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      Drinking Water Nitrate and Human Health: An Updated Review


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          Nitrate levels in our water resources have increased in many areas of the world largely due to applications of inorganic fertilizer and animal manure in agricultural areas. The regulatory limit for nitrate in public drinking water supplies was set to protect against infant methemoglobinemia, but other health effects were not considered. Risk of specific cancers and birth defects may be increased when nitrate is ingested under conditions that increase formation of N-nitroso compounds. We previously reviewed epidemiologic studies before 2005 of nitrate intake from drinking water and cancer, adverse reproductive outcomes and other health effects. Since that review, more than 30 epidemiologic studies have evaluated drinking water nitrate and these outcomes. The most common endpoints studied were colorectal cancer, bladder, and breast cancer (three studies each), and thyroid disease (four studies). Considering all studies, the strongest evidence for a relationship between drinking water nitrate ingestion and adverse health outcomes (besides methemoglobinemia) is for colorectal cancer, thyroid disease, and neural tube defects. Many studies observed increased risk with ingestion of water nitrate levels that were below regulatory limits. Future studies of these and other health outcomes should include improved exposure assessment and accurate characterization of individual factors that affect endogenous nitrosation.

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          Most cited references153

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            Altered immune responses in mice lacking inducible nitric oxide synthase.

            Nitric oxide (NO) is important in many biological functions. It is generated from L-arginine by the enzyme NO synthase (NOS). The cytokine-inducible NOS (iNOS) is activated by several immunological stimuli, leading to the production of large quantities of NO which can be cytotoxic. To define the biological role of iNOS further, we generated iNOS mutant mice. These are viable, fertile and without evident histopathological abnormalities. However, in contrast to wild-type and heterozygous mice, which are highly resistant to the protozoa parasite Leishmania major infection, mutant mice are uniformly susceptible. The infected mutant mice developed a significantly stronger Th1 type of immune response than the wild-type or heterozygous mice. The mutant mice showed reduced nonspecific inflammatory response to carrageenin, and were resistant to lipopolysaccharide-induced mortality.
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              Workgroup Report: Drinking-Water Nitrate and Health—Recent Findings and Research Needs

              Human alteration of the nitrogen cycle has resulted in steadily accumulating nitrate in our water resources. The U.S. maximum contaminant level and World Health Organization guidelines for nitrate in drinking water were promulgated to protect infants from developing methemoglobinemia, an acute condition. Some scientists have recently suggested that the regulatory limit for nitrate is overly conservative; however, they have not thoroughly considered chronic health outcomes. In August 2004, a symposium on drinking-water nitrate and health was held at the International Society for Environmental Epidemiology meeting to evaluate nitrate exposures and associated health effects in relation to the current regulatory limit. The contribution of drinking-water nitrate toward endogenous formation of N-nitroso compounds was evaluated with a focus toward identifying subpopulations with increased rates of nitrosation. Adverse health effects may be the result of a complex interaction of the amount of nitrate ingested, the concomitant ingestion of nitrosation cofactors and precursors, and specific medical conditions that increase nitrosation. Workshop participants concluded that more experimental studies are needed and that a particularly fruitful approach may be to conduct epidemiologic studies among susceptible subgroups with increased endogenous nitrosation. The few epidemiologic studies that have evaluated intake of nitrosation precursors and/or nitrosation inhibitors have observed elevated risks for colon cancer and neural tube defects associated with drinking-water nitrate concentrations below the regulatory limit. The role of drinking-water nitrate exposure as a risk factor for specific cancers, reproductive outcomes, and other chronic health effects must be studied more thoroughly before changes to the regulatory level for nitrate in drinking water can be considered.

                Author and article information

                Int J Environ Res Public Health
                Int J Environ Res Public Health
                International Journal of Environmental Research and Public Health
                23 July 2018
                July 2018
                : 15
                : 7
                : 1557
                [1 ]Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, 9609 Medical Center Dr. Room 6E138, Rockville, MD 20850, USA; rena.jones@ 123456nih.gov
                [2 ]Department of Epidemiology and Biostatistics, Texas A&M University, School of Public Health, College Station, TX 77843, USA; jdbrender@ 123456sph.tamhsc.edu
                [3 ]Department of Toxicogenomics, GROW-school for Oncology and Developmental Biology, Maastricht University Medical Center, P.O Box 616, 6200 MD Maastricht, The Netherlands; t.dekok@ 123456maastrichtuniversity.nl (T.M.d.K.); s.vanbreda@ 123456maastrichtuniversity.nl (S.G.v.B.)
                [4 ]The Center for Health Effects of Environmental Contamination, The University of Iowa, 455 Van Allen Hall, Iowa City, IA 52242, USA; peter-weyer@ 123456uiowa.edu
                [5 ]U.S. Geological Survey, Water Mission Area, National Water Quality Program, 12201 Sunrise Valley Drive, Reston, VA 20192, USA; btnolan@ 123456usgs.gov
                [6 ]ISGlobal, 08003 Barcelona, Spain; cvillanueva@ 123456isiglobal.org
                [7 ]IMIM (Hospital del Mar Medical Research Institute), 08003 Barcelona, Spain
                [8 ]Department of Experimental and Health Sciences, Universitat Pompeu Fabra (UPF), 08003 Barcelona, Spain
                [9 ]CIBER Epidemiología y Salud Pública (CIBERESP), 28029 Madrid, Spain
                Author notes
                [* ]Correspondence: wardm@ 123456mail.nih.gov
                Author information
                © 2018 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                : 17 May 2018
                : 14 July 2018

                Public health
                drinking water,nitrate,cancer,adverse reproductive outcomes,methemoglobinemia,thyroid disease,endogenous nitrosation,n-nitroso compounds


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