Aging nerve agents

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. 

OPs are known to induce time-delayed neurotoxicity. This is due to the inhibition of an esterase in nerve tissue, neuropathy target esterase (NTE), that is also found in muscle and blood cells. The NTE level in the blood is an indicator of the inhibition of the enzyme. Inhibition of NTE and aging, the process of following the OP binding to an active esterase site that prevents the reactivation of the site, is important for selection of an antidote against certain OP nerve agents. It is of primary concern for Novichok agent. There is little information available on OP-caused neurotoxicity and the cardiac toxicity. 

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