chemical analysis, prevention, and low-level dosimetry of heterocyclic … · with a new analytical...

[CANCER RESEARCH (SUPPL.) 52, 2l03s-2t07s. April 1, 1992]

Chemical Analysis, Prevention, and Low-Level Dosimetry of Heterocyclic Aminesfrom Cooked Food1

James S. Felton,2 Mark G. Knize, Michelle Roper, Esther Fultz, Nancy H. Shen, and Kenneth W. TurteltaubBiomÃ©dicalSciences Division, Lawrence Livermore National Laboratory, L'nirenily of California, Livermore, California 94550

Abstract

Potent mutagenic and carcinogenic heterocyclic amines are producedfrom heated food derived from muscle. These compounds are present atpart-per-billion levels and consist primarily of the amino-imidazoazaar-ene class of chemicals. Additional mutagens present in the meat are notas clearly characterized. Commercial fried-beef patties (hamburgers)have low levels of 2-amino-3,8-dimethylimidazo|4,5-/]quinoxaline(MelQx) and 2-amino-3,4,8-trimethylimidazo|4,5-/|quinoxaline (4,8-DiMelQx), 0.1-0.68 ng/g meat for MelQx and slightly lower for 4,8-DiMelQx. The formation of these heterocyclic amines can be reduced bymicrowave pretreatment of meat, with the resulting liquid being pouredoff before frying. The \mes/Salmonella mutagenic activity was reducedto 5-10% of that of non-microwave-treated samples. MelQx and Di-MelQx concentrations were reduced to 12% and 50% of levels in thenon-microwave-treated samples, respectively. MelQx adducts, as measured by accelerator mass spectrometry, were found to be linear withdoses from 5 mg/kg to 500 ng/kg. Linear DNA binding at low doses isimportant for assuming linear risk estimation from the high animal-feeding doses causing cancer to the low human-dietary exposures. Extrapolating from the rodent IDÂ«,,dose to humans gives a maximumcredible risk from consumption of heterocyclic amines of approximately1/1000 exposed individuals.

Introduction

More than 50 years ago, extracts from heated animal musclepainted on the skin of mice were found to be carcinogenic (1).Solvent extracts of horse muscle heated at 275Â°C,when painted

every second day on the mice, gave a statistically significantincrease in the number of mammary tumors. This finding wasbrought to our attention by Dr. Sugimura, who directed research approximately 40 years later at the National CancerCenter, Tokyo, showing that the smoke condensate and charredsurface of broiled fish and beef were mutagenic in the Ames/Salmonella test (2). In the past 10 years, numerous papers havebeen published about the heterocyclic amines responsible formutagenic activity of cooked fish and beef. These same compounds are likely responsible for the carcinogenic activity ofthe heated horse muscle (3-6). Over the last 10 years, 17heterocyclic amines have been isolated and identified fromheated amino acids or cooked meat products (4). Perhapsbecause of their occurrence in cooked meats and their mutagenic and carcinogenic effects, the amino-imidazoazaareneshave received considerable attention (7). These compounds haveone or two heterocyclic rings fused to an amino-imidazo ring.Mutagenic activity of these compounds in Salmonella variesover several orders of magnitude and is increased when thereare three rings rather than two and when hetero-atoms arepresent in the third ring (8). Methyl substitution on the imid-azole ring is also important for increased mutagenic activity.

1Presented at "Nutrition and Cancer." the first conference of the InternationalConference Series on Nutrition and Health Promotion. April 17-19, 1991.Atlanta, GA. This work was supported by United States DOE Contract W-7405-ENG-48, NIEHS Grant IAG-222YO1-ES-70158, National Cancer InstituteGrant RO1-40811, and a National Meat and Livestock Board grant.

2To whom requests for reprints should be addressed, at Biomedicai Sciences

Division, Lawrence Livermore National Laboratory. University of California,P. O. Box 5507. Livermore. CA 94550.

All of the heterocyclic amines tested for carcinogenicity werepositive in mice and rats (9), and IQ1 was shown to cause liver

tumors in nonhuman primates after a very short latency (10).This report discusses the levels of the heterocyclic amines in

fried ground beef and the risk for initiating human cancer. Thepretreatment of beef with microwave heating to reduce thelevels of precursors and the formation of these carcinogensduring subsequent cooking is also discussed. Finally, the relationship of low-dose human carcinogen exposure to high-doseanimal-feeding experiments will be discussed within the contextof DNA binding at extremely low doses, based upon analyseswith a new analytical tool, accelerator mass spectrometry.

Isolation and Quantitation of Heterocyclic Amines

The compounds responsible for mutagenic activity in cookedfoods have been isolated using the Ames/Salmonella test activity as a guide to the chemical purification of the biologicallyactive molecules. The heterocyclic amines IQ and MelQ wereisolated and identified from broiled sardines in the early 1980s(11, 12) and were found to be present at a level of a few partsper billion. Original purifications typically began with tens ofkilograms of cooked foods, which were subjected to many-stepprocedures to isolate the amounts necessary for structural identification (7, 13, 14).

Heterocyclic amine mutagen-carcinogens produced fromheating processes were categorized into five groups by Ã–vervikand Gustafsson (6). New methods to quantify a major portionof the chemically characterized heterocyclic amines in foodswere recently developed (15). These methods will enable reasonably accurate quantitation in a larger variety of foods. Comparisons of the content of heterocyclic amines in specific dietsand the relative amounts of individual heterocyclic amines inindividual foods will now be much easier.

Structures of four commonly characterized heterocyclicamines in cooked foods are shown in Fig. 1. Table 1 shows therelative abundances of the four different heterocyclic amines incooked muscle. The mass percentages show that PhIP comprises 83-93% of the combined mass of these four compounds,with smaller amounts of MelQx, 4,8-DiMeIQx, and IQ. Thesefour studies described in Table 1 indicate that the relative massamounts of heterocyclic amines detected are consistent amonglaboratories, using various analytical methods. These four compounds contribute approximately 80% of the mutagenic activitybut an unknown percentage of the mass of biologically activecompounds present. Although the relative amounts are consistent, quantitative determinations of the amounts of heterocyclicamines per gram of cooked food cover a 10-fold range (Table1). Many more samples, with examples from the range ofpractical cooking conditions, are still needed to determine thedietary content of heterocyclic amines.

3The abbreviations used are: IQ. 2-amino-.Vmcthy limidazo[4,5-^]quinoline;MelQ. 2-amino-3,8-dimethylimidazo[4,5-/]quinoline; PhIP. 2-amino-l-methyl-6-phenylimidazo[4.5-A ]pyridine; 4.8-DiMeIQx. 2-amino-3,4.8-trimethylimi-dazo[4.5-/]quinoxaline; TD50, daily dose/kg that gives '/2 the animals cancer overa lifetime of exposure .

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HETEROCYCLIC AMINES FROM COOKED FOOD

NH2

MelQx

4,8-DiMeldx PhIP

Fig. I. Structures of IQ, MelQx, 4,8-DiMeIQx, and PhIP. four heterocyclicamine mutagen-carcinogens found in cooked meats.

Table 1 Percentage ofmutagen by mass in various cooked-food (muscle) extracts

% of 4 heterocyclicamines assayed

SampleFried

beefFried beef (13

min. 190'C)

Broiled fish ( 16min. 260T)

Dry heated beefextractIQ(0.02-0.36)Â°0.12

ND*0.21

3.28-MelQx(0.91-8.3)6.2

148.5

8.04.8-DiMeIQx(0.1-2.0)0.37

3.00.13

3.2PhIP(9.7-49)93

839186Ref.71516e

Â°Range, in ng/g, for the studies.* ND, not determined.' R. T. Taylor, E. Fultz, and M. G. Knize, unpublished results.

Table 2 MelQx and 4,8-DiMelQx content of commercial hamburgersHamburgers were purchased, pooled to make a 100-g sample, homogenized,

extracted, and partially purified over a column of \AD-2 resin, as describedpreviously (24). The eluant was split into four samples and two were spiked withMelQx and 4,8-DiMeIQx to determine the yield. Each was processed andquantified for MelQx and 4,8-DiMeIQx as described by Gross (15).

Vendor 1Vendor 2Vendor 3MelQx

(ng/g)0.68"

0.26O.I4,8-DiMeIQx

(ng/g)0.28

0.08ND*

1Average of replicate analysis.*ND, not detected.

230, 300, and 400 revertants/g reported by Knize et al. (17),Barrington et al. ( 18), and Doolittle et al. ( 19), respectively, forbeef patties cooked at 200Â°C.This calculation ignores the

contribution from other known mutagenic amines (such as IQ)and from unknown heterocyclic amines. There are several possible explanations for the lack of concordance observed. Mu-tagen inhibitors may be present in the meat extracts, therebylowering the mutagenic response of the mixture. Our experienceand that of others (20) suggests that there is little or noobservable inhibiting effect on mutagenic activity for extractsof meat. Errors in the mass of the quantitative standards usedin the Ames/'Salmonella test or high performance liquid chro-

matography analysis are also possible. Published ranges for theAmes/Salmonella analysis of the pure synthetic compounds (4)do not account for differences of this magnitude. This quantitative discrepancy has not been addressed previously but needsto be explained to ensure valid measurements of heterocyclicamines in the diet. Ultimately, risk assessment calculations willdepend on quantitative determinations based upon accurateestimates of the carcinogen levels.

Assessing human dietary intake of heterocyclic amine muta-gens is difficult because of the variety of foods and preparationmethods used. Cooking temperature and time are importantvariables affecting the formation of mutagens during cooking(18, 21, 22). Determination of the dietary intake of heterocyclicamine carcinogens for North Americans will require surveyingfoods cooked as consumed by the public.

Studies of the heterocyclic amine content of commerciallycooked foods have not been reported, but the mutagenic activityhas been shown to vary severalfold among different vendorsand between visits to the same vendor (22). Foods in theNetherlands cooked under normal household conditionsshowed significant mutagenic activity (23). Table 2 shows preliminary analyses of commercially cooked hamburgers forMelQx and 4,8-DiMeIQx, using a modification of the solid-phase extraction and high performance liquid chromatographydetection method of Gross (15). The amounts are lower thanreported in laboratory studies (see Table 1) but are easilydetectable. Efforts should emphasize the analysis of PhIP infood samples, because it appears to be the most abundantheterocyclic amine in laboratory-cooked meat patties (Table 1).The much higher levels of mutagenic activity and heterocyclicamine content in laboratory studies suggest that cooking athome may be a more important source of exposure.

Most studies do not compare the Ames/Salmonella testspecific activity of the synthetic standards with the Ames/Salmonella test activity accounted for by the mass amounts ofmutagens identified from complex mixtures. For beef cookedat 190Â°C(15), the contribution of the mutagenic activity of

pure synthetic MelQx and DiMelQx exceeds the total mutagenic activity typically measured in crude meat samples cookedfor similar times and temperatures. The expected mutagenicactivity can be calculated by multiplying the mutagenic activityin strain TA 1538 for synthetic MelQx (99 revertants/ng) bythe mass amount, 8.3 ng, measured in the fried beef. Thisresults in 822 revertants/g meat. Similarly, the expected mutagenic activity contribution for 4,8-DiMeIQx (2 ng x 208revertants/ng) is 416 revertants/g meat and for PhIP (48.5 ngx 2 revertants/ng) is 97 revertants/g meat. The sum of thesegives the calculated expected mutagenic activity of 1335TA 1538 revertants/g of meat.

The calculated sum is 3-6-fold higher than typical values of

Newly Identified Heterocyclic Amine Mutagens in Foodsfrom Food-derived Precursors

Because heterocyclic amines in cooked foods are present atparts per billion concentrations, unknown compounds are difficult to identify, because complete spectroscopic data cannotbe readily obtained even after starting with 10-100 kg of meat.Additionally, compounds with partially characterized structuresneed to be synthesized for structural confirmation. This synthesis effort has proven to be substantial and usually requirescomplex synthetic solutions.

Table 3 shows the mass spectral data for a group of partiallycharacterized mutagens isolated from foods, from foods withmutagen-increasing additives (24), or from natural meat components after simple heating. Three of these mutagens, withmolecular weights of 202, 216, and 244, have at least oneoxygen atom in their proposed structure (7, 26, 27). Mutagenicoxygen-containing heterocyclic molecules are unusual, al-

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though a series of mutagenic nitrobenzofurans and nitrona-phthofurans were reported (28, 29). Two of these oxygen-

containing heterocycles appear to contribute a substantial massof mutagen to fried pork patties (25).

The first four compounds listed in Table 3 have few abundantmass fragments. Those listed are typical for the known amino-

imidazoazaarenes, with losses of 1, 15, and 28 mass units. Thecompound with a molecular weight of 244 shows a large fragment (loss of 43 mass units), and this is reflected in theproposed, not fully aromatic, pyranobenzimidazole structure.

The highest priority for elucidating the structures of thesepartially characterized mutagens lies with those found in unadulterated meat (without mutagen-increasing substancesadded). The remarkable correspondence between mutagensfound in model systems and cooked foods (4) suggests thathuman dietary foods need to be analyzed for compounds isolated from model reactions as well. Additionally, PhIP, whichwas first isolated from fried beef, has now been implicated asan important genotoxic compound in cigarette smoke (30).

Prevention of Mutagen Formation

Since potent mutagenic activity was first observed in cookedmeats, many studies aiming to reduce mutagen formation havebeen conducted. Addition to the meat of specific constituentsthat inhibit mutagen-forming reactions has had some success(31, 32) but has not been widely used.

A practical method for removing known mutagen precursorswas devised by Taylor et al. (33). It was found that shortmicrowave oven treatment of uncooked meat releases a clearliquid containing many of the precursors of mutagen formation.Pouring off of the liquid, followed by frying of the ground-meatpatty, results in 5-10% of the mutagenic activity of a non-microwave-pretreated control. Table 4 shows preliminary dataindicating that a reduction in MelQx and 4,8-DiMeIQx contentin the meat correlates with the decrease in total mutagenic

Table 3 Mass spectral peaks and source of new heterocyclic amine mutagens

Molecularweight176190202216244Mass

peaks(relative

intensity)176(100)175(76)161

(22)148(11)177(9)190(100)189(81)161

(35)175(27)188(17)202(100)201

(75)187(11)203

(9)174(8)216(100)215(88)201

(40)115(25)217(19)244(100)201

(60)228(23)200(19)227(19)Sources

of newmutagenBeefMeat

mixture +creatineThreonine

+creatinePorkBeef

+creatineMeatmixture +creatineBeefPorkMeat

mixture +creatineGlutamic

acid + creatine + glucoseRef.1314*2526147251427

Table 4 Microwave pretreatment to reduce MelQx, 4,8-DiMeIQx, andSalmonella mutagenic activity

Meat patties were microwave pretrealed in a Petri dish for 0-3 min, theresulting clear meat liquid was decanted, and the meat was fried. Mutagenicactivity was determined from the linear portion of dose-response curves, aspreviously described (26). Heterocyclic amines were quantified by the method ofGross (15), with the average of triplicate analyses used to calculate the percentageof the control.

Microwavepretreatment

time (min) beforefrying at

200'C. 6 min/

sideControl

(no pretreatment)0.51.01.52.03.0%of

controlMcIQx100

11748

NO"37

12%of

control4,8-DiMeIQx100

21590

ND7350%of

control TA 1538mutagenic

activity100

843813106

Â°ND, not determined.

activity obtained with increasing times of microwave oven pretreatment (80% power, with subsequent frying of the meat pattyat 250Â°Cfor 6 min/side). The decreases in MelQx and 4,8-

DiMeIQx are significant. Additional determinations are neededto better quantitate these reductions.

As noted for the meat samples in Table 1, there is also adiscrepancy between the mutagenic activity and the quantitativemeasure of the heterocyclic amines (Table 4). The decrease inmutagenic activity to 10% at 2 min is not accounted for by thedecrease in MelQx to 37% and the decrease of 4,8-DiMeIQxto 73% of the original amounts. A specific heterocyclic aminemay be differentially lost or an inhibitor may be formed afterthe microwave treatment. More investigation of these possibilities is needed.

DNA Dosimetry

Understanding the risk from exposure to chemical carcinogens depends on measuring their doses to important targettissues and their ultimate reactivities with critical macromole-cules. We are using a new and very sensitive method, acceleratormass spectrometry, as well as 12P-postlabeling of DNA adducts,

to measure heterocyclic amine doses to target macromolecules.In our initial experiments, we measured the adduction of

MelQx to DNA, in mice, at exposures (stomach intubation)relevant to human dietary doses (as low as 500 ng/kg bodyweight). [14C]MeIQx bound to DNA was detected at as low as1 DNA adduci/IO" nucleotides. MelQx adduci levels were

shown to be linear from 5 mg/kg to 500 ng/kg (34).Further enhancement of sensilivily is being achieved by low

ering the nalural I4C level in mouse lissue, by feeding micepelroleum-based diels. Prolein is purified from yeasl lhal aregrown on a carbon source derived from petroleum. Preliminarysludies suggesl lhal 14Cdeplelion in ine animals will allow a 5-fold increase in sensilivily.4 This increase, coupled wilh goodconlrol of 14Cbackground in Ihe laboralory and mulliple label

ing of carbon aloms in ihe molecules sludied, should allowrouline analysis below ihe level of 1 DNA adduci/IO12 nucleo-lides (1 adduci/1000 cells). This will enable accurale measure-menls, in animals, of chemical binding lo macromolecules aldoses of carcinogen equivalent to those consumed by humans.

We have also used "P-posllabeling lo sludy the number,amounts, and nature of specific DNA adducts. PhlP-DNAadduci levels were measured al 1, 10, and 20 mg/kg, in the

' J. S. Felton, E. Fultz, and M. G. Knize, unpublished results. * K. W. Turteltaub, unpublished observations.

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mouse. Guanine adducts were found to be the principal type;three different thin-layer chromatography spots were seen whenreactive intermediates of PhIP were reacted with 2'-deoxynu-cleotide-3'-phosphates. Binding was highest in the pancreas,

followed by the thymus, heart, and liver. These results are verysimilar to those of Takayama et al. (35), who examined in vivoDNA binding with PhIP in the rat.

Estimate of Human Cancer Risk

We have made a preliminary determination of a maximumcredible risk for these compounds, by using an average TD50from rat tumor data (0.7 mg/kg/day) (9) and then extrapolatinglinearly by using an estimated human life time dose for a dietcooked to well done levels and having a large amount (500 g/day) of meat, fish, or chicken (12.5 Â¿Â¿gof heterocyclic amines/day). The assumption that the relationship is linear is supportedby the linearity of DNA binding at the 500 ng/kg dose in theaccelerator mass spectrometry experiments noted earlier. Thesestudies show that pharmacokinetics and DNA repair affectingDNA adduct formation are not concentration dependent butare linear throughout the studied dose range, covering 5 ordersof magnitude. The calculation depends on the assumptionsmade regarding animal life time corrections and body surfacearea and indicates approximately 1 in 1000 risk.

Another calculation by Adamson (36), using estimated mu-tagen exposures for the United States population and using theTD50 derived from the rat tumor studies, also indicated a riskof about 1 in 1000. Adamson also compared the TD50 for IQin the monkey and adjusted for a life time of exposure, becausethe nonhuman primates showed very short latency for IQ-

induced hepatocarcinomas, and he again calculated a 1 in 1000risk. These risk calculations contain a number of generalizations and assumptions but emphasize that human risk fromdietary ingestion of these heterocyclic amines may be quiteimportant.

More moderate risks were calculated by Gaylor and Kadlubar(37) (1 in 10,000) and Hatch5 (less than 1 in 10,000). Both

studies estimate the overall risk to the North American population rather than the high-exposure group used in the previousstudies. The variation of the heterocyclic amine content of themeat with cooking time and temperature leads to a large range(~ 1000-fold) of ingested dose of carcinogen among the cooked-food-consuming population and, thus, in the outcome of therisk calculations. These risk estimates need to be supported orrefuted by using much more rigorous data than used here.Conclusions from both the maximum reliable risk estimatesand the more conservative population estimates indicate thatheterocyclic amines are important in cancer etiology, becauserisks greater than 1 in 1,000,000 are deemed significant.

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1992;52:2103s-2107s. Cancer Res James S. Felton, Mark G. Knize, Michelle Roper, et al. Heterocyclic Amines from Cooked FoodChemical Analysis, Prevention, and Low-Level Dosimetry of

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