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Figure 9. Compounds in coffee (chlorogenic and caffeic acid) and coumarins.

and humans. Pre- or postharvest contamination of various food crops by mycotoxigenic fungi is a common problem; approximately 25% of the world's food supply is contaminated by mycotoxins annually. The severity of mycotoxin contamination of agricultural commodities varies from year to year, depending on factors such as excessive moisture in the field and in storage, temperature extremes, humidity, drought, variations in harvesting practices, and insect infestation. Although the actual resultant economic loss to agriculture is difficult to determine with accuracy, it is considerable.

Many mycotoxins have been implicated in outbreaks of human diseases. Some are potent animal and presumed human carcinogens. In domestic animals, such as dairy cattle, swine, and poultry, mycotoxin contamination is known to reduce growth efficiency, lower feed conversion, lower reproductive rates, impair resistance to infectious diseases, reduce vaccination efficacy, and induce pathologic damage to the liver and other organs. For these reasons, mycotoxins pose a major threat to public and animal health. A few classes of mycotoxins that are problems in foods will be considered here.

Aflatoxin B,

Aflatoxin Bj (AFBj) represents a group of potent mycotoxins produced by strains of the filamentous fungus Aspergillus flavus and A. parasiticus. Of the Aspergillus mycotoxins, AFBj has generated the greatest concern and has stimulated the most research because of its extreme toxicity and its widespread occurrence in staple foods and feeds (such as corn, peanuts, and cottonseed). For these reasons, the U.S. FDA regulates AFBj in foods. The current action level, the concentration above which the commodity is condemned and discarded, is 20 ppb of total af-latoxins. This regulatory value was established in the 1960s, in large part from the analytical detection limits at that time. The action level for the major AFBj metabolite present in milk and milk products, aflatoxin Mx (AFM^, is 0.5 ppb in fluid milk. Other regulatory guidelines for AFBx include 20 ppb in corn for dairy cows, 300 ppb in corn for finishing beef cattle and swine, and 100 ppb for breeding stock. Permissible AFBj concentrations in cottonseed for beef cattle, swine, and poultry is 300 ppb. These regulatory concentrations generally preclude detectable AFBx in the various products from these animals. Worldwide, established tolerances for AFE^ in animal feeds range from 10 to 600 ppb.

Prevention of Aspergillus infection in foods and feeds is the most desirable method of reducing contamination. Despite the best agricultural practices, however, AFBj contamination is mostly unavoidable. Thus, several methods of reducing postharvest product contamination have been developed. Some of these methods involve early identification and segregation of grossly contaminated kernels of corn or peanuts, or electronic devices to identify and reject grains that exhibit fluorescence due to AFBj. Ammoniation results in nearly complete elimination of aflatoxins and associated toxicity in commodities, and it is suitable for treating large batches of product (19). This method has not yet been approved by the FDA for interstate shipments, but it is in use in some states. Another experimental strategy is the use of inorganic adsorbent feed additives that prevent absorption of mycotoxins in animals. Hydrated sodium calcium aluminosilicate (HSCAS), an FDA-approved anticak-ing agent, significantly reduces AFBj bioavailability as well as many of its specific toxic effects in pigs (20).

The many toxic effects of AFBj are initiated by its conversion, principally by hepatic and extrahepatic microsomal CYPs, to a variety of metabolites (Fig. 10). The reputed carcinogenic intermediate is the AFBr8,9-epoxide. Presumably because of its extreme reactivity (it has a half-life of approximately 0.5 s), the AFBr8,9-epoxide has been isolated only indirectly from biological systems as adducts of glutathione (GSH), DNA bases, or other macromolecules. Most other metabolic products are less toxic than parent AFBi, the most prevalent of which is AFM1( so named for its appearance in the milk of dairy cows that consume AFBj-contaminated feeds. Other detoxified metabolites produced from the CYP oxidation of AFBX include aflatoxin Qx (AFQj) and aflatoxin P2 (Fig. 10). Soluble NADPH-dependent cytosolic enzymes reduce AFBX to produce af-latoxicol (AFL), which is nearly as toxic, mutagenic, and carcinogenic as the parent compound. Thus AFL is not considered a detoxified metabolite. Because the reduction is reversible, AFL is postulated to represent a storage form ofAFBj.

The most critical detoxification AFBj route is via glutathione S-transferase (GST) using GSH as cofactor. Species whose GST has a high affinity for the AFBj-8,9-epoxide are generally protected from the toxic and carcinogenic effects of AFB1; regardless of how well the epoxide is formed by CYPs. The AFBj-S^-epoxide is a substrate for GST, producing some form of nontoxic AFBi-GSH adduct that is often the simple sulfhydryl derivative of AFBrGSH. Aflatoxin Bj may also be detoxified via conjugation with sulfates and glucuronic acid. The AFBj-8,9-epoxide may also be catalytically (by epoxide hydrolase) or spontaneously hydrolyzed to the AFBr8,9-dihydrodiol. A soluble AFBj aldo-keto reductase (AFAR) has also been isolated from liver and extrahepatic tissues from human, rat, and other species that has strong affinity for reducing the AFBj-diol, thereby contributing to epoxide detoxification (21).

The electrophilic and highly reactive AFB r8,9-epoxide is reportedly responsible for the carcinogenic and mutagenic action of AFBj. This intermediate binds to cellular nucleophiles, such as DNA. Activated AFBi binds exclusively to guanyl residues, and the AFB1-N7-guanine (AFBr N7 Gua) adduct is the most predominant (Fig. 10). Additional adducts have been isolated, of which the "ring-opened" derivative of AFBj-N'-Gua, the formamido-pyrimidine, or AFBrFAPyr, is the most common. In hepatic DNA from livers of rats injected with AFBlt approximately 80% of the adducts present are AFBrN7-Gua, whereas the AFB1-FAPyr comprises approximately 7% (22). The formation of these adducts is the presumed first step in the development of heritable mutations from which tumors may arise. Repair of these genetic lesions occurs in living cells enzymatically or spontaneously, and the removed adduct is excreted in the urine. The ring-opened adduct appears to be more resistant to DNA repair enzymes. In rats treated with a single dose of AFBj, the

AFBrN7-Gua was rapidly removed with an apparent halflife of 7.5 h, whereas other adducts, such as FAPyr, were removed much more slowly (23).

Aflatoxin Bj is a potent acute toxin that primarily targets the liver. The primary lesions include hemorrhagic necrosis, fatty infiltration, and bile duct proliferation. In pigs, guinea pigs, and dogs, these effects are found most commonly in the centrilobular region, whereas in ducklings and rats, the periportal region is the site of action. Vertebrate species show considerable variation in susceptibility to the acute effects of AFB1; and no species appears to be totally resistant. Poultry, rainbow trout, rats, and monkeys are particularly sensitive to the acute effects of AFBj. Mice and hamsters are much less sensitive (24).

Aflatoxin Bj is carcinogenic in a wide variety of animals. As is the case following acute exposures, the major target organ is the liver, although tumors in other organs result from long-term dietary exposure to AFBj. Aflatoxin Bx at 0.4 ppb fed over a 14-month period resulted in a 14% incidence of hepatocellular carcinomas in rainbow trout, the most sensitive animal species known to the carcinogenic effects of this mycotoxin. By contrast, only a 5% tumor incidence was observed during a similar time frame in Fischer rats exposed to 5 ppb.

Epidemiological data indicate that at least in sub-Saharan Africa and Southeast Asia, where AFBj contamination in foods is considerable, dietary AFBj is an important risk factor for human hepatocellular carcinoma (HCC). In these geographical areas there is a linear relationship between levels of AFBj contamination of food and the incidence of HCC. A factor that complicates epidemiology is that the incidence of hepatitis B virus infection, which is another reputed factor for HCC in humans, is also high in these regions. Specific biomarkers of human exposure to AFBj, such as adducts of DNA and serum albumin, have proven to be valuable tools in the study of the role of dietary AFBj in human cancer. Measurement of these biomarkers in samples of blood or urine has allowed a direct determination of actual AFBj exposure in populations, which is an improvement over performing random dietary analysis for AFBj and imprecise dietary recall surveys.

Although the majority of interest in possible health effects has correctly focused on dietary exposure to AFB1( workers in food and grain production, harvest, transport, and processing industries are also exposed to considerable amounts of airborne, respirable AFBj-contaminated grain dusts. For example, airborne dust sampled in a corn-processing plant contained 107 ng/m3 AFBj, and the daily occupational exposure to this toxin was estimated to be between 40 and 856 ng (25). In another survey, concentrations of AFBj in smaller, more easily retained airborne grain particles were found to contain more AFBj than did larger grain particles; AFBj in particles under 7 /¡m were as high as 1,814 ppb, whereas particles in the size range of 7 to 11 nm had an average content of 695 ppb (26).

Some studies indicate that inhalation exposure to AFBj may result in adverse health effects to those exposed. Aflatoxin-contaminated peanut dusts have been associated with liver and lung cancer in Dutch peanut-processing workers who were continually exposed to be-

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