top" rowspan="1" colspan="1">Li et al. 2016</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">Increased number of skin macrophages</td>
<td align="left" valign="top" rowspan="1" colspan="1">Fe</td>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">Yun et al. 2015</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">Increased neutrophil influx to the skin</td>
<td align="left" valign="top" rowspan="1" colspan="1">Ti</td>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">Goncalves, 2011</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">Increased number of skin mast cells</td>
<td align="left" valign="top" rowspan="1" colspan="1">Ag</td>
<td align="left" valign="top" rowspan="1" colspan="1">size</td>
<td align="left" valign="top" rowspan="1" colspan="1">Kang H et al. 2017</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">Altered T-cell response to mitogens/allergens</td>
<td align="left" valign="top" rowspan="1" colspan="1">Pd</td>
<td align="left" valign="top" rowspan="1" colspan="1">size, sol</td>
<td align="left" valign="top" rowspan="1" colspan="1">
<xref rid="R395" ref-type="bibr">Reale et al. 2011</xref>
</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">Increased IgE-independent mast cell degranulation</td>
<td align="left" valign="top" rowspan="1" colspan="1">many</td>
<td align="left" valign="top" rowspan="1" colspan="1">size, SA, crg</td>
<td align="left" valign="top" rowspan="1" colspan="1">
<xref rid="R191" ref-type="bibr">Johnson et al. 2017</xref>
</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1">Chronic effects</td>
<td align="left" valign="top" rowspan="1" colspan="1">Compromised skin repair mechanisms</td>
<td align="left" valign="top" rowspan="1" colspan="1">Ag</td>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">Vieira et al. 2017</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">Aggravation of allergic lesion severity</td>
<td align="left" valign="top" rowspan="1" colspan="1">Si</td>
<td align="left" valign="top" rowspan="1" colspan="1">size</td>
<td align="left" valign="top" rowspan="1" colspan="1">
<xref rid="R150" ref-type="bibr">Hirai et al. 2012b</xref>
</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">Compromised barrier integrity > increased penetration of allergens</td>
<td align="left" valign="top" rowspan="1" colspan="1">Ag</td>
<td align="left" valign="top" rowspan="1" colspan="1">size, sol</td>
<td align="left" valign="top" rowspan="1" colspan="1">Koohi et al. 2011</td>
</tr>
</tbody>
</table>
<table-wrap-foot>
<fn id="TFN4">
<p id="P137">Adverse Outcome Pathway (AOP) steps in the sensitization and elicitation phases of allergic contact dermatitis, metal nanomaterials shown to impact individual steps and cells involved, and physicochemical properties associated with effects are shown. Physicochemical properties of interest include size, agglomeration (agg), surface modification (mod), surface area (SA), solubility (sol), surface charge (crg), morphology (mor), crystallinity (cry), hydrophobicity (hyd), surface chemistry (SC). 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.</p>
</fn>
</table-wrap-foot>
</table-wrap>
<table-wrap id="T5" position="float" orientation="landscape">
<label>Table 5.</label>
<caption>
<p id="P138">Summary of major findings from studies characterizing the effect of metal nanomaterials on respiratory allergy grouped by metal.</p>
</caption>
<table frame="hsides" rules="groups">
<colgroup span="1">
<col align="left" valign="middle" span="1"></col>
<col align="left" valign="middle" span="1"></col>
<col align="left" valign="middle" span="1"></col>
<col align="left" valign="middle" span="1"></col>
<col align="left" valign="middle" span="1"></col>
<col align="left" valign="middle" span="1"></col>
<col align="left" valign="middle" span="1"></col>
<col align="left" valign="middle" span="1"></col>
<col align="left" valign="middle" span="1"></col>
</colgroup>
<thead>
<tr>
<th align="left" valign="middle" rowspan="1" colspan="1">Metal</th>
<th align="center" valign="middle" rowspan="1" colspan="1">Author/year</th>
<th align="left" valign="middle" rowspan="1" colspan="1">Material</th>
<th align="center" valign="middle" rowspan="1" colspan="1">Size</th>
<th align="left" valign="middle" rowspan="1" colspan="1">Animal or cell type</th>
<th align="left" valign="middle" rowspan="1" colspan="1">Mode</th>
<th align="center" valign="middle" rowspan="1" colspan="1">Exposure route</th>
<th align="center" valign="middle" rowspan="1" colspan="1">Dose</th>
<th align="center" valign="middle" rowspan="1" colspan="1">Findings</th>
</tr>
</thead>
<tbody>
<tr>
<td rowspan="2" align="left" valign="top" colspan="1">Aluminum</td>
<td rowspan="2" align="left" valign="top" colspan="1">
<xref rid="R48" ref-type="bibr">Braydich-Stolle et al. 2010</xref>
</td>
<td align="center" valign="top" rowspan="1" colspan="1">Al</td>
<td align="center" valign="top" rowspan="1" colspan="1">48.08±21.0 nm</td>
<td rowspan="2" align="left" valign="top" colspan="1">Human A549 type ∥ pneumocyte U937 alveolar macrophage
<break></break>
3:1 co-culture</td>
<td rowspan="2" align="left" valign="top" colspan="1"></td>
<td rowspan="2" align="left" valign="top" colspan="1">
<italic>In vitro</italic>
</td>
<td rowspan="2" align="left" valign="top" colspan="1">5–500 μg/mL 24 h</td>
<td align="left" valign="top" rowspan="1" colspan="1">Exposure impaired bacterial phagocytic function</td>
</tr>
<tr>
<td align="center" valign="top" rowspan="1" colspan="1">AI
<sub>2</sub>
O
<sub>3</sub>
</td>
<td align="center" valign="top" rowspan="1" colspan="1">32.71 ± 28.3 nm</td>
<td align="left" valign="top" rowspan="1" colspan="1">Exposure impaired bacterial phagocytic function, induction of NFκB pathway</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1">Cerium</td>
<td align="left" valign="top" rowspan="1" colspan="1">Park E-J et al. 2009</td>
<td align="center" valign="top" rowspan="1" colspan="1">CeO
<sub>2</sub>
</td>
<td align="center" valign="top" rowspan="1" colspan="1">130 nm</td>
<td align="left" valign="top" rowspan="1" colspan="1">M ICR mouse</td>
<td align="left" valign="top" rowspan="1" colspan="1">-</td>
<td align="left" valign="top" rowspan="1" colspan="1">Intratracheal Instillation</td>
<td align="left" valign="top" rowspan="1" colspan="1">50, 100, 200, 400 mg/kg</td>
<td align="left" valign="top" rowspan="1" colspan="1">Differentiation of naive T-cells and TH1 cytokine production</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">
<xref rid="R294" ref-type="bibr">Meldrum et al. 2018</xref>
</td>
<td align="center" valign="top" rowspan="1" colspan="1">CeO
<sub>2</sub>
</td>
<td align="center" valign="top" rowspan="1" colspan="1"><25nm APS 166.5 nm agglomerates</td>
<td align="left" valign="top" rowspan="1" colspan="1">F BALB/c mouse</td>
<td align="left" valign="top" rowspan="1" colspan="1">HDM</td>
<td align="left" valign="top" rowspan="1" colspan="1">Intranasal Instillation</td>
<td align="left" valign="top" rowspan="1" colspan="1">75 or 750 μg/kg</td>
<td align="left" valign="top" rowspan="1" colspan="1">Repeated exposure to CeO
<sub>2</sub>
NP in the presence of HDM caused increased lung eosinophils, mast cells, plasma IgE, IL-4, and goblet cell metaplasia</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1">Cobalt</td>
<td align="left" valign="top" rowspan="1" colspan="1">Cho et al. 2012</td>
<td align="center" valign="top" rowspan="1" colspan="1">Co
<sub>3</sub>
O
<sub>4</sub>
</td>
<td align="center" valign="top" rowspan="1" colspan="1">18.4± 5.0 nm</td>
<td align="left" valign="top" rowspan="1" colspan="1">F Wistar rat</td>
<td align="left" valign="top" rowspan="1" colspan="1">-</td>
<td align="left" valign="top" rowspan="1" colspan="1">Intratracheal
<break></break>
Instillation</td>
<td align="left" valign="top" rowspan="1" colspan="1">150 cm
<sup>2</sup>
SA</td>
<td align="left" valign="top" rowspan="1" colspan="1">Exposure caused pulmonary alveolar proteinosis and TH1/TH17 dominant response</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">Verstaelen et al. 2014</td>
<td align="center" valign="top" rowspan="1" colspan="1">CoO</td>
<td align="center" valign="top" rowspan="1" colspan="1">7.1 nm</td>
<td align="left" valign="top" rowspan="1" colspan="1">BEAS-2B, A549 epithelial cells</td>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">
<italic>In vitro</italic>
</td>
<td align="left" valign="top" rowspan="1" colspan="1">1–60 μg/mL</td>
<td align="left" valign="top" rowspan="1" colspan="1">Alterations in expression of genes associated with innate immunity, T-cell activation, and leukocyte adhesion</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1">Copper</td>
<td align="left" valign="top" rowspan="1" colspan="1">Cho et al. 2012</td>
<td align="center" valign="top" rowspan="1" colspan="1">CuO</td>
<td align="center" valign="top" rowspan="1" colspan="1">23.1 ± 7.2 nm</td>
<td align="left" valign="top" rowspan="1" colspan="1">F Wistar rat</td>
<td align="left" valign="top" rowspan="1" colspan="1">-</td>
<td align="left" valign="top" rowspan="1" colspan="1">Intratracheal
<break></break>
Instillation</td>
<td align="left" valign="top" rowspan="1" colspan="1">150 cm
<sup>2</sup>
SA</td>
<td align="left" valign="top" rowspan="1" colspan="1">No immunoinflammatory reaction</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">
<xref rid="R361" ref-type="bibr">Park et al. 2015</xref>
</td>
<td align="center" valign="top" rowspan="1" colspan="1">CuO</td>
<td align="center" valign="top" rowspan="1" colspan="1"><50 nm</td>
<td align="left" valign="top" rowspan="1" colspan="1">F BALB/c mouse</td>
<td align="left" valign="top" rowspan="1" colspan="1">OVA</td>
<td align="left" valign="top" rowspan="1" colspan="1">Intranasal Instillation</td>
<td align="left" valign="top" rowspan="1" colspan="1">25, 50, 100 μg/kg</td>
<td align="left" valign="top" rowspan="1" colspan="1">Increased AHR, IgE and mucus production</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">Lai et al. 2018</td>
<td align="center" valign="top" rowspan="1" colspan="1">CuO</td>
<td align="center" valign="top" rowspan="1" colspan="1">46.5 nm</td>
<td align="left" valign="top" rowspan="1" colspan="1">C57BL/6 mouse</td>
<td align="left" valign="top" rowspan="1" colspan="1">-</td>
<td align="left" valign="top" rowspan="1" colspan="1">Intranasal delivery</td>
<td align="left" valign="top" rowspan="1" colspan="1">1, 2.5, 5, 10 mg/kg</td>
<td align="left" valign="top" rowspan="1" colspan="1">Aggravated pulmonary inflammation, collagen accumulation and expression of progressive fibrosis markers in lungs</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1">Iron</td>
<td align="left" valign="top" rowspan="1" colspan="1">
<xref rid="R361" ref-type="bibr">Park et al. 2015</xref>
</td>
<td align="center" valign="top" rowspan="1" colspan="1">Fe
<sub>2</sub>
O
<sub>3</sub>
</td>
<td align="center" valign="top" rowspan="1" colspan="1">1013 ± 4.2 nm</td>
<td align="left" valign="top" rowspan="1" colspan="1">M ICR mouse</td>
<td align="left" valign="top" rowspan="1" colspan="1">-</td>
<td align="left" valign="top" rowspan="1" colspan="1">Intratracheal instillation</td>
<td align="left" valign="top" rowspan="1" colspan="1">0.5, 1, or 2 mg/kg</td>
<td align="left" valign="top" rowspan="1" colspan="1">TH1-polarized inflammatory response, GM-CSF, MCP-1, and MIP-1 increase, and increased expression of CD80, CD86, and MHC II expression on lung APCs</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">
<xref rid="R354" ref-type="bibr">Park et al 2010c</xref>
</td>
<td align="center" valign="top" rowspan="1" colspan="1">Fe
<sub>3</sub>
O
<sub>4</sub>
</td>
<td align="center" valign="top" rowspan="1" colspan="1">5.3 + 3.6 nm</td>
<td align="left" valign="top" rowspan="1" colspan="1">M ICR mouse</td>
<td align="left" valign="top" rowspan="1" colspan="1">-</td>
<td align="left" valign="top" rowspan="1" colspan="1">Intratracheal instillation</td>
<td align="left" valign="top" rowspan="1" colspan="1">250, 500, 1,000 μg/kg</td>
<td align="left" valign="top" rowspan="1" colspan="1">Increases in TH1/TH2 cytokines, B cells, and IgE levels</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1">Gold</td>
<td align="left" valign="top" rowspan="1" colspan="1">
<xref rid="R174" ref-type="bibr">Hussain et al. 2011</xref>
</td>
<td align="center" valign="top" rowspan="1" colspan="1">Au</td>
<td align="center" valign="top" rowspan="1" colspan="1">40 nm</td>
<td align="left" valign="top" rowspan="1" colspan="1">M BALB/c mouse</td>
<td align="left" valign="top" rowspan="1" colspan="1">TDI</td>
<td align="left" valign="top" rowspan="1" colspan="1">Aspiration</td>
<td align="left" valign="top" rowspan="1" colspan="1">40 μL @ 0.8 mg/kg</td>
<td align="left" valign="top" rowspan="1" colspan="1">3x AHR increase</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">Baretto et al. 2015</td>
<td align="center" valign="top" rowspan="1" colspan="1">Au</td>
<td align="center" valign="top" rowspan="1" colspan="1">6.3 nm</td>
<td align="left" valign="top" rowspan="1" colspan="1">Swiss Webster and A/J mouse</td>
<td align="left" valign="top" rowspan="1" colspan="1">OVA</td>
<td align="left" valign="top" rowspan="1" colspan="1">Intranasal Instillation</td>
<td align="left" valign="top" rowspan="1" colspan="1">6, 60 μg/kg</td>
<td align="left" valign="top" rowspan="1" colspan="1">Inhibited allergen-induced accumulation of inflammatory cells, pro-inflammatory cytokine production. In A/J mice, AuNPs prevented mucus production and AHR</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1">Nickel</td>
<td align="left" valign="top" rowspan="1" colspan="1">Cho et al. 2012</td>
<td align="center" valign="top" rowspan="1" colspan="1">NiO</td>
<td align="center" valign="top" rowspan="1" colspan="1">5.3 nm</td>
<td align="left" valign="top" rowspan="1" colspan="1">F Wistar rat</td>
<td align="left" valign="top" rowspan="1" colspan="1">-</td>
<td align="left" valign="top" rowspan="1" colspan="1">Intratracheal Instillation</td>
<td align="left" valign="top" rowspan="1" colspan="1">150 cm
<sup>2</sup>
SA</td>
<td align="left" valign="top" rowspan="1" colspan="1">Exposure caused pulmonary alveolar proteinosis and TH1/TH17 dominant responses</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">Baker et al. 2016</td>
<td align="center" valign="top" rowspan="1" colspan="1">Ni</td>
<td align="center" valign="top" rowspan="1" colspan="1">20 nm</td>
<td align="left" valign="top" rowspan="1" colspan="1">M C57BL/6 WT or T-bet−/− mouse</td>
<td align="left" valign="top" rowspan="1" colspan="1">-</td>
<td align="left" valign="top" rowspan="1" colspan="1">Aspiration</td>
<td align="left" valign="top" rowspan="1" colspan="1">4 mg/kg</td>
<td align="left" valign="top" rowspan="1" colspan="1">Increased airway remodeling in T-bet knockout mice with susceptibility to TH2 responses</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">
<xref rid="R243" ref-type="bibr">Lee et al. 2016</xref>
</td>
<td align="center" valign="top" rowspan="1" colspan="1">NiO</td>
<td align="center" valign="top" rowspan="1" colspan="1">5.3 ± 0.4 nm</td>
<td align="left" valign="top" rowspan="1" colspan="1">F Wistar rat</td>
<td align="left" valign="top" rowspan="1" colspan="1">-</td>
<td align="left" valign="top" rowspan="1" colspan="1">Intratracheal Instillation</td>
<td align="left" valign="top" rowspan="1" colspan="1">50, 100, 200 cm
<sup>2</sup>
</td>
<td align="left" valign="top" rowspan="1" colspan="1">Acute neutrophilic inflammation, and eosinophils recruited at days 3 and 4 via eotaxin release</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">Chang et al. 2017</td>
<td align="center" valign="top" rowspan="1" colspan="1">NiO</td>
<td align="center" valign="top" rowspan="1" colspan="1">-</td>
<td align="left" valign="top" rowspan="1" colspan="1">M Wistar rat</td>
<td align="left" valign="top" rowspan="1" colspan="1">-</td>
<td align="left" valign="top" rowspan="1" colspan="1">Intratracheal Instillation</td>
<td align="left" valign="top" rowspan="1" colspan="1">0.015–0.24 mg/kg</td>
<td align="left" valign="top" rowspan="1" colspan="1">Alterations in TH1/TH2 balance were indicative of nitrative stress and NFk-B activation</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1">Platinum</td>
<td align="left" valign="top" rowspan="1" colspan="1">
<xref rid="R353" ref-type="bibr">Park et al. 2010b</xref>
</td>
<td align="center" valign="top" rowspan="1" colspan="1">Pt</td>
<td align="center" valign="top" rowspan="1" colspan="1">20.9 ± 11.4 nm</td>
<td align="left" valign="top" rowspan="1" colspan="1">M ICR mouse</td>
<td align="left" valign="top" rowspan="1" colspan="1">-</td>
<td align="left" valign="top" rowspan="1" colspan="1">Intratracheal Instillation</td>
<td align="left" valign="top" rowspan="1" colspan="1">-</td>
<td align="left" valign="top" rowspan="1" colspan="1">Increase in serum IgE, lung TH2 cytokines, and decrease in CD4/8 ratio</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">Onizawa et al. 2009</td>
<td align="center" valign="top" rowspan="1" colspan="1">Pt</td>
<td align="center" valign="top" rowspan="1" colspan="1">2 ± 0.4 nm</td>
<td align="left" valign="top" rowspan="1" colspan="1">DBA/2 mouse</td>
<td align="left" valign="top" rowspan="1" colspan="1">-</td>
<td align="left" valign="top" rowspan="1" colspan="1">Intranasal instillation</td>
<td align="left" valign="top" rowspan="1" colspan="1">x3 d</td>
<td align="left" valign="top" rowspan="1" colspan="1">PtNP exerted protective effects from cigarette smoke, prevented NFk-B activation, and neutrophilic inflammation</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1">Silica</td>
<td align="left" valign="top" rowspan="1" colspan="1">
<xref rid="R46" ref-type="bibr">Brandenberger et al. 2013</xref>
</td>
<td align="center" valign="top" rowspan="1" colspan="1">Si</td>
<td align="center" valign="top" rowspan="1" colspan="1">90 nm</td>
<td align="left" valign="top" rowspan="1" colspan="1">F BALB/c mouse</td>
<td align="left" valign="top" rowspan="1" colspan="1">OVA</td>
<td align="left" valign="top" rowspan="1" colspan="1">Intranasal instillation</td>
<td align="left" valign="top" rowspan="1" colspan="1">0, 10, 100,400 μg</td>
<td align="left" valign="top" rowspan="1" colspan="1">Co-exposure during sensitization caused dose-dependent enhancement of OVA-specific IgE, lung eosinophils, mucus cell metaplasia, and TH2/TH17 cytokine production</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1">Silver</td>
<td align="left" valign="top" rowspan="1" colspan="1">Park H et al. 2010</td>
<td align="center" valign="top" rowspan="1" colspan="1">Ag</td>
<td align="center" valign="top" rowspan="1" colspan="1">6 ± 0.29 nm</td>
<td align="left" valign="top" rowspan="1" colspan="1">F C57BL/6 mouse</td>
<td align="left" valign="top" rowspan="1" colspan="1">OVA</td>
<td align="left" valign="top" rowspan="1" colspan="1">Inhalation</td>
<td align="left" valign="top" rowspan="1" colspan="1">5 × 20 ppm, 40 mg/kg</td>
<td align="left" valign="top" rowspan="1" colspan="1">Decreased AHR, TH2 cytokines, and ROS levels</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">
<xref rid="R181" ref-type="bibr">Jang et al. 2012</xref>
</td>
<td align="center" valign="top" rowspan="1" colspan="1">Ag</td>
<td align="center" valign="top" rowspan="1" colspan="1">6.0 ± 0.29 nm</td>
<td align="left" valign="top" rowspan="1" colspan="1">F BALB/c mouse</td>
<td align="left" valign="top" rowspan="1" colspan="1">OVA</td>
<td align="left" valign="top" rowspan="1" colspan="1">Inhalation</td>
<td align="left" valign="top" rowspan="1" colspan="1">20 ppm/40 mg/kg 5× for 24 h</td>
<td align="left" valign="top" rowspan="1" colspan="1">Suppressed mucus production via VEGF signaling alterations</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="center" valign="top" rowspan="1" colspan="1"></td>
<td align="center" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">
<xref rid="R465" ref-type="bibr">Su et al. 2013</xref>
</td>
<td align="center" valign="top" rowspan="1" colspan="1">Ag</td>
<td align="center" valign="top" rowspan="1" colspan="1">33 nm</td>
<td align="left" valign="top" rowspan="1" colspan="1">F BALB/c mouse</td>
<td align="left" valign="top" rowspan="1" colspan="1">OVA</td>
<td align="left" valign="top" rowspan="1" colspan="1">Inhalation</td>
<td align="center" valign="top" rowspan="1" colspan="1">3.3 ± 0.7 mg/m
<sup>3</sup>
6h/7 × 7 d</td>
<td align="left" valign="top" rowspan="1" colspan="1">Increased OVA IgE, proteins associated with immune processes were altered</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">
<xref rid="R69" ref-type="bibr">Chuang et al. 2013</xref>
</td>
<td align="center" valign="top" rowspan="1" colspan="1">Ag</td>
<td align="center" valign="top" rowspan="1" colspan="1">33 nm</td>
<td align="left" valign="top" rowspan="1" colspan="1">F BALB/c mouse</td>
<td align="left" valign="top" rowspan="1" colspan="1">OVA</td>
<td align="left" valign="top" rowspan="1" colspan="1">Inhalation</td>
<td align="center" valign="top" rowspan="1" colspan="1">3.3 mg/m
<sup>3</sup>
6h/d × 7 d</td>
<td align="left" valign="top" rowspan="1" colspan="1">Increased Penh, recruitment of neutrophils, lymphocytes, and eosinophils to the airways</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">
<xref rid="R517" ref-type="bibr">Xu et al. 2013</xref>
</td>
<td align="center" valign="top" rowspan="1" colspan="1">Ag</td>
<td align="center" valign="top" rowspan="1" colspan="1">141 nm</td>
<td align="left" valign="top" rowspan="1" colspan="1">F BALB/c mouse</td>
<td align="left" valign="top" rowspan="1" colspan="1">OVA</td>
<td align="left" valign="top" rowspan="1" colspan="1">IP Injection</td>
<td align="center" valign="top" rowspan="1" colspan="1">0.4, 2, 10 mg/kg</td>
<td align="left" valign="top" rowspan="1" colspan="1">ncreased OVA-IgG and TH2 responses, local activation and recruitment of leukocytes</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1">Titanium</td>
<td align="left" valign="top" rowspan="1" colspan="1">Ahn et al. 2005</td>
<td align="center" valign="top" rowspan="1" colspan="1">TiO
<sub>2</sub>
</td>
<td align="center" valign="top" rowspan="1" colspan="1">0.29 μm</td>
<td align="left" valign="top" rowspan="1" colspan="1">M Sprague-Dawley rat</td>
<td align="left" valign="top" rowspan="1" colspan="1">-</td>
<td align="left" valign="top" rowspan="1" colspan="1">Intratracheal Instillation</td>
<td align="center" valign="top" rowspan="1" colspan="1">4 mg/kg</td>
<td align="left" valign="top" rowspan="1" colspan="1">Increased BAL IL-13 levels, IL-13-producing mast cells, and goblet cell hyperplasia</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">
<xref rid="R359" ref-type="bibr">Park et al. 2009</xref>
</td>
<td align="center" valign="top" rowspan="1" colspan="1">TiO
<sub>2</sub>
</td>
<td align="center" valign="top" rowspan="1" colspan="1">20 nm</td>
<td align="left" valign="top" rowspan="1" colspan="1">ICR mouse</td>
<td align="left" valign="top" rowspan="1" colspan="1">-</td>
<td align="left" valign="top" rowspan="1" colspan="1">Intratracheal Instillation</td>
<td align="center" valign="top" rowspan="1" colspan="1">5, 20, or 50 mg/kg</td>
<td align="left" valign="top" rowspan="1" colspan="1">Increased BAL and serum IgE levels, altered TH1/TH2 cytokines, increased B cell distribution</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">Larsen et al. 2009</td>
<td align="center" valign="top" rowspan="1" colspan="1">TiO
<sub>2</sub>
</td>
<td align="center" valign="top" rowspan="1" colspan="1">28 nm</td>
<td align="left" valign="top" rowspan="1" colspan="1">F BALB/c mouse</td>
<td align="left" valign="top" rowspan="1" colspan="1">OVA</td>
<td align="left" valign="top" rowspan="1" colspan="1">IP Injection</td>
<td align="center" valign="top" rowspan="1" colspan="1">2–250 μg</td>
<td align="left" valign="top" rowspan="1" colspan="1">TH2 adjuvancy, increased IgE, IgG1, and eosinophil levels</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">
<xref rid="R399" ref-type="bibr">Rossi et al. 2010</xref>
</td>
<td align="center" valign="top" rowspan="1" colspan="1">TiO
<sub>2</sub>
</td>
<td align="center" valign="top" rowspan="1" colspan="1">10 × 40 nm</td>
<td align="left" valign="top" rowspan="1" colspan="1">F BALC/c/Sca mouse</td>
<td align="left" valign="top" rowspan="1" colspan="1">OVA</td>
<td align="left" valign="top" rowspan="1" colspan="1">Inhalation</td>
<td align="center" valign="top" rowspan="1" colspan="1">2 h/d, 3 d/w, x4 w @ 10 mg/m
<sup>3</sup>
</td>
<td align="left" valign="top" rowspan="1" colspan="1">Allergic pulmonary inflammation suppressed by TiO
<sub>2</sub>
NP</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">Gustafsson et al. 2011</td>
<td align="center" valign="top" rowspan="1" colspan="1">TiO
<sub>2</sub>
</td>
<td align="center" valign="top" rowspan="1" colspan="1">21 nm</td>
<td align="left" valign="top" rowspan="1" colspan="1">M Dark Agouti rat</td>
<td align="left" valign="top" rowspan="1" colspan="1">-</td>
<td align="left" valign="top" rowspan="1" colspan="1">Intratracheal instillation</td>
<td align="center" valign="top" rowspan="1" colspan="1">5 mg/kg</td>
<td align="left" valign="top" rowspan="1" colspan="1">ncreased eosinophil, DC numbers in lungs, lymphocytes recruited mostly CD4+, also included CD8+ T-cells, B-cells, and CD25+ T-cells</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">
<xref rid="R174" ref-type="bibr">Hussain et al. 2011</xref>
</td>
<td align="center" valign="top" rowspan="1" colspan="1">TiO
<sub>2</sub>
</td>
<td align="center" valign="top" rowspan="1" colspan="1">15 nm</td>
<td align="left" valign="top" rowspan="1" colspan="1">M BALB/c mouse</td>
<td align="left" valign="top" rowspan="1" colspan="1">TDI</td>
<td align="left" valign="top" rowspan="1" colspan="1">Aspiration</td>
<td align="center" valign="top" rowspan="1" colspan="1">40 μL @ 0.8 mg/kg</td>
<td align="left" valign="top" rowspan="1" colspan="1">2× increase AHR</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">Scarino et al. 2012</td>
<td align="center" valign="top" rowspan="1" colspan="1">TiO
<sub>2</sub>
</td>
<td align="center" valign="top" rowspan="1" colspan="1">5 nm APS, 168/171 nm agg.</td>
<td align="left" valign="top" rowspan="1" colspan="1">M Brown Norway rat</td>
<td align="left" valign="top" rowspan="1" colspan="1">OVA</td>
<td align="left" valign="top" rowspan="1" colspan="1">Inhalation</td>
<td align="center" valign="top" rowspan="1" colspan="1">9.4 or 15.7 mg/m
<sup>3</sup>
</td>
<td align="left" valign="top" rowspan="1" colspan="1">Significantly decreased lung leukocytes and plasma/BAL IL-4, IL-6, and IFN-γ over OVA controls</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">
<xref rid="R192" ref-type="bibr">Jonasson et al. 2013</xref>
</td>
<td align="center" valign="top" rowspan="1" colspan="1">TiO
<sub>2</sub>
</td>
<td align="center" valign="top" rowspan="1" colspan="1">21 nm</td>
<td align="left" valign="top" rowspan="1" colspan="1">F BALB/c mouse</td>
<td align="left" valign="top" rowspan="1" colspan="1">OVA</td>
<td align="left" valign="top" rowspan="1" colspan="1">Inhalation</td>
<td align="center" valign="top" rowspan="1" colspan="1">32 ± 1 μg</td>
<td align="left" valign="top" rowspan="1" colspan="1">Aggravated allergic response dependent on dose and timing</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">Fu et al. 2014</td>
<td align="center" valign="top" rowspan="1" colspan="1">TiO
<sub>2</sub>
</td>
<td align="center" valign="top" rowspan="1" colspan="1">21 nm</td>
<td align="left" valign="top" rowspan="1" colspan="1">M Sprague-Dawley rat</td>
<td align="left" valign="top" rowspan="1" colspan="1">-</td>
<td align="left" valign="top" rowspan="1" colspan="1">Intratracheal Instillation</td>
<td align="center" valign="top" rowspan="1" colspan="1">0.5, 4.0, 32 mg/kg 2x/w × 4 w</td>
<td align="left" valign="top" rowspan="1" colspan="1">Deposition in lymph nodes, increased T and B-cell proliferation following mitogen stimulation, enhanced NK activity in spleen, increased B-cells in the blood</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">Choi et al. 2014</td>
<td align="center" valign="top" rowspan="1" colspan="1">TiO
<sub>2</sub>
</td>
<td align="center" valign="top" rowspan="1" colspan="1">P25</td>
<td align="left" valign="top" rowspan="1" colspan="1">M New Zealand White Rabbit</td>
<td align="left" valign="top" rowspan="1" colspan="1">-</td>
<td align="left" valign="top" rowspan="1" colspan="1">Intratracheal instillation</td>
<td align="center" valign="top" rowspan="1" colspan="1">10, 50, 250 μg</td>
<td align="left" valign="top" rowspan="1" colspan="1">Dose-dependent eosinophil influx and inflammation in the lung, but not neutrophil or lymphocyte influx</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">
<xref rid="R139" ref-type="bibr">Gustafsson et al. 2014</xref>
</td>
<td align="center" valign="top" rowspan="1" colspan="1">TiO
<sub>2</sub>
</td>
<td align="center" valign="top" rowspan="1" colspan="1">21 nm</td>
<td align="left" valign="top" rowspan="1" colspan="1">M Dark Agouti rat M Brown Norway rat</td>
<td align="left" valign="top" rowspan="1" colspan="1">OVA</td>
<td align="left" valign="top" rowspan="1" colspan="1">Inhalation</td>
<td align="center" valign="top" rowspan="1" colspan="1">168–159 μg/d × 10 d</td>
<td align="left" valign="top" rowspan="1" colspan="1">Exposure decreased eosinophilia in OVA-sensitized DA and BN rats, but neutrophils/lymphocyte increase in DA rats</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">
<xref rid="R297" ref-type="bibr">Mishra et al. 2016</xref>
</td>
<td align="center" valign="top" rowspan="1" colspan="1">TiO
<sub>2</sub>
</td>
<td align="center" valign="top" rowspan="1" colspan="1">4–8 nm</td>
<td align="left" valign="top" rowspan="1" colspan="1">BALB/c mouse</td>
<td align="left" valign="top" rowspan="1" colspan="1">OVA</td>
<td align="left" valign="top" rowspan="1" colspan="1">IP Injection</td>
<td align="center" valign="top" rowspan="1" colspan="1">200 μg</td>
<td align="left" valign="top" rowspan="1" colspan="1">Augmented AHR, biochemical markers of damage, and induced a mixed TH1/TH2 response</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">
<xref rid="R210" ref-type="bibr">Kim et al. 2017</xref>
</td>
<td align="center" valign="top" rowspan="1" colspan="1">TiO
<sub>2</sub>
</td>
<td align="center" valign="top" rowspan="1" colspan="1">75 nm</td>
<td align="left" valign="top" rowspan="1" colspan="1">F BALB/c mouse</td>
<td align="left" valign="top" rowspan="1" colspan="1">OVA</td>
<td align="left" valign="top" rowspan="1" colspan="1">Inhalation</td>
<td align="center" valign="top" rowspan="1" colspan="1">50 μg/m
<sup>3</sup>
× 3 d</td>
<td align="left" valign="top" rowspan="1" colspan="1">Exposure exacerbated AHR and inflammation, increases in IL-1, IL-18</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1">Zinc</td>
<td align="left" valign="top" rowspan="1" colspan="1">
<xref rid="R400" ref-type="bibr">Roy et al 2014b</xref>
</td>
<td align="center" valign="top" rowspan="1" colspan="1">ZnO</td>
<td align="center" valign="top" rowspan="1" colspan="1"><50nm</td>
<td align="left" valign="top" rowspan="1" colspan="1">F BALB/c mouse</td>
<td align="left" valign="top" rowspan="1" colspan="1">OVA</td>
<td align="left" valign="top" rowspan="1" colspan="1">IP Injection</td>
<td align="center" valign="top" rowspan="1" colspan="1">0.25, 0.5, 1, 3 mg</td>
<td align="left" valign="top" rowspan="1" colspan="1">Administration with OVA caused increased OVA-IgG1, IgE, eosinophil, and mast cell numbers in lungs and spleen</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">
<xref rid="R400" ref-type="bibr">Roy et al 2014a</xref>
</td>
<td align="center" valign="top" rowspan="1" colspan="1">ZnO</td>
<td align="center" valign="top" rowspan="1" colspan="1"><50nm</td>
<td align="left" valign="top" rowspan="1" colspan="1">F BALB/c mouse</td>
<td align="left" valign="top" rowspan="1" colspan="1">OVA</td>
<td align="left" valign="top" rowspan="1" colspan="1">IP Injection</td>
<td align="center" valign="top" rowspan="1" colspan="1">1, 2, 4, and 12 mg/mL</td>
<td align="left" valign="top" rowspan="1" colspan="1">Adjuvant effect on OVA allergy by signaling through TLRs and Src kinase leading to inflammatory responses</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">
<xref rid="R168" ref-type="bibr">Huang et al. 2015</xref>
</td>
<td align="center" valign="top" rowspan="1" colspan="1">ZnO</td>
<td align="center" valign="top" rowspan="1" colspan="1">181.5 nm low dose 360.0 nm high dose</td>
<td align="left" valign="top" rowspan="1" colspan="1">F BALB/c mouse</td>
<td align="left" valign="top" rowspan="1" colspan="1">OVA</td>
<td align="left" valign="top" rowspan="1" colspan="1">Aspiration</td>
<td align="center" valign="top" rowspan="1" colspan="1">0.1/0.5 mg/kg</td>
<td align="left" valign="top" rowspan="1" colspan="1">Exposure simultaneous to OVA sensitization resulted in eosinophil recruitment and TH2 adjuvancy</td>
</tr>
</tbody>
</table>
<table-wrap-foot>
<fn id="TFN5">
<p id="P139">Summary of findings from
<italic>in vivo</italic>
studies investigating immune effects of metal nanomaterials in the lung and select
<italic>in vitro</italic>
studies in pulmonary cells, grouped by metal. AHR: airway hyperreactivity; APC: antigen-presenting cell; APS: average particle size; DC: dendritic cell; HDM: house dust mite; IP: intraperitoneal; LPS: lipopolysaccharide; MHC: major histocompatibility complex; OVA: ovalbumin; ROS: reactive oxygen species; RSV: respiratory syncytial virus; TLR: Toll-like receptor; WT: wild-type.</p>
</fn>
</table-wrap-foot>
</table-wrap>
<table-wrap id="T6" position="float" orientation="landscape">
<label>Table 6.</label>
<caption>
<p id="P140">Summary of major findings from studies comparing the effects of various physicochemical properties of metal nanomaterials on respiratory allergy grouped by property of interest.</p>
</caption>
<table frame="hsides" rules="groups">
<colgroup span="1">
<col align="left" valign="middle" span="1"></col>
<col align="left" valign="middle" span="1"></col>
<col align="left" valign="middle" span="1"></col>
<col align="left" valign="middle" span="1"></col>
<col align="left" valign="middle" span="1"></col>
<col align="left" valign="middle" span="1"></col>
<col align="left" valign="middle" span="1"></col>
<col align="left" valign="middle" span="1"></col>
<col align="left" valign="middle" span="1"></col>
<col align="left" valign="middle" span="1"></col>
<col align="left" valign="middle" span="1"></col>
</colgroup>
<thead>
<tr>
<th colspan="2" align="left" valign="middle" rowspan="1">Property investigated</th>
<th colspan="2" align="center" valign="middle" rowspan="1">Author/year</th>
<th colspan="2" align="center" valign="middle" rowspan="1">Metal</th>
<th align="center" valign="middle" rowspan="1" colspan="1">Study design</th>
<th colspan="3" align="center" valign="middle" rowspan="1">Property variations</th>
<th align="center" valign="middle" rowspan="1" colspan="1">Findings</th>
</tr>
</thead>
<tbody>
<tr>
<td colspan="2" align="left" valign="top" rowspan="1">Size</td>
<td colspan="2" align="left" valign="top" rowspan="1">
<xref rid="R81" ref-type="bibr">de Haar et al. 2006</xref>
</td>
<td colspan="2" align="center" valign="top" rowspan="1">Ti</td>
<td align="left" valign="top" rowspan="1" colspan="1">F BALB/cANNCrl mouse</td>
<td colspan="3" align="left" valign="top" rowspan="1">Fine TiO
<sub>2</sub>
: 250 nm, 6.6 m
<sup>2</sup>
/g</td>
<td align="left" valign="top" rowspan="1" colspan="1">Exposure to equal mass doses of fine and ultrafine TiO
<sub>2</sub>
resulted in</td>
</tr>
<tr>
<td colspan="2" align="left" valign="top" rowspan="1"></td>
<td colspan="2" align="left" valign="top" rowspan="1"></td>
<td colspan="2" align="center" valign="top" rowspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1"> Ovalbumin, 200 μg intranasal</td>
<td colspan="3" align="left" valign="top" rowspan="1">Ultrafine TiO
<sub>2</sub>
: 29.0 nm, 49.8 m
<sup>2</sup>
/g</td>
<td align="left" valign="top" rowspan="1" colspan="1"> increased TH2 cytokines and serum OVA-specific IgE and IgGI only</td>
</tr>
<tr>
<td colspan="2" align="left" valign="top" rowspan="1"></td>
<td colspan="2" align="left" valign="top" rowspan="1"></td>
<td colspan="2" align="center" valign="top" rowspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td colspan="3" align="left" valign="top" rowspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1"> in animals exposed to ultrafine TiO
<sub>2</sub>
</td>
</tr>
<tr>
<td colspan="2" align="left" valign="top" rowspan="1"></td>
<td colspan="2" align="left" valign="top" rowspan="1">
<xref rid="R531" ref-type="bibr">Yoshida et al. 2011</xref>
</td>
<td colspan="2" align="center" valign="top" rowspan="1">Si</td>
<td align="left" valign="top" rowspan="1" colspan="1">F BALB/c mouse, Ovalbumin</td>
<td colspan="3" align="left" valign="top" rowspan="1">Amorphous silica</td>
<td align="left" valign="top" rowspan="1" colspan="1">Smaller particles induced higher levels of OVA-specific IgE, IgG, and</td>
</tr>
<tr>
<td colspan="2" align="left" valign="top" rowspan="1"></td>
<td colspan="2" align="left" valign="top" rowspan="1"></td>
<td colspan="2" align="center" valign="top" rowspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">Intranasal: 10, 50, or 250 μg/ mouse x3</td>
<td colspan="3" align="left" valign="top" rowspan="1">30, 70, 300, or 1000 nm</td>
<td align="left" valign="top" rowspan="1" colspan="1"> IgG1. Splenocytes from mice exposed to the smallest particle pro-</td>
</tr>
<tr>
<td colspan="2" align="left" valign="top" rowspan="1"></td>
<td colspan="2" align="left" valign="top" rowspan="1"></td>
<td colspan="2" align="center" valign="top" rowspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td colspan="3" align="left" valign="top" rowspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1"> duced higher levels of TH2 cytokines than other groups.</td>
</tr>
<tr>
<td colspan="2" align="left" valign="top" rowspan="1"></td>
<td colspan="2" align="left" valign="top" rowspan="1">
<xref rid="R260" ref-type="bibr">Liu et al. 2010</xref>
</td>
<td colspan="2" align="center" valign="top" rowspan="1">Ti</td>
<td align="left" valign="top" rowspan="1" colspan="1">Rats, Intratracheal instillation</td>
<td colspan="3" align="left" valign="top" rowspan="1">5 or 200 nm TiO
<sub>2</sub>
</td>
<td align="left" valign="top" rowspan="1" colspan="1">Decreased chemotactic ability, expression of Fc receptors/MHC II by</td>
</tr>
<tr>
<td colspan="2" align="left" valign="top" rowspan="1"></td>
<td colspan="2" align="left" valign="top" rowspan="1"></td>
<td colspan="2" align="center" valign="top" rowspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">0.5, 5, or 50 μg/mL</td>
<td colspan="3" align="left" valign="top" rowspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1"> alveolar macrophages. Phagocytic function was increased at low</td>
</tr>
<tr>
<td colspan="2" align="left" valign="top" rowspan="1"></td>
<td colspan="2" align="left" valign="top" rowspan="1"></td>
<td colspan="2" align="center" valign="top" rowspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td colspan="3" align="left" valign="top" rowspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1"> doses and decreased at high doses</td>
</tr>
<tr>
<td colspan="2" align="left" valign="top" rowspan="1"></td>
<td colspan="2" align="left" valign="top" rowspan="1">Chang et al. 2014</td>
<td colspan="2" align="center" valign="top" rowspan="1">Ti</td>
<td align="left" valign="top" rowspan="1" colspan="1">M Sprague Dawley rat</td>
<td colspan="3" align="left" valign="top" rowspan="1">21 nm TiO
<sub>2</sub>
NP: 80% anatase, 20% rutile,</td>
<td align="left" valign="top" rowspan="1" colspan="1">Increased macrophage accumulation and alteration of TH1/TH2 status</td>
</tr>
<tr>
<td colspan="2" align="left" valign="top" rowspan="1"></td>
<td colspan="2" align="left" valign="top" rowspan="1"></td>
<td colspan="2" align="center" valign="top" rowspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">Intratracheal instillation: x2, x4 w</td>
<td colspan="3" align="left" valign="top" rowspan="1">1–2 μm TiO
<sub>2</sub>
: anatase</td>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
</tr>
<tr>
<td colspan="2" align="left" valign="top" rowspan="1"></td>
<td colspan="2" align="left" valign="top" rowspan="1"></td>
<td colspan="2" align="center" valign="top" rowspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">0.5, 4, 32 mg/kg</td>
<td colspan="3" align="left" valign="top" rowspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
</tr>
<tr>
<td colspan="2" align="left" valign="top" rowspan="1"></td>
<td colspan="2" align="left" valign="top" rowspan="1">Ban et al. 2013</td>
<td colspan="2" align="center" valign="top" rowspan="1">Fe</td>
<td align="left" valign="top" rowspan="1" colspan="1">F BALB/c mouse, Ovalbumin</td>
<td colspan="3" align="left" valign="top" rowspan="1">Submicron Fe
<sub>2</sub>
O
<sub>3</sub>
: 147±48nm, 6 m
<sup>2</sup>
/g</td>
<td align="left" valign="top" rowspan="1" colspan="1">High and medium doses of both Fe particles caused decreases in</td>
</tr>
<tr>
<td colspan="2" align="left" valign="top" rowspan="1"></td>
<td colspan="2" align="left" valign="top" rowspan="1"></td>
<td colspan="2" align="center" valign="top" rowspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">Intratracheal instillation:</td>
<td colspan="3" align="left" valign="top" rowspan="1">Fe
<sub>2</sub>
O
<sub>3</sub>
NP: 35±14nm, 39 m
<sup>2</sup>
/g</td>
<td align="left" valign="top" rowspan="1" colspan="1"> eosinophil influx and OVA-specific IgE levels. However, at the low</td>
</tr>
<tr>
<td colspan="2" align="left" valign="top" rowspan="1"></td>
<td colspan="2" align="left" valign="top" rowspan="1"></td>
<td colspan="2" align="center" valign="top" rowspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">4x (100, 250, or 500 μg/mouse)</td>
<td colspan="3" align="left" valign="top" rowspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1"> dose, submicron particles had no effect on allergy, whereas nano-</td>
</tr>
<tr>
<td colspan="2" align="left" valign="top" rowspan="1"></td>
<td colspan="2" align="left" valign="top" rowspan="1"></td>
<td colspan="2" align="center" valign="top" rowspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td colspan="3" align="left" valign="top" rowspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1"> particles had an adjuvant effect on the TH2 response to OVA</td>
</tr>
<tr>
<td colspan="2" align="left" valign="top" rowspan="1">SA</td>
<td colspan="2" align="left" valign="top" rowspan="1">
<xref rid="R399" ref-type="bibr">Rossi et al. 2010</xref>
</td>
<td colspan="2" align="center" valign="top" rowspan="1">Ti</td>
<td align="left" valign="top" rowspan="1" colspan="1">F BALB/c/Sca mouse, Ovalbumin</td>
<td colspan="3" align="left" valign="top" rowspan="1">Rutile TiO
<sub>2</sub>
NP: <5 μm, 2 m
<sup>2</sup>
/g</td>
<td align="left" valign="top" rowspan="1" colspan="1">Allergic pulmonary inflammation was dramatically suppressed in asth-</td>
</tr>
<tr>
<td colspan="2" align="left" valign="top" rowspan="1"></td>
<td colspan="2" align="left" valign="top" rowspan="1"></td>
<td colspan="2" align="center" valign="top" rowspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1"> Inhalation: 10±2mg/m
<sup>3</sup>
× 12</td>
<td colspan="3" align="left" valign="top" rowspan="1">Rutile TiO
<sub>2</sub>
NP: 10 × 40 nm, 132 m
<sup>2</sup>
/g</td>
<td align="left" valign="top" rowspan="1" colspan="1"> matic mice exposed to either size TiO
<sub>2</sub>
. Leukocyte number, cyto-</td>
</tr>
<tr>
<td colspan="2" align="left" valign="top" rowspan="1"></td>
<td colspan="2" align="left" valign="top" rowspan="1"></td>
<td colspan="2" align="center" valign="top" rowspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td colspan="3" align="left" valign="top" rowspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1"> kines, chemokines, and antibodies were significantly decreased.</td>
</tr>
<tr>
<td colspan="2" align="left" valign="top" rowspan="1"></td>
<td colspan="2" align="left" valign="top" rowspan="1">Parketal. 2015</td>
<td colspan="2" align="center" valign="top" rowspan="1">Si</td>
<td align="left" valign="top" rowspan="1" colspan="1">F BALB/c mouse, Ovalbumin</td>
<td colspan="3" align="left" valign="top" rowspan="1">Spherical SiNP: 12.7 m
<sup>2</sup>
/g</td>
<td align="left" valign="top" rowspan="1" colspan="1">Acute SiNP exposure induced significant airway inflammation and</td>
</tr>
<tr>
<td colspan="2" align="left" valign="top" rowspan="1"></td>
<td colspan="2" align="left" valign="top" rowspan="1"></td>
<td colspan="2" align="center" valign="top" rowspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1"> Intranasal inoculation</td>
<td colspan="3" align="left" valign="top" rowspan="1">Mesoporous SiNP: 70.6 m
<sup>2</sup>
/g</td>
<td align="left" valign="top" rowspan="1" colspan="1"> AHR. Spherical SiNPs induced the greatest degree of exacerbation</td>
</tr>
<tr>
<td colspan="2" align="left" valign="top" rowspan="1"></td>
<td colspan="2" align="left" valign="top" rowspan="1"></td>
<td colspan="2" align="center" valign="top" rowspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td colspan="3" align="left" valign="top" rowspan="1">PEGylated SiNP: 12.7 m
<sup>2</sup>
/g</td>
<td align="left" valign="top" rowspan="1" colspan="1"> of allergic effects in the OVA model</td>
</tr>
<tr>
<td colspan="2" align="left" valign="top" rowspan="1"></td>
<td colspan="2" align="left" valign="top" rowspan="1">
<xref rid="R144" ref-type="bibr">Han et al. 2016</xref>
</td>
<td colspan="2" align="center" valign="top" rowspan="1">Si</td>
<td align="left" valign="top" rowspan="1" colspan="1">F BALB/c mouse</td>
<td colspan="3" align="left" valign="top" rowspan="1">Spherical SiNP: 12.7 m
<sup>2</sup>
/g, 119.6nm</td>
<td align="left" valign="top" rowspan="1" colspan="1">Sensitized mice exposed to S-SiNP and M-SiNP exhibited elevated</td>
</tr>
<tr>
<td colspan="2" align="left" valign="top" rowspan="1"></td>
<td colspan="2" align="left" valign="top" rowspan="1"></td>
<td colspan="2" align="center" valign="top" rowspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1"> Ovalbumin</td>
<td colspan="3" align="left" valign="top" rowspan="1">Mesoporous SiNP: 70.6 m
<sup>2</sup>
/g, 100.5 nm</td>
<td align="left" valign="top" rowspan="1" colspan="1"> AHR over controls. M-SiNPs induced the greatest degree adjuvan-</td>
</tr>
<tr>
<td colspan="2" align="left" valign="top" rowspan="1"></td>
<td colspan="2" align="left" valign="top" rowspan="1"></td>
<td colspan="2" align="center" valign="top" rowspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1"> Intranasal inoculation: 10 mg/kg 6x</td>
<td colspan="3" align="left" valign="top" rowspan="1">PEGylated SiNP: 12.7 m
<sup>2</sup>
/g, 439.1 nm</td>
<td align="left" valign="top" rowspan="1" colspan="1"> ticity, whereas PEG-SiNP caused the least toxic effects</td>
</tr>
<tr>
<td colspan="2" align="left" valign="top" rowspan="1">MOD</td>
<td colspan="2" align="left" valign="top" rowspan="1">CRG Seydoux et al. 2016</td>
<td colspan="2" align="center" valign="top" rowspan="1">Au</td>
<td align="left" valign="top" rowspan="1" colspan="1">F BALB/c mouse</td>
<td colspan="3" align="left" valign="top" rowspan="1">90 nm AuNP:</td>
<td align="left" valign="top" rowspan="1" colspan="1">APCs preferentially took up cationic AuNPs, causing upregulation of</td>
</tr>
<tr>
<td colspan="2" align="left" valign="top" rowspan="1"></td>
<td colspan="2" align="left" valign="top" rowspan="1"></td>
<td colspan="2" align="center" valign="top" rowspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1"> AuNP intranasal instillation: 10 μg</td>
<td colspan="3" align="left" valign="top" rowspan="1">NH
<sub>2</sub>
-PVA, 7.2 mV</td>
<td align="left" valign="top" rowspan="1" colspan="1"> co-stimulatory molecules. Positive AuNPs enhanced OVA-specific</td>
</tr>
<tr>
<td colspan="2" align="left" valign="top" rowspan="1"></td>
<td colspan="2" align="left" valign="top" rowspan="1"></td>
<td colspan="2" align="center" valign="top" rowspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td colspan="3" align="left" valign="top" rowspan="1">COOH-PVA 8.2 mV</td>
<td align="left" valign="top" rowspan="1" colspan="1"> CD4+ T-cell stimulation in the lung draining lymph nodes</td>
</tr>
<tr>
<td colspan="2" align="left" valign="top" rowspan="1"></td>
<td colspan="2" align="left" valign="top" rowspan="1">
<xref rid="R285" ref-type="bibr">Marzaioli et al. 2014</xref>
</td>
<td colspan="2" align="center" valign="top" rowspan="1">Si</td>
<td align="left" valign="top" rowspan="1" colspan="1">F BALB/c mouse, Ovalbumin</td>
<td colspan="3" align="left" valign="top" rowspan="1">Amorphous SiO
<sub>2</sub>
NP 15 nm:</td>
<td align="left" valign="top" rowspan="1" colspan="1">Uncoated SiO
<sub>2</sub>
NPs induced proinflammatory and immunomodulatory</td>
</tr>
<tr>
<td colspan="2" align="left" valign="top" rowspan="1"></td>
<td colspan="2" align="left" valign="top" rowspan="1"></td>
<td colspan="2" align="center" valign="top" rowspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1"> Intratracheal instillation: 50 μg</td>
<td colspan="3" align="left" valign="top" rowspan="1">Uncoated 38 mV, PEGylated 26 mV,</td>
<td align="left" valign="top" rowspan="1" colspan="1"> effects with increases in lung inflammatory cells, TH2 cytokines.</td>
</tr>
<tr>
<td colspan="2" align="left" valign="top" rowspan="1"></td>
<td colspan="2" align="left" valign="top" rowspan="1"></td>
<td colspan="2" align="center" valign="top" rowspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td colspan="3" align="left" valign="top" rowspan="1">Phosphate-coated 43 mV, Amino-coated 0 mV</td>
<td align="left" valign="top" rowspan="1" colspan="1"> Amino and phosphate surface modifications mitigated these</td>
</tr>
<tr>
<td colspan="2" align="left" valign="top" rowspan="1"></td>
<td colspan="2" align="left" valign="top" rowspan="1"></td>
<td colspan="2" align="center" valign="top" rowspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td colspan="3" align="left" valign="top" rowspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1"> effects, whereas PEG coating did not.</td>
</tr>
<tr>
<td colspan="2" align="left" valign="top" rowspan="1"></td>
<td colspan="2" align="left" valign="top" rowspan="1">
<xref rid="R340" ref-type="bibr">Omlor et al. 2017</xref>
</td>
<td colspan="2" align="center" valign="top" rowspan="1">Au</td>
<td align="left" valign="top" rowspan="1" colspan="1">F BALB/c mouse, Ovalbumin</td>
<td colspan="3" align="left" valign="top" rowspan="1">5 nm AuNP, PEGylated or citrated</td>
<td align="left" valign="top" rowspan="1" colspan="1">Asthmatic condition increased nanoparticle uptake. Systemic uptake is</td>
</tr>
<tr>
<td colspan="2" align="left" valign="top" rowspan="1"></td>
<td colspan="2" align="left" valign="top" rowspan="1"></td>
<td colspan="2" align="center" valign="top" rowspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1"> Intranasal instillation</td>
<td colspan="3" align="left" valign="top" rowspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1"> higher for PEGylated AuNP compared to citrated AuNPs, but both</td>
</tr>
<tr>
<td colspan="2" align="left" valign="top" rowspan="1"></td>
<td colspan="2" align="left" valign="top" rowspan="1"></td>
<td colspan="2" align="center" valign="top" rowspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td colspan="3" align="left" valign="top" rowspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1"> inhibited inflammatory infiltrates and AHR, wherein inhibition was</td>
</tr>
<tr>
<td colspan="2" align="left" valign="top" rowspan="1"></td>
<td colspan="2" align="left" valign="top" rowspan="1"></td>
<td colspan="2" align="center" valign="top" rowspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td colspan="3" align="left" valign="top" rowspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1"> more significant following exposure to citrated AuNPS</td>
</tr>
<tr>
<td colspan="2" align="left" valign="top" rowspan="1"></td>
<td colspan="2" align="left" valign="top" rowspan="1">Vennemann</td>
<td colspan="2" align="center" valign="top" rowspan="1">Zr</td>
<td align="left" valign="top" rowspan="1" colspan="1">F Wistar rat</td>
<td colspan="3" align="left" valign="top" rowspan="1">APTS, TODS, PGA, or acrylic acid coated</td>
<td align="left" valign="top" rowspan="1" colspan="1">Surface coating had minimal effects on inflammation in the lungs of</td>
</tr>
<tr>
<td colspan="2" align="left" valign="top" rowspan="1"></td>
<td colspan="2" align="left" valign="top" rowspan="1">et al. 2017</td>
<td colspan="2" align="center" valign="top" rowspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1"> Intratracheal instillation</td>
<td colspan="3" align="left" valign="top" rowspan="1">9–1 Onm ZrO
<sub>2</sub>
NPs</td>
<td align="left" valign="top" rowspan="1" colspan="1"> rats, but had significant effects on allergic response.</td>
</tr>
<tr>
<td colspan="2" align="left" valign="top" rowspan="1">Size MOD</td>
<td colspan="2" align="left" valign="top" rowspan="1">Alessandrini</td>
<td colspan="2" align="center" valign="top" rowspan="1">Ag</td>
<td align="left" valign="top" rowspan="1" colspan="1">F BALB/c mice, Ovalbumin</td>
<td colspan="3" align="left" valign="top" rowspan="1">PVP-coated AgNP: 97 nm, 6.2 m
<sup>2</sup>
/g, 7mV</td>
<td align="left" valign="top" rowspan="1" colspan="1">Ag50-PVP significantly reduced OVA-induced inflammatory infiltrate in</td>
</tr>
<tr>
<td colspan="2" align="left" valign="top" rowspan="1"></td>
<td colspan="2" align="left" valign="top" rowspan="1">et al. 2017</td>
<td colspan="2" align="center" valign="top" rowspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1"> Intratracheal instillation: 1–50 μg</td>
<td colspan="3" align="left" valign="top" rowspan="1">PVP-coated AgNP: 134nm, 4.5 m
<sup>2</sup>
/g, 7mV</td>
<td align="left" valign="top" rowspan="1" colspan="1"> sensitized mice. Lung microbiome was altered dependent</td>
</tr>
<tr>
<td colspan="2" align="left" valign="top" rowspan="1"></td>
<td colspan="2" align="left" valign="top" rowspan="1"></td>
<td colspan="2" align="center" valign="top" rowspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td colspan="3" align="left" valign="top" rowspan="1">Citrate-AgNP: 20 nm, 30 m
<sup>2</sup>
/g, 45 mV</td>
<td align="left" valign="top" rowspan="1" colspan="1"> on coating.</td>
</tr>
<tr>
<td colspan="2" align="left" valign="top" rowspan="1"></td>
<td colspan="2" align="left" valign="top" rowspan="1">
<xref rid="R432" ref-type="bibr">Seiffert et al. 2015</xref>
</td>
<td colspan="2" align="center" valign="top" rowspan="1">Ag</td>
<td align="left" valign="top" rowspan="1" colspan="1">Brown Norway and Sprague-Dawley rats</td>
<td colspan="3" align="left" valign="top" rowspan="1">PVP-coated AgNP: 20 or iiOnm</td>
<td align="left" valign="top" rowspan="1" colspan="1">Smaller AgNPs increased AHR on d 1, which persisted to d 7 for the</td>
</tr>
<tr>
<td colspan="2" align="left" valign="top" rowspan="1"></td>
<td colspan="2" align="left" valign="top" rowspan="1"></td>
<td colspan="2" align="center" valign="top" rowspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1"> Intratracheal instillation: 0.1 mg/kg</td>
<td colspan="3" align="left" valign="top" rowspan="1">Citrate-capped AgNP: 20 or iiOnm</td>
<td align="left" valign="top" rowspan="1" colspan="1"> citrate AgNPs only. 20 nm AgNP was more pro-inflammatory but</td>
</tr>
<tr>
<td colspan="2" align="left" valign="top" rowspan="1"></td>
<td colspan="2" align="left" valign="top" rowspan="1"></td>
<td colspan="2" align="center" valign="top" rowspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td colspan="3" align="left" valign="top" rowspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1"> little difference between different surface coatings</td>
</tr>
<tr>
<td colspan="2" align="left" valign="top" rowspan="1"></td>
<td colspan="2" align="left" valign="top" rowspan="1">CRY
<xref rid="R163" ref-type="bibr">Horie et al. 2015</xref>
</td>
<td colspan="2" align="center" valign="top" rowspan="1">Zn</td>
<td align="left" valign="top" rowspan="1" colspan="1">F C57BL/6N mouse, Ovalbumin</td>
<td colspan="3" align="left" valign="top" rowspan="1">Rutile TiO
<sub>2</sub>
, AI(OH)
<sub>3</sub>
surf: 30–50 nm 37.1 m
<sup>2</sup>
/g</td>
<td align="left" valign="top" rowspan="1" colspan="1">Serum total and OVA IgE, IgG1 increased in mice treated with the</td>
</tr>
<tr>
<td colspan="2" align="left" valign="top" rowspan="1"></td>
<td colspan="2" align="left" valign="top" rowspan="1"></td>
<td colspan="2" align="center" valign="top" rowspan="1">Ti</td>
<td align="left" valign="top" rowspan="1" colspan="1"> Pharyngeal aspiration: 50 μg</td>
<td colspan="3" align="left" valign="top" rowspan="1">ZnO: 21 nm, 49.6 m
<sup>2</sup>
/g</td>
<td align="left" valign="top" rowspan="1" colspan="1"> uncoated ZnO particle. However, ZnCI
<sub>2</sub>
did not produce similar</td>
</tr>
<tr>
<td colspan="2" align="left" valign="top" rowspan="1"></td>
<td colspan="2" align="left" valign="top" rowspan="1"></td>
<td colspan="2" align="center" valign="top" rowspan="1">Si</td>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td colspan="3" align="left" valign="top" rowspan="1">ZnO, SiO
<sub>2</sub>
Surface: 25 nm, unknown SA, ZnCI
<sub>2</sub>
</td>
<td align="left" valign="top" rowspan="1" colspan="1"> exacerbations. TiO
<sub>2</sub>
and SiO
<sub>2</sub>
did not affect OVA-lgE or IgG levels.</td>
</tr>
<tr>
<td colspan="2" align="left" valign="top" rowspan="1"></td>
<td colspan="2" align="left" valign="top" rowspan="1"></td>
<td colspan="2" align="center" valign="top" rowspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td colspan="3" align="left" valign="top" rowspan="1">Amorphous SiO
<sub>2</sub>
: 7nm 300 m
<sup>2</sup>
/g, 34 nm 80 m
<sup>2</sup>
/g</td>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1">SA</td>
<td colspan="2" align="left" valign="top" rowspan="1">Sandberg</td>
<td colspan="2" align="center" valign="top" rowspan="1">Si</td>
<td colspan="3" align="left" valign="top" rowspan="1">LPS-primed RAW264.7 mouse macrophages, pri-</td>
<td align="left" valign="top" rowspan="1" colspan="1">64 nm Si, 650cm
<sup>2</sup>
/mg</td>
<td colspan="2" align="left" valign="top" rowspan="1">Non-crystalline SiO
<sub>2</sub>
particles in both nano and micron size ranges</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td colspan="2" align="left" valign="top" rowspan="1">et al. 2012</td>
<td colspan="2" align="center" valign="top" rowspan="1"></td>
<td colspan="3" align="left" valign="top" rowspan="1"> mary rat lung macrophages</td>
<td align="left" valign="top" rowspan="1" colspan="1">369 nm Si, 90 cm
<sup>2</sup>
/mg</td>
<td colspan="2" align="left" valign="top" rowspan="1"> induced IL-1β release from LPS-primed macrophages following</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td colspan="2" align="left" valign="top" rowspan="1"></td>
<td colspan="2" align="center" valign="top" rowspan="1"></td>
<td colspan="3" align="left" valign="top" rowspan="1"> 0, 50, 100, 250, 500 μg/mL, 6h</td>
<td align="left" valign="top" rowspan="1" colspan="1">~20nm Fumed Si (aerosol), 1880cm
<sup>2</sup>
/mg 500nm-10 μm Fused Si (suprasil), 23cm
<sup>2</sup>
/mg</td>
<td colspan="2" align="left" valign="top" rowspan="1"> uptake, phagosomal leakage, and activation of the NALP3 inflam-</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td colspan="2" align="left" valign="top" rowspan="1"></td>
<td colspan="2" align="center" valign="top" rowspan="1"></td>
<td colspan="3" align="left" valign="top" rowspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td colspan="2" align="left" valign="top" rowspan="1"> masome. Particle surface area, reactivity, and uptake all influenced</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td colspan="2" align="left" valign="top" rowspan="1"></td>
<td colspan="2" align="center" valign="top" rowspan="1"></td>
<td colspan="3" align="left" valign="top" rowspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td colspan="2" align="left" valign="top" rowspan="1"> the degree of mediator release by cells</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td colspan="2" align="left" valign="top" rowspan="1">Vandebriel</td>
<td colspan="2" align="center" valign="top" rowspan="1">Ti</td>
<td colspan="3" align="left" valign="top" rowspan="1">F BALB/c mouse, Ovalbumin</td>
<td align="left" valign="top" rowspan="1" colspan="1">Uncoated TiO
<sub>2</sub>
NP:</td>
<td colspan="2" align="left" valign="top" rowspan="1">Rutile TiO
<sub>2</sub>
NP caused the greatest increase in OVA-specific serum IgE</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td colspan="2" align="left" valign="top" rowspan="1">et al. 2018</td>
<td colspan="2" align="center" valign="top" rowspan="1"></td>
<td colspan="3" align="left" valign="top" rowspan="1"> Intranasal exposure: 120 μg TiO
<sub>2</sub>
</td>
<td align="left" valign="top" rowspan="1" colspan="1">10–30 nm rutile or 10–25 nm anatase</td>
<td colspan="2" align="left" valign="top" rowspan="1"> and IgGI. Neutrophils recruited by rutile, but not anatase</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td colspan="2" align="left" valign="top" rowspan="1">SOL
<xref rid="R185" ref-type="bibr">Jeong et al. 2015</xref>
</td>
<td colspan="2" align="center" valign="top" rowspan="1">Co</td>
<td colspan="3" align="left" valign="top" rowspan="1">F Rat, Intratracheal Instillation</td>
<td align="left" valign="top" rowspan="1" colspan="1">CoO: 65.4± 2.8 nm, 92.65% solubility</td>
<td colspan="2" align="left" valign="top" rowspan="1">Soluble CoNP induced eosinophilic inflammation, whereas insoluble</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td colspan="2" align="left" valign="top" rowspan="1"></td>
<td colspan="2" align="center" valign="top" rowspan="1"></td>
<td colspan="3" align="left" valign="top" rowspan="1"> 80, 200, 800 μg/mL @ 0.5 mL</td>
<td align="left" valign="top" rowspan="1" colspan="1">Co
<sub>3</sub>
O
<sub>4</sub>
: 20.2 ± 0.4 nm, 11.46% solubility</td>
<td colspan="2" align="left" valign="top" rowspan="1"> CoONP induced neutrophilic inflammation</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td colspan="2" align="left" valign="top" rowspan="1">
<xref rid="R65" ref-type="bibr">Cho et al. 2011</xref>
</td>
<td colspan="2" align="center" valign="top" rowspan="1">Zn</td>
<td colspan="3" align="left" valign="top" rowspan="1">F Wistar rat</td>
<td align="left" valign="top" rowspan="1" colspan="1">10.7±0.7nm ZnONP 50 or 150cm
<sup>2</sup>
/rat</td>
<td colspan="2" align="left" valign="top" rowspan="1">ZnONP induced eosinophilia, proliferation of airway epithelial cells,</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td colspan="2" align="left" valign="top" rowspan="1"></td>
<td colspan="2" align="center" valign="top" rowspan="1"></td>
<td colspan="3" align="left" valign="top" rowspan="1"> Intratracheal instillation</td>
<td align="left" valign="top" rowspan="1" colspan="1">Zn
<sup>2+</sup>
ions 92.5 μg/rat</td>
<td colspan="2" align="left" valign="top" rowspan="1"> goblet cell hyperplasia, and increased IgE levels, and decreased</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td colspan="2" align="left" valign="top" rowspan="1"></td>
<td colspan="2" align="center" valign="top" rowspan="1"></td>
<td colspan="3" align="left" valign="top" rowspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td colspan="2" align="left" valign="top" rowspan="1"> IgA- findings which were also seen following instillation of Zn ions</td>
</tr>
</tbody>
</table>
<table-wrap-foot>
<fn id="TFN6">
<p id="P141">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</p>
</fn>
</table-wrap-foot>
</table-wrap>
<table-wrap id="T7" position="float" orientation="landscape">
<label>Table 7.</label>
<caption>
<p id="P142">Metal nanomaterials and corresponding physicochemical properties shown to influence immunological processes involved in the development and augmentation of asthma.</p>
</caption>
<table frame="hsides" rules="groups">
<colgroup span="1">
<col align="left" valign="middle" span="1"></col>
<col align="left" valign="middle" span="1"></col>
<col align="left" valign="middle" span="1"></col>
<col align="left" valign="middle" span="1"></col>
<col align="left" valign="middle" span="1"></col>
</colgroup>
<thead>
<tr>
<th align="left" valign="middle" rowspan="1" colspan="1">AOP step</th>
<th align="center" valign="middle" rowspan="1" colspan="1">Metal nanomaterial effect</th>
<th align="left" valign="middle" rowspan="1" colspan="1">Metal</th>
<th align="center" valign="middle" rowspan="1" colspan="1">Properties implicated</th>
<th align="center" valign="middle" rowspan="1" colspan="1">Source</th>
</tr>
</thead>
<tbody>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1"> Sensitization Bioavailability</td>
<td align="left" valign="top" rowspan="1" colspan="1">Increased potential for inhalation</td>
<td align="left" valign="top" rowspan="1" colspan="1">many</td>
<td align="left" valign="top" rowspan="1" colspan="1">dustiness</td>
<td align="left" valign="top" rowspan="1" colspan="1">Evans et al. 2003</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">Evasion of uptake by pulmonary macrophages</td>
<td align="left" valign="top" rowspan="1" colspan="1">Si</td>
<td align="left" valign="top" rowspan="1" colspan="1">size, crg, mod</td>
<td align="left" valign="top" rowspan="1" colspan="1">
<xref rid="R339" ref-type="bibr">Oh et al. 2010</xref>
</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">Evasion of entrapment by pulmonary mucus</td>
<td align="left" valign="top" rowspan="1" colspan="1">ND</td>
<td align="left" valign="top" rowspan="1" colspan="1">size, crg</td>
<td align="left" valign="top" rowspan="1" colspan="1">
<xref rid="R316" ref-type="bibr">Murgia et al. 2016</xref>
</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">Prolonged retention in airways</td>
<td align="left" valign="top" rowspan="1" colspan="1">Al</td>
<td align="left" valign="top" rowspan="1" colspan="1">spec, mor</td>
<td align="left" valign="top" rowspan="1" colspan="1">Park et al. 2017</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">Direct translocation across lung epithelial tissue to lymphatics</td>
<td align="left" valign="top" rowspan="1" colspan="1">Au</td>
<td align="left" valign="top" rowspan="1" colspan="1">size, crg</td>
<td align="left" valign="top" rowspan="1" colspan="1">Kreyling et al. 2014</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1"> Molecular initating event</td>
<td align="left" valign="top" rowspan="1" colspan="1">Increased potential for metal antigen formation</td>
<td align="left" valign="top" rowspan="1" colspan="1">Ti</td>
<td align="left" valign="top" rowspan="1" colspan="1">size</td>
<td align="left" valign="top" rowspan="1" colspan="1">
<xref rid="R492" ref-type="bibr">Vamanu et al. 2008</xref>
</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">Increased protease activity of protein allergens</td>
<td align="left" valign="top" rowspan="1" colspan="1">Au</td>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">
<xref rid="R387" ref-type="bibr">Radauer-Preiml et al. 2016</xref>
</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1"> Cellular response</td>
<td align="left" valign="top" rowspan="1" colspan="1">Adsorption of LPS to nanomaterial surface</td>
<td align="left" valign="top" rowspan="1" colspan="1">Au</td>
<td align="left" valign="top" rowspan="1" colspan="1">size, hyd, mod</td>
<td align="left" valign="top" rowspan="1" colspan="1">
<xref rid="R248" ref-type="bibr">Li et al. 2017</xref>
</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">Increased recruitment of DC to lung</td>
<td align="left" valign="top" rowspan="1" colspan="1">Al</td>
<td align="left" valign="top" rowspan="1" colspan="1">mod</td>
<td align="left" valign="top" rowspan="1" colspan="1">Li et al. 2010</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">Direct activation of DC</td>
<td align="left" valign="top" rowspan="1" colspan="1">Ti</td>
<td align="left" valign="top" rowspan="1" colspan="1">size, cry</td>
<td align="left" valign="top" rowspan="1" colspan="1">
<xref rid="R511" ref-type="bibr">Winter et al. 2011</xref>
</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">Release of DAMPs from immune cells > activation of DC</td>
<td align="left" valign="top" rowspan="1" colspan="1">Zn</td>
<td align="left" valign="top" rowspan="1" colspan="1">size, mor, SA</td>
<td align="left" valign="top" rowspan="1" colspan="1">Hsaio et al. 2011</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">Release of DAMPs from epithelial cells > activation of DC</td>
<td align="left" valign="top" rowspan="1" colspan="1">Ag</td>
<td align="left" valign="top" rowspan="1" colspan="1">size, mod, SA, sol</td>
<td align="left" valign="top" rowspan="1" colspan="1">
<xref rid="R141" ref-type="bibr">Hamilton et al. 2014</xref>
</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1"> Organ response</td>
<td align="left" valign="top" rowspan="1" colspan="1">Increased CD4
<sup>þ</sup>
T-cell presentation efficiency</td>
<td align="left" valign="top" rowspan="1" colspan="1">Ti</td>
<td align="left" valign="top" rowspan="1" colspan="1">size, mor, cry</td>
<td align="left" valign="top" rowspan="1" colspan="1">Schanen et al. 2009</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">Increased polarization of CD4
<sup>þ</sup>
T-cells to T
<sub>H</sub>
2 phenotype</td>
<td align="left" valign="top" rowspan="1" colspan="1">Si</td>
<td align="left" valign="top" rowspan="1" colspan="1">size, mod, SA</td>
<td align="left" valign="top" rowspan="1" colspan="1">
<xref rid="R491" ref-type="bibr">Vallhov et al. 2012</xref>
</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">Increased number of B-cells</td>
<td align="left" valign="top" rowspan="1" colspan="1">Ti</td>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">
<xref rid="R359" ref-type="bibr">Park et al. 2009</xref>
</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">Alteration in B-cell expansion/maturation</td>
<td align="left" valign="top" rowspan="1" colspan="1">Au</td>
<td align="left" valign="top" rowspan="1" colspan="1">size</td>
<td align="left" valign="top" rowspan="1" colspan="1">
<xref rid="R241" ref-type="bibr">Lee et al. 2014</xref>
</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">Increased production of total IgE</td>
<td align="left" valign="top" rowspan="1" colspan="1">Pt</td>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">
<xref rid="R353" ref-type="bibr">Park et al. 2010b</xref>
</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">Increased production of allergen-specific IgE</td>
<td align="left" valign="top" rowspan="1" colspan="1">Zn</td>
<td align="left" valign="top" rowspan="1" colspan="1">size, sol, cry</td>
<td align="left" valign="top" rowspan="1" colspan="1">
<xref rid="R163" ref-type="bibr">Horie et al. 2015</xref>
</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1">Elicitation</td>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1">  Organism response-early phase reaction</td>
<td align="left" valign="top" rowspan="1" colspan="1">Increased IgE-dependent mast cell degranulation</td>
<td align="left" valign="top" rowspan="1" colspan="1">Au</td>
<td align="left" valign="top" rowspan="1" colspan="1">size, mod</td>
<td align="left" valign="top" rowspan="1" colspan="1">
<xref rid="R169" ref-type="bibr">Huang et al. 2009</xref>
</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">Increased IgE-independent mast cell degranulation</td>
<td align="left" valign="top" rowspan="1" colspan="1">many</td>
<td align="left" valign="top" rowspan="1" colspan="1">size, SA, crg</td>
<td align="left" valign="top" rowspan="1" colspan="1">
<xref rid="R191" ref-type="bibr">Johnson et al. 2017</xref>
</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">Increased number of lung mast cells</td>
<td align="left" valign="top" rowspan="1" colspan="1">Ce</td>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">
<xref rid="R294" ref-type="bibr">Meldrum et al. 2018</xref>
</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">Altered mast cell exocytic function and granule release</td>
<td align="left" valign="top" rowspan="1" colspan="1">Si</td>
<td align="left" valign="top" rowspan="1" colspan="1">SA</td>
<td align="left" valign="top" rowspan="1" colspan="1">
<xref rid="R290" ref-type="bibr">Maurer-Jones et al. 2010</xref>
</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">Altered expression of Fc receptors on immune cells</td>
<td align="left" valign="top" rowspan="1" colspan="1">Ti</td>
<td align="left" valign="top" rowspan="1" colspan="1">size</td>
<td align="left" valign="top" rowspan="1" colspan="1">
<xref rid="R260" ref-type="bibr">Liu et al. 2010</xref>
</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1">  Organism response- late phase reaction</td>
<td align="left" valign="top" rowspan="1" colspan="1">Increased endothelial adhesion molecule expression</td>
<td align="left" valign="top" rowspan="1" colspan="1">Al</td>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">Oesterling et al. 2008</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">Increased neutrophil recruitment</td>
<td align="left" valign="top" rowspan="1" colspan="1">Ag</td>
<td align="left" valign="top" rowspan="1" colspan="1">size, sol</td>
<td align="left" valign="top" rowspan="1" colspan="1">
<xref rid="R15" ref-type="bibr">Arai et al. 2015</xref>
</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">Increased eosinophil recruitment</td>
<td align="left" valign="top" rowspan="1" colspan="1">Co</td>
<td align="left" valign="top" rowspan="1" colspan="1">sol</td>
<td align="left" valign="top" rowspan="1" colspan="1">
<xref rid="R185" ref-type="bibr">Jeong et al. 2015</xref>
</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">Increased lymphocyte recruitment</td>
<td align="left" valign="top" rowspan="1" colspan="1">Zr</td>
<td align="left" valign="top" rowspan="1" colspan="1">mod</td>
<td align="left" valign="top" rowspan="1" colspan="1">
<xref rid="R497" ref-type="bibr">Vennemann et al. 2017</xref>
</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">Increased AHR</td>
<td align="left" valign="top" rowspan="1" colspan="1">Ag</td>
<td align="left" valign="top" rowspan="1" colspan="1">size, mod</td>
<td align="left" valign="top" rowspan="1" colspan="1">
<xref rid="R432" ref-type="bibr">Seiffert et al. 2015</xref>
</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">Increased airway smooth muscle contractility</td>
<td align="left" valign="top" rowspan="1" colspan="1">Co/Fe</td>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">
<xref rid="R200" ref-type="bibr">Kapilevich et al. 2012</xref>
</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">Mucus cell metaplasia/muus hyeprsecretion</td>
<td align="left" valign="top" rowspan="1" colspan="1">Ti</td>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">
<xref rid="R60" ref-type="bibr">Chen et al. 2011</xref>
</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1">  Chronic effects</td>
<td align="left" valign="top" rowspan="1" colspan="1">Epithelial cell proliferation</td>
<td align="left" valign="top" rowspan="1" colspan="1">Zn</td>
<td align="left" valign="top" rowspan="1" colspan="1">sol</td>
<td align="left" valign="top" rowspan="1" colspan="1">
<xref rid="R65" ref-type="bibr">Cho et al. 2011</xref>
</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">Increased fibroblast MMP activity extracellular matrix remodeling</td>
<td align="left" valign="top" rowspan="1" colspan="1">Ti</td>
<td align="left" valign="top" rowspan="1" colspan="1">size, cry, mor</td>
<td align="left" valign="top" rowspan="1" colspan="1">Armand et al. 2012</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">Myofibroblast accumulation</td>
<td align="left" valign="top" rowspan="1" colspan="1">Cu</td>
<td align="left" valign="top" rowspan="1" colspan="1"></td>
<td align="left" valign="top" rowspan="1" colspan="1">Lai et al. 2018</td>
</tr>
</tbody>
</table>
<table-wrap-foot>
<fn id="TFN7">
<p id="P143">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.</p>
</fn>
</table-wrap-foot>
</table-wrap>
</floats-group>
</pmc>
</record>

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