Heterocyclic Amines, Meat, and Cancer

After scientists discovered the carcinogenic components in cigarette smoke, they questioned whether carcinogens could also be found in foods that were smoked or burned, such as meats In 1977, cancer-causing compounds, now known to be heterocyclic amine, were discovered in food as a result of normal household cooking processes. A total of 20 compounds fall into the category of heterocyclic amines, often abbreviated HCAs. Table 1 shows the chemical name and abbreviation of those most commonly studied.

Table 1. Chemical names and abbreviations for HCAs mentioned in this article

Chemical Name	Abbreviation	Year Discovered
2-Amino-3methylimidazo[4,5-f]quinoline	IQ	1980
2-Amino-3,4-dimethylimidazo[4,5-f]quinoline	MeIQ	1980
2-Amino-3,8-dimethylimidazo[4,5-f]quinoxaline	MeIQx	1981
2-Amino-1-methyl-6-phenylimiazo[4,5-b]pyridine	PhIP	1986

The compounds found in food are formed when creatine

Creatine

Creatine is a nitrogenous organic acid that occurs naturally in vertebrates and helps to supply energy to all cells in the body, primarily muscle. This is achieved by increasing the formation of Adenosine triphosphate...

 (a protein found in muscle tissue), other amino acids, and monosaccharides, are heated together at high temperatures (125-300^o C or275-572^o F) or cooked for long periods of time. HCAs form at lower end of this range when the cooking time is long; at the higher end of the range HCAs are formed within minutes The most potent of the HCAs, MeIQ, is almost 24 times more carcinogenic than aflatoxin

Aflatoxin

Aflatoxins are naturally occurring mycotoxins that are produced by many species of Aspergillus, a fungus, the most notable ones being Aspergillus flavus and Aspergillus parasiticus. Aflatoxins are toxic and among the most carcinogenic substances known...

, a carcinogen produced by mold

Most of the 20 HCAs are more toxic than benzopyrene

Benzopyrene

Benzo[a]pyrene, C20H12, is a five-ring polycyclic aromatic hydrocarbon whose metabolites are mutagenic and highly carcinogenic. Benzo[a]pyrene is listed as a Group 1 carcinogen by the IARC. It belongs to a class of polycyclic aromatic compounds known as benzopyrenes, which consist of a benzene...

, a carcinogen found in cigarette smoke and coal tar. MeIQ, IQ and 8-MeIQx have been reported as the most potent mutagens using the Ames test

Ames test

The Ames test is a biological assay to assess the mutagenic potential of chemical compounds. A positive test indicates that the chemical is mutagenic and therefore may act as a carcinogen, since cancer is often linked to mutation. However, a number of false-positives and false-negatives are known...

 These HCAs are 100 times more potent carcinogens than PhIP, the compound most commonly found as a result of normal cooking procedures

HCAs in Cooked Ground Beef

A review of 14 studies of HCA content in ground beef cooked under home conditions found in northern Europe and the U.S. found a range of values, shown in Table 2. Because a standard serving of meat in the U.S. is 3 ounces, Table 2 includes a projection of the maximum amount of HCAs that could be found in a ground beef patty.

Table 2. Content of four HCAs in ground beef

HCA	Amount, ng/g	Maximum amount in 3 ounces of ground beef (in ng)
IQ	n.d.-1.6	136
MeIQ	n.d.-1.7	145
MeIQx	n.d.-16.4	1395
PhIP	n.d.-68	5783

( n.d.= none detected )

Ground Beef Consumption in the U.S.

Meat is a major component of American diets. Disappearance data from 1960 show the combined annual consumption per person of beef, pork, and chicken at 148 pounds; in 2004 that amount increased to 195 pounds a year Ground beef made up 42% of the market share for beef in 2000. Beef consumption, particulary ground and processed beef, is highest in households with incomes at or below 130 percent of the poverty level. Patterns of beef intake by race/ethnicity show that non-Hispanic whites and Asians consumed the least amount of beef. Non-Hispanic Blacks had the highest beef consumption with the highest per capita intake of processed beef, ground beef, and steaks compared to three other race/ethnicity groups. More than half of beef purchased in the U.S. comes from retail stores and is prepared at home. Ground beef makes up the highest per capita intakes of beef both at home and away from home. Ground beef consumption is highest among males age 12-19 who consume on average 50 pounds per year per person. The 12-19 age group showed the highest consumption of ground beef for females, but the amount(28.5 lbs) is much lower compared to that of males

Formation of HCAs during Cooking

HCA formation during cooking depends on the type of meat, the temperature of the cooking surface, the degree of browning, and the length of cooking time. Meats that are lower in fat and water content show higher concentrations of HCAs after cooking. More HCAs are formed when pan surface temperatures are higher than 220^oC (428^oF)such as with most frying or grilling. However, HCAs also form at lower temperatures when the cooking time is long, as in roasting. HCA concentrations are higher in browned or burned crusts that results from high cooking temperatures The pan drippings and meat bits that remain after meat is fried have high concentrations of HCAs. Beef, chicken and fish have higher concentrations than pork. Sausages are high in fat and water and show lower concentrations of HCA after cooking.

Ground beef patties show lower levels of HCAs if they are flipped every minute until the endpoint temperature is reached. Beef patties cooked from the frozen state show no difference in HCA levels compared to room-temperature patties

Human Exposure to HCAs

Dietary exposure to HCAs has been estimated at 1-17 ng/kg bodyweight per day.Table 3 shows the average daily lifetime consumption of HCAs for subgroups of the U.S. populationThis analysis was based on the food intake data of 27215 people participating in the 1994 to 1996 Continuing Survey of Food Intakes by Individuals (CSFII) survey. Approximately 16 percent of HCA exposure came from hamburgers.

Table 3. Lifetime average weighted intake of four HCAs by men and women in the U.S.

HCA Type	Lifetime Average Intake-All Women, ng/day	Lifetime Average Intake- All Men, ng/kg/day
PhIP	6.0	6.2
MeIQx	1.1	1.2
DiMeQx	0.20	0.21
IQ	.23	.18

African American males had 50-100% higher intakes than white males and African American boys consumed three times as many HCAs as white males. (Table 4).

Table 4. Estimated mean intakes of HCAs among children under 16 by ethnicity, ng/kg/day

HCA Type	White	African American	Asian/Pacific Islander
PhIP	6.1	12.0	10.0
MeIQx	1.2	1.8	1.9
DiMeQx	0.23	0.51	0.27
IQ	0.16	0.24	0.29

HCAs and Cancer Risk

HCAs contribute to the development of cancer by causing mutations in genes, causing new cells to grow in an uncontrolled manner and form a tumor. Epidemiological studies have linked consumption of well-done meats with an increased risk of certain cancers, including cancer of the colon or rectum
Scientists who analyzed all research articles on the topic of meat consumption and colon cancer, estimated that red meat consumption contributed to 7 to 9% of colon cancer cases in European men and women.

Animal Studies

Long-terms studies of rats showed that PhIP causes cancer of the colon and mammary gland in rats . Female rats given doses of 0, 12.4, 25, 50, 100 or 200 ppm of PhIP in their feed showed a dose-dependent incidence of adenocarcinomas. The offspring of female rats who were exposed to PhIP while pregnant had a higher prevalence of adenocarcinomas than offspring of rats who had not been exposed. This was true even for the offspring that were not exposed to any PhIP themselves. PhIP was also found to be transferred mothers to offspring in their milk.

Epidemiological Studies

The effects of HCAs and well-done cooked meat on humans are less well established. Meat consumption, especially of well-done meat and meat cooked at a high temperature is often used as an indirect measure of exposure to HCAs. A review was made of all research studies reported between 1996 and 2007 that examined relationships between HCAs, meat, and cancer. Twenty-two studies were found; of these 18 showed a relationship between either meat intake or HCA exposure and some form of cancer. HCA exposure was measured in 10 of the studies, and of those 70% showed an association with cancer. The authors concluded that a high intake of well-done meat and/or high exposure to certain HCAs may be associated with cancer of the colon, breast, prostate, pancreas, lung, stomach, and esophagus.

A recent study found that the relative risk for colorectal cancer was increased at intakes >41.4 ng/day There was some evidence of increased relative risk with intakes of MeIQx greater than or equal to 19.9 ng.day, but the trend was not as strong as for PhIP.

Recent studies have had mixed results, finding no relationship between dietary heterocyclic amines and lung cancer, no relationship between HCA intake and prostate cancer risk, but suggesting a positive association between red meat, PhIP, and bladder cancer , and increased risk of advanced prostate cancer with intakes of meat cooked at high temperatures .

Although not all research studies report an association between HCA and/or meat intake and cancers, the U.S. Department of Health and Human Services Public Health Service National Toxicology Program found sufficient evidence to label four HCAs as "reasonably anticipated to be a human carcinogen" in its twelfth Report on Carcinogens, published in 2011.The HCA known as IQ was first listed in in the tenth report in 2002. MeIQ, MeIQx, and PhIP were added to the list of anticipated carcinogens in 2004 The Report on Carcinogens states that MeIQ has been associated with rectal and colon cancer, MeIQx with lung cancer, IQ with breast cancer, and PhIP with stomach and breast cancer. However, no current federal guidelines focus on the recommended consumption limit of HCA levels in meat.

Insufficient studies have been done to ascertain a cause and effect relationship. The attribution of individual HCAs on human illness is difficult to make because they do not occur individually in foods. Other elements of the diet, such as fat or carbohydrate intake may enhance or reduce the effects of HCAs in the human body.