CBRNE – T-2 Mycotoxins
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Trichothecene mycotoxins are low molecular weight (250-500 Daltons) nonvolatile compounds produced by more than 350 species of fungi. [1] While the toxin confers survival advantage to the fungi, it is pathogenic to animals and humans. [2] All trichothecenes share a common 12,13-epoxytrichothene skeleton and are subdivided into 4 chemical groups (A, B, C, D). [3] T-2 mycotoxin is the most extensively studied of the trichothecenes, and, according to current declassified literature, it is the only mycotoxin known to have been used as a biological weapon. [4]
Unlike most biological toxins that do not affect the skin, T-2 mycotoxin is a potent active dermal irritant. Moreover, it is the only potential biological weapon agent that can be absorbed through intact skin causing systemic toxicity. [5] Clinical symptoms may be present within seconds of exposure. While larger amounts of T-2 toxin is required for a lethal dose than for other chemical warfare agents such as VX, soman, or sarin, its potent effect as a blistering agent is well noted. T-2 mycotoxins can be delivered via food or water sources, as well as, via droplets, aerosols, or smoke from various dispersal systems and exploding munitions. [6] These properties make T-2 mycotoxin a potentially viable biological warfare agent. The reported LD 50 of T-2 toxin is approximately 1 mg/kg. [7]
Trichothecene mycotoxins are extremely stable proteins that are resistant to heat and ultraviolet light inactivation. These substances are relatively insoluble in water but highly soluble in ethanol, methanol, and propylene glycol. Heating to 500ºF for 30 minutes can inactivate the toxin, and exposure to sodium hypochlorite can destroy the toxic activity of the toxin. [8]
In 1931, several Ukrainian veterinarians reported a unique disease in horses that was characterized by lip edema, stomatitis, oral necrosis, rhinitis, and conjunctivitis. This clinical effect progressed through well-defined stages including pancytopenia, coagulopathy, neurologic compromise, superinfections, and death. On autopsy, the afflicted animals were found to have diffuse hemorrhage and necrosis of the entire alimentary tract giving rise to the name alimentary toxic aleukia (ATA). [9]
The potential use for T-2 mycotoxin as a biological weapon was later realized in Orenburg, Russia, during World War II when civilians consumed wheat that was unintentionally contaminated with the Fusarium fungi. The victims developed protracted lethal illness with a disease pattern similar to ATA. In 1940, Soviet scientists coined the term stachybotryotoxicosis to describe the acute syndrome (sore throat, bloody nasal discharge, dyspnea, cough, and fever) resulting from the inhalation of Stachybotrys mycotoxin. Twenty years later, the trichothecene mycotoxin was discovered, and the T-2 toxin was isolated. [10]
The allegations surrounding the use of T-2 mycotoxin as a biological warfare agent remains a controversy to this day. Based on extensive eyewitness and victim accounts, the aerosolized form of T-2 mycotoxin called “yellow rain” was delivered by low-flying aircraft that dropped the yellow oily liquid on the victims.
T-2 mycotoxin has been allegedly used during the military conflicts in Laos (1975-81), Kampuchea (1979-81), and Afghanistan (1979-81) to produce lethal and nonlethal casualties. More than 6300 deaths in Laos, 1000 in Kampuchea, and 3000 in Afghanistan have been attributed to yellow rain exposure. [11] Although several United States chemical weapons experts have matched samples from the Laos conflict to trichothecene signature, these charges have been disputed by other weapons experts who contend T-2 mycotoxins may have occurred naturally in Laos and that exposure was due to the ingestion of contaminated foods. [12] Moreover, the same experts contend that yellow discoloration described on the foliage was merely the residue from fecal matter of honey bees. [10]
Victim reports from the 1991 Desert Storm campaign have also alleged the possibility of a T-2 mycotoxin exposure from a detonated Iraqi missile over a US military camp in Saudi Arabia. [12] According to UNSCOM, Iraq researched trichothecene mycotoxins, including T-2 mycotoxin, and was capable of its possession. [9] However, these matters remain unresolved, and much of the key information and data from these incidents remain classified.
For related information, see Medscape’s Disaster Preparedness and Aftermath Resource Center.
Trichothecene mycotoxins are markedly cytotoxic and potentially immunosuppressive. They are potent fast-acting inhibitors of protein and nucleic acid synthesis. Molecular studies involving the use of rodent and human cell lines suggest T-2 toxin also induces apoptosis, programmed cell death, through reactive oxygen species–mediated mitochondrial pathway. [13, 14] Typically, T-2 toxin is thought to bind and inactivate the peptidyl-transferase activity at the transcription site. [15] This results in the inhibition of protein synthesis, the effect of which is most pronounced in actively proliferating cells such as those found in the skin, gastrointestinal tract, and bone marrow. Additionally, T-2 toxin is thought to disrupt DNA polymerases, terminal deoxynucleotidyl transferase, monoamine oxidase, and several proteins involved in the coagulation pathway. [16]
The trichothecene mycotoxins are well absorbed by topical, oral, and inhalational routes. As a dermal irritant and blistering agent, it is thought to be 400 times more potent than sulfur mustard. As an inhalational agent, its activity is considered comparable to that of mustard or lewisite. [7] Mycotoxin is unique in that the systemic toxicity can result from any route of exposure (dermal, oral, or inhalational).
United States
Trichothecene mycotoxin exposures in the United States have largely been due to accidental ingestion of contaminated foodstuff. In 1993, however, an unusually high number of fatal pulmonary hemorrhages in infants originating from a small region of Ohio raised suspicion that the cause may have been due to trichothecene mycotoxin exposure in the homes secondary to mold overgrowth. [17] Moreover, several cases of sudden infant death syndrome (SIDS) were thought to be related to Stachybotrys mycotoxin exposure in the homes secondary to mold overgrowth resulting from a flood. [18] No well-documented epidemiologic information is available for exposure to T-2 mycotoxin as a result of bioweapon deployment other than the alleged uses in the previously mentioned military conflicts.
International
Several cases of “sick building syndrome” have been reported in Montreal, Canada. Dust samples collected and analyzed from the ventilation systems of suspected office buildings revealed trace amounts of at least 4 trichothecenes including T-2 toxin. This was dismissed as mold overgrowth in the ventilation system. [19]
No human mortality or morbidity data are reported for T-2 mycotoxin use as a bioweapon. Information regarding mortality from ingestion of contaminated food is quite varied, with 10-60% mortality rate reported in Russia’s Orenburg district. [10] Mortality figures from the Kampuchea and Afghanistan uses of mycotoxin as a bioweapon do not report mortality rates, only total number of deaths. [11] Not knowing the number of exposed individuals as related to the number of fatalities makes the calculation of mortality rates impossible.
Joffee A. Fusarium Species: Their Biology and Toxicology. NY: John Wiley & Sons; 1986. 225-292.
Darling, Woods, et al. USAMRIID’s Medical Management of Biological Casualties Handbook. USAMRIID. 2004. Available at http://www.usamriid.army.mil/education/bluebookpdf/usamriid%20blue%20book%205th%20edition.pdf.
McGovern TW, Christopher GW. Biological warfare and its cutaneous manifestations. The Electronic Textbook of Dermatology. 1995-2001. [Full Text].
Ueno Y. Trichothecene mycotoxins: Mycology, chemistry, and toxicology. Advances in food and nutrition research. 1989. 3:301-353.
Franz DR, Jahrling PB, Friedlander AM, McClain DJ, Hoover DL, Bryne WR, et al. Clinical recognition and management of patients exposed to biological warfare agents. JAMA. 1997 Aug 6. 278(5):399-411. [Medline].
Marrs TC, Edginton JA, Price PN, Upshall DG. Acute toxicity of T2 mycotoxin to the guinea-pig by inhalation and subcutaneous routes. Br J Exp Pathol. 1986 Apr. 67(2):259-68. [Medline].
Wannemacher RW Jr, Wiener SL. Trichothecene mycotoxins. Sidell FR, Takafuji ET, Franz DR. Medical Aspects of Chemical and Biological Warfare. Falls Church, Va: Office of the Surgeon General, US Dept of the Army; 1997. 655-676.
Blazes DL, Lawler JV, Lazarus AA. When biotoxins are tools of terror. Early recognition of intentional poisoning can attenuate effects. Postgrad Med. 2002 Aug. 112(2):89-92, 95-6, 98. [Medline].
Zilinskas RA. Iraq’s biological weapons. The past as future?. JAMA. 1997 Aug 6. 278(5):418-24. [Medline].
Holstege CP, Bechtel LK, Reilly TH, Wispelwey BP, Dobmeier SG. Unusual but potential agents of terrorists. Emerg Med Clin North Am. 2007 May. 25(2):549-66; abstract xi. [Medline].
Haig AM. Chemical Warfare in Southeast Asia and Afghanistan: Report to the Congress From Secretary of State Alexander M. Haig. US Department of State. March 22, 1982.
Schieffer HB. Facts, not Rhetoric, on Yellow Rain. Nature. July 1983. 304:10.
Wu J, Jing L, Yuan H, Peng SQ. T-2 toxin induces apoptosis in ovarian granulosa cells of rats through reactive oxygen species-mediated mitochondrial pathway. Toxicol Lett. 2011 May 10. 202(3):168-77. [Medline].
Bouaziz C, Sharaf El Dein O, El Golli E, Abid-Essefi S, Brenner C, Lemaire C, et al. Different apoptotic pathways induced by zearalenone, T-2 toxin and ochratoxin A in human hepatoma cells. Toxicology. 2008 Dec 5. 254(1-2):19-28. [Medline].
Henghold WB 2nd. Other biologic toxin bioweapons: ricin, staphylococcal enterotoxin B, and trichothecene mycotoxins. Dermatol Clin. 2004 Jul. 22(3):257-62, v. [Medline].
Johnsen H, Odden E, Johnsen BA, Bøyum A, Amundsen E. Cytotoxicity and effects of T2-toxin on plasma proteins involved in coagulation, fibrinolysis and kallikrein-kinin system. Arch Toxicol. 1988 Jan. 61(3):237-40. [Medline].
Dearborn DG, Smith PG, Brooks LJ, Carroll-Pankhurst C, Kosick R, Dahms BB. Update: pulmonary hemorrhage/hemosiderosis among infants-Cleveland, Ohio 1993-1996. MMWR Morbidity Mortality Weekly Report. 1997. 46:33-35.
Richards CA. Stachybotrys atra suspected in three infant deaths: 18 others sickened. Journal of Pediatric Infectious Disease. 1997. 10:1-8.
Pestka JJ, Yike I, Dearborn DG, Ward MD, Harkema JR. Stachybotrys chartarum, trichothecene mycotoxins, and damp building-related illness: new insights into a public health enigma. Toxicol Sci. 2008 Jul. 104(1):4-26. [Medline].
Schoenthal. Mycotoxins in food and the plague of Athens. Journal of Nutritional Medicine. 1994. 4:83-85.
Dohnal V, Jezkova A, Jun D, Kuca K. Metabolic pathways of T-2 toxin. Curr Drug Metab. 2008 Jan. 9(1):77-82. [Medline].
Zapor M, Fishbain JT. Aerosolized biologic toxins as agents of warfare and terrorism. Respir Care Clin N Am. 2004 Mar. 10(1):111-22. [Medline].
Wannemacher RW. Dermal toxicity of T-2 toxin in guinea pigs, rats and cynomolgus monkeys. Tricothecenes and Other Mycotoxins. 1985. 423-432.
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Tucker JB. Mycotoxins and Gulf War Illness: A Possible Link [The National Gulf War Resource Center Web site]. The National Gulf War Resource Center. Available at http://www.ngwrc.org/. Accessed: 2001.
Chan W Park, MD, FAAEM Adjunct Assistant Professor, Division of Emergency Medicine, Duke University Medical Center; Director of Simulation Medicine, Durham Veterans Affairs Medical Center
Chan W Park, MD, FAAEM is a member of the following medical societies: American Academy of Emergency Medicine, American College of Emergency Physicians, Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.
Kevin Scott Koehler, MD Resident Physician, Department of Emergency Medicine, Naval Medical Center Portsmouth
Disclosure: Nothing to disclose.
Chris Luttig, MD, MPH Resident Physician, Departments of Emergency Medicine and Internal Medicine, Virginia Commonwealth University Health System
Chris Luttig, MD, MPH is a member of the following medical societies: American College of Physicians, American Medical Association, Emergency Medicine Residents’ Association
Disclosure: Nothing to disclose.
Thomas M Stein, MD
Thomas M Stein, MD is a member of the following medical societies: American College of Emergency Physicians, American Medical Association, Association of Military Surgeons of the US, National Association of EMS Physicians, Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.
Michael R Melia, MD Department of Emergency Medicine, Naval Medical Center, Portsmouth, Virginia
Michael R Melia, MD is a member of the following medical societies: American College of Emergency Physicians
Disclosure: Nothing to disclose.
Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Received salary from Medscape for employment. for: Medscape.
Zygmunt F Dembek, PhD, MPH, MS, LHD Associate Professor, Department of Military and Emergency Medicine, Adjunct Assistant Professor, Department of Preventive Medicine and Biometrics, Uniformed Services University of the Health Sciences, F Edward Hebert School of Medicine
Zygmunt F Dembek, PhD, MPH, MS, LHD is a member of the following medical societies: American Chemical Society, New York Academy of Sciences
Disclosure: Nothing to disclose.
Jerry L Mothershead, MD Medical Readiness Consultant, Medical Readiness and Response Group, Battelle Memorial Institute; Advisor, Technical Advisory Committee, Emergency Management Strategic Healthcare Group, Veteran’s Health Administration; Adjunct Associate Professor, Department of Military and Emergency Medicine, Uniformed Services University of the Health Sciences
Jerry L Mothershead, MD is a member of the following medical societies: American College of Emergency Physicians, National Association of EMS Physicians
Disclosure: Nothing to disclose.
Michael P Allswede, DO Program Director, Disaster and Emergency Medicine Residency, Conemaugh Memorial Hospital; Director, Strategic Medical Intelligence, Inc
Disclosure: Nothing to disclose.
Lanny F Littlejohn, MD Staff Emergency Physician and Medical Director for Tactical Combat Casualty Care, Department of Emergency Medicine, Naval Medical Center, Portsmouth, Virginia
Lanny F Littlejohn, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Emergency Physicians, American Medical Association, Special Operations Medical Association, and Undersea and Hyperbaric Medical Society
Disclosure: Nothing to disclose.
Donald A Locasto, MD Assistant Professor, Department of Emergency Medicine, University of Cincinnati College of Medicine
Disclosure: Nothing to disclose.
CBRNE – T-2 Mycotoxins
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