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12 Naturally Occumng Carcinogens The production of toxic compounds by living cells has long been recognized. Some of these chemicals, especially those produced by microbes and plant cells, have carcinogenic activity. Although some of these compounds are integral components of foods that are relatively common in the diet of humans, many of them have been found either in unusual food sources or in foods contaminated by microorganisms or unwanted plant materials. The potential hazards to human health posed by these components or contaminants of foods range from slight to very great. For example, very low levels of exposure to chemicals with relatively weak carcinogenic activity in laboratory animals may pose little risk to human populations. On the other hand, the presence of aflatoxin B1 in foods is a matter of great concern, since aflatoxin B1 is a potent carcinogen for a number of species and epidemiological data suggest that this carcinogen may play a role in the development of cancer in humans living in some parts of Africa and in the Far East (Peers et al., 1976; van Rensburg et al., 1974~. Much of the literature on the carcinogenic products of living cells has been collected and evaluated by working groups of the International Agency for Research on Cancer (1976) and by the National Research Coun- cil (National Academy of Sciences, 1973~. Accordingly, these compre- hensive reviews are often cited in this chapter instead of the primary literature. In addition, several recent reviews on naturally occurring carcinogens include exhaustive lists of primary references pertaining to these carcinogens. The overviews also cite literature on certain aspects of these carcinogens not covered in this chapter, such as their metabolic activation and deactivation, the reactions of electrophilic derivatives with cellular macromolecules, and the biochemical and biological consequences of the latter reactions (Hirono, 1981; Miller and Miller, 1979; Miller et al., 1979; Schoental, 1976~. MYCOTOXINS By definition, mycotoxins are toxic secondary products resulting from the metabolism of molds. In this chapter, the committee has reviewed only those toxic metabolites of mold that occur as natural contaminants of food or feed or that demonstrate some evidence of car- cinogenicity in mammals when administered orally. Although at least 45 mycotoxins have been identified as eliciting some type of carcino- genic or mutagenic response, only 17 of them have been reported to occur naturally in food or feed (Stoloff, in press) (or only 13, if the aflatoxin group is considered as a single compound). 234 12-1

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Naturally Occu~nng Carcinogens 235 The selection of the mycotoxins discussed in this section was based on the extent of their occurrence in food and/or the data demon- strating their carcinogenicity. These compounds include: aflatoxins, sterigmatocystin, ochratoxin A, zearalenone, T-2 toxin, patulin, pen- icillic acid, griseofulvin, luteoskyrin, cyclochlorotine, and ergot. Aflatoxins A very extensive effort has gone into the study of this group of mycotoxins, especially to examine its most potent member, aflatoxin B1. Much more is known about the occurrence and toxicity of the aflatoxins than about any other mycotoxin and, probably, most other natural contaminants. The scattered data pertaining to worldwide occurrence of aflatoxins in food were compiled for a conference on mycotoxins, which was spon- sored by the Food and Agriculture Organization, the United Nations Environment Program, and the World Health Organization (1977~. More recently, Stoloff (in press) compiled data on the occurrence of afla- toxins in the United States. The aflatoxin-producing molds Aspergillus flavus and A. parasiti- cus are ubiquitous. They are frequently encountered as outgrowths on stored commodities under conditions prevailing in many tropical areas. In the United States, aflatoxin contamination is generally restricted to those crops invaded by the aflatoxin-producing molds before harvest most frequently peanuts, corn, and cottonseed, and to a much lesser extent tree nuts, including almonds, walnuts, pecans, and pistachios. The extent of contamination is greater in the southeastern United States. In the United States, humans are exposed to aflatoxin mostly from corn and peanuts (U.S. Food and Drug Administration, 1979~. Other direct dietary sources, such as tree nuts, are of minor significance, either because contamination is infrequent or because only small quantities are consumed. It is unlikely that secondary exposures result from the ingestion of aflatoxin residues in tissues of animals fed aflatoxin-contaminated feed (Stoloff, 1979), except for aflatoxin M1, a metabolite that appears in the milk of lactating mammals exposed to aflatoxins. But, although large amounts of milk are consumed, this exposure is negligi- ble compared to the direct exposure from peanuts and corn. Aflatoxins are classified as unavoidable contaminants. In the United States, the maximum allowable limit of total aflatoxins in consumer peanut products is currently 20 ~g/kg (U.S. Food and Drug Administration, 1980b' 12-2

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236 DIET, NUTRITION, AND CANCER Epidemiological Evidence. Oettle (1965) was the first investi- gator to draw serious attention to the hypothesis that aflatoxin ingestion might cause liver cancer. He suggested that the geographic distribution of liver cancer in Africa could be explained by differing levels of exposure to aflatoxin in the diet. Keen and Martin (1971) reported an apparent association between the consumption of groundnuts contaminated with aflatoxin and the occurrence of liver cancer in different areas of Swaziland. Alpert _ al. (1971) made a similar correlation of contaminated foodstuffs and incidence of hepatoma by tribe and by province or district in Uganda. In a later study in Swaziland, Peers et al. (1976) analyzed aflatoxin levels in foods consumed by a representative sample of the population in 11 geographic areas. He reported a significant correlation between aflatoxin contam- ination and incidence of primary liver cancer among adult males. A similar study in the Murang'a district of Kenya (Peers and Linsell, 1973) indicated that there was a correlation between aflatoxin levels in dietary staples of three district subdivisions and the incidence of liver cancer. Mozambique has particularly high rates of liver cancer, perhaps the highest in the world, and studies of aflatoxin contamina- tion of foods indicated that the estimated daily intake of aflatoxin in that country was higher than that reported for any other country (van Rensburg et al., 1974~. One problem recognized by the researchers in all of these studies is the inadequacy of the data on liver cancer incidence, since cancer registration is not well established in these areas. Detailed studies of aflatoxin contamination of ingested foodstuffs have also been conducted in Thailand, where there was an overall corre- lation between estimated aflatoxin intakes in two regions and liver cancer incidence (Shank et al., 1972a,b; Wogan, 1975~. The frequency with which aflatoxin was detected in foods has also been correlated with liver cancer mortality in Guangxi province in China (Armstrong, 1980~. In Taiwan, where liver cancer mortality rates are high, Tung and Ling (1968) reported that dietary staples (e.g., peanuts and peanut oil, which is widely used in cooking) are frequently contaminated with aflatoxin. Linsell and Peers (1977) observed a strong correlation between estimated levels of aflatoxin ingested and liver cancer incidence from various studies conducted in Africa and Asia. They further noted that there were no areas where high levels of aflatoxin ingestion have been associated with low rates of liver cancer. Although the studies described above suggest that aflatoxin causes primary hepatocellular carcinoma (PHC), numerous other reports have also documented a high correlation between PHC and exposure to hepati- tis B virus (Chien et al., 1981; Prince et al., 1975; Simons et al., 1972; Tong et al., l9lr; Vogel et al., lY7057 These studies BE not indicate whether present or past exposure to this virus is more closely associated with the development of PHC. However, Kew et al. (1979) 12-3

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Naturally Occurring Carcinogens 237 reported that active hepatitis B viral infection is present in approxi- mately 80% to 90% of the patients with PHC. Approximately 5% to 10% of the victims of hepatitis B infection actually develop chronic active hepatitis with persistent liver damage. The liver cells of these indi- viduals are believed to regenerate more rapidly, thereby increasing the likelihood that a biochemical lesion that initiates neoplasia will become fixed in the genes of the subsequent cell population. The worldwide occurrence of hepatitis B viral infection is similar to that of primary hepatocellular carcinoma. However, it is possible that the influences of aflatoxin and hepatitis B virus on the risk for PHC are not completely independent. Van Rensburg (1977) reviewed the evidence for both risk factors and concluded that preexisting viral in- fection is probably a prerequisite for malignant transformation by afla- toxin. The possibility that aflatoxin may also be involved in the etiology of esophageal cancer is suggested by the correlation between mortality from esophageal cancer and the consumption of large amounts of pickled vegetables and other fermented or moldy food in Linxian county of Henan province in northern China (Yang, 1980~. Although Aspergillus flavus has been isolated from some products, it is difficult to determine the role of aflatoxin in the etiology of this disease because these foods also contain other fungal species, mutagens, and carcinogens, including _-nitroso compounds. Epidemiological studies have not been undertaken in Western coun- tries, but there have been reports indicating the presence of aflatoxin B1 in autopsy samples from liver cancer patients in Czechoslovakia (Dvoratkova _ al., 1977), New Zealand (Becroft and Webster, 1972), and the United States (Sire; et al., 1981). Siraj et al. (1981) detected aflatoxin B1 in four of the six liver samples obtained from patients with PHC in the United States. The significance of these findings is not yet known. Experimental Evidence: Carcinogenicity. Aflatoxin B1 is the most potent hepatocarcinogen known, being about 1,000 times more powerful than butter yellow (p-dimethylaminoazobenzene) in rats. The carcinogenicity of aflatoxins has been examined in several studies in variety of species and strains of laboratory animals, including mice, marmosets, tree shrews, trout, ducks, rhesus monkeys, hamsters, and several strains of rats (Wogan, 1973~. Of the various species tested, the male Fischer 344 rat was the most sensitive to aflatoxin-induced carcinogenesis (Wogan, 1973~. Aflatoxin B1 induced mainly hepatocellular carcinomas in rats. However, other studies in rats have indicated that it may also induce a very low incidence of carcinomas of the glandular stomach (Butler and Barnes, 1966), cancers of the colon (Newberne and Rogers, 1973; Wogan and Newberne, 1967), renal epithelial neoplasia (Epstein et al., 1969), 12-4

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238 DIET, NUTRITION, AND CANCER and lung adenomas (Newberne et al., 1967~. Within a susceptible species and strain, males are much more susceptible than females to challenge with aflatoxin (Wogan and Newberne, 1967~. Mice are resistant to aflatoxin-induced carcinogenesis under con- ditions that result in 100% tumor incidence in Fischer rats. However, hepatomas were induced in 82 of 105 inbred (C57BL X C3H)F1 mice in- jected intraperitoneally during the first 7 days after birth with doses of aflatoxin B1 as low as 1.25 Agog body weight (bw) and killed 82 weeks later (Vesselinovitch et al., 1972~. In comparison to Fischer rats, nonhuman primates (170 animals in 12 different investigations) were relatively resistant to aflatoxin-induced carcinogenesis (Stoloff and Friedman, 1976~. Liver tumors do not occur spontaneously in monkeys (O'Gara and Adamson, 1972), but a female rhesus monkey developed a primary liver carcinoma after ingesting approximately 500 mg of aflatoxin B1 over a 6-year period (Adamson et al., 1973~. In another study, one of nine marmosets developed liver tumors after 50 weeks on a diet (5 days a week) containing aflatoxin B1 at 2 Agog (tin et al., 1974~. However, the authors also observed liver cirrhosis,which is not a symptom of aflatoxicosis in rats. Reddy _ al. (1976) reported that 9 of 18 tree shrews intermittently fed aflatoxin B1 at 2 Agog diet developed liver cancers after 74 to 172 weeks of treatment. Experimental Evidence: Mutagenicity. Aflatoxin B1 was shown to be mutagenic to Salmonella typhimurium strains TA98 and TA100 with and with- out S9 fraction (Ueno et al., 1978~. It was positive in the Bacillus subtilis rec assay (Ueno and Kubota, 1976~. In FM3A mouse cells, afla- toxin induced 8-azaguanine-resistant mutants as well as chromosome aber- rations (Umeda et al., 1977~. Aflatoxin M1, the metabolite of aflatoxin B1, was mutagenic in the Ames test (Won" and Hsieh, 1976), but inactive in B. subtilis rec assay (Ueno and Kubota, 1976~. Other Mycotoxins Table 12-1 summarizes the data on the occurrence, carcinogenicity, and mutagenicity of mycotoxins other than aflatoxins that may be found in food. Although most of these mycotoxins are mutagenic in bacterial systems and other short-term tests and/or are carcinogenic in laboratory animals, there are no epidemiological studies pertaining to their role in neoplasia in humans. Summary and Conclusions: M l~to~ns amd Othec ~ycocu~i``s A consistent body of evidence, all based on correlational data, associates the contamination of foods by aflatoxin with a high incidence of liver cancer in parts of Africa and Asia, but there is no epidemiologi- cal evidence that aflatoxin contamination of foodstuffs is related to 12-5

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240 DIET, NUTRITION, AND CANCER cancer risk in the United States. Epidemiological studies have also indicated a high correlation between primary hepatocellular carcinoma and exposure to hepatitis B viral infection. Aflatoxin is carcinogenic in several species of animals, including rats, mice, trout, ducks, monkeys, and marmosets, and there is evidence of dose response. It induces mainly tumors of the liver and, to a lesser extent, tumors in the kidney, lung, stomach, and colon, more readily in males and in the young. The carcinogenicity of aflatoxin is paralleled by its mutagenicity in various systems. There is no reliable information about the role of other mycotoxins · · · . In carc~nogenes~s In humans. HYDRAZINES IN MUSHROOMS Epidemiological Evidence. No epidemiological studies have been conducted to determine the effects of hydrazines on carcinogenesis in humans. Agaricus bisporus Agaricus bisporus is a commonly eaten cultivated mushroom in Europe, North America, and other parts of the world. The exact consumption figures for Agaricus bisporus are unknown, but the U.S. Department of Agriculture (1981) has estimated that approximately 213 million kilograms of this mushroom were available for consumption (production and imports) in the United States during 1980. Agaricus bisporus contains agaritine -- 6-N-~-L(+~-glutamyl]-4- hydroxymethylphenylhydrazine (Toth et al., 1978) -- and 4-(hydroxy- methyl~benzenediazonium ion (Levenberg, 1962~. 4-Hydroxymethylphenyl- hydrazine and 4-methylphenylhydrazine, which are breakdown products of agaritine, have also been found in A. bisporus (Levenberg, 1964~. Experimental Evidence: Carcinogenicity. N'-Acetyl-4-(hydroxy- methyl~phenylhydrazine as a 0.0625% solution in drinking water admin- istered continuously to Swiss mice from 6 weeks of age to the end of their lives induced lung and blood vessel tumors (Toth et al., 1978~. 4-(Hydroxymethyl~benzenediazonium tetrafluoroborate administered to Swiss mice in 26 weekly subcutaneous injections at 50 ~g/g bw resulted in an increased incidence of tumors of the subcutis and skin (Toth _ al., 1981~. 4-Methylphenylhydrazine hydrochloride administered to Swiss mice in 7 weekly intragastric instillations of 250 ~g/g bw induced lung and blood vessel tumors (Toth et al., 1977~. 12-7

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Naturally Occulting Carcinogens 241 Experimental Evidence: Mutagenicity. N'-Acetyl-4-(hydroxy- methyl~phenylhydrazine was most mutagenic in S. typhimurium TA1537 without metabolic activation, and it exhibited marginal DNA-modifying activity only when the S9 fraction was included (Rogan et al., in press). 4-(Hydroxymethyl~benzenediazonium tetrafluoroborate was weakly mutagenic in TA1535 and strongly mutagenic in TA1537, exhibiting tox- icity in both strains (Rogan et al., in press). Agaritine produced equivocal results in both in vitro assays. There was a slight enhancement of mutagenicity in S. typhimurium TA1537 with- out metabolic activation, and marginal DNA-modifying activity in the presence of S9 fraction (Rogan et al., in press). 4-Methylphenylhydrazine hydrochloride was also found to be mutagenic with and without S9 fraction in S. typhimurium TA98 and TA100 (Shimizu et al., 1978~. ~ GYromitra esculenta Each year, approximately 1 million people throughout the world eat the mushroom Gyromitra esculenta (Simons, 1971~; 100,000 of these people reside in the United States (S. Miller, personal communication). The literature contains more than 500 reports of poisonings resulting from the ingestion of this mushroom. Some of these incidents were fatal (Franke et al., 1967~. Experimental Evidence: Carcinogenicity. Eleven hydrazines and hydrazones have been identified in G. esculenta. Studies have been conducted to determine the carcinogenicity of many of these compounds. Continuous administration of 0.0078% N-methyl-N-formylhydrazine (MFH) in drinking water to 6-week-old outbred Swiss mice for life pro- duced tumors of the liver, lung, gallbladder, and bile duct. A higher dose (0.0156% MFH) given under identical conditions had no tumorigenic effect, since it proved too toxic for the animals (Toth and Nagel, 1978~. Subsequently, the carcinogenicity of MFH was confirmed in mice (Toth and Patil, 1980, 1981) and in Syrian hamsters (Toth and Patil, 1979~. Acetaldehyde methylformylhydrazone, the main ingredient of G. escu- lenta, was administered to Swiss mice in propylene glycol in 52 weekly intragastric instillations at 100 ~g/g bw (Toth et al., 1981~. The treatment induced tumors of the lungs, preputial glands, forestomach, and clitoral glands. Drinking water solutions of 0.001% hydrazine, 0.01% methylhydrazine, and 0.001% methylhydrazine sulfate were administered continuously to 5- and 6-week-old randomly bred Swiss mice for their lifetimes. Hydrazine 12-8

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A. 242 DIET, NUTRITION, AND CANCER and methylhydrazine sulfate significantly increased the incidence of lung tumors in Swiss mice, whereas methylhydrazine enhanced the development of this neoplasm by shortening its latent period (Toth, 1972). A 0.01% solution of methylhydrazine was administered daily in the drinking water of 6-week-old randomly bred Syrian golden hamsters for the remainder of their lifetimes. The treatment produced malignant histiocytomas of the liver and tumors of the cecum (Toth and Shimizu 1973). Experimental Evidence: Mutagenicity. _-Methyl-N-formylhydrazine, which is present in G. esculenta, was mutagenic only in S. typhimurium TA1537 without activation and had no DNA-modifying activity (Rogan et al., in press). Methylhydrazine was mutagenic in S. typhimurium TA1535 and TA1537. The addition of S9 fraction activating system enhanced the mutagenicity in both strains (Rogan et al., in press). The DNA modifying activity was observed earlier by van Wright et al. (1977~. Summary and Conclusions: Hydrazines Studies have shown that some chemical constituents of the Agaricus bisporus mushroom are carcinogenic in mice and mutagenic in bacterial systems. One constituent has also been shown to be carcinogenic in ham- sters. But the findings of these studies are not sufficient for conclu- sions to be drawn concerning the risk to humans. Some derivatives of hydrazines in the fungus Gyromitra esculenta have proven carcinogenic in a number of organs and tissues of mice and hamsters. Two of them were mutagenic in bacterial systems. There are no epidemiological studies concerning the carcinogenicity of these mushrooms in humans. PLANT CONST ITUENTS AND METABOLITES Pyrrolizidine Alkaloids Pyrrolizidine alkaloids occur in many nonedible plant species, including the genera Senecio (ragworts), Crotalaria (rattleboxes), and Heliotropium (heliotropes), in amounts ranging from trace amounts to as much as 5% of the dry weight. In general, members of this group that contain a nuclear double bond alpha to an esterified carbinol are very potent toxins in the liver and lung of rodents and certain farm live- stock (Hirono, 1981; Hirono et al., 1979; International Agency for Research on Cancer, 1976~. Experimental Evidence: Carcinogenicity. Monocrotaline, retrorsine, lasiocarpine, heliotrine, senkirkine, symphytine, and petasitenine, all 12-9

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Naturally Occurring Carcinogens 243 of which are a, S-unsaturated esters, are carcinogenic when administered to rats orally or parenterally under conditions that permit long-term survivals. Most frequently, tumor induction has involved multiple doses of the alkaloids at moderate levels (e.g., a 0.01% solution of petasite- nine in drinking water for 480 days) (Hirono et al., 1979), but low in- cidences of tumors after long latent periods have apparently resulted from only one or a few doses. Tumors have also been induced in rats after the administration of plants, such as coltsfoot (Tussilago far- fare) or comfrey (Symphytum sp.), which contain high levels of pyrrol- izidine alkaloids. The tumors occur most frequently in the liver, but some have developed in other tissues, including the skin and lungs. Plants containing the pyrrolizidine alkaloids may contaminate forages and food grains. Such contamination has resulted in acute and chronic poisoning of livestock in some parts of the world (Schoental, 1976~. Humans may also be exposed by consuming such alkaloid-containing plants as drugs or foods. For example, one species of comfrey (Sym- phytum officinale) is consumed as a green vegetable in Japan (Hirono et al., 1979)e The carcinogenic potency of some pyrrolizidine alkaloids and their widespread occurrence have led to the suggestion that these a,5-unsaturated esters may play a role in the induction of hepatic cancer in humans in some parts of the world; however, there are no reliable data to support this hypothesis. Experimental Evidence: Mutagenicity. Retrorsine, lasiocarpine, heliotrine, senkirkine, symphytine, and petasitenine, but not monocrota- line, have been shown to be mutagenic in the Salmonella/microsome assay (Hirono et al., 1979; Wehner et al., 1979; Yamanaka et al., 1979~. Allylic and Propenylic Benzene Derivatives Numerous allylic and propenylic benzene derivatives are present in the essential oils of a wide variety of plants (Guenther, 1948-1952; Guenther and Althausen, 1949), and some of these plants or their ex- tracts are used as flavoring agents for human foods or as medicines consumed by humans. Of the known naturally occurring allylic benzene derivatives, safrole (l-allyl-3,4-methylenedioxybenzene), which is a major component of oil of sassafras, and estragole (l-allyl-4-methoxy- benzene), which is present in tarragon and anise, have been the most comprehensively studied. Experimental Evidence: Carcinogenicity. Safrole has induced low- to-moderate incidences of hepatic tumors in adult rats fed at levels of 0.5% or more of the diet for as long as 2 years (International Agency for Research on Cancer, 1976~. Both safrole and estragole induced hepatic tumors and subcutaneous angiosarcomas within 18 months after they were fed to adult female CD-1 mice at levels of 0.25%-0.5% for ap- proximately 1 year (Miller _ al., 1979~. Administration of less than 12-10

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244 DIET, NUTRITION,AND CANCER 1 mg of either compound or of methyl eugenol to CD-1 or (C57BL/6 x C3H/He)F1 male mice prior to weaning resulted in a high incidence of hepatomas by the age of 12 months (Miller et al., 1979~. Experimental Evidence: Mutagenicity. Safrole was mutagenic _ vitro and in the host mediated assay (Green and Savage, 1978~. However, McCann et al. (1975), Swanson et al. (1979), and Wislocki et al. (1977) reported that it was not mutagenic in the Ames test. It was positive in Bacillus subtilis rec assay (Rosenkranz and Poirier, 1979) and in Saccharomyces cerevisiae D3 (Simmon, 1979~. Estragole was mutagenic to S. typhimurium TA100 (Swanson et al., 1979~. Eugenol was not mutagenic to Ames Salmonella strains in vitro and in the host-mediated assay (Green and Savage, 1978; Swanson et al., 1979~. Bracken Fern Toxin~s) Bracken fern (Pteridium aquilinum) occurs widely in nature and is consumed by humans in several parts of the world, especially in Japan (Hirono, 1981~. For at least 30 years, it has been known that consump- tion of this plant causes damage to the bone marrow and intestinal mucosa of cattle, but the precise compounds) responsible for these toxic effects have not been identified. Epidemiological Evidence: Carcinogenicity. In a prospective cohort study in Japan, Hirayama (1979) found a significantly higher risk of esophageal carcinoma associated with the daily intake of hot gruel or bracken fern every day, especially in people who ate both foods daily. However, Howe et al. (1980) found no association between bladder cancer and consumption of fiddlehead greens (related to bracken fern) in a case-control study in Canada. Experimental Evidence: Carcinogenicity. The carcinogenicity of bracken fern was first suspected by Pamukcu in 1960, who found polyps in the urinary bladder mucosa of cattle fed large amounts of bracken fern for long periods (Pamukcu and Bryan, 1979~. Since that time, ingestion of high levels of bracken fern (25% to 40% of the diet) has been found to result in the formation of urinary bladder carcinomas in cattle, urinary bladder carcinomas and intestinal adenocarcinomas in rats, urinary bladder tumors in guinea pigs, pulmonary adenomas in mice, and intestinal adenocarcinomas in Japanese quail (Evans, 1976~. Hirono (1981) reported that the greatest concentration of the toxin~s) is present in young plants before the fronds have uncurled, and the carcinogenic activity of the rhizome is greater than that of the stalk or fronds. The toxicity of the fern is reduced, but not eliminated, by cooking. 12-11

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266 DIET, NUTRITION, AND CANCER Lijinsky, W., M. Greenblatt, and C. Kommineni. 1973. Feeding studies of nitrilotriacetic acid and derivatives in rats. J. Natl. Cancer Inst. 50:1061-1063. Li jinsky, W. , M. D. Reuber, and W. B. Manning. 1980. Potent carcino- genicity of nitrosodiethanolamine in rats. Nature 288:589-590. Lin, J. J., C. Liu, and D. J. Svoboda. 1974. Long-term effects of aflatoxin B1 and viral hepatitis on marmoset liver. Lab. Invest. 30:267-278. Lin, R. S., and I. I. Kessler. 1981. A multifactorial model for pan- creatic cancer in man: Epidemiological evidence. J. Am. Med. Assoc. 245:147-152. Linsell, C. A., and F. G. Peers. 1977. Aflatoxin and liver cell cancer. Trans. R. Soc. Trap. Med. Hyg. 71:471-473. Litton Bionetics, Inc. 1975. Mutagenic evaluation of compound 001401554 tannic acid. Prepared for the Bureau of Foods, Food and Drug Admin- istration under Contract No. 73-56. Litton Bionetics, Inc., Kensington, Md. 33 pp. MacMahon, B., S. Yen, D. Trichopoulos, K. Warren, and G. Nardi. 1981. Coffee and cancer of the pancreas. N. Engl. J. Med. 304:630-633. Magee, P. N., and J. M. Barnes. 1967. Carcinogenic nitroso compounds. Adv. Cancer Res. 10:163-246. Magee, P. N., R. Montesano, and R. Preussmann. 1976. N-Nitroso com- pounds and related carcinogens. Pp. 491-625 in C. E. Searle, ed. Chemical Carcinogens. ACS Monograph 173. American Chemical Society, Washington, D.C. Martin, P. M. D., and P. Keen. 1978. The occurrence of zearalanone in raw and fermented products from Swaziland and Lesotho. Sabouraudia 26:15-22. Martinez, I. 1969. Factors associated with cancer of the esophagus, mouth and pharynx in Puerto Rico. J. Natl. Cancer Inst. 42:1069- 1094. Matsumoto, H., and H. H. Higa. 1966. Studies on methylazoxymethanol, the aglycone of cycasin: Methylation of nucleic acids in vitro. Biochem. J. 98:20C-22C. Matsushima, T., H. Matsumoto, A. Shirai, M. Sawamura, and T. Sugimura. 1979. Mutagenicity of the naturally occurring carcinogen cycasin and 12-33

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Naturally Occurring Carcinogens 267 synthetic methylazoxymethanol conjugates in Salmonella typhimurium. Cancer Res. 39:3780-3782. McCann, J., E. Choi, E. Yamasaki, and B. N. Ames. 1975. Detection of carcinogens as mutagens in the Salmonella/microsome test: Assay of 300 chemicals. Proc. Natl. Acad. Sci. U.S.A. 72:513S-5139. Meinsma, L. 1964. [In Dutch; English Summary.] Nutrition and cancer. Voeding 25:357-365. Miller, C. T., C. I. Neutel, R. C. Nair, L. D. Marrett, J. M. Last, and W. E. Collins. 1978. Relative importance of risk factors in bladder carcinogenesis. J. Chronic Dis. 31:51-56. Miller, E. C., and J. A. Miller. 1979. Naturally occurring chemical carcinogens that may be present in foods. Pp. 123-165 in A. Neuberger and T. H. Jukes, eds. International Review of Biochemistry, Volume 27. Biochemistry of Nutrition 1. University Park Press, Baltimore, Md. Miller, E. C., J. A. Miller, I. Hirono, T. Sugimura, and S. Takayama, eds. 1979. Naturally Occurring Carcinogens-Mutagens and Modulators of Carcinogenesis. Japan Scientific Societies Press, Tokyo; Univer- sity Park Press, Baltimore, Md. 399 pp. Miller, J. A. 1973. Naturally occurring substances that can induce tumors. Pp. 508-549 in Toxicants Occurring Naturally in Foods, Second edition. Food and Nutrition Board, National Academy of Sciences, Washington, D.C. Miller, J. A., E. C. Miller, and D. H. Phillips. In press. The meta- bolic activation and carcinogenicity of alkylbenzenes that occur naturally in many spices. In H. Stich, ed. Carcinogens and Mutagens in the Environment. Volume 1, Food Products. CRC Press, Boca Raton, Fla. Mirvish, S. S. 1968. The carcinogenic action and metabolism of ure then and N-hydroxyure than. Adv. Cancer Res. 11:1-42. Mirvish, S. S. 1981. Inhibition of the formation of carcinogenic N- nitroso compounds by ascorbic acid and other compounds. Pp. 557- 587 in J. H. Burchenal and H. F. Oettgen, eds. Cancer: Achievements, Challenges, and Prospects for the 1980s, Volume 1. G rune and Stratton, New York, London, Toronto, Sydney, and San Francisco. Mirvish, S. S., A. Cardesa, L. Wallcave, and P. Shubik. 1975. Induction of mouse lung adenomas by amines or ureas plus nitrite and by N-nitroso compounds: Effect of ascorbate, garlic acid, thiocyanate, and caffeine. J. Natl. Cancer Inst. 5S:633-636. 12-34

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268 DIET, NUTRITION, AND CANCER Mirvish, S. S., K. Karlowski, D. F. Birt, and J. P. Sams. 1980. Dietary and other factors affecting nitrosomethylurea (NMU) formation in the rat stomach. Pp. 271-277 in E. A. Walker, L. Griciute, M. Castegnaro, M. Borzsonyi, and W. Davis, eds. N-Nitroso Compounds: Analysis, Formation and Occurrence. IARC Scientific Publications No. 31. International Agency for Research on Cancer, Lyon, France. Montesano, R., and H. Bartsch. 1976. Mutagenic and carcinogenic N- nitroso compounds: Possible environmental hazards. Mutat. Res. 32:179-227. Nagao, M., Y. Takahashi, K. Wakabayashi, and T. Sugimura. 1979. Mutagens in coffee and tea. Mutat. Res. 68:101-106. National Academy of Sciences. 1965. Chemicals Used in Food Processing. Food and Nutrition Board, National Academy of Sciences, Washington, D.C. 296 pp. National Academy of Sciences. 1973. Toxicants Occurring Naturally in Foods. Second edition. Food and Nutrition Board, National Academy of Sciences, Washington, D.C. 624 pp. National Academy of Sciences. 1981. The Health Effects of Nitrate, Nitrite, and N-Nitroso Compounds. Part 1 of a 2-Part Study by the Committee on Nitrite and Alternative Curing Agents in Food. National Academy Press, Washington, D.C. 544 pp. National Cancer Institute. In press. Carcinogenesis bioassay of zearale- none. NTP-81-37. National Toxicology Program, National Cancer Insti- tute, Bethesda, Md. Nelson, A. A., O. G. Fitzhugh, H. J. Morris, and H. O. Calvery. 1942. Neurofibromas of rat ears produced by prolonged feeding of crude ergot. Cancer Res. 2:11-15. Newberne, P. M. 1978. Final Report on Contract No. FDA 74-2181. Dietary Nitrite in the Rat. May 18, 1978. Food and Drug Admin- istration, U.S. Department of Health, Education, and Welfare, Washington, D.C. 162 pp. Newberne, P. M. 1979. Nitrite promotes lymph oma incidence in rats. Science 204:1079-1081. Newberne, P. M., and A. E. Rogers. 1973. Rat colon carcinomas asso- ciated with aflatoxin and marginal vitamin A. J. Natl. Cancer Inst. 50:439-448. 12-35

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Naturally ()ccu~nng Carcinogens 269 Newberne, P. M., C. E. Hunt, and G. N. Wogan. 1967. Neoplasms in the rat associated with administration of urethan and aflatoxin. Exp. Mol. Pathol. 6:285-299. Nomura, T. 1975. Letter to the Editor: Urethan (ethyl carbamate) as a cosolvent of drugs commonly used parenterally in humans. Cancer Res. 35:2895-2899. Novick, A. 1956. Mutagens and antimutagens. Brookhaven Symp. Biol. 8:201-215. Oettle, A. G. 1965. The aetiology of primary carcinoma of the liver in Africa: A critical appraisal of previous ideas with an outline of the mycotoxin hypothesis. S. Afr. Med. J. 39:917-825. O'Gara, R. W., and R. H. Adamson. 1972. Spontaneous and induced neoplasms in nonhuman primates. Pp. 190-238 in R. N. Fiennes, ed. Pathology of Simian Primates. Part I: General Pathology. S. Karger, Basel, Munich, Paris, London, New York, and Sydney. Ohshima, H., and H. Bartsch. 1981. Quantitative estimation of endogenous nitrosation in humans by monitoring N-nitrosoproline excreted in the urine. Cancer Res. 41:3658-3662. Ough, C. S. 1976. Ethylcarbamate in fermented beverages and foods. I. Naturally occurring ethylcarbamate. J. Agric. Food Chem. 24:323-328. Pamukcu, A. M., and G. T. Bryan. 1979. Bracken fern, a natural uri- nary bladder and intestinal carcinogen. Pp. 89-99 in E. C. Miller, J. A. Miller, I. Hirono, T. Sugimura, and S. Takayama, eds. Naturally Occurring Carcinogens-Mutagens and Modulators of Carcinogenesis. Japan Scientific Societies Press, Tokyo; University Park Press, Baltimore, Md. Pamukcu, A. M., E. Erturk, S. Yalc~iner, U. Milli, and G. T. Bryan. 1978. Carcinogenic and mutagenic activities of milk from cows fed bracken fern (Pteridium aquilinum). Cancer Res. 38:1556-1560. Pamukcu, A. M., S. Yalginer, J. F. Hatcher, and G. T. Bryan. 1980. Quercetin, a rat intestinal and bladder carcinogen present in bracken fern (Pteridium aquilinum). Cancer Res. 40:3468-3472. Parks, N. J., K. A. Krohn, C. A. Mathis, J. H. Chasko, K. R. Geiger, M. E. Gregor, and N. F. Peek. 1981. Nitrogen-13-labeled nitrite and nitrate: Distribution and metabolism after intratracheal administration. Science 212:58-61. 12-36

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270 DIET, NUTRITION, AND CANCER Peers, F. G., and C. A. Linsell. 1973. Dietary aflatoxins and liver cancer--A population based study in Kenya. Br. J. Cancer 27:473-484. Peers, F. G., G. A. Gilman, and C. A. Linsell. 1976. Dietary afla- toxins and human liver cancer. A study in Swaziland. Int. J. Cancer 17:167-176. Pienta, R. J. 1981. Transformation of Syrian hamster embryo cells by diverse chemicals and correlation with their reported carcinogenic and mutagenic activities. Chem. Mutagens 6:175-202. Preussmann, R., B. Spiegelhalder, G. Eisenbrand, G. Wurtele, and I. Hotmann. 1981. Urinary excretion of N-nitrosodiethanolamine in rats following its epicutaneous and intrathecal administration and its formation in viva following skin application of diethanolamine. Cancer Lett. 13:227-231. Prince, A. N., W. Szmuness, J. Michon, J. Demaille, G. Diebolt, J. Linhard, C. Quenum, and M. Sankale. 1975. A case/control study of the associa- tion between primary liver cancer and hepatitis B infection in Senegal. Int. J. Cancer 16:376-383. Purchase, I. F. H., and J. J. van der Watt. 1970. Carcinogenicity of sterigmatocystin. Food Cosmet. Toxicol. 8:289-295. Radomski, J. L., E. M. Glass, and W. B. Deichmann. 1971. Transitional cell hyperplasia in the bladders of dogs fed DL-tryptophan. Cancer Res. 31:1690-1694. Radomski, J. L., D. Greenwald, W. L. Hearn, N. L. Block, and F. M. Woods. 1978. Nitrosamine formation in bladder infections and its role in the etiology of bladder cancer. J. Urol. 120:48-58. Reddy, J. K., D. J. Svoboda, and M. S. Rao. 1976. Induction of liver tumors by aflatoxin B1 in the tree shrew (Tupaia glis), a non- human primate. Cancer Res. 36:151-160. Rogan, E. G., B. A. Walker, R. Gingell, D. Nagel, and B. Toth. In press. Microbial mutagenicity of selected hydrazines. Mutation Res. Rosenkranz, H. S., and Z. Leifer. 1981. Determining the DNA-modifying activity of chemicals using DNA-polymerase deficient Escherichia coli. Chem. Mutagens 6:109-147 12-37

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Naturally Occurring Carcinogens 271 Rosenkranz, H. S., and L. A. Poirier. 1979. Evaluation of the mutageni- city and DNA modifying activity of carcinogens and noncarcinogens in microbial systems. J. Natl. Cancer Inst. 62:873-891. Schmahl, D. 1980. Combination effects in chemical carcinogenesis. Arch. Toxicol. Suppl. 4:29-40. Schoental, R. 1976. Carcinogens in plants and microorganisms. Pp. 626- 689 in C. E. Searle, ed. Chemical Carcinogens. ACS Monograph 173. American Chemical Society, Washington, D.C. Schoental, R., A. Z. Joffe, and B. Yagen. 1979. Cardiovascular lesions and various tumors found in rats given T-2 toxin, a trichothecene metabolite of Fusarium. Cancer Res. 39:2179-2189. Sen, N. P., S. Seaman, and M. McPherson. 1980. Further studies on the occurrence of volatile and non-volatile nitrosamines in foods. Pp. 457-463 in E. A. Walker, L. Griciute, M. Castegnaro, M. Borzsonyi, and W. Davis, eds. N-Nitroso Compounds: Analysis, Formation and Occurrence. IARC Scientific Publications No. 31. International Agency for Research on Cancer, Lyon, France. Shank, R. C., and P. M. Newberne. 1976. Dose-response study of the carcinogenicity of dietary sodium nitrite and morpholine in rats and hamsters. Food Cosmet. Toxicol. 14:1-8. Shank, R. C., N. Bhamarapravati, J. E. Gordon, and G. N. Wagan. 1972a. Dietary aflatoxins and human liver cancer. IV. Incidence of primary liver cancer in two municipal populations of Thailand. Food Cosmet. Toxicol. 10:171-179. Shank, R. C., J. E. Gordon, G. N. Wogan, A. Nondasuta, and B. Subhamani. 1972b. Dietary aflatoxins and human liver cancer. III. Field sur- vey of rural Thai families for ingested aflatoxins. Food Cosmet. Toxicol. 10:71-84. Shennan, D. H. 1973. Letter to the Editor: Renal carcinoma and coffee consumption in 16 countries. Br. J. Cancer 28:473-474. Shimizu, H., K. Hayashi, and N. Takemura. 1978. Relationships between the mutagenic and carcinogenic effects of hydrazine derivatives. Nippon Eiseigaku Zasshi 33:474-485. Simmon, V. F. 1979. In vitro assays for recombinogenic activity of chemical carcinogens and related compounds with Saccharomyces cerevisiae D3. J. Natl. Cancer Inst. 62:901-909. 12-38

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272 DIET, NUTRITION, AND CANCER Simmon, V. F., H. S. Rosenkranz, E. Zeiger, and L. A. Poirer. 1979. Mutagenic activity of chemical carcinogens and related compounds in the intraperitoneal host-mediated assay. J. Natl. Cancer Inst. 62:911-918. Simon, D., S. Yen, and P. Cole. 1975. Coffee drinking and cancer of the lower urinary tract. J. Natl. Cancer Inst. 54:587-591. Simons, D. M. 1971. The mushroom toxins. Del. Med. J. 43:177-187. Simons, M. J., E. H. Yap, and K. Shanmugaratnam. 1972. Australia antigen in Singapore Chinese patients with hepatocellular carcinoma and compar- ison groups: Influence of technique sensitivity on differential fre- quencies. Int. J. Cancer 10:320-325. Siraj, M. Y., A. W. Hayes, P. D. Unger, G. R. Hogan, N. J. Ryan, and B. B. Wray. 1981. Analysis of aflatoxin B1 in human tissues with high- pressure liquid chromatography. Toxicol. Appl. Pharmacol. 58:422-430. Spiegelhalder, B., G. Eisenbrand, and R. Preussmann. 1980. Occur- ence of volatile nitrosamines in foods: A survey of the West German market. Pp. 467-477 in E. A. Walker, L. Griciute, M. Castegnaro, M. Borzsonyi, and W. Davis, eds. N-Nitroso Compounds: Analysis, Formation and Occurrence. IARC Scientific Publications No. 31. International Agency for Research on Cancer, Lyon, France. Stark, A. A., J. M. Townsend, G. N. Wogan, A. L. Demain, A. Manmade, and A. C. Ghosh. 1978. Mutagenicity and antibacterial activity of mycotoxins produced by Penicillium islandicum Sopp and Penicillium regulosum. J. Environ. Pathol. Toxicol. 2:313-324. Stephany, R. W., and P. L. Schuller. 1980. Daily dietary intakes of nitrate, nitrite, and volatile N-nitrosamines in the Netherlands using the duplicate portion sampling technique. Oncology 37:203- 210. Stich, H. F., and W. D. Powrie. In press. Plant phenolics as genotoxic agents and as modulators for the mutagenicity of other food compounds. In H. Stich, ed. Carcinogens and Mutagens in the Environment. Volume 1, Food Products. CRC Press, Boca Raton, Fla. Stob, M. 1973. Estrogens in foods. Pp. 550-557 in Toxicants Occurring Naturally in Foods, Second edition. Food and Nutrition Board, National Academy of Sciences, Washington, D.C. Stocks, P. 1970. Cancer mortality in relation to national consumption of cigarettes, solid fuel, tea and coffee. Br. J. Cancer 24:215-225. 12-39

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Naturally Occurring Carcinogens 273 Stoloff, L. 1979. Mycotoxin residues in edible animal tissues. Pp. 157-166 in Interactions of Mycotoxins in Animal Production. Pro- ceedings of a Symposium. National Academy of Sciences, Washington, D.C. Stoloff, L. In press. Mycotoxins as potential environmental carcinogens. In H. Stich, ed. Carcinogens and Mutagens in the Environment. Volume 1, Food Products. CRC Press, Boca Raton, Fla. Stoloff, L., and L. Friedman. 1976. Information bearing on the evalua- tion of the hazard to man from aflatoxin ingestion. PAG Bulletin 6:21-32. Sugiyama, K., T. Tanaka, and H. Mori. 1979. [In Japanese; English Summary.] Carcinogenicity examination of sodium nitrate in mice. Gifu Daigaku Igakubu Kiyo 27:1-6. Swanson, A. B., D. D. Chambliss, J. C. Blomquist, E. C. Miller, and J. A. Miller. 1979. The mutagenicities of sat role, estragole, eugenol, trans-anethole, and some of their known or possible metab- olites for Salmonella typhimurium mutants. Mutat. Res. 60:143-153. Tannenbaum, S. R., D. Fett, V. R. Young, P. D. Land, and W. R. Bruce. 1978. Nitrite and nitrate are formed by endogenous synthesis in the human intestine. Science 200:1487-1489. Timson, J. 1975. Theobromine and theophylline. Mutat. Res. 32:169- 177. Tong, M. J., S.-C. Sun, B. T. Schaeffer, N.-K. Chang, K.-J. Lo, and R. L. Peters. 1971. Hepatitis-associated antigen and hepatocellu- lar carcinoma in Taiwan. Ann. Intern. Med. 75:687-691. Toth, B. 1972. Hydrazine, methylhydrazine and methylhydrazine sulfate carcinogenesis in Swiss mice. Failure of ammonium hydroxide to interfere in the development of tumors. Int. J. Cancer 9:109-118. Toth, B., and D. Nagel. 1978. Tumors induced in mice by N-methyl-N- formylhydrazine of the false morel Gyromitra esculenta. J. Natl. Cancer Inst. 60:201-204. Toth, B., and K. Patil. 1979. Carcinogenic effects in the Syrian golden hamster of N-methyl-N-fonmylhydrazine of the false morel mushroom GYromitra esculenta. J. Cancer Res. Clin. Oncol. 93:109- 121. Toth, B., and K. Patil. 1980. The tumorigenic effect of low dose levels of N-methyl-N-formylhydrazine in mice. Neoplasma 27:25-31. 12-40

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