Linking
Evidence and Experience
Mycotoxins
Ruth A.
Etzel, MD, PhD
Mycotoxins, chemicals produced by fungi, may have developed to serve as a
chemical defense system against insects, microorganisms, nematodes, grazing
animals, and humans. Approximately 400 known mycotoxins exist. This article
describes the major mycotoxins that affect human health and highlights the
mycotoxins with potential bioterrorist use.
Mycotoxins can benefit humans by their use as antibiotics (penicillins),
immunosuppressants (cyclosporine), and in control of postpartum hemorrhage
and migraine headaches (ergot alkaloids). Mycotoxins are also capable of
producing illness and death in humans and animals.
Exposure to mycotoxins may occur through ingestion,
inhalation, and dermal exposure. The
mycotoxins were discovered when epidemics of illness were traced to
ingestion of moldy food. Massive mycotoxin contamination of food resulting
in outbreaks of illness occurs only rarely today in developing countries.
The primary concern in developed countries is the long-term effects of
ingesting food contaminated with low levels of mycotoxins. Although ergot
alkaloids are described here because of their historical importance, today
the most commonly encountered mycotoxins in animal feed and human foods are
aflatoxins, fumonisins, and deoxynivalenol (vomitoxin).
Aflatoxins
Aflatoxins, produced by
Aspergillus flavus and A parasiticus, are common contaminants of peanuts,
soybeans, grains, and cassava (a root), especially in tropical areas. In the
1960s, aflatoxins were found to be potent carcinogens in animals, the most potent of which is
aflatoxin B1. Epidemiologic studies have demonstrated that aflatoxin B1
ingestion is an important risk factor for hepatocellular cancer in humans. Persons with both
hepatitis B infection and aflatoxin B1 exposure have a higher risk for
hepatocellular cancer than those with only hepatitis B infection or only
aflatoxin exposure.
In Qidong, Jiangsu Province,
China, hepatocellular carcinoma is the leading cause of cancer deaths and
exposure to dietary aflatoxins is widespread. Ongoing clinical trials there
indicate that oltipraz, an antischistosomal drug, can decrease the
metabolism of aflatoxin B1 to its carcinogenic form and increase the
detoxification pathways of its metabolites.
Intervention with drugs such as oltipraz and improved storage conditions of
staple foods are measures under investigation to reduce the incidence of
hepatocellular cancer in regions of higher risk.
In addition to chronic effects, aflatoxin exposure can sometimes result in
acute aflatoxicosis with vomiting, abdominal pain, hepatitis, and death.
Although acute toxicity is rare, epidemics have been reported following
ingestion of food heavily contaminated with A flavus.8 The acute lethal dose for
adults is 10 to 20 mg of aflatoxin.
Ergot Alkaloids
The ergot alkaloids, produced by Claviceps purpura, were the first
mycotoxins recognized to cause epidemic disease in humans. Persons who
ingested these mycotoxins, found primarily on moldy rye grain, developed
ergotism. A gangrenous form of ergotism was common in central Europe from
the 9th to the 14th century. The first symptom
was a prickly sensation in the limbs, which then became swollen, inflamed,
and subject to sensations of intense heat and cold. Peripheral
vasoconstriction resulted in gangrene and limb loss. In the Middle Ages,
this was known as St Anthony's fire because it was often cured by a visit to
the shrine of St Anthony, which happened to be in an ergot-free region of
France. A convulsive form of ergotism involving the nervous system occurred
in Europe from the late 16th to the late 19th century. It was also reported
in the United States and historians have hypothesized that it may have been
a factor in the Salem witchcraft trials of 1692.
The vasoconstrictive properties of ergot alkaloids have made them useful in
treating migraine headaches (ergotamine tartrate) and postpartum hemorrhage
(methyl ergonovine). Ergotism following ingestion of contaminated food is
very rare today; it is more commonly reported following therapeutic
administration of ergot alkaloids.
Fumonisins
The fumonisins are a group of mycotoxins isolated from corn contaminated
with
Fusarium moniliforme, F proliferatum, and A ochraceus. The fumonisins
were discovered in 1988 following the 1970 outbreak of equine
leukoencephalomalacia in South Africa.
Fumonisins seem to be universally present in corn and corn-based products. Extensive investigations have documented
that consumption of corn and corn-based products contaminated with fumonisin
B1 causes equine leukoencephalomalacia and porcine pulmonary edema, fatal
diseases in farm animals. In 1989
and 1990, fatal outbreaks of equine leukomalacia, porcine prenatal and
neonatal mortality, and porcine pulmonary edema occurred in the United
States. Evidence
of human health effects from ingestion of fumonisin-contaminated foods
primarily derives from studies in South Africa, China, and northern Italy.
These studies suggest a link between fumonisin exposure and esophageal
cancer.
The fumonisins have been shown to disrupt sphingolipid metabolism.
Sphingolipids play a role in membrane and lipoprotein structure and in cell
regulation as second messengers for growth factors, differentiation factors,
and cytokines.
Disruption of sphingolipid metabolism and its effect on human development is
under study.
Fumonisin exposure may play a role in birth defects. A 1990 cluster of
neural tube defects in south Texas generated the hypothesis that ingestion
of high levels of fumonisins in corn-based products might be linked to human
birth defects, such as anencephaly and spina bifida. Mexican
Americans' risks of neural tube defects are much higher than those of
non-Hispanic whites. When the
cluster of affected pregnancies occurred, US corn-based products had
relatively high levels of fumonisins, 2 to 3 times higher than normal.
Mexican American women in Texas, unlike their non-Hispanic counterparts, eat
a lot of corn in the form of tortillas (90 g/d vs 17 g/d). Fumonisin has been shown to interfere
with cellular folate uptake and it is
possible that exposure to dietary fumonisins may help explain the lack of
effectiveness of folic acid in reducing neural tube defects in Mexican
Americans.
Trichothecenes
Fusarium and
Stachybotrys species produce mycotoxins called trichothecenes.
When ingested by humans, these mycotoxins produce alimentary toxic aleukia.
This disease first appeared in 1913 in far eastern Siberia and was
reportedly responsible for the death of at least 100 000 Russian people
between 1942 and 1948. Affected persons developed necrotic ulcers in the
nose, mouth, throat, stomach, and intestines, complicated by hemorrhage from
the nose, mouth, gastrointestinal tract, and kidneys. Alimentary toxic
aleukia was associated with eating wheat and corn that had been under snow
during the winter and contaminated with Fusarium and Stachybotrys molds.
Dermal exposure to the Stachybotrys fungus may cause a severe skin reaction.
The dermatitis was first described among workers handling fodder, using
infected straw for fuel, or sleeping on mattresses made of infected straw
and is characterized by hyperemia, encrustations, and necrosis.
The acute toxicosis resulting from the inhalation of the Stachybotrys
mycotoxin, first described by Soviet scientists in the 1940s, has been
termed stachybotryotoxicosis. The
symptoms include sore throat, bloody discharge from the nose, dyspnea,
cough, low-grade fever, and chest tightness.
Vomitoxin
Another trichothecene mycotoxin is deoxynivalenol, also known as vomitoxin,
frequently a contaminant of wheat and corn. In China from 1961 to 1985,
multiple outbreaks of vomiting illness were attributed to consumption of
vomitoxin-contaminated grain. In India
in 1987, nearly 100 persons became ill after they consumed wheat products
from which vomitoxin and other trichothecene mycotoxins were recovered. In 1997
to 1998, approximately 1700 US children became ill with vomiting, nausea,
headache, and abdominal cramps linked to eating burritos. Although
levels of vomitoxin in the burritos were less than 1 ppm, the Food and Drug
Administration (FDA) advisory level, vomitoxin could not be eliminated as
the causal agent because this advisory level is set for adults and may not
be applicable to children. Ingestion of mycotoxin-contaminated food is the
most important route of exposure; 2 other routes should be recognized, as
both dermal absorption and inhalation of macrocyclic trichothecene
mycotoxins have been associated with human illnesses.
Satratoxin
Satratoxin is produced by Stachybotrys atra (also known as S chartarum).
This fungus can grow on any cellulose product in the presence of water.
Dissemination of spores into indoor air occurs when the fungus is disturbed.
An epidemiologic study in 1994 found that 10 infants with life-threatening
acute pulmonary bleeding were more likely than a matched group of 30
comparison infants to live in homes with S atra and other molds in the air. The
findings linking S atra and other fungi to infant pulmonary hemorrhage are
controversial and have undergone careful scrutiny.
Additional research is needed to determine whether the reported association
between infant pulmonary hemorrhage and exposure to toxigenic S atra is
causal.
Exposure to S atra has subsequently been associated with acute pulmonary
hemorrhage in an infant in Kansas City, Mo, and with
pulmonary hemosiderosis in a 7-year-old in Houston, Tex. The Texas investigators cultured S atra
from the patient's bronchoalveolar fluid. Trichothecenes suppress the immune
system, leading to increased susceptibility to a variety of infectious
diseases.
Prevention
Both drought and flooding contribute to problems with mycotoxins. Fungi are
usually unable to penetrate intact seed kernels; drought may weaken the
plant, allowing penetration of the fungus. Mycotoxin problems in food may be
greater during years of extreme drought. Intense
rain and flooding can also increase mycotoxin problems; intense rain events
have increased by 20% since 1900.
Massive contamination with mold is detectable and problems can be avoided by
not eating visibly moldy foods. The consumer cannot tell that processed
products have elevated levels of aflatoxins, vomitoxin, or fumonisins;
furthermore, these mycotoxins are not destroyed by heating. The FDA has set
action levels, informal nonbinding guidelines, for aflatoxins in food. The
FDA has advisory levels for vomitoxin but no established action levels and
has recently released a draft guidance document for industry on fumonisin
levels in human foods and animal feed.
Mycotoxins and Biological Warfare
One of the earliest uses of mycotoxins in warfare occurred in sixth century
BC when the Assyrians poisoned enemy wells with rye ergot. By the late
1990s, several countries had weaponized aflatoxin and there was suspicion
that trichothecenes were also under investigation for use in biological
warfare.
Controversy exists about the purported use of T2 (a trichothecene mycotoxin)
in aerosol form (yellow rain) in Laos, Kampuchea, and Afghanistan in the
1970s and 1980s. The only effective methods to prevent exposure are physical
protection of the skin and the airway; treatment is limited to supportive
care. Clinicians should be alert for cases of unusual illness and report
them to the local health department. Historically, every discovery of the
acute health effects of mycotoxins has been prompted by reports of unusual
illnesses from alert clinicians; vigilance and early reporting are the most
promising lines of defense against the potential bioterrorist use of
mycotoxins.
Author/Article Information
Author Affiliation: Division of Environmental and Occupational Health,
George Washington University, School of Public Health and Health Services,
Washington, DC.
Corresponding Author and Reprints: Ruth A. Etzel, MD, PhD, US Public Health
Service, Alaska Native Medical Center, 4320 Diplomacy Dr, Anchorage, AK
99508 (e-mail:
retzel@earthlink.net).
Contempo Updates Section Editor: Janet M. Torpy, MD,
Fishbein Fellow.
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