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Carcinogenesis Advance Access originally published online on November 1, 2006
Carcinogenesis 2006 27(12):2367-2370; doi:10.1093/carcin/bgl165
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© The Author 2006. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

A meat and potato war: implications for cancer etiology

James S. Felton* and Mark G. Knize

Biosciences Directorate, Lawrence Livermore National Laboratory Livermore, CA 94551, USA

*To whom correspondence should be addressed at: Chemistry, Materials, and Life Sciences Division, Lawrence Livermore National Laboratory, P.O. Box 808, L-452, 7000 East Avenue, Livermore, CA 94551, USA. Tel: +1 925 422 5656; Fax: +1 925 422 2282; Email: felton1{at}llnl.gov


   Abstract
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 Abstract
Commentary
 References
 
Cooking foods clearly has a beneficial impact for humans; the microbial content can be decreased, proteins made more digestible and the flavor and texture improved. But at the same time, amino acids, creatine and sugars, which occur naturally in meats, may be involved in reactions that generate heterocyclic amine (HA) carcinogens during cooking. Recently, another amine carcinogen, acrylamide, was found at relatively high levels in cooked carbohydrate-rich foods, especially potatoes. In this commentary acrylamide will be compared with the meat carcinogens (HAs) with respect to formation, human intake and health consequences—it's a meat and potato war. What conclusion about risks from these dietary carcinogens can we make from the available scientific data?

Abbreviations: HA, heterocyclic amine; IQ, 2-amino-3-methylimidazo[4,5-f]quinoline; MeIQx, 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline; PhIP, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine)


   Commentary
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 Abstract
 Commentary
References
 
Environment-related cancers, those shown to change in the population with human migration, are frequently found in the breast, colon and prostate, similar to the cancers induced in rodents (along with liver), from exposure to selected heterocyclic amines (HAs). Acrylamide, an alkene amine, recently discovered in starchy foods to be in relatively high amounts (micrograms per gram of food), is reported to be a mammary carcinogen in rodents. Because of their prevalence in the human diet, these rodent carcinogens may have an effect on human disease incidence.

A critical question, then, is: Do individuals who eat small quantities of these carcinogens over a lifetime have an increased cancer risk?

Carcinogen formation
Over 25 years ago Dr. Takashi Sugimura and his group showed that cooking meat and fish produced potent bacterial mutagens (1), but the chemicals responsible were unknown. Shortly thereafter, Dr. Kasai described the structure of the first mutagen isolated from cooked meat, 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) (2), and later, 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) (3). Our group at Lawrence Livermore National Laboratory (LLNL) was able to identify 2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline (DiMeIQx) (4) and PhIP (2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine) (5). Structures for some of these, as well as acrylamide, are shown in Fig. 1. Using analytical methods, that allowed routine detection of HAs in cooked foods, scientists determined the types of food and cooking conditions responsible for human HA exposures (6–9). Model systems to identify the precursors and the conditions under which these compounds are formed were also developed (10–12). These studies showed that HAs can sometimes be detected in cooked muscle meats such as beef, pork, chicken, fish and lamb over a range from 0.1 to hundreds of parts per billion when the meat is overcooked over flames, under a broiler or pan fried (13).


Figure 1
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  		Figure 1 Chemical structure of heated food carcinogens, acrylamide and the HAs (IQ, MeIQx, DiMeIQx and PhIP).

 
An example of the range of human exposure to HAs is shown in a space analysis of meats cooked commercially in restaurants (Table I). For top loin steaks, cooked well-done but purchased from different restaurants, the total amount of HAs differed 19-fold. For flank steaks prepared at the same restaurant but on different days, PhIP levels varied from 2 to 25 ng/g. Differences in cooking methods, times and temperatures utilized by the cook to achieve the requested well-done state is a likely explanation for the large variation, and this variation is largely responsible for the difficulties in assessing human exposure.


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  		Table I Amine carcinogens in heated foods, (ng/g) (p.p.b.) cooked weight

 
Like HAs, acrylamide is sometimes formed during cooking from natural components in the food. Temperatures in the normal cooking range (baking and deep-frying) produce acrylamide from asparagine and glucose, precursors that are present naturally in starchy plant food (14). Examples of foods and the range of acrylamide levels detected are shown in Table 1. Toasted plant food like breads, crackers and cereals are prominent sources of acrylamide, along with the potato derived French fries and potato chips. Most foods that contain acrylamide are cooked commercially and contain the acrylamide when purchased. HAs, on the other hand, are not present when raw meat is purchased, but instead are produced during meal preparation in restaurants and homes. It is interesting that many foods containing HAs or acrylamide are perceived as healthy foods, like chicken, wheat bread, and veggie crisps. For HAs, local education in food preparation in the home or restaurant should be effective in reducing carcinogen formation, but for acrylamide, changes in industrial food preparation practices may have to be implemented to reduce exposure.

Human intake
Several authors have estimated the average daily intakes for HAs and acrylamide and there is a good consensus in the predicted exposures. Studies estimating the intake of HAs include Layton et al. (15) which calculated an average 26 ng/kg body wt/day for a US population, Zimmerli et al. (16) who estimated 5 ng/kg body wt/day for a Swiss population, and Augustsson et al. who estimated 2.5 ng/kg body mass/day for an elderly Swedish population (17).

Acrylamide intakes are clearly greater. A mean intake of 480 ng/kg body wt/day was estimated for the Dutch population (18). Intakes of 490 and 460 ng/kg body wt/day for men and women, respectively, were estimated for Norwegians (19), and the U.S. Food and Drug Administration estimates exposures to be 370 ng/kg body wt/day in the US (20). This is >10 times the HA exposure level.

Health consequences
A primary difference between the HAs and acrylamide is the relative potency of the compounds in genetic toxicology tests. The HAs are extremely potent mutagens in Salmonella (21), CHO cells (22) and the Big Blue rat (23). However, acrylamide is consistently negative in microbial mutation tests (24) and gives inconsistent results in mammalian cell assays (25,26) with and without metabolic activation. A weak, yet statistically significant mutagenic response at some doses of acrylamide was shown in cultured cells from the Big Blue mouse for the cII transgene (27).

As mentioned above, the heterocylic amines have been shown in numerous feeding studies to cause tumors in rodents in various organs relevant to human cancer sites. Acrylamide, too, is a rodent carcinogen, with testicular mesotheliomas and thyroid adenomas seen in males and fibroadenomas of the mammary gland see in females (28–30). It is interesting that acrylamide seems to give primarily endocrine-related cancers. Rats exposed to the HA, PhIP, generate tumors that are predominantly found in the steroid hormone controlled organs like breast and prostate. PhIP has been reported to interact at the estrogen receptor which may explain why PhIP is able to act as a complete carcinogen in the rodent (31). The strong genotoxicity of PhIP, which has been shown to be targeted to critical genes related to cell-cycle control and regulation, coupled with this hormone receptor activation, may enhance cancer progression (32).

The International Agency for Research on Cancer (IARC) considers acrylamide and the HA, IQ, to be ‘probable human carcinogens’ (33,34). In addition, the U.S. National Toxicology Program has designated acrylamide and selected HAs (IQ, MeIQ, MeIQx, PhIP) as ‘reasonably anticipated to be human carcinogens’ (35). Epidemiological studies relating to the doneness of meat cooking (HA exposure) and cancer outcome suggest effects at the aforementioned breast, colon and prostate sites, plus esophagus, gastric cardia, larynx, lung, blood (lymphoma), stomach and pancreas. We compiled 30 such studies (36). Most of these studies show positive associations between exposure to well-done meat and cancer, but some are negative, as would be expected given the variety of cancer sites and diets evaluated. In addition, many of these studies showed substantial relative risks (RR) when the meat intake was coupled with genetic susceptibility related to metabolism and repair.

Historically, human studies of acrylamide exposure focused mainly on industrial and inhalation exposures (37). In one study of 8500 workers, pancreatic cancer was weakly correlated with high-dose acrylamide exposure; however, smoking has been raised as a possible confounding factor in this study. Three dietary case–control studies evaluated acrylamide intake and cancer effects at selected sites. No evidence of positive correlations were seen between dietary intake and cancer incidence (38–40). More recently, no significant risk was seen between acrylamide and cancers of the oral cavity and pharynx, esophagus, large bowel, larynx, breast, ovary and prostate (41). A recent large prospective study also found no evidence linking acrylamide exposure and colorectal cancer (42).

It appears that no one toxicology test or epidemiology study is sufficient to predict the health consequences of dietary compounds consumed in food. A battery of tests and multiple epidemiology studies are still needed for risk evaluation.

The evidence for human cancer risk from HA exposure is highly suggestive, but despite the higher intake of acrylamide and its carcinogenic potency in rodents, a human cancer risk cannot be established for acrylamide outside the workplace. It may be time to reconsider the 16th century idea of Paracelsus that ‘the dose makes the poison’. In the case of these two classes of amine carcinogens produced from heating, the potency of the HAs appears to have won the war; it is meat over potatoes.


   Acknowledgments
 
The authors thank Dr Kristen Kulp for her helpful editorial comments. Work was performed under the auspices of the USDOE under contract: W-7405-Eng-48 and supported by NCI grants CA55861.

Conflict of Interest Statement: None declared.


   References
Top
 Abstract
 Commentary
 References
 

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Received July 31, 2006; revised August 22, 2006;
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