MUSTARD GAS

Classification | Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

Specific Substances

1) 1,1-Thiobis(2-chloroethane)
2) 1-Chloro-2-(beta-chloroethylthio)ethane
3) 2,2-Dichlorodiethyl sulfide
4) 2,2-Dichloroethyl sulfide
5) Bis (2-chloroethyl)sulfide
6) Di-2-chloroethyl sulfide
7) Dichlorodiethylsulfide
8) Distilled mustard
9) Gelbkreuz
10) HD
11) Kampstoff "Lost"
12) Mustard gas
13) Mustard HD
14) Mustard vapor
15) Mustard, sulfur
16) S lost
17) S mustard
18) Schwefel-Lost
19) Sulfur mustard
20) Sulfur mustard gas
21) Yellow cross liquid
22) Yperite
23) Molecular Formula: C4-H8-Cl2-S
24) CAS 505-60-2
25) DISTILLED MUSTARD GAS
26) GAS, MUSTARD

1.2.1) MOLECULAR FORMULA
1) C4-H8-Cl2-S ClCH2CH2-S-CH2Ch2Cl (ClCH2CH2)2S

Available Forms Sources

1) Mustard is available in a pure and technical grade which contains excess sulfur as polysulfide (Lewis, 1997).
2) Lewisite is added to some types of mustard ammunition (2:3 ratio) to increase the effectiveness at lower temperatures (OPCW , 1997).
3) An additional copolymer, styrene-butyl acrylate, added to mustard raises the viscosity known as Thickened HD (THD). It is not hazardous except in a fine powder form (OPCW , 1997; SBCCOM , 2001).

1) The mustard agent, H, is a mixture of 70% bis(2-chloroethyl)sulfide and 30% sulfur impurities produced by an unstable Levinstein process ((HSDB, 2002); USACHPPM , 2001).
2) Mustard is prepared by bubbling ethylene through sulfur chloride, or from hydrogen sulfide and thiodiglycol (Lewis, 1997).
3) The German process to produce mustard treats beta, beta-dihydroxyethyl sulfide with hydrochloric acid gas (Budavari, 2000).
4) Mustard gas is stored in artillery shells, ton containers, and other munitions. Stockpiles in the United States are located at Aberdeen Proving Ground, MD; Anniston Army Depot, AL; Blue Grass Army Depot, KY; Pine Bluff, AR; Pueblo Depot Activity, CO, Tooele Army Depot, UT; and Umatilla Depot Activity, OR (USACHPPM , 2001a).

1) Mustard gas is used in organic synthesis and medicine and as a vesicant agent in chemical warfare (Borak & Sidell, 1992; Dacre & Goldman, 1996; Lewis, 1997).
2) Mustard gas has been tested as an antineoplastic agent, but the tests have been minimal ((HSDB, 2002); Sittig, 1991).
3) It was formerly used as a topical medication for the treatment of psoriasis ((HSDB, 2002)).
4) Mustard gas is used as a model compound in biological studies on alkylating agents, in organic synthesis, and in medicine (Hathaway et al, 1996; (HSDB, 2002); Lewis, 1997; Sittig, 1991).
5) "Yellow rain," a mixture of mycotoxins, mustard gas, and nerve agents (tabun, sarin, and soman), was used in the Iran-Iraq war in 1984. A case fatality rate of 20% was reported (Balali-Mood & Gorji, 1993; Drasch et al, 1987; Eisenmenger et al, 1991; Heyndrickx & Heyndrickx, 1990; Momeni et al, 1992; Pour-Jafari & Moushtaghi, 1992).

Overview

Life Support

Clinical Effects

0.2.1)

A) USES: Mustard gas is used primarily as a vesicant agent in chemical warfare. It may also be used in organic synthesis.
B) TOXICOLOGY: Mustard gas crosslinks DNA and prevents normal cell division. The skin is the major target; once inside the skin, mustard gas damages the cells separating the epidermis (upper layer) from the dermis (lower layer). The two layers separate with the space between them becoming a blister. Similar effects occur in the airways and eyes, except blisters do not appear. Mustard gas may also induce long-term mutagenic and carcinogenic effects.
C) EPIDEMIOLOGY: Mustard gas has historically been used as a chemical warfare agent. Its use is prohibited by the Geneva Protocol (1925) and the Chemical Weapons Convention (1993). It has a potential use as a terrorist weapon of mass destruction. From July 1917 to the end of World War I, British causalities from mustard gas amounted to at least 125,000 with approximately 1859 deaths. Following World War II (1945 to 1948), large stockpiles of chemical weapons, including mustard gas, were dumped into the Baltic sea, leading to mustard gas poisoning of 23 fishermen in 1984. It was also used by Iraqi forces during the Iran-Iraq conflict.
D) WITH POISONING/EXPOSURE

1) INGESTION: It produces nausea and vomiting, abdominal pain, bloody diarrhea, and prostration resulting in dehydration.
2) DERMAL: Signs and symptoms occur within 2 to 24 hours of exposure. Itching and erythema occur 2 to 3 hours after dermal exposure to the gas or liquid; erythema spreads over the next 24 hours and yellowish blisters appear and can become ulcerated, which heal in 4 to 6 weeks after a transitory melanoderma. Thinner skin (neck, axillae, and groin) is more susceptible than thicker skin (soles and palms).
3) INHALATION: Cough, dyspnea, and possibly pulmonary edema may occur up to 24 hours after inhalation of the gas. Ulceration of airway mucosa may occur. Mild pulmonary exposure produces rhinorrhea, sneezing, epistaxis, hoarseness, and cough within 12 to 24 hours of exposure. Severe exposure produces additional symptoms of productive cough and shortness of breath (mild to severe) 2 to 4 hours after exposure.
4) EYES: Lacrimation, itching, burning, and dryness (gritty feeling) may occur with usual onset of 4 to 12 hours after exposure. Conjunctivitis appears early, developing 4 to 6 hours after exposure. Moderate exposure produces the above plus redness, eyelid swelling, and moderate pain. These symptoms usually begin 3 to 6 hours postexposure. Severe exposure produces marked swelling of lids, photophobia, corneal ulceration, and severe pain with onset of 1 to 2 hours after exposure. Loss of vision may occur. Visual disturbance may persist for up to 10 days.

0.2.3)

A) DYSPNEA AND PAROXYSMAL COUGH are common. FEVER may occur.

0.2.4)

A) WITH POISONING/EXPOSURE

1) SEVERE EYE IRRITANT inducing edema, burning discomfort, photophobia, lacrimation, and/or blepharospasm. CORNEAL ULCERATION and/or BLINDNESS ranging from burning discomfort to destruction of the eyeball may occur after severe exposure. LOCAL THROMBOSIS/ISCHEMIA with delayed hemorrhage has developed several days after exposure. PATHOGNOMONIC SIGNS are porcelain-white areas in the episcleral tissue with sausage-shaped varicose veins.
2) RECURRENT KERATITIS of previously damaged areas may occur up to 40 YEARS after an acute exposure; opacification of the entire cornea may develop. The mechanism of action is not known, but it could be immune system mediated.

0.2.5)

A) DYSRHYTHMIAS occur rarely.

0.2.13)

A) Leukopenia, thrombocytopenia, and anemia may develop.

0.2.20)

A) Possible human teratogen.

Laboratory Monitoring

Treatment Overview

0.4.2)

A) The role of gastrointestinal decontamination is not clear for mustard ingestion. Most patients will have severe vomiting and gastrointestinal irritation, so it is unlikely that gastric lavage will remove additional poison. Activated charcoal is also unlikely to be of utility since the toxic effects occur rapidly upon contact with tissue.
B) Treat systematic effects as outlined in the INHALATION EXPOSURE section.

0.4.3)

A) PERSONNEL PROTECTION

1) Rescue personnel must wear protective clothing, eye protection, and lung protection respirator or air pack.

B) MANAGEMENT OF MILD TO MODERATE TOXICITY

1) Initial treatment of victims should include immediate removal of the victim from the contaminated area, stabilization of general and hemodynamic status, maintenance of the airway, and oxygenation. Remove contaminated clothing and wash exposed skin thoroughly with soap and water as soon as possible (ideally within 2 minutes as mustard fixes to the skin within minutes). In a mass casualty situation, if water is in short supply, adsorbent powders such as flour, talcum powder or Fuller's earth may be applied to the skin and then wiped off with a damp cloth. Administer inhaled beta agonists to patients with bronchospasm.

C) MANAGEMENT OF SEVERE TOXICITY

1) Patients with significant airway or pulmonary toxicity should be intubated. Maintain adequate nutritional status and replace loss of fluid and electrolytes. Monitor CBC. If neutropenia develops, place the patient in isolation, and administer granulocyte stimulating factors. Sodium thiosulfate can be administered intravenously (12.5 g IV over 10 minutes) or via nebulizer (2.5% solution). Animal studies suggests that it may reduce damage if given within 20 to 30 minutes of exposure.
2) DERMAL EXPOSURE: Remove contaminated clothing and wash thoroughly with soap and water as soon as possible (within minutes). If skin erythema is mild, no treatment is required. For pruritus, use topical steroid cream or compound calamine lotion (containing 1% each of phenol and menthol). If the blisters have been broken, remove the ragged roof; if not broken, drain under aseptic conditions. Clean the area with tap water or saline with application of petrolatum gauze when the areas are small. For large blisters, apply thick layer of 10% mefenide acetate (Sulfamylon(R)) or silver sulfadiazine burn cream. Appropriate antibiotics drug may be given locally or systemically if infection develops.
3) EYE EXPOSURE: Irrigate exposed eyes with copious amounts of tepid water for at least 15 minutes. Sterile petroleum jelly is used to prevent the lid margins from sticking together. In mild lesions, a steroid antibiotic eye ointment can be applied. In severe lesions, administer mydriatics (one drop of atropine sulfate solution (1%)). To prevent infection, administer a few drops of 15% solution of sodium sulfacetamide every 4 hours; if infection develops administer every 2 hours.
4) INHALATION EXPOSURE: Administer inhaled beta agonists for bronchospasm or persistent cough. Administer supplemental oxygen. Inhaled sodium thiosulfate (2.5% solution nebulized) may help prevent injury. Patients with severe respiratory distress required intubation. Bronchoscopy may be required to remove pseudomembranes from the respiratory tract.

D) DECONTAMINATION

1) PREHOSPITAL: Move patient from the toxic environment to fresh air. As soon as possible, remove contaminated clothing and wash exposed area extremely thoroughly with soap and water. Cut away and discard contaminated hair. Dilute (0.5%) hypochlorite solutions (prepared by a 10:1 dilution of 5% chlorine bleach with water) may also be used for skin decontamination. Irrigate eyes with water or saline.
2) HOSPITAL: If the patient has not had prehospital skin and eye decontamination, remove contaminated clothing and wash exposed area extremely thoroughly with soap and water. Cut away and discard contaminated hair. Dilute (0.5%) hypochlorite solutions (prepared by a 10:1 dilution of 5% chlorine bleach with water) may also be used for skin decontamination. Irrigate eyes with water or saline. The role of gastrointestinal decontamination is not clear for mustard ingestion. Most patients will have severe vomiting and gastrointestinal irritation, so it is unlikely that gastric lavage will remove additional poison. Activated charcoal is also unlikely to be of utility since the toxic effects occur rapidly upon contact with tissue.

E) AIRWAY MANAGEMENT

1) Maintain open airway and perform orotracheal intubation if there are symptoms of airway or pulmonary injury.

F) ANTIDOTE

1) There is no specific antidote. Animal studies have suggested benefit from sodium thiosulfate and N-acetyl-cysteine (NAC) administered shortly after exposure. There is no human data supporting the use of either therapy, but both have limited side effects. Use of either agent, or both, should be considered if they can be administered soon after exposure. Sodium thiosulfate: Adults: IV: 12.5 g IV over 10 minutes, Inhaled: 2.5% solution nebulized. NAC: IV: 150 mg/kg infusion over 60 minutes followed by 50 mg/kg infusion over 4 hours followed by 6.25 mg/kg/hr infusion for 16 hours. ORAL: 140 mg/kg orally followed by 70 mg/kg every 4 hours for 17 doses.

G) ENHANCED ELIMINATION

1) Hemodialysis is of no benefit in mustard exposure.

H) PATIENT DISPOSITION

1) HOME CRITERIA: There is no role for home management of any patient with mustard gas exposure.
2) OBSERVATION CRITERIA: Any patient with exposure to mustard gas via any route (ingestion, dermal, inhalational or ocular) should be sent to a medical facility for evaluation and treatment.
3) ADMISSION CRITERIA: Patients with significant dermal burns, persistent respiratory symptoms, or severe eye involvement should be admitted. Patients who are discharged should have frequent follow up for CBC monitoring.
4) CONSULT CRITERIA: Consult a medical toxicologist or poison center for any patient with sulfur mustard exposure. Consult an ophthalmologist for any patients with mustard gas burns to the eye. Consult a pulmonologist for any patients with significant or persistent respiratory distress; bronchoscopy may be necessary. Consult a gastroenterologist for any ingestion as endoscopy may be necessary to assess the extent of injury.
5) TRANSFER CRITERIA: Patients with severe or extensive dermal burns should be transferred to a burn unit.

I) PHARMACOKINETICS

1) ABSORPTION: Mustard gas can be toxic by ingestion, inhalation, and skin and eye contact. The latent period for absorption is inversely related to the dose, temperature, and humidity. About 20% of a dermal dose is absorbed through human skin. It can penetrate the skin by contact with either the liquid or vapor.
2) DISTRIBUTION: It accumulates primarily in the adipose tissue. Protein binding is about 10%, volume of distribution is 74.4 L/kg. It is eliminated in the urine as metabolites. Mustard gas is a lipophilic agent, however, its biotransformation is governed by its reaction in aqueous media. The key reaction in sulfur mustard toxicity is the intramolecular cyclization to form an electrophilic ethylene episulfonium intermediate.

0.4.4)

A) EYE EXPOSURE: Irrigate exposed eyes with copious amounts of tepid water for at least 15 minutes. Sterile petroleum jelly is used to prevent the lid margins from sticking together. In mild lesions a steroid antibiotic eye ointment can be applied. In severe lesions, administer mydratics (one drop of atropine sulfate solution (1%)). To prevent infection, administer a few drops of 15% solution of sodium sulfacetamide every 4 hours, if infection develops administer every 2 hours.
B) Treat systematic effects as outlined in the INHALATION EXPOSURE section.

0.4.5)

A) OVERVIEW

1) Remove contaminated clothing and wash exposed area extremely thoroughly with soap and water. Cut away and discard contaminated hair. Dilute (0.5%) hypochlorite solutions (prepared by a 10:1 dilution of 5% chlorine bleach with water) may also be used for skin decontamination. If skin erythema is mild, no treatment is required. For pruritus, use topical steroid cream or compound calamine lotion (containing 1% each of phenol and menthol). If the blisters have been broken, remove the ragged roof; if not broken, drain under aseptic conditions. Clean the area with tap water or saline with application of petrolatum gauze when the areas are small. For large blisters, apply thick layer of 10% mefenide acetate (Sulfamylon(R)) or silver sulfadiazine burn cream. Appropriate antibiotics drug may be given locally or systemically if infection develops.
2) The US Military issues the M291 Skin Decontamination Kit which replaced the M2581A Skin Decontamination Kit. Each M291 Kit contains six individual decontamination packets each containing Ambergard XE-555 resin powder. The previously used M2581A Skin Decontamination Kit contained towelettes soaked with phenol+hydroxide and chloramine. A dilute (0.5 percent) hypochlorite (bleach) solution can also be used. Fuller's earth, flour, or talcum powder have been recommended as alternative dermal decontamination agents. These alternative agents are not currently used by the US Military.
3) Treat systematic effects as outlined in the INHALATION EXPOSURE section.

Range Of Toxicity

Clinical Effects

Summary Of Exposure

Vital Signs

3.3.1)

A) DYSPNEA AND PAROXYSMAL COUGH are common. FEVER may occur.

3.3.2)

A) DYSPNEA AND PAROXYSMAL COUGH occurred in 8 persons examined after exposure in the Iran-Iraq war (Requena et al, 1988).

3.3.3)

A) FEVER may occur (ITI, 1985).

Heent

3.4.1)

A) WITH POISONING/EXPOSURE

3.4.3)

A) WITH POISONING/EXPOSURE

1) ACUTE (EARLY) EFFECTS

a) SUMMARY: TARGET ORGAN: The eye is the MOST SENSITIVE TARGET ORGAN for effects of mustard gas vapor (Dacre & Goldman, 1996; Borak & Sidell, 1992; NATO, 1973). All of the following ocular effects may occur following exposure to mustard gas (Geraci, 2008; (Garigan, 1996)):

1) Pain
2) Lacrimation
3) Photophobia
4) Swelling
5) Blepharospasm
6) Ulceration
7) Delayed healing of cornea
8) Opacification

b) CONJUNCTIVITIS: Mustard gas was a moderate eye irritant in humans at 100 mg/m(3)/6 hours and a mild eye irritant in rabbits at 200 mg/m(3)/2 minutes ((RTECS, 2002)). The median incapacitating dose for eye injury was 200 mg/min/m(3) (EPA, 1985). Conjunctivitis is the first ocular effect seen after acute exposure (Shohrati et al, 2007; Blodi, 1971).
c) LACRIMATION often occurs (Shohrati et al, 2007; (Garigan, 1996); Vogt et al, 1984) .
d) EDEMA of the eyelids may be delayed by several hours after exposure. Eyelids may become swollen and inflamed, causing them to shut. Casualties complaining of not being able to see almost always have eyelids that are swollen shut, not due to eye damage itself (Sidell et al, 1998).
e) CORNEAL ULCERATION/OPACITY with burning discomfort may occur at a later stage of poisoning (Shohrati et al, 2007; Sidell et al, 1998; Bismuth et al, 1995; ITI, 1995; Grant & Schuman, 1993) . A drop of the pure chemical directly on the eye may destroy the eyeball (Blodi, 1971).
f) PHOTOPHOBIA has been produced (Shohrati et al, 2007; Grant & Schuman, 1993; Aasted et al, 1987).
g) LOCAL THROMBOSIS/ISCHEMIA followed by delayed hemorrhage due to leakage through damaged vessel walls has occurred several days after exposure in severe local injury to the eye; proliferation of new blood vessels has followed (Grant & Schuman, 1993).
h) BLINDNESS: Loss of vision and/or permanent eye damage can occur (Geraci, 2008; Lewis, 1993; Aasted et al, 1987; Windholz et al, 1983; Solberg et al, 1997).
i) In a study of 40 sulfur mustard-exposed patients, blurred vision (50%), itching (42.5%), burning sensation (37.5%), photophobia (30%), tearing (27.5%), reading difficulties (10%), red eye (10%), eye pain (2.5%), and foreign body sensation (2.5%) were reported (Shohrati et al, 2007).
j) PATHOGNOMONIC SIGNS of mustard gas poisoning are porcelain-white areas in the episcleral tissues adjacent to the cornea with local formation of large, tortuous, sausage-shaped varicose veins (Grant & Schuman, 1993).
k) ONSET: Acute effects typically appear up to 24 hours after exposure (ITI, 1995).

2) LONG-TERM EFFECTS

a) DELAYED EFFECTS: About 0.5% of persons with ocular injury from mustard gas exposure develop late complications and require prolonged ophthalmologic treatment (Shohrati et al, 2007; Solberg et al, 1997). These may include:

1) RECURRENT KERATITIS of previously damaged areas with ulceration and deterioration may occur up to 40 YEARS after exposure; corneal irregularity and/or infiltration have developed with impairment of vision (Geraci, 2008; (Sidell, 2000); Grant & Schuman, 1993; Blodi, 1971; Amalric et al, 1965) .

a) KERATOPATHY: A 32-year-old man developed keratopathy several years after exposure to mustard gas. Slit lamp examination 8 years after exposure revealed bilateral limbal changes with tortuous blood vessels and full-thickness corneal alterations. Ten years after exposure, the right eye had porcelain-white episcleral changes and adjacent peripheral ulcerative keratopathy. At this time, confocal microscopy showed irregular-appearing epithelial and basal epithelial cells in both central corneas. Within the anterior corneal stroma, spindle-like keratocytes, diffuse fibrillar inhomogeneities and the presence of highly reflective material were noted (Pleyer et al, 1999).
b) Chronic conjunctivitis generally precedes onset of delayed keratopathy (Blodi, 1971).
c) Delayed mustard gas keratopathy is of the stromal type, starting near the limbus in the interpalpebral fissure (Blodi, 1971). There may be an irregular thinning of the cornea; opacities are generally anterior; sensation may be absent (Amalric et al, 1965).
d) Opacification may progress to involve the entire cornea (Blodi, 1971).
e) Histological findings have revealed degenerative changes involving all layers of the cornea; deposits of hyalin, calcium, and crystals may occur (Blodi, 1971).
f) Further work by Khateri et al (2003) to examine the effects of wartime exposure to mustard gas during the Iran-Iraq war (1980-1988) found that of those who survived the initial exposure, chronic ocular damage was reported in 39.3% (n=13,362 ) of cases. Of those exposures, 35% (n=11,900) developed mild lesions, 3.6% (n=1224) had moderate lesions, and 0.7% (n=238) severe. Injury to the eye by mustard gas can result in common histologic and ultrastructural effects, which produce acute symptoms and can lead to later complications. These later effects can include nuclear thickening or necrosis, loss of polarity or corneal epithelial basal cells (includes diffuse corneal opacity, severe thinning and vascularization), with stromal responses, including edema, degenerating fibroblasts and inflammatory cellular infiltrates (Khateri et al, 2003).
g) Forty Iranian veterans were evaluated 16 to 20 years after severe mustard gas intoxication. In 39 patients, ocular complications included itching in 42.5%, burning sensation in 37.5%, photophobia in 30%, tearing in 27.5%, reading difficulties in 10%, red eye in 10%, eye pain in 2.5.%, and foreign body sensation in 2.5%. Objective findings included chronic conjunctivitis in 17.5%, perilimbal hyperpigmentation in 17.5%, vascular tortuosity in 15%, corneal thinning in 15%, limbal ischemia in 12.5%, corneal opacity in 10%, corneal vascularization in 7.5%, and corneal epithelial defect in 5% (Balali-Mood et al, 2005).

2) In one study, 600 patients (aged 19 to 80 years) were evaluated 19 years after exposure to mustards. Primary ocular complications were reported in 96.2% of patients. Mild and moderate ocular complications (as defined below) occurred in 36.7% and 1% of patients, respectively. No severe complications were reported. Delayed ocular complications (chronic and recurrent conjunctivitis; mustard keratopathy) were reported in 37.7% of patients. The following criteria were used to classify the ophthalmic complications (Ghassemi-Broumand et al, 2008).

a) Mild: Photophobia, foreign body sensation, burning, itching, lacrimation, redness, blurred vision, pain, and difficulty while reading; objective signs including hyperemia, conjunctival edema, subconjunctival hemorrhage, conjunctival vascular dilation (microaneurysm and telangiectasis), conjunctival concretion, and visual acuity of 0.9 to 1.
b) Moderate: Presence of mild manifestations in addition to mild corneal involvement (including opacity of epithelial, subepithelial, and stromal layers of the cornea, bandlike keratopathy, pannus of less than 2 mm, hyperpigmentation around the limbus, precipitation of iron in the cornea without the presence of melting, and neovascularization of the cornea), impairment on the Schirmer test, and assessable retina and optic nerve with visual acuity of 0.5 to 0.8.
c) Severe: Presence of moderate manifestations in addition to severe involvement of the cornea (including melting and thinning of the cornea, precipitation of hyaline-like substances, deep neovascularization of the cornea, diffuse opacity of the cornea, and descemetocele), severe impairment on Schirmer test, and non-assessable retina with visual acuity of 0.4 to less than 0.1.

3) In a cohort study of 367 chemical war victims, 20 years after exposure to mustard gas, photophobia was reported in 36.8% of the subjects with mustard gas exposure, compared with 20.3% in the controls (p =/< 0.001). Ocular surface discomfort (burning, itching, and redness) was reported by 29.2% of mustard gas exposed subjects, compared with 19.5% in the controls (p=0.034) . Foreign-body sensation, tearing, pain, blurring of vision, and dry eye sensation were also reported but were not significantly different between the two groups. Bulbar conjunctival abnormalities (9.3% compared with 1.6% in the controls; p=0.004) and limbal tissue changes (3% compared with 0% in the controls; p=0.048) were the most frequent signs in the cases. Tearing and abnormalities in the lids and cornea were also reported but were not significantly different between the two groups (Ghasemi et al, 2008).
4) The severity of ocular involvement and the correlation between late ocular and lung complications in war veterans (n=292) exposed to sulfur mustard were evaluated in a cross-sectional study. Pulmonary and ocular involvements were observed in 96.3% and 32.5%, respectively. Severe, moderate, mild, and normal pulmonary involvements were identified in 68.9%, 16.1%, 11.2%, and 3.8% patients, respectively. Severe, moderate, mild, and normal ocular involvements were identified in 12.6%, 5.4%, 13.8%, and 68.2% patients, respectively. Overall, there was only a weak correlation between the severity of ocular and pulmonary involvements (p=0.049) (Ghasemi et al, 2012).
5) In a study of 112 Iranian survivors of Iran-Iraq war, 83.9% of patients had subjective ocular problems and 70.6% had objective ocular problems, after a minimum of 19 years from the first exposure to mustard gas. Abnormal ocular findings included severe conjunctival vascular tortuosity in 73 patients (65.2%; mean: 13.71 years after exposure), corneal neovascularization in 22 patients (19.6%; mean: 16.54 years after exposure), conjunctival/limbal vessels with ampulliform dilatation in 20 patients (17.9%; mean: 9.33 years after exposure), and delayed keratitis in 11 patients (9.8%; mean: 19.54 years after exposure). These eye findings were more common in patients with moderate-severe respiratory symptoms (Sedghipour et al, 2012).

b) MICROBIOLOGICAL EVALUATION

1) In a comparative case series of 289 mustard gas casualties, signs of chronic blepharitis were observed in 150 (52%) patients. Microbiological profiles of the eyelid margin flora isolated from these patients were compared with results from 100 unexposed patients with chronic blepharitis. Higher rates of Staphylococcus epidermidis (78% vs 57%; p less than 0.01) and Staphylococcus aureus (30% vs 3%; p less than 0.001) were observed in the exposed group compared with the control group. In addition, greater resistance to common antibiotics was noted in the exposed group compared with the control group. Positive cultures for fungal species were observed more frequently in the exposed group compared with the control group (30% vs 4%; p less than 0.01). The most commonly isolated fungi were Cladosporium spp. (8% vs 2%; p less than 0.05) and Candida spp. (8% vs 1%; p less than 0.05) (Karimian et al, 2011).

Cardiovascular

3.5.1)

A) DYSRHYTHMIAS occur rarely.

3.5.2)

A) CONDUCTION DISORDER OF THE HEART

1) WITH POISONING/EXPOSURE

a) Sinus dysrhythmias, first- and second-degree heart block, premature ventricular contractions, and premature atrial contractions, and possibly cardiac arrest have been reported following exposure to mustard gas. These symptoms were observed within the first week after exposure but all resolved within 6 months. In studies, 30% of exposed patients experienced nonspecific ST-segment changes (Geraci, 2008). Cardiac irregularities appear to occur only following extremely acute, high doses (generally attainable only in laboratory settings) ((Sidell, 2000); NATO, 1973).

B) CORONARY ARTERY FINDING

1) WITH POISONING/EXPOSURE

a) In a case-control study, 40 mustard gas-poisoned patients (mean age, 54.8 +/- 9.6 years) and 40 unexposed patients (mean age, 58.3 +/- 11.6 years) underwent coronary artery angiography for chest pain. Coronary artery ectasia (defined as arterial dilatation that exceeds the diameter of the adjacent segments or the largest artery by 150%), mostly in the left anterior descending artery, was observed in 15 (37.5%) exposed patients compared with 2 (5%) in the unexposed group (p=0.001; odds ratio, 11.4). It was suggested that mustard gas can cause oxidative stress which is one of the major pathological mechanisms in developing atherosclerosis (Shabestari et al, 2011).

Respiratory

3.6.2)

A) IRRITATION SYMPTOM

1) WITH POISONING/EXPOSURE

a) IMMEDIATE (EARLY) EFFECTS

1) Mild to moderate immediate symptoms include dyspnea, chest tightness, sneezing, rhinorrhea, hoarseness, aphonia, epistaxis, hacking coughs, and tachypnea. Serious respiratory problems (eg, tracheobronchitis, bronchopneumonitis, pulmonary edema, hemorrhage, acute respiratory distress syndrome, pulmonary fibrosis) may occur hours to days after exposure (Weibrecht et al, 2012; Geraci, 2008; (Garigan, 1996)). Respiratory dysfunction is the most common cause of death ((Garigan, 1996)).
2) Dose-dependent damage occurs to the mucosa of the respiratory tract, beginning with the upper airways and descending to the lower airways as the amount of mustard increases. Little effect on the lung parenchyma occurs, with damage mostly confined to the airways and the tissue immediately surrounding the airways, except after an overwhelming exposure and as a terminal event ((Sidell, 2000)). Irritation or ulceration of the respiratory tract can occur from acute exposure, with rhinitis, laryngitis, cough, dyspnea, inflammation, and bronchopneumonia(Dacre & Goldman, 1996; ITI, 1995; Ruhl et al, 1994; Borak & Sidell, 1992; Vogt et al, 1984; Windholz et al, 1983) . Early respiratory manifestations include hemorrhagic inflammation of the tracheobronchial tree accompanied by severe erosions (Freitag et al, 1991).
3) Airway damage begins in the upper airways with sinus pain, irritation of the nose, sore throat, and hacking cough. If greater than a minimal amount is inhaled, voice changes may occur with hoarseness or voice loss. Following inhalation of a large amount, damage to the lower airways occurs with shortness of breath and a severe productive cough. Prognosis is most ominous with a shorter onset of time to lower airway effects. If lower airway effects begin earlier than 4 hours after exposure, death is likely (Sidell et al, 1998).
4) DYSPNEA and/or PAROXYSMAL COUGH occurred in 8 persons examined after exposure in the Iran-Iraq war (Requena et al, 1988).
5) Lung dysfunction is the most common cause of death following mustard gas exposure ((Garigan, 1996)). Pulmonary lesions may be fatal; the most common cause of death is from pulmonary infection about 1 week after acute exposure (EPA, 1985; Vogt et al, 1984).
6) Death may also occur from mechanical asphyxia due to obstruction of the bronchi or trachea by fragments of necrotic tissue (pseudomembrane) (NATO, 1973).
7) The main non-dermal toxic effects of sulfur mustard, in a study of 1428 exposed patients, were found on the respiratory tract. In 30 severe cases, arterial blood gases revealed mainly hypoxia and respiratory acidosis. Respiratory complications were progressive in spite of supportive management (Balali-Mood & Gorji, 1993).

b) DELAYED EFFECTS

1) Cough may occur 1 to 48 hours after acute exposure; pulmonary impairment may be severe (Ruhl et al, 1994; Windholz et al, 1983) .

c) LONG-TERM FOLLOW-UP

1) Dyspnea (83%)
2) Coughing (71%)
3) Chest pain (18%)
4) Orthopnea (9%)
5) Hemoptysis (6%)
6) Wheezing, rhonchi, rales (29%)
7) Chest x-ray abnormalities (7%)
8) Restrictive Pattern on Spirometry (10%)

1) The following SEQUELAE were found in a study of 1428 patients exposed to mustard gas during the Iran-Iraq war (Balali-Mood & Gorji, 1993):
2) Among 197 veterans of the Iran-Iraq war exposed to mustard gas, at a 10 year follow-up evaluation the following SEQUELAE were noted (Emad & Rezaian, 1997):

1) Asthma (11%)
2) Chronic bronchitis (59%)
3) Airway Narrowing (scarring or granuloma formation) (10%)
4) Pulmonary Fibrosis (12%)

3) The following late toxic effects of mustard gas on the respiratory system of 40 severely intoxicated Iranian veterans were reported 16 to 20 years after exposure (Hefazi et al, 2005):

1) COPD in 14 (35%)
2) Bronchiectasis in 13 (32.5%)
3) Asthma in 10 (25%)
4) Large airway narrowing in 6 (15%)
5) Pulmonary fibrosis in 3 (7.5%)
6) Simple chronic bronchitis in 2 (5%)

a) Thirty-five complications were reported in their pure form; 5 patients had a combination of 2 or 3 complications.

d) The severity of ocular involvement and the correlation between late ocular and lung complications in war veterans (n=292) exposed to sulfur mustard were evaluated in a cross-sectional study. Pulmonary and ocular involvements were observed in 96.3% and 32.5%, respectively. Severe, moderate, mild, and normal pulmonary involvements were identified in 68.9%, 16.1%, 11.2%, and 3.8% patients, respectively. Severe, moderate, mild, and normal ocular involvements were identified in 12.6%, 5.4%, 13.8%, and 68.2% patients, respectively. Overall, there was only a weak correlation between the severity of ocular and pulmonary involvements (p=0.049) (Ghasemi et al, 2012).

B) INJURY OF UPPER RESPIRATORY TRACT

1) WITH POISONING/EXPOSURE

a) The following upper airway effects following acute mustard gas exposures are reported ((Garigan, 1996)):

1) Sinusitis
2) Hoarseness
3) Sore throat
4) Pseudomembrane formation (may cause airway obstruction)

b) In one study, 600 patients (aged 19 to 80 years) were evaluated 19 years after exposure to mustards. Primary respiratory complications were reported in 80.7% of patients. Mild and moderate respiratory complications (as defined below) occurred in 45% and 0.8% of patients, respectively. No severe complications were reported. Delayed respiratory complications (gene mutations leading to cancers, bronchiolitis, chronic bronchitis, bronchospasm, pulmonary fibrosis, tracheomalacia, and bronchiectasis) were reported in 45.8% of patients. The following criteria were used to classify the respiratory complications (Ghassemi-Broumand et al, 2008):

1) Mild: Forced vital capacity (FVC) and forced expiratory volume in 1 second (FEV1) of 65% to 80% of predicted, prominent lesions on high resolution CT or abnormal lung auscultation.
2) Moderate: FVC and FEV1 of 50% to 65% of predicted and abnormal lung auscultation.
3) Severe: FVC and FEV1 below 50% of predicted in association with cyanosis, respiratory distress, or tracheal stenosis on bronchoscopy.

c) In an observational case series study of 50 chemical war victims, chronic laryngitis was observed in 82% (n=41) of patients approximately 20 years after exposure. These patients were experiencing persistent respiratory complaints (exertional dyspnea, chronic cough, sputum, chest discomfort) for several years. Different degrees of dysphonia including hoarseness and harshness were observed in 16 (32%) and 7 (14%) of patients, respectively. Laryngoscopic examination revealed various degrees of inflammation (edema and erythema) in supraglottic (n=9; 18%) and subglottic regions (n=3; 6%). Functional disorders of the true vocal chords were observed in 7 (14%) patients and hypertrophy and hyper adduction of false vocal chords were observed in 24 (48%) patients (Akhavan et al, 2009).
d) DELAYED EFFECTS: Delayed toxic effects, including chronic bronchitis, bronchiectasis, frequent bronchopneumonia, and pulmonary fibrosis have been reported after mustard gas exposure (Zojaji et al, 2009).

C) ACUTE LUNG INJURY

1) WITH POISONING/EXPOSURE

a) Pulmonary edema and hemorrhage can occur, although it is uncommon except in the terminal stages ((Sidell, 2000); (Garigan, 1996); Aasted et al, 1987) and then is fatal (NATO, 1973).

D) PNEUMONITIS

1) WITH POISONING/EXPOSURE

a) Risk of mortality from influenza, pneumonia, and chronic respiratory disease was higher than expected in persons occupationally exposed to mustard gas (Easton et al, 1988). Bronchopneumonitis may commonly occur following acute mustard gas exposures ((Garigan, 1996)).
b) DELAYED EFFECTS: Delayed toxic effects, including chronic bronchitis, bronchiectasis, frequent bronchopneumonia, and pulmonary fibrosis have been reported after mustard gas exposure (Zojaji et al, 2009).

E) SEQUELA

1) WITH POISONING/EXPOSURE

a) Increased susceptibility to respiratory tract infections and evidence of bronchitis and bronchiectasis have been reported as long-term sequelae in occupational workers exposed to chronic low-doses of mustard over months to years ((Sidell, 2000)). Bronchial asthma and hyperreactivity of the airways may be a late complication of mustard gas exposure. Garigan (1996) reports the following chronic pulmonary changes following severe acute exposures to mustard gas ((Garigan, 1996)):

1) Bronchiectasis
2) Chronic bronchitis
3) Bronchial hyperreactivity
4) Emphysema

1) Emad et al (1999) reported the cellular constituents in bronchoalveolar lavage of patients with mustard gas-induced asthma and chronic bronchitis are similar to those of patients with asthma and chronic bronchitis from other common causes (Emad & Rezaian, 1999).

b) DELAYED EFFECTS: Delayed toxic effects, including chronic bronchitis, bronchiectasis, frequent bronchopneumonia, and pulmonary fibrosis have been reported after mustard gas exposure (Zojaji et al, 2009).
c) Iranian soldiers exposed to mustard gas experienced secondary complications of chronic infections, suppurative bronchitis, and extensive stenotic process of the entire tracheobronchial tree and life-threatening sequelae. Scars, ulcers, and strictures developed in the central airways after a delay of up to 15 months, with progressive deterioration of gas exchange being common. Recurrence rate of stenosis was high, with intervals of less than 6 months being normal (Freitag et al, 1991).
d) Further work by Khateri et al (2003) to examine the effects of wartime exposure to mustard gas during the Iran-Iraq war (1980-1988) found that of those who survived the initial exposure, respiratory disorders were the most common long-term medical complaint. Based on 34,000 Iranians known to have sustained mustard agent exposure, 42.5% (14,4500 cases) of the exposed population exhibited chronic lung lesions and associated symptoms. Of those cases, 37% (12,920 cases) were classified as mild, 4.5% moderate (1530 cases), and 1.0% (340 cases) were severe.
e) Because mustard gas can lead to severe inflammation of the tracheobronchial epithelium, those who survive the initial injury can develop significant scarring, which can lead to degradation of pulmonary function and development of pulmonary fibrosis (a late finding of massive mustard gas inhalation). Overall, these changes can increase the susceptibility to pulmonary disease (ie, chronic fibrosis and bronchitis). The authors concluded that these results may help to establish guidelines to evaluate the long-term effects of chemical warfare and plan appropriate therapy (Khateri et al, 2003).
f) Iranian veterans (n=40) evaluated 16 to 20 years after their initial exposure presented with the following respiratory signs and symptoms: cough (all patients), expectoration (all patients), dyspnea (85%), hemoptysis (60%), wheezing (95%), crackles (50%), and stridor (10%). Mild and moderate hypoxemia was observed in 67.5% and 27.5% of patients, respectively. Pulmonary function tests were performed and revealed obstructive pattern in 57.5%, restrictive in 22.5%, and mixed in 15% (Balali-Mood et al, 2005).

Neurologic

3.7.2)

A) CENTRAL NERVOUS SYSTEM FINDING

1) WITH POISONING/EXPOSURE

a) Dizziness, generalized malaise, anorexia, and lethargy can occur after acute exposure (Aasted et al, 1987). Mental or intellectual dullness is common following an acute mustard gas exposure ((Garigan, 1996)).

B) CENTRAL STIMULANT ADVERSE REACTION

1) WITH POISONING/EXPOSURE

a) CNS EXCITATION with seizures may occur, followed by CNS DEPRESSION (Dacre & Goldman, 1996; NATO, 1973) . CNS excitation resulting in seizures appear to occur only following extremely acute, high doses ((Sidell, 2000)). No severe CNS abnormalities were reported in mustard casualties of the Iran-Iraq War.

C) NEUROLOGICAL FINDING

1) WITH POISONING/EXPOSURE

a) World War II German Mustard gas plant workers developed debility, loss of vitality, sensory hypersensitivity, decreased libido and sexual potency, neuralgia, and disorders of cardiac autonomic regulation (Dacre & Goldman, 1996).
b) Studies of 40 severely intoxicated Iranian veterans 16 to 20 years after exposure revealed motor nerve disorders in the left (37.5%) and right (35%) tibial and the left (12.5%) and right (20%) peroneal nerves. Sensory nerve disorders were observed in the left tibial (75%) and right peroneal (72.5%) nerves (Balali-Mood et al, 2005).

D) HEADACHE

1) WITH POISONING/EXPOSURE

a) HEADACHE may occur (Weibrecht et al, 2012; NATO, 1973).

E) NEUROPATHIC PAIN

1) WITH POISONING/EXPOSURE

a) Patients may experience neuropathic pain for years after exposure to mustard gas. Allodynia, paresthesias, stinging, burning, and itching have been reported in patients exposed to mustard gas. Sunlight and shifts in temperature may aggravate these symptoms (Geraci, 2008).

Gastrointestinal

3.8.2)

A) NAUSEA, VOMITING AND DIARRHEA

1) WITH POISONING/EXPOSURE

a) Nausea, vomiting, diarrhea (or bloody diarrhea) and dehydration can be caused by ingestion or systemic absorption (Geraci, 2008; (Garigan, 1996); Ruhl et al, 1994; Borak & Sidell, 1992; Requena et al, 1988; Vogt et al, 1984) . Nausea and vomiting are common and occur within the first few hours after mustard exposure, occurring at about the time the initial lesions become apparent (Geraci, 2008; (Sidell, 2000)). Hematemesis may occur, but is not common (Pierard et al, 1990). Early nausea and vomiting are generally transient and not severe. Nausea and vomiting occurring days later are most likely due to generalized cytotoxic activity of mustard with damage to the mucosa of the GI tract ((Sidell, 2000)). Diarrhea is not common after an inhalation exposure ((Sidell, 2000)).
b) Systemic effect is due to destruction of the rapidly dividing epithelial cells of the gut from the radiomimetic action of sulfur mustard, with subsequent loss of fluids and electrolytes (NATO, 1973; Sidell et al, 1998).
c) Exposure to contaminated food, water, air, or saliva may also damage the mucosal surfaces (Geraci, 2008).
d) LATE EFFECTS: Mustard gas-induced pulmonary damage may be related to distal esophagitis and gastroesophageal reflux disease (Geraci, 2008).

B) ABDOMINAL PAIN

1) WITH POISONING/EXPOSURE

a) Epigastric pain may occur (Geraci, 2008; Dacre & Goldman, 1996; NATO, 1973).

C) LOSS OF APPETITE

1) WITH POISONING/EXPOSURE

a) Loss of appetite and cachexia may occur during the first week after exposure (Geraci, 2008; Pierard et al, 1990).

Hematologic

3.13.1)

A) Leukopenia, thrombocytopenia, and anemia may develop.

3.13.2)

A) MYELOSUPPRESSION

1) WITH POISONING/EXPOSURE

a) Leukopenia, thrombocytopenia, and anemia have occurred because of depressed myelopoiesis; destruction of precursor cells of the bone marrow results in pancytopenia (Geraci, 2008; (Sidell, 2000); Dacre & Goldman, 1996; Borak & Sidell, 1992; Momeni et al, 1992; Vogt et al, 1984) . Bone marrow damage is usually not evident for 3 to 5 days after exposure. However, several studies have reported that bone marrow suppression may become evident about 4 hours after exposure to mustard gas (Geraci, 2008; (Garigan, 1996)). Leukopenia typically develops at days 3 through 5 after exposure and reaches a nadir in 3 to 9 days, depending on extent of exposure ((Sidell, 2000)). Following absorption of a large amount of mustard gas, the bone marrow is damaged, resulting in a decrease in white blood cells, red blood cells, and platelets. Death may occur due to overwhelming infection (Sidell et al, 1998).

B) COAG./BLEEDING TESTS ABNORMAL

1) WITH POISONING/EXPOSURE

a) Decreased blood coagulation time of unknown origin has been observed following vapor exposure (Sinclair, 1948).

C) EOSINOPHIL COUNT RAISED

1) WITH POISONING/EXPOSURE

a) Eosinophilia was the most commonly seen laboratory finding in 14 children exposed in the Iraq-Iran war (Momeni & Aminjavaheri, 1994).

Reproductive

3.20.1)

A) Possible human teratogen.

3.20.2)

A) HUMANS

1) Exposure to mustard gas was linked to a greater than expected incidence of cleft lip and cleft palate in Iranian children born in one hospital between 1983 and 1988 during the Iran-Iraq war (Taher, 1992). The exposures were poorly documented, however, and were not reported for the comparison group from 5 other hospitals.

B) RELATED COMPOUNDS

1) Therapeutic doses of the closely chemically-related compounds, nitrogen mustard, have been associated with birth defects when given to pregnant cancer patients (NATO, 1973).
2) In a study of the children of married Iranian males aged 18 to 85 years injured at least once by chemical warfare agents during the Iran-Iraq war and who had completely recovered, the overall incidence of congenital abnormalities was 258/1000 as compared to 33/1000 in controls. 25 percent of these men indicated that their wives had also been exposed to chemical warfare agents. Exposures included mustard gas, nerve agents, cyanide, and riot control agents (Pour-Jafari, 1994). Because of mixed exposures and both paternal and maternal exposure in 1/4 of cases, the role of mustard gas exposure in the development of noted congenital abnormalities in these children is unclear.

C) LACK OF EFFECT

1) Two women who were occupationally exposed to mustard gas in a chemical plant conceived and delivered healthy children (Geraci, 2008).

D) ANIMAL STUDIES

1) Specific developmental abnormalities of the musculoskeletal system were observed in rats exposed to mustard gas via the oral route ((RTECS, 2002)), but such effects may only occur at doses toxic to the dams (Dacre & Goldman, 1996).
2) Mustard gas was not teratogenic in rats or rabbits given up to 2.0 or 0.8 mg/kg/day, respectively (Hackett PL, Rommereim RL & Burton FG et al, 1987).

3.20.3)

A) ANIMAL STUDIES

1) In a 2-generation study in rats, mustard gas given by gavage at daily doses as high as 0.4 mg/kg 5 days/week for 13 weeks prior to mating and through lactation for 42 weeks had no effect on reproduction or pregnancy outcome of either generation (Sasser et al, 1996).

Carcinogenicity

3.21.1)

A) IARC Carcinogenicity Ratings for CAS505-60-2 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):

1) IARC Classification

a) Listed as: Mustard gas (Sulfur mustard)
b) Carcinogen Rating: 1

1) The agent (mixture) is carcinogenic to humans. The exposure circumstance entails exposures that are carcinogenic to humans. This category is used when there is sufficient evidence of carcinogenicity in humans. Exceptionally, an agent (mixture) may be placed in this category when evidence of carcinogenicity in humans is less than sufficient but there is sufficient evidence of carcinogenicity in experimental animals and strong evidence in exposed humans that the agent (mixture) acts through a relevant mechanism of carcinogenicity.

3.21.3)

A) CARCINOMA

1) Increased mortality from 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 (Sittig, 1985; Borak & Sidell, 1992; Dacre & Goldman, 1996).
2) A 2-year, prospective, descriptive study of 43 Iranian war veterans exposed to mustard gas reported 2 patients with thyroid cancers (undifferentiated thyroid carcinoma and papillary carcinoma of a thyroglossal cyst) and 1 patient with nasopharyngeal carcinoma, 12 to 14 years after mustard gas exposure (Zojaji et al, 2009).
3) In one study, squamous cell carcinoma was the most commonly reported cancer in patients exposed to mustards (Ghassemi-Broumand et al, 2008).
4) A cross-sectional descriptive study evaluated 800 men with late cutaneous effects 14 to 20 years after wartime exposure to sulfur mustard gas. Nine patients (1.1%) developed malignant cutaneous neoplasms (5 cases of basal cell carcinoma and 1 case each of squamous cell carcinoma, Bowen disease, dermatofibrosarcoma protuberans, and mycosis fungoides (tumoral). In 7 of the 9 patients, the malignancies developed at the site of a mustard gas-induced dermal scar (Emadi et al, 2008).
5) CASE REPORT: Eight years after exposure to mustard gas, a 16-year-old boy presented with numerous confluent red-yellowish ulcerated skin tumors on his right lower leg and knee. Biopsy of the lesion revealed porocarcinoma with mainly squamous, partially ductal differentiation. Metastases were observed in several regional lymph nodes and the vertebral body of T12. Following his leg amputation, he was treated with a combined surgico-radio-chemotherapy of the metastases, but he died 9 months later (Helmke et al, 2002).
6) Mortality from all cancers for the period 1930-1952 was similarly elevated about two-fold over expected in British men exposed to mustard gas in World War I and in a similar group not exposed to mustard gas; in both groups cancers of the lung and pleura predominated (Case & Lea, 1955).

a) The design of this early study was not controlled for possible effects of smoking, and it is possible that the selection of the two study groups based on presence of chronic bronchitis may have introduced smoking as a source of bias (Norman, 1975; IARC, 1975).

7) American World War I veterans who received a single exposure to mustard gas had a suggestive but not significant increase in incidence of and mortality from lung cancer through 1955 (Beebe, 1960); similar conclusions were obtained when the same group was followed through 1965 (Norman, 1975).
8) Japanese workers occupationally exposed to mustard gas from 1929-1945 had greater than 30-fold increased deaths from cancers of the respiratory tract (Wada et al, 1968).

a) These workers were also exposed to Lewisite (chlorvinylarsine), diphenylcyanarsine, hydrocyanic acid, phosgene, and chloroacetophenone (Wada et al, 1968).
b) Two cases of tracheal cancer and one each of uvular and laryngeal cancer have been reported in detail from this Japanese worker population (Kurozumi et al, 1977).
c) Further follow-up found a Standardized Mortality Ratio for this group of greater than 3.5 for lung cancer (Yamakido et al, 1996). Cancers occurred more often at sites with greater direct mustard gas exposure, and 24.5 percent of directly exposed workers developed lung or other cancers as opposed to 15.6 percent of administrators and other workers not directly exposed (Yamakido et al, 1996). Double point mutations in the p53 oncogene have been identified in a small subset of these workers and may be a specific marker for mustard gas exposure (Takeshima et al, 1994).

9) Deaths from cancer of the larynx, pharynx, buccal cavity, and upper respiratory tract and lung were significantly increased over expected rates in British mustard gas workers exposed during World War II; risks for pharyngeal and lung cancers were related to duration of exposure (Easton et al, 1988; Dacre & Goldman, 1996).

3.21.4)

A) CARCINOMA

1) Mustard gas is considered carcinogenic and neoplastic by RTECS criteria. In the rat and mouse via the inhalation and the intravenous exposure routes, mustard gas caused tumors in the skin, appendages, lungs, thorax, and blood (leukemia). By the subcutaneous exposure route, it was found to cause tumors at the site of application ((RTECS, 2002)).
2) CARCINOGENIC in rats by inhalation at 100 mcg/m(3)/1 year (intermittent exposure), producing tumors of the skin and appendages ((RTECS, 2002)).
3) NEOPLASTIC in mice by inhalation at 1,250 mg/m(3)/15 minutes, producing tumors of the lung, thorax and respiratory system and leukemia ((RTECS, 2002)).
4) EQUIVOCAL TUMOR AGENT in mice at 6 mg/kg/6 weeks (intermittent exposure), producing tumors at the site of subcutaneous injection ((RTECS, 2002)).
5) NEOPLASTIC in mice at 600 mg/kg/6 days IV (intermittent exposure), producing tumors of the lung, thorax, and respiratory system ((RTECS, 2002)).
6) NTP - Mustard gas is listed in the 9th Annual Report on Carcinogens by the National Toxicology Program ((RTECS, 2002)).
7) Oral doses of mustard gas at levels as high as 0.4 mg/kg for 5 days/week for a total of 42 weeks induced dose-dependent acanthoses and benign neoplasms in the forestomach of rats over 2 generations (Sasser et al, 1996).

Genotoxicity

Dermatologic

3.14.2)

A) SKIN IRRITATION

1) WITH POISONING/EXPOSURE

a) EARLY EFFECTS

1) SEVERE SKIN IRRITATION was produced at 2000 mg/m(3)/1 hour in humans using the standard Draize test; irritation was produced at 65 mcg in humans ((RTECS, 2002)). The median incapacitating dose for skin absorption was 2000 mg/min/m(3) (EPA, 1985). Mustard gas has more severe vesicant and irritant properties than its nitrogen analogue, nitrogen mustard. The first effect on the skin is often pallor, followed within a few hours by erythema, which is similar to that of a sunburn, with burning and itching. Over the next few hours small blisters (vesicles) appear that gradually combine to form large blisters. Clinical effects may progress for several days. Four to 6 days after exposure, necrosis is complete and separation of the necrotic slough begins; edema and erythema may persist. Approximately 16 to 20 days postexposure, separation is complete and reepithelialization has begun; healing may take 3 to 8 weeks (Rice, 2003; Sidell et al, 1998).
2) SUPERFICIAL INJURY is generally produced except at very high-level exposures because of the alkylating activity of mustard gas (Grant & Schuman, 1993).
3) The order of dermal effects is as follows (from initial to last effects) ((Garigan, 1996)):

1) No evidence of injury will be evident for several hours after exposure
2) Itching with or without dryness and pallor
3) Erythema
4) Vesicles
5) Bullae
6) Necrosis and ulceration
7) Hypo- or Hyperpigmentation

4) Healing and other effects that may be noted are as follows (Sidell et al, 1998; (Garigan, 1996)) :

1) Healing of erythema: 3 to 7 days
2) Healing of ulcers: 6 to 8 weeks and occurs much more slowly in human as compared with animals
3) Skin injuries more severe in humid and warm climates
4) Most severe at warm and moist sites (eg, genitalia, perineal regions, groin, lower back and axillae, underarms, neck ) (Geraci, 2008; Sidell et al, 1998; (Garigan, 1996))

5) The time elapsing to the first dermal effects is shorter with large amounts of mustard and is shorter after liquid exposure than after vapor exposure (Sidell et al, 1998). More recent research suggests that injury to human skin commences at the level of the basal keratinocyte (Rice, 2003).
6) Light-skinned people, younger patients, and women may develop more severe skin lesions (Geraci, 2008).
7) In studies, the most common skin diagnosed disorders in patients exposed to sulfur mustard were eczema, seborrheic dermatitis, cherry angioma, and urticaria. Genitalia, face, and axilla are the most frequently involved areas (Shohrati et al, 2007).

a) The following cutaneous complications have been reported following exposure to sulfur mustard: chronic skin lesions (70% to 90%), xerosis (25% to 55%), hyperpigmentation (20% to 50%), hypopigmentation (2% to 15%), burning (15% to 50%), pain (3% to 10%), redness (6% to 10%), and mustard scar (2% to 13%; atrophic changes, hypertrophic scar, or keloid formation). Vascular changes such as telangiectasia and cherry angioma have also been reported (Shohrati et al, 2007).
b) HISTOPATHOLOGIC CHANGES: Mustard gas produces the following histopathologic changes of skin, including 4 distinct patterns: 1) Interface dermatitis, vacuolar type and lichenoid type, 2) Spongiotic dermatitis and bullous dermatitis (with or without acantholysis), 3) Pigmentary disorder pattern, increase of epidermal melanization, and 4) Alteration of dermis/hypodermis, sclerodermoid pattern, vasculopathy, and appendageal inflammatory response (Shohrati et al, 2007).

8) CASE REPORT: A 28-year-old fisherman developed pain, erythema, and blisters on his forearm and knee within 6 hours of exposure to 50 mL of sulfur mustard from multiple artillery shells entangled in a clam net. He presented 16 hours later with bullous lesions with surrounding erythema on the right forearm and the patellar surface of the left knee. He also experienced blurred vision, headache, malaise, and mild shortness of breath. Following supportive care, including dermal decontamination, antibiotics, pain medications, and tetanus vaccine, he gradually recovered and was discharged on day 5. A urinalysis confirmed the presence of sulfur mustard. A spot urine test for arsenic, a common additive to sulfur mustard, revealed a total arsenic concentration of 36 mcg/L (reference range, 0 to 35 mcg/L), 34.9 mcg/L of organic arsenic, and 9.4 mcg/L of methylated arsenic (Weibrecht et al, 2012).

B) SKIN ULCER

1) WITH POISONING/EXPOSURE

a) VESICANT: Mustard gas may produce erythema, severe pruritus (itching), blistering, and/or ulceration and necrosis of exposed skin (Weibrecht et al, 2012; Geraci, 2008; Sidell et al, 1998; Dacre & Goldman, 1996; ITI, 1995; Vena et al, 1994; Borak & Sidell, 1992) Sittig, 1991 .
b) The earliest sign is a sunburnlike erythema (Requena et al, 1988). Focal brown discoloration may be present. Most common sites are areas covered by clothing, especially the groin, genitalia, and axillae ((Garigan, 1996); Pierard et al, 1990).

1) In milder cases the erythema may spontaneously resolve (Requena et al, 1988; Pierard et al, 1990).
2) Children exposed during the Iraq-Iran war (1980-1988) had a shorter delay in onset of skin lesions than adults; lesions began within 4 to 18 hours after exposure, and erythema within 20 to 30 hours in children.
3) Severity of skin lesions was also greater in children than in adults (Momeni & Aminjavaheri, 1994).

c) Vesicles and bullae may appear and break down within 24 to 48 hours after higher exposures (Borak & Sidell, 1992; Pierard et al, 1990; Jelenko, 1974).

1) In the early stages there is a subepidermal blister involving basal cell degeneration, exudation of fluid into the resulting space, and few or no inflammatory cells present (Requena et al, 1988).
2) PAS-positive basement membrane zone was noted on the dermal side of the blister (Requena et al, 1988).
3) Necrotic epidermis may form the top of the blister (Requena et al, 1988).
4) The blisters were generally resorbed in approximately 1 week (Pierard et al, 1990; Requena et al, 1988).
5) Brown or black hyperpigmentation usually occurs after resolution of the burns, especially on the neck, axillae, and genital region (Pierard et al, 1990; Requena et al, 1988). Three years following mustard gas dermal exposure, hyperpigmentation (most common) was observed in 106 patients (37.6%), but hypopigmentation was also observed in a few patients (Dowlati & Pierard, 1993).

d) Ulceration may follow at the site of vesicle formation (Jelenko, 1974).
e) Most severe exposures involve extensive areas of the skin, severe erythemas, and detachment of the epidermis (Pierard et al, 1990).
f) BIOPSY specimens from blisters following mustard gas exposures during the Iran-Iraq wars have shown epidermal hyperplasmia with or without atypia. Several lesions corresponded to xerodermoid-type lesions. Many binucleated keratinocytes and bowenoid changes were reported (Dowlati & Pierard, 1993).

1) Skin biopsies from patients with mustard gas blisters revealed a separation of the basal cells from one another, with development of multinucleated cells (Bismuth et al, 1995).

C) BLISTERING ERUPTION

1) WITH POISONING/EXPOSURE

a) Delayed effects may appear from 5 to 24 hours after exposure (Weibrecht et al, 2012; ITI, 1995; Ruhl et al, 1994; Momeni et al, 1992). Vesicles may first appear on the skin up to 7 to 12 days following exposure (Dacre & Goldman, 1996).
b) The latent period varied with the inverse of the severity of the exposure; lesions were apparent within 2 to 3 hours with high-level exposures, and up to 8 to 10 hours after milder exposure (Requena et al, 1988).
c) Delayed cutaneous sensitization of the cell-mediated type may develop 2 to 4 weeks after exposure. Patch tests are negative (Pierard et al, 1990).

D) DISCOLORATION OF SKIN

1) WITH POISONING/EXPOSURE

a) Residual pigmentation was seen in 8 persons exposed during the Iran-Iraq war (Bismuth et al, 1995; Requena et al, 1988) . Hyperpigmentation is common, but hypopigmentation may also occur (Shohrati et al, 2007).

E) SEQUELA

1) WITH POISONING/EXPOSURE

a) Long-term sequelae reported following mustard exposure includes pigmentation abnormalities of the skin, chronic skin ulceration and scar formation, alopecia, xerosis, keloids and skin cancer ((Sidell, 2000); Dowlati & Pierard, 1993). Skin cancers can occur at the site of the old scar formation (Khateri et al, 2003). A causal relationship was reported to exist between mustard and these conditions.
b) CASE SERIES: Ongoing studies to examine the effects of wartime exposure to mustard gas during the Iran-Iraq war (1980-1988) found that of those known to be exposed (n=34,000), chronic skin lesions were reported in 24.5% (n=8338) of cases. Of those cases, 23% (n=7820) had mild lesions, 15% (n=510) had moderate skin lesions, and only 8 persons developed severe skin lesions (Khateri et al, 2003).
c) Forty Iranian veterans were evaluated 16 to 20 years after severe intoxication with mustard gas. Dermal complications were reported in 35 patients. Itching was reported in 65% and a burning sensation in 20%. Hyperpigmentation was observed in 55%, erythematous papular rash in 42.5%, dry skin in 40%, multiple cherry angiomas in 37.5%, atrophy in 27.5%, hypopigmentation in 25%, hair loss in 10%, eczema in 7.5%, and hypertrophy in 2.5% (Balali-Mood et al, 2005).
d) In one study, 600 patients (aged 19 to 80 years) were evaluated 19 years after exposure to mustards. Primary cutaneous complications were reported in 83.8% of patients. Mild and moderate cutaneous complications (as defined below) occurred in 31.3% and 0.2% of patients, respectively. No severe complications were reported. Delayed cutaneous complications (mustard scars [atrophic and pigmentary areas with cherry angiomas] and skin dryness) were reported in 31.5% of patients. The following criteria were used to classify the cutaneous complications (Ghassemi-Broumand et al, 2008).

1) Mild: Burning and itching, skin dryness, hypo- and/or hyperpigmentation of less than 18% of the body surface, alopecia, generalized vitiligo, psoriasis of less than 20% of the body surface, mild and limited eczema, lichen simplex, limited prurigo, limited scars in uncovered areas, single keloids, chronic urticaria or angioedema, localized bullous lesions, and recurrent superficial fungal involvement.
2) Moderate: Hypo- and/or hyperpigmentation of more than 18% of uncovered body surface, severe and generalized eczema, generalized prurigo, generalized scars, keloids with limitation of motion, recurrent generalized bullous lesions, long-term and generalized itching, and psoriasis of more than 20% of the body surface.
3) Severe: Skin cancers except basal cell carcinoma.

e) A cross-sectional descriptive study evaluated 800 men with late cutaneous effects 14 to 20 years after wartime exposure to sulfur mustard gas. The following signs or disorders were reported: xerosis (39.6%), hyperpigmentation (19%), cherry angioma (17.3%), seborrheic dermatitis (12.7%), eczema (12.2%), acneiform lesions (11.6%), tinea versicolor (7%), multiple melanocytic nevi (6.1%), mustard scar (5.5%), urticaria and/or angioedema (5.1%), lichen simplex (4.1%), keratosis pilaris (3.6%), vitiligo (3.6%), alopecia areata (2.5%), herpes simplex infection (2.2%), hypopigmentation (2.2%), psoriasis (2%), hypertrophic scar (1.3%), aphthous stomatitis (1.3%), actinic keratosis (1.2%), lichen planus (1.1%) (Emadi et al, 2008).

3.14.3)

A) ANIMAL STUDIES

1) SKIN ULCERATION

a) Direct application to the skin of rabbits and guinea pigs produced vascular leakage, leukocyte infiltration, and necrosis of basal epidermal cells within 8 hours; a crust-covered ulcer appeared over 24 to 72 hours, and repair and healing occurred over the next 10 days (Vogt et al, 1984).

Immunologic

3.19.2)

A) ACUTE ALLERGIC REACTION

1) WITH POISONING/EXPOSURE

a) Cutaneous sensitization may occur with repeated exposure of 1 to 3 weeks (NATO, 1973).
b) Sensitized individuals may have a shorter latent period than nonsensitized persons for development of dermal symptoms (NATO, 1973).
c) Characteristic sensitization reactions are a morbilliform rash and eczematoid dermatitis around old skin lesions (NATO, 1973).
d) Mustard gas did not cause hypersensitivity in 8 persons acutely exposed in the Iran-Iraq war (Requena et al, 1988). In 50 patients exposed during this conflict, 80% had increased IgG levels, 65% had increased IgE levels, and 15% had decreased levels of serum gammaglobulin levels (Balali-Mood & Gorji, 1993).

B) INFECTIOUS DISEASE

1) WITH POISONING/EXPOSURE

a) Following absorption of a large amount of mustard, bone marrow damage resulting in decreased white and red blood cells may occur, with overwhelming infection often resulting (Sidell et al, 1998). Death may occur despite antibiotic use in these cases.

C) SEQUELA

1) WITH POISONING/EXPOSURE

a) Immune system studies were conducted on 40 male veterans (mean age 43.8 years) exposed to sulfur mustard 16 to 20 years prior to the study during the Iran/Iraq war. Results were compared with 35 age-matched controls. WBC, RBC, and hematocrit were significantly elevated in the exposed group, compared with the controls. The percentage of monocytes and CD3+ lymphocytes were significantly elevated in the exposed group and the percentage of CD16+56 positive cells was significantly lower compared with the controls.

1) The authors speculated that the elevations in WBC count were a reflection of the history of chronic respiratory tract infections in the exposed group and the elevation in RBCs and hematocrit was a reflection of ongoing chronic hypoxia secondary to respiratory tract damage. The relationship of the CD3+ cell changes was less clear (Mahmoudi et al, 2005).

Laboratory Monitoring

Monitoring Parameters Levels

4.1.1)

A) Monitor serum electrolytes, glucose, CBC, renal function tests, and liver enzymes.
B) Obtain an ECG and institute continuous cardiac monitoring.
C) Monitor CBC daily for 2 weeks for evidence of neutropenia or thrombocytopenia.
D) Monitor arterial blood gases and/or pulse oximetry, chest radiograph, and pulmonary function tests in patients with respiratory symptoms.
E) Monitor carefully for evidence of infection (dermal, eye or systemic).
F) Analyses of thiodiglycol (a metabolite) in the urine can be a method of quantifying the degree of exposure to mustard gas, but it is not widely available or useful in guiding therapy.

4.1.2)

A) BLOOD/SERUM CHEMISTRY

1) A level of 1.1 mg of mustard gas per kg tissue wet weight was found in the blood at autopsy after a fatal acute exposure (Drasch et al, 1987). Other than for confirming the diagnosis, measuring levels of mustard gas or its metabolites is unlikely to be of value in managing acute poisoning.

B) HEMATOLOGIC

1) Monitor hematological parameters including CBC for possible myelosuppressive effects. Leukopenia is usually evident at 7 to 10 days following a severe acute exposure ((Garigan, 1996)).

C) ACID/BASE

1) Monitor arterial blood gases or pulse oximetry in all casualties. In severe cases, arterial blood gases reveal mainly hypoxia and respiratory acidosis.

4.1.3)

A) URINARY LEVELS

1) The parent compound could be detected at levels of 1 to 1.5 ng/mL in urine up to a week after acute exposure but not several days later (Vycudilik, 1985).

a) This may have been because mustard gas is relatively unstable under aqueous conditions, with a half-life of 2 to 3 minutes at 37 degrees C (Lawley, 1976).

2) Another source reported that the presence of sulfur mustard can be confirmed using urinary sulfur mustard metabolite (SBMTE) testing up to 11 days after exposure (Weibrecht et al, 2012).
3) Mustard gas was not detectable in urine seven days after a fatal acute exposure (Drasch et al, 1987).
4) Thiodiglycol, a metabolite of mustard gas, was present in the urine of fifteen individuals exposed in the Iran-Iraq war at 5 to 336 ng/mL, with most samples in the range of 10 to 100 ng/mL; values were within the control range approximately two weeks later (Wils et al, 1988).

a) Control values ranged from 1 to 21 ng/mL (Wils et al, 1988) but have occasionally been as high as 52 ng/mL (Machata & Vycudilik, 1984).
b) Thiodiglycol was present in the urine of 25 victims of mustard gas exposure on the 12th day at concentrations greater than 30 ng/mL (Bismuth et al, 1995).

4.1.4)

A) OTHER

1) MONITORING

a) Before the 1970s, chemical munitions were disposed of in US waters. A fisherman was exposed to sulfur mustard from multiple artillery shells entangled in a clam net, about 100 miles off the northeastern coast of the US. Blister fluid, urine, and blood can be used to confirm the presence of sulfur mustard. The Agency for Toxic Substances and Disease Registry (http://www.atsdr.cdc.gov/mhmi/mmg164.html) can be used to obtain more information about decontamination and securing the contaminated location. The Laboratory Response Network, which consists of 62 state, territorial, and metropolitan laboratories, has been formed by CDC (contact number: 770-488-7100), Federal Bureau of Identification, and the Association of Public Health Laboratories, to help in responding to mass exposures. Their web site (http://www.bt.cdc.gov/chemical/lab.asp) can be accessed to obtain information about collection and shipping of blood, urine, and other biological samples (Weibrecht et al, 2012). To obtain more information about the US Army Chemical Material Activity Programs, the Public Affairs Office may also be contacted (contact number: 800-488-0648). The CDC may be contacted for more information about chemical weapons (contact number: 800-CDC-INFO) (Centers for Disease Control and Prevention (CDC), 2013).
b) If respiratory tract irritation is present, monitor arterial blood gases and chest x-ray.
c) Monitor dermal effects, which are delayed and progressive and behave as a chemical burn or radiomimetic effect.

2) PULMONARY FUNCTION TESTS

a) Monitor pulmonary function tests in patients with respiratory signs or symptoms.

Radiographic Studies

1) Following severe inhalation exposures, lower respiratory tract injuries may occur. An infiltrate may be seen on chest radiograph within the first two days (Smith, 1999).
2) If respiratory tract irritation is present, monitor chest x-ray.

Methods

1) Mustard was reportedly detected by gas chromatography-mass spectrometry in urine at a few parts per billion up to a week after acute exposure (IARC, 1975; Vycudilik, 1985; Drasch et al, 1987). A gas chromatographic method has a lower limit of detection of 45 ng/mL after prior extraction of blood (Maisonneuve et al, 1992).

a) Quantitative determination was made in body tissues by electrothermal atomic absorption spectrometry after extraction with dichloromethane, thin-layer chromatography, and derivitization with gold chloride (Drasch et al, 1987).

2) Thiodiglycol, a metabolite of mustard gas, can be detected in urine of exposed individuals in the range of 10 to 100 ng/mL and above (Wils et al, 1988).

a) The thiodigylcol was converted to mustard gas with concentrated hydrochloric acid, followed by adsorption onto Tenax-GC and gas chromatography/mass spectrometry; the use of an internal standard of deuterated thiodiglycol improved sensitivity and reproducibility (Wils et al, 1988).

3) Detection tubes containing 4-(4'-nitrobenzyl)pyridine complexed with bivalent mercury, nickel and magnesium salts and purified silica gel as carrier can be used to detect airborne levels in the range of 0.5 to 1 mcg/L air (IARC, 1975).
4) Mustard gas-DNA adducts can be separated by HPLC after acid hydrolysis and identified by GC-MS. The lower limit of detection was 10 pmol (Ludlum et al, 1994).
5) Clark et al (1999) described the use of a headspace sampling technique in conjunction with thermal desorption and gas chromatography-mass spectrometry for an in-vitro screening method for evaluating decontamination of sulfur mustard by reactive dermal formulations. A lower detection limit of 1 ng and a coefficient of <20% were reported for residual mustard gas in repetitive measurements.

Treatment

Life Support

Patient Disposition

6.3.1)

6.3.1.1) ADMISSION CRITERIA/ORAL

A) Patients with significant dermal burns, persistent respiratory symptoms, or severe eye involvement should be admitted. Patients who are discharged should have frequent follow up for CBC monitoring.

6.3.1.2) HOME CRITERIA/ORAL

A) There is no role for home management of any patient with mustard gas exposure.

6.3.1.3) CONSULT CRITERIA/ORAL

A) Consult a medical toxicologist or poison center for any patient with sulfur mustard exposure. Consult an ophthalmologist for any patients with mustard gas burns to the eye. Consult a pulmonologist for any patients with significant or persistent respiratory distress; bronchoscopy may be necessary. Consult a gastroenterologist for any ingestion as endoscopy may be necessary to assess the extent of injury.
B) Before the 1970s, chemical munitions were disposed of in US waters. A fisherman was exposed to sulfur mustard from multiple artillery shells entangled in a clam net, about 100 miles off the northeastern coast of the US. Blister fluid, urine, and blood can be used to confirm the presence of sulfur mustard. The Agency for Toxic Substances and Disease Registry (http://www.atsdr.cdc.gov/mhmi/mmg164.html) can be used to obtain more information about decontamination and securing the contaminated location. The Laboratory Response Network, which consists of 62 state, territorial, and metropolitan laboratories, has been formed by CDC (contact number: 770-488-7100), Federal Bureau of Identification, and the Association of Public Health Laboratories, to help in responding to mass exposures. Their web site (http://www.bt.cdc.gov/chemical/lab.asp) can be accessed to obtain information about collection and shipping of blood, urine, and other biological samples (Weibrecht et al, 2012). To obtain more information about the US Army Chemical Material Activity Programs, the Public Affairs Office may also be contacted (contact number: 800-488-0648). The CDC may be contacted for more information about chemical weapons (contact number: 800-CDC-INFO) (Centers for Disease Control and Prevention (CDC), 2013).

6.3.1.4) PATIENT TRANSFER/ORAL

A) Patients with severe or extensive dermal burns should be transferred to a burn unit.

6.3.1.5) OBSERVATION CRITERIA/ORAL

A) Any patient with exposure to mustard gas via any route (ingestion, dermal, inhalational or ocular) should be sent to a medical facility for evaluation and treatment.

6.3.3)

6.3.3.1) ADMISSION CRITERIA/INHALATION

6.3.3.2) HOME CRITERIA/INHALATION

A) There is no role for home management of any patient with mustard gas exposure.

6.3.3.3) CONSULT CRITERIA/INHALATION

A) Consult a medical toxicologist or poison center for any patient with sulfur mustard exposure. Consult an ophthalmologist for any patients with mustard gas burns to the eye. Consult a pulmonologist for any patients with significant or persistent respiratory distress; bronchoscopy may be necessary. Consult a gastroenterologist for any ingestion as endoscopy may be necessary to assess the extent of injury.
B) In 1970s, chemical munitions were disposed of in US waters. A fisherman was exposed to sulfur mustard from multiple artillery shells entangled in a clam net, about 100 miles off the northeastern coast of the US. Blister fluid, urine, and blood can be used to confirm the presence of sulfur mustard. The Agency for Toxic Substances and Disease Registry (http://www.atsdr.cdc.gov/mhmi/mmg164.html) can be used to get more information about decontamination and securing the contaminated location. The Laboratory Response Network, which consists of 62 state, territorial, and metropolitan laboratories, has been formed by CDC (contact number: 770-488-7100), Federal Bureau of Identification, and the Association of Public Health Laboratories, to help in responding to mass exposures. Their web site (http://www.bt.cdc.gov/chemical/lab.asp) can be accessed to obtain information about collection and shipping of blood, urine, and other biological samples (Weibrecht et al, 2012).

6.3.3.4) PATIENT TRANSFER/INHALATION

A) Patients with severe or extensive dermal burns should be transferred to a burn unit.

6.3.3.5) OBSERVATION CRITERIA/INHALATION

A) Any patient with exposure to mustard gas via any route (ingestion, dermal, inhalational or ocular) should be sent to a medical facility for evaluation and treatment.

Monitoring

Oral Exposure

6.5.1)

A) PREHOSPITAL: Move patient from the toxic environment to fresh air. As soon as possible, remove contaminated clothing and wash exposed area extremely thoroughly with soap and water. Cut away and discard contaminated hair. Dilute (0.5%) hypochlorite solutions (prepared by a 10:1 dilution of 5% chlorine bleach with water) may also be used for skin decontamination. Irrigate eyes with water or saline.

6.5.2)

A) HOSPITAL: The role of gastrointestinal decontamination is not clear for mustard ingestion. Most patients will have severe vomiting and gastrointestinal irritation, so it is unlikely that gastric lavage will remove additional poison. Activated charcoal is also unlikely to be of utility since the toxic effects occur rapidly upon contact with tissue.
B) ACTIVATED CHARCOAL

1) If activated charcoal is given, it should be administered with 150 mL of a 2% sodium thiosulfate solution. The efficacy of activated charcoal following oral mustard gas exposures has not been established.
2) CHARCOAL ADMINISTRATION

a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.

3) CHARCOAL DOSE

a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).

1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).

b) ADVERSE EFFECTS/CONTRAINDICATIONS

1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).

4) Oral treatment, following exposure to mustard gas, with 40 grams activated charcoal orally 3 times every 4 hours has been recommended (Heyndrickx & Heyndrickx, 1990), but there is no data to support this specific regimen.

6.5.3)

A) MONITORING OF PATIENT

1) Monitor serum electrolytes, glucose, CBC, renal function tests, and liver enzymes.
2) Obtain an ECG and institute continuous cardiac monitoring.
3) Monitor CBC daily for 2 weeks for evidence of neutropenia or thrombocytopenia.
4) Monitor arterial blood gases and/or pulse oximetry, chest radiograph, and pulmonary function tests in patients with respiratory symptoms.
5) Monitor carefully for evidence of infection (dermal, eye or systemic).
6) Analyses of thiodiglycol (a metabolite) in the urine can be a method of quantifying the degree of exposure to mustard gas, but it is not widely available or useful in guiding therapy.

B) EXPERIMENTAL THERAPY

1) Various treatment combinations of parenteral dexamethasone, promethazine, vitamin E, heparin, and sodium thiosulfate have shown protective effects against mustard gas poisoning in laboratory animals. Doses were many times greater than those prescribed in humans for other indications. These agents may have some value, but clinical trials have not been conducted and their place in therapy is speculative. The pharmacology of these agents should be considered before they are given.
2) COOLING THERAPY

a) The effects of temperature on the development of sulfur mustard (HD)-induced toxicity were studied in cultures of human skin keratinocytes and on hairless guinea pig skin. At higher temperatures (37 degrees C) a decline in cell viability occurred rapidly and the effects peaked at 48 hours. Cells incubated at temperatures of 25 degrees C demonstrated no significant HD-induced toxicity up to 4 days post-exposure. However, the protective effects of a cooler environment were significantly less when the cells were incubated at 31 degrees C and lost viability over the ensuing days. In hairless guinea pigs, moderate cooling (5 to 10 degrees C) of HD exposed sites starting 5 minutes after the exposure and continuing for 6 hours, was associated with significant reduction in the severity of skin lesions. The authors noted the difficulty in extrapolating this information to actual human exposures, but suggested that limited cooling of the skin (limited injured area) may be a harmless, and economical way to minimize skin injury (Mi et al, 2003).

3) AMIFOSTINE

a) One animal study evaluated prophylactic efficacy of amifostine (an organophosphorothioate) and its analogues (DRDE-06, DRDE-07, DRDE-08; different chain length and substitution at the sulfur atom) against sulfur mustard toxicity. All agents (dose 0.2 LD50) were administered by intraperitoneal route (IP) to mice 30 minutes before dermal application of sulfur mustard. Amifostine and DRDE-07 significantly reduced sulfur mustard (155 mg/kg in PEG 300, equal to 19-fold LD50) induced mortality when administered IP either 30 minutes before or simultaneously. Amifostine and DRDE-07 (LD50: 1049 or 1248 mg/kg, respectively), also significantly protected the mice against dermally applied sulfur mustard, when administered by oral route as a pretreatment (30 or 60 minutes). However, DRDE-07 protected mice when administered as a pretreatment or simultaneously. Both agents significantly reduced the DNA damage induced by sulfur mustard . In addition, DRDE-07 protected mice significantly with respect to the decrease in body weight and the depletion of GSH induced by sulfur mustard. Overall, the prophylactic effect of oral DRDE-07 was better than amifostine (Vijayaraghavan et al, 2001).

4) DOXYCYCLINE

a) Guinea pigs in groups of six were pretreated with either subcutaneous injection of the protease inhibitor doxycycline (30 mg/kg) or normal saline and were then exposed to 0.1 mL of either sulfur mustard (0.2 mg/kg) or 0.5% ethanol in normal saline via injection into the trachea. Doxycycline pretreatment decreased gelatinase activity, decreased tracheal inflammation, and decreased microscopic epithelial changes (Guignabert et al, 2005).

5) CUROSURF AND SALBUTAMOL

a) Male specific-pathogen-free guinea pigs were exposed to intratracheal sulfur mustard. Two groups of six received either Curosurf 62.5 mg/kg or 125 mg/kg one hour after sulfur mustard exposure and another group of six received salbutamol 10 mcg/kg intratracheally immediately after exposure. Both Curosurf and Salbutamol improved 24-hour survival, compared with controls. Low dose Curosurf appeared more effective than high dose Curosurf. Salbutamol appeared more effective than Curosurf (van Helden et al, 2004).

C) SODIUM THIOSULFATE

1) SODIUM THIOSULFATE has been proposed to be of possible value as a "mustard scavenger" in human cases of mustard gas poisoning because of its low toxicity (Karakcijev, 1973; Weger, 1975; Gille, 1969; Golikov & Stojkov, 1983; Borak & Sidell, 1992; Dacre & Goldman, 1996). Dose recommended includes 50 mL of a 25% sodium thiosulfate solution (12.5 grams total) administered intravenously over 10 minutes ((Garigan, 1996)).

a) The doses used in animal experiments were many times those administered to humans for other indications, and the potential benefits are not known. There is no data to support its use after lesions have developed.

D) ACETYLCYSTEINE

1) N-acetylcysteine (NAC; Mucomyst) is a potential mustard gas antagonist ((Garigan, 1996)). The benefit of this treatment is not yet clarified in humans.
2) DOSING: 150 mg/kg infusion over 60 minutes followed by 50 mg/kg infusion over 4 hours followed by 6.25 mg/kg/hr infusion for 16 hours (Daly et al, 2008; Prod Info ACETADOTE(R) IV injection, 2006; Prescott et al, 1979). ORAL: 140 mg/kg orally followed by 70 mg/kg every 4 hours for 17 doses (Betten et al, 2007; Tsai et al, 2005; Woo et al, 2000; Woo et al, 1995).
3) It has been proposed that NAC be administered prophylactically to personnel entering combat zones or otherwise at risk for mustard gas exposure, but this has never been evaluated (Bobb et al, 2005).
4) ANIMAL STUDIES: In animal studies, NAC administered orally, topically, and intravenously reduced mustard gas-induced tissue damage. It possessed protective effects to the skin and respiratory tract. Liposomal NAC instilled via broncheoalveolar lavage into the lungs of exposed rats reduced mustard gas-induced lung injury by approximately 80% for up to an hour after exposure (Geraci, 2008).
5) ANIMAL STUDIES (INHALED NAC): In an animal study, 14 anesthetized pigs were exposed to sulfur mustard vapors (100 mcg/kg for 10 minutes) and developed acute lung injury. Eight pigs received multiple inhaled doses of NAC (1 mL of 200 mg/L Mucomyst(TM) at 30 min, 2, 4, 6, 8, and 10 hours postexposure). In the control group (n=6), 5 animals survived to 12 hours. All 6 animals had significantly reduced arterial PaO2 and saturation levels, arterial blood pH and bicarbonate, and increased PaCO2. All 8 animals in the NAC-treated groups survived and had significantly improved arterial blood oxygen saturation, bicarbonate concentrations, and shunt fraction (proportion of blood passing through the lungs remaining unoxygenated because of perfusion/ventilation mismatch) compared with the control group. In addition, significantly fewer neutrophils and lower concentrations of protein in lavage were observed compared with the control group (Jugg et al, 2013).

E) PROMETHAZINE

1) PROMETHAZINE, a sulfhydryl-scavenging agent, or other antihistamines have been used to treat human poisonings by mustard gas (Heulley et al, 1956; (Fulgosi, 1956; Foulhoux, 1963; Seidel & Westphal, 1973). They are used to antagonize vasodilation and leakage from injured tissue.

F) CORTICOSTEROID

1) DEXAMETHASONE and PREDNISONE have been effective in antagonizing the pulmonary toxicity of mustard gas poisoning in experimental animals and humans (Vojvodic et al, 1985; Requena et al, 1988).
2) Prednisone has been given in doses of 60 to 125 milligrams per day for pulmonary toxicity (Requena et al, 1988a).

G) BURN

1) Severe irritation or burns of the esophagus or gastrointestinal tract would be predicted to occur following liquid mustard ingestion. Observe patients with ingestion carefully for the possible development of esophageal or gastrointestinal tract irritation or burns. If signs or symptoms of esophageal irritation or burns are present, consider endoscopy to determine the extent of injury.
2) Perforation, bleeding, and late stricture formation could result. If severe irritation or burns of the esophagus or gastrointestinal tract are suspected, surgical consultation is advised.

H) FLUID/ELECTROLYTE BALANCE REGULATION

1) Follow fluid-electrolyte status carefully and replace losses as necessary. Initial vomiting is rarely severe and can be relieved with atropine or common antiemetics. Later vomiting and diarrhea are generally indicative of systemic cytotoxicity and require fluid replacement ((Sidell, 2000)).

Inhalation Exposure

6.7.1)

A) TIME IS OF THE ESSENCE in decontaminating mustard gas to prevent damage to the lung and other tissues from inhalation exposure; once the mustard gas has reacted with tissue, the course of permanent damage may be irrevocable.
B) Administer inhaled beta agonists for bronchospasm or persistent cough. Administer supplemental oxygen. Inhaled sodium thiosulfate (2.5% solution nebulized) may help prevent injury. Patients with severe respiratory distress required intubation. Bronchoscopy may be required to remove pseudomembranes from the respiratory tract.

6.7.2)

A) MONITORING OF PATIENT

B) EXPERIMENTAL THERAPY

3) AMIFOSTINE

4) DOXYCYCLINE

5) CUROSURF AND SALBUTAMOL

C) SODIUM THIOSULFATE

1) SODIUM THIOSULFATE - has been proposed to be of possible value as a "mustard scavenger" in human cases of mustard gas poisoning because of its low toxicity (Karakcijev, 1973; Weger, 1975) 1980, 1981; (Gille, 1969; Golikov & Stojkov, 1983; Borak & Sidell, 1992; Dacre & Goldman, 1996). A nebulizing mist of 2.5 percent solution of sodium thiosulfate may have some value in neutralization if exposure has occurred in the past 15 minutes. A recommended parenteral dose includes 50 mL of a 25% sodium thiosulfate solution (12.5 grams total) administered intravenously over 10 minutes ((Garigan, 1996)).

a) The doses used in animal experiments were many times those administered to humans for other indications, and the potential benefits are not known.

D) ACETYLCYSTEINE

1) N-acetylcysteine (NAC; Mucomyst) is a potential mustard gas antagonist ((Garigan, 1996)). The benefit of this treatment is not yet clarified in humans.
2) DOSING: 150 mg/kg infusion over 60 minutes followed by 50 mg/kg infusion over 4 hours followed by 6.25 mg/kg/hr infusion for 16 hours (Daly et al, 2008; Prod Info ACETADOTE(R) IV injection, 2006; Prescott et al, 1979). ORAL: 140 mg/kg orally followed by 70 mg/kg every 4 hours for 17 doses (Betten et al, 2007; Tsai et al, 2005; Woo et al, 2000; Woo et al, 1995).
3) It has been proposed that NAC be administered prophylactically to personnel entering combat zones or otherwise at risk for mustard gas exposure, but this has never been evaluated (Bobb et al, 2005).
4) ANIMAL STUDIES: In animal studies, NAC administered orally, topically, and intravenously reduced mustard gas-induced tissue damage. It possessed protective effects to the skin and respiratory tract. Liposomal NAC instilled via broncheoalveolar lavage into the lungs of exposed rats reduced mustard gas-induced lung injury by approximately 80% for up to an hour after exposure (Geraci, 2008).
5) ANIMAL STUDIES (INHALED NAC): In an animal study, 14 anesthetized pigs were exposed to sulfur mustard vapors (100 mcg/kg for 10 minutes) and developed acute lung injury. Eight pigs received multiple inhaled doses of NAC (1 mL of 200 mg/L Mucomyst(TM) at 30 min, 2, 4, 6, 8, and 10 hours postexposure). In the control group (n=6), 5 animals survived to 12 hours. All 6 animals had significantly reduced arterial PaO2 and saturation levels, arterial blood pH and bicarbonate, and increased PaCO2. All 8 animals in the NAC-treated groups survived and had significantly improved arterial blood oxygen saturation, bicarbonate concentrations, and shunt fraction (proportion of blood passing through the lungs remaining unoxygenated because of perfusion/ventilation mismatch) compared with the control group. In addition, significantly fewer neutrophils and lower concentrations of protein were observed in bronchioalveolar lavage fluid compared with the control group (Jugg et al, 2013).

E) PROMETHAZINE

1) PROMETHAZINE, a sulfhydryl-scavenging agent, or other antihistamines have been used to treat human poisonings by mustard gas (Heulley et al, 1956) (Fulgosi, 1956; Foulhoux, 1963; Seidel & Westphal, 1973). They are used to antagonize vasodilation and leakage from injured tissue.

F) CORTICOSTEROID

1) DEXAMETHASONE AND PREDNISONE have been effective in antagonizing the pulmonary toxicity of mustard gas poisoning in experimental animals and humans (Vojvodic et al, 1985; Requena et al, 1988).
2) Prednisone has been given in doses of 60 to 125 milligrams per day for pulmonary toxicity (Requena et al, 1988).
3) Patients with chronic bronchitis from exposure to mustard gas in the Iran-Iraq war were randomized to receive IV methylprednisolone 500 mg for 3 days followed by 250 mg for another 3 days. On day 7 they received 150 mg and, on day 8, 100 mg of prednisolone (n=39). A second group received oral methylpredisolone 1 mg/kg and the dose was gradually reduced over the 8 day period (n=26). Significant improvement in spirometry indexes were observed in approximately half of the patients in both groups over the 8 day period; however, spirometry indices were not significantly different between the groups before and after treatment (Ghanei et al, 2005).

G) BRONCHITIS

1) Toxic bronchitis is common following inhalation of mustard gas, which results in hypoxia secondary to abnormalities in the ventilation-perfusion ration. Individuals with a history of hyperreactive airways disease may be at high risk. Therapy with bronchodilators may be necessary ((Sidell, 2000)). Consider steroid therapy if a prior history of asthma or hyperreactive airways disease is obtained.
2) BRONCHOSPASM SUMMARY

a) Administer beta2 adrenergic agonists. Consider use of inhaled ipratropium and systemic corticosteroids. Monitor peak expiratory flow rate, monitor for hypoxia and respiratory failure, and administer oxygen as necessary.

3) ALBUTEROL/ADULT DOSE

a) 2.5 to 5 milligrams diluted with 4 milliliters of 0.9% saline by nebulizer every 20 minutes for three doses. If incomplete response, administer 2.5 to 10 milligrams every 1 to 4 hours as needed OR administer 10 to 15 milligrams every hour by continuous nebulizer as needed. Consider adding ipratropium to the nebulized albuterol; DOSE: 0.5 milligram by nebulizer every 30 minutes for three doses then every 2 to 4 hours as needed, NOT administered as a single agent (National Heart,Lung,and Blood Institute, 2007).

4) ALBUTEROL/PEDIATRIC DOSE

a) 0.15 milligram/kilogram (minimum 2.5 milligrams) diluted with 4 milliliters of 0.9% saline by nebulizer every 20 minutes for three doses. If incomplete response administer 0.15 to 0.3 milligram/kilogram (maximum 10 milligrams) every 1 to 4 hours as needed OR administer 0.5 mg/kg/hr by continuous nebulizer as needed. Consider adding ipratropium to the nebulized albuterol; DOSE: 0.25 to 0.5 milligram by nebulizer every 20 minutes for three doses then every 2 to 4 hours as needed, NOT administered as a single agent (National Heart,Lung,and Blood Institute, 2007).

5) ALBUTEROL/CAUTIONS

a) The incidence of adverse effects of beta2-agonists may be increased in older patients, particularly those with pre-existing ischemic heart disease (National Asthma Education and Prevention Program, 2007). Monitor for tachycardia, tremors.

6) CORTICOSTEROIDS

a) Consider systemic corticosteroids in patients with significant bronchospasm. PREDNISONE: ADULT: 40 to 80 milligrams/day in 1 or 2 divided doses. CHILD: 1 to 2 milligrams/kilogram/day (maximum 60 mg) in 1 or 2 divided doses (National Heart,Lung,and Blood Institute, 2007).

7) A late sequelae of mustard inhalation is a tracheal/bronchial stenosis necessitating bronchoscopy and other procedures. Long-term sensitivity to smoke, dust, and similar airborne particles, most likely a result of clinically inapparent bronchospasm, has been reported ((Sidell, 2000)).

H) OXYGEN

1) SUMMARY

a) Intubate casualties with severe pulmonary signs early to assist in ventilation and allow suctioning of necrotic and inflammatory debris ((Sidell, 2000)). Administer oxygen as required for respiratory distress (Requena et al, 1988). Oxygen therapy may be required for prolonged periods of time, depending primarily on the intensity of the mustard gas exposure.

2) CONTINUOUS POSITIVE AIRWAY PRESSURE

a) NASAL CPAP: In one study, nasal continuous positive airway pressure (CPAP) treatment significantly reduced respiratory events and nocturnal hypoxemia during sleep in 57 mustard gas-exposed patients (mean age, 48.14 +/- 8.04 years) (Vahedi et al, 2014).

I) BRONCHOSCOPY

1) Tracheotomy may be required in cases of rapidly developing upper airway pseudomembrane to prevent complete airway obstruction. Bronchoscopy may be necessary for the removal of intact pseudomembranes or fragments of pseudomembranes from the tracheal or respiratory tract. Tracheal obstruction has occurred by a pseudomembrane. Early use of positive end-expiratory pressure or continuous positive airway pressure may be of benefit in severe cases. A need for continuous ventilatory support suggests a poor prognosis ((Sidell, 2000); Prakash, 1991).
2) Progressive deterioration of gas exchange, after a delay of up to 15 months with scars, ulcers, and strictures, is common. Bronchoscopy is essential in evaluating the progressive medical conditions. Repeated bougienage of the stenotic tracheobronchial lesions and laser photoresection of scarring tissue may be necessary. Recurrence rate of stenosis is high, averaging less than 6 months (Freitag et al, 1991; Prakash, 1991).

J) FLUID/ELECTROLYTE BALANCE REGULATION

1) Parenteral fluid and electrolyte therapy may be necessary (Requena et al, 1988). Initial vomiting is rarely severe and can be relieved with atropine or common antiemetics. Later vomiting and diarrhea are generally indicative of systemic cytotoxicity and require fluid replacement ((Sidell, 2000)).

K) ACUTE LUNG INJURY

1) ONSET: Onset of acute lung injury after toxic exposure may be delayed up to 24 to 72 hours after exposure in some cases.
2) NON-PHARMACOLOGIC TREATMENT: The treatment of acute lung injury is primarily supportive (Cataletto, 2012). Maintain adequate ventilation and oxygenation with frequent monitoring of arterial blood gases and/or pulse oximetry. If a high FIO2 is required to maintain adequate oxygenation, mechanical ventilation and positive-end-expiratory pressure (PEEP) may be required; ventilation with small tidal volumes (6 mL/kg) is preferred if ARDS develops (Haas, 2011; Stolbach & Hoffman, 2011).

a) To minimize barotrauma and other complications, use the lowest amount of PEEP possible while maintaining adequate oxygenation. Use of smaller tidal volumes (6 mL/kg) and lower plateau pressures (30 cm water or less) has been associated with decreased mortality and more rapid weaning from mechanical ventilation in patients with ARDS (Brower et al, 2000). More treatment information may be obtained from ARDS Clinical Network website, NIH NHLBI ARDS Clinical Network Mechanical Ventilation Protocol Summary, http://www.ardsnet.org/node/77791 (NHLBI ARDS Network, 2008)

3) FLUIDS: Crystalloid solutions must be administered judiciously. Pulmonary artery monitoring may help. In general the pulmonary artery wedge pressure should be kept relatively low while still maintaining adequate cardiac output, blood pressure and urine output (Stolbach & Hoffman, 2011).
4) ANTIBIOTICS: Indicated only when there is evidence of infection (Artigas et al, 1998).
5) EXPERIMENTAL THERAPY: Partial liquid ventilation has shown promise in preliminary studies (Kollef & Schuster, 1995).
6) CALFACTANT: In a multicenter, randomized, blinded trial, endotracheal instillation of 2 doses of 80 mL/m(2) calfactant (35 mg/mL of phospholipid suspension in saline) in infants, children, and adolescents with acute lung injury resulted in acute improvement in oxygenation and lower mortality; however, no significant decrease in the course of respiratory failure measured by duration of ventilator therapy, intensive care unit, or hospital stay was noted. Adverse effects (transient hypoxia and hypotension) were more frequent in calfactant patients, but these effects were mild and did not require withdrawal from the study (Wilson et al, 2005).
7) However, in a multicenter, randomized, controlled, and masked trial, endotracheal instillation of up to 3 doses of calfactant (30 mg) in adults only with acute lung injury/ARDS due to direct lung injury was not associated with improved oxygenation and longer term benefits compared to the placebo group. It was also associated with significant increases in hypoxia and hypotension (Willson et al, 2015).

L) EXPERIMENTAL THERAPY

1) INTERFERON-GAMMA: In one study, interferon-gamma (100 mcg every other day for 6 months) was effective in improving the quality-of-life and relieving respiratory symptoms of 15 patients with chronic sulfur mustard-induced pulmonary complications. Interferon-gamma therapy significantly reduced the severity of cough (p=0.001), dyspnea (p less than 0.001), morning dyspnea (p less than 0.001), sputum production (p less than 0.001), and hemoptysis (p less than 0.001) (Panahi et al, 2014).

M) ANTIBIOTIC

1) During the initial first 3 to 4 days following inhalation exposure, bacterial superinfection is generally not present. Withhold antibiotic therapy until the identity of a specific organism is available. A progressive leukopenia, beginning at day 4 or 5, may signal severe immune system dysfunction. In these cases, sepsis typically supervenes ((Sidell, 2000)).
2) Ampicillin has been used to treat secondary respiratory tract infection in mustard gas poisoning victims (Requena et al, 1988).
3) Antibiotics should be chosen based on clinical suspicion, sputum grams stains, and cultures, and blood cultures when indicated.

N) MYELOSUPPRESSION

1) Following dermal or inhalation exposure, significant amounts of mustard may be absorbed systemically ((Sidell, 2000)). Bone marrow damage is usually not evident for 3 to 5 days after exposure. However, several studies have reported that bone marrow suppression may become evident about 4 hours after exposure to mustard gas (Geraci, 2008; (Garigan, 1996)). Leukopenia typically develops at days 3 through 5 after exposure and reaches a nadir in 3 to 9 days, depending on extent of exposure. A poor prognosis is expected when leukopenia with a cell count less than 200 cells/mm(3) develops or a rapid drop in cell count. The gut should be sterilized with nonabsorbable antibiotics at the onset of leukopenia. Cellular replacement, either peripheral or marrow, should be instituted as indicated ((Sidell, 2000))
2) Granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF), or filgrastim, may be effective in accelerating bone marrow recovery after exposure to sulfur mustard gas.
3) There is little data on the use of hematopoietic colony stimulating factors to treat neutropenia after drug overdose or idiosyncratic reactions. These agents have been shown to shorten the duration of severe neutropenia in patients receiving cancer chemotherapy (Hartman et al, 1997; Stull et al, 2005). They have also been used to treat agranulocytosis induced by nonchemotherapy drugs (Beauchesne & Shalansky, 1999). They may be considered in patients with severe neutropenia who have or are at significant risk for developing febrile neutropenia.

a) Filgrastim: The usual starting dose in adults is 5 micrograms/kilogram/day by intravenous infusion or subcutaneous injection (Prod Info NEUPOGEN(R) injection, 2006).
b) Sargramostim: Usual dose is 250 micrograms/square meter/day infused IV over 4 hours (Prod Info LEUKINE(R) injection, 2006).
c) Monitor CBC with differential.

O) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Eye Exposure

6.8.1)

A) TIME IS OF THE ESSENCE in preventing serious or permanent injury to the eye. If the eye has been exposed to mustard droplets, the droplets disappear from the eye very quickly, thus late flushing of the eye is generally of no benefit ((Sidell, 2000)).
B) Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes.
C) It has been recommended to neutralize with a topical 2.5 per cent solution of sodium thiosulfate following water irrigation to the eyes.
D) Perform an ophthalmologic exam when decontamination is complete. Certain ocular effects of acute exposure may be delayed from several hours up to 40 YEARS (Grant & Schuman, 1993; Blodi, 1971; Amalric et al, 1965).

6.8.2)

A) INJURY OF GLOBE OF EYE

1) INITIAL THERAPY: For minor eye lesions, use soothing eye solutions 3 to 4 times daily. Prevention of infection and scarring are important. More severe lesions should be treated in a hospital setting with irrigations, topical antibiotics (3 to 4 times/day) and topical mydriatics to prevent later synechiae formation ((Sidell, 2000); Aasted et al, 1987). Topical corticosteroids are applied for the first 2 days (Smith, 1999). Keep the patient in a dim room or provide sunglasses to reduce discomfort due to photophobia.

a) CONSULTATION: It is recommended that this therapy be done by or in consultation with an ophthalmologist.

2) DELAYED KERATITIS: For delayed mustard gas keratitis involving only corneal irregularity, significant improvement in vision may be obtained by wearing contact lenses (Grant & Schuman, 1993).

a) For more severe cases involving infiltration of fatty materials or calcium, lamellar or penetrating keratoplasty may provide relief from recurring discomfort and improvement in visual acuity (Grant & Schuman, 1993; Blodi, 1971; Amalric et al, 1965).
b) Transient blindness is usually due to eyelid edema and edema of other structures and not due to corneal damage. Recovery of vision may be within days in cases of milder injuries, or within a month or longer in cases of more severe damage ((Sidell, 2000)).

B) EXPERIMENTAL THERAPY

1) In rabbits with eye exposure to 2% nitrogen mustard, treatment with eye drops containing zinc desferrioxamine 3.5 millimolar and 0.1% dexamethasone was associated with more rapid corneal re-epithelization, less corneal neovascularization, and less severe increases in intraocular pressure compared, with treatment with either agent alone or placebo (Morad et al, 2005). Dosage was 2 drops per eye every hour for 12 hours, then every 2 hours for 4 weeks.

C) CHELATION THERAPY

1) CHELATION of calcium to remove deposits within the cornea has had varying success (Blodi, 1971), and is generally not recommended.

D) SURGICAL PROCEDURE

1) CORNEAL TRANSPLANTS have been performed on some patients with good results for at least one year (Blodi, 1971).

E) GENERAL TREATMENT

1) For treatment guidelines in cases with coincident dermal or inhalation exposures, see the treatment recommendations in the INHALATION EXPOSURES or DERMAL EXPOSURES sections.

F) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Dermal Exposure

6.9.1)

A) DERMAL DECONTAMINATION

1) SUMMARY: Remove contaminated clothing and wash exposed area extremely thoroughly with soap and water. Cut away and discard contaminated hair. Dilute (0.5%) hypochlorite solutions (prepared by a 10:1 dilution of 5% chlorine bleach with water) may also be used for skin decontamination. If skin erythema is mild, no treatment is required. For pruritus, use topical steroid cream or compound calamine lotion (containing 1% each of phenol and menthol). If the blisters have been broken, remove the ragged roof; if not broken, drain under aseptic conditions. Clean the area with tap water or saline with application of petrolatum gauze when the areas are small. For large blisters, apply thick layer of 10% mefenide acetate (Sulfamylon(R)) or silver sulfadiazine burn cream. Appropriate antibiotics drug may be given locally or systemically if infection develops.
2) Mustards penetrate wood, leather, rubber, paints and cell walls. Alkalinity and higher temperatures increase the rate of mustard gas hydrolysis. TIME IS OF THE ESSENCE in decontaminating the exposed patient; once mustard gas has reacted with tissue it cannot be removed without inducing further injury. Decontamination must occur within 1 or 2 minutes after exposure to be effective in preventing or decreasing tissue damage from mustard. Mustard fixes to the skin within minutes, and tissue damage begins early. Decontamination initiated when lesions first appear will be ineffective ((Sidell, 2000)). Late decontamination may prevent the spread of mustard remaining on the skin to other areas of the skin.
3) For initial decontamination of the skin, hypochlorite (0.5%) has been recommended. However, in the Iran-Iraq War, prolonged washing with water was shown to be as effective (Smith, 1999). Decontamination of affected areas with calcium chloride and magnesium oxide, followed by washing with soap and water, is also effective. Wash the exposed area thoroughly with water, then neutralize with a 1/6 M (2.5%) solution of sodium thiosulfate. Alternatively, immediately after exposure and before vesicles have formed, wash exposed area thoroughly with oil or other aliphatic hydrocarbon-based solvent, then wash extremely thoroughly with soap and water (Dorr & Fritz, 1980).
4) When water for decontamination is in limited supply, adsorbent powders such as flour, talcum powder, or Fuller's earth may be applied to the skin, allowed to adsorb the sulfur mustard, and then are wiped off with a moist cloth or paper towel (Borak & Sidell, 1992; Heyndrickx & Heyndrickx, 1990; Dacre & Goldman, 1996).

a) Chlorine-active compounds such as chloramine powder and dilute (0.5%) hypochlorite solutions (prepared by a 10:1 dilution of 5% chlorine bleach with water) may also be used for skin decontamination (Borak & Sidell, 1992). Heyndrickx & Heyndrickx (1990) reported applying towels soaked in 2 parts per 1000 chloramine-T (Dakin solution with an oxidizing effect) to the affected areas every 2 hours for the first day, followed by wound treatment with 1% silver sulfadiazine ointment twice daily (Heyndrickx & Heyndrickx, 1990).
b) The US Military issues the M291 Skin Decontamination Kit which replaced the M2581A Skin Decontamination Kit. Each M291 Kit contains six individual decontamination packets each containing Ambergard XE-555 resin powder. The previously used M2581A Skin Decontamination Kit contained towelettes soaked with phenol+hydroxide and chloramine. A dilute (0.5%) hypochlorite (bleach) solution can also be used. Fuller's earth, flour, or talcum powder have been recommended as alternative dermal decontamination agents. These alternative agents are not currently used by the US Military.

5) Wash the exposed area thoroughly with water, then neutralize with a 1/6 M (2.5 percent) solution of sodium thiosulfate (Dorr & Fritz, 1980).

a) PREPARATION OF SODIUM THIOSULFATE: dilute 4 milliliters sodium thiosulfate injection USP (10%) with 6 milliliters of sterile water; prepare fresh for each use (Dorr & Fritz, 1980).
b) Alternatively, immediately after exposure and before vesicles have formed, wash exposed area thoroughly with oil or other aliphatic hydrocarbon-based solvent, then extremely thoroughly with soap and water (Jelenko, 1974).

B) PRETREATMENT/PREVENTION OF ABSORPTION

1) ANIMAL STUDY: A topical skin protectant called IB1, has been tested in pigs to evaluate the effectiveness of a topically applied pretreatment that would act as a barrier and prevent the absorption of sulfur mustard and VX. The barrier cream was found to be effective immediately after application, and remained effective for a least 12 hours (testing was not performed beyond this time period). At the time of this review, the formulation has been submitted for approval in Phase 1 clinical trials in human volunteers (Kadar et al, 2003).
2) ANIMAL STUDY: In guinea pigs exposed to mechlorethamine (a nitrogen mustard derivative), pretreatment of the skin with an ointment containing zinc oxide, zinc chloride, and dimethylpolysiloxane in a base of petroleum jelly was most effective in preventing vessicant-induced skin injury (Kenar et al, 2005).

C) CLOTHING

1) Potential for Secondary Contamination: HIGH: discard and isolate any contaminated clothing at the site. Medical personnel treating mustard-exposed patients have developed toxicity.

6.9.2)

A) SUPPORT

1) Initial treatment of victims should include immediate removal of the victim from the contaminated area, stabilization of general and hemodynamic status, maintenance of the airway, oxygenation, and other appropriate symptomatic therapy. The role of systemic corticosteroid therapy for prophylaxis against pulmonary complications is debatable. For more detailed discussion regarding treatment of pulmonary complications following inhaled sulfur mustard gas, see treatment recommendations in INHALATION EXPOSURE section.
2) Various treatment combinations of parenteral dexamethasone, promethazine, vitamin E, heparin, and sodium thiosulfate have shown protective effects against mustard gas poisoning in laboratory animals. Doses were many times greater than those prescribed in humans for other indications. These agents may have some value, but clinical trials have not been conducted and their place in therapy is speculative. The pharmacology of these agents should be considered before they are given.

B) SODIUM THIOSULFATE

1) SODIUM THIOSULFATE has been proposed to be of possible value as a "mustard scavenger" in human cases of mustard gas poisoning because of its low toxicity (Karakcijev, 1973; Weger, 1975) 1980, 1981; (Gille, 1969; Golikov & Stojkov, 1983; Borak & Sidell, 1992; Dacre & Goldman, 1996). A nebulizing mist of 2.5 percent solution of sodium thiosulfate may have some value in neutralization if exposure has occurred in the past 15 minutes. Parenteral dose recommended includes 50 mL of a 25% sodium thiosulfate solution (12.5 grams total) administered intravenously over 10 minutes ((Garigan, 1996)).

C) ACETYLCYSTEINE

D) PROMETHAZINE

E) CORTICOSTEROID

1) DEXAMETHASONE AND PREDNISONE have been effective in antagonizing the pulmonary toxicity of mustard gas poisoning in experimental animals and humans (Vojvodic et al, 1985; Requena et al, 1988). Use topical corticosteroids only for patients with cutaneous erythema without ulceration (Smith, 1999).
2) Prednisone has been given in doses of 60 to 125 milligrams per day for pulmonary toxicity (Requena et al, 1988).

F) BURN

1) TOPICAL THERAPY - Topical antiseptic solutions of povidone-iodine and 3% sulfadiazine cream have been used (Requena et al, 1988; Borak & Sidell, 1992).

a) In several studies, povidone-iodine applied to the skin immediately after exposure to mustard gas, reduced the incidence of dermal damage significantly (Geraci, 2008).

2) HEALING TIME - Burns usually heal in 4 to 6 weeks (Aasted et al, 1987).

a) Burn healing is slow and infection is common (Borak & Sidell, 1992).

3) BLISTERS

a) Leave small blisters (<1 cm) intact. Irrigate the blister area at least once daily. Apply a topical antibiotic to the blisters and the surrounding area. Do not occlude. Larger blisters (>1 cm) should be unroofed. Irrigate the underlying area 2 to 4 times daily with saline, sterile water, or clean soapy water. Liberally cover area with a topical antibiotic cream or ointment (1% silver sulfadiazine, mafenide acetate, bacitracin, etc.). In the case of multiple or large areas of vesication, the patient should be hospitalized for frequent and careful cleaning. A whirlpool bath may be useful. In general, skin lesions should be treated the same as that of second degree thermal burns ((Sidell, 2000)). Healing normally takes weeks to months, but generally is complete with the exception of persistent pigment changes.
b) APPLICATION

1) These recommendations apply to patients with MINOR chemical burns (FIRST DEGREE; SECOND DEGREE: less than 15% body surface area in adults; less than 10% body surface area in children; THIRD DEGREE: less than 2% body surface area). Consultation with a clinician experienced in burn therapy or a burn unit should be obtained if larger area or more severe burns are present. Neutralizing agents should NOT be used.

c) DEBRIDEMENT

1) After initial flushing with large volumes of water to remove any residual chemical material, clean wounds with a mild disinfectant soap and water.
2) DEVITALIZED SKIN: Loose, nonviable tissue should be removed by gentle cleansing with surgical soap or formal skin debridement (Moylan, 1980; Haynes, 1981). Intravenous analgesia may be required (Roberts, 1988).
3) BLISTERS: Removal and debridement of closed blisters is controversial. Current consensus is that intact blisters prevent pain and dehydration, promote healing, and allow motion; therefore, blisters should be left intact until they rupture spontaneously or healing is well underway, unless they are extremely large or inhibit motion (Roberts, 1988; Carvajal & Stewart, 1987).

d) TREATMENT

1) TOPICAL ANTIBIOTICS: Prophylactic topical antibiotic therapy with silver sulfadiazine is recommended for all burns except superficial partial thickness (first-degree) burns (Roberts, 1988). For first-degree burns bacitracin may be used, but effectiveness is not documented (Roberts, 1988).
2) SYSTEMIC ANTIBIOTICS: Systemic antibiotics are generally not indicated unless infection is present or the burn involves the hands, feet, or perineum.
3) WOUND DRESSING:

a) Depending on the site and area, the burn may be treated open (face, ears, or perineum) or covered with sterile nonstick porous gauze. The gauze dressing should be fluffy and thick enough to absorb all drainage.
b) Alternatively, a petrolatum fine-mesh gauze dressing may be used alone on partial-thickness burns.

4) DRESSING CHANGES:

a) Daily dressing changes are indicated if a burn cream is used; changes every 3 to 4 days are adequate with a dry dressing.
b) If dressing changes are to be done at home, the patient or caregiver should be instructed in proper techniques and given sufficient dressings and other necessary supplies.

5) Analgesics such as acetaminophen with codeine may be used for pain relief if needed.

e) TETANUS PROPHYLAXIS

1) The patient's tetanus immunization status should be determined. Tetanus toxoid 0.5 milliliter intramuscularly or other indicated tetanus prophylaxis should be administered if required.

G) FLUID/ELECTROLYTE BALANCE REGULATION

1) Carefully monitor fluid-electrolyte status and undertake replacement therapy as indicated. Fluids may be lost into edematous areas, but fluid replacement is of less magnitude than that required for thermal burns. Do NOT overhydrate mustard burn patients. Initial vomiting is rarely severe and can be relieved with atropine or common antiemetics. Later vomiting and diarrhea are generally indicative of systemic cytotoxicity and require fluid replacement ((Sidell, 2000)).

H) MYELOSUPPRESSION

1) Following dermal or inhalation exposure, significant amounts of mustard may be absorbed systemically ((Sidell, 2000)). Bone marrow damage is usually not evident for 3 to 5 days after exposure. However, several studies have reported that bone marrow suppression may become evident about 4 hours after exposure to mustard gas (Geraci, 2008; (Garigan, 1996)). Leukopenia typically develops at days 3 through 5 after exposure and reaches a nadir in 3 to 9 days, depending on extent of exposure. A poor prognosis is expected when leukopenia with a cell count less than 200 cells/mm(3) develops or a rapid drop in cell count. The gut should be sterilized with nonabsorbable antibiotics at the onset of leukopenia. Cellular replacement, either peripheral or marrow, should be instituted as indicated ((Sidell, 2000))
2) There is little data on the use of hematopoietic colony stimulating factors to treat neutropenia after drug overdose or idiosyncratic reactions. These agents have been shown to shorten the duration of severe neutropenia in patients receiving cancer chemotherapy (Hartman et al, 1997; Stull et al, 2005). They have also been used to treat agranulocytosis induced by nonchemotherapy drugs (Beauchesne & Shalansky, 1999). They may be considered in patients with severe neutropenia who have or are at significant risk for developing febrile neutropenia.

I) EXPERIMENTAL THERAPY

1) DEXAMETHASONE AND DICLOFENAC

a) In a mouse model of sulfur mustard induced skin injury, treatment with topical DEXAMETHASONE and DICLOFENAC significantly reduced inflammatory parameters (extent of edema, level of prostaglandin E levels, area of skin damage, and extent of cytotoxic injury) when applied up to 4 hour after exposure. However, it did not completely prevent the second stage of injury (ie, cytotoxic process) related to extensive damage to the epithelial layer (Dachir et al, 2004).

2) VARMA MIXTURE

a) In an animal study, eyes of rats were exposed to 3 mcmoles of a mustard gas mixture (CEES, half mustard, 2-chloroethyl ethyl sulfide). These rats were compared with rats (controls) who were not treated with the mustard gas mixture. CEES produced rat corneal pathological changes, including severe progressive opacification of the cornea with epithelial detachment, stromal edema, inflammation, and loss of integrity of endothelial cells. Initially, the exposed rat eyes were washed with 3 mL of Varma mixture (40 mM sodium pyruvate, 10 mM alpha ketoglutarate, 2.5 mM calcium pantothenate, 75 mM taurine in basal Tyrode's solution) 5 minutes after CEEs exposure, then every 30 minutes for 8 hours, and then every hour for 8 hours the second day. The Varma mixture attenuated the corneal damage induced by CEEs in rat eyes and was effective in maintaining corneal transparency as well as maintaining the structural integrity of corneal epithelium, stroma, and endothelium to near-normal appearance (Varma et al, 2000).

3) SILIBININ

a) In one study, the protective effect of silibinin in a cell culture model (HaCa T cells) after exposure to sulfur mustard was evaluated. The water-soluble prodrug silibinin-bis-succinat (SIL-BS) 10, 50, 100 mcM doses were used for 24 hours to treat HaCaT cells after exposure to sulfur mustard 30, 100, and 300 mcM for 30 minutes. SIL-BS had a dose-dependent protective effect against sulfur mustard cytotoxicity, especially against necrosis. SIL-BS 10 mcM did not provide significant protection against 100 and 300 mcM sulfur mustard; however, significant protections were observed following SIL-BS 50 mcM and 100 mcM SIL-BS. Following SIL-BS 10 to 50 mcM, apoptosis and interleukin production did not change; however, they increased following SIL-BS 100 mcM (Balszuweit et al, 2013).

4) SUPEROXIDE DISMUTASE

a) NOT EFFECTIVE - Various superoxide dismutases (SODs) injected intraperitoneally or intralesionally to guinea pigs with mustard gas skin burns were NOT protective when given one hour post-exposure and repeated daily for 7 days (Eldad et al, 1998).

J) SURGICAL PROCEDURE

1) Sulfur mustard dermal burns may require skin grafting in some cases. Skin grafting in human cases is rarely needed, but was successful in a patient following a deep mustard gas-induced burn ((Sidell, 2000)).
2) SURGICAL EXCISION: In guinea pigs with experimental mustard gas burns, surgical excision of exposed skin 6 hours post-burn (but not full thickness skin grafting) was associated with a significantly shorter healing time (Kjellstrom et al, 1997).
3) DERMABRASION: Exposures of sulfur mustard vapor on porcine skin resulted in toxic lesions. Dermal burns were debrided at 4 days post-exposure, with the resulting lesions assessed at various time points up to 8 weeks following the debridement. The authors reported accelerated rates of re-epithelialization in the dermabrasion group vs control (untreated) by a factor of up to three (Rice et al, 2000).
4) LASER DEBRIDEMENT has been suggested for human dermal exposures to potentiate wound healing by removal of alkylated laminin variants. Laser debridement may also eliminate viable keratinocytes with residual mustard-induced DNA damage (Smith, 1999).
5) ANIMAL STUDY: In an animal study of a weanling pig model, 12 treatment strategies were tested to determine the best treatment for superficial dermal (second degree) cutaneous sulfur mustard injuries, in order to return the damaged skin to optimal appearance and normal function in the shortest period of time. Animals were exposed to sulfur mustard and developed superficial injuries on their ventral abdominal surface. The following treatment adjuncts were tested after laser debridement: Flexzan Foam Adhesive Dressing, Frozen cultured epithelial porcine allograft, DuoDerm Signal, Amino-Plex Spray, ReCell Autologous Cell Harvesting Device, Vacuum Assisted Closure(TM) V.A.C (Application of topical negative pressure), Biobrane, AQUACEL(R) Ag, ACTICOAT 7 Day Antimicrobial Dressing, Silon-TSR, APLIGRAF(R), Promogran(R) Matrix Wound Dressing. To obtain early re-epithelization, shallow laser debridement through the basement membrane zone (100 mcm) produced better results than deeper debridement (300 to 400 mcm). Overall, the best treatment adjuncts were Vacuum Assisted Closure(TM) V.A.C, Amino-Plex Spray, and ReCell Autologous Cell Harvesting Device (Graham et al, 2009).

K) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Enhanced Elimination

1) Hemodialysis is of NO benefit in mustard exposure. On the contrary, hemodialysis appears to have deleterious effects since mustard becomes fixed to tissue within minutes ((Sidell, 2000)).

Abstracts

Range Of Toxicity

Summary

Minimum Lethal Exposure

1) 1% mortality at 150 mg-min/m(3) (USACHPPM , 2001a).
2) The median lethal dose of mustard by inhalation is 1500 mg-min/m(3) and 10,000 mg-min/m(3) for skin absorption (Sittig, 1991).

1) One ppm in air is a lethal concentration of mustard for dogs (OHM/TADS , 2001).
2) 0.650 ppm mustard results in a 33% mortality rate in rabbits (OHM/TADS , 2001).
3) In mice, sulfur mustard was more toxic when administered percutaneously than subcutaneously (percutaneous LD50 5.7 mg/kg in female and 2.4 mg/kg in male mice, subcutaneous LD50 23 mg/kg in female and 3.4 mg/kg in male mice) (Vijayaraghavan et al, 2004).

Maximum Tolerated Exposure

1) OTHER: Olfactory fatigue may occur (NATO, 1973); therefore ODOR IS NOT AN ADEQUATE WARNING SIGN FOR OVEREXPOSURE.

1) Ct50: 12-200 mg-min/m(3) (eye injuries)
2) Ct50: 100-200 mg-min/m(3) (pulmonary injuries)
3) Ct50: 200-1000 mg-min/m(3) (erythema)

1) Exposure to mustard at 1.4 mg-min/m(3) via inhalation caused no adverse effects (USACHPPM , 2001a).

Serum Plasma Blood Concentrations

7.5.2)

A) TOXIC CONCENTRATION LEVELS

1) CONCENTRATION LEVEL

a) Levels detected at autopsy in various body tissues (in mg/kg of tissue) were fat: 15.1; skin with subcutaneous fatty tissue: 11.8; brain: 10.7; kidney: 5.6; muscle: 3.9; liver: 2.4; cerebrospinal fluid: 1.9; spleen: 1.5; lung: 0.8; liquid from a skin blister: below detection limit (Drasch et al, 1987).

Workplace Standards

1) Not Listed

1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): 1 ; Listed as: Mustard gas (Sulfur mustard)

a) 1 : The agent (mixture) is carcinogenic to humans. The exposure circumstance entails exposures that are carcinogenic to humans. This category is used when there is sufficient evidence of carcinogenicity in humans. Exceptionally, an agent (mixture) may be placed in this category when evidence of carcinogenicity in humans is less than sufficient but there is sufficient evidence of carcinogenicity in experimental animals and strong evidence in exposed humans that the agent (mixture) acts through a relevant mechanism of carcinogenicity.

4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
5) MAK (DFG, 2002): Category 1 ; Listed as: Bis(beta-chloroethyl)sulfide (mustard gas)

a) Category 1 : Substances that cause cancer in man and can be assumed to make a significant contribution to cancer risk. Epidemiological studies provide adequate evidence of a positive correlation between the exposure of humans and the occurence of cancer. Limited epidemiological data can be substantiated by evidence that the substance causes cancer by a mode of action that is relevant to man.

6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): K ; Listed as: Mustard Gas

a) K : KNOWN = Known to be a human carcinogen

1) Not Listed

Toxicity Information

7.7.1)

A) References: ITI, 1995 Lewis, 2000 OPCW, 1997 RRIS, 2001 RTECS, 2002 SBCCOM, 2001 USACHPPM, 2001a

1) ICt50- (INHALATION)HUMAN:

a) 1500 mg-min/m(3) (OPCW, 1997; SBCCOM, 2001; USACHPPM, 2001a)

2) LD50- (ORAL)HUMAN:

a) 700 mcg/kg
b) 0.7 mg/kg (RRIS, 2001; SBCCOM, 2001; USACHPPM, 2001a)

3) LD50- (SKIN)HUMAN:

a) 100 mg/kg

4) LD50- (SKIN)MOUSE:

a) 92 mg/kg

5) LD50- (SUBCUTANEOUS)MOUSE:

a) 20 mg/kg -- nausea or vomiting, ataxia, convulsions or effect on seizure threshold

6) LD50- (ORAL)RAT:

a) 17 mg/kg

7) LD50- (SKIN)RAT:

a) 5 mg/kg -- ataxia, nausea or vomiting, convulsions or effect on seizure threshold

8) LD50- (SUBCUTANEOUS)RAT:

a) 1500 mcg/kg -- gastrointestinal hypermotiltiy, diarrhea, weight loss or weight gain, change in food intake behavior

9) TCLo- (INHALATION)MOUSE:

a) 1250 mg/m(3) for 15M- continuous -- neoplastic effects (Lewis, 2000)

10) TCLo- (INHALATION)RAT:

a) 100 mcg/m(3) for 1Y-intermittent

Pharmacology Toxicology

Toxicologic Mechanism

1) As a bifunctional alkylating agent, it can form covalent cross-links between the double strands of DNA (Grant & Schuman, 1993).

a) It mainly alkylates and cross-links the purine bases (Fox & Scott, 1980; (Dacre & Goldman, 1996).
b) It can also alkylate proteins and other macromolecules (Ross, 1962).

1) It reacts mainly with the thiol group of cysteine in proteins (Hirade & Ninomiya, 1949).

2) Once inside the skin, mustard gas damages the cells separating the epidermis (upper layer) from the dermis (lower layer). The two layers separate with the space between them becoming a blister. Similar effects occur in the airways and eyes, except blisters do not appear (Sidell et al, 1998).
3) While the chemical reaction with biological tissue occurs rapidly, symptoms are typically delayed by 2 to 24 hours (Grant & Schuman, 1993; Sidell et al, 1998).

Physicochemical

Physical Characteristics

Ph

1) No information found at the time of this review.

Molecular Weight

Other

1) 0.6 mg/m(3) (SBCCOM , 2001)
2) 0.03 mg/L or 0.015 mg/m(3) ((HSDB, 2002))

Animal Toxicology

References

General Bibliography

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MUSTARD GAS

Classification | Detailed evidence-based information

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Specific Substances

Available Forms Sources

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Clinical Effects

Laboratory Monitoring

Treatment Overview

Range Of Toxicity

Summary Of Exposure

Vital Signs

Heent

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Workplace Standards

Toxicity Information

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Physical Characteristics

Ph

Molecular Weight

Other

General Bibliography