Nitrogen mustards toxic effects

Caution There is no antidote for nitrogen mustard toxicity decontamination of all potentially exposed areas within minutes after exposure is the only effective method to decrease tissue damage. Other than that, treatment is mainly supportive. 

HN-2 has the greatest blistering power of the nitrogen mustards in vapor form but is intermediate as a liquid blistering agent. It produces toxic eye effects more rapidly than does HD. 

Mechlorethamine was the first nitrogen mustard. It is directly toxic. With its half-life of only a few minutes infusion directly into arteries supplying the tumor is the preferred mode of administration. Its spectrum of adverse effects is similar to that of cyclophosphamide. 

Bone marrow toxicity is the major side effect of chlorambucil. Nausea is uncommon or mUd, and hair loss does not occur. Chlorambucil shares the immunosuppressive, teratogenic, and carcinogenic properties of the nitrogen mustards. 

Studies of occupational exposures to sulfur mustard indicate an elevated risk of respiratory tract and skin tumors following long-term exposure to acutely toxic concentrations. Overall, several factors are important regarding the assessment of the carcinogenicity of sulfur mustard. Increased cancer incidence in humans appears to be associated only with exposures that caused severe acute effects, and occupational exposures tended to involve repeated exposures and repeated injury of the same tissues. Because the therapeutic use of the sulfur mustard analog nitrogen mustard is associated with an increased incidence of CML, the reports of CML in HD-exposed individuals appear to be relevant to the eareinogenicity of sulfur mustard. 

Toxic effects of sulfur mustard and ethyleneimine on animals were described in the 19th century. The powerful vesicant action of sulfur mustard led to its u.se in World War I. and medical examination of the victims revealed that tissues were damaged at sites distant from the area of contact." Such systemic elTects included leukopenia, bone marrow aplasia, lymphoid tissue suppression, and ulceration of the gastrointestinal tract. Sulfur mustard was shown to be active against animal tumors, but it was too nonspecific for clinical use. A variety of nitrogen mustards were synthesized between the two world wars. Some of these compounds (e.g.. 

Ocular, percutaneous, inhalation, ingestion, and injection are all possible routes of exposure. Effects may be local, systemic, or both. All of the nitrogen mustards are oily liquids that are colorless to pale yellow and evaporate slowly. They are more dangerous than sulfur mustard but, like sulfur mustard, they are derivatives of ammonia. The most toxic and most volatile of the three nitrogen mustards is HN-2, but HN-3 is used more because it is stable. 

The animal toxicity reported for HN-3 is described in Table 1. Evidence shows it causes leukemia and cancers of the lungs, liver, uterus, and large intestine in animals. Nitrogen mustards also produce developmental effects in animals. 

The second exception is that while an antidote is available for systemic effects of Lewisite exposure, there are no antidotes for nitrogen mustard or sulfur mustard toxicity, with one minor caveat if given within minutes after exposure, intravenous sodium thiosulfate may prevent death due to sulfur mustard exposure (25). Otherwise, the medical management for skin, ocular, and respiratory exposure is only supportive. One guideline physicians can follow is to keep skin, eye, and airway lesions free from infection. 

M3. Marshall, W. H., Hoppe, E. T., and Stark, F., The effect of ambient oxygen tension on the toxicity and therapeutic effect of mechlorethamine (nitrogen mustard). Arch. Surg. 86, 932-939 (1963). 

Recognizing the fact that ROS play a role in the pathogenesis of mustard-induced ocular injuries, compounds that inhibit the formation of ROS or prevent their toxic effects would be beneficial in the treatment of mustard-induced ocular injuries. The topical application of low concentrations of Zn/DFO or Ga/DFO after comeal exposure to nitrogen mustards markedly reduced conjunctival, comeal, iris, and anterior chamber injury. In the cornea, the healing of epithehal erosions was faster, the long-term opacification was reduced, and the levels of neovascularization were lowered. In the anterior chamber, decreased inflammation and better maintenance of intraocular pressure were achieved. Cataractous changes were also notably milder (Banin et al., 2003). 

Table 6. Effect of thiosulphate and cysteine on LD50 of nitrogen mustards. Reproduced from the paper by Connors, T.A., Jeny, A and Jones, M. (1964), Reduction of the toxicity of radiomimetic alkylating agents in rats by thiol pretreatment-III. The mechanism of the protective action of thiosulphate. Biochem. Pharmacol., 13, 1545-1550... 

In 1986, Vojvodic and colleagues reported a study of the protective effects of a number of compounds and combinations of compounds on the toxicity of nitrogen and sulphur mustards (Vojvodic et al., 1986). Protective indices similar to those obtained by Callaway and Pearce (1958) were reported. Work on the value of thiosulphate in the treatment of mustard gas poisoning has also been reported by Fasth and Sorbo (1973). Sodium thiosulphate has been recommended as a local treatment for accidentally extravasated doses of nitrogen mustards (Dorr et al., 1988). 

Fasth A and Sorbo B (1973). Protective effect of thiosulfate and metabolic thiosulfate precursors against toxicity of nitrogen mustard (HN2). Biochem Pharmacol, 22, 1337-1351. 

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