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What the Primary Care Pediatrician Should Know aboutSyndromes Associated with Exposures to Mycotoxins

Ruth A. Etzel, MD, PhD

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D isease associated with exposure to myco-toxins is known as the “Great Masquer-ader” of the 21st century because of its

complex natural history involving different tis-sues and resembling different diseases at eachstage in its evolution. It can present with a varietyof nonspecific clinical signs and symptoms suchas rash, conjunctivitis, epistaxis, apnea, cough,wheezing, nausea, and vomiting. Some cases ofvomiting illness, bone marrow failure, acute pul-monary hemorrhage, and recurrent apnea and/or“pneumonia” are associated with exposure tomycotoxins. Familiarity with the symptoms ofexposure to the major classes of mycotoxinsenables the clinician to ask pertinent questionsabout possible fungal exposures and to removethe infant or child from the source of exposure,which could be contaminated food(s), clothingand furniture, or the indoor air of the home.Failure to prevent recurrent exposure often resultsin recurrent illness. A variety of other conditions,including hepatocellular and esophageal cancerand neural tube defects, are associated with con-sumption of foods contaminated with mycotox-ins. Awareness of the short- and long-term con-sequences of exposures to these natural toxinshelps pediatricians to serve as better advocatesfor children and families.

rom the Division of Environmental and Occupational Health, Georgeashington University, School of Public Health and Health Services,ashington, DCarts of this review appeared previously in reference 16 and inhapter 16, “Mycotoxins and Human Disease” in Microbial Toxins:olecular and Cellular Biology, edited by Thomas Proft (Norfolk,ngland: Horizon Bioscience), 2005, pp. 447-472.urr Probl Pediatr Adolesc Health Care 2006;36:282-305538-5442/$ - see front matter2006 Mosby, Inc. All rights reserved.

soi:10.1016/j.cppeds.2006.05.003

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ntroduction

During the past decade, a paradigm shift has takenlace with respect to pediatricians’ understanding ofhe links between exposures to fungi and healthroblems. Once considered to be an issue of concernnly for immunocompromised children or those livingn developing countries in Africa and Asia, a growingody of evidence now documents that immunocompe-ent children in the United States and other industrial-zed countries can experience symptoms secondary tohe allergic properties of fungi and/or the toxic prop-rties of mycotoxins. Pediatricians have long beenware of the importance of preventing invasive fungalnfections among children with immune compromisend they are very familiar with handling allergies toungi. Primary care pediatricians are less aware of theoxic properties of fungi and many find themselvesonfused and somewhat puzzled by the often contra-ictory messages currently flooding the media.This article will highlight some of the acute presen-

ations that should prompt a clinician to considerxposure to mycotoxins in the differential diagnosis.urrently there are four pediatric syndromes that cane associated with exposures to mycotoxins. Theseypically have been characterized as “idiopathic” butn fact the possibility of an etiologic link to fungi andycotoxins has rarely been considered. For each

yndrome, this article will describe possible mycotox-ns to consider, a diagnostic approach, and whenvidence is available, possible interventions. In a busyractice, the clinician must act before all of theesearch questions have been definitively answered.herefore a preventive approach is recommended ineeping with the Hippocratic injunction to do no harm.The article will then describe some of the long-termealth effects associated with mycotoxins. Because ofheir long latency periods, the pediatrician will rarelyee patients with mycotoxin-associated cancers but

hould nonetheless be able to provide guidance to

Curr Probl Pediatr Adolesc Health Care, September 2006

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oncerned parents. The literature on the toxic effectsf fungi is expanding rapidly and additional informa-ion will soon be available for the clinician.Fungi are omnipresent in our environment. Theyrow on foods routinely consumed by animals andumans. Fungi also are plentiful in the outdoor air.he concentrations of fungi in the outdoor air varyccording to season and weather conditions.1 In sub-rctic climates, outdoor concentrations of fungi aresually highest in spring and autumn.2 Fungi are alsoresent in most indoor environments; they enter homeshrough doorways, windows, and heating and aironditioning systems. The most common fungi foundndoors are Cladosporium, Penicillium, Aspergillus,nd Alternaria.3,4 Fungi require water and nutrients torow. Problems may develop indoors when the pres-nce of standing water leads to excessive growth ofungi.5-7 Water may come into a home from leaks inoofs and walls, or from flooding.8-10 Nutrients re-uired by fungi often come from cellulose items in theome, such as wallpaper, wood, or cardboard.Certain fungi such as Stachybotrys chartarum (previ-usly and commonly known as Stachybotrys atra) andrichoderma species require chronically water-damagednvironments to grow.11 Because of this requirement,hey tend to be found indoors less frequently than

able 1. Selected mycotoxin-producing fungi of relevance to children’s he

Fungus Mycotoxins

spergillus flavus Aflatoxinsspergillus parasiticus

usarium verticillioides Fumonisinsusarium proliferatumspergillus ochraceus

Trichothecenes, Nonmausarium culmorum Deoxynivalenolusarium graminearumusarium cerealisusarium sporotrichiodes T-2 toxin

Trichothecenes, Macrotachybotrys chartarum Satratoxinsrichoderma viridirichothecium roseum

spergillus ochraceus Ochratoxinsspergillus nigerspergillus alliaceusenicillium verrucosum

enicillium expansum Patulin

usarium graminearum Zearalenone

laviceps purpurea Ergot alkaloids

ladosporium, Penicillium, Aspergillus, and Alternaria. h

urr Probl Pediatr Adolesc Health Care, September 2006

ndoors, when fungi are disturbed, they can disseminatepores into the confined space of a building.Under some circumstances, fungi produce tox-

ns.12-14 Mycotoxins on the fungal spores are easilybsorbed by the airways, intestinal lining, and skin.15

he word mycotoxin is derived from “myco” meaningungus and “toxin” meaning naturally produced poi-on. Fungi probably developed toxins to serve as ahemical defense against insects, microorganisms,ematodes, grazing animals, and humans.16 About 400ycotoxins have been identified, and there are prob-

bly many more. The name of a mycotoxin is usuallyerived from the fungus producing it. Aflatoxin, theoxin from Aspergillus flavus, gets its first letter “A”rom the genus Aspergillus, “fla” from the speciesavus appended with “toxin.” Some mycotoxins arenown by a chemical name (eg, deoxynivalenol) or bytoxic manifestation (eg, vomitoxin).Certain mycotoxins are beneficial to children and

dolescents. They are used as antibiotics (penicil-in), immunosuppressants (cyclosporine A), and forhe abortive treatment of migraine headaches (er-otamine). Mycotoxins also can be harmful tohildren and adolescents, even in the absence ofiable fungi. Table 1 lists fungi that produce theycotoxins of primary importance to children’s

Associated health effects

Vomiting, hepatitisLiver cancer

VomitingNeural tube defectsEsophageal cancer

clicVomiting

Alimentary toxic aleukiaVomiting, hemorrhage

Protein synthesis inhibitionHemorrhage

Balkan nephropathyRenal cancer

Vomiting, cancer (suspect)

Estrogenic effects, cervical cancer (suspect)

Ergotism

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atoxins, patulin, zearalenone, ergot alkaloids) anddentifies some of their associated health effects.16

Diseases associated with exposures to mycotoxins canresent with a variety of nonspecific clinical signs andymptoms in infants and children such as rash, conjunc-ivitis, epistaxis, apnea, cough, wheezing, nausea, andomiting. A century ago, syphilis was called the “Greatasquerader” because of its complex natural history

nvolving different tissues and resembling different dis-ases at each stage in its evolution. In the 21st century theGreat Masquerader” is disease caused by mycotoxins.ecause of the variety of ways that mycotoxin-relatediseases manifest clinically, the chance of confusinghem with other diseases is great. Moreover, manyediatricians have little experience detecting or evenuspecting that mycotoxins might be involved in pediat-ic diseases. The symptoms can easily be mistaken forhose of other illnesses such as pneumonia or influenza.urther complicating the picture is the fact that theiverse clinical manifestations associated with exposureso mycotoxins may not be readily identifiable as a singlelinical entity. The reason that the clinician shouldonsider exposure to mycotoxins in the differential diag-osis of puzzling and recurrent symptoms is that effec-ive treatment involves removing the infant or child fromhe source of exposure. Just as a child with carbononoxide poisoning will continue to be symptomatic

and could die) if he returns to a home with an elevatedarbon monoxide level, so the child with symptomselated to a specific fungal exposure will likely becomeymptomatic again on returning to a home with highevels of certain fungal spores or spore fragments in their. Unless the clinician considers this potential etiologynd asks questions about exposure to moldy items andnvironments, the opportunity to prevent further harmill be missed.Mycotoxins can have protean manifestations; the

ymptoms depend on the specific toxin or mixture ofoxins, the age, sex, and diet of the child, the dose, andhether exposure is by ingestion, inhalation, skin anducosal exposure, or a combination of two or more of

hese routes.14,17 The most well-characterized presenta-ions among infants and children are summarized in

able 2. Clinical presentations of mycotoxin-associated diseasesmong infants and children

omiting illnessone marrow failurecute pulmonary hemorrhageecurrent apnea and/or “pneumonia”

able 2 under four headings: vomiting illness, bone e

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arrow failure, acute pulmonary hemorrhage, and recur-ent episodes of apnea and/or “pneumonia.”

cute Clinical Presentationsomiting Illnesses

Illustrative Case History 1. A previouslyhealthy 12-year-old boy presented to the clinicwith the chief complaint of abdominal cramps,vomiting, headache, and dizziness that beganabout 15 minutes after eating lunch at the schoolcafeteria. He denied diarrhea, diplopia, blurredvision, flushing, or paresthesias. Three hoursearlier he ate three beef burritos made from wheatflour tortillas. Several other classmates became illat the same time. On examination the boy waswell-hydrated, afebrile, and acyanotic. Results ofthe physical examination were unremarkable. Hiscarboxyhemoglobin level was 0.5%.

This case history presents a scenario that shouldrompt the alert clinician to investigate the possibilityf food poisoning from preformed toxins such asycotoxins. Mycotoxin ingestion should be consid-

red in a previously healthy child who developsomiting within minutes to 8 hours after eating. Thehysical examination is within normal limits. Acuteomiting secondary to ingestion of mycotoxin-con-aminated food usually is self-limiting and the symp-oms resolve within a few hours. Children present withredominant nausea and vomiting; fever is typicallybsent. The vomiting may be accompanied by head-che and dizziness, but rarely is diarrhea a predomi-ant symptom. If present, it is watery and fecaleukocytes are absent. A thorough history can offermportant clues to diagnosis. The history should em-hasize the number of minutes after eating that theomiting started, occurrence of similar symptoms iniblings or classmates, and occurrence in animals orets after eating leftover food.18 The differential diag-osis of headache, dizziness, nausea, and vomitinghould include carbon monoxide poisoning. Otherreformed toxins that can cause vomiting includetaphylococcus aureus toxins and Bacillus cereusoxins. Heavy metals that can cause vomiting includeopper, tin, cadmium, and zinc.19

Mycotoxins that Should be Considered. Fourroups of mycotoxins merit consideration when ahild presents with a vomiting illness within hours of

ating: trichothecenes, especially deoxynivalenol (also


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nown as vomitoxin) and T-2 toxin, fumonisins,flatoxins, and patulin. Table 3 lists the major clinicaleatures of each, which will be described separatelyelow.Trichothecenes. The first group of mycotoxins that

an cause vomiting among children is the trichoth-cene mycotoxins, including vomitoxin and T-2. Pro-uced by species of Fusarium, these nonmacrocyclicrichothecenes can contaminate grain products andetain their toxicity even after the grain is baked orooked. Ingestion of heavily contaminated food resultsn vomiting within hours.20

Vomitoxin, one of the most common mycotoxinsausing vomiting among children, frequently contam-nates wheat and corn. The estimated tolerable dailyntake of vomitoxin is 1.5 �g/kg body weight and 3.0g/kg body weight for infants and adults, respective-

y.21 Multiple outbreaks of vomiting illness during961 to 1985 in China were linked to consumption ofoods made with grain contaminated with vomi-oxin.22 In 1987, nearly 100 persons in India becamell after they consumed wheat products from whichomitoxin and other trichothecene mycotoxins wereecovered.18 In 1997 and 1998, approximately 1700chool children in the United States developed vom-

able 3. Clinical features of vomiting illness from exposure to mycotoxin

Toxin Latent period Clinical feat

omitoxin 3-15 min VomitingNauseaHeadacheAbdominal crampsPrompt resolutionNo sequelae

-2 5 min-1 h NauseaVomitingDiarrhea (bloody)Abdominal painDizziness“Burning” in mouthSymptoms improve in

flatoxins �8 h VomitingDiarrheaAbdominal painDizzinessSeizuresFeverHepatic toxicity can o

umonisins N/A NauseaVomiting

atulin N/A NauseaVomiting

ting, nausea, headache, and abdominal cramps after c


ating burritos.23 Vomitoxin was identified as a con-aminant in the burritos and might have caused theutbreaks, which subsided within 24 hours of onset.23

Aflatoxins. A second group of mycotoxins that canause vomiting among children is the aflatoxins. Pro-uced by A. flavus and A. parasiticus, these mycotox-ns commonly contaminate peanuts, maize, soybeans,nd cassava, especially in tropical areas. Massiveflatoxin ingestion can result in acute aflatoxicosisith vomiting, abdominal pain, hepatitis, and some-

imes death. The acute lethal dose for adults is 10 to 20g, whereas the acute lethal dose for children is

stimated to be about 3 mg.24 In developing countries,pidemics have been reported following ingestion ofood heavily contaminated with A. flavus.24-30 One ofhe largest reported outbreaks of aflatoxin poisoningccurred in Kenya in 2004.28-30 Three hundred seven-een people became ill and 125 died.29 About 22% ofhe patients were aged � 5 years and 29% were aged

to 14 years.28 Diet clearly affects the toxicity offlatoxins. In animal studies, rats deficient in B vita-ins and fed aflatoxins showed signs of aflatoxicosis;

ats with adequate B vitamins did not show signs offlatoxicosis.31,32

Fumonisins. A third group of mycotoxins that can

Foods associated

Food made from wheat (eg, burritos)

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umonisins are universally present in corn and corn-ased products.33 They are produced by Fusariumerticillioides, Fusarium proliferatum, and Aspergilluschraceus. Both fumonisin exposure and aflatoxinxposure are epidemiologically associated with food-orne disease outbreaks.33-38 Because contaminationith more than one fungus is a common occurrence, it

s likely that interaction between toxins is a key factoretermining the severity of the child’s symptoms.able 4 lists the interactions of fungal toxins and other

isk factors in the development of food-borne diseaseutbreaks.Patulin. A fourth mycotoxin that can cause vomiting

mong children is patulin. Patulin comes from aumber of fungal species, including Penicillium, As-ergillus, and Byssochlamys. The apple-rotting fungusenicillium expansum is the most commonly encoun-

ered producer of patulin. Apple juice and other appleroducts can contain patulin when rotten apples haveeen processed.39 Alcoholic fermentation of fruituices destroys patulin; fermented products such asider do not usually contain patulin.40 Symptoms inumans reportedly due to patulin toxicosis are nausea,omiting, and gastrointestinal disturbances, althoughublished literature on the occurrence of these symp-oms among children is sparse.41,42 No reports of

able 4. Interaction of fungal toxins and risk factors in the development

Geographic region/country

Age-standardized incidence(No. of cases per 100,000)

Fungaldie

outhern India Deccan Plateau; gastrointestinaldisease35-37

Moldy soFusariAltern

astern and CentralKenya

Makueni 16.7Thika 1.930

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dapted from: Joint Expert Committee on Food Additives. Safety evaluationeproduced by permission.

able 5. Questions to consider in the history if ingestion of mycotoxinss suspected

ave other persons who ate the same food become ill?id the symptoms begin within minutes to 3 hours of eating?id any pets or animals eat the same food and become sick?as diarrhea absent or a minor part of the illness?

utbreaks have been published. i

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Diagnostic Approach. If acute ingestion of myco-oxins is a concern, the clinician should consider theuestions in Table 5. There are no definitive diagnosticests to confirm that a child’s illness is associated withonsumption of mycotoxins in food. Neither hospitalaboratories nor public health laboratories in thenited States routinely perform testing for mycotox-

ns. Identifying the etiologic agent is therefore diffi-ult. If multiple people in the same family or groupevelop symptoms of nausea and vomiting withoutiarrhea or fever after eating together, a sample of theuspected food(s) should be obtained for possiblenalysis. In food-borne illness outbreaks, the localealth department should be consulted to assist inetermining whether and where the food sampleshould be analyzed because the specialized analysesor mycotoxins are usually only conducted in nationalaboratories of the US Food and Drug Administrationnd the US Department of Agriculture.Intervention. Mycotoxin contamination in food isreatest during years of extreme drought.43 Fungisually are unable to penetrate intact seed kernels butrought conditions can weaken the plant and allowenetration to occur. Severe rain and flooding can alsoncrease mycotoxin contamination of crops; intenseain events have increased 20% in the last century.44,45

hus both drought and flooding can contribute toycotoxin contamination of food. Visibly moldy

oods should not be eaten. Contamination with lowerevels of mycotoxins, however, cannot be detected byight, smell, or taste. Few food items undergo anyesting to detect mycotoxins. The US Food and Drugdministration establishes action levels for aflatoxins

d-borne disease outbreaks

ion of majorstaples

Mycotoxin contaminationDietary and other

risk factors

m and maizespergillus,pp.35,38

Sorghum: fumonisin B1(0.14-7.8 mg/kg);aflatoxin B1 (trace-0.08mg/kg)

Low socioeconomicstatus; lack ofaccess to otherfoods such asrice35

Maize: fumonisin B1 (0.25-65 mg/kg); aflatoxin B1(0.05-0.93 mg/kg)

illus spp.30 Maize: total aflatoxin inMakueni (27.19-103.21�g/kg); in Thika 3.83-14.78 �g/kg)30

Hepatitis B surfaceantigenpositivity29

rtain mycotoxins in food. Geneva: World Health Organization; 2001:151-5.

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he US Food and Drug Administration sets advisoryevels for vomitoxin, but no established action levels.he Food and Drug Administration has a draft guid-nce document for industry on fumonisin levels inuman foods and animal feeds,46 but no advisoryevels or action levels for fumonisin have been set.

Case 1 Follow-Up. The 12-year-old boy recov-ered completely within 2 hours. A cafeteria workersaved a sample of the beef burritos that had beenserved for lunch on the day the children became illand it was sent to the US Food and Drug Admin-istration. The level of vomitoxin detected in theburrito was 0.3 milligrams per kilogram, lower thanthe advisory level (1 milligram per kilogram) set bythe US Food and Drug Administration. Vomitoxincould not, however, be ruled out as a possibilitybecause this advisory level does not account for thespecial vulnerabilities of children.

one Marrow Failure

Illustrative Case History 2. An 8-month-oldwhite Hispanic male was brought to the clinic witha fever of 102.4°F and neutropenia. Six days earlierduring a clinic visit for diarrhea, irritability, and rashhe was noted to have mouth sores and a 3-mmpustule on his back. At that time his white blood cellcount was 5500 per cubic millimeter with a differ-ential count of 1% polymorphonuclear forms, 68%lymphocytes, 29% monocytes, 2% eosinophils, andadequate platelets. The pediatrician instructed theparents to return if the infant developed a fever.

The infant was admitted directly from the clinicto the hospital. Examination revealed a well-hydrated healthy-appearing infant in no acutedistress with a very mild papular rash. No hyper-pigmentation, café-au-lait spots, or Mees lineswere seen. Palpebral conjunctiva were injected.His heart sounds were normal and his chest wasclear to auscultation. Neurologic examinationwas entirely normal. The abdomen was soft andnontender. The spleen was palpable three finger-breaths below the left costal margin. Results of thephysical examination were otherwise unremarkable.

His white blood cell count was 7000 per cubicmillimeter with a differential count of 3% poly-


morphonuclear forms, 77% lymphocytes, 13%monocytes, 7% eosinophils, and 206,000 plate-lets. His hemoglobin was 12.4 g/dL, hematocritwas 36.6%, and reticulocytes were 0.14%. Bloodchemistry results showed a glucose of 84 mg/dL,urea nitrogen 9 mg/dL, creatinine 0.3 mg/dL,sodium 138 mmol/L, potassium 4.9 mmol/L,chloride 104 mmol/L, CO2 21 mmol/L, alanineaminotransferase 61 U/L, alkaline phosphatase291 U/L, aspartate aminotransferase 69 U/L, totalbilirubin 0.2, and erythrocyte sedimentation rate27. Urine analysis was normal. Direct antibodytest (DAT), Anti-IgG was positive. Nonspecificcold antibodies were found.

His past history revealed that he had beenhealthy until about 6 weeks before admissionwhen he developed “itchy eyes.” Three weeksbefore admission he developed a cough and afever of 102 to 103°F. Radiograph of the chestshowed patchy hilar and infrahilar infiltrates bi-laterally. He was given a presumptive diagnosisof pneumonia and treated with azithromycin. Noblood tests were taken.

The initial hospital evaluation included a bonemarrow biopsy that showed dilute bone marrowwith erythroid hypoplasia and paucity of mature redcell precursors. There was slight myeloid hyperpla-sia with a maturation block at the band stage. Noevidence of leukemia or myelodysplastic syndromewas found. He had a normal male karyotype withno numerical or structural chromosome aberrations.He received granulocyte colony-stimulating factor50 �g subcutaneously; the following day his whiteblood cell count was 6300 per cubic millimeter with16% neutrophils. Six days later his absolute neutro-phil count rose to 15,200 cells per cubic millimeterand the granulocyte colony-stimulating factor treat-ments were discontinued. Cultures of blood andurine showed no growth of bacteria and he wasdischarged from the hospital.

Over the next month, the hemoglobin droppedprogressively to 5.7 g/dL. Iron was 96 �g/dL,ferritin was 72.3, iron saturation was 41, totaliron-binding capacity was 232, and the erythro-poietin level was 1060 mIU/mL (normal � 19mIU/mL). The platelet count was 150,000. Hehad a normal partial thromboplastin time, pro-thrombin time, and international normalized ra-

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tio. He underwent the first of several bloodtransfusions. A repeat bone marrow at age 10months was dilute but showed a decreased num-ber of red cell precursors and no mature red cellprecursors. His platelets dropped to 57,000 andhe received platelet transfusions, cefepime, andgranulocyte colony-stimulating factor. A weeklater the hemoglobin was 13.4 g/dL, the hemato-crit 36.9%, mean corpuscular volume 84.4 fL,mean corpuscular hemoglobin 30.7 pg, and meancorpuscular hemoglobin concentration 36.3 g/dL.The platelet count was 97,000. Immunologictesting for hepatitis B and C, cytomegalovirus,Epstein–Barr virus, and mycoplasma was nega-tive. Figure 1 shows the time sequence of thisillness; neutropenia was the first manifestation,followed by anemia, and then thrombocytopenia.

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Mycotoxins that Should be Considered. This caseistory of neutropenia of unknown etiology shouldrompt the alert clinician to investigate the possibilityf exposure to toxic agents including trichotheceneycotoxins.Trichothecenes. Ingestion of foods heavily contam-

nated with trichothecene mycotoxins is well recog-ized as a cause of neutropenia. This has, however,arely been described outside of Russia, where it wasriginally named alimentary toxic aleukia. Affectedatients progress to develop pancytopenia.47 When thelatelet count drops below 5000 per millimeter, patientsevelop necrotic ulcers in the nose, mouth, throat, stom-ch, and intestines and begin bleeding from the nose,outh, and gastrointestinal tract. At this stage fatalities

re common. The disease was first documented in 1913n far Eastern Siberia and was reportedly responsible forhe death of at least 100,000 Russian people between

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leukia was linked with consumption of grains (in-luding wheat, millet, and corn) that had been coveredith snow during winter and were contaminated withusarium and Stachybotrys fungi.Although this disease is unfamiliar to most primary

are pediatricians, it is well known to large animaleterinarians. The fact that trichothecenes cause dis-ase when ingested by farm animals is extensivelyocumented in the veterinary literature.49-52

Skin and mucous membrane exposure to the tri-hothecene mycotoxins can cause a severe skin rashith which clinicians are rarely familiar. The der-atitis, first described among workers handling

odder and those who used infected straw for fuel orlept on mattresses made of infected straw, isharacterized by hyperemia, encrustations, and ne-rosis.53 Young children may present with a macu-opapular rash and numerous painful oral ulcers thatake it difficult to eat. An erythematous, indurated

esion was described in an 11-year-old male withevere aplastic anemia; cultures of the lesion re-ealed Trichoderma longibrachiatum.54

Diagnostic Approach. A bone marrow biopsy isequired to make the diagnosis. In the differentialiagnosis, other causes of neutropenia should be con-idered, including exposure to radiation, leukemia,anconi’s anemia, cyclic neutropenia, chronic benigneutropenia, and severe chronic neutropenia. To testor Fanconi’s anemia, an autosomal-recessive disease,hromosome breakage in peripheral blood lympho-ytes should be evaluated.The evaluation should include a thorough historyf exposure to toxic agents such as radiation,hemotherapy, or other drugs or chemicals. Hospitalaboratories in the US do not routinely test forrichothecene mycotoxins in human tissue. Identify-ng the etiologic agent is therefore difficult. Thelassic history includes diarrhea and rash that per-

hours 3-9ToxinIngestion

NauseaVomitingDiarrhea

IG 2. Time course of adverse events preceding bone marrow

ist for about a week before symptomatic improve- r


ent. As shown in Figure 2, bone marrow failureollows about 2 weeks later.Intervention. Therapy is supportive. If exposure to

richothecene mycotoxins is being considered as aossible etiology, the mainstay of treatment is toemove the child from any chronically water-damagednvironments to prevent recurrences.

Case 2 Follow-Up. The infant’s parents re-ported that there was a longstanding ongoingtoilet leak in the master bedroom of their house.They saw aquatic midges (small winged insects)coming out of the ventilation ducts. The areabehind the toilet was chronically wet and blackmold was present. An air sample collected in thewall cavity of the master bathroom showed 1932colony-forming units (CFU) per cubic meter ofPenicillium species. Stachybotrys species wasidentified microscopically from a sample of thebathroom drywall.

Following an extensive hematologic evaluation,no etiology could be identified and the physicianconcluded that the infant’s bone marrow failurewas likely secondary to the fungal exposure in thehouse. The child improved dramatically after hisparents vacated that house and has since been ingood health.

cute Pulmonary Hemorrhage

Although ingestion is the most widely docu-ented route of exposure to mycotoxins, inhalation

s increasingly being recognized as an importantoute.55 Unlike the gastrointestinal effects second-ry to ingestion of mycotoxins, the effects of inhala-ion of mycotoxins are different for children at differ-nt ages of exposure. This may be because the

2 weeksSymtomsImprove

Bone MarrowFailure

re. (Color version of figure is available online.)

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f life, and some mycotoxins have an affinity forapidly dividing cells.56

Illustrative Case History 3. An 8-month-oldblack male was brought to the emergency roombecause of cyanosis, tachypnea, and grunting.Mother reported an episode of epistaxis 2 daysbefore admission. The infant had been deliveredby cesarean delivery at 37 weeks and had anuneventful neonatal course. He had six previoushospital admissions for afebrile episodes in whichhe became apneic, limp, and cyanotic and themother noted frothy blood coming out of themouth. On each admission he required mechani-cal ventilation and radiographs of the chestshowed bilateral alveolar infiltrates.

Physical examination revealed an agitated in-fant with a temperature of 36.5°C, pulse of 140beats per minute, and respirations of 60 perminute with grunting and rib retractions. Bloodpressure was 103/70 mm Hg. His skin wascyanotic but without bruises, petechiae, or rashes.There were lacy reticular plaques on the buccalmucosa and the posterior pharynx. The heartsounds were normal. Chest auscultation revealedrales bilaterally. Abdomen was soft and non-tender. Twelve hours after admission he devel-oped pulmonary failure and was placed on me-chanical ventilation. Bright red blood was notedin the endotracheal tube after atraumatic intuba-tion. Hemoglobin was 7.8 g/dL, and hematocritwas 26.6% with 10.10% reticulocytes. Analysisof the urine showed hemoglobinuria. The infantdied on the first day of hospitalization.

Mycotoxins that Should be Considered. This caseistory of massive pulmonary hemorrhage of unknowntiology should prompt the alert clinician to investigatehe possibility of exposure to toxigenic fungi includingrichothecene mycotoxins. The link between exposure toungi in the home environment and acute pulmonaryemorrhage was discovered in 1994 when a case-controltudy found that 10 infants with life-threatening acuteulmonary bleeding who were admitted to a children’sospital were more likely than a matched group of 30omparison infants to live in severely water-damagedomes with Stachybotrys and other fungi in the indoorir.57 Exposure to Stachybotrys and other toxigenic

ungi, including Trichoderma, has subsequently been i

90

ssociated with acute pulmonary hemorrhage amongnfants in other areas of the United States58-63 andew Zealand.64 The rapidly growing lungs of infantsnder 1 year of age appear to be especially vulnerableo the effects of the trichothecene mycotoxins pro-uced by Stachybotrys and Trichoderma.65 Theseycotoxins are lipid-soluble and readily absorbed by

he airways.65 They are among the most potent proteinynthesis inhibitors known.66 The effects of the tricho-hecene mycotoxins are more than 10 times greater vianhalation than via intravenous exposure.65 Stachybot-ys also produces a hemolysin and several proteinaseshich can degrade vascular collagen.67

There have been a number of studies in animalodels that document pulmonary hemorrhage follow-

ng exposure to the spores of toxigenic fungi. It appearshat the effects are more serious for the infant than for thedult animal. Yike and colleagues instilled conidia of. chartarum directly into the tracheas of 4-day-old ratups. The pups suffered fatal pulmonary hemor-hage.68 Among adult mice, however, intranasal expo-ure to Stachybotrys spores resulted in severe alveolarnd interstitial inflammation with hemorrhagic exu-ate in the alveoli, but no overt hemorrhage.69

Apnea also has been documented following expo-ure to fungal spores. One day after Yike instilledpores in the tracheas of the rat pups, 28% of themxperienced apnea more than 3 seconds in duration.68

ike showed that when a dose of 4 � 105 spores perram was instilled in the trachea of infant rat pups,3% of the pups suffered fatal pulmonary hemorrhage;hen the dose was increased to 8 � 105 spores perram, 83% of the pups suffered fatal pulmonaryemorrhage.68 This suggested a dose-response rela-ionship in infant animals between increased exposureo Stachybotrys and pulmonary hemorrhage.Like any new discovery, the findings linkingtachybotrys and other fungi to acute pulmonaryemorrhage have undergone careful scrutiny. Ana-ysts not involved in the original study reanalyzedhe data employing different assumptions and foundhat the relationship between S. chartarum andnfant pulmonary hemorrhage remained statisticallyignificant.70 Additional studies are needed to de-ermine whether the association between infantulmonary hemorrhage and exposure to toxigenicungi is causal.71,72

Diagnostic Approach. The causes of acute pulmo-ary hemorrhage in a previously healthy infant can

nclude trauma, foreign body, infection, and suffo-


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ation. The evaluation should include a carefulistory and physical examination. Laboratory testsnclude a complete blood count with differential,eticulocyte count and platelet count, manual reviewf the peripheral smear for evidence of hemolysis,artial thromboplastin time, prothrombin time, andleeding time, renal function tests, and analysis ofrine. The key to acute management of acuteulmonary hemorrhage is endoscopic evaluation ofhe airway to determine the area of bleeding andossibly the specific site or lesion responsible.73

ronchoalveolar lavage should be done to look foremosiderin-laden macrophages. A finding of morehan 50% of the macrophages containing hemosid-rin is pathognomonic of pulmonary hemosiderosis.ack of hemosiderin-laden macrophages may indi-ate that the infant is experiencing the first occur-ence of alveolar bleeding. It takes approximately0 to 70 hours for hemosiderin-laden macrophageso appear after acute pulmonary hemorrhage.74 En-oscopy may be indicated to evaluate gastrointesti-al bleeding with aspiration, and an electrocardio-ram and echocardiogram to look for cardiacisease. The mortality from acute pulmonary hem-rrhage in children is 21% despite prompt andhorough evaluation and treatment.73

Intervention. Although no randomized controlledrials have yet been performed, it may be helpful toreat infants with acute pulmonary hemorrhage withethylprednisolone (1 mg/kg every 6 hours while

ntubated and 1 mg/kg/d after extubation).75,76

To prevent recurrence, the American Academy ofediatrics suggests that infants with acute pulmo-ary hemorrhage not be returned to moldy homenvironments.11,77 A significant reduction in recur-ent pulmonary hemorrhage was documented fol-owing the recommendation that each infant withcute pulmonary hemorrhage be removed from theesidence in which the infant was living when theulmonary hemorrhage occurred.75 Before routineecommendations to move, five of seven infants hadecurrent pulmonary hemorrhage; after the recommenda-ion to move, 1 of 21 had recurrent pulmonary hemor-hage. The Center for Indoor Environments and Health athe University of Connecticut has published guidance forlinicians on the recognition and management of healthffects related to mold exposure indoors.78 Figure 3

hows that infants exposed to extensive indoor fungal


ontamination can present with an acute life-threaten-ng event.

Case 3 Follow-Up. Post-mortem examinationof the 8-month-old male showed extensive alve-olar and interstitial hemosiderosis with pulmonaryarterial and right ventricular hypertrophy. Homeevaluation after the infant’s death revealed a chron-ically water damaged environment with evidence oftoxigenic fungi on walls and other surfaces.

ecurrent Apnea and/or “Pneumonia”

Illustrative Case History 4. A 10-month-oldAlaska Native male was brought to the emer-gency room with the chief complaints of cough,fever, and decreased appetite. The mother re-ported that the infant had approximately seven“spells” of coughing and not being able tobreathe. On arrival the infant’s rectal temperaturewas 105.7°F, the pulse was 144, and the respira-tions were 44 per minute. He was noted to haveretractions and audible wheezes. A radiographshowed active infiltrates in the right upper lobe.He was admitted to the hospital with a presump-tive diagnosis of pneumonia and reactive airwaysdisease.

A complete blood count showed a white bloodcell count of 10,200 with a differential count of45% polymorphonuclear forms, 14% band forms,39% lymphocytes, 2% monocytes, and adequateplatelets. The hemoglobin was 10.8 g/dL andhematocrit was 32.1%. Blood chemistry resultsshowed a glucose of 128 mg/dL, urea nitrogen 6mg/dL, creatinine 0.2 mg/dL, sodium 139mmol/L, potassium 3.9 mmol/L, chloride 101mmol/L, and CO2 23 mmol/L.

The infant was treated with intravenous ceftri-axone and albuterol by nebulizer. After less than24 hours in the hospital the infant improved andthe mother asked that he be discharged. He wasdischarged home on amoxicillin-clavulinic acidsuspension.

Within 3 hours of discharge, the infant wasbrought back to the emergency room by hismother because he started coughing hard. Theinfant’s temperature was 98.4°F; his pulse was176 and his respirations were 68 per minute. Hewas readmitted to the hospital. The past history

291

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revealed that the infant was the 6 pound 15.4 ounceproduct of a full-term pregnancy and spontaneousvaginal delivery. At 2 weeks of age the infant wasadmitted to the hospital with “concern of not breath-ing.” The mother reported a 2-day history of coughand four cyanotic episodes. After 1 day of observa-tion the infant was breathing well and was dis-charged home. The infant was diagnosed with“pneumonia” at age 2 months and again at age 5months; each time he was brought to the emergencyroom with cough and dyspnea and fleeting infil-trates were seen on chest radiographs. He wastreated presumptively with antibiotics. Blood cul-tures showed no growth of bacteria.

Mycotoxins that Should be Considered. This caseistory of recurrent apnea, cyanotic episodes, cough,nd “pneumonia” in an anemic infant should prompthe alert clinician to investigate the possibility of

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92

ng after pulmonary hemorrhage is pulmonary hemo-iderosis. Infants with pulmonary hemosiderosis havenemia and recurrent or chronic cough, dyspnea,heezing, and often cyanosis.77 Unlike older children,emoptysis may be absent in infants. Pulmonaryemosiderosis in infants has been epidemiologicallyinked to exposure to toxigenic molds in the home.57 Aertinent feature is prompt deterioration after returningome from the hospital and subsequent rehospitaliza-ion only hours later. One published case study foundn association between pulmonary hemosiderosis andxposure to fungi in the indoor environment.79 Stachy-otrys was cultured from the bronchoalveolar lavageuid of a 7-year-old child with pulmonary hemosider-sis in Houston, Texas.79

Diagnostic Approach. The evaluation of infantsith recurrent apnea and/or “pneumonia” should in-

lude a careful history and physical examination. Theifferential diagnosis can include trauma, foreignody, suffocation, pneumonia, and Heiner’s syn-

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pplied in children with pulmonary infiltrates, gastro-ntestinal bleeding, iron-deficiency anemia, peripheralosinophilia, and failure to thrive80; its associationith milk is uncertain.A complete blood count with differential, reticulo-

yte count, and platelet count should be ordered.oagulation studies, metabolic panel, cultures oflood and urine, skeletal survey, electroencephalo-ram, and an endoscopic evaluation of the airway withronchoalveolar lavage are suggested. If abundantemosiderin-laden macrophages are found and inhala-ion of fungal spores is a possible concern, the clini-ian should consider the questions in Table 6. It is notecessary to measure the quantity of mold spores inhe air of an infant’s home. If mold is detectable byight or smell, the parents or guardians should deter-ine the water source and fix it. Fungi cannot growithout water. Evaluation of the types and quantitiesf fungi in the indoor air of a home is not usuallyecommended, but may occasionally be done foresearch purposes. The parents should be advised toonsult a certified industrial hygienist with experiencen bioaerosol measurements in the indoor air. Infantshould not be permitted to remain in the home whileesting is done.If bioaerosol measurements are taken, they may beifficult for the clinician to interpret. Table 7 listsalues that can be used as “rules of thumb” forssessing the number of fungal spores found in thendoor air. Mean levels of culturable fungal counts areategorized into five groups (group 1: low � 100FU/m3; group 2: medium 101 to 300 CFU/m3; group: high 301 to 1000 CFU/m3; group 4: very high 1001

able 6. Questions to consider in the history if inhalation of fungi andycotoxins is suspected

as the house or apartment been flooded?s there any water-damaged wood or cardboard in the house?as there been a roof or plumbing leak?ave occupants seen any mold?ave occupants noticed a musty smell?

able 7. Rules of thumb for fungi in the indoor air

ow �100 CFU/m3

edium 101 to 300 CFU/m3

igh 301 to 1000 CFU/m3

ery high 1001 to 5000 CFU/m3

xtremely high �5000 CFU/m3

FU, colony-forming units.

o 5000 CFU/m3; group 5: extremely high � 5000 d


FU/m3).81 Concentrations of 100 Alternariaonidia/m3 and 3000 Cladosporium conidia/m3 areevels that may induce respiratory symptoms.82 Al-hough no indoor guidelines have been set in thenited States, experts have suggested that even 150FU/m3 is considered to be high if there are dominant

pecies of fungi along with a few other species.4,83

he acceptable levels for airborne fungi are in the 200FU/m3 range.84 This is exclusive of the toxigenic

ungi, which are considered unacceptable in indoorir.6

Intervention. To prevent growth of molds, parentshould be advised to mop up water and remove allater-damaged items (including carpets) within 24ours of a flood or leak. If this is done, toxigenic fungiill not have the opportunity to grow. If some mold is

lready present, the affected area needs to be washedith soap and water, followed with a solution of oneart bleach to four parts water. Protective gloves andespiratory protection should be worn during cleanp.85 Most importantly, infants and children should beemoved from the house until the cleanup is com-leted. If exposures to fungal toxins were responsibleor an infant’s symptoms, the infant will usuallymprove quickly once he is out of the contaminatednvironment.

Case 4 Follow-Up. The infant’s mother raisedthe issue of inadequate housing; the family of sixlived in a one-bedroom trailer with a significantroof leak for the past year and water damage tothe interior that had not been remediated. Themother stated that she did not feel comfortabletaking the recovering infant back there because ofthe mold. She relocated to another trailer withoutwater damage and the infant’s symptomsdisappeared.

iseases with Long Latency Periods

The pediatrician will only rarely encounter condi-ions linked to chronic ingestion of fungi and myco-oxins because they may take years to develop. None-heless, a familiarity with some of the chronic effectsill prepare the pediatrician to answer questions from

amilies and communities. The most serious chronicealth effect associated with ingestion of mycotoxinss cancer. The specific mycotoxins consumed will

etermine the type of cancer.

293

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epatocellular Carcinoma

The most extensively documented mycotoxin-asso-iated cancer is hepatocellular carcinoma.86 In the960s the aflatoxins were discovered to be potentarcinogens in laboratory animals.87 In 1993 the In-ernational Agency for Research on Cancer deter-ined that aflatoxin B1 (the most potent of the

flatoxins) was a human carcinogen.88 Epidemiologictudies clearly document that ingestion of aflatoxin B1s a risk factor for hepatocellular carcinoma in hu-ans.31 Figure 4 shows that hepatocellular cancer

ollows many years after the acute symptoms offlatoxin ingestion (vomiting, abdominal pain,emetemesis, fever, diarrhea, dizziness, and seizures)ave occurred. Persons who have both hepatitis Bnfection and aflatoxin B1 exposure have a higher riskor hepatocellular cancer than those who have onlyepatitis B infection or only aflatoxin exposure.89

ersons with hepatocellular carcinoma who have beeneavily exposed to aflatoxins have more p53 mutationst codon 249 than do those with little exposure toflatoxins.90-97 Hepatocellular cancer is rarely diag-osed in persons younger than 20 years of age born inhe United States89 except among Alaska Nativehildren.98 In hyperendemic areas (such as Taiwan)he mean age at which hepatocellular carcinoma oc-urs in children is 10.6 years.99

Intervention. Recent studies demonstrate that pri-ary prevention of hepatocellular cancer in children is

ossible. Universal immunization programs for hepa-itis B have been shown to reduce the incidence ofepatocellular carcinoma in children in Taiwan100 andlaska.98 Although universal vaccination is the most

rucial step, efforts also are underway to reducehildren’s exposures to aflatoxins. In Qidong, Jiangsurovince, China (where hepatocellular carcinoma is

he leading cause of cancer deaths and exposure toietary aflatoxins is widespread) ongoing clinical trials

VomitingHematemesis

DiarrheaAbdominal Pain

FeverDizzinessSeizures

~ 8 hours wToxin Exposure

IG 4. Time course of adverse events preceding hepatocellula

ave documented that oltipraz, an antishistosomal b

94

rug, can lower the biologically effective dose offlatoxins by decreasing the metabolism of aflatoxin

1 to its carcinogenic form and increasing the detox-fication pathways of its metabolites.101 In high-riskegions intervention with drugs such as oltipraz andmproved storage conditions of staple foods are mea-ures being investigated to reduce the incidence ofepatocellular carcinoma.102 Table 8 shows that di-tary factors, including nutritional deficiencies, appearo increase the risk.103-114

sophageal CancerFumonisins. The fumonisins were discovered in988 following an outbreak of equine leukoencepha-omalacia in South Africa in 1970.115 Extensive inves-igations document that consumption of corn andorn-based products contaminated with fumonisin B1auses fatal diseases in farm animals including leu-oencephalomalacia in horses and pulmonary edeman pigs.33 In 1989 and 1990 corn grown in the Unitedtates had high levels of fumonisins; fatal outbreaks ofquine leukomalacia and porcine prenatal and neonatalortality and pulmonary edema occurred.116-118 Epi-

emiologic studies suggest a link between exposure toumonisin B1 and esophageal cancer.

33 Table 9 showsvidence from studies in South Africa, China, Iran,taly, Kenya, Zimbabwe, Brazil, and the United Statesinking esophageal cancer to ingestion of fumonisin-ontaminated foods.33,119-167

enal CancerOchratoxin A. Tumors of the upper urinary tractave been associated with exposure to ochratoxin A,he most toxic of the ochratoxins.34 Ochratoxins areroduced by Aspergillus ochraceus, Aspergillus allia-eus, and Penicillium verrucosum growing on cerealrains (barley, oats, rye, corn, and wheat) and othertems including coffee, milk powder, wine, and beer.he ochratoxins were the first group of mycotoxins to

yearsHepatotoxicity

Hepatocellular Carcinoma

cinoma. (Color version of figure is available online.)

eeks

e found after the discovery of the aflatoxins.168 The


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nternational Agency for Research on Cancer hasetermined that there is sufficient evidence in experi-ental animals for the carcinogenicity of ochratoxin.169 Ochratoxin A is categorized as possibly carci-ogenic to humans (group 2B).169

alkan Nephropathy

Ochratoxin A is also a potent nephrotoxin. Out-reaks of Balkan nephropathy, a fatal, chronic renalisease occurring in limited areas of Bulgaria, theormer Yugoslavia, and Romania, have been associ-ted with ochratoxin A.170,171 Levels of ochratoxin Are higher in the blood of patients with Balkanephropathy than in the blood of unaffected people.169

Intervention. Investigations are underway to explorehe use of aspartame, a structural analog of ochratoxin

and phenylalanine, in preventing the nephrotoxicffects of ochratoxin A exposure.172 Aspartame com-etitively prevents the binding of ochratoxin to serumlbumin. Investigations are also being conducted toxplore ways to reduce the genotoxic effects of och-atoxin. The quantity of DNA adducts that are inducedy ochratoxin A in animals can be reduced dramaticallyy pretreatment of the animals with aspirin and indome-hicin, which inhibit prostaglandin H synthase.173

ther Associations of Mycotoxinsith Health Effects

The associations between liver cancer and aflatoxinsnd esophageal cancer and fumonisins have beenhown in numerous epidemiologic studies. Scientists

able 8. Interaction of fungal toxins and risk factors in the development

Geographicregion/country

Age-standardizedincidence (No. of cases

per 100,000)

Fungal infection ofmajor dietary staples

iangsu County,China

Haimen: 52-65 (mortalityrate)103,104

No studies

ranskei, SouthAfrica

Kentani: 2.4-7.7Lusikisiki: 13105,106

Maize-based food andhome-grownmaize107-109


peculate that other cancers, such as testicular cancer o


nd cervical cancer, could possibly be associated withycotoxin exposure; these associations are considered

peculative. Further evaluation is merited to reach aefinitive conclusion.

uspected Testicular Cancer

Some researchers speculate that ochratoxin A maye linked to testicular cancer. Epidemiologic informa-ion suggests a carcinogenic exposure in early life maylay a role in the development of this cancer.174

esticular cancer has a peak in occurrence at age 25 to4 years and is rare among elderly men. It is plausiblehat exposures to ochratoxin A in early life mightnduce lesions in testicular DNA. Testicular growth atuberty may promote these lesions to testicular can-er.174 In humans, ochratoxin A levels were twice asigh in umbilical cord blood as in maternal blood athe time of delivery,175 suggesting that active placen-al transfer may be occurring.In experimental studies, in utero transfer of ochra-

oxin A has been documented in mice,176 rats,177 andumans.178 The hypothesis that ochratoxin A is asso-iated with testicular cancer is consistent with evi-ence from animal studies showing that the risk ofancer increases if exposure to a carcinogen occurs intero or in infancy rather than in adult life.179

strogenic EffectsZearalenone. Estrogenic effects have been associ-

ted with eating foods contaminated with zearalenone,mycotoxin produced by Fusarium graminearum andther Fusarium species. Found in corn, wheat, barley,

r cancer

Mycotoxin contaminationDietary and other risk

factors

ze: Fumonisin B (0.16-26 mg/kg)atoxin B1 (�31 �g/kg)

eoxynivalenol (0.89 mg/kg)104

Microcystins103

toxin B1 (16 ng/kg body weight)ealthy maize: fumonisin B (2.0-2.1g/kg)

Low socioeconomic status;nutritionaldeficiencies110-114

dy maize: fumonisin B (32-67 mg/kg)eoxynivalenol (2.9 mg/kg), nivalenol.6 mg/kg), zearalenone (1.4 mg/kg),atoxin B1 (0.66 �g/kg), moniliformin.5 mg/kg)


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Age-standardizedincidence (No. of

cases per 100,000)

Fungal infection of majordietary staples

Mycotoxin contaminationDietary and other risk

factors

ranskei, SouthernAfrica (rural)

Males: Lusikisiki, 51;Bizana, 37;Butterworth, 43;Centane, 56106

Maize: F. verticillioides andF. graminearum107-

109,119-122

Healthy maize: fumonisin B(2.0-2.1 mg/kg) Moldymaize: fumonisin B (32-67 mg/kg)

Deoxynivalenol (2.9 mg/kg), nivalenol (4.6 mg/kg), zearalenone (1.3mg/kg), aflatoxin B1(0.66 �g/kg),moniliformin (3.5 mg/kg)

Vitamin A, E, and B12, folate,seleniumdeficiencies105,111,113,114

Smoking: some relationshipAlcohol: somerelationship110,123,124

enan, Hebai, Linxian,and Shanxiprovinces, northernChina

Yancheng, 135;Hebei, 140;Linxian, 108125

Wheat, maize, dried sweetpotato, rice, soya bean;Penicillium spp.,Aspergillus spp., F.verticillioidespredominant fungi126-131

Healthy maize: fumonisinB1 (0.7-3.5 mg/kg). Onestudy: fumonisin B1 (35mg/kg)

Moldy maize: fumonisin B1(74 mg/kg) Aflatoxin B1(8.6-10 �g/kg), type A(630 �g/kg) and B(2400 �g/kg);trichothecenes,deoxynivalenol (0.02-3.5mg/kg), nivalenol (0.05-09 mg/kg), zearalenone(0.06 mg/kg)

Low intake of vitamins A andC. Inverse relationship withmolybdenum, manganese,zinc; no relationship withpickled vegetables

Alcohol intake: noassociation; smoking: mildrisk factor

Nitrosamines: Breadinoculated with fungi andtumor induction in ratesophagus125,132-135

azandaran, Province,Gonbad region,Caspian littoral ofIran

Females: 262Males: 206136,137

Aspergillus, Fusarium,Penicillium spp. onmaize. F. verticillioidesand F. proliferatumimportant spp. Alternariaalternata136-140

Healthy maize: fumonisin B(1.6-6.1 mg/kg)Aflatoxins, polycyclicaromatichydrocarbons,nitrosamines

Micronutrient deficiencies:iron, manganese, copper,zinc, vitamins A, Criboflavin.

Nonsignificant roles foralcohol and tobaccosmoking (women). Nass,mixture of opium, lime,and ash, risk factor inmen.

Thermal irritation with hot tea,bread contaminated withsilica, fiber, consumption ofsour pomegranate seeds,black pepper, andgarlic136,141-144

ruili-Venezia Giullia,northeast Italy

Pordenone ProvinceMales: 17145

Fumonisin-producingFusarium species (ref146)

Fumonisins: fumonisin B1(0.15-0.38 mg/kg),fumonisin B2 (0.06-0.91 mg/kg)

Consumption of polenta. Lowintake of micronutrientssuch as riboflavin andniacin; interactive role ofalcohol145,147

estern and centralKenya

45% of cases148 Maize: F. verticillioides149-

151

Healthy maize: fumonisin B(0.06-1.0 mg/kg) Poorquality maize:fumonisin B1 (3.6-12mg/kg)

Dietary patterns and tribalcustoms vary; alcoholconsumption;geographical and ethnicvariations148

imbabwe Males: Harare: 30Bulawayo: 59152

No studies Breakfast cereals: totalfumonisin B (4.9 mg/kg)153

No studies

harleston County,South Carolina, USA

Black males, 170(death rate)154-156

No studies Maize-based human foodsFumonisin B1 (0.1-1.9 mg/

kg)Fumonisin B2 (0.07-0.46

mg/kg)157

Low socioeconomic status,tobacco and alcohol(“moonshine” distilledfrom fermented maizemeal); low intake of

fresh fruits154,156

96 Curr Probl Pediatr Adolesc Health Care, September 2006

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arly 1960s after an unusually high incidence ofstrogenic signs occurred in swine.180 Metabolites ofearalenone cause infertility in both males and fe-ales.181,182 It is the only mycotoxin whose known

ffect is primarily an estrogenic one.183,184 Also,earalenone is the only mycotoxin that is useful inommercial agriculture; its derivatives, such as zearale-ol, give enhanced growth rates in cattle when used at theroper time and in the proper amounts.185 Its estrogenicroperties make exposure a concern for human health.lthough studies are ongoing, researchers speculate that

he mycotoxin may be associated with precocious pu-erty and possibly cervical cancer.186 It can adopt aonformation resembling 17-beta-estradiol that allows ito bind to the estrogen receptor in target cells.187

Zearalenone has been implicated in several incidentsf precocious pubertal changes in children.188 Forxample, zearalenone was found in the blood of childrenn Puerto Rico with precocious puberty.189 It is undernvestigation as a possible etiology for an increase inremature telarche in the southeast part of Hungary since989.190 Further investigation will be needed beforehese associations are fully understood.191

rgotism

Ergotism was the first chronic condition associatedith ingesting mycotoxins. During the 9th to the 14th

entury the ergot alkaloids, produced by Clavicepsurpura, were recognized to cause epidemic disease in

able 9. Interaction of fumonisins and other fungal toxins and risk factor



cases per 100,000)

Fungal infectiondietary sta

outhern Brazil Santa Catarina,Parana, Rio Grandedo Sul

Males: 18158

Maize: F. verticillflavus159-165


ersons who consumed moldy rye grain.192 The first a


ymptom was a prickly sensation in the limbs, follow-ng which the limbs became swollen, inflamed, andubject to sensations of intense heat and cold. Periph-ral vasoconstriction resulted in gangrene and limboss. During the late 16th to the late 19th century, aonvulsive form of ergotism involving the nervousystem occurred in Europe and the United States.193

Ergotism following ingestion of contaminated foods very rare today. It is important for clinicians toecognize the symptoms because they may occur aside effects following therapeutic administration ofrgot alkaloids.194,195

atulin

Patulin is suspected to have carcinogenic properties,lthough the International Agency for Research onancer concluded that no evaluation could be made of

he carcinogenicity of patulin to humans and that thereas inadequate evidence in experimental animals.196

study of the combined effects of patulin on repro-uction, long-term toxicity, and carcinogenicity sug-ested a harmless intake of 43 �g/kg body weight peray. On the basis of this work and using a safety factorf 100, the Joint Food and Agriculture OrganizationWorld Health Organization Expert Committee onood Additives set a provisional tolerable daily intakef 0.4 �g/kg body weight in 1995.197 A child weigh-ng 10 kg would reach the provisional tolerable dailyntake of 4 �g by drinking 80 mL of apple juice, while

he development of esophageal cancer

ajor Mycotoxincontamination

Dietary and other riskfactors

s, A. Animal mycotoxicosis:Fumonisin B1 (38 mg/kg); Fumonisin B2 (12mg/kg)

Maize samples:Fumonisin B1 (2.7-11mg/kg) Fumonisin B2(2.3-10 mg/kg)

Maize-based food:Fumonisin B1 (0.04-12mg/kg) Fumonisin B2(0.01-10 mg/kg)

Markets andsupermarkets:Fumonisin B1 (� 32mg/kg)

Farm workers, smoking anddrinking: regional variation;hot beverages (maté andchimarrao)161,162,166,167

rtain mycotoxins in food. Geneva: World Health Organization; 2001;151-5.

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aily intake of 8 �g by drinking 160 mL of appleuice. Because infants and children consume far morepple juice, kilogram per kilogram, than adults, patu-in’s potential association with human cancer shoulde followed closely.198

eural Tube DefectsFumonisins. Neural tube defects are associated with

xcessive consumption of foods contaminated withumonisins. A cluster of neural tube defects thatccurred in South Texas in 1990 generated the hypoth-sis that ingestion of high levels of fumonisins inorn-based products was linked to birth defects such asnencephaly and spina bifida in humans.199-203 Mex-can Americans have neural tube defect rates that areuch higher than those of non-Hispanic whites.200

uring the period when the cluster of affected preg-ancies occurred, US corn-based products had rela-ively high levels of fumonisins (two to three timesigher than normal). Mexican American women inexas, unlike their non-Hispanic counterparts, usuallyat a lot of corn, in the form of tortillas (90 g per dayersus 17 g per day).199 A case-control study showedhat increasing levels of the postpartum sphinganine-o-sphingosine ratio (a biomarker for fumonisin expo-ure) were associated with an increased odds ratio foreural tube defects.203 Fumonisins interfere with cel-ular folate uptake.204 Studies in China and Southfrica lend support to this association (Table0).205-207

The fumonisins can disrupt sphingolipid metabo-

able 10. Interaction of fungal toxins and risk factors in the developmen

Geographicregion/country


cases per 100,000)

Fungal infection ofdietary staples

outhern Texas,USA

Lower Rio Grandevalley:27/10,000199,201,203

Case-control study, 11999, Texas HealDepartment

No data on fungalcontamination

hina Hebei and ShanxiProvinces:60/10,000205

Penicillium, Aspergilspp., F. verticillioidwheat, maize126,1

ranskei andMpumulangaSouth Africa

Umzimkulu: 38/10,000Mpumulanga: 3.6/10,000206,207

F. verticillioides, F.proliferatum, F.graminearum, F.subglutinans109


ism.208 Sphingolipids play a role in membrane and b

98

ipoprotein structure and in cell regulation as secondessengers for growth factors, differentiation factors,

nd cytokines.208 Additional research is being con-ucted to identify how disruption of sphingolipidetabolism may affect the development of the human

ervous system.

ummary and Importance to thelinicianPediatricians should be able to recognize that some

ases of vomiting illnesses, bone marrow failure, acuteulmonary hemorrhage, and recurrent apnea and/orpneumonia” may be caused by mycotoxins. Diseasesaused by mycotoxins are great masqueraders. Famil-arity with the symptoms of exposure to the majorlasses of mycotoxins mentioned in this review willnable the clinician to ask pertinent questions aboutossible fungal exposures and to remove the infant orhild from the source of the exposure, which could beontaminated food(s), clothing, and furniture, or in-oor air. Failure to prevent recurrent exposure oftenesults in recurrent illness. Table 11 lists warning signshat should prompt the primary care pediatrician to askuestions about exposures to fungi.Pediatricians also should recognize that other condi-

ions, including hepatocellular and esophageal cancernd neural tube defects, although less well-researched,re associated with consumption of foods contami-ated with mycotoxins. Pediatricians can serve as

eural tube defects

rMycotoxin contamination Dietary and other risk factors

- Maize-based foods: 1.2 mg/kg156 1997-1998 study ofmaize meal: degermed,0.15 mg/kg; whole 1.2mg/kg

Tortillas; sphingonine:sphingasine ratio in serum;protective effect of folatesupplementation201,203

Healthy maize: fumonisin B1(0.7-3.5 mg/kg); onestudy 35 mg/kg

Moldy maize: fumonisin B1(74 mg/kg)

Low socioeconomic status;nutritional deficiencies125

Healthy maize: fumonisin B1(0.3-0.6 mg/kg)

Moldy maize: fumonisin B1(5-9 mg/kg)

Low socioeconomic status;nutritionaldeficiencies105,110,111,113,114


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ware of the short- and long-term consequences ofxposures to natural toxins.

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