Sulfur mustard

The sulfur mustards, or sulphur mustards,^[2] commonly known as mustard gas, are a class of related cytotoxic, vesicant chemical warfare agents with the ability to form large blisters on exposed skin. Pure sulfur mustards are colorless, viscous liquids at room temperature. However, when used in impure form, such as warfare agents, they are usually yellow-brown in color and have an odor resembling mustard plants, garlic or horseradish, hence the name. Mustard gas was originally assigned the name LOST, after the scientists Lommel and Steinkopf, who developed a method for the large-scale production of the agent for the German Army in 1916.^[3]

Mustard agents are regulated under the 1993 Chemical Weapons Convention (CWC). 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 chemical warfare. Mustard agents can be deployed on the battlefield via spraying from aircraft, or more typically by means of air-dropped bombs or artillery shells.

Synthesis

Sulfur mustard is the organic compound described with the formula (Cl-CH₂CH₂)₂S. In the Depretz method, sulfur mustard is synthesized by treating sulfur dichloride with ethylene:

SCl₂ + 2 C₂H₄ → (Cl-CH₂CH₂)₂S

In the Meyer method, thiodiglycol is produced from chloroethanol and potassium sulfide and chlorinated with phosphorus trichloride:^[4]

3 (HO-CH₂CH₂)₂S + 2 PCl₃ → 3 (Cl-CH₂CH₂)₂S + 2 P(OH)₃

In the Meyer-Clarke method, concentrated hydrochloric acid (HCl) instead of PCl₃ is used as the chlorinating agent:

(HO-CH₂CH₂)₂S + 2 HCl → (Cl-CH₂CH₂)₂S + 2 H₂O

Thionyl chloride and phosgene have also been used as chlorinating agents.

It is a viscous liquid at normal temperatures. The pure compound has a melting point of 14 °C (57 °F) and decomposes before boiling at 218 °C (424.4 °F).

Mechanism of toxicity

The compound readily eliminates a chloride ion by intramolecular nucleophilic substitution to form a cyclic sulfonium ion. This very reactive intermediate tends to permanently alkylate the guanine nucleotide in DNA strands, which prevents cellular division and generally leads directly to programmed cell death,^[5] or, if cell death is not immediate, the damaged DNA may lead to the development of cancer.^[5] Sulfur mustard is not very soluble in water but is very soluble in fat, contributing to its rapid absorption into the skin.^[5]

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 (sulfonium, ammoniums, etc.) that are good alkylating agents. Examples are bis(2-chloroethyl)ether, the (2-haloethyl)amines (nitrogen mustards), and sulfur sesquimustard, which has two α-chloroethyl thioether groups (ClH₂C-CH₂-S-) connected by an ethylene (-CH₂CH₂-) group. These compounds have a similar ability to alkylate DNA, but their physical properties, e.g. melting point, vary.

Physiological effects

Mustard gas 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 gas rarely suffer immediate symptoms, and mustard-contaminated areas may appear completely normal, victims can unknowingly receive high dosages. However, 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 gas vapour 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. According to the Medical Management of Chemical Casualties handbook, there have been experimental cases in humans where the patient has suffered miosis, or pinpointing of pupils, as a 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 gas 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.^[6] Severe mustard gas burns (i.e. where more than 50% of the victim's skin has been burned) are often fatal, with death occurring after some days or even weeks have passed. Mild or moderate exposure to mustard agent is unlikely to kill, though victims invariably 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 gas burns have an increased risk of developing cancer in later life.

Skin damage can be reduced if povidone-iodine, (Betadine), in a base of glycofurol^[7] is rapidly applied, but since mustard agent initially has no symptoms, exposure is usually not recognised until skin irritation begins, at which point it is too late for countermeasures. The vesicant property of mustard gas can be neutralised by oxidation or chlorination, using household bleach (sodium hypochlorite), or by nucleophilic attack using e.g. decontamination solution "DS2" (2% NaOH, 70% diethylenetriamine, 28% ethylene glycol monomethyl ether) can be used. 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 gas burns heal slowly, and, as with other types of burn, there is a risk of sepsis caused by pathogens such as Staphylococcus aureus and Pseudomonas aeruginosa.

A British nurse treating soldiers with mustard gas 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 agonising 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.^[8]

Formulations

In its history, various types and mixtures of sulfur mustard 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,^[9][10] reacting dry ethylene with sulfur monochloride under controlled conditions. Undistilled sulfur mustard contains 20–30% impurities, for which reason 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, thus releasing the agent to the atmosphere^[1]

• HD – Codenamed Pyro by the British, and Distilled Mustard by the US.^[1] Distilled sulfur mustard (bis(2-chloroethyl) sulfide); approximately 96% pure. The term "mustard gas" usually refers to this variety of sulfur mustard. A much-used path of synthesis was based upon the reaction of thiodiglycol with hydrochloric acid.
• HT – Codenamed Runcol by the British, and Mustard T- mixture by the US.^[1] A mixture of 60% sulfur mustard (HD) and 40% T (bis[2-(2-chloroethylthio)ethyl] ether), 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.^[11]
• HQ – A blend of distilled mustard (HD) and sesquimustard (Q) (Gates and Moore 1946).

Sulfur mustard agents (class)

The complete list of effective sulfur mustard agents commonly stock-piled is as follows:

History

Development

Mustard gas was possibly developed as early as 1822 by César-Mansuète Despretz (1798–1863).^[12] Despretez described the reaction of sulfur dichloride and ethylene but never made mention of any irritating properties of the reaction product, which makes the claim doubtful. In 1854, another French chemist Alfred Riche (1829–1908) repeated the procedure but did not describe any adverse physiological properties. In 1860, British scientist Frederick Guthrie synthesized and characterized the compound, and he also noted its irritating properties, especially in tasting.^[13] In 1886, chemist Albert Niemann, known as a pioneer in cocaine chemistry, repeated the reaction, but, this time, blister-forming properties were recorded. In 1886, Viktor Meyer published a paper describing a synthesis that produced good yields. He reacted 2-chloroethanol with aqueous potassium sulfide and treated the resulting thiodiglycol with phosphorus trichloride. The purity of this compound was much higher and the adverse health effects on exposure, as a consequence, much more severe. These symptoms presented themselves in an assistant, and, in order to rule out that the assistant was suffering from a mental illness (psychosomatic symptoms), Meyer had the compound tested on rabbits, which then died. In 1913, English chemist Hans Thacher Clarke (of Eschweiler-Clarke fame) replaced phosphorus trichloride with hydrochloric acid in Meyer's recipe while working with Emil Fischer in Berlin. Clarke was hospitalized for 2 months for burns after a flask broke, and, according to him, Fischer's subsequent report on this incident to the German Chemical Society set Germany on the chemical weapons track.^[14] Germany in World War I relied on the Meyer-Clarke method with a 2-chloroethanol infrastructure already in place in the dye industry of that time.

Use

Mustard gas was first used effectively in World War I by the German army against British soldiers near Ypres in 1917 and later also against the French Second Army. The name Yperite comes from its usage by the German army near the city of Ypres. The Allies did not use the gas until November 1917 at Cambrai, after they captured a large stock of German mustard-filled shells. It took the British over a year to develop their own mustard gas weapon (their only option was the Despretz–Niemann–Guthrie process), first using it in September 1918 during the breaking of the Hindenburg Line.

Mustard gas was dispersed as an aerosol in a mixture with other chemicals, giving it a yellow-brown color and a distinctive odour. Mustard gas has also been dispersed in such munitions as aerial bombs, land mines, mortar rounds, artillery shells, and rockets.^[1] Mustard gas was lethal in only about 1% of cases; its effectiveness was as an incapacitating agent. Countermeasures against the gas were relatively ineffective, since a soldier wearing a gas mask was not protected against absorbing it through the skin.

Furthermore, mustard gas was a persistent agent which would remain in the environment for days and continue to cause sickness. If mustard gas contaminated a soldier's clothing and equipment, then other soldiers he came into contact with would also be poisoned. Towards the end of the war it was even used in high concentrations as an area-denial weapon, which often forced soldiers to abandon heavily contaminated positions.

Since then, mustard gas has also been reportedly used in several wars, often where those it is used against cannot retaliate:^[15]

• Australia against Germany in September 1918^[16]
• United Kingdom against the Red Army in 1919^[17]
• Spain and France against Rif insurgents in Morocco in 1921–1927^[15][18]
• Italy in Libya in 1930^[15]
• Soviet Union in Xinjiang, Republic of China during the Soviet Invasion of Xinjiang against the 36th Division (National Revolutionary Army) in 1934 and in the Xinjiang War (1937) in 1936–1937^[17][18]
• Italy against Abyssinia (now Ethiopia) from 1935 to 1940^[15]
• Germany against Poland and the Soviet Union in a few incidents during the Second World War^[15]
• Poland against Germany in 1939 during an isolated incident, British product^[15]
• Japan against China in 1937–1945^[17]
• Egypt against North Yemen in 1963–1967^[15]
• Iraq against Iran and Kurds in 1983–1988^[17][19]
• Possibly Sudan against insurgents in the civil war, in 1995 and 1997^[15]

In 1943, during the Second World War, a U.S. stockpile exploded aboard a supply ship that was bombed in an air raid in the harbor of Bari, Italy, eventually killing 83 of the 628 hospitalized military victims who were exposed to the mustard gas.^[20] The deaths and incident were partially classified for many years.

From 1943 to 1944, mustard gas experiments were performed on POWs held by the United States in tropical Queensland by British and U.S. Army experimenters, resulting in severe injuries. One test site, Brook Island, was chosen to simulate Japanese-held Pacific islands.^[21][22]

The use of poison gas, including mustard gas, during warfare, a practice known as chemical warfare, was prohibited by the Geneva Protocol of 1925 and the subsequent Chemical Weapons Convention of 1993, which also prohibits the development, production and stockpiling of such weapons.

Development of the First Chemotherapy Drug

As early as 1919 it was known that mustard gas was a suppressor of hematopoiesis.^[23] Additionally, autopsies on 75 soldiers who had died of mustard gas in World War II were done by researchers from the University of Pennsylvania who reported decreased white blood cell counts.^[20] This led to the US's Office of Scientific Research and Development (OSRD) to fund Yale University to conduct research on the chemical warfare agents during World War II.^[20][24] 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 the compound was tried on its first human patient in December 1942. The results of this study weren't published until 1946 after being declassified.^[24] In a parallel track, after the Air Raid on Bari in December 1943, the Army's doctors noted that white blood cell counts were reduced in exposed patients. Because the fact that the Allies had chemical munitions in the area was potentially embarrassing, the incident was classified until after the war was over.

After World War II was over the Bari incident and the Yale group's work with nitrogen mustard eventually converged prompting a search for other similar compounds. Due to its use in previous studies, the nitrogen mustard known as "HN2" became the first chemotherapy drug mustine.

Disposal

Most of the sulfur mustard found in Germany after World War II was dumped into the Baltic Sea. Between 1966 and 2002, fishermen have found around 700 chemical weapons in the Bornholm region, most of which contained sulfur mustard. One of the more frequently dumped weapons was the "Sprühbüchse 37" (SprüBü37, Spray Can 37, 1937 being the year of its fielding with the German Army). These weapons contain sulfur mustard mixed with a thickener, which renders it a tarlike viscosity. When the content of the SprüBü37 comes in contact with water, only the sulfur mustard in the outer layers of the lumps of viscous mustard hydrolyses, leaving amber-coloured residues that still contain most of the active sulfur mustard. On mechanically breaking these lumps, e.g., with a fishing net's drag board or with the hands, the enclosed sulfur mustard 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. Shells containing sulfur mustard and other toxic ammunition from World War I (as well as conventional explosives) can still occasionally be found in France and Belgium; they used to be disposed of by explosion at sea, but current environmental regulations prohibit this and so the French government is building an automated factory to dispose of the backlog of shells.

In 1972, the United States Congress banned the practice of disposing chemical weapons into the ocean. However, 64 million pounds of nerve and mustard agents had already been dumped into the ocean waters off the United States by the U.S. Army. According to a 1998 report created by William Brankowitz, a deputy project manager in the U.S. Army Chemical Materials Agency, the Army created at least 26 chemical weapons dump sites in the ocean off at least 11 states on both the west and east coasts (Operation CHASE, Operation Geranium, etc.). Additionally because of poor records, they currently only know the rough whereabouts of half of them.

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 short tons of mustard agent was stored in one-ton (907.2 kg) containers on the base under heavy guard. A disposal plant built on site 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 closest schools were fitted with overpressurization units to protect the students and staff 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 US Army and Federal Emergency Management Agency program.^[25] Unexploded shells containing mustard agent and other chemical agents are still present in several test ranges in proximity to Edgewood area schools, but the smaller amounts (4–14 pounds; 2–6 kg) present considerably less risk. They are being systematically detected and excavated for disposal. There are several other sites in the United States where the remaining U.S. stockpiles of chemical agents are awaiting destruction in compliance with international chemical weapons treaties; the largest mustard agent stockpile, approximately 6,196 short tons, was stored at the Deseret Chemical Depot in Utah. Destruction of this stockpile began in 2006. As of May 2011, the last ton container of mustard agent was destroyed at the Utah site and none remains. U.S. mustard agent and other chemical agent storage is managed by the US Army's Chemical Materials Agency.^[26] The Chemical Materials Agency (CMA) manages disposal operations at five of the remaining seven stockpile sites, located in Alabama, Arkansas, Indiana, Utah, and Oregon; disposal projects at the other two sites, located in Kentucky and Colorado, are managed by the U.S. Army Element, Assembled Chemical Weapons Alternatives (ACWA).^[27]

In 2008, many mustard gas bombs (empty) were recovered in an excavation at the Marrangaroo Army Base west of Sydney, Australia.^[28][29] In 2009, a mining survey near Chinchilla, Queensland uncovered 144 105mm Howitzer shells, some containing Mustard H, buried by the US Army during World War II.^[29][30] In 2010, a clamming vessel pulled up World War I munition shells from the waters south of Long Island. Multiple crewmembers became symptomatic with skin blistering and respiratory irritation severe enough to require hospitalization. This was the first instance of occupational non-military mustard gas exposure in the United States.^[31]

A large British stockpile of mustard gas that had been manufactured and stored at Rhydymwyn, Wales, since the war was destroyed in 1958.^[32]

Detection in biological fluids

Urinary concentrations of the thiodiglycol hydrolysis products of sulfur mustard 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. Intact sulfur mustard was detected in postmortem fluids and tissues of a man who died one week post-exposure.^[33]

See also

References

External links

• Textbook of Military Medicine – Intensive overview of mustard gas Includes many references to scientific literature
• Detailed information on physical effects and suggested treatments
• Iyriboz Y (2004). "A Recent Exposure to Mustard Gas in the United States: Clinical Findings of a Cohort (n = 247) 6 Years After Exposure". MedGenMed 6 (4): 4. PMC 1480580. PMID 15775831. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1480580.  Shows photographs taken in 1996 showing people with mustard gas burns.
• An overview of the sulfur and nitrogen mustard agents (Caution: contains graphic images)
• Questions and Answers for Mustard Gas
• UMDNJ-Rutgers University CounterACT Research Center of Excellence A research center studying sulfur mustard, includes searchable reference library with many early references on sulfur mustard.
• Treatment of Mustard Gas Burns – published in the BMJ in 1946
• Nightmare in Bari
• surgical treatment of Sulfur Mustard Burns