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

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

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Toxins: Established and Emergent ThreatsabFig. 19-2. Structures of tetrodotoxin (left) and saxitoxin (right).Illustration: Courtesy of Richard Sweeny.From 1956 to 1958, nearly 500 Japanese citizens diedfrom puffer fish ingestion, prompting the immediateelucidation of the toxin. 62 The structure of TTX (seeFigure 19-2, left) was determined in 1964, 63–65 and Kishisynthesized the toxin. 66 TTX remains widely used inresearch today and is available to scientists from manycommercial sources. STX synthesis (see Figure 19-2,right) was first published in 1977. 67 Like TTX, STXis a potent, selective, sodium channel blocker. STX,only one component of PSP toxins, is the product ofthe dinoflagellates Gonyaulax catenella and Gonyaulaxtamarensis. STX has been isolated in certain mollusksthat feed on Gonyaulax catenella 68 and is believed tobioaccumulate to cause toxicity in humans.Mechanism of Action and ToxicityBoth TTX and STX are water-soluble, heat-stablemolecules 61,69–72 and can be absorbed through the mucousmembranes and small intestine. 73,74 Both inhibitneuromuscular transmission by binding to the voltagegatedsodium channel (Figure 19-3). As selective,voltage-dependent, sodium channel blockers, bothtoxins exert major neurotoxic effects by preventing actionpotential generation and propagation (see Exhibit19-1). Six different binding sites on the voltage-gatedsodium channel have been identified, each site correspondingto a locus on the protein where groupsof neurotoxins can bind (Figure 19-4). Both TTX andSTX occupy binding site 1, 75 which is on the S6 transmembranedomain. This domain forms the mouthof the pore in the three-dimensional structure of thechannel on the extracellular face (see Figure 19-3). TTXand STX will bind irreversibly to the sodium channel,occluding the pore. In this way, TTX and STX act assodium channel blockers, sterically preventing sodiumion access through the channel. In the context of thebrief description of action potential generation above,prevention of sodium ion movement by either toxinhas catastrophic effects on normal neuronal function.The end result is blockade of nerve conduction andmuscle contraction (see Figure 19-4). The toxins arereversible and do not lead to damage of the nerve orskeletal muscle. 73,74,76 Another similar feature is thatthese toxins inhibit cardiac and smooth muscle athigher concentrations. One difference between the twotoxins is that STX lacks the emetic and hypothermicaction of TTX 77 ; the mechanism behind this differenceis not well understood. Other cardiovascular effects forthese sodium channel toxins have been noted. STX hasbeen demonstrated to induce hypotension by directaction on vascular smooth muscle or through blockingvasomotor nerves. 78 It also decreases conductionat the AV node. 79 Both toxins have effects in the brain.STX inhibits the respiratory centers of the central nervoussystem 79 while TTX action produces blockadeof sodium channels in the axon of the magnocellularneurons of the neurohypophysis, inhibiting release ofvasopressin. Children appear to be more sensitive toSTX than adults. 80,81As a selective sodium channel blocker, TTX binds itsmolecular target tightly with extremely strong kinetics(Kd = 10-9 nM). Toxicology of TTX and STX is reportedin the literature based primarily on mouse data. Bothtoxins are extremely potent, with an approximate LD 508 to 10 μg/kg in mice. 69 Toxicity studies in mice examinedintoxication by IV administration, while the routeof exposure in humans is generally through ingestion.Deaths have been reported following human ingestionof both toxins, 61,70 and it is estimated that 1 to 2 mg623

Medical Aspects of Chemical WarfareFig. 19-3. Three-dimensional representation of a voltage-gated sodium channel sitting in a phospholipid bilayer membrane.The linear protein folds to form a pore in the cell membrane, providing a central, electrically charged aperture through whichsodium ions can pass. The toxins bind to regions of the channel structure occluding the pore, preventing sodium ions fromentering and traversing the channel pore.Na + : sodium ionSTX: saxitoxinTTX: tetrodotoxinof TTX is a lethal dose for an average adult human. 69Respiratory toxicity of STX is less well understood inevery model system than systemic toxicity; however,data from aerosol deposition studies in mice exposedto STX aerosol give LC 50(lethal concentration; theconcentration of the chemical in air that kills 50% ofthe test animals in a given time) values < 1 μg/kg. 71Thus, in these studies, STX is at least 10-fold more toxicto mice by aerosol exposure than by systemic administration.The mechanism of this enhanced toxicity isunknown.Toxin Exposure, Health Effects, and TreatmentIntoxication by TTX is the most common lethalmarine poisoning 82 and most often occurs by theconsumption of contaminated food. Ingestion of TTXcontaminatedfoods occurs throughout Southeast Asiaand the Pacific, most commonly in Japan, where pufferfish is a delicacy. Additionally, neurologic illnessesassociated with ingestion of Florida puffer fish havebeen reported since 2002. Signs and symptoms of TTXintoxication usually begin within 30 to 60 minutes afteringestion of the toxin. Anxiety, nausea, vomiting, andparesthesias of the lips, fingers, and tongue are allcommon. In cases of severe poisoning, clinical signsand symptoms include marked paresthesias, loss ofconsciousness, generalized flaccid paralysis, respiratoryarrest, and death. Dizziness, dyspnea, and fixed,dilated pupils have also been reported. Patients withmore moderate poisoning generally retain consciousness.There are reports of unresponsive patients whowere nonetheless fully cognizant of events aroundthem. 83PSP typically results from the consumption of mussels,clams, oysters, mollusks, starfish, sand crabs,624

<strong>Medical</strong> <strong>Aspects</strong> <strong>of</strong> <strong>Chemical</strong> <strong>Warfare</strong>Fig. 19-3. Three-dimensional representation <strong>of</strong> a voltage-gated sodium channel sitting in a phospholipid bilayer membrane.<strong>The</strong> linear protein folds to form a pore in the cell membrane, providing a central, electrically charged aperture through whichsodium ions can pass. <strong>The</strong> toxins bind to regions <strong>of</strong> the channel structure occluding the pore, preventing sodium ions fromentering and traversing the channel pore.Na + : sodium ionSTX: saxitoxinTTX: tetrodotoxin<strong>of</strong> TTX is a lethal dose for an average adult human. 69Respiratory toxicity <strong>of</strong> STX is less well understood inevery model system than systemic toxicity; however,data from aerosol deposition studies in mice exposedto STX aerosol give LC 50(lethal concentration; theconcentration <strong>of</strong> the chemical in air that kills 50% <strong>of</strong>the test animals in a given time) values < 1 μg/kg. 71Thus, in these studies, STX is at least 10-fold more toxicto mice by aerosol exposure than by systemic administration.<strong>The</strong> mechanism <strong>of</strong> this enhanced toxicity isunknown.Toxin Exposure, Health Effects, and TreatmentIntoxication by TTX is the most common lethalmarine poisoning 82 and most <strong>of</strong>ten occurs by theconsumption <strong>of</strong> contaminated food. Ingestion <strong>of</strong> TTXcontaminatedfoods occurs throughout Southeast Asiaand the Pacific, most commonly in Japan, where pufferfish is a delicacy. Additionally, neurologic illnessesassociated with ingestion <strong>of</strong> Florida puffer fish havebeen reported since 2002. Signs and symptoms <strong>of</strong> TTXintoxication usually begin within 30 to 60 minutes afteringestion <strong>of</strong> the toxin. Anxiety, nausea, vomiting, andparesthesias <strong>of</strong> the lips, fingers, and tongue are allcommon. In cases <strong>of</strong> severe poisoning, clinical signsand symptoms include marked paresthesias, loss <strong>of</strong>consciousness, generalized flaccid paralysis, respiratoryarrest, and death. Dizziness, dyspnea, and fixed,dilated pupils have also been reported. Patients withmore moderate poisoning generally retain consciousness.<strong>The</strong>re are reports <strong>of</strong> unresponsive patients whowere nonetheless fully cognizant <strong>of</strong> events aroundthem. 83PSP typically results from the consumption <strong>of</strong> mussels,clams, oysters, mollusks, starfish, sand crabs,624

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