Elsevier

Nitric Oxide

Volume 22, Issue 2, 15 February 2010, Pages 110-119
Nitric Oxide

Review
Nutritional epidemiology in the context of nitric oxide biology: A risk–benefit evaluation for dietary nitrite and nitrate

https://doi.org/10.1016/j.niox.2009.08.004Get rights and content

Abstract

The discovery of the nitric oxide (NO) pathway in the 1980s represented a critical advance in understanding cardiovascular disease, and today a number of human diseases are characterized by NO insufficiency. In the interim, recent biomedical research has demonstrated that NO can be modulated by the diet independent of its enzymatic synthesis from l-arginine, e.g., the consumption of nitrite- and nitrate-rich foods such as fruits, leafy vegetables, and cured meats along with antioxidants. Regular intake of nitrate-containing food such as green leafy vegetables may ensure that blood and tissue levels of nitrite and NO pools are maintained at a level sufficient to compensate for any disturbances in endogenous NO synthesis. However, some in the public perceive that dietary sources of nitrite and nitrate are harmful, and some epidemiological studies reveal a weak association between foods that contain nitrite and nitrate, namely cured and processed meats, and cancer. This paradigm needs revisiting in the face of undisputed health benefits of nitrite- and nitrate-enriched diets. This review will address and interpret the epidemiological data and discuss the risk–benefit evaluation of dietary nitrite and nitrate in the context of nitric oxide biology. The weak and inconclusive data on the cancer risk of nitrite, nitrate and processed meats are far outweighed by the health benefits of restoring NO homeostasis via dietary nitrite and nitrate. This risk/benefit balance should be a strong consideration before there are any suggestions for new regulatory or public health guidelines for dietary nitrite and nitrate exposures.

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

References (101)

  • D.D. Alexander et al.

    Quantitative assessment of red meat or processed meat consumption and kidney cancer

    Cancer Detect. Prev.

    (2009)
  • R.S. Murphy et al.

    Trends in cured meat consumption in relation to childhood and adult brain cancer in the United States

    Food Control

    (1998)
  • J.O. Lundberg et al.

    Inorganic nitrate is a possible source for systemic generation of nitric oxide

    Free Radic. Biol. Med.

    (2004)
  • M. Govoni et al.

    The increase in plasma nitrite after a dietary nitrate load is markedly attenuated by an antibacterial mouthwash

    Nitric Oxide

    (2008)
  • D.L. Archer

    Evidence that ingested nitrate and nitrite are beneficial to health

    J. Food Prot.

    (2002)
  • C. Duncan et al.

    Protection against oral and gastrointestinal diseases: importance of dietary nitrate intake, oral nitrate reduction and enterosalivary nitrate circulation

    Comp. Biochem. Physiol. A Physiol.

    (1997)
  • R. Weller et al.

    Nitric oxide release accounts for the reduced incidence of cutaneous infections in psoriasis

    J. Am. Acad. Dermatol.

    (1997)
  • R. Weller et al.

    Nitric oxide is generated on the skin surface by reduction of sweat nitrate

    J. Invest. Dermatol.

    (1996)
  • L.L. Duffy et al.

    Growth of Listeria monocytogenes on vacuum-packed cooked meats: effects of pH, aw, nitrite and ascorbate

    Int. J. Food Microbiol.

    (1994)
  • A.O. Gill et al.

    Interactive inhibition of meat spoilage and pathogenic bacteria by lysozyme, nisin and EDTA in the presence of nitrite and sodium chloride at 24 °C

    Int. J. Food Microbiol.

    (2003)
  • J.D. Legan et al.

    Modeling the growth boundary of Listeria monocytogenes in ready-to-eat cooked meat products as a function of the product salt, moisture, potassium lactate, and sodium diacetate concentrations

    J. Food Prot.

    (2004)
  • P.J. McClure et al.

    Predictive modelling of growth of Listeria monocytogenes. The effects on growth of NaCl, pH, storage temperature and NaNO2

    Int. J. Food Microbiol.

    (1997)
  • J.H. Schlyter et al.

    The effects of diacetate with nitrite, lactate, or pediocin on the viability of Listeria monocytogenes in turkey slurries

    Int. J. Food Microbiol.

    (1993)
  • D.L. Seman et al.

    Modeling the growth of Listeria monocytogenes in cured ready-to-eat processed meat products by manipulation of sodium chloride, sodium diacetate, potassium lactate, and product moisture content

    J. Food Prot.

    (2002)
  • A.K. Pradhan et al.

    Quantitative risk assessment for Listeria monocytogenes in selected categories of deli meats: impact of lactate and diacetate on listeriosis cases and deaths

    J. Food Prot.

    (2009)
  • N.S. Bryan et al.

    Dietary nitrite restores NO homeostasis and is cardioprotective in endothelial nitric oxide synthase-deficient mice

    Free Radic. Biol. Med.

    (2008)
  • M.B. Katan

    Nitrate in foods: harmful or healthy?

    Am. J. Clin. Nutr.

    (2009)
  • Y. Tang et al.

    Nitric oxide bioactivity of traditional Chinese medicines used for cardiovascular indications

    Free Radic. Biol. Med.

    (2009)
  • E.A. Jansson et al.

    Protection from nonsteroidal anti-inflammatory drug (NSAID)-induced gastric ulcers by dietary nitrate

    Free Radic. Biol. Med.

    (2007)
  • V. Kipnis et al.

    Impact of exposure measurement error in nutritional epidemiology

    J. Natl. Cancer Inst.

    (2008)
  • A. Schatzkin et al.

    Could exposure assessment problems give us wrong answers to nutrition and cancer questions?

    J. Natl. Cancer Inst.

    (2004)
  • S. Dentzer

    Communicating medical news – pitfalls of health care journalism

    N. Engl. J. Med.

    (2009)
  • R. Sinha et al.

    Meat intake and mortality: a prospective study of over half a million people

    Arch. Intern. Med.

    (2009)
  • L. Langseth

    Nutritional epidemiology: possibilities and limitations

  • A.B. Hill

    The environment and disease: association or causation?

    Proc. R. Soc. Med.

    (1965)
  • L. Anderson

    Abortion and Possible Risk for Breast Cancer: Analysis and Inconsistencies

    (1994)
  • G.P. Young et al.

    The genetics, epidemiology, and early detection of gastrointestinal cancers

    Curr. Opin. Oncol.

    (1992)
  • C.V. Phillips et al.

    The missed lessons of Sir Austin Bradford Hill

    Epidemiol. Perspect. Innov.

    (2004)
  • How to Understand and Interpret Food and Health-Related Scientific Studies, International Food Information Council...
  • P. Boffetta et al.

    False-positive results in cancer epidemiology: a plea for epistemological modesty

    J. Natl. Cancer Inst.

    (2008)
  • S. Yusuf et al.

    Vitamin E supplementation and cardiovascular events in high-risk patients. The heart outcomes prevention evaluation study investigators

    N. Engl. J. Med.

    (2000)
  • F. Visioli et al.

    Mediterranean food and health: building human evidence

    J. Physiol. Pharmacol.

    (2005)
  • N. Kimura et al.

    Coronary heart disease in seven countries. X. Rural southern Japan

    Circulation

    (1970)
  • H.L. Taylor et al.

    Coronary heart disease in seven countries. IV. Five-year follow-up of employees of selected U.S. railroad companies

    Circulation

    (1970)
  • H.L. Taylor et al.

    Coronary heart disease in seven countries. XI. Five years of follow-up of railroad men in Italy

    Circulation

    (1970)
  • H. Blackburn et al.

    Coronary heart disease in seven countries. XVI. The electrocardiogram in prediction of five-year coronary heart disease incidence among men aged forty through fifty-nine

    Circulation

    (1970)
  • R. Buzina et al.

    Coronary heart disease in seven countries. V. Five-year follow-up in Dalmatia and Slavonia

    Circulation

    (1970)
  • C. Aravanis et al.

    Coronary heart disease in seven countries. IX. The Greek islands of Crete and Corfu

    Circulation

    (1970)
  • F. Fidanza et al.

    Coronary heart disease in seven countries. VII. Five-year experience in rural Italy

    Circulation

    (1970)
  • H. Garg

    Diet and Cardiovascular Disease: The Role of Antioxidants and Nitrite

    (2006)
  • Cited by (93)

    View all citing articles on Scopus
    View full text