Mustard gas
| 1. Name |
| 1.1 Substance |
| 1.2 Group |
| 1.3 Synonyms |
| 1.4 Identification numbers |
| 1.4.1 CAS |
| 1.4.2 Other numbers |
| 1.5 Brand names/Trade names |
| 1.6 Manufacturers, importers |
| 2. SUMMARY |
| 2.1 Main risks and target organs |
| 2.2 Summary of clinical effects |
| 2.3 Relevant laboratory analyses/sample collection |
| 2.4 First-aid measures and management principles |
| 3. PHYSICO-CHEMICAL PROPERTIES |
| 3.1 Origin of the substance |
| 3.2 Chemical structure (formula, molecular weight) |
| 3.3 Physical properties |
| 3.3.1 Colour |
| 3.3.2 State/form |
| 3.3.3 Description |
| 3.4 Other characteristics |
| 4. USES/HIGH RISK CIRCUMSTANCES OF POISONING |
| 4.1 Uses |
| 4.1.1 Uses |
| 4.1.2 Description |
| 4.2 High risk circumstances of poisoning |
| 4.3 Occupationally exposed populations |
| 5. ROUTES OF ENTRY |
| 5.1 Oral |
| 5.2 Inhalation |
| 5.3 Dermal |
| 5.4 Eye |
| 5.5 Parenteral |
| 5.6 Others |
| 6. KINETICS |
| 6.1 Absorption by route of exposure |
| 6.2 Distribution by route of exposure |
| 6.3 Biological half-life by route of exposure |
| 6.4 Metabolism |
| 6.5 Elimination and excretion by route of exposure |
| 7. TOXICOLOGY |
| 7.1 Mode of action |
| 7.2 Range of toxicity |
| 7.2.1 Human data |
| 7.2.1.1 Adults |
| 7.2.1.2 Children |
| 7.2.2 Relevant animal data |
| 7.2.3 Relevant in vitro data |
| 7.2.4 Workplace standards |
| 7.2.5 Acceptable daily intake (ADI) and other guideline levels |
| 7.3 Carcinogenicity |
| 7.4 Teratogenicity |
| 7.5 Mutagenicity |
| 7.6 Interactions |
| 8. Toxicological analyses |
| 9. CLINICAL EFFECTS |
| 9.1 Acute poisoning |
| 9.1.1 Ingestion |
| 9.1.2 Inhalation |
| 9.1.3 Skin exposure |
| 9.1.4 Eye contact |
| 9.1.5 Parenteral exposure |
| 9.1.6 Other |
| 9.2 Chronic poisoning |
| 9.2.1 Ingestion |
| 9.2.2 Inhalation |
| 9.2.3 Skin exposure |
| 9.2.4 Eye contact |
| 9.2.5 Parenteral exposure |
| 9.2.6 Other |
| 9.3 Course, prognosis, cause of death |
| 9.4 Systematic description of clinical effects |
| 9.4.1 Cardiovascular |
| 9.4.2 Respiratory |
| 9.4.3 Neurological |
| 9.4.3.1 CNS |
| 9.4.3.2 Peripheral nervous system |
| 9.4.3.3 Autonomic nervous system |
| 9.4.3.4 Skeletal and smooth muscle |
| 9.4.4 Gastrointestinal |
| 9.4.5 Hepatic |
| 9.4.6 Urinary |
| 9.4.6.1 Renal |
| 9.4.6.2 Other |
| 9.4.7 Endocrine and reproductive systems |
| 9.4.8 Dermatological |
| 9.4.9 Eyes, ears, nose, throat: local effects |
| 9.4.10 Haematological |
| 9.4.11 Immunological |
| 9.4.12 Metabolic |
| 9.4.12.1 Acid-base disturbances |
| 9.4.12.2 Fluid and electrolyte disturbances |
| 9.4.12.3 Other |
| 9.4.13 Allergic reactions |
| 9.4.14 Other clinical effects |
| 9.4.15 Special risks |
| 9.5 Other |
| 10. MANAGEMENT |
| 10.1 General principles |
| 10.2 Relevant laboratory analyses |
| 10.2.1 Sample collection |
| 10.2.2 Biomedical analysis |
| 10.2.3 Toxicological analysis |
| 10.3 Life support procedures and symptomatic/specific treatment |
| 10.4 Decontamination |
| 10.5 Elimination |
| 10.6 Antidote treatment |
| 10.6.1 Adults |
| 10.6.2 Children |
| 10.7 Management discussion |
| 11. ILLUSTRATIVE CASES |
| 11.1 Case reports from the literature |
| 11.2 Internally-extracted data on cases |
| 12. ADDITIONAL INFORMATION |
| 12.1 Availability of antidotes |
| 12.2 Specific preventative mesaures |
| 12.3 Other |
| 13. REFERENCES |
| 14. AUTHOR(S), REVIEWER(S), ADDRESS(ES), DATE(S) |
1. Name
1.1 Substance
Mustard gas (sulphur mustard)
1.2 Group
Alkylating agents
1.3 Synonyms
1, 1' thiobis [2 chloroethane]
bis-(2-chloroethyl) sulphide
beta, beta' dichloroethyl sulphide
2, 2' dichloroethyl sulphide
bis (beta-chloroethyl) sulphide
1-chloro-2 (beta-chlorodiethylthio) ethane
sulphur mustard
yellow cross liquid
Kampfstoff "Lost"
Yperite
H
HT
HD
1.4 Identification numbers
1.4.1 CAS
505-60-2
1.4.2 Other numbers
No other numbers found.
1.5 Brand names/Trade names
To be filled in by centre using the monograph.
1.6 Manufacturers, importers
To be filled in by centre using the monograph.
2. SUMMARY
2.1 Main risks and target organs
Acute poisoning - Main risks
Mustard gas is a powerful irritant and vesicant, used as a
chemical warfare agent. The main risk of acute poisoning
exists with the use of sulphur mustard vapour in war and
occasionally during laboratory work. However, due to its
persistence poisoning may occur at a later stage.
Target organs: Skin, eyes, respiratory tract, bone
marrow.
Chronic toxicity - Main risks
Workers employed in the manufacture of mustard gas are at an
increased risk to develop cancer. Risk of mortality from
influenza, pneumonia and chronic respiratory disease was also
reported to be higher in persons occupationally exposed to
mustard gas.
Delayed toxic effects of sulphur mustard may occur months and
years after exposure, mainly with respiratory disorders.
Target organs: Lung, larynx, pharynx, oral cavity, bone
marrow and sexual organs.
2.2 Summary of clinical effects
Acute poisoning
Effects of exposure to mustard gas vapour or liquid are
typically delayed for several hours. The delay is shorter in
case of liquid contamination. In the first hour after
exposure to mustard gas vapour or liquid no signs or symptoms
are usually produced, but nausea, retching, vomiting and eye
smarting have been occasionally reported.
Exposure to superlethal concentrations may induce
convulsions, coma and death within one hour after
exposure.
Nausea, fatigue, headache, eye inflammation with intense eye
pain, lachrymation, blepharospasm, photophobia and
rhinorrhoea, followed by reddening of face and neck, soreness
of throat and increased pulse and respiratory rate develop at
two to six hours post exposure.
Six to twenty four hours post exposure the above symptoms are
generally increased in severity and are accompanied by skin
inflammation followed by blister formation in the warmest
areas such as genito-perineal area, buttocks, axillae and on
the inner aspects of thighs.
In the next twenty four hours the condition generally
worsens, blistering becomes more marked, coughing appears.
Mucus, pus and necrotic slough may be expectorated. Intense
itching of skin and increased skin pigmentation occur.
The blood count may reveal anaemia and neutropenia four days
post exposure. In general, initial leukocytosis on the first
2 to 3 days after exposure is followed by leukopenia in
severe intoxicated patients.
A few hours after the ingestion of mustard contaminated food
or water, the following signs and symptoms develop: nausea,
vomiting, abdominal pain, bloody vomiting and diarrhoea with
signs of shock and prostration in severe poisoning. The
patients who are severly intoxicated may die during the
second week after exposure due to respiratory complications
and septic shock.
Chronic toxicity
Increased risk of cancer of oral cavity and respiratory tract
has been observed in workers chronically exposed to mustard
gas. Development of cancer is likely after a single exposure.
Cases of leukaemia, lung and stomach cancers were observed in
Iranian combatants who were exposed once to sulphur
mustard.
2.3 Relevant laboratory analyses/sample collection
Blood, urine and blister fluids should be collected for
haematological, biochemical and toxicological analyses.
Acute overdose
Full blood count, serum electrolytes, urea, protein levels.
Arterial blood gasses determination is indicated in cases of
pulmonary oedema and Adult respiratory distress syndrome.
Culture of sputum and eye exudate. Blood cultures where
indicated.
Skin blisters may be aspirated and the fluid obtained
analysed for thiodiglycol. The same estimation may be
performed in blood and urine in order to differentiate
blistering produced by mustard gas from that produced by
other agents such as Lewisite. Contents of blisters are not
toxic to attendants (Sulzberger, 1943). However, secondary
exposure of the nursing and technical staff occured in Iran
after caring for the patients and handling the blister
fluid.
Chronic toxicity
Mutagenicity can be evaluated by counting sister chromatid
exchanges in lymphocytes (Wulf et al., 1985).
2.4 First-aid measures and management principles
Life support
Support respiratory and cardiovascular function. Treat
pulmonary oedema and respiratory distress syndrome. The
patients with severe leukopenia (_1000 WBC/mm) should be
isolated to avoid secondary infection and septic shock.
Eye decontamination
Irrigate the eyes immediately with copious amounts of normal
saline or water for at least 15 minutes. Since sulphur
mustard is lipid soluble, it is advisable to use diluted
infant shampoo as well.
Skin decontamination
Remove any contaminated clothing. Wash exposed area
thoroughly with water and neutral soap. Areas of liquid
contamination should be decontaminated using Fullers' earth.
Washing with organic solvents such as paraffin followed by
the use of soap and water has also been recommended.
Gut decontamination
Emesis should not be induced. Gastric lavage is indicated
after ingestion of food or water contaminated with mustard
gas. Airways should be protected by cuffed endotracheal
intubation. Prior to gastric lavage stomach contents should
be diluted by 100 to 200 mL of milk or water.
Activated charcoal is of unproven benefit, but may be
used.
Symptomatic treatment
Provide adequate analgesia. Routine use of morphine is not
indicated due to its depression of respiration.
Correct fluid and electrolyte imbalance carefully, avoiding a
net positive fluid balance. Systemic and inhaled
corticosteroids are effective in antagonizing pulmonary
toxicity.
Treat eyes with antibiotics, preferably sulphacetamide 20%
solution, and mydriatics. In case of keratitis the use of
corticosteroid eye drops is contraindicated.
Dark glasses are helpful, but contact lenses are
contraindicated. Reassure the patient that visual recovery is
usual. Seek ophthalmological opinion.
Treat skin lesions with standard therapy for severe chemical
burns, preferably with silver sulphadiazine cream.
Treat infection with appropriate antibiotic.
Observe patients who ingested contaminated food or water with
mustard gas for the development of complications caused by
gastrointestinal tract burns, such as haemorrhage and
perforation.
Blood transfusion may be required in patients with bone
marrow depression.
3. PHYSICO-CHEMICAL PROPERTIES
3.1 Origin of the substance
Mustard gas is a synthetic substance prepared by
treating ethylene with sulfur chloride (Levinstein process)
or by treating 2, 2'- dihydroxyethyl sulfide with HCl gas
(German process) (Merck Index, 1989). The synthesis was first
reported by Victor Meyer in 1886. Mustard gas was first used
as a chemical warfare agent in 1917.
3.2 Chemical structure (formula, molecular weight)
(ClCH2CH2)2S
CH2CH2Cl
/
S
\
CH2CH2Cl
MW 159.08
3.3 Physical properties
3.3.1 Colour
Colourless or yellow liquid (1 atm. and
15°C).
3.3.2 State/form
Oily liquid at 1 atm. and 15°C.
3.3.3 Description
Melting point: 13 to 14°C
Boiling point: 215 to 217°C
Vapour pressure at: 0°C 0.025 mm
30°C 0.090 mm
Solubility: very sparingly in water; soluble in fats
and organic solvents.
Heavier than water.
Weak mustard or garlic like odour.
3.4 Other characteristics
Hydrolysed by water to thiodiglycol and hydrochloric
acid. Half life for hydrolysis is 5 minutes at 37°C.
Hydrolysis is catalysed by increased temperature and presence
of alkalies. Oxidized by bleaching powder and chloramines
into sulfoxides (harmless) and sulfones (possess vesicant
activity) and sulfides.
Vapour has marked penetrating power; penetrates cloth,
leather, wood and paint on metallic surfaces. Metal, glass
and glazed tiles are impermeable. Persistent in the
environment. Hydrolyses with water only occurs after thorough
mixing. Since it is heavier than water it sinks and it is
believed that it can provide a continuing local source of
poison for some time. Dangerous oily film of sulphur mustard
remains on the water surface.
Contact with sea water turns mustard gas from its normal
liquid state to viscous or even solid one. It is believed
that large quantities lie loose in lumps on the sea bed of
Baltic sea where gas bombs were dumped at the end of the
second world war (Perera & Thomas, 1987).
It decomposes at high temperatures and produces toxic
compounds containing sulphur and chlorine oxides with strong
lachrymatory actions.
4. USES/HIGH RISK CIRCUMSTANCES OF POISONING
4.1 Uses
4.1.1 Uses
4.1.2 Description
In chemical warfare with intention to:
(a) to prevent or delay certain activities within
restricted areas;
(b) to disturb or exhaust personnel by compelling them
to wear respirators or to remain on gas-proof premises
for lengthy periods (under special weather conditions
only) (Lundquist, 1983).
It may be used as liquid or vapour and may be
delivered by artillery shell, rocket, bomb or aircraft
spray.
The use is likely to be influenced by the following
meteorological factors:
(a) Temperature. High temperatures increase the
toxicity of mustard gas. Low temperature may freeze it
and so increase its persistence. The danger of
carrying such an agent into a warm building on boots
and equipment and so giving off toxic vapour, should
be born in mind.
(b) Rain. Heavy rain reduces its toxicity.
(c) Atmospheric stability. Persistence of vapour is
prolonged by inversion (the air temperature higher
than that of the ground).
4.2 High risk circumstances of poisoning
Mustard gas is suitable for tactical attacks in limited
operations or restricted areas putting army personnel at the
highest risk of exposure. Civilian inhabitants in the
neighbourhood of military activities may be exposed to some
risk of being affected by both chemical contamination and
drifting chemical clouds (Lundquist, 1983). Due to its
persistency mustard gas can remain in the ground and in water
for a long time especially so in cold conditions. Exposure
may therefore occur some time after the attack.
Furthermore 'accidental' release following an attack on
stocks of mustard gas can cause several casualties as well as
severe environmental damage (Marshall, 1987).
Accidental exposure may occur during dumping of unused
mustard gas or during coincidental encounters with improperly
disposed of containers.
Food and water are easily contaminated when exposed to liquid
or vapour forms of mustard gas. Intoxication is likely
following ingestion of contaminated food and water. Mustard
gas is freely soluble in oils and fats and large quantities
can be absorbed by food with a high fat content. Only food
sealed in impermeable containers such as tins, glass or
glazed earthenware jars and foil wrappings is completely
protected (See Section 12.2 for Decontamination of food and
water).
Laboratory workers involved in organic synthesis of sulphur
mustard and also health professionals, who are involved in
the caring of the patients and handling of blister fluids,
are at risk.
4.3 Occupationally exposed populations
Military staff in the battle field are at risk of acute
exposure in case of chemical warfare. Chemical accidents with
sulphur mustard may occur during manufacturing,
transportation, storage and use.
Workers employed in the manufacture of mustard gas are
believed to be at risk of developing cancers of the oral
cavity and the respiratory tract (Wada et al. 1968, Easton
et al. 1988).
5. ROUTES OF ENTRY
5.1 Oral
Oral exposure is likely if food or water are
contaminated with mustard gas. Air that is polluted with
sulphur mustard may cause oesophagogastric damage if
swallowed.
5.2 Inhalation
Usual route of entry.
5.3 Dermal
Mustard gas has a marked penetrating power making skin a
common route of entry.
5.4 Eye
Usual route of entry.
5.5 Parenteral
Unknown.
5.6 Others
Unknown.
6. KINETICS
6.1 Absorption by route of exposure
Mustard gas is absorbed in the respiratory tract when
inhaled.
It has been demonstrated that 80% of sulphur mustard applied
to the skin evaporates, 10% remains in the skin and 10% gets
absorbed systemically (Renshaw, 1946). It can penetrate the
skin by contact with either the liquid or vapour. The rate of
penetration is proportional to dose, temperature and
humidity.
6.2 Distribution by route of exposure
Equilibrium between blood and tissues was achieved
within 5 minutes after perfusion of the lung in dog (IARC,
1975).
Mustard gas is highly fat soluble and expected to accumulate
in those tissues with a high fat content.
Levels of mustard in the tissues of an Iranian patient who
died 7 days after exposure to mustard gas were qualitatively
analysed (Drasch et al., 1987). The concentrations of sulphur
mustard determined by GC/MS and atomic absorption
spectrophotometer in the tissues were as follows:
fat (from thigh) 15.1 mg/kg
brain 10.7 mg/kg
abdominal skin 8.4 mg/kg
kidney 5.6 mg/kg
muscle 3.9 mg/kg
liver 2.4 mg/kg
cerebrospinal fluid 1.9 mg/L
spleen 1.5 mg/kg
blood 1.1 mg/L.
6.3 Biological half-life by route of exposure
The precise half life is not known.
The parent compound could be detected in human urine up to a
week after acute exposure but not several days later
(Vycudilik, 1985).
6.4 Metabolism
Metabolic studies with radioactively labelled mustard
gas were performed in rodents (Somani & Babu, 1989). The
following metabolic pathways were proposed: hydrolyses to
thiodiglycol and S-oxidation to sulfoxide and sulfone,
followed by conjugation. Urinary metabolites in rats
consisted of thiodiglycol and conjugates (15%),
glutathione-bis-beta-chloroethylsulfide conjugates (45%),
glutathione-bis-beta chloroethylsulfone (7%),
bis-beta-chloroethylsulfone and conjugates (8%), and small
amounts of cysteine conjugates.
Urinary metabolites formed from intraperitoneal injection in
rats were bis-cysteinylethylsulfone and thiodiglycol.
6.5 Elimination and excretion by route of exposure
The urinary excretion of unmetabolized sulphur mustard
is low (Drasch et al., 1987). This is probably caused by its
strong fixation to the lipid compartments of the body (See
6.2).
The major portion of mustard gas excreted in the urine
represents compounds formed by alkylation, followed by
metabolites formed by enzymatic action.
The majority of an intravenously-injected dose of 1.5 mg/kg
35S-mustard gas was excreted in the urine within 72 hours in
mice and rats; approximately 6% was eliminated in the faeces
(IARC, 1975).
7. TOXICOLOGY
7.1 Mode of action
Sulphur mustard is an alkylating agent. Alkylating
agents bind covalently to various nucleophilic molecules such
as DNA, RNA, proteins and components of cell membranes
(Somani & Babu, 1989).
DNA: Mustard gas causes cross linking of DNA strands.
Alkylation of DNA can result in the disruption of its
function, i.e. coding errors, breakage of the strand, low
fidelity repair, inhibition of replication and cell
death.
It has been proposed that DNA damage can be followed by
release of plasminogen activator which may play a role in
skin blistering by disrupting the dermal-epidermal
junction.
RNA: Alkylation of RNA molecules can result in altered
translation and altered protein synthesis resulting in cell
death.
Proteins: Binding to proteins mainly with the thiol group of
cysteine produces structural changes which may alter the
normal physiology of the cell i.e. altered enzyme
activity.
Membranes: Mustard gas can either alkylate structural
proteins located in the cell membrane or induce lipid
peroxidation which may result in irreversible changes and
cell death.
NAD+ depletion: The cell has a capacity to repair damaged DNA
but the repair process can further disrupt functioning of the
cell. Enzymes involved in the DNA repair mechanism utilise
NAD+ and cause NAD+ depletion. Consequently glycolysis
becomes inhibited which could lead to cell death
(Papirmeister, 1983).
7.2 Range of toxicity
7.2.1 Human data
7.2.1.1 Adults
Death has been recorded by dermal
exposure after 1 hour at 64 mg/kg, and by
inhalation at 1500 mg min/m3 (Marshall,
1987).
The toxicity of mustard gas vapour is
expressed in terms of the profile of exposure
(Ct) in mg min/m3, and that of liquid in
œg/cm2.
Effects on eyes:
50 mg min/m3 maximum safe dosage
70 mg min/m3 mild reddening of the eyes
100 mg min/m3 partial incapacitation due to
eye effects
200 mg min/m3 total incapacitation due to
temporary blindness
Effects on skin:
100 to 400 mg min/m3 erythema
200 to 1000 mg min/m3 skin burns
750 to10000 mg min/m3 severe incapacitating
skin burn
50 œg/cm2 erythema in 5 min.
250-500 œg/cm2 blistering in 5 min.
Increased temperature enhances the effects.
7.2.1.2 Children
Not known.
7.2.2 Relevant animal data
LD50 (percutaneous):rat 9 mg/kg
dog 20 mg/kg
rabbit 100 mg/kg
LC50 (inhalation): rat 100 mg/m3 for 10 minutes
rabbit 280 mg/m3 for 10 minutes
monkey 80 mg/m3 for 10 minutes
7.2.3 Relevant in vitro data
Mutagenicity and genotoxicity of mustard gas
were observed in several in vitro tests such as
bacterialscreening tests, human Hela cells and mouse
lymphocytes (Dabney, 1989).
Increased sister chromatid exchanges were seen in
lymphocytes of exposed fishermen (Wulf, et al.
1985).
7.2.4 Workplace standards
McNamara et al., (1975) proposed the following
workplace standards with personal protective
devices:
Ceiling 0.4 mg/m3
CL - 6 minutes 0.3 mg/m3
CL - 3 hours 0.01 mg/m3
CL - five 8 hour days 0.003 mg/m3.
A ceiling is the concentration that must not be
exceeded for any period of time and places a limit on
the maximum upper excursion of concentration during
the averaging hours.
A control limit (CL) is the maximum average airborne
concentration of a substance to which it is believed
that essentially all members of a specified population
can be exposed for a specified period without adverse
effects.
7.2.5 Acceptable daily intake (ADI) and other guideline levels
ADI is not determined.
Mc Namara et al. (1975) have also proposed the levels
of exposure for the general population:
Ceiling 0.01 mg/m3
CL - 3 hours 0.00033 mg/m3
CL - 8 hours 0.00017 mg/m3
CL - 72 hours 0.00001 mg/m3
The definitions for a ceiling and a control limit (CL)
are given in Section 7.2.4.
7.3 Carcinogenicity
Mustard gas is a well documented animal carcinogen and
is listed as an accepted human carcinogen (IARC, 1975).
Increased mortality from oral cavity and respiratory tract
cancer has been shown in several studies in humans exposed to
mustard gas, with risk of mortality being greater from
chronic occupational exposure than from sporadic exposure
(Case & Lea, 1955; Wada et al. 1968; Easton et al.,
1988)
7.4 Teratogenicity
Teratogenic potential of orally administered sulphur
mustard was evaluated in rats and rabbits. Maternal toxicity
was observed at all concentrations of mustard gas but
significant fetal effects such as decreased weights, reduced
ossification and skeletal anomalies were observed only at the
highest dose (2 mg/kg). It was concluded that sulphur mustard
is not teratogenic in rats and rabbits (Somani & Babu,
1989).
However, nitrogen mustards, compounds related to sulphur
mustard and used in cancer chemotherapy were shown to be
teratogenic in all laboratory species tested (Schardein,
1985). Multiple defects including cleft palate, central
nervous system, jaw, limb and digit abnormalities were
observed. In humans, digital defects and kidney malformations
were described.
7.5 Mutagenicity
Simple mutations, structural chromosomal aberrations,
sex chromosome loss and nondisjunction and heritable
translocations have all been observed in numerous in vitro
tests (Dabney, 1989).
Sister chromatid exchanges were measured in fishermen exposed
to leaking mustard gas shells (Wulf et al., 1985) and were
found to be significantly higher than in a control group
matched for sex, age and tobacco consumption.
7.6 Interactions
No information found.
8. Toxicological analyses
To be completed.
9. CLINICAL EFFECTS
9.1 Acute poisoning
A characteristic feature of exposure to sulphur mustard
is an asymptomatic period which may last for up to two hours.
The duration of this latent period depends on the mode of
exposure, environmental temperature and individual
sensitivity.
9.1.1 Ingestion
A few hours after ingestion nausea, vomiting,
abdominal pain, bloody vomiting and diarrhoea, and in
cases of severe poisoning shock and prostration, may
be expected. Systemic toxic effects in the respiratory
tract, skin, eye, and bone marrow may occur
thereafter.
9.1.2 Inhalation
20 to 60 minutes post exposure: Usually none,
but nausea, retching, vomiting and eye smarting can
occur. Respiratory irritation with coughing and
dyspnoea may also occur.
2 to 6 hours post exposure: Nausea, fatigue, headache,
rhinorrhea, sore throat. Voice becomes hoarse and may
be completely lost. Pulse and respiratory rate are
increased. Eye symptoms and signs are described in
Section 9.1.4.
6 to 24 hours post exposure: Increase in severity of
above effects.
48 hours post exposure: Severe coughing, mucus, pus
and slough may be expectorated.
4 days or more post exposure: Initial leukocytosis
followed by leucopenia.
9.1.3 Skin exposure
20 to 60 minutes post exposure: Usually none,
but a mild erythema with pruritus may occur.
2 to 6 hours post exposure: Nausea, fatigue, headache,
reddening of the face and neck, increased pulse and
respiratory rate.
6 to 24 hours: Increase in severity of above effects.
Inflammation of inner thighs, genitalia, perineum,
buttocks, axillae followed by blister formation.
Blisters vary in size are pendulous and filled with
clear yellow fluid.
48 hours post exposure: condition worsened. Marked
blistering, intense itching of the skin and increased
skin pigmentation occur.
4 days or more post exposure: leucopenia.
9.1.4 Eye contact
20 to 60 minutes post exposure: usually none,
but eye smarting is possible.
2 to 6 hours post exposure: inflammation, intense
pain, lachrymation, blepharospasm, photophobia.
1 to 10 days post exposure: corneal epithelial loss
and stromal opacification. Secondary infection and
uveitis may occur, but are uncommon. Late:
abnormalities of limbal and vascular bed, ischemia and
ulceration.
9.1.5 Parenteral exposure
Not known.
9.1.6 Other
Not known.
9.2 Chronic poisoning
9.2.1 Ingestion
Not known.
9.2.2 Inhalation
Increased incidence of cancer of oral cavity
and respiratory tract was reported among workers
employed in the manufacture of mustard gas (Wada et
al. 1968, Easton et al. 1988).
Nishimoto et al. (1970) found high prevalence of
chronic obstructive lung disease in workers exposed
repeatedly to mustard gas or lewisite.
Delayed toxic effects, mainly on the respiratory tract
(obstructive and restrictive lung disease), and
malignancy may occur years after a single
exposure.
9.2.3 Skin exposure
Exposure may result in diffuse changes of skin
pigmentation with areas of hyperpigmentation and
hypopigmentation and scarring of the skin.
9.2.4 Eye contact
Direct exposure of sulphur mustard droplets to
the eyes have occured amongst Iranian combatants in
the field. As a result erosive keratoconjunctivitis
and blepharospasms occured.
9.2.5 Parenteral exposure
Not known.
9.2.6 Other
Not known.
9.3 Course, prognosis, cause of death
Most of the victims with minimal exposure to mustard gas
recover without any consequences.
The majority of eye lesions are resolved in 28 days post
exposure.
Superficial skin lesions heal in 14 to 21 days, while deep
skin lesions may be expected to heal in up to 60 days.
However, residual scaring with itching may last up to 10
years and longer.
The time course for the resolution of respiratory tract
lesions is difficult to predict but lung function tests may
provide a useful guide. Initial obstructive lung disease
followed by restrictive lung disease.
Initial leukocytosis followed by leucopenia is a usual
finding in mustard gas poisoning and recovers within 14 days.
Marked leucopenia is a sign of sinister prognosis, leading to
overwhelming infection and multiple organ failure and
death.
Death may also result due to pulmonary oedema, Adult
respiratory distress syndrome, airway obstruction, arrythmias
and cardiac arrest.
9.4 Systematic description of clinical effects
9.4.1 Cardiovascular
Acute: Arrhythmias - AV block and possibly
cardiac arrest (NATO, 1973).
Chronic: None described.
Acute-on-chronic: None described.
9.4.2 Respiratory
Acute: Coughing and tachypnoea. Inflammation
of bronchial mucosa with bleeding, purulent
secretions, and sloughing of the necrotic mucosa.
Haemorrhagic oedema in peribronchial alveoli. In
severe cases a syndrome similar to adult respiratory
distress syndrome can develop.
Chronic: Chronic bronchitis. Bronchial stenosis.
Significantly increased incidence (p < 0.001) of lung
cancer was reported in workers employed in the
manufacture of mustard gas (Easton et al., 1988). Wada
et al. (1968) observed an increased incidence of
cancer, while Nishimoto et al. (1970) reported an
increased incidence of chronic obstructive lung
disease in Japanese factory workers involved in
production of mustard gas.
Acute respiratory tract infections were shown to be a
more common cause of death in the elderly exposed to
mustard gas compared to the un-exposed (Easton et al.,
1988).
9.4.3 Neurological
9.4.3.1 CNS
Acute: Apathy, mental disturbance
and anxiety states were reported among
soldiers exposed to mustard gas during the
First World War. Neuropsychiatric disorders
including insomnia, anxiety, agitation,
depression and acute psychosis were observed
in Iranian combatants.
Chronic: The above features may persist for
some time.
Occasionally chronic psychosis with a poor
response to treatment has occured.
9.4.3.2 Peripheral nervous system
Cases of peripheral polyneuropathy
have been observed.
9.4.3.3 Autonomic nervous system
None described.
9.4.3.4 Skeletal and smooth muscle
None described.
9.4.4 Gastrointestinal
Acute: Nausea, vomiting, abdominal pain, bloody
diarrhoea.
Chronic: Perforation, bleeding and late stricture
formation can result from burns in the
gastrointestinal tract.
9.4.5 Hepatic
None described.
Transient elevation of transaminases were observed in
Iranian patients with sulphur mustard
poisoning.
9.4.6 Urinary
9.4.6.1 Renal
None described.
Transient elevation of proteinuria and
haematuria were observed in Iranian
patients.
9.4.6.2 Other
None described.
9.4.7 Endocrine and reproductive systems
None described.
Cases of abnormal sperm shape, oligospermia and
occasionally azospermia were observed in Iranian
patients.
9.4.8 Dermatological
Acute: (a) Striking erythema of the skin,
accompanied by intense itching particularly in
axillary and genito perineal areas. As erythema fades,
areas of increased pigmentation appear; (b) Blistering
of the skin. Blisters vary in size, are delicate and
can be easily rubbed off. Rubbing can lead to the
development of new crops of blisters (Nikolsky's
sign), which can appear as late as two weeks post
exposure. Blisters are uncomfortable and may feel
tense, but are not painful. However, when they appear
over joints, they are reputedly painful and may hinder
movement of these joints. Blisters are filled with
fluid which may cause blistering if applied to skin.
Healing is characterised by hyper and
hypo-pigmentation changes; (c) Deep burning, which can
lead to full thickness skin loss, accompanied with
severe pain. Skin burns characteristically take longer
to heal than typical thermal burns.
Chronic: Diffuse changes of skin pigmentation with
areas of hyperpigmentation. Scarring of the
skin.
9.4.9 Eyes, ears, nose, throat: local effects
Acute:
Eyes: marked conjunctivitis, local oedema,
blepharospasm, lachrymation, miosis, photophobia,
severe eye pain.
Nose: profuse rhinorrhea and rarely epistaxis.
Oral cavity, pharynx, larynx: inflammation and
ulceration of the palate, nasopharynx, oropharynx and
larynx, with hoarseness of voice and temporary
aphonia.
Chronic:
Eyes: corneal ulceration, adhesions of the iris to the
lens capsule, visual impairment and permanent
blindness.
Oral cavity, pharynx, larynx: Increased incidence of
cancer was reported in British workers employed in the
production of mustard gas (Easton et al.,
1988).
9.4.10 Haematological
Acute: Early leucocytosis, followed by mild
leucopenia. Severe leukopenia, trombocytopenia and
erythropenia indicate bone marrow depression.
Chronic: Bone marrow depression leading to leukaemia.
9.4.11 Immunological
Immunosuppression, by sulphur mustard,
observed either as cellular (mainly T-cells) or
humoral (IgA suppression) was observed in Iranian
patients.
Acute: See 9.4.13.
Chronic: See 9.4.13.
9.4.12 Metabolic
9.4.12.1 Acid-base disturbances
Acute: Tachypnoea may cause
respiratory alkalosis which may be followed
by acidosis due to pulmonary oedema and
chemical burns.
Chronic: None described.
9.4.12.2 Fluid and electrolyte disturbances
Acute: Dehydration.
Chronic: None described.
9.4.12.3 Other
None described.
9.4.13 Allergic reactions
Acute: Cutaneous sensitization may occur from
repeated exposure of 1 to 3 weeks.
Chronic: Sensitivity to mustard gas. A morbilliform
rash and eczematoid dermatitis around old skin lesions
are characteristic of sensitization reactions (NATO,
1973).
Acute-on-chronic: Sensitized individuals may have a
shorter latent period than nonsensitized persons for
development of dermal symptoms (NATO, 1973).
9.4.14 Other clinical effects
None described.
9.4.15 Special risks
Pregnancy: The risk for the development of
fetal malformations following the exposure to nitrogen
mustards was estimated to 1:3 (Schardein, 1985), but
no information was found on sulphur mustard. Fetal
abnormalities such as cleft lip was observed in a few
cases of the Iranian victims.
Breast feeding: No information found, but due to high
solubility of mustard gas in fats it could be expected
that it would appear in the milk of the exposed
lactating mothers.
Enzyme deficiency: No data available.
9.5 Other
None described.
10. MANAGEMENT
10.1 General principles
Management of mustard gas poisoning consists of
decontamination and symptomatic treatment. The importance of
rapid and efficient decontamination can not be
overemphasized.
10.2 Relevant laboratory analyses
10.2.1 Sample collection
To be completed.
10.2.2 Biomedical analysis
Full blood count, serum electrolytes, urea,
protein levels. Arterial blood gasses determination is
indicated in case of pulmonary toxicity.
Culture of sputum and eye exudate.
Blood cultures where indicated.
Skin blisters may be aspirated and the fluid obtained
analysed for thiodiglycol. The same estimation may be
performed in blood and urine in order to differentiate
blistering produced by mustard gas from that produced
by other agents such as Lewisite. Contents of blisters
are not toxic to attendants. (Sulzberger,
1943).
10.2.3 Toxicological analysis
To be completed.
10.3 Life support procedures and symptomatic/specific treatment
Life support:
Mantain respiratory and circulatory function.
Replace extracellular fluid loss, electrolytes and proteins.
Blood transfusion is indicated in case of bone marrow depression.
Symptomatic treatment:
GENERAL:
Analgesics. The choice of analgesic depends on the severity
of pain in each individual. Mild analgesics can be given
together with diazepam to dissociate pain from panic. Routine
use of morphine is contraindicated due to its depression of
respiration. Carbamazepine 200 mg thrice daily has been
reported to control intense burning pain during skin healing
(Newman-Taylor & Morris, 1991). Give appropriate antibiotics
as indicated. Antiemetics, i.e. phenothiazines if vomiting
persits.
SKIN:
Bland lotions (Prapoderm) for erythema and mild blistering.
Silver sulphadiazine. Corticosteroid preparations (i.e.
Hydrocortisone lotion, Beclomethasone dipropionate) reduce
irritation and itching. Antihistamines (i.e. promethazine,
dimethidine) can be of value in reducing itching. Skin
grafting may occasionaly be necessary in full thickness
burns.
EYES:
Start immediate irrigation with normal saline or water. Use
Vaseline on follicular margins to prevent sticking. Avoid
cocaine because it may produce sloughing of the corneal
epithelium. Topical corticosteroids (i.e. 1% prednisolone
four times a day) should be continued until all signs of
inflammation have gone in order to prevent late corneal
dissolution. In case of corneal erosion and keratitis topical
corticosteroid must not be used. Use Chloramphenicol eye
drops, as appropriate. Mydriatics i.e. hyoscine (0.5%) is
administered to prevent sticking of the iris to the lens.
Dark glasses may alleviate photophobia. Give reassurance
that ocular and visual recovery is usual. Contact lenses are
contraindicated. Topical ascorbate and citrate drops are
indicated when severe burns with limbal ischaemia and
epithelial defects persist for more than 5 days and are
accompanied by structural changes. Apply 10% potassium
ascorbate and 10% sodium citrate alternatively each once an
hour (half hourly drops) for 14 hours. These drops can be
safely discontinued when a stable epithelial covering
develops. Seek ophthalmological opinion.
10.4 Decontamination
Remove victims from the source of decontamination.
Eye decontamination: Irrigate the eyes immediately with
copious amounts of normal saline or water for at least 15
minutes.
A solution of diluted infant shampoo may be useful for eye
decontamination.
Skin decontamination: Remove any contaminated clothing. Wash
exposed area thoroughly with water and neutral soap. Areas
of liquid contamination should be decontaminated using
Fullers' earth. Washing with organic solvents such as
paraffin oil followed by the use of soap and water has also
been recommended.
Gut decontamination: Emesis should not be induced. Gastric
lavage is indicated after ingestion of mustard gas. Airways
should be protected by cuffed endotracheal intubation. Prior
to gastric lavage stomach contents should be diluted by 100
to 200 ml of milk or water. Activated charcoal is of
unproven benefit but may be used.
10.5 Elimination
No reliable method established.
10.6 Antidote treatment
10.6.1 Adults
No specific antidote is available. See 10.7.
10.6.2 Children
No specific antidote is available. See 10.7.
10.7 Management discussion
Bone marrow depression in severe intoxicated patients
may be seen as an irreversible consequence of mustard gas
poisoning. Granulocyte, platelet and red cell transfusions as
well as bone marrow transplantation have been recommended for
treatment of aplastic anaemia. The value of Granulocyte
Colony Stimulating Factor has not been assessed but may be of
use.
Several independent scientists (Callaway & Pearce, 1958;
Fasth & Sorbo, 1973; Vojvodic et al., 1985) have shown that
cysteine, thiosulfate and other thiols reduce the toxicity of
sulphur and nitrogen mustards (Nitrogen mustards are used in
chemotherapy of malignant diseases). The use of thiols has
been proposed in the treatment of mustard gas poisoning, but
has not been established.
Numerous other supportive measures were used in treating
causalties from the Iran-Iraq war: H2 antagonists to prevent
stress ulceration. Heparin has been used to prevent deep
venous thrombosis. A single large dose of methyl prednisolone
(2 g) may prevent general tissue damage. Administration of
Vitamins C, B12 and folate may be of use.
Haemodialysis and haemoperfusion have been suggested,
although there is no firm theoretical basis for such
therapy.
11. ILLUSTRATIVE CASES
11.1 Case reports from the literature
Mustard gas was used for the first time by Germans in
1917 at Ypres. More than 14,000 British casualties were
produced in the first three months and by the end of the
first world war more than 120,000 British mustard casualties
had occurred. The most commonly injured areas of the body
were: eyes (86.1%), respiratory tract (75.3%), scrotum
(42.1%), face (26.6%), anus (23.9%), back (12.9%), armpits
(12.5%), neck (12%).
Adolph Hitler was exposed to mustard gas during the first
world war. He described his personal experience in "Mein
Kampf" (Vol. 1, 1924): "During the night of October 13 to
14th (1918) the British opened an attack with gas on the
front south of Ypres. They used the yellow gas whose effect
was unknown to us, at least from personal experience. I was
destined to experience it that very night. On a hill south of
Werwick, in the evening of 13 October, we were subjected to
several hours of heavy bombardment with gas bombs, which
continued through the night with more or less intensity.
About midnight a number of us were put out of action, some
for ever. Towards morning I also began to feel pain. It
increased with every quarter of an hour, and about seven
o'clock my eyes were scorching as I staggered back and
delivered the last dispatch I was destined to carry in this
war. A few hours later my eyes were like glowing coals, and
all was darkness around me."
During the second world war mustard gas was not used but
Lundquist (1983) reports of a large number of Allied soldiers
and sailors who were exposed to mustard gas towards the ends
of second world war as a result of German bombing of the
harbour at Bari in Italy. Of the two dozen ships destroyed,
one was carrying a cargo of about 100 thousand kilograms of
mustard-gas bombs. Much of the mustard gas was released into
the water and some of it dissolved in the floating oil. More
than 1000 people were killed and of these deaths more than
100 were determined to have been specifically caused by
mustard-gas poisoning and many more to have been due to
various indirectly associated reasons, such as disablement
followed by drowning.
Eleven fishermen have become exposed to mustard gas from
leaking shells that were dumped into the Baltic sea after the
Second World War (Wulf et al., 1985). They presented with
very inflamed skin, especially in the axilla and in the
genitofemoral regions, yellow blisters on the hands and legs,
painful irritation of the eyes and transient blindness. In
two pulmonary oedema developed. Haemoglobin values,
leucocyte, differential and platelet counts, lactate
dehydrogenase and aspartate aminotransferase activities and
serum creatinine were normal. Sister chromatid exchange count
was significantly higher than in a control group. All the
fishermen recovered, but might have an increased cancer
risk.
It is believed that mustard gas was used by Iraq in the
recent war against Iran. Dunn (1986) reports of an attack in
1984 using aerial bombs which, upon exploding at ground
level, released a grey cloud with a garlic like smell.
Victims of the attack suffered severe eye, bronchial and lung
damage accompanied by a skin rash. Several deaths followed
acute pulmonary dysfunction. It has been suggested that
during this attack mustard gas had been released from a bomb
in a form of micronized aerosol particles which were
sufficiently small to create only a skin rash, rather than
the typical skin lesions.
Bockmeyer (1985) reports of three Iranian patients who were
treated in Germany following exposure to mustard gas during
the Iran-Iraq war. They all suffered from first or second
degree skin burns, corrosive changes in the mouth and pharynx
and damage to the respiratory tract. In the second week
changes in the blood picture appeared with the impairment of
clotting. All three patients had to be ventilated and two of
them required tracheotomy. Daily lavage with Prednisolon-21
hemisuccinate sodium and Dexapanthenol solution was also
used. N-acetylcystein was applied intravenously and as an
aerosol. All three patients recovered in three months.
Leipner et al. (1987) describe a late sequel of poisoning
with mustard gas, not described in the literature to date, in
a 22 years old patient. The patient was admitted to the
hospital two years post exposure for dermatomyositis. Chest
X-ray revealed lung fibrosis, mediastinal emphysema and
pulmonary hypertension. CAT scan of the thorax confirmed the
X-ray findings. Fibrosis was located in the dorsobasal
periphery of the right lung. Perivascular collections of air
were observed in the left lung communicating via the left
hilus with the mediastinal emphysema. This finding suggested
the presence of bronchial or lung parenchyma fistulas.
Bronchoscopy did not reveal any large defects in the trachea
and large bronchi. Lung function tests showed a restrictive
ventilatory disorder without a considerable obstructive
component.
Thirty nine Iranian soldiers and doctors exposed to sulphur
mustard in the Iran-Iraq war were treated in the UK during
1985 and 1986 (Rees et al., 1991). They all suffered from
skin burns and most had mucosal damage and eye inflammation.
Severe cough which responded poorly to symptomatic treatment
was the most common respiratory effect. Airflow obstruction
was a prominent feature. Low arterial PO2 was a common
finding. Chest x rays showed various abnormalities such as
lobar consolidation and widespread ill-defined opacities.
Three patients required artificial ventilation and two of
these died with respiratory, renal and bone marrow failure 7
and 14 days after exposure. In these patients remarkable
sloughing was shown in the tracheal and bronchial mucosa.
Bone marrow depression was common in patients with evidence
of moderate exposure. One patient died due to adrenal
haemorrhage associated with thrombocytopenia.
Newman-Taylor and Morris (1991) reported about another five
Iranian soldiers treated in the UK in 1988, 11 days after
exposure to mustard gas. They had injuries of the skin, eyes,
mouth, upper respiratory tract and lungs. Skin burns involved
the exposed areas, axillae, buttocks and genitalia. The
treatment of skin burns included twice daily saline baths,
silver sulphadiazine cream dressings and paraffin gauze. Pain
was a prominent feature and was treated with opiates and
antihistamines. Carbamazepine 600 mg daily was successfully
used to control the pain unresponsive to opiates and
antihistamines. The eyes of the patients were severely
inflamed with a non-ulcerated keratitis and haemorrhagic
conjunctivitis which were treated with dexamethasone and
ascorbate drops 3-hourly. Three patients suffered severe
inflammation and ulceration of oral and laryngeal mucosae and
were treated with simple mouth washes. All patients had
productive cough, four of them had inspiratory crackles,
airway obstruction and hypoxemia. One patient had a lung
abscess caused by Methicillin resistant Staphylococcus
aureus. This patient also showed suppressed leucocyte
response to infection. Respiratory infections were treated
with antibiotics. The skin and the eyes recovered in 2 to 6
weeks without damage. The respiratory function improved
slowly but steadily during the six weeks of hospitalisation.
Nebulized bronchodilators were used but did not provide much
symptomatic or objective benefit.
A follow up study of Japanese workers who were engaged in the
manufacture of mustard gas between 1929 and 1945 showed that
they had experienced 33 deaths from cancer of the respiratory
tract, compared with 0.9 expected. The tumours occurred
centrally and were of squamous or undifferentiated cell type
(Wada et al., 1968).
Easton et al. (1988) also provided evidence that chronic
exposure to mustard gas can cause cancers of respiratory
tract. Significant excesses of malignant tumours of oral
cavity, pharynx, larynx and lungs were observed among British
workers employed in manufacture of mustard gas during the
second world war. Incidence of deaths from nonmalignant acute
and chronic respiratory diseases was also increased.
The reports on the possible long term respiratory effects of
acute exposure to mustard gas are controversial. One follow
up study on soldiers who were exposed to mustard gas during
the first world war suggests that mustard gas had no effect
on the development of lung cancer later in life (Case & Lea,
1955), while the other provided evidence that the incidence
was slightly increased among those war veterans exposed to
mustard gas (Beebe, 1960). It is probably unlikely that a
single exposure to mustard gas can cause cancer.
11.2 Internally-extracted data on cases
None available.
12. ADDITIONAL INFORMATION
12.1 Availability of antidotes
None established. See also 10.7.
12.2 Specific preventative mesaures
When food is suspected to be contaminated it should be
destroyed. However, where food is scarce the following
measures have been proposed (Ministry of Defence, 1987):
All food that was exposed to liquid forms of mustard gas
should be destroyed.
All high fat content food such as butter, fat, milk, cheese,
meat, bacon should be destroyed.
Low fat content food that has been contaminated with the
vapour form of mustard gas should be washed with 2% sodium
bicarbonate solution, peeled where applicable and cooked by
boiling. Low fat content dry foods should be exposed to the
air for 48 hours.
Sugar, salt and foods of high water content such as fruit
and vegetables, sugar, salt may be made unpalatable by the
formation of acid products of hydrolyses.
Open water sources may become contaminated, but there is no
practicable means of decontaminating water in the field.
Water from deep sources such as springs and wells is likely
to be contaminated.
12.3 Other
Special equipment is available to test for the presence
of sulphur mustard in the environment.
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14. AUTHOR(S), REVIEWER(S), ADDRESS(ES), DATE(S)
Authors: Dr L. Perharic Walton
National Poisons Unit
Guy's Hospital, London
Avonely Rd
London SE14 6TE
Dr R.L. Maynard
Department of Health
Hannibal House
Elephant & Castle
London SE 1 5ER
Dr V.S.G. Murray
National Poisons Unit
Guy's Hospital, London
Avonely Rd
London SE14 6TE
Date: May 1991
Reviewer: Dr J. Szajewski
Warsaw Poison Centre
Peer Review: 17/10/95, INTOX-8, Berlin.
Group: Fountain J, Besbelli N, Borges A, Goto K,
Hanafy M, and Burgess J.
Finalised: IPCS, September 1996