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List of IARC Group 1 Agents - Carcinogenic to humans
Mustard gas
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Mustard gas

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Mustard gas or sulfur mustard is any of several chemical compounds that contain the chemical structure SCH2CH2Cl. In the wider sense, compounds with the substituent SCH2CH2X and NCH2CH2X are known as sulfur mustards and nitrogen mustards (X = Cl, Br), respectively. Such compounds are potent alkylating agents, which can interfere with several biological processes. Also known as mustard agents, this family of compounds are infamous cytotoxic and blister agents. The name mustard gas is technically incorrect: the substances, when dispersed, are often not gases but a fine mist of liquid droplets. Mustard gases form blisters on exposed skin and in the lungs, often resulting in prolonged illness ending in death. The typical mustard gas is the organosulfur compound called bis(2-chloroethyl) sulfide.

History as chemical weapons

Sulfur mustard is a type of chemical warfare agent. As a chemical weapon, mustard gas was first used in World War I, and has been used in several armed conflicts since then, including the Iran–Iraq War, resulting in more than 100,000 casualties. Today, sulfur-based and nitrogen-based mustard agents are regulated under Schedule 1 of the 1993 Chemical Weapons Convention, as substances with few uses other than in chemical warfare (though since then, mustard gas has been found to be useful in cancer chemotherapy). Mustard agents could be deployed by means of artillery shells, aerial bombs, rockets, or by spraying from aircraft.

Mechanism of cellular toxicity

Mustard gas alkylating an amino group via conversion to a sulfonium ion (2-chloroethylthiiranium)

Sulfur mustards readily eliminate chloride ions by intramolecular nucleophilic substitution to form cyclic sulfonium ions. These very reactive intermediates tend to permanently alkylate nucleotides in DNA strands, which can prevent cellular division, leading to programmed cell death. Alternatively, if cell death is not immediate, the damaged DNA can lead to the development of cancer.Oxidative stress would be another pathology involved in mustard gas toxicity.

In the wider sense, compounds with the structural element BC2H4X, where X is any leaving group and B is a Lewis base, are known as mustards. Such compounds can form cyclic "onium" ions (sulfonium, ammonium, etc.) that are good alkylating agents. Other such compounds are bis(2-haloethyl)ethers (oxygen mustards), the (2-haloethyl)amines (nitrogen mustards), and sesquimustard, which has two α-chloroethyl thioether groups (ClC2H4S−) connected by an ethylene bridge (−C2H4−). These compounds have a similar ability to alkylate DNA, but their physical properties vary.

Physiological effects

Soldier with moderate mustard agent burns sustained during World War I showing characteristic bullae on the neck, armpit, and hands

Mustard gases react with DNA, which interferes with cellular division and can lead to mutations.

Mustard gases are extremely toxic and have powerful blistering effects on victims. Their alkylating capabilities make them strongly carcinogenic and mutagenic. Furthermore, they are highly lipophilic, which accelerates their absorption into the body. Because people exposed to mustard agents rarely suffer immediate symptoms, and contaminated areas may appear completely normal, victims can unknowingly receive high doses. Within 24 hours of exposure, victims experience intense itching and skin irritation. If this irritation goes untreated, blisters filled with yellow fluid (pus) can start to form wherever the agent contacted the skin. These are chemical burns and are very debilitating. Mustard gases easily penetrate clothing fabrics such as wool or cotton, so it is not only exposed skin that gets burned. If the victim's eyes were exposed, then they become sore, starting with conjunctivitis (also known as pink eye), after which the eyelids swell, resulting in temporary blindness. Extreme ocular exposure to mustard gas vapors may result in corneal ulceration, anterior chamber scarring, and neovascularization. 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 agents cause 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. Burns that are severe (i.e. covering more than 50% of the victim's skin) are often fatal, with death occurring after only days or weeks. Mild or moderate exposure to mustard gases is unlikely to kill, though victims still require lengthy periods of medical treatment and convalescence before recovery is complete.

Mustard gases' carcinogenic and mutagenic effects mean that victims, even if they fully recover, have an increased risk of developing cancer later in 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. The long-term ocular complications include burning, tearing, itching, photophobia, presbyopia, pain, and foreign-body sensations.

Typical appearance of bullae on an arm caused by vesicant burns

Mustard gases' blistering effects can be neutralized by oxidation or chlorination, using household bleach (sodium hypochlorite), or by nucleophilic attack using decontamination solutions such as "DS2" (2% NaOH, 70% diethylenetriamine, 28% 2-methoxyethanol). After initial decontamination of the victim's wounds is complete, medical treatment is similar to that required by any conventional burn. The degree of pain and discomfort suffered by the victim is also comparable. Mustard agent burns do not heal quickly, and (as with other types of burns) 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 (NAC) 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:

They cannot be bandaged or touched. We cover them with a tent of propped-up sheets. Gas burns must be agonizing because usually the other cases do not complain, even with the worst wounds, but gas cases are invariably beyond endurance and they cannot help crying out.

Formulations

Lewisite (top row) and mustard gas (bottom row) test with concentrations from 0.01% to 0.06%

In its history, various types and mixtures of mustard gas have been employed. These include:

  • H – Also known as HS ("Hun Stuff") or Levinstein mustard. This is named after the inventor of the "quick but dirty" Levinstein Process for manufacture, reacting dry ethylene with disulfur dichloride under controlled conditions. Undistilled mustard gas contains 20–30% impurities, which means it does not store as well as HD. Also, as it decomposes, it increases in vapor pressure, making the munition it is contained in likely to split, especially along a seam, releasing the agent to the atmosphere.
  • HD – Codenamed Pyro by the British, and Distilled Mustard by the US.Distilled mustard of 95% or higher purity. The term "mustard gas" usually refers to this variety of mustard.
  • HT – Codenamed Runcol by the British, and Mustard T- mixture by the US. A mixture of 60% mustard and 40% O-mustard, a related vesicant with lower freezing point, lower volatility and similar vesicant characteristics.
  • HL – A blend of distilled mustard (HD) and lewisite (L), originally intended for use in winter conditions due to its lower freezing point compared to the pure substances. The lewisite component of HL was used as a form of antifreeze.
  • HQ – A blend of distilled mustard (HD) and sesquimustard (Q) (Gates and Moore 1946).

Commonly-stockpiled mustard agents (class)

Chemical Code Trivial name CAS number PubChem Structure
Bis(2-chloroethyl) sulfide H, HD Mustard 505-60-2 CID 10461 from PubChem Sulfur mustard.svg
1,2-Bis(2-chloroethylsulfanyl) ethane Q Sesquimustard 3563-36-8 CID 19092 from PubChem Sesquimustard.svg
2-Chloroethyl ethyl sulfide Half mustard 693-07-2 CID 12733 from PubChem Chloroethyl ethyl sulfide.svg
Bis(2-(2-chloroethylsulfanyl)ethyl) ether T O-Mustard 63918-89-8 CID 45452 from PubChem O-Mustard.svg
2-Chloroethyl chloromethyl sulfide 2625-76-5 2-Chlorethylchlormethylsulfid.svg
Bis(2-chloroethylsulfanyl) methane HK 63869-13-6 Bis(2-chlorethylthio)methan.svg
1,3-Bis(2-chloroethylsulfanyl) propane 63905-10-2 Bis-1,3-(2-chlorethylthio)-n-propan.svg
1,4-Bis(2-chloroethylsulfanyl) butane 142868-93-7 Bis-1,4-(2-chlorethylthio)-n-butan.svg
1,5-Bis(2-chloroethylsulfanyl) pentane 142868-94-8 Bis-1,5-(2-chlorethylthio)-n-pentan.svg
Bis((2-chloroethylsulfanyl)methyl) ether 63918-90-1 Bis(2-chlorethylthiomethyl)ether.svg

History

Development

Mustard gases were possibly developed as early as 1822 by César-Mansuète Despretz (1798–1863). 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 (1829–1908), 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 (psychosomatic symptoms), Meyer had this compound tested on laboratory rabbits, most of which died. In 1913, the English chemist Hans Thacher Clarke (known for the Eschweiler-Clarke reaction) 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 gas can have the effect of turning a patient's skin different colors, including shades of red, orange, pink, and in unusual cases, blue. 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

Pallets of 155 mm artillery shells containing "HD" (distilled mustard gas agent) at the Pueblo Chemical Depot. The distinctive color-coding scheme on each shell is visible

Mustard gas was first used in World War I by the German army against British and Canadian soldiers near Ypres, Belgium, "on the night of July 12, 1917." Later also against the French Second Army. Yperite is "a name used by the French, because the compound was first used at Ypres." The Allies did not use mustard gas 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 (the only option available to the British was the Despretz–Niemann–Guthrie process). This was used first in September 1918 during the breaking of the Hindenburg Line.

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 gas was dispersed as an aerosol in a mixture with other chemicals, giving it a yellow-brown color. 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. A common countermeasure was using a urine-soaked mask or facecloth to prevent or reduce injury, a readily available remedy attested by soldiers in documentaries (e.g. They Shall Not Grow Old in 2018) and others (such as forward aid nurses) interviewed between 1947 and 1981 by the British Broadcasting Corporation for various World War One history programs; however, the effectiveness of this measure is unclear.

Mustard gas can remain in the ground for weeks, and it continues to cause ill effects. If mustard agent contaminates one's clothing and equipment while cold, then other people with whom they share an enclosed space could become poisoned as contaminated items warm up enough material to become an airborne toxic agent. An example of this was depicted in a British and Canadian documentary about life in the trenches, particularly once the "sousterrain" (subways and berthing areas underground) 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.

US Army World War II gas identification poster, c. 1941–1945

Since World War I, mustard gas has been used in several wars and other conflicts, usually against people who cannot retaliate in kind:

In 1943, during World War II, a shipment of mustard gas from the US exploded aboard SS John Harvey 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 gas was dumped by the British in the sea near Port Elizabeth, South Africa, resulting in many cases of burns among trawler crews.

The use of toxic gases or other chemicals, including mustard gas, 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 (OSRD) 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 (also called chlormethine), to be used.

Disposal

In the United States, storage and incineration of mustard gas and other chemical weapons were carried out by the U.S. Army Chemical Materials Agency. Disposal projects at the two remaining American chemical weapons sites were carried out near Richmond, Kentucky, and Pueblo, Colorado. Although not yet declassified, toxicology specialists who dealt with the accidental puncturing of World War I gas stockpiles add that Air Force bases in Colorado have been 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 lb (11,000 kg). The United Nations definition of a weapon of mass destruction for mustard gas is 30,000 lb (14,000 kg), typically the Marines and other coalition allies discovered caches of 25,000 pounds (11,000 kg) located across a road from 5,000 pounds (2,300 kg) caches as multiple memoirs 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 (2,800 tonnes) stored at the production facility of Stormont Chemicals in Cornwall, Ontario, Canada, were loaded onto 187 boxcars for the 900 miles (1,400 km) journey to be buried at sea on board a 400 foot (120 m) long barge 40 miles (64 km) south of Sable Island, southeast of Halifax, at a depth of 600 fathoms (1,100 m). 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 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 "Sprühbüchse 37" (SprüBü37, Spray Can 37, 1937 being the year of its fielding with the German Army). 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 (as well as conventional explosives) 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 Operation CHASE, Operation Geranium, etc.). 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 1,044 tonnes (1,151 short tons) 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 United States' mustard agent stockpile was stored at the Edgewood Area of Aberdeen Proving Ground in Maryland. Approximately 1,621 tons of mustard agents 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 (CSEPP), a joint program of the Army and the Federal Emergency Management Agency (FEMA). Unexploded shells containing mustard gases 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 (4 to 14 pounds (1.8 to 6.4 kg)) 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, at approximately 6,200 short tons, was stored at the Deseret Chemical Depot in northern Utah. The incineration of this stockpile began in 2006. In May 2011, the last of the mustard agents in the stockpile were incinerated at the Deseret Chemical Depot, and the last artillery shells containing mustard gas were incinerated in January 2012.

In 2008, many empty aerial bombs that contained mustard gas 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 near the Flemish villages of Passendale and Moorslede. The majority of the bombs were filled with mustard agents. The bombs were left over 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.

A large amount of chemical weapons, including mustard gas, was found in a neighborhood of Washington DC. The cleanup was completed in 2021.

Post-war accidental exposure

In 2002, an archaeologist at the Presidio Trust archaeology lab in San Francisco was exposed to mustard gas, 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 blistering and respiratory irritation severe enough to require hospitalization.

WWII-era tests on men

Mustard gas test subjects enter gas chamber, Edgewood Arsenal, March 1945

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 sulfur mustards and other chemical agents including nitrogen mustards 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.

Arms of four test subjects after exposure to nitrogen mustard 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

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

See also

Further reading

External links

Wikimedia Commons has media related to Sulfur mustard.

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