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Key Event Title
Key Event Components
Key Event Overview
AOPs Including This Key Event
|AOP Name||Role of event in AOP||Point of Contact||Author Status||OECD Status|
|AChE inhibition - acute mortality||KeyEvent||Dan Villeneuve (send email)||Under Development: Contributions and Comments Welcome||Under Development|
|sodium channel inhibition 3||KeyEvent||Kellie Fay (send email)||Under Development: Contributions and Comments Welcome|
Key Event Description
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
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 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).
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.