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

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Toxic Inhalational Injury and Toxic Industrial ChemicalsPrematurityGeneticsNutritionhormonesImmature structureImmature defenseDisrupted alveolargenesisAltered lungstructureInitiationof injurySusceptibilityOxygenEnvironmentand toxinsLunginjuryVentilationDisruption epithelial and/orendothelial barrierEdema, inflammationMatrixaccumulationCellularproliferationFibroblastproliferationPersistent/chronicinflammationRepairEpi/endotproliferationApoptosisCellulardifferentiationTissueremodelingMatrixdegradationAltered lungstructureProgression of injuryNormallungChronic lungdiseaseMechanism of lung injury and repair.Fig. 10-2. Pathophysiology of toxic gas inhalation.Epi/Endot: epithelial and/or endothelialAdapted with permission from: Copland I, Tanswell K, Post M. Principals of lung development, growth, and repair. In:Notter RH, Finkelstein JN, Holm BA, eds. Lung Injury: Mechanisms, Pathophysiology, and Therapy. Boca Raton, Fla: Taylor &Francis Group; 2005: 19–66.protein levels were the most sensitive early indicatorsof pulmonary edema. In experiments in rats exposed toPFIB, as the mass exposure concentration increased, theearlier tissue injury occurred. Epithelial and endothelialcell blebbing occurred, which progressed overtime to endothelial swelling and fenestrations of theepithelial barrier, denudement of the alveolar surface,and interstitial edema. 45 PFIB and phosgene exposurealso caused alteration of the production of specificsurfactant phospholipids, which can have importantimplications for reduced lung compliance and the subsequenttreatment of this injury. 54 In rats exposed to thepyrolysis products of Teflon at 450ºC, ultrastructuralchanges in the lung consisted of pulmonary edema,hemorrhage, and necrotic tracheobronchial epithelium,accompanied by pneumocyte bleb formation, denuda-349
Medical Aspects of Chemical Warfaretion, and fragmentation. 55Lung tissue and cellular responses to inhalationexposure can also be manifested in the form of cellmembrane destruction. This can be measured to somedegree by determining the extent of lipid peroxidation,an indicator of oxidative stress caused by theabundance of free radicals. Lipid peroxidation is aprocess whereby the rigid lipid bilayer of the membranebecomes more fluid, resulting in the activationof intracellular metabolic pathways regulated byaltered enzyme function. One of the more importantpathways is the arachidonic acid (AA) pathway, whichleads to the production of mediators of inflammationand edema such as the leukotrienes. The othermetabolic arm of the AA pathway leads to vasoactivecompounds such as prostaglandins, which are in partresponsible for vascular tone. Both leukotrienes andprostaglandins have been implicated in toxic-gas–inducedacute lung injury. 56–59 Adenlyate cyclase is yetanother injury-activated enzyme system responsiblefor the cleavage of adenosine triphosphate to formadenosine 3’,5’-cyclic monophosphate (cAMP), whichis required for endothelial and epithelial tight-junctionformation. The initial step in this process is damage tomembrane surface β-adrenergic receptors, which aid inthe regulation of cAMP formation. With the deactivationof cAMP formation, tight junctions become morepermeable and allow the passage of fluid or waterinto intracellular and extracellular spaces. DecreasedcAMP production and the resultant pulmonary edemahave been implicated in toxic-gas–induced acute lunginjury. 39Acute exposure to nitrogen dioxide causes a rangeof pathological effects characterized by increasedepithelial permeability and the proliferation of Claraand type II epithelial cells. 60 Chronic exposure inducesbronchiolitis, alveolar bronchiolarization, ciliatedcysts, and emphysema. Exposure effects may be morepronounced in those with preexisting compromisedlung function such as asthma. In experiments in anasthmatic population exposed to 1 ppm nitrogen dioxide,increased levels of mediators of inflammation andvasoactive compounds were measured in the BALF. 61Metabolites of the cyclooxygenase pathway of the AAcascade, such as 6-keto-prostaglandin F 1-α (responsiblefor bronchodilation) were decreased; however, bothprostaglandin D 2and thromboxane B 2(responsible forbronchoconstriction) were increased. Elevated levels ofleukotrienes such as C 4, D 4, and E 4, which are productsof the lipoxygenase pathway of the AA cascade relatedto bronchial hyperresponsiveness, were also involvedin the inflammatory response.Exposure to smoke has been shown to cause sufficientlysevere acute lung injury to ultimately resultin death. In human smoke-related fatalities, the lungswere shown to exhibit soot staining in the tracheobronchialmucosa, and they were heavy (edematous) andhyperemic. Light microscopy indicated pulmonarycongestion, and electron microscopy revealed carbonparticles as well as interstitial and intraalveolaredema. 62Inflammatory PathwaysInflammation is a critical result of toxic-gas–inhalation injury. Many studies have demonstrateda decrease in the number of macrophages, which areimportant in clearance mechanisms, and an increasein neutrophils, which aid in detoxification of toxicmediators and metabolites. These shifts in cell populationsgenerally occur over time and are usually afunction of the gas involved, the depth of inhalation,the concentration, and the duration of exposure. Inthe case of some inhaled gases, the chemical reactionin the tissue can produce deleterious amounts of freeradicals. These radicals in turn can damage migratingcells such as neutrophils, causing them to dumptheir toxic proteases, proinflammatory cytokines andchemokines, and additional toxic free radicals suchas the hydroxyl species •OH and superoxide anionO 2 - into the intracellular environment, causing greaterdamage. This additive effect may account for some ofthe latent injury responses seen following inhalationof gases such as phosgene and possibly other irritants,some of which have well-described latency (1–24hours) effects.Markers of inflammation and the timing of theirrelease after exposure can provide useful informationabout the potential therapeutic window for eventualand successful treatment. Many studies have focusedon cytokines, which are produced by a variety of whitecells, fibroblasts, and epithelial and endothelial cells,to assess the inflammatory response. Cytokines canhave a wide range of proinflammatory and antiinflammatoryeffects in tissue injury responses. Thesecompounds serve as important mediators of tissue andinjury repair processes and as such represent suitablemarkers of inflammation injury and signal transductionpathways (Table 10-5). 63For example, in phosgene-exposed mice, BALF cytokineand chemokine analysis over 72 hours clearlydemonstrated that the cytokine interleukin-6 and thechemokine macrophage inflammatory protein-2, theanalog in mice for human interleukin-8, were both significantlyincreased within 4 to 8 hours of exposure. 64Both interleukin-1β and tumor necrosis factor-α weresignificantly increased 24 to 72 hours after exposure.The data support the postulation that tumor necrosis350
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The Coat of Arms1818Medical Departm
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Textbooks of Military MedicinePubli
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MEDICAL ASPECTS o fCHEMICAL WARFARE
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ContentsContributorsForeword by The
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ContributorsMICHAEL ADLER, PhDResea
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DONALD M. MAXWELL, MSResearch Chemi
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ForewordThe US military has been co
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PrefaceA significant concern for th
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PrologueThe original edition of Med
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xxii
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Medical Aspects of Chemical Warfare
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Nerve AgentsChapter 5NERVE AGENTSFR
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Nerve AgentsAbout 10,000 to 30,000
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Nerve Agentsphorofluoridate (DFP) w
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Nerve AgentsFig. 5-2. This schemati
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Nerve AgentsExhibit 5-1 continuedis
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Nerve Agentsactivity but only 15% t
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Nerve AgentsTABLE 5-3CHEMICAL, PHYS
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Nerve AgentsTABLE 5-4EFFECTS OF EXP
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Nerve Agentsaffecting the other eye
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Nerve Agentsmay cause severe rhinor
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Nerve Agentsof jerks and tremor.Cen
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Nerve Agentsand they were decreased
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Nerve Agentsnerve agent toxicity on
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Nerve Agentspatient. Decontaminatio
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Nerve AgentsFig. 5-5. The Mark I ki
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Nerve Agentsadministered intramuscu
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Nerve Agentsthat hydroxamine reacti
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Nerve AgentsOral administration may
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Nerve AgentsTABLE 5-7RECOMMENDED TH
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Nerve Agentsimpairment such as whee
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Nerve Agentssuboptimal, manner. The
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Nerve Agentsthan those who did not.
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Nerve Agentssible for binding nerve
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Nerve Agentsfor comparison was not
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Nerve AgentsTABLE 5-11EFFECTS OF PY
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Nerve Agentstivity of smooth muscle
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Nerve Agents38. Grob D, Lilienthal
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Nerve Agents77. McDonough JH, Shih
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Nerve Agents117. McLeod CG Jr, Sing
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Nerve Agents154. Tryphonas l, Veino
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Nerve Agents193. Funckes AJ. Treatm
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Nerve Agents235. Suzuki T, Morita H
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Nerve Agents274. Pellegrini JE, Bak
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Page 321 and 322: Medical Aspects of Chemical Warfare
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Page 375 and 376: PROCESSMedical Aspects of Chemical
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Triage of Chemical CasualtiesChapte
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Triage of Chemical Casualtiesreceiv
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Triage of Chemical Casualtiesentran
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Triage of Chemical Casualtiescatego
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Triage of Chemical CasualtiesIn a f
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Triage of Chemical Casualtiesnose)
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Triage of Chemical CasualtiesWith n
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Triage of Chemical Casualties14. Sa
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Decontamination of Chemical Casualt
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• Analyze using GC-MS with methan
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Abbreviations and AcronymsAbBreviat
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Abbreviations and AcronymsPADPRP: p
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