Regulation of Dietary Nitrate and Nitrite: Balancing Essential Physiological Roles with Potential Health Risks

Chapter
Part of the Nutrition and Health book series (NH)

Abstract

Human consumption of dietary nitrate and nitrite is controversial. Exposure through processed meats is associated with gastrointestinal cancer risk while consumption of nitrate from plant food sources, the source of over 80 % of human nitrate consumption, is associated with potential cardiovascular benefits. Identifying the physiological contexts in which dietary nitrate and nitrite produce health benefits and risks is necessary for clear guidance regarding dietary consumption of nitrate-containing foods. Development and application of nitrate and nitrite concentrations in national food databases will assist scientists and regulatory agencies in addressing these questions in prospective epidemiological studies.

Keywords

Accepted daily intake Dietary recommendations World Health Organization Food safety Risk benefit evaluation 

References

  1. 1.
    European Food Safety Authority. Nitrate in vegetables: scientific opinion of the panel on contaminants in the food chain. EFSA J. 2008;689:1–79.Google Scholar
  2. 2.
    Pennington J. Dietary exposure models for nitrates and nitrites. Food Control. 1998;9:385–95.CrossRefGoogle Scholar
  3. 3.
    Santamaria P. Nitrate in vegetables; content, toxicity and EC regulation. J Sci Food Agric. 2005;86(1):10–7.CrossRefGoogle Scholar
  4. 4.
    Spiegelhalder B, Eisenbrand G, Preussmann R. Influence of dietary nitrate on nitrite content of human saliva: possible relevance to in vivo formation of N-nitroso compounds. Food Cosmet Toxicol. 1976;14(6):545–8.CrossRefPubMedGoogle Scholar
  5. 5.
    Petersson J, Carlstrom M, Schreiber O, Phillipson M, Christoffersson G, Jagare A, et al. Gastroprotective and blood pressure lowering effects of dietary nitrate are abolished by an antiseptic mouthwash. Free Radic Biol Med. 2009;46(8):1068–75.CrossRefPubMedGoogle Scholar
  6. 6.
    Jansson EA, Huang L, Malkey R, Govoni M, Nihlen C, Olsson A, et al. A mammalian functional nitrate reductase that regulates nitrite and nitric oxide homeostasis. Nat Chem Biol. 2008;4(7):411–7.CrossRefPubMedGoogle Scholar
  7. 7.
    van Faassen EE, Bahrami S, Feelisch M, Hogg N, Kelm M, Kim-Shapiro DB, et al. Nitrite as regulator of hypoxic signaling in mammalian physiology. Med Res Rev. 2009;29(5):683–741.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Camargo JA, Alonso A. Ecological and toxicological effects of inorganic nitrogen pollution in aquatic ecosystems: a global assessment. Environ Int. 2006;32(6):831–49.CrossRefPubMedGoogle Scholar
  9. 9.
    Monteny GJ, The EU. Nitrates Directive: a European approach to combat water pollution from agriculture. ScientificWorldJournal. 2001;1 Suppl 2:927–35.CrossRefPubMedGoogle Scholar
  10. 10.
    World Health Organization. Recommendations; nitrate and nitrite. In: Guidelines for drinking water quality. 3rd ed. Geneva: WHO; 2004. p. 417–20.Google Scholar
  11. 11.
    Center for Disease Control and Prevention (CDC). Methemoglobinemia following unintentional ingestion of sodium nitrite–New York. MMWR Morb Mortal Wkly Rep. 2002;51(29):639–42.Google Scholar
  12. 12.
    Butler AR, Feelisch M. Therapeutic uses of inorganic nitrite and nitrate: from the past to the future. Circulation. 2008;117(16):2151–9.CrossRefPubMedGoogle Scholar
  13. 13.
    McKnight GM, Duncan CW, Leifert C, Golden MH. Dietary nitrate in man: friend or foe? Br J Nutr. 1999;81(5):349–58.CrossRefPubMedGoogle Scholar
  14. 14.
    L’Hirondel JL, Avery AA, Addiscott T. Dietary nitrate: where is the risk? Environ Health Perspect. 2006;114(8):A458–9; author reply A459–61.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    L’hirondel J, L’hirondel JL. Nitrate and man: toxic, harmless or beneficial? Wallingford, UK: CABI; 2001.CrossRefGoogle Scholar
  16. 16.
    Powlson DS, Addiscott TM, Benjamin N, Cassman KG, de Kok TM. vanGrinsven H, et al. When does nitrate become a risk for humans? J Environ Qual. 2008;37(2):291–5.CrossRefPubMedGoogle Scholar
  17. 17.
    Greer FR, Shannon M. Infant methemoglobinemia: the role of dietary nitrate in food and water. Pediatrics. 2005;116(3):784–6.CrossRefPubMedGoogle Scholar
  18. 18.
    Churchill JJ. Re-examining “nitrate toxicity”: a call for a more rational approach to effluent limits for nitrogen in decentralized wastewater treatment. In: Paper presented at Eleventh Individual and Small Community Sewage Systems Conference Proceedings, Warwick; 2007Google Scholar
  19. 19.
    National Primary Drinking Water Regulations: Final Rule, 40. Federal Register. 1991;CFR Parts 141–143(56 (20)):3526–97.Google Scholar
  20. 20.
    Mensinga TT, Speijers GJ, Meulenbelt J. Health implications of exposure to environmental nitrogenous compounds. Toxicol Rev. 2003;22(1):41–51.CrossRefPubMedGoogle Scholar
  21. 21.
    Gangolli SD, van den Brandt PA, Feron VJ, Janzowsky C, Koeman JH, et al. Nitrate, nitrite and N-nitroso compounds. Eur J Pharmacol. 1994;292(1):1–38.PubMedGoogle Scholar
  22. 22.
    Hord NG, Tang Y, Bryan NS. Food sources of nitrates and nitrites: the physiologic context for potential health benefits. Am J Clin Nutr. 2009;90(1):1–10.CrossRefPubMedGoogle Scholar
  23. 23.
    van Velzen AG, Sips AJ, Schothorst RC, Lambers AC, Meulenbelt J. The oral bioavailability of nitrate from nitrate-rich vegetables in humans. Toxicol Lett. 2008;181(3):177–81.CrossRefPubMedGoogle Scholar
  24. 24.
    Hord NG, Ghannam J, Garg H, Tang YP, Bryan NS. Nitrate and nitrite content of human, formula, bovine and soy milks: implications for dietary nitrite and nitrate recommendations Breastfeed Med. 2010 [Epub ahead of print].Google Scholar
  25. 25.
    Lundberg JO, Feelisch M, Bjorne H, Jansson EA, Weitzberg E. Cardioprotective effects of vegetables: is nitrate the answer? Nitric Oxide. 2006;15(4):359–62.CrossRefPubMedGoogle Scholar
  26. 26.
    Li H, Thompson I, Carter P, Whitely A, Bailey M, Leifert C, et al. Salivary nitrate–an ecological factor in reducing oral acidity. Oral Microbiol Immunol. 2007;22(1):67–71.CrossRefPubMedGoogle Scholar
  27. 27.
    Webb AJ, Patel N, Loukogeorgakis S, Okorie M, Aboud Z, Misra S, et al. Acute blood pressure lowering, vasoprotective, and antiplatelet properties of dietary nitrate via bioconversion to nitrite. Hypertension. 2008;51(3):784–90.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Kapil V, Milsom AB, Okorie M, Miliki-Toyserkani S, Akram F, Rehman F, et al. Inorganic nitrate supplementation lowers blood pressure in humans: role for nitrite-derived NO. Hypertension. 2010;56(2):274–81.CrossRefPubMedGoogle Scholar
  29. 29.
    Sobko T, Marcus C, Govoni M, Kamiya S. Dietary nitrate in Japanese traditional foods lowers diastolic blood pressure in healthy volunteers. Nitric Oxide. 2010;22(2):136–40.CrossRefPubMedGoogle Scholar
  30. 30.
    Stokes KY, Dugas TR, Tang Y, Garg H, Guidry E, Bryan NS. Dietary nitrite prevents hypercholesterolemic microvascular inflammation and reverses endothelial dysfunction. Am J Physiol Heart Circ Physiol. 2009;296(5):H1281–8.CrossRefPubMedGoogle Scholar
  31. 31.
    Garg HK, Bryan NS. Dietary sources of nitrite as a modulator of ischemia/reperfusion injury. Kidney Int. 2009;75(11):1140–4.CrossRefPubMedGoogle Scholar
  32. 32.
    Elrod JW, Calvert JW, Gundewar S, Bryan NS, Lefer DJ. Nitric oxide promotes distant organ protection: evidence for an endocrine role of nitric oxide. Proc Natl Acad Sci U S A. 2008;105(32):11430–5.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Lundberg JO, Gladwin MT, Ahluwalia A, Benjamin N, Bryan NS, Butler A, et al. Nitrate and nitrite in biology, nutrition and therapeutics. Nat Chem Biol. 2009;5(12):865–9.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Ward MH, Kilfoy BA, Weyer PJ, Anderson KE, Folsom AR, Cerhan JR. Nitrate intake and the risk of thyroid cancer and thyroid disease. Epidemiology. 2010;21(3):389–95.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Jiang R, Camargo Jr CA, Varraso R, Paik DC, Willett WC, Barr RG. Consumption of cured meats and prospective risk of chronic obstructive pulmonary disease in women. Am J Clin Nutr. 2008;87(4):1002–8.PubMedPubMedCentralGoogle Scholar
  36. 36.
    Panesar NS. Downsides to the nitrate-nitrite-nitric oxide pathway in physiology and therapeutics? Nat Rev Drug Discov. 2008;7(8):710. author reply 710.CrossRefPubMedGoogle Scholar
  37. 37.
    Santarelli RL, Pierre F, Corpet DE. Processed meat and colorectal cancer: a review of epidemiologic and experimental evidence. Nutr Cancer. 2008;60(2):131–44.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Norat T, Bingham S, Ferrari P, Slimani N, Jenab M, Mazuir M, et al. Meat, fish, and colorectal cancer risk: the European Prospective Investigation into cancer and nutrition. J Natl Cancer Inst. 2005;97(12):906–16.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Alexander DD, Miller AJ, Cushing CA, Lowe KA. Processed meat and colorectal cancer: a quantitative review of prospective epidemiologic studies. Eur J Cancer Prev. 2010;19(5):328–41.CrossRefPubMedGoogle Scholar
  40. 40.
    Rao GS, Osborn JC, Adatia MR. Drug-nitrite interactions in human saliva: effects of food constituents on carcinogenic N-nitrosamine formation. J Dent Res. 1982;61(6):768–71.CrossRefPubMedGoogle Scholar
  41. 41.
    Cassens RG. Residual nitrite in cured meat. Food Technol. 1997;51:53–5.Google Scholar
  42. 42.
    Combet E, Paterson S, Iijima K, Winter J, Mullen W, Crozier A, et al. Fat transforms ascorbic acid from inhibiting to promoting acid-catalysed N-nitrosation. Gut. 2007;56(12):1678–84.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Combet E, Preston T, McColl KE. Development of an in vitro system combining aqueous and lipid phases as a tool to understand gastric nitrosation. Rapid Commun Mass Spectrom. 2010;24(5):529–34.CrossRefPubMedGoogle Scholar
  44. 44.
    Santarelli RL, Vendeuvre JL, Naud N, Tache S, Gueraud F, Viau M, et al. Meat processing and colon carcinogenesis: cooked, nitrite-treated, and oxidized high-heme cured meat promotes mucin-depleted foci in rats. Cancer Prev Res (Phila). 2010;3(7):852–64.CrossRefGoogle Scholar
  45. 45.
    World Cancer Research Fund, American Institute of Cancer Research. Food, nutrition, physical activity, and the prevention of cancer: a global perspective. Second Expert Report; 2007.Google Scholar
  46. 46.
    de Kok TM, Engels LG, Moonen EJ, Kleinjans JC. Inflammatory bowel disease stimulates formation of carcinogenic N-nitroso compounds. Gut. 2005;54(5):731.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Combet E, El Mesmari A, Preston T, Crozier A, McColl KE. Dietary phenolic acids and ascorbic acid: influence on acid-catalyzed nitrosative chemistry in the presence and absence of lipids. Free Radic Biol Med. 2010;48(6):763–71.CrossRefPubMedGoogle Scholar
  48. 48.
    Lundberg JO, Govoni M. Inorganic nitrate is a possible source for systemic generation of nitric oxide. Free Radic Biol Med. 2004;37(3):395–400.CrossRefPubMedGoogle Scholar
  49. 49.
    Dejam A, Hunter CJ, Schechter AN, Gladwin MT. Emerging role of nitrite in human biology. Blood Cells Mol Dis. 2004;32(3):423–9.CrossRefPubMedGoogle Scholar
  50. 50.
    Bryan NS, Fernandez BO, Bauer SM, Garcia-Saura MF, Milsom AB, Rassaf T, et al. Nitrite is a signaling molecule and regulator of gene expression in mammalian tissues. Nat Chem Biol. 2005;1(5):290–7.CrossRefPubMedGoogle Scholar
  51. 51.
    Lundberg JO, Weitzberg E. NO generation from inorganic nitrate and nitrite: role in physiology, nutrition and therapeutics. Arch Pharm Res. 2009;32(8):1119–26.CrossRefPubMedGoogle Scholar
  52. 52.
    Zweier JL, Li H, Samouilov A, Liu X. Mechanisms of nitrite reduction to nitric oxide in the heart and vessel wall. Nitric Oxide. 2010;22(2):83–90.CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Grosse Y, Baan R, Straif K, Secretan B, El Ghissassi F, Cogliano V. Carcinogenicity of nitrate, nitrite, and cyanobacterial peptide toxins. Lancet Oncol. 2006;7(8):628–9.CrossRefPubMedGoogle Scholar
  54. 54.
    Bryan, Ivy Inorganic nitrite and nitrate: Evidence to support consideration as dietary nutrients Nutr Res. 2015;35(8):643–54.Google Scholar
  55. 55.
    Otten JJ, Hellwig J, Meyers LD. editors. Dietary reference intakes: the essential guide to nutrient requirements. Washington, DC: National Academy Press, Food and Nutrition Board, Institute of Medicine, National Academy of Sciences; 2006.Google Scholar
  56. 56.
    Katan MB. Nitrate in foods: harmful or healthy? Am J Clin Nutr. 2009;90(1):11–2.CrossRefPubMedGoogle Scholar
  57. 57.
    Joshipura KJ, Hung HC, Li TY, Hu FB, Rimm EB, Stampfer MJ, et al. Intakes of fruits, vegetables and carbohydrate and the risk of CVD. Public Health Nutr. 2009;12(1):115–21.CrossRefPubMedGoogle Scholar
  58. 58.
    Jenkins DJ, Wong JM, Kendall CW, Esfahani A, Ng VW, Leong TC, et al. The effect of a plant-based low-carbohydrate (“Eco-Atkins”) diet on body weight and blood lipid concentrations in hyperlipidemic subjects. Arch Intern Med. 2009;169(11):1046–54.CrossRefPubMedGoogle Scholar
  59. 59.
    de Lorgeril M, Salen P, Martin JL, Monjaud I, Delaye J, Mamelle N. Mediterranean diet, traditional risk factors, and the rate of cardiovascular complications after myocardial infarction: final report of the Lyon Diet Heart Study. Circulation. 1999;99(6):779–85.CrossRefPubMedGoogle Scholar
  60. 60.
    Kapil V, et al. Dietary nitrate provides sustained blood pressure lowering in hypertensive patients: a randomized, phase 2, double-blind, placebo-controlled study. Hypertension. 2015;65(2):320–7.CrossRefPubMedGoogle Scholar
  61. 61.
    Institute of Medicine. A population-based policy and systems change approach to prevent and control hypertension. Washington, DC: The National Academy of Sciences; 2010.Google Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.School of Biological and Population Health SciencesOregon State UniversityCorvallisUSA

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