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

Medical DiagnosticsThe estimated LCt 50of phosgene concentration in airrelated to exposure time through inhalation is 500ppm/min. 156 The aerosol exposure that is lethal to100% of the exposed population (LCt 100) is estimatedto range from 1,300 ppm/min to 1,600 ppm/min. 159The nonlethal levels of phosgene are estimated to beless than 300 ppm/min, and 25 ppm/min is regardedas the threshold for lung damage. 156Phosgene odor can be recognized at levels greaterthan 1.5 ppm/min, with irritation in the mucus membranesoccurring at 3 ppm/min or higher. 157 Exposurelimits that cause adverse health effects can be reachedeither by longer exposure to lower concentration orshorter exposure to higher concentration. In one study,however, workers exposed to daily phosgene concentrationsabove 1 ppm but less than 50 ppm showedno difference in mortality or morbidity compared toworkers in the same plant who were unexposed. 160The concentrations of phosgene in air that causeacute effects have been studied in many animal models.A review of previous animal studies in the literaturewas performed by Diller and Zante to estimate theapproximate inhalation-dose–toxicity relationship formany species of animals. 161 In this report, animal LCt 50ranged from approximately 200 ppm/min for cats to2000 ppm/min for goats. Guinea pigs and mice hadthe same approximate value as humans, 500 ppm/min.Dogs and rabbits had higher LCt 50values than humans(1000 ppm/min and 1500 ppm/min, respectively),while nonhuman primates and rats had estimatedlower LCt 50values than humans (300 ppm/min and400 ppm/min, respectively). 161Phosgene Metabolism and Markers for PhosgeneExposurePhosgene is very reactive and is believed to bequickly transformed in vivo. Phosgene reacts withamino, hydroxyl, and thiol groups. In the blood, itcan react with a variety of proteins, including albuminand hemoglobin. It also reacts with GSH and cysteine.Because chloroform is metabolized to phosgene inthe body, it is expected that low levels of phosgene’sprotein adducts and metabolites can be found in thegeneral background population because of low-levelincidental exposure to chloroform. Studies are neededto accurately determine this reference range.Glutathione and Glutathione AdductsBecause phosgene is a highly reactive acylatingagent, it is expected to interact with the body’s antioxidantdefense system. GSH is a tripeptide thiol consistingof cysteine, glutamic acid, and glycine, whichserves as both a scavenger of reactive compounds toprotect cells and as a store for cysteine moieties. 162 GSHis found in general concentrations in healthy adultsin the millimolar range. 162,163 GSH can be oxidized toglutathione disulfide (GSSG), a simple dimer of GSHjoined by a disulfide linkage. The ratio of the GSH redoxcouple in vitro has been determined to be between100:1 and 10:1 GSH to GSSG. 162,163 When depleted, GSHfails to protect cellular oxidation and leads to irreversibleoxidative damage. 164Phosgene was found to react with GSH to forman acylated dimer, diglutathionyl dithiocarbonate(GSCOSG; Figure 22-13). 165 This marker for phosgenemetabolism was first discovered by Pohl et al 165 in themetabolism of chloroform in the liver, where phosgenewas believed to be generated by enzymatic action fromchloroform. The bisglutathione adduct GSCOSG wasdetected in vivo in the bile of rats exposed to chloroformand in vitro in rat liver microsomes. Pohl et al alsofound a decrease in GSH levels in the rats. 165 GSCOSGwas found directly by mixing phosgene with GSH inbuffer solution. 166The in-vivo generation of GSSG and CO has alsobeen reported in the blood of mice exposed to haloforms.167 The observation of GSSG and CO may belinked to the further metabolism of GSCOSG aftergeneration, but there are no studies that have identifiedthis potential relationship.GSH is also found in tissue, so similar reactions withGSH and phosgene are expected in the bronchoalveolarregion. In the excised lung tissue from rabbits andmice inhalationally exposed to phosgene, there wasHOONH 2OOOHONHNHH 2 NHOChemical Formula: C 21 H 32 N 6 O 13 S 2Molecular Weight: 640.64SOHNHOOOONHFig. 22-13. Structure of diglutathionyl dithiocarbonate.SO735