JAMA ARTICLE: Linking Evidence and Experience

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This information is just out! 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. Table 1 lists 4 major classes of mycotoxins and their health effects. Exposure to mycotoxins may occur through ingestion, inhalation, and dermal exposure. 1, 2 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, 3 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. 4 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. 5 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.6 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. 7 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. 9, 10 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. 's fire because it was often cured by a visit to the shrine of St. , 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 1692.11 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. 12, 13 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. 14 Fumonisins seem to be universally present in corn and corn-based products. 15 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. 15 In 1989 and 1990, fatal outbreaks of equine leukomalacia, porcine prenatal and neonatal mortality, and porcine pulmonary edema occurred in the United States. 16-18 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. 15 The fumonisins have been shown to disrupt sphingolipid metabolism. 19 Sphingolipids play a role in membrane and lipoprotein structure and in cell regulation as second messengers for growth factors, differentiation factors, and cytokines.19 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.20-23 Mexican Americans' risks of neural tube defects are much higher than those of non-Hispanic whites. 22 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).20 Fumonisin has been shown to interfere with cellular folate uptake 24 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. 23 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 25 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. 26 The acute toxicosis resulting from the inhalation of the Stachybotrys mycotoxin, first described by Soviet scientists in the 1940s, has been termed stachybotryotoxicosis. 27 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. 28 In India in 1987, nearly 100 persons became ill after they consumed wheat products from which vomitoxin and other trichothecene mycotoxins were recovered. 29 In 1997 to 1998, approximately 1700 US children became ill with vomiting, nausea, headache, and abdominal cramps linked to eating burritos. 30 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. 31 The findings linking S atra and other fungi to infant pulmonary hemorrhage are controversial and have undergone careful scrutiny. 32-34 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, 35 and with pulmonary hemosiderosis in a 7-year-old in Houston, TX. 36 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. 37 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. 38 Intense rain and flooding can also increase mycotoxin problems; intense rain events have increased by 20% since 1900.39, 40 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. 41 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. 42 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. 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