Mustard gas


Mustard gas, though technically not a gas and often called sulfur mustard by scholarly sources, is the prototypical substance of the sulfur-based family of cytotoxic and vesicant chemical warfare agents, which can form large blisters on exposed skin and in the lungs. They have a long history of use as a blister-agent in warfare and, along with organoarsenic compounds such as Lewisite, are the most well-studied of such agents. Related chemical compounds with similar chemical structure and similar properties form a class of compounds known collectively as sulfur mustards or mustard agents. Pure sulfur mustards are colorless, viscous liquids at room temperature. When used in impure form, such as warfare agents, they are usually yellow-brown and have an odor resembling mustard plants, garlic, or horseradish, hence the name. The common name of "mustard gas" is inaccurate because the sulfur mustard is not actually vaporized, but dispersed as a fine mist of liquid droplets. Mustard gas was originally assigned the name LOST, after the scientists Wilhelm Lommel and Wilhelm Steinkopf, who developed a method of large-scale production for the Imperial German Army in 1916.
Mustard agents are regulated under the 1993 Chemical Weapons Convention. Three classes of chemicals are monitored under this Convention, with sulfur and nitrogen mustard grouped in Schedule 1, as substances with no use other than in chemical warfare. Mustard agents could be deployed by means of artillery shells, aerial bombs, rockets, or by spraying from warplanes or other aircraft.
Mustard gas can be readily decontaminated through reaction with chloramine-T.

Synthesis and reactions

Mustard gas is the organic compound with formula 2S. In the Depretz method, mustard gas is synthesized by treating sulfur dichloride with ethylene:
In the Levinstein process, disulfur dichloride is used instead:
In the Meyer method, thiodiglycol is produced from chloroethanol and potassium sulfide and chlorinated with phosphorus trichloride:
In the Meyer-Clarke method, concentrated hydrochloric acid instead of PCl3 is used as the chlorinating agent:
Thionyl chloride and phosgene, the latter of which is also a choking agent, have also been used as chlorinating agents, with the added possibility of both agents producing additional mechanisms of toxicity if they remain as impurities in the finished product.
Mustard gas is a viscous liquid at normal temperatures. The pure compound has a melting point of and decomposes before boiling at.
Reaction of mustard gas with sodium ethoxide gives divinyl sulfide:

Mechanism of cellular toxicity

The compound readily eliminates a chloride ion by intramolecular nucleophilic substitution to form a cyclic sulfonium ion. This very reactive intermediate tends to cause permanent alkylation of the guanine nucleotide in DNA strands, which prevents cellular division and generally leads directly to programmed cell death, or, if cell death is not immediate, the damaged DNA may lead to the development of cancer. Oxidative stress would be another pathology involved in mustard gas toxicity. Mustard gas is not very soluble in water but is very soluble in fat, contributing to its rapid absorption into the skin.
In the wider sense, compounds with the structural element BCH2CH2X, where X is any leaving group and B is a Lewis base are known as mustards. Such compounds can form cyclic "onium" ions that are good alkylating agents. Examples are bisether, the amines, and sulfur sesquimustard, which has two α-chloroethyl thioether groups connected by an ethylene group. These compounds have a similar ability to alkylate DNA, but their physical properties, e.g. melting points, may vary.

Physiological effects

Mustard agent has extremely powerful vesicant effects on its victims. In addition, it is strongly mutagenic and carcinogenic, due to its alkylating properties. It is also lipophilic. Because people exposed to mustard agent rarely suffer immediate symptoms, and mustard-contaminated areas may appear completely normal, victims can unknowingly receive high dosages. Within 24 hours of exposure to mustard agent, victims experience intense itching and skin irritation, which gradually turns into large blisters filled with yellow fluid wherever the mustard agent contacted the skin. These are chemical burns and are very debilitating. Mustard agent vapor easily penetrates clothing fabrics such as wool or cotton, so it is not only the exposed skin of victims that gets burned. If the victim's eyes were exposed then they become sore, starting with conjunctivitis, after which the eyelids swell, resulting in temporary blindness. In rare cases of extreme ocular exposure to mustard gas vapors, corneal ulceration, anterior chamber scarring, and neovascularization have occurred. In these severe and infrequent cases, corneal transplantation has been used as a treatment option. Miosis, when the pupil constricts more than usual, may also occur, which is probably the result of the cholinomimetic activity of mustard. At very high concentrations, if inhaled, mustard agent causes bleeding and blistering within the respiratory system, damaging mucous membranes and causing pulmonary edema. Depending on the level of contamination, mustard agent burns can vary between first and second degree burns, though they can also be every bit as severe, disfiguring and dangerous as third degree burns. Severe mustard agent burns are often fatal, with death occurring after days or even weeks have passed. Mild or moderate exposure to mustard agent is unlikely to kill, though victims require lengthy periods of medical treatment and convalescence before recovery is complete.
The mutagenic and carcinogenic effects of mustard agent mean that victims who recover from mustard agent burns have an increased risk of developing cancer in later life. In a study of patients 25 years after wartime exposure to chemical weaponry, c-DNA microarray profiling indicated that 122 genes were significantly mutated in the lungs and airways of mustard gas victims. Those genes all correspond to functions commonly affected by mustard gas exposure, including apoptosis, inflammation, and stress responses.
burns
The vesicant property of mustard agent can be neutralized by oxidation or chlorination, using household bleach, or by nucleophilic attack using e.g. decontamination solution "DS2". After initial decontamination of the victim's wounds is complete, medical treatment is similar to that required by any conventional burn. The amount of pain and discomfort suffered by the victim is comparable as well. Mustard agent burns heal slowly, and, as with other types of burn, present a risk of sepsis caused by pathogens such as Staphylococcus aureus and Pseudomonas aeruginosa. The mechanisms behind mustard gas's effect on endothelial cells are still being studied, but recent studies have shown that high levels of exposure can induce high rates of both necrosis and apoptosis. In vitro tests have shown that at low concentrations of mustard gas, where apoptosis is the predominant result of exposure, pretreatment with 50 mM N-acetyl-L-cysteine was able to decrease the rate of apoptosis. NAC protects actin filaments from reorganization by mustard gas, demonstrating that actin filaments play a large role in the severe burns observed in victims.
A British nurse treating soldiers with mustard agent burns during World War I commented:

Formulations

In its history, various types and mixtures of mustard gas have been employed. These include:
The complete list of effective mustard gas agents commonly stockpiled is as follows:
ChemicalCodeTrivial nameCAS numberPubChemStructure
BissulfideH/HDMustard505-60-2
1,2-Bis--ethaneQSesquimustard3563-36-8
Bis--etherTO-mustard63918-89-8
2-Chloroethyl chloromethyl sulfide2625-76-5
Bis--methaneHK63869-13-6
Bis-1,3--n-propane63905-10-2
Bis-1,4--n-butane142868-93-7
Bis-1,5--n-pentane142868-94-8
Bis--ether63918-90-1

History

Development

Mustard agent was possibly developed as early as 1822 by César-Mansuète Despretz. Despretz described the reaction of sulfur dichloride and ethylene but never made mention of any irritating properties of the reaction product. In 1854, another French chemist, Alfred Riche, repeated this procedure, also without describing any adverse physiological properties. In 1860, the British scientist Frederick Guthrie synthesized and characterized the mustard agent compound and noted its irritating properties, especially in tasting. Also in 1860, chemist Albert Niemann, known as a pioneer in cocaine chemistry, repeated the reaction, and recorded blister-forming properties. In 1886, Viktor Meyer published a paper describing a synthesis that produced good yields. He combined 2-chloroethanol with aqueous potassium sulfide, and then treated the resulting thiodiglycol with phosphorus trichloride. The purity of this compound was much higher and consequently the adverse health effects upon exposure were much more severe. These symptoms presented themselves in his assistant, and in order to rule out the possibility that his assistant was suffering from a mental illness, Meyer had this compound tested on laboratory rabbits, most of which died. In 1913, the English chemist Hans Thacher Clarke replaced the phosphorus trichloride with hydrochloric acid in Meyer's formulation while working with Emil Fischer in Berlin. Clarke was hospitalized for two months for burns after one of his flasks broke. According to Meyer, Fischer's report on this accident to the German Chemical Society sent the German Empire on the road to chemical weapons.
Mustard agent can have the effect of turning a patient's skin different colors, including reds, oranges, pinks, and in unusual cases, blues. The German Empire during World War I relied on the Meyer-Clarke method because 2-chloroethanol was readily available from the German dye industry of that time.

Use

Mustard agent was first used effectively in World War I by the German army against British and Canadian soldiers near Ypres, Belgium, in 1917 and later also against the French Second Army. The name Yperite comes from its usage by the German army near the town of Ypres. The Allies did not use mustard agent until November 1917 at Cambrai, France, after the armies had captured a stockpile of German mustard shells. It took the British more than a year to develop their own mustard agent weapon, with production of the chemicals centred on Avonmouth Docks. This was used first in September 1918 during the breaking of the Hindenburg Line.
Mustard agent was dispersed as an aerosol in a mixture with other chemicals, giving it a yellow-brown color and a distinctive odor. Mustard agent has also been dispersed in such munitions as aerial bombs, land mines, mortar rounds, artillery shells, and rockets. Exposure to mustard agent was lethal in about 1% of cases. Its effectiveness was as an incapacitating agent. The early countermeasures against mustard agent were relatively ineffective, since a soldier wearing a gas mask was not protected against absorbing it through his skin and being blistered. The effectiveness of using a urine-soaked mask or facecloth to prevent or reduce injury, a common anecdotal field-expedient remedy attested by soldiers in documentaries e.g. They Shall Not Grow Old in 2018 and others interviewed between 1947 and 1981 by the British Broadcasting Corporation for various World War One history programs on being gassed remains unclear.
Mustard agent is a persistent weapon that remains on the ground for weeks, and it continues to cause ill effects. If mustard agent contaminates a soldier's clothing and equipment while cold, then the other soldiers or nurses with whom they share an enclosed space could become poisoned as contaminated items warms up enough to become an airborne toxic agent, and an example of this was depicted in a British and Canadian documentary about life in the trenches particularly once the "sousterrain" were completed in Belgium and France. Towards the end of World War I, mustard agent was used in high concentrations as an area-denial weapon that forced troops to abandon heavily contaminated areas.
Since World War I, mustard agent has been used in several wars or other conflicts, usually against people who cannot retaliate in kind:
In 1943, during the Second World War, an American shipment of mustard agent exploded aboard a supply ship that was bombed during an air raid in the harbor of Bari, Italy. Eighty-three of the 628 hospitalized victims who had been exposed to the mustard agent died.
After WWII, stockpiled mustard agent was dumped by the British in the sea near Port Elizabeth, South Africa, resulting in burn cases among trawler crews.
The use of toxic gases or other chemicals, including mustard agent, during warfare is known as chemical warfare, and this kind of warfare was prohibited by the Geneva Protocol of 1925, and also by the later Chemical Weapons Convention of 1993. The latter agreement also prohibits the development, production, stockpiling, and sale of such weapons.
In September 2012 a US official stated that the rebel militant group ISIS was manufacturing and using mustard gas in Syria and Iraq, which was allegedly confirmed by the group's head of chemical weapons development, Sleiman Daoud al-Afari, who has since been captured.

Development of the first chemotherapy drug

As early as 1919 it was known that mustard agent was a suppressor of hematopoiesis. In addition, autopsies performed on 75 soldiers who had died of mustard agent during World War I were done by researchers from the University of Pennsylvania who reported decreased counts of white blood cells. This led the American Office of Scientific Research and Development to finance the biology and chemistry departments at Yale University to conduct research on the use of chemical warfare during World War II. As a part of this effort, the group investigated nitrogen mustard as a therapy for Hodgkin's lymphoma and other types of lymphoma and leukemia, and this compound was tried out on its first human patient in December 1942. The results of this study were not published until 1946, when they were declassified. In a parallel track, after the air raid on Bari in December 1943, the doctors of the U.S. Army noted that white blood cell counts were reduced in their patients. Some years after World War II was over, the incident in Bari and the work of the Yale University group with nitrogen mustard converged, and this prompted a search for other similar chemical compounds. Due to its use in previous studies, the nitrogen mustard called "HN2" became the first cancer chemotherapy drug, mustine, to be used.

Disposal

In the United States, storage and incineration of mustard agent and other poison gases was carried out by the U.S. Army Chemical Materials Agency. Disposal projects at the two remaining American chemical weapons sites, will be carried out at their sites near Richmond, Kentucky, and Pueblo, Colorado. Although not yet Declassified, toxicology specialists who dealt with the accidental puncturing of World War 1 gas stockpiles add Air Force bases in Colorado has being made available to assist veterans of the 2003 American war with Iraq in which many Marines were exposed to gas as caches of up to 25,000 pounds the United Nations definition of a weapon of mass destruction for mustard gas is 30000 lb, typically the Marines and other coalition allies discovered caches of 25,000 pounds located across a road from 5,000 lb caches as multiple memoires attest.) These were discovered by the assistance of host country allies or through leaks affecting personnel in an area with a weapon and gas cache called an "asp".
New detection techniques are being developed in order to detect the presence of mustard gas and its metabolites. The technology is portable and detects small quantities of the hazardous waste and its oxidized products, which are notorious for harming unsuspecting civilians. The immunochromatographic assay would eliminate the need for expensive, time-consuming lab tests and enable easy-to-read tests to protect civilians from sulfur-mustard dumping sites.
In 1946, 10,000 drums of mustard gas stored at the production facility of Stormont Chemicals in Cornwall, Ontario, Canada were loaded onto 187 boxcars for the 900-mile journey to be buried at sea on board a long barge south of Sable Island, southeast of Halifax at a depth of 600 fathoms. The dump location is 42 degrees, 50 minutes north by 60 degrees, 12 minutes west.
A large British stockpile of old mustard agent that had been made and stored since World War I at M. S. Factory, Valley near Rhydymwyn in Flintshire, Wales, was destroyed in 1958.
Most of the mustard gas agent found in Germany after World War II was dumped into the Baltic Sea. Between 1966 and 2002, fishermen have found about 700 chemical weapons in the region of Bornholm, most of which contain mustard gas. One of the more frequently dumped weapons was the "Sprühbüchse 37". These weapons contain mustard gas mixed with a thickener, which gives it a tar-like viscosity. When the content of the SprüBü37 comes in contact with water, only the mustard gas in the outer layers of the lumps of viscous mustard hydrolyzes, leaving behind amber-colored residues that still contain most of the active mustard gas. On mechanically breaking these lumps, e.g., with the drag board of a fishing net or by the human hand, the enclosed mustard gas is still as active as it had been at the time the weapon was dumped. These lumps, when washed ashore, can be mistaken for amber, which can lead to severe health problems. Artillery shells containing mustard gas and other toxic ammunition from World War I can still be found in France and Belgium. These were formerly disposed of by explosion undersea, but since the current environmental regulations prohibit this, the French government is building an automated factory to dispose of the accumulation of chemical shells.
In 1972, the U.S. Congress banned the practice of disposing of chemical weapons into the ocean by the United States. 29,000 tons of nerve and mustard agents had already been dumped into the ocean off the United States by the U.S. Army. According to a report created in 1998 by William Brankowitz, a deputy project manager in the U.S. Army Chemical Materials Agency, the army created at least 26 chemical weapons dumping sites in the ocean offshore from at least 11 states on both the East Coast and the West Coast. In addition, due to poor recordkeeping, about one-half of the sites have only their rough locations known.
In June 1997, India declared its stock of chemical weapons of of mustard gas. By the end of 2006, India had destroyed more than 75 percent of its chemical weapons/material stockpile and was granted extension for destroying the remaining stocks by April 2009 and was expected to achieve 100 percent destruction within that time frame. India informed the United Nations in May 2009 that it had destroyed its stockpile of chemical weapons in compliance with the international Chemical Weapons Convention. With this India has become the third country after South Korea and Albania to do so. This was cross-checked by inspectors of the United Nations.
Producing or stockpiling mustard gas is prohibited by the Chemical Weapons Convention. When the convention entered force in 1997, the parties declared worldwide stockpiles of 17,440 tonnes of mustard gas. As of December 2015, 86% of these stockpiles had been destroyed.
A significant portion of the stockpile of mustard agent in the United States was stored at the Edgewood Area of Aberdeen Proving Ground in Maryland. Approximately 1,621 tons of mustard agent were stored in one-ton containers on the base under heavy guard. A chemical neutralization plant was built on the proving ground and neutralized the last of this stockpile in February 2005. This stockpile had priority because of the potential for quick reduction of risk to the community. The nearest schools were fitted with overpressurization machinery to protect the students and faculty in the event of a catastrophic explosion and fire at the site. These projects, as well as planning, equipment, and training assistance, were provided to the surrounding community as a part of the Chemical Stockpile Emergency Preparedness Program, a joint program of the Army and the Federal Emergency Management Agency. Unexploded shells containing mustard agent and other chemical agents are still present in several test ranges in proximity to schools in the Edgewood area, but the smaller amounts of poison gas present considerably lower risks. These remnants are being detected and excavated systematically for disposal. The U.S. Army Chemical Materials Agency oversaw disposal of several other chemical weapons stockpiles located across the United States in compliance with international chemical weapons treaties. These include the complete incineration of the chemical weapons stockpiled in Alabama, Arkansas, Indiana, and Oregon. Earlier, this agency had also completed destruction of the chemical weapons stockpile located on Johnston Atoll located south of Hawaii in the Pacific Ocean. The largest mustard agent stockpile, of about 6,196 tons, was stored at the Deseret Chemical Depot in northern Utah. The incineration of this stockpile began in 2006. In May 2011, the last one-ton tank of mustard agent was incinerated at the Deseret Chemical Depot, and the last mustard agent artillery shells at Deseret were incinerated in January 2012.
In 2008, many empty mustard agent aerial bombs were found in an excavation at the Marrangaroo Army Base just west of Sydney, Australia. In 2009, a mining survey near Chinchilla, Queensland, uncovered 144 105-millimeter howitzer shells, some containing "Mustard H", that had been buried by the U.S. Army during World War II.
In 2014, a collection of 200 bombs was found on the boundary between the Flemish villages of Passendale and Moorslede. The majority of the bombs were filled with mustard agent. The bombs are a leftover from the German army and were meant to be used in the Battle of Passchendale in World War I. It was the largest collection of chemical weapons ever found in Belgium.

Post-War accidental exposure

In 2002, an archaeologist at the Presidio Trust archaeology lab in San Francisco was exposed to mustard agent, which had been dug up at the Presidio of San Francisco, a former military base.
In 2010, a clamming boat pulled up some old artillery shells of World War I from the Atlantic Ocean south of Long Island, New York. Multiple fishermen suffered from skin blistering and respiratory irritation severe enough to require their hospitalization.

WWII-era tests on men

From 1943 to 1944, mustard agent experiments were performed on Australian service volunteers in tropical Queensland, Australia, by British Army and American experimenters, resulting in some severe injuries. One test site, the Brook Islands National Park, was chosen to simulate Pacific islands held by the Imperial Japanese Army.
The United States tested mustard gas and other chemical agents including nitrogen mustard and lewisite on up to 60,000 servicemen during and after WWII. The experiments were classified secret and as with Agent Orange, claims for medical care and compensation were routinely denied, even after the WWII-era tests were declassified in 1993. The Department of Veterans Affairs stated that it would contact 4,000 surviving test subjects but failed to do so, eventually only contacting 600. Skin cancer, severe eczema, leukemia, and chronic breathing problems plagued the test subjects, some of whom were as young as 19 at the time of the tests, until their deaths, but even those who had previously filed claims with the VA went without compensation.
and lewisite agents. African-American servicemen were tested alongside white men in separate trials to determine whether their skin color would afford them a degree of immunity to the agents, and Nisei servicemen, some of whom had joined after their release from Japanese American Internment Camps were tested to determine susceptibility of Japanese military personnel to these agents. These tests also included Puerto-Rican subjects.

Detection in biological fluids

Urinary concentrations of the thiodiglycol hydrolysis products of mustard gas have been used to confirm a diagnosis of chemical poisoning in hospitalized victims. The presence in urine of 1,1'-sulfonylbismethylthioethane, a conjugation product with glutathione, is considered a more specific marker, since this metabolite is not found in specimens from unexposed persons. Intact mustard gas was detected in postmortem fluids and tissues of a man who died one week post-exposure.