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AOP: 302


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

Lung surfactant function inhibition leading to decreased lung function

Short name
A name that succinctly summarises the information from the title. This name should not exceed 90 characters. More help
Lung surfactant function inhibition leading to decreased lung function
The current version of the Developer's Handbook will be automatically populated into the Handbook Version field when a new AOP page is created.Authors have the option to switch to a newer (but not older) Handbook version any time thereafter. More help
Handbook Version v2.0

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

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
Brendan Ferreri-Hanberry   (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
  • Jorid Birkelund Sørli
  • Emilie Da Silva
  • Yi Zuo
  • Brendan Ferreri-Hanberry


This field is used to identify coaches who supported the development of the AOP.Each coach selected must be a registered author. More help
  • Sabina Halappanavar
  • Cinzia La Rocca

OECD Information Table

Provides users with information concerning how actively the AOP page is being developed and whether it is part of the OECD Workplan and has been reviewed and/or endorsed. OECD Project: Assigned upon acceptance onto OECD workplan. This project ID is managed and updated (if needed) by the OECD. OECD Status: For AOPs included on the OECD workplan, ‘OECD status’ tracks the level of review/endorsement of the AOP . This designation is managed and updated by the OECD. Journal-format Article: The OECD is developing co-operation with Scientific Journals for the review and publication of AOPs, via the signature of a Memorandum of Understanding. When the scientific review of an AOP is conducted by these Journals, the journal review panel will review the content of the Wiki. In addition, the Journal may ask the AOP authors to develop a separate manuscript (i.e. Journal Format Article) using a format determined by the Journal for Journal publication. In that case, the journal review panel will be required to review both the Wiki content and the Journal Format Article. The Journal will publish the AOP reviewed through the Journal Format Article. OECD iLibrary published version: OECD iLibrary is the online library of the OECD. The version of the AOP that is published there has been endorsed by the OECD. The purpose of publication on iLibrary is to provide a stable version over time, i.e. the version which has been reviewed and revised based on the outcome of the review. AOPs are viewed as living documents and may continue to evolve on the AOP-Wiki after their OECD endorsement and publication.   More help
OECD Project # OECD Status Reviewer's Reports Journal-format Article OECD iLibrary Published Version
1.87 Under Development
This AOP was last modified on May 26, 2024 20:39

Revision dates for related pages

Page Revision Date/Time
Reduced tidal volume February 16, 2021 11:55
Loss of alveolar capillary membrane integrity May 17, 2023 15:35
Inhibition of lung surfactant function October 27, 2021 11:13
Alveolar collapse October 27, 2021 11:33
Decrease, Lung function September 08, 2021 04:54
Inhibition of LS function. leads to Alveolar collapse July 03, 2019 13:21
Inhibition of LS function. leads to Decreased lung function April 27, 2021 08:21
Alveolar collapse leads to Reduced tidal volume July 03, 2019 13:24
Alveolar collapse leads to Decreased lung function April 27, 2021 08:21
Alveolar collapse leads to Loss of alveolar capillary membrane integrity February 01, 2022 05:42
Loss of alveolar capillary membrane integrity leads to Decreased lung function April 27, 2021 08:21
Reduced tidal volume leads to Decreased lung function April 27, 2021 08:19
Loss of alveolar capillary membrane integrity leads to Inhibition of LS function. April 27, 2021 08:19
Loss of alveolar capillary membrane integrity leads to Reduced tidal volume April 27, 2021 08:20


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

Inhalation of substances, chemicals, particles and mixtures is the main route of occupational exposure. This adverse outcome pathway (AOP) describes the connections between the inhibition of lung surfactant function, and how this is connected to decreased lung function. Lung surfactant is a thin layer of lipids and proteins that lines the respiratory parts of the lungs. Decreased lung function in humans is characterized by symptoms such as coughing, difficult breathing, tightness in the chest, fever and vomiting (AO) [1, 2]. In experimental animals acute inhalation toxicity is defined as the total of adverse effects caused by a substance following a single uninterrupted exposure by inhalation over a short period of time (24 hours or less) to a substance capable of being inhaled [3]. This AOP describes one of the pathways that can lead to decreased lung function seen as respiratory clinical signs of toxicity in humans and experimental animals.

The main function of lung surfactant is to lower the surface tension at the air-liquid interface during the breathing cycle. Inhaling substances that reach the alveoli can potentially interact with and inhibit the lung surfactant function (MIE). Inhibition leads to an increase in minimum surface tension and alveolar collapse (KE1), the individual alveoli can stay closed or be open again by the force of the inhaled air. If the alveolus stays closed, this reduces the tidal volume (KE3), reducing the area for gas exchange in the lungs and reduces blood oxygenation (hypoxemia). If the alveolus reopens, this can lead to loss of capillary membrane integrity due to shear stress on the epithelium (KE2) and bleeding into the lungs. Blood components (such as albumin and fibrin) reaching the air-liquid interface will further disrupt lung surfactant function by interacting with the lung surfactant (feedback loop between KE2 and MIE) [4-7] leading to the exacerbation of the process. The combination of alveolar collapse, loss of capillary membrane integrity and reduced tidal volume leads to decreased lung function. The MIE (lung surfactant function inhibition) can be examined in vitro by measuring the effect of a substance or mixture of substances on the lung surfactant function. The effects of blood entering the lung and interacting with lung surfactant can likewise be studied in the in vitro assay. Reduced tidal volume can be measured in vivo, using experimental animals in whole body plethysmographs that are exposed to the substance in question, while monitoring respiration parameters. The effect of reduced tidal volume, hypoxemia, can be measured by analysing the oxygenation of the blood both from experimental animals, and patients that have inhaled substances leading to immediate adverse lung effects. The loss of capillary membrane integrity can be examined in experimental animals, by analysing liquid flushed from the lungs (broncho-alveolar lavage), and in lavage from patients undergoing examination during acute lung injury [8].   

Decreased lung function is observed frequently in humans [2]. Similar symptoms are seen in experimental animals [1]. Lung surfactant function impairment in vitro has been strongly associated with induction of acute lung toxicity both in humans and in experimental animals [1].

In addition to lung surfactant function impairment, there are potentially several other pathways leading to decreased lung function, e.g. inflammatory cells activation, activation of the immune system, damage to the epithelial cells of the lungs, interaction with the nervous system in the lungs; however other AOPs may describe this process, and can be linked to this proposed AOP. Additionally decreased lung function may have long term effects on the lungs, such as development of fibrosis (AOP 173) or asthma and COPD (AOP 196 and AOP 148).



  1. Sørli, J.B., et al., Prediction of acute inhalation toxicity using in vitro lung surfactant inhibition. ALTEX, 2017. 35(1): p. 26-36.
  2. Alexeeff, G.V., et al., Characterization of the LOAEL-to-NOAEL uncertainty factor for mild adverse effects from acute inhalation exposures. Regul Toxicol Pharmacol, 2002. 36(1): p. 96-105.
  3. OECD (2018). "Guidance document on inhalation toxicity studies series on testing and assessment No. 39 (Second Edition)."
  4. Banerjee, R.R., Interactions between hematological derivatives and dipalmitoyl phosphatidyl choline: implications for adult respiratory distress syndrome. Colloids Surf. B Biointerfaces, 2004. 34(2): p. 95-104.
  5. Gunasekara, L., et al., A comparative study of mechanisms of surfactant inhibition. Biochim. Biophys. Acta, 2008. 1778(2): p. 433-444.
  6. Gunther, A., et al., Surfactant alteration and replacement in acute respiratory distress syndrome. Respir. Res, 2001. 2(6): p. 353-364.
  7. Zuo, Y.Y., et al., Chitosan enhances the in vitro surface activity of dilute lung surfactant preparations and resists albumin-induced inactivation. Pediatr. Res, 2006. 60(2): p. 125-130.
  8. Nakos, G., et al., Bronchoalveolar lavage fluid characteristics of early intermediate and late phases of ARDS. Alterations in leukocytes, proteins, PAF and surfactant components. Intensive Care Med, 1998. 24(4): p. 296-303.

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 1672 Inhibition of lung surfactant function Inhibition of LS function.
KE 1673 Alveolar collapse Alveolar collapse
KE 1498 Loss of alveolar capillary membrane integrity Loss of alveolar capillary membrane integrity
KE 1677 Reduced tidal volume Reduced tidal volume
AO 1250 Decrease, Lung function Decreased lung function

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

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
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. More help
Term Scientific Term Evidence Link
human Homo sapiens High NCBI
mouse Mus musculus High NCBI
rat Rattus norvegicus Moderate NCBI

Sex Applicability

The sex for which the AOP is known to be applicable. More help
Sex Evidence
Mixed High

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