Medical Aspects of Chemical Warfare (2008) - The Black Vault

Medical Aspects of Chemical WarfareFig. 13-9. Chemical structure of CN.and 247ºC, respectively. Density of the solid is 1.318 g/cm 3 at 20ºC, and density of the liquid is 1.187 g/m 3 at58ºC. The vapor is 5.3 times heavier than air. 14Although CN was not produced in sufficient quantitiesto be used in World War I, Japan used the agent asearly as 1930 against aboriginal Taiwanese. 128 CN wasused as the tear gas of choice for the 3 decades after itsintroduction, but its use markedly declined after thedevelopment of CS. 96Physiological EffectsCN and CS are SN2 alkylating agents with activatedhalogen groups that react with nucleophilic sites andcombine with intracellular sulfhydryl groups on enzymessuch as lactic dehydrogenase to inactivate theenzymes. The effects are transient because the enzymesare rapidly reactivated. It has been suggested that tissueinjury may be related to inactivation of certain ofthese enzyme systems. Pain can occur without tissueinjury and may be mediated by bradykinin. On contactwith skin and mucous membranes, CN releases chlorineatoms, which are reduced to hydrochloric acid,causing local irritation and burns. 129CN, which is converted to an electrophilic metabolite,reacts with sulfhydryl groups and other nucleophilicsites of biomolecules. Alkylation of sulfhydrylcontainingenzymes leads to enzyme inhibition withdisruption of cellular processes. Castro 130 investigatedthe effects of CN on human plasma cholinesterase,based on the potential to disrupt enzyme functions. Hefound CN to inhibit the cholinesterase via a nonsulfhydrylinteraction, concluding that the toxic effects ofCN may be due to alkylation of sulfhydryl-containingenzymes. 130Animal StudiesOCCH 2ClToxicology. Comparative acute and repeat dosetoxicity studies have been conducted in various animalspecies (review and summarized by McNamara et al 27 ).The studies produced highly variable results, promptingsubsequent studies in the mid-1960s designed toprovide more quantitative data. In these studies, CNin acetone was dispersed from commercially availablethermal grenades. Sublethal effects observed onexposure to CN consisted of lacrimation, conjunctivitis,copious nasal secretions, salivation, hyperactivity,dyspnea, and lethargy, which occurred in all animals.CN is considered a more toxic lacrimator than CS orCR, and at high concentrations it has caused cornealepithelial damage and chemosis. CN, as well as CS andCR, causes almost instant pain in the eyes, excessiveflow of tears, and closure of the eyelids. 71The primary cause of death following CN inhalationappeared to be from pulmonary damage. The LCt 50values for various species were reported to be 8,878;7,984; and 7,033 mg•min/m 3 for the rat, guinea pig,and dog, respectively. The pathological observationsin the animals that died from CN inhalation includedpulmonary congestion, edema, emphysema, tracheitis,bronchitis, and bronchopneumonia. The pathologicalfindings in animals following death by CN inhalationreported by Ballantyne and Swanston 40 included congestionof alveolar capillaries, alveolar hemorrhage,and excessive secretions in the bronchi and bronchioles.The researchers also reported areas of acuteinflammatory cell infiltration of the trachea, bronchi,and bronchioles. McNamara et al 131 exposed guineapigs, dogs, and monkeys to thermally generated CNon 10 consecutive days at Cts ranging from 2,300 to4,000 mg•min/m 3 , for a total of 31,445 mg•min/m 3 . 131This dosage would be expected to be lethal to about75% of the guinea pigs and 100% of the monkeys if administeredas a single dose. However, these exposuresresulted in the death of only five guinea pigs and nodeaths in the monkeys. When administered in divideddosages, the toxicity of CN is considerably lower.These findings were confirmed in additional studiesin which dogs were exposed on 10 consecutive days toCts ranging from 3,000 to 7,000 mg•min/m 3 for a totaldosage of 60,000 mg•min/m 3 . Subsequent repeateddose studies in guinea pigs, dogs, and monkeys exposeddaily for 10 days to Cts ranging from 4,200 to13,000 mg•min/m 3 were lethal to the majority of theanimals for all species tested. Overall, these studiesdemonstrated the lack of cumulative toxicity of CNwhen administered in divided dosages.Kumar et al 132 subjected mice to multiple exposuresof CN and CR at concentrations equivalent to 0.05LCt 50— 87 mg/m 3 for CN and 1,008 mg/m 3 for CR— for15 minutes per day for 5 and 10 days. Biochemical endpointsmeasured included blood glucose, plasma urea,transaminase enzymes (serum glutamic:oxaloacetictransaminase and serum glutamic:pyruvic transaminase),liver acid phosphatase, liver glutathione levels,and hepatic lipid peroxidation (malondialdehydeformation). Clinical parameters affected by repeatedexposures included decreased hepatic glutathione460