<!DOCTYPE html> <html lang="en"> <div class="pull-right"> <h1>SNAPSHOT</h1> <h4>Created at: 2020-05-26 00:39</h4> </div> <!-- Title Section, includes id, name and short name --> <div id="title"> <h2>AOP ID and Title:</h2> <hr> < div class="title"> AOP 282: Reactive oxygen species generated from photoreactive chemicals leading to photo toxic reactions </div> <div class="title">AOP 282: Adverse outcome pathway on photochemical toxicity initiated by light exposure </div> <strong>Short Title: ROS-mediated chemical phototoxicity</strong> <br></div> <!-- graphical representation --> <h2>Graphical Representation</h2> <img src="https://aopwiki.org/system/dragonfly/production/2019/04/02/4fizjsebq_AOP_Graphic_Template_ROS_20190402 .jpg" , height="500" , width="700"> </img> <!-- end graphical representation --> <hr > <h2>Graphical Representation</h2> <img src="https://test. aopwiki.org/system/dragonfly/production/2022/03/14/pwd6qnmck_Flow_diagram_220314 .jpg" height="500" width="700" alt=""/ > <!-- Author section, includes text of author names as they have been entered by the user --><div id="authors"> <h2>Authors</h2> <hr> < p><span style="font-family:arial,helvetica,sans-serif">Yoshiki Seto, Satomi Onoue</span></p> <p><span style="font-family:arial,helvetica,sans-serif">Satomi Onoue, Yoshiki Seto </span></p> <p><span style="font-family:arial,helvetica,sans-serif">Laboratory of Biopharmacy, School of Pharmaceutical Sciences, University of Shizuoka</span></p> <p><span style="font-family:arial,helvetica,sans-serif">Corresponding Author: Satomi Onoue</span></p> <br></div> <!-- Status Section, lists status of aop --><div id="status"> <h2>Status</h2> panel panel-default "> <table class="table table-bordered table-striped "> <thead> <th >Author status</th> <th >OECD status</th> <th >OECD project</th> <th >SAAOP status</th> <div class="table-responsive "> <table class="table table-bordered table-fullwidth "> <thead class="thead-light" > <tr> <th scope="col" >Author status</th> <th scope="col" >OECD status</th> <th scope="col" >OECD project</th> <th scope="col" >SAAOP status</th> </tr> </thead> <tbody class="tbody-striped"> <tr> <td>Under development: Not open for comment. Do not cite</td> <td>EAGMST Under Review</td> <td>Under Review</td> <td>1.49</td> <td>Included in OECD Work Plan</td> </tr> </tbody> </table> </div> </div> <!-- Abstract Section, text as generated by author --><div id="abstract"> <h2>Abstract</h2> <hr> <p><span style="font-family:arial,helvetica,sans-serif">Phototoxicity is an adverse reaction in the light-exposed tissues triggered by normally harmless doses of sunlight <!--[if supportFields]><span <h2>Abstract</h2> <p><span style="font-family:arial,helvetica,sans-serif">Phototoxicity is an adverse reaction in the light-exposed tissues triggered by normally harmless doses of sunlight <!--[if supportFields]><span lang=EN-US style='font-size:10.5pt;font-family:"Times New Roman","serif"; mso-fareast-font-family:"ＭＳ 明朝";mso-fareast-theme-font:minor-fareast; mso-ansi-language:EN-US;mso-fareast-language:JA;mso-bidi-language:AR-SA'><span style='mso-element:field-begin'></span><span style='mso-spacerun:yes'> </span>ADDIN EN.CITE <span style='mso-element:field-begin'></span><span style='mso-spacerun:yes'> </span>ADDIN EN.CITE.DATA <![if gte mso 9]><xml> 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Recently, high-intensity UV rays from the sun have reached the Earth’s surface with the destruction of the ozone layer, and interest in phototoxic events has increased enormously. Notably, phototoxic reactions against exogenous agents are caused by the combined effects of environmental light and external agents, including drugs, cosmetics, and foods <!--[if supportFields]><span lang=EN-US style='font-size:10.5pt;font-family:"Times New Roman","serif"; mso-fareast-font-family:"ＭＳ 明朝";mso-fareast-theme-font:minor-fareast; mso-ansi-language:EN-US;mso-fareast-language:JA;mso-bidi-language:AR-SA'><span style='mso-element:field-begin'></span><span style='mso-spacerun:yes'> </span>ADDIN EN.CITE <span style='mso-element:field-begin'></span><span style='mso-spacerun:yes'> </span>ADDIN EN.CITE.DATA <![if gte mso 9]><xml> 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</xml><![endif]><span style='mso-element:field-end'></span><span style='mso-element:field-separator'></span></span><![endif]-->(Epstein, 1983; Stein and Scheinfeld, 2007)<!--[if gte mso 9]><xml> 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</xml><![endif]--><!--[if supportFields]><span lang=EN-US style='font-size:10.5pt;font-family:"Times New Roman","serif";mso-fareast-font-family: "ＭＳ 明朝";mso-fareast-theme-font:minor-fareast;mso-ansi-language:EN-US; mso-fareast-language:JA;mso-bidi-language:AR-SA'><span style='mso-element:field-end'></span></span><![endif]-->. </span><!--![endif]----><!--![endif]----><!--![endif]----></p> <p> </p> <p><span style="font-family:arial,helvetica,sans-serif">In this AOP, the primary trigger for a compound to be considered with respect to potential to create photochemical and photobiological reactions is the absorption of photon energy from light ranging from 290 to 700 nm. The extent of absorption depends on the wavelength of light and the type of absorbing chromophores in the light-exposed tissues. A molecule is excited by absorption of photon energy, and the photoactivated molecule induces photochemical reactions via energy transfer (type I photochemical reaction) and free radical generation (type II photochemical reaction). These photochemical reactions result in generation of radicals and reactive oxygen species, and the reactive species react with biomolecules. Generated radicals of a target chemical bind to DNA and proteins, resulting in formation of these photo-adducts, and reactive oxygen species (ROS), including singlet oxygen and superoxide, induce oxidation of biomolecules. These key events bring inflammatory events in the light-exposed tissues <!--[if supportFields]><span lang=EN-US style='font-size:10.5pt;font-family:"Times New Roman","serif";mso-fareast-font-family: "ＭＳ 明朝";mso-fareast-theme-font:minor-fareast;mso-ansi-language:EN-US; mso-fareast-language:JA;mso-bidi-language:AR-SA'><span style='mso-element:field-begin'></span><span style='mso-spacerun:yes'> </span>ADDIN EN.CITE <span style='mso-element:field-begin'></span><span style='mso-spacerun:yes'> </span>ADDIN EN.CITE.DATA <![if gte mso 9]><xml> 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</xml><![endif]><span style='mso-element:field-end'></span><span style='mso-element:field-separator'></span></span><![endif]-->(Brendler-Schwaab et al. , 2004; Epstein and Wintroub, 1985; Quintero and Miranda, 2000)<!--[if gte mso 9]><xml> 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</xml><![endif]--><!--[if supportFields]><span lang=EN-US style='font-size:10.5pt;font-family:"Times New Roman","serif";mso-fareast-font-family: "ＭＳ 明朝";mso-fareast-theme-font:minor-fareast;mso-ansi-language:EN-US; mso-fareast-language:JA;mso-bidi-language:AR-SA'><span style='mso-element:field-end'></span></span><![endif]-->.</span></p> <p> </p> <p><span style="font-family:arial,helvetica,sans-serif">This AOP describes the pathway of photochemical toxicity between attack of ROS generated from photoactivated chemicals to membranes and inflammatory events in light-exposed tissues.</span></p> <br></div> <!-- Background Section, text as generated by author --> <div id="background"> <h2>AOP Development Strategy</h2> <div id="context"> <h3>Context</h3> <p>The primary event in any photosensitization process can be the absorption of photons of the appropriate wavelength, which allows chromophore to reach an excited state. The excitation energy is often transferred to oxygen molecules, followed by generation of ROS. These appear to be the principal intermediate species in the phototoxic response. In cells, this cascade gives rise to local oxidative stress and damage to genomic DNA, proteins, and lipids within cell membranes. From the standpoint of risk assessment, ROS generation from photoirradiated chemicals has been considered to be one of key determinants in recognizing their phototoxic potential. The ROS assay has been designed to assess photoreactivity of pharmaceuticals, of which the principle is to monitor types I and II photochemical reactions of the test chemicals when exposed to simulated sunlight. This simple analytical test could be used to screen potential chemical scaffolds, leads, and candidate drugs to identify and/or select away from those having phototoxic potential. The validation study for the ROS assay has been carried out by the Japan Pharmaceutical Manufacturers Association (JPMA), supervised by the Japanese Center for the Validation of Alternative Methods (JaCVAM). The validation study indicates satisfactory outcomes in terms of transferability, intra- and inter-laboratory variability, and predictive capacity. Thus, a negative result in this ROS assay would indicate a very low probability of phototoxicity, whereas a positive result would be a flag for follow-up assessment. ROS assay was successfully adopted as ICH S10 guideline (2014) and OECD test guideline 495 (2019).</p> <br> </div> <!-- AOP summary, includes summary of each of the events associated with this aop --><div id="aop_summary"> <h2>Summary of the AOP</h2> <!-- event table --> <h3>Events</h3> <h3>Molecular Initiating Events (MIE), Key Events (KE), Adverse Outcomes (AO)</h3> <div class="panel panel-default "> <table class="table table-bordered table-striped" > < thead> <h3>Molecular Initiating Events (MIE), Key Events (KE), Adverse Outcomes (AO)</h3> <div class="table-responsive "> <table class="table table-bordered table-fullwidth"> <thead class="thead-light"> <tr> <th scope="col">Sequence</th> <th scope="col">Type</th> <th scope="col">Event ID</th> <th scope="col">Title</th> <th scope="col">Short name</th > </tr> </ thead> <tbody> <tr> <th>Sequence</th > <th>Type</th > <th>Event ID</th > <th>Title</th > <th>Short name</th > <td></td > <td>MIE</td > <td>1115</td > <td><a href="/events/1115">Increase, Reactive oxygen species</a></td > <td>Increase, ROS</td > </tr> </thead> <tbody> <tr> <td></td> <td>MIE</td> <td>1592</td> <td><a href="/events/1592">ROS generation from photoactivated chemicals</a></td> <td>ROS generation</td> </tr> <tr><td></td><td></td><td></td><td></td><td></td></tr> <tr> <td></td> <td>KE </td> <td>1594 </td> <td><a href="/events/1594">Oxidation of membrane lipids</a ></td> <td>Oxidation of membrane lipids </td> </tr> <tr> <td></td> <td>KE</td> <td>1595</td> <td><a href="/events/1595">Oxidation/denatuation of membrane proteins</a></td> <td>Oxidation/denatuation of membrane proteins</td> </tr> <tr><td></td><td></td><td></td><td></td><td></td></tr> <tr> <td></td> <td>AO</td> <td>1599</td> <td><a href="/events/1599">Inflamatory events in light-exposed tissues</a></td> <td>Inflammatory events</td> </tr> </tbody> </table> </div> <!-- rel table --> <h3>Key Event Relationships</h3> <div class="panel panel-default"> <table class="table table-bordered table-striped"> <thead> <tr> <td></td><td></td><td></td><td ></td><td></td></tr> <tr> <th>Upstream Event</th > <th>Rel ationship Type</th > <th>Downstream Event</th > <th>Evidence</th > <th>Quantitative Understanding</th > <td></td> <td>KE</td> <td>1594</td > <td><a href="/events/1594">Oxid ation of membrane lipids</a></td > <td>Oxidation of membrane lipids</td> </tr> <tr> <td></td > <td>KE</td> <td>1595</td > <td><a href="/events/1595">Oxidation/denatuation of membrane proteins</a></td> <td>Oxidation/denatuation of membrane proteins</td > </tr> </thead> <tbody> <tr> <td><a href="/relationships/1845">ROS generation from photoactivated chemicals</a></td> <td>adjacent</td> <td>Oxidation of membrane lipids</td> <td>High</td> <td>Low</td> </tr> <tr> <td><a href="/relationships/1846">ROS generation from photoactivated chemicals</a></td> <td>adjacent</td> <td>Oxidation/denatuation of membrane proteins</td> <td>High</td> <td>Low</td> </tr> <tr> <td><a href="/relationships/1850">Oxidation of membrane lipids</a></td> <td>adjacent</td> <td>Inflamatory events in light-exposed tissues</td> <td>High</td> <td>Low</td> </tr> <tr> <td><a href="/relationships/1851">Oxidation/denatuation of membrane proteins</a></td> <td>adjacent</td> <td>Inflamatory events in light-exposed tissues</td> <td>High</td> <td>Low</td> </tr> <tr><td></td><td></td><td></td><td></td><td></td></tr> </tbody> </table> </div> <!-- stressor table --> <h3>Stressors</h3> <br> <div class="panel panel-default"> <table class="table table-bordered table-striped"> <thead> <tr> <th>Name</th > <th>Evidence</th > <td></td> <td>AO</td > <td>1599</td> <td><a href="/events/1599">Inflamatory events in light-exposed tissues</a></td> <td>Inflammatory events</td > </tr> </thead> <t body> <tr> <td>Light (290-700 nm)</td> <td>High</td> </tr> <tr> <td>Photoreactive chemicals</td> <td>High</td> </tr> <tr> <td>Reactive oxygen species</td> <td>High</td> </tr> </tbody> </table> </div> </t body> </table> </div> <h3>Key Event Relationships</h3> <div class="table-responsive"> <table class="table table-bordered table-fullwidth"> <thead class="thead-light"> <tr> <th scope="col">Upstream Event</th> <th scope="col">Relationship Type</th> <th scope="col">Downstream Event</th> <th scope="col">Evidence</th> <th scope="col">Quantitative Understanding</th> </tr> </thead> <tbody class="tbody-striped"> <tr> <td><a href="/relationships/3513">Increase, Reactive oxygen species</a></td> <td>adjacent</td> <td>Oxidation of membrane lipids</td> <td>High</td> <td>Low</td> </tr> <tr> <td><a href="/relationships/3514">Increase, Reactive oxygen species</a></td> <td>adjacent</td> <td>Oxidation/denatuation of membrane proteins</td> <td>High</td> <td>Low</td> </tr> <tr> <td><a href="/relationships/1850">Oxidation of membrane lipids</a></td> <td>adjacent</td> <td>Inflamatory events in light-exposed tissues</td> <td>High</td> <td>Low</td> </tr> <tr> <td><a href="/relationships/1851">Oxidation/denatuation of membrane proteins</a></td> <td>adjacent</td> <td>Inflamatory events in light-exposed tissues</td> <td>High</td> <td>Low</td> </tr> <tr> <td></td> <td></td> <td></td> <td></td> <td></td> </tr> </tbody> </table> </div> <h3>Stressors</h3> <div class="table-responsive"> <table class="table table-bordered table-fullwidth"> <thead class="thead-light"> <tr> <th scope="col">Name</th> <th scope="col">Evidence</th> </tr> </thead> <tbody class="tbody-striped"> <tr> <td>Light (290-700 nm)</td> <td>High</td> </tr> <tr> <td>Photoreactive chemicals</td> <td>High</td> </tr> <tr> <td>Reactive oxygen species</td> <td>High</td> </tr> </tbody> </table> </div> </div> <!-- end summary --><!-- Overall assessment section, *** what is included here? *** --><div id="overall_assessment"> <h2>Overall Assessment of the AOP</h2> <p><span style="font-family:arial,helvetica,sans-serif">The focus of this AOP is on photochemical toxicity, especially photoactivation of target chemicals followed by generation of ROS. ROS generated from photoirradiated chemicals can react with molecules on the membranes, including lipids and proteins, and the reactions may lead to inflammatory events in the UV-exposed tissues. </span></p> <p><span style="font-family:arial,helvetica,sans-serif">The focus of this AOP is on photochemical toxicity, especially photoactivation of target chemicals followed by generation of ROS. ROS generated from photoirradiated chemicals can react with molecules on the membranes, including lipids and proteins, and the reactions may lead to inflammatory events in the UV-exposed tissues. </span></p> <p> </p> <p><span style="font-family:arial,helvetica,sans-serif">Phototoxicity is an adverse reaction triggered by normally harmless doses of sunlight. There are two types of photosensitive disorders, endogenous and exogenous phototoxicity, and the observable changes to the sunlight-exposed tissues are essentially detrimental, and include the following appearance; (i) immediate faint erythema during exposure, (ii) delayed erythemal responses, (iii) abnormal keratinisation and vacuolated cells, (iv) formation of desquamating layer, and (v) desquamation (peeling) <!--[if supportFields]><span lang=EN-US style='font-size:10.5pt; font-family:"Times New Roman","serif";mso-fareast-font-family:"ＭＳ 明朝"; mso-fareast-theme-font:minor-fareast;mso-ansi-language:EN-US;mso-fareast-language: JA;mso-bidi-language:AR-SA'><span style='mso-element:field-begin'></span><span style='mso-spacerun:yes'> </span>ADDIN EN.CITE <span style='mso-element:field-begin'></span><span style='mso-spacerun:yes'> </span>ADDIN EN.CITE.DATA <![if gte mso 9]><xml> 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</xml><![endif]><span style='mso-element:field-end'></span><span style='mso-element:field-separator'></span></span><![endif]-->(Moore, 1998; Moore, 2002; Roberts, 2001)<!--[if gte mso 9]><xml> 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</xml><![endif]--><!--[if supportFields]><span lang=EN-US style='font-size:10.5pt;font-family:"Times New Roman","serif";mso-fareast-font-family: "ＭＳ 明朝";mso-fareast-theme-font:minor-fareast;mso-ansi-language:EN-US; mso-fareast-language:JA;mso-bidi-language:AR-SA'><span style='mso-element:field-end'></span></span><![endif]-->. Recently, high-intensity UV rays from the sun have reached the Earth’s surface with the destruction of the ozone layer, and interest in phototoxic events has increased enormously. Notably, phototoxic reactions against exogenous agents are caused by the combined effects of UV irradiation and external agents, including drugs, cosmetics and foods <!--[if supportFields]><span lang=EN-US style='font-size:10.5pt;font-family:"Times New Roman","serif"; mso-fareast-font-family:"ＭＳ 明朝";mso-fareast-theme-font:minor-fareast; mso-ansi-language:EN-US;mso-fareast-language:JA;mso-bidi-language:AR-SA'><span style='mso-element:field-begin'></span><span style='mso-spacerun:yes'> </span>ADDIN EN.CITE <EndNote><Cite><Author>Stein</Author><Year>2007</Year><RecNum>47</RecNum><DisplayText>(Stein and Scheinfeld, 2007)</DisplayText><record><rec-number>47</rec-number><foreign-keys><key app="EN" db-id="wadztfe5qpsstuefdflp9wxupps099f2vvw2">47</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Stein, K. R.</author><author>Scheinfeld, N. S.</author></authors></contributors><auth-address>New York Medical College, Department of Dermatology, Metropolitan Hospital Center, New York, NY 10029, USA.</auth-address><titles><title>Drug-induced photoallergic and phototoxic reactions</title><secondary-title>Expert Opin Drug Saf</secondary-title></titles><pages>431-43</pages><volume>6</volume><number>4</number><keywords><keyword>Allergens/*adverse effects</keyword><keyword>Animals</keyword><keyword>Dermatitis, Photoallergic/*diagnosis/immunology/pathology</keyword><keyword>Dermatitis, Phototoxic/*diagnosis/immunology/pathology</keyword><keyword>Humans</keyword><keyword>Photosensitivity Disorders/*diagnosis/etiology/pathology</keyword><keyword>Ultraviolet Rays/adverse effects</keyword></keywords><dates><year>2007</year><pub-dates><date>Jul</date></pub-dates></dates><accession-num>17688387</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;dopt=Citation&amp;list_uids=17688387</url></related-urls></urls></record></Cite></EndNote><span style='mso-element:field-separator'></span></span><![endif]-->(Stein and Scheinfeld, 2007)<!--[if supportFields]><span lang=EN-US style='font-size:10.5pt;font-family:"Times New Roman","serif"; mso-fareast-font-family:"ＭＳ 明朝";mso-fareast-theme-font:minor-fareast; mso-ansi-language:EN-US;mso-fareast-language:JA;mso-bidi-language:AR-SA'><span style='mso-element:field-end'></span></span><![endif]-->. Phototoxic skin responses after administration of photosensitive drugs, so-called drug-induced phototoxicity, have been recognized as undesirable side effects, and several classes of drugs, even when not toxic by themselves, may become reactive under exposure to environmental light, inducing undesired phototoxic responses <!--[if supportFields]><span lang=EN-US style='font-size:10.5pt;font-family:"Times New Roman","serif"; mso-fareast-font-family:"ＭＳ 明朝";mso-fareast-theme-font:minor-fareast; mso-ansi-language:EN-US;mso-fareast-language:JA;mso-bidi-language:AR-SA'><span style='mso-element:field-begin'></span><span style='mso-spacerun:yes'> </span>ADDIN EN.CITE <EndNote><Cite><Author>Epstein</Author><Year>1983</Year><RecNum>38</RecNum><DisplayText>(Epstein, 1983)</DisplayText><record><rec-number>38</rec-number><foreign-keys><key app="EN" db-id="wadztfe5qpsstuefdflp9wxupps099f2vvw2">38</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Epstein, J. H.</author></authors></contributors><titles><title>Phototoxicity and photoallergy in man</title><secondary-title>J Am Acad Dermatol</secondary-title></titles><pages>141-7</pages><volume>8</volume><number>2</number><keywords><keyword>Acute Disease</keyword><keyword>Allergens</keyword><keyword>Anti-Infective Agents/immunology</keyword><keyword>Antigen-Antibody Complex</keyword><keyword>Chronic Disease</keyword><keyword>DNA/metabolism</keyword><keyword>Dermatitis, Contact/etiology</keyword><keyword>Humans</keyword><keyword>Immunity, Cellular</keyword><keyword>Methoxsalen/metabolism</keyword><keyword>Photosensitivity Disorders/*etiology/immunology/metabolism</keyword><keyword>Porphyrins/metabolism</keyword><keyword>Salicylamides/immunology</keyword><keyword>Sunburn/etiology</keyword><keyword>Sunlight/adverse effects</keyword><keyword>Urticaria/etiology</keyword></keywords><dates><year>1983</year><pub-dates><date>Feb</date></pub-dates></dates><accession-num>6338062</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;dopt=Citation&amp;list_uids=6338062</url></related-urls></urls></record></Cite></EndNote><span style='mso-element:field-separator'></span></span><![endif]-->(Epstein, 1983)<!--[if supportFields]><span lang=EN-US style='font-size:10.5pt;font-family:"Times New Roman","serif";mso-fareast-font-family: "ＭＳ 明朝";mso-fareast-theme-font:minor-fareast;mso-ansi-language:EN-US; mso-fareast-language:JA;mso-bidi-language:AR-SA'><span style='mso-element:field-end'></span></span><![endif]-->.</span></p> <p> </p> <p><span style="font-family:arial,helvetica,sans-serif">The primary trigger for a compound to be considered with respect to potential to create photochemical and photobiological reaction is the absorption of UV and visible light ranging from 290 to 700 nm. The extent of absorption depends on the wavelength of light and the type of absorbing chromophores in the UV-exposed tissues. UV radiation is usually divided into several ranges based on its physiologic effects: (1) UVA (near UV): 320–400 nm (UVA I: 340–400 nm and UVA II: 320–340 nm), (2) UVB (middle UV): 290–320 nm, and (3) UVC (far UV): 180–290 nm <!--[if supportFields]><span lang=EN-US style='font-size:10.5pt;font-family:"Times New Roman","serif"; mso-fareast-font-family:"ＭＳ 明朝";mso-fareast-theme-font:minor-fareast; mso-ansi-language:EN-US;mso-fareast-language:JA;mso-bidi-language:AR-SA'><span style='mso-element:field-begin'></span><span style='mso-spacerun:yes'> </span>ADDIN EN.CITE <span style='mso-element:field-begin'></span><span style='mso-spacerun:yes'> </span>ADDIN EN.CITE.DATA <![if gte mso 9]><xml> 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</xml><![endif]><span style='mso-element:field-end'></span><span style='mso-element:field-separator'></span></span><![endif]-->(Svensson et al., 2001; Vassileva et al., 1998)<!--[if gte mso 9]><xml> 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The sun emits ultraviolet radiation in the UVA, UVB, and UVC bands, but because of absorption by the atmosphere's ozone layer, the main ultraviolet radiation that reaches the Earth's surface is UVA <!--[if supportFields]><span lang=EN-US style='font-size:10.5pt;font-family:"Times New Roman","serif"; mso-fareast-font-family:"ＭＳ 明朝";mso-fareast-theme-font:minor-fareast; mso-ansi-language:EN-US;mso-fareast-language:JA;mso-bidi-language:AR-SA'><span style='mso-element:field-begin'></span><span style='mso-spacerun:yes'> </span>ADDIN EN.CITE <EndNote><Cite><Author>Dubakiene</Author><Year>2006</Year><RecNum>90</RecNum><DisplayText>(Dubakiene and Kupriene, 2006)</DisplayText><record><rec-number>90</rec-number><foreign-keys><key app="EN" db-id="wadztfe5qpsstuefdflp9wxupps099f2vvw2">90</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Dubakiene, R.</author><author>Kupriene, M.</author></authors></contributors><auth-address>Republican Center of Allergology, Vilnius University, Antakalnio 124, Vilnius 10200, Lithuania. ruta.dubakiene@mf.vu.lt</auth-address><titles><title>Scientific problems of photosensitivity</title><secondary-title>Medicina (Kaunas)</secondary-title></titles><pages>619-24</pages><volume>42</volume><number>8</number><keywords><keyword>Adult</keyword><keyword>Child</keyword><keyword>Dermatitis, Photoallergic/diagnosis/etiology/prevention &amp; control</keyword><keyword>Dermatitis, Phototoxic/diagnosis/etiology/prevention &amp; control</keyword><keyword>Diagnosis, Differential</keyword><keyword>Drug Therapy/adverse effects</keyword><keyword>Humans</keyword><keyword>Pharmaceutical Preparations/adverse effects</keyword><keyword>*Photosensitivity Disorders/chemically</keyword><keyword>induced/diagnosis/etiology/prevention &amp; control</keyword><keyword>Skin Tests</keyword><keyword>Sunburn/etiology/prevention &amp; control</keyword><keyword>Sunscreening Agents/administration &amp; dosage/adverse effects</keyword></keywords><dates><year>2006</year></dates><accession-num>16963827</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;dopt=Citation&amp;list_uids=16963827</url></related-urls></urls></record></Cite></EndNote><span style='mso-element:field-separator'></span></span><![endif]-->(Dubakiene and Kupriene, 2006)<!--[if supportFields]><span lang=EN-US style='font-size:10.5pt;font-family:"Times New Roman","serif"; mso-fareast-font-family:"ＭＳ 明朝";mso-fareast-theme-font:minor-fareast; mso-ansi-language:EN-US;mso-fareast-language:JA;mso-bidi-language:AR-SA'><span style='mso-element:field-end'></span></span><![endif]-->. Absorption of light through the skin and eyes, primarily in the 290–700 nm range, varies with wavelength, such that light in the red region of the spectrum reaches well into the subcutis layer; whereas at 300 nm or shorter wavelength, only an estimated 10% passes through the epidermis <!--[if supportFields]><span lang=EN-US style='font-size: 10.5pt;font-family:"Times New Roman","serif";mso-fareast-font-family:"ＭＳ 明朝"; mso-fareast-theme-font:minor-fareast;mso-ansi-language:EN-US;mso-fareast-language: JA;mso-bidi-language:AR-SA'><span style='mso-element:field-begin'></span><span style='mso-spacerun:yes'> </span>ADDIN EN.CITE <EndNote><Cite><Author>Epstein</Author><Year>1989</Year><RecNum>1378</RecNum><DisplayText>(Epstein, 1989)</DisplayText><record><rec-number>1378</rec-number><foreign-keys><key app="EN" db-id="wadztfe5qpsstuefdflp9wxupps099f2vvw2">1378</key></foreign-keys><ref-type name="Book">6</ref-type><contributors><authors><author>Epstein, J. H.</author></authors></contributors><titles><title>Photomedicine</title></titles><dates><year>1989</year></dates><pub-location>New York</pub-location><publisher>Plenum press</publisher><urls></urls></record></Cite></EndNote><span style='mso-element:field-separator'></span></span><![endif]-->(Epstein, 1989)<!--[if supportFields]><span lang=EN-US style='font-size:10.5pt;font-family:"Times New Roman","serif";mso-fareast-font-family: "ＭＳ 明朝";mso-fareast-theme-font:minor-fareast;mso-ansi-language:EN-US; mso-fareast-language:JA;mso-bidi-language:AR-SA'><span style='mso-element:field-end'></span></span><![endif]-->. Thus, penetration and absorption of light in the UV-exposed tissues is important factor in drug-induced phototoxicity as Grotthus-Draper law of photobiology states; only light that is absorbed can be active in photochemical and photobiological processes.</span></p> <p> </p> <p><span style="font-family:arial,helvetica,sans-serif">When a drug molecule absorbs a photon energy, electrons can be prompted from occupied orbitals (the ground state) to an unoccupied orbital (S1, S2) depending upon bond type and associated energy level. Furthermore, unpaired singlet state electrons (opposite spin) may be converted to triplet state (parallel spin) by inversion of the spin via intersystem crossing of the absorbed energy. To return to the ground state from S1, S2/T1, T2, energy must be dissipated by internal conversion, fluorescence (from singlet state), phosphorescence (from triplet state) or via chemical reaction, giving rise to photoproducts and/or potential external reactions with biomolecules.</span></p> <p> </p> <p><span style="font-family:arial,helvetica,sans-serif">In addition, molecular oxygen, a triplet radical in its ground state, appears to be the predominant acceptor of excitation energy as its lowest excited level (singlet state) has a comparatively low value. An energy transfer from excited triplet photosensitizer to the oxygen (type II photochemical reaction) could produce excited singlet oxygen which might, in turn, participate in a lipid- and protein-membrane oxidation or induce DNA damage. An electron or hydrogen transfer could lead to the formation of free radical species (type I photochemical reaction), producing a direct attack on the biomolecules or in the presence of oxygen, to evolve towards secondary free radicals such as peroxyl radicals or the very reactive hydroxyl radical, a known intermediate in the oxidative damage of biomolecules. This toxic pathway corresponds to successive reactions which involve the appearance of superoxide anion radical, its dismutation to from hydrogen peroxide followed with the hydrogen peroxide reduction to form hydroxyl radical. Herein, excitation of the drug by light may give rise to ROS such as singlet oxygen and superoxide, which may be one of causative molecules for the drug-induced phototoxicity <!--[if supportFields]><span lang=EN-US style='font-size:10.5pt;font-family:"Times New Roman","serif"; mso-fareast-font-family:"ＭＳ 明朝";mso-fareast-theme-font:minor-fareast; mso-ansi-language:EN-US;mso-fareast-language:JA;mso-bidi-language:AR-SA'><span style='mso-element:field-begin'></span><span style='mso-spacerun:yes'> </span>ADDIN EN.CITE <span style='mso-element:field-begin'></span><span style='mso-spacerun:yes'> </span>ADDIN EN.CITE.DATA <![if gte mso 9]><xml> 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</xml><![endif]><span style='mso-element:field-end'></span><span style='mso-element:field-separator'></span></span><![endif]-->(Brendler-Schwaab et al., 2004; Epstein and Wintroub, 1985)<!--[if gte mso 9]><xml> 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</xml><![endif]--><!--[if supportFields]><span lang=EN-US style='font-size:10.5pt;font-family:"Times New Roman","serif";mso-fareast-font-family: "ＭＳ 明朝";mso-fareast-theme-font:minor-fareast;mso-ansi-language:EN-US; mso-fareast-language:JA;mso-bidi-language:AR-SA'><span style='mso-element:field-end'></span></span><![endif]-->.</span></p> <hr> <h3>Domain of Applicability</h3> <strong>Life Stage Applicability</strong><div class="panel panel-default "> <table class="table table-bordered table-striped "> <thead> <h3>Domain of Applicability</h3> <strong>Life Stage Applicability</strong> <div class="table-responsive "> <table class="table table-bordered table-fullwidth "> <thead class="thead-light" > <tr> <th>Life Stage</th> <th>Evidence</th> <th scope="col" >Life Stage</th> <th scope="col" >Evidence</th> </tr> </thead> <tbody> <tr> <td>All life stages</td> <td>High</td> </tr> <tbody class="tbody-striped" > <tr> <td>All life stages</td> <td>High</td> </tr> </tbody> </table> </div> <strong>Taxonomic Applicability</strong><div class="panel panel-default "> <table class="table table-bordered table-striped "> <thead> <tr> <th>Term</th> <th>Scientific Term</th> <th>Evidence</th> <th>Links</th> <strong>Taxonomic Applicability</strong> <div class="table-responsive "> <table class="table table-bordered table-fullwidth "> <thead class="thead-light" > <tr> <th scope="col" >Term</th> <th scope="col" >Scientific Term</th> <th scope="col" >Evidence</th> <th scope="col" >Links</th> </tr> </thead> <tbody> <tr> <td>human</td> <td>Homo sapiens</td> <td>High</td> <td> <a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=9606" , target="_blank">NCBI</a> </td> </tr> <tbody class="tbody-striped" > <tr> <td>human</td> <td>Homo sapiens</td> <td>High</td> <td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=9606" target="_blank">NCBI</a></td> </tr> </tbody> </table> </div> <strong>Sex Applicability</strong><div class="panel panel-default "> <table class="table table-bordered table-striped "> <thead> <strong>Sex Applicability</strong> <div class="table-responsive "> <table class="table table-bordered table-fullwidth "> <thead class="thead-light" > <tr> <th>Sex</th> <th>Evidence</th> <th scope="col" >Sex</th> <th scope="col" >Evidence</th> </tr> </thead> <tbody> <tr> <td>Mixed</td> <td>High</td> </tr> <tbody class="tbody-striped" > <tr> <td>Mixed</td> <td>High</td> </tr> </tbody> </table> </div> <p><span style="font-family:arial,helvetica,sans-serif"><strong>Chemicals:</strong> This AOP applies to a wide range of chemicals. Phototoxic chemicals are recognized to have following characteristics: (i) absorption of light within the range of natural sunlight (290-700 nm); (ii) generation of a reactive species following absorption of UV-visible light; (iii) distribution to light-exposed tissues (e.g., skin and eye) (ICH S10).</span></p> <p><span style="font-family:arial,helvetica,sans-serif"><strong>Chemicals:</strong> This AOP applies to a wide range of chemicals. Phototoxic chemicals are recognized to have following characteristics: (i) absorption of light within the range of natural sunlight (290-700 nm); (ii) generation of a reactive species following absorption of UV-visible light; (iii) distribution to light-exposed tissues (e.g., skin and eye) (ICH S10).</span></p> <p><span style="font-family:arial,helvetica,sans-serif"><strong>Sex:</strong> This AOP applies to both males and females. </span></p> <p><span style="font-family:arial,helvetica,sans-serif"><strong>Life stages:</strong> The relevant life stages for this AOP are all life stages after born.</span></p> <p><span style="font-family:arial,helvetica,sans-serif"><strong>Taxonomic:</strong> This AOP mainly applies to human. </span></p> <h3>Essentiality of the Key Events</h3> <p><span style="font-family:arial,helvetica,sans-serif">The essentiality of KEs for this AOP was rated high on the basis of experimental evidence in the investigations related to each of KEs and published guidelines. For details see the table on “Support for Essentiality of KEs”.</span></p> <h3>Essentiality of the Key Events</h3> <p><span style="font-family:arial,helvetica,sans-serif">The essentiality of KEs for this AOP was rated high on the basis of experimental evidence in the investigations related to each of KEs and published guidelines. For details see the table on “Support for Essentiality of KEs”.</span></p> <h3>Weight of Evidence Summary</h3> <p> <span style="font-family:arial,helvetica,sans-serif">Support for biological plausibility of KERs</span></p> <h3>Weight of Evidence Summary</h3> <p> <span style="font-family:arial,helvetica,sans-serif">Support for biological plausibility of KERs</span></p> <table border="1" cellpadding="0" cellspacing="0"> <tbody> <tr> <td style="height:33px; width:111px"> <p><span style="font-family:arial,helvetica,sans-serif">MIE => KE 1</span></p> </td> <td style="height:33px; width:255px"> <p><span style="font-family:arial,helvetica,sans-serif">Generated ROS from photoactivated chemicals can react with membrane lipids, and oxidation of membrane lipids could be occurred. </span></p> </td> <td style="height:33px; width:215px"> <p><span style="font-family:arial,helvetica,sans-serif">Biological Plausibility of the MIE => KE 1 is high.</span></p> <p> </p> <p><span style="font-family:arial,helvetica,sans-serif">The relationship between MIE and KE 1 is consistent with chemical and biological knowledge <!--[endif]---->(Girotti, 1990; Girotti, 2001; Onoue and Tsuda, 2006).</span><!--![endif]----></p> </td> </tr> <tr> <td style="height:82px; width:111px"> <p><span style="font-family:arial,helvetica,sans-serif">MIE => KE 2</span></p> </td> <td style="height:82px; width:255px"> <p><span style="font-family:arial,helvetica,sans-serif">Generated ROS from photoactivated chemicals can react with membrane proteins, and oxidation/denaturation of membrane proteins could be occurred.</span></p> </td> <td style="height:82px; width:215px"> <p><span style="font-family:arial,helvetica,sans-serif">Biological Plausibility of the MIE => KE 2 is high.</span></p> <p><span style="font-family:arial,helvetica,sans-serif"><!--[endif]----> </span><!--![endif]----></p> <p><span style="font-family:arial,helvetica,sans-serif">The relationship between MIE and KE 2 is consistent with biological knowledge <!--![endif]----><!--[endif]----><!--[endif]---->(Dalle Carbonare and Pathak, 1992; Valenzeno, 1987).</span><!--![endif]----><!--![endif]----></p> </td> </tr> <tr> <td style="height:37px; width:111px"> <p><span style="font-family:arial,helvetica,sans-serif">KE 1 => AO</span></p> </td> <td style="height:37px; width:255px"> <p><span style="font-family:arial,helvetica,sans-serif">Oxidation of membrane lipids relates with damage produced in the cellular membrane, leading to inflammatory events. </span></p> </td> <td style="height:37px; width:215px"> <p><span style="font-family:arial,helvetica,sans-serif">Biological Plausibility of the KE 1 => AO is high.</span></p> <p><span style="font-family:arial,helvetica,sans-serif"><!--[endif]----><!--[endif]----> </span><!--![endif]----><!--![endif]----></p> <p><span style="font-family:arial,helvetica,sans-serif">The relationship between KE 1 and AO is consistent with biological knowledge <!--![endif]----><!--![endif]----><!--[endif]----><!--[endif]----><!--[endif]---->(Castell et al., 1994).</span><!--![endif]----><!--![endif]----><!--![endif]----></p> </td> </tr> <tr> <td style="height:37px; width:111px"> <p><span style="font-family:arial,helvetica,sans-serif">KE 2 => AO</span></p> </td> <td style="height:37px; width:255px"> <p><span style="font-family:arial,helvetica,sans-serif">Oxidation/denaturation of protein provides the necrosis of the living tissues as an inflammatory event. </span></p> </td> <td style="height:37px; width:215px"> <p><span style="font-family:arial,helvetica,sans-serif">Biological Plausibility of the KE 2 => AO is high.</span></p> <p><span style="font-family:arial,helvetica,sans-serif"><!--[endif]----><!--[endif]----><!--[endif]----> </span><!--![endif]----><!--![endif]----><!--![endif]----></p> <p><span style="font-family:arial,helvetica,sans-serif">The relationship between KE 2 and AO is consistent with biological knowledge <!--![endif]----><!--![endif]----><!--![endif]----><!--[endif]----><!--[endif]----><!--[endif]----><!--[endif]---->(Dalle Carbonare and Pathak, 1992; Opie, 1962).</span><!--![endif]----><!--![endif]----><!--![endif]----><!--![endif]----></p> </td> </tr> </tbody> </table> <p> </p> <p><span style="font-family:arial,helvetica,sans-serif"><!--[endif]----><!--[endif]----><!--[endif]----><!--[endif]----></span></p> <p> </p> <p> </p> <p><span style="font-family:arial,helvetica,sans-serif">Support for Essentiality of KEs</span></p> <table border="1" cellpadding="0" cellspacing="0"> <tbody> <tr> <td style="height:208px; width:73px"> <p><span style="font-family:arial,helvetica,sans-serif">MIE</span></p> </td> <td style="height:208px; width:236px"> <p><span style="font-family:arial,helvetica,sans-serif">ROS generation from photoactivated chemicals</span></p> </td> <td style="height:208px; width:272px"> <p><span style="font-family:arial,helvetica,sans-serif">High; well-accepted generation of reactive oxygen species from photo-activated chemicals associated with phototoxic reactions with 200 of chemicals evaluated in qualitative endpoints <!--[endif]---->(Onoue et al., 2014; Onoue et al., 2013a; Onoue et al., 2008a; Onoue and Tsuda, 2006; Seto et al., 2013b). The event has described in ICH S10 guideline as a crucial factor of phototoxic reactions (ICH, 2014).<!--![endif]----></span></p> </td> </tr> <tr> <td style="height:82px; width:73px"> <p><span style="font-family:arial,helvetica,sans-serif">KE 1</span></p> </td> <td style="height:82px; width:236px"> <p><span style="font-family:arial,helvetica,sans-serif">Oxidation of membrane lipids</span></p> <p><span style="font-family:arial,helvetica,sans-serif"><!--[endif]----> <!--![endif]----></span></p> <p><span style="font-family:arial,helvetica,sans-serif"><!--[endif]----> <!--![endif]----></span></p> </td> <td style="height:82px; width:272px"> <p><span style="font-family:arial,helvetica,sans-serif">High; Oxidative stress to lipids associated with the phototoxic reactions <!--![endif]----><!--[endif]----><!--[endif]---->(Girotti, 1990; Girotti, 2001; Onoue and Tsuda, 2006).<!--![endif]----><!--![endif]----></span></p> </td> </tr> <tr> <td style="height:26px; width:73px"> <p><span style="font-family:arial,helvetica,sans-serif">KE 2</span></p> </td> <td style="height:26px; width:236px"> <p><span style="font-family:arial,helvetica,sans-serif">Oxidation/denaturation of membrane proteins</span></p> </td> <td style="height:26px; width:272px"> <p><span style="font-family:arial,helvetica,sans-serif">High; accepted oxidation/denaturation of proteins associated with the phototoxic reactions <!--![endif]----><!--![endif]----><!--[endif]----><!--[endif]----><!--[endif]---->(Dalle Carbonare and Pathak, 1992; Valenzeno, 1987).<!--![endif]----><!--![endif]----><!--![endif]----></span></p> </td> </tr> <tr> <td style="width:73px"> <p><span style="font-family:arial,helvetica,sans-serif">Adverse outcome</span></p> </td> <td style="width:236px"> <p><span style="font-family:arial,helvetica,sans-serif">Inflammatory events in sunlight-exposed tissues</span></p> </td> <td style="width:272px"> <p><span style="font-family:arial,helvetica,sans-serif">Photoreactive agents indicated inflammatory events, including edema, dyskeratosis, and necrosis, in light-exposed tissues after sunlight exposure <!--[endif]----><!--[endif]----><!--[endif]----> <!--![endif]----><!--![endif]----><!--![endif]----><!--[endif]----><!--[endif]----><!--[endif]----><!--[endif]---->(Moore, 1998; Moore 2002; Roberts, 2001).<!--![endif]----><!--![endif]----><!--![endif]----><!--![endif]----></span></p> </td> </tr> </tbody> </table> <p><span style="font-family:arial,helvetica,sans-serif"><!--[endif]----><!--[endif]----><!--[endif]----><!--[endif]----></span></p> <p> </p> <p><span style="font-family:arial,helvetica,sans-serif">Empirical Support for KERs</span></p> <table border="1" cellpadding="0" cellspacing="0" style="width:584px"> <tbody> <tr> <td style="height:128px; width:196px"> <p>MIE =<span style="font-family:arial,helvetica,sans-serif">> KE 1: ROS generation leads to Oxidation of membrane lipids</span></p> </td> <td style="height:128px; width:387px"> <p><span style="font-family:arial,helvetica,sans-serif">Empirical support of the MIE => KE 1 is strong.</span></p> <p><span style="font-family:arial,helvetica,sans-serif">Rationale:</span></p> <p><span style="font-family:arial,helvetica,sans-serif">Lipid peroxidation was occurred by ROS-generating chemicals under exposure to simulated sunlight <!--[endif]---->(Onoue et al., 2011, Onoue and Tsuda, 2006). </span><!--![endif]----></p> <p><span style="font-family:arial,helvetica,sans-serif">A photoreactive chemical indicated dose-dependent increases in ROS generation and lipid peroxidation after exposure to a fixed dose of simulated sunlight (Seto et al., 2013a).</span></p> </td> </tr> <tr> <td style="height:82px; width:196px"> <p><span style="font-family:arial,helvetica,sans-serif">MIE => KE 2: ROS generation leads to Oxidation/denaturation of membrane proteins</span></p> </td> <td style="height:82px; width:387px"> <p><span style="font-family:arial,helvetica,sans-serif">Empirical support of the MIE => KE 2 is moderate.</span></p> <p><span style="font-family:arial,helvetica,sans-serif">Rationale:</span></p> <p><span style="font-family:arial,helvetica,sans-serif">ROS generated from photosensitizing agents led to oxidation and denaturation of proteins <!--![endif]----><!--[endif]----><!--[endif]---->(Dalle Carbonare and Pathak, 1992).</span><!--![endif]----><!--![endif]----></p> </td> </tr> <tr> <td style="height:37px; width:196px"> <p><span style="font-family:arial,helvetica,sans-serif">KE 1 => AO: Oxidation of membrane lipids leads to Inflammatory events</span></p> </td> <td style="height:37px; width:387px"> <p><span style="font-family:arial,helvetica,sans-serif">Empirical support of the KE 1=> AO is strong.</span></p> <p><span style="font-family:arial,helvetica,sans-serif">Rationale:</span></p> <p><span style="font-family:arial,helvetica,sans-serif">Increases in lipid peroxidation and inflammatory-related cytokines were observed in the murine skin, and naringenin, an anti-oxidant, attenuated these increases in a dose-dependent manner <!--![endif]----><!--![endif]----><!--[endif]----><!--[endif]----><!--[endif]---->(Martinez et al., 2015).</span><!--![endif]----><!--![endif]----><!--![endif]----></p> <p><span style="font-family:arial,helvetica,sans-serif">Benzoyl peroxide, a ROS generator, led to lipid peroxidation and GSH depletion, and the changes caused the gene expression of pro-inflammatory cytokines <!--![endif]----><!--![endif]----><!--![endif]----><!--[endif]----><!--[endif]----><!--[endif]----><!--[endif]---->(Valacchi et al., 2001).</span><!--![endif]----><!--![endif]----><!--![endif]----><!--![endif]----></p> </td> </tr> <tr> <td style="height:37px; width:196px"> <p><span style="font-family:arial,helvetica,sans-serif">KE 2 => AO: Oxidation/denaturation of membrane proteins leads to Inflammatory events</span></p> </td> <td style="height:37px; width:387px"> <p><span style="font-family:arial,helvetica,sans-serif">Empirical support of the KE 2=> AO is moderate.</span></p> <p><span style="font-family:arial,helvetica,sans-serif">Rationale:</span></p> <p><span style="font-family:arial,helvetica,sans-serif">Denaturation of proteins induced necrosis and inflammatory in the skin (Opie, 1962).</span></p> </td> </tr> </tbody> </table> <p><!--[endif]----><!--[endif]----><!--[endif]----><!--[endif]----><!--![endif]----><!--![endif]----><!--![endif]----><!--![endif]----><!--![endif]----><!--![endif]----><!--![endif]----><!--![endif]----><!--![endif]----><!--![endif]----><!--![endif]----><!--![endif]----></p> <h3>Quantitative Consideration</h3> <p><span style="font-family:arial,helvetica,sans-serif">Although there is empirical information on KERs as described above sections, the overall quantitative understanding of the AOP is insufficient to directly link a measure of KEs to a quantitative prediction of KERs. </span></p> <h3>Quantitative Consideration</h3> <p><span style="font-family:arial,helvetica,sans-serif">Although there is empirical information on KERs as described above sections, the overall quantitative understanding of the AOP is insufficient to directly link a measure of KEs to a quantitative prediction of KERs. </span></p> <p> </p> <p><span style="font-family:arial,helvetica,sans-serif">As a pre-MIE, light absorption of chemicals is an important event for phototoxic reactions induced by photoreactive chemicals. Quantitative endpoint on absorption of light (290–700 nm) was recognized in the previous report (Henry et al., 2009), and, for photoreactive chemicals, the criterion on molar extinction coefficient (MEC) was determined to be 1,000 M<sup>-1</sup>·cm<sup>-1</sup>. Most of chemicals with MEC values of over 1,000 M<sup>-1</sup>·cm<sup>-1</sup> generated significant ROS, including singlet oxygen and/or superoxide <!--[endif]---->(Onoue et al., 2013b; Onoue and Tsuda, 2006), and the qualitative criteria on ROS generation was determined to evaluate chemical phototoxicity <!--[endif]---->(Onoue et al., 2014; Onoue et al., 2013a; Onoue et al., 2008b).</span> <!--![endif]----><!--![endif]----></p> </div> <!-- potential consierations, text as entered by author --><div id="considerations_for_potential_applicaitons"> <h2>Considerations for Potential Applications of the AOP (optional)</h2> <hr> <p><span style="font-family:arial,helvetica,sans-serif">The MIE and KEs in this AOP could contribute to assays development for photosafety evaluation and an AOP-based IATA construction. AOP-based IATA can be applied for various aims including screening of chemicals, prioritization of chemicals for further testing, and risk assessment. </span></p> <h2>Considerations for Potential Applications of the AOP (optional)</h2> <p><span style="font-family:arial,helvetica,sans-serif">The MIE and KEs in this AOP could contribute to assays development for photosafety evaluation and an AOP-based IATA construction. AOP-based IATA can be applied for various aims including screening of chemicals, prioritization of chemicals for further testing, and risk assessment. </span></p> <p> </p> <p><span style="font-family:arial,helvetica,sans-serif">The regulatory applicability of the AOP would be to use experimental results from assays based on MIE and KEs as indictors for the risk of phototoxic reactions. </span></p> <p> </p> <p><span style="font-family:arial,helvetica,sans-serif">Combined use of photobiochemical properties and tissue exposure data would be of help for photosafety evaluation of chemicals. Risk assessment would be possible when exposure data in light-exposed tissues combined with assay data based on AOP.</span></p> </div> <!-- reference section, text as of right now but should be changed to be handled as table --><div id="references"> <h2>References</h2> <hr> <p><span style="font-family:arial,helvetica,sans-serif">Brendler-Schwaab S, Czich A, Epe B, Gocke E, Kaina B, Muller L, et al. Photochemical genotoxicity: principles and test methods. Report of a GUM task force. Mutation research. 2004;566:65-91.</span></p> <p><span style="font-family:arial,helvetica,sans-serif">Castell JV, Gomez-Lechon MJ, Grassa C, Martinez LA, Miranda MA, Tarrega P. Photodynamic lipid peroxidation by the photosensitizing nonsteroidal antiinflammatory drugs suprofen and tiaprofenic acid. Photochem Photobiol. 1994;59:35-9.</span></p> <p><span style="font-family:arial,helvetica,sans-serif">Dalle Carbonare M, Pathak MA. Skin photosensitizing agents and the role of reactive oxygen species in photoaging. J Photochem Photobiol B. 1992;14:105-24.</span></p> <p><span style="font-family:arial,helvetica,sans-serif">Dubakiene R, Kupriene M. Scientific problems of photosensitivity. Medicina (Kaunas). 2006;42:619-24.</span></p> <p><span style="font-family:arial,helvetica,sans-serif">Epstein JH. Phototoxicity and photoallergy in man. J Am Acad Dermatol. 1983;8:141-7.</span></p> <p><span style="font-family:arial,helvetica,sans-serif">Epstein JH. Photomedicine. New York: Plenum press; 1989.</span></p> <p><span style="font-family:arial,helvetica,sans-serif">Epstein JH, Wintroub BU. Photosensitivity due to drugs. Drugs. 1985;30:42-57.</span></p> <p><span style="font-family:arial,helvetica,sans-serif">Girotti AW. Photodynamic lipid peroxidation in biological systems. Photochem Photobiol. 1990;51:497-509.</span></p> <p><span style="font-family:arial,helvetica,sans-serif">Girotti AW. Photosensitized oxidation of membrane lipids: reaction pathways, cytotoxic effects, and cytoprotective mechanisms. J Photochem Photobiol B. 2001;63:103-13.</span></p> <p><span style="font-family:arial,helvetica,sans-serif">Henry B, Foti C, Alsante K. Can light absorption and photostability data be used to assess the photosafety risks in patients for a new drug molecule? J Photochem Photobiol B. 2009;96:57-62.</span></p> <p><span style="font-family:arial,helvetica,sans-serif">ICH. ICH Guideline S10 Guidance on Photosafety Evaluation of Pharmaceuticals.: International Council on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use; 2014.</span></p> <p><span style="font-family:arial,helvetica,sans-serif">Martinez RM, Pinho-Ribeiro FA, Steffen VS, Caviglione CV, Vignoli JA, Barbosa DS, et al. Naringenin Inhibits UVB Irradiation-Induced Inflammation and Oxidative Stress in the Skin of Hairless Mice. Journal of natural products. 2015;78:1647-55.</span></p> <p><span style="font-family:arial,helvetica,sans-serif">Moore DE. Mechanisms of photosensitization by phototoxic drugs. Mutation research. 1998;422:165-73.</span></p> <p><span style="font-family:arial,helvetica,sans-serif">Moore DE. Drug-induced cutaneous photosensitivity: incidence, mechanism, prevention and management. Drug safety. 2002;25:345-72.</span></p> <p><span style="font-family:arial,helvetica,sans-serif">Onoue S, Hosoi K, Toda T, Takagi H, Osaki N, Matsumoto Y, et al. Intra-/inter-laboratory validation study on reactive oxygen species assay for chemical photosafety evaluation using two different solar simulators. Toxicology in vitro : an international journal published in association with BIBRA. 2014;28:515-23.</span></p> <p><span style="font-family:arial,helvetica,sans-serif">Onoue S, Hosoi K, Wakuri S, Iwase Y, Yamamoto T, Matsuoka N, et al. Establishment and intra-/inter-laboratory validation of a standard protocol of reactive oxygen species assay for chemical photosafety evaluation. Journal of applied toxicology : JAT. 2013a;33:1241-50.</span></p> <p><span style="font-family:arial,helvetica,sans-serif">Onoue S, Igarashi N, Yamada S, Tsuda Y. High-throughput reactive oxygen species (ROS) assay: an enabling technology for screening the phototoxic potential of pharmaceutical substances. J Pharm Biomed Anal. 2008a;46:187-93.</span></p> <p><span style="font-family:arial,helvetica,sans-serif">Onoue S, Kawamura K, Igarashi N, Zhou Y, Fujikawa M, Yamada H, et al. Reactive oxygen species assay-based risk assessment of drug-induced phototoxicity: classification criteria and application to drug candidates. J Pharm Biomed Anal. 2008b;47:967-72.</span></p> <p><span style="font-family:arial,helvetica,sans-serif">Onoue S, Seto Y, Ochi M, Inoue R, Ito H, Hatano T, et al. In vitro photochemical and phototoxicological characterization of major constituents in St. John's Wort (Hypericum perforatum) extracts. Phytochemistry. 2011;72:1814-20.</span></p> <p><span style="font-family:arial,helvetica,sans-serif">Onoue S, Suzuki G, Kato M, Hirota M, Nishida H, Kitagaki M, et al. Non-animal photosafety assessment approaches for cosmetics based on the photochemical and photobiochemical properties. Toxicology in vitro : an international journal published in association with BIBRA. 2013b;27:2316-24.</span></p> <p><span style="font-family:arial,helvetica,sans-serif">Onoue S, Tsuda Y. Analytical studies on the prediction of photosensitive/phototoxic potential of pharmaceutical substances. Pharmaceutical research. 2006;23:156-64.</span></p> <p><span style="font-family:arial,helvetica,sans-serif">Opie EL. On the relation of necrosis and inflammation to denaturation of proteins. The Journal of experimental medicine. 1962;115:597-608.</span></p> <p><span style="font-family:arial,helvetica,sans-serif">Quintero B, Miranda MA. Mechanism of photosensitization induced by drugs: A general survey. Ars Pharmaceutica. 2000;41:27-46.</span></p> <p><span style="font-family:arial,helvetica,sans-serif">Roberts JE. Ocular phototoxicity. J Photochem Photobiol B. 2001;64:136-43.</span></p> <p><span style="font-family:arial,helvetica,sans-serif">Seto Y, Inoue R, Kato M, Yamada S, Onoue S. Photosafety assessments on pirfenidone: photochemical, photobiological, and pharmacokinetic characterization. J Photochem Photobiol B. 2013a;120:44-51.</span></p> <p><span style="font-family:arial,helvetica,sans-serif">Seto Y, Kato M, Yamada S, Onoue S. Development of micellar reactive oxygen species assay for photosafety evaluation of poorly water-soluble chemicals. Toxicology in vitro : an international journal published in association with BIBRA. 2013b;27:1838-46.</span></p> <p><span style="font-family:arial,helvetica,sans-serif">Stein KR, Scheinfeld NS. Drug-induced photoallergic and phototoxic reactions. Expert Opin Drug Saf. 2007;6:431-43.</span></p> <p><span style="font-family:arial,helvetica,sans-serif">Svensson CK, Cowen EW, Gaspari AA. Cutaneous drug reactions. Pharmacological reviews. 2001;53:357-79.</span></p> <p><span style="font-family:arial,helvetica,sans-serif">Valacchi G, Rimbach G, Saliou C, Weber SU, Packer L. Effect of benzoyl peroxide on antioxidant status, NF-kappaB activity and interleukin-1alpha gene expression in human keratinocytes. Toxicology. 2001;165:225-34.</span></p> <p><span style="font-family:arial,helvetica,sans-serif">Valenzeno DP. Photomodification of biological membranes with emphasis on singlet oxygen mechanisms. Photochem Photobiol. 1987;46:147-60.</span></p> <p><span style="font-family:arial,helvetica,sans-serif">Vassileva SG, Mateev G, Parish LC. Antimicrobial photosensitive reactions. Archives of internal medicine. 1998;158:1993-2000.</span></p> <br></div> <div id="appendicies"> <h2>Appendix 1</h2> <h3>List of MIEs in this AOP</h3> <div> <div> < h4><a href="/events/1592 ">Event: 1592: ROS generation from photo activated chemical s</a><br>< /h4> <h5>Short Name: ROS generation</h5 > </div> <div > <!-- loop to find all aops that use this event -- > <h4>AOPs Including This Key Event</h4> div class="panel panel-default" > <table class="table table-bordered table -striped"> <thead> <h4><a href="/events/1115 ">Event: 1115: Increase, Re active oxygen specie s</a></h4> <h5>Short Name: Increase, ROS</h5> <h4>Event Component</h4 > <div class="table-responsive" > <table class="table table-bordered table-fullwidth"> <thead class="thead-light"> <tr > <th scope="col">Process</th> <th scope="col">Object</th> <th scope="col">Action</th > </tr> </thead> <tbody class="tbody -striped"> <tr> <th>AOP ID and Name</th > <th>Event Type</th > <td>reactive oxygen species biosynthetic process</td > <td>reactive oxygen species</td> <td>increased</td > </tr> </thead> <t body> <tr> <td><a href="/aops/282">Aop:282 - Reactive oxygen species generated from photoreactive chemicals leading to phototoxic reactions</a></td> <td>MolecularInitiatingEvent</td> </tr> </tbody> </table> </div> </t body> </table> </div> <!-- loop to find stressors under e vent -- > <div > <h4>Stressors</h4> <div class="panel panel-default" > <table class="table table-bordered table-striped" > <thea d> <tr> <th>Name</th > </tr> </thea d> <tbody > <tr> <td>Light (290-700 nm) </td> </ tr> <tr > <td>Photo reactive chemicals </td> </tr > </tbody > </table > </div > </div > <br> <h4>AOPs Including This Key Event</h4> <div class="table-responsive"> <table class="table table-bordered table-fullwidth"> <thead class="thead-light"> <tr> <th scope="col">AOP ID and Name</th> <th scope="col">Event Type</th> </tr> </thead> <tbody class="tbody-striped"> <tr> <td><a href="/aops/186">Aop:186 - unknown MIE leading to renal failure and mortality</a></td> <td>KeyEvent</td> </tr> <tr> <td><a href="/aops/213">Aop:213 - Inhibition of fatty acid beta oxidation leading to nonalcoholic steatohepatitis (NASH)</a></td> <td>KeyEvent</td> </tr> <tr> <td><a href="/aops/303">Aop:303 - Frustrated phagocytosis-induced lung cancer</a></td> <td>KeyEvent</td> </tr> <tr> <td><a href="/aops/383">Aop:383 - Inhibition of Angiotensin-converting enzyme 2 leading to liver fibrosis</a></td> <td>KeyEvent</td> </tr> <tr> <td><a href="/aops/382">Aop:382 - Angiotensin II type 1 receptor (AT1R) agonism leading to lung fibrosis</a></td> <td>KeyEvent</td> </tr> <tr> <td><a href="/aops/384">Aop:384 - Hyperactivation of ACE/Ang-II/AT1R axis leading to chronic kidney disease </a></td> <td>KeyEvent</td> </tr> <tr> <td><a href="/aops/396">Aop:396 - Deposition of ionizing energy leads to population decline via impaired meiosis</a></td> <td>KeyEvent</td> </tr> <tr> <td><a href="/aops/409">Aop:409 - Frustrated phagocytosis leads to malignant mesothelioma</a></td> <td>KeyEvent</td> </tr> <tr> <td><a href="/aops/413">Aop:413 - Oxidation and antagonism of reduced glutathione leading to mortality via acute renal failure</a></td> <td>KeyEvent</td> </tr> <tr> <td><a href="/aops/416">Aop:416 - Aryl hydrocarbon receptor activation leading to lung cancer through IL-6 toxicity pathway</a></td> <td>KeyEvent</td> </tr> <tr> <td><a href="/aops/418">Aop:418 - Aryl hydrocarbon receptor activation leading to impaired lung function through AHR-ARNT toxicity pathway</a></td> <td>KeyEvent</td> </tr> <tr> <td><a href="/aops/386">Aop:386 - Deposition of ionizing energy leading to population decline via inhibition of photosynthesis</a></td> <td>KeyEvent</td> </tr> <tr> <td><a href="/aops/387">Aop:387 - Deposition of ionising energy leading to population decline via mitochondrial dysfunction</a></td> <td>KeyEvent</td> </tr> <tr> <td><a href="/aops/319">Aop:319 - Binding to ACE2 leading to lung fibrosis</a></td> <td>KeyEvent</td> </tr> <tr> <td><a href="/aops/451">Aop:451 - Interaction with lung resident cell membrane components leads to lung cancer</a></td> <td>KeyEvent</td> </tr> <tr> <td><a href="/aops/476">Aop:476 - Adverse Outcome Pathways diagram related to PBDEs associated male reproductive toxicity</a></td> <td>MolecularInitiatingEvent</td> </tr> <tr> <td><a href="/aops/492">Aop:492 - Glutathione conjugation leading to reproductive dysfunction via oxidative stress</a></td> <td>KeyEvent</td> </tr> <tr> <td><a href="/aops/497">Aop:497 - ERa inactivation alters mitochondrial functions and insulin signalling in skeletal muscle and leads to insulin resistance and metabolic syndrome</a></td> <td>KeyEvent</td> </tr> <tr> <td><a href="/aops/500">Aop:500 - Activation of MEK-ERK1/2 leads to deficits in learning and cognition via ROS and apoptosis</a></td> <td>KeyEvent</td> </tr> <tr> <td><a href="/aops/505">Aop:505 - Reactive Oxygen Species (ROS) formation leads to cancer via inflammation pathway</a></td> <td>MolecularInitiatingEvent</td> </tr> <tr> <td><a href="/aops/513">Aop:513 - Reactive Oxygen (ROS) formation leads to cancer via Peroxisome proliferation-activated receptor (PPAR) pathway</a></td> <td>MolecularInitiatingEvent</td> </tr> <tr> <td><a href="/aops/521">Aop:521 - Essential element imbalance leads to reproductive failure via oxidative stress</a></td> <td>KeyEvent</td> </tr> <tr> <td><a href="/aops/540">Aop:540 - Oxidative Stress in the Fish Ovary Leads to Reproductive Impairment via Reduced Vitellogenin Production</a></td> <td>MolecularInitiatingEvent</td> </tr> <tr> <td><a href="/aops/462">Aop:462 - Activation of reactive oxygen species leading the atherosclerosis</a></td> <td>MolecularInitiatingEvent</td> </tr> <tr> <td><a href="/aops/299">Aop:299 - Deposition of energy leading to population decline via DNA oxidation and follicular atresia</a></td> <td>KeyEvent</td> </tr> <tr> <td><a href="/aops/311">Aop:311 - Deposition of energy leading to population decline via DNA oxidation and oocyte apoptosis</a></td> <td>KeyEvent</td> </tr> <tr> <td><a href="/aops/332">Aop:332 - Excessive reactive oxygen species leading to growth inhibition via lipid peroxidation and reduced cell growth</a></td> <td>MolecularInitiatingEvent</td> </tr> <tr> <td><a href="/aops/331">Aop:331 - Excessive reactive oxygen species leading to growth inhibition via lipid peroxidation and cell death</a></td> <td>MolecularInitiatingEvent</td> </tr> <tr> <td><a href="/aops/326">Aop:326 - Excessive reactive oxygen species leading to growth inhibition via uncoupling of oxidative phosphorylation and reduced cell proliferation</a></td> <td>MolecularInitiatingEvent</td> </tr> <tr> <td><a href="/aops/333">Aop:333 - Excessive reactive oxygen species leading to growth inhibition via lipid peroxidation and reduced cell proliferation</a></td> <td>MolecularInitiatingEvent</td> </tr> <tr> <td><a href="/aops/327">Aop:327 - Excessive reactive oxygen species production leading to mortality (1)</a></td> <td>MolecularInitiatingEvent</td> </tr> <tr> <td><a href="/aops/328">Aop:328 - Excessive reactive oxygen species production leading to mortality (2)</a></td> <td>MolecularInitiatingEvent</td> </tr> <tr> <td><a href="/aops/329">Aop:329 - Excessive reactive oxygen species production leading to mortality (3)</a></td> <td>MolecularInitiatingEvent</td> </tr> <tr> <td><a href="/aops/330">Aop:330 - Excessive reactive oxygen species production leading to mortality (4)</a></td> <td>MolecularInitiatingEvent</td> </tr> <tr> <td><a href="/aops/26">Aop:26 - Calcium-mediated neuronal ROS production and energy imbalance</a></td> <td>KeyEvent</td> </tr> <tr> <td><a href="/aops/534">Aop:534 - Succinate dehydrogenase (SDH) inhibition leads to cancer through oxidative stress</a></td> <td>KeyE vent</td> </tr> <tr > <td><a href="/aops/273">Aop:273 - Mitochondrial complex inhibition leading to liver injury</a></td> <td>KeyEvent</td> </tr> <tr > <td><a href="/aops/488">Aop:488 - Increased reactive oxygen species production leading to decreased cognitive function</a></td> <td>MolecularInitiatingEvent</td> </tr> <tr> <td><a href="/aops/298">Aop:298 - Increase in reactive oxygen species (ROS) leading to human treatment-resistant gastric cancer</a></td> <td>MolecularInitiatingEvent</td> </tr> <tr> <td><a href="/aops/27">Aop:27 - Cholestatic Liver Injury induced by Inhibition of the Bile Salt Export Pump (ABCB11)</a></td> <td>KeyEvent</td> </tr> <tr> <td><a href="/aops/511">Aop:511 - The AOP framework on ROS-mediated oxidative stress induced vascular disrupting effects </a></td> <td>MolecularInitiatingEvent</td> </tr > <tr> <td><a href="/aops/207">Aop:207 - NADPH oxidase and P38 MAPK activation leading to reproductive failure in Caenorhabditis elegans</a></td> <td>KeyEvent</td> </tr> <tr> <td><a href="/aops/423">Aop:423 - Toxicological mechanisms of hepatocyte apoptosis through the PARP1 dependent cell death pathway </a></td> <td>MolecularInitiatingEvent</td> </tr> <tr> <td><a href="/aops/481">Aop:481 - AOPs of amorphous silica nanoparticles: ROS-mediated oxidative stress increased respiratory dysfunction and diseases.</a></td> <td>MolecularInitiatingEvent</td > </tr> <tr> <td><a href="/aops/282">Aop:282 - Adverse outcome pathway on photochemical toxicity initiated by light exposure</a></t d> <td>MolecularInitiatingEvent</td> </ tr> <tr> d><a href="/aops/569">Aop:569 - Decreased DNA methylation of FAM50B/PTCHD3 leading to IQ loss of children via PI3K-Akt pathway</a></td > <td>KeyEvent</td> </tr> <tr> <td><a href="/aops/324">Aop:324 - Excessive reactive oxygen species leading to growth inhibition via uncoupling of oxidative phosphorylation and cell death</a></td> <td>MolecularInitiatingEvent</t d> </tr> <tr> <td><a href="/aops/325">Aop:325 - Excessive reactive oxygen species leading to growth inhibition via uncoupling of oxidative phosphorylation and reduced cell growth</a></td > <td>MolecularInitiatingEvent</td> </tr> <td><a href="/aops/595">Aop:595 - Nanoplastic effect</a></td> MolecularInitiatingEvent</td> </tr> <tr> <td><a href="/aops/596">Aop:596 - Excessive reactive oxygen species leading to growth inhibition via protein oxidation and cell injury/death</a> </td> <td>MolecularInitiatingEvent</td> </tr> <td><a href="/aops/598">Aop:598 - Excessive reactive oxygen species leading to growth inhibition via protein oxidation and reduced cell proliferation</a></td> d>MolecularInitiatingEvent</td > </tr> <tr> <a href="/aops/599">Aop:599 - Excessive reactive oxygen species leading to growth inhibition via fatty acid oxidation and cell injury/death</a></td> <td>MolecularInitiatingEvent </td> </tr> <tr> <td><a href="/aops/600">Aop:600 - Excessive reactive oxygen species leading to growth inhibition via fatty acid oxidation and reduced cell growth</a></td > <td>MolecularInitiatingEvent</td> </tr> <tr> <td><a href="/aops/601">Aop:601 - Excessive reactive oxygen species leading to growth inhibition via fatty acid oxidation and reduced cell proliferation</a></td> <td>MolecularInitiatingEvent</td> </tr > <tr> <td><a href="/aops/602">Aop:602 - Excessive reactive oxygen species leading to growth inhibition via oxidative DNA damage</a></td> <td>MolecularInitiatingEvent</td> </tr> <tr > <td><a href="/aops/603">Aop:603 - Excessive reactive oxygen species leading to growth inhibition via protein oxidation and cell cycle disruption</a></td> <td>MolecularInitiatingEvent</td> </tr> <tr > <td><a href="/aops/608">Aop:608 - Thyroid Hormone Excess Leading to Reduced, Swimming Performance via Hypomyelination</a></td> <td>KeyEvent</td > </tr> </tbody> </table> </div> <!-- biological organization --> <div> < h4>Biological Context</h4> <div class="panel panel-default "> <table class="table table-bordered table-striped "> <thead> <tr> <th >Level of Biological Organization</th> </tr> </thead> <tbody> <tr> <td>Molec ular</td> </tr> </tbody> </table> </div> <h4>Biological Context</h4> <div class="table-responsive "> <table class="table table-bordered table-fullwidth "> <thead class="thead-light" > <tr><th scope="col" >Level of Biological Organization</th></tr> </thead> <tbody class="tbody-striped"> Cell ular</td></tr> </tbody> </table> </div> <!-- end of bio org --> <!-- c ell term -- > <div > <h4>Cell term</h4> <div class="table-responsive"> <table class="table table-bordered table-fullwidth"> <thead class="thead-light"> <tr><th scope="col">C ell term</th></tr> </thead > <tbody class="tbody-striped"> <tr><td>cell</td></tr> </tbody> </table > </div> <!-- end of cell term --> <!-- o rgan term -- > <div > <h4>Organ term</h4> <div class="table-responsive"> <table class="table table-bordered table-fullwidth"> <thead class="thead-light"> <tr><th scope="col">O rgan term</th></tr> </thead > <tbody class="tbody-striped"> <tr><td>organ</td></tr> </tbody> </table > </div> <!-- end of organ term --> <!-- Evidence for Perturbation of This Event by Stressors --> <h3>Evidence for Perturbation by Stressor</h3> <hr> <h4>Overview for Molecular Initiating Event</h4> <p>Several classes of chemicals cause ROS generation under light exposure, and the ROS generation can be monitored by ROS assay (Onoue et al., 2014, Onoue et al., 2013, Onoue et al. , 2008, Seto et al. , 2013). The criteria of ROS assay for photosafety assessment of chemicals were defined <!--[if supportFields]><span lang=EN-US style='font-size:10.5pt; font-family:"Times New Roman","serif";mso-fareast-font-family:"ＭＳ 明朝"; mso-fareast-theme-font:minor-fareast;mso-ansi-language:EN-US;mso-fareast-language: JA;mso-bidi-language:AR-SA'><span style='mso-element:field-begin'></span><span style='mso-spacerun:yes'> </span>ADDIN EN.CITE <span style='mso-element:field-begin'></span><span style='mso-spacerun:yes'> </span>ADDIN EN.CITE.DATA <![if gte mso 9]><xml> 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</xml><![endif]><span style='mso-element:field-end'></span><span style='mso-element:field-separator'></span></span><![endif]-->(Onoue et al., 2014, Onoue et al., 2013)<!--[if gte mso 9]><xml> 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</xml><![endif]--><!--[if supportFields]><span lang=EN-US style='font-size:10.5pt;font-family:"Times New Roman","serif";mso-fareast-font-family: "ＭＳ 明朝";mso-fareast-theme-font:minor-fareast;mso-ansi-language:EN-US; mso-fareast-language:JA;mso-bidi-language:AR-SA'><span style='mso-element:field-end'></span></span><![endif]-->.</p> <br> <br> <!-- end Evidence for Perturbation of This Event by Stressors --> < h4>Domain of Applicability</h4> <br> <!-- loop to find taxonomic applicability under event --> <div> <strong>Taxonomic Applicability</strong><div class="panel panel-default "> <table class="table table-bordered table-striped "> <thead> <tr> <th>Term</th> <th>Scientific Term</th> <th>Evidence</th> <th>Links</th> <h4>Domain of Applicability</h4> <strong>Taxonomic Applicability</strong> <div class="table-responsive "> <table class="table table-bordered table-fullwidth "> <thead class="thead-light" > <tr> <th scope="col" >Term</th> <th scope="col" >Scientific Term</th> <th scope="col" >Evidence</th> <th scope="col" >Links</th> </tr> </thead> <tbody> <tr > <td>human </td> <td>Homo sapiens</td> <td>High </td> < td> <a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=9606" , target="_blank">NCBI</a> </td> </tr> <tbody class="tbody-striped"> <tr > <td>Vertebrates</td > <td>Vertebrates</td> <td>High</td> <td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=0" target="_blank">NCBI</a> </td> </tr> <tr> <td>human</td> <td>Homo sapiens</td> <td>Moderate</td> <td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=9606" target="_blank">NCBI</a></td> </tr> <tr> <td>human and other cells in culture </td> <td>human and other cells in culture</ td> <td>Moderate</td> <td>< a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=0" target="_blank">NCBI</a></td> </tr> <tr> <td>mouse</td> <td>Mus musculus</td> <td>Moderate</td> <td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=10090" target="_blank">NCBI</a></td> </tr> <tr> <td>crustaceans</td> <td>Daphnia magna</td> <td>High</td> <td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=35525" target="_blank">NCBI</a></td> </tr> <tr> <td>Lemna minor</td> <td>Lemna minor </td> <td>High</td> <td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=4472" target="_blank">NCBI</a></td> </tr> <tr> <td>zebrafish</td> <td>Danio rerio</td> <td>High</td> <td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=7955" target="_blank">NCBI</a></td> < /tr> </tbody> </table> </div> </div> <!-- end loop for taxons --> <!-- life stages --> <div> <strong>Life Stage Applicability</strong><div class="panel panel-default "> <table class="table table-bordered table-striped "> <thead> <strong>Life Stage Applicability</strong> <div class="table-responsive "> <table class="table table-bordered table-fullwidth "> <thead class="thead-light" > <tr> <th>Life Stage</th> <th>Evidence</th> <th scope="col" >Life Stage</th> <th scope="col" >Evidence</th> </tr> </thead> <tbody> <tr> <td>All life stages</td> <td>High</td> </tr> <tbody class="tbody-striped" > <tr> <td>All life stages</td> <td>High</td> </tr> </tbody> </table> </div> </div> <!-- end life stages --> <!-- sex terms --> <div> <strong>Sex Applicability</strong><div class="panel panel-default "> <table class="table table-bordered table-striped "> <thead> <strong>Sex Applicability</strong> <div class="table-responsive "> <table class="table table-bordered table-fullwidth "> <thead class="thead-light" > <tr> <th>Sex</th> <th>Evidence</th> <th scope="col" >Sex</th> <th scope="col" >Evidence</th> </tr> </thead> <tbody> < tr> <td>Mixed</td> <td>High</td> </tr> <tbody class="tbody-striped" > <tr> <td>Unspecific</td> <td>High</td> </ tr> <tr> <td>Mixed</td> <td>High</td> </tr> </tbody> </table> </div> </div> <!-- e nd sex terms --> <p>ROS is a normal constituent found in all organisms, <em>lifestages, a nd sexes.</em></p> <div> <p><strong>Chemicals:</strong> This MIE applies to a wide range of chem icals. The chemicals absorb photon energy from light within the range of natural sunlight (290-700 nm) <!--[endif]---->(ICH, 2014, Onoue and Tsuda, 2006).<!--![endif]----> </p> <h4>Key Event Description</h4> <p>Biolog ical State: increased reactive oxygen species (ROS) </p><p><!--[endif]----> </p><p>Biological compartment: an entire cell -- may be cytosolic, may also enter organelles. </p> <p><strong>Sex:</strong> This MIE applies to both males and females . </p><p>Reactive oxygen species (ROS) are O<sub>2</sub>- derived molecules that can be both free radicals (e.g. superoxide, hydroxyl, peroxyl, alcoxyl) and non-radicals (hypochlorous acid, ozone and singlet oxygen) (Bedard and Krause 2007; Ozcan and Ogun 2015). ROS production occurs naturally in all kinds of tissues inside various cellular compartments, such as mitochondria and peroxisomes (Drew and Leeuwenburgh 2002; Ozcan and Ogun 2015). Furthermore, these molecules have an important function in the regulation of several biological processes – they might act as antimicrobial agents or triggers of animal gamete activation and capacitation (Goud et al. 2008; Parrish 2010; Bisht et al. 2017). <br /> However, in environmental stress situations (exposure to radiation, chemicals, high temperatures) these molecules have its levels drastically increased, and overly interact with macromolecules, namely nucleic acids, proteins, carbohydrates and lipids, causing cell and tissue damage (Brieger et al. 2012; Ozcan and Ogun 2015) . </p><p><strong>Life stages:</strong> The relevant life stages for this MIE are all life stages after born.</ p><div> < p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">Reactive oxygen species (ROS) refers to the chemical species superoxide, hydrogen peroxide, and their secondary reactive products. In the biological context, ROS are signaling molecules with important roles in cell energy metabolism, cell proliferation, and fate. Therefore, balancing ROS levels at the cellular and tissue level is an important part of many biological processes. Disbalance, mainly an increase in ROS levels, can cause cell dysfunction and irreversible cell damage.</span></span></ p><p><strong>Taxonomic:</strong> This MIE mainly applies to human. <!--![endif]----></p> <br> </div> <!-- event text --> <h4>Key Event Description</h4> <p>In the primary event, photoreactive chem icals are excited by the absorption of photon energy. The energy of the photoactivated chemicals transfer to oxygen and then generates the reactive oxygen species (ROS), including superoxide (O<sub>2</sub><sup>−</sup>) via type I reaction and singlet oxygen (<sup>1 </sup>O<sub>2 </sub>) via type II reaction, as principal intermediate species in phototoxic reaction <!--[if supportFields]><span lang=EN-US style=' font-size:10.5pt; font-family:"Times New Roman"," serif"; mso-fareast- font-family:"ＭＳ 明朝";mso-fareast-theme- font:minor-fareast; mso-ansi-language:EN-US;mso-fareast-language:JA;mso-bidi-language:AR-SA'>< span'mso-element:field-begin'> </span><span'mso-spacerun:yes'> </span>ADDIN EN.CITE <span style='mso-element:field-begin'> </span><span'mso-spacerun:yes'> </span>ADDIN EN.CITE.DATA <![if gte mso 9]><xml > 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</xml><![endif]--><!--[if supportFields]><span lang=EN-US style='font-size:10.5pt;font-family:"Times New Roman","serif";mso-fareast-font-family: "ＭＳ 明朝";mso-fareast-theme-font:minor-fareast;mso-ansi-language:EN-US; mso-fareast-language:JA;mso-bidi-language:AR-SA'><span style='mso-element:field-end'></span></span><![endif]-->.</p> <br> <h4>How it is Measured or Detected</h4> <p>On the basis of the pathogenesis of drug-induced phototoxicity, a reactive oxygen species (ROS) assay was proposed to evaluate the phototoxic risk of chemicals. The ROS assay can monitor generation of ROS, such as singlet oxygen and superoxide, from photoirradiated chemicals, and the ROS data can be used to evaluate the photoreactivity of chemicals <!--[if supportFields]><span lang=EN-US style='font-size:10.5pt;font-family:"Times New Roman","serif"; mso-fareast-font-family:TimesNewRomanPSMT;mso-font-kerning:0pt;mso-ansi-language: EN-US;mso-fareast-language:JA;mso-bidi-language:AR-SA'><span style='mso-element: field-begin'></span><span style='mso-spacerun:yes'> </span>ADDIN EN.CITE <span style='mso-element:field-begin'></span><span style='mso-spacerun:yes'> </span>ADDIN EN.CITE.DATA <![if gte mso 9]><xml> 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</xml><![endif]><span style='mso-element:field-end'></span><span style='mso-element:field-separator'></span></span><![endif]-->(Onoue et al. , 2014, Onoue et al. , 2013, Onoue and Tsuda, 2006)<!--[if gte mso 9]><xml> 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></xml><![endif]--><!--[if supportFields]><span lang=EN-US style='font-size:10.5pt;font-family:"Times New Roman","serif";mso-fareast-font-family: TimesNewRomanPSMT;mso-font-kerning:0pt;mso-ansi-language:EN-US;mso-fareast-language: JA;mso-bidi-language:AR-SA'><span style='mso-element:field-end'></span></span><![endif]-->. The ROS assay is a recommended approach by guidelines to evaluate the phototoxic risk of chemicals <!--[if supportFields]>< spanlang=EN-US style=' font-size:10.5pt; font-family:"Times New Roman"," serif"; mso-fareast-font-family:TimesNewRomanPSMT;mso-font-kerning:0pt;mso-ansi-language: EN-US;mso-fareast-language:JA;mso-bidi-language:AR-SA'><span style='mso-element: field-begin'></span><span style='mso-spacerun:yes'> </span>ADDIN EN.CITE <EndNote><Cite><Author>ICH</Author><Year>2014</Year><RecNum>1121</RecNum><DisplayText>(ICH, 2014, PCPC, 2014)</DisplayText><record><rec-number>1121</rec-number><foreign-keys><key app="EN" db-id="wadztfe5qpsstuefdflp9wxupps099f2vvw2">1121</key></foreign-keys><ref-type name="Government Document">46</ref-type><contributors><authors><author>ICH</author></authors></contributors><titles><title>ICH Guideline S10 Guidance on Photosafety Evaluation of Pharmaceuticals.</title></titles><dates><year>2014</year></dates><publisher>Intern ational Council on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use</publisher><urls></urls></record></Cite><Cite><Author>PCPC</Author><Year>2014</Year><RecNum>1226</RecNum><record><rec-number>1226</rec-number><foreign-keys><key app="EN" db-id="wadztfe5qpsstuefdflp9wxupps099f2vvw2">1226</key></foreign-keys><ref-type name="Government Document">46</ref-type><contributors><authors><author>PCPC</author></authors></contributors><titles><title>PCPC 2014 safet y evaluation guidelines; Chapter 7: Evalua tion of P hotoirritation and Photoall ergy potential</title></titles><dates><year>2014</year></dates><publisher>Personal Care Products Council</publisher><urls></urls></record></Cite></EndNote><span style='mso-element:field-separator'></span></span><![endif]-->(ICH, 2014, PCPC, 2014)<!--[if supportFields]><span lang=EN-US style='font-size:10.5pt;font-family:"Times New Roman","serif"; mso-fareast-font-family:TimesNewRomanPSMT;mso-font-kerning:0pt;mso-ansi-language: EN-US;mso-fareast-language:JA;mso-bidi-language:AR-SA'><span style='mso-element: field-end'></span></span><![endif]-->.</p > <br> <p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">ROS are produced from both exogenous stressors and normal endogenous cellular processes, such as the mitochondrial electron transport chain (ETC). Inhibition of the ETC can result in the accumulation of ROS. Exposure to chemicals, heavy metal ions, or ionizing radiation can also result in increased production of ROS. Chemicals and heavy metal ions can deplete cellular antioxidants reducing the cell’s ability to control cellular ROS and resulting in the accumulation of ROS. Cellular antioxidants include glutathione (GSH), protein sulfhydryl groups, superoxide dismutase (SOD). </span></span></p> <p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">ROS are rad icals, ions, or molecules that have a single unpaired electron in their outermost shell of electrons, which can be categorized into two groups: free oxygen radicals and non-radical ROS [Liou et al., 2010]. </span></span></p> <p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif"><Free oxygen radicals></span></span></p> <div> <table cellspacing="0" class="MsoTableGrid" style="border-collapse:collapse; border:none"> <tbody> <tr> <td style="border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:2px solid black; vertical-align:top; width:290px"> <p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif"> superoxide</span></span></p> </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:2px solid black; vertical-align:top; width:290px"> <p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">O<sub>2 </sub>·<sup>- </sup></span></span></p> </td> </tr> <tr> <td style="border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:290px"> <p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">hydroxyl radical</span></span></p> </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:290px"> <p><span style=" font-size:16px"><span style=" font-family:Arial,Helvetica,sans- serif">·OH</span></span></p> </td> </tr> <tr> <td style="border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:290px"> <p><span style="font-size:16px"><span style=" font-family:Arial,Helvetica,sans-serif">nitric oxide</span></span></p> </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:290px"> <p><span style=" font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">NO·</span></span></p> </td> </tr> <tr> <td style="border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:290px"> <p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">organic radicals</span></ span></p> </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:290px"> <p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">R· </span></ span></p> </td> </tr> <tr> <td style="border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:290px"> <p> <span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">peroxyl radicals </span></ span></p> </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:290px"> <p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">ROO·</span> </span></p> </td> </tr> <tr> <td style="border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:290px" > <p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">alkoxyl radicals</span></span></p> </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:290px"> <p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">RO·</span></span></p> </td> </tr> <tr> <td style="border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:290px"> <p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">thiyl radicals</span></span></p> </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:290px"> <p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">RS·</span></span></p> </td> </tr> <tr> <td style="border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:290px"> <p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">sulfonyl radicals</span></span></p> </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:290px"> <p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">ROS·</span></span></p> </td> </tr> <tr> <td style="border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:290px"> <p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">thiyl peroxyl radicals</span></span></p> </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:290px"> <p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">RSOO·</span></span></p> </td> </tr> <tr> <td style="border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:290px"> <p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">disulfides</span></span></p> </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:290px"> <p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">RSSR</span></span></p> </td> </tr> </tbody> </table> </div> <p><span style="font-size:16px" ><span style="font-family:Arial,Helvetica,sans-serif"><Non-radical ROS> </span></span></p> <div> <table cellspacing="0" class="MsoTableGrid" style="border-collapse:collapse; border:none" > <tbody> <tr> <td style="border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:2px solid black; vertical-align:top; width:290px"> <p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">hydrogen peroxide</span></span></p> </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:2px solid black; vertical-align:top; width:290px"> <p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">H<sub>2</sub>O<sub>2</sub></span></span></p> </td> </tr> <tr> <td style="border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:290px"> <p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">singlet oxygen</span></span></p> </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:290px"> <p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif"><sup>1</sup>O<sub>2</sub></span></span></p> </td> </tr> <tr> <td style="border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:290px"> <p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">ozone/trioxygen</span></span></p> </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:290px"> <p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">O<sub>3</sub></span></span></p> </td> </tr> <tr> <td style="border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:290px"> <p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">organic hydroperoxides</span></span></p> </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:290px"> <p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">ROOH</span></span></p> </td> </tr> <tr> <td style="border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:290px"> <p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">hypochlorite</span></span></p> </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:290px"> <p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">ClO<sup>-</sup></span></span></p> </td> </tr> <tr> <td style="border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:290px"> <p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">peroxynitrite</span></span></p> </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:290px"> <p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">ONOO<sup>-</sup></span></span></p> </td> </tr> <tr> <td style="border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:290px"> <p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">nitrosoperoxycarbonate anion</span></span></p> </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:290px"> <p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">O=NOOCO<sub>2</sub><sup>-</sup></span></span></p> </td> </tr> <tr> <td style="border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:290px"> <p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">nitrocarbonate anion</span></span></p> </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:290px"> <p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">O<sub>2</sub>NOCO<sub>2</sub><sup>-</sup></span></span></p> </td> </tr> <tr> <td style="border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:290px"> <p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">dinitrogen dioxide</span></span></p> </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:290px"> <p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">N<sub>2</sub>O<sub>2</sub></span></span></p> </td> </tr> <tr> <td style="border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:290px"> <p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">nitronium</span></span></p> </td> <td style="border-bottom:2px solid black; border-left:none; border-right:2px solid black; border-top:none; vertical-align:top; width:290px"> <p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">NO<sub>2</sub><sup>+</sup></span></span></p> </td> </tr> <tr> <td colspan="2" style="border-bottom:2px solid black; border-left:2px solid black; border-right:2px solid black; border-top:none; vertical-align:top; width:580px"> <p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">highly reactive lipid- or carbohydrate-derived carbonyl compounds</span></span></p > </td> </tr> </tbody> </table> </div> <p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">Potential sources of ROS include NADPH oxidase, xanthine oxidase, mitochondria, nitric oxide synthase, cytochrome P450, lipoxygenase/cyclooxygenase, and monoamine oxidase [Granger et al., 2015]. ROS are generated through NADPH oxidases consisting of p47<sup>phox</sup> and p67<sup>phox</sup>. ROS are generated through xanthine oxidase activation in sepsis [Ramos et al., 2018]. Arsenic produces ROS [Zhang et al., 2011]. Mitochondria-targeted paraquat and metformin mediate ROS production [Chowdhury et al., 2020]. ROS are generated by bleomycin [Lu et al., 2010]. Radiation induces dose-dependent ROS production [Ji et al., 2019]. </span></ span></p> <p><span style=" font-size:16px"><span style=" font-family:Arial,Helvetica,sans- serif">ROS are generated in the course of cellular respiration, metabolism, cell signaling, and inflammation [Dickinson and Chang 2011; Egea et al. 2017]. Hydrogen peroxide is also made by the endoplasmic reticulum in the course of protein folding. Nitric oxide (NO) is produced at the highest levels by nitric oxide synthase in endothelial cells and phagocytes. NO production is one of the main mechanisms by which phagocytes kill bacteria [Wang et al., 2017]. The other species are produced by reactions with superoxide or peroxide, or by other free radicals or enzymes.</span></span></p> <p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">ROS activity is principally local. Most ROS have short half-lives, ranging from nano- to milliseconds, so diffusion is limited, while reactive nitrogen species (RNS) nitric oxide or peroxynitrite can survive long enough to diffuse across membranes [Calcerrada et al. 2011]. Consequently, local concentrations of ROS are much higher than average cellular concentr ations, and signaling is typically controlled by colocalization with redox buffers [Dickinson and Chang 2011; Egea et al. 2017]. </span></span></p> <p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">Although their existence is limited temporally and spatially, ROS interact with other ROS or with other nearby molecules to produce more ROS and participate in a feedback loop to amplify the ROS signal, which can increase RNS. Both ROS and RNS also move into neighboring cells, and ROS can increase intracellular ROS signaling in neighboring cells [Egea et al. 2017].</span></span></p> <p>In the primar y event, photoreactive chemicals are excited by the absorp tion of p hoton energy. The en ergy of the photoactivated chemicals transfer to oxygen and then generates the reactive oxygen species (ROS), including superoxide (O<sub>2</sub><sup>−</sup>) via type I reaction and singlet oxygen (<sup>1</sup>O<sub>2</sub>) via type II reaction, as principal intermediate species in phototoxic reaction (Foote, 1991, Onoue et al. , 2009).</p> </div > <h4>How it is Measured or Detected</h4> <p>Photocolorimetric assays (Sharma et al. 2017; Griendling et al. 2016) or through commercial kits purchased from specialized companies.</p> <p>Yuan, Yan, et al., (2013) described ROS monitoring by using H<sub>2</sub>-DCF-DA, a redox-sensitive fluorescent dye. Briefly, the harvested cells were incubated with H<sub>2</sub>-DCF-DA (50 µmol/L final concentration) for 30 min in the dark at 37°C. After treatment, cells were immediately washed twice, re-suspended in PBS, and analyzed on a BD-FACS Aria flow cytometry. ROS generation was based on fluorescent intensity which was recorded by excitation at 504 nm and emission at 529 nm.</p> <p>Lipid peroxidation (LPO) can be measured as an indicator of oxidative stress damage Yen, Cheng Chien, et al., (2013).</p> <p>Chattopadhyay, Sukumar, et al. (2002) assayed the generation of free radicals within the cells and their extracellular release in the medium by addition of yellow NBT salt solution (Park et al., 1968). Extracellular release of ROS converted NBT to a purple colored formazan. The cells were incubated with 100 ml of 1 mg/ml NBT solution for 1 h at 37 °C and the product formed was assayed at 550 nm in an Anthos 2001 plate reader. The observations of the ‘cell-free system’ were confirmed by cytological examination of parallel set of explants stained with chromogenic reactions for NO and ROS.</p> <p>On the basis of the pathogenesis of drug-induced phototoxicity, a reactive oxygen species (ROS) assay was proposed to evaluate the phototoxic risk of chemicals. The ROS assay can monitor generation of ROS, such as singlet oxygen and superoxide, from photoirradiated chemicals, and the ROS data can be used to evaluate the photoreactivity of chemicals (Onoue et al. , 2014, Onoue et al. , 2013, Onoue and Tsuda, 2006). The ROS assay is a recommended approach by guidelines to evaluate the phototoxic risk of chemicals (ICH, 2014, PCPC, 2014).</p> <div> <p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif"><strong><Direct detection></strong></span></span></p> <p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">Many fluorescent compounds can be used to detect ROS, some of which are specific, and others are less specific. </span></span></p> <p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">・ROS can be detected by fluorescent probes such as <em>p</em>-methoxy-phenol derivative [Ashoka et al., 2020].</span></span></p> <p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">・Chemiluminescence analysis can detect the superoxide, where some probes have a wider range for detecting hydroxyl radical, hydrogen peroxide, and peroxynitrite [Fuloria et al., 2021].</span></span></p> <p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">・ROS in the blood can be detected using superparamagnetic iron oxide nanoparticles (SPION)-based biosensor [Lee et al., 2020].</span></span></p> <p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">・Hydrogen peroxide (H<sub>2</sub>O<sub>2</sub>) can be detected with a colorimetric probe, which reacts with H<sub>2</sub>O<sub>2</sub> in a 1:1 stoichiometry to produce a bright pink colored product, followed by the detection with a standard colorimetric microplate reader with a filter in the 540-570 nm range.</span></span></p> <p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">・The levels of ROS can be quantified using multiple-step amperometry using a stainless steel counter electrode and non-leak Ag|AgCl reference node [Flaherty et al., 2017].</span></span></p> <p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">・Singlet oxygen can be measured by monitoring the bleaching of <em>p</em>-nitrosodimethylaniline at 440 nm using a spectrophotometer with imidazole as a selective acceptor of singlet oxygen [Onoue et al., 2014].</span></span></p> <p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif"><strong><Indirect Detection></strong></span></span></p> <p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">Alternative methods involve the detection of redox-dependent changes to cellular constituents such as proteins, DNA, lipids, or glutathione [Dickinson and Chang 2011; Wang et al. 2013; Griendling et al. 2016]. However, these methods cannot generally distinguish between the oxidative species behind the changes and cannot provide good resolution for the kinetics of oxidative activity.</span></span></p> </div> <h4>References</h4> <p>Foote CS. Definition of type I and type II photosensitized oxidation. Photochem Photobiol. 1991;54:659.</p> <h4>References</h4> <p>Akai, K., et al. (2004). "Ability of ferric nitrilotriacetate complex with three pH-dependent conformations to induce lipid peroxidation." Free Radic Res. Sep;38(9):951-62. doi: 10.1080/1071576042000261945</p> <p>Ashoka, A. H., et al. (2020). "Recent Advances in Fluorescent Probes for Detection of HOCl and HNO." ACS omega, 5(4), 1730-1742. doi:10.1021/acsomega.9b03420</p> <p>B.H. Park, S.M. Fikrig, E.M. 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Journal of applied toxicology : JAT. 2013;33:1241-50.</p> <p>Onoue S, Kawamura K, Igarashi N, Zhou Y, Fujikawa M, Yamada H, et al. Reactive oxygen species assay-based risk assessment of drug-induced phototoxicity: classification criteria and application to drug candidates. J Pharm Biomed Anal. 2008;47:967-72.</p> <p>Onoue S, Seto Y, Gandy G, Yamada S. Drug-induced phototoxicity; an early<em> in vitro</em> identification of phototoxic potential of new drug entities in drug discovery and development. Current drug safety. 2009;4:123-36.</p> <p>Onoue S, Tsuda Y. Analytical studies on the prediction of photosensitive/phototoxic potential of pharmaceutical substances. Pharmaceutical research. 2006;23:156-64.</p> <p>Ozcan, Ayla, and Metin Ogun. 2015. “Biochemistry of Reactive Oxygen and Nitrogen Species.” In Basic Principles and Clinical Significance of Oxidative Stress, edited by Sivakumar Joghi Thatha Gowder. Rijeka: IntechOpen.</p> <p>Parrish, A. R. 2010. “2.27 - Hypoxia/Ischemia Signaling.” In Comprehensive Toxicology (Second Edition), edited by Charlene A. McQueen, 529–42. Oxford: Elsevier.</p> <p>PCPC. PCPC 2014 safety evaluation guidelines; Chapter 7: Evaluation of Photoirritation and Photoallergy potential. Personal Care Products Council; 2014.</p> <p>Ramos, M. F. P., et al. (2018). "Xanthine oxidase inhibitors and sepsis." Int J Immunopathol Pharmacol. 32:2058738418772210. doi:10.1177/2058738418772210</p> <p>Ravanat, J. L., et al. (2014). "Radiation-mediated formation of complex damage to DNA: a chemical aspect overview." Br J Radiol 87(1035): 20130715.</p> <p>Schutzendubel, A. and Polle, A. (2002). "Plant responses to abiotic stresses: heavy metal-induced oxidative stress and protection by mycorrhization." Journal of Experimental Botany, 53(372), 1351–1365. https://doi.org/10.1093/jexbot/53.372.1351</p> <p>Seto Y, Kato M, Yamada S, Onoue S. 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" Toxicology and Applied Pharmacology, 256(2), 114-121. doi:10.1016/j.taap.2011.07.016</p> <h3>List of Key Events in the AOP</h3> <div> <div> <h4><a href="/events/1594">Event: 1594: Oxidation of membrane lipids</a><br>< /h4> <h5>Short Name: Oxidation of membrane lipids</h5> </div> <div> <!-- loop to find all aops that use this event --> <h4>AOPs Including This Key Event</h4> <div class="panel panel-default"> <table class="table table-bordered table-striped"> <thead> <tr> <th>AOP ID and Name</th> <th>Event Type</th> </tr> </thead> <tbody> <tr> <td><a href="/aops/282">Aop:282 - Reactive oxygen species generated from photoreactive chemicals leading to phototoxic reactions</a></td> <td>KeyEvent</td> </tr> </tbody> </table> </div> </div> <h4><a href="/events/1594">Event: 1594: Oxidation of membrane lipids</a></h4> <h5>Short Name: Oxidation of membrane lipids</h5> <!-- loop to find stressors under e vent --> <div> <h4>Stressors </h4> <div class="panel panel-default "> <table class="table table-bordered table-striped "> <thead> <tr> <th>Name</th> </tr> </ thead> <tbody > <tr> <td>Photoactivated chemicals</td> </tr > <tr> <td>Reactive oxygen species</td > </tr> </tbody> </table> </div> </div> <br> <!-- biological organization --> <div> <h4>Biological Context</h4> <div class="panel panel-default" > <table class="table table-bordered table -striped"> <thead > <tr> <th>Level of Biolog ical Organization</th> </tr> </thead> <tbody> <tr> <td>Cellular </td> </tr> </tbody> </table> </div> </div> <!-- end of bio org --> <h4>AOPs Including This Key E vent</h4> <div class="table-responsive "> <table class="table table-bordered table-fullwidth "> <thead class=" thead-light" > <tr> <th scope="col">AOP ID and Name</th > <th scope="col">Event Type</th > </tr> </thead > <tbody class="tbody -striped"> <tr > <td><a href="/aops/282">Aop:282 - Adverse outcome pathway on photochem ical toxicity initiated by light exposure</a></td> KeyEvent </td> </tr> </tbody> </table> </div> <!-- cell term -- > <div > <h4>Stressors</h4> <div class="table-responsive"> <table class="table table-bordered table-fullwidth"> <thead class="thead-light"> <tr><th scope="col">Name</th></tr> </thead> <tbody> <tr><td>Photoactivated chemicals</td></tr > <tr><td>Reactive oxygen species</td></tr> </tbody> </table > </div> <!-- end of cell term --> <!-- o rgan term -- > <div > <h4>Biological Context</h4> <div class="table-responsive"> <table class="table table-bordered table-fullwidth"> <thead class="thead-light"> <tr><th scope="col">Level of Biological O rganization</th></tr> </thead> <tbody class="tbody-striped" > <tr><td>Cellular</td></tr> </tbody> </table > </div> <!-- end of organ term --> <!-- Evidence for Perturbation of This Event by Stressors --> <!-- end Evidence for Perturbation of This Event by Stressors --> < h4>Domain of Applicability</h4> <br> <!-- loop to find taxonomic applicability under event --> <div> <strong>Taxonomic Applicability</strong><div class="panel panel-default "> <table class="table table-bordered table-striped "> <thead> <tr> <th>Term</th> <th>Scientific Term</th> <th>Evidence</th> <th>Links</th> <h4>Domain of Applicability</h4> <strong>Taxonomic Applicability</strong> <div class="table-responsive "> <table class="table table-bordered table-fullwidth "> <thead class="thead-light" > <tr> <th scope="col" >Term</th> <th scope="col" >Scientific Term</th> <th scope="col" >Evidence</th> <th scope="col" >Links</th> </tr> </thead> <tbody> <tr> <td>human</td> <td>Homo sapiens</td> <td>High</td> <td> <a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=9606" , target="_blank">NCBI</a> </td> </tr> <tbody class="tbody-striped" > <tr> <td>human</td> <td>Homo sapiens</td> <td>High</td> <td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=9606" target="_blank">NCBI</a></td> </tr> </tbody> </table> </div> </div> <!-- end loop for taxons --> <!-- life stages --> <div> <strong>Life Stage Applicability</strong><div class="panel panel-default "> <table class="table table-bordered table-striped "> <thead> <strong>Life Stage Applicability</strong> <div class="table-responsive "> <table class="table table-bordered table-fullwidth "> <thead class="thead-light" > <tr> <th>Life Stage</th> <th>Evidence</th> <th scope="col" >Life Stage</th> <th scope="col" >Evidence</th> </tr> </thead> <tbody> <tr> <td>All life stages</td> <td>High</td> </tr> <tbody class="tbody-striped" > <tr> <td>All life stages</td> <td>High</td> </tr> </tbody> </table> </div> </div> <!-- end life stages --> <!-- sex terms --> <div> <strong>Sex Applicability</strong><div class="panel panel-default "> <table class="table table-bordered table-striped "> <thead> <strong>Sex Applicability</strong> <div class="table-responsive "> <table class="table table-bordered table-fullwidth "> <thead class="thead-light" > <tr> <th>Sex</th> <th>Evidence</th> <th scope="col" >Sex</th> <th scope="col" >Evidence</th> </tr> </thead> <tbody> <tr> <td>Mixed</td> <td>High</td> </tr> <tbody class="tbody-striped" > <tr> <td>Mixed</td> <td>High</td> </tr> </tbody> </table> </div> </div> <!-- end sex terms --> <div> <p><strong>Chemicals:</strong> This KE applies to a wide range of chemicals. The chemicals generate a reactive species, such as reactive oxygen species, following absorption of photon energy from light within the range of natural sunlight (290-700 nm) <!--[endif]---->(ICH, 2014, Onoue and Tsuda, 2006).<!--![endif]----></p> <p><strong>Chemicals:</strong> This KE applies to a wide range of chemicals. The chemicals generate a reactive species, such as reactive oxygen species, following absorption of photon energy from light within the range of natural sunlight (290-700 nm) <!--[endif]---->(ICH, 2014, Onoue and Tsuda, 2006).<!--![endif]----></p> <p><!--[endif]----></p> <p><strong>Sex:</strong> This KE applies to both males and females. </p> <p><strong>Life stages:</strong> The relevant life stages for this KE are all life stages after born.</p> <p><strong>Taxonomic:</strong> This KE mainly applies to human. <!--![endif]----></p> <br> </div> <!-- event text --> <h4>Key Event Description</h4> <p>Lipid peroxidation of membrane lipids has been considered to be one of the major mechanisms in phototoxic skin responses induced by photoreactive chemicals <!--[endif]---->(Castell et al., 1994, Girotti, 1990, 2001, Onoue et al., 2011, Onoue and Tsuda, 2006, Seto et al., 2013).<!--![endif]----></p> <h4>Key Event Description</h4> <p>Lipid peroxidation of membrane lipids has been considered to be one of the major mechanisms in phototoxic skin responses induced by photoreactive chemicals <!--[endif]---->(Castell et al., 1994, Girotti, 1990, 2001, Onoue et al., 2011, Onoue and Tsuda, 2006, Seto et al., 2013).<!--![endif]----></p> <br> <h4>How it is Measured or Detected</h4> <p>An<em> in vitro</em> system using thiobarbituric acid can monitor lipid peroxidation by photoactivated chemicals <!--[if supportFields]><span <h4>How it is Measured or Detected</h4> <p>An<em> in vitro</em> system using thiobarbituric acid can monitor lipid peroxidation by photoactivated chemicals <!--[if supportFields]><span lang=EN-US style='font-size:10.5pt;font-family:"Times New Roman","serif"; mso-fareast-font-family:"ＭＳ 明朝";mso-fareast-theme-font:minor-fareast; mso-ansi-language:EN-US;mso-fareast-language:JA;mso-bidi-language:AR-SA'><span style='mso-element:field-begin'></span><span style='mso-spacerun:yes'> </span>ADDIN EN.CITE <span style='mso-element:field-begin'></span><span 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</xml><![endif]><span style='mso-element:field-end'></span><span style='mso-element:field-separator'></span></span><![endif]-->(Onoue et al., 2011, Onoue and Tsuda, 2006)<!--[if gte mso 9]><xml> 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</xml><![endif]--><!--[if supportFields]><span lang=EN-US style='font-size:10.5pt;font-family:"Times New Roman","serif";mso-fareast-font-family: "ＭＳ 明朝";mso-fareast-theme-font:minor-fareast;mso-ansi-language:EN-US; mso-fareast-language:JA;mso-bidi-language:AR-SA'><span style='mso-element:field-end'></span></span><![endif]-->.</p> <br> <h4>References</h4> <p>Castell JV, Gomez-Lechon MJ, Grassa C, Martinez LA, Miranda MA, Tarrega P. Photodynamic lipid peroxidation by the photosensitizing nonsteroidal antiinflammatory drugs suprofen and tiaprofenic acid. Photochem Photobiol. 1994;59:35-9.</p> <h4>References</h4> <p>Castell JV, Gomez-Lechon MJ, Grassa C, Martinez LA, Miranda MA, Tarrega P. Photodynamic lipid peroxidation by the photosensitizing nonsteroidal antiinflammatory drugs suprofen and tiaprofenic acid. Photochem Photobiol. 1994;59:35-9.</p> <p>Girotti AW. Photodynamic lipid peroxidation in biological systems. Photochem Photobiol. 1990;51:497-509.</p> <p>Girotti AW. Photosensitized oxidation of membrane lipids: reaction pathways, cytotoxic effects, and cytoprotective mechanisms. J Photochem Photobiol B. 2001;63:103-13.</p> <p>ICH. ICH Guideline S10 Guidance on Photosafety Evaluation of Pharmaceuticals.: International Council on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use; 2014.</p> <p>Onoue S, Seto Y, Ochi M, Inoue R, Ito H, Hatano T, et al. In vitro photochemical and phototoxicological characterization of major constituents in St. John's Wort (Hypericum perforatum) extracts. Phytochemistry. 2011;72:1814-20.</p> <p>Onoue S, Tsuda Y. Analytical studies on the prediction of photosensitive/phototoxic potential of pharmaceutical substances. Pharmaceutical research. 2006;23:156-64.</p> <p>Seto Y, Inoue R, Kato M, Yamada S, Onoue S. Photosafety assessments on pirfenidone: photochemical, photobiological, and pharmacokinetic characterization. J Photochem Photobiol B. 2013;120:44-51.</p> <br> <!-- end event text --></div> <div> <div> <h4><a href="/events/1595">Event: 1595: Oxidation/denatuation of membrane proteins</a><br></h4> <h5>Short Name: Oxidation/denatuation of membrane proteins</h5> </div> <h4><a href="/events/1595">Event: 1595: Oxidation/denatuation of membrane proteins</a></h4> <h5>Short Name: Oxidation/denatuation of membrane proteins</h5> <div> <!-- loop to find all aops that use this event --> <h4>AOPs Including This Key Event</h4> <div class="panel panel-default "> <table class="table table-bordered table-striped "> <thead> <tr> <th >AOP ID and Name</th> <th >Event Type</th> </tr> </thead> <tbody> <tr> <td><a href="/aops/282">Aop:282 - Reactive oxygen species generated from photoreactive chemicals leading to phototoxic reactions</a></td> <td>KeyEvent</td> </tr> </tbody> </table> </div> </div> <!-- loop to find stressors under event --> <div> <h4>Stressors</h4> <div class="panel panel-default"> <table class="table table-bordered table-striped"> <thead> <tr> <th>Name</th> </tr> </thead> <tbody> <tr> <td>P hotoactivated chemicals</td> </tr> <tr> <td>Reactive oxygen species</td> </tr> </tbody> </table> </div> </div> <br> <!-- biological organization --> <div> <h4>Biological Context</h4> <div class="panel panel-default"> <table class="table table-bordered table-striped"> <thead> <tr > <th>Level of Biological Organization</th> </tr> </thead> <tbody> <tr> <td>Cellular </td> </tr> </tbody> </table> </div> </div> <!-- end of bio org --> <h4>AOPs Including This Key Event</h4> <div class="table-responsive "> <table class="table table-bordered table-fullwidth "> <thead class="thead-light" > <tr> <th scope="col" >AOP ID and Name</th> <th scope="col" >Event Type</th> </tr> </thead> <tbody class="tbody-striped" > <tr> <td><a href="/aops/282">Aop:282 - Adverse outcome pathway on p hotochemical toxicity initiated by light exposure</a></td > <td>KeyEvent </td> </tr> </tbody> </table> </div> <!-- cell term -- > <div > <h4>Stressors</h4> <div class="table-responsive"> <table class="table table-bordered table-fullwidth"> <thead class="thead-light"> <tr><th scope="col">Name</th></tr> </thead> <tbody> <tr><td>Photoactivated chemicals</td></tr > <tr><td>Reactive oxygen species</td></tr> </tbody> </table > </div> <!-- end of cell term --> <!-- o rgan term -- > <div > <h4>Biological Context</h4> <div class="table-responsive"> <table class="table table-bordered table-fullwidth"> <thead class="thead-light"> <tr><th scope="col">Level of Biological O rganization</th></tr> </thead> <tbody class="tbody-striped" > <tr><td>Cellular</td></tr> </tbody> </table > </div> <!-- end of organ term --> <!-- Evidence for Perturbation of This Event by Stressors --> <!-- end Evidence for Perturbation of This Event by Stressors --> < h4>Domain of Applicability</h4> <br> <!-- loop to find taxonomic applicability under event --> <div> <strong>Taxonomic Applicability</strong><div class="panel panel-default "> <table class="table table-bordered table-striped "> <thead> <tr> <th>Term</th> <th>Scientific Term</th> <th>Evidence</th> <th>Links</th> <h4>Domain of Applicability</h4> <strong>Taxonomic Applicability</strong> <div class="table-responsive "> <table class="table table-bordered table-fullwidth "> <thead class="thead-light" > <tr> <th scope="col" >Term</th> <th scope="col" >Scientific Term</th> <th scope="col" >Evidence</th> <th scope="col" >Links</th> </tr> </thead> <tbody> <tr> <td>human</td> <td>Homo sapiens</td> <td>High</td> <td> <a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=9606" , target="_blank">NCBI</a> </td> </tr> <tbody class="tbody-striped" > <tr> <td>human</td> <td>Homo sapiens</td> <td>High</td> <td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=9606" target="_blank">NCBI</a></td> </tr> </tbody> </table> </div> </div> <!-- end loop for taxons --> <!-- life stages --> <div> <strong>Life Stage Applicability</strong><div class="panel panel-default "> <table class="table table-bordered table-striped "> <thead> <strong>Life Stage Applicability</strong> <div class="table-responsive "> <table class="table table-bordered table-fullwidth "> <thead class="thead-light" > <tr> <th>Life Stage</th> <th>Evidence</th> <th scope="col" >Life Stage</th> <th scope="col" >Evidence</th> </tr> </thead> <tbody> <tr> <td>All life stages</td> <td>High</td> </tr> <tbody class="tbody-striped" > <tr> <td>All life stages</td> <td>High</td> </tr> </tbody> </table> </div> </div> <!-- end life stages --> <!-- sex terms --> <div> <strong>Sex Applicability</strong><div class="panel panel-default "> <table class="table table-bordered table-striped "> <thead> <strong>Sex Applicability</strong> <div class="table-responsive "> <table class="table table-bordered table-fullwidth "> <thead class="thead-light" > <tr> <th>Sex</th> <th>Evidence</th> <th scope="col" >Sex</th> <th scope="col" >Evidence</th> </tr> </thead> <tbody> <tr> <td>Mixed</td> <td>High</td> </tr> <tbody class="tbody-striped" > <tr> <td>Mixed</td> <td>High</td> </tr> </tbody> </table> </div> </div> <!-- end sex terms --> <div> <p><strong>Chemicals:</strong> This KE applies to a wide range of chemicals. The chemicals generate a reactive species, such as reactive oxygen species, following absorption of photon energy from light within the range of natural sunlight (290-700 nm) <!--[endif]---->(ICH, 2014, Onoue and Tsuda, 2006).<!--![endif]----></p> <p><strong>Chemicals:</strong> This KE applies to a wide range of chemicals. The chemicals generate a reactive species, such as reactive oxygen species, following absorption of photon energy from light within the range of natural sunlight (290-700 nm) <!--[endif]---->(ICH, 2014, Onoue and Tsuda, 2006).<!--![endif]----></p> <p><!--[endif]----></p> <p><strong>Sex:</strong> This KE applies to both males and females. </p> <p><strong>Life stages:</strong> The relevant life stages for this KE are all life stages after born.</p> <p><strong>Taxonomic:</strong> This KE mainly applies to human.</p> <p><!--![endif]----></p> <br> </div> <h4>Key Event Description</h4> <p>Reactive oxygen species yielded from photoactivated chemicals can cause cross-linking of proteins and oxidation of sulfydryl groups resulting in disulfide cross-links <!--[endif]---->(Dalle Carbonare and Pathak, 1992).<!--![endif]----></p> <!-- event text --> <h4>Key Event Description </h4> <p>Reactive oxygen species yielded from photoactivated chemicals can cause cross-linking of proteins and oxidation of sulfydryl groups resulting in disulfide cross-link s <!--[endif]---->(Dalle Carbonare and Pathak, 1992).<!--![endif]----></p> <h4>How it is Measured or Detected </h4> <p>As for in vitro systems, sodium dodecylsulfate polyacrylamide gel electrophoresis (SDS-PAGE) and other gel electrophoresis methodologies can detect denaturation of protein s <!--[endif]---->(Dalle Carbonare and Pathak, 1992). <!--![endif]----></p> <br> <h4>How it is Measured or Detected</h4> <p>As for in vitro systems, sodium dodecylsulfate polyacrylamide gel electrophoresis (SDS-PAGE) and other gel electrophoresis methodologies can detect denaturation of proteins <!--[endif]---->(Dalle Carbonare and Pathak, 1992). <!--![endif]----></p> <br> <h4>References</h4> <p>Dalle Carbonare M, Pathak MA. Skin photosensitizing agents and the role of reactive oxygen species in photoaging. J Photochem Photobiol B. 1992;14:105-24.</p> <h4>References</h4> <p>Dalle Carbonare M, Pathak MA. Skin photosensitizing agents and the role of reactive oxygen species in photoaging. J Photochem Photobiol B. 1992;14:105-24.</p> <p>ICH. ICH Guideline S10 Guidance on Photosafety Evaluation of Pharmaceuticals.: International Council on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use; 2014.</p> <p>Onoue S, Tsuda Y. Analytical studies on the prediction of photosensitive/phototoxic potential of pharmaceutical substances. Pharmaceutical research. 2006;23:156-64.</p> <br> <!-- end event text --></div> <h3>List of Adverse Outcomes in this AOP</h3> <div> <div> <h4><a href="/events/1599">Event: 1599: Inflamatory events in light-exposed tissues</a><br>< /h4> <h5>Short Name: Inflammatory events</h5> </div> <h4><a href="/events/1599">Event: 1599: Inflamatory events in light-exposed tissues</a></h4> <h5>Short Name: Inflammatory events</h5> <h4>AOPs Including This Key Event</h4> <div class="table-responsive"> <table class="table table-bordered table-fullwidth"> <thead class="thead-light"> <tr> <th scope="col">AOP ID and Name</th> <th scope="col">Event Type</th> </tr> </thead> <tbody class="tbody-striped"> <tr> <td><a href="/aops/282">Aop:282 - Adverse outcome pathway on photochemical toxicity initiated by light exposure</a></td> <td>AdverseOutcome</td> </tr> <tr> <td><a href="/aops/495">Aop:495 - Androgen receptor activation leading to prostate cancer</a></td> <td>KeyEvent</td> </tr> </tbody> </table> </div> <div> <!-- loop to find all aops that use this event --> <h4>AOPs Including This Key Event </h4> <div class="panel panel-default "> <table class="table table-bordered table-striped"> <thead> <tr> <th>AOP ID and Name</th> <th>Event Type</th > </tr> </ thead> <tbody> <tr> <td><a href="/aops/282">Aop:282 - Reactive oxygen species generated from photoreactive chemicals leading to phototoxic reactions</a></td > <td>AdverseOutcome</td> </tr> </tbody> </table> </div> </div> <!-- loop to find stressors under event --> <div> <h4>Stressors</h4> <div class="panel panel-default"> <table class="table table-bordered table-striped"> <thead> <tr> <th> Name</th> </tr> </thead> <tbody> <tr> <td>Light (290-700 nm)</td> </tr> <tr> <td>Photoreactive chemicals</td> </tr> <tr> <td>Reactive oxygen species</td> </tr> </tbody> </table> </div> </div> <br> <!-- biological organization --> <div> <h4>Biological Context</h4> <div class="panel panel-default"> <table class="table table-bordered table-striped"> <thead> <tr> <th>Level of Biological Organization</th> </tr> </thead> <tbody> <tr> <td>Organ</td> </tr> </tbody> </table> </div> </div> <!-- end of bio org --> <!-- cell term --> <div> <h4>Stressors </h4> <div class="table-responsive "> <table class="table table-bordered table-fullwidth" > < thead class="thead-light" > <tr><th scope="col"> Name</th></tr> </thead> <tbody> <tr><td>Light (290-700 nm)</td></tr> <tr><td>Photoreactive chemicals</td></tr> <tr><td>Reactive oxygen species</td></tr> </tbody> </table> </div> <!-- end of cell term --> <!-- o rgan term -- > <div > <h4>Biological Context</h4> <div class="table-responsive"> <table class="table table-bordered table-fullwidth"> <thead class="thead-light"> <tr><th scope="col">Level of Biological O rganization</th></tr> </thead> <tbody class="tbody-striped" > <tr><td>Organ</td></tr> </tbody> </table > </div> <!-- end of organ term --> <!-- Evidence for Perturbation of This Event by Stressors --> <!-- end Evidence for Perturbation of This Event by Stressors --> < h4>Domain of Applicability</h4> <br> <!-- loop to find taxonomic applicability under event --> <div> <strong>Taxonomic Applicability</strong><div class="panel panel-default "> <table class="table table-bordered table-striped "> <thead> <tr> <th>Term</th> <th>Scientific Term</th> <th>Evidence</th> <th>Links</th> <h4>Domain of Applicability</h4> <strong>Taxonomic Applicability</strong> <div class="table-responsive "> <table class="table table-bordered table-fullwidth "> <thead class="thead-light" > <tr> <th scope="col" >Term</th> <th scope="col" >Scientific Term</th> <th scope="col" >Evidence</th> <th scope="col" >Links</th> </tr> </thead> <tbody> <tr> <td>human</td> <td>Homo sapiens</td> <td>High</td> <td> <a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=9606" , target="_blank">NCBI</a> </td> </tr> <tbody class="tbody-striped" > <tr> <td>human</td> <td>Homo sapiens</td> <td>High</td> <td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=9606" target="_blank">NCBI</a></td> </tr> </tbody> </table> </div> </div> <!-- end loop for taxons --> <!-- life stages --> <div> <strong>Life Stage Applicability</strong><div class="panel panel-default "> <table class="table table-bordered table-striped "> <thead> <strong>Life Stage Applicability</strong> <div class="table-responsive "> <table class="table table-bordered table-fullwidth "> <thead class="thead-light" > <tr> <th>Life Stage</th> <th>Evidence</th> <th scope="col" >Life Stage</th> <th scope="col" >Evidence</th> </tr> </thead> <tbody> <tr> <td>All life stages</td> <td>High</td> </tr> <tbody class="tbody-striped" > <tr> <td>All life stages</td> <td>High</td> </tr> </tbody> </table> </div> </div> <!-- end life stages --> <!-- sex terms --> <div> <strong>Sex Applicability</strong><div class="panel panel-default "> <table class="table table-bordered table-striped "> <thead> <strong>Sex Applicability</strong> <div class="table-responsive "> <table class="table table-bordered table-fullwidth "> <thead class="thead-light" > <tr> <th>Sex</th> <th>Evidence</th> <th scope="col" >Sex</th> <th scope="col" >Evidence</th> </tr> </thead> <tbody> <tr> <td>Mixed</td> <td>High</td> </tr> <tbody class="tbody-striped" > <tr> <td>Mixed</td> <td>High</td> </tr> </tbody> </table> </div> </div> <!-- end sex terms --> <div> <p><strong>Chemicals:</strong> This AO applies to a wide range of chemicals. Phototoxic chemicals are recognized to have following characteristics: (i) absorption of light within the range of natural sunlight (290-700 nm); (ii) generation of a reactive species following absorption of UV-visible light; (iii) distribution to light-exposed tissues (e.g., skin and eye) in ICH S10 guideline for photosafety assessment (ICH, 2014).</p> <p><strong>Chemicals:</strong> This AO applies to a wide range of chemicals. Phototoxic chemicals are recognized to have following characteristics: (i) absorption of light within the range of natural sunlight (290-700 nm); (ii) generation of a reactive species following absorption of UV-visible light; (iii) distribution to light-exposed tissues (e.g., skin and eye) in ICH S10 guideline for photosafety assessment (ICH, 2014).</p> <p><strong>Sex:</strong> This AO applies to both males and females. </p> <p><strong>Life stages:</strong> The relevant life stages for this AO are all life stages after born.</p> <p><strong>Taxonomic:</strong> This AO mainly applies to human.</p> <br> </div> <!-- event text --> <h4>Key Event Description</h4> <p>Photoirritation is frequently characterized as exaggerated sunburn sometimes mediated by oxidative stress in the cell membrane, and hyperpigmentation and desquamation may occur as a residual effect of a phototoxic reaction. Theoretically, if a high concentration of a phototoxic drug accumulates in the skin and the appropriate wavelength of light is present, any individual will develop a phototoxic reaction. In particular, peroxidation of membrane lipid could be induced by some photosensitizers under photo-irradiation, and this photochemical reaction certainly correlates with damage produced in the cell membrane, leading to the skin photoirritation <!--[endif]---->(Castell et al. , 1994, Onoue et al. , 2009).<!--![endif]----></p> <br> <h4>How it is Measured or Detected</h4> <p>Inflammatory events induced by photoreactive chemicals can be detected <em>in vivo</em> phototoxicity testing and photopatch test in clinical (Epstein, 1964, ICH, 2014, Onoue et al., 2009). <!--![endif]----></p> <h4>Key Event Description</h4> <p>Photoirritation is frequently characterized as exaggerated sunburn sometimes mediated by oxidative stress in the cell membrane, and hyperpigmentation and desquamation may occur as a residual effect of a phototoxic reaction. Theoretically, if a high concentration of a phototoxic drug accumulates in the skin and the appropriate wavelength of light is present, any individual will develop a phototoxic reaction. In particular, peroxidation of membrane lipid could be induced by some photosensitizers under photo-irradiation, and this photochemical reaction certainly correlates with damage produced in the cell membrane, leading to the skin photoirritation <!--[endif]---->(Castell et al. , 1994, Onoue et al. , 2009).<!--![endif]----></p> <br> <h4>How it is Measured or Detected</h4> <p>Inflammatory events induced by photoreactive chemicals can be detected <em>in vivo</em> phototoxicity testing and photopatch test in clinical (Epstein, 1964, ICH, 2014, Onoue et al., 2009). <!--![endif]----></p> <h4>Regulatory Significance of the AO</h4> <p>Inflammatory events in light-exposed tissues are considered to be the endpoint of ROS-mediated chemical phototoxicity, especially photoirritant reactions (ICH, 2014, Onoue et al., 2009). </p> <h4>Regulatory Significance of the AO</h4> <p>Inflammatory events in light-exposed tissues are considered to be the endpoint of ROS-mediated chemical phototoxicity, especially photoirritant reactions (ICH, 2014, Onoue et al., 2009). </p> <br> <h4>References</h4> <p>Castell JV, Gomez-Lechon MJ, Grassa C, Martinez LA, Miranda MA, Tarrega P. Photodynamic lipid peroxidation by the photosensitizing nonsteroidal antiinflammatory drugs suprofen and tiaprofenic acid. Photochem Photobiol. 1994;59:35-9.</p> <h4>References</h4> <p>Castell JV, Gomez-Lechon MJ, Grassa C, Martinez LA, Miranda MA, Tarrega P. Photodynamic lipid peroxidation by the photosensitizing nonsteroidal antiinflammatory drugs suprofen and tiaprofenic acid. Photochem Photobiol. 1994;59:35-9.</p> <p>Epstein S. The Photopatch Test; Its Technique, Manifestations, and Significance. Ann Allergy. 1964;22:1-11.</p> <p>ICH. ICH Guideline S10 Guidance on Photosafety Evaluation of Pharmaceuticals.: International Council on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use; 2014.</p> <p>Onoue S, Seto Y, Gandy G, Yamada S. Drug-induced phototoxicity; an early<em> in vitro</em> identification of phototoxic potential of new drug entities in drug discovery and development. Current drug safety. 2009;4:123-36.</p> <br> <!-- end event text --></div> <h2>Appendix 2</h2> <h2>List of Key Event Relationships in the AOP</h2> <!-- Evidence for relationship links section, this lists the relationships and then supports them --> <div id="evidence_supporting_links"> <hr> <h 3>List of Adjacent Key Event Relationships</h3> <div>1845 ">Relationship: 1845: ROS generation leads to Oxidation of membrane lipids</a></h4> <div id="evidence_supporting_links"> <h3>List of Adjacent Key Event Relationships</h3> <div> <h4><a href="/relationships/3513 ">Relationship: 3513: Increase, ROS leads to Oxidation of membrane lipids</a></h4> <h4>AOPs Referencing Relationship</h4> <div class="panel panel-default "> <table class="table table-bordered table-striped"> < thead> <div class="table-responsive "> <table class="table table-bordered table-fullwidth"> <thead class="thead-light"> <tr> <th scope="col">AOP Name</th> <th scope="col">Adjacency</th> <th scope="col">Weight of Evidence</th> <th scope="col">Quantitative Understanding</th> </tr> </ thead> <tbody class="tbody-striped"> <tr> <th>AOP Name</th > <th>A djacency</th > <th>Weight of Evidence</th > <th>Quantitative Understanding</th > <td><a href="/aops/282">Adverse outcome pathway on photochemical toxicity initiated by light exposure</a></td > <td>a djacent</td > <td>High</td > <td>Low</td > </tr> </thead> <tbody> <tr> <th><a href="/aops/282">Reactive oxygen species generated from photoreactive chemicals leading to phototoxic reactions</a></th> <th>adjacent</th> <th>High </th> <th>Low</th> </tr> </tbody> </table> </div> <h4>Evidence Supporting Applicability of this Relationship</h4> <br> <!-- loop to find taxonomic applicability under relationship --> <div> <strong>Taxonomic Applicability</strong><div class="panel panel-default "> <table class="table table-bordered table-striped "> <thead> <tr> <th>Term</th> <th>Scientific Term</th> <th>Evidence</th> <th>Links</th> </tbody> </table> </div> <h4>Evidence Supporting Applicability of this Relationship</h4> <div> <strong>Taxonomic Applicability</strong> <div class="table-responsive "> <table class="table table-bordered table-fullwidth "> <thead class="thead-light" > <tr> <th scope="col" >Term</th> <th scope="col" >Scientific Term</th> <th scope="col" >Evidence</th> <th scope="col" >Links</th> </tr> </thead> <tbody> <tr> <td>human</td> <td>Homo sapiens</td> <td>High</td> <td> <a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=9606" , target="_blank">NCBI</a> </td> </tr> <tbody class="tbody-striped" > <tr> <td>human</td> <td>Homo sapiens</td> <td>High</td> <td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=9606" target="_blank">NCBI</a></td> </tr> </tbody> </table> </div> </div> <!-- end loop for taxons --> <!-- loop to find life stages under relationship --> <div> <strong>Life Stage Applicability</strong><div class="panel panel-default "> <table class="table table-bordered table-striped "> <thead> </div> <div> <strong>Life Stage Applicability</strong> <div class="table-responsive "> <table class="table table-bordered table-fullwidth "> <thead class="thead-light" > <tr> <th>Life Stage</th> <th>Evidence</th> <th scope="col" >Life Stage</th> <th scope="col" >Evidence</th> </tr> </thead> <tbody> <tr> <td>All life stages</td> <td>High</td> </tr> <tbody class="tbody-striped" > <tr> <td>All life stages</td> <td>High</td> </tr> </tbody> </table> </div> </div> <!-- end loop for life stages --> <!-- sex terms --> <div> <strong>Sex Applicability</strong><div class="panel panel-default "> <table class="table table-bordered table-striped "> <thead> </div> <div> <strong>Sex Applicability</strong> <div class="table-responsive "> <table class="table table-bordered table-fullwidth "> <thead class="thead-light" > <tr> <th>Sex</th> <th>Evidence</th> <th scope="col" >Sex</th> <th scope="col" >Evidence</th> </tr> </thead> <tbody> <tr> <td>Mixed</td> <td>High</td> </tr> <tbody class="tbody-striped" > <tr> <td>Mixed</td> <td>High</td> </tr> </tbody> </table> </div> </div> <!-- end sex terms --> < p><strong>Chemicals:</strong> This KER applies to a wide range of chemicals. The chemicals absorb photon energy from light within the range of light (290-700 nm) <!--[endif]----> (ICH, 2014, Onoue and Tsuda, 2006).<!--![endif]----></p> <p><!--[endif]---->< /p> </div> <p><strong>Chemicals:</strong> This KER applies to a wide range of chemicals. The chemicals absorb photon energy from light within the range of light (290-700 nm) (ICH, 2014, Onoue and Tsuda, 2006).</p> <p><strong>Sex:</strong> This KER applies to both males and females. </p> <p><strong>Life stages:</strong> The relevant life stages for this KER are all life stages after born.</p> <p><strong>Taxonomic:</strong> This KER mainly applies to human. <!--![endif]----> </p><p><strong>Taxonomic:</strong> This KER mainly applies to human.</p> <h4>Key Event Relationship Description</h4> <p>Some photoactivated chemicals can generate reactive oxygen species (ROS) after photoactivation of chemicals by irradiation of light (290–700 nm). ROS generated from photoactivated chemicals can react with membrane lipids and lead to oxidation of membrane lipids.</p> <h4>Key Event Relationship Description</h4> <p>Some photoactivated chemicals can generate reactive oxygen species (ROS) after photoactivation of chemicals by irradiation of light (290–700 nm). ROS generated from photoactivated chemicals can react with membrane lipids and lead to oxidation of membrane lipids.</p> <h4>Evidence Supporting this KER</h4> <strong>Biological Plausibility</strong> <div> <p>Photoactivated chemicals generate ROS, and the ROS-generating chemicals cause lipid peroxidation under exposure to light (290–700 nm) in chemical and biological systems (Girotti, 1990, 2001, Onoue and Tsuda, 2006).</p> </div> <!-- if nothing shows up in any of these fields, then evidence supporting this KER will not be displayed --> <h4>Evidence Supporting this KER</h4> <strong>Biological Plausibility</strong> <p>Photoactivated chemicals generate ROS, and the ROS-generating chemicals cause lipid peroxidation under exposure to light (290–700 nm) in chemical and biological systems <!--[if supportFields]><span lang=EN-US style='font-size:10.5pt; font-family:"Times New Roman","serif";mso-fareast-font-family:"ＭＳ 明朝"; 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</xml><![endif]><span style='mso-element:field-end'></span><span style='mso-element:field-separator'></span></span><![endif]-->(Girotti, 1990, 2001, Onoue and Tsuda, 2006)<!--[if gte mso 9]><xml> 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</xml><![endif]--><!--[if supportFields]><span lang=EN-US style='font-size:10.5pt;font-family:"Times New Roman","serif";mso-fareast-font-family: "ＭＳ 明朝";mso-fareast-theme-font:minor-fareast;mso-ansi-language:EN-US; mso-fareast-language:JA;mso-bidi-language:AR-SA'><span style='mso-element:field-end'></span></span><![endif]-->.</p> <strong>Empirical Evidence</strong> <p>Lipid peroxidation was occurred by ROS-generating chemicals under exposure to simulated sunlight <!--[endif]----> (Onoue et al. , 2011, Onoue and Tsuda, 2006). <!--![endif]----></p> <p><!--[endif]----> </p> <strong>Empirical Evidence</strong> <p>Lipid peroxidation was occurred by ROS-generating chemicals under exposure to simulated sunlight (Onoue et al. , 2011, Onoue and Tsuda, 2006). </p> <p>A photoreactive chemical indicated dose-dependent increases in ROS generation and lipid peroxidation after exposure to a fixed dose of simulated sunlight (Seto et al. , 2013).</p> <p> </p><p><!--![endif]----></p> <!--<!% unless aop_rel.relationship.relationship_taxons.blank? %>--> <!--<!%= render 'snapshot_taxons', taxons: aop_rel.relationship.relationship_taxons %>--> <!--<!% unless aop_rel.relationship.taxon_evidence.blank? %>--> <!--<h3>Domain of Applicability</h3>--> <!--<!%== aop_rel.relationship.taxon_evidence %>--> <!--<!% end %>--> <!--<!% end %>--> <h4>References</h4> <p>Girotti AW. Photodynamic lipid peroxidation in biological systems. Photochem Photobiol. 1990;51:497-509.</p> <h4>References</h4> <div> <p>Girotti AW. Photosensitized oxidation of membrane lipids: reaction pathways, cytotoxic effects, and cytoprotective mechanisms. J Photochem Photobiol B. 2001;63:103-13.</p> <p>ICH. ICH Guideline S10 Guidance on Photosafety Evaluation of Pharmaceuticals.: International Council on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use; 2014.</p> <p>Onoue S, Seto Y, Ochi M, Inoue R, Ito H, Hatano T, et al. In vitro photochemical and phototoxicological characterization of major constituents in St. John's Wort (Hypericum perforatum) extracts. Phytochemistry. 2011;72:1814-20.</p> <p>Onoue S, Tsuda Y. Analytical studies on the prediction of photosensitive/phototoxic potential of pharmaceutical substances. Pharmaceutical research. 2006;23:156-64.</p> <p>Seto Y, Inoue R, Kato M, Yamada S, Onoue S. Photosafety assessments on pirfenidone: photochemical, photobiological, and pharmacokinetic characterization. J Photochem Photobiol B. 2013;120:44-51.</p> </div> </div> <br> <div>1846 ">Relationship: 1846: ROS generation leads to Oxidation/denatuation of membrane proteins</a></h4> <div> <h4><a href="/relationships/3514 ">Relationship: 3514: Increase, ROS leads to Oxidation/denatuation of membrane proteins</a></h4> <h4>AOPs Referencing Relationship</h4> <div class="panel panel-default "> <table class="table table-bordered table-striped"> < thead> <div class="table-responsive "> <table class="table table-bordered table-fullwidth"> <thead class="thead-light"> <tr> <th scope="col">AOP Name</th> <th scope="col">Adjacency</th> <th scope="col">Weight of Evidence</th> <th scope="col">Quantitative Understanding</th> </tr> </ thead> <tbody class="tbody-striped"> <tr> <th>AOP Name</th > <th>A djacency</th > <th>Weight of Evidence</th > <th>Quantitative Understanding</th > <td><a href="/aops/282">Adverse outcome pathway on photochemical toxicity initiated by light exposure</a></td > <td>a djacent</td > <td>High</td > <td>Low</td > </tr> </thead> <tbody> <tr> <th><a href="/aops/282">Reactive oxygen species generated from photoreactive chemicals leading to phototoxic reactions</a></th> <th>adjacent</th> <th>High </th> <th>Low</th> </tr> </tbody> </table> </div> <h4>Evidence Supporting Applicability of this Relationship</h4> <br> <!-- loop to find taxonomic applicability under relationship --> <div> <strong>Taxonomic Applicability</strong><div class="panel panel-default "> <table class="table table-bordered table-striped "> <thead> <tr> <th>Term</th> <th>Scientific Term</th> <th>Evidence</th> <th>Links</th> </tbody> </table> </div> <h4>Evidence Supporting Applicability of this Relationship</h4> <div> <strong>Taxonomic Applicability</strong> <div class="table-responsive "> <table class="table table-bordered table-fullwidth "> <thead class="thead-light" > <tr> <th scope="col" >Term</th> <th scope="col" >Scientific Term</th> <th scope="col" >Evidence</th> <th scope="col" >Links</th> </tr> </thead> <tbody> <tr> <td>human</td> <td>Homo sapiens</td> <td>High</td> <td> <a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=9606" , target="_blank">NCBI</a> </td> </tr> <tbody class="tbody-striped" > <tr> <td>human</td> <td>Homo sapiens</td> <td>High</td> <td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=9606" target="_blank">NCBI</a></td> </tr> </tbody> </table> </div> </div> <!-- end loop for taxons --> <!-- loop to find life stages under relationship --> <div> <strong>Life Stage Applicability</strong><div class="panel panel-default "> <table class="table table-bordered table-striped "> <thead> </div> <div> <strong>Life Stage Applicability</strong> <div class="table-responsive "> <table class="table table-bordered table-fullwidth "> <thead class="thead-light" > <tr> <th>Life Stage</th> <th>Evidence</th> <th scope="col" >Life Stage</th> <th scope="col" >Evidence</th> </tr> </thead> <tbody> <tr> <td>All life stages</td> <td>High</td> </tr> <tbody class="tbody-striped" > <tr> <td>All life stages</td> <td>High</td> </tr> </tbody> </table> </div> </div> <!-- end loop for life stages --> <!-- sex terms --> <div> <strong>Sex Applicability</strong><div class="panel panel-default "> <table class="table table-bordered table-striped "> <thead> </div> <div> <strong>Sex Applicability</strong> <div class="table-responsive "> <table class="table table-bordered table-fullwidth "> <thead class="thead-light" > <tr> <th>Sex</th> <th>Evidence</th> <th scope="col" >Sex</th> <th scope="col" >Evidence</th> </tr> </thead> <tbody> <tr> <td>Mixed</td> <td>High</td> </tr> <tbody class="tbody-striped" > <tr> <td>Mixed</td> <td>High</td> </tr> </tbody> </table> </div> </div> <!-- end sex terms --> < p><strong>Chemicals:</strong> This KER applies to a wide range of chemicals. The chemicals absorb photon energy from light within the range of light (290-700 nm) <!--[endif]----> (ICH, 2014, Onoue and Tsuda, 2006).<!--![endif]----></p> <p><!--[endif]---->< /p> </div> <p><strong>Chemicals:</strong> This KER applies to a wide range of chemicals. The chemicals absorb photon energy from light within the range of light (290-700 nm) (ICH, 2014, Onoue and Tsuda, 2006).</p> <p><strong>Sex:</strong> This KER applies to both males and females. </p> <p><strong>Life stages:</strong> The relevant life stages for this KER are all life stages after born.</p> <p><strong>Taxonomic:</strong> This KER mainly applies to human. <!--![endif]----></p> <h4>Key Event Relationship Description</h4> <p>Some photoactivated chemicals can generate reactive oxygen species (ROS) after photoactivation of chemicals by irradiation of light (290–700 nm). ROS generated from photoactivated chemicals can react with membrane proteins and lead to oxidation/denaturation of membrane proteins.</p> <!-- if nothing shows up in any of these fields, then evidence supporting this KER will not be displayed --> <h4>Evidence Supporting this KER</h4> <strong>Biological Plausibility</strong> <p>Photoactivated chemicals by UVA generate ROS including singlet oxygen, superoxide, and hydroxyl radicals, and the generated ROS cause cross-linking of proteins and denaturation of proteins as oxidative damages by photoactivated chemicals <!--[if supportFields]><span lang=EN-US style='font-size:10.5pt; font-family:"Times New Roman","serif";mso-fareast-font-family:"ＭＳ 明朝"; mso-fareast-theme-font:minor-fareast;mso-ansi-language:EN-US;mso-fareast-language: JA;mso-bidi-language:AR-SA'><span style='mso-element:field-begin'></span><span style='mso-spacerun:yes'> </span>ADDIN EN.CITE <span style='mso-element:field-begin'></span><span style='mso-spacerun:yes'> 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</xml><![endif]><span style='mso-element:field-end'></span><span style='mso-element:field-separator'></span></span><![endif]-->(Dalle Carbonare and Pathak, 1992)<!--[if gte mso 9]><xml> 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</xml><![endif]--><!--[if supportFields]><span lang=EN-US style='font-size:10.5pt;font-family:"Times New Roman","serif";mso-fareast-font-family: "ＭＳ 明朝";mso-fareast-theme-font:minor-fareast;mso-ansi-language:EN-US; mso-fareast-language:JA;mso-bidi-language:AR-SA'><span style='mso-element:field-end'></span></span><![endif]-->.</p> <strong>Empirical Evidence</strong> <p>ROS generated from photosensitizing agents led to oxidation and denaturation of proteins, resulting in cross-linking of proteins and oxidation of sulfydryl groups <!--[if supportFields]><span lang=EN-US style='font-size:10.5pt;font-family:"Times New Roman","serif";mso-fareast-font-family: "ＭＳ 明朝";mso-fareast-theme-font:minor-fareast;mso-ansi-language:EN-US; mso-fareast-language:JA;mso-bidi-language:AR-SA'><span style='mso-element:field-begin'></span><span style='mso-spacerun:yes'> </span>ADDIN EN.CITE <span style='mso-element:field-begin'></span><span style='mso-spacerun:yes'> </span>ADDIN EN.CITE.DATA <![if gte mso 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</xml><![endif]><span style='mso-element:field-end'></span><span style='mso-element:field-separator'></span></span><![endif]-->(Dalle Carbonare and Pathak, 1992)<!--[if gte mso 9]><xml> 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</xml><![endif]--><!--[if supportFields]><span lang=EN-US style='font-size:10.5pt;font-family:"Times New Roman","serif";mso-fareast-font-family: "ＭＳ 明朝";mso-fareast-theme-font:minor-fareast;mso-ansi-language:EN-US; mso-fareast-language:JA;mso-bidi-language:AR-SA'><span style='mso-element:field-end'></span></span><![endif]-->.</p> <!--<!% unless aop_rel.relationship.relationship_taxons.blank? %>--> <!--<!%= render 'snapshot_taxons', taxons: aop_rel.relationship.relationship_taxons %>--> <!--<!% unless aop_rel.relationship.taxon_evidence.blank? %>--> <!--<h3>Domain of Applicability</h3>--> <!--<!%== aop_rel.relationship.taxon_evidence %>--> <!--<!% end %>--> <!--<!% end %>--> <p><strong>Taxonomic:</strong> This KER mainly applies to human.</p> <h4>Refer ences </h4> < p>Dalle Carbonare M, Pathak MA. Skin photosensitizing agents and the role of reactive oxygen species in photoaging. J Photochem Photobiol B. 1992;14:105-24.</p> <h4>Key Event Relationship Description</h4> <div> <p>Some photoactivated chemicals can generate reactive oxygen species (ROS) after photoactivation of chemicals by irradiation of light (290–700 nm). ROS generated from photoactivated chemicals can react with membrane proteins and lead to oxidation/denaturation of membrane proteins.</p> </div> <h4>Evid ence Supporting this KER </h4> <strong>Biological Plausibility</strong> <p>Photoactivated chemicals by UVA generate ROS including singlet oxygen, superoxide, and hydroxyl radicals, and the generated ROS cause cross-linking of proteins and denaturation of proteins as oxidative damages by photoactivated chemicals (Dalle Carbonare and Pathak, 1992).</p> <strong>Empirical Evidence</strong> <p>ROS generated from photosensitizing agents led to oxidation and denaturation of proteins, resulting in cross-linking of proteins and oxidation of sulfydryl groups (Dalle Carbonare and Pathak, 1992).</p> <h4>References</h4> <div> < p>Dalle Carbonare M, Pathak MA. Skin photosensitizing agents and the role of reactive oxygen species in photoaging. J Photochem Photobiol B. 1992;14:105-24.</p><p>ICH. ICH Guideline S10 Guidance on Photosafety Evaluation of Pharmaceuticals.: International Council on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use; 2014.</p> <p>Onoue S, Tsuda Y. Analytical studies on the prediction of photosensitive/phototoxic potential of pharmaceutical substances. Pharmaceutical research. 2006;23:156-64.</p> </div> </div> <br> <div> <div> <h4><a href="/relationships/1850">Relationship: 1850: Oxidation of membrane lipids leads to Inflammatory events</a></h4> <h4>AOPs Referencing Relationship</h4> <div class="panel panel-default "> <table class="table table-bordered table-striped"> < thead> <div class="table-responsive "> <table class="table table-bordered table-fullwidth"> <thead class="thead-light"> <tr> <th scope="col">AOP Name</th> <th scope="col">Adjacency</th> <th scope="col">Weight of Evidence</th> <th scope="col">Quantitative Understanding</th> </tr> </ thead> <tbody class="tbody-striped"> <tr> <th>AOP Name</th > <th>A djacency</th > <th>Weight of Evidence</th > <th>Quantitative Understanding</th > <td><a href="/aops/282">Adverse outcome pathway on photochemical toxicity initiated by light exposure</a></td > <td>a djacent</td > <td>High</td > <td>Low</td > </tr> </thead> <tbody> <tr> <th><a href="/aops/282">Reactive oxygen species generated from photoreactive chemicals leading to phototoxic reactions</a></th> <th>adjacent</th> <th>High </th> <th>Low</th> </tr> </tbody> </table> </div> <h4>Evidence Supporting Applicability of this Relationship</h4> <br> <!-- loop to find taxonomic applicability under relationship --> <div> <strong>Taxonomic Applicability</strong><div class="panel panel-default "> <table class="table table-bordered table-striped "> <thead> <tr> <th>Term</th> <th>Scientific Term</th> <th>Evidence</th> <th>Links</th> </tbody> </table> </div> <h4>Evidence Supporting Applicability of this Relationship</h4> <div> <strong>Taxonomic Applicability</strong> <div class="table-responsive "> <table class="table table-bordered table-fullwidth "> <thead class="thead-light" > <tr> <th scope="col" >Term</th> <th scope="col" >Scientific Term</th> <th scope="col" >Evidence</th> <th scope="col" >Links</th> </tr> </thead> <tbody> <tr> <td>human</td> <td>Homo sapiens</td> <td>High</td> <td> <a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=9606" , target="_blank">NCBI</a> </td> </tr> <tbody class="tbody-striped" > <tr> <td>human</td> <td>Homo sapiens</td> <td>High</td> <td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=9606" target="_blank">NCBI</a></td> </tr> </tbody> </table> </div> </div> <!-- end loop for taxons --> <!-- loop to find life stages under relationship --> <div> <strong>Life Stage Applicability</strong><div class="panel panel-default "> <table class="table table-bordered table-striped "> <thead> </div> <div> <strong>Life Stage Applicability</strong> <div class="table-responsive "> <table class="table table-bordered table-fullwidth "> <thead class="thead-light" > <tr> <th>Life Stage</th> <th>Evidence</th> <th scope="col" >Life Stage</th> <th scope="col" >Evidence</th> </tr> </thead> <tbody> <tr> <td>All life stages</td> <td>High</td> </tr> <tbody class="tbody-striped" > <tr> <td>All life stages</td> <td>High</td> </tr> </tbody> </table> </div> </div> <!-- end loop for life stages --> <!-- sex terms --> <div> <strong>Sex Applicability</strong><div class="panel panel-default "> <table class="table table-bordered table-striped "> <thead> </div> <div> <strong>Sex Applicability</strong> <div class="table-responsive "> <table class="table table-bordered table-fullwidth "> <thead class="thead-light" > <tr> <th>Sex</th> <th>Evidence</th> <th scope="col" >Sex</th> <th scope="col" >Evidence</th> </tr> </thead> <tbody> <tr> <td>Mixed</td> <td>High</td> </tr> <tbody class="tbody-striped" > <tr> <td>Mixed</td> <td>High</td> </tr> </tbody> </table> </div> </div> <!-- end sex terms --> < p><strong>Chemicals:</strong> This KER applies to a wide range of chemicals. The chemicals generate ROS under exposure to light (290-700 nm) (ICH, 2014, Onoue and Tsuda, 2006).<!--![endif]----></p> </div> <p><strong>Chemicals:</strong> This KER applies to a wide range of chemicals. The chemicals generate ROS under exposure to light (290-700 nm) (ICH, 2014, Onoue and Tsuda, 2006).<!--![endif]----></p> <p><!--[endif]----></p> <p><strong>Sex:</strong> This KER applies to both males and females. </p> <p><strong>Life stages:</strong> The relevant life stages for this KER are all life stages after born.</p> <p><strong>Taxonomic:</strong> This KER mainly applies to human. <!--![endif]----></p> <h4>Key Event Relationship Description</h4> <p>Oxidation of membrane lipids can lead to inflammatory events via oxidative damage of cellular membranes and increases in expression of pro-inflammatory cytokines.</p> <h4>Key Event Relationship Description</h4> <p>Oxidation of membrane lipids can lead to inflammatory events via oxidative damage of cellular membranes and increases in expression of pro-inflammatory cytokines.</p> <!-- if nothing shows up in any of these fields, then evidence supporting this KER will not be displayed --> <h4>Evidence Supporting this KER</h4> <strong>Biological Plausibility</strong> <p>Lipid peroxidation in cellar membrane is an oxidative damage of cellular membrane, and viability of cells decreases by lipid peroxidation of photoreactive chemicals <!--[if supportFields]><span lang=EN-US <h4>Evidence Supporting this KER</h4> <p>Lipid peroxidation in cellar membrane is an oxidative damage of cellular membrane, and viability of cells decreases by lipid peroxidation of photoreactive chemicals <!--[if supportFields]><span lang=EN-US style='font-size:10.5pt;font-family:"Times New Roman","serif";mso-fareast-font-family: "ＭＳ 明朝";mso-fareast-theme-font:minor-fareast;mso-ansi-language:EN-US; mso-fareast-language:JA;mso-bidi-language:AR-SA'><span style='mso-element:field-begin'></span><span style='mso-spacerun:yes'> </span>ADDIN EN.CITE <span style='mso-element:field-begin'></span><span style='mso-spacerun:yes'> </span>ADDIN EN.CITE.DATA <![if gte mso 9]><xml> 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</xml><![endif]><span style='mso-element:field-end'></span><span style='mso-element:field-separator'></span></span><![endif]-->(Castell et al., 1994)<!--[if gte mso 9]><xml> 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</xml><![endif]--><!--[if supportFields]><span lang=EN-US style='font-size:10.5pt;font-family:"Times New Roman","serif";mso-fareast-font-family: "ＭＳ 明朝";mso-fareast-theme-font:minor-fareast;mso-ansi-language:EN-US; mso-fareast-language:JA;mso-bidi-language:AR-SA'><span style='mso-element:field-end'></span></span><![endif]-->.</p> <strong>Empirical Evidence</strong> <p>Increases in lipid peroxidation and inflammatory-related cytokines were observed in the murine skin, and naringenin, an anti-oxidant, attenuated these increases in a dose-dependent manner <!--[endif]---->(Martinez et al., 2015).<!--![endif]----></p> <strong>Empirical Evidence</strong> <p>Increases in lipid peroxidation and inflammatory-related cytokines were observed in the murine skin, and naringenin, an anti-oxidant, attenuated these increases in a dose-dependent manner <!--[endif]---->(Martinez et al., 2015).<!--![endif]----></p> <p><!--[endif]---->Benzoyl peroxide, a ROS generator, led to lipid peroxidation and GSH depletion, and the changes caused the gene expression of pro-inflammatory cytokines in human keratinocytes <!--[endif]---->(Valacchi et al., 2001). <!--![endif]----><!--![endif]----></p> <!--<!% unless aop_rel.relationship.relationship_taxons.blank? %>--> <!--<!%= render 'snapshot_taxons', taxons: aop_rel.relationship.relationship_taxons %>--> <!--<!% unless aop_rel.relationship.taxon_evidence.blank? %>--> <!--<h3>Domain of Applicability</h3>--> <!--<!%== aop_rel.relationship.taxon_evidence %>--> <!--<!% end %>--> <!--<!% end %>--> <h4>References</h4> <p>Castell JV, Gomez-Lechon MJ, Grassa C, Martinez LA, Miranda MA, Tarrega P. Photodynamic lipid peroxidation by the photosensitizing nonsteroidal antiinflammatory drugs suprofen and tiaprofenic acid. Photochem Photobiol. 1994;59:35-9.</p> <h4>References</h4> <p>Castell JV, Gomez-Lechon MJ, Grassa C, Martinez LA, Miranda MA, Tarrega P. Photodynamic lipid peroxidation by the photosensitizing nonsteroidal antiinflammatory drugs suprofen and tiaprofenic acid. Photochem Photobiol. 1994;59:35-9.</p> <p>ICH. ICH Guideline S10 Guidance on Photosafety Evaluation of Pharmaceuticals.: International Council on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use; 2014.</p> <p>Martinez RM, Pinho-Ribeiro FA, Steffen VS, Caviglione CV, Vignoli JA, Barbosa DS, et al. Naringenin Inhibits UVB Irradiation-Induced Inflammation and Oxidative Stress in the Skin of Hairless Mice. Journal of natural products. 2015;78:1647-55.</p> <p>Onoue S, Tsuda Y. Analytical studies on the prediction of photosensitive/phototoxic potential of pharmaceutical substances. Pharmaceutical research. 2006;23:156-64.</p> <p>Valacchi G, Rimbach G, Saliou C, Weber SU, Packer L. Effect of benzoyl peroxide on antioxidant status, NF-kappaB activity and interleukin-1alpha gene expression in human keratinocytes. Toxicology. 2001;165:225-34.</p> </div> <br> <div> <div> <h4><a href="/relationships/1851">Relationship: 1851: Oxidation/denatuation of membrane proteins leads to Inflammatory events</a></h4> <h4>AOPs Referencing Relationship</h4> <div class="panel panel-default "> <table class="table table-bordered table-striped"> < thead> <div class="table-responsive "> <table class="table table-bordered table-fullwidth"> <thead class="thead-light"> <tr> <th scope="col">AOP Name</th> <th scope="col">Adjacency</th> <th scope="col">Weight of Evidence</th> <th scope="col">Quantitative Understanding</th> </tr> </ thead> <tbody class="tbody-striped"> <tr> <th>AOP Name</th > <th>A djacency</th > <th>Weight of Evidence</th > <th>Quantitative Understanding</th > <td><a href="/aops/282">Adverse outcome pathway on photochemical toxicity initiated by light exposure</a></td > <td>a djacent</td > <td>High</td > <td>Low</td > </tr> </thead> <tbody> <tr> <th><a href="/aops/282">Reactive oxygen species generated from photoreactive chemicals leading to phototoxic reactions</a></th> <th>adjacent</th> <th>High </th> <th>Low</th> </tr> </tbody> </table> </div> <h4>Evidence Supporting Applicability of this Relationship</h4> <br> <!-- loop to find taxonomic applicability under relationship --> <div> <strong>Taxonomic Applicability</strong><div class="panel panel-default "> <table class="table table-bordered table-striped "> <thead> <tr> <th>Term</th> <th>Scientific Term</th> <th>Evidence</th> <th>Links</th> </tbody> </table> </div> <h4>Evidence Supporting Applicability of this Relationship</h4> <div> <strong>Taxonomic Applicability</strong> <div class="table-responsive "> <table class="table table-bordered table-fullwidth "> <thead class="thead-light" > <tr> <th scope="col" >Term</th> <th scope="col" >Scientific Term</th> <th scope="col" >Evidence</th> <th scope="col" >Links</th> </tr> </thead> <tbody> <tr> <td>human</td> <td>Homo sapiens</td> <td>High</td> <td> <a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=9606" , target="_blank">NCBI</a> </td> </tr> <tbody class="tbody-striped" > <tr> <td>human</td> <td>Homo sapiens</td> <td>High</td> <td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=9606" target="_blank">NCBI</a></td> </tr> </tbody> </table> </div> </div> <!-- end loop for taxons --> <!-- loop to find life stages under relationship --> <div> <strong>Life Stage Applicability</strong><div class="panel panel-default "> <table class="table table-bordered table-striped "> <thead> </div> <div> <strong>Life Stage Applicability</strong> <div class="table-responsive "> <table class="table table-bordered table-fullwidth "> <thead class="thead-light" > <tr> <th>Life Stage</th> <th>Evidence</th> <th scope="col" >Life Stage</th> <th scope="col" >Evidence</th> </tr> </thead> <tbody> <tr> <td>All life stages</td> <td>High</td> </tr> <tbody class="tbody-striped" > <tr> <td>All life stages</td> <td>High</td> </tr> </tbody> </table> </div> </div> <!-- end loop for life stages --> <!-- sex terms --> <div> <strong>Sex Applicability</strong><div class="panel panel-default "> <table class="table table-bordered table-striped "> <thead> </div> <div> <strong>Sex Applicability</strong> <div class="table-responsive "> <table class="table table-bordered table-fullwidth "> <thead class="thead-light" > <tr> <th>Sex</th> <th>Evidence</th> <th scope="col" >Sex</th> <th scope="col" >Evidence</th> </tr> </thead> <tbody> <tr> <td>Mixed</td> <td>High</td> </tr> <tbody class="tbody-striped" > <tr> <td>Mixed</td> <td>High</td> </tr> </tbody> </table> </div> </div> <!-- end sex terms --> < p><strong>Chemicals:</strong> This KER applies to a wide range of chemicals. The chemicals generate ROS under exposure to light (290-700 nm) <!--[endif]---->(ICH, 2014, Onoue and Tsuda, 2006).<!--![endif]----></p> </div> <p><strong>Chemicals:</strong> This KER applies to a wide range of chemicals. The chemicals generate ROS under exposure to light (290-700 nm) <!--[endif]---->(ICH, 2014, Onoue and Tsuda, 2006).<!--![endif]----></p> <p><!--[endif]----></p> <p><strong>Sex:</strong> This KER applies to both males and females. </p> <p><strong>Life stages:</strong> The relevant life stages for this KER are all life stages after born.</p> <p><strong>Taxonomic:</strong> This KER mainly applies to human. <!--![endif]----></p> <h4>Key Event Relationship Description</h4> <p>Oxidation/denaturation of membrane proteins can lead to inflammatory events via oxidative damage of cellular membranes and increases in expression of pro-inflammatory cytokines. </p> <h4>Key Event Relationship Description</h4> <p>Oxidation/denaturation of membrane proteins can lead to inflammatory events via oxidative damage of cellular membranes and increases in expression of pro-inflammatory cytokines. </p> <p>Necrosis in living tissues can be occurred as an inflammatory events via oxidative damages of membrane proteins.</p> <!-- if nothing shows up in any of these fields, then evidence supporting this KER will not be displayed --> <h4>Evidence Supporting this KER</h4> <strong>Biological Plausibility</strong> <p>Oxidative damage of membrane proteins by photoactivated chemicals can cause oxidation and denaturation of proteins, and damaged proteins induces inflammatory events (necrosis) <!--[if supportFields]><span lang=EN-US <h4>Evidence Supporting this KER</h4> <p>Oxidative damage of membrane proteins by photoactivated chemicals can cause oxidation and denaturation of proteins, and damaged proteins induces inflammatory events (necrosis) <!--[if supportFields]><span lang=EN-US style='font-size:10.5pt;font-family:"Times New Roman","serif";mso-fareast-font-family: "ＭＳ 明朝";mso-fareast-theme-font:minor-fareast;mso-ansi-language:EN-US; mso-fareast-language:JA;mso-bidi-language:AR-SA'><span style='mso-element:field-begin'></span><span style='mso-spacerun:yes'> </span>ADDIN EN.CITE <span style='mso-element:field-begin'></span><span style='mso-spacerun:yes'> </span>ADDIN EN.CITE.DATA <![if gte mso 9]><xml> 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</xml><![endif]><span style='mso-element:field-end'></span><span style='mso-element:field-separator'></span></span><![endif]-->(Dalle Carbonare and Pathak, 1992, Opie, 1962)<!--[if gte mso 9]><xml> 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</xml><![endif]--><!--[if supportFields]><span lang=EN-US style='font-size:10.5pt;font-family:"Times New Roman","serif";mso-fareast-font-family: "ＭＳ 明朝";mso-fareast-theme-font:minor-fareast;mso-ansi-language:EN-US; mso-fareast-language:JA;mso-bidi-language:AR-SA'><span style='mso-element:field-end'></span></span><![endif]-->.</p> <strong>Empirical Evidence</strong> <p>Denaturation of proteins induced necrosis and inflammatory in the skin <!--[if supportFields]><span <strong>Empirical Evidence</strong> <p>Denaturation of proteins induced necrosis and inflammatory in the skin <!--[if supportFields]><span lang=EN-US style='font-size:10.5pt;font-family:"Times New Roman","serif"; mso-fareast-font-family:"ＭＳ 明朝";mso-fareast-theme-font:minor-fareast; mso-ansi-language:EN-US;mso-fareast-language:JA;mso-bidi-language:AR-SA'><span style='mso-element:field-begin'></span><span style='mso-spacerun:yes'> </span>ADDIN EN.CITE <EndNote><Cite><Author>Opie</Author><Year>1962</Year><RecNum>1374</RecNum><DisplayText>(Opie, 1962)</DisplayText><record><rec-number>1374</rec-number><foreign-keys><key app="EN" db-id="wadztfe5qpsstuefdflp9wxupps099f2vvw2">1374</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Opie, E. L.</author></authors></contributors><titles><title>On the relation of necrosis and inflammation to denaturation of proteins</title><secondary-title>J Exp Med</secondary-title><alt-title>The Journal of experimental medicine</alt-title></titles><periodical><full-title>J Exp Med</full-title><abbr-1>The Journal of experimental medicine</abbr-1></periodical><alt-periodical><full-title>J Exp Med</full-title><abbr-1>The Journal of experimental medicine</abbr-1></alt-periodical><pages>597-608</pages><volume>115</volume><edition>1962/03/01</edition><keywords><keyword>Amino Acids/*pharmacology</keyword><keyword>Electrolytes/*pharmacology</keyword><keyword>*Inflammation</keyword><keyword>*Kidney</keyword><keyword>*Liver</keyword><keyword>*Necrosis</keyword><keyword>Proteins/*chemistry</keyword><keyword>*Skin</keyword><keyword>*Water</keyword></keywords><dates><year>1962</year><pub-dates><date>Mar 1</date></pub-dates></dates><isbn>0022-1007 (Print)&#xD;0022-1007 (Linking)</isbn><accession-num>14482110</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/14482110</url></related-urls></urls><custom2>2137504</custom2><language>eng</language></record></Cite></EndNote><span style='mso-element:field-separator'></span></span><![endif]-->(<a href="#_ENREF_4" title="Opie, 1962 #1374">Opie, 1962</a>)<!--[if supportFields]><span lang=EN-US style='font-size:10.5pt;font-family:"Times New Roman","serif";mso-fareast-font-family: "ＭＳ 明朝";mso-fareast-theme-font:minor-fareast;mso-ansi-language:EN-US; mso-fareast-language:JA;mso-bidi-language:AR-SA'><span style='mso-element:field-end'></span></span><![endif]-->.</p> <!--<!% unless aop_rel.relationship.relationship_taxons.blank? %>--> <!--<!%= render 'snapshot_taxons', taxons: aop_rel.relationship.relationship_taxons %>--> <!--<!% unless aop_rel.relationship.taxon_evidence.blank? %>--> <!--<h3>Domain of Applicability</h3>--> <!--<!%== aop_rel.relationship.taxon_evidence %>--> <!--<!% end %>--> <!--<!% end %>--> <h4>References</h4> <p>Dalle Carbonare M, Pathak MA. Skin photosensitizing agents and the role of reactive oxygen species in photoaging. J Photochem Photobiol B. 1992;14:105-24.</p> <h4>References</h4> <p>Dalle Carbonare M, Pathak MA. Skin photosensitizing agents and the role of reactive oxygen species in photoaging. J Photochem Photobiol B. 1992;14:105-24.</p> <p>ICH. ICH Guideline S10 Guidance on Photosafety Evaluation of Pharmaceuticals.: International Council on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use; 2014.</p> <p>Onoue S, Tsuda Y. Analytical studies on the prediction of photosensitive/phototoxic potential of pharmaceutical substances. Pharmaceutical research. 2006;23:156-64.</p> <p>Opie EL. On the relation of necrosis and inflammation to denaturation of proteins. The Journal of experimental medicine. 1962;115:597-608.</p> </div> <br> </div> <!-- end relationship loop --> </div> </div> </div> </div> </div> <footer class="footer"> <div class="navbar navbar-fixed-bottom navbar-inverse"> <div class="container"> <ul class="nav navbar-nav"> <li ><a href="/info_pages/2">Help</a></a></li> <li ><a href="/info_pages/3">About</a></a></li> <li ><a href="/info_pages/4">FAQ</a></a></li> <li ><a href="/info_pages/5">Downloads</a></a></li> <li><a href="/metrics_summary">Metrics </a></li> </ul> </div> </div> <br / > <br / > <br /> </footer> </div> </div> </div ></main> <nav class="navbar navbar-expand nav-footer navbar-dark bg-dark mt-auto"> <div class="container-fluid"> <ul class="navbar-nav mx-auto" > <li class="nav-item"><a class="nav-link" href="/info_pages/2" target="_blank">Help</a></li> <li class="nav-item"><a class="nav-link" href="/info_pages/10">About</a></li> <li class="nav-item"><a class="nav-link" href="/info_pages/4">FAQ</a></li > <li class="nav-item d-none d-sm-block"><a class="nav-link" href="/info_pages/5">Download Options</a></li> <li class="nav-item"><a class="nav-link" href="/metrics_summary">Metrics</a></li> <li class="nav-item"><a class="nav-link" href="/info_pages/3">Release Notes</a></li> </ul> </div> </nav> <script crossorigin="anonymous" integrity="sha256-9/aliU8dGd2tb6OSsuzixeV4y/faTqgFtohetphbbj0=" src="https://code.jquery.com/jquery-3.5.1.min.js"></script> <script crossorigin="anonymous" integrity="sha256-VazP97ZCwtekAsvgPBSUwPFKdrwD3unUfSGVYrahUqU=" src="https://code.jquery.com/ui/1.12.1/jquery-ui.min.js"></script> <script crossorigin="anonymous" integrity="sha256-sXPRAPYJk5w3GI/IBiN2AK31ZAMCcJ/5LRpLHpsk5vY=" src="https://cdn.jsdelivr.net/npm/@rails/ujs@6.0.3-2/lib/assets/compiled/rails-ujs.js"></script> <script crossorigin="anonymous" integrity="sha256-9nt4LsWmLI/O24lTW89IzAKuBqEZ47l/4rh1+tH/NY8=" src="https://cdn.jsdelivr.net/npm/bootstrap@4.5.2/dist/js/bootstrap.bundle.min.js"></script> <script crossorigin="anonymous" integrity="sha256-5VhCqFam2Cn+yjw61zbBNrbHVJ6SRydPeKopYlngbiQ=" src="https://cdn.jsdelivr.net/npm/cookieconsent@3.1.1/build/cookieconsent.min.js" data-cfasync="false"></script> <script src="https://test.aopwiki.org/lib/tablefilter/tablefilter.js"></script> <script src="https://cdn.jsdelivr.net/npm/chart.js"></script> <script src="/assets/application-7c71e5202f7a0f0d978208f437dd5368a7309ecc5aee0b03d202edd1b7757494.js"></script> <script> function getCookie(cookieName) { let cookies = decodeURIComponent(document.cookie).split(';'); for (let idx = 0; idx < cookies.length; idx++) { let cookie = cookies[idx].trim().split("="); if (cookie[0] === cookieName) { return cookie[1]; } } return ""; } function setGtagConfig() { gtag('config','UA-172534727-1',{'send_page_view':getCookie("cookieconsent_status")==="allow"}); } window.dataLayer=window.dataLayer||[]; function gtag(){dataLayer.push(arguments);} gtag('js',new Date()); setGtagConfig(); window.cookieconsent.initialise({ "palette": { "popup": {"background":"#252e39" }, "button": {"background":"#14a7d0" } }, "theme": "classic", "position": "bottom-right", "type": "opt-out", "content": { "dismiss": "I accept cookies", "deny": "I refuse cookies" }, onStatusChange: function() { setGtagConfig(); } }); </script> <script type="text/javascript" id="flash"> </script ></body>