Blistering agents: Mustard gas and Lewisite

Mustard gas
The name mustard is because the original product had a strong smell of mustard, due to impurity. Though the present day product is odorless, when combining with a number of substances in the field has a garlic odor, or rotten onion odor. Mustard gas is synonymous of sulphur mustard, or yperite. It is a 2,2’-di(chloro-ethyl)-sulphide. The name yperite (or yprite) comes from the Belgian village of Ypres where it was used for the first time by the German army in 1917. In German it was called "Lost"
The name "blistering" refer to the production of blisters and burns in the affected skin. However mustard agent causes lung and eye injuries, as well as intestinal mucosa injury if ingested. It should be called blistering and tissue-injuring agent.
Mustard was synthesized in 1822, its blistering and tissue injuring properties were observe in the 1860s. After its use in World War 1, in the 1930s it was discovered that activity was unchanged if the sulphur atom was substituted by a nitrogen atom. These new agents are called nitrogen-mustards, for instance 2,2’three(chloroethyl)amine, or HN3. In studying mustard gas toxicity it was noticed that both sulphur mustard and nitrogen mustards were causing bone marrow depression few weeks after exposure. There was bone marrow hypoplasia and lymph nodes hypoplasia. This observation led to the idea of utilizing these agents in the treatment of prolipherative disorder of bone marrow and lymph nodes such as leukemia and limphoma. In the 1940s Gilman of Yale University pioneered the use of nitrogen mustards in the treatment of limphoma. Since then nitrogen mustards have become an important group of cancer chemotherapy agents. Among the most common nitrogen mustards are Chlorambucil (Leukeran) and Cyclophosphamide (Cytoxan). These cancer chemotherapy agents are cell-cycle phase non specific, which means are acting on the dividing cells, though to a more or less degree they still can have toxicity to non proliferating cells. At the dosage of 0,1 mg/Kg body weight / daily Chlorambucil, and of 3 mg/Kg body weight/daily Cyclophosphamide, are active in a number of leukemia, lymphoma and solid tumors. As collateral toxicity they are carcinogenic, mutagenic, suppressing gonadal activity with amenorrhea – azoospermia. The immune response is depressed, and in combination with the bone marrow depression both will cause increased incidence of microbial infection, delayed healing, gengival bleeding and stomatitis. There will be loss of hair in the scalp. The common mechanism is attack to DNA strand (alkylation, by which the name alkylating agents). Now all the described action are seen in the delayed damage caused by mustard gas exposure, and explain the observed pathology, for instance burns which are healing very slowly compared with burns from other causes.
Yet the blistering and direct tissue injury effect of mustard gas (sulphur mustard) are acute and their basic mechanism is against structural proteins and peptides in to the cells and cell membranes. This activity has carefully been eliminated or strongly reduced in cancer chemotherapy by molecular manipulation and dosage of nitrogen mustards..

Physical and chemical properties
Though is frequently called mustard gas, in reality is a liquid with low volatility. It does behave like a gas around the site of explosion when used in rockets or artillery shells. It can be mixed with mainly two other substances, Lewisite and chlorinated rubber polymer (thickened mustard). Lewisite (2 part of Lewisite and three parts of mustard) makes the mixture more active at lower temperature. The addition of chlorinate rubber polymer makes the mixture more persistent and more difficult to remove by decontamination.
Mustard is somewhat soluble in water, where it is slowly hydrolyzed (inactivated). In running water due to surface mixing inactivation proceed more rapidly, while in stagnant water persistency can be of several months. This is due to the tendency of large volume of mustard agent in stagnant water to remain in undissolved bulk. Hydrolysis is more rapid in alkaline environment. Bleaching powder and chloramines react rapidly with mustard and non-poisonous oxidized products are formed. This is the base for water and hypochlorite (bleach) use in decontamination procedure.

Mustards form colored complex molecules with para-nitrobenzpyridine thus making possible to detect minute amount. There exist single and three color detector paper, as well as water testing kits. They are not presently available.

Ordinary clothing gives little or no protection against mustard agent. In addition to the respiratory route, mustard penetrates the skin and is easily absorbed by the intestine if ingested. Masks only do protect the eyes and lungs during gas spreading, but are otherwise useless because the gas does penetrate through the skin. Special full gear total body equipment is therefore needed for protection, including a hood and overboots.
All this equipment is available only in special ad hoc military units. Is unrealistic to expect it to be available for the population by en large, and even for paramedical civilian personnel. One has to use good sense and being alert. Arriving on the scene of an attack the mustard agent can be found persisting everywhere but much less so in the air because is not a gas and will not persist in great amount in the air. This despite the presence of odor of garlic, or rotten onion. However conjunctivitis has been reported after exposure of one hour duration in barely perceptible odor environment. In case of smelling of garlic, rotten onion, "fishy" smelling, geranium oil smelling (Lewisite) is advised to move oneself and the exposed individual somewhere else to carry out decontamination. Rubber surgical type gloves must be wear and changed frequently. Water used for washing is still containing active mustard and must be disposed of accordingly.

Signs and symptoms
There will be a delay of some two hours between exposure and the onset of symptoms. The described mechanism of action does take that much of time at the cellular level. However if mustard has been mixed with Lewisite, this agent is immediately and acutely causing pain, clearly because somehow does damage or stimulate immediately the superficial pain fibers. If immediate pain is referred by exposed individual this means Lewisite was present in the mixture. Fortunately decontamination procedure and first aid are the same whether Lewisite was present or not.
So about two to four hours after the exposure there will a series of worsening signs of inflammation of eyes, lung and skin. Depending on the amount of exposure there will be aching of the eyes follows by inflammatory signs of conjunctivitis, abundant tears and swelling of the lids. Hoarseness and cough and sneeze, rhinorrhea, burning of the throat. Cough will be initially dry then may progress to copious expectoration. The skin will be red in the contaminated part, and blisters will then appears. Some areas might be more affected then other typically arm pit and perineum, or popliteal fossa and anterior elbow. The severity of lesions will determine their progression. It is at this stage decontamination of at least skin and eyes will arrest damage of agent persistency and reduce infective complication.
Nothing much can be done about ingested mustard. There might be loss of appetite, and vomit and bloodstained feces or bloody diarrhea in the worst cases.
Later damage and consequences will be the one mentioned in the cancer chemotherapy collateral damage.

Prophylaxis and treatment. Decontamination
There is no drug treatment available to prevent the effect of mustard.
There is no specific treatment available for the treatment of mustard lesions, the aim of therapy is to 1) Relieve symptoms 2) Prevent infections 3) Promote healing.
We are talking of decontamination of eyes skin mucous membrane and wounds. All contaminated clothing should be removed wearing rubber gloves and placed in plastic bag without touching the outer surface of the bags. Bags should be closed by one other person, placed in a second bag and given to patients or family. (This is to avoid unnecessary accumulation in one site only of contaminated material. If possible and alternatively a specific contaminated waste disposal method will be followed) The family must be instructed in burying the bags or else empty the bags content, without touching it, in heavy chlorinated (bleach) water for decontamination, and washed without touching it with large load of detergent.
Fresh surely uncontaminated cloth should be given to wear, if appropriate, at the end of decontamination. If burns are present they should receive first aid dressing and referred – transported to the designated referral hospital accordingly

Should be gently washed with water, diluted baby shampoo can be used instead of soap, then rinsed with saline solution (physiologic, 0,9%), or if available, isotonic sodium bicarbonate (1,26%). Saline solution and or isotonic sodium bicarbonate, both diluted to tolerance, can be used to rinse mouth and throat. Liquid used for washing should be disposed off with intelligence. If eyelids are swollen they should gently be separated before washing. If corneal lesion obviously present antibiotic eye ointment and atropine eye ointment should be applied b.i.d (twice a day) to prevent infection and adhesion of the iris, and application should be continued till medically indicated. Systemic antibiotics are indicated if infection is obviously spreading.

Main decontamination for skin is done with diluted hypochlorite solution, 0,05% dilution can be obtained mixing ten cc. of 4,5% commercially available hypochlorite (bleach, Javel water,) in one liter of water, then with water and soap, finally washing with water again, in the order given. Rinsing fluids should be treated as still potentially damaging. Known more affected areas such as armpit, perineum and genitalia, popliteal and antebrachial fossa, should carefully be insisted upon. Fresh surely uncontaminated clothes or track suites or pajamas should then be used for redressing.

Wounds should be inspected, if particle present they should be removed with sterile, if available, forceps. It is mandatory to remove ‘thickened’ mustard (mustard combined with rubber polymers), if necessary kerosene should be used to facilitate removal. Further diluted hypochlorite solution, 0,005% which is one to two cc per liter of commercially available 4,5% hypochlorite (bleach) solution, should be used to irrigate the wound. (NATO manual suggest irrigation of wounds with a more concentrated solution, 0,3% to 0,5% for two minutes followed by rinsing. However NATO manual discourage "wet" shower type decontamination, with the only exception of open contaminated wound. While increasing the concentration of hypochlorite should increase the degree of decontamination, yet that concentration is irritating and possibly damaging exposed tissue. –J Burn Care Rehabil, 1991 sep-Oct; 12(5) 420-4. If at all possible a lower concentration is probably better). Water, if possible sterile, or boiled, or at least drinkable should then be used for final rinsing before sterile dressing applied. Anything removed from wound being suspected of contamination should be dealt with in a bleach solution to minimize possible vaporizing of gas.
If appropriate ad hoc showers are available, one should add bleach to the water tank in the proportion given, which is 10 cc of 5% bleach per liter of water. The shower area should be decontaminated in between patients with higher concentration of bleach chlorinated water with common household detergent added using common floor cleaning swap.

There are chlorinated powders and ointments which offer better deactivation (NATO manual recommend this type of "dry" decontamination) and do away with the need of water and washing and the risk of contaminated water, but they are not presently available. 

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