Chemical agents (f.e. sulfur mustard). TheChemical warfare agents

Chemical warfare uses the toxic properties of chemical substances as weapons. About 70 different chemicals have been used or stockpiled as chemical warfare agents during the 20th century and they are considered “weapons of mass destruction”. The term chemical weapon is applied to any toxic chemical or its precursor that can cause death, injury, temporary incapacitation or sensory irritation through its chemical action. Munitions or other delivery devices designed to deliver chemical weapons, whether filled or unfilled, are also considered weapons themselves.INTRODUCTIONThe term chemical weapon is applied to any toxic chemical or its precursor that can cause death, injury, temporary incapacitation or sensory irritation through its chemical action. Munitions or other delivery devices designed to deliver chemical weapons, whether filled or unfilled, are also considered weapons themselves.The use of nonliving toxic products produced by living organisms such as the botulinum toxin are also considered chemical warfare under the provisions of the Chemical Weapons Convention (CWC). About 70 different chemicals have been used or stockpiled as chemical warfare agents during the 20th century and they are considered “weapons of mass destruction”.The most volatile agents are non-persistent agents (for example hydrogen cyanide) whereas the less volatile agents are persistent agents (f.e. sulfur mustard). TheChemical warfare agents can be classified depending on their mechanism of action, toxic properties andphysiological effects produced on humans on the following categories:• Nerve agents• Vesicants or blistering agents• Bloods agents or cyanogenic agents• Choking agents or pulmonary agents• Riot-control agents or tear gases• Psychomimetic agents• Toxins 1. Nerve agentsThe organophosphate nerve agents tabun (GA), sarin (GB), soman (GD), and cyclosarin (GF) are among the most toxic chemical warfare agents known.  Together they comprise the G-series nerve agents, named after the German scientists that first synthesized them. The last agent synthesized was a substance known by its code name VX as suitable as a CW agent of persistent type in the United States.   The chemical-warfare agents discussed here are highly toxic organophosphate ester Vxderivatives of phosphonic acid.    As nerve agents are soluble in fat and water, they can be absorbed through the eyes, respiratory tract, and skin, producing localized effects; then pass into the respiratory tract, producing more generalized effects. Organophosphate (OP) nerve agents have been specifically designed and formulated to cause death, major injuries, or incapacitation to enemy forces in wartime.Mechanism of actionThe acute toxicity of the nerve agents is considered to be initiated by inhibition of acetylcholinesterase (AChE), an enzyme responsible for deactivating the neurotransmitter acetylcholine at neuronal synapses and myoneural junctions. Nerve agents phosphorylate the enzyme, thereby preventing deactivation of acetylcholine. Although the inhibited cholinesterase can be reactivated by the process of dephosphorylation, that is not possible once the nerve agent-cholinesterase complex undergoes “aging,” ( the loss a loss of an alkyl or alkoxy group).Muscarinic effects include pinpoint pupils; blurred or dim vision; conjunctivitis; eye and head pain; hypersecretion by salivary, lacrimal, sweat, and bronchial glands; narrowing of the bronchi; nausea, vomiting, diarrhea, and crampy abdominal pains; urinary and fecal incontinence; and slow heart rate.Nicotinic effects include skeletal muscle twitching, cramping, and weakness. Nicotinic stimulation can obscure certain muscarinic effects and produce rapid heart rate and high blood pressure.Relatively small to moderate vapor exposure causes pinpoint pupils, rhinorrhea, bronchoconstriction, excessive bronchial secretions, and slight to moderate dyspnea. Mild to moderate dermal exposure results in sweating and muscular fasciculations at the site of contact, nausea, vomiting, diarrhea, and weakness. The onset of these mild to moderate signs and symptoms following dermal exposure may be delayed for as long as 18 hours. Higher exposures (any route) cause loss of consciousness, seizures, muscle fasciculations, flaccid paralysis, copious secretions, apnea, and death.ANTIDOTESAtropine is the classical antidote in cases of poisoning by organo-phosphorus compounds. It relieves the symptoms but does not attack the cause of the injury. Atropine becomes bound to the receptors for acetylcholine, which are present in the cholinergic synapse. When acetylcholine is bound, the signal is transmitted but if atropine bounds to the receptor, then no such transmission takes place. Atropine protects against the excess of acetylcholine which results from inhibition of acetylcholinesterase but hass effects only within certain parts of the cholinergic nervous system.     The various nerve agents cause poisoning which are more or less easy to treat with oximes. From this standpoint, VX and sarin are the easiest to treat and all oximes used increase the chances of surviving. Obidoxime is the most effective against tabun poisoning but also HI-6 has a positive effect. Soman is the most difficultly to treat and can only be treated with HI-6.Soman poisoning is complicated by the inhibited enzyme going through an “ageing” process fast. Following the ageing, the enzyme cannot be reactivated by any oxime. It is possible that HI-6 has some further positive antidote effect in addition to its reactivating ability.A diazepam tablet is also generally given as a pretreatment, primarily affecting the central nervous system. Diazepam strengthens the effect of other nerve agent antidotes. There will be better prospects of survival and less injury, reducing the convulsions that the organophosphorus cause. Diazepam also provides protection against permanent brain damage which may result from heavy exposure to nerve agents.2. Blister agents Blister agents, or vesicants, are one of the most common CW agents. These oily substances act via inhalation and contact with skin. They affect the eyes, respiratory tract, and skin, first as an irritant and then as a cell poison. As the name suggests, blister agents cause large and often life-threatening skin blisters that resemble severe burns.Examples include:  Phosgene oximeLewisite   MECHANISM OF ACTIONMUSTARDSAfter absorption into the body, mustard rapidly cyclizes (seconds to minutes) in extracellular water. This cyclic compound is extremely reactive and quickly binds to intra- and extra-cellular enzymes, proteins, and other substances. The toxic effects of mustard agent depend on its ability to covalently bind other substances. The chlorine atom is spiked off the ethyl group and the mustard agent is transferred to a reactive sulphonium or ammonium ion. This ion can bind to a large number of different biological molecules such as the  guanine nucleotide by attacking  the N-7 nucleophilic center of the guanine base. Since mustard agent contains two “reactive groups”, a second attack after the displacement of the second chlorine forms the second alkylation step that results in the formation of interstrand that can cross-link DNAstrands. This prevents cellular division and generally leads to apoptosis via p53, or, if cell death is not immediate, the damaged DNA may lead to the development of mutations that can lead to tumors.Damage from mustard results from DNA alkylation and crosslinking in rapidly dividing cells, such as basal keratinocytes, mucosal epithelium, and bone marrow precursor cells. This leads to cellular death and inflammatory reaction, and, in the skin, protease digestion of anchoring filaments at the epidermal-dermal junction and the formation of blisters. Mustard possesses mild cholinergic activity, which may be responsible for effects such as early gastrointestinal symptoms and miosis.Death often occurs between the fifth and tenth day after exposure because of pulmonary insufficiency and infection complicated by a compromised immune response from agent-induced bone marrow damage.LEWISITEThe toxicological effects of ocular exposure to lewisite are mediated by the interaction of inorganic arsenite (AsO33?) with thiol groups of biologically active proteins, including dihydrolipoic acid (DHA). DHA is a co-factor in several critical enzyme systems critically involved in energy production. For example, As3+ interaction with the E3 component of the pyruvate dehydrogenase complex prevents the conversion of pyruvate to acetyl-CoA, impairing ATP production and resulting in energy depletion, metabolic failure, and cytotoxicityMEDICAL MANAGEMENTThe management of a patient exposed to mustard may be simple, as in the provision of symptomatic care for a sunburn-like erythema, or extremely complex that need hospitalization providing total management with burns, immunosuppression, and multi-system involvement. LONG TERM EFFECTSA single, severe exposure to mustard may have contributed to other airway problems, such as chronic bronchitis, based on WWI data. Several eye diseases, such as chronic conjunctivitis and delayed keratitis. Skin scarring and pigment changes may follow a severe skin lesion from mustard; cancer sometimes develops in scarred skin. Mustard is classed as a mutagen and carcinogen based on laboratory studies. However, there are no data to implicate mustard as a reproductive toxin in man, and there is no evidence that mustard is a causative factor in non-airway, non-skin cancer in man. 3. Bloods agents  or cyanogenic agentsBlood agents are distributed via the blood and generally enter the body via inhalation. They inhibit the ability of blood cells to utilize and transfer oxygen. Thus, blood agents are poisons that effectively cause the body to asphyxiate.Examples of blood agents include:• Hydrogen cyanide (AC)• Cyanogen chloride (CK)• Arsine (SA).MECHANISM OF ACTIONCyanide exists normally in human tissues and is usually metabolized by sulfur in the presence of a hepatic enzyme, rhodanese, into thiocyanante, which is excreted in the urine. Under normal conditions, the cyanide anion is attracted to iron in the ferric state (Fe+++). In the mitochondrion of the human cell, cytochrome A3 in the cytochrome oxidase complex contains Fe+++. Cyanide is bound to cytochrome A3 and thus inhibits the effect of cytochrome oxidase. This enzyme complex is responsible for the utilization of oxygen within the cell. In the presence of cyanide, even though there is plenty of dissolved oxygen in the blood, the cells cannot use the available oxygen. As a result, cells must utilize anaerobic metabolism, or the creation of energy without the benefit of oxygen, which causes severe lactic acidosis. When cells cannot get enough energy, they die. Cells in the brain and heart are the first ones to be affected. Acute cyanide poisoning occurs after inhaling the agent, but may also occur after drinking solutions of cyanide (it is sometimes used with suicidal intent) or by skin contact with large amounts of liquid cyanide.TREATMENTPatients who have inhaled significant doses of cyanide must be rapidly treated with appropriate antidotes to prevent brain damage. Cyanide is attracted to iron (Fe+++) in a form of hemoglobin called methemoglobin. In fact, cyanide will preferentially leave the cytochrome oxidase enzyme in the cell and bind to circulating methemoglobin. Drugs such as amyl nitrite and sodium nitrite, which are found in the cyanide treatment kit, increase blood concentrations of methemoglobin. Adding sodium thiosulfate completes the detoxification process. Patients should be treated with IV saline for hydration; sodium bicarbonate and intubation with hyperventilation should be used for the metabolic acidosis. Oxygenation should be maintained with high-flow oxygen by mask or by endotracheal tube. Monitor and treat significant arrhythmias.4. Pulmonary agentsPulmonary agents or choking agents compose a class of chemical compounds that disrupt normal breathing. They encompass a wide array of gases, including chlorine, ammonia, phosgene, organo-halides, and nitrogen oxides. These compounds have figured prominently in military conflicts; notably, the US Civil War, World War, and the Iraq War. Unlike other chemical weapons, theyplay important roles in the civilian and commercial sectors. For example, manufacturers use chlorine and ammonia to refrigerate food, purify water, and synthesize common household products. MECHANISM OF ACTION AND PHYSICAL PROPERTIESChoking agents function in liquid, gaseous, or aerosolized forms. In their gaseous form, they operate primarily by irritating the respiratory tract including the mucous membranes, nasal passage, throat, airways, and lungs-and inducing swelling in these areas. Chlorine is a dense, greenish gas at room temperature, and is relatively insoluble in water. Upon inhalation, water inside the body oxidizes chlorine gas to produce hypochlorous acid (HClO). HClO penetrates cells and reacts with proteins to degrade cellular structures.    Chloropicrin, meanwhile, is a colorless, highly volatile liquid featuring a sharp odor. A powerful oxidant, it reacts readily with aluminum, magnesium, and their associated alloys to produce a toxic, corrosive gas. Phosgene gas, like chloropicrin, is also colorless. Liquid phosgene reacts violently with water and ammonia-decomposing rapidly in both to produce hydrochloric acid and urea, respectively. It also evaporates quickly from the skin, allowing for effective decontamination with water.There is no antidote against any of the choking agents. Medical treatment for those exposed to chlorine, phosgene, or chloropicrin is largely supportive and decontaminative in nature. Specific strategies include secretion management, oxygen therapy, and administration of high-dose steroids to reduce respiratory swelling. Intubation and mechanical ventilation maybe required. Caregivers should exercise caution in using sedatives on patients whose airways and breathing are not controlled. 5. Riot-control agentsThe molecular target of capsaicin, TRPV1 is a transient receptor potential (TRP) ion channel expressed in nociceptors, the pain?sensing peripheral sensory nerves of the trigeminal, vagal, and dorsal root ganglia (DRG). Nociceptor nerve endings are present in all organs and the body surface, including the skin, cornea, conjunctiva, and the mucous membranes of the upper and lower airways and lung. Chemical structures of commonly used tear gas agents o?chlorobenzylidene malononitrile (CS), 1?chloroacetophenone (CN), and dibenzb,f?1,4?oxazepine (CR).TRPA1 is activated by a large variety of structurally unrelated irritant chemicals.A traditional pharmacological ligand–receptor model cannot explain this sensitivity to multiple chemicals. Biochemical studies revealed a reactivity?based activation mechanism of TRPA1, in which electrophilic and oxidizing activators modify cysteine residues in the N?terminal domain of TRPA1, resulting in covalent modification leading to channel activation. Thus, TRPA1 can be considered a peripheral neuronal reactivity detector, signaling the danger of imminent injury by electrophilic or oxidant exposures. Owing to their electrophilic properties, tear gas agents likely react with many other biomolecules in the eyes, respiratory tract, and skin. The nature of these targets is largely unknown. Similar to acrolein and related electrophiles, tear gas agents may damage and deplete biological redox systems in the lining fluids of epithelia and within cells and mitochondria, modify structural proteins and nucleic acids, and inactivate enzymes. There has been minimal research on endocrine effects, immunologic consequences, and histological changes from CS exposure, but some animal studies indicate that potential effects may occur.  6. PSYCHOMIMETIC CHEMICALS  Psychomimetic agents, which have been described in a military context,include muscarinic antagonists, cannabinoids, indoles and anxiogenics. The only psychomimetic chemical used as warfare weapon is BZ, 3-Quinuclidinyl benzilate . BZ is an anti-cholinergic glycolate related to atropine that acts as a competitive antagonist of the postjunctional muscarinic receptors at ganglia and parasympathetic innervations onto smooth muscle and exocrine glands. By blocking the ability of muscarinic receptors to respond to the synaptic release of acetylcholine, BZ inhibits parasympathetic signaling and drives the ocular nerves toward sympathetic dominance. This shifts the pupillary balance toward mydriasis, failure of accommodation, and lacrimal paralysis. Thus, Bz effects on the eye are the opposite of the OPNAs, resulting in mydriasis, the loss of near-focus, and dry eye. Like nerve agents, once nor mal cholinergic signaling is restored, the ocular effects of BZ are fully reversed.Unlike the prodromic effects of many agents on the ocular system, ocular symptoms of BZ inhalation occur secondary to general signs of intoxication, such as incoordination, confusion, and slurred speech.ANTIDOTENo specific antidote has been found to reverse the action of BZ definitively. In the past, physostigmine was used to reverse the effects of anticholinergic agents. However, numerous adverse effects associated with its use in reversing poisonings are reported in the literature. Subsequently, the use of physostigmine has diminished greatly in the setting of acute anticholinergic toxicityIf the exposed patient is markedly agitated, administration of a benzodiazepine. Depresses all levels of CNS (eg, limbic and reticular formation), possibly by increasing activity of GABA. Induces sedation and helps cease seizure activity.7. TOXINSToxins are defined as potent toxic chemicals produced by living organisms that inhibit protein synthesis causing severe cytotoxic effects. Of the hundreds known, fewer than 20 have been used as weapons.RICINDerived from beans of the castor plant, ricin is composed of two haemagglutinins and two toxins (RCL III and RCL IV). The toxins consist of two polypeptide chains (A and B), joined by a disulfide bond. The B chain binds to cell surface glycoproteins; the A chain acts on the 28S ribosomal RNA, which inhibit protein synthesis causing cell death. High-dose inhalation is rapidly fatal; lower doses result in death within 3 days.4BOTULINUM TOXINUMClostridium botulinum produces the most toxic chemical known. Seven serologically distinct neurotoxins exist (A to G, with three subtypes of A) and structurally they consist of two polypeptide chains. A dose of 200–300 pg kg?1of Neurotoxin A is lethal. All serotypes of the toxin permanently inhibit the pre-synaptic release of ACh, blocking neurotransmission at peripheral cholinergic synapses (including the NMJ), post-ganglionic parasympathetic synapses and peripheral ganglia. Recovery occurs after the formation of new terminal boutons. Trivalent antitoxins are effective for several serotypes and pentavalent antitoxin is under development. BIBLIOGRAPHY1.ORGANISATION FOR THE PROHIBITION OF CHEMICAL WEAPONS; Brief Description of Chemical Weapons 27/11/2017) 2. K. Ganesan, S. K. Raza, and R. Vijayaraghavan; J Pharm Bioallied Sci. 2010 Jul-Sep; 2(3): 166–178.doi:  10.4103/0975-7406.68498 3. Dave Mosher and Diana Yukari, Apr. 28, 2017. Here’s why nerve agents are some of the most deadly chemicals on Earth. Bussines insider. Research Council. 2003. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 3. Washington, DC: The National Academies Press. 5. Agency for Toxic Substances and Disease Registry. 2003. Medical Management Guidelines for Nerve Agents. Division of Toxicology, U.S. Department of Health and Human Services. Public Health Service; Atlanta, GA. 6. MEDICAL MANAGEMENT OFCHEMICAL CASUALTIES HANDBOOK, Second Edition, ( 1995)Aberdeen Proving Ground, MD 21010-5425,  UNITED STATES ARMY MEDICAL RESEARCH INSTITUTE OF CHEMICAL DEFENSE. 7. Patrick M. McNutt, Tracey L. Hamilton, in Handbook of Toxicology of Chemical Warfare Agents (Second Edition), 2015 8. Barry R. Schneider,  Enciclopaedia Britannica. (2006) 9.Sanjana Ravi, UPMC Center for Health Security, 2014. Pulmonary or Choking Agents 10. James Geoghegan, Jeffrey L Tong, MB, Continuing Education in Anaesthesia Critical Care & Pain, Volume 6, Issue 6, Chemical warfare agents,  2006, Pages 230-234, 11. Ann N Y Acad Sci, Willey-Blackwell Online ( 2016 )Aug; 1378(1): 96–107. Tear gas: an epidemiological and mechanistic reassessment