Sarin

Sarin (NATO designation GB short for G-series, B) is an extremely toxic organophosphorus compound that has been often used as a chemical weapon due to its extreme potency as a nerve agent.

Sarin is a volatile, colorless and odorless liquid. Exposure can be lethal even at very low concentrations, and death can occur within one to ten minutes after direct inhalation of a lethal dose due to suffocation from respiratory paralysis, unless antidotes are quickly administered. People who absorb a non-lethal dose and do not receive immediate medical treatment may suffer permanent neurological damage.

Sarin is widely considered a weapon of mass destruction. Production and stockpiling of sarin was outlawed as of April 1997 by the Chemical Weapons Convention of 1993, and it is classified as a Schedule 1 substance.

Health effects

Like some other nerve agents that affect the neurotransmitter acetylcholine, sarin attacks the nervous system by interfering with the degradation of the neurotransmitter acetylcholine at neuromuscular junctions. Death usually occurs as a result of asphyxia due to the inability to control the muscles involved in breathing.

Initial symptoms following exposure to sarin are a runny nose, tightness in the chest, and constriction of the pupils (miotic action). Soon after, the person will have difficulty breathing and experience nausea and drooling. This progresses to losing control of bodily functions, which may cause the person to vomit, defecate, and urinate. This phase is followed by twitching and jerking. Ultimately, the person becomes comatose and suffocates in a series of convulsive spasms. Common mnemonics for the symptomatology of organophosphate poisoning, including sarin, are the "killer Bs" of bronchorrhea and bronchospasm because they are the leading cause of death, and SLUDGE – salivation, lacrimation, urination, defecation, gastrointestinal distress, and emesis (vomiting). Death may follow in one to ten minutes after direct inhalation, but may also occur after a delay ranging from hours to several weeks, in cases where exposure is limited but no antidote is applied.

Sarin has a high volatility (ease with which a liquid can turn into vapour) relative to similar nerve agents, making inhalation very easy, and may even absorb through the skin. A person's clothing can release sarin for about 30 minutes after it has come in contact with sarin gas, which can lead to exposure of other people.

Management

Treatment measures have been described. Treatment is typically with the antidotes atropine and pralidoxime. Atropine, an antagonist to muscarinic acetylcholine receptors, is given to treat the physiological symptoms of poisoning. Since muscular response to acetylcholine is mediated through nicotinic acetylcholine receptors, atropine does not counteract the muscular symptoms. Pralidoxime can regenerate cholinesterases if administered within approximately five hours. Biperiden, a synthetic acetylcholine antagonist, has been suggested as an alternative to atropine due to its better blood–brain barrier penetration and higher efficacy.

Mechanism of action

Sarin is a potent inhibitor of acetylcholinesterase, an enzyme that degrades the neurotransmitter acetylcholine after it is released into the synaptic cleft. In vertebrates, acetylcholine is the neurotransmitter used at the neuromuscular junction, where signals are transmitted between neurons from the peripheral nervous system to muscle fibres. Normally, acetylcholine is released from the neuron to stimulate the muscle, after which it is degraded by acetylcholinesterase, allowing the muscle to relax. A build-up of acetylcholine in the synaptic cleft, due to the inhibition of acetylcholinesterase, means the neurotransmitter continues to act on the muscle fibre, so that any nerve impulses are effectively continually transmitted.

Sarin acts on acetylcholinesterase by forming a covalent bond with the particular serine residue at the active site. Fluoride is the leaving group, and the resulting organo-phosphoester is robust and biologically inactive.

Its mechanism of action resembles that of some commonly used insecticides, such as malathion. In terms of biological activity, it resembles carbamate insecticides, such as Sevin, and the medicines pyridostigmine, neostigmine, and physostigmine.

Diagnostic tests

Controlled studies in healthy men have shown that a nontoxic 0.43 mg oral dose administered in several portions over a 3-day interval caused average maximum depressions of 22 and 30%, respectively, in plasma and erythrocyte acetylcholinesterase levels. A single acute 0.5 mg dose caused mild symptoms of intoxication and an average reduction of 38% in both measures of acetylcholinesterase activity. Sarin in blood is rapidly degraded either in vivo or in vitro. Its primary inactive metabolites have in vivo serum half-lives of approximately 24 hours. The serum level of unbound isopropyl methylphosphonic acid (IMPA), a sarin hydrolysis product, ranged from 2–135 μg/L in survivors of a terrorist attack during the first four hours post-exposure. Sarin or its metabolites may be determined in blood or urine by gas or liquid chromatography, while acetylcholinesterase activity is usually measured by enzymatic methods.

A newer method called "fluoride regeneration" or "fluoride reactivation" detects the presence of nerve agents for a longer period after exposure than the methods described above. Fluoride reactivation is a technique that has been explored since at least the early 2000s. This technique obviates some of the deficiencies of older procedures. Sarin not only reacts with the water in the blood plasma through hydrolysis (forming so-called 'free metabolites'), but also reacts with various proteins to form 'protein adducts'. These protein adducts are not so easily removed from the body, and remain for a longer period of time than the free metabolites. One clear advantage of this process is that the period, post-exposure, for determination of sarin exposure is much longer, possibly five to eight weeks according to at least one study.

Toxicity

As a nerve gas, sarin in its purest form is estimated to be 26 times more deadly than cyanide. The LD₅₀ of subcutaneously injected sarin in mice is 172 μg/kg.

Sarin is highly toxic, whether by contact with the skin or breathed in. The toxicity of sarin in humans is largely based on calculations from studies with animals. The lethal concentration of sarin in air is approximately 28–35 mg per cubic meter per minute for a two-minute exposure time by a healthy adult breathing normally (exchanging 15 liters of air per minute, lower 28 mg/m³ value is for general population). This number represents the estimated lethal concentration for 50% of exposed victims, the LCt₅₀ value. The LCt₉₅ or LCt₁₀₀ value is estimated to be 40–83 mg per cubic meter for exposure time of two minutes. Calculating effects for different exposure times and concentrations requires following specific toxic load models. In general, brief exposures to higher concentrations are more lethal than comparable long time exposures to low concentrations. There are many ways to make relative comparisons between toxic substances. The list below compares sarin to some current and historic chemical warfare agents, with a direct comparison to the respiratory LCt₅₀:

• Hydrogen cyanide, 2,860 mg/(min·m³) – Sarin is 81 times more lethal
• Phosgene, 1,500 mg/(min·m³) – Sarin is 43 times more lethal
• Sulfur mustard, 1,000 mg/(min·m³) – Sarin is 28 times more lethal
• Chlorine, 19,000 mg/(min·m³) – Sarin is 543 times more lethal

Production and structure

Sarin is a chiral molecule because it has four chemically distinct substituents attached to the tetrahedral phosphorus center. The S_P form (the (–) optical isomer) is the more active enantiomer due to its greater binding affinity to acetylcholinesterase.

It is almost always manufactured as a racemic mixture (a 1:1 mixture of its enantiomeric forms) as this involves a much simpler synthesis while providing an adequate weapon.

A number of production pathways can be used to create sarin. The final reaction typically involves attachment of the isopropoxy group to the phosphorus with an alcoholysis with isopropyl alcohol. Two variants of this final step are common. One is the reaction of methylphosphonyl difluoride with isopropyl alcohol, which produces a racemic mixture of sarin enantiomers with hydrofluoric acid as a byproduct:

The second process, known as the "Di-Di" process, uses equimolar quantities of methylphosphonyl difluoride (Difluoro) and methylphosphonyl dichloride (Dichloro). This reaction gives sarin, hydrochloric acid and other minor byproducts. The Di-Di process was used by the United States for the production of its unitary sarin stockpile.