CHEMICAL TERRORISM

Chemical terrorism and nerveagentsAllister Vale

Timothy C Marrs

Paul Rice

AbstractSarin and VX were released on civilians in Japan on 11 occasions in the

period 1994 to 1995. Clinicians must be prepared, therefore, to treat

casualties from nerve agent exposure. This requires an understanding

of the mechanisms of nerve agent toxicity and the factors that influence

their clinical impact. Clinicians need to be able to make a rapid and accu-

rate diagnosis and use atropine, an oxime and diazepam optimally.

Keywords atropine; diazepam; nerve agents; oximes; sarin; soman;

tabun; VX

Chemical terrorism

The acquisition of chemical weapons by some twenty countries,

as well as by terrorists, has increased the likelihood of their use

worldwide. In World War I, chlorine, cyanide, phosgene and

sulphur mustard were used. Although available, nerve agents

were not used in World War II, but were employed by Iraq

against that country’s own Kurdish population, and there have

been allegations that nerve agents were employed during the

Iran-Iraq War. Sarin and VX were released on the civilian

population in Japan on 11 occasions in 1994e5.

As these releases in Japan indicate, there are important

differences between on-target military attacks against relatively

well-protected armed forces and nerve agent attacks initiated by

terrorists against a civilian population. In contrast to military

personnel, civilians are unlikely to be pre-treated with

pyridostigmine or protected by personal protective equipment

(PPE).

Allister Vale MD FRCP FRCPE FRCPG FFOM FAACT FBTS is Director of the National

Poisons Information Service (Birmingham Unit) and the West Midlands

Poisons Unit at City Hospital, Birmingham, UK. Competing interests:

none declared.

Timothy C Marrs OBE DSc FRCP FRCPath FBTS FSB MRSC Consulting Clinical

Toxicologist at the National Poisons Information Service (Birmingham

Unit) at City Hospital, Birmingham, UK. Competing interests: none

declared.

Paul Rice BM FRCPath FRCP FSB is Chief Scientist for Biomedical Sciences at

Dstl Porton Down, Salisbury, UK. Competing interests: none declared.

MEDICINE 40:2 77

Nomenclature

Two classes of nerve agent are recognized: G and V. Tabun

(NATO designation GA), sarin (GB) and soman (GD) were

synthesized in Germany in 1936, 1938 and 1944, respectively. GE

and GF were synthesized subsequently. The V agents were

introduced later and are exemplified by VX, synthesized in the

1950s. The G agents are both dermal and respiratory hazards,

whereas the V agents, unless aerosolized, are contact poisons.

Mechanisms of toxicity

Nerve agents are chemically related to organophosphorus insecti-

cides and have a similar mechanism of toxicity, but their mamma-

lian acute toxicity is considerably greater, particularly via the

dermal route. Nerve agents phosphonylate the serine hydroxyl

group at the active site of the enzyme acetylcholinesterase (AChE).1

This results in accumulation of acetylcholine (ACh), which in

turn leads to enhancement and prolongation of cholinergic

effects and depolarization blockade. The rate of spontaneous

reactivation of AChE is variable, which partly accounts for the

differences in acute toxicity between the nerve agents.

With soman in particular, an additional reaction occurs

termed ‘aging’. This involves monodealkylation of the dialkyl-

phosphonyl enzyme, which is then resistant to spontaneous

hydrolysis and reactivation by oximes (e.g. pralidoxime). Mono-

dealkylation occurs to some extent with all dialkylphosphony-

lated AChE complexes, but is generally of clinical importance

only in relation to the treatment of soman poisoning, in which it

is a serious problem.

The approximate aging half-lives of human AChE inhibited by

soman, sarin and tabun are 1.3 minutes, 3 hours and 13 hours,

respectively. With soman, therefore, aging is so fast that no

clinically relevant spontaneous reactivation of AChE is possible

before it has occurred, and recovery of function depends on

resynthesis of the enzyme. As a consequence, it is important that

an oxime is administered as soon as possible after exposure to

soman, to enable some reactivation of AChE before all the

enzyme becomes ‘aged’. Aging occurs more slowly and reac-

tivation relatively rapidly with nerve agents other than soman,

but early oxime administration is still clinically important in

patients poisoned with these agents. Reactivation of tabun-

inhibited acetylcholinesterase is slow or non-existent; this is

due not to aging but to its unique chemical structure.

Physicochemical properties

These are shown in Table 1.

Toxicity of nerve agents

The LCt50 (concentration in the air which kills half of the test

animals) by inhalation (30-minute exposure) in the mouse is 15

mg.m�3, 5 mg.m�3 and 1 mg.m�3 for tabun, sarin and soman,

respectively. By the subcutaneous route, the LD50 (dose required

to kill half of the test animals) in the rabbit is 375 mg/kg, 30 mg/

kg, 20 mg/kg and 14 mg/kg for tabun, sarin, soman and VX,

respectively.

� 2011 Published by Elsevier Ltd.

Physicochemical properties

Physical state

Is the nerve agent a volatile or non-volatile liquid? Sarin (volatility

22,000 mg.m�3 at 25�C) is much more volatile than tabun (610

mg.m�3 at 25�C), whereas VX is non-volatile (10.5 mg.m�3 at 25�C)

Vapour pressure

This is a measure of how quickly nerve agents evaporate and is

increased by rises in ambient temperature. For example, the vapour

pressure of sarin is 0.52 mmHg at 0�C and 2.9 mmHg at 25�C,

whereas that of tabun is 0.004 mmHg at 0�C and 0.07 mmHg at

25�C

Vapour density

Nerve agents with a high vapour density compared to air (e.g.

VX e 9.2) remain at ground level and tend to accumulate in

low-lying areas

Solubility in water

The solubility of tabun is 9.8 g/100 g; that of soman is 2.1 g/100 g

Odour

Tabun is said to have an almond/fruity odour; the other agents are

odourless when pure

Stability

Stability is the ability of nerve agents to survive dissemination and

transport to sites of deployment

Persistence

Non-persistent agents (e.g. sarin) disperse rapidly after release and

are immediate, short-duration hazards. They may be rendered

persistent using a ‘thickening agent’ (e.g. polyethylmethacrylate).

In contrast, persistent agents (e.g. VX) continue to be a contact

hazard and may vaporize over time to produce an inhalation

hazard.

Table 1

CHEMICAL TERRORISM

Routes of delivery

The major routes of delivery of nerve agents would be in air

(indoor and outdoor), water (hence the solubility of the nerve

agent is important) and food.

Meteorological factors

Meteorological factors are important for air delivery, because the

wind may disperse volatile agents, and a higher ambient

temperature increases the volatility and reduces persistence.

Some agents may freeze on clothing and then vaporize if carried

indoors. Rain tends to dilute toxicity and may promote hydrolysis

of the nerve agent.

Making the diagnosis

The diagnosis of nerve agent poisoning is based on the patient’s

history, clinical presentation and laboratory tests. In a patient

with a positive history, characteristic symptoms and depressed

erythrocyte AChE activity, the diagnosis is not difficult to make.

Unfortunately, the history may be unobtainable and the clinical

features may not be recognized as such by those clinicians who

have no personal experience of diagnosing cholinergic crisis as

MEDICINE 40:2 78

a result of nerve agent poisoning. Only the number of casualties

may prompt consideration of the diagnosis.

Features

Sidell2,3 has reviewed the features andmanagement of nerve agent

poisoning. Systemic nerve agent poisoningmay follow inhalation,

ingestion or dermal exposure, though the onset of systemic toxicity

is slower by the latter route. Miosis, which may be painful and last

for several days, occurs rapidly following ocular exposure to

a nerve agent and appears to be a very sensitive index of expo-

sure.4 Ciliary muscle spasm may impair accommodation and

conjunctival injection and eye painmay occur. Contact with liquid

nerve agent may produce localized sweating and fasciculation,

which may spread to involve whole muscle groups. Chest tight-

ness, increased salivation, rhinorrhoea and bronchorrhoea occur

within seconds/minutes of inhalation of a nerve agent. In contrast,

ingestion of food or water contaminated with nerve agent may

cause abdominal pain, nausea, vomiting, diarrhoea and involun-

tary defecation, though the onset of symptoms may be delayed.

Miosis may also occur as a systemic feature, though more

usually it follows direct exposure. Abdominal pain, nausea and

vomiting, involuntary micturition and defecation, muscle weak-

ness and fasciculation, tremor, restlessness, ataxia and convul-

sions may follow dermal exposure, inhalation or ingestion of

a nerve agent. Bradycardia, tachycardia and hypertension may

occur, dependent on whether muscarinic or nicotinic effects

predominate. If exposure is substantial, death may occur from

respiratory failure within minutes, whereas mild or moderately

exposed individuals usually recover completely, though electro-

encephalogram (EEG) abnormalities have been reported in those

severely exposed to sarin in Japan.5,6

Management

The general principles of management have been reviewed,7 and

include maintaining vital body functions, undertaking adequate

clinical monitoring, minimizing further absorption of the nerve

agent and using atropine, oxime and diazepam optimally.

Patients who are moderately or severely poisoned, as shown,

for example, by drowsiness, coma, hypotension, severe bron-

chorrhoea and marked muscle fasciculation, require treatment in

a critical care unit as soon as possible as further deterioration

may occur and mechanical ventilation may be required.

Bronchorrhoea requires prompt relief with intravenous atropine

and supplemental oxygen should be given to maintain PaO2 > 10

kPa (75 mmHg). If these measures fail, the patient should be intu-

bated and mechanical ventilation (with positive end-expiratory

pressure) should be instituted.

In severely poisoned patients who are hypotensive, it may be

necessary not only to expand plasma volume but also to use an

inotrope such as dobutamine 2.5e10 micrograms/kg/min or

adrenaline (epinephrine) 0.5e2.0 micrograms/kg/min. Careful

attention must be given to fluid and electrolyte balance and

adjustments to infusion fluids made as necessary. Heart rate,

blood pressure, ECG and arterial blood gases should be moni-

tored routinely. Cardiac arrhythmias should be treated conven-

tionally and hypoxia must be considered as a possible aetiology.

The management of convulsions and muscle fasciculation

with diazepam is discussed below.

� 2011 Published by Elsevier Ltd.

CHEMICAL TERRORISM

Minimizing absorption of the nerve agent

In principle, after resuscitation and stabilization of the casualty,

if exposure was dermal, thorough skin decontamination should

be carried out by removing all contaminated clothing and

washing affected skin thoroughly with soap and cold water,

including exposed areas (e.g. hands, arms, face, neck and hair).

This should be done without care-givers themselves being

contaminated and casualties becoming hypothermic. However,

given the circumstances of likely exposure and the number of

casualties, decontamination may be difficult to achieve in prac-

tice. The removal and appropriate storage of contaminated

clothing may be all that can be done. It is essential that decon-

tamination does not lead to delays in the administration of

antidotes to those who are severely poisoned. If exposure is by

inhalation, skin decontamination is unnecessary.

Atropine and oximes

Atropine competes with ACh and other muscarinic agonists for

a common binding site on the muscarinic receptor, thus effec-

tively antagonizing the actions of ACh at muscarinic receptor

sites. If rhinorrhoea or bronchorrhoea develops, atropine (2 mg

in an adult; 20 micrograms/kg in a child) should be administered

intravenously immediately and the dose repeated (with doubling

of the dose in severe cases) at least every 2-5 minutes until

secretions are minimal and the patient is atropinized (dry skin

and sinus tachycardia). In severe cases, very large doses of

atropine may be required.

Although HI-6 is probably the best antidote overall,8 it is not

yet generally available. However, with the possible exception of

the treatment of cyclosarin and soman poisoning, when HI-6 is

preferred, a review of the available experimental evidence

suggests that there are no clinically important differences

between pralidoxime, obidoxime and HI-6 in the treatment of

poisoning due to other nerve agents.1

An oxime, such as pralidoxime chloride, should be administered

parenterally in a dose of 30 mg/kg every 4 hours to patients with

systemic featureswho require atropine.Alternatively, an infusionof

pralidoxime chloride (8e10 mg/kg/hour) may be given, the infu-

sion rate depending on the severity. The duration of oxime treat-

ment depends on the presence of features, the clinical response and

the red blood cell (RBC) AChE activity. It is recommended that an

oxime should be administered for as long as atropine is indicated. In

most individuals, this will be less than 48 hours.

Diazepam

Intravenous diazepam 10e20 mg (1e5 mg in children) is useful

in controlling apprehension, agitation, fasciculation and

convulsions.9 The dose may be repeated as required. In some

experimental studies, addition of diazepam to an atropine and

oxime regimen further increased survival.

Human butyrylcholinesterase

The successful experimental use of a protein bioscavenger, human

plasma-derived butyrylcholinesterase (huBuChE), as a post-

MEDICINE 40:2 79

exposure treatment against dermal exposure to VX up to 2 h

post-exposure has been demonstrated, though the best survival

outcomes were seen when the huBuChE was administered before

the onset of observable signs of systemic poisoning.10,11

Treatment of casualties outside hospital

Healthcare workers should don adequate self-protection before

decontaminating casualties, because secondary contamination

has been reported. If available, pressure-demand, self-contained

breathing apparatus should be used in contaminated areas.

Casualties should be moved to hospital as soon as possible.

Casualties should receive antidotal treatment as soon as

possible after exposure. This is of particular importance in

poisoning with soman, because of the very rapid aging of the

soman-enzyme complex. In casualties who develop rhinorrhoea

and bronchorrhoea, atropine and whatever oxime is available

should be administered as a matter of urgency. This can be

achieved most conveniently by the use of an autoinjector.1 A

REFERENCES

1 Marrs TC, Rice P, Vale JA. The role of oximes in the treatment of

nerve agent poisoning in civilian casualties. Toxicol Rev 2006; 25:

297e323.

2 Medical aspects of chemical and biological warfare. In: Sidell FR,

Takafuji ET, Franz DR, eds. Medical aspects of chemical and biological

warfare. Washington DC: Office of the Surgeon General at TMM

Publications, 1997.

3 Sidell FR. Clinical considerations in nerve agent intoxication. In:

Somani SM, ed. Chemical warfare agents. San Diego: Academic Press,

1992; 155e194.

4 Nozaki H, Hori S, Shinozawa Y, et al. Relationship between pupil size

and acetylcholinesterase activity in patients exposed to sarin vapor.

Intensive Care Med 1997; 23: 1005e7.

5 Murata K, Araki S, Yokoyama K, et al. Asymptomatic sequelae to

acute sarin poisoning in the central and autonomic nervous system 6

months after the Tokyo subway attack. J Neurol 1997; 244: 601e6.

6 Sekijima Y, Morita H, Yanagisawa N. Follow-up of sarin poisoning in

Matsumoto. Ann Intern Med 1997; 127: 1042.

7 Vale JA, Rice P, Marrs TC. Managing civilian casualties affected by

nerve agents. In: Marrs TC, Maynard RL, Sidell FR, eds. Chemical

warfare agents: toxicology and treatment. 2 edn. Chichester: John

Wiley & Sons, 2007; 249e260.

8 Lundy PM, Hamilton MG, Sawyer TW, Mikler J. Comparative protective

effects of HI-6 and MMB-4 against organophosphorous nerve agent

poisoning. Toxicology 2011; 285: 90e6.

9 Marrs TC. The role of diazepam in the treatment of nerve agent

poisoning in a civilian population. Toxicol Rev 2004; 23: 145e57.

10 Mumford H, Price E, Lenz DE, Cerasoli DM. Post-exposure therapy

with human butyrylcholinesterase following percutaneous VX

challenge in guinea pigs. Clin Toxicol 2011; 49: 287e97.

11 Lenz DE, Clarkson ED, Schulz SM, Cerasoli DM. Butyrylcholinesterase

as a therapeutic drug for protection against percutaneous VX. Chem

Biol Interact 2010; 187: 249e52.

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