Organophosphates (OP) are chemical substances that are produced by the process of esterification between phosphoric acid and alcohol. Organophosphates can undergo hydrolysis with the liberation of alcohol from the esteric bond. These chemicals are the main components of herbicides, pesticides, and insecticides. OPs are also the main components of nerve gas. Acute or chronic exposure to OPs can produce varying levels of toxicity in humans, animals, plants, and insects. OPs also are widely used in the production of plastics and solvents.
From the clinical perspective, OPs are of interest because of the toxicity produced from exposure. Nerve gas and OP pesticides (OPP) are of particular importance because of the cholinergic symptoms produced from exposure.
Pioneers in the study of nerve gas include two French organic chemists, Jean Louis Lassange and Phillipe de Clermont. In the early 1930s, the German scientist Willy Lange first described the toxidromes associated with exposure to nerve gas as a choking sensation and dimming of vision. These are the cholinergic effects of exposure of the nervous system to OPs. Experiments were conducted by Gerhard Schrader to harvest the use of these substances as insecticides. The Nazis in pre-World War II Germany saw the potential use of this chemical for warfare and later produced the G series of nerve gas during World War II, specifically sarin, tabun, and soman. The British were able to synthesize the VX nerve gas, more powerful and more potent than the G series.
The postwar period witnessed the entry of the United States into the synthesis of Ops after some American companies gained access to the works of Gerhard Schrader. The OPs produced were used as insecticides, with parathion and malathion being the first OPPs to be synthesized in the US.
Nerve gas has been used from World War I to the present day a chemical warfare agent. It was used extensively in World War II and the Gulf War. The most recent use of nerve gas was in the current war in Syria in 2013.
In peacetime, the most extensive use of nerve gas was in 1994 and 1995 when Sarin was used for terrorism in Japan.
The effects of nerve gas  on the body can be profound. Nerve gas overstimulate the muscarinic and nicotinic receptors as a result of the accumulation of ACh. This can cause seizure, agitation, and at high doses respiratory arrest that is centrally induced. Peripheral overstimulation of the muscarinic and nicotinic receptors can cause a cholinergic crisis which is manifested by excessive sweating, salivation, lacrimation, blurry vision from miosis, and respiratory discomfort from bronchospasm.
The most commonly used OPPs are the following:
Another class of insecticides is carbamates which are chemically similar to OPPs. They are derivatives of carbamic acid and cause carbamylation of acetylcholine esterase (AChE) at the level of neuronal synapses. Their binding to AChE is reversible, and the duration of action is about 24 hours.
Common nerve gasses are classified into three groups:
G series – (developed by the Germans during WWII)
V series (developed by the British)
“Newcomer" (developed by the Russians in the former Soviet Union in the late 70s and early 80s)
Mechanism of Action
Loewi demonstrated in 1921 that Acetyl Choline (ACh) is a chemical that can transmit nerve impulses from one nerve to another via synapses. ACh is a neurotransmitter that is derived from acetyl coenzyme A (Acetyl COA). Acetyl COA is derived from glucose and choline by a reaction catalyzed by choline acetyltransferase (CAT). ACh is stored in the presynaptic membrane in packages called vesicles. Each package is released upon stimulation. Acetylcholine esterase (AChE) uses a hydrolytic process to break down the neurotransmitter ACh into choline and acetate thereby terminating its effect on the muscarinic and nicotinic receptors.
OPs have the ability to irreversibly bind to AChE and prevent the breakdown of Acetylcholine ACh. “Liberation” of ACh leads to overstimulation of both the muscarinic and nicotinic receptors.
Nicotinic and muscarinic receptors are widely distributed in the body.
Stimulations of each of the specific receptors will cause the following clinical signs and symptoms:
Organophosphates manifest their clinical presentation mainly on the respiratory, gastrointestinal, cardiovascular, and central nervous system
Exposure to Organophosphates
Data on exposure to nerve gas and OPPs are very limited. Most of the exposure to OPP is in rural areas where extensive use of herbicides, pesticides, and insecticides are common. Exposure might be accidental or intentional.
Exposure can be via food products such as wheat, flour, and cooking oil. Ant and roach spray might also be a potential source of exposure. Routes of exposure include the following:
Worldwide, approximately 3 million people are exposed to OPs with about 300,000 mortalities. In the United States, about 8,000 are exposed to organophosphates with very few deaths. Since 2013, there are stricter government regulations for the sale of OPs.
By the Geneva Convention of 1925, the sale of nerve gas is considered a war crime. The most recent reported cases of extensive use of nerve gas are in the ongoing conflict in Syria.
Adverse effects from exposure to OPPs can be classified based on the length of exposure.
The main effect of acute exposure to OPs is poisoning. OPP can be absorbed via the skin and integumentary system, respiratory system via inhalation, or by direct ingestion. The most rapid clinical manifestation of OPP is seen via inhalation. Chronic exposure to OP can cause the same effects as seen in acute exposure. However, in chronic exposure, there is also impairment of memory, speech loss, lack of coordination, and impaired judgment. Chronic exposure to OP can also cause flu-like symptoms like nausea, vomiting, malaise, and weakness. Peripheral polyneuropathy has been linked to chronic exposure. Exposure to some OPs has been associated with the possible development of cancer. Based on a report by the International Agency for Research on Cancer, malathion, diazinon, tetrachlorvinphos, and parathion are classified as possible carcinogens. The hallmark of exposure to either OPP or nerve gas is the ability of these substances to inhibit the action AChE, the enzyme responsible for the breakdown of ACh. OPPs bind irreversibly to AChE in the plasma, red blood cells, and at the level of the synapses in both the PNS and the CNS. The buildup of ACh leads to the overstimulation of both the nicotinic receptors and the muscarinic receptors.
The complications from exposure to nerve gas or OPP is related to each system that is affected. Overstimulation of both the nicotinic and muscarinic receptors is responsible for the clinical manifestation of these complications.
Central Nervous System
Gastrointestinal and Metabolic Systems
OPs have potential benefits as pesticides, but their use comes with risk. They also have been used as nerve agents due to their toxicity. As a result of their significant health risks, practitioners should be familiar with the signs and symptoms of toxic exposure as well as the treatment.
Exposure to organophosphates can be life-threatening. To improve patients outcome and enhance patient safety, early recognition of the toxidromes associated with organophosphate poisoning is important. Coordination and transfer of care from the Emergency Room to the Intensive Care Unit should be facilitated in a timely manner. A multidisciplinary approach with the active participation of all the health care providers is very important for the good clinical outcome. A good resource to use is the Poison Control Center.
|||Robb EL,Baker MB, Organophosphate Toxicity . 2019 Jan [PubMed PMID: 29261901]|
|||Adeyinka A,Kondamudi NP, Cholinergic Crisis . 2019 Jan [PubMed PMID: 29494040]|
|||Fatal sarin poisoning in Syria 2013: forensic verification within an international laboratory network., John H,van der Schans MJ,Koller M,Spruit HET,Worek F,Thiermann H,Noort D,, Forensic toxicology, 2018 [PubMed PMID: 29367863]|
|||Prehospital management of sarin nerve gas terrorism in urban settings: 10 years of progress after the Tokyo subway sarin attack., Tokuda Y,Kikuchi M,Takahashi O,Stein GH,, Resuscitation, 2006 Feb [PubMed PMID: 16325985]|
|||Pancreatitis as a complication of anticholinesterase insecticide intoxication., Dressel TD,Goodale RL Jr,Arneson MA,Borner JW,, Annals of surgery, 1979 Feb [PubMed PMID: 426552]|
|||Sarin (GB, O-isopropyl methylphosphonofluoridate) neurotoxicity: critical review., Abou-Donia MB,Siracuse B,Gupta N,Sobel Sokol A,, Critical reviews in toxicology, 2016 Nov [PubMed PMID: 27705071]|
|||Organophosphate poisoning., Marrs TC,, Pharmacology & therapeutics, 1993 [PubMed PMID: 8415873]|
|||Organophosphate poisoning., Rusyniak DE,Nañagas KA,, Seminars in neurology, 2004 Jun [PubMed PMID: 15257517]|
|||Acute and late complications of organophosphate poisoning., Faiz MS,Mughal S,Memon AQ,, Journal of the College of Physicians and Surgeons--Pakistan : JCPSP, 2011 May [PubMed PMID: 21575537]|
|||Muscle and neuronal nicotinic acetylcholine receptors. Structure, function and pathogenicity., Kalamida D,Poulas K,Avramopoulou V,Fostieri E,Lagoumintzis G,Lazaridis K,Sideri A,Zouridakis M,Tzartos SJ,, The FEBS journal, 2007 Aug [PubMed PMID: 17651090]|
|||Muscarinic agonists for the treatment of cognition in schizophrenia., Sellin AK,Shad M,Tamminga C,, CNS spectrums, 2008 Nov [PubMed PMID: 19037177]|
|||Muscarinic receptors: their distribution and function in body systems, and the implications for treating overactive bladder., Abrams P,Andersson KE,Buccafusco JJ,Chapple C,de Groat WC,Fryer AD,Kay G,Laties A,Nathanson NM,Pasricha PJ,Wein AJ,, British journal of pharmacology, 2006 Jul [PubMed PMID: 16751797]|
|||Organic insecticides., Peter JV,Cherian AM,, Anaesthesia and intensive care, 2000 Feb [PubMed PMID: 10701030]|
|||Neurological manifestations of organophosphorous insecticide poisoning., Wadia RS,Sadagopan C,Amin RB,Sardesai HV,, Journal of neurology, neurosurgery, and psychiatry, 1974 Jul [PubMed PMID: 4853328]|
|||Peter JV,Sudarsan TI,Moran JL, Clinical features of organophosphate poisoning: A review of different classification systems and approaches. Indian journal of critical care medicine : peer-reviewed, official publication of Indian Society of Critical Care Medicine. 2014 Nov [PubMed PMID: 25425841]|
|||Cardiac and electrocardiographical manifestations of acute organophosphate poisoning., Karki P,Ansari JA,Bhandary S,Koirala S,, Singapore medical journal, 2004 Aug [PubMed PMID: 15284933]|
|||Paul UK,Bhattacharyya AK, ECG manifestations in acute organophosphorus poisoning. Journal of the Indian Medical Association. 2012 Feb [PubMed PMID: 23029843]|
|||Jamal GA, Neurological syndromes of organophosphorus compounds. Adverse drug reactions and toxicological reviews. 1997 Aug [PubMed PMID: 9512762]|
|||Eyer P, Neuropsychopathological changes by organophosphorus compounds--a review. Human & experimental toxicology. 1995 Nov [PubMed PMID: 8588945]|
|||[PubMed PMID: 11444336]|
|||Severe acute pancreatitis caused by organophosphate poisoning., Hamaguchi M,Namera A,Tsuda N,Uejima T,Maruyama K,Kanai T,Sakata I,, Chudoku kenkyu : Chudoku Kenkyukai jun kikanshi = The Japanese journal of toxicology, 2006 Oct [PubMed PMID: 17133981]|
|||Acute renal failure due to the inhalation of organophosphates: successful treatment with haemodialysis., Rubio CR,Felipe Fernández C,Manzanedo Bueno R,Del Pozo BA,García JM,, Clinical kidney journal, 2012 Dec [PubMed PMID: 26069807]|
|||Acute renal failure from organophospate poisoning: a case of success with haemofiltration., Agostini M,Bianchin A,, Human & experimental toxicology, 2003 Mar [PubMed PMID: 12723899]|