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CBRNE - T-2 Mycotoxins

  • Author: Chan W Park, MD, FAAEM; Chief Editor: Zygmunt F Dembek, PhD, MPH, MS, LHD  more...
 
Updated: Mar 09, 2016
 

Background

Overview

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]

Historical significance

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.

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Pathophysiology

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]

Routes of exposure

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).

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Epidemiology

Frequency

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]

Mortality/Morbidity

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.

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Contributor Information and Disclosures
Author

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.

Coauthor(s)

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.

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.

Specialty Editor Board

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.

Chief Editor

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.

Additional Contributors

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.

Acknowledgements

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.

References
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