Aop: 280


A descriptive phrase which references both the Molecular Initiating Event and Adverse Outcome.It should take the form “MIE leading to AO”. For example, “Aromatase inhibition leading to reproductive dysfunction” where Aromatase inhibition is the MIE and reproductive dysfunction the 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

α-diketone-induced bronchiolitis obliterans

Short name
A name that succinctly summarises the information from the title. This name should not exceed 90 characters. More help
α-diketone-induced bronchiolitis obliterans

Graphical Representation

A graphical representation of the AOP.This graphic should list all KEs in sequence, including the MIE (if known) and AO, and the pair-wise relationships (links or KERs) between those KEs. More help
Click to download graphical representation template Explore AOP in a Third Party Tool


The names and affiliations of the individual(s)/organisation(s) that created/developed the AOP. More help

Jan Boeij, Harry Vrielingh, Pieter Hiemstra, Inga Tluczkiewicz

Point of Contact

The user responsible for managing the AOP entry in the AOP-KB and controlling write access to the page by defining the contributors as described in the next section.   More help
Agnes Aggy   (email point of contact)


Users with write access to the AOP page.  Entries in this field are controlled by the Point of Contact. More help
  • Marvin Martens
  • Agnes Aggy


Provides 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. OECD Status - Tracks the level of review/endorsement the AOP has been subjected to. OECD Project Number - Project number is designated and updated by the OECD. SAAOP Status - Status managed and updated by SAAOP curators. 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 Do not cite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 July 16, 2022 18:37

Revision dates for related pages

Page Revision Date/Time
Interaction of α-diketones with arginine residues January 30, 2019 10:23
Proteasomal dysfunction January 30, 2019 10:24
Airway epithelial injury January 30, 2019 10:25
Increase, Inflammation January 30, 2019 10:26
Induction, Epithelial Mesenchymal Transition January 30, 2019 10:27
Fibroproliferative airway lesions January 30, 2019 10:28
Bronchiolitis obliterans January 30, 2019 10:28
Interaction of α-diketones with arginine residues leads to Proteasomal dysfunction January 30, 2019 10:41
Proteasomal dysfunction leads to Airway epithelial injury January 30, 2019 10:42
Airway epithelial injury leads to Increase, Inflammation January 30, 2019 10:43
Increase, Inflammation leads to EMT January 30, 2019 10:58
Increase, Inflammation leads to Fibroproliferative airway lesions January 30, 2019 10:57
EMT leads to Fibroproliferative airway lesions January 30, 2019 10:59
Fibroproliferative airway lesions leads to Bronchiolitis obliterans January 30, 2019 11:01


A concise and informative summation of the AOP under development that can stand-alone from the AOP page. The aim is to capture the highlights of the AOP and its potential scientific and regulatory relevance. More help

Bronchiolitis obliterans (BO) is a severe respiratory illness due to the obstruction of the smallest airways of the lungs, the bronchioles. Inhalation of the -diketone diacetyl has been associated with the development of this disease in employees of the microwave popcorn production industry. Exposure of laboratory animals to diacetyl as well as other α-diketones results in airway epithelial injury, ultimately resulting in BO-like lesions. The electrophilic α-diketones interact with arginine residues causing altered structure and functioning of proteins. However, the critical proteins causing the observed toxicity have not yet been identified. Upon severe or repeated exposure to α-diketones the epithelium of the airways becomes severely damaged or the airways become completely denuded. In these injured regions of the airways the intrinsic regenerative capacity of the epithelium, via proliferation of basal cells and subsequent differentiation, is lost. This leads to compensatory proliferation in the adjacent mesenchyme in which fibroblast to myofibroblast transition may take place under the influence of inflammatory signals. Another possible cause of fibrogenesis is through the occurrence of epithelial-mesenchymal transition (EMT) within the injured airway epithelium. Excessive proliferation of fibrotic cells leads to the occlusion of the bronchioles resulting in dry cough, wheezing, shortness of breath and a strongly reduced lung function, the symptoms of BO.

This AOP is linked to EU-ToxRisk case study “ RDT: Popcorn Lung – read-across on diketones” in which the effects of α-diketone exposures are investigated using ex-vivo human precision cut lung slices and primary human bronchial epithelial cells cultured at the air-liquid interface.

AOP Development Strategy


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. More help


Provides a description of the approaches to the identification, screening and quality assessment of the data relevant to identification of the key events and key event relationships included in the AOP or AOP network.This information is important as a basis to support the objective/envisaged application of the AOP by the regulatory community and to facilitate the reuse of its components.  Suggested content includes a rationale for and description of the scope and focus of the data search and identification strategy/ies including the nature of preliminary scoping and/or expert input, the overall literature screening strategy and more focused literature surveys to identify additional information (including e.g., key search terms, databases and time period searched, any tools used). 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


Molecular Initiating Events (MIE)
An MIE is a specialised KE that represents the beginning (point of interaction between a prototypical stressor and the biological system) of an AOP. More help
Key Events (KE)
A measurable event within a specific biological level of organisation. More help
Adverse Outcomes (AO)
An AO is a specialized KE that represents the end (an adverse outcome of regulatory significance) of an AOP. More help
Type Event ID Title Short name
MIE 1584 Interaction of α-diketones with arginine residues Interaction of α-diketones with arginine residues
KE 1585 Proteasomal dysfunction Proteasomal dysfunction
KE 1586 Airway epithelial injury Airway epithelial injury
KE 149 Increase, Inflammation Increase, Inflammation
KE 1457 Induction, Epithelial Mesenchymal Transition EMT
KE 1587 Fibroproliferative airway lesions Fibroproliferative airway lesions
AO 1588 Bronchiolitis obliterans Bronchiolitis obliterans

Relationships Between Two Key Events (Including MIEs and AOs)

This table summarizes 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. More help
Title Adjacency Evidence Quantitative Understanding

Network View

This network graphic is automatically generated based on the information provided in the MIE(s), KEs, AO(s), KERs and Weight of Evidence (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

Prototypical Stressors

A structured data field that can be used to identify one or more “prototypical” stressors that act through this AOP. Prototypical stressors are stressors for which responses at multiple key events have been well documented. More help

Life Stage Applicability

The life stage for which the AOP 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. More help

Sex Applicability

The sex for which the AOP is known to be applicable. More help

Overall Assessment of the AOP

Addressess the relevant biological domain of applicability (i.e., in terms of taxa, sex, life stage, etc.) and Weight of Evidence (WoE) for the overall AOP as a basis to consider appropriate regulatory application (e.g., priority setting, testing strategies or risk assessment). More help

Domain of Applicability

Addressess the relevant biological domain(s) of applicability in terms of sex, life-stage, taxa, and other aspects of biological context. More help

Essentiality of the Key Events

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. More help

Evidence Assessment

Addressess the biological plausibility, empirical support, and quantitative understanding from each KER in an AOP. More help

Known Modulating Factors

Modulating factors (MFs) may alter the shape of the response-response function that describes the quantitative relationship between two KES, thus having an impact on the progression of the pathway or the severity of the AO.The evidence supporting the influence of various modulating factors is assembled within the individual KERs. More help

Quantitative Understanding

Optional field to provide quantitative weight of evidence descriptors.  More help

Considerations for Potential Applications of the AOP (optional)

Addressess 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. More help


List of the literature that was cited for this AOP. More help