Anticholinesterases, nerve agents

Public and congressional concern about BZ-like incapacitating agents did not attain critical mass until 1979, when the Army decided that a comprehensive review of all subjects who had received glycolates would be prudent. It wanted a similar review of anticholinesterase nerve agents and called upon the National Academy of Sciences (NAS) for assistance. 

The chemical warfare (CW) nerve agents primarily addressed in this chapter include the anticholinesterase nerve agents tabun (GA), sarin (GB), soman (GD), cyclosarin (GF), and VX, all of which are, or have been, part of the US domestic munitions inventories (Carnes, 1989 NRC, 1999 Opresko et al, 1998). Russian VX (often represented as VR) will be evaluated in the following chapter by Radilov et al. (2009). Other, less well-characterized nerve agents such as compound GE, VG (Amiton ) or Vx will be evaluated as data allow. 

Term used originally to describe the anticholinesterase nerve agents discovered to have been produced by Germany just before and during World War II. The G stands for Germany. See GA, GB, GD, GE, GF. 

Isopropyl ethylphosphonofluoridate. Ethyl sarin anticholinesterase nerve agent similar to GB qv. 

Cyclohexyl methylphosphonofluoridate. Cyclosarin. Anticholinesterase nerve agent similar to sarin, see GB. Liquid, vapour pressure at 25°C 0.07 mmHg volatility at 25°C 680 mg/m3. 

The conducting system of the heart may also be affected by anticholinesterase nerve agents and pesticides producing dysrhythmias and ECG changes. 

Presently available methods to diagnose and biomonitor exposure to anticholinesterases, e.g., nerve agents, rely mostly on measurement of residual enzyme activity of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) in blood. More specific methods involve analysis of the intact poison or its degradation products in blood and/or urine. These approaches have serious drawbacks. Measurement of cholinesterase inhibition in blood does not identify the anticholinesterase and does not provide reliable evidence for exposure at inhibition levels less than 20 %. The intact poison and its degradation products can only be measured shortly after exposure. Moreover, the degradation products of pesticides may enter the body as such upon ingestion of food products containing these products. 

Rapid advances in chemistry during the nineteenth and twentieth centuries, coupled with the success of mustard gas as a toxic weapon in World War I, attracted attention to the warfare potential of chemical agents. This led to support for research on lethal nerve agents during and immediately after World War II. The research was followed by the development of treatment methods, and prominent among these was the use of cholinesterase reactivators to reverse the lethal effects of anticholinesterase nerve gases. 

The potency of the anticholinesterase activity of nerve agents and other organophosphates is expressed by the bimolecnlar rate constant (k ) for the reaction of the phosphate compound with the enzyme and by the molar concentration causing 50% inhibition of the enzyme when tested in vitro (I50). I50 data for several organophosphate nerve agents have been tabnlated by Dacre (1984). The relationship between I50 and kj as a function of time (t) is expressed by the following equation (Eto, 1974) ... 

The use of the subchronic rat study for developing an oral RfD for GD is complicated by the fact that rodents have a mnch lower RBC-AChE activity level compared to hnmans (ElUn, 1981, see Table 1). By itself, this could cause rats to be relatively more sensitive than hnmans to anticholinesterase compounds however, the lower RBC-ChE activity may be offset by the presence of aliesterase in rat blood. Aliesterase, which is not present in hnmans (Cohen et al., 1971), is known to bind to and thereby rednce the toxicity of cholinesterase inhibitors (Fonnnm and Sterri, 1981). Other species differences, snch as the rates of aging of the nerve agent-ChE complex, the rates of synthesis of plasma cholinesterase in the liver, and the levels of AChE in various parts of the nervous system (see Ivanov et al., 1993) may also resnlt in differences in species sensitivities. There are insufficient data to determine the relative snsceptibilities of humans and rodents to GD therefore, for the pnrpose of this assessment, the EPA method will be followed which assumes that humans may be as mnch as ten times more sensitive to a chemical than laboratory animals. 

AH of the nerve agents under consideration are anticholinesterase compounds and induce accumulation of the neurotransmitter acetylcholine (ACh) at neural synapses and neuromuscular junctions by phosphorylating acetylcholinesterase (AChE). Depending on the route of exposure and amount absorbed, the PNS and/or CNS can be affected and muscarinic and/or nicotinic receptors may be stimulated. Interaction with other esterases may also occur, and direct effects to the nervous system have been observed. 

Nerve agents are toxic anticholinesterase compounds by all routes of exposure, and exhibit a steep dose-response. Detailed descriptions of nerve agent toxicity may be found in reviews by Bakshi et al (2000), NRC (1999, 2003), Mioduszewski et al (1998), Marts (2007), Opresko et al (1998), Sidell (1997), Somani and Husain (2001), Munro et al. (1994), and others. 

Anticholinesterase effects of nerve agent exposure can be characterized as muscarinic, nicotinic, or CNS. Muscarinic effects occur in the parasympathetic system and, depending on the amount absorbed, can be expressed as conjunctival congestion, miosis, ciliary spasm, nasal discharge, increased bronchial secretion, bronchoconstriction, anorexia, emesis, abdominal cramps, sweating, diarrhea, salivation, bradycardia, and hypotension. Nicotinic effects are those that... 

---