US Army Medical Institue of Chemical Defense - Chemical Warfare Protection
Mustard gas, referred to as HD (bis-(2-chloroethyl) sulfide), is a vesicant that causes blistering of the skin and mucous membranes upon contact. It is a potent alkylating agent which has been used as a chemical warfare agent in at least 18 conflicts since World War I. It has re-emerged as a potential threat to both military and civilian personnel due to an increase in terrorist activities around the globe.
HD can damage DNA, RNA, proteins and other cellular components and be lethal. The onset, type and severity of clinical symptoms depend upon the form of mustard agent, route of exposure and concentration. Inhalation of HD can damage lung, gastrointestinal tract and hematopoetic organs that can cause lethality depending upon the concentration of this agent. Exposure to high doses of HD can also damage the central nervous system causing death within a short period of time. Many of these signs, symptoms and damage resemble those produced by ionizing radiation; therefore, mustard agents have also been referred to as radiomimetic agents. The latent adverse effects of HD may include increased risk of cancer, cataracts, somatic (during your life time) and heritable (passing genetic defects from one generation to another) mutations, birth defects, and mental and developmental retardation (if fetuses are exposed).
Although promising therapies have been examined, there are no effective pharmacological countermeasures available to reduce damage when administered either before or after exposure to mustard agents. Therefore, the development of countermeasures against these chemicals has become an urgent issue, because of the increased threat of use by the terrorists against military and civilian personnel.
In order to develop an effective countermeasure, it is essential to understand the mechanisms that are involved in the initiation and progression of damage following exposure to sulfur mustard. Besides the alkylation of DNA, increased oxidative damage, and inflammation may contribute to acute and chronic damage produced by sulfur mustard. HD also depletes glutathione one of the most important intracellular antioxidants for protection against free radical damage. Therefore, supplementation with antioxidants appears to be a rational choice for reducing the damage following HD exposure. Indeed, a few studies have shown that supplementation with glutathione-elevating agents such as n-acetylcysteine or other free radical scavengers prior to exposure to HD provides a degree of protection.
The PMC antioxidant mixture will be tested for protective efficacy against dilute HD inhalation toxicity in the dilute HD embulization model The mixture will be administered orally (50, 100 and 200 mg/kg) three days before and after exposure to 0.35 mg total dose of HD. At 4 and 24 hr lung tissue will be collected for histologic (right lung) and biochemical (left lung) analyses of oxidative damage and inflammation. Biochemical analysis will be done by PMC, and histopathologic analysis will be done by Comparative Pathology Branch, USAMRICD.
This study will be initiated in the fall of 2007.