Also known as HCAs
Introduction
Heterocyclic amines (HCAs) are formed during the cooking of meat, by condensation of creatinine with amino acids. Four individual HCAs are listed in the Report on Carcinogens as reasonably anticipated to be a human carcinogen (in separate listings):
2-Amino-3,4-dimethylimidazo[4,5-f]quinoline (MeIQ) was first listed in the Eleventh Report on Carcinogens (2004).
2-Amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) was first listed in the Eleventh Report on Carcinogens (2004).
2-Amino-3-methylimidazo[4,5-f]quinoline (IQ) was first listed in the Tenth Report on Carcinogens (2002).
2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) was first listed in the Eleventh Report on Carcinogens (2004).
The profiles for these four HCAs follow. The evidence for carcinogenicity from cancer studies in experimental animals and humans is discussed separately for each HCA. However, most of the information on mechanisms of carcinogenesis, properties, use, production, exposure, and regulations is common to all four listed HCAs and therefore is combined into one section following the discussions of cancer studies.
Note on Cancer Studies of Selected HCAs in Humans
Epidemiological evidence suggests that consumption of well-done or grilled meat may be associated with increased cancer risk in humans. However, the presence of an individual HCA in cooked meat is highly correlated with the presence of other HCAs and with many other constituents, including protein, animal fat, nitrosamines, and substances other than HCAs formed during cooking, such as polycyclic aromatic hydrocarbons. Furthermore, the carcinogenic effects of these HCAs may be inhibited or enhanced by many factors, including interactions of HCA mixtures. It is therefore difficult for human epidemiological studies to establish associations between cancer risk and specific HCAs. For each of these four selected HCAs, the data from epidemiological studies are insufficient to evaluate whether the increased cancer risk is due specifically to consumption of that particular HCA in food (NTP 2002).
2-Amino-3,4-dimethylimidazo[4,5-f]quinoline: CAS No. 77094-11-2
Reasonably anticipated to be a human carcinogen
First listed in the Eleventh Report on Carcinogens (2004)
Also known as MeIQ
Figure1
Chemical Structure of 2-Amino-3,4-dimethylimidazo[4,5-f]quinoline
Carcinogenicity
MeIQ is reasonably anticipated to be a human carcinogen based on sufficient evidence of carcinogenicity from studies in experimental animals and supporting genotoxicity data.
Cancer Studies in Experimental Animals
Oral exposure to MeIQ caused tumors at several different tissue sites in mice and rats. In mice of both sexes, MeIQ increased the combined incidence of benign and malignant forestomach tumors (papilloma, squamous-cell carcinoma, and sarcoma). In female mice, it also caused cancer of the cecum and colon (adenocarcinoma) and increased the combined incidence of benign and malignant liver tumors (fibrosarcoma and hepatocellular adenoma and carcinoma). In rats of both sexes, MeIQ increased the combined incidence of benign and malignant colon tumors (adenoma and adenocarcinoma) and caused cancer of the oral cavity and Zymbal gland (squamous-cell carcinoma). In addition, MeIQ caused skin cancer (squamous-cell carcinoma) in male rats and cancer of the mammary gland (adenocarcinoma) in female rats (NTP 2002).
Cancer Studies in Humans
The evidence from epidemiological studies is inadequate to evaluate the relationship between human cancer and exposure specifically to MeIQ. In one case-control study, MeIQ intake was associated with increased risks for rectal and colon cancer but not for urinary-bladder or kidney cancer (Augustsson et al. 1999).
2-Amino-3,8-dimethylimidazo[4,5-f]quinoxaline: CAS No. 77500-04-0
Reasonably anticipated to be a human carcinogen
First listed in the Eleventh Report on Carcinogens (2004)
Also known as MeIQx
Figure2
Chemical Structure of 2-Amino-3,8-dimethylimidazo[4,5-f]quinoxaline
Carcinogenicity
MeIQx is reasonably anticipated to be a human carcinogen based on sufficient evidence of carcinogenicity from studies in experimental animals and supporting genotoxicity data.
Cancer Studies in Experimental Animals
MeIQx caused tumors in two rodent species, at several different tissue sites, and by two different routes of exposure. Oral exposure to MeIQx increased the combined incidence of benign and malignant liver tumors (hepatocellular adenoma and carcinoma) in mice and rats of both sexes and the combined incidence of benign and malignant lung tumors (adenoma and adenocarcinoma) in female mice. It also caused lymphoma and leukemia in male mice. In rats, orally administered MeIQx also increased the combined incidence of benign and malignant Zymbal-gland tumors (sebaceous-gland adenoma and squamous-cell papilloma and carcinoma) in both sexes, and it caused skin cancer in males and cancer of the cl*toral gland in females (squamous-cell carcinoma in both cases). Newborn mice exposed to MeIQx by intraperitoneal injection developed benign liver tumors (hepatocellular adenoma). In cynomolgus monkeys, MeIQx administered by stomach tube for 84months did not cause cancer. This finding was attributed to a low level of metabolic activation of MeIQx via N-hydroxylation in this species; however, the study period may not have been long enough for detection of tumors (NTP 2002).
In rats, administration of N-hydroxy-MeIQx (a metabolite of MeIQx) by intraperitoneal injection caused soft-tissue tumors at the injection site (NTP 2002).
Cancer Studies in Humans
The evidence from epidemiological studies is inadequate to evaluate the relationship between human cancer and exposure specifically to MeIQx. Case-control studies (one study for each tissue site) suggested that MeIQx may increase the risk of benign colon tumors (adenoma) (Sinha et al. 2001) and lung cancer (Sinha et al. 2000b). MeIQx intake was not associated with cancer risk in case-control studies of urinary-bladder, kidney, or colon cancer (Augustsson et al. 1999). The results for breast cancer were conflicting, with two studies reporting increased risk (De Stefani et al. 1997; Sinha et al. 2000a) and one study reporting decreased risk (Delfino et al. 2000).
2-Amino-3-methylimidazo[4,5-f]quinoline: CAS No. 76180-96-6
Reasonably anticipated to be a human carcinogen
First listed in the Tenth Report on Carcinogens (2002)
Also known as IQ
Figure 3
Chemical Structure of 2-Amino-3-methylimidazo[4,5-f]quinoline
Carcinogenicity
IQ is reasonably anticipated to be a human carcinogen based on sufficient evidence of carcinogenicity from studies in experimental animals.
Cancer Studies in Experimental Animals
IQ caused tumors in several species of experimental animals, at several different tissue sites, and by several different routes of exposure. In rats of both sexes, oral exposure to IQ-caused cancer of the liver (hepatocellular carcinoma), large intestine (adenocarcinoma), and Zymbal gland (squamous-cell carcinoma). It also caused cancer of the mammary gland (adenocarcinoma) and cl*toral gland (squamous-cell carcinoma) in female rats and cancer of the small intestine (adenocarcinoma) and skin (squamous-cell carcinoma) in male rats. In mice of both sexes, oral exposure to IQ increased the combined incidences of benign and malignant tumors of the liver (hepatocellular adenoma and carcinoma), forestomach (papilloma and squamous-cell carcinoma), and lung (adenoma and adenocarcinoma). Newborn mice administered IQ by intraperitoneal injection developed benign and malignant liver tumors (hepatocellular adenoma and carcinoma). Male rats administered IQ by intrarectal infusion developed cancer of the colon (carcinoma) and skin (squamous-cell carcinoma) and benign liver tumors (hepatocellular adenoma). In cynomolgus monkeys, IQ administered orally caused liver cancer (hepatocellular carcinoma) (NTP 1999).
Cancer Studies in Humans
The evidence from epidemiological studies is inadequate to evaluate the relationship between human cancer and exposure specifically to IQ. One case-control study suggested that IQ intake increased the risk of breast cancer (De Stefani et al. 1997), but another case-control study found no association between IQ and cancer of the colon, rectum, urinary bladder, or kidney (Augustsson et al. 1999).
2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine: CAS No. 105650-23-5
Reasonably anticipated to be a human carcinogen
First listed in the Eleventh Report on Carcinogens (2004)
Also known as PhIP
Figure4
Chemical Structure of 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine
Carcinogenicity
PhIP is reasonably anticipated to be a human carcinogen based on sufficient evidence of carcinogenicity from studies in experimental animals and supporting genotoxicity data.
Cancer Studies in Experimental Animals
PhIP caused tumors in two rodent species, at several different tissue sites, and by two different routes of exposure. Oral exposure to PhIP caused lymphoma in mice of both sexes and in male rats. In rats, it also caused prostate cancer (carcinoma) and cancer of the small intestine and colon (adenocarcinoma) and in males and mammary-gland cancer (adenocarcinoma) in females. In a short-term study using mice with a mutation that made them susceptible to intestinal and mammary-gland tumors, oral administration of PhIP increased the combined incidence of benign and malignant tumors of the small intestine (adenoma and adenocarcinoma) in males. PhIP administered to newborn male mice by intraperitoneal injection caused benign liver tumors (hepatocellular adenoma) (NTP 2002).
N-hydroxy-PhIP (a metabolite of PhIP) administered by intraperitoneal injection caused intestinal polyps in Apc knockout mice (which are unable to produce the tumor-suppressor protein APC). In ACI/Seg rats (a strain with high spontaneous incidence of prostate cancer) administered N-hydroxy-PhIP by intraperitoneal injection, the incidences of colon tumors and rare urinary-bladder tumors were increased, though not significantly (NTP 2002).
Cancer Studies in Humans
The evidence from epidemiological studies is inadequate to evaluate the relationship between human cancer and exposure specifically to PhIP. Case-control studies suggest that PhIP may increase the risk of breast or stomach cancer. However, the association with stomach cancer was based on only one study (De Stefani et al. 1998), and the association with breast cancer was found in two of three studies (De Stefani et al. 1997; Delfino et al. 2000; Sinha et al. 2000a). No association between PhIP intake and cancer risk was found in case-control studies of urinary-bladder, kidney, lung, colon, or prostate cancer (Augustsson et al. 1999; Norrish et al. 1999; Sinha et al. 2000b). PhIP intake was associated with increased risk of benign colon tumors (adenoma) in one study, but the risk was not significantly increased when the statistical analysis controlled for intake of other HCAs (Sinha et al. 2001).
Heterocyclic Amines (Selected)
Studies on Mechanisms of Carcinogenesis
Studies have consistently shown that MeIQ, MeIQx, IQ, and PhIP cause mutations in most test systems, including bacteria, rodents exposed in vivo, and cultured rodent and human cells. Moreover, compared with other well-known mutagens, such as benzo[a]pyrene, these HCAs show a high degree of potency. MeIQ, MeIQx, IQ, and PhIP also caused sister chromatid exchange, micronucleus formation, and unscheduled DNA synthesis, and most of these HCAs induced DNA damage and chromosomal aberrations in in vivo studies in rodents and in in vitro studies with human and rodent cell cultures (IARC 1993; NTP 2002).
When ingested by humans or administered orally to experimental animals, HCAs are readily absorbed and rapidly distributed. They are metabolized by both phaseI (activation) and phaseII (conjugation) enzymes. The major phaseI activation pathway is N-hydroxylation by the enzyme CYP1A2 (a member of the cytochrome P450 family). Further activation by phaseII enzymes, in the liver or in other tissues, is necessary for formation of the arylnitrenium ion, which ultimately binds to DNA (NTP 2002).
HCA-induced DNA adducts have been characterized and detected in humans and other mammalian species both in vitro and in vivo, and the major adduct for each HCA is similar in all species examined. In humans, DNA adducts form at dietarily relevant levels of HCA exposure and usually are present at higher frequencies than in rodents administered an equivalent dose. HCA-induced adducts have been identified in human colon tissue, breast tissue, and prostate tumors. The DNA adduct data indicate that metabolic activation of HCAs is more efficient in humans than in experimental animals and that rapid acetylators (individuals who produce an efficient version of the enzyme N-acetyltransferase) may be at higher risk of cancer than slow acetylators (individuals who produce less-efficient versions of this enzyme). In studies with experimental animals, HCA-induced DNA adducts were formed in a dose-dependent manner and were associated with carcinogenesis (NTP 2002).
Mutations involving guanine (such as G:C to T:A transversions) have been detected in proto-oncogenes and tumor-suppressor genes, including Ki-ras, Ha-ras, Apc, p53, and β-catenin, suggesting that HCA-induced adducts are involved. The observed mutation patterns provide evidence for a mutational profile or “fingerprint” for PhIP-induced colon tumors and MeIQ-induced forestomach and Zymbal-gland tumors in mice (NTP 2002).
Properties
MeIQ, MeIQx, IQ, and PhIP are heterocyclic amines formed by condensation of creatinine with amino acids during the cooking of meat. (Creatinine is a breakdown product of creatine, an important constituent of muscle.) All of these HCAs share a common imidazole ring structure with an exocyclic amino group and, therefore, are known chemically as amino-imidazoazaarenes. Most HCAs, including MeIQ, MeIQx, and IQ, are fully planar aromatic structures with no bulky out-of-plane functionalities; however, PhIP possesses a phenyl moiety that is not necessarily coplanar with the main bicyclic imidazopyridine. All of these HCAs occur as crystalline solids and are soluble in dimethylsulfoxide or methanol. Physical and chemical properties of MeIQ, MeIQx, IQ, and PhIP are listed in Table1.
Table1
Properties of MeIQ, MeIQx, IQ, and PhIP.
Use
MeIQ, MeIQx, IQ, and PhIP have no known commercial uses (IARC 1993).
Production
MeIQ, MeIQx, IQ, and PhIP are produced in small quantities for research purposes (IARC 1993). They are formed naturally during the cooking of muscle-derived foods (meat and fish) as by-products of the Maillard (or browning) reaction (Felton et al. 2000; Robbana-Barnat et al. 1996). It is postulated that the amino-imidazo part of HCAs is formed from creatine, while the remaining parts of the compound are likely formed from Strecker degradation products, such as pyridines or pyrazines, which are formed in the Maillard reaction between hexose sugars and amino acids (Jägerstad et al. 1984; Skog et al. 1998). Formation of HCAs in food reportedly is affected by temperature, processing time, acidity, precursor concentrations, and types of amino acid present (Keating et al. 1999). In general, higher temperatures and longer cooking times increase the amount of HCAs produced (Knize et al. 1994; Skog et al. 1995). HCA formation also increases with cooking methods that use direct or efficient transfer of heat from the source to the food; frying or grilling of muscle meats produces more HCAs than do indirect-heat methods such as stewing, steaming, or poaching (Layton et al. 1995).
Exposure
Exposure to MeIQ, MeIQx, IQ, or PhIP occurs primarily through the consumption of cooked meats; however, HCAs have also been detected in processed food flavorings, beer, wine, and cigarette smoke. Dietary exposure to total HCAs has been estimated to range from less than 1 to 17ng/kg of body weight per day (Layton et al. 1995).
Total HCA concentrations in cooked meat generally range from less than 1 to about 500ng/g (0.001 to 0.5ppm) but usually are less than 100ng/g (Knize et al. 1998; Layton et al. 1995; Salmon et al. 2000; Sinha et al. 1995; Sinha et al. 1998a; Sinha et al. 1998b). Pan residues usually contain higher HCA concentrations than the meat itself; therefore, gravy made from meat drippings and grease may have relatively high concentrations of HCAs. In four studies, reviewed by Keating et al. (1999), total daily HCA intakes (including MeIQx, IQ, and PhIP, but not MeIQ) ranged from 160 to 1,800ng per person. In general, the dietary intake of these four HCAs is greatest for PhIP, followed by MeIQx, IQ, and MeIQ.
As discussed above (under Production), the concentration of HCAs in food is a function of cooking method; dietary intake is therefore a function of cooking method, doneness preference, and consumption frequency (Keating et al. 1999). Several studies have reported on possible methods for reducing dietary HCA (Knize et al. 1999; Salmon et al. 2000; Skog et al. 1997). Effective methods include using cooking temperatures below 200°C (392°F), turning meat more frequently during cooking, precooking meat in a microwave oven for at least two minutes and draining off the liquid before conventional cooking, and applying marinades before grilling. However, some marinades are more effective than others; PhIP and MeIQx concentrations were reduced by teriyaki sauce or turmeric-garlic sauce, but increased by a honey barbecue sauce (Nerurkar et al. 1999).
Occupational exposure to HCAs may occur by inhalation of aerosolized particles formed during the cooking process. PhIP and MeIQx were detected in smoke condensate formed during frying of beef patties and bacon (Thiébaud et al. 1995), and MeIQx was detected in aerosol from cooking of stir-fried fish (Yang et al. 1998). PhIP was detected in airborne particles, diesel-exhaust particles, and incineration ash from garbage-burning plants (Manabe et al. 1993).
Specific exposure information for each of these four HCAs follows.
MeIQ
MeIQ is found less frequently in food and generally at lower concentrations than are other HCAs, including MeIQx, PhIP, and IQ. The highest concentrations were detected in cooked fish, ranging from 0.03 to 72ng/g; the concentrations were highest in grilled sun-dried sardines and lower in fried or broiled fish (IARC 1993; Lynch et al. 1995). MeIQ was found at low levels or was not detectable in cooked beef, pork, or chicken; various studies reported concentrations ranging from 0.02ng/g (in pork) to 1.7ng/g (in well-done bacon) (Johansson and Jägerstad 1994; Lynch et al. 1995). It was also detected in gravy, coffee beans, and cigarette smoke. In a Swiss population, daily MeIQ intake was estimated to be 0.6ng/kg of body mass (Zimmerli et al. 2001).
MeIQx
MeIQx has been detected in beef, pork, chicken, and fish. The highest concentrations were found in well-done grilled chicken, beef (hamburger or steak), and bacon. Very-well-done grilled or barbecued chicken contained 9ng/g, and very-well-done oven-broiled or pan-fried skinless, boneless chicken breasts contained 3ng/g (Sinha et al. 1995). In one study, MeIQx concentrations in beef ranged from nondetectable to 8.2ng/g in steak and from nondetectable to 4.6ng/g in hamburger patties, depending on the cooking method and degree of doneness (Sinha et al. 1998b). Another study found that fish contained about 1.2ng/g (Johansson and Jägerstad 1994). Pork, other than bacon, contains very little MeIQx; MeIQx was detected at 0.9 to 18ng/g in bacon and 1.4 to 27ng/g in bacon fat (Gross et al. 1993). MeIQx also occurs in processed food flavors (bouillon and gravy concentrates) and wine. In three large U.S. cohort studies (two Nurses’ Health Studies and the Health Professionals Follow-Up Study), estimated mean daily intake of MeIQx ranged from 33 to 44.8ng/g of food consumed (Byrne et al. 1998). Daily MeIQx intake was estimated to be 2.61ng/kg of body mass (Layton et al. 1995). MeIQx also has been found in air and surface water.
IQ
IQ was originally isolated from broiled fish, fried ground beef, and beef extracts. It has since been detected in fried chicken, fried eggs, fried fish, broiled ground beef, minute steaks, meatballs, pork chops, and cigarette smoke condensate. Reported concentrations in foods range from less than 0.1 to more than 150ng/g, with most less than 1ng/g (Chiu et al. 1998; IARC 1993; Skog et al. 1995). However, Sinha et al. (1998b) did not detect IQ in hamburgers, steaks, or roast beef cooked by varying methods to three levels of doneness. The highest reported IQ concentration occurred in broiled sun-dried sardines. Daily IQ intake from meat and fish was estimated to be 0.28ng/kg of body mass (Layton et al. 1995).
PhIP
Evidence that the U.S. general population is exposed to PhIp comes from the 2013–2014 National Health and Nutrition Examination Survey, which found that the 95th-percentile concentration of PhIP in urine was 15.8ng/L, based on a sample of 2,569 individuals of all ages, both genders, and all race and ethnicity groups (CDC 2018). The primary source of exposure is ingestion of food. PhIP is the most abundant HCA detected in foods and has been found in beef, pork, chicken, lamb, and fish. The highest concentrations were detected in very-well-done grilled chicken; however, concentrations varied considerably from study to study. High concentrations (over 100ng/g) were found in well-done steak and hamburgers. Concentrations of PhIP in fish varied greatly according to the type of fish and method of cooking; one study reported levels ranging from 1.7 to 73ng/g in salmon cooked at 200°C by various methods (pan broiled, oven cooked, or barbecued) for various lengths of time (Gross and Grüter 1992), but another study (Skog et al. 1997) reported substantially lower levels (0.02 to 2.2ng/g) for cod and Baltic herring fillets pan fried at temperatures ranging from 150°C to 225°C. PhIP was found at lower concentrations in pork (0.1 to 2.3ng/g). It was also detected in processed food flavors, beer, and wine at concentrations ranging from 0.01 to 480ng/g and in cigarette smoke. In the same three large U.S. cohort studies cited above for MeIQx, mean daily PhIP intake ranged from 285.5 to 457ng/day (Byrne et al. 1998). Daily PhIP intake was estimated to be 17ng/kg of body mass (Layton et al. 1995). PhIP has also been found in air and surface water.
Regulations
No regulations or guidelines relevant to reduction of exposure to heterocyclic amines were identified.
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