Editor’s Note: Large European and American studies are the most recent to examine the link between red meat and cancer. Medscape talked to the study authors and reviewed other evidence to determine whether there is reason to have a beef about eating beef.
RED MEAT AND COLORECTAL CANCER
The preponderance of data gathered in recent decades has supported a link between colorectal cancer (CRC) and red meat consumption, especially processed (cured) red meat (hot dogs, bologna, sausages, bacon, ham, lunch meats).[1] A dose-response relationship was demonstrated by Chan and colleagues,[2] who reported that the risk for CRC increased by 21% for every 50 g/day of processed red meat intake and by 29% for every 100 g/day consumed.
Biologic plausibility for this relationship has been proposed and potential mechanisms of carcinogenesis examined. Pro-cancer factors in red meat might be excess fat, protein, or iron, or heat-induced mutagens. Red meat contains high levels of heme iron (the “red” in red meat), which has a catalytic effect on the endogenous formation of carcinogenic N-nitroso compounds and on the formation of cytotoxic and genotoxic aldehydes by lipoperoxidation.[3] Processed meats contain nitrites and sodium. Cooking meat at high temperatures or on an open flame produces heterocyclic amines (HCAs) and polycyclic aromatic hydrocarbons (PAHs), which are potent carcinogens. Despite numerous investigations, to date none of these hypotheses have been able to convincingly explain the link between red meat intake and cancer risk.[1] For example, in a study that demonstrated a dose-dependent effect of red meat intake on colon cancer, the etiologically relevant compound in cooked meat was thought to be HCAs.[4] However, grilled and fried chicken contain much higher levels of HCAs than beef, but the intake of poultry is not related to cancer risk.[5]
The investigation into the role of red meat consumption in cancer of the colon has extended to cancer precursors and to cancers at different colorectal subsites. A meta-analysis found high ingestion of red and processed meat to be positively associated with increased risk for colorectal adenoma.[6,7] The population-based Norwegian Women and Cancer cohort examined associations of meat intake with incident cancer at different subsites within the colon in 84,538 women, finding that high processed red meat intake (especially sausages) was associated with increased risk for cancer of the proximal colon, distal colon, and rectum.[8]
Researchers were looking not only at the link between red meat and cancer, but also at the mechanisms that would explain such a link, because saturated fat was no longer believed to be sufficiently explanatory. Genetic polymorphisms that might increase susceptibility to CRC through gene-environment interactions have been the subject of study. Because products of high-temperature meat cooking, including PAHs and HCAs, require metabolic activation to exert carcinogenesis, it was believed that metabolizing isoenzymes such as N-acetyltransferase 1 (NAT1) and 2 (NAT2) might modify risk for CRC. Findings have been variable. Shin and colleagues[9] suggest that genetic polymorphisms involved in the metabolic activation of HCAs may indeed modify the risk for colorectal polyps, a possible precursor to cancer.
RED MEAT AND OTHER CANCERS
Until recently, much of the research has looked at the possible link between red meat and CRC. Research on red and processed meat consumption, cooking methods, and the risk for other cancers (and cancer precursors) has produced mixed results:
• Prostate cancer: Positive association between prostate cancer and high intake of red meat cooked at high temperatures, pan-fried, or well-done.[10]
• Pancreatic cancer: No association with red or processed meat or fish; high poultry consumption might be associated with pancreatic cancer.[11]
• Bladder cancer: Processed meat intake associated with bladder cancer.[12]
• Esophageal cancer: Meta-analyses finding that red and processed meats may increase risk for esophageal cancer[13,14] Higher fish intake lowers risk.[15]
• Barrett esophagus: No association found between red meat intake or N-nitrosation-related factors and Barrett esophagus.[16]
• Lung cancer: High intake of red meat raises risk for lung cancer by 35%.[17]
• Hepatocellular carcinoma: Total intake of fish related to reduced risk.[18]
• Renal cell carcinoma: Red meat increases the risk for renal cell carcinoma.[19]
• Breast cancer: Not consistently related to meat intake.[20]
• Endometrial cancer: A modest association between heme iron, total iron, and liver intake (not with red or processed meats) [21]; however, other studies found no association between intake of red or processed meat and endometrial cancer.[22]
In aggregate, studies examining the link between red meat and various types of cancers suggest that meat is one dietary factor that increases cancer risk.[23]
THE LENGTH OF YOUR LIFE ON MEAT
Another question of interest is whether meat consumption is related to mortality. In some studies, vegetarians have been shown to live longer, but lifestyle factors other than meat in the diet could play a role in their longevity. The findings about red meat and mortality in nonvegetarians, however, have been inconsistent.
In a study using data from the National Health and Nutrition Examination Survey-III, neither red or processed meat, nor white meat consumption, was consistently associated with all-cause or cause-specific mortality.[24] Similarly, in more than 50,000 Japanese men and women, moderate meat consumption (up to 100 g/day) was not associated with increased mortality from ischemic heart disease, stroke, or total cardiovascular disease among either sex.[25] In contrast, red meat intake was associated with death from ischemic heart disease in Chinese adults.[26]
The National Institutes of Health/AARP Diet and Health Study[27] (NIH-AARP study) was a prospective investigation of red, white, and processed meat intakes as risk factors for total mortality, and cause-specific mortality, in 545,881adults followed for 10 years. The chief findings were modest increases in risk for total mortality, as well as cancer and cardiovascular mortality, with higher intakes of red and processed meat in both men and women. In contrast, higher white meat consumption was associated with a small reduction in total and cancer mortality in both men and women. The investigators were unable to determine the causes of higher mortality, but they speculated that these could be (in relation to cancer) the aforementioned HCAs, PAHs, or N-nitroso compounds and (in relation to cardiovascular disease) elevated blood pressure and dyslipidemia.
STILL UNCONVINCED
Much of the skepticism about the red meat-cancer-mortality connection derives from the nature of the research demonstrating these links. By necessity, this research is observational and can’t prove causality. Methodologic issues and nonsignificant findings are among the study limitations cited by those who consider the overall evidence for a connection between red meat and cancer to be weak.[28,29] Critics often point to the many variables that can confound the observed associations, such as the fact that people who eat little red meat might follow generally healthy lifestyles with respect to diet, exercise, stress reduction, avoidance of environmental exposure to toxins, and other factors.
In a recent review of 35 published studies about red meat and CRC, Alexander and Cushing[30]explored the complexity of conducting this type of research and the difficulty encountered in trying to analytically isolate the independent effects of red meat consumption. The findings of many previous studies that supported positive associations between red meat and cancer or mortality were questioned on the basis of the following:
• Weakly positive, nonsignificant associations between meat consumption and CRC;
• Insufficient duration of follow-up: Some large studies followed patients for as few as 6 years;
• Lack of positive associations in women;
• Few evaluations of potential underlying mechanisms of increased risk (eg, heme iron content), and inconsistent findings;
• Limited statistical power to assess gene-environment interactions;
• Lack of a universally accepted definition of red meat; sometimes inclusive of processed meat;
• Residual or uncontrolled confounding variables: smoking, body mass index, total calorie consumption, alcohol intake, amount of physical exercise, education level, dietary factors (intake of fruits and vegetables, fiber, etc.); and
• Lack of a clear dose-response relationship.
These authors concluded that “the currently available epidemiologic evidence is not sufficient to support a clear and unequivocal independent positive association between red meat intake and colorectal cancer.” It has been suggested that red meat consumption represents a marker for mortality risk rather than a risk factor itself.[31]
MEAT, MORTALITY, AND CANCER: THE LATEST FINDINGS
US study. The approach taken by Pan and colleagues[32] to the “red meat question” was to determine whether the increased incidences of cancer and other chronic conditions associated with red meat consumption corresponded with an increase in mortality. Their large-scale, prospective, longitudinal study used 2 cohorts: the Health Professionals Follow-Up Study and the Nurses’ Health Study.
First author An Pan describes the study’s main findings. “We found that red meat was associated with increased mortality risk, which is consistent with the recent EPIC study,[33] and also several previous studies, such as the NIH-AARP study.[27]Our study also suggests that replacing red meat with other healthy food choices is associated with reduced risk. The association in our study was quite linear, suggesting that there is no threshold effect, the less the better. But we certainly need more studies to confirm this.”
A higher intake of red meat was associated with an increased risk for total, cardiovascular, and cancer mortality — associations that were relatively greater for processed red meat. A strength of this study was that every 4 years, the researchers obtained updated dietary information from participants. In a previous study that found higher intakes of red and processed meat to be associated with higher mortality, dietary intake was assessed only at baseline.[27]
These studies still fail to fully explain the effect of red meat consumption on mortality, but the researchers speculate that some previously identified culprits — N-nitroso compounds, HCAs, PAHs, or heme iron content — could be involved, as well as other constituents of meat, such as saturated fat and sodium.
Men and women with the highest intakes of red meat were less likely to be physically active. To answer critics who claim that the study’s findings are confounded by such variables, Pan and colleagues “carefully controlled for lifestyle factors (eg, smoking, drinking, physical activity, body mass index, other dietary factors) in our statistical models. The results can be considered as being independent of those factors. Although we may not be able to fully account for all confounding factors, we did not observe significant interactions with those lifestyle factors in our study.”
With respect to mortality from different types of cancer, the study was not designed to stratify according to different types of cancer, says Pan. However, “red meat was associated with deaths from several major cancers, such as CRC and lung cancer, but the associations were very modest for breast and prostate cancer.”
European (EPIC) study. The meat-mortality connection received more support this year with the publication of the EPIC study,[33] in which a large European cohort (almost a half million individuals) were followed for a median of 12.7 years. A high consumption of processed meat, but not red meat, was related to increased all-cause mortality. The risk for cancer death was 43% higher and the risk for cardiovascular death was 70% higher in people who ate more than 160 g/day of processed meats than in those who ate 10.0-19.9 g/day. The study’s most important finding, according to lead author Sabine Rohrmann, “is that mortality increases with increasing amounts of processed meat consumed. We estimate, based on our results, that 3.3% of total mortality is due to high processed meat consumption. This is lower than the preventable fraction that has been calculated from US studies, which reported that about 8% in the Nurses’ Health study and 20% in the NIH-AARP cohort was preventable.”
An interaction with smoking suggested that mortality was significantly higher in current and former smokers. The study had several other interesting findings. Rather than being associated with zero meat consumption, the lowest mortality rates were found among those who consumed about 10-20 g of processed meat per day (equivalent to eating processed meat once or twice a week.) This, although unexpected, is consistent with previous studies showing that vegetarians and nonvegetarians who eat low amounts of meat have similar mortality rates.
The association between mortality and processed meat consumption was stronger in lean individuals than in obese or overweight individuals. Rohrmann says that this finding is difficult to explain. “We see a statistically significant interaction (eg, different effects by body mass index group), but the risk estimates are not that different. It might just be chance due to small numbers or perhaps, because obesity is a stronger risk factor for mortality than processed meat consumption, we cannot detect the association as clearly.”
The evidence on mortality presented by EPIC also agrees with observations from other analyses that high intakes of red meat and processed meat are associated with chronic diseases such as diabetes, heart disease, and stroke.[34,35]
WILL RED MEAT ‘KILL US’?
One estimate says that the US per-capita daily consumption of meat is 128 g (4.5 oz), of which 80 g (2.8 oz) is red meat,[36] while other estimates suggest that red meat consumption is considerably higher. Although red meat consumption has plateaued somewhat in the United States, it is on the rise throughout much of the developed world, despite sensational headlines warning of the dangers of continuing to eat so much red meat.
The US study by Pan and colleagues found that substituting fish, poultry, nuts, legumes, low-fat dairy products, and whole grains for red meat in the diet was associated with significantly reduced mortality. The EPIC investigators commented that reduction of processed meat consumption to less than 20 g/day would prevent about 3% of all deaths.
Where does all of this leave clinicians and their patients? Should we, for example, advise patients at risk for CRC, or recurrence of CRC, to reduce their intake of red meat and to stop eating processed red meats altogether? The American Institute for Cancer Research (AICR) believes that the time has come to do so. Their recommendation is to “limit consumption of red meats (such as beef, pork, and lamb) and avoid processed meats.” To reduce risk for cancer, the AICR suggests eating no more than 18 oz (cooked weight) per week of red meat (beef, pork, lamb) and avoid processed red meats (ham, bacon, salami, hot dogs, and sausages).[37] The National Comprehensive Cancer Network also recommends limiting red and processed meat in the diet of cancer survivors.[38]
On the other hand, do the nutritional benefits of red meat, along with the methodologic limitations of the recent red meat studies (and the fear of backlash from industry), justify making no recommendations of this kind? Conducting more research to more closely identify the mechanisms involved in the development of cancer with high consumption of processed meats, or of red meat cooked in certain ways, is an alternative. More research might also clarify the gene-environment interactions operating when high consumers of red meat develop cancer or die prematurely. Like everything else that is “bad for you,” people will have to make their own choices, but we should at least make them informed ones.