Advertisement

Journal of Medical Toxicology

, Volume 15, Issue 4, pp 287–294 | Cite as

Hydrogen Sulfide Toxicity: Mechanism of Action, Clinical Presentation, and Countermeasure Development

  • Patrick C. NgEmail author
  • Tara B. Hendry-Hofer
  • Alyssa E. Witeof
  • Matthew Brenner
  • Sari B. Mahon
  • Gerry R. Boss
  • Philippe Haouzi
  • Vikhyat S. Bebarta
Review

Abstract

Introduction

Hydrogen sulfide (H2S) is found in various settings. Reports of chemical suicide, where individuals have combined readily available household chemicals to produce lethal concentrations of H2S, have demonstrated that H2S is easily produced. Governmental agencies have warned of potential threats of use of H2S for a chemical attack, but currently there are no FDA-approved antidotes for H2S. An ideal antidote would be one that is effective in small volume, readily available, safe, and chemically stable. In this paper we performed a review of the available literature on the mechanism of toxicity, clinical presentation, and development of countermeasures for H2S toxicity.

Discussion

In vivo, H2S undergoes an incomplete oxidation after an exposure. The remaining non-oxidized H2S is found in dissolved and combined forms. Dissolved forms such as H2S gas and sulfhydryl anion can diffuse between blood and tissue. The combined non-soluble forms are found as acid-labile sulfides and sulfhydrated proteins, which play a role in toxicity. Recent countermeasure development takes into account the toxicokinetics of H2S. Some countermeasures focus on binding free hydrogen sulfide (hydroxocobalamin, cobinamide); some have direct effects on the mitochondria (methylene blue), while others work by mitigating end organ damage by generating other substances such as nitric oxide (NaNO2).

Conclusion

H2S exists in two main pools in vivo after exposure. While several countermeasures are being studied for H2S intoxication, a need exists for a small-volume, safe, highly effective antidote with a long shelf life to treat acute toxicity as well as prevent long-term effects of exposure.

Keywords

Hydrogen sulfide Countermeasure Sulfide Mitochondrial toxin 

Notes

Funding

M. Brenner, SB Mahon, GR Boss, P Haouzi, VS Bebarta, TB Hendry‐Hofer, AE Witcoff are supported in part by NIH 5U01NS087964‐04.

Compliance with ethical standards

Conflict of interest

The authors disclose no additional conflicts of interest.

References

  1. 1.
    OSHAFactSheet, U.S. Department of Labor. Available at: https://www.osha.gov/OshDoc/data_Hurricane_Facts/hydrogen_sulfide_fact.pdf. Last accessed: November 9, 2018.
  2. 2.
    Burnett WW, King EG, Grace M, Hall WF. Hydrogen sulfide poisoning: review of 5 years’ experience. Can Med Assoc J. 1977;117(11):1277–80.PubMedPubMedCentralGoogle Scholar
  3. 3.
    Arnold IM, Dufresne RM, Alleyne BC, Stuart PJ. Health implication of occupational exposures to hydrogen sulfide. J Occup Med. 1985;27(5):373–6.CrossRefGoogle Scholar
  4. 4.
    Reddy SJ, Schwartz MD, Morgan BW. Suicide fads: frequency and characteristics of hydrogen sulfide suicides in the United States. West J Emerg Med. 2011;12(3):300–4.Google Scholar
  5. 5.
    Anderson AR. Characterization of chemical suicides in the United States and its adverse impact on responders and bystanders. West J Emerg Med. 2016;17(6):680–3.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    TSA issues Security Awareness Message on potential use of H2S in terrorist attack. Hazmat/Safety. Bulk Transporter. Available at: https://www.bulktransporter.com/hazmatsafety/tsa-issues-security-awareness-message-potential-use-h2s-terrorist-attack. Last Accessed 5 Nov 2018.
  7. 7.
    Strickland J, Cummings A, Spinnato JA, Liccione JJ, Foureman GL. Toxicological review of hydrogen sulfide. U.S. Environmental Protection Agency, Washington, DC. June 2003. Available at: https://cfpub.epa.gov/ncea/iris/iris_documents/documents/toxreviews/0061tr.pdf. Last Accessed 30 Mar 2019.
  8. 8.
    Hydrogen sulfide: a potential first responder hazard. New York State office of Homeland Security, Emergency Managers Advisory. Available at: https://info.publicintelligence.net/NYhydrogensulfide.pdf. Last Accessed 5 Nov 2018.
  9. 9.
    Hendrickson RG, Chang A, Hamilton RJ. Co-worker fatalities from hydrogen sulfide. Am J Ind Med. 2004;45(4):346–50.CrossRefGoogle Scholar
  10. 10.
    Edinburgh: Blackwood & Sons, Williams J. Australia details ‘sophisticated’ plot by ISIS to take down plane. New York Times [News], 2017. Available at: https://www.nytimes.com/2017/08/04/world/australia/sydney-airport-terror-plot-isis.html. Last Accessed 14 Mar 2018.
  11. 11.
    McKirdy E, Smith K. Foiled plot to blow up plane, unleash gas revealed in Australia. CNN World. Available at: https://www.cnn.com/2017/08/03/asia/australia-plane-terror-plot-isis/index.html. Last Accessed 5 Nov 2018.
  12. 12.
    Abe K, Kimura H. The possible role of hydrogen sulfide as an endogenous neuromodulator. J Neurosci. 1996;16(3):1066–71.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Suarez FL, Furne JK, Springfield J, Levitt MD. Morning breath odor: influence of treatments of sulfur gases. J Dent Res. 2000;79(10):1773–7.CrossRefGoogle Scholar
  14. 14.
    Kimura H. Hydrogen sulfide: its production and functions. Exp Physiol. 2011;96(9):833–5.CrossRefGoogle Scholar
  15. 15.
    Haggard HW. The fate of sulfides in the blood. J Biol Chem. 1921;49:519–29.Google Scholar
  16. 16.
    Klingerman CM, Trushin N, Prokopczyk B, Haouzi P. H2S concentrations in the arterial blood during H2S administration in relation to its toxicity and effects on breathing. Am J Phys Regul Integr Comp Phys. 2013;305:R630–8.Google Scholar
  17. 17.
    Haouzi P, Sonobe T, Torsell-Tubbs N, Prokopczyk B, Chenuel B, Klingerman CM. In vivo interactions between cobalt or ferric compounds and the pools of sulphide in the blood during and after H2S poisoning. Toxicol Sci. 2014;141(2):493–504.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Hildebrandt TM, Grieshaber MK. Three enzymatic activities catalyze oxidation of sulfide to thiosulfate in mammalian and invertebrate mitochondria. FEBS J. 2008;275:3352–61.CrossRefGoogle Scholar
  19. 19.
    Olson KR. A practical look at the chemistry and biology of hydrogen sulfide. Antioxid Redox Signal. 2012;17(1):32–44.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Carroll JJ, Mather AE. The solubility of hydrogensulphide in water from 0-90C and pressures to 1Mpa. Geochim Cosmochin Acta. 1989;53:1163–70.CrossRefGoogle Scholar
  21. 21.
    DeBruyn WJ, Swartz E, Hu JH, Shorter JA, Davidovits P, Worsnop DR, et al. Henry’s law solubilities and Setchenow coefficients for biogenic reduced sulfur species obtained from gas-liquid uptake measurements. J Geophys Res. 1995;100:7245–51.CrossRefGoogle Scholar
  22. 22.
    Reiffenstein RJ, Hurlbert WC, Roth SH. Toxicology of hydrogen sulfide. Annu Rev Pharmacol Toxicol. 1992;32:109–13.CrossRefGoogle Scholar
  23. 23.
    Haouzi P, Sonobe T, Judenjerc-Haouzi A. Developing effective countermeasures against acute hydrogen sulfide intoxication: challenges and limitations. Ann NY Aca Sci. 2016;1374(1):29–40.CrossRefGoogle Scholar
  24. 24.
    Jiang J, Chan A, Ali S, Saha A, Haushalter JK, Lam WL, et al. Hydrogen sulfide—mechanisms of toxicity and development of an antidote. Sci Rep. 2016;6:20831.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Eghbal MA, Pennefather PS, O’Brien PJ. H2S cytotoxicity mechanism involves reactive oxygen species formation and mitochondrial depolarisation. Toxicology. 2004;203(1–3):69–76.CrossRefGoogle Scholar
  26. 26.
    Cheung JY, Wang J, Zhang XQ, Song J, Davidyock M, Prado FJ, et al. Methylene blue counteracts H2S induced cardiac ion channel dysfunction and ATP reduction. Cardiovasc Toxicol. 2018;18(5):407–19.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Ogawa H, Takahashi K, Miura S, Imagawa T, Saito S, Tominaga M, et al. H2S functions as a nociceptive messenger through transient receptor potential Ankyrin 1 (TRPA1) activation. Neuroscience. 2012;218:335–43.CrossRefGoogle Scholar
  28. 28.
    Ujike A, Otsuguro K, Miyamoto R, Yamaguchi S, Ito S. Bidirectional effects of hydrogen sulfide via ATP-sensitive K+ channels and transient receptor potential A1 channels in RIN14B cells. Euro J Pharmacol. 2015;764:4643–470.CrossRefGoogle Scholar
  29. 29.
    Steinritz D, Stenger B, Dietrich A, Gudermann T, Popp T. TRPs in Tox: involvement of transient receptor potential-channels in chemical induced organ toxicity—a structured review. Cells 2018 ; 7(8).Google Scholar
  30. 30.
    Beauchamp RO, Bus JS, Popp JA, Boreiko CJ, Andjelkovich DA. A critical review of the literature on hydrogen sulfide toxicity. Crit Rev Toxicol. 1984;13(1):25–97.CrossRefGoogle Scholar
  31. 31.
    Anantharam P, Whitley EM, Mahama B, Kim DS, Imerman PM, Shao D, et al. Characterizing a mouse model for evaluation of countermeasures against hydrogen sulfide-induced neurotoxicity and neurological sequelae. Ann N Y Acad Sci. 2017;1400(1):46–64.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Ng PC, Hendry-Hofer TB, Garrett N, Brenner M, Mahon SB, Maddry JK, et al. Intramuscular cobinamide versus saline for treatment of severe hydrogen sulfide toxicity in swine. Clin Toxicol. 2019;57(3):189–96.CrossRefGoogle Scholar
  33. 33.
    Scheler W, Kabisch R. The antagonistic effect on the acute H2S-toxication in mice by methemoglobin-forming agents. Acta Biol Med Ger. 1963;11:194–9.PubMedGoogle Scholar
  34. 34.
    Smith RP, Gosselin RE. On the mechanism of sulfide inactivation by methemoglobin. Toxicol Appl Pharmacol. 1966;8(1):159–72.CrossRefGoogle Scholar
  35. 35.
    Beck JF, Bradbury CM, Connors AJ, Donini JC. Nitrite as an antidote for acute hydrogen sulfide intoxication? Am Ind Hyg Assoc J. 1981;42(11):805–9.CrossRefGoogle Scholar
  36. 36.
    Cronican AA, Frawley KL, Ahmed H, Pearce LL, Peterson J. Antagonism of acute sulfide poisoning in mice by nitrite anion without methemoglobinemia. Chem Res Toxicol. 2015;28(7):1398–408.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Judenherc-Haouzi A, Sonobe T, Bebarta VS, Haouzi P. On the efficacy of cardio-pulmonary resuscitation and epinephrine following cyanide- and H2S intoxication-induced cardiac asystole. Cardiovasc Toxicol. 2018;18(5):436–49.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Truong DH, Mihajlovic A, Gunness P, Hindmarsh W, O’Brien PJ. Prevention of hydrogen sulfide (H2S)- induced mouse lethality and cytotoxicity by hydroxocobalamin. Toxicology. 2007;242(1–3):16–22.CrossRefGoogle Scholar
  39. 39.
    Haouzi P, Chenuel B, Sonobe T. High dose hydroxocobalamin administered after H2S exposure counteracts sulfide poisoning induced cardiac depression in sheep. Clin Toxicol(Phila). 2015;53(1):28–36.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Brenner M, Benavides S, Mahob SB, Lee J, Yoon D, Mukai D, et al. The vitamin b12 analog cobinamide is an effective hydrogen sulfide antidote in a lethal rabbit model. Clin Toxicol(Phila). 2014;52(5):490–7.CrossRefGoogle Scholar
  41. 41.
    Bebarta VS, Garrett N, Brenner M, Mahon SB, Maddry JK, Boudreau S, et al. Efficacy of intravenous cobinamide versus hydroxocobalamin or saline for treatment of severe hydrogen sulfide toxicity in a swine (Sus scrofa ) model. Acad Emerg Med. 2017;24(9):1088–98.CrossRefGoogle Scholar
  42. 42.
    Salnikov DS, Makarov SV, Eldik R, Kucherenko PN, Boss GR. Kinetics and mechanism of the reaction of hydrogen sulfide with diaquacobinamide in aqueous solution. Eur J Inorg Chem. 2014;2014(25):4123–33.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Lee J, Mahon SB, Mukai D, Burney T, Katebian BS, Chan A, et al. The vitamin B12 analog cobinamide is an effective antidote for oral cyanide poisoning? J Med Toxicol. 2016;12(4):370–9.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Bebarta VS, Tanen DA, Boudreau S, Castaneda M, Zarzabal LA, Vargas T, et al. Intravenous cobinamide versus hydroxocobalamin for acute treatment of severe cyanide poisoning in a swine (Sus scrofa) model. Ann Emerg Med. 2014;64(6):612–9.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Anantharam P, Kim DS, Whitley EM, Mahama B, Imerman P, Padhi P, et al. Midazolam efficacy against acute hydrogen sulfide-induced mortality and neurotoxicity. J Med Toxicol. 2018;14(1):79–90.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Judenherc-Haouzi A, Zhang XQ, Sonobe T, Song J, Rannals MD, Wang J, et al. Methylene blue counteracts H2S toxicity-induced cardiac depression by restoring L-type Ca channel activity. Am J Phys Regul Integr Comp Phys. 2016;310(11):R1030–44.Google Scholar
  47. 47.
    Haouzi P, Tubbs N, Cheung J, Judenherc-Haouzi A. Methylene blue administration during and after life-threatening intoxication by hydrogen sulfide: efficacy studies in adult sheep and mechanisms of action. Toxicol Sci. 2019;168(2):443–59.CrossRefGoogle Scholar
  48. 48.
    Truong DH, Eghbal MA, Hindmarsh W, Roth SH, O’Brien PJ. Molecular mechanisms of hydrogen sulfide toxicity. Drug Metab Rev. 2006;38(4):733–44.CrossRefGoogle Scholar
  49. 49.
    Guidotti TL. Hydrogen sulfide intoxication. Handb Clin Neurol. 2015;131:111–33.CrossRefGoogle Scholar
  50. 50.
    Bitterman N, Talmi Y, Lerman A, Melamed Y, Taitelman U. The effect of hyperbaric oxygen on acute experimental sulfide poisoning in the rat. Toxicol Appl Pharmacol. 1986;84(2):325–8.CrossRefGoogle Scholar
  51. 51.
    Smith RP, Kruszyna R, Kruszyna H. Management of acute sulfide poisoning. Archives of Environmental health: An International Journal. 1976;31(3):166–9.CrossRefGoogle Scholar
  52. 52.
    Smith L, Kruszyna H, Smith RP. The effect of methemoglobin on the inhibition of cytochrome c oxidase by cyanide, sulfide or azide. Biochem Pharmacol. 1977;26(23):2247–50.CrossRefGoogle Scholar

Copyright information

© American College of Medical Toxicology 2019

Authors and Affiliations

  • Patrick C. Ng
    • 1
    • 2
    Email author
  • Tara B. Hendry-Hofer
    • 2
  • Alyssa E. Witeof
    • 2
  • Matthew Brenner
    • 3
    • 4
  • Sari B. Mahon
    • 3
  • Gerry R. Boss
    • 5
  • Philippe Haouzi
    • 6
  • Vikhyat S. Bebarta
    • 1
    • 2
  1. 1.Denver Health and Hospital AuthorityRocky Mountain Poison and Drug CenterDenverUSA
  2. 2.Department of Emergency MedicineUniversity of Colorado Anschutz Medical CampusAuroraUSA
  3. 3.Beckman Laser Institute and Medical ClinicUniversity of CaliforniaIrvineUSA
  4. 4.Division of Pulmonary and Critical Care Medicine, Department of MedicineUniversity of CaliforniaIrvineUSA
  5. 5.Department of MedicineUniversity of CaliforniaSan DiegoUSA
  6. 6.Division of Pulmonary and Critical Care Medicine, Department of MedicinePennsylvania State University, College of MedicineHersheyUSA

Personalised recommendations