ReviewNutritional epidemiology in the context of nitric oxide biology: A risk–benefit evaluation for dietary nitrite and nitrate
Introduction
Today, we are bombarded with media reports of studies relating diet to a number of chronic diseases, including coronary heart disease, cancer, type 2 diabetes and osteoporosis. For the past several decades, observational studies of diet and cancer have yielded many inconsistent results [1], [2]. Given the limited variation in dietary intakes within many study populations and the seemingly weak diet–cancer associations that have been observed, results of such studies depend critically on an accurate assessment of dietary exposure [3], [4]. Measurement error in exposure can lead to serious errors in the reported relative risks of cancer for dietary intakes and can substantially reduce the statistical power to detect true existing relationships [3], [4]. Extreme caution is required when interpreting associations, or the lack thereof, between dietary factors and disease.
Overall, the media does a fairly good job of reporting the limitations of the studies and the fact that the published results are merely expressions of risk probability. However, a recent, prominent Perspective article in the New England Journal of Medicine [5] noted that all too frequently, what is conveyed about health and disease by many journalists is wrong or misleading, especially when they ignore complexities or fail to provide context. When this happens, the public health messages conveyed are inevitably distorted or inadequate. Therefore, the news media need to become more knowledgeable and to more fully embrace their role in delivering accurate, complete and balanced messages about health.
This is especially needed when the results being communicated to the public are diet-health associations, due mainly to the complexity of the diet compared to a drug/placebo clinical trial. There has been a dramatically increased interest in nutrition and health over the past decade. What we eat or don’t eat is constantly being linked to various diseases, and there is a constant flow of anxiety-provoking media headlines on television, radio, print and more recently the Internet. “Carcinogen-of-the-month” reporting has become very alarming to consumers, and dietary epidemiological studies always seem to be contradicting each other, leading to much nutrition nonsense and food faddism. Because of these fears, consumers become sporadic or chronic avoiders of specific foods and ingredients, such as salt, fat, soft drinks, artificial sweeteners, carbohydrates in general, coffee/caffeine and meat products.
In a recent issue of Archives of Internal Medicine, Sinha et al. [6] reported in a large prospective study that red and processed meat intakes were associated with modest increases in total mortality, cancer mortality, and cardiovascular disease mortality. Like many other studies, it failed to completely consider several additional factors that can contribute to chronic disease, including participants’ behavior as to alcohol and tobacco use, exercise, weight and access to health care. It also failed to recognize the role of beef, pork and other red meat in providing essential and under-consumed nutrients. In response to such reporting deficiencies, many individuals become either confused or alarmed about their own personal situation. There are also calls by numerous public health and consumer organizations to change our lifestyles as a matter of public policy. Therefore, it is important for participants in the social debate to also understand the strengths and limits of epidemiological research. We will review the science of epidemiology, introduce the criteria for interpretation of the data and then discuss some published reports on diet and risk of disease. Since foods are heterogenous and complex in terms of their composition and contribution to the overall diet, ascribing an individual component of food as “good” or “bad” is fraught with difficulty. We will present a cursory review of current epidemiological data, but we will also focus primarily on the context of nitrite and nitrate in foods and what is reported about them, in order to present a balanced view of dietary sources of essential nutrients and a potential risk–benefit evaluation.
Section snippets
Epidemiology as a scientific discipline
Modern epidemiology is the branch of medicine that deals with the study of the causes, distribution and control of disease frequency in human populations. Historically, epidemiology began as the study of epidemics of infectious disease. Epidemiology essentially looks for patterns of disease (time, place, exposures, personal characteristics). Nothing affects our health more than what we choose to eat. Many studies relate the association between processed meats and cancer to their nitrite and
Interpretation of epidemiological studies demands causation criteria
To evaluate research findings in any area of scientific investigation, certain scientific standards, established by experts in each field, need to be applied. This is especially true when trying to determine the health effects of the inclusion or exclusion or varying levels of components in the diets of humans. The eminent British biostatistician and epidemiologist A. Bradford Hill published a seminal paper in 1965 [11] offering a number of interpretation criteria that would be useful when
Diet and cardiovascular disease
Now with these epidemiological criteria in mind, we will present the available data on certain foods and risk of specific diseases, namely cardiovascular disease (CVD) and cancer. Nothing is more important to our health than our diet, and there are well-established and recognized dietary patterns that confer health benefits. Numerous dietary epidemiological data have generally indicated an inverse relationship between dietary intake of fruits and vegetables and incidence of both CVD and cancer.
Diet and cancer
In contrast to the evidence on diet and CVD, epidemiological data on the consumption of meats and the risk of cancer sometimes reveal a slightly increased risk. Since dietary factors, which can be numerous and complex, may yield both positive and negative risk associations, they are of great interest to the research community, public health agencies and to the public. A total of 1,479,350 new cancer cases and 562,340 deaths from cancer are projected to occur in the U.S. in 2009 [31]. The U.S.
Antimicrobial benefits of nitrite in the food supply
Despite the very weak associations sometimes reported between dietary nitrite/nitrate and cancer, we must not forget the essential nature of these “curative” salts in the safety of the food we eat. The antibotulinal properties of nitrite have long been recognized. The use of nitrite to preserve meat has been employed either indirectly or directly for thousands of years. Nitrite inhibits outgrowth of Clostridium botulinum spores in temperature-abused (i.e., non-refrigerated) meat products. The
Risk–benefit evaluation
Nitrite is now known to be an intrinsic signaling molecule [71], [72] capable of producing NO under appropriate conditions as well as forming nitrosothiols [71], [73]. Nitrite has been shown to increase regional blood flow [74], increasing oxygen delivery to hypoxic tissues. Enhancing nitrite availability through therapeutic intervention by administering bolus nitrite prior to cardiovascular insult has shown remarkable effects in reducing the injury from myocardial infarction, ischemic liver
Conclusion
A long history of safe use as a food additive, minimal endogenous production of N-nitrosamines and natural metabolism of ingested nitrite all argue that nitrite as currently used in foods is a safe food additive and even beneficial to human health. Dietary intake of nitrate is a well-known marker of a health-promoting fruit and vegetable diet. In addition, nitrite and nitrate per se, as individual chemical compounds, have never been shown to be carcinogens in animal or human studies. Nitrate
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