Where Do We Stand on Red Meat Consumption and Human Health?

In 2015, a Working Group of the International Agency for Research on Cancer [IARC] classified ‘processed meat’ as a Group 1 carcinogen, concluding that a review of epidemiological and supporting population-based case-control studies provided ‘sufficient evidence’ that high consumption of processed meat causes colorectal cancer [1]. The IARC concluded that consumption of ‘red meat’ lacked clear associations with colorectal cancer in high quality studies, and thus limited evidence for carcinogenicity of red meat; factoring in mechanistic studies, however, the Working Group classified red meat consumption as ‘probably carcinogenic to humans’ [1].

It’s important to define what differentiates ‘red meat’ and ‘processed meat’. Red meat includes unprocessed mammalian muscle meats from beef, veal, lamb, mutton, pork, or goat meat, which is typically consumed cooked [1]. Processed meat includes the use of methods like salting, curing, smoking or other industrial processes to enhance flavour and preservation [1]. “High” consumption is defined as >200g/d, while the mean intake for meat eaters is 50-100g/d [1].

To be classified as “carcinogenic to humans”, the IARC prioritizes epidemiological studies, supported by population-based case-control studies, which have to accumulate to a point where there are ‘consistent associations…in different populations, which make chance, bias, and confounding unlikely as explanations…’ for the results other than that the agent – in this case processed meat – causally increases risk for cancer [1].

For the purposes of this article, ‘red meat’ as defined by the IARC will be referred to as unprocessed meat. Processed meat will retain its IARC definition.

 

But Association Isn’t Causation?

This is true. But the statement should never be used to summarily dismiss an observation. Observational epidemiology has provided the “proof” for causation in relation to cancer before, with regard to cigarette smoking: we didn’t wait for randomised controlled trials to prove smoking causes cancer.

Observational epidemiology is a powerful tool in health sciences, so if we can “convict” smoking using this tool, why can’t we do the same for meat? Because diet is a complex interplay of multiple factors and variables. Cigarettes, on the other hand, are a clearly identifiable agent that increase risk independent of other variables like diet, BMI, age, and lifestyle. In light of sensationalist media headlines following the IARC decision, it’s important to reemphasize the recent publication in the International Journal of Cancer that “meat consumption is not tobacco smoking” [2].

One of the primary issues with the IARC analysis is the lack of clear associations from the studies with diet patterns as a whole. The limitations of looking at single nutrients or standalone foods in relation to multifactorial disease processes, without regard to the overall diet pattern, is now a recognized issue in nutrition science [3]. This is particularly relevant to the role of meat in the diet, as high levels of processed meat are inversely associated with overall diet quality, in particular low intakes of fibre, vegetables and fruit, and greater likelihood of smoking [4][5].

An example of this issue can be seen in meat eaters’ diametrically opposed paradigm: vegetarianism. Several recent epidemiological studies have failed to find that vegetarian diets reduce risk of colorectal cancer, total cancers, or all-cause mortality compared to non-vegetarian diets [6][7]. Have vegetarian diets suddenly become a risk factor? No, these studies are highlighting limitations in how we quantify disease risk relative to dietary exposure. For example, in the Oxford-EPIC study in the U.K., subjects were divided according to 4 strata: those who ate meat, fish but no meat, dairy and/or eggs but no meat or fish, and no animal produce at all [6]. Colorectal cancer rates overall in the cohort were 13% lower than the national average, but interestingly vegetarians in this cohort had rates of colorectal cancer similar to the national average [6]. In contrast, meat eaters had a moderate mean intake – 78g and 69g for men and women, respectively – and had vegetable and fruit intake which, although less than the vegetarian groups, was still higher than average [6]. In this regard, it would appear that the diet as a whole of those who consumed meat was relatively nutritionally balanced.

What the Oxford-EPIC study is really giving us insight into is the false nutritional dichotomy that the healthfulness of a diet is defined by the presence or absence of meat. It should be emphasised that this study is not an outlier, and multiple prospective studies have found no difference in risk for colorectal cancer between vegetarians and non-vegetarians [8]. This should not be interpreted as a reflection of the respective diets, which are difficult to quantify as a whole through the methodology used in prospective studies, but as a reflection of issues with binary constructs based around meat consumption or lack thereof, and a failure to quantify key variables [9]. An example of this issue can be found in a recent large Australian cohort study, where there was no difference in all-cause mortality between vegetarian and non-vegetarian subjects [7]. Attempting to isolate the health effects of diet from other variables which the Oxford-EPIC study did not do, the researchers subcategorized non-meat eaters into vegetarians, semi-vegetarians and pesco-vegetarians; yet meat eaters were divided dichotomously by eating meat or not eating meat [7][9].

Consequently, typifying the limitation of research in this area, there were no means of quantifying meat intake relative to quality (processed vs. unprocessed), dose or frequency of consumption, or relative to vegetable and fruit intake: the subdivisions afforded to vegetarian diets have yet to be applied to meat-inclusive diets [9]. Another important observation is that defining a diet by the absence of meat gives rise to a false rebuttable presumption of healthfulness in a vegetarian diet: the authors in this study, however, were sharp to recognise that “vegetarian” defined by the absence of meat may still encompass conventional unhealthy foods in the typical Western diet [7]. Indeed, it is noted that the mere label of “vegetarian” defined simply by the absence of meat gives no indication of healthfulness of the diet pattern: refined grains, added sugars, trans fats, french fries, sodas, and sodium are all vegetarian [3].

Thus, we can see the issues with the IARC undertaking – although a noble review of over 800 epidemiological studies, together with supporting case-control and mechanistic studies – in determining the carcinogenic potential or unprocessed and processed meats. We should take their conclusions seriously, but consider them directive of a deeper analysis. In particular, the inconsistencies in relation to unprocessed meats are borne out in the population-based studies highlighted above and present a number of issues, namely:

1. The healthfulness of a diet is not dichotomous, defined by the presence or absence of red meat;
2. The diet pattern as a whole is more relevant than presence or absence of a standalone food;
3. We need to look closer at the nuances in the picture of red meat and health.

Let’s look deeper at these nuances.

 

A Closer Look at Diet Patterns

In 1978 a paper was published in the Journal of the National Cancer Institute entitled, ‘Diet in the epidemiology of cancer of the rectum and colon’ [10] in which no association was found between consumption of beef or other meat in men with colorectal cancer compared to healthy controls, but increases in risk were found with reduced frequency of vegetable consumption. The greatest reduction in risk was associated with frequent consumption of cruciferous vegetables in particular, specifically cabbage, Brussels sprouts and broccoli [10].

This paper is instructive, coming at a time where a pivotal change was occurring in the typical adult diet in Western industrialised countries. Data from the National Health and Nutrition Examination Survey [NHANES] in the United States indicates that from 1977 to 1996, the typical diet increased significantly in overall dietary energy, with the food groups contributing most to increased energy density including salty snacks, soft drinks, pizza, with significant contributions from candy, fruit drinks, french fries, cheeseburgers, and Mexican food [11]. The increase in consumption of these foods reflected an increase in the proportion of calories consumed away from home, with adults consuming up to 30% of daily energy from restaurants and fast-food establishments [11]. Of particular note, the consumption of meat consumed alone, i.e. as a meal, decreased significantly: the data showed that hamburgers and cheeseburgers consumed in 1996 were primarily consumed in a restaurant or fast-food establishment [11]. In conjunction with this shift to convenience energy-dense foods, beneficial components of diet declined significantly. Data indicates that less than 14% of US adults meet vegetable requirements, a paltry 1.5 cup per day serving is not even achieved by over 50% of the population [12].

This significant shift in diet composition is critical to evaluating the role of red meat in health, and in particular in relation to cancer. In a review of case-control studies, 67% of included studies found an inverse association between cruciferous vegetable intake and cancer risk, with the strongest evidence in relation to bowel cancers [13]. Intake of total vegetables and cruciferous vegetables in particular are significantly inversely associated with reduced risk of CVD [14]. More particularly, when we look at the prevalence of consumption of meats in restaurants or fast-food establishments, and the types of foods – cheeseburgers, hamburgers, Mexican food and pizza – it should hardly be surprising that the epidemiology in the period failing to distinguish between unprocessed and processed meat might find associations with colorectal cancer and cardiovascular disease [CVD].

This limitation has been acknowledged. A recent review of epidemiological studies published since the IARC decision confirmed that high [>50g/d] processed meat intake is strongly associated with colorectal cancer [15]. In relation to unprocessed meats, the 12-year European Prospective Investigation into Cancer and Nutrition (EPIC) study found that unprocessed red meats and white meats were not associated with increased risk for cancer or CVD [5]. Data from the 1986-2010 NHANES III in the U.S. found no associated with unprocessed meat consumption and cancer or CVD, an analysis in which the authors factored in overall diet quality, finding that the lack of association in adults regularly consuming unprocessed meat correlated with higher vegetable consumption, lower BMI and waist circumference, and lower rates of hypertension [16].

There is consistent large population-based research showing increased risk for colorectal cancer from high processed meat consumption, however, it may be more appropriate to conclude that the risk is associated with a particular overall diet pattern and lifestyle as high processed meat intake is also consistently associated with poor lifestyle and diet quality [17][4][5]. A particular interaction in the context of overall diet patterns is that of high processed meat coupled with high refined carbohydrate intake, which may influence carcinogenic mechanisms in colorectal tissues [18].

It is important to emphasise in relation to unprocessed red meat that, despite popular beliefs, rates of actual consumption in developed countries are in fact relatively modest (19). Recommendations for meat consumption in developed countries are on average 142g/d, while actual consumption is the U.S. according to NHANES III data is 49g/d [19][20]. This is consistent with an analysis of meat consumption in 14 developed countries, which showed that while intakes are variable across different countries, the intake of unprocessed red meat is consistently moderate and within recommended levels [21]. This means we have to look deeper into the underlying mechanisms at play within overall diet patterns which may dictate the healthfulness of the presence or absence of red meat.

 

A Closer Look at “Presence” Vs. “Absence”

What might be the effect of the typical Western diet pattern that implicates foods like red meat? The recent surge of research into the human microbiome has generated interesting findings in this regard. In conditions characterised by intestinal inflammation such as bowel cancer [and Inflammatory Bowel Disease], the microbiota differs in bacterial composition between healthy and diseased populations [22]. Such alterations in the microbiota are implicated in the pathogenesis of intestinal diseases, and diet has been implicated as a significant driver of these alterations [23].

The microbiome reflects human beings’ ability to respond to nutritional changes in both the short and long-term [24]. Bacteria are specialized in the fermentation of different dietary substrates, as a result food choices and diet patterns provide substrates for the selective growth of specific species [23]. The most pronounced difference in the human microbiome is driven by the presence of structurally diverse non-digestible carbohydrates, including resistant starch [RS], non-starch polysaccharides [NSP], and other prebiotic fibres which reach the colon and undergo selective microbial fermentation [25]. High intake of fibre/NSP results in a shift to increased populations of short-chain fatty acid [SCFA] producing microbes [26][27]. SCFA’s, in particular butyrate, exert anti-inflammatory effects in the colon, and are associated with inhibition of tumorigenesis, carcinogenic detoxification, and antineoplastic activity [22].

Conversely, ‘Western’ diet patterns high in total fat, refined sugar, animal protein, and low in fibre negatively impacts the microbiome to abundant levels of Firmicutes and lower Bacteroidetes, and significantly lower levels of SCFA [27]. This profile is associated with increased levels of pro-inflammatory proteobacteria, and increased secondary bile acid metabolites, which are potentially carcinogenic and increase levels of pathogenic bile-tolerant bacteria [28][29]. It’s important to look closer at this – is the issue the presence of animal protein, or lack of fibre? The detriment to high animal protein is in fact mediated by the presence or absence of fibre, and has been shown where a high protein intake is coupled with low fibre intake of 8-12g/d [30]. With fibre intake at 31g/d, no evidence of increased putrefaction, toxic metabolites, or decrease in SCFA’s was noted despite high protein [180g/d] intake [31]. Alterations in the microbiome are thus primarily associated with the presence or absence of fibre [25].

In the absence of fibre, high fat Western diets increase bile acid production which pass to the colon and undergo metabolism to secondary bile acids associated with colon cancer [22][28]. Two recent studies elegantly illustrate this issue. The first study compared the microbiome of African-Americans – a high risk-factor population for colorectal cancer – to age-matched native Africans, finding that the African-American subjects consuming a Western diet showed increased expression of microbial conversion of bile acids into pro-carcinogenic secondary metabolites, while the native Africans consuming a high-fibre/NSP diet showed an abundance of SCFA-producing bacteria and high butyrate levels [22]. The second study switched African-Americans onto the native African diet while native Africans were fed a Western-style diet: within two weeks the high-risk African-Americans displayed increased SCFA levels, reduced inflammation and other biomarkers of colon cancer, while increased risk factors were found in in the native Africans [32]. Cumulatively, this demonstrates a clear association between diet pattern and colon cancer [22][32]. These findings confirm the consistent observational epidemiology associating a dose-response between dietary fibre intake and reduced risk of colorectal cancer [33].

Another nuanced aspect to the “presence” vs. “absence” question is the effect of the low levels of vegetables, specifically cruciferous vegetables, and whole fruit intake across developed countries. What this corresponds to is a significant absence of bioactive food components that have emerged as essential for the maintenance of health and reduction of disease risk, but have traditionally been a niche research area because they were considered biologically inert [34][35]. In this respect, it is important to understand that almost all dietary carcinogens require metabolic activation – this includes heterocyclic amines [HAA], polycyclic aromatic hydrocarbons [PAH], and N-nitroso compounds [NOC] [35]. All of these compounds are specifically implicated in the role of red meat in promoting colorectal carcinogenesis [36]. Non-nutritive dietary compounds like isothiocyanates in cruciferous vegetables, organosulfur compounds in garlic and onions, catechins in green tea, flavanoids in dark pigment fruits like blueberries, and conjugated linoleic acids found in – oh, the irony! – animal produce, notably milk, yogurts and cheeses, all act as “blocking agents” which prevent the activation of potentially carcinogenic compounds ingested through diet [35]. Of particular note is the isothiocyanates in cruciferous vegetables, which have evidence from in vitro, animal, and human studies demonstrating potent carcinogenic detoxification [37][38][39]. This effect is due to the unique chemoprotective effect of monofunctional activity of isothiocyanates selectively inducing phase-II conjugate detoxification without inducing carcinogenic biotransformation through phase-I enzymes [39].

It is important to also understand that the compounds primarily associated with carcinogenic effects of meat – HAA and PAH – are not unique to red meat, but are a byproduct of cooking method and equally applicable to fish or poultry subjected to high heat [40]. One of the factors considered more specific to red meat include NOC, which are produced from nitrates and nitrites present in high concentrations in processed meat and cause DNA damage [40]. This would appear to define the difference in colorectal cancer risk between processed meat and unprocessed meat [36]. Taking risk assessment in this case as a whole, it is reasonable to state that this increase in NOC from high processed meat intake also occurs, given the associations between high processed meat and low diet quality, in the context of the absence of any protective dietary constituents.

This is particularly relevant when considering the mechanistic evidence in relation to unprocessed meat, which the IARC decided was sufficient to conclude it as ‘probably carcinogenic to humans.’ However, arguably this does not extrapolate from the mechanistic and animal models. Animal models often use levels of meat or compounds of interest at levels not representative of typical human consumption, and exclude protective bioactive food components [41]. An example of this can be seen with studies on another component of red meat – heme iron – implicated in carcinogenesis through promoting endogenous NOC formation [42]. However, calcium, vitamin C, and a-tocopherol [an isomer of vitamin E] at levels obtained through the typical human diet inhibit heme-mediated formation of endogenous NOC [43][44]. Animal studies finding a direct role for heme iron use low-calcium feeds, a misleading experimental diet given the potential protective effect of the mineral [45][40]. In a recent randomized controlled trial in humans, high red meat consumption [300g/d] was associated with increased formation of NOC, an effect that was inhibited by the SCFA butyrate achieved through supplementing the red meat diet with 40g/d high-amylose maize starch [46]. This corroborates the feeding trials in African and African-American men showing the protective effect of increasing butyrate concentrations in the colon through high dietary fiber intake [22][32].

Taken together with the data on actual meat consumption in the population, the following points can be made:

• The Western diet pattern as a whole is the risk factor, independent of red meat consumption. This is corroborated by the recent trials finding no difference in risk for colorectal cancer or CVD between vegetarians and non-vegetarians in different populations [6][7].
• The absence of vegetables from the diet – particularly cruciferous vegetables – is a greater risk for disease than the presence of meat.
• The absence of fiber from the diet is a greater risk for disease than the presence of meat.
• The absence of non-nutritive bioactive food components from the typical diet is a significant and underappreciated omission increasing risk for disease.
• Many of the aforementioned carcinogenic processes and compounds are not unique to meat, but to cooking method.

 

Can Meat Be Consumed as Part of Healthy Diet?

It’s a rare incidence in nutrition science that we have a rigorously conducted randomized controlled trial to demonstrate something, but in this case, we do. The Dietary Approaches to Stop Hypertension [DASH] Diet, was developed in the 1990’s and is a diet proven to reduce cardiovascular disease risk through specific food-based recommendations for vegetable intake, fruit, low-fat dairy, whole grains, fish, white meat, and nuts. The original DASH diet was designed to be low in total fat, saturated fat, and limited red meat.

So, what happens when you slap daily servings of red meat on top of the DASH diet? Your cardiovascular disease risk goes down, with LDL-cholesterol declining by 10% [47]. Known as the BOLD trial [Beef in an Optimally Lean Diet], subjects consumed either 113g or 153g lean red meat per day while adhering to the other DASH diet recommendations [47]. The BOLD trial reduced LDL to the same degree as the original meat-limited DASH diet, and interestingly reduced apolipoprotein B, an LDL subparticle strongly implicated in atherosclerosis, to a greater degree [47].

This confirms the central theme of this article: that the diet pattern as a whole is, and always should have been, the emphasis. In the context of a diet pattern with high fibre, whole grain, vegetable, fruit and dairy intake, the addition of unprocessed meat is not an issue.

 

Conclusions

It would be reckless to ignore the processed meat categorization on carcinogenicity in humans: the epidemiology is consistent, extensive, and supported by high quality case-control studies. It’s further supported by the mechanistic understanding of the effects of high NOC content in processed meats, which unlike unprocessed meats are pre-formed from the curing process. Limiting processed meats to <50g per day appears to be a sound judgment call having regard to the totality of the evidence [15].

In relation to unprocessed meat, however, I concur with researchers calling for a paradigm shift in dietary advice regarding red meat [48]. The most obvious element to this is the continued general advice to limit red meat consumption, notwithstanding that this simply isn’t an issue as borne in the date showing consumption in developing countries is well within range [48]. Red meat makes significant contributions to micronutrient status and associated health benefits, in particular nutrients that are absent or limited in other food groups [19]. This paradigm shift can and should occur concomitant with the other shift currently underway in nutrition science, that of moving toward a food-based advice paradigm. In this respect, people can be counselled toward benefitting from the nutrient-dense food group that is unprocessed red meat, in the context of an overall diet pattern that reduces risk of disease.

That diet pattern in sum is one which:

1. Includes moderate amounts of unprocessed beef, lamb and pork.
2. Diversifies animal protein intake to include regular consumption of oily fish and white meats.
3. Has a high – >30g/d – intake of dietary fiber.
4. Has a broad intake of whole grains and vegetables to benefit from the structurally diverse nature of indigestible fibers.
5. Is high in cruciferous vegetables.
6. Is high in dark-pigment fruits.
7. Has a regular intake of dairy from whole milk and low-fat [i.e. higher protein] sources.

Understanding the role of diet patterns allows us to see the forest for the trees in nutrition. Unprocessed red meat was once caught as a tree isolated from the forest of the industrialized, processed typical Western diet. Knowing this, we can see the bigger picture and understand that in the context of an otherwise nutrient-dense diet, unprocessed red meat intake is not a major risk for adverse health effects.

 

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