Chemical Warfare Agent: Toxicity and Health Effects of Sarin Gas (GB)

Zeravan A. S. Ali Ali; Azzam A. Mosa Mosa; Mohammed A. Hami Hami; Rana T Altaee

doi:10.47419/bjbabs.v5i4.296

Authors

Zeravan A. S. Ali Ali Department of Chemistry, College of Science, University of Duhok, Kurdistan region, Iraq https://orcid.org/0009-0009-1369-3073
Azzam A. Mosa Mosa Department of Chemistry, College of Science, University of Duhok, Kurdistan region, Iraq. https://orcid.org/0000-0002-4375-8546
Mohammed A. Hami Hami Department of Chemistry, Faculty of Science, University of Zakho, Kurdistan-Region, Iraq https://orcid.org/0000-0003-0250-0634
Rana T Altaee Department of Chemistry, College of Education for Pure Science, University of Mosul, Iraq https://orcid.org/0000-0001-6657-4718

DOI:

https://doi.org/10.47419/bjbabs.v5i4.296

Keywords:

Acetylcholine, Acetylcholinesterase enzyme, Sarin gas

Abstract

Chemical warfare agents (CWAs) are toxic substances used to cause harm, injury, or incapacitation to an adversary in the context of warfare and related military activities. Sarin stands as an exemplar among agents, embodying some of the most potent compounds ever developed. This strength originates from its ability to permanently inhibit the acetylcholinesterase (AChE) enzyme, leading to the accumulation of acetylcholine (ACh) at synaptic junctions, which, in turn, induces stimulation of muscarinic and nicotinic receptors. The main objective of the current article is to summarize the negative influence of sarin gas on health and its role in the incidence of several pathological conditions in people who’s exposed to the gas. From this point of view, the clinical features of sarin exposure (health effect and related diseases) and the influence of nerve agents on deactivation of cholinesterase were the main area covered in this article. Furthermore, and for better understanding of the gas behavior and its toxicity, it was important to discuss the features of the gas, discovery, mechanism of toxicity, and pharmacological management. Lately, various approaches have also been reported with esteem of sarin detection, destruction, attacks, and treatment approaches after sarin poisoning.

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References

Szinicz L. History of chemical and biological warfare agents. Toxicology. 2005;214(3):167–181. 10.1016/j.tox.2005.06.011.

Hammond JW. Poison gas: the myths versus reality. Greenwood Publishing Group; 1999. p. 1–184.

Sidell FR, Takafuji ET, Franz DR. Textbook of Military Medicine, Part I, Warfare, Weaponry, and the Casualty, Medical Aspects of Chemical and Biological Warfare; 1997. p. 1–721.

Chauhan S, D’Cruz R, Faruqi S, Singh KK, Varma S, Singh M, et al. Chemical war- fare agents. Environmental Toxicology and Pharmacology. 2008;26(2):113–122. 10.1016/j.etap.2008.03.003.

Balali-Mood M, Shariat M. Treatment of organophosphate poisoning. Experience of nerve agents and acute pesticide poisoning on the effects of oximes. Journal of Physiology-Paris. 1998;92(5-6):375–378. 10.1016/S0928-4257(99)80008-4.

Barnaby F. Iran-Iraq War: the use of chemical weapons against the Kurds. Ambio. 1988;17(6):407–408.

Dingeman J, Jupa R. Chemical warfare in the Iran-Iraq conflict. Strategy & Tactics. 1987;113:51–52.

Holstege CP, Kirk M, Sidell FR. Chemical warfare: nerve agent poisoning. Critical care clinics. 1997;13(4):923–942.

Gupta RC. Handbook of toxicology of chemical warfare agents. Academic Press; 2015. .

Balali-Mood M, Balali-Mood K. Neurotoxic disorders of organophosphorus com- pounds and their managements. Arch Iran Med . 2008;11(1):65–89. 18154426.

Moshiri M, Darchini-Maragheh E, Balali-Mood M. Advances in toxicology and medical treatment of chemical warfare nerve agents. DARU Journal of Pharmaceu- tical Sciences. 2012;20(1):81–81. 10.1186/2008-2231-20-81.

Kim K, Tsay OG, Atwood DA, Churchill DG. Destruction and detection of chemical warfareagents. Chemicalreviews. 2011;111(9):5345–5403. 10.1021/cr100193y.

Romano JA, Salem H, Lukey BJ, routledge. Chemical Warfare Agents Chemistry, Pharmacology, Toxicology, and Therapeutics, Second Edition. CRC Press; 2008. .

Willis K, Salem H, Sidell F. Sarin (GB). Sarin (GB). 2014;.

Delfino RT, Ribeiro TS, Figueroa-Villar JD. Organophosphorus compounds as chemical warfare agents: a review. J Braz Chem Soc. 2009;20(3):407–428. 10.1590/S0103-50532009000300003.

Sidell FR, Borak J. Chemical warfare agents: II. Nerve agents. Ann Emerg Med. 1992;21(7):865–871. 10.1016/s0196-0644(05)81036-4.

Pearson GS, Magee RS. CRITICAL EVALUATION OF PROVEN CHEMICAL WEAPON DESTRUCTION TECHNOLOGIES. Pure Appl Chem. 2002;74(2):187–316. 10.1351/pac200274020187.

Vaiss VS, Borges I, Leitao AA. Sarin degradation using brucite. The Journal of Physical Chemistry C. 2011;115(50):24937–24944. 10.1021/jp208598c.

Wiener SW, Hoffman RS. Nerve agents: a comprehensive review. J Intensive Care Med . 2004;19(1):22–37. 10.1177/0885066603258659.

Fulco CE, Liverman CT, Sox HC, National Academies Press (US). Gulf War and health: Volume 1. Depleted uranium, pyridostigmine bromide, sarin, and vaccines. vol. 1; 2000. 10.17226/9953.

Gordon JJ, Inns RH, Johnson MK, Leadbeater L, Maidment MP, Upshall DG, et al. The delayed neuropathic effects of nerve agents and some other organophosphorus compounds. vol. 52; 1983. p. 71–82. 10.1007/BF00354767.

Somani S, Solana R, Dube S. Toxicodynamics of nerve agents. San Diego, CA, Academic Press; 1992. .

Shih ML, McMonagle JD, Dolzine TW, Gresham VC. Metabolite pharma- cokinetics of soman, sarin and GF in rats and biological monitoring of expo- sure to toxic organophosphorus agents. J Appl Toxicol . 1994;14(3):195–199. 10.1002/jat.2550140309.

Abou-Donia MB, Siracuse BO-isopropyl methylphosphonofluoridate) neurotoxicity: critical review. Crit Rev Toxicol . 2016;46(10):845–875. 10.1080/10408444.2016.1220916.

Dawson R. Review of oximes available for treatment of nerve agent poisoning. J Appl Toxicol . 1994;14(5):317–331. 10.1002/jat.2550140502.

Whalley CE, McGuireJM, Miller DB, Jakubowski EM, Mioduszewski RJ, Thomson SA, et al. Kinetics of sarin (GB) following a single sublethal inhalation exposure in theguinea pig. Inhal Toxicol. 2007;19(8):667–681. 10.1080/08958370701353296.

Khmelevtsova L, Sazykin IS, Sazykina MA, Seliverstova EY. Prokaryotic cytochromes P450 (Review). Applied Biochemistry and Microbiology. 2017;53:401–409. 10.1134/S0003683817040093.

Ahn T, Yun CH. Molecular mechanisms regulating the mitochondrial targeting of microsomal cytochrome P450 enzymes. Curr Drug Metab . 2010;11(10):830–838. 10.2174/138920010794479655.

Lin JH, Lu AY. Interindividual variability in inhibition and induction of cytochrome P450 enzymes. Annu Rev Pharmacol Toxicol . 2001;41:535–567. 10.1146/an- nurev.pharmtox.41.1.535.

Josse D, Lockridge O, Xie W, Bartels CF, Schopfer LM, Masson P. The active site of human paraoxonase (PON1). J Appl Toxicol . 2001;21(S1):7–11. 10.1002/jat.789.

Colovic MB, Krstić DZ, Lazarević-Pašti TD, Bondžić AM, Vasić VM. Acetyl- cholinesterase Inhibitors: Pharmacology and Toxicology. Current neuropharma- cology. 2013;11(3):315–335. 10.2174/1570159X11311030006.

Quinn DM. Acetylcholinesterase: enzyme structure, reaction dynamics, and virtual transition states. Chemical reviews. 1987;87(5):955–979. 10.1021/cr00081a005.

Greenfield SA, Zimmermann M, Bond CE. Non-hydrolytic functions of acetyl- cholinesterase. Thesignificanceof C-terminalpeptides. FEBS J . 2008;275(4):604–611. 10.1111/j.1742-4658.2007.06235.x.

He XC, Feng S, Wang ZF, Shi Y, Zheng S, Xia Y, et al. Study on dual-site inhibitors of acetylcholinesterase: Highly potent derivatives of bis- and bifunc- tional huperzine B. Bioorganic & Medicinal Chemistry. 2007;15(3):1394–1408. 10.1016/j.bmc.2006.11.009.

Soreq H, Seidman S. Acetylcholinesterase — new roles for an old actor. nature reviews neuroscience. 2001;2(4):294–302. 10.1038/35067589.

Sussman JL, Harel M, Frolow F, Oefner C, Goldman A, Toker L, et al. Atomic struc- ture of acetylcholinesterase from Torpedo californica: a prototypic acetylcholine- binding protein. Science. 1991;253(5022):872–879. 10.1126/science.1678899.

Abou-Donia MB. Organophosphorus ester-induced chronic neurotoxicity. Arch Environ Health . 2003;58(8):484–497. 10.3200/AEOH.58.8.484-497.

Delfino RT, Ribeiro TS, Figueroa-Villar JD. Organophosphorus compounds as chemical warfare agents: a review. J Braz Chem Soc . 2009;20(3):407–428. 10.1590/S0103-50532009000300003.

Harel M, Quinn DM, Nair HK, Silman I, Sussman JL. The X-ray Structure of a Transition State Analog Complex Reveals the Molecular Origins of the Catalytic Power and Substrate Specificity of Acetylcholinesterase. Journal of the American Chemical Society. 1996;118(10):2340–2346. 10.1021/ja952232h.

Nemukhin AV, Lushchekina SV, Bochenkova AV, Golubeva AA, Varfolomeev SD. Characterization of a complete cycle of acetylcholinesterase catalysis by ab initio QM/MM modeling. Journal of molecular modeling. 2008;14(5):409–416. 10.1007/s00894-008-0287-y.

Millard CB, Koellner G, Ordentlich A, Shafferman A, Silman I, Sussman JL. Reac- tion Products of Acetylcholinesterase and VX Reveal a Mobile Histidine in the Cat- alytic Triad. Journal of the American Chemical Society. 1999;121(42):9883–9884. 10.1021/ja992704i.

Barak D, Kaplan D, Ordentlich A, Ariel N, Velan B, Shafferman A. The aro- matic “trapping” of the catalytic histidine is essential for efficient catalysis in acetyl- cholinesterase. Biochemistry. 2002;41(26):8245–8252. 10.1021/bi020143t.

Kaplan D, Barak D, Ordentlich A, Kronman C, Velan B, Shafferman A. Is aromatic- ity essential for trapping the catalytic histidine 447 in human acetylcholinesterase? Biochemistry. 2004;43(11):3129–3136. 10.1021/bi030206n.

Colovic M, Krstić DZ, Lazarević-Pašti TD, Bondžić AM, Vasić VM. Acetyl- cholinesterase Inhibitors: Pharmacology and Toxicology. Curr Neuropharmacol. 2013;11(3):315–335. 10.2174/1570159X11311030006.

Park SE, Kim ND, Yoo YH. Acetylcholinesterase plays a pivotal role in apoptosome formation. Cancer Res. 2004;64(8):2652–2655. 10.1158/0008-5472.can-04-0649.

Unwin N. Nicotinic acetylcholine receptor and the structural basis of neuromus- cular transmission: insights from Torpedo postsynaptic membranes. Quarterly reviews of biophysics. 2013;46(4):283–322. 10.1017/S0033583513000061.

Tu A. Chemical and Biological Weapons and Terrorism. CRC Press; 2017. .

Jokanović M. Current understanding of the mechanisms involved in metabolic detoxification of warfare nerve agents. Toxicology letters. 2009;188(1):1–10. 10.1016/j.toxlet.2009.03.017.

Spradling KD, Lumley LA, Robison CL, Meyerhoff JL, Dillman JF. Transcrip- tional responses of the nerve agent-sensitive brain regions amygdala, hippocam- pus, piriform cortex, septum, and thalamus following exposure to the organophos- phonate anticholinesterase sarin. Journal of neuroinflammation. 2011;8(1):1–21. 10.1186/1742-2094-8-84.

Sox HC, Liverman CT, Fulco CE. Gulf War and Health: Volume 1: Depleted Ura- nium, Sarin, Pyridostigmine Bromide, and Vaccine. vol. 1. National Academies Press; 2000. .

Brown MA, Brix KA. Review of health consequences from high-, intermediate- and low-level exposure to organophosphorus nerve agents. J Appl Tox- icol . 1998;18(6):393–408. 10.1002/(sici)1099-1263(199811/12)18:6<393::aid- jat528>3.0.co;2-0.

Grob D. THE MANIFESTATIONS AND TREATMENT OF POISON- ING DUE TO NERVE GAS AND OTHER ORGANIC PHOSPHATE ANTI- CHOLINESTERASE COMPOUNDS. AMA Arch Intern Med. 1956;98(2):221–239. 10.1001/archinte.1956.00250260095010.

Karalliedde L, Wheeler H, Maclehose R, Murray V. Possible immediate and long- term health effects following exposure to chemical warfare agents. Public Health. 2000;114(4):238–248. 10.1038/sj.ph.1900659.

Westfall TC, Macarthur H, Westfal DP. Chapter 8: Neurotransmission: The Auto- nomic and Somatic Motor Nervous Systems. Access Medicine; 2011. p. 171–218.

Nishiwaki Y, Maekawa K, Ogawa Y, Asukai N, Minami M, Omae K, et al. Effects of sarin on the nervous system in rescue teamstaff members and police officers 3 years after the Tokyosubway sarin attack. Environ Health Perspect . 2001;109(11):1169– 1173. 10.1289/ehp.011091169.

Nakajima T, Sasaki K, Ozawa H, Sekjima Y, Morita H, Fukushima Y, et al. Urinary metabolites of sarin in a patient of the Matsumoto sarin incident. Arch Toxicol . 1998;72(9):601–603. 10.1007/s002040050549.

Abu-Qare A, Abou-Donia M. Sarin: health effects, metabolism, and methods of analysis. Food and Chemical Toxicology. 2002;40(10):1327–1333. 10.1016/s0278- 6915(02)00079-0.

Rengstorff RH. Accidental exposure to sarin: vision effects. vol. 56. Archives of Toxicology; 1985. p. 201–203. 10.1007/BF00333427.

Marrs TC, MD, DSc, FRCP, FRCPath. Toxicology of Organophosphate Nerve Agents. Wiley Online Library; 2007. p. 191–221. 10.1002/9780470060032.ch8.

Moylan-Jones R, Thomas DP. Cyclopentolate in treatment of sarin mio- sis. British journal of pharmacology. 1973;48(2):309–313. 10.1111/j.1476- 5381.1973.tb06917.x.

Ohbu S, Yamashina A, Takasu N, Yamaguchi T, Murai T, Nakano K, et al. Sarin poisoningonTokyosubway. SouthMedJ. 1997;90(6):587–593. 10.1097/00007611- 199706000-00002.

GreathouseB, Zahra F,Brady MF. AcetylcholinesteraseInhibitors Toxicity. National Library of Medicine; 2023. .

Thavaselvam D, Flora SS. Chemical and biological warfare agents. Biomarkers in Toxicology. 2014;p. 521–538. 0.1016/B978-0-12-404630-6.00030-0.

Sidell FR. Soman and sarin: clinical manifestations and treatment of acci- dental poisoning by organophosphates. Clinical toxicology. 1974;7(1):1–17. 10.3109/15563657408987971.

Namba T, Nolte CT, Jackrel J, Grob D. Poisoning due to organophosphate insecticides. Acute and chronic manifestations. Am J Med . 1971;50(4):475–492. 10.1016/0002-9343(71)90337-8.

Newmark J, MD J. Nerve Agents. The neurologist. 2007;13(1):20–32. 10.1097/01.nrl.0000252923.04894.53.

Carey JL, Dunn C, Gaspari RJ. Central respiratory failure during acute organophosphate poisoning. Respir Physiol Neurobiol . 2013;189(2):403–410. 10.1016/j.resp.2013.07.022.

Gundavarapu S, Zhuang J, Barrett EG, Xu F, Russell RG, Sopori ML. A critical role of acute bronchoconstriction in the mortality associated with high-dose sarin inhalation: effects of epinephrine and oxygen therapies. Toxicol Appl Pharmacol . 2014;274(2):200–208. 10.1016/j.taap.2013.11.007.

Brent J, Burkhart K, Dargan P, Hatten B, Megarbane B, Palmer R, et al. Critical care toxicology: diagnosis and management of the critically poisoned patient. Springer; 2017. .

Liu L, Zhao M, Yu X, Zang W. Pharmacological Modulation of Vagal Nerve Activity in Cardiovascular Diseases. Neuroscience Bulletin . 2019;35(1):156–166. 10.1007/s12264-018-0286-7.

Oberst FW, Ross RS, Christensen MK, Crook JW, Crethull P, Umland CW. Resus- citation of Dogs Poisoned by Inhalation of the Nerve Gas GB . Military Medicine. 1956;119(6):377–386. 10.1093/milmed/119.6.377.

Ludomirsky A, Klein HO, Sarelli P, Becker B, Hoffman S, Taitelman U, et al. Q- T prolongation and polymorphous (”torsade de pointes”) ventricular arrhyth- mias associated with organophosphorus insecticide poisoning. Am J Cardiol . 1982;49(7):1654–1658. 10.1016/0002-9149(82)90242-9.

Millerioux J, Cruz C, Bazire A, Polly V, Lallement G, Lefeuvre L, et al. Evalua- tion of in vitro tests to assess the efficacy of formulations as topical skin protectants against organophosphorus compounds. Toxicology in Vitro. 2009;23(1):127–133. 10.1016/j.tiv.2008.09.014.

Sivam SP, Hoskins B, Ho IK. An assessment of comparative acute toxicity of diisopropyl-fluorophosphate, tabun, sarin, and soman in relation to cholinergic and GABAergic enzyme activities in rats. Fundam Appl Toxicol . 1984;4(4):531–538.10.1016/0272-0590(84)90042-3.

Hefazi M, Maleki M, Mahmoudi M, Tabatabaee A, Mood MB. Delayed compli- cations of sulfur mustard poisoning in the skin and the immune system of Ira- nian veterans 16-20 years after exposure. Int J Dermatol . 2006;45(9):1025–1031. 10.1111/j.1365-4632.2006.03020.x.

Leikin JB, Thomas RG, Walter FG, Klein R, Meislin HW. A review of nerve agent exposure for the critical care physician. Crit Care Med . 2002;30(10):2346–2354. 10.1097/00003246-200210000-00026.

John H, Balszuweit F, Kehe K, Worek F, Thiermann H. CHAPTER 50 - Toxicoki- netics of Chemical Warfare Agents: Nerve Agents and Vesicants. Handbook of Tox- icology of Chemical Warfare Agents. 2009;p. 755–790. 10.1016/B978-012374484- 5.00050-X.

Kadar T, Fishbine E, Meshulam J, Sahar R, Amir A, Barness I. A topical skin pro- tectant against chemical warfare agents. Isr Med Assoc J . 2003;5(10):717–719. 14719467.

Nakamura T, Matsui M, Uchida K, Futatsugi A, Kusakawa S, Matsumoto N, et al. M(3) muscarinic acetylcholine receptor plays a critical role in parasympathetic con- trol of salivation in mice. J Physiol . 2004;558(Pt 2):561–575. 10.1113/jphys- iol.2004.064626.

Caulfield MP. Muscarinic receptors–characterization, coupling and function. Phar- macol Ther . 1993;58(3):319–379. 10.1016/0163-7258(93)90027-b.

Balalimoud M, Balali MK. Neurotoxic disorders of organophosphorus compounds and their managements. Arch Iran Med . 2008;11(1):65–89. 18154426.

Abend Y, Goland S, Evron E, Sthoeger ZM, Geltner D. Acute renal fail- ure complicating organophosphate intoxication. Ren Fail . 1994;16(3):415–417. 10.3109/08860229409044881.

Albright RK. Renal Involvement in Organophosphate Poisoning-Reply. JAMA. 1984;252(11):1408–1408. 10.1001/jama.1984.03350110014010.

Betrosian A, Balla M, Kafiri G, Kofinas G, Makri R, Kakouri A. Multiple sys- tems organ failure from organophosphate poisoning. J Toxicol Clin Toxicol . 1995;33(3):257–260. 10.3109/15563659509017994.

Wedin GP, Pennente CM, Sachdev SS. Renal involvement in organophosphate poi- soning. JAMA . 2017;252(11):1408–1408. 6471259.

Ballantyne B, Marrs TC. Severe fenitrothion poisoning complicated by rhabdomy- olysis in psychiatric patient. vol. 55. Toxicology; 2013. p. 129–132.

Futagami K, Hirano N, Iimori E, Motomura K, Ide M, Kataoka Y, et al. Severe fenitrothion poisoning complicated by rhabdomyolysis in psychiatric patient. Acta Med Okayama. 2001;55(2):129–132. 10.18926/AMO/32011.

Shilderman EB, Levy A. Transient and reversible nephrotoxicity of sarin in rats. J Appl Toxicol . 2007;27(2):189–194. 10.1002/jat.1204.

Senanayake N, Karalliedde L. Neurotoxic effects of organophosphorus insec- ticides. An intermediate syndrome. N Engl J Med . 2006;316(13):761–763.10.1056/NEJM198703263161301.

Karalliedde L, Baker D, Marrs TC. Organophosphate-Induced Intermediate Syn- drome. Toxicological Reviews. 2007;25(1):1–14. 10.2165/00139709-200625010- 00001.

Yang CC, Deng JF. Intermediate syndrome following organophosphate insecticide poisoning. J Chin Med Assoc . 2012;70(11):467–472. Available from: http://www. atsdr.cdc.gov/csem/csem.asp. 10.1016/S1726-4901(08)70043-1.

Heide E. Cholinesterase inhibitors: Including insecticides and chemical warfare nerve agents Part 5: The intermediate syndrome. Agency for toxic substances and disease registry; 2012. p. 1–153.

Moshiri M, Maragheh ED, Mood MB. Advances in toxicology and medical treat- ment of chemical warfare nerve agents. Daru. 2012;20(1):225–236. 10.1186/2008- 2231-20-81.

Rickett DL, Glenn JF, Beers ET. Central respiratory effects versus neuromuscular actions of nerve agents. Neurotoxicology . 1986;7(1):225–236. 3714123.

Emerick GL, Peccinini RG, d Oliveira GH. Organophosphorus-induced delayed neuropathy: a simple and efficient therapeutic strategy. Toxicol Lett . 2010;192(2):238–244. 10.1016/j.toxlet.2009.10.032. Epub 2009 Nov 13.

Jokanović M, Kosanović M, Brkić D, Vukomanović P. Organophosphate induced delayed polyneuropathy in man: an overview. Clin Neurol Neurosurg . 2011;113(1):7–10. 10.1016/j.clineuro.2010.08.015.

Mood MB, Saber H. Recent advances in the treatment of organophosphorous poi- sonings. Iran J Med Sci. 2012;27(2):74–91. 23115436.

Chen Y. Organophosphate-induced brain damage: Mechanisms, neuropsychiatric and neurological consequences, and potential therapeutic strategies. NeuroToxi- cology. 2012;33(3):391–400. 10.1016/j.neuro.2012.03.011.

Anderjaska VA, Figueiredo TH, Apland JP, Qashu F, Braga MFM. Primary brain targets of nerve agents: the role of the amygdala in comparison to the hippocampus. Neurotoxicology . 2009;30(5):772–776. 10.1016/j.neuro.2009.06.011. Epub 2009 Jul 8.

Kadar T, Cohen G, Sahar R, Alkalai D, Shapira S. Long-term study of brain lesions following soman, in comparison to DFP and metrazol poisoning. Hum Exp Toxicol

. 1992;11(6):517–523. 10.1177/096032719201100613.

Kadar T, Shapira S, Cohen G, Sahar R, Alkalay D, Raveh L. Sarin- induced neuropathology in rats. Hum Exp Toxicol . 1995;14(3):252–259. 10.1177/096032719501400304.

Morrison RS, Kinoshita Y, Johnson MD, Guo W, Garden GA. p53-Dependent Cell Death Signaling in Neurons. Neurochemical Research . 2003;28:15–27. 10.1023/A:1021687810103.

Gunay N, Kose B, Demiryurek S, Ceylan NO, Sari I, Demiryurek AT. Protective effects of Y-27632 on acute dichlorvos poisoning in rats. The American Journal of Emergency Medicine. 2010;28(3):268–274. 10.1016/j.ajem.2008.11.020.

Ferri KF, Kroemer G. Organelle-specific initiation of cell death pathways. Nat Cell Biol. 2001;3(11):255–263. 10.1038/ncb1101-e255.

Nicotera P, Leist M, Manzo L. Neuronal cell death: a demise with different shapes. Trends Pharmacol Sci . 1999;20(2):46–51. 10.1016/s0165-6147(99)01304-8.

Seto Y. Analytical and on-site detection methods for chemical warfareagents. Yaku- gaku Zasshi . 2006;126(12):1279–1299. 10.1248/yakushi.126.1279.

Murray GM. Detection and Screening of Chemicals Related to the Chem- ical Weapons Convention. Chemical Weapons Chemicals Analysis; 2006. 10.1002/9780470027318.a0403.pub2.

Marsillach J, Richter RJ, Kim JH, Stevens RC, MacCoss MJ, Tomazela D, et al. Biomarkers of organophosphorus (OP) exposures in humans. Neurotoxicology. 2011;32(5):656–660. 10.1016/j.neuro.2011.06.005.

Noort D, Benschop HP, Black RM. Biomonitoring of Exposure to Chemical Warfare Agents: A Review. Toxicology and Applied Pharmacology. 2002;184(2):116–126. 10.1006/taap.2002.9449.

Barak R, Ordentlich A, Barak D, Fischer M, Benschop HP, De Jong LPA, et al. Direct determination of the chemical composition of acetylcholinesterase phosphonyla- tion products utilizing electrospray-ionization mass spectrometry. FEBS Letters. 1997;407(3):347–352. 10.1016/S0014-5793(97)00375-X.

Fidder A, Noort D, de Jong LPA, Benschop HP, Hulst AG. N7-(2- hydroxyethylthioethyl)-guanine: a novel urinary metabolite following exposure to sulphur mustard. Archives of Toxicology . 1996;70:854–855. 10.1007/s002040050350.

Black RM, Read RW. Biological fate of sulphur mustard, 1,1’-thiobis(2- chloroethane): identification of beta-lyase metabolites and hydrolysis products in human urine. Xenobiotica . 1995;25(2):167–173. 10.3109/00498259509061842.

Black RM, Harrison JM, Read RW. The interaction of sarin and soman with plasma proteins: the identification of a novel phosphonylation site. Archives of Toxicology

. 1999;73:123–126. 10.1007/s002040050596.

Driskell WJ, Shih M, Needham LL, Barr DB. Quantitation of organophosphorus nerve agent metabolites in human urine using isotope dilution gas chromatography- tandem mass spectrometry. J Anal Toxicol . 2002;26(1):6–10. 10.1093/jat/26.1.6.

Mawhinney DB, Hamelin EI, Fraser R, Silva SS, Pavlopoulos AJ, Kobelski RJ. The determination of organophosphonate nerve agent metabolites in human urine by hydrophilic interaction liquid chromatography tandem mass spectrom- etry. J Chromatogr B Analyt Technol Biomed Life Sci . 2007;852(1-2):235–243. 10.1016/j.jchromb.2007.01.023.

Steiner WE, Harden CS, Hong F, Klopsch SJ, Hill HH, McHugh VM. Detec- tion of Aqueous Phase Chemical Warfare Agent Degradation Products by Negative Mode Ion Mobility Time-of-Flight Mass Spectrometry [IM(tof)MS]. Journal of the American Society for Mass Spectrometry. 2006;17(2):241–245. 10.1016/j.jasms.2005.11.004.

Gäb J, Melzer M, Kehe K, Richardt A, Blum MM. Quantification of hydrol- ysis of toxic organophosphates and organophosphonates by diisopropyl fluo- rophosphatase from Loligo vulgaris by in situ Fourier transform infrared spec- troscopy. Quantification of hydrolysis of toxic organophosphates and organophos- phonates by diisopropyl fluorophosphatase from Loligo vulgaris by in situ Fourier transform infrared spectroscopy Analytical biochemistry. 2009;385(2):187–193. 10.1016/j.ab.2008.11.012.

Suzuki O, Seno H, Suzuki KW, Ishii A. Situations of poisoning and analyti- cal toxicology in Japan. Forensic Science International. 2000;113(1-3):331–338. 10.1016/S0379-0738(00)00255-3.

D’Agostino PA, Hancock JR, Provost LR. Packed capillary liquid chromatography- electrospray mass spectrometry analysis of organophosphorus chemical warfare agents. JChromatogr A. 1999;840(2):289–294. 10.1016/s0021-9673(99)00264-2.

Minami M, Hui DM, Katsumata M, Inagaki H, Boulet CA. Method for the anal- ysis of the methylphosphonic acid metabolites of sarin and its ethanol-substituted analogue in urine as applied to the victims of the Tokyo sarin disaster. Journal of Chromatography B: Biomedical Sciences and Applications. 1997;695(2):237–244. 10.1016/S0378-4347(97)00203-X.

Creasy WR, Rodríguez AA, Stuff JR, Warren RW. Atomic emission detec- tion for the quantitation of trimethylsilyl derivatives of chemical-warfare-agent related compounds in environmental samples. Journal of Chromatography A. 2020;709(2):333–344. 10.1016/0021-9673(95)00451-R.

Senyurt EI, Schoenitz M, Dreizin EL. Rapid destruction of sarin surrogates by gas phase reactions with focus on diisopropyl methylphosphonate (DIMP). Defence Technology. 2021;17(3):703–714. 10.1016/j.dt.2020.06.008.

Krutzsch W, Myjer E, Trapp R. The Chemical Weapons Convention: A Commen- tary. vol. 57. Oxford University Press; 2014. 10.1093/law/9780199669110.001.0001.

Tucker JB. Chemical Weapons: Buried in the Backyard. Bulletin of the Atomic Scientists. 2001;57(5).

Paka VT, Chechko VA. Inspection of Bottom Sediments near Under- water Sources of Chemical Pollution. Oceanology . 2018;58:737–741. 10.1134/S0001437018050119.

Koniuszewski A. Land Degradation From Military Toxics: Public Health Con- siderations and Possible Solution Paths. Land Restoration. 2016;p. 119–131. 10.1016/B978-0-12-801231-4.00013-6.

Amato E, Alcaro L, Corsi I, Torre CD, Farchi C, Focardi S, et al. An integrated ecotoxicological approach to assess the effects of pollutants released by unexploded chemical ordnance dumped in the southern Adriatic (Mediterranean Sea). Marine Biology . 2006;149:17–23. 10.1007/s00227-005-0216-x.

Zegers EJP, Fisher EM. Gas-Phase Pyrolysis of Diethyl Methylphospho- nate. Combustion Science and Technology . 1996;116-117(1-6):69–89. 10.1080/00102209608935544.

Wilson C, Cooper NJ, Briggs ME, Cooper AI, Adams DJ. Investigating the break- down of the nerve agent simulant methyl paraoxon and chemical warfare agents GB and VX using nitrogen containing bases. Organic & Biomolecular Chemistry . 2018;16:9285–9291. 10.1039/c8ob02475h.

Nawała J, Jóźwik P, Popiel S. Thermal and catalytic methods used for destruction of chemical warfare agents. International Journal of Environmental Science and Technology. 2019;16:3899–3912. 10.1007/s13762-019-02370-y.

Trubitsyn DA, Vorontsov AV. Experimental Study of Dimethyl Methylphospho- nate Decomposition over Anatase TiO2. The Journal of Physical Chemistry B. 2005;109(46). 10.1021/jp053793q.

Zegers EJP, Fisher EM. Gas-Phase Pyrolysis of Diisopropyl Methylphosphonate. Combustion and Flame. 1998;115(1-2). 10.1016/S0010-2180(98)00003-0.

Council NR. Recommendations for the Disposal of Chemical Agents and Muni- tions. National Academies Press; 1994. .

Flamm KJ, Kwan Q, Nulty WB. Chemical-Stockpile Disposal Program. Chemical agent and munition disposal. Summary of the US Army’s experience. Final report, July 1972-August 1987; 1987.

Council NR. Incineration Processes and Environmental Releases, in Waste Incin- eration & Public Health. National Academies Press (US); 2000. .

Thiermann H, Aurbek N, Worek F. Treatment of nerve agent poisoning. Issues in Toxicology. Domestic Preparedness; 2016. p. 1–42. 10.1039/9781782628071-00001.

Hrvat NM, Kovarik Z. Counteracting poisoning with chemical warfare nerve agents. Arh Hig Rada Toksikol. 2020;71(4):266–284. 10.2478/aiht-2020-71-3459.

Ground AP. Medical Management of Chemical Casualties Handbook; 2000. .

Marshall SM, Fedele P, Lake WA. Guidelines for Incident Commander’s Use of Firefighter Protective Ensemble (FFPE) with Self-Contained Breathing Appara- tus (SCBA) for Rescue Operations During a Terrorist Chemical Agent Incident. research gate. 2001;.

Abraham RB, Weinbroum AA. Resuscitative challenges in nerve agent poisoning. Eur J Emerg Med . 2003;10(3):169–175. 10.1097/00063110-200309000-00003.

Tokuda Y, Kikuchi M, Takahashi O, Stein GH. Prehospital manage- ment of sarin nerve gas terrorism in urban settings: 10 years of progress after the Tokyo subway sarin attack. Resuscitation . 2006;28(2):193–202. 10.1016/j.resuscitation.2005.05.023.

Caisberger F,Pejchal J,MisikJ,Kassa J,ValisM, KucaK. Thebenefit ofcombinations of oximes for the ability of antidotal treatment to counteract sarin-induced brain damageinrats. BMC Pharmacologyand Toxicology. 2018;19(35). 10.1186/s40360- 018-0227-0.

Shih TM, Rowland TC, McDonough JH. Anticonvulsants for nerve agent-induced seizures: The influence of the therapeutic dose of atropine. J Pharmacol Exp Ther . 1983;320(1):154–161. 10.1124/jpet.106.111252. Epub 2006 Oct2.

Lenhart MK. medical aspects of chemical warfare. Office of The Surgeon General Department of the Army, United States of America; 2008. p. 155–219.

Nair VP, Hunter JM. Anticholinesterases and anticholinergic drugs. Con- tinuing Education in Anaesthesia Critical Care & Pain. 2004;4(5):164–168. 10.1093/bjaceaccp/mkh045.

Sokolovsky M, Gurwitz D, Kloog J. Biochemical characterization of the muscarinic receptors. Adv Enzymol Relat Areas Mol Biol. 1983;55:137–196.

Hurst G. Medical management of chemical casualties handbook. Government Printing Office; 2015. .

Stoner HB, Barnes JM, Duff JI. Studies on the toxicity of alkyl tin compounds. Br J Pharmacol Chemother. 1955;10(1):16–25. 10.1111/j.1476-5381.1955.tb00053.x.

Geoghegan J, Tong JL. Chemical warfare agents; 2006. 10.1093/bjaceaccp/mkl052.

WILSON IB, GINSBURG S. Reactivation of acetylcholinesterase inhibited by alkylphosphates. Arch Biochem Biophys . 1955;45(2):569–571. 10.1016/0003- 9861(55)90075-8.

Vickers NJ. Animal Communication: When I’m Calling You, Will You Answer Too? Current Biology. 2017;27(14):R713–R715. 10.1016/j.cub.2017.05.064.

Sidell FR. Quantification of hydrolysis of toxic organophosphates and organophos- phonates by diisopropyl fluorophosphatase from Loligo vulgaris by in situ Fourier transform infrared spectroscopy. NCJRS Virtual Library; 1997.

Jr JHM, Shih TM. Neuropharmacological mechanisms of nerve agent-induced seizure and neuropathology. Neurosci Biobehav Rev . 1997;21(5):559–579. 10.1016/s0149-7634(96)00050-4.

Tattersall J. Seizure activity post organophosphate exposure. Front Biosci (Land- mark Ed) . 2009;14(1):3688–3711. 10.2741/3481.