Carcinogenicity aflatoxins

Liver cancer can also be a consequence of exposure to hepatotoxic chemicals. Natural hepatocarcinogens include fungal aflatoxins. Synthetic hepato-carcinogens include nitrosoamines, certain chlorinated hydrocarbons, polychlorinated biphenyls (PCBs), chloroform, carbon tetrachloride, dimethyl-benzanthracene, and vinyl chloride.Table 5.15 lists the chemical compounds that induce liver cancer or cirrhosis in experimental animals or... 

The number of clear human epidemiologic studies is small. A total of approximately 50 compounds (c.g., benzene, vinyl chloride) and complex e.xposures (e.g., aluminum production, tobacco smoke) have sufficient data available to permit their classification as human carcinogens. The most potent human carcinogens known, the aflatoxins. are of natural origin. Their presence in food products through infestation by toxin-producing fungi constitute a serious problem in several tropical and subtropical countries. 

Assessment of whether a chemical has the potential to cause adverse effects in humans arises usually from direct observation of an effect in animals or humans, such as the acute poisoning episodes that have occurred when potatoes contain high levels of glycoalkaloids. Epidemiological studies have also been used to infer a possible relationship between intake of a particular type of food, or constituent of that food, and the potential to cause an adverse effect. Such observations led to the characterisation of the aflatoxins as human carcinogens. However, natural toxic substances that occur in plant foods have often been identified through observations in animals, particularly farm animals. It was observations of adverse effects in farm animals that led to the further characterisation of the phytoestrogens and the mycotoxins. In other instances, the concern arises from the chemical similarity to other known toxins. 

Two of the most carcinogenic compounds known dibenzo[a,l]pyrene, a polycyclic aromatic hydrocarbon (PAH) and aflatoxin Bi, a fungal metabolite. 

It is of interest to compare the shapes and sizes of various molecules with appreciable carcinogenic activity. For example, aflatoxin B] (VI), found in moldy peanuts and grain, is one of the most powerful carcinogens known. Its crystal structure was determined by van Soest and Peerdeman (46-48). 

The mode of action of this carcinogen is believed to involve epoxidation of a double bond (49), as indicated in Figure 3 in this Figure the similarities of the shapes, and particularly of the sites of activation of aflatoxin, BP and DMBA are demonstrated. Aflatoxin has functional groups at each end of the molecule, unlike an activated PAH which has functional groups only at one end of the molecule. 

Induced mutagenesis in Escherichia coli is an active process involving proteins with DNA replication, repair, and recombination functions. The available evidence suggests that mutations are generated at sites where DNA has been damaged and that they arise via an error-prone repair activity. In an attempt to understand what specific contributions to mutagenesis are made by DNA lesions, we have studied the mutational specificity of some carcinogens, such as benzo[a]pyrene and aflatoxin, whose chemical reactions with DNA are... 

The well characterized reactions of carcinogens such as benzols] pyrene and aflatoxin B with DNA (39-50) suggested to us that an analysis of the kinds of mutations these agents induced could shed light on the contribution of specific DNA lesions to mutagenesis. 

Work in my laboratory has been supported by grants from the NIH. I am indebted to many of my present and former colleagues, in particular to Drs. A.J. Warren and P.L. Foster for their work on the mutagenic specificity of chemical carcinogens and to Dr. J.H. Miller for his collaborative effort in studying the mutagenic specificity of benzola]pyrene and aflatoxin B. ... 

Dash wood RH, Arbogst DN, Fong AT, Pereira C, Hendricks JD and Baily GS. 1989. Quantitative interrelationships between aflatoxin B1 carcinogen dose, indole-3-carbinol anto-carcinogen dose, target organ DNA adduction and final tumor response. Carcinogenesis 10 175-181. 

The potent carcinogen aflatoxin B1 is activated by generation of an epoxide on a dihydrofuran moiety [43]. The potent MBIs contained in grapefruit juice and in the herbal medication St J ohn s Wort are furanocoumarin compounds [44—46]. A similar moiety is also incorporated in the HIV protease inhibitor L-754,394, a potent CYP3A4 MBI [47]. 

There have also been reports of neoplasms in native bottomfeeding fish with a suggestion that carcinogenic hydrocarbons from motor boat exhausts, rotenone and insecticides such as DDT may be involved as causative agents (59.). Similarly (an) unidentified carcinogen(s) are suspected in the case of adematous polyps of gastric mucosa of fish, reported recently (60). The diet of these fish was free of aflatoxins. 

Aflatoxin Bi (AFB) is a mold metabolite which has been observed to be acutely toxic and carcinogenic to a wide variety of animals (5,6) and has been implicated in human primary hepatic carcinoma (7, 8). Diets deficient in protein have been reported to increase the susceptibility of mammals to acute AFB toxicity and the induction of cancer (2, 9, 10, 11, 12, 13). Increased dietary proteins have increased the carcinogenic activity of AFB fed to rats (1 4) and trout (15.). Supportive of this latter finding has been the reported direct relationship between dietary protein content and AFB-DNA adduct formation in vivo in rats (16, 17). 

Afiatoxin is one of the most mutagenic and carcinogenic natural compounds described to date. Traditional methods for the measurement of aflatoxins fall into two groups ... 

No. The FDA went too far. Aflatoxins can indeed cause liver toxicity in animals and are also carcinogenic. But they produce these adverse effects only at levels far above the FDA set limit. We should ensure some safety margin to protect humans, but 20 ppb is unnecessarily low and the policy that there is no safe level is not supported by scientific studies. Indeed, it s not even certain that aflatoxins represent a cancer risk to humans because animal testing is not known to be a reliable predictor of human risk. Moreover, the carcinogenic potency of aflatoxins varies greatly even among the several animal species in which they have been tested. Human evidence that aflatoxins cause cancer is unsubstantiated. There is no sound scientific basis for the FDA s position. 

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