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Am J Clin Nutr 2004 Williams 1106 22

Am J Clin Nutr 2004 Williams 1106 22

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Aflatoxin in developed countries
Aflatoxin in developed countries

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04/21/2013

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Review Article
Human aflatoxicosis in developing countries: a review of toxicology,exposure, potential health consequences, and interventions
1–3
 Jonathan H Williams, Timothy D Phillips, Pauline E Jolly, Jonathan K Stiles, Curtis M Jolly, and Deepak Aggarwal
ABSTRACT
Aflatoxins are well recognized as a cause of liver cancer, but theyhave additional important toxic effects. In farm and laboratory ani-mals, chronic exposure to aflatoxins compromises immunity andinterferes with protein metabolism and multiple micronutrients thatare critical to health. These effects have not been widely studied inhumans,buttheavailableinformationindicatesthatatleastsomeof theeffectsobservedinanimalsalsooccurinhumans.Theprevalenceandlevelofhumanexposuretoaflatoxinsonaglobalscalehavebeenreviewed,andtheresultingconclusionwasthat
Ȃ
4.5billionpersonsliving in developing countries are chronically exposed to largelyuncontrolledamountsofthetoxin.Alimitedamountofinformationshows that, at least in those locations where it has been studied, theexisting aflatoxin exposure results in changes in nutrition and im-munity.Theaflatoxinexposureandthetoxicaffectsofaflatoxinsonimmunity and nutrition combine to negatively affect health factors(including HIV infection) that account for
40% of the burden of disease in developing countries where a short lifespan is prevalent.Foodsystemsandeconomicsrenderdeveloped-countryapproachesto the management of aflatoxins impractical in developing-countrysettings, but the strategy of using food additives to protect farmanimals from the toxin may also provide effective and economicalnew approaches to protecting human populations.
Am J Clin Nutr 
2004;80:1106–22.
KEY WORDS
Aflatoxin, chronic exposure, health risks, in-fectious diseases, iron, zinc, selenium, vitamin, protein, nutrition,immunity,HIV,developingcountry,preventionstrategies,foodad-ditives
INTRODUCTION
Aflatoxin is a common contaminant of foods, particularly inthe staple diets of many developing countries. This toxin is pro-duced by fungal action during production, harvest, storage, andfood processing, and it is considered by the US Food and DrugAdministration (FDA) to be an unavoidable contaminant of foods.TheFDA’sgoalhasbeentominimizecontamination;thisgoalwasrealizedbyimplementingregulationsthatrequiredspe-cial attention to the management of the problem. However, themethods used to ensure minimal contamination in developedcountries cannot realistically be used in developing countries,because of the characteristics of the food systems and the tech-nological infrastructure in those countries; therefore, aflatoxinsareuncontrolledinthesesituations.Theresultisa“divide”intheprevalence of aflatoxicosis exposure between people living indeveloped and developing countries.The World Health Organization (WHO) does not recognizeaflatoxinsasahigh-priorityproblembecauseoftheiranalysisof factorscontributingtotheburdenofdiseaseacrosstheworld(1).For developing countries where a short lifespan is prevalent, thepriority issues identified by the WHO and their importance asfactors contributing to the burden of disease [as measured bydisability-adjustedlifeyears(DALYs)]arepresentedin
Table1
,andaflatoxinisnotidentifiedasahigh-priorityriskbytheWHO.By application of the logic (derived from the current medicalfocus on the carcinogenicity of aflatoxin) that aflatoxin is re-flected in the incidence of liver cancer alone, the priorities de-fined in Table 1 are justified. However, our review of literatureshowsthat,becauseoftheimmunologicandnutritionalaffectsof aflatoxin, there is a reasonable probability that the 6 top WHOriskfactors(whichaccountfor43.6%oftheDALYsincountrieswhere short lifespan is prevalent), as well as the risks of livercancer, are modulated by aflatoxin.This review does not focus on aflatoxin as a risk factor forcancer,becausethatsectorofaflatoxin-relatedpathologyiswelldocumented and reviewed. Rather, it concentrates on the immu-nologic and nutritional effects and the associated modulation of infectious diseases. It also examines the scale, levels, and broadconsequences of human exposure and new approaches to themanagement of the problem.
BACKGROUND
Aflatoxinswerefirstisolatedsome40yagoafteroutbreaksof diseaseanddeathinturkeys(2)andofcancerinrainbowtrout(3,4) fed on rations formulated from peanut and cottonseed meals.Thetoxinsareproducedassecondarymetabolitesby
 Aspergillus flavus
and
Aspergillus parasiticus
fungi when the temperaturesare between 24 and 35 °C, and they will form within many com-modities whenever the moisture content exceeds 7% (10% with
1
From the Peanut Collaborative Research Program, Griffin, GA (JHWand DA); the College of Veterinary Medicine, Texas A & M University,College Station, TX (TDP); the School of Public Health, The University of Alabama at Birmingham (PEJ); the Department of Microbiology/Immunol-ogy, Morehouse School of Medicine, Atlanta (JKS); and the Department of Agricultural Economics, Auburn University, Auburn, AL(CMJ).
2
Supported by USAID grant LAG-G-00-96-90013-00 to the Peanut Col-laborative Research Program.
3
Reprints not available. Address correspondence to JH Williams, PeanutCollaborative Research Program, 1109 Experiment Street, Griffin, GA30223. E-mail: twillia@griffin.uga.edu.Received December 9, 2003.Accepted for publication April 15, 2004.
1106
Am J Clin Nutr 
2004;80:1106–22. Printed in USA. © 2004 American Society for Clinical Nutrition
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ventilation). The fungi responsible are ubiquitous and can affectmany of the developing-country dietary staples of rice, corn,cassava, nuts, peanuts, chilies, and spices. The result is that, atlatitudes between 40°N and 40°S of the equator, contaminationof stored, inadequately dried produce is possible. Fungal inva-sion and contamination often begin before harvest and can bepromoted by production and harvest conditions. Genotypes (5),drought(6),soiltypes(7),andinsectactivity(8)areimportantindetermining the likelihood of preharvest contamination (9).Timelyharvestandrapidandadequatedryingbeforestoragearealso important (5). Even commodities dried to a satisfactorydegree before storage can develop local pockets favorable toaflatoxin growth as a result of moisture generated by insect res-piration and local condensation. Farmers of aflatoxicosis-pronecropsintheUnitedStatesexploitallofthesefactstomanagetheproblem, but contamination is not easily prevented without sig-nificant investment in production, drying, and storage facilities.These investments currently add significantly to the cost of de-livering “safe” food to the people of the United States and theEuropean Union. Despite the investment in these facilities, siz-ablelossesstilloccurregularlyintheUnitedStateswhenfarmersare unable to meet even the more relaxed standards allowed foranimal feeds (10).Economicpressureshavecreatedadoublestandardforallow-able contamination of commodities destined for human and an-imalconsumption.Humanfoodsareallowed4–30ppbaflatoxin,dependingonthecountryinvolved(11,12).Asaconsequenceof thesuccessfulregulationofaflatoxinindevelopedcountries,thehuman medical research literature is clearly focused on the car-cinogenic aspects of aflatoxin, which reflects the concerns of North Americans and Europeans about the consequences of long-termcumulativeexposure,whichistheonlyconcernatthelowconcentrationsofaflatoxinsthattheirfoodsystemsachieve.Thisliteratureiswellreviewed(13)andisthereforecoveredonlybriefly here. In contrast, grains for animal feed in the UnitedStates are allowed 300 ppb aflatoxin (14), because this concen-tration not only provides protection against acute aflatoxicosisbut also is low enough to allow most of the grain produced to betraded. In these animal feeding situations, the long-term risk of cancer is not a concern, except for the most susceptible species.Consequently,veterinaryresearchhasexaminedhigherlevelsof exposure but for shorter time periods. This research providesmost of the information on the toxicities of aflatoxin at interme-diateratesofexposure(100–500ppb)andisthemostpotentiallyrelevantinformationthatisappropriateforthehumansituationindeveloping countries where no control of aflatoxin is exercised.However, the differences between species in response to afla-toxin introduce a measure of speculation into the extension of farm animal–derived information to the human situation.
TOXICOLOGY
Aflatoxins are a group of closely related compounds withsmalldifferencesinchemicalcomposition(
Figure1
).AflatoxinB
1
(AFB
1
)isthemostprevalentformandalsothemostpotentof these toxins (15). In animals the toxin is processed through anumberofcompetingpathways.Thesepathwayshavebeenwellreviewed (16) and are summarized in
Figure 2
. The differencesin susceptibility to aflatoxin across species and between personsdependlargelyonthefractionofthedosethatisdirectedintothevarious possible pathways, with harmful “biological” exposurebeing the result of activation to the epoxide and the reaction of the epoxide with proteins and DNA. There is also evidence that
TABLE 1
World Health Organization priority health risks and associated burden of disease in disability-adjusted life years (DALYs) for developing countrieswhere short lifespan is prevalent
1
Risk factor Percentage of DALYs
%
Underweight 14.9Unsafe sex 10.2Unsafe water 5.5Indoor smoke from solid fuels 3.7Zinc deficiency 3.2Iron deficiency 3.1Vitamin A deficiency 3.0Blood pressure 2.5Tobacco use 2.0Cholesterol 1.9
1
From reference 1.
FIGURE 1.
Chemical structures of aflatoxins.
FIGURE 2.
Pathways and consequences for aflatoxin in animal metab-olism. Hydroxylated metabolites include aflatoxin M
1
. GSH, glutathione.Reprinted from Eaton D, Ramsdell HS, Neal G. Biotransformation of afla-toxins.In:EatonD,GroopmanJD,eds.Thetoxicologyofaflatoxins:humanhealth, veterinary, and agricultural significance. London: Academic Press,1993:45–72, with permission from Elsevier.
HUMAN AFLATOXICOSIS IN DEVELOPING COUNTRIES
1107
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the fractions that follow the different possible pathways are in-fluencedbydosage,perhapsbecauseofthesaturationofthemostchemically competitive processes (16). Susceptibility to afla-toxin is greatest in the young, and there are very significantdifferences between species, persons of the same species (ac-cording to their differing abilities to detoxify aflatoxin by bio-chemical processes), and the sexes (according to the concentra-tions of testosterone). The toxicity of aflatoxin also variesaccording to many nutritional factors (17), and recovery fromproteinmalnutritionisdelayedbyexposuretoaflatoxin(18,19).Aflatoxicosis is the poisoning that results from ingesting af-latoxins. Two forms of aflatoxicosis have been identified: thefirst is acute severe intoxication, which results in direct liverdamageandsubsequentillnessordeath,andthesecondischronicsubsymptomatic exposure. A review of the literature across allspecies provides clear evidence that the dose and duration of exposure to aflatoxin clearly have a major effect on the toxicol-ogy and may cause a range of consequences:
1
) large doses leadto acute illness and death, usually through liver cirrhosis;
2
)chronic sublethal doses have nutritional and immunologic con-sequences; and
3
) all doses have a cumulative effect on the risk of cancer. This review focuses on the nutritional and immuno-logic consequences.
Acute illness and death
The symptoms of severe aflatoxicosis include hemorrhagicnecrosisoftheliver,bileductproliferation,edema,andlethargy.Animal studies have found 2 orders of magnitude difference inthe median lethal dose for AFB
1.
Susceptible species such asrabbits and ducks have a low (0.3 mg/kg) median lethal dose,whereas chickens (18 mg/kg) and rats have greater tolerance.Adult humans usually have a high tolerance of aflatoxin, and,in the reported acute poisonings, it is usually the children whodie (15).
Cancers
For humans, aflatoxin is predominantly perceived as an agentpromoting liver cancers, although lung cancer is also a risk amongworkershandlingcontaminatedgrain(20).Theincreasedrisk of hepatomas is caused by deletion mutations in the P53tumor–suppressing gene and by activation of dominant onco-genes (21). The risk of cancers due to exposure to the variousforms of aflatoxin is well established (22) and is based on thecumulative lifetime dose. The International Cancer ResearchInstitute identifies aflatoxin as a Class 1 carcinogen, resulting inthe regulation of this toxin to very low concentrations in tradedcommodities [20 ppb in grains and 0.5 ppb in milk in the UnitedStates; 4 ppb in foods in some European countries (11)].However, in many developing countries, epidemics of hepa-titis B virus (HBV) and hepatitis C virus (HCV) affect
ͨ
20% of the population. A strong synergy is observed between aflatoxinandthesebiologicalagentsforlivercancer.InhepatitisBsurfaceantigen–positive subjects, aflatoxin is
Ȃ
30 times more potentthan in persons without the virus (23), and the relative risk of cancer for HBV patients increases from
Ȃ
5 with only HBVinfectionto
Ȃ
60whenHBVinfectionandaflatoxinexposurearecombined(24).InsomeareaswhereaflatoxincontaminationandHBV occur together, hepatomas are the predominant cancer(64% of cancers; 25), and they may be a predominant cause of death:
Ȃ
10% of males in Gambia die of liver cancer (CP Wild,personal communication, 1999), and in Qidong, China, 10% of all adult deaths were due to this cancer (26). Thus, to minimizethe risk of liver cancer, it is critically important that exposure of HBV- and HCV-infected persons to aflatoxin is minimized.A factor in this greater potency of aflatoxin in HBV-positivepeople is the finding that HBV positivitity reduces the person’sabilitytodetoxifyaflatoxin(27).Whereasthissynergyisrecog-nizedasanimportantfactorforcancer,itisalsoofgreatpotentialimportanceforimmunologicandnutritionaltoxicities,becauseitincreases the level of biological exposure.
Immunologic suppression
As stated earlier, most of the information summarized belowisderivedfromstudiesoffarmanimalsorfromanimalmodelsinwhich the exposure is chronic but not high enough to cause thesymptoms usually associated with acute aflatoxicosis. Humanexposure is likely to be more variable than that in these studies,because of the highly variable distribution of contaminationwithin foods. Aflatoxin M
1
(AFM
1
) in human urine reflects ex-posure over the previous 24 h and is usually found in approxi-matelyone-thirdofthemembersofasamplepopulation,whereasaflatoxin-albumin adduct data, which reflect exposure over alonger period, are present in most (
90%) of the same popula-tions (24, 28, 29). This difference provides some uncertaintyabout the extension of animal data to humans, but some publi-cationsshowthattheseanimalresponsesarerelevanttohumans,at least in broad terms. The threshold dose for immunotoxiceffects in humans is not known.In animal experiments, AFB
1
has been shown to induce thy-mic aplasia (30), reduce T-lymphocyte function and number,suppress phagocytic activity, and reduce complement activity(30–32). Many studies conducted in poultry, pigs, and ratsshowedthatexposuretoaflatoxinincontaminatedfoodresultsinsuppressionofthecell-mediatedimmuneresponses(17,33–37).Thymicandbursalinvolution,suppressionoflymphoblastogen-esis, impairment of delayed cutaneous hypersensitivity (37, 38),and graft-versus-host reaction (39, 40) also occur in animalsexposed to aflatoxin. Splenic CD4 (helper T) cell numbers andinterleukin 2 (IL-2) production decreased significantly whenmice were treated with AFB
1
at a dose of 0.75 mg/kg (41).Impairment of cellular function by aflatoxin seems to be dueto its effects on such factors as the production of lymphokinesand antigen processing by macrophages (42), as well as adecreaseinorlackoftheheat-stableserumfactorsinvolvedinphagocytosis (43).Macrophagesplayamajorroleinhostdefensesagainstinfec-tion. They present antigen to lymphocytes during the develop-ment of specific immunity and serve as supportive accessorycells to lymphocytes. Macrophages also increase their phago-cytic activity and release various active products, such as cyto-kines and reactive intermediates, to carry out nonspecific im-mune responses (44). Several reports suggest that aflatoxinimpairs the function of macrophages in animal species (45, 46).In addition to its reported effect in reducing phagocytic activityinrabbitalveolarmacrophages(43),aflatoxinhasmorerecentlybeenshowninvitrotoinhibitphagocyticcellfunctioninnormalhumanperipheralbloodmonocytes(46).AFB
1
atconcentrations
ͧ
100pg/mLwascytotoxictothemonocytes,andconcentrationsof 0.5 to 1 pg/mL inhibited monocyte phagocytic activity andintracellular killing of 
Candida albicans
; however, superoxide
1108
WILLIAMS ET AL
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