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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
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
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
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.
Respiratory
o Cough, dyspnea and wheezing
o Delayed signs can include hemoptysis.
Cardiovascular
o Tachycardia
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
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]
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]
Prehospital Care
Decontamination is of paramount importance to avoid crosscontamination. Remove all clothing, and wash the patient in
soap and water.
Consultations
Medication Summary
Antidotes, adsorbent
Class Summary
These agents are used to neutralize toxins.[25]
View full drug information
Granulocyte-stimulating factors
Class Summary
These agents are used to correct severe neutropenia.
View full drug information
Filgrastim (Neupogen)
Complications