Immunological and Hematological Complications of Sulfur Mustard Poisoning

  • Bamdad Riahi-Zanjani
  • Mahmoud MahmoudiEmail author


Sulfur mustard (SM) is an incapacitating chemical warfare agent, which has been widely employed in particular regions. The short and long term biological effects of SM have been clinically and basically studied. Sulfur mustard has been demonstrated to induce a broad continuum of pathological effects in affected individuals. In addition to skin, lung, eyes and gastrointestinal manifestations, SM has been shown to induce hematological and immunological complications. The acute and chronic immune-hematological outcomes of individuals exposed to SM are reviewed here. It seems that the dysfunctions of the immune system in these patients may contribute to the increased incidence of a myriad of diseases that have been documented in SM exposed veterans, including cancers. As the toxic effects of SM are progressive and the clinical outcome of veterans can worsen over time, developing additional therapeutic strategies is needed. Some of these strategies might be based on immunopotentiating interventions.


Sulfur mustard Immuno-hematological complications Veterans 


  1. Adelipour M, Imani Fooladi AA, Yazdani S, Vahedi E, Ghanei M, Nourani MR (2011) Smad molecules expression pattern in human bronchial airway induced by sulfur mustard. Iran J Allergy Asthma Immunol 10:147–154PubMedGoogle Scholar
  2. Attaran D, Lari SM, Towhidi M, Marallu HG, Ayatollahi H, Khajehdaluee M, Ghanei M, Basiri R (2010) Interleukin-6 and airflow limitation in chemical warfare patients with chronic obstructive pulmonary disease. Int J Chron Obstruct Pulmon Dis 5:335–340PubMedPubMedCentralGoogle Scholar
  3. Bahar K, Deihimi I, Elyasi H (1988) Study of the components of the immune system in chemical warfare victims with Sulfur mustard. The first congress in chemical warfare in Iran, Mashhad, pp 63–71.Google Scholar
  4. Balali-Mood M, Afshari R, Zojaji R, Kahrom H, Kamrani M, Attaran D, Mousavi SR, Zare GA (2011) Delayed toxic effects of sulfur mustard on respiratory tract of Iranian veterans. Hum Exp Toxicol 30:1141–1149CrossRefPubMedGoogle Scholar
  5. Balali-Mood M, Hefazi M (2005) The pharmacology, toxicology, and medical treatment of sulphur mustard poisoning. Fundam Clin Pharmacol 19:297–315CrossRefPubMedGoogle Scholar
  6. Balali-Mood M, Hefazi M (2006) Comparison of early and late toxic effects of sulfur mustard in Iranian veterans. Basic Clin Pharmacol Toxicol 99:273–282CrossRefPubMedGoogle Scholar
  7. Balali-Mood M, Hefazi M, Mahmoudi M, Jalali E, Attaran D, Maleki M, Razavi ME, Zare G, Tabatabaee A, Jaafari MR (2005) Long-term complications of sulphur mustard poisoning in severely intoxicated Iranian veterans. Fundam Clin Pharmacol 19:713–721CrossRefPubMedGoogle Scholar
  8. Balali-Mood M, Mousavi S, Balali-Mood B (2008) Chronic health effects of sulphur mustard exposure with special reference to Iranian veterans. Emerg Health Threats J 1:e7PubMedPubMedCentralGoogle Scholar
  9. Balali-Mood M, Tabarestani M, Farhoodi M, Panjvan IF (1991) Study of clinical and laboratory findings of sulfur mustard in 329 war victims. Med J Islamic Republic Iran 34:7–15Google Scholar
  10. Blank JA, Joiner RL, Houchens DP, Dill GS, Hobson DW (1991) Comparative immunotoxicity of 2,2’-dichlorodiethyl sulfide and cyclophosphamide: evaluation of L1210 tumor cell resistance, cell-mediated immunity, and humoral immunity. Int J Immunopharmacol 13:251–257CrossRefPubMedGoogle Scholar
  11. Boxer LA, Harris RE, Baehner RL (1979) Regulation of membrane peroxidation in health and disease. Pediatrics 64:713–718PubMedGoogle Scholar
  12. Chew BP, Park JS (2004) Carotenoid action on the immune response. J Nutr 134:257S–261SPubMedGoogle Scholar
  13. Coutelier JP, Lison D, Simon O, Willems J (1991) Effect of sulfur mustard on murine lymphocytes. Toxicol Lett 58:143–148CrossRefPubMedGoogle Scholar
  14. Delves PJ, Martin SJ, Burton DR, Roitt IM (2011) Roitt’s essential immunology. John Wiley & Sons, New YorkGoogle Scholar
  15. Ghanei M (2004) Delayed haematological complications of mustard gas. J Appl Toxicol 24:493–495CrossRefPubMedGoogle Scholar
  16. Ghanei M, Harandi AA (2011) Molecular and cellular mechanism of lung injuries due to exposure to sulfur mustard: a review. Inhal Toxicol 23:363–371CrossRefPubMedGoogle Scholar
  17. Ghasemi H, Ghazanfari T, Yaraee R, Pourfarzam S, Soroush MR, Faghihzadeh S, Babaei M, Naghizadeh MM, Mohammad Hassan Z (2012) Evaluation of the tear and serum levels of IL-8 in sulfur mustard intoxicated patients 20 years after exposure. Cutan Ocul Toxicol 31:132–137CrossRefPubMedGoogle Scholar
  18. Ghazanfari T, Kariminia A, Yaraee R, Faghihzadeh S, Ardestani SK, Ebtekar M, Mostafaie A, Foroutan A, Rezaei A, Shams J, Mahmoudi M, Vaez-Mahdavi MR, Soroush MR, Jalali-Nadoushan M, Moaiedmohseni S, Ajdary S, Darabi H, Naghizadeh MM, Kazemi H, Hassan ZM (2013) Long term impact of sulfur mustard exposure on peripheral blood mononuclear subpopulations–Sardasht-Iran Cohort Study (SICS). Int Immunopharmacol 17:931–935CrossRefPubMedGoogle Scholar
  19. Ghotbi L, Hassan Z (2002) The immunostatus of natural killer cells in people exposed to sulfur mustard. Int Immunopharmacol 2:981–985CrossRefPubMedGoogle Scholar
  20. Gold MB, Scharf BA (1995) Hematological profile of the euthymic hairless guinea pig following sulfur mustard vesicant exposure. J Appl Toxicol 15:433–438CrossRefPubMedGoogle Scholar
  21. Hambrook JL, Howells DJ, Schock C (1993) Biological fate of sulphur mustard (1,1’-thiobis(2-chloroethane)): uptake, distribution and retention of 35S in skin and in blood after cutaneous application of 35S-sulphur mustard in rat and comparison with human blood in vitro. Xenobiotica 23:537–561CrossRefPubMedGoogle Scholar
  22. Han S, Espinoza LA, Liao H, Boulares AH, Smulson ME (2004) Protection by antioxidants against toxicity and apoptosis induced by the sulphur mustard analog 2-chloroethylethyl sulphide (CEES) in Jurkat T cells and normal human lymphocytes. Br J Pharmacol 141:795–802CrossRefPubMedPubMedCentralGoogle Scholar
  23. Hassan ZM, Ebtekar M (2001) Modeling for immunosupression by sulfur mustard. Int Immunopharmacol 1:605–610CrossRefPubMedGoogle Scholar
  24. Hassan ZM, Ebtekar M, Ghanei M, Taghikhani M, Noori Daloii MR, Ghazanfari T (2006) Immunobiological consequences of sulfur mustard contamination. Iran J Allergy Asthma Immunol 5:101–108PubMedGoogle Scholar
  25. Hefazi M, Maleki M, Mahmoudi M, Tabatabaee A, Balali-Mood M (2006) Delayed complications of sulfur mustard poisoning in the skin and the immune system of Iranian veterans 16–20 years after exposure. Int J Dermatol 45:1025–1031CrossRefPubMedGoogle Scholar
  26. Heinrich A, Balszuweit F, Thiermann H, Kehe K (2009) Rapid simultaneous determination of apoptosis, necrosis, and viability in sulfur mustard exposed HaCaT cell cultures. Toxicol Lett 191:260–267CrossRefPubMedGoogle Scholar
  27. Hektoen L, Corper HC (1920) The effect of mustard gas (dichloroethylsulphid[e]) on antibody formation. J Infect Dis 28:279–285Google Scholar
  28. Hughes DA (1999) Effects of dietary antioxidants on the immune function of middle-aged adults. Proc Nutr Soc 58:79–84CrossRefPubMedGoogle Scholar
  29. Keramati MR, Balali-Mood M, Mousavi SR, Sadeghi M, Riahi-Zanjani B (2013) Biochemical and hematological findings of Khorasan veterans 23 years after sulfur mustard exposure. J Res Med Sci 18:855–859PubMedPubMedCentralGoogle Scholar
  30. Keyhani A (1988) Study of cellular immunity in contaminated Iranian veterans with sulfur mustard. The first congress in chemical warfare in Iran, Mashhad, pp 326–334Google Scholar
  31. Keyhani A, Eslami MB, Razavimanesh H (2007) The short-term effect of mustard gas on the serum immunoglobulin levels. Iran J Allergy Asthma Immunol 6:15–19PubMedGoogle Scholar
  32. Kindred JE (1947) Histologic changes occurring in the hemopoietic organs of albino rats after single injections of 2-chloroethyl vesicants; a quantitative study. Arch Pathol (Chic) 43:253–295Google Scholar
  33. Kindred JE (1949) The blood cells and the hemopoietic and other organs of dogs giver intravenous injections of 2-chloroethyl vesicants. Arch Pathol (Chic) 47:378–398Google Scholar
  34. Klaassen C (2013) Casarett & Doull’s toxicology: the basic science of poisons, 8th edn. McGraw-Hill Education, New YorkGoogle Scholar
  35. Krumbhaar EB, Krumbhaar HD (1919) The blood and bone marrow in yelloe cross gas (mustard gas) poisoning: changes produced in the bone marrow of fatal cases*. J Med Res 40:497–508 3PubMedPubMedCentralGoogle Scholar
  36. Mahmoudi M, Hefazi M, Rastin M, Balali-Mood M (2005) Long-term hematological and immunological complications of sulfur mustard poisoning in Iranian veterans. Int Immunopharmacol 5:1479–1485CrossRefPubMedGoogle Scholar
  37. Mehrani H, Ghanei M, Aslani J, Tabatabaei Z (2011) Plasma proteomic profile of sulfur mustard exposed lung diseases patients using 2-dimensional gel electrophoresis. Clin Proteomics 8:2CrossRefPubMedPubMedCentralGoogle Scholar
  38. Meydani SN, Wu D, Santos MS, Hayek MG (1995) Antioxidants and immune response in aged persons: overview of present evidence. Am J Clin Nutr 62:1462S–1476SPubMedGoogle Scholar
  39. Mohammadhoseiniakbari H, Ghanei M, Eajazi A, Mohammadi Z, Daftari Besheli L (2008) Delayed effects of sulfur mustard poisoning on CD4+ and CD8+ lymphocytes in Iranian veterans 25 years after exposure. Med Sci Monit 14:CR580–CR583PubMedGoogle Scholar
  40. Naghii MR (2002) Sulfur mustard intoxication, oxidative stress, and antioxidants. Mil Med 167:573–575PubMedGoogle Scholar
  41. Namazi S, Niknahad H, Razmkhah H (2009) Long-term complications of sulphur mustard poisoning in intoxicated Iranian veterans. J Med Toxicol 5:191–195CrossRefPubMedPubMedCentralGoogle Scholar
  42. Pant SC, Vijayaraghavan R, Kannan GM, Ganesan K (2000) Sulphur mustard induced oxidative stress and its prevention by sodium 2,3-dimercapto propane sulphonic acid (DMPS) in mice. Biomed Environ Sci 13:225–232PubMedGoogle Scholar
  43. Pechura CM, Rall DP (1993) Veterans at risk: the health effects of mustard gas and lewisite. National Academies Press (US), Washington (DC)Google Scholar
  44. Pourfarzam S, Ghazanfari T, Yaraee R, Ghasemi H, Hassan ZM, Faghihzadeh S, Ardestani SK, Kariminia A, Fallahi F, Soroush MR, Merasizadeh J, Mahlojirad M, Naghizadeh MM, Ghanei M (2009) Serum levels of IL-8 and IL-6 in the long term pulmonary complications induced by sulfur mustard: Sardasht-Iran Cohort Study. Int Immunopharmacol 9:1482–1488CrossRefPubMedGoogle Scholar
  45. Razavimanesh A (1988) Evaluation of immune system on patient exposed to sulfur mustard. University of Tehran Press, TehranGoogle Scholar
  46. Riahi B, Rafatpanah H, Mahmoudi M, Memar B, Fakhr A, Tabasi N, Karimi G (2011) Evaluation of suppressive effects of paraquat on innate immunity in Balb/c mice. J Immunotoxicol 8:39–45CrossRefPubMedGoogle Scholar
  47. Riahi-Zanjani B, Balali-Mood M, Mousavi SR, Karimi G, Sadeghi M, Shirmast E, Mahmoudi M (2014) Serum cytokine profiles of Khorasan veterans 23 years after sulfur mustard exposure. Cytokine 70:161–164Google Scholar
  48. Rothlein R, Dustin ML, Marlin SD, Springer TA (1986) A human intercellular adhesion molecule (ICAM-1) distinct from LFA-1. J Immunol 137:1270–1274PubMedGoogle Scholar
  49. Rowell M, Kehe K, Balszuweit F, Thiermann H (2009) The chronic effects of sulfur mustard exposure. Toxicology 263:9–11CrossRefPubMedGoogle Scholar
  50. Shabestari MM, Jabbari F, Gohari B, Moazen N, Azizi H, Moghiman T, Ibrahimzadeh S, Amirabadi A (2011) Coronary artery angiographic changes in veterans poisoned by mustard gas. Cardiology 119:208–213CrossRefPubMedGoogle Scholar
  51. Shaker Z, Hassan ZM, Sohrabpoor H, Mosaffa N (2003) The immunostatus of T helper and T cytotoxic cells in the patients ten years after exposure to sulfur mustard. Immunopharmacol Immunotoxicol 25:423–430CrossRefPubMedGoogle Scholar
  52. Shohrati M, Ghanei M, Shamspour N, Babaei F, Abadi MN, Jafari M, Harandi AA (2010) Glutathione and malondialdehyde levels in late pulmonary complications of sulfur mustard intoxication. Lung 188:77–83CrossRefPubMedGoogle Scholar
  53. Sims JE, Smith DE (2010) The IL-1 family: regulators of immunity. Nat Rev Immunol 10:89–102CrossRefPubMedGoogle Scholar
  54. Sohrabpour H (1984) Clinical manifestations of chemical agents on Iranian combatants during Iran-Iraq conflict. Arch Belg (Suppl):291–7Google Scholar
  55. Somani S (1992) Chemical warfare agents. Jovanovich Publishers, New YorkGoogle Scholar
  56. Spurr CL (1947) Influence of nitrogen mustards on the antibody response. Proc Soc Exp Biol Med 64:259–261CrossRefPubMedGoogle Scholar
  57. Tabarestani M, Balau-Mood M, Farhoodi M (1990) Hematological findings of sulphur mustard poisoning in Iranian combatants. Med J Islamic Republic Iran 4:185–190Google Scholar
  58. Tabarestani M, Farhoudi M, Balali-Mood M (1988) Stem cell and erythroid precursors disorders in three patients with sulfur mustard poisoning. Proceedings of the first international medical congress on Chemical Warfare Agents in IranGoogle Scholar
  59. Victor VM, Rocha M, De la Fuente M (2003) Regulation of macrophage function by the antioxidant N-acetylcysteine in mouse-oxidative stress by endotoxin. Int Immunopharmacol 3:97–106CrossRefPubMedGoogle Scholar
  60. Victor VM, Rocha M, De la Fuente M (2004) Immune cells: free radicals and antioxidants in sepsis. Int Immunopharmacol 4:327–347CrossRefPubMedGoogle Scholar
  61. Willems J (1989) Clinical management of mustard gas casualties. Ann Med Mil Belg 3:1–61Google Scholar
  62. Yaraee R, Ghazanfari T, Ebtekar M, Ardestani SK, Rezaei A, Kariminia A, Faghihzadeh S, Mostafaie A, Vaez-Mahdavi MR, Mahmoudi M, Naghizadeh MM, Soroush MR, Hassan ZM (2009) Alterations in serum levels of inflammatory cytokines (TNF, IL-1alpha, IL-1beta and IL-1Ra) 20 years after sulfur mustard exposure: Sardasht-Iran cohort study. Int Immunopharmacol 9:1466–1470CrossRefPubMedGoogle Scholar
  63. Zakery Neia M (1995) Statistical data of malignances of the people exposed to sulfur mustard. Proceedings of the 5th congress of long-term consequences of chemical warfare, Iran, pp 32–34Google Scholar
  64. Zandiyeh T (1991) Immunologic changes in chemically veterans. The first congress of Biochemistry in Islamic Republic of Iran, Mashhad, pp 131–137Google Scholar
  65. Zimmerman T (1942) As cited in: Smith HW (1943) Review of the literature on the systemic action of mustard gas to August 1, 1943. OSRD Report No. 1717. New York University. Prepared for the Office of Scientific Research and DevelopmentGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  1. 1.Medical Toxicology Research Center, School of Medicine, Mashhad University of Medical SciencesMashhadIran
  2. 2.Department of Immunology and AllergyImmunology Research Center, School of Medicine, Mashhad University of Medical SciencesMashhadIran

Personalised recommendations