Chemical warfare agents mechanisms

As explained in Chapter 1, the toxicity of natural xenobiotics has exerted a selection pressure upon living organisms since very early in evolutionary history. There is abundant evidence of compounds produced by plants and animals that are toxic to species other than their own and which are nsed as chemical warfare agents (Chapter 1). Also, as we have seen, wild animals can develop resistance mechanisms to the toxic componnds prodnced by plants. In Anstralia, for example, some marsupials have developed resistance to natnrally occnrring toxins produced by the plants upon which they feed (see Chapter 1, Section 1.2.2). 

Brinkley et al. demonstrated89 a simple to use, easy to interpret, low cost, and environmentally friendly colorimetric detector of the chemical warfare agent - mustard gas (HD, l,l-thiobis(2-chloroethane)). An optically transparent xerogel encapsulating Cu(II) acetate was fabricated to detect HD analogues and can serve as the optical sensor based on metal-ligand charge-transfer mechanism. 

Renshaw, B. Mechanisms in production of cutaneous injuries by sulfur and nitrogen mustards. IN Chemical Warfare Agents, and Related Chemical Problems, 2 vol. (Summary Technical Report of Division 9, National Defense Research Cornmittee.) Washington, D.C. U.S. Office of Scientific Research and Development. 1946. p. 479-518. 

Cellular and molecular mechanisms of neurotoxicity are also influenced by the fact that neurons are postmitotic and do not divide. Thus, the capacity for replacement of damaged cells does not exist in the nervous system, whereas most other organ systems have a well-established capacity for regeneration. Many neurotoxins can cause encephalopathy and an important concept in neurotoxicology is the delayed manifestation of symptoms sometimes up to years after the exposure started. Several agents show a lag time between exposure and neurotoxicity. Examples are the organophosphate chemical warfare agents [245], bismuth intoxications [246] and methylmercury... 

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. 

Neurotransmitters are removed by translocation into vesicles or destroyed in enzyme-catalysed reactions. Acetylcholine must be removed from the synaptic cleft to permit repolarization and relaxation. A high affinity acetylcholinesterase (AChE) (the true or specific AChE) catalyses the hydrolysis of acetylcholine to acetate and choline. A plasma AChE (pseudo-AChE or non-specific AChE) also hydrolyses acetylcholine. A variety of plant-derived substances inhibit AChE and there is considerable interest in AChE inhibitors as potential therapies for cognition enhancement and for Alzheimer s disease. Organophosphorous compounds alkylate an active site serine on AChE and the AChE inhibition by this mechanism is the basis for the use of such compounds as insecticides (and unfortunately also as chemical warfare agents). Other synthetics with insecticidal and medical applications carbamoylate and thus inactivate AChE (Table 6.4). 

Water/soap wash Chemical warfare agents have a generally low solubility and slow rate of diffusion in both fresh water and seawater. Therefore, the major effect of water and water combined with soap (especially alkaline soaps) is via a slow breakdown of the compound (i.e., hydrolysis) or through dilution of the agent and the mechanical force of the wash. When other chemical deactivation means are not available, washing with water or soap and water is a good alternative. 

For the development of new chemical weapons (CWs), a number of criteria are necessary a research base including scientists and equipment, access to information, chemical and arms industries, and of course financial support. It is noteworthy that the development of CWs is possible not only for states but also for terrorists. It is necessary to stress that the intention of this chapter is not to describe new CWs or chemical warfare agents (CWAs) but to comment on a number of trends in toxicology with the aim that these chemicals may be proposed for inclusion in the Chemical Weapons Convention (CWC) verification mechanisms. However, the text of the CWC is comprehensive and covers practically all chemicals that may be misused as CWs. 

For the purposes of this chapter, the term reproduction will be used primarily in reference to vertebrate species of animals (especially mammals) and will be inclusive of development (Figure 36.1), which is sometimes treated as a separate topic in toxicology texts. This particular chapter emphasizes what is currently known about the adverse effects of known chemical warfare agents and selected environmental contaminants on male and female reproductive function, as well as xenobiotic-induced effects on the growth, maturation, and sexual differentiation of the embryo and fetus. Endocrine disruption is an extremely common mechanism of action for xenobiotics associated with impaired reproductive function and will be discussed along... 

Xenobiotic-induced liver injury has become the most frequent cause of acute liver failure in humans in the USA and around the world, exceeding all other causes combined (Watkins and Seef, 2006). Owing to its detoxification mechanisms, the liver protects the individual against xenobiotic-induced injury. Certainly, the liver toxicity caused by chemical warfare agents is a potential area of concern. 

Some of the important chemical warfare agents that may pose risks to animal health are described below. For the information on their mechanism of action, readers are referred to Section II of this book. 

Adler, M., Oyler, G., Apland, J.P. et al. (2008). Mechanism of action of botulism neurotoxin and overview of medical countermeasures for intoxication In Chemical Warfare Agents Chemistry, Pharmacology, Toxicology, and Therapeutics (Romano, J.A., Jr., Lukey, B.J., Salem, H., eds), pp. 389-422. CRC Press, Boca Raton, FL. 

Smith, K.J., Hurst, C.G., Moeller, R.B., Skelton, H.G., Sidell, F.R. (1995). Sulfur mustard its continuing threat as a chemical warfare agent, the cutaneous lesions induced, progress in understanding its mechanism of action, its long-term health effects, and new developments for protection and therapy. J. Am. Acad. Dermatol. 32 16S-16. 

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