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:
) large doses leadto acute illness and death, usually through liver cirrhosis;
)chronic sublethal doses have nutritional and immunologic con-sequences; and
) 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
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).
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
30 times more potentthan in persons without the virus (23), and the relative risk of cancer for HBV patients increases from
5 with only HBVinfectionto
60whenHBVinfectionandaflatoxinexposurearecombined(24).InsomeareaswhereaflatoxincontaminationandHBV occur together, hepatomas are the predominant cancer(64% of cancers; 25), and they may be a predominant cause of death:
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.
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
) 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
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
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
100pg/mLwascytotoxictothemonocytes,andconcentrationsof 0.5 to 1 pg/mL inhibited monocyte phagocytic activity andintracellular killing of
; however, superoxide
WILLIAMS ET AL
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