Toxicity mechanisms, mustard agents

Field First Aid Decontaminate At Once for All Exposed Victims Although sulfur mustards cause cellular changes within minutes of contact, the onset of pain and other clinical effects are delayed for one to twenty-four hours. Sulfur mustards are alkylating agents that may cause bone marrow suppression and neurologic and gastrointestinal toxicity. However, the biochemical mechanisms of action are not clearly understood by anyone. The death rate from exposure to sulfur mustard during World War I was 2-3 percent,... 

Despite the fact that alkylating agents exhibit a common mechanism of action, their clinical use varies depending on differences in pharmacokinetics, metabolism, hpid solubility, ability to penetrate membranes, and toxicity. They can be classified as nitrogen-containing mustard derivatives (mechorethamine, chlorambucil, melfalan, cyclophosphamide, ifos-famide), derivatives of ethylenimine (thiotepa), nitrosoureas (carmustine, lomustine, strep-tozocin), alkylsulfonates (busulfan), and derivatives of platinum (cwplatin, carboplatin). 

The final type of chemical toxicity that will be presented are the vesicants, chemicals that cause blisters on the skin. There are two classes of blisters that implicate different mechanisms of vesication. Intraepidermal blisters are usually formed due to the loss of intercellular attachment caused by cytotoxicity or cell death. The second class occurs within the epidermal-dermal junction (EDJ) due to chemical-induced defects in the basement membrane components. The classic chemical associated with EDJ blisters is the chemical warfare agent sulfur mustard (bis-2-chloroethyl sulfide HD). HD is a bifunctional alkylating agent that is highly reactive with many biological macromolecules, especially those containing nucleophilic groups such as DNA and proteins. 

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... 

Agents acting by an Sn 2 mechanism can be more selective in the nucleophile sites they attack, since they form transition complexes with some molecules more readily than with others. Other agents in vivo may, because of their chemical structure, concentrate in certain areas, giving effects not predicted from model experiments. This is the case with dimethylmyleran, a sulphonoxyalkane, quite unreactive to nucleophiles in vitro, but quite toxic in vivo. Presumably this is due to its reaction with nucleophiles, which are in the lipid phase where it concentrates. Similarly the biological activity of the aromatic nitrogen mustard chlorambucil is considerably influenced by complexing with serum proteins. 

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