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Aop: 302

AOP Title

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Lung surfactant function disruption leading to acute inhalation toxicity

Short name:

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Lung surfactant function disruption leading to acute inhalation toxicity

Graphical Representation

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Authors

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Point of Contact

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Jorid Birkelund Sørli   (email point of contact)

Contributors

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  • Jorid Birkelund Sørli

Status

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Author status OECD status OECD project SAAOP status
Under development: Not open for comment. Do not cite


This AOP was last modified on July 12, 2019 07:48

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Revision dates for related pages

Page Revision Date/Time
Substance - lung surfactant interaction July 03, 2019 13:15
Disruption of lung surfactant function July 03, 2019 13:16
Alveolar collapse July 03, 2019 13:16
Alveolar reopening July 03, 2019 13:17
Loss of barrier function July 03, 2019 13:18
Blood extravasation into the lungs July 03, 2019 13:19
Reduced lung volume July 03, 2019 13:19
Impaired oxygenation of the blood July 03, 2019 13:20
Acute inhalation toxicity July 03, 2019 13:20
Substance - LS interaction leads to Disruption of LS function. July 03, 2019 13:21
Alveolar collapse leads to Reduced lung volume July 03, 2019 13:24
Disruption of LS function. leads to Alveolar collapse July 03, 2019 13:21
Alveolar collapse leads to Alveolar reopening July 03, 2019 13:22
Alveolar reopening leads to Loss of barrier function July 03, 2019 13:22
Loss of barrier function leads to Blood extravasation into the lungs July 03, 2019 13:23
Blood extravasation into the lungs leads to Acute inhalation toxicity July 03, 2019 13:23
Reduced lung volume leads to Impaired oxygenation of the blood July 03, 2019 13:24
Impaired oxygenation of the blood leads to Acute inhalation toxicity July 03, 2019 13:25

Abstract

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Inhalation of substances, chemicals, particles and mixtures is the main route of occupational exposure. This adverse outcome pathway (AOP) describes the connections between the interaction of substances with the lung surfactant layer lining the respiratory parts of the lungs, and how this is connected to acute inhalation toxicity. 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 [1]. This AOP describes one of the triggers that can lead to acute inhalation toxicity. Acute lung toxicity in humans is characterized by symptoms such as coughing, difficult breathing, tightness in the chest, fever and vomiting (AO) [2, 3].

 

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 (MIE) and disrupt the lung surfactant function (KE1). Disruption leads to an increase in minimum surface tension and alveolar collapse (KE2), 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 lung volume (KE6), reducing the area for gas exchange in the lungs and reduces blood oxygenation (KE7). If the alveolus reopens (KE3), this can lead to loss of barrier function due to shear stress on the epithelium (KE4) and bleeding into the lungs (KE5). Blood components (such as albumin and fibrin) reaching the air-liquid interface will further disrupt lung surfactant function (KE1) [4-7] leading to the exacerbation of the process. The combination of bleeding into the lungs and impaired oxygenation due to collapsed alveoli leads to acute inhalation toxicity. KER 1-2 (KER1) can be examined in vitro by measuring the effect of a substance or mixture of substances on the lung surfactant function assay. The effects of blood entering the lung and further inhibiting lung surfactant function KER 1-5 (KER6) can likewise be studied in the in vitro assay. Reduced lung volume caused by alveolar collapse KER 2-6 (KER7) can be measured in vivo, using experimental animals in whole body plethysmographs that are exposed to the substance in question, while monitoring respiration parameters. Reduced oxygenation as a result of reduced lung volume KER 6-7 (KER8) can be measured by analysing the oxygenation of the blood both from experimental animals, and patients that have inhaled substances leading to acute lung injury. The loss of barrier function due to shear stress during alveoli reopening KER 3-4 (KER4) can be measured in vitro in cell cultures of epithelial lung cells. The trans-epithelial electrical resistance (TEER) across the cultured cells can be measured during the course of substance exposure [8]. It can also 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 [9].   

Acute inhalation toxicity is observed frequently in humans [2]. Similar symptoms are seen in experimental animals [3]. Lung surfactant function impairment in vitro has been strongly associated with induction of acute inhalation toxicity and acute lung injury both in humans and in experimental animals [2].

In addition to lung surfactant function impairment, there are several other pathways leading to acute inhalation toxicity, 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 acute lung injury can have long term effects on the lungs, such as development of fibrosis (AOP 173) or asthma and COPD (AOP 196 and AOP 148).

 

1.         OECD, Acute Inhalation Toxicity Guideline 403. 1981.

2.         Sørli, J.B., et al., Prediction of acute inhalation toxicity using in vitro lung surfactant inhibition. ALTEX, 2017. 35(1): p. 26-36.

3.         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.

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.         Balogh Sivars, K., et al., A 3D Human Airway Model Enables Prediction of Respiratory Toxicity of Inhaled Drugs In Vitro. Toxicol Sci, 2018. 162(1): p. 301-308.

9.         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.


Background (optional)

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Summary of the AOP

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Events: Molecular Initiating Events (MIE)

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Key Events (KE)

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Adverse Outcomes (AO)

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Sequence Type Event ID Title Short name
MIE 1671 Substance - lung surfactant interaction Substance - LS interaction
KE 1672 Disruption of lung surfactant function Disruption of LS function.
KE 1673 Alveolar collapse Alveolar collapse
KE 1674 Alveolar reopening Alveolar reopening
KE 1675 Loss of barrier function Loss of barrier function
KE 1676 Blood extravasation into the lungs Blood extravasation into the lungs
KE 1677 Reduced lung volume Reduced lung volume
KE 1678 Impaired oxygenation of the blood Impaired oxygenation of the blood
AO 1679 Acute inhalation toxicity Acute inhalation toxicity

Relationships Between Two Key Events
(Including MIEs and AOs)

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Title Adjacency Evidence Quantitative Understanding
Substance - LS interaction leads to Disruption of LS function. adjacent High Moderate
Disruption of LS function. leads to Alveolar collapse adjacent High Moderate
Alveolar collapse leads to Alveolar reopening adjacent High Moderate
Alveolar reopening leads to Loss of barrier function adjacent Moderate Moderate
Loss of barrier function leads to Blood extravasation into the lungs adjacent Moderate Moderate
Blood extravasation into the lungs leads to Acute inhalation toxicity adjacent Moderate Low
Reduced lung volume leads to Impaired oxygenation of the blood adjacent Moderate Moderate
Impaired oxygenation of the blood leads to Acute inhalation toxicity adjacent Low Low
Alveolar collapse leads to Reduced lung volume non-adjacent Moderate Moderate

Network View

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Overall Assessment of the AOP

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Domain of Applicability

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Essentiality of the Key Events

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Evidence Assessment

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Quantitative Understanding

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Considerations for Potential Applications of the AOP (optional)

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References

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