Nerve Agents: Lethal Organo- Phosphorus Compounds
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Nerve Agents: Lethal organo-phosphorus compounds inhibiting cholinesterase
Source: A FOA Briefing Book on Chemical Weapons
Among lethal CW agents, the nerve agents have had an entirely
dominant role since the Second World War. Nerve agents acquired
their name because they affect the transmission of nerve impulses
in the nervous system. All nerve agents belong chemically to the
group of organo-phosphorus compounds. They are stable and easily
dispersed, highly toxic and have rapid effects both when absorbed
through the skin and via respiration. Nerve agents can be
manufactured by means of fairly simple chemical techniques. The
raw materials are inexpensive and generally readily available.
It was not until the early 1930's that German chemists observed that
organo-phosphorus compounds could be poisonous. In 1934, Dr
Gerhard Schrader, a chemist at IG Farben, was given the task of
developing a pesticide. Two years later a phosphorus compound
with extremely high toxicity was produced for the first time.
According to contemporary regulations, discoveries with military
implications had to be reported to the military authorities, which
was also done with Schrader's discovery. This phosphorus
compound, given the name tabun, was the first of the substances
later referred to as nerve agents.
A factory for production of the new CW agent was built and a total
of 12 000 tonnes of tabun were produced during the years 1942-
1945. At the end of the war the Allies seized large quantities of this
nerve agent. Up to the end of the war, Schrader and his co-workers
synthesized about 2 000 new organo-phosphorus compounds,
including sarin (1938). The third of the "classic" nerve agents,
soman, was first produced in 1944. These three nerve agents are
known as G agents in the American nomenclature. The manufacture
of sarin never started properly and up to 1945 only about 0.5 tonne
of this nerve agent was produced in a pilot plant.
Immediately after the war, research was mainly concentrated on
studies of the mechanisms of the nerve agents in order to discover
more effective forms of protection against these new CW agents.
The results of these efforts led, however, not only to better forms of
protection but also to new types of agents closely related to the
By the mid-1950's a group of more stable nerve agents had been
developed, known as the V-agents in the American nomenclature.
They are approximately ten-fold more poisonous than sarin and are
thus among the most toxic substances ever synthesized.
The first publication of these substances appeared in 1955. The
authors, R. Ghosh and J.F. Newman, described one of the
substances, known as Amiton, as being particularly effective
against mites. At this time, intensive research was being devoted to
the organo-phosphorus insecticides both in Europe and in the
United States. At least three chemical firms appear to have
independently discovered the remarkable toxicity of these
phosphorus compounds during the years 1952-53. Surprisingly
enough, some of these substances were available on the market as
pesticides. Nonetheless, they were soon withdrawn owing to their
considerable toxicity also to mammals.
In the United States, the choice fell in 1958 on a substance known
by its code name VX as suitable as a CW agent of persistent type.
Full-scale production of VX started in April 1961 but its structure
was not published until 1972.
Physical and Chemical Properties
The most important nerve agents included in modern CW arsenals are:
Tabun, O-ethyl dimethylamidophosphorylcyanide, with the
American denomination GA. This nerve agent is the easiest to
manufacture. Consequently, it is more likely that developing
countries start their CW arsenal with this nerve agent whereas
industrialized countries consider tabun to be out-of-date and of
limited use. Sarin, isopropyl methylphosphonofluoridate, with the
American denomination GB, a volatile substance mainly taken up
through inhalation. Soman, pinacolyl methylphosphonofluoridate,
with the American denomination GD, a moderately volatile
substance which can be taken up by inhalation or skin contact.
Cyclohexyl methylphosphonofluoridate, with the American
denomination GF, a substance with low volatility which is taken up
through skin contact and inhalation of the substance either as a gas
or aerosol. O-ethyl S-diisopropylaminomethyl
methylphosphonothiolate, better known under the American
denomination VX, a persistent substance which can remain on
material, equipment and terrain for long periods. Uptake is mainly
through the skin but also through inhalation of the substance as a
gas or aerosol.
The formulae for some nerve agents are:
Tabun, GA: (CH3)2N-P(=O)(-CN)(-OC2H5)
Sarin, GB: CH3-P(=O)(-F)(-OCH(CH33)2)
Soman, GD: CH3-P(=O)(-F)(-CH(CH3)C(CH3)3
The same type of phosphorus compounds are used as, for example,
insecticides. In the structure of insekticides P(=O) has generally
been replaced by P(=S) and a less reactive group than (-F), (-CN)
or (-SCH2CH2N[CH(CH3)2]2) is used.
All nerve agents in pure state are colourless liquids. Their volatility
varies widely. The consistency of VX may be likened to an
involatile oil and is therefore classified as belonging to the group of
persistent CW agents. Its effect is mainly through direct contact
with the skin. Sarin is at the opposite extreme, being an easily
volatile liquid (comparable with, e.g., water), and mainly taken up
through the respiratory organs. The volatilities of soman, tabun and
GF are between those of sarin and VX.
By addition of a thickener it is possible for, e.g., soman, to be
transferred from the category of volatile CW agents to the
Sarin is very soluble in water whereas other nerve agents are more
sparingly soluble. VX has the unexpected property of being soluble
in cold water but sparingly soluble in warm water (>9.5 oC).
The most important chemical reactions of nerve agents take place
directly at the phosphorus atom. The P-X bond is easily broken by
nucleophilic reagents, such as water or hydroxyl ions (alkali). In
aqueous solution at neutral pH the nerve agents decompose slowly,
whereas the reaction is greatly accelerated following the addition of
alkali. The result is a non-toxic phosphoric acid.
The formation of the non-toxic phosphoric acid is also accelerated
by rise in temperature or by a catalyst (e.g., hypochlorite ions from
bleaching powder). This hydrolysis forms the basis of most
decontamination procedures utilizing decomposition. In general, we
may assume that an area exposed to G-agents decontaminates itself
within a few days. However, V-agents may remain on the ground
for several weeks because of their greater stability with respect to
water and their much lower volatility. At pH-levels between 7 and
10 large quantities of VX are transformed into an extremely non-
volatile product of hydrolysis which is incapable of penetrating
skin. Admittedly, this is less toxic than VX but still implies a risk
The nucleophilic attack on the phosphorous atom (P) also forms
the basis of different types of coulour reaction used in detecting
Most chemical ammunition can be described as unitary, which
implies that it contains one active ready-to-use CW agent. Binary
technology implies that the final stage in the synthesis of the nerve
agent is moved from the factory into the warhead, which thus
functions as a chemical reactor. Two initial substances which are
stored in separate containers are mixed and allowed to react and
form the nerve agent when the ammunition (bomb, projectile,
grenade, etc.) is on its way towards the target.
Until the actual moment of use, the ammunition contains only
relatively non-toxic initial substances. It is therefore considered to
be safer to manufacture, store, transport and, finally, destroy.
However, some critics question whether this practically untested
type of new ammunition is reliable. The technique for mixing
substances in bombs and rockets is complicated and requires space.
The reaction has to be controlled (e.g., the temperature) and the
process should preferably take place without solvents.
-The principle for the use of binary weapons. Two
canisters with the two liquid components are placed one after the
other in the shell. When the shell is fired, forces of inertia will
press the liquid contents in the front canister backwards and burst
the wall separating the canisters. The rifling in the barrel gives the
shell a spinning velocity of about 15,000 r.p.m. which contributes
to the mixing.-
In 1991 Iraq declared to the United Nations Special Commission
(UNSCOM) a different binary munitions concept. According to
this the munitions were stored containing one component. Shortly
before use the munitions were opened and the second component
was added. Thus the reaction began even before the munitions were
Binary components for the three most common nerve agents
(American code names are given in brackets) are the following:
Sarin (GB-2): methylphosphoryldifluoride (DF) + isopropanol. The isopropanol is included in a mixture (OPA) with isopropylamine which binds the hydrogen fluoride generated.
Soman (GD-2): methylphosphoryldifluorid (DF) + pinacolylalcohol.
VX-2: O-ethyl O-2-diisopropylaminoethyl methylphosphonite (QL) + sulphur.
Mechanism of Action
A characteristic of nerve agents is that they are extremely toxic and
that they have very rapid effect. The nerve agent, either as a gas,
aerosol or liquid, enters the body through inhalation or through the
skin. Poisoning may also occur through consumption of liquids or
foods contaminated with nerve agents.
The route for entering the body is of importance for the period
required for the nerve agent to start having effect. It also influences
the symptoms developed and, to some extent, the sequence of the
different symptoms. Generally, the poisoning works faster when the
agent is absorbed through the respiratory system than via other
routes. This is because the lungs contain numerous blood vessels
and the inhaled nerve agent can therefore rapidly diffuse into the
blood circulation and thus reach the target organs. Among these
organs, the respiratory system is one of the most important. If a
person is exposed to a high concentration of nerve agent, e.g., 200
mg sarin/m3 (see table) death may occur within a couple of
Poisoning takes longer when the nerve agent enters the body
through the skin. Nerve agents are more or less fat-soluble and can
penetrate the outer layers of the skin. However, it takes some time
before the poison reaches the deeper blood vessels. Consequently,
the first symptoms do not occur until 20-30 minutes after the initial
exposure but subsequently the poisoning process may be rapid if
the total dose of nerve agent is high. The toxic effect of nerve
agents depends on them becoming bound to an enzyme,
acetylcholinesterase, and thereby inhibit this vital enzyme's normal
biological activity in the cholinergic nervous system.
When exposed to a low dose of nerve agent, causing minor
poisoning, characteristic symptoms are increased production of
saliva, a running nose and a feeling of pressure on the chest. The
pupil of the eye becomes contracted (miosis) which impairs night-
vision. The accommodation capacity of the eye is also reduced so
that short-range vision deteriorates and the victim feels pain when
he tries to focus on an object nearby. This is accompanied by
headache. More unspecific symptoms are tiredness, slurred speech,
hallucinations and nausea.
Exposure to a higher dose leads to a more dramatic development
and symptoms are more pronounced. Bronchoconstriction and
secretion of mucous in the respiratory system leads to difficulty in
breathing and to coughing. Discomfort in the gastrointestinal tract
may develop into cramp and vomiting. Involuntary discharge of
urine and defecation may also form part of the picture. The
discharge of saliva is powerful and the victim may experience
running eyes and swetting. Symptoms from the skeletal muscles are
very typical. If the poisoning is moderate, this may express itself as
muscular weakness, local tremors or convulsions.
When exposed to a high dose of nerve agent, the muscular
symptoms are more pronounced. The victim may suffer convulsions
and lose consciousness. To some extent, the poisoning process may
be so rapid that earlier mentioned symptoms may never have time to
Muscular paralysis caused by nerve agents also affects the
respiratory muscles. Nerve agents also affect the respiratory centre
of the central nervous system. The combination of these two effects
is the direct cause of death. Consequently, death caused by nerve
agents is a kind of death by suffocation.
The figure shows examples of poisoning results caused by different
doses of sarin vapour. In similarity to other poisons, different
individuals are more or less sensitive to nerve agents. The figure
shows that the lethal dose for the most sensitive individuals is
about 70 mg.min/m3 and about twice this level for more resistant
The toxic effect depends on both the concentration of nerve agent
in the air inhaled (C) and the time of exposure (t). In extremely
high concentrations there is a simple relationship, C t, which gives
a certain toxic effect. Inhalation of sarin vapour with a
concentration of 100 mg/m3 for one minute gives the same result as
inhalation of 50 mg/m3 for two minutes. However, at low
concentrations this relationship does not apply since the human
body is capable of some degree of detoxification. In order to obtain
a corresponding effect, it is then necessary to have relatively longer
periods of exposure. The values given in the table for toxicity of
nerve agents apply to high concentrations.
Antidotes and Methods of Treatment
Nerve agents have an extremely rapid effect. If medical methods of
treatment are to serve any purpose, they must be introduced
immediately. In many countries, the armed forces have access to an
auto-injector containing antidotes to nerve agents. It is so simple to
use that the soldier can easily give himself or another person an
The Swedish auto-injector.
One example is the Swedish auto-injector, which contains two
active components: HI-6 (500 mg) and atropine (2 mg). HI-6 is an
oxime which directly reacts with the cause of the injury, i.e., nerve
agent-inhibited acetylcholinesterase. HI-6 functions as a reactivator
which restores the enzyme to an operational condition. Oximes
have a poor penetration capacity into the brain and thus mainly
work in the peripheral nervous system.
The various nerve agents cause poisoning which are more or less
easy to treat with oximes. From this standpoint, VX and sarin are
the easiest to treat and all oximes used increase the chances of
surviving poisoning with these nerve agents. Obidoxime is the most
effective against tabun poisoning but also HI-6 has a positive effect.
Soman causes the most difficultly treated poisoning and can only
be treated with HI-6.
Soman poisoning is complicated by the inhibited enzyme going
through an "ageing" process. Following the ageing the enzyme
cannot be reactivated by any oxime. It is possible that HI-6 has
some further positive antidote effect in addition to its reactivating
The other active component in the auto-injector is atropine.
Atropine is the classical antidote in cases of poisoning by organo-
phosphorus compounds. It is a medication which releaves the
symptoms but does not attack the cause of the injury. Atropine
becomes bound to the receptors for acetylcholine, which are
present in the cholinergic synapse (see figure). When acetylcholine
is bound, the signal is transmitted but if atropine has become
bound to the receptor, then no such transmission takes place.
Atropine thus gives protection against the excess of acetylcholine
which results from inhibition of acetylcholinesterase. Atropine has
effects only within certain parts of the cholinergic nervous system.
There are two types of acetylcholine receptors, the nicotinic which
are found, e.g., in the skeletal muscles, and the muscarinic, which
are found in, e.g., smooth muscles, glands and the central nervous
system. Atropine blocks the muscarinic receptors. Atropine and
oxime may therefore be considered to complement each other and
the two antidotes also have a synergetic effect, i.e., they boost each
An additional auto-injector can be given to victims of nerve agents
if their situation does not improve within ten minutes.
Subsequently, the victim should be treated by qualified medical
staff who should initially inject additional atropine and an anti-
convulsant drug, diazepam. In cases of severe poisoning by nerve
agents, large doses of atropine (grammes) may be required. The
level of operational acetylcholinesterase is gradually restored by the
body's own production but this process requires at least two weeks.
During this period, and possibly also later, the victim may require
medical care not only for mental disorders such as difficulty in
sleeping, amnesia, difficulties in concentrating, and anxiety, but
also for muscular weakness. Mental problems may also occur efter
long exposure to extremely low concentrations to nerve agents.
There are also medical antidotes which can be taken preventively.
These antidotes are taken as tablets and used when ordered in
connection with maximum C-preparedness. One of the tablets
contains a carbamate, pyridostigmine, as active ingredient.
Pyridostigmine inhibits acetylcholinesterase and protects the
enzyme against inhibitory effects of nerve agents. The dose is low
and leads to about 25 per cent inhibition. The pyridostigmine-
inhibited enzyme is continuously released to active state and
thereby can reasonably effectively maintain the transfer of nerve
impulses despite injury caused by nerve agents. The effect is
restricted to the peripheral cholinergic nervous system since the
substance does not enter the brain.
Pyridostigmine does not cause any side effects since there is a large
excess of enzyme in the cholinergic synapse. In actual fact, 1-2 per
cent of functional enzyme is sufficient to have a functioning
synapse. This explains why carbamate pretreatment has such good
Pretreatment with carbamate should be combined with oxime
therapy (the auto-injector) after the poisoning in order to provide
maximum effect. This combination reduces the toxic effects of all
A diazepam tablet is also generally given as a pretreatment,
primarily affecting the central nervous system. Diazepam
strengthens the effect of other nerve agent antidotes. There will be
better prospects of survival and less injury. Diazepam also provides
protection against permanent brain damage which may result from
heavy exposure to nerve agents.
Pretreatment has best effect if a warning system is available and
operative, since the tablets need about 30 min. to have effect after
being swallowed. The best protective effect is achieved after about
two hours, which is followed by decreasing efficacy. If the situation
so requires, treatment can be repeated at eight-hourly intervals for
some days. The tablets should not be taken once nerve agent injury
has occurred. Admittedly, diazepam has a positive effect but
pyridostigmine at that stage will aggravate the injury.
Toxicity of the most important nerve agents to man
Tabun 200 4 000
Sarin 100 1 700
Soman 100 300
VX 50 10
The values are estimates of the doses which have lethal effects on
man. LD50 expresses the dose at which 50 per cent of the exposed
population will die as a result of their injuries. A different measure
is used for inhalation, the product of the concentration (C) and the
length of exposure (t). Again, L stands for lethal and 50 for 50 per
cent effect. The toxicity sequence is the same for the two routes of
exposure but the differences are much greater in skin exposure.
This is mainly caused by the more volatile nerve agents evaporating
from naked skin. If the evaporation is prevented, e.g., by tightly
fitting clothing, the difference will be less.
Physical Properties of Nerve Agents
Property Tabun Sarin Soman GF VX
Molecular weight 162. 1140. 1182. 2180. 2267.4
Density g/cm3* 1.0731. 0891. 0221. 1201. 008
Boiling-point oC 24714716792**300
Melting-point oC-50-56-42< -30-39
Vapour pres. mm Hg*0.072.90.30.060.0007
Solubility in water % *10oo2~23 (oo < 9,5oC)* = at 25 oC ** = at 10 mm Hg
A simplified picture of a cholinergic synapse, with the
nerve in which acetyllcholine is formed and the receiving side
(muscles, glands, etc.) with receptors. Acetylcholine is formed and
released from the nerve cell. On the other side of the synapse it
binds to a muscle cell receptor for a split second. The signal to, e.g.
bend an arm or take a breath has now been transferred from the
nervous system to the performing muscle. In the presence of nerve
agent the enzyme acetylcholinesterase, which is responsible for
breaking down acetylcholine, is inhibited. The receptor keep on
sending signals to the muscle cell, which leads to muscle cramp.
Effect of Nerve Agents and Antidotes on the Enzyme Acetylcholinesterase
The toxic effect of nerve agents depends on the substance
inhibiting the enzyme acetylcholinesterase in the cholinergic nerve
system. This enzyme is responsible for breaking down the signal
substance acetylcholine, a process requiring two steps - acetylation
by means of a serine in the active site and hydrolysis:
Enzyme-OH + CH3C(=O)-O-(CH2)2-N+(CH3)3
reacts with the release of choline to give
which is rapidly hydrolysed to
Enzyme-OH + CH3COOH
Degradation of the signal substance in the cholinergic synapse
takes place extremely rapidly depending on the enzyme being
available in large amounts and also since it is extremely effective.
Under optimum conditions, each enzyme molecule hydrolyzes
about 15 000 acetylcholine molecules per second. The reaction
mechanism for nerve agents is similar but with the important
difference that the rate of the final, hydrolyzing step is negligible.
Consequently, the enzyme becomes irreversibly inhibited, with the
nerve agent covalently bound to the enzyme via the serine in the
releases X- to give
Inhibition of acetylcholinesterase is thus a progressive process and
the degree of inhibition depends not only on the concentration of
nerve agent but also on the time of exposure. Soman is the most
potent inhibitor of acetylcholinesterase among the nerve agents. A
concentration of 10-9 M is sufficient to inhibit the enzyme by more
than 50 per cent within 10 minutes.
Reactivation Using Oxime
Oximes, with the general formula R-CH=NOH, can reactivate the
phosphorylated enzyme. The oxime attacks the P-O bond whereby
an operational enzyme and a phosphorylated oxime, which is
rapidly hydrolyzed to non-toxic products, are formed. The
efficiency of such reactivation depends strongly on the types of all
the three components involved - enzyme, oxime and nerve agent.
In the "ageing" reaction, the phosphorylated enzyme is dealkylated:
reacts to give
The reaction is catalyzed by the enzyme itself and the reaction may
be extremely fast. Soman-inhibited acetylcholinesterase becomes
"aged" within a few minutes. After the "ageing", the inhibited
enzyme is even more resistant to hydrolysis and reactivation with
oxime is without effect.
Pretreatment With the Carbamate Pyridostigmine
Carbamates, with the general formula R1R2-N-C(O)-O-R3, inhibit
acetylcholinesterase. They carbamylate the enzyme with a
mechanism analogous to the substrate and nerve agent reactions.
The carbamylated enzyme hydrolyzes slowly with a half-life of
about 30 minutes.