Food and Chemical Toxicology 92 (2016) 236e244

Contents lists available at ScienceDirect

Food and Chemical Toxicology

journal homepage: www.elsevier.com/locate/foodchemtox

Invited review

The impact of red and processed meat consumption on cancer and

other health outcomes: Epidemiological evidences
ndez a, b, O.P. Luzardo a, b, *
Luis D. Boada a, b, L.A. Henríquez-Herna
a
Toxicology Unit, Research Institute of Biomedical and Health Sciences (IUIBS), University of Las Palmas de Gran Canaria, Plaza Dr. Pasteur s/n, 35016 Las
Palmas de Gran Canaria, Spain
b
Spanish Biomedical Research Centre in Physiopathology of Obesity and Nutrition (CIBERObn), Plaza Dr. Pasteur s/n, 35016 Las Palmas de Gran Canaria,
Spain

a r t i c l e i n f o a b s t r a c t

Article history: Meat is one of the staples of the human diet, which provides high-quality nutrients, but that also con-
Received 19 February 2016 stitutes a relevant source of cholesterol and saturated fatty acids. Epidemiologic studies have linked
Received in revised form consumption of red or processed meat with obesity, type 2 diabetes, cardiovascular diseases, and can-
8 April 2016
cers. Most epidemiological studies suggest that a high intake of meat, especially processed meat, is
Accepted 11 April 2016
Available online 20 April 2016
associated with increased colorectal cancer risk. Potential reasons for the association between high meat
intake and colorectal cancer risk include some chemicals naturally contained in meat, or generated by
the processing and cooking. From the literature it can be concluded that there is enough epidemiological
evidence linking processed meat intake and colorectal cancer risk, but there is limited evidence
regarding unprocessed red meat intake and the disease. On the contrary, there is only limited evidence
linking meat intake with other diseases such as cardiovascular disease, type 2 diabetes or other cancers.
Nevertheless, the literature suggest that dietary intervention may be a promising approach for pre-
vention of cancers of the colon, esophagus, liver, stomach and bladder, and type 2 diabetes and car-
diovascular disease which still need to be confirmed by further well designed prospective studies and
experimental research.
© 2016 Elsevier Ltd. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 236
2. Meat consumption and cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237
2.1. Meat consumption and colorectal cancer (CRC) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237
2.2. Meat consumption and esophageal adenocarcinoma (EAC) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 240
2.3. Meat consumption and gastric cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 240
2.4. Meat consumption and liver cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 240
2.5. Meat consumption and bladder cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 240
3. Meat consumption and diabetes mellitus type 2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 241
4. Meat consumption and cardiovascular disease (CVD) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 241
5. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 242
Transparency document . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 242
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 242

1. Introduction
* Corresponding author. Toxicology Unit, Department of Clinical Sciences, Uni-
versidad de Las Palmas de Gran Canaria, Paseo Blas Cabrera Felipe s/n, 35016 Las
Palmas de Gran Canaria, Spain. Meat is an integral part of human diet and constitutes a major
E-mail address: octavio.perez@ulpgc.es (O.P. Luzardo). source of protein and fat for populations all over the world.

http://dx.doi.org/10.1016/j.fct.2016.04.008
0278-6915/© 2016 Elsevier Ltd. All rights reserved.
 L.D. Boada et al. / Food and Chemical Toxicology 92 (2016) 236e244
Although this is a food rich in saturated fat and cholesterol, its
consumption has increased considerably in recent years. Thus, for
Food and Agriculture Organization (FAO), world meat consumption
(per capita) has increased from over 30 kg per person per year in
1980 to 41 kg per person per year in 2005 (Daniel et al., 2011b;
Rohrmann and Linseisen, 2015). Even more so, in last years, over-
all meat consumption has continued to rise in developed countries,
but the demand for meat in developing countries is also on the rise,
due to increasing economic development (Speedy, 2003). In fact,
rising consumption of meat in developing countries has created a
new food revolution (Delgado, 2003). Its relevance in people's diets
in many regions of the world is justified because meat consumption
contributes to the intake of a number of vitamins and minerals such
as vitamin B, vitamin A, zinc and iron. Obviously, it is also an
important source of proteins, providing essential amino acids
(Walker et al., 2005).
The epidemiologic literature usually classifies the meat
consumed as ”red”, ”white”, and processed meat. Although it does
not exist a clear classification of meat and subtypes, in general all
meats obtained from mammals are red meats because they contain
more myoglobin than white meat (obtained from chicken or fish)
(Clonan et al., 2016). In most cases, the muscle meat from beef, veal,
pork, lamb, horse, goat, and deer is defined as ”red” meat, while
”white” meat refers to poultry. ”Processed meat” includes all types
of meat products, such as sausages, cold cuts and other meats,
which have undergone a process to extend their shelf life and
which have been mixed with ingredients such as curing salt or salt.
Although country-specific intake varies enormously for both red
meats (3.0e124.2 g/d) and processed meats (2.5e66.1 g/d), overall,
processed meat intakes have been stable over time on a global level
(1990e2010), whereas red meat intake has increased during this
period (Micha et al., 2015). Nevertheless, not all types of prepara-
tions of meat can reliably be allocated to a group, and the selected
definitions may vary from those used in individual studies.
Although meat is consumed on a regular basis by the majority of
the population, there is concern raised by many observational
studies that high intake of red and/or processed meat is associated
with chronic diseases such as obesity, type 2 diabetes, cardiovas-
cular disease, and a variety of cancers (Klurfeld, 2015). Thus, a
recent meta-analysis indicates that higher consumption of red
meat and processed meat is associated with an increased risk of
total, cardiovascular, and cancer mortality (Wang et al., 2015b). It is
well known that among factors that contribute to the onset of
cancer, around 95% are environmental factors, encompassing as
pivotal pillars lifestyle (tobacco, alcohol, physical activity, and diet),
external stimuli (radiation, pollution, infections, etc.), while in-
heritance account only for 5% of tumors (Baena Ruiz and Salinas
Hernandez, 2014). In this scenario, although red and processed
meat consumption has been linked to the risk of various cancers
and other health outcomes (Table 1), the type of cancer that is best
studied in relation to meat consumption is colorectal cancer (CRC).
2. Meat consumption and cancer
As cited previously, nowadays the consumption of red meat has
been linked to the increased incidence of CRC (Kim et al., 2013), but
also to cancers of the esophagus (Zhu et al., 2014), gastric cancers
(Zhu et al., 2013), liver cancer (Freedman et al., 2010), and bladder
cancer (Lumbreras et al., 2008). Other cancers have also been
related to meat consumption but less consistently, such as tumors
of the pancreas, prostate, kidney, lung, breast, and non-Hodgkin
lymphoma (Abid et al., 2014; Alexander et al., 2010; Inoue-Choi
et al., 2016; Lumbreras et al., 2008; Pericleous et al., 2014; Yang
et al., 2015). On the contrary, poultry and fish intake has been
associated with lower risk of digestive and respiratory cancers
237
(Daniel et al., 2011a). In prospective studies in populations showing
higher intake of poultry and fish (that coincides with lower intake
of red meat), an inverse associations for cancers of the esophagus,
liver, colon, rectum, anus, lung, and pleura were observed (Daniel
et al., 2011a).
2.1. Meat consumption and colorectal cancer (CRC)
Numerous caseecontrol and cohort studies have evaluated the
relation between meat consumption and higher CRC risk, and most
of those studies indeed observed such a positive association. In
1996, the Colon Cancer Panel of the World Health Organization
Consensus Conference on Nutrition in Prevention and Therapy on
Cancer concluded that consumption of red meat and processed
meat was probably associated with increased risk for CRC and
recommended that consumption of fish and poultry should be
preferred to red meat (Scheppach et al., 1999). More recently, in a
summary evaluation of the studies published thus far, the World
Cancer Research Fund in 2007 came to the conclusion that high
consumption of red meat and processed meat were convincingly
associated with CRC risk (WCRF, 2007). This was confirmed in the
2011 updated report: per 50 g increase in daily processed meat
consumption, the relative risk (RR) increased by 18% (95% CI
1.10,1.28); per 100 g increase in daily red meat consumption, the RR
increased by 17% (95% CI 1.05, 1.31) (WCRF, 2011). Underlining this,
the International Agency for Research on Cancer (IARC) recently
declared that there is sufficient evidence in human beings for the
carcinogenicity of the consumption of processed meat although the
evidence for the carcinogenicity of the red meat is limited (Bouvard
et al., 2015). Consequently, it has been recommended a restriction
of red and/or processed meat intake (Klurfeld, 2015). Therefore,
different International Agencies and independent researchers have
done recommendations of maximum meat intake to minimize the
risk. Thus, for the prevention of cancer, the American Cancer So-
ciety specifically advises limiting intake of red and processed meats
and choosing fish and poultry instead of beef, pork or lamb (Kushi
et al., 2006). In addition, in a recent market basket-based study, the
authors recommended to diminish the monthly consumption of
meat and charcuterie products to reduce the carcinogenic risk
associated to the consumption of these foods for consumers,
although in this case, due to the environmental carcinogens present
in meat and derivatives (Hernandez et al., 2015a).
As CRC is the third most common cancer worldwide following
lung and breast cancer, and the fourth most common cause of
cancer death after lung, stomach, and liver cancer, identifying
strategies to reduce its incidence is critical for Public Health Au-
thorities (Ferlay et al., 2010). As for other cancers, it has to be
highlighted that the vast majority of CRC cases have been linked to
environmental causes rather than to heritable genetic changes
(Demeyer et al., 2015). The highest CRC incidence has been reported
in European countries, North America and Oceania, where the
incidence rate reaches 44.8 cases per 100,000 in men and 32.2
cases per 100,000 in women. On the contrary, Western Africa has
the lowest rate with 4.5 cases and 3.8 per 100,000 people in men
and women, respectively. This variability highlights the relevant
role potentially played by environmental factors in CRC, being the
diet the most important risk factor in addition to age, male sex and
hereditary factors, which are responsible for 35% of CRC (Baena and
Salinas, 2015).
In this context, the high meat/low vegetable intake is considered
the reference high-risk diet for CRC. Even more so, vegetarian diets
seem to be associated with an overall lower incidence of CRC.
Although studies evaluating CRC risk in vegetarians and vegans
have yielded inconsistent and mixed results, “vegetarians” who eat
fish in particular have been reported to have the lowest risk
238 L.D. Boada et al. / Food and Chemical Toxicology 92 (2016) 236e244

Table 1
Main scientific references cited in the text linking meat consumption with cancer and other health outcomes.

Author/Institution Type of study Year Conclusion

Colorectal cancer
WHOa Report 1996 White meat consumption is recommended instead of red/processed meat
WCRF Report 2007 Red meat/processed meat CRC
WCRF Report 2011 Processed meat > red meat associated to CRC risk
Aune et al. Meta-analysis 2013 Increased CRA risk associated to processed/red meat
IARC Report 2015 CRC risk for processed meat sufficient
CRC risk for red meat limited
Carr et al. Meta-analysis 2015 Beef and lamb (red meat) associated to CRC risk
Esophageal cancer
Salehi et al. Meta-analysis 2013 Processed meat increased EAC risk
Lin et al. Case-control 2015 Processed meat associated to ESCC risk
Petrick et al. Review 2015 Processed/Red meat associated to EAC risk
Gastric cancer
Larsson et al. Meta-analysis 2006 Processed meat increased GC risk
WCRF Report 2007 GC risk for meat insufficient
Zhu et al. Meta-analysis 2013 Processed meat > red meat associated to GC risk
Liver cancer
Cross et al. Cohort 2007 Red meat associated to LC risk
Bladder cancer
Li et al. Meta-analysis 2014 processed meat might be associated to BC risk
Diabetes mellitus type 2
Pan et al. Cohort/Meta-analysis 2011 Processed > red meat associated to DM2 risk
Lajous et al. Cohort 2012 Processed meat associated to DM2 risk
Bendinelli et al. Cohort 2013 Red > total meat associated to DM2 risk
Battaglia Richi et al. Review 2015 Processed > red meat associated to DM2
cardiovascular disease
Kaluza et al. Meta-analysis 2012 Processed/Red meat associated to stroke

Abbreviations: WCRF, World Cancer Research Fund; IARC, International Agency for Research on Cancer; ESCC, esophageal squamous-cell carcinoma; EAC, Esophageal
adenocarcinoma; CRA, colorectal adenoma; CC, colorectal cancer; EC, esophageal cancer; GC, gastric cancer; LC, liver cancer; BC, bladder cancer; DM2, Diabetes mellitus type 2.
a
Colon Cancer Panel of the World Health Organization Consensus Conference on Nutrition in Prevention and Therapy on Cancer.

(compared with non-vegetarians) (Gilsing et al., 2015; Orlich et al.,
2015).
In any case, other risk dietary patterns are emerging, such as
high intakes of processed meat and refined carbohydrates
(Boutron-Ruault et al., 1999). Thus, the strong association with
refined cereal products is consistent with the hypothesis of a role of
hyperinsulinism in colorectal carcinogenesis proposed by certain
authors (Alaejos et al., 2008; Boutron-Ruault et al., 1999), and also
with other studies showing a non-fully consistent relationship
between changes in regulation of energy homeostasis and obesity
and CRC. In this sense, it is worth mentioning that in general, men
have greater risk for CRC in comparison to women, and it has been
suggested that this may be related to the greater tendency to store
fat in abdomen in men than in women (Davoodi et al., 2013).
Obesity has been associated with increased risk of CRC, and insulin
resistance and hyperinsulinemia (due to the fact that insulin
stimulates proliferation and growth of cells and inhibits apoptosis)
have been considered as important underlying mechanisms linking
obesity, sedentary life and certain dietary habits to CRC (Yoon et al.,
2015). A recent meta-analysis suggested that higher levels of in-
sulin, C-peptide, and HOMA-IR were significantly associated with
increased risk of colorectal adenoma independently of adiposity,
thus suggesting that insulin resistance and hyperinsulinemia could
contribute in part to the described association between obesity and
CRC risk (Yoon et al., 2015). Thus, chronic hyperinsulinemia could
promote colorectal carcinogenesis by several mechanisms, such as
the increase of insulin-like growth factor-1 (IGF-1) bioavailability,
the stimulation of ovarian androgen synthesis and growth hor-
mone receptor expression, or the inhibition of the production of sex
hormone binding globulins (SHBG) and IGF-1 binding proteins. In
addition to these mechanisms, it has been also described that
environmental carcinogens found in meat could modulate IGF-1
serum values, and therefore might influence the carcinogenic
processes in the colorectal tissue (Boada et al., 2007; Luzardo et al.,
2012; Zumbado et al., 2010). Although this point need to be
explored in depth, several meta-analyses consistently demon-
strated that hyperinsulinemia and insulin resistance, marked by
higher levels of circulating insulin and C-peptide, were associated
with increased CRC risk (Chen et al., 2013; Chi et al., 2013).
Nevertheless, other mechanisms have been proposed to explain
the causal association between the consumption of red meat/pro-
cessed and cancer risk (mainly, CRC). Thus, for red meat (consid-
ering as such the meat mainly from cattle, sheep, pigs, lamb, beef
and goats), it has been proposed a role attributable to the oncogenic
effects of heme iron (Kim et al., 2013). Thus, it has been suggested
that heme iron could initiate carcinogenesis through lipid peroxi-
dation processes (Bastide et al., 2015). In addition to this, the role of
other carcinogens usually found in meat has been also explored.
Thus, heterocyclic amines (HAAs) and polycyclic aromatic hydro-
carbons (PAHs) that are found on the surface of well-done (charred)
meat have been proposed as initiators of the carcinogenic process,
particularly as it has been demonstrated that these chemicals in-
crease in meat when it is cooked at high temperature for a long
time or it is directly exposed over an open flame (Sinha et al., 1994).
However, HAAs require bioactivation by N-acetyltransferase 2
(NAT2): HAA-metabolites are substrates for O-acetylation primarily
by NAT2 to form the reactive N-acetoxy species that are able to bind
to DNA, and therefore polymorphisms of the genes implicated
could be also involved in this process. On the other hand, it has
been proposed that red meat intake also enhances the exposure to
other promoters of cancer (and possible carcinogens) such as N-
nitroso compounds (NOCs) (Norat et al., 2002). Although experi-
mental evidence is limited, it has been postulated that these
chemicals linked to high meat consumption, could be not absorbed
by the small intestine and thus transferred into the large intestine
lumen, having deleterious effects on epithelial cells of the colon
when are present in excess (Kim et al., 2013). In terms of geno-
toxicity and metabolic disturbances, these compounds may be
 L.D. Boada et al. / Food and Chemical Toxicology 92 (2016) 236e244
either directly active or after conversion to metabolites by the
microbiota. Nonetheless, all the previously cited compounds might
also act synergistically in increasing CRC risk (Blachier et al., 2007).
For processed meats (defined as meat preserved by smoking,
curing or salting or by the addition of chemical preservatives), their
usually high content in nitrates, converted to carcinogenic nitro-
samines, has been proposed as one of the major links with cancer
risk (Joosen et al., 2009). The ingested nitrate is reduced to nitrite
by the bacterial flora in the mouth and digestive tract. In turn, ni-
trite reacts with amines, amides and other nitrosation precursors in
the gastrointestinal tract to form NOCs, and most NOCs are potent
animal carcinogens (IARC, 1978). In addition, it has been described
that processed meat consumption increased the probability of
having detectable levels of dioxin-like polychorobiphenyls (DL-
PCBs), a well-known group of carcinogenic chemicals (Boada et al.,
2014). In any case, independently of the chemical o mix of chem-
icals involved, there is a large amount of data showing consistent
associations of CRC with consumption of processed meat in
different populations, and that this risk is even higher than that of
the unprocessed red meat. Even more, in a recent report summa-
rizing evidence of the European Prospective Investigation into
Cancer and Nutrition Study (EPIC) involving 448,568 men and
women, Rohrmann et al. (2013) concluded that all-causes mortality
was significantly related only to processed red meat and not to red
meat intake (Rohrmann et al., 2013).
As reported above, the carcinogenic potential of meat and de-
rivatives may be highly modulated by the presence in meat and
processed meat of a number of carcinogenic environmental pol-
lutants, such as DL-PCBs, organochlorine pesticides, and especially
PAHs (Domingo and Nadal, 2016; Hernandez et al., 2015a, 2015b).
In any case, as in all carcinogenic processes, the development of CRC
is a multistep process and individual compounds present in meat
may not be the only responsible for the potential carcinogenic ef-
fect, and other active or modulatory agents could also be respon-
sible or contributors for the biological effect.
As for other cancers, the relevance of gen/environment in-
teractions should be also taken into account in the reported asso-
ciation between meat intake and CRC, which would explain, at least
partially, the specific geographical distribution of the disease. Thus,
the differential distribution could be determined, not only by the
differential pattern of consumption of meat, but also by the dis-
tribution of acetylation phenotypes across the populations all over
the world. For instance, as mentioned above NAT2 is involved in the
bioactivation of HAAs, and more than 25 genetic polymorphisms
have been identified for NAT2, that therefore may have different
effects on such activation. In this sense, it should be noted that the
frequency of the slow NAT2 phenotype varies dramatically among
populations, from approximately 5% in Canadian Inuit, to 10% in
Japanese, 50% in Europeans and 90% in North Africans. It is notable
that populations with the highest frequencies for the rapid acety-
lation phenotype (Native Alaskans and Japanese Americans) also
have the highest CRC incidence rates in the world, and those with
the lowest rapid acetylation phenotype frequencies have very low
CRC rates (e.g., in North African population) (Wang et al., 2015a). In
the same way, a recent ecological study has shown that NAT2
phenotype significantly improved the international correlation that
exists between country-specific meat consumption and CRC inci-
dence (Ognjanovic et al., 2006). Although the documented rela-
tionship among acetylation capability, meat intake and CRC seems
to be plausible, and a number of studies have suggested a strong
association between CRC and red meat consumption among in-
dividuals with the rapid NAT2 phenotype, these results are not
considered to be consistent enough, because of the heterogeneity of
the studies, the possibility of biases derived of the assumption that
infers NAT2 activity directly from genotype, the selection of the
239
study populations, sample sizes, or analysis strategies employed in
such studies.
In contrast to red and processed meat (which is mainly pro-
duced from red meat), white meat has not been associated with
increased risks for CRC (Larsson and Wolk, 2006). This difference
was proposed to be mainly due to the absence of endogenous for-
mation of intestinal carcinogenic NOCs. In controlled dietary
intervention studies, intake of red meat, but not white meat, has
been shown to increase endogenous formation of NOCs in a dose-
response manner (Norat et al., 2002). It has been suggested that
this effect is mediated by heme iron, which is highly abundant in
red meat (Cross et al., 2010).
We must bear in mind that the main determinant of the reddish
color of the flesh, and therefore responsible for its classification as
red meat, is the concentration of myoglobin, which can be up to 2%
in the case of ox or lamb meat, and much lower in pork and veal
(Carr et al., 2016b). Thus, if the potential carcinogenic effect of red
meat is driven by the above mentioned carcinogenic potential of
the heme iron, the risk might vary according to red meat subtype
consumed. However, studies evaluating individual associations
between specific red meat subtypes and risks for CRC are scarce and
with controversial results. Nonetheless, a recent meta-analysis has
summarized the overall epidemiological evidence related to meat
subtypes, and has reported that beef and lamb consumption is
associated with an increased CRC risk (RR 1.11, 95% CI 1.01 to 1.22;
and RR 1.24, 95% CI 1.08 to 1.44, respectively), while no association
was observed for pork (RR 0.95, 95% CI 0.78 to 1.16) (Carr et al.,
2016b).
Because CRC risk factors, clinic pathological features, incidence
rates, stage at diagnosis, prognosis, and response to risk factors
and to treatment may vary across anatomic sub-sites, it is
necessary to evaluate if the association between meat intake and
CRC is homogenous in all CRC sub-sites. To date, evidence on the
relation between red meat and CRC risk by sub-site location is
scarce. In fact, although only a limited number of studies have
investigated such a relation (i.e. rectal vs. proximal, defined as
extending from the cecum up to the splenic flexure, and vs. distal
colon, that includes the descending and the sigmoid colon and the
recto-sigmoid junction). In a meta-analysis of three cohorts by
Larsson and Wolk (2006) the authors observed that associations
for red meat tend to be stronger for rectal cancers, whereas pro-
cessed meat associations were stronger for distal colon cancers
(Larsson and Wolk, 2006). Nevertheless as mentioned the data are
scarce and future studies are needed to elucidate potentially
distinct mechanisms underlying the relationship between the
intake of processed meat and unprocessed red meat and CRC
subtypes risk. In addition, it has been recently suggested that the
duration (time) of the high meat consumption could be a relevant
factor in the association between CRC and meat intake although
the results are inconclusive, recent processed meat intake within
the past four years has not been associated with risk of distal
colon cancer (Bernstein et al., 2015). However, more studies are
necessary because scarce information exists regarding time of
intake and CRC risk.
In conclusion, most studies indicate that a significant and pos-
itive association exists between CRC risk and high intake of pro-
cessed meat, although there is less evidence that high intake of
unprocessed red meat be substantially associated to CRC risk.
Nevertheless unprocessed or processed meat intake does not seem
to be associated with poorer survival among patients with CRC
(Carr et al., 2016a). In any case, it is advisable to follow the rec-
ommendations for consumption of processed red meat based on
the epidemiological evidence and the available scientific literature,
as those published by the World Cancer Research Fund (WCRF,
2007).
240 L.D. Boada et al. / Food and Chemical Toxicology 92 (2016) 236e244
2.2. Meat consumption and esophageal adenocarcinoma (EAC)
Esophageal adenocarcinoma (EAC) incidence has experienced a
fivefold increase from the 1970s to the present, and it has become
the main esophageal malignancy in many Western countries.
Although the role of diet and lifestyle habits in this cancer is not
well defined, and their role in relation to other risk factors is yet to
be investigated, there is, however, an increasing amount of evi-
dence highlighting the role of dietary habits in the development of
EAC, especially in relation to the consumption of animal-derived
proteins and high glycemic index foods (Realdon et al., 2015;
Thrift and Whiteman, 2012). Thus, a high incidence of esophageal
squamous-cell carcinoma (ESCC) has been recently linked to con-
sumption of processed meat (Lin et al., 2015). However, findings
from previous studies on the associations between processed meat
and tumors of the esophagus were not fully consistent. For
example, a recent literature review reported that processed meat
was significantly associated with EAC, but not with ESCC (Salehi
et al., 2013).
In summary nowadays, although there is only limited evidence
that processed meat consumption could be a risk factor for EAC, it
has been suggested that the reduction/omission of processed (and
red) meat intake could be useful to reduce development of the
disease (Daniel et al., 2011a; Petrick et al., 2015).
2.3. Meat consumption and gastric cancer
Although the incidence of gastric cancer has decreased steadily
over the last 50 years worldwide, the malignancy remains the
second leading cause of cancer death globally (Carr et al., 2013; Zhu
et al., 2013). In this scenario, identification of risk factors potentially
involved in the development of this disease is essential. Among the
factors that could play a remarkable role in the morbidity and
mortality of this cancer the infection with Helicobacter pylori is a
well-established risk factor for non-cardia gastric cancer. However,
only a small proportion of those infected with H. pylori go on to
develop gastric cancer (Jemal et al., 2010), suggesting the contri-
bution of other risk factors.
The decline in incidence rates of gastric cancer has been
attributed, at least in part, to improvements in diet and food storage
and, in particular, the introduction of refrigeration, because
refrigeration has reduced the need for salt and other methods of
food preservation. In fact, increased consumption of “old-style”
processed meat (mainly bacon) has been associated with an
increased risk of gastric cancer (Larsson et al., 2006b). In addition,
the results of a recent meta-analysis performed by Zhu et al. (2013)
indicated that red and processed meat seemed to be associated
with a 45% increase of gastric cancer risk when the highest reported
intake was compared with the lowest, being, high beef, bacon, ham
and sausage consumption associated with increased gastric cancer
risk, while no association was found with pork, indicating that meat
type probably play a role (Zhu et al., 2013).
Although the biological mechanisms for this association are
unknown, as in the case of CRC, heme iron content has been
involved as potential factor influencing the association between red
and processed meat intake and gastric cancer. As indicated above,
heme iron is much more abundant in red meat than white meat
(Cross et al., 2003), and the same reasons indicated for CRC would
also help to explain why the meat type could play a role in carci-
nogenic processes in the stomach. In this sense, the influence of the
heme content of meat (particularly red meat) may sum up to the
endogenous formation of carcinogenic NOCs, which are formed in
processed meat containing high amount of salt and/or nitrates
(Tricker, 1997), and to other carcinogens usually found in meat,
such as the above mentioned HAAs and PAHs. To date several
epidemiologic studies have reported a statistically significant pos-
itive association between the intake of nitrosamines and gastric
cancer risk (La Vecchia et al., 1995; Larsson et al., 2006a). However
the additive effects of several carcinogens should be also
considered.
Nonetheless, it is also possible that the relationship between
processed meat consumption and gastric cancer risk could be
restricted to certain subgroups of the population, as also occurs in
the case of CRC. In this case a population-specific gradients could be
related to specific genetic polymorphisms coding for enzymes
involved in the metabolism of NOCs, or with those people, which
are infected with H. pylori (Gonzalez et al., 2006). Nevertheless, a
comprehensive review by the World Cancer Research Fund
concluded that the evidence of the association between meat
intake and gastric cancer was insufficient (WCRF, 2007).
In conclusion, a number of studies suggest that meat intake
could be associated with higher gastric cancer risk, and that this
association seems to be stronger for processed meat. However,
although an association between processed meat consumption and
gastric cancer risk is biologically plausible, epidemiologic studies
on this relationship have yielded inconsistent results to date. Thus,
the increased association between red meat and gastric cancer risk
still needs evidence from well-designed prospective cohort studies.
2.4. Meat consumption and liver cancer
In addition to esophagus, stomach, colon and rectum, meat
intake has been associated with an elevated risk of liver cancer. In
this case the evidences have been for red, but not processed meat.
Hepatocellular Carcinoma (HCC) is one of the most common can-
cers worldwide. The major risk factors for HCC are hepatitis B or
hepatitis C infection, cirrhosis and aflatoxin contamination of food,
although other factors such as alcohol drinking, obesity, smoking
and diabetes were also found to be associated with increased risk of
HCC (Yeh et al., 2015). Considering the rising incidence of HCC,
especially in Europe and North America, identifying of new risk
factors and protective factors is important for HCC prevention, as
will provide new approaches and strategies to lowering its inci-
dence (El-Serag, 2011). As for other gastrointestinal cancers, a
number of epidemiological studies have shown that dietary factors
are closely correlated with liver cancer, and a healthy diet is known
to reduce the rates of liver cancer (Venook et al., 2010).
In any case, data on meat intake and cancers of the liver are still
limited. A positive association between red meat intake and liver
cancer was found in the prospective National Institutes of Health
(NIH)eAARP Diet and Health Study (Cross et al., 2007). It is worth to
note that red meat is an important dietary source of saturated and
monounsaturated fatty acids, and that fatty acid deposition in the
liver can lead to nonalcoholic fatty liver disease, which in turn may
increase the risk of chronic liver disease and HCC (Freedman et al.,
2010). However, other epidemiological studies did not found any
association between red meat/processed meat with HCC risk.
Nevertheless, a number of studies suggest that a vegetable-based
dietary pattern is associated with reduced liver cancer risk
(Zhang et al., 2013), and that a high level of white meat or fish
consumption can also reduce the risk of HCC (Luo et al., 2014).
These studies suggest that dietary intervention may be a promising
approach for prevention of HCC, which still need to be confirmed by
further well-designed prospective studies and experimental
research findings.
2.5. Meat consumption and bladder cancer
Worldwide, bladder cancer is recognized as the ninth most
common cancer, with statistics showing 357,000 newly diagnosed
 L.D. Boada et al. / Food and Chemical Toxicology 92 (2016) 236e244
cases and 145,000 related deaths for both genders in 2002 (Parkin
et al., 2005). Several epidemiologic studies have demonstrated the
importance of environmental components (i.e., diet) affecting the
occurrence of this type of cancer (Cohen and Johansson, 1992),
although the best known risk factors for lower urinary tract cancer
include cigarette smoke and occupational exposures to aromatic
amines (Lumbreras et al., 2008).
Meat intake has been suspected of being a risk factor for bladder
cancer, but the results of the studies conducted so far are contra-
dictory (Steinmaus et al., 2000). Thus, elevated rates of bladder
cancer were found among subjects who had the most frequent
intake of meat compared to those with the least daily intake rate
(Chyou et al., 1993). On the contrary, other epidemiological studies
found an inverse association between bladder cancer risk and meat
intake (Riboli et al., 1991). A recent meta-analysis evaluating 14
studies on red meat and 11 studies on processed meat concluded
that there was an absence of an association between red meat
intake and bladder cancer, but suggested that high consumption of
processed meat probably correlated with rising risk of bladder
cancer (Li et al., 2014).
It has been argued that the effect of meat intake on bladder
cancer could be due to the already mentioned presence of HAAs in
meat, when it is cooked at high temperatures, as well as to the
presence of other known carcinogens, such as dioxin-like PCBs or
carcinogenic PAHs (Boada et al., 2015). A number of studies linking
particular genotypes of enzymes involved in the metabolism of
HAAs and bladder cancer risk reinforce such possibility (Henriquez-
Hernandez et al., 2012). As previously discussed for CRC, HAAs
require enzymatic activation to achieve their biological effects, and
the involvement of N-acetyltransferases (NAT), for which several
polymorphisms have been described in humans. Therefore, as for
the rest of cancers discussed in this review, genetic variations in the
genes encoding these metabolic enzymes might contribute the
inter-individual variations of genetic susceptibility to bladder
cancer (Hein et al., 2000). In this sense, Lumbreras et al. (2008)
stated that exposure to HAAs through the consumption of meat
may be a bladder cancer risk factor among subjects with the NAT2
rapid genotype (Lumbreras et al., 2008).
In summary, although the evidence of the association between
meat intake and bladder cancer is limited, the ubiquitous exposure
to HAAs (and other environmental carcinogens) through cooked
meat consumption or processed meat together with high frequency
of the NAT2 rapid acetylation polymorphism in human populations
suggests that meat intake (mainly processed meat, and mainly due
to the presence of HAAs) must be taken into account as a risk factor
for bladder cancer.
3. Meat consumption and diabetes mellitus type 2
Recent evidence from the epidemiologic literature suggests that
the increasing consumption of red meat, especially in its processed
forms, may be related to the increasing rates of type 2 diabetes
mellitus in the world, especially in Western countries (Battaglia
Richi et al., 2015). Thus, Pan et al. (2011) stated that the risk of
suffering type-2 diabetes increased with consumption of processed
red meat (Pan et al., 2011). According to this study the hazard ratio
for diabetes increased by 51% [95% CI 25e83%] per 50 g of processed
red meat per day per person. For unprocessed red meat the hazard
ratio for diabetes was lower, 19% [95% CI 4e37%] per 100 g per
person per day.
On the other hand, the EPIC InterAct Study also found a signif-
icant correlation between new cases of diabetes and the con-
sumption of red meat in a large European cohort. According to this
study a 50 g per day increase in the consumption of red and pro-
cessed meat predicted an increase in risk of 8% [95% CI 5e12%] and
241
12% [95% CI 5e19%], respectively, in a 12 years period follow-up
(Bendinelli et al., 2013; Langenberg et al., 2012). Consistently with
these results, the French E3N study pointed in the same direction
showing a clear association between the risk of new diabetes and
consumption of processed red meat, but not with unprocessed red
meat (Lajous et al., 2012). In addition, results of observational
studies also demonstrate the protective effect of high fiber and
coffee intake and reduced red meat consumption on type 2 dia-
betes mellitus risk, reinforcing such associations (Yoon et al., 2015).
Several hypotheses have been proposed to explain the epide-
miological findings that associate high meat intake ratios and type-
2 diabetes. Thus, greater consumption of meat, mainly processed
meat, could decrease insulin sensitivity because of its high protein
and fat content. In fact, both amino acids and fatty acids can
enhance insulin secretion and thereby counteract a reduction in
insulin sensitivity (Krebs et al., 2003; Roden et al., 2000). On the
other hand, both amino acids and fatty acids may also inhibit in-
sulin action via mTOR (a serine/threonine protein kinase that reg-
ulates cell growth, cell proliferation, cell motility, cell survival,
protein synthesis, autophagy, and transcription), toxic lipid in-
termediates, inflammatory pathways or oxidative stress (Simcox
and McClain, 2013). In this scenario it has to be highlighted that
elevated branched chain amino acids can also play a relevant role
on the incidence of type 2 diabetes (Newgard, 2012).
In summary, although currently the role played by meat con-
sumption on DM2 is not well-known (mainly because the absence
of controlled trials reporting the effect of red meat consumption on
insulin sensitivity and glucose metabolism), evidence from epide-
miological studies leads to the conclusion that long-term con-
sumption of increasing amounts of red meat and particularly of
processed meat may result in a certain increase in the risk of type 2
diabetes. As a consequence the restrictive recommendations for
consumption of processed red meat that have been made to pre-
vent cancer incidence, may be also valid to prevent type-2 diabetes.
4. Meat consumption and cardiovascular disease (CVD)
Among many well-known factors influencing the risk of car-
diovascular diseases (CVD), including ischemic heart disease, diet
has an important role (Levitan et al., 2009). Red meat intake is
commonly considered a risk factor for CVD because of its saturated
fat and cholesterol contents (Rohrmann and Linseisen, 2015). In
fact, the epidemiological studies developed in US populations, the
”Health Professionals Follow-up Study” and the ”Nurses' Health
Study” have demonstrated a significant increase in cardiovascular
mortality with increasing consumption of unprocessed red meat
(18% increase per serving) and of processed red meat (21% increase
per serving) (Micha et al., 2010). In addition, high consumption of
red and processed meat seems to be related to increased risk of
coronary heart disease and stroke, as well as increased CVD mor-
tality (Kaluza et al., 2012; Pan et al., 2012). In this sense, the meta-
analysis performed by Micha et al. (2010) found a significantly
positive association of processed meat intake with coronary heart
disease (RR ¼ 1.42; 95% CI 1.07, 1.89 per 50 g increase in daily
consumption), but not with consumption of unprocessed red meat
(RR ¼ 1.00; 95% CI 0.82, 1.23). However the association between
meat intake and cardiovascular disease has not been fully estab-
lished and need to be explored in depth, because in many studies
no significant associations have been observed (Abete et al., 2014).
Several hypotheses have been formulated to explain the po-
tential association of meat intake (mainly processed meat) with the
risk of CVD. For instance, the addition of salt or preservatives to
meat for conservation purposes may increase the sodium and ni-
trate content of meat (processed meats could contain about 400%
more sodium and 50% more nitrates per g, although this depends
242 L.D. Boada et al. / Food and Chemical Toxicology 92 (2016) 236e244
strongly on the type of meat and the methods used) (Linseisen
et al., 2006). Furthermore, processed meats such as sausages,
have a higher content of saturated fatty acids and cholesterol than
fresh red meat; reaching the proportion of fat in sausages more
than 50% of weight. The possibility exists that unprocessed and
processed meats have differential relationships with car-
diometabolic outcomes, and that differences in fats and preserva-
tive contents could, at least partly, account for these differences
(Lajous et al., 2014). Future research should separately consider
potential adverse health effects and underlying mechanisms of
unprocessed vs. processed meats.
Nevertheless, current clinical and policy efforts should espe-
cially focus on reducing processed meat consumption as specif-
ically advocated by the American Heart Association's 2006 Dietary
Recommendations and 2020 Impact Goals (Lichtenstein et al.,
2006; Lloyd-Jones et al., 2010).
5. Conclusion
The main conclusion of this review is that the available evidence
confirms that there is enough epidemiological evidence linking
processed meat intake and CRC risk (Table 1). However, there is
limited evidence regarding unprocessed red meat intake and the
disease, and also the evidence is limited about the link of meat
intake with other diseases such as cardiovascular disease, type 2
diabetes or other cancers. Nevertheless, the revised literature
suggest that dietary intervention (mainly reducing processed meat
intake) may be a promising approach for prevention of cancers of
the colon, esophagus, liver, stomach and bladder, and type 2 dia-
betes and cardiovascular disease.
Limitations in the present review should be acknowledged. For
many issues concerning meat intake and cancer, the evidence is not
definitive, and the published studies are contradictory. In addition,
the assessment of epidemiological studies itself involves risk bias
assumptions because of the heterogeneity of the studies. Un-
doubtedly, further researches will be needed in the future since in
some important issues the potential association between meat
intake and health outcomes remains unclear.
Transparency document
Transparency document related to this article can be found
online at http://dx.doi.org/10.1016/j.fct.2016.04.008.
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