eMedicine Specialties > Emergency Medicine > Warfare - Chemical, Biological, Radiological, Nuclear and Explosives

CBRNE - T-2 Mycotoxins

Author: Chan W Park, MD, Attending Physician, Research Coordinator, Naval Medical Center Portsmouth
Coauthor(s): Michael R Melia, MD, Resident, Department of Emergency Medicine, Naval Medical Center, Portsmouth, Virginia; Lanny F Littlejohn, MD,, Resident and Medical Director for Tactical Combat Casualty Care, Department of Emergency Medicine, Naval Medical Center, Portsmouth, Virginia; Thomas M Stein, MD, FACEP, Assistant Professor, Department of Emergency Medicine, Medical College of Pennsylvania-Hahnemann University; Medical Director, Emergency Medical Support Services and LifeFlight, Department of Emergency Medicine, Allegheny General Hospital
Contributor Information and Disclosures

Updated: Aug 19, 2008

Introduction

Background

Overview
 
Trichothecene mycotoxins are low molecular weight (250-500 Daltons) nonvolatile compounds produced by more than 350 species of fungi. While the toxin confers survival advantage to the fungi, it is pathogenic to animals and humans. All trichothecenes share a common 12,13-epoxytrichothene skeleton and are subdivided into 4 chemical groups (A, B, C, D). 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.

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. 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. 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.

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.

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).

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.

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. 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. Moreover, the same experts contend that yellow discolorationdescribed on the foliage was merely the residue from fecal matter of honey bees.

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. According to UNSCOM, Iraq researched trichothecene mycotoxins, including T-2 mycotoxin, and was capable of its possession. However, these matters remain unresolved, and much of the key information and data from these incidents remain classified.

Pathophysiology

Trichothecene mycotoxins are markedly cytotoxic and potentially immunosuppressive. They are potent fast-acting inhibitors of protein and nucleic acid synthesis. T-2 toxin is thought to bind and inactivate the peptidyl-transferase activity at the transcription site. 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.  

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. Mycotoxin is unique in that the systemic toxicity can result from any route of exposure (dermal, oral, or inhalational). 

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. 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. 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 T2 toxin. This was dismissed as mold overgrowth in the ventilation system.

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. Mortality figures from the Kampuchea and Afghanistan uses of mycotoxin as a bioweapon do not report mortality rates, only total number of deaths. Not knowing the number of exposed individuals as related to the number of fatalities makes the calculation of mortality rates impossible.

Clinical

History

• Patients with cutaneous symptoms may report seeing clouds of a yellow-colored smoke or aerosol, but blue and green aerosols have also been reported.
• Patients may report yellow droplets on clothing.
• Immediate skin pain and burning on exposed surfaces is described. Eye pain and burning also should be reported.
• Suspicion of the toxin being placed in an ingested food source may exist. Ingested toxin probably has no taste, since no documentation supports a foul odor or taste in previous epidemics of toxin ingestion. This is further supported by the historical experience that many individuals become ill when exposed to contaminated food without any suspicion of having ingested tainted food.
• The most common symptoms occurring with most exposures include skin (or oral) pain (burning) and redness or rash, vomiting, diarrhea, dyspnea, and bleeding.

Physical

The early signs and symptoms of T-2 toxin poisoning does reflect the route of exposure. However, irrespective to the route of entry, the systemic toxicity follows a protracted course of illness that is well characterized. Early symptoms can manifest within seconds of exposure depending on the dose of exposure. Symptoms become prominent after minutes to hours upon exposure. They are described by the respective organ system.  

• Neurologic: No specific neurologic signs or symptoms are related to the toxin except for mild ataxia, which reflects systemic toxicity.
• Head, eyes, ears, nose, throat (HEENT)
  • Ocular exposure causes tearing, pain, conjunctivitis, and blurred vision.
  • Nasal mucosa results in sinus irritation, pain, rhinorrhea, sneezing, and potentially epistaxis.
  • Oral and oropharyngeal exposure results in pain and blood-tinged saliva and sputum.
• Respiratory
  • Cough, dyspnea and wheezing
  • Delayed signs can include hemoptysis. 
• Cardiovascular
  • Tachycardia
  • Vascular collapse in severe toxin exposure
• Gastrointestinal
  • Nausea and vomiting
  • Anorexia
  • Watery diarrhea with abdominal cramping
• Dermal
  • Painful erythema and tenderness
  • Blistering and bullous lesions, leading to desquamation
  • Necrosis and sloughing of dermal layer
• Systemic
  • Severe toxin exposure can result in early systemic toxicity. 
  • Severe dizziness, ataxia, and prostration
  • Tachycardia
  • Hypothermia
  • Vascular collapse
• Hematologic
  • Upon chronic exposure to T-2 toxin, the clinical syndrome of alimentary toxic aleukia (ATA) ensues. This presentation mirrors the stages of radiation sickness. The 4 stages are as follows:
    • Stage 1: This stage may be seen in the emergency department. This stage results from the acute injury to the exposed cells and tissue. The symptoms reflect the route of toxin exposure.
    • Stage 2: This stage occurs weeks after the exposure. Insult to the bone marrow initially produces a transient lymphocytosis. This is soon followed by bone marrow suppression due to the antimitotic effects of T-2 toxin. The result is significant leukopenia, granulocytopenia, and thrombocytopenia.
    • Stage 3: This stage also occurs weeks after the exposure and is considered the hemorrhagic stage. The patient exhibits petechial hemorrhages, especially of the mucosal areas of the nasopharynx and oropharynx. These lesions develop to form ulcerated and necrotic lesions, which can result in significant bleeding from the esophagus and the gastrointestinal tract. Moreover, the edema that accompanies the mucosal injury may threaten the airway. Also, severe coagulopathy may occur. During this stage, the patient is at a higher risk for sepsis because the immune system is significantly compromised.  
    • Stage 4: During the recovery phase, the necrotic lesions heal and the bone marrow recovers.

• Search for CME/CE on This Topic »

• Bioterrorism and Warfare Center
• Biological Warfare
• Personal Protective Equipment