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13 Mutagensin Food As interest in the possible relationship between diet and cancer has increased in recent years, so have attempts to determine whether chemical carcinogens may be present in our foods. The foods that we eat contain a vast number of separate chemical entities: several thousand as additives and many times this number as natural constitu- ents. Of course, most of these chemicals are present in relatively low concentrations, but if potent carcinogens exist, even at low con- centrations in commonly consumed foods, they may warrant concern. The problem, therefore, is how to test the very large number of chemicals present in the complex mixtures we call food to determine whether or not they may be contributing to our risk for cancer. An adequately performed chronic feeding study in rodents to determine whether a chemical is a carcinogen takes several years to complete and analyze and can cost more than $500,000. Therefore, the use of simpler and less expensive tests may be considered, at least to help us determine which chemicals to subject to long-term studies. As discussed elsewhere in this report, initiation of the carcino- genic process may involve an alteration in the genetic material of a cell. Therefore, it is reasonable to suppose that chemicals that alter DNA (e.g., cause mutations) will have a high probability of being initiators of carcinogenesis. The fact that DNA is chemically similar in all living organisms means that even chemicals that cause mutations in bacteria can be suspected as potential carcinogens in humans. In several extensive studies conducted in independent lab- oratories, the correlations between mutagenic activity in bacteria and carcinogenicity in mammals have been analyzed (McCann and Ames, 1976; McCann et al., 1975; Purchase et al., 1978; Simmon, 1979; Sugimura et al., 1976~. It is clear from these and other studies that a chemical found to be mutagenic in any living system should be suspected of being carcinogenic. However, it is impossible to provide a single number to express the degree of confidence with which a mutagen can be considered to be a carcinogen or with which a nonmutagen can be regarded as a noncarcinogen. This uncertainty arises from several sources, the most important of which is that the correlation between mutagenicity and carcinogenicity is highly de- pendent upon the class of chemical being investigated. For some classes of chemical carcinogens, such as aromatic amines, polycyclic hydrocarbons, and direct alkylating agents, there appears to be a high degree of correlation. However, it is difficult to detect the mutagenic activity of some types of carcinogens, especially highly chlorinated compounds. Therefore, judgment must be exercised, in- cluding a careful consideration of the structure and likely metabo- lites of the chemical under test, when the significance of a positive or negative mutagenicity test is being evaluated. 13-1 277

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278 DIET, NUTRITION,AND CANCER The utility of mutagenicity tests in identifying chemical carcino- gens and the subsequent removal of these compounds from products to which humans are exposed can be illustrated by several historical ex- amples. These would include the food preservatives 2-~2-furyl)-3- (5-nitrofuryl~acrylamide (AF-2), which was extensively used in Japan, the flame retardant chemical tris(2,3-dibromopropyl~phosphate, which was widely used in children's sleepwear in the United States, and the hair dye ingredient 2,4-diaminoanisole. The fact that simple muta- genicity tests correctly predicted the carcinogenic potential of these chemicals adds to our confidence that correctly interpreted muta- genicity data can assist us in identifying environmental carcinogens. The most widely used of the mutagenicity assays is the Salmonella plate incorporation test, commonly known as the Ames test. In this assay, a chemical is tested for its ability to induce mutations in different strains of a bacterium (Salmonella typhimurium). Most chemical carcinogens and mutagens do not interact directly with DNA. They require alteration by enzymes in order to become activated. This process of "metabolic activation" cannot usually be accomplished by enzymes present in bacteria. Therefore, in the Salmonella test, an extract of mammalian liver (usually from the rat) is added to provide the enzymes necessary for metabolic activation. Many mutagenic test systems other than S. typhimurium have been used to test chemicals (see review by Hollstein and McCann, 1979~. In the discussion that follows, however, most of the studies discussed involve S. typhimurium. Mutagenicity assays have also been used to investigate the interactions between chemicals. This has resulted in the discovery of both comutagens, which enhance mutagenic activity of other chemicals, and inhibitors of mutagenesis. The knowledge that a chemical is a comutagen or an inhibitor of mutagenesis can provide us with a useful tool for investigating the metabolic fate and genetic interactions of chemicals. Modification of mutagenic activity, par- ticularly as determined in _ vitro test systems, frequently has no relevance to _ viva effects. Specific in vitro effects of modifiers of mutagenesis, such as inhibition of a particular metabolizing enzyme, for example, may not operate or may even have the opposite effect in living organisms. However, where modification of mutagenesis is ob- served, the mechanism should be elucidated. MUTAGENS RESULTING FROM COOKING OF FOODS Benzo[~]pyrene and Other Polynuclear Aromatic Hydrocarbons Almost 20 years ago Lijinsky and Shubik (1964) and Seppilli and Sforzolini (1963) reported that beef grilled over a gas or charcoal fire contained a variety of polycyclic aromatic hydrocarbons (PAH's). Benzo~a~pyrene was found in charcoal-broiled steak in levels up to 8 g/kg (Lijinsky and Shubik, 1964~. The source of the PAM's resulting 13-2

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Mutagens in Food! 279 from charcoal broiling was the smoke generated when pyrolyzed fat dripped from the meat onto the hot coals. Thus, meats with the highest fat content acquired the highest levels of these chemicals (Lijinsky and Ross, 1967~. When meat was cooked in a manner that prevented expo- sure to the smoke generated by the dripping fat, this source of contam- ination was either reduced or eliminated (Lijinsky and Ross, 1967; Lintas _ al., 1979; Masuda et al., 1966~._ _ PAM's have also been found in a variety of smoked foods and in roasted coffee (Howard and Fazio, 1980~. Vegetables can easily become contaminated by PAM's from air, soil, or water; fish and shellfish can assimilate such chemicals from their marine environments (Howard and Fazio, 1980~. However, unless vegetables or seafood are obtained from highly contaminated environments, the major source of PAR will probably be the smoking or cooking of food. Mutagens from Pyrolyzed Proteins and Amino Acids During the past few years, it has become clear that PAM's account for only a small fraction of the mutagenic (and, therefore, potentially carcinogenic) activity that occurs in foods during cooking. Nagao et al. (1977a) used dimethylsulfoxide to prepare extracts of the charred surfaces of broiled fish and meat. They found that the mutagenic acti- vities of these extracts for histidine-requiring strains of S. typhi- murium were hundreds or thousands of times greater than could be accounted for by the reported benzo~aipyrene contents of these cooked foods. For example, the mutagenic activity of charcoal-broiled beef- steak was the equivalent to that of approximately 4,500 fig of benzo~a]- pyrene per kilogram of steak, even though Lijinsky and Shubik (1964) had reported that charcoal-broiled steak contained no more than 8 fig of this chemical per kilogram. The mutagenic activity in the broiled fish and beef could also be detected in S. typhimurium strain TADS, implying that the agent could induce frameshift mutations (Nagao et al., 1977a; Sugimura et al., 1977~. Positive results in these assays depended on the presence of an _ vitro metabolic activation system utilizing the postmitochon- drial supernatant from homogenized livers of rats pretreated with polychlorinated biphenyls. Bjeldanes et al. (in press, a, b) have re- cently completed a series of detailed studies on the cooking condi- tions under which mutagenic activity is produced in various types of fish, meats (including organ meats), as well as eggs, milk, cheese, and tofu. To determine what constituent or constituents of fish and meat contribute to the mutagenic activity produced by cooking, studies have been conducted to examine the mutagenicity of smoke condensates from various substances. Smoke obtained from pyrolyzed proteins, such as lysozyme and histone, was found to be highly mutagenic to S. typhi- murium, whereas smoke condensates from pyrolyzed DNA, RNA, starch, or vegetable oil were only slightly mutagenic (Nagao et al., 1977b). 13-3

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280 DIET, NUTRITION, AND CANCER Pyrolysis of tryptophan resulted in more mutagenic activity than did any other common amino acid, but almost all of the amino acids tested yielded some mutagenic activity when pyrolyzed (Matsumoto et al., 1977; Nagao et al., 1977c). Purification of the mutagenic products resulting from pyrolysis of tryptophan resulted in the isolation of two previously unknown amino-Y- carbolines that are potent mutagens: 3-amino-1,4,-dimethyl-5H-pyrido- [4,3-b~indole (referred to as Trp-P-l, for "Tryptophan Pyrolysate 1") and 3-amino-1-methyl-5H-pyrido[4,3-b~indole (Trp-P-2) (Akimoto et al., 1977; Sugimura et al., 1977; Takeda et al., 1977~. The mutagenic activity resulting from pyrolysis of L-glutamic acid was shown to be due to the formation of 2-amino-6-methyldipyrido- [1,2-a:3'2'-diimidazole (Glu-P-l) and 2-aminodipyrido[1,2-a:3',2'-d]- imidazole (Glu-P-2) (Yamamoto et al., 1978~. The structural simi- larity between these products of glutamic acid pyrolysate and Trp-P-1 and Trp-P-2 is evident from Figure 13-1. Wakabayashi et al. (1978) isolated a different, but structurally related, heterocyclic mutagen from pyrolyzed lysine. This compound was 3,4-cyclopentenopyrido[3,2-aicarbazole (Lys-P-l). Pyrolysis of phenylalanine resulted in the formation of the mutagen 2-amino-5- phenylpyridine (Phe-P-l) (Sugimura et al., 1977~. When soybean globulin was pyrolyzed, the substances that contrib- uted to the mutagenic activity were compounds not previously identified as pyrolysis products of any individual amino acid. These compounds, 2-amino-9H-pyrido[2,3-b~indole (A~C) and 2-amino-3-methyl-9H-pyrido- [2,3-b~indole (Medic), are quite closely related to the Y-carboline compounds Trp-P-1 and Trp-P-2 (Yoshida et al., 1978~. Uyeta _ al. (1979) found that both Trp-P-1 and Trp-P-2 were present in pyrolysates of casein and gluten. Yamaguchi et al. (1979) identified Glu-P-2 in the tar resulting from pyrolysis of casein. These investigators estimated that Glu-P-2 and Glu-P-1 accounted for approximately 10% of the total mutagenic activity of the pyrolysate. Analyses have confirmed that at least some of the mutagenic pyrolysis products of amino acids are present in cooked foods. For example, Trp-P-1 has been found in "very well done" broiled beef and Glu-P-2 in broiled cuttlefish, although they account for less than 10% of the total mutagenic activity in extracts of these foods (Yamaguchi et al., 1980a,b). Similarly, sardines broiled to a dark brown color contain Trp-P-l, Trp-P-2, and Phe-P-l, although most of the mutagenic activity in these fish was due to the presence of other compounds (Yamaizumi et al., 1980) (Table 13-1~. Pieces of beef or chicken grilled in a high gas flame contained A~C and MeA~C (Matsumoto et al., 1981~. Similarly, A~C could be identified in grilled onions. 13-4

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Mutagens in Food 2X1 From Amino Acids: CH3 NH2 HCH3 Trp-P-1 4NH2 CH3 Glu-P-1 Lysine pyrolysate NJ0N W H Lys-P-1 From Proteins: N>lN~ NH2 H ARC Tryptophan pyrolysates Glutamic acid pyrolysates Soybean globulin pyrolysates CH3 ~NH2 H Trp-P 2 O ~r NH2 Glu-P-2 Phenylalanine pyrolysate JJ tN1NH2 Phe-P-1 ~N~N4NH2 H MeAaC FIGURE 13-1. Some mutagens from pyrolysates and from cooked foods. (Figure continued on next page.) 13-5

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282 DIET, NUTRITION, AND CANCER Figure 13-1 (continued): Some mutagens from pyrolysates and from cooked foods. From Broiled Sardines: N=( 1 / N CH3 NH2 IQ From Broiled Beef: Protein pyrolysate NH2 N=< H3C~,N`~N CH3 MeIQx Protein pyrolysates NH2 NJ4` cH3 MeIQ Two previously unknown mutagens were isolated from broiled sardines (Kasai et al., 1979~. These were 2-amino-3-methylimidazo[4,5-fiquino- line (IQ) and 2-amino-3,4-dimethyllmidazo[4,5-fjquinoline (MeIQj, which are extraordinarily potent mutagens to S. typh~murium strain TA98 (Kasai _ al., 1980a,b,c). Except for the beef that contained IQ and possibly that containing MeIQ and 2-amino-3,8-dimethylimidazo-[4,5-f]- quinoxaline (MeIQx), the foods listed as sources of mutagens in Table 13-1 appear to have been very well cooked and even charred on the surfaces to produce the mutagenic compounds identified in the table. Information on mutagens formed by cooking foods at lower temperatures is discussed in the next section. As discussed in Chapter 3, the mutagenic activity of a chemical in bacteria indicates potential genotoxicity and possible carcinogenicity in mammals. To test for carcinogenic activity, it is necessary to use mammalian cell systems and intact mammals. Whenever other test systems also indicate genotoxic activity, it is more likely that a bacterial mutagen can act as a carcinogen. 13-6

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GO o o o o o 4- o u' 4- o oD cd is a) To a: c to - ~ A: v ~ : o ~ v c o ~ c, ~ so , x: ~ ~ o ~ ~ Hi En ~ ~ - lo ~ ~ o c) c c so ~ v ~ cr' :~ ~ ~: 13-7 283 o o o o o ~ ~ ~ ~ ~ 4 ~ 0 0 a, ~ a, AD ~ ~ ~ 0 0 ~ 0 0` ~ ~ _' ~ ~ ~ ~ _1 ~ 0` e e e e e e e e e e ~ e 01 01 01 01 a1 010101 ala1 01 a1 01 .1 o1 "1 "1 a1 "1"I-1 "1~1 .1 1 Val ~ ~ ~ ~ ~ 0 0 0 0 0 ~ ~ ~ ~ ~ ~ g "0 "o "o "0 0 ~ ~ ~ N ~ N ~ ~ ~ ~ ~ ~ ~ N 0 ~ 0 0 0 0 0 0 0 ~ ~ : ~ ~ `~, `` ~ ~ - _ 1 C 0 = 64 ~ 0 0 0 )" ~ 0 ~ 0` e e e - 1~1~1 01 01 01 "Ivl~l .1.1 .1 U~ e e e O 0 00 - u~ _I 0 `0 l 0 ~ 0 0 1 eC: 0 0 ~ V O C} O O O ~1 It' O `0 I_ O O O O O C~ O 0 z CJ 0 ~ i 0 vl ~1 0 0 :~: 0 c o ~ o ~4 c) ~ ~ ~ ~ ~4 a-r tJ o ~ c~ Id b b ~d b C~ C~ C~ C~ C o C~ o o 0` C 1 _t ~ I ~ 0 1 1 ~ :^ ~ :~:1 ~ ~ b eC ~ ~ ~ ^ V +1 1 0 _I ~ 1_ ~ ~ _ - ~ ~i B C ~ N ~ 413 O | b ~ J: 1 ^ - ^ ~ 1 CV' CL ~ 1 O ~ ~ ~4 _t 1 ~ 1 ~ ~ 1 0 ~ 0 o~l 0 ~ ~ 0 0 0 1 ~ ~ ~ ~ ~ ~ ~^ 3 ~ :~1 1 ~L c~ ~ C~ b 1 C 0 a~ _I b _t _. ~ ~ 0 0 0 b b O O O O C~ ~ 1 ~ 1 C~ _1 ~ C 0 1 0 - 1 _I :^ O :^ O b aC _. ~ O :^ ~ V _ V " - ~ =1 1 0 ~ 1 :~1a ~ ~ ~ - 1 ~ _' 1 C~ 1 1 O O O ~ =1 ~ o c I 1 ~ ~ _1 -~ _ ~: ^ ~C b <~: O I C~ I :>. I N e~ ~ P. ~ 0 o 5 ~ c s o b O O O O O O ~ U~ `0 `0 1 C 1 ~ :^ O ~ O aC: C aC C V ~ V _I _~ _ ~ _ 1 ~ 1 1 0 C~ ~ ~ ~ 1 1 O O O O C N q' '=~ a=~ C~ ~ e~ l l l I ~ ~ ~ ~ ~ 0e ~ ~ aC: E" C 0 0 P. O o z 0 0 00 U) b V 0. 0 0 ~0 0 z 0

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284 DIET, NUTRITION, AND CANCER Four of the mutagenic pyrolysates derived from amino acids or protein--Trp-P-l, Trp-P-2, Glu-P-l, and AolC--have been shown to in- duce sister chromatic exchanges in a permanent line of human lympho- blastoid cells (Tohda et al., 1980~. In addition, the basic fraction extracted from pyrolyzed tryptophan was found to cause mutations re- sulting in resistance to ouabain or 8-azaguanine in cultured Chinese hamster lung cells (Inui et al., 1980~. Trp-P-l, Trp-P-2, and Glu- P-1 can transform primary Syrian golden hamster embryo cells (Takayama _ al., 1977, 1979~. The cells transformed by Trp-P-2 have been shown to grow in soft agar and to result in tumors when inoculated into the cheek pouches of young hamsters with unimpaired immunocompetence (Taka- yama et al., 1978~. Although these findings support the potential car- cinogenicity of these chemicals, a definitive determination of carcino- genicity must be made in whole animals. Several of the mutagenic pyrolysates of amino acids or proteins have been tested for carcinogenicity in viva. Neoplastic nodules, which are presumed to be precancerous changes, were found in the livers of Wistar rats given the basic fraction from pyrolyzed trypto- phan at 0.2% in the diet (Matsukura et al., 1981b). Neither neoplas- tic nodules nor liver tumors had previously been observed in this strain of rats in this laboratory. Subcutaneous injection of Trp-P-1 (1.5 mg once a week for 20 weeks) induced sarcomas in Syrian golden hamsters and in Fischer rats (Ishikawa et al., 1979~. Trp-P-2 did not induce tumors in either hamsters or rats under the same experimental conditions (Ishikawa _ al., 1979~. Trp-P-1 and Trp-P-2 produced liver tumors in CDF1 (BALB/c x DBA) mice that were fed a diet con- taining 0.02% of either of these chemicals (Matsukura et al., 1981a). Some of these liver tumors metastasized to the lung. Female mice were more susceptible to these carcinogens than were the males. Six of nine female ACI rats fed 0.1% Trp-P-2 in their diet developed neoplastic nodules of the liver, and one of the six developed a hemangioendothe- lial sarcoma of the liver (Hosaka _ al., 1981~. None of the control animals developed such nodules or tumors. Glu-P-l, Glu-P-2, AaC, and MeArxC induced hepatomas in mice. Glu-P-1 and Glu-P-2 also induced hemangioendotheliomas between the scapulae of mice fed diets contain- ing 0.05% of either of these chemicals (Sugimura, in press). Thus, it appears that the identification of several of the mutagenic compounds found in pyrolysates of proteins and amino acids was an accurate pre- dictor of carcinogenicity. However, the presence of a carcinogenic chemical in a pyrolyzed amino acid or protein mixture does not neces- sarily imply that the carcinogen will also be present in normally cooked, uncharred food. Mutagens Fo~u~ed from Meat at Lower Temperatures In the experiments concerning the formation of mutagenic pyrolysis products from amino acids and proteins, temperatures of 250C or greater were used (Matsumoto et al., 1977; 1978; Uyeta et al., 1979~. However, it is now known that simply boiling beef stock at temperatures 13-8

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Mutagens in Food 285 of approximately 100C results in the formation of bacterial mutagens (Commoner _ al., 1978; Vithayathil et al., 1978~. In fact, the forma-_ Lion of mutagens in beef stock has been detected at temperatures as low as 68C (Dolara et al., 1979~. Frying of fish at 190C produces mutagenic activity (Krone and Iwaoka, 1981~. Mutagenic activity also results when hamburgers are broiled, even when the surface temperature does not exceed 130C (Weisburger and Spingarn, 1979~. A portion of the mutagenic activity formed from heated beef extract or from fried beef was found to be due to a chemical with a molecular weight of 198 (Spingarn et al., 1980a), which has now been shown to be IQ (Kasai et al., 1980a). MeIQx, another heterocyclic mutagenic compound that has not been identified as an amino acid or protein pyrolysate, has also been found in fried beef (Kasai et al., 1981~. However, the frying temperature was not specified. Weisburger and Spingarn (1979) suggested that this mutagen, formed in beef at moderate temperatures, may result from a browning reaction between sugars and amines rather than from the pyrolysis of proteins. Mutagen Formation Involving Carbohydrates If the formation of IQ during the cooking of beef results from a browning reaction, it might be expected that the browning of starchy foods could also result in the formation of mutagens. Spingarn et al. (1980b) have observed that the frying of potatoes and the toasting of bread result in the formation of mutagenic activity, but the chemi- cal~s) responsible for this activity and their source during the cooking process remain to be determined. Browning of foods results from the reaction of amines with sugars. Using a model system for the browning reaction, Spingarn and Garvie (1979) found that mutagenic activity occurred when any of six different sugars, including glucose, were refluxed with ammonium hydroxide. Sev- eral laboratories have found that heating a mixture of the amino acid lysine with glucose at temperatures between 100C and 121C results in products that are mutagenic (Powrie et al., 1981; Shinohara et al., 1980; Yoshida and Okamoto, 1980~. The increase in mutagenic activity with time paralleled the increase in browning (Shinohara et al., 1980~. Mutagenic activity could also be produced by using certain amino acids other than lysine (Powrie et al., 1981; Yoshida and Okamoto, 1980) or by using fructose rather than glucose (Powrie et al., 1981~. Chromosome aberrations are alterations in the structures of chromo- somes that can be observed through a microscope. Such aberrations are not likely to be heritable. The significance of their induction in cells _ vitro is not clear, particularly for chemicals unable to in- duce heritable mutations or _ vivo chromosome aberrations. Pyrazine and four of its alkyl derivatives--compounds formed by heating mixtures of sugars and amino acids (Koehler et al., 1969~-- were found to be nonmutagenic to S. typhimurium but capable of induc- ing chromosome aberrations in cultured Chinese hamster ovary (CHO) 13-9

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286 DIET, NUTRITION, AND CANCER cells (Stich et al., 1980~. Commercial caramel and caramelized sam- ples of several sugars prepared by heating sugar solutions also caused chromosome aberrations in CHO cells (Stich et al., 1981b). Similarly, furan and six of its derivatives, which can be produced in foods by heating carbohydrates (Maya, 1979), were found to cause chromosome aberrations in CHO cells but to be nonmutagenic to bacteria (Stich et al., 1981a). PLANT FLAVONOIDS Among the most widespread of the known naturally occurring mutagens (possible carcinogens) that are normal constituents of many foods are the mutagenic flavonoids. Among the flavonol aglycones that have been shown to be mutagenic to S. typhimurium are quercetin, kaempferol, and galangin (Bjeldanes and Chang, 1977; Brown, 1980; Hardigree and Epler, 1978; Ma cGregor and Jurd, 1978). Quercetin has also been reported to induce gene conversion in yeast (Hardigree and Epler, 1978), transforma- tion of both hamster embryo cells (Umezawa et al., 1977) and BALB/c 3T3 mouse cells (Meltz and MacGregor, 1981), and mutations and single- stranded DNA breaks in L5178Y mouse cells (Meltz and MacGregor, 1981~. Both quercetin and kaempferol have been reported to cause mutations in V79 Chinese hamster cells (Maruta et al., 1979) and heritable mutations (sex-linked recessive lethals) in the fruit fly Drosophila melanogaster (Watson, 1982~. In some mutagenic plant products consumed by humans, the mutagenic substances isolated were identified as flavonoids. For example, most of the mutagenic activity of an acid hydrolysate of green tea could be accounted for by three flavonoids: kaempferol, quercetin, and myricetin (Uyeta et al., 1981~. The flavonoids kaempferol and isorha~nnetin were found to be responsible for most of the mutagenic activity found in Japa- nese pickles (Takahashi et al., 1979~. The mutagen in the spice of sumac was found to be quercetin (Seino et al., 1978~. Isorhamnetin and quercetin were the major mutagens in a methanol extract of dill weed (Fukouka et al., 1980~. Brown (1980) reported that the edible portions of most food plants contain flavonoid glycosides, especially quercetin and kaempferol. He estimated that the average daily intake of flavonoids in the U.S. diet is approximately 1 g and that the daily intake of mutagenic flavonoid glycosides may be equivalent to approximately 50 mg of quercetin. Approximately 25% of the flavonoid intake is derived from tea, coffee, cocoa, fruit jams, red wine, beer, and vinegar (Brown, 1980~. In view of the mutagenic activity and widespread distribution of certain flavonoids, particularly quercetin, it is important to deter- mine the carcinogenic potential of these chemicals. At present, the data concerning the carcinogenicity of quercetin are contradictory. Pamukcu et al. (1980) reported that adding 0.1% quercetin to the diet 13-10

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Mutagens in Food 2SB7 of albino Norwegian rats for 58 weeks resulted in the induction of tumors in the epithelium of the intestine and urinary bladder. How- ever, when Saito et al. (1980) fed 2% quercetin to ddY mice throughout the lives of the animals, they found no significant increase in tumor incidence. At doses as high as 10% quercetin in the diet fed through- out life, no significant increase in tumor incidence was observed in ACT rats (Hirono et al., 1981) or in hamsters (Morino et al., 1982~. The reason for the discrepancy between the findings of Pamukcu et al. and the other investigators is not clear, but may relate to differences in sensitivity among the species and strain tested. Flavonols often exist in plants in the form of glycosides. For example, rutin is a glycoside of quercetin that can be hydrolyzed to release quercetin by enzymatic or chemical treatment. Such hydrolysis, mediated by intestinal bacteria, occurs when glycosides are consumed in foods. Rutin and other glycosides of mutagenic flavonoids have been shown to be mutagenic to S. typhimurium following treatment with glyco- sidase-containing extracts of the mold Aspergillus niger (Nagao et al., 1981), the snail Helix pomatia (Brown and Dietrich, 1979), rat cecal contents (Brown and Dietrich, 1979), or human feces (Tamura et al., 1980~. Mutagenic activity of rutin has also been reported in S. typhi- murium in the absence of glycosidase treatment, but only at doses higher than those required when such treatment is used (Hardigree and Epler, 1978). MUTAGENIC ACTIVITY IN EXTRACTS OF FOODS AND BEVERAGES Several food substances have been reported to contain mutagenic activity, although the specific chemicals responsible for this activity have not yet been identified. For example, coffee is mutagenic to Salmonella typhimurium strain TA100, whether it is brewed, instant, or decaffeinated (Aeschbacher and Wurzner, 1980; Aeschbacher et al., 1980; Nagao et al., 1979~. Although caffeine has been reported to be muta- genic to bacteria (Clarke and Wade, 1975; Demerec et al., 1948, 1951; Gezelius and Fries, 1952; Glass and Novick, 1959; Johnson and Bach, 1965; Kubitschek and Bendigkeit, 1958, 1964; Novick, 1956), it could not have been responsible for the mutagenicity of coffee observed in these reports, since decaffeinated coffee was as mutagenic as regular coffee and caffeine itself was not detected as a mutagen under the test conditions used (Aeschbacher et al., 1980; Nagao et al., 1979~. Studies examining the possible carcinogen~city of coffee are discussed in Chap- ter 12. Black tea, green tea, and roasted tea were mutagenic to S. typhi- murium strain TA100 in the absence of added enzymes (Nagao et al., 1979~. When extracts of Aspergillus niger or human feces containing enzymes capable of hydrolyzing glycosides were added, tea became muta- genic to S. typhimurium strain TA98 (Nagao et al., 1979; Tamura et al., 1980~. Acid hydrolysis of green or black tea also caused mutagenic 13-11

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Mutagens in Food 293 REFERENCES Aeschbacher, H. U., and H. P. Wurzner. 1980. An evaluation of instant and regular coffee in the Ames mutagenicity test. Toxicol. Lett. 5:139-145. Aeschbacher, H. U., C. Chappuis, and H. P. Wurzner. 1980. Mutagenicity testing of coffee: A study of problems encountered with the Ames Salmonella test system. Food Cosmet. Toxicol. 18:605-613. Akimoto, H., A. Kawai, H. Nomura, M. Nagao, T. Kawachi, and T. Sugimura. 1977. Syntheses of potent mutagens in tryptophan pyrolysates. Chem. Lett. 9:1061-1064. Arimoto, S., T. Negishi, and H. Hayatsu. 1980a. Inhibitory effect of hemin on the mutagenic activities of carcinogens. Cancer Lett. 11:29-33. Arimoto, S., Y. Ohara, T. Namba, T. Negishi, and H. Hayatsu. 1980b. Inhibition of the mutagenicity of amino acid pyrolysis products by hemin and other biological pyrrole pigments. Biochem. Biophys. Res. Commun. 92:662-668. Baird, M. B., and L. S. Birnbaum. 1979. Inhibition of 2-fluorenamine- induced mutagenesis in Salmonella typhimurium by vitamin A. J. Natl. Cancer Inst. 63:1093-1096. Bjeldanes, L. F., and G. W. Chang. 1977. Mutagenic activity of querce- tin and related compounds. Science 197:577-578. Bjeldanes, L. F., M. M. Morris, J. S. Felton, S. Healy, D. Stuermer, P. Berry, H. Timourian, and F. T. Hatch. In press a. Mutagens from the cooking of food. II. Survey by Ames/Salmonella test of mutagen formation in the major protein-rich foods of the American diet. Food Chem. Toxicol. Bjeldanes, L. F., M. M. Morris, J. S. Felton, S. Healy, D. Stuermer, P. Berry, H. Timourian, and F. T. Hatch. In press b. Mutagens from the cooking of food. III. Secondary sources of cooked dietary pro- tein. Food Chem. Toxicol. Brown, J. P. 1980. A review of the genetic effects of naturally occurring flavonoids, anthraquinones and related compounds. Mutat. Res. 75:243-277. 13-17

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302 DIET, NUTRITION, AND CANCER Tsuda, M., M. Nagao, T. Hirayama, and T. Sugimura. 1981. Nitrite con- converts 2-amino-a-carboline, an indirect mutagen, into 2-hydroxy-~- carboline, a non-mutagen, and 2-hydroxy-3-nitroso-~-carboline, a direct mutagen. Mutat. Res. 83:61-68. Umezawa, K., A. Shirai, T. Matsushima, and T. Sugimura. 1978. Comu- tagenic effect of norharman and barman with 2-acetylaminofluorene derivatives. Proc. Natl. Acad. Sci. U.S.A. 75:928-930. Uyeta, M., T. Kanada, M. Mazaki, S. Taue, and S. Takahashi. 1979. Assaying mutagenicity of food pyrolysis products using the Ames test. Pp. 169-176 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. Uyeta, M., S. Taue, and M. Mazaki. 1981. Mutagenicity of hydrolysates of tea infusions. Mutat. Res. 88:233-240. Vithayathil, A. J., B. Commoner, S. Nair, and P. Madyastha. 1978. Isola- tion of mutagens from bacterial nutrients containing beef extract. J. Toxicol. Environ. Health 4:189-202. Wakabayashi, K., K. Tsuji, T. Kosuge, K. Takeda, K. Yamaguchi, K. Shudo, Y. Iitaka, T. Okamoto, T. Yahagi, M. Nagao, and T. Sugimura. 1978. Isolation and structure determination of a mutagenic substance in L-lysine pyrolysate. Proc. Jpn. Acad. 54(B):S69-571. Wakabayashi, K., M. Nagao, T. Kawachi, and T. Sugimura. 1981. Co-muta- genic effect of norharman with N-nitrosamine derivatives. Mutat. Res. 80:1-7. Watson, W. A. F. 1982. The mutagenic activity of quercetin and kaempferol in Drosophila melanogaster. Mutat. Res. 103:145-147. Weisburger, J. H., and N. E. Spingarn. 1979. Mutagens as a function of mode of cooking of meats. Pp. 177-184 in E. C. Miller, J. A. Miller, I. Hirono, T. Sugimura, and S. Takayama, eds. Naturally Occurring Carcinogens-Mutagens and Modulators of Carcinogenesis. Japan Scien- tific Societies Press, Tokyo; University Park Press, Baltimore, Md. Yamaguchi, K., H. Zenda, K. Shudo, T. Kosuge, T. Okamoto, and T. Sugimura. 1979. Presence of 2-aminodipyrido[1,2-a:3',2'-diimidazole in casein pyrolysate. Gann 70:849-850. Yamaguchi, K., K. Shudo, T. Okamoto, T. Sugimura, and T. Kosuge. 198Oa. Presence of 3-amino-1,4-dimethyl-5H-pyrido[4,3-b~indole in broiled beef. Gann 71:745-746. 13-26

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