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Event: 445

Key Event Title

The KE title should describe a discrete biological change that can be measured. It should generally define the biological object or process being measured and whether it is increased, decreased, or otherwise definably altered relative to a control state. For example “enzyme activity, decreased”, “hormone concentration, increased”, or “growth rate, decreased”, where the specific enzyme or hormone being measured is defined. More help

Respiratory distress/arrest

Short name
The KE short name should be a reasonable abbreviation of the KE title and is used in labelling this object throughout the AOP-Wiki. The short name should be less than 80 characters in length. More help
Respiratory distress/arrest

Biological Context

Structured terms, selected from a drop-down menu, are used to identify the level of biological organization for each KE. Note, KEs should be defined within a particular level of biological organization. Only KERs should be used to transition from one level of organization to another. Selection of the level of biological organization defines which structured terms will be available to select when defining the Event Components (below). More help

Organ term

Further information on Event Components and Biological Context may be viewed on the attached pdf.The biological context describes the location/biological environment in which the event takes place.  For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable.  For individual/population events, the organ context is not applicable. More help
Organ term
respiration organ

Key Event Components

Further information on Event Components and Biological Context may be viewed on the attached pdf.Because one of the aims of the AOP-KB is to facilitate de facto construction of AOP networks through the use of shared KE and KER elements, authors are also asked to define their KEs using a set of structured ontology terms (Event Components). In the absence of structured terms, the same KE can readily be defined using a number of synonymous titles (read by a computer as character strings). In order to make these synonymous KEs more machine-readable, KEs should also be defined by one or more “event components” consisting of a biological process, object, and action with each term originating from one of 22 biological ontologies (Ives, et al., 2017; See List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling). The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signalling by that receptor).Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description. To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons. If a desired term does not exist, a new term request may be made via Term Requests. Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add. More help
Process Object Action
respiratory distress increased

Key Event Overview

AOPs Including This Key Event

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE. Clicking on the name of the AOP will bring you to the individual page for that AOP. More help
AOP Name Role of event in AOP Point of Contact Author Status OECD Status
AChE inhibition - acute mortality KeyEvent Cataia Ives (send email) Under Development: Contributions and Comments Welcome Under Development
sodium channel inhibition 3 KeyEvent Cataia Ives (send email) Under Development: Contributions and Comments Welcome


This is a structured field used to identify specific agents (generally chemicals) that can trigger the KE. Stressors identified in this field will be linked to the KE in a machine-readable manner, such that, for example, a stressor search would identify this as an event the stressor can trigger. NOTE: intermediate or downstream KEs in one AOP may function as MIEs in other AOPs, meaning that stressor information may be added to the KE description, even if it is a downstream KE in the pathway currently under development.Information concerning the stressors that may trigger an MIE can be defined using a combination of structured and unstructured (free-text) fields. For example, structured fields may be used to indicate specific chemicals for which there is evidence of an interaction relevant to this MIE. By linking the KE description to a structured chemical name, it will be increasingly possible to link the MIE to other sources of chemical data and information, enhancing searchability and inter-operability among different data-sources and knowledgebases. The free-text section “Evidence for perturbation of this MIE by stressor” can be used both to identify the supporting evidence for specific stressors triggering the MIE as well as to define broad chemical categories or other properties that classify the stressors able to trigger the MIE for which specific structured terms may not exist. More help

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) can be selected from an ontology. 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

Life Stages

The structured ontology terms for life-stage are more comprehensive than those for taxa, but may still require further description/development and explanation in the free text section. More help

Sex Applicability

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

Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. For example, the biological state being measured could be the activity of an enzyme, the expression of a gene or abundance of an mRNA transcript, the concentration of a hormone or protein, neuronal activity, heart rate, etc. The biological compartment may be a particular cell type, tissue, organ, fluid (e.g., plasma, cerebrospinal fluid), etc. The role in the biology could describe the reaction that an enzyme catalyses and the role of that reaction within a given metabolic pathway; the protein that a gene or mRNA transcript codes for and the function of that protein; the function of a hormone in a given target tissue, physiological function of an organ, etc. Careful attention should be taken to avoid reference to other KEs, KERs or AOPs. Only describe this KE as a single isolated measurable event/state. This will ensure that the KE is modular and can be used by other AOPs, thereby facilitating construction of AOP networks. More help
  • Acute respiratory failure describes the inability of the lungs to exchange gas effectively and to maintain a normal acid-base balance as a result of failure of the respiratory system anywhere from the medullary respiratory controllers to the chest bellows and the lungs, including the upper airways (Chokroverty 2011 in Carey 2013). Respiratory failure is a multi-factorial process; including a direct depressant effect on the respiratory center in the brainstem, constriction of and increased airway secretions, and paralysis of respiratory muscles ((Bartholomew et al., 1985; Rickett et al., 1986) in Carey 2013). 

  • Respiratory failure can occur from local muscarinic effects (bronchoconstriction, bronchorrhea, pulmonary edema), central depression of the respiratory center, or flaccid paralysis through depolarization of respiratory muscles (Hulse 2014).

  • Other pulmonary complications commonly seen during acute cholinergic syndrome include local airway effects, alveolar fluid and bronchorrhea, acute respiratory distress syndrome (ARDS), central nervous system effects, and neuromuscular junction effects (Hulse 2014).

  • Respiratory distress is characterized symptomatically through gasping and difficulty breathing.

How It Is Measured or Detected

One of the primary considerations in evaluating AOPs is the relevance and reliability of the methods with which the KEs can be measured. The aim of this section of the KE description is not to provide detailed protocols, but rather to capture, in a sentence or two, per method, the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements. Methods that can be used to detect or measure the biological state represented in the KE should be briefly described and/or cited. These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA).Key considerations regarding scientific confidence in the measurement approach include whether the assay is fit for purpose, whether it provides a direct or indirect measure of the biological state in question, whether it is repeatable and reproducible, and the extent to which it is accepted in the scientific and/or regulatory community. Information can be obtained from the OECD Test Guidelines website and the EURL ECVAM Database Service on Alternative Methods to Animal Experimentation (DB-ALM). ?
  • In humans, spirometry is used to measure lung function. The ratio of volume of air expired in one second (FEV1) to forced vital capacity (FVC) should be close to 80%. A decreased FEV 1/FVC is indicative of impaired ventilation. Other common pulmonary function tests include airway resistance and measurements of maximal flow rate, diffusion capacity, and oxygen and carbon dioxide content of arterial and venous blood. Blood gas analysis measures the arterial partial pressure of oxygen and carbon dioxide to determine gas exchange (Leikauf). 

  • In animals, common pulmonary function measurements include tests of lung compliance and airway resistance. The lung is deflated and then inflated with incremental volumes and pressure is recorded; the lung is then deflated with incremental volumes and again recorded. Compliance is calculated as the slope of the volume-pressure curve, and indicates the properties of the lung parenchyma. Airway resistance, a measure of bronchoconstriction, can be measured by plethysmography (Leikauf).

  • Measurements of cardio-respiratory function in fish exposed to aqueous solutions of toxic chemicals may be conducted in respirometer metabolism chambers. Anesthetized fish are immobilized by spinal transection, and inserted with a urine catheter, dorsal aortic cannula, electrodes, and attachment of an oral membrane. Predose measurements are taken before chemical exposure. Fish are monitored for 24 to 48 hours, and measurements taken every 2 hours. Ventilation rate (VR) and cough response (CR) are determined using freestanding stainless steel electrodes. Ventilation volume (V), oxygen consumption (VO), and oxygen utilization (U) may be obtained using dissolved oxygen (DO) concentrations in inspired and expired water from the chambers (McKim 1987).

  • In humans, bronchoconstriction is characterized by coughing, wheezing, rapid shallow breathing, a sensation of chest tightness, substernal pain, and dyspnea. Airway hyperreactivity, a lowered threshold dose of a toxicant needed to induce bronchoconstriction,  is tested by measuring airway resistance following inhalation of increasing doses of a metacholine aerosol (Leikauf).

  • In animals, pulmonary edema is measured by lung wet weight: dry weight ratio. Lung water content, expressed as the wet (undessicated) weight of the whole lung or that of a single lobe, is normalized to the weight of the lung or the animal after dessication. Pulmonary edema can also be detected by pulmonary lavage, in which the fluid lining the pulmonary epithelium is recovered and analyzed for signs of inflammation or damage (Leikauf).

  • In animals, inhalation studies are used to expose an organism within a chamber to a toxicant at a concentration for a period of time (Leikauf).

  • Morphological techniques include gross and histological examination of the nasal passages, larynx, bronchi, and parenchyma for inflammation or structural damage (Leikauf).

  • In vitro tests such as isolated perfused lung, airway microdissection, and lung tissue culture (Leikauf).

Domain of Applicability

This free text section should be used to elaborate on the scientific basis for the indicated domains of applicability and the WoE calls (if provided). While structured terms may be selected to define the taxonomic, life stage and sex applicability (see structured applicability terms, above) of the KE, the structured terms may not adequately reflect or capture the overall biological applicability domain (particularly with regard to taxa). Likewise, the structured terms do not provide an explanation or rationale for the selection. The free-text section on evidence for taxonomic, life stage, and sex applicability can be used to elaborate on why the specific structured terms were selected, and provide supporting references and background information.  More help
  • This key event is thought to be applicable to terrestrial, air-breathing organisms. The relevance of this event to fish or other animals without lungs is questionable.

  • Central respiratory depression is the predominant mechanism causing death in humans; in other animals, the predominant mechanism varies by species. Nonhuman primates dosed with lethal sarin and soman vapor experienced apnea, hypoxia, and phrenic nerve signal failure within 5 minutes. Diaphragmatic NMJ function was 70 to 80% of normal, indicating the predominance of central effects at the time of arrest (Hulse 2014).

  • Monkeys have a respiratory system that most closely resembles that of humans. Rats and mice are commonly used, but display differences in respiratory anatomy and function that may complicate extrapolation to humans (Leikauf).

  • A study of respiratory failure in multiple species - mouse, rat, guinea-pig, rabbit, cat, dog, monkey, sheep, and goat - exposed to anticholinergic drugs, found that impaired respiration in animals treated with AChE inhibiting drugs with specific effects dependent on species, drug used, and administered dose (De Candole, 1953).


List of the literature that was cited for this KE description. Ideally, the list of references, should conform, to the extent possible, with the OECD Style Guide ( (OECD, 2015). More help
  • Carey, J.L., Dunn, C., Gaspari, R.J. 2013. Central respiratory failure during acute organophosphate poisoning. Respiratory Physiology & Neurobiology. 189(2), 403-410.

  • Chokrovetry, S. 2011. Chapter 64- Sleep and breathing in neuromuscular disorders. Handbook of Clinical Neurology. 99, 1087-1108.

  • De Candole, C.A., Douglas, W.W., Evans, C.L., Holmes, R., Spencer, K.E., Torrance, R.W., Wilson, K.M. 1953. The failure of respiration in death by anticholinesterase poisoning. Br J Pharmacol Chemother. 8(4):466-75.

  • Leikauf, G.D. Toxic responses of the Respiratory System.  In Casarett and Doull's Toxicology: The Basic Science of Poisons. 9th ed. pp 793-837.

  • Hulse, E.J., Davies, J.O., John Simpson, A., Sciuto, A.M., Eddleston, M. 2013. Respiratory Complications of Organophosphorus Nerve Agent and Insecticide Poisoning. Implications for Respiratory and Critical Care. American Journal of Respiratory and Critical Care Medicine. 190(12).

  • McKim, J.M., Schmieder, P.K., Carlson, R.W., Hunt, E.P. (1987). Use of respiratory-cardiovascular responses of rainbow trout (Salmo gairdneri) in identifying acute toxicity syndromes in fish: Part 1. Pentachlorophenol, 2,4-dinitrophenol, tricaine methanesulfonate and 1-octanol. Environmental Toxicology and Chemistry, Vol. 6, 295-312.