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[1][2].

Nerve Gas

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[3][4].

In peacetime, the most extensive use of nerve gas was in 1994 and 1995 when Sarin was used for terrorism in Japan[4].

The effects of nerve gas [5] 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[6].

Chronic exposure to nerve gas like Sarin can lead to the following neuroendocrine manifestations[7][8][9]:

• Delayed neurotoxicity
• Chronic neurotoxicity
• Endocrine disruption

Pesticides

The most commonly used OPPs are the following:

1. Parathion
2. Chlorpyrifos   
3. Diazinon
4. Dichlorvos 
5. Phosmet 
6. Fenitrothion
7. Tetrachlorvinphos
8. Azamethiphos
9. Azinphos-Methyl
10. Malathion
11. Methyl Parathion

Carbamates

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.

Nerve Gas

Common nerve gasses are classified into three groups:

G series –  (developed by the Germans during WWII)

• Sarin
• Soman
• Tabun

V series (developed by the British)

• VE
• VG
• VM
• VR
• VM
• VX

Novick

“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[8].

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.

Nicotinic Receptors

• Nicotinic receptors are of two types: Central and peripheral
• Central nicotinic receptors Nn or N2 are located in the central nervous system (CNS). They can also be found in the sympathetic, parasympathetic ganglia of the peripheral nervous system (PNS) and the adrenal medulla
• Peripheral nicotinic receptors Nm or NI are located at the level of the neuromuscular junctions

Muscarinic Receptors

• All five subtypes of muscarinic receptors (M1-M5) are present in the CNS.
• The postganglionic peripheral muscarinic receptors provide parasympathetic innervation to the heart, exocrine glands, and the smooth muscles of the internal organs. Innervation of the sweat gland is via the sympathetic postganglionic fibers[10][11].

Stimulations of each of the specific receptors will cause the following clinical signs and symptoms[12]:

Nicotinic receptors

• N1 Neuromuscular junction - Fasciculation and muscular weakness
• N2 Autonomous nervous system - Hypertension and tachycardia

Muscarinic receptors

• M2 Heart - Hypotension bradycardia
• M2, M3 Eyes - Miosis
• M2, M3 Gastrointestinal system - Abdominal cramps, drooling, salivation
• M2, M3 Respiratory system - Bronchospasm, bronchorrhea, rhinorrhea
• M2, M3 Smooth muscle of internal organ - Abdominal cramps, urinary urgency
• M1, M2, M3, M4, M5 Central Nervous System - Seziure, anxiety, agitation

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:

• Inhalation
• Direct contact
• Ingestion

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

Adverse effects from exposure to OPPs can be classified based on the length of exposure.

• Acute - Occurs within minutes to 24 hours
• Subacute- Occurs between 24 hours and 2 weeks
• Chronic - Exposure beyond weeks to years

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[13][14].

Complications

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[15].

 Respiratory System

• Aspiration pneumonia from excessive salivation
• Progressive respiratory failure from respiratory muscle weakness, especially diaphragmatic muscle
• Severe bronchospasm
• Noncardiogenic pulmonary edema[14]

Cardiovascular System

• Arrhythmias, especially ventricular tachycardia
• Bradycardia
• Hypertension
• Hypotension
• Prolonged QTc[16][17]

Central Nervous System

• Psychosis
• Seizure
• Change in mental status
• Hallucination[18][19]

Gastrointestinal and Metabolic Systems 

• Electrolyte abnormalities from fluid and electrolyte losses from the gastrointestinal tract[20]
• Pancreatitis
• Hyperglycemia
• Low bicarbonate [5][21]  

Renal System

• Acute kidney injury[22]
• There are few case reports of acute kidney injury associated with exposure to OPPs. Treatment is usually conservative management or hemodialysis.[23][22]

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.