LI Medved’s Research Centre of Preventive Toxicology, Food and Chemical Safety, Ministry of Health, Ukraine (State Enterprise), Kyiv, Ukraine

Abstract. The hostilities on the territory of our state are accompanied by the destruction of the infrastructure of cities and industrial enterprises, which critically increased the risk of toxic gas emissions (including chlorine) and the occurrence of mass poisoning.

Aim. To summarize modern knowledge about the molecular mechanisms of chlorine gas toxicity, clinical biomarkers of the toxic process, and modern treatment strategy.

Material and Methods. Information data of the Ministry of Health of Ukraine, the State Emergency Service of Ukraine (SES of Ukraine), the American Health Service (CDC), the American Association of Poison Control Centers (AAPCC), materials of scientific libraries PubMed, Medline, Elsevier. Content analysis, systematic and comparative analysis were used.

Results and their Discussion. Chemical accidents with the release of chlorine and the occurrence of mass poisonings are registered in various countries. Until now, the mechanisms of the toxic action of chlorine remain completely unstudied, especially at the level of intracellular structures. The results of recent studies demonstrate that irritant and irritant-necrotic effects are not directly caused by chlorine molecules, but by their hydration products – hydrochloric and hypochlorous acids. These acids directly provide a high production of reactive superoxides and nitrogen oxidants, which form oxidative stress in the epithelial cells of the mucous membrane of the bronchopulmonary structure in deeper tissues. The destruction of the cells of the ciliated epithelium occurs, the functioning of ion channels is disturbed and the permeability of cell membranes increases, inflammatory reactions develop: hyperemia, edema, bronchospasm, and surfactant destruction. These processes are facilitated by a massive release of biologically active substances – proinflammatory cytokines – IL-1β, IL-6, IL-18, nuclear factor (NF-KB), 8-isoprostane and tumor necrosis factor (TNF-β) – one of the main biomarkers of oxidative stress. These processes cause: damage to intracellular structures – mitochondria; imbalance in the functioning of the signaling molecule cAMP and disruption of autophagy processes; a decrease in the energy potential of cells with the development of endothelial dysfunction, a violation of the vascular mechanisms of NO homeostasis, both in the cells of the respiratory tract and outside the lungs, which contributes to anatomical damage and impaired function of the organs of the cardiovascular system and kidneys.

Conclusion. The mechanism of the toxic action of chlorine at the level of intracellular structures undoubtedly requires further study.

Another relevant direction of research may be the search for new sensitive biomarkers of the toxic process, which will allow us to objectively assess the severity of poisoning and increase the effectiveness of the rather complex process of treating patients, in the absence of antidotes.

Key Words: chlorine gas, toxicity, mechanism of action, acute poisoning, treatment of poisoning.

СПИСОК ВИКОРИСТАНИХ ДЖЕРЕЛ/REFERENCES

1. Звіт про основні результати діяльності Державної служби України з надзвичайних ситуацій у 2018 році. [Електрон. ресурс]. – Режим доступу: URL: http://www.dsns.gov.ua/files/2018/1/26/Zvit%202018(КМУ).pdf.

2. Chlorine. PubChem. The National Centerfor Biotechnology Information. URL: https://pubchem.ncbi.nlm.nih.gov/compound/Chlorine.

3. American Association of Poison Control Centers (AAPCC). [Electron. resource]. Access mode: URL: https://www.aapcc.org/.

4. “29 people taken to hospital after chlorine gas released at London’s Olympic park”. The Guardian. [Electron. resource]. Access mode: URL:https://www.theguardian.com/uk-news/2022/mar/23/people-suffer-breathing-difficultiesafter-reported-release-of-gas-at-london-olympic-park.

5. Mohan A, Kumar SN, Rao MH, et al. Acute accidental exposure to chlorine gas: clinical presentation, pulmonary functions and outcomes. Indian J Chest Dis Allied Sci. 2010 JulSep;52(3):149-52.

6. Moulick ND, Banavali S,Abhyankar AD, et al. Acute accidental exposure to chlorine fumes - a study of 82 cases. Indian J Chest Dis Allied Sci. 1992 Apr-Jun;34(2):85-9.

7. Новашов А. «Смерть ходила поряд». 36 років тому в Кемерові внаслідок викиду хлору загинули десятки людей». Репортаж від 15.11.2019. Радіо Свобода. Рубрика: Північ. Реалії. [Електрон. ресурс]. – Режим доступу: URL: https://www.sibreal.org/a/30264627.html.

8. Handbook of Toxicology of Chemical Warfare Agents. First Edition, Ramesh C. Gupta, Editor, Academic Press, Elsevier, San Diego, CA, USA, 2009. Hardback, 1147 pages. ISBN 978-0-12-374484-5.9. Romano JA. Jr, Lukey BJ, Salem H. Chemical Warfare Agents. Chemistry, Pharmacology, Toxicology, and Therapeutics. – NY: CRC Press, 2007. - 723 p.

10. Convention on the prohibition of the development, production, stockpiling, and use of chemical weapons and on their destruction. – The Hague: Technical secretariat of the organization for the prohibition of chemical weapons, 2005. – 165p.

11. 600 жителів Іраку постраждали через хімічну атаку ІДІЛ. Ракети з хімікатами випущені по невеликому містечку Таза на півночі країни. Газета «Лівий берег». [Електрон. ресурс]. – Режим доступу: URL: https://lb.ua/world/2016/03/12/330075_600_zhiteley_iraka_postradali_izza.html.

12. В Іраку через витік хлору постраждали десятки людей. Інтернет видання «РБК-Україна». [Електрон. ресурс]. – Режим доступу: URL: https://www.rbc.ua/ukr/news/irake-utechki-hlora-postradali-desyatki-lyudey-1552715106.html.

13. Організація із заборони хімічної зброї. Офіційний сайт. [Електрон. ресурс]. – Режим доступу: URL: https://www.opcw.org/about-us/member-states/syria.

14. Morim A, Guldner GT. Chlorine Gas Toxicity. 2021 Jul 25. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan. PMID:30725898.

15. Das R, Blanc PD. Chlorine gas exposure and the lung: a review. Toxicol Ind Health. 1993 May-Jun. 9(3):439-55.

16. The Chemistry of Chlorine, Bromine, Iodine and Astatine: Pergamon Texts in Inorganic Chemistry, Volume 7. ByA. J. Downsand C.J. Adams. PUBLISHER:Elsevier Science. 481 pages. ISBN: 9781483158327.

17. Chlorine. PubChem. The National Center for Biotechnology Information. URL: https://pubchem.ncbi.nlm.nih.gov/compound/Chlorine.

18. Squadrito GL,Postlethwait EM,Matalon S. Elucidating mechanisms of chlorine toxicity: reaction kinetics, thermodynamics, and physiological implications. Am J Physiol Lung Cell Mol Physiol. 2010 Sep;299(3):L289-300. doi:10.1152/ajplung.00077.2010.

19. Yadav AK, Bracher A, Doran SF, et al. Mechanisms and modification of chlorine-induced lung injury in animals. Proc Am Thorac Soc. 2010 Jul;7(4):278-83.doi:10.1513/pats.201001-009SM.

20. Jurkuvenaite A, Benavides GA, Komarova S, et al. Upregulation of autophagy decreases chlorine-induced mitochondrial injury and lung inflammation. Free Radic Biol Med. 2015 Aug;85:83-94.doi:10.1016/j.freeradbiomed.2015.03.039.

21. Honavar J, Samal AA, Bradley KM, et al. Chlorine gas exposure causes systemic endothelial dysfunction by inhibiting endothelial nitric oxide synthase-dependent signaling. Am J Respir Cell Mol Biol. 2011 Aug;45(2):419-25. doi:10.1165/rcmb.2010-0151OC.

22. Samal A, Honovar J, Roger C, et al. Potential for chlorine gasinduced injury in the extrapulmonary vasculature. Proc Am Thorac Soc. 2010 Jul; 7(4):290-3. doi:10.1513/pats.201001-006SM.

23. Carlisle M, Lam A, Svendsen ER, et al. Chlorine-induced cardiopulmonary injury. Ann N Y Acad Sci.2016 Jun;1374(1):159-67.doi: 10.1111/nyas.13091.

24. Wigenstam E, Elfsmark L, Koch B, et al. Acute respiratory changes and pulmonary inflammation involving a pathway of TGF-β1 induction in a rat model of chlorine-induced lung injury. Toxicol Appl Pharmacol. 2016 Oct 15;309:44-54.doi:10.1016/j.taap.2016.08.027.

25. Elfsmark L, Ågren L, Akfur C, et al. 8-Isoprostane is an early biomarker for oxidative stress in chlorine-induced acute lung injury. Toxicol Lett. 2018 Jan 5;282:1-7. doi:10.1016/j.toxlet.2017.10.007.

26. Ford DA, Honavar J, Albert CJ, et al. Formation of chlorinated lipids post-chlorine gas exposure. J Lipid Res. 2016 Aug;57(8):1529-40. doi:10.1194/jlr.M069005.

27. Hoyle GW. Mitigation of chlorine lung injury by increasing cyclic AMPlevels. Proc Am Thorac Soc. 2010 Jul;7(4):284-9.doi:10.1513/pats.201001-002SM.

28. White CW,Martin JG. Chlorine gas inhalation: human clinical evidence of toxicity and experience in animal models. Proc Am Thorac Soc. 2010 Jul;7(4):257-63.doi:10.1513/pats.201001-008SM.

29. Tuong AH, Despréaux Th, Loeb Th., et al. Emergency management of chlorine gas exposure – a systematic review. Volume 57, 2019 -Issue 2.https://doi.org/10.1080/15563650.2018.1519193.

30. Zellner T, Eyer F. Choking agents and chlorine gas - History, pathophysiology, clinical effects and treatment. Toxicol Lett. 2020 Mar 1;320:73-79. doi:10.1016/j.toxlet.2019.12.005.

31. Govier P,Coulson JM.Civilian exposure to chlorine gas: A systematic review. Toxicol Lett. 2018 Sep 1;293:249-252. doi:10.1016/j.toxlet.2018.01.014.

32. Khilji MF. Clinical Presentations and Outcomes of Industrial Chlorine Gas Exposure Incidence in Oman. Prehosp Disaster Med. 2021 Feb;36(1):18-24. doi:10.1017/S1049023X20001375.

33. Chen TF, Wang CH, Hermes GL, et al. Chlorine inhalation injury with acute respiratory distress syndrome treated by extra-corporeal membrane oxygenation system. Glob J Medical Clin Case Rep. 2020 7(1):005-009. doi:10.17352/2455-5282.000079.

34. Costa LG, Hodgson Е. Current Protocols in Toxicology. – NY: John Wiley & Sons, 2005. – 2759 p.

35. Hoffman RS, Nelson LS, Goldfrank LR. et al. Goldfrank’s Manual of Toxicological Emergencies. – NY: McGraw-Hil, 2007. – 1126 p.

36. Achanta S, Jordt S-E. Toxic effects of chlorine gas and potential treatments: a literature review. Toxicol Mech Methods. 2021 May;31(4):244-256. doi:10.1080/15376516.2019.1669244.

37. Cevik Y,Onay M,Akmaz I, et al. Mass casualties from acute inhalation of chlorine gas. South Med J. 2009 Dec; 102(12):1209-13. doi:10.1097/SMJ.0b013e3181bfdc67.

38. Culley JM, Richter J, Donevant S, et al. Validating signs and symptoms from an actual mass casualty incident to characterize an irritant gas syndrome agent (IGSA) Exposure: a first step in the development of a Novel IGSA Triage Algorithm. J EmergNurs. 2017 Jul; 43(4):333-338. doi:10.1016/j.jen.2016.11.001.

Стаття надійшла до редакції 07.06.2022 / The article was received June 07, 2022.