Toxicology and pharmacology of the chemical warfare agent sulfur mustard.

There have been reports of chemical attacks in which sulfur mustard might have been used (a) on Iranian soldiers and civilians during the Gulf War in 1984 and 1985 and (b) in an Iraqi chemical attack on the Iranian-occupied village of Halbja in 1988, resulting in many civilian casualties. Heavy use of chemical warfare in Afghanistan by the Soviet military is a recent innovation in military tactics that has been highly successful and may ensure further use of chemical agents in future military conflicts and terrorist attacks as a profitable adjunct to conventional military arms. Mustard is a poisonous chemical agent that exerts a local action on the eyes, skin, and respiratory tissue, with subsequent systemic action on the nervous, cardiac, and digestive systems in humans and laboratory animals, causing lacrimation, malaise, anorexia, salivation, respiratory distress, vomiting, hyperexcitability, and cardiac distress. Under extreme circumstances, dependent upon the dose and length of exposure to the agent, necrosis of the skin and mucous membranes of the respiratory system, bronchitis, bronchopneumonia, intestinal lesions, hemoconcentration, leucopenia, convulsions with systemic distress, and death occur. Severe mustard poisoning in humans is associated with systemic injury, which is manifested as headache, epigastric distresses, anorexia, diarrhea, and cachexia and is usually observed at mustard doses of 1000 mg/min/m3 with damage to hematopoietic tissues and progressive leucopenia. Sulfur mustard is a cell poison that causes disruption and impairment of a variety of cellular activities that are dependent upon a very specific integral relationship. These cytotoxic effects are manifested in widespread metabolic disturbances whose variable characteristics are observed in enzymatic deficiencies, vesicant action, abnormal mitotic activity and cell division, bone marrow disruption, disturbances in hematopoietic activity, and systemic poisoning. Indeed, mustard gas readily combines with various components of the cell such as amino acids, amines, and proteins. Although evidence of an association between lung cancer and mustard gas encountered on the battlefields of World War I is at best suggestive if not problematical (Case and Lea, 1955; Beebe, 1960; Norman, 1975), the epidemiological data accumulated from the poison gas factories in Japan (Yamada et al., 1953; Wada et al., 1968; Inada et al., 1978; Shigenobu, 1980; Nishimoto et al., 1983; Hirono et al., 1984; Takuoka et al., 1986), in Germany (Weiss, 1958; Hellmann, 1970a; Weiss and Weiss, 1975; Klehr, 1984) and in England (Manning et al., 1981; Easton et al., 1988) are substantial (International Agency for Research on Cancer, 1975). Unfortunately, attempts to seek confirmatory and substantial evidence in laboratory animals such as mice (Boyland and Horning, 1949; Heston, 1950; Heston, 1953a; McNamara et al., 1975) and rats (Griffin et al., 1951; McNamara et al., 1975; Sasser et al., 1996) have not been consistent. Sulfur mustard has been shown to be mutagenic in a variety of different species using many different laboratory techniques from fruit flies, microorganisms and mammalian cell cultures (Fox and Scott, 1980). Evidence is slowly accumulating from human data (Hellmann, 1970a; Lohs, 1975; Wulf et al., 1985). Evidence for the teratogenicity of mustard has been negative in assessment of fetotoxicity and adverse effects of mustard on the reproductive potential of both human and animal studies. Indeed, investigations of women adversely affected by mustard are minimal because most of the studies have been performed on former men employees of poison gas factories and have been negative or questionable. We have recently emphasized the need to assess the affect of a suspected teratogen on maternal toxicity in laboratory animals before any conclusions can be made. (ABSTRACT TRUNCATED)