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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 T2 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 500F 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.

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 speciesmediated
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).

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.
Physical

Patients with cutaneous symptoms may report seeing clouds of a


yellow-colored smoke or aerosol, but blue and green aerosols
have also been reported.[12]

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.[3]

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.[20]

The most common symptoms occurring with most exposures include


skin (or oral) pain (burning) and redness or rash, vomiting,
diarrhea, dyspnea, and bleeding.[2]

Physical
The early signs and symptoms of T-2 toxin poisoning do 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)


o Ocular exposure causes tearing, pain, conjunctivitis, and
blurred vision.
o Nasal mucosa results in sinus irritation, pain,
rhinorrhea, sneezing, and potentially epistaxis.
o Oral and oropharyngeal exposure results in pain and
blood-tinged saliva and sputum.

Respiratory
o Cough, dyspnea and wheezing
o Delayed signs can include hemoptysis.

Cardiovascular
o Tachycardia

o Vascular collapse in severe toxin exposure

Gastrointestinal
o Nausea and vomiting
o Anorexia
o Watery diarrhea with abdominal cramping

Dermal
o Painful erythema and tenderness
o Blistering and bullous lesions, leading to desquamation
o Necrosis and sloughing of dermal layer

Systemic
o Severe toxin exposure can result in early systemic
toxicity.
o Severe dizziness, ataxia, and prostration
o Tachycardia
o Hypothermia
o Vascular collapse

Hematologic: Upon chronic exposure to T-2 toxin, the clinical


syndrome of alimentary toxic aleukia (ATA) ensues.[2] This
presentation mirrors the stages of radiation sickness. The 4
stages are as follows:
o 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.
o 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.
o 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.
o Stage 4: During the recovery phase, the necrotic lesions
heal and the bone marrow recovers.

Laboratory Studies
With growing health concerns related to mold exposures and its
related morbidity and mortality, devices have been developed to
detect environmental mycotoxin exposure. To date, no data exist to
differentiate the expected background levels of these substances from
potential toxic and/or intentional contamination.
T-2 toxin is rapidly metabolized to HT-2, T2-triol, and T-2 tetraol
within hours after exposure.[21] While these toxin metabolites may be
detected in body fluids, tissue, and stomach contents for up to 28
days following exposure, these results are unlikely to be available
to help the medical provider manage the patient. Newer urine assays
detect T-2 metabolite for up to one week after exposure.[9] Definitive
diagnosis must be made in a reference laboratory using thin-layer or
gas-liquid chromatography, mass or nuclear magnetic resonance
spectrometry, radioimmunoassay, and enzyme-linked immunosorbent assay
(ELISA) techniques.[22]

Perform immediate postexposure laboratory studies to assess for


other disease conditions in the differential diagnosis.

When considering T-2 mycotoxin exposure as the cause of the


illness, collect nasal, throat, or respiratory secretions and
send for mass spectrometric evaluation.

Collect serum, urine, and/or tissue samples for toxin detection


from patients who are in the postexposure phase. ELISA
screening tests and antibody assays that screen for mycotoxin
exposure are available.

Observing the absolute lymphocyte count over time may


differentiate those individuals destined to develop bone marrow
suppression.

Coagulation panel may help identify patients who are at risk


for developing severe coagulopathy.

Imaging Studies
No specific imaging tests help diagnose T-2 toxin exposure.

Procedures
Warning: This is a potent dermally active toxin that is transmissible
if not properly decontaminated. Do not approach the patient without
observing universal precaution.
Decontamination procedure is as follows:

Remove all of the patient's clothing, and clean and scrub the
entire skin surface with soap and water. Washing the
contaminated area of the skin within 6 hours postexposure can
remove 80-98% of the toxin and has been demonstrated to prevent
skin lesions and death in experimental animals.[23]

Contain clothing to avoid contamination of the health care


environment.

Prehospital Care

Warning: Mycotoxin is a potent dermally active toxin that is


transmissible in the health care setting. Do not approach the
patient without observing universal precaution.

Use hazardous materials teams in patient rescue and


decontamination.

Decontamination is of paramount importance to avoid crosscontamination. Remove all clothing, and wash the patient in
soap and water.

Available only to the US Department of Defense and many NATO


military forces is the Reactive Skin Decontamination Lotion
(RSDL). The proposed mechanism of action is neutralization of
traditional chemical warfare agents by a combination of
physical removal and nucleophilic breakdown, which renders the
original toxic substance nontoxic.[24]

For patients in extremis, attention to airway, breathing, and


circulation per Advanced Trauma Life Support (ATLS) protocol
needs to occur immediately as decontamination is being
performed.

o While one team member is caring for issues involving the


airway, breathing, and circulation, another member should
be concerned primarily with patient decontamination.
o Remove all clothing, and clean and scrub the patient's
entire skin surface with soap and water. Washing the
contaminated area of the skin within 6 hours post
exposure can remove 80-98% of the toxin and has been
demonstrated to prevent skin lesions and death in
experimental animals.[23]
o Contain clothing to avoid contamination of the health
care environment.

Provide supportive measures addressing cardiovascular status as


necessary.

If the patient complains of eye pain or tearing, irrigate the


eyes with copious amounts of water.

No specific antidote exists for this toxin. General supportive


measures are indicated.

Emergency Department Care

Warning: Mycotoxin is a potent dermally active toxin that is


transmissible in the health care setting. Do not approach the
patient without observing universal precaution.

Never assume that a patient has been decontaminated in the


prehospital setting. Reassess the patient's decontamination
status. If the degree of prehospital decontamination is
uncertain, rewash the patient to ensure the safety of staff and
facility.

For patients in extremis, attention to airway, breathing, and


circulation per ATLS protocol needs to occur immediately as
decontamination is being performed.
o While one team member is caring for issues involving the
airway, breathing, and circulation, another member should
be concerned primarily with patient decontamination.
o Remove all clothing, and clean and scrub the patient's
entire skin surface with soap and water. Washing the
contaminated area of the skin within 6 hours postexposure
can remove 80-98% of the toxin and has been demonstrated
to prevent skin lesions and death in experimental
animals.[23]

o Contain clothing to avoid contamination of the health


care environment.

While no human studies have been conducted, survival benefits


have been shown in animal models with the following treatment
after T-2 toxin exposure.
o Use of activated charcoal to absorb T-2 toxin from the
gut regardless of the portal of entry within 1 hour of
exposure.[25]
o Dexamethasone administration (1 mg/kg at 12, 24, and 48
h) increased the survival rate in mice from zero to
greater than 50%.[26]

No specific antidote is available for T-2 mycotoxin exposure.


Provide supportive measures, addressing respiratory and
cardiovascular status as necessary.

If the patient complains of eye pain or tearing, irrigate the


eyes with copious amounts of water.

Consultations

Required consultants are dictated by the disease course.


Pulmonary consultation may be required for severe dyspnea of
hemoptysis. A hematologist may be consulted for patients
presenting with severe pancytopenia.

Contact the local poison control center for additional clinical


guidance. Some larger cities' poison control centers may have
specific guidelines to follow concerning weapons of mass
destruction.

Consult the Federal Bureau of Investigation and Department of


Homeland Security in any situation when nuclear, biological, or
chemical weapon exposure is suspected.
o Federal Bureau of Investigations
o Department of Homeland Security

Medication Summary

The use of activated charcoal is advocated to patients who have


orally ingested the toxin. Some sources advocate the use of activated
charcoal even after inhalational exposure with the rationale being
that the toxin that is adherent to the oral mucosa may be bound.[27]
While not clinically tested in human, theoretical use exists for
administering colony-stimulating factors to patients presenting with

bone marrow suppression.

Antidotes, adsorbent
Class Summary
These agents are used to neutralize toxins.[25]
View full drug information

Activated charcoal (Liqui-Char, Super-Char, Insta-Char,


Actidose)

Believed to adsorb ingested toxin, thereby preventing absorption and


removing toxin from the GI tract, preventing further cellular damage.

Granulocyte-stimulating factors
Class Summary
These agents are used to correct severe neutropenia.
View full drug information

Filgrastim (Neupogen)

Granulocyte colony-stimulating factor that activates and stimulates


production, maturation, migration, and cytotoxicity of neutrophils.
Although not demonstrated or indicated for use in T-2 mycotoxin
exposure, may be theoretical use for granulocyte-stimulating factors
for patients presenting with severe neutropenia; in this setting,
conduct use with hematology consultation.

Further Inpatient Care

In all suspected cases involving T-2 mycotoxin exposure, admission to


the hospital is warranted. Supportive care should be instituted with
particular attention to the prevention of superinfection. Depending
on the time of exposure and the presenting symptoms, serial
lymphocyte count may help identify patients who are
immunocompromised.
Inpatient & Outpatient Medications

Although not proven clinically, a theoretical use exists for


administering colony-stimulating factors to patients presenting with
bone marrow suppression.

Complications

Airway compromise may be observed when the disease process includes


significant airway edema or hemorrhage.
Prognosis

Prognosis of mycotoxin exposure is difficult to assess, since the


amount of toxin in previous human ingestions has not been documented.
Death from actual toxin ingestion is much less of a concern than the
sequelae of immune compromise and successive infection. This is
supported by the documented history of the ingestion version of the
disease (ATA). No current literature predicts the outcome of T-2
mycotoxin poisoning.
Patient Education

For patient education resources, see the Bioterrorism and Warfare


Center, as well as Biological Warfare and Personal Protective
Equipment.