Relationship: 433



Respiratory distress/arrest leads to Increased Mortality

Upstream event


Respiratory distress/arrest

Downstream event


Increased Mortality

Key Event Relationship Overview


AOPs Referencing Relationship


AOP Name Adjacency Weight of Evidence Quantitative Understanding
Acetylcholinesterase inhibition leading to acute mortality adjacent High Low

Taxonomic Applicability


Sex Applicability


Life Stage Applicability


Key Event Relationship Description


In cases of lethal cholinergic poisoning, mortality results from asphyxiation due to respiratory failure.

Evidence Supporting this KER


Biological Plausibility


  • A functioning respiratory system is essential for delivering oxygen to organ tissues throughout an organism. Thus, mortality results following respiratory failure.

Empirical Evidence


  • In a study of suicidal ingestion of organophosphorus insecticides 15 out of 36 people died from respiratory paralysis, in spite of receiving ventilation support in the form of artificial respiration. (Wadia 1974)

  • In Sri Lanken cohort study, 376 patients with confirmed organophosphate poisoning were observed during the duration of their admission at 3 hospitals. 24% of patients in the study required intubation and half of the intubated patients died (Eddleston 2007). 

  • A study in a rodent model of dichlorvos poisoning, found that poisoning caused a rapid lethal central apnea, followed by delayed impairment of pulmonary gas exchange with prominent airway secretions (Gaspari 2007 in Peter 2014).

  • A study of OP exposure in cats, dogs, rabbits, monkeys, sheep, goats, mice, rats, and guinea pigs found asphyxiation to be the cause of death (Candole 1953).

  • A study of cats exposed to the nerve agents, soman, sarin, tabun, and VX, concluded that central respiratory drive was the dominant cause of respiratory failure. Nerve agents were infused up until respiratory arrest, when the phrenic nerve was stimulated to test diaphragmatic contraction. Immediately following cessation of spontaneous respiration, stimulation at 100 Hz produced a tetanic contraction of the diaphragm (Rickett 1986).

  • Reduced oxygen utilization leads to mortality in trout (McKim, 1987) 

  • An acute (24-h) exposure of fingerling rainbow trout to acephate found a dose-dependent relationship between inhibition of AChE, respiratory activity, and mortality.  The LC50 values ranged from 1880-3160 mg/L, with 76-89% inhibition of AChE in dead fish (at a concentration of 950-4000 mg/L), and significant increase in respiration rates at a concentration of 2,000 mg/L (Duangsawasdi 1977, 1979). 

  • In an acute exposure of Labeo rohita to malathion the fish were observed to be gulping air at the surface and a significant respiration rate/oxygen consumption rate, resulting in fish sinking to the bottom of the test vessels having little to no opercular movements followed by death (Patil 2008).  

  • Birds die from respiratory distress after continued cholinergic stimulation exhausts the respiratory muscles. (Blackwell's Five-Minute Veterinary Consult: Avian)

  • Male quail (8-14 weeks old) exposed to a single dose of either dichlorvos or fenitrothion via subcutaneous injection at four treatment levels resulted in an 80% reduction of brain AChE, and a concurrent significant increase in acetylcholine as compared to controls, with mortality preceded by respiratory distress (Kobayashi 1983).

Uncertainties and Inconsistencies


  • No known qualitative inconsistencies or uncertainties associated with this relationship.

Quantitative Understanding of the Linkage


  • We are unaware of any correlative relationships of significant predictive value with regard to this KER.

Response-response Relationship




Known modulating factors


Known Feedforward/Feedback loops influencing this KER


Domain of Applicability




  • Carey JL, Dunn C, Gaspari RJ., Central respiratory failure during acute organophosphate poisoning. Respir Physiol Neurobiol. 2013 Nov 1;189(2):403-10.

  • Duangsawasdi M. 1977. Organophosphate insecticide toxicity in rainbow trout (Salmo gairdneri). Effects of temperature and investigations on the sites of action. PhD thesis. University of Manitoba, Manitoba, Canada.

  • Duangsawasdi M, Klaverkamp JF. 1979. Acephate and fenitrothion toxicity in rainbow trout: Effects of temperature stress and investigations on the sites of action. In Aquatic Toxicology, Vol 2, STP 667. ASTM International, Philadelphia, PA, USA, pp 35–51.

  • Eddleston M, Mohamed F, Davies JO, Eyer P, Worek F, Sheriff MH, Buckley NA. 2006. Respiratory failure in acute organophosphorus pesticide self-poisoning. QJM. 99(8):513-22. 

  • McKim, J.M., Schmieder, P.K., Niemi, G.J., Carlson, R.W., Henry, T.R. 1987. Use of respiratory‐cardiovascular responses of rainbow trout (Salmo gairdneri) in identifying acute toxicity syndromes in fish: Part 2. Malathion, carbaryl, acrolein, and benzaldehyde. Environ Toxicol Chem 6:313–328.

  • Gaspari, R.J., Paydarfar, D. 2007. Pathophysiology of respiratory failure following acute dichlorvos poisoning in a rodent model. Neurotoxicology. 28(3): 664-71.

  • Kobayashi H, Yuyama A, Kudo M, Matsusaka N. 1983. Effects of organophosphorus compounds, O,O‐dimethyl‐o‐(2,2‐dichlorovinyl)phosphate (DDVP) and O,O‐dimethyl‐o‐(3‐methyl 4‐nitrophenyl)phosphorothioate (fenitrothion), on brain acetylcholine content and acetylcholinesterase activity in Japanese quail. Toxicology 28:219–227.

  • Peter, J.V., Sudarsan, T.I. and Moran, J.L. 2014. Clinical features of organophosphate poisoning: A review of different classification systems and approaches. Indian J Crit Care Med. 18(11): 735–745.

  • Rickett, D.L., Glenn, J.F., Beers, E.T. 1986. Central respiratory effects versus neuromuscular actions of nerve agents. Neurotoxicology. 7(1): 225-36.

  • Wadia, R. S., Sadagopan, C., Amin, R. B., and Sardesai, H.V. 1974. Neurological manifestations of organophosphorus insecticide poisoning. J Neurol Neurosurg Psychiatry. 37(7): 841–847.

  • 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.