J R Army Med Corps 2002; 149: 358-370 J R Army Med Corps: first published as 10.1136/jramc-148-04-05 on 1 December 2002. Downloaded from Vesicants (Blister Agents) MUSTARD AND NITROGEN remained when the sulphur atom was MUSTARDS substituted by a nitrogen atomThus it became possible to synthesise the nitrogen Introduction mustards with similar properties, of which Blister or vesicant agents are likely to be used there are three: both to produce casualties and to force (1)N-ethyl-2,2'di(chloroethyl)amine, opposing troops to wear full protective (HN1). equipment. These will degrade fighting (2)N methyl-2,2'di(chloroethyl)amine, rather than kill (although very severe (HN2). exposure to vesicants can be fatal). Blister (3) 2,2',2"tri(chloroethyl)amine, (HN3). agents can be thickened in order to enhance persistency and contaminate terrain, ships, All of the above nitrogen mustards are aircraft, vehicles or equipment. The vesicant alkylating agents and HN2 was introduced in agents include sulphur mustard (H - HD 1935 as the first chemotherapeutic refers to distilled mustard), nitrogen mustard agentFrom a military standpoint, HN3 is the (HN), the arsenical vesicants such as principal representative of the group of Lewisite (L) (this may well be used in a nitrogen mustards and is the only nitrogen mixture with H), and the halogenated mustard likely to be used in war oximes, eg. phosgene oxime, (CX) whose properties and effects are very different from Physical and Chemical those of the other vesicants. Properties Vesicants burn and blister the skin or any The mustards are able to penetrate most other part of the body surface they contact. tissues they come into contact with and a They act on the eyes, mucous membranes, great number of materials: woods, leather, lungs, skin and blood-forming organs: bone rubber, plants, etc. Mustards are very marrow and spleen. They damage the persistent in cold and temperate climates. In http://militaryhealth.bmj.com/ respiratory tract when inhaled and cause warmer climates the persistence of mustards vomiting and diarrhoea when ingestedBlister is reduced but the hazard from vapour agents may also cause bone marrow increases. It is possible to increase the suppression and have effects on other germ persistency by thickening mustard with finely cells. powdered material such as chlorinated rubberThese thickened mustards are very MUSTARD AGENTS difficult to remove by decontaminating Sulphur mustard was used extensively in processes World War I and has been used more recently Mustards may be hydrolysed in water but in Iran/IraqProtection against these agents thorough mixing is required for this to be can only be achieved by a full protective achieved. Alkalinity and higher temperatures on September 24, 2021 by guest. Protected copyright. ensemble. The respirator alone protects increase the rate of hydrolysis. In running against eye and lung damage, but does not water, the contact surfaces are frequently give sufficient protection against systemic changed and persistency is only a few days, effects. Extensive, slow healing skin lesions but in stagnant water, they can persist for and other effects will place a heavy burden several months. Mustard is more dense than on the medical services. water, but small droplets remain on the water Sulphur mustard is the best known of surface and present a special hazard in these agents. It was first synthesised in 1822, contaminated areas. Spreading can also and its vesicant properties were discovered in occur when decontaminating the skin with the middle of the nineteenth century. It was aqueous solutions; this effect can be used for the first time as a CW agent in 1917 minimised by flushing with copious amounts near Ypres,Belgium, from which it derives its of water and emulsifying agents. French name (Yperite). Mustard is 2,2'- The bivalent sulphur atom of sulphur di(chloro-ethyl)-sulphide. It is also known by mustard confers very good reducing the name "Lost" in German. properties. Oxidants will oxidise mustard to a In the US, the symbol HD has been given greater or lesser extent (depending on their to the distilled product; this abbreviation will strength) to sulphoxide, sulfone or sulphate. be used in this section. In 1935 it was Of these, only the sulfone has appreciable discovered that the vesicant properties vesicant properties. Nitrogen mustards are 359 J R Army Med Corps: first published as 10.1136/jramc-148-04-05 on 1 December 2002. Downloaded from much less easily oxidised than sulphur Chemical inactivation is often effected by mustard. chlorinating compounds incorporated into adsorbing powders, ointments, solutions or Detection organic solvents.Water should not be used to Mustard agents can be detected by a variety decontaminate mustard (except for the eyes) of means - single and three colour detector – this will disperse the agent over the skin. papers will detect liquid agent and are available for individual issue. Monitoring Additional Procedures devices for vapour hazard and water testing Time is of the essence - decontamination kits are also available. within 2 minutes of contact may prevent or greatly reduce the clinical effects of mustard Protection exposure. However, a degree of protection is Ordinary clothing gives little or no provided by late decontamination. Chemical protection against mustard agents - a inactivation using chlorination is effective respirator, NBC suit, gloves and foot against mustard and Lewisite, less so against protection are required. Due to slow HN3, and is ineffective against phosgene absorption of mustard by many materials, oxime. In the case of thickened mustard, protective equipment must be changed where the usual procedure is inadequate, the regularly. There is no drug available to bulk of the agent may have to be scraped off prevent the effects of mustard on the skin with a knife or similar objectThis should be and the mucous membranes; the only followed by wetting the surface with a cloth practical preventative method is physical drenched in an organic solvent, e.g., petrol protection. Anti-Gas barrier creams were (unleaded gasoline) and subsequent developed in WW2 and subsequently (Figure application of the usual decontaminating 17); work to develop and deploy more procedure. If water is available in abundant effective protective topical barrier creams is amounts, these procedures should be progressing in some NATO countries. followed by copious washingIf the combat clothing is contaminated, it should be removed as soon as possible. Mechanism of Action The exact mechanism of action is not known, however, work over the last decade has revealed many specific mechanisms which may contribute to the development of the mustard injuryCentral to many of these mechanisms is the ability of sulphur and http://militaryhealth.bmj.com/ nitrogen mustards to alkylate a very wide range of biologically important mole- culesSulphur and nitrogen mustards are Fig 17. Anti Gas ointments and cake from post-WW2. bifunctional alkylating agents, containing two reactive chloroethyl functions. Inter- Decontamination action products with cellular components Exposure to mustard is not always noticed can occur via formation of ethylene- immediately because of the latent and sign- sulfonium (sulphur mustards) or ethyleni- free period that may occur after skin monium ions (nitrogen mustards) through exposure. cyclisation and subsequent binding. In deoxyribonucleic acid (DNA), mono- on September 24, 2021 by guest. Protected copyright. Decontamination of Mucous Membranes and functional adducts are predominantly Eye formed (the second chloroethyl function is The substances used for skin decon- converted into hydroxyethyl), but bi- tamination are generally too irritant to be functional binding, leading to formation of used on mucous membranes and the eyes. cross-links, does occur. Additionally, alky- The affected tissues should be flushed lation of ribonucleic acid (RNA), proteins, immediately with water from a water bottle cellular membrane components and cross- (canteen). The eyes can be flushed with links between DNA and proteins can be the copious amounts of water, or (if available) cause of cellular damage. Guanine is affected isotonic sodium bicarbonate (1.26%) or most of the DNA- and RNA-bases. saline (0.9%) The binding of reactive sulphur or nitrogen mustard species to DNA produces a range of Decontamination of the Skin effects. Each soldier is given the means for a - Due to their relative instability, N7- preliminary decontamination of the skin; this alkylated guanine residues may be is based on physical adsorption or on the released from the DNA. Upon DNA combination of physical adsorption and replication, the remaining apurinic sites chemical inactivation. Physical adsorption do not provide a proper template of can be achieved by adsorbing powders. information, resulting in erroneous 360 J R Army Med Corps: first published as 10.1136/jramc-148-04-05 on 1 December 2002. Downloaded from incorporation of nucleotides. This may significantly. A latent period of 4 -12 hours lead to mutations and synthesis of non- follows mild exposure, after which there is functional proteins. lachrymation and a sensation of grit in the - After damage to DNA, cellular repair eyes. The conjunctivae and the lids become mechanisms may not be error free These red and oedematous. Serious exposure processes thus may also give rise to irritates the eyes after 1 to 3 hours and erroneous DNA replication. produces severe lesions. - Crosslinks, in particular interstrand crosslinks, between two guanines for Mustard burns of the eyes may be divided example, may play an important role in thus: the cytotoxicity of the sulphur and - Mild conjunctivitis (75% of cases in World nitrogen mustards. They inhibit the DNA War 1) - recovery takes 1 to 2 weeks. replication process. - Severe conjunctivitis with minimal corneal involvement (15% of cases in World War Toxicity 1), blepharospasm, oedema of the lids and Three distinct levels of biological action can conjunctivae occur, as may "orange-peel be discerned following exposure to mustards: roughening" of the cornea - recovery takes cytostatic, mutagenic and cytotoxic effects.