Aop: 424

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

Oxidative stress [MIE] Leading to Decreased Lung Function [AO] via CFTR dysfunction

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
Ox stress-mediated CFTR/ASL/CBF/MCC impairment

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

Karsta Luettich, Philip Morris Products S.A., Philip Morris International R&D, Neuchatel, Switzerland

Hasmik Yepiskoposyan, Philip Morris Products S.A., Philip Morris International R&D, Neuchatel, Switzerland

Monita Sharma, PETA Science Consortium International e.V., Stuttgart, Germany

Frazer Lowe, Broughton Nicotine Services, Earby, Lancashire, United Kingdom

Damien Breheny, British American Tobacco (Investments) Ltd., Group Research and Development, Southampton, United Kingdom

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
Karsta Luettich   (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
  • Karsta Luettich
  • Hasmik Yepiskoposyan
  • Monita Sharma
  • Frazer Lowe
  • Damien Breheny

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
This AOP was last modified on September 28, 2021 04:49
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
Cystic Fibrosis Transmembrane Regulator Function, Decreased August 03, 2021 02:31
Oxidative Stress June 19, 2021 14:42
Airway Surface Liquid Height, Decreased September 09, 2021 03:34
Mucociliary Clearance, Decreased September 10, 2021 07:19
Cilia Beat Frequency, Decreased September 10, 2021 01:38
Decrease, Lung function September 08, 2021 04:54
Oxidative Stress leads to CFTR Function, Decreased September 28, 2021 04:27
CFTR Function, Decreased leads to ASL Height, Decreased September 07, 2021 10:14
ASL Height, Decreased leads to CBF, Decreased September 28, 2021 07:54
CBF, Decreased leads to MCC, Decreased September 28, 2021 08:04
MCC, Decreased leads to Decreased lung function September 28, 2021 08:05
Acrolein September 28, 2021 08:23
Ozone September 28, 2021 08:26
Cigarette smoke September 28, 2021 09:07

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

This AOP evaluates one of the major processes known to be involved in regulating efficient mucociliary clearance (MCC). MCC is a key aspect of the innate immune defense against airborne pathogens and inhaled chemicals and is governed by the concerted action of its functional components, the cilia and the airway surface liquid (ASL), which is composed of mucus and periciliary layers (Bustamante-Marin and Ostrowski, 2017). For MCC to be efficient, the depth of the ASL has to be constantly adjusted to allow for efficient cilia beating and mucus transport (Antunes and Cohen, 2007). The cystic fibrosis transmembrane regulator (CFTR) is an integral membrane glycoprotein that functions as cAMP-activated and phosphorylation-regulated Cl– channel at the apical membrane of epithelial cells (Farinha et al., 2013) and the major Cl– channel that mediates fluid and electrolyte transport. CFTR function is critical to normal ASL homeostasis. Exposure to inhaled oxidants, such as ozone and cigarette smoke, leads to decreased CFTR gene and protein expression as well as CFTR internalization, thereby reducing or abolishing short-circuit currents (Qu et al., 2009; Cantin et al., 2006a; Cantin et al., 2006b; Clunes et al., 2012; Sloane et al., 2012; Rasmussen et al., 2014). Consequently, ASL height (or volume) decreases. Disturbances in any of the processes regulating ASL volume, mucus production, mucus viscoelastic properties, or ciliary function can cause MCC dysfunction and are linked to airway diseases such as chronic obstructive pulmonary disease (COPD) or asthma, both of which are characterized by decreased lung function and bear a significant risk of increased morbidity and mortality.

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

With a surface area of ~100 m2 and ventilated by 10,000 to 20,000 liters of air per day (National Research Council, 1988; Frohlich et al., 2016), the lungs are a major barrier that protect the body from a host of external factors that enter the respiratory system and may cause lung pathologies. Mucociliary clearance (MCC) is a key aspect of the innate immune defense against airborne pathogens and inhaled particles and is governed by the concerted action of its functional components, the cilia and the airway surface liquid (ASL), which comprises mucus and the periciliary layer (Bustamante-Marin and Ostrowski, 2017). In healthy subjects, ≥10 mL airway secretions are continuously produced and transported daily by the mucociliary escalator. Disturbances in any of the processes regulating ASL volume, mucus production, mucus viscoelastic properties, or ciliary function can cause MCC dysfunction and are linked to airway diseases such as chronic obstructive pulmonary disease (COPD) or asthma, both of which bear a significant risk of increased morbidity and mortality. The mechanism by which exposure to inhaled toxicants might lead to mucus hypersecretion and thereby impact pulmonary function has already been mapped in AOP148 on decreased lung function. However, whether an exposure-related decline in lung function is solely related to excessive production of mucus is debatable, particularly in light of the close relationship between mucus, ciliary function, and efficient MCC. To date, no single event has been attributed to MCC impairment, and it is likely that events described in this AOP as well as in AOPs 148 and 411 have to culminate to lead to decreased lung function.

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 1392 Oxidative Stress Oxidative Stress
2 KE 1906 Cystic Fibrosis Transmembrane Regulator Function, Decreased CFTR Function, Decreased
3 KE 1907 Airway Surface Liquid Height, Decreased ASL Height, Decreased
4 KE 1908 Cilia Beat Frequency, Decreased CBF, Decreased
5 KE 1909 Mucociliary Clearance, Decreased MCC, Decreased
6 AO 1250 Decrease, Lung function Decreased lung function

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
Title Adjacency Evidence Quantitative Understanding

Network View

The AOP-Wiki automatically generates a network view of the AOP. This network graphic is based on the information provided in the MIE, KEs, AO, KERs and WoE summary tables. The width of the edges representing the KERs is determined by its WoE confidence level, with thicker lines representing higher degrees of confidence. This network view also shows which KEs are shared with other AOPs. 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
Name Evidence Term
Acrolein Moderate
Ozone Moderate
Cigarette smoke High

Life Stage Applicability

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

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

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 experimental evidence to support the biological plausibility of the KERs from MIE to AO is moderate to strong overall for the AOP presented here, while there is a moderate concordance of dose-response relationships. The weakest evidence is for the KER of decreased CFTR function leading to decreased ASL height, due to both insufficient experimental evidence of causality and a scarcity of quantitative data on dose-related responses and temporal concordances. In terms of essentiality, we have rated all KEs either moderate or high.

AOPs such as this one can play a central role in risk assessment strategies for a wide variety of regulatory purposes by providing mechanistic support to an integrated approach to testing and assessment (IATA; (Clippinger et al., 2018)). IATAs are flexibleframeworks that can be adapted to best address the regulatory question or purpose at hand. More specifically, this AOP can be applied to the risk assessment of inhaled toxicants, by enabling the development of testing strategies through the assembly of existing information and the generation of new data where they are currently lacking. Targeted approaches to fill data gaps can be developed using new approach methodologies (NAMs) informed by this AOP.

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

All KE proposed in this AOP occur and are measurable in several species, including frogs, mice, rats, guinea pigs, ferrets, sheep, and humans. The majority of the supporting empirical evidence derives from studies in rodent and human systems, and—with the exception of CFTR function, which is known to vary from species to species (Higgins, 1992)—experimental findings in animals appear to be highly translatable to humans.

Data regarding the applicability of KE to all life-stages from birth to adulthood are available for the MIE (Oxidative Stress), KE1 (Cystic Fibrosis Transmembrane Regulator Function, Decreased), KE4 (Cilia Beat Frequency, Decreased), KE5 (Mucociliary Clearance, Decreased), and AO (Decreased Lung Function), and indicate that they apply to all life stages. There are no data related to ASL regulation and homeostasis relative to organismal health, but it is reasonable to assume that KE3 (Airway Surface Liquid Height, Decreased), through its impact on MCC, can affect all life-stages. It is also worth noting here that age-dependent decreases in CBF, MCC, and lung function have been demonstrated in several species (e.g., guinea pigs, mice, and humans) and reflect normal physiological aging processes (Bailey et al., 2014; Grubb et al., 2016; Ho et al., 2001; Joki and Saano, 1997; Paul et al., 2013; Sharma and Goodwin, 2006).

Gender-specific data relevant to the AOP are not as widely available as species-specific data, and to our knowledge, the role of gender has not been systematically evaluated for all KE described here. Informative evidence on gender differences stems from patients with chronic pulmonary diseases, such as cystic fibrosis, asthma, COPD, and bronchiectasis, that are characterized by decreased lung function. For example, epidemiological data indicate more rapid lung function decline and shorter life expectancy in females with cystic fibrosis (genetic CFTR dysfunction; Corey and Farewell, 1996; Harness-Brumley et al., 2014; Olesen et al., 2010; Rosenfeld et al., 1997), and earlier disease onset, more severe disease and more rapid lung function decline in females with COPD (acquired CFTR dysfunction; Prescott et al., 1997; Sørheim et al., 2010) but higher prevalence of COPD in males although this gender gap is closing (Ntritsos et al., 2018). Considering the expression pattern of CFTR and its function as well as the importance of efficient MCC—brought about by the interactions of ciliary function, ASL homeostasis and mucus properties—for normal physiological function, we consider this AOP applicable to both genders.

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 definition of essentiality implies that the modulation of upstream KEs impacts the downstream KEs in an expected fashion. If blocked or failing to occur, the KEs in the current AOP will not necessarily stop the progression to subsequent KEs. Due to the complex biology of motile cilia formation and function, ASL homeostasis, mucus properties and MCC, the KEs and AO may be triggered because of alternative pathways or biological redundancies. However, when exacerbated, the KEs promote the occurrence of downstream events eventually leading to the AO. The causal pathway starting from the exposure to oxidants and leading to decreased lung function involves parallel routes with KEs (also see AOP411), each of which is sufficient to cause the downstream KE to occur. Oxidant-induced decreases in ASL height via CFTR function decline lead to decreased CBF and decreased MCC. Based on the evidence we judge the key events MIE (Oxidative Stress), KE1 (Cystic Fibrosis Transmembrane Regulator Function, Decreased), KE4 (Cilia Beat Frequency, Decreased), and KE5 (Mucociliary Clearance, Decreased) as highly essential and suggest moderate essentiality for KE3 (Airway Surface Liquid Height, Decreased).

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

We judge the overall biological plausibility of this AOP as strong. Several KER (i.e., Oxidative stress leading to decreased CFTR function, Decreased CFTR function leading to decreased ASL height) are supported by multiple studies across different species with ample empirical evidence reflecting both dose-response and time concordance. Other KER, such as Decreased ASL height leading to reduced CBF, lack this expanse of empirical evidence, or the evidence does not fully support the causality between the KE (Decreased CBF leading to decreased MCC) even though the relationship is logical and plausible.

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

Overall, our quantitative understanding of the AOP network is moderate. There is robust evidence that provides an insight into several KER presented here, and the dose response and temporal relationship between the two KE in question are well described and quantified for different stressors across different test systems (Oxidative stress leading to decreased CFTR function, Decreased CFTR function leading to decreased ASL height; Decreased CBF leading to decreased MCC). In some instances, we are less confident in our quantitative understanding. For example, for the KER Decreased ASL height leading to decreased CBF, empirical evidence supporting causality between the two KE is lacking as is quantitative evidence. Dose response data as well as data supportive of the KE causality are limited for the KER Decreased MCC leading to decreased lung function

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

Given the individual and public health burden of the consequences of lung function impairment, gaining a greater understanding of the underlying mechanisms is extremely important in the risk assessment of respiratory toxicants. An integrated assessment of substances with the potential to be inhaled, either intentionally or unintentionally, could incorporate inhalation exposure and dosimetry modelling to inform an in vitro approach with appropriate exposure techniques and cell systems to assess KEs in this AOP (EPA’s Office of Chemical Safety and Pollution Prevention, 2019). Standardization and robustness testing of assays against explicit performance criteria using suitable reference materials can greatly increase the level of confidence in their use for KE assessment (Petersen et al., In Press). Much of the empirical evidence that supports the KERs in the qualitative AOP described here was obtained from in vitro studies using well-established methodologies for biological endpoint assessment. Being chemical agnostic, this AOP can be applied to a variety of substances that share the AO. For example, impaired MCC and decreased lung function have a long-known relationship with smoking, but little is known about the consequences of long-term use of alternative inhaled nicotine delivery products such as electronic cigarettes and heated tobacco products. This AOP can form the basis of an assessment strategy to evaluate the effects of exposure to aerosol from these products based on the KEs identified here.

References

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

Antunes, M.B., and Cohen, N.A. (2007). Mucociliary clearance–a critical upper airway host defense mechanism and methods of assessment. Curr. Opin. Allergy Clin. Immunol. 7, 5-10.

Bailey, K.L., Bonasera, S.J., Wilderdyke, M., Hanisch, B.W., Pavlik, J.A., DeVasure, J., et al. (2014). Aging causes a slowing in ciliary beat frequency, mediated by PKCε. Am. J. Physiol. Lung Cell. Mol. Physiol. 306, L584-L589.

Bustamante-Marin, X.M., and Ostrowski, L.E. (2017a). Cilia and Mucociliary Clearance. Cold Spring Harb. Persp. Biol. 9, a028241.

Cantin, A.M., Bilodeau, G., Ouellet, C., Liao, J., and Hanrahan, J.W. (2006a). Oxidant stress suppresses CFTR expression. Am. J. Physiol. Cell Physiol. 290, C262-270. 

Cantin, A.M., Hanrahan, J.W., Bilodeau, G., Ellis, L., Dupuis, A., Liao, J., et al. (2006b). Cystic Fibrosis Transmembrane Conductance Regulator Function Is Suppressed in Cigarette Smokers. Am. J. Respir. Crit. Care Med. 173, 1139-1144.

Clippinger, A.J., Allen, D., Behrsing, H., BéruBé, K.A., Bolger, M.B., Casey, W., et al. (2018). Pathway-based predictive approaches for non-animal assessment of acute inhalation toxicity. Toxicol. In Vitro 52, 131-145.

Clunes, L.A., Davies, C.M., Coakley, R.D., Aleksandrov, A.A., Henderson, A.G., Zeman, K.L., et al. (2012). Cigarette smoke exposure induces CFTR internalization and insolubility, leading to airway surface liquid dehydration. FASEB J. 26), 533-545.

Corey, M., and Farewell, V. (1996). Determinants of mortality from cystic fibrosis in Canada, 1970–1989. Am. J. Epidemiol. 143, 1007-1017.

EPA’s Office of Chemical Safety and Pollution Prevention (2019). "FIFRA Scientific Advisory Panel Meeting Minutes and Final Report No. 2019-01 Peer Review on Evaluation of a Proposed Approach to Refine the Inhalation Risk Assessment for Point of Contact Toxicity: A Case Study Using a New Approach Methodology (NAM) December 4 and 6, 2018 FIFRA Scientific Advisory Panel Meeting". U.S. Environmental Protection Agency).

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