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A Tale of Two Poisons

Updated: Aug 19, 2019



Author: Jonathan Kuo


Imagine you’re walking through an airport. While walking toward your terminal, you stumble into a nondescript woman, who accidentally spills part of her drink on your torso. You quickly excuse yourself and rush to your terminal, which is boarding its final passengers. You’re a bit out of breath at this point and feel a tad nauseous, but you figure it's just from the stress of working for the past few days and from the fact that you rarely exercise anyway. Minutes later, as you’re settling into your seat, you begin feeling nauseous. You puke, you find it increasingly difficult to breathe, and you eventually die from apnea, or cessation of breathing.


Although this scenario may seem reminiscent of an action movie, a similar event occurred this February when Kim Jong-un’s half-brother Kim Jong-nam was assassinated at Kuala Lumpur International Airport in Malaysia. According to the BBC, Kim was attacked by two young women, one who splashed a liquid on his face, and one who covered Kim’s face with a cloth laced with liquid. After alerting the receptionist at the airport of his distress, he was quickly rushed to the hospital, but died from a seizure en route. An autopsy revealed that the nerve agent VX was involved in his death [1].


VX is one of those nasty chemicals that governments outlaw and chemists refuse to work with. Synthesized by British scientist Dr. Ranajit Ghosh in 1952 when he was searching for an alternative pesticide to the organochloride DDT (dichlorodiphenyltrichloroethane), VX belongs to a similar class of compounds called organophosphates. Organophosphates are deadly because they inhibit an enzyme called acetylcholinesterase (AChE), which helps break down the neurotransmitter acetylcholine during synaptic transmission. AChE’s active site has two main portions that interact with molecules: an anionic site that forms electrostatic interactions and an esteratic site made of several catalytic amino acids. Both sites are located deep within a gorge consisting of aromatic amino acids, contr

ibuting to the high specificity of AChE. When AChE acts normally on acetylcholine, the quaternary nitrogen moiety of choline—basically the part of acetylcholine attached to a nitrogen atom—is held in place by the anionic site, positioning the acetyl group in the esteratic site. AChE then hydrolyzes acetylcholine, resulting in acetic acid and choline as shown in Figure 1. However, when an organophosphate such as VX interacts with AChE, the phosphate moiety of VX covalently binds to and blocks the esteratic site, preventing normal AChE function, as shown in Figure 2 [2].


Typically, acetylcholine binds to muscarinic receptors, receptors found in classical neuromuscular junctions; autonomic motor fibers; and nicotinic receptors, receptors found throughout the cerebral cortex, hippocampus, and brainstem. Upon administration of VX, acetylcholine lingers in these areas, repeatedly stimulating postsynaptic neurons and resulting in symptoms typical of excess cholinergic signaling—first sweating and twitching, then nausea, vomiting, diarrhea, coma, and eventually respiratory system failure. Because acetylcholine also plays a role in the brain, cognitive effects may occur; but these symptoms have not been precisely identified since patients exposed to VX typically die before a psychological examination.

An important detail of Kim Jong-nam’s assassination, however, is that the two women involved in the attack did not die. Acute toxins such as VX are typically characterized by a measure called LD50, which is the minimum dose of a toxin that kills 50% of a sample population. Bajgar reports that, in humans, an oral dose of VX has an LD50 of 5 mg/70kg - which is easily less than a drop of liquid for the average woman. Because of VX’s high toxicity, as well as its extremely low volatility, it is unlikely that both women managed to avoid any contact with VX or simply wipe VX off of their skin.

VX has one more property that makes it a good assassination weapon: it’s a binary poison. In other words, VX can be synthesized as two relatively non-lethal compounds: Agent QL (a phosphonite compound) and either Agent NE (elemental sulfur) or Agent NM (a sulfur-based compound). This offers two reasonable methods that could have allowed the women to survive the attack: a) they could have self-administered VX antidotes such as atropine, which blocks muscarinic receptors to protect the nervous system from excess stimulation, or obidoxime, which stops organophosphates from binding to acetylcholinesterase. Or b) each women was given one of the ingredients to VX, which would then react on Kim Jong-nam’s face without killing themselves. It’s more likely that Agent NM (sulfur compound) was used rather than Agent NE (elemental sulfur), because the reaction between Agent QL and Agent NE is highly exothermic [4], and no descriptions of burns to his face have been reported [1].

Fortunately, it’s likely that VX won’t pose any human risk from mad scientists messing around in their basements or conspiracy theorists trying to destroy the world. Synthesis of VX is achieved through a four-step process known as the transester process, which is relatively short in the world of organic chemistry: phosphorous trichloride is methylated and reacted with ethanol, undergoes nucleophilic attack by an ethanolamine, then reacted with sulfur; the mixture is left to isomerize in situ (in its original solution) to produce a mixture of two enantiomers of VX, both of which are deadly [5]. However, such a synthesis requires a well-equipped chemistry laboratory to prevent inhalation of toxic fumes at any step of the process as well as a good knowledge of organic chemistry to work up products and actually isolate VX from any side products made during the synthesis. Additionally, the reagents to make VX require some sort of chemical license to work with, which can be hard to obtain for the average citizen.

VX and other organophosphates could pose a greater risk from governments seeking to engage in chemical warfare. Chemical warfare itself established a precedent for its modern use during World War I, which involved usage of chemicals such as chlorine gas (Cl2), phosgene (COCl2), and mustard gas (C4H8Cl2S). Nerve agents soon followed these toxic agents, with a set of nerve agents known as the G-series synthesized by German scientists (hence the name G-series); this series includes well-known agents such as sarin and soman. However, due partly to the sheer destruction caused by chemical agents, they played a far less prominent role in World War II than they did in World War I. Indeed, chemical agents have been banned multiple times in the modern era, beginning with the Geneva Protocol in 1925, then followed by the Biological and Toxin Weapons Convention (BTWC) in 1972 and further sanctions such as the 1993 Chemical Weapons Convention in future years [6]. However, as demonstrated by the attack on Kim Jong-nam, chemical warfare has certainly not been untouched by political entities such as North Korea, and thus could play a role in future armed conflicts.

In general, you shouldn’t be too worried about attacks from organophosphates such as VX unless you’re a high-profile individual that is at risk for assassination, in which case VX is merely one item on your bucket list of dangers. So, feel no fear: you can walk through airports safely, and chemical attacks might be one of the few scenarios where the TSA’s no-liquid policy might actually save your life.


References:

[1] North Korean leader's brother Kim Jong-nam killed at Malaysia airport. BBC News. http://www.bbc.com/news/world-asia-38971655. Published February 14, 2017.

[2] Massoulié J, Pezzementi L, Bon S, Krejci E, Vallette F-M. Molecular and cellular biology of cholinesterases. Progress in Neurobiology. 1993;41(1):31-91. doi:10.1016/0301-0082(93)90040-y.

[3] Cholinesterase Inhibitors: Including Insecticides and Chemical Warfare Nerve Agents Part 4 - Section 11 Management Strategy 3: Medications 2-PAM (2-Pyridine Aldoxime Methylchloride) (Pralidoxime). Centers for Disease Control and Prevention. https://www.atsdr.cdc.gov/csem/csem.asp?csem=11&po=23. Published October 16, 2010.

[4] Tucker J. War of Nerves: Chemical Warfare from World War I to Al-Qaeda. New York, NY: Anchor; 2007.

[5] Benschop HP, Jong LPAD. Nerve agent stereoisomers: analysis, isolation and toxicology. Accounts of Chemical Research. 1988;21(10):368-374. doi:10.1021/ar00154a003.

[6] Chemical and Biological Weapons. International Committee of the Red Cross. https://www.icrc.org/en/document/chemical-biological-weapons. Published April 8, 2013.

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