VX (nerve agent)

VX is an extremely toxic synthetic chemical compound in the organophosphorus class, specifically, a thiophosphonate. In the class of nerve agents, it was developed for military use in chemical warfare after translation of earlier discoveries of organophosphate toxicity in pesticide research. In its pure form, VX is an oily, relatively non-volatile liquid that is amber-like in colour. Because of its low volatility, VX persists in environments where it is dispersed.
The substance is extremely deadly: VX fatalities occur with exposure to tens of milligram quantities via inhalation or absorption through skin. It is more potent than sarin, another nerve agent with a similar mechanism of action. On such exposure, these agents severely disrupt the body's signaling between the nervous and muscular systems, leading to a prolonged neuromuscular blockade, flaccid paralysis of all the muscles in the body including the diaphragm, and death by asphyxiation.
VX, short for "venomous agent X", is one of the best known of the V nerve agents and originated from pesticide development work at Imperial Chemical Industries. It was developed further at Porton Down in England during the early 1950s, based on research first done by Gerhard Schrader, a chemist working for IG Farben in Germany during the 1930s. It is now one of a broader V-series of agents which are classified as nerve agents. VX has been allegedly used in warfare and has been used in several assassinations.
As it is dangerous due to its persistence rather than as a vapor hazard, VX is considered an area denial weapon. As a chemical weapon, it is categorized as a weapon of mass destruction by the United Nations and is banned by the Chemical Weapons Convention of 1993, where production and stockpiling of VX exceeding per year is outlawed. The only exception is for "research, medical or pharmaceutical purposes outside a single small-scale facility in aggregate quantities not exceeding per year per facility".
During the Cold War, the United States chemical weapons program concentrated on large-scale VX production, producing at least 4,400 tons, alongside sarin and mustard gas. The Soviet chemical weapons program declared production of 15,557 tons of the similar VR nerve agent, also called "Russian VX". There are unconfirmed reports VX was used by Cuban forces in the Angolan Civil War, and by Iraqi forces in the Iran–Iraq War. The first confirmed attacks and killing using VX were strings of assassination attempts by Aum Shinrikyo, a Japanese doomsday cult, in 1994 and 1995. Three men were hospitalized and one died four days later. On February 13, 2017, Kim Jong Nam, was assassinated in Kuala Lumpur International Airport, widely believed to ordered by his brother, North Korean leader Kim Jong Un. He died within 15 minutes of exposure.

Physical properties

VX is an odorless and tasteless chiral organophosphorous chemical with a molecular weight of 267.37 g/mol. Under standard conditions it is an amber-coloured liquid with a boiling point of, and a freezing point of. Its density is similar to that of water. It has a log P value of 2.047, meaning it is relatively hydrophobic with about 100-fold more partitioning into octanol, over water. Its low vapor pressure of gives it a low volatility, resulting in a high persistence in the environment.
When weaponized, it can be dispersed as a liquid, aerosol or as a mixture with a clay or talc thickening agent.

Mechanism of action

VX is an acetylcholinesterase inhibitor.
It blocks the function of the enzyme acetylcholinesterase. Normally, when a motor neuron is stimulated, it releases the neurotransmitter acetylcholine into the space between the neuron and an adjacent muscle cell, the synaptic cleft. When acetylcholine binds to nicotinic receptors at the neuromuscular junction, it stimulates muscle contraction. To avoid a state of constant muscle contraction, the acetylcholine is then broken down into the inactive substances acetic acid and choline by AChE. VX blocks the action of AChE, resulting in an accumulation of acetylcholine in the space between the neuron and muscle cell. On a molecular level, this leads to the ongoing stimulation and eventual fatigue of all affected muscarinic and nicotinic ACh receptors. This results in initial violent contractions, followed by sustained supercontraction restricted to the fluid of the subjunctional endplate and prolonged, depolarizing neuromuscular blockade. The prolonged blockade results in flaccid paralysis of all the muscles in the body, and it is such sustained paralysis of the diaphragm muscle that causes death by asphyxiation.
Accumulation of acetylcholine in the brain also causes neuronal excitotoxicity, due to activation of nicotinic receptors and glutamate release.
The extreme toxicity of VX is partly due to the fact that the inhibitor was designed to be an excellent structural mimic for the transition state of the natural substrate of acetylcholinesterase. VX has a very high "on-rate" to react with the target enzyme and form a stable P-O-C bond. However, compared with other highly toxic nerve agents like soman or sarin, VX undergoes relatively slow "aging". Aging is a time-dependent side reaction that occurs on nerve agents after phosphorylation and renders the nerve agent-acetylcholinesterase complex highly resistant to regeneration by any known antidote. Slower aging by VX suggests it should be possible to develop more effective antidotes and treatments.
The reaction products of acetylcholinesterase with VX before and after the "aging" reaction were solved in near atomic resolution by X-ray crystallography to aid in antidote development. The X-ray structures revealed the specific parts of the VX molecule that interact with key residues and sub-sites of the target enzyme. The structural kinetic of phosphorylation followed by aging also showed an unexpected conformational change in the catalytic triad suggestive of an "induced fit" between the VX molecule and acetylcholinesterase.

Chemistry

Synthesis

VX is chiral at its phosphorus atom. The individual enantiomers are identified as S_P--VX, and R_P--VX.
VX is produced via the transester process, which gives a racemic mixture of the two enantiomers. This entails a series of steps whereby phosphorus trichloride is methylated to produce methyl phosphonous dichloride. The resulting material is reacted with ethanol to form a diester. This is then transesterified with N,''N''-diisopropylaminoethanol to produce QL,
a mixed phosphonite. Finally, this immediate precursor is reacted with sulfur to form VX.
VX can also be delivered in binary chemical weapons which mix in-flight to form the agent prior to release. Binary VX is referred to as VX2, and is created by mixing QL with sulfur as is done in the Bigeye aerial chemical bomb. It may also be produced by mixing with sulfur compounds, as with the liquid dimethyl polysulfide mixture in the canceled XM736 8-inch projectile program.

Solvolysis

Like other organophosphorus nerve agents, VX may be destroyed by reaction with strong nucleophiles. The reaction of VX with concentrated aqueous sodium hydroxide results in two competing solvolysis reactions: cleavage of either the P–O or P–S esters. Although the P–S cleavage is the dominant pathway, the product of P–O bond cleavage is the toxic phosphonic thioester EA-2192 and both reactions are slow. In contrast, reaction with the hydroperoxide anion leads to exclusive cleavage of the P–S bond and a more rapid overall reaction.

Symptoms of exposure

Early symptoms of skin contact include local sweating and muscular twitching at the area of exposure, followed by nausea or vomiting. Early symptoms of exposure to VX vapor include rhinorrhea and tightness in the chest with shortness of breath. Miosis may be an early sign of agent exposure but is not usually used as the only indicator of exposure.

Toxicology

VX is extremely toxic. The potentially fatal dose is only slightly higher than the dose having any effect at all, and the effects of a fatal dose are so rapid that there is little time for treatment. The median lethal dose, the exposure required to kill half of a tested population, as estimated for 70 kg human males via exposure to the skin is reported to be 5 to 10 mg.

Treatment

When treating VX exposure, primary consideration is given to removal of the liquid agent from the skin, before removal of the individual to an uncontaminated area or atmosphere. After this, the victim is decontaminated by washing the contaminated areas with household bleach and flushing with clean water, followed by removal of contaminated clothing and further skin decontamination. When possible, decontamination is completed before the casualty is taken for further medical treatment.
An individual known to have been exposed to a nerve agent, or who exhibits definite signs or symptoms of nerve-agent exposure is generally given the antidotes atropine and pralidoxime, and in the case of convulsions an injected sedative or antiepileptic such as diazepam. In several nations the nerve agent antidotes are issued for military personnel in the form of an autoinjector such as the United States military Mark I NAAK.
Atropine blocks a subset of acetylcholine receptors known as muscarinic acetylcholine receptors, so that the buildup of acetylcholine produced by loss of the acetylcholinesterase function has a reduced effect on their target receptor. 2-PAM reactivates the acetylcholinesterase enzyme, thus reversing the effects of VX. VX and other organophosphates block AChE activity by binding to and covalently inactivating the enzyme via transfer of the phosphonate moiety from VX to the active site of AChE; this inactivates AChE and produces an inactive by-product from the remaining portion of the VX molecule. Pralidoxime removes this phosphate group.