4.1. Digestion and metabolism

The composition of red meat and processed meat, as well as their potential contaminants, is described in detail in Section 1 of this Monograph. Red meat and processed meat are sources of high-quality protein, fat in highly variable amounts, and a range of micronutrients. The impact of the digestion of protein and fat, and the modifications that these macronutrients may undergo in the processing of meat, is addressed in this section. The specific components of red meat and processed meat, including haem iron, lipid oxidation products, heterocyclic aromatic amines (HAAs), polycyclic aromatic hydrocarbons (PAHs), and N-nitroso compounds (NOCs), that are potentially involved in carcinogenesis are discussed in Section 4.5.

After the hydrolytic breakdown of dietary proteins by the activity of proteases, and the absorption of the resultant amino acids and dipeptides in the proximal gut, fermentation of excess proteins may yield toxic compounds. The amount of protein that enters the colon depends on the protein content of the ingested food and the protein digestibility (Windey et al., 2012). Digestibility of dairy and animal proteins exceeds 90%, and is generally higher than the digestibility of plant proteins (70–90%). Storage and processing of meat before consumption may alter its protein digestibility. Cooking of beef affected bovine myofibrillar protein susceptibility to proteases in vitro, with increased or decreased rates depending on the nature of the proteases, and the time and temperature parameters (Santé-Lhoutellier et al., 2008). Similarly, Bax et al. (2012) reported that ageing and mincing had little impact on the in vitro digestion of pig muscle proteins, but heat treatment had temperature-dependent effects. At 70 °C, the proteins underwent denaturation, enhancing the speed of pepsin digestion by increasing enzyme accessibility to protein cleavage sites. At above 100 °C, the proteins underwent oxidation-related aggregation, slowing the speed of pepsin digestion, but improving overall meat protein digestibility. In a study of miniature pigs fed meat from a calf, the true ileal protein digestibility averaged 95%, and was not affected by cooking temperature or by the level of meat intake (Bax et al., 2013). Chemical oxidation of pig myofibrillar proteins has been shown to reduce protein digestibility in vitro (Santé-Lhoutellier et al., 2007). Overall, the impact of thermal denaturation and oxidation of meat proteins during processing and storage on their digestibility, as well as the formation of carcinogenic compounds during digestion, is not well known.

On a normal mixed diet, the amount of protein rather than the source determines the quantity that reaches the colon (Silvester & Cummings, 1995). Hence, high-meat, low-fibre diets may stimulate protein fermentation in the colon, producing short- and branched-chain fatty acids, ammonia, phenolic and indolic compounds, and hydrogen sulfide (O’Keefe, 2008). Bacterial proteases and peptidases are more active when pH is neutral to alkaline. In the proximal colon, pH is more acidic due to the production of short-chain fatty acids, primarily from carbohydrate fermentation, but also from reductive deamination of many amino acids. In more distal parts of the colon, pH is higher and protein fermentation becomes more prominent. In relation to meat intake, ammonia and hydrogen sulfide are the most critical compounds because of their known toxicity (Attene-Ramos et al., 2007; Windey et al., 2012). Meat is rich in sulfur-containing amino acids, possibly leading to higher hydrogen sulfide concentrations in the colon. However, hydrogen sulfide in the gut originates from both the fermentation of sulfur-containing amino acids and dietary sulfate.

A diet high in red meat or processed meat may contain high levels of fat. The digestion of food lipids consists of a series of enzyme-catalysed steps resulting in absorbable components, whereby the release of bile from the gallbladder is essential. It has been suggested that dietary fat promotes the development of cancer of the colorectum (Boyle et al., 1985; Reddy, 1992). Several mechanisms have been postulated to explain this association, including the stimulating effect of high-fat intake on the secretion of secondary bile acids in the gut; this proposed mechanism has received the most attention. These bile acids may promote tumour formation by acting as aggressive surfactants on the mucosa, thus increasing cell loss and proliferation (Bruce, 1987; Owen, 1997; Bernstein et al., 2005). Other proposed mechanisms for the promoting role of dietary fat include an increase in the amount of free fatty acids in the colonic lumen, which may damage the colonic epithelium and induce cell proliferation, and an augmented risk for obesity (Calle & Kaaks, 2004). Dietary fat intake is also associated with peroxidation of unsaturated fatty acids (see Section 4.5.2).

[The Working Group noted that the digestion of red meat and processed meat provides energy and supplies essential nutrients, such as amino acids, iron, other minerals (including zinc), long-chain fatty acids, and various vitamins. At the same time, the digestion of protein and fat yields intrinsically toxic compounds. However, protein and fat are also present in dairy, fish, poultry, and other food products (Demeyer et al., 2015).]

4.2. Mechanisms of carcinogenesis

This section summarizes the evidence for the key characteristics of carcinogens (Smith et al., 2016), concerning whether red and processed meat intake is genotoxic, induces epigenetic effects, induces oxidative stress, and alters cell proliferation, cell death, and nutrient supply. Other mechanistic effects of red and processed meat intake, including whether it induces chronic inflammation and modulates receptor-mediated effects, are also addressed. Potential indirect mediators and studies of hemin and hemin chloride are summarized. Within each topic, studies are presented according to species (human and experimental systems) and test system (in vivo and in vitro), and red meat and processed meat studies are presented separately.

4.2.1. Genetic and related effects

Red meat and processed meat have been tested in studies of DNA damage, gene mutation, chromosomal damage, and epigenetic end-points. These studies are summarized in Table 4.1 to Table 4.6.

(a) Exposed humans

(i) DNA damage and DNA adducts

See Table 4.1.

Table 4.1

Genetic and related effects of red meat or processed meat in exposed humans.

Regarding studies of red meat, Lewin et al. (2006) conducted a randomized crossover study in 21 human subjects fed diets that were high in red meat (420 g/day), vegetarian, or high in red meat and fibre for 15 days. Compared with vegetarian diet, red meat intake significantly increased levels of O⁶-carboxymethyl guanine (O⁶-CMG), a DNA adduct putatively related to NOCs, in exfoliated colon cells. This adduct was detected by immunohistochemistry using polyclonal antiobodies. [The Working Group noted the lack of specificity of this method for this particular adduct).]

Increased levels of O⁶-methylguanine (O⁶-MeG), also a DNA adduct putatively related to NOCs, were shown by immunohistochemistry using monoclonal antibodies in rectal biopsies of human volunteers after an intake period of 4 weeks that was high in red meat (300 g/day) in a randomized crossover study (Le Leu et al., 2015).

No statistically significant associations were found between dietary intake of well-done meat assessed by questionnaire and DNA adducts putatively related to 2-amino-1-methyl-6-phenylimidazo[4, 5-b]pyridine (PhIP) in normal breast tissue (Zhu et al., 2003). The study included 106 women newly diagnosed with cancer of the breast, of which 49 women underwent reduction mammoplasty. PhiP–DNA adducts were assessed by immunohistochemistry using polyclonal antibodies. [The Working Group noted the lack of specificity of this method for these adducts. The type of meat was not specified]

Fried meat [not specified] intake, assessed by food frequency questionnaire (FFQ), was significantly correlated with the presence of bulky, non-specific DNA adducts (³²P-postlabelling analysis) in the breast tissue of 44 women undergoing reduction mammoplasty (Rohrmann et al., 2009a).

Chien & Yeh (2010) showed that barbecued pork meat exposure increased oxidative DNA lesions in urine. They gave one meal of barbecued pork meat (reported as 15 or 30 g/kg bw) to eight or five volunteers, respectively. Statistically significant increases in urinary 8-hydroxy-2′-deoxyguanosine (8-OHdG) were observed 2 or 3 days after barbecued pork meat consumption. A correlation was found between PAH metabolites and 8-OHdG in urine (Chien & Yeh, 2010). [The Working Group noted the very high reported intake level of pork meat and of the borderline significance of the results.]

Regarding processed meat, the study by Rohrmann et al. (2009a) previously mentioned reported a significant correlation of intake (assessed by FFQ) with the presence of bulky, non-specific DNA adducts (³²P-postlabelling analysis) in the breast tissue of 44 women undergoing reduction mammoplasty.

(ii) Gene mutation

See Table 4.1.

Regarding red meat, no association was found between K-RAS mutation frequency and meat consumption, assessed by FFQ, in colorectal cancer samples from 43 patients (O’ Brien et al., 2000). Similarly, there was no association between tumours with K-RAS mutations and meat consumption in a large cohort study of 448 patients with cancer of the colon and 160 patients with cancer of the rectum from the Netherlands Cohort Study (NLCS) (Brink et al., 2005).

In the randomized crossover study by Lewin et al. (2006) previously mentioned, no K-RAS mutations were present in the exfoliated colon cells of volunteers fed diets that were high in red meat (420 g/day), vegetarian, or high in red meat and fibre for 15 days.

A positive association between haem iron intake and risk of cancer of the colorectum harbouring G→A transitions in K-RAS and APC genes, and TP53 overexpression was found in a prospective study (Gilsing et al., 2013). In the European Prospective Investigation into Cancer and Nutrition (EPIC) study in Norfolk, England, TP53 mutations in cancer of the colorectum were examined in relation to dietary and lifestyle factors (Park et al., 2010). Higher daily total meat and red meat intake (assessed by FFQ) was significantly associated with harbouring TP53 mutations in cancer of the colorectum.

In a case–control study in the Netherlands, Diergaarde et al. (2003) evaluated the association between dietary factors and APC mutations in sporadic colon carcinomas (184 cases, 259 controls). Direct sequencing was used to screen the mutation cluster region of APC in the colon tumours. Red meat intake appeared to be associated with APC mutated tumours: the odds ratios (ORs) for the association between the two highest tertiles (58–87 g/day and ≥ 86 g/day) of red meat intake and APC mutations were 1.5 (95% confidence interval, CI, 0.7–3.0) and 1.7 (95% CI, 0.8–3.6), respectively.

Regarding processed meat, analyses of APC mutations and APC promoter 1A methylation were performed on 185 archival colorectal cancer samples from participants of the EPIC-Norfolk study, with the aim of relating these to a 7-day dietary and lifestyle data collected prospectively (Gay et al., 2012). Truncating APC mutations and APC promoter 1A methylation were identified in 43% and 23% of colorectal cancer samples analysed, respectively. Cases with APC mutations or APC promoter 1A methylation consumed significantly higher levels of processed meat and iron from red meat and red meat products. In a logistic regression model adjusted for age, sex, and cigarette smoking status, each 19 g/day (one standard deviation, SD) increment increase in processed meat consumption was associated with APC mutations with GC→AT transitions (OR, 1.68; 95% CI, 1.03–2.75).

(iii) Faecal water genotoxicity

See Table 4.2

Table 4.2

DNA damage induction by human faecal water following meat consumption.

Rieger et al. (1999) first reported that a diet high in fat and meat increased faecal water genotoxicity (tested with comet assay in HT-29 cell cultures) in seven healthy volunteers over a period of 12 days. Compared with a diet rich in vegetables and poor in fat and meat, a diet rich in fat (total energy intake, 50%), meat, and sugar, and poor in vegetables and free of wholemeal products [no exact composition was given], significantly increased faecal water genotoxicity. [type of meat was not specified].

Faecal water genotoxicity (tested with comet assay in HT-29 cell cultures) from two randomized controlled studies of red meat (60 or 420 g/day), a vegetarian diet, or haem iron supplements for 15 days in volunteers (n = 21) was evaluated by Cross et al. (2006). Diet had no effect on faecal water genotoxicity (i.e. red meat had no effect). This study was performed under the same conditions as those described by Rieger et al. (1999), but did not confirm those results.

Hughes et al. (2002) studied the effect of vegetables, tea, or soy on faecal water genotoxicity (tested with comet assay in Caco-2 cell cultures) in 11 volunteers fed a high–red meat (420 g/day) diet for 15 days. Low to moderate levels of genotoxicity were observed. [The Working Group noted that the study did not contain a control group consuming a low–red meat diet.]

Faecal water from volunteers (n = 12) fed a red meat (420 g/day, males; 366 g/day, females) or vegetarian diet (Joosen et al., 2009) was tested for genotoxicity by comet assay in Caco-2 cells. Surprisingly, the vegetarian diet produced more DNA strand breaks than the red meat diet. No effect of diet was found in a similar study by the same authors (Joosen et al., 2010) assessing faecal water genotoxicity in volunteers (n = 13) fed a red meat versus fish diet.

More recently, Hebels et al. (2012) showed increased faecal water genotoxicity in a heterogeneous group of inflammatory bowel disease/irritable bowel syndrome patients (n = 12) after 7 days of high–red meat intake (300 g/day), compared with the results obtained before the intervention. In 10 of the subjects, faecal water genotoxicity significantly increased with red meat intake (tested with both standard comet assay and the formamidopyrimidine procedure to measure oxidative damage in Caco-2 cells). Microarray analyses in colon biopsies indicated significant modulation of various signalling pathways (e.g. cytoskeleton remodelling, development, and immune response) (Hebels et al., 2012).

Regarding processed meat, the study by Joosen et al. (2009) previously described found that faecal water from subjects on the vegetarian diet compared with that from subjects on the processed meat diet produced more DNA strand breaks, as assessed by comet assay in Caco-2 cells.

(iv) Mutagenic activity in urine

See Table 4.3

Table 4.3

Bacterial mutagenic activity of human urine following meat consumption.

The first report of mutagenic activity in the urine of subjects after ingestion of meat was published in 1982 (Baker et al. 1982). Fried pork (150 g) was given to five subjects, and bacterial mutagenicity of urine was determined. Peaks in urinary mutagenicity (in Salmonella typhimurium strains TA98 and TA1538 with S9) were detected 2–4 hours after ingestion.

Dolara et al. (1984) reported a modest increase in mutagenic activity in the urine of subjects fed pork fried in a pan at 200 °C. Mutagenic activity (in S. typhimurium strain TA1538 with S9) was present in 3 of 13 samples analysed and was much lower than that reported by Baker et al. (1982). Hayatsu et al. (1985) also documented mutagenicity (S. typhimurium strain TA98 with S9) in the urine of three volunteers 1.5 hours after consumption of fried ground beef.

Doolittle et al. (1989) studied the effects of different cooking methods on mutagenicity. As a small part of the study, the urinary mutagenicity of different cooking procedures was compared in 12 subjects (6 males, 6 females). Fried meat increased urinary mutagenicity (S. typhimurium strains TA98 and TA100 with S9) compared with boiled or baked meat.

Gabbani et al. (1998) determined urinary mutagenicity 24 hours after ingestion of two pan-fried hamburgers (2 × 100 g) in 32 volunteers. GSTM1 and NAT2 genotypes were also evaluated. Urinary mutagenicity was tested in S. typhimurium strains TA98 and YG1024, with the latter overexpressing O-acetyltransferase. Mutagenicity (a doubling over the spontaneous revertant number) was seen in the YG1024 strain (in 23 of 32 samples), but not in the TA98 strain. Furthermore, NAT2 slow acetylators had higher urinary mutagenicity. Similar results (i.e. increased mutagenic activity after a pan-fried hamburger meal) were shown by Pavanello et al. (2002) in a larger group of subjects (n = 50).

Peters et al. (2004) studied urinary mutagenesis in a group of 60 volunteers who consumed red meat cooked at 100 °C for 7 days followed by red meat cooked at 250 °C for an additional 7 days. Both unhydrolysed and acid-hydrolysed urine samples, containing unmetabolized mutagens and both metabolized and unmetabolized mutagens, respectively, were tested in S. typhimurium strain YG1024. Unhydrolysed and hydrolysed urine samples were 22 and 131 times more mutagenic, respectively, in subjects who consumed red meat cooked at 250 °C compared with those who consumed red meat cooked at 100 °C.

Shaughnessy et al. (2011) reported increased mutagenic activity (in S. typhimurium strains TA98 and YG1024) in the hydrolysed urine and faeces of subjects (n = 8) who consumed red and processed meat cooked at a high temperature of 250 °C (11 minutes/side) for a period of 2 weeks.

Regarding processed meat, the previously mentioned study by Baker et al. (1982) reported increased urinary mutagenicity (in S. typhimurium strains TA98 and TA1538 with S9) in five subjects fed fried bacon (150 g). Similarly, Dolara et al. (1984) reported a modest increase in mutagenic activity in the urine of subjects consuming pan-fried bacon.

(v) Epigenetics

Regarding red meat, microRNA expression in the rectal mucosa of volunteers consuming a high–red meat diet, with or without supplementation with butyrylated high-amylose maize starch (HAMSB), was evaluated by Humphreys et al. (2014). Volunteers received the high–red meat diet for 4 weeks, with washout periods and different orders of treatments. HAMSB significantly lowered a cluster of microRNAs (miR17–92, designated oncomir-1) associated with carcinogenesis. This effect was attributed more to a decrease of these microRNAs by HAMSB than an increase of these microRNAs by red meat.

Tarallo et al. (2014) showed an association between microRNA (miR-92a) levels in the plasma of healthy individuals and consumption of processed meat and other dietary factors (Tarallo et al., 2014).

(b) Human cells in vitro

See Table 4.4

Table 4.4

Genetic and related effects of meat extract in human cells in vitro.

The basic fraction of a beef extract did not induce chromosomal aberrations in human lymphocyte cultures (irrespective of the presence of S9) (Aeschbacher & Ruch, 1989). A small but statistically significant increase in sister-chromatid exchange was seen in the presence of S9.

No study of processed meat in human cells in vitro was available to the Working Group.

(c) Non-human mammals in vivo

See Table 4.5

Table 4.5

Genetic and related effects of red meat or processed meat in non-human mammals in vivo.

(i) DNA damage

In studies of DNA adducts after red meat consumption, Winter et al. (2011) quantified O⁶-MeG adducts by immunohistochemistry in CBJ57 mouse colonocytes after mice were fed different diets (containing 15% or 30% protein as casein or red meat, 30% protein with high-amylose maize starch) for 4 weeks. O⁶-MeG and para-cresol, a protein metabolite with reported genotoxic activity, significantly increased (P < 0.02) with consumption of red meat compared with casein. O⁶-MeG adducts were present at the apex of the crypts. Starch attenuated the increase in DNA adduct levels.

DNA damage in colonocytes (assessed by comet assay) was measured in Sprague-Dawley rats fed diets containing 25% cooked lean red meat (300 g/kg diet) or casein (15% or 25%), with or without high-amylose maize starch for 4 weeks (Toden et al., 2006). When starch was absent from the diet, red meat caused a significant increase in DNA damage (26%) compared with casein (P < 0.05). When starch was present in the diet, the red meat effect was not significant. The same authors later fed rats diets of 15%, 25%, or 35% cooked beef or chicken, with or without high-amylose maize starch (Toden et al., 2007). DNA single- and double-strand breaks (assessed by comet assay in colonocytes) were significantly higher in the groups fed high levels of both meats compared with those fed low levels of meat. Red meat was more active than chicken, and starch prevented the damage. Apoptotic cells were also increased by red meat (see Section 4.2.3).

The effect of red meat on colonocyte DNA damage was also studied in pigs (Belobrajdic et al., 2012). Ten male animals (Large White strain) were fed diets containing 300 g/kg of cooked red meat or the same diet supplemented with arabinoxylans (arabinoxylan-rich fraction from wheat) for 4 weeks. The comet assay was performed on colonocytes, together with additional determinations (short-chain-fatty-acids (SCFA), phenol, cresol in the feces, bacterial profile). There was a significant decrease in DNA damage in the diet supplemented with arabinoxylans.

Regarding processed meat, 7-methyldeoxyguanosine levels were measured by immuno-slot-blot assay in the colonic DNA of Swiss mice fed hot dogs containing beef or pork (18% of the diet) for 7 days. The levels of this non-mutagenic adduct were similar in control (n = 5) and treated mice (n = 4) (Mirvish et al., 2002).

(ii) Gene mutation

Dolara et al. (1980) reported no increase in the mutagenicity of the urine after administration of a beef extract to Swiss albino mice. Similarly, the beef extract did not have a mutagenic effect as assessed by intrasanguine host-mediated assay.

Regarding processed meat, the mutagenic activity detected by intrasanguine host-mediated assay in NMRI mice given an extract of pan-fried sausage was very low (Gocke et al., 1982). An extract of pan-fried sausage (500 mg/kg bw) fed to pregnant female C57Bl mice did not increase the frequency of coat-coloured spots in the mouse spot test (Gocke et al., 1982).

(iii) Chromosomal aberrations

A basic extract of pan-fried sausage (up to 1000 mg/kg bw) did not increase the frequency of micronucleated erythrocytes in mouse bone marrow (Gocke et al., 1982).

The caecal water from Sprague-Dawley rats fed a high fat, low fibre, and low calcium diet containing barbecued beef as the protein source (equivalent to 17% of the total diet) for 2 weeks significantly increased all the parameters assessed – micronuclei, nucleoplasmic bridges, and nuclear buds –in the WIL2-NS human B-lymphoblastoid cell line. Control rats were fed 17% casein as the protein source in a diet low in fat, and high in fibre and calcium (Benassi et al., 2007).

(d) Non-mammalian experimental systems

See Table 4.6

Table 4.6

Genetic and related effects of red meat or processed meat in non-mammalian experimental systems.

(i) Drosophila

No study of red meat in Drosophila was available to the Working Group. Regarding processed meat, an extract of pan-fried sausage did not increase the frequency of sex-linked recessive lethals in Drosophila (Gocke et al., 1982).

(ii) Bacteria

In red meat studies in vitro, extracts of the charred surface of broiled beef meat and fish, together with smoke produced from the broiling of fish, were first demonstrated to be mutagenic by Sugimura and colleagues Nagao et al. (1977). The charred parts of medium-broiled beef were suspended in dimethyl sulfoxide and tested using the Ames test. The dimethyl sulfoxide extract of the charred meat was mutagenic in S. typhimurium strain TA98 with S9 prepared from the liver of rats treated with polychlorinated biphenyl (PCB). This mutagenic activity was much higher than that anticipated from the benzo[a]pyrene (BaP) content of the cooked food.

Commoner et al. (1978) reported that cooked red meat was highly mutagenic (in S. typhimurium strain TA1538). Hamburger meat cooked rare, medium, or well done was extracted with methylene chloride, dried, and dissolved in dimethyl sulfoxide. Mutagenic activity was dependent on the presence of S9. The mutagens formed did not belong to the class of BaP or protein and amino acid pyrolysis products. Mutagens were produced during common cooking procedures, including the use of electrically heated hot plates.

A sharp rise in the frequency of mutations in S. typhimurium strain TA1538 with S9 was detected when beef was boiled for different periods of time and reached temperatures between 140 °C and 180 °C. The mutagenic activity of the beef (hamburger) cooked under different conditions was limited to the surface layer; uncooked meat or microwave-cooked meat did not produce mutagenic activity (Dolara et al., 1979).

Similarly, Pariza et al. (1979) demonstrated that the mutagenic activity of pan-fried hamburger meat was dependent on cooking time and temperature. Mutagenic activity (in S. typhimurium strain TA1538) was not detected in uncooked hamburger or hamburger pan-fried at 143 °C. In contrast, hamburger pan-fried at 191 °C or 210 °C for up to 10 minutes generated considerable mutagenic activity. Higher mutagenic activity was observed when S9 was from Aroclor 1254–treated rats.

Another study with S. typhimurium strain TA98 showed meat cooked only at a high temperature of 250 °C had mutagenic activity (Peters et al., 2004).

Dolara et al. (1980) reported that the mutagenic activity of a beef extract required the presence of S9 fractions from the liver of rats treated with PCB or 3-methylcholanthrene, but no induction was necessary when the liver came from Swiss albino mice. CD-1 mice had intermediate activation capabilities, which increased after the addition of 0.75% butylhydroxyanisole to their diet. S9 from the liver of human donors had low-activation capabilities.

Regarding processed meat, an extract of pan-fried sausage was mutagenic in S. typhimurium strains TA1538 and TA98 in the presence of S9 mix (Gocke et al., 1982).

4.3. Precancerous lesions

4.4. Cancer susceptibility

4.5. Meat components potentially involved in carcinogenesis

4.5.2. Lipid oxidation products

(a) Lipid oxidation in meat

The oxidation of unsaturated fatty acids in meat results in the formation of lipid oxidation products, which are in part cytotoxic and genotoxic (Kanner, 2007; Guéraud et al., 2010). Polyunsaturated fatty acids are especially sensitive to oxidation, which proceeds via a free radical chain reaction involving initiation, propagation, and termination steps. Transition metals, especially iron, catalyse this reaction, in the presence of oxygen, producing unstable ROS, including superoxide, hydrogen peroxide, and hydroxyl radicals. The ROS initiates a chain of oxidative reactions, generating lipoperoxyl radicals and lipid hydroperoxides. Lipid hydroperoxides may decompose to several low-molecular-mass breakdown products, such as aldehydes and hydroxyalkenals, or condense to polymers. The main lipid peroxidation by-products are malondialdehyde (MDA) and 4-HNE (Marnett, 2000; Fig. 4.1); both of these lipid oxidation end products are risk factors to human health (Kanner, 2007; Bastide et al., 2011). MDA is most abundant and can reach 300 µM or more in meat products (Kanner, 2007). It is also toxic and binds to DNA and proteins, or undergoes further oxidation to more reactive epoxy derivatives that can be mutagenic in bacterial, mammalian, and human cells (Basu & Marnett, 1983; Esterbauer, 1993; Guéraud et al., 2010; Bastide et al., 2011). In foods, MDA is bound mainly to the lysine residues of proteins, from which it is released in the course of digestion, as N-α-acetyl-ϵ-(2-propenal)lysine (Piche et al., 1988).

Fig. 4.1

Generic scheme of polyunsaturated fatty acid peroxidation

The fat fraction of meat also contains cholesterol, and it is known that dietary fatty acids and dietary cholesterol are co-oxidized (Kanner, 2007). Cholesterol oxidation via lipid free radicals results in the formation of many oxidation by-products, such as oxycholesterol, which has cytotoxic, pro-oxidant, and proinflammatory activities (Lemaire-Ewing et al., 2005). The amount of oxycholesterol in cholesterol-rich food products, including precooked meat and poultry, can reach 10–100 µM (Kanner, 2007).

The degree of lipid oxidation during the manufacturing of processed meat and storage of fresh and processed meat before consumption depends on many factors, such as the iron and polyunsaturated fatty acid content; the presence of endogenous or added antioxidants, and other additives; and the processing and storage conditions (Morrissey et al., 1998). When good storage and processing practices are followed, the levels of lipid oxidation products in meat at the time of consumption are low. Oxidation of myoglobin and other proteins also occurs, which can interfere with lipid oxidation (Faustman et al., 2010).

(b) Lipid oxidation during digestion of meat

The composition of meat and the conditions prevailing in the different compartments of the digestive tract, including interactions with other foods, determine the extent of formation of lipid oxidation products during the digestion of meat. Saliva in the mouth, acidic gastric juice in the stomach, emulsifying pancreatic and bile juice in the small intestine, and anaerobic fermentation by the microbiota in the large intestine all influence lipid oxidation in the gut. Kanner & Lapidot (2001) showed that lipid oxidation in heated muscle tissue was enhanced in the stomach due to the low pH and dissolved oxygen.

Extensive evidence is available indicating that haem iron in red and processed meat is a key factor in promoting lipid oxidation (Carlsen et al., 2005). Feeding rats heated red turkey cutlets, which are high in haem, increased lipid hydroperoxides and MDA in the stomach (Gorelik et al., 2008). As previously noted, urinary excretion of DHN-MA was increased in rats fed haem and in humans fed blood sausage (Pierre et al., 2006). Plasma MDA concentrations were higher in rats fed beef versus chicken (Toden et al., 2010). Higher MDA, 4-HNE, and hexanal concentrations resulted from in vitro duodenal and colonic digests of beef compared with pork, followed by chicken (Van Hecke et al., 2014a).

A large proportion of ingested haem iron reaches the colon (Pierre et al., 2008), and could thus stimulate oxidation reactions in the colonic contents. However, lower MDA, 4-HNE, and hexanal concentrations resulted from in vitro colonic compared with duodenal digests (Van Hecke et al., 2014a, b; Vanden Bussche et al., 2014). This could be due to the anaerobic conditions in the colon, degradation or metabolism into other compounds. The colonic microbial composition likely also has an influence on oxidation processes (Huycke & Moore, 2002; Sun et al., 2010; Martin et al., 2015).

The high-fat content of many processed meats is likely to result in an increased production of lipid oxidation products. In vitro digestion of a heated pork product containing 5% or 20% pork lard resulted in a higher production of 4-HNE and hexanal compared with heated lean pork containing 1% fat (Van Hecke et al., 2014b). The fatty acid profile is also important. Urinary MDA and DHN-MA in rats increased when haem iron was combined with fish oil (high in n-3 fatty acids) and safflower oil (high in n-6 fatty acids), but not with hydrogenated coconut oil (98% saturated fatty acids) (Guéraud et al., 2015). Similarly, levels of hepatic 4-HNE-histidine protein adducts were higher when haem iron was combined with safflower oil compared with hydrogenated coconut oil.

During the heating of meat, the content of free Fe²⁺ increases through destruction of the haem-porphyrin moiety, oxymyoglobin releases oxygen with production of hydrogen peroxide, and antioxidant enzymes (e.g. glutathione peroxidase) are inactivated (Kanner, 1994). This stimulates the Fenton reaction, and thus the formation of lipid oxidation products. Rats consuming cooked meat products had increased faecal TBARS and urinary DHN-MA compared with rats consuming raw meats (Santarelli et al., 2010). Similarly, heating compared with not heating a pork product increased the formation of MDA, 4-HNE, and hexanal before and during digestion (Van Hecke et al., 2015).

Nitrite salt is widely used as a curing agent in meat processing. Nitrite has antioxidant properties in processed meat. The formed nitric oxide myoglobin, nitric oxide ferrous complexes, and S-nitrosocysteine have antioxidant properties, and nitric oxide inhibits the Fenton reaction (Kanner, 1994). In acidic conditions, such as in the stomach, nitrous acid generates dinitrogen trioxide and water, which is in equilibrium with nitric oxide (NO) and nitrogen dioxide (NO₂) (Honikel, 2008). The balance between NO and ROS has been described as a determinant of the effect of nitrite on oxidant reactions whereby a 1:1 ratio of NO to ROS enhances lipid peroxidation, whereas an excess of NO inhibits oxidation (Darley-Usmar et al., 1995). A study using rats showed that addition of nitrite to meat products reduced TBARS in faecal water (Santarelli et al., 2010). Chenni et al. (2013) found that intake of nitrite through drinking-water (1 g/L) reduced haem-induced lipid peroxidation in the colon of rats by 25%. During in vitro digestion of different nitrite-cured meat products, the formation of lipid oxidation products was markedly inhibited (Van Hecke et al., 2014a, b; 2015). However, this inhibition was less efficient when the fat content of the diet was high (20% fat), and absent when the meat products were subjected to intense heating. The intensely heated meat products, in which nitrite was less efficient at preventing oxidant reactions, contained less residual nitrite.

(c) Absorption, distribution, metabolism, and excretion

A vast amount of literature is available concerning the biotransformation of lipid oxidation products. With respect to toxic aldehydes, the Working Group refers to extensive reviews of Esterbauer et al. (1991) and of Guéraud et al. (2010), and of Poli et al. (2008) for 4-HNE specifically. Most lipid peroxidation–derived aldehydes such as 4-HNE can travel across membranes by passive diffusion. Metabolism occurs in most cells and tissues, and is rapid and complete. As a first and major step is conjugation with glutathione by Michael addition, which may be considered a detoxification reaction, facilitating urinary excretion. Other modifications of the aldehyde function may also occur (e.g. reduction into an alcohol or oxidation into an acid). The liver and the kidneys are the organs primarily involved in the elimination of 4-HNE. DHN-MA appears to be the major urinary metabolite of 4-HNE. MDA is metabolized to carbon dioxide and water via transformation into acetaldehyde, but it is also found unmodified in urine and plasma (Guéraud et al., 2010).

(d) Mechanisms of carcinogenesis

Due to their chemical reactivity, aldehyde breakdown products of lipid oxidation can covalently modify nucleic acids, proteins, and lipids (Guéraud et al., 2010). They also serve as biomarkers of oxidative stress, and are important in cell signalling in both pathological and physiological conditions, mainly in cell cycle regulation. 4-HNE is able to exert cytotoxic, mutagenic, and genotoxic effects. Similarly, MDA has mutagenic and genotoxic properties (Esterbauer, 1993; Guéraud et al., 2010).

After meat consumption, the levels of lipid peroxidation products and their adducts or metabolites increase. For instance, lipid hydroperoxides and MDA accumulation increased more than twofold in the stomach contents of rats fed red turkey cutlets and after pyloric ligation. Postprandial plasma MDA levels increased significantly by 50%. The addition of red wine polyphenols altered these outcomes (Gorelik et al., 2008). In a human study by Brown et al. (1995), urinary MDA increased from 2.1 to 23.1 µmol/day with the consumption of high quantities of cooked meat over a 7-day period. After consumption of red meat by rats and humans, excretion of both MDA and DHN-MA increased in the urine (Pierre et al., 2006, 2008).

4.5.5. N-Nitroso compounds

The following discussion is restricted to studies involving exposure to NOCs as a result of the consumption of red meat or processed meat, together with studies that reported findings directly relevant to the issue of whether such exposure may contribute to any risk of cancer. The weight accorded to such data depended, among many other considerations, on current knowledge of the carcinogenicity of individual NOCs and of NOCs as a class. See IARC Monographs Volume 89 (IARC, 2007) and Volume 100E (IARC, 2012b) for NOCs, and Volume 94 (IARC, 2010) for ingested nitrate and nitrite.

NOCs can be produced during processing, storage, and preparation of foods. They are formed by the reaction of secondary amines (R₁NHR₂) and N-alkylamides (R₁NH·CO·R₂) with nitrite in food or in the acidic environment of the stomach (Honikel, 2008). Metabolism of nitrosamines or spontaneous breakdown of nitrosamides can give rise to reactive alkylating intermediates, which can be identified by their reaction with DNA and other macromolecules. Nitrosation of primary amino acids, including glycine and methionine, may also give rise to alkylating intermediates (Issenberg 1976; Mirvish, 1995). NOCs are genotoxic carcinogens associated with particular mutational signatures (Rao, 2013).

The general term NOC covers all substances with N-nitroso groups, including N-nitrosamines and N-nitrosamides. However, the analytical method generally used to analyse NOCs in digestion does not differentiate between N-nitrosamines and other compounds such as S-nitrosothiols, O-nitroso compounds, and iron nitrosyls (Kuhnle & Bingham, 2007). Given this lack of specificity, the term ATNC has been used to describe the substances measured by this technique. Nitrosyl haem and nitrosothiols have been identified as major constituents of both faecal and ileal ATNC, and the formation of these compounds increases significantly after consumption of a diet rich in red meat. Nitrosothiols are readily formed under the acidic conditions of the stomach, a process that is promoted by haem. Haem becomes easily nitrosylated under the anaerobic and reductive conditions of the lower gut to form nitrosyl haem, which is an NO donor and can act as a nitrosating agent. In turn, nitrosothiols can act as NO donors and nitrosating species. Thus, the combined actions of haem and free thiol groups can promote the endogenous formation of NOCs (Kuhnle et al., 2007).

Nitrite used in meat processing is involved in many reactions with myoglobin, proteins, and lipids (Honikel, 2008; Skibsted, 2011; Demeyer et al., 2015; Fig. 4.2). When combined with myoglobin, these reactions result in nitrosomyoglobin in cured meat and nitrosyl haemochromogen after cooking, which are responsible for the characteristic colour of cured meats. Residual nitrite in cured meat proteins may be important as a “hidden NO-generating pool”, a source of nitric oxide for numerous reactions during the storage and cooking of cured meats (Skibsted, 2011).

Fig. 4.2

Nitric oxide formed from nitrite during meat curing can participate in numerous reactions modifying proteins and pigments

The occurrence of nitrate, nitrite, and NOCs in meat is discussed in Section 1. Mirvish et al. (2002) reported that NOC and NOC precursor levels in hot dogs were about 10 and 4 times higher, respectively, than those in fresh meat. The NOC precursors were considered of greater relevance to carcinogenicity, as they are more stable and approximately 1000 times more abundant than NOCs. The main NOC precursors identified were N-glycosyl amino acids and peptides. Dich et al. (1996) described dietary intake of nitrate, nitrite, and N-nitrosodimethylamine (NDMA) in 5304 men and 4750 women who participated in the Finnish Mobile Clinic Health Examination Survey in 1967–1972. Dietary nitrite was mainly provided by meat products (specified as cured meats, cooked sausage, and salami), contributing about 95% of the total intake. The mean daily intake of NDMA was calculated to be 0.052 µg, approximately half of which was derived from meat products.

(a) Absorption, distribution, metabolism, and excretion

Few studies have reported on the absorption, distribution, metabolism, and excretion of NOCs after meat consumption. Human saliva contains nitrate and nitrite due to enterosalivary circulation (Mirvish et al., 2000). Since rats convert a low amount of salivary nitrate into nitrite, it has been argued that the rat may not be a good model for humans (Cockburn et al., 2013). Therefore, Chenni et al. (2013) tested the relevance of this enterosalivary cycle by giving haem iron–fed rats drinking-water containing sodium nitrite, mimicking human salivary nitrite levels. They observed increased faecal ATNC. Phillips et al. (1975) showed that NDMA is absorbed in the rat stomach and the small intestine. Zhou et al. (2014) also reported increased urinary ATNC in rats fed sodium nitrite and/or hot dogs. In a rat model, Santarelli et al. (2010) showed that a combination of nitrite curing, cooking, and oxidation of red meat increased faecal ATNC. In addition, rats fed a diet containing commercially purchased hot dogs or fermented, raw, dry sausages had increased faecal ATNC compared with those fed a control diet without meat (Santarelli et al., 2013). Intake of sodium nitrite (0.17 g/L) and sodium nitrate (0.23 g/L) through drinking-water increased faecal ATNC in rats on a 1% haemoglobin diet (Chenni et al., 2013).

Several mechanisms have been proposed to explain the effect of red meat on the formation of NOCs. Lunn et al. (2007) observed no difference in ATNC levels in the ileal output of ileostomists and in the faecal output of healthy subjects consuming large amounts of red meat. In contrast to the stomach contents, which consisted only of nitrosothiols, nitrosyl iron was present in higher concentrations than nitrosothiols in ileal and faecal samples, with no difference in ATNC composition between both sample types (Kuhnle et al., 2007). Thus nitrosothiols formed in the acidic stomach may release NO once they are exposed to the alkaline and reductive conditions of the small and large intestine, thereby stimulating the nitrosylation of haem iron. However, the consequences of the formation of these products are unclear (Hogg, 2007). On the one hand, nitrosyl haem and nitrosothiols could act as nitrosating agents and promote the formation of NOCs in the intestinal epithelium (Kuhnle et al., 2007). On the other hand, nitrosothiols and nitrosyl iron may act as a protective mechanism by capturing NO and facilitating its excretion, thereby limiting the formation of DNA alkylating agents.

In a series of human intervention studies, Bingham and colleagues demonstrated a dose–response increase in faecal excretion of ATNC with red meat intake. This was not observed with vegetable proteins, white meat, or an Fe²⁺ supplement, but mimicked by a haem iron supplement (provided by blood sausage) (Bingham et al., 1996; Hughes et al., 2001; Bingham et al., 2002; Cross et al., 2003). Holtrop et al. (2012) conducted three dietary trials in obese men consuming body weight maintenance or weight loss diets, and measured NOCs in faecal samples. The meat-based weight loss diets increased levels of faecal NOCs (P < 0.001). Red meat intake was positively correlated with the faecal log NOC concentrations (r = 0.60; P < 0.001).

The genotoxic effects of faecal ATNC were investigated using different comet assay protocols in individuals consuming high levels of red meat (Cross et al., 2006a). The inter-individual effects were variable, and diet, mean transit time, and weight had no effect on faecal water genotoxicity; see also Lewin et al. (2006), as discussed in Section 4.2. Rats treated with the N-nitrosopeptide N-acetyl-Nʹ-prolyl-Nʹ-nitrosoglycine showed the presence of O⁶-CMG in the intact small intestine. This was also observed in HT-29 cells treated with diazoacetate (Lewin et al., 2006). Since the analysis of ATNC includes both toxic and non-toxic compounds, the quantification of O⁶-CMG might offer a more specific insight into the formation of genotoxic NOCs.

Although Lunn et al. (2007) and Kuhnle et al. (2007) observed no difference between ileal and faecal ATNC and its individual components, suggesting no influence of the colonic microbiota on NOC formation, other research has suggested a major facilitating role of the gut microbiota. Using a pig caecum model containing nitrate and amines/amides, Engemann et al. (2013) showed large inter-individual variation in porcine microbiota to form N-nitrosamines N-nitrosomorpholine (NMOR) and N-nitrosopyrrolidine (NPYR), and N-nitrosamides N-methyl-N-nitrosourea and N-ethyl-N-nitrosourea. Moreover, a clear increase in NOCs was observed in time, with the microbiota responsible for the reduction of nitrate to nitrite. In accordance, Vanden Bussche et al. (2014) found considerable inter-individual variation in human microbiota for the in vitro formation of the NOC-specific DNA adduct O⁶-CMG during fermentation of white and red meat. This large inter-individual variation was also acknowledged by Van Hecke et al. (2014a, b; 2015). However, in vitro formation of O⁶-CMG was stimulated by a higher haem iron content, a higher fat content, and more intense heating conditions, while nitrite curing was not perceived to be of influence, despite the large impact of the applied microbiota (Van Hecke et al., 2014a, b, 2015).

A broad body of evidence indicates that the formation of NOCs may be inhibited by agents including ascorbic acid and α-tocopherol (Mirvish, 1986). The inhibitory effects of nitrite, l-ascorbic acid, and α-tocopherol on the formation of NOCs in processed meat products were evaluated by comparing samples of sausage with different concentrations of these reductants (Pourazrang et al., 2002). Revertants in the S. typhimurium (TA100) microsome assay were significantly reduced (P < 0.05) by 60% when the reductants were added to the samples. In the study of Hughes et al. (2002) described in Section 4.2 evaluated the effect of soy and other dietary components on faecal NOC excretion with consumption of a high–red meat (420 g/day) diet in 11 male volunteers randomized to 15-day dietary periods. Soy significantly suppressed faecal ATNC concentrations (P = 0.02), but vegetables and tea extract did not affect mean faecal ATNC concentrations or faecal water genotoxicity. However, faecal weight increased and was associated with reduced transit time, decreasing contact between ATNC concentrations, nitrite, and ammonia and the large bowel mucosa.

(b) Mechanisms of carcinogenesis

For decades, experimental animal data have afforded insight into the increased risk of cancer in humans that is attributable to the consumption of different categories of meat, and specifically the possible role of NOCs (Olsen et al., 1984); see also Santarelli et al. (2010), as discussed in Section 4.3.

G→A transitions in K-RAS occur in cancer of the colorectum and are characteristic of the effects of alkylating agents such as NOCs (Bingham et al., 1996). The methylating agent N-methyl-N-nitrosourea produced predominantly (> 80%) transitions (GC→AT), whereas potassium diazoacetate, a stable form of nitrosated glycine, produced transitions (GC→AT) and transversions (GC→TA and AT→TA) in equivalent amounts (Gottschalg et al., 2007). The similarity in the patterns of mutations induced by potassium diazoacetate with those observed in mutated P53 in human gastrointestinal tract tumours suggests that nitrosation of glycine (or glycine derivatives) may contribute to characteristic human P53 mutation profiles.

(c) Epidemiological studies

Studies addressing the association between risk of cancer and dietary intake of nitrate, nitrite, or nitrosamines refer to meat as well as other relevant foods (Loh et al., 2011). [The Working Group noted that dietary intake of nitrate and nitrite does not necessarily reflect NOC intake.]

In the EPIC-Norfolk study (Loh et al., 2011), dietary NDMA intake was significantly associated with an increased risk of cancer of the rectum in women. There was no significant association between cancer risk across quartiles and dietary nitrite and endogenous NOCs. In a case–control study in Canada, NDMA intake was associated with a higher risk of cancer of the colorectum, specifically rectal carcinoma. Risk of cancer of the colorectum also increased with the consumption of NDMA-containing meats (Zhu et al., 2014). Individuals with high-NDMA and low–vitamin E intake had a significantly higher risk than those with both low-NDMA and low–vitamin E intake.

Intake of dietary nitrites and nitrosamines was positively associated with risk of cancer of the lower urinary tract in American men of Japanese ancestry (Wilkens et al., 1996). Consumption of processed meats, in particular bacon, sausage, and ham, was also significantly associated with an increased risk in American men of Japanese ancestry. Three food items accounted for all of the NOC intake: sausage (46%), bacon (33%), and luncheon meats (21%).

The association between nitrate, nitrite, and nitrosamine intake and glioma was examined by Michaud et al. (2009). Risk of glioma was not elevated among individuals in the highest intake category of nitrate, nitrite, or NDMA compared with those in the lowest intake category. In a population-based case–control study of glioma in adults, increased odds ratios were observed in males who consumed high levels of bacon, corned meats, apples, melons, and oil (Giles et al., 1994). Elevated odds ratio in men, but not women, were associated with the intake of NDMA.

4.5.6. Interactions between NOCs, haem iron, and HAAs

Haem in red meat stimulates the endogenous production of NOCs. The effect of red meat and processed meat on endogenous nitrosation, as well as DNA damage (see Section 4.2), was investigated by Joosen et al. (2009). Faecal NOC concentrations in 5 males and 11 females on vegetarian diets were low (2.6 and 3.5 mmol/g, respectively), but significantly increased in those fed meat diets (preserved red meat, 175 ± 19 nmol/g; red meat, 185 ± 22 nmol/g; P = 0.75). The meat diets contained 420 g/day (males) or 366 g/day (females) of meat. The nitrite-cured meat diet had the same effect as the fresh red meat diet on endogenous nitrosation, but increased faecal water–induced oxidative DNA damage.

A high–red meat diet (420 g/day) significantly increased nitrosyl iron and nitrosothiols in ileal and faecal samples compared with a vegetarian diet (Kuhnle et al., 2007). Faecal nitrosyl iron and haem were strongly correlated (r = 0.776; P < 0.0001), suggesting that nitrosyl haem is the main source of nitrosyl iron. Nitrosation of HAAs is depicted in Fig. 4.3 (Lakshmi et al., 2005b). Lakshmi et al. (2005a) demonstrated hemin potentiation of NO-mediated nitrosation using the HAA IQ as a target and by monitoring the formation of ¹⁴C-2-nitrosoamino-3-methylimidazo[4,5-f]quinoline (N-NO-IQ) by high-performance liquid chromatography. Faecal NOCs (Mirvish et al., 2003) and urinary nitrite and nitrate were increased in mice with dextran sulfate sodium–induced colitis, which was consistent with increased expression of inducible NO synthase and NO synthesis.

Fig. 4.3

Nitrosation of heterocyclic aromatic amines

IQ and MeIQx can be converted to their corresponding N-nitrosamines, N-NO-IQ and 2-nitrosoamino-3,8-dimethylimidazo[4,5-f]quinoxaline (N-NO-MeIQx) (Zenser et al., 2009). N-NO-IQ and N-NO-MeIQx have been shown to form several putative adducts in common with those formed by 2-hydroxyamino-3-methylimidazo[4,5‑f]quinoline (N-OH-IQ) and 2-hydroxyamino-3,8-dimethylimidazo[4,5-f]quinoxaline (N-OH-MeIQx). These N-nitrosamines might be alternatives to their hydroxylamine analogues, as activated intermediates leading to the initiation of cancer of the colon in individuals with colitis.

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