Aop: 196

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

Volatile Organic Chemicals Activate TRPA1 Receptor to Induce Sensory Pulmonary Irritation

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
TRPA1 activation leads to pulmonary sensory irritation

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

Jeanelle Martinez and Thomas Eling

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
Jeanelle Martinez   (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
  • Jeanelle Martinez

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 Under Development
This AOP was last modified on November 01, 2018 10:33
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
TRPA1 activation, TRPA1 Receptor September 16, 2017 10:17
Opening of calcium channel, Calcium influx October 25, 2017 16:59
Trigeminal nerve activation September 24, 2018 12:08
SP (Substance P) release, Local increase of SP September 16, 2017 10:17
Trigeminal and/or vagal nerve excitation causes Airway Hyper-responsiveness,Cough, Dyspnea September 24, 2018 12:14
Increased Respiratory irritability and Chronic Cough, September 24, 2018 12:51
Increased CGRP, neuronal release of CGRP September 16, 2017 10:17
Irritation of nasal mucosa inducing sneeze reflex September 16, 2017 10:17
Increased neurokinin A (NKA) by neuronal cells September 16, 2017 10:17
TRPA1 activation, TRPA1 Receptor leads to Opening of calcium channel, Calcium influx November 29, 2016 21:13
Opening of calcium channel, Calcium influx leads to Excitation, Trigeminal nerve excitation December 03, 2016 16:38
Excitation, Trigeminal nerve excitation leads to SP (Substance P) release, Local increase of SP June 23, 2017 11:14
Excitation, Trigeminal nerve excitation leads to Increased CGRP June 23, 2017 13:12
Excitation, Trigeminal nerve excitation leads to Increased NKA June 23, 2017 16:37
SP (Substance P) release, Local increase of SP leads to Respiratory irritability September 24, 2018 12:47
Increased CGRP leads to Respiratory irritability June 27, 2017 18:23
Increased NKA leads to Respiratory irritability September 24, 2018 12:48
Respiratory irritability leads to Increased Airway Hyper-responsiveness,Cough, Dyspnea September 24, 2018 12:20
Excitation, Trigeminal nerve excitation leads to Irritation induced sneezing June 23, 2017 14:42
Dibenzo[B,F][1,4]Oxazepine January 17, 2017 14:50
2-Chlorobenzalmalononitrile January 20, 2017 11:39

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

Pulmonary irritation induced by chemical exposure can be divided into two types. One type of irritation, corrosive irritation causes inflammation from tissue destruction and appears to be limited to inhalation of industrial chemicals for example hydrochloric acid, chlorine gas, and ammonia. The second type, sensory irritation is caused by sensory stimulation mediated by activation of specific receptors located in the trigeminal nerve endings and occurs at concentrations that do not result in tissue destruction. Our focus is to develop an adverse outcome pathway (AOP) for sensory irritants.  Many inhalable chemicals are sensory irritants (Alarie et al 1966, 1973, Schaper et al., 1993) that can cause physiological responses including pain, mucus production, nasal obstruction, sneezing, coughing, and decreases in respiration rate (Brunning et al., 2014). The target organ of respiratory irritants is ultimately the airways causing inflammation of the trachea, bronchitis, and bronchiolitis. A receptor present in the upper airways is the TRPA1 (transient receptor potential cation channel, subfamily A, member 1) that induces a physiological response to make the subject aware of the presence of chemicals and initiate several defensive biological responses. A wide range of chemicals activates TRPA1 (Bessac and Jordt, 2010). The activation of TRPA1 acts as a gatekeeper of inflammation/irritation and is a critical endpoint in the regulation of exposure to volatile organic chemicals (Bautista et al., 2013; Lehman et al., 2015).

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

Exposure to airborne pollutants can cause a number of harmful effects including irritation. Airborne pollutants are typically associated with industrial activities, cigarette smoke and automobile exhaust. However, inhalation exposure to irritant gases and vapors frequently occurs in occupational and ambient environments. Each year new and untested inhalable chemicals are added to the environment and the lack of appropriate toxic information may result in an underestimation of occupation risks due to exposure of airborne irritants. Assays or tests are needed to first determine and then characterize the potential irritant respiratory response of uncharacterized current and newly added volatile chemicals. To develop suitable assays it is necessary to understand the fundamental biochemical and physiology processes initiating the development and progression of irritation. The presented AOP is focused on the critical biochemical event, the activation of the TRP receptors, then describing the subsequent biochemical processes and pathways and how they interact with each other resulting in pulmonary irritation.

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
1 MIE 1215 TRPA1 activation, TRPA1 Receptor TRPA1 activation, TRPA1 Receptor
2 KE 1218 Opening of calcium channel, Calcium influx Opening of calcium channel, Calcium influx
3 KE 1220 Trigeminal nerve activation Excitation, Trigeminal nerve excitation
4 KE 1222 SP (Substance P) release, Local increase of SP SP (Substance P) release, Local increase of SP
5 KE 1433 Increased CGRP, neuronal release of CGRP Increased CGRP
6 KE 1435 Increased neurokinin A (NKA) by neuronal cells Increased NKA
7 AO 1223 Trigeminal and/or vagal nerve excitation causes Airway Hyper-responsiveness,Cough, Dyspnea Increased Airway Hyper-responsiveness,Cough, Dyspnea
8 AO 1434 Irritation of nasal mucosa inducing sneeze reflex Irritation induced sneezing
9 AO 1226 Increased Respiratory irritability and Chronic Cough, Respiratory irritability

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

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

Sex Applicability

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

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

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

Life Stage Applicability: Exposure to toxic gases and vapor and in particular reactive chemicals activate TRPV1, ASICs and TRPA1 and induce neurogenic inflammation and pain and coughing responses. The activation of TRPA1 and TRPV1 also stimulates the release of inflammatory peptide SP, NKA and CGRP, which play a role in the asthmatic and irritation symptoms, observed after one-time and (Caceres et al., 2009) frequent exposure to inhaled irritants. These receptors may become hyper sensitized leading to chronic airway inflammation and cough. Exposure to high levels of TRPA1 agonists can induce reactive airway dysfunction syndrome or RADS, characterized by asthma like symptoms (Brooks et al., 1985). Bessac and Jordt (2008) proposed that exposure to an irritant and hence activation of TRPA1 may sensitize TRPA1 through inflammatory pathways and thereby establishing a hypersensitivity to other reactive irritants. TRPA1 but not TRPV1 appear to play an important role in allergic airway inflammation and hyper-reactivity associated with asthma. In a mouse model of asthma, the ovalbumin challenged mouse, ovalbumin induces a Th2 directed allergic response that included increase in leukocyte in the bronchoalveolar lavage fluid, increases in inflammatory cytokines and increase mucus production. In TRPA1 (-/-) mice, however these responses to ovalbumin were significantly reduced. Treatment of mice with a tear gas and TRPA1 agonist increased CGRP, SP and neurokinin A in wild type mice with greatly reduced levels in the TRPA1 (-/-) mice appearing in the alveolar fluid. Likewise treatment of wild type mice with ovalbumin also increase increased with level of neurokinin A with a diminished level in the TRPA1 (-/-) mice. These results indicate TRPA1 has a critical role in the development of asthma after allergen challenge (Caceres et al., 2009

Taxonomic Applicability,: The data used to support the KERs in this AOP derives from experimental studies conducted in rats, knockout mice or cell cultures from fibroblasts, ovary epithelium. TRP channels are present in primary sensory neruons, and also non-nueuronal tissues including epithelium, fibroblasts, and smooth muscle (Kissin, 2008). The majority of the KEs in this AOP seem to be highly conserved across species. It is unclear if these KERs of the present AOP are also applicable for other species rather than human, primates, rats and mice.

Sex Applicability: There is definitely potential for sex applicability to play a role in airway irritation and chemical sensitization. It has been demonstrated that TRP channels in sensory neurons are regulated by prolactin, in a sex-dependent manner. Prolactin plays a role in the sensitization of TRP channels and may promote antinocioceeptive effects (Patel, et al., 2013).In female mice dorsal root ganglia neurons, TRPV1 activity was enhanced with prolactin at 10-25 ng/ml whereas male mice required >0.8-1 mcg/ml PRL. ASICs activity has also been shown to be upregulated by prolactin in female rats (Li et al., 2016). </em>

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

Molecular Initiating Event Summary, Key Event Summary

Macro-molecular:

The critical importance of the activation of TRPA1 receptor in the pulmonary response to irritants is strongly supported by the results of studies (Bautista et.al., 2006; Caceres et al., 2009) with mice deficient in TRPA1 (TRPA1-/- mice). The TRPA1 -/- mice have significant lower decrease in the respiration rate and symptoms of irritation after exposure to inhalable irritants than wild type mice. Many electrophiles and oxidants are very potent irritants and covalently link to and modify and thus activate the critical receptor(s) that initiate the irritation response (Bessac and Jordt, 2010, Bautista et al., 2013). Some members of this reactive group are isocyanates, α, β-unsaturated aldehydes, heavy metals and peroxides.

Cell/Tissue:

The trigeminal chemosensory nerve endings in the nasal mucosa and airway are a first line of defense against irritant chemicals. In these nerve endings are TRP calcium ion channels, TRPV1 and TRPA1, with TRPA1 acting as the major sensor to noxious chemicals. Irritants, electrophiles, oxidants, as well as endogenous chemicals, activate TRPA1 causing an influx of Ca+2 into the nerve. This results in excitation of the trigeminal nerves and the initiation of airway reflex responses coughing, sneezing and pain. A clear time dependent relationship occurs between the activation of the receptor and Ca ion flux and the biological effects (Bessac et aal., 2008).

Reactive irritants like the isothiocyanates form adducts with thiol residues present in the receptor active site causing prolonged nerve activation (Hinman et al., 2006; Peterlin et al., 2007; Macpherson et al., 2007). The activation of TRPA1 with electrophilic irritants results in the covalent binding of the chemicals to cysteine and lysine residues of TRPA1 forming a “foreign protein” or hapten leading sensitization and enhanced responses to subsequent exposure to the irritant (Vandebriel et al., 2011).

The cellular responses include excitation of the trigeminal nerves causes the release of neuropeptides substance P, NK and CGRP that promote neurogenic inflammation, vasodilation, and fluid leakage. Substance P and NK bind to NK receptors that are expressed in the plasma membrane of cell bodies and dendrites of neurons.

Organ/Organ System:

As the irritant reach the lower airways the sensory nerve activation causing the following organ response or pulmonary responses: bronchial constriction spams and increased mucus production and further neurogenic inflammation. Increased eosinophils and T helper cells and the associated inflammatory cytokines (IL-2, Il-4, IL-10, Il-13) are observed (Caceres et al., 2009; Belvisi et al., 2011). Trigeminal activation also results in a vagal response that slows the respiration rate, which is the basis for the use of RD50, or the irritant concentration that induces a 50% decrease in respiration rates in mice (Alarie, 1981).

Individual

Exposure to irritants the activation of TRPA1 couples with its interaction with TRPV1 can eventually lead to the following organism responses or clinical manifestations: chronic cough, pain, airway inflammation, COPD and asthmatic like conditions (Bessac and Jordt, 2008, Chen and Haclos, 2015, Baraldi et al., 2010.)

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

Summary Table 1. Concordance of dose-response relationships Strong in vitro dose response relationships for the activation of TRPA1 by known irritants are published in the literature. In general, a good correlation exists between the potency as measure in vitro and the irritation observed mice in as measure by the Alarie test for sensory irritation.

2. Temporal concordance among the key events and adverse effect; There is good agreement between the sequences of biochemical and physiological events leading to pulmonary irritation ( Bassec and Jordt 2009, Bessac and Jordt, 2010, Baustista et al, 2006).

3. Strength, consistency, and specificity of association of adverse effect and initiating event There is excellent strength, as well as good consistency and high specificity, of the association between the activation of TRP receptors and irritation. The critical importance of the activation of TRPA1 receptor in the pulmonary responses to irritants is strongly supported by the results of studies with mice deficient in TRPA1 (TRPA1-/- mice) (Bautista et.al., 2006; Caceres et al., 2009).

4. Biological plausibility, coherence, and consistency of the experimental evidence The in vitro, and in vivo experimental evidence is logical and consistent with the hypothesis that the activation of the TRP receptors, in particular, the activation of TRPA1 is the key initiation event in pulmonary irritation (Bautista et al 2013, Bessac and Jirdt, 2009).

5. Uncertainties, inconsistencies, and data gaps. A database containing more than 350 RD50 values that is a measure of irritation in vivo obtained from experimental animals is available (Schaper 1993) but only a few of these irritants has been tested in in vitro assays to directly measure the activation of TRPA1 (Bessac and Jordt, 2010; Bos et al., 2002, Lehmann 2016). A real gap in the information of irritation and activation by TRPA1 is the lack of potency data on the activation of TRPA1 by known irritants.

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

Summary Table The most effective chemicals with the lowest EC50 to activate the TRPA1 calcium channel are unsurprisingly the electrophiles like tear gases, acrolein, or cinnamaldehyde (Bandell et al., 2004; Jordt et al., 2004; Macpherson et al., 2007; and Mukhopadhyaty et al., 2011). Other chemicals with higher EC50’s include hydrogen peroxide, formaldehye, and Crotonaldehyde (Mukhopadhyaty et al., 2011; Sawada et al., 2008).

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 AOP would be enhanced by the addition of results confirming the activation of TRPA1 by the chemicals established as irritants with reported RD50. This information would confirm what irritants and their toxicity is mediate by these biochemical processes initiated by TRPA1 activation. If a significant number of these irritants are not activators of TRP receptors, it would stimulate the search for additional biochemical mechanisms for irritants. Furthermore the additional data would permit a comparison of the RD50 and EC50 . This comparison may allow a determination if an in vitro assay for TRP activation using, for example, fibroblasts can be used determine if an uncharacterized chemical is potential chemical irritant and if the values are useful in setting exposure limits.

References

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

Alarie, Y. Dose-response analysis in animal studies: prediction of human responses. Environ Health Perspect 42, 9-13 (1981).

Baraldi, P. G., Preti, D., Materazzi, S. & Geppetti, P. Transient receptor potential ankyrin 1 (TRPA1) channel as emerging target for novel analgesics and anti-inflammatory agents. J Med Chem 53, 5085-5107, doi:10.1021/jm100062h (2010).

Bautista, D. M. et al. TRPA1 mediates the inflammatory actions of environmental irritants and proalgesic agents. Cell 124, 1269-1282, doi:10.1016/j.cell.2006.02.023 (2006).

Belvisi, M. G., Dubuis, E. & Birrell, M. A. Transient receptor potential A1 channels: insights into cough and airway inflammatory disease. Chest 140, 1040-1047, doi:10.1378/chest.10-3327 (2011).

Bandell, M. et al. Noxious Cold Ion Channel TRPA1 Is Activated by Pungent Compounds and Bradykinin. Neuron 41, 849-857, doi:10.1016/S0896-6273(04)00150-3 (2004).

Bessac, B. F. & Jordt, S. E. Breathtaking TRP channels: TRPA1 and TRPV1 in airway chemosensation and reflex control. Physiology (Bethesda) 23, 360-370, doi:10.1152/physiol.00026.2008 (2008).

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