Aop: 282

Title

Each AOP should be given a descriptive title that takes the form “MIE leading to AO”. For example, “Aromatase inhibition [MIE] leading to reproductive dysfunction [AO]” or “Thyroperoxidase inhibition [MIE] leading to decreased cognitive function [AO]”. In cases where the MIE is unknown or undefined, the earliest known KE in the chain (i.e., furthest upstream) should be used in lieu of the MIE and it should be made clear that the stated event is a KE and not the MIE. More help

Reactive oxygen species generated from photoreactive chemicals leading to phototoxic reactions

Short name
A short name should also be provided that succinctly summarises the information from the title. This name should not exceed 90 characters. More help
ROS-mediated chemical phototoxicity

Graphical Representation

A graphical summary of the AOP listing all the KEs in sequence, including the MIE (if known) and AO, and the pair-wise relationships (links or KERs) between those KEs should be provided. This is easily achieved using the standard box and arrow AOP diagram (see this page for example). The graphical summary is prepared and uploaded by the user (templates are available) and is often included as part of the proposal when AOP development projects are submitted to the OECD AOP Development Workplan. The graphical representation or AOP diagram provides a useful and concise overview of the KEs that are included in the AOP, and the sequence in which they are linked together. This can aid both the process of development, as well as review and use of the AOP (for more information please see page 19 of the Users' Handbook).If you already have a graphical representation of your AOP in electronic format, simple save it in a standard image format (e.g. jpeg, png) then click ‘Choose File’ under the “Graphical Representation” heading, which is part of the Summary of the AOP section, to select the file that you have just edited. Files must be in jpeg, jpg, gif, png, or bmp format. Click ‘Upload’ to upload the file. You should see the AOP page with the image displayed under the “Graphical Representation” heading. To remove a graphical representation file, click 'Remove' and then click 'OK.'  Your graphic should no longer be displayed on the AOP page. If you do not have a graphical representation of your AOP in electronic format, a template is available to assist you.  Under “Summary of the AOP”, under the “Graphical Representation” heading click on the link “Click to download template for graphical representation.” A Powerpoint template file should download via the default download mechanism for your browser. Click to open this file; it contains a Powerpoint template for an AOP diagram and instructions for editing and saving the diagram. Be sure to save the diagram as jpeg, jpg, gif, png, or bmp format. Once the diagram is edited to its final state, upload the image file as described above. More help

Authors

List the name and affiliation information of the individual(s)/organisation(s) that created/developed the AOP. In the context of the OECD AOP Development Workplan, this would typically be the individuals and organisation that submitted an AOP development proposal to the EAGMST. Significant contributors to the AOP should also be listed. A corresponding author with contact information may be provided here. This author does not need an account on the AOP-KB and can be distinct from the point of contact below. The list of authors will be included in any snapshot made from an AOP. More help

Yoshiki Seto, Satomi Onoue

Laboratory of Biopharmacy, School of Pharmaceutical Sciences, University of Shizuoka

Corresponding Author: Satomi Onoue

Point of Contact

Indicate the point of contact for the AOP-KB entry itself. This person is responsible for managing the AOP entry in the AOP-KB and controls write access to the page by defining the contributors as described below. Clicking on the name will allow any wiki user to correspond with the point of contact via the email address associated with their user profile in the AOP-KB. This person can be the same as the corresponding author listed in the authors section but isn’t required to be. In cases where the individuals are different, the corresponding author would be the appropriate person to contact for scientific issues whereas the point of contact would be the appropriate person to contact about technical issues with the AOP-KB entry itself. Corresponding authors and the point of contact are encouraged to monitor comments on their AOPs and develop or coordinate responses as appropriate.  More help
Satomi Onoue   (email point of contact)

Contributors

List user names of all  authors contributing to or revising pages in the AOP-KB that are linked to the AOP description. This information is mainly used to control write access to the AOP page and is controlled by the Point of Contact.  More help
  • Yoshiki Seto
  • Satomi Onoue

Status

The status section is used to provide AOP-KB users with information concerning how actively the AOP page is being developed, what type of use or input the authors feel comfortable with given the current level of development, and whether it is part of the OECD AOP Development Workplan and has been reviewed and/or endorsed. “Author Status” is an author defined field that is designated by selecting one of several options from a drop-down menu (Table 3). The “Author Status” field should be changed by the point of contact, as appropriate, as AOP development proceeds. See page 22 of the User Handbook for definitions of selection options. More help
Author status OECD status OECD project SAAOP status
Under development: Not open for comment. Do not cite EAGMST Under Review 1.49 Included in OECD Work Plan
This AOP was last modified on January 07, 2020 10:28
The date the AOP was last modified is automatically tracked by the AOP-KB. The date modified field can be used to evaluate how actively the page is under development and how recently the version within the AOP-Wiki has been updated compared to any snapshots that were generated. More help

Revision dates for related pages

Page Revision Date/Time
ROS generation from photoactivated chemicals July 04, 2019 04:19
Oxidation of membrane lipids July 04, 2019 21:15
Oxidation/denatuation of membrane proteins July 04, 2019 21:19
Inflamatory events in light-exposed tissues July 04, 2019 21:25
ROS generation leads to Oxidation of membrane lipids July 09, 2019 05:54
ROS generation leads to Oxidation/denatuation of membrane proteins July 09, 2019 05:56
Oxidation of membrane lipids leads to Inflammatory events July 09, 2019 06:00
Oxidation/denatuation of membrane proteins leads to Inflammatory events July 09, 2019 06:03
Light (290-700 nm) February 18, 2019 20:30
Photoreactive chemicals March 25, 2019 22:35
Reactive oxygen species August 15, 2017 10:43

Abstract

In the abstract section, authors should provide a concise and informative summation of the AOP under development that can stand-alone from the AOP page. Abstracts should typically be 200-400 words in length (similar to an abstract for a journal article). Suggested content for the abstract includes the following: The background/purpose for initiation of the AOP’s development (if there was a specific intent) A brief description of the MIE, AO, and/or major KEs that define the pathway A short summation of the overall WoE supporting the AOP and identification of major knowledge gaps (if any) If a brief statement about how the AOP may be applied (optional). The aim is to capture the highlights of the AOP and its potential scientific and regulatory relevance More help

Phototoxicity is an adverse reaction in the light-exposed tissues triggered by normally harmless doses of sunlight (Moore, 1998; Moore, 2002; Roberts, 2001).  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 (Epstein, 1983; Stein and Scheinfeld, 2007).

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 (Brendler-Schwaab et al. , 2004; Epstein and Wintroub, 1985; Quintero and Miranda, 2000).

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.

Background (optional)

This optional subsection should be used to provide background information for AOP reviewers and users that is considered helpful in understanding the biology underlying the AOP and the motivation for its development. The background should NOT provide an overview of the AOP, its KEs or KERs, which are captured in more detail below. Examples of potential uses of the optional background section are listed on pages 24-25 of the User Handbook. More help

Summary of the AOP

This section is for information that describes the overall AOP. The information described in section 1 is entered on the upper portion of an AOP page within the AOP-Wiki. This is where some background information may be provided, the structure of the AOP is described, and the KEs and KERs are listed. More help

Events:

Molecular Initiating Events (MIE)
An MIE is a specialised KE that represents the beginning (point of interaction between a stressor and the biological system) of an AOP. More help
Key Events (KE)
This table summarises all of the KEs of the AOP. This table is populated in the AOP-Wiki as KEs are added to the AOP. Each table entry acts as a link to the individual KE description page.  More help
Adverse Outcomes (AO)
An AO is a specialised KE that represents the end (an adverse outcome of regulatory significance) of an AOP.  More help
Sequence Type Event ID Title Short name
KE 1594 Oxidation of membrane lipids Oxidation of membrane lipids
KE 1595 Oxidation/denatuation of membrane proteins Oxidation/denatuation of membrane proteins
AO 1599 Inflamatory events in light-exposed tissues Inflammatory events

Relationships Between Two Key Events (Including MIEs and AOs)

This table summarises all of the KERs of the AOP and is populated in the AOP-Wiki as KERs are added to the AOP. Each table entry acts as a link to the individual KER description page.To add a key event relationship click on either Add relationship: events adjacent in sequence or Add relationship: events non-adjacent in sequence.For example, if the intended sequence of KEs for the AOP is [KE1 > KE2 > KE3 > KE4]; relationships between KE1 and KE2; KE2 and KE3; and KE3 and KE4 would be defined using the add relationship: events adjacent in sequence button.  Relationships between KE1 and KE3; KE2 and KE4; or KE1 and KE4, for example, should be created using the add relationship: events non-adjacent button. This helps to both organize the table with regard to which KERs define the main sequence of KEs and those that provide additional supporting evidence and aids computational analysis of AOP networks, where non-adjacent KERs can result in artifacts (see Villeneuve et al. 2018; DOI: 10.1002/etc.4124).After clicking either option, the user will be brought to a new page entitled ‘Add Relationship to AOP.’ To create a new relationship, select an upstream event and a downstream event from the drop down menus. The KER will automatically be designated as either adjacent or non-adjacent depending on the button selected. The fields “Evidence” and “Quantitative understanding” can be selected from the drop-down options at the time of creation of the relationship, or can be added later. See the Users Handbook, page 52 (Assess Evidence Supporting All KERs for guiding questions, etc.).  Click ‘Create [adjacent/non-adjacent] relationship.’  The new relationship should be listed on the AOP page under the heading “Relationships Between Two Key Events (Including MIEs and AOs)”. To edit a key event relationship, click ‘Edit’ next to the name of the relationship you wish to edit. The user will be directed to an Editing Relationship page where they can edit the Evidence, and Quantitative Understanding fields using the drop down menus. Once finished editing, click ‘Update [adjacent/non-adjacent] relationship’ to update these fields and return to the AOP page.To remove a key event relationship to an AOP page, under Summary of the AOP, next to “Relationships Between Two Key Events (Including MIEs and AOs)” click ‘Remove’ The relationship should no longer be listed on the AOP page under the heading “Relationships Between Two Key Events (Including MIEs and AOs)”. More help

Network View

The stressor field is a structured data field that can be used to annotate an AOP with standardised terms identifying stressors known to trigger the MIE/AOP. Most often these are chemical names selected from established chemical ontologies. However, depending on the information available, this could also refer to chemical categories (i.e., groups of chemicals with defined structural features known to trigger the MIE). It can also include non-chemical stressors such as genetic or environmental factors. Although AOPs themselves are not chemical or stressor-specific, linking to stressor terms known to be relevant to different AOPs can aid users in searching for AOPs that may be relevant to a given stressor. More help

Stressors

The stressor field is a structured data field that can be used to annotate an AOP with standardised terms identifying stressors known to trigger the MIE/AOP. Most often these are chemical names selected from established chemical ontologies. However, depending on the information available, this could also refer to chemical categories (i.e., groups of chemicals with defined structural features known to trigger the MIE). It can also include non-chemical stressors such as genetic or environmental factors. Although AOPs themselves are not chemical or stressor-specific, linking to stressor terms known to be relevant to different AOPs can aid users in searching for AOPs that may be relevant to a given stressor. More help

Life Stage Applicability

Identify the life stage for which the KE is known to be applicable. More help
Life stage Evidence
All life stages High

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) can be selected. In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help
Term Scientific Term Evidence Link
human Homo sapiens High NCBI

Sex Applicability

The authors must select from one of the following: Male, female, mixed, asexual, third gender, hermaphrodite, or unspecific. More help
Sex Evidence
Mixed High

Overall Assessment of the AOP

This section addresses the relevant biological domain of applicability (i.e., in terms of taxa, sex, life stage, etc.) and WoE for the overall AOP as a basis to consider appropriate regulatory application (e.g., priority setting, testing strategies or risk assessment). The goal of the overall assessment is to provide a high level synthesis and overview of the relative confidence in the AOP and where the significant gaps or weaknesses are (if they exist). Users or readers can drill down into the finer details captured in the KE and KER descriptions, and/or associated summary tables, as appropriate to their needs.Assessment of the AOP is organised into a number of steps. Guidance on pages 59-62 of the User Handbook is available to facilitate assignment of categories of high, moderate, or low confidence for each consideration. While it is not necessary to repeat lengthy text that appears elsewhere in the AOP description (or related KE and KER descriptions), a brief explanation or rationale for the selection of high, moderate, or low confidence should be made. More help

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. 

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) (Moore, 1998; Moore, 2002; Roberts, 2001).  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 (Stein and Scheinfeld, 2007).  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 (Epstein, 1983).

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 (Svensson et al., 2001; Vassileva et al., 1998).  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 (Dubakiene and Kupriene, 2006).  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 (Epstein, 1989).  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.

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.

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 (Brendler-Schwaab et al., 2004; Epstein and Wintroub, 1985).

Domain of Applicability

The relevant biological domain(s) of applicability in terms of sex, life-stage, taxa, and other aspects of biological context are defined in this section. Biological domain of applicability is informed by the “Description” and “Biological Domain of Applicability” sections of each KE and KER description (see sections 2G and 3E for details). In essence the taxa/life-stage/sex applicability is defined based on the groups of organisms for which the measurements represented by the KEs can feasibly be measured and the functional and regulatory relationships represented by the KERs are operative.The relevant biological domain of applicability of the AOP as a whole will nearly always be defined based on the most narrowly restricted of its KEs and KERs. For example, if most of the KEs apply to either sex, but one is relevant to females only, the biological domain of applicability of the AOP as a whole would be limited to females. While much of the detail defining the domain of applicability may be found in the individual KE and KER descriptions, the rationale for defining the relevant biological domain of applicability of the overall AOP should be briefly summarised on the AOP page. More help

Chemicals: 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).

Sex: This AOP applies to both males and females. 

Life stages: The relevant life stages for this AOP are all life stages after born.

Taxonomic: This AOP mainly applies to human. 

Essentiality of the Key Events

An important aspect of assessing an AOP is evaluating the essentiality of its KEs. The essentiality of KEs can only be assessed relative to the impact of manipulation of a given KE (e.g., experimentally blocking or exacerbating the event) on the downstream sequence of KEs defined for the AOP. Consequently evidence supporting essentiality is assembled on the AOP page, rather than on the independent KE pages that are meant to stand-alone as modular units without reference to other KEs in the sequence.The nature of experimental evidence that is relevant to assessing essentiality relates to the impact on downstream KEs and the AO if upstream KEs are prevented or modified. This includes: Direct evidence: directly measured experimental support that blocking or preventing a KE prevents or impacts downstream KEs in the pathway in the expected fashion. Indirect evidence: evidence that modulation or attenuation in the magnitude of impact on a specific KE (increased effect or decreased effect) is associated with corresponding changes (increases or decreases) in the magnitude or frequency of one or more downstream KEs.When assembling the support for essentiality of the KEs, authors should organise relevant data in a tabular format. The objective is to summarise briefly the nature and numbers of investigations in which the essentiality of KEs has been experimentally explored either directly or indirectly. See pages 50-51 in the User Handbook for further definitions and clarifications.  More help

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”.

Evidence Assessment

The biological plausibility, empirical support, and quantitative understanding from each KER in an AOP are assessed together.  Biological plausibility of each of the KERs in the AOP is the most influential consideration in assessing WoE or degree of confidence in an overall hypothesised AOP for potential regulatory application (Meek et al., 2014; 2014a). Empirical support entails consideration of experimental data in terms of the associations between KEs – namely dose-response concordance and temporal relationships between and across multiple KEs. It is examined most often in studies of dose-response/incidence and temporal relationships for stressors that impact the pathway. While less influential than biological plausibility of the KERs and essentiality of the KEs, empirical support can increase confidence in the relationships included in an AOP. For clarification on how to rate the given empirical support for a KER, as well as examples, see pages 53- 55 of the User Handbook.  More help

 Support for biological plausibility of KERs

MIE => KE 1

Generated ROS from photoactivated chemicals can react with membrane lipids, and oxidation of membrane lipids could be occurred. 

Biological Plausibility of the MIE => KE 1 is high.

The relationship between MIE and KE 1 is consistent with chemical and biological knowledge (Girotti, 1990; Girotti, 2001; Onoue and Tsuda, 2006).

MIE => KE 2

Generated ROS from photoactivated chemicals can react with membrane proteins, and oxidation/denaturation of membrane proteins could be occurred.

Biological Plausibility of the MIE => KE 2 is high.

 

The relationship between MIE and KE 2 is consistent with biological knowledge (Dalle Carbonare and Pathak, 1992; Valenzeno, 1987).

KE 1 => AO

Oxidation of membrane lipids relates with damage produced in the cellular membrane, leading to inflammatory events. 

Biological Plausibility of the KE 1 => AO is high.

 

The relationship between KE 1 and AO is consistent with biological knowledge (Castell et al., 1994).

KE 2 => AO

Oxidation/denaturation of protein provides the necrosis of the living tissues as an inflammatory event. 

Biological Plausibility of the KE 2 => AO is high.

 

The relationship between KE 2 and AO is consistent with biological knowledge (Dalle Carbonare and Pathak, 1992; Opie, 1962).

Support for Essentiality of KEs

MIE

ROS generation from photoactivated chemicals

High; well-accepted generation of reactive oxygen species from photo-activated chemicals associated with phototoxic reactions with 200 of chemicals evaluated in qualitative endpoints (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).

KE 1

Oxidation of membrane lipids

 

 

High; Oxidative stress to lipids associated with the phototoxic reactions (Girotti, 1990; Girotti, 2001; Onoue and Tsuda, 2006).

KE 2

Oxidation/denaturation of membrane proteins

High; accepted oxidation/denaturation of proteins associated with the phototoxic reactions (Dalle Carbonare and Pathak, 1992; Valenzeno, 1987).

Adverse outcome

Inflammatory events in sunlight-exposed tissues

Photoreactive agents indicated inflammatory events, including edema, dyskeratosis, and necrosis, in light-exposed tissues after sunlight exposure  (Moore, 1998; Moore 2002; Roberts, 2001).

Empirical Support for KERs

MIE => KE 1: ROS generation leads to Oxidation of membrane lipids

Empirical support of the MIE => KE 1 is strong.

Rationale:

Lipid peroxidation was occurred by ROS-generating chemicals under exposure to simulated sunlight (Onoue et al., 2011, Onoue and Tsuda, 2006). 

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).

MIE => KE 2: ROS generation leads to Oxidation/denaturation of membrane proteins

Empirical support of the MIE => KE 2 is moderate.

Rationale:

ROS generated from photosensitizing agents led to oxidation and denaturation of proteins (Dalle Carbonare and Pathak, 1992).

KE 1 => AO: Oxidation of membrane lipids leads to Inflammatory events

Empirical support of the KE 1=> AO is strong.

Rationale:

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 (Martinez et al., 2015).

Benzoyl peroxide, a ROS generator, led to lipid peroxidation and GSH depletion, and the changes caused the gene expression of pro-inflammatory cytokines (Valacchi et al., 2001).

KE 2 => AO: Oxidation/denaturation of membrane proteins leads to Inflammatory events

Empirical support of the KE 2=> AO is moderate.

Rationale:

Denaturation of proteins induced necrosis and inflammatory in the skin (Opie, 1962).

Quantitative Understanding

Some proof of concept examples to address the WoE considerations for AOPs quantitatively have recently been developed, based on the rank ordering of the relevant Bradford Hill considerations (i.e., biological plausibility, essentiality and empirical support) (Becker et al., 2017; Becker et al, 2015; Collier et al., 2016). Suggested quantitation of the various elements is expert derived, without collective consideration currently of appropriate reporting templates or formal expert engagement. Though not essential, developers may wish to assign comparative quantitative values to the extent of the supporting data based on the three critical Bradford Hill considerations for AOPs, as a basis to contribute to collective experience.Specific attention is also given to how precisely and accurately one can potentially predict an impact on KEdownstream based on some measurement of KEupstream. This is captured in the form of quantitative understanding calls for each KER. See pages 55-56 of the User Handbook for a review of quantitative understanding for KER's. More help

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.    

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-1·cm-1.  Most of chemicals with MEC values of over 1,000 M-1·cm-1 generated significant ROS, including singlet oxygen and/or superoxide (Onoue et al., 2013b; Onoue and Tsuda, 2006), and the qualitative criteria on ROS generation was determined to evaluate chemical phototoxicity (Onoue et al., 2014; Onoue et al., 2013a; Onoue et al., 2008b).

Considerations for Potential Applications of the AOP (optional)

At their discretion, the developer may include in this section discussion of the potential applications of an AOP to support regulatory decision-making. This may include, for example, possible utility for test guideline development or refinement, development of integrated testing and assessment approaches, development of (Q)SARs / or chemical profilers to facilitate the grouping of chemicals for subsequent read-across, screening level hazard assessments or even risk assessment. While it is challenging to foresee all potential regulatory application of AOPs and any application will ultimately lie within the purview of regulatory agencies, potential applications may be apparent as the AOP is being developed, particularly if it was initiated with a particular application in mind. This optional section is intended to provide the developer with an opportunity to suggest potential regulatory applications and describe his or her rationale.To edit the “Considerations for Potential Applications of the AOP” section, on an AOP page, in the upper right hand menu, click ‘Edit.’ This brings you to a page entitled, “Editing AOP.” Scroll down to the “Considerations for Potential Applications of the AOP” section, where a text entry box allows you to submit text. In the upper right hand menu, click ‘Update AOP’ to save your changes and return to the AOP page or 'Update and continue' to continue editing AOP text sections.  The new text should appear under the “Considerations for Potential Applications of the AOP” section on the AOP page. More help

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. 

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. 

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.

References

List the bibliographic references to original papers, books or other documents used to support the AOP. More help

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.

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.

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.

Dubakiene R, Kupriene M. Scientific problems of photosensitivity. Medicina (Kaunas). 2006;42:619-24.

Epstein JH. Phototoxicity and photoallergy in man. J Am Acad Dermatol. 1983;8:141-7.

Epstein JH. Photomedicine. New York: Plenum press; 1989.

Epstein JH, Wintroub BU. Photosensitivity due to drugs. Drugs. 1985;30:42-57.

Girotti AW. Photodynamic lipid peroxidation in biological systems. Photochem Photobiol. 1990;51:497-509.

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