Risk of Nitrate Residues in Food Products and Drinking Water

Abstract

Although nitrate is the essential nutrient of our body, the excess amount of it as residues strongly causes disease. Nitrate comes from plant and animal foods that are vital to our metabolism. The nitrate is absorbed through the soil by plants and becomes an herbal protein that is placed in the food chain. If the nitrate is absorbed more than the plant requirement, it will be accumulated into the plant’s organs. Since nitrogen fertilizers increase the weight and yield of the plants, farmers consume large amounts of which. Hence, we investigate the consumption of nitrogen fertilizers in the world and the standard allowable residual nitrate in food and water considering the accumulation of nitrate in water and food. Excess amount of nitrate in the soil enters the drinking water after leaching or directly transported from groundwater to surface water and drinking water. The entry of the excess amount of nitrate from food products and drinking water into our bodies causes dangerous diseases such as different types of cancers, methemoglobinemia, osteoporosis, kidney stones, and some other diseases. The present article, besides indicating the benefits of nitrate for Treatment purposes and demonstrating the state of nitrate accumulation in food and water as well as its standards, deals with diseases caused by it and presents some remedies to reduce the risks.

Introduction

Nitrogen is one of the substances that is commonly used in agriculture and causes several concerns. In particular, it is used in large quantities as fertilizer in agricultural systems [1, 2]. Due to its chemical and physical properties, it can reach fresh water through runoff [3]. The high concentration of nitrogen dispersed in the environment can lead to eutrophication and have adverse effects on aquatic ecosystems [4].

The most common form of anthropogenic nitrogen in water is nitrate (NO^-₃). Nitrate can be found in the natural background at levels ranging from 0 to 2.0 mg L⁻¹ [5]. However, in areas with intensive agriculture or a high population, specifically in developing countries, its concentration in water can be more than 100 times higher [6]. The information recorded in some regions where the nitrate concentration can easily reach 100 mg L⁻¹ or even up to 500 mg L⁻¹ is very alarming [7-9].

Contamination of freshwater by nitrates is a serious risk to human health, especially when it reaches drinking water. In this respect, the World Health Organization (WHO) announced that the permissible nitrate concentration in drinking water should not exceed 50 mg L⁻¹ [7]. In fact, the consumption of drinking water by humans with higher concentrations of NO^-₃ can cause various diseases [5].

In particular, Nitrate and nitrite exist in soluble form in the environment or enters the environment by microorganisms through the oxidation of nitrogenous compounds [10-12]. In the natural cycle of nitrogen, bacteria convert it to nitrate. They are absorbed to produce protein in plants. Herbivores consume this nitrate to produce protein in their body. In the return of this cycle, nitrate is excreted from the body of animals or returns to the soil after death from the body of the animal or plant by microbial decomposition and is converted to nitrite and nitrogen afterward [13]. In particular, the risk of certain cancers and birth defects may arise from the consumption of nitrate, and nitrate is reduced to nitrite, which can ultimately form N-nitroso compounds that are known animal carcinogens, and can possibly lead to stomach cancer. Colon cancer, kidney cancer, brain cancer, etc. for humans [14].

Over the last two centuries, with the increase of agricultural and industrial activities, the nitrogen cycle has changed and nitrate has accumulated into vital resources [15, 16]. Improper use of chemical nitrogen fertilizers is the most important cause of nitrate increase [17] that enter the environment by human hands [18, 19]. From the agricultural cycle, excess nitrate is mainly found in fresh vegetables and fruits [20] and processed meat, and partially in dairy products and legumes [19]. Due to the high consumption of fresh products, these foods are the main source of nitrate accumulation and its transfer in the food chain. According to Lian-feng et al. (2011), the highest concentration of nitrate is found in vegetables, especially their leafy forms [21]. Although the total amount of nitrate allowed to enter the body of an adult weighing 70 kg is 51 mg per day, i.e., 0.7 mg per kg of body weight, we absorb large amounts of it due to the consumption of food and water containing excess nitrate [22-24].

In general, besides all therapy purposes of nitrate that we will mention, an excess amount of it entering the soil, water, and human food cycle can cause a lot of damage. Therefore, preventing entry, removal, or reduction of this element is one of the important human concerns.

Meat products contain up more than m <2.7 to 945 mg of nitrate per kilogram and dairy products up to more than <3 to 27 mg of nitrate per kilogram. Also, some vegetables and fruits have 200-2500 mg/kg nitrate due to excessive consumption of nitrogen fertilizers [25]. Among different types of fresh food products, leafy vegetables do have about 80 percentage of the entry of nitrate into our body [26] ; since their juiciness have practically absorbed more nitrate. That is why their feeding is more dangerous compared to other products [27]. Due to the importance of this matter, there are many reports on the state of nitrate accumulatiofertilin in fresh and processed vegetables [28-30].

Consumption of nitrogen fertilizers in the world

Due to the increased activity in agriculture and the use of chemical fertilizers, contamination potential assessment is very critical [31]. Nitrate accumulation has increased dramatically in the world over the past decades due to emissions from sources such as livestock, agricultural waste, and chemical fertilizers [32]. Nitrate accumulation occurs more in plant products as a result of excessive use of chemical nitrogen fertilizers [28-30]. According to FAO statistics, the demand for chemical fertilizers (nitrogen), Phosphate, and potash in 2016 were 185.063 million tons, which in 2016 increased to 186.67 million tons, and this amount with an average annual growth of 1.9 percent at the end of 2022 will reach to 200.919 million tons [33].

It is also expected that from 2016 to 2020, the demand for these fertilizers will increase by 2.4 percent [34]. This is while in developed countries, the standards for the use of chemical fertilizers, especially nitrogen types, have been developed and strongly they seek to reduce their consumption. According to Lenka et al. (2013), the residual soil nitrate (RSN) up to a depth of 100 cm at harvest time should not exceed 150 kg N ha^{− 1}, which should be reduced compared to the average consumption of 240 kg N ha^{− 1} [35]. Other sources even state that the RSN allowed for the EU is 90-100 kg N ha^{− 1} [36].

Nitrate standards

Nitrate limit in the food cycle

The amount of nitrate remaining in food is proportional to the amount of nitrate in the soil and therefore compared to the allowable level of nitrate in the soil [37]. The tolerable standard level of nitrate for our body has been expressed in different sources. According to the European Commission’s Food Science Committee, the permissible daily intake of nitrate (ADI) in 1995 was

3.6 mg/kg of body weight [38] which in 2003 was reported by the Food and Agriculture Organization. Global health for adults with an average weight of 60 kg 3.7 mg/kg [39]. According to a report, the average daily concentration of excess nitrate uptake in an adult is about 75-100 mg, of which 80-90% it is a vegetable and the rest is water. Due to the need to consume healthy vegetables, global standards were set more than 40 years ago for the nitrate limit in a variety of vegetables (Table 1) [40].

Nitrate limit in water

Drinking water contains variable amounts of nitrate. The permitted amount in water is regulated in Europe (50 nitrate ion (mg/l)) and the US (10 nitrate-nitrogen (mg/l), equivalent to 44 nitrate ion (mg/l)) due to the concerns about methemoglobinemia disease. Nitrate in drinking water derives from bacterial nitrogen fixation and from the decomposition of organic material in the soil. Excessive use of nitrogen-containing fertilizers may also be critical, although there is a complex relationship between nitrate application, nitrate uptake by plants, and nitrate leachingw which has been extensively reviewed [41].

Accumulation of nitrate in water and food

Excess amount of nitrate accumulates in soil and water in several ways and finally reaches our body. First and foremost, it is absorbed directly from the soil and after accumulation reaches our body through livestock products. Moreover, it enters groundwater or surface water from washed soil and afterwards reaches the sources of drinking water. On the other hand, it enters directly into surface or groundwater through agricultural runoff and then it reaches the sources of drinking water. However, feeding on plants, livestock products, and nitrate-contaminated water means an increase in nitrate in the food chain and eventually in our bodies [42].

Nitrate concentrations in surface water are usually low. However, it can Reach higher levels through agricultural runoff. Nitrate concentration rise up when the river is fed by nitrate-rich aquifers. In the last 20 years, the concentration of nitrate in the water of many European countries has doubled [39]. In the United States, its concentration in groundwater is about 4-9 mg/l [43], while in developing countries such as India, due to agricultural activities, the concentration of nitrate in groundwater in agricultural areas has been reported to be more than 1500 mg/l [39]. Denmark and the Netherlands with an annual increase of 0.3-1.2 mg/l nitrate are encountered in agricultural waters. In 15 European countries, the amount of nitrate above 50 mg/l in drinking water has been reported, while its standard in drinking water of surface water origin should be less than 10 mg/l [44, 45].

Diseases caused by nitrate residues in water and food

Higher concentrations of nitrate occur where fertilizers are applied to the land. A regulatory restriction for nitrate in public drinking water supplies was established to protect against infant Methemoglobinemia. In addition, the risk of certain cancers and birth defects may increase with nitrate consumption, and nitrate is reduced to nitrite, which can react with amines and amides to form N-nitroso compounds known to be carcinogenic [14]. Finally, excess nitrates are easily accumulated in human bodies by eating vegetables, fruits, red and white meat, dairy products, grains, and their products [46].

Extra amount of nitrate is absorbed by the salivary glands, which are converted to nitrite by symbiotic bacteria in the oral cavity. This nitrite is converted to NO and other bioactive nitrogen oxides [47]. Some of the excess amounts of nitrate are also rapidly absorbed into the bloodstream through the proximal intestine. Nitrate residues cause perilous, diseases such as cancer, diabetes, osteoporosis, kidney stones, and some other new diseases [10]. High nitrate uptake in gastric cancer in the UK, Chile, Japan, Hungary, and Italy has also been proven because Nitrite in the stomach reacts with amines and amides, so the stomach is at risk of synthesizing an internal carcinogenic compound [48].

There are two views on the relationship between nitrate and cancer. One is that after nitrate enters the body, gastrointestinal bacteria convert it to nitrite, which combines with secondary amines to form carcinogens such as (NAD) and (NOC) [49] and Second, nitrite provides the nutrient raw material for tumor cells and provides the NO signaling molecule necessary for tumor cell growth, in which nitrite indirectly accelerates disease by proliferating and stimulating malignant cancer cells [50].

An increased nitrate concentration in drinking water supplies causes methemoglobinemia in infants and cancer of the alimentary canal; no other group of carcinogens produces such an extensive variety of tumors [51, 52]. The residual carcinogenic potential of nitrate in drinking water is an important issue of the day and many studies have shown the prevalence of various cancers Such as stomach, esophagus, thyroid, and bladder are associated with nitrate levels of drinking water [53]. Methemoglobin is one of the most well-known effects of excess nitrate uptake. In this complication, the enzyme “nitrate reductase” (in saliva or stomach) converts nitrate to nitrite. Combining nitrite with hemoglobin makes methemoglobin, which is unable to carry oxygen. Infants up to 6 months of age are most sensitive because they have higher levels of the enzyme nitrate reductase and therefore more nitrate is converted to nitrite in their body [54]. In severe cases, the disease causes brain damage and eventually death due to suffocation due to lack of oxygen [53, 55]. Infants and children have been reported to be more vulnerable to nitrate than women and the elderly [56, 57]. If even small amounts of nitrate are present in the food of children and infants, they are very vulnerable because their stomach acidity is lower than that of adults [55]. High plasma nitrate concentrations also cause kidney problems and are a major cause of some deaths [58]. Combines it with calcium to form excretable calcium nitrate from the kidneys. There are two serious problems with this condition: first, calcium must be taken from the bones, which in turn causes osteoporosis [59, 60], and second, calcium nitrate must be excreted by the kidneys. This is due to high amounts in them and causes kidney stones and kidney failure [61]. The relationship between excessive nitrate intake and thyroid malfunction has also been reported in different countries [25]. The range of the effects and damage of nitrate in our body correlated to the amount of absorption, duration, and how we are exposed to nitrate. Other factors such as age, sex, diet, family traits, lifestyle, and health status should also be considered [62]. Excess amount of nitrate, less than dangerous level for adults, cause childhood diabetes and acute respiratory infections in children [63].

Based on the study of Lowe (2021), more than 30 epidemiological studies have demonstrated a link between nitrates in drinking water and detrimental health effects since 2005 [64]. Conditions that lead to nitrate contamination in water, such as open defecation, the proximity of septic tanks to water sources, and the use of mineral fertilizers, are common in Indonesia, which has done little research on the assessment of nitrate in drinking water. Estimates of daily nitrate intake, calculated at 50% and 95% exposure to the maximum drinking water nitrate concentration in the two villages, were higher than levels pertinent to birth defects, thyroid conditions, and colorectal cancer observed in other research. There was a large difference in nitrate concentration level between and in the villages at different water sources. Table 2 reports some studies on Nitrate- related disease from contaminated water.

Nitrate removal

Increased use of artificial fertilizers, the disposal of animals and farming wastes, and land-use changes are the main causes responsible for the gradual increase in nitrate levels in groundwater supplies [44, 102]. Because nitrate is highly soluble and mobile, an excess amount of nitrate can be released to surface and groundwater, therewith decreasing the water quality [103-105].

Bioremediation and biodegradation are one of the most environmentally-friendly, cost effective, and practical method for removal of the pollutants out of soil or water [106]. Biological denitrification is one of the main approaches of biological nitrate removal in the dissimilatory pathway, has been shown to be economic and environmentally friendly, due to its selective removal ability to the complete elimination of nitrate and formation of harmless final products [107]. See different technologies for nitrate removal in Table 3.

Nitrate benefits

Inorganic nitrate is synthesized by humans and is consumed in large amounts in a healthy vegetable-rich diet. Recently, it has been demonstrated that supplementation of the diet with nitrate has many effects that may be useful in future studies in the prevention and treatment of a wide range of diseases. The next few years should shed light that we can guide whether we should be taking more or less of this substance in our diet. In particular, it is hoped that we can identify individuals (such as those with high blood pressure and atherosclerosis) who are definitely benefit from increased nitrate and conversely individuals (such as those with esophageal dysplasia) who should avoid foods containing a high concentration of nitrate [13]. Much has been reported about inorganic nitrate in scientific journals and popular press. Articles in the 1970s warned us that inorganic nitrate could theoretically be metabolized in the human body to the compounds which are carcinogenic. Recently, There is a record that nitrate can be metabolically converted to nitrite and nitric oxide, providing a beneficial protective function to improve exercise performance and prevent vascular disease, prevent infection, and protect the stomach [13].

Dietary amounts of nitrate obviously have strong effects in humans, including blood pressure reduction, inhibition of platelet aggregation, and vasoreactivity. In animal models, nitrate protects against ischemic-reperfusion injuries and a wide range of cardiovascular disorders. Furthermore, nitrate unexpectedly decreases whole body oxygen cost during exercise with preserved or even improved maximal performance. Oxidative stress and reduced NO bioavailability are significantly associated with the development of hypertension and other forms of cardiovascular diseases. A major goal for the effects of nitrate and its reaction products can be the mitochondrion and modulation of oxidative stress. All in vivo effects of nitrate can be achieved with high intake of vegetables. A theory is emerging suggesting nitrate as an active component in vegetables plays an important role in the beneficial health effects of this food group, including protection against cardiovascular disease and diabetes [95].

Although Injectable gallium nitrate which is a treatment for hypercalcemia of malignancy due to its immunosuppressive properties, has few adverse effects at therapeutic doses, high-dose infusions may result in severe nephrotoxicity, exclusively in patients who are not adequately hydrated, and severe anemia [118].

Organic nitrates are extensively used in the management of coronary artery disease. These drugs are given to patients with stable angina pectoris and also to patients with unstable angina pectoris, heart failure, and acute myocardial infarction. Although they are advantageous for the treatment of these disorders, their therapeutic value is compromised by the rapid development of tolerance during ongoing therapy [119].

A double-blind randomized crossover eight-week pre-experiment included 16 patients with severe congestive heart failure who received isosorbide dinitrate or placebo followed by the opposite treatment for another eight weeks. This initial trial suggests that long-term vasodilator therapy may be clinically beneficial in congestive heart failure [120].

Long-acting nitrates could reverse CHF-induced changes in drenoceptors (AR) and angiotensin II receptor (ATR) subtypes in the kidney, and restore heart function to protect kidney function. In Comparision with monotherapy, the combination of olmesartan and nitrates indicates significant advantages in regulating AR and ATR subtypes [121].

The findings of a systematic review demonstrate that silver nitrate may be effective in managing the clinical symptoms of recurrent aphthous stomatitis (RAS), and no side effects have been reported so far. To confirm these findings, more high-quality RCTs is needed [122].

Nitrate intake from vegetables is inversely linked with atherosclerotic vascular disease (ASVD) mortality independent of lifestyle and cardiovascular risk factors in this population of elderly women without widspread ASVD or diabetes. These results support the idea that nitrate-rich vegetables may reduce the risk of age-related mortality from ASVD. Independent of other risk factors, higher plant nitrate was correlated to reduced CCA-IMT and a lower risk of an ischemic cerebrovascular disease event [123].

Webb et al (2008) showed a significant reduction in systolic and diastolic blood pressure within 3 h of ingestion of 500 ml of beetroot juice (a rich source of nitrate) [124]. This is consistent with previous results from Lundberg and Weitzberg’s group (2006) showing a significant blood pressure-lowering effect from 3 days of supplementation with sodium nitrate [125].

In 1867, the organic nitrate, Amyl of nitrite firstly used as a therapeutic agent in the treatment of angina pectoris but was replaced later by the organic nitrate, nitroglycerin (NTG), owing to the ease of administration and longer duration of action. The administration of NTG, continues to be used in the treatment of angina pectoris and heart failure during the birth of modern pharmacology [126]. The nitrates/nitrites are classified as agents that directly relax vascular smooth muscle and relax other smooth muscles including ureteral, bronchial, and uterine smooth muscle [127-130].

Nitric oxide (NO), produced from L-arginine and oxygen by NO synthases, is a pleiotropic signaling molecule involved in the regulation of cardiovascular and metabolic systems. The inorganic anions nitrate and nitrite, originating from dietary and endogenous sources, generate NO bioactivity in a process involving symbiotic oral bacteria and host enzymes in blood and tissues. The cardio-metabolic effects of dietary nitrate from experimental and clinical studies include improved endothelial function, increased exercise performance, lowering of blood pressure, and reversal of metabolic syndrome, as well as antidiabetic effects.

The underlying mechanisms of nitrate’s metabolic health effects are being revealed, including reduction of oxidative stress, interaction with mitochondrial respiration, and activation of key metabolic regulatory pathways (Lundberg et al. 2018). Besides, a couple of researches provided evidence on the Potential Benefit of inorganic Nitrate in Acute Kidney Injury and Renal Cell Cancer [131, 132].

In conclusion, an effective way to control the concentration of nitrate in food and drinking water is to prevent contamination of which. This means that forms of proper management of agricultural practices, septic tanks, sewer leakage control, as well as management of fertilizer and manure application and storage of animal manures, as well as Educate consumers and farmers and increase organic production should be encouraged. Despite the effectiveness of nitrate in the treatment of diseases, in the case of soil and water contamination with the excess amount of nitrate, the most cost-effective and efficient approach is the use of the biological method.

References

References

1. Regni L, Proietti P. Effects of Nitrogen Foliar Fertilization on the Vegetative and Productive Performance of the Olive Tree and on Oil Quality. Agriculture. 2019; 9DOI
2. Tei F, De Neve S, Haan J, Kristensen HL. Nitrogen management of vegetable crops. Agricultural Water Management. 2020; 240DOI
3. Dodds WK, Smith VH. Nitrogen, phosphorus, and eutrophication in streams. Inland Waters. 2016; 6(2)DOI
4. Bartucca ML, Mimmo T, Cesco S, Del Buono D. Nitrate removal from polluted water by using a vegetated floating system. The Science of the Total Environment. 2016; 542(Pt A)DOI
5. Usharani K., Keerthi KV. Nitrate Bioremoval by Phytotechnology using Utricularia aurea Collected from Eutrophic Lake of Theerthamkara, Kerala, India. Pollution. 2020; 6(1)DOI
6. Galloway JN, Townsend AR, Erisman JW, Bekunda M, Cai Z, Freney JR, Martinelli LA, Seitzinger SP, Sutton MA. Transformation of the Nitrogen Cycle: Recent Trends, Questions, and Potential Solutions. Science. 2008. DOI
7. Ward MH, Jones RR, Brender JD, Kok TM, Weyer PJ, Nolan BT, Villanueva CM, Breda SG. Drinking Water Nitrate and Human Health: An Updated Review. International Journal of Environmental Research and Public Health. 2018; 15(7)DOI
8. Taneja P, Labhasetwar P, Nagarnaik P, Ensink JHJ. The risk of cancer as a result of elevated levels of nitrate in drinking water and vegetables in Central India. Journal of Water and Health. 2017; 15(4)DOI
9. Weinthal E., Vengosh A., Marei A., Kloppmann W.. The water crisis in the gaza strip: prospects for resolution. Ground Water. 2005; 43(5)DOI
10. EVS, N., Nitrite. Human Health Fact Sheet. Argonne National Laboratory. EVS. 2005.
11. Organization WH. Guidelines for drinking-water quality: second addendum. Vol. 1, Recommendations. World Health Organization. 2008.
12. Santamaria P. Nitrate in vegetables: toxicity, content, intake and EC regulation. Journal of the Science of Food and Agriculture. 2006; 86(1)DOI
13. Gilchrist M, Winyard PG, Benjamin N. Dietary nitrate--good or bad?. Nitric Oxide: Biology and Chemistry. 2010; 22(2)DOI
14. Essien EE, Said Abasse K, Côté A, Mohamed KS, Baig MMFA, Habib M, Naveed M, Yu X, Xie W, Jinfang S, Abbas M. Drinking-water nitrate and cancer risk: A systematic review and meta-analysis. Archives of Environmental & Occupational Health. 2022; 77(1)DOI
15. Galloway JN, Cowling EB. Reactive nitrogen and the world: 200 years of change. Ambio. 2002; 31(2)DOI
16. Camargo JA, Alonso A, Salamanca A. Nitrate toxicity to aquatic animals: a review with new data for freshwater invertebrates. Chemosphere. 2005; 58(9)DOI
17. Peterson J, et al. Radiological and chemical fact sheets to support health risk analyses for contaminated areas. Argonne National Laboratory Environmental Science Division. 2007; 133:40-41.
18. Yang C, Wu D, Chang C. Nitrate in drinking water and risk of death from colon cancer in Taiwan. Environment International. 2007; 33(5)DOI
19. Gangolli S. D., Brandt P. A., Feron V. J., Janzowsky C., Koeman J. H., Speijers G. J., Spiegelhalder B., Walker R., Wisnok J. S.. Nitrate, nitrite and N-nitroso compounds. European Journal of Pharmacology. 1994; 292(1)DOI
20. Gupta S, Gupta R., Chhabra S., Eskiocak S, Gupta A, Gupta R. Health issues related to N pollution in water and air. Current Science. 2008; 94
21. Lian-feng S, Rong-ping C, Fa-wen Z, Jian-tao Y, You L. Discussion on Nitrogen and Phosphorus Removal Process Characteristics of Improved Oxidation Ditch. Procedia Environmental Sciences. 2011; 11DOI
22. Grinsven HJ, Rabl A, Kok TM. Estimation of incidence and social cost of colon cancer due to nitrate in drinking water in the EU: a tentative cost-benefit assessment. Environmental Health. 2010; 9(1)DOI
23. Coss A, Cantor KP, Reif JS, Lynch CF, Ward MH. Pancreatic cancer and drinking water and dietary sources of nitrate and nitrite. American Journal of Epidemiology. 2004; 159(7)DOI
24. Brody JG, Aschengrau A, McKelvey W, Swartz CH, Kennedy T, Rudel RA. Breast cancer risk and drinking water contaminated by wastewater: a case control study. Environmental Health: A Global Access Science Source. 2006; 5DOI
25. WHO. Background document for development of WHO guidelines for drinking-water quality. World Health Organization; Arsenic in Drinking-Water Geneva. 2011.
26. Shokrzadeh M, et al. The measurement of nitrate and nitrite content in leek and spinach sampled from central cities of Mazandaran State of Iran. World Applied Sciences Journal. 2007; 2(2):121-124.
27. Sadeghi Pour Marvi M, Tabakhian S. Determination of Nitrogen and Phosphorous Requirement for Promising Line of Lettuce in Varamin. 2008.
28. Rezaei M, et al. Determining nitrate and nitrite content in beverages, fruits, vegetables, and stews marketed in Arak, Iran. International scholarly research notices. 2014; 2014
29. Qiu W, Zhifan W, Huang C, Bao-Ming C, Yang R. Nitrate accumulation in leafy vegetables and its relationship with water.. Journal of Soil Science and Plant Nutrition. 2014; 14
30. Bondonno CP, Liu AH, Croft KD, Ward NC, Puddey IB, Woodman RJ, Hodgson JM. Short-term effects of a high nitrate diet on nitrate metabolism in healthy individuals. Nutrients. 2015; 7(3)DOI
31. Yousefi H, Haghizadeh A, Yarahmadi Y, Hasanpour P, Noormohamadi P. Groundwater pollution potential evaluation in Khorramabad-Lorestan Plain, western Iran. Journal of African Earth Sciences. 2018; 147DOI
32. Nemčić-Jurec J, Jazbec A. Point source pollution and variability of nitrate concentrations in water from shallow aquifers. Applied Water Science. 2016; 7(3)
33. FAO. World Fertilizer Trends and Outlook to 2022.. Rome. 2019.
34. FAO F. Agriculture Organization of the United Nations (FAO). World fertilizer trends and outlook to, 2020. 2017.
35. Lenka, S., S, Singh AK, Lenka NK. Soil water and nitrogen interaction effect on residual soil nitrate and crop nitrogen recovery under maize–wheat cropping system in the semi-arid region of northern India. Agriculture, ecosystems & environment. 2013; 179:108-115.
36. Hofman G. Nutrient management legislation in European countries. NUMALEC Report. Concerted action, Fair6–CT98–4215. Nutrient management legislation in European countries. NUMALEC Report. Concerted action, Fair6–CT98–4215. 1999.
37. Ward Mary H., deKok Theo M., Levallois Patrick, Brender Jean, Gulis Gabriel, Nolan Bernard T., VanDerslice James. Workgroup Report: Drinking-Water Nitrate and Health—Recent Findings and Research Needs. Environmental Health Perspectives. 2005; 113(11)DOI
38. SCF, Scientific Committee for Food. First annual report on chemically defined flavouring substances. 1995.
39. Organization WH. Atrazine in drinking-water: background document for development of WHO guidelines for drinking-water quality. 2003, World Health Organization.
40. Corré W.J, Breimer T. Nitrate and nitrite in vegetables. 1979: Pudoc.
41. Addiscott, TM. Nitrate, agriculture and the environment. 2005: CABI..
42. Authority EFS. Nitrate in vegetables‐Scientific Opinion of the Panel on Contaminants in the Food chain. EFSA Journal, 2008. 6(6): p. 689.. 2008; 6(6):689.
43. Protection, U.S.E.P.A.O.o.G.-W. Guidelines for delineation of wellhead protection areas. 1987: United States Environmental Protection Agency, Office of Ground Water Protection..
44. WHO C. Health hazards from nitrates in drinking-water. 1985.
45. group Ew. The mutagenicity and carcinogenicity of vinyl chloride: a historical review and assessment. 1988.
46. Well H. Agency for Toxic Substances and Disease Registry (ATSDR). 2015.
47. Bryan Nathan, Grinsven Hans. The Role of Nitrate in Human Health. Advances in Agronomy. 2013; 119DOI
48. Forman D, Shuker D. Helicobacter pylori and gastric cancer-A case study in molecular epidemiology. Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis. 1997; 379(S1):S159.
49. Catsburg CE, Gago-Dominguez M, Yuan J, Castelao J, Cortessis VK, Pike MC, Stern MC. Dietary sources of N-nitroso compounds and bladder cancer risk: findings from the Los Angeles bladder cancer study. International Journal of Cancer. 2014; 134(1)DOI
50. Huangfu M, Wang M, Tan Z, Wang X. Analytical solutions for steady seepage into an underwater circular tunnel. Tunnelling and Underground Space Technology. 2010; 25DOI
51. Ovez B. Batch biological denitrification using Arundo donax, Glycyrrhiza glabra, and Gracilaria verrucosa as carbon source. Process Biochemistry. 2006; 41DOI
52. Ashok V, Hait S. Remediation of nitrate-contaminated water by solid-phase denitrification process-a review. Environmental Science and Pollution Research International. 2015; 22(11)DOI
53. Chetty AA, Prasad S. Flow injection analysis of nitrate and nitrite in commercial baby foods. Food Chemistry. 2016; 197(Pt A)DOI
54. Zhang P, Lee J, Kang G, Li Y, Yang D, Pang B, Zhang Y. Disparity of nitrate and nitrite in vivo in cancer villages as compared to other areas in Huai River Basin, China. The Science of the Total Environment. 2018; 612DOI
55. Cassidy N, Duggan E. Potential pitfalls with the treatment of acquired methaemoglobinaemia. 2015.
56. Walkuska Grazyna, Wilczek Agnieszka. Influence of Discharged Heated Water on Aquatic Ecosystem Fauna. Polish Journal of Environmental Studies. 2010; 19
57. Obek E. Bioaccumulation of heavy metals from the secondary treated municipal wastewater by Lemna gibba L. Fresenius Environmental Bulletin., b,. 2009; 18:2160-2166.
58. Maas R, Xanthakis V, Göen T, Müller J, Schwedhelm E, Böger RH, Vasan RS. Plasma Nitrate and Incidence of Cardiovascular Disease and All-Cause Mortality in the Community: The Framingham Offspring Study. Journal of the American Heart Association. 2017; 6(11)DOI
59. Zuin M, et al. Nitrates and osteoporosis: Which relationship?. 43. 2017; European Journal of Internal Medicine:e22-e23.
60. Weyer P. J., Cerhan J. R., Kross B. C., Hallberg G. R., Kantamneni J., Breuer G., Jones M. P., Zheng W., Lynch C. F.. Municipal drinking water nitrate level and cancer risk in older women: the Iowa Women's Health Study. Epidemiology (Cambridge, Mass.). 2001; 12(3)DOI
61. Kaur S, Khera KS, Kondal JK. Heavy metal induced histopathological alterations in liver, muscle and kidney of freshwater cyprinid, Labeo rohita (Hamilton). Journal of Entomology and Zoology Studies. 2018; 6(2):2137-2144.
62. Lundberg JO, Carlström M, Weitzberg E. Metabolic Effects of Dietary Nitrate in Health and Disease. Cell Metabolism. 2018; 28(1)DOI
63. Haftbaradaran S., Khoshgoftarmanesh A. H., Malakouti M. J.. Assessment, mapping, and management of health risk from nitrate accumulation in onion for Iranian population. Ecotoxicology and Environmental Safety. 2018; 161DOI
64. Lowe C, Kurscheid J, Lal A, Sadler R, Kelly M, Stewart D, Laksono B, Amaral S, Gray D. Health Risk Assessment for Exposure to Nitrate in Drinking Water in Central Java, Indonesia. International Journal of Environmental Research and Public Health. 2021; 18(5)DOI
65. Blaisdell J, Turyk ME, Almberg KS, Jones RM, Stayner LT. Prenatal exposure to nitrate in drinking water and the risk of congenital anomalies. Environmental Research. 2019; 176DOI
66. Quist AJL, Inoue-Choi M, Weyer PJ, Anderson KE, Cantor KP, Krasner S, Freeman LEB, Ward MH, Jones RR. Ingested nitrate and nitrite, disinfection by-products, and pancreatic cancer risk in postmenopausal women. International Journal of Cancer. 2018; 142(2)DOI
67. Stayner LT, Almberg K, Jones R, Graber J, Pedersen M, Turyk M. Atrazine and nitrate in drinking water and the risk of preterm delivery and low birth weight in four Midwestern states. Environmental Research. 2017; 152DOI
68. Jones RR, Weyer PJ, DellaValle CT, Robien K, Cantor KP, Krasner S, Beane Freeman LE, Ward MJ. Ingested Nitrate, Disinfection By-products, and Kidney Cancer Risk in Older Women. Epidemiology (Cambridge, Mass.). 2017; 28(5)DOI
69. McElroy JA, Trentham-Dietz A, Gangnon RE, Hampton JM, Bersch AJ, Kanarek MS, Newcomb PA. Nitrogen-nitrate exposure from drinking water and colorectal cancer risk for rural women in Wisconsin, USA. Journal of Water and Health. 2008; 6(3)DOI
70. Espejo-Herrera N, Gràcia-Lavedan E, Boldo E, Aragonés N, Pérez-Gómez B, Pollán M, Molina AJ, et al. Colorectal cancer risk and nitrate exposure through drinking water and diet. International Journal of Cancer. 2016; 139(2)DOI
71. Fathmawati N, Fachiroh J, Gravitiani E, Sarto N, Husodo AH. Nitrate in drinking water and risk of colorectal cancer in Yogyakarta, Indonesia. Journal of Toxicology and Environmental Health. Part A. 2017; 80(2)DOI
72. Schullehner J, Hansen B, Thygesen M, Pedersen CB, Sigsgaard T. Nitrate in drinking water and colorectal cancer risk: A nationwide population-based cohort study. International Journal of Cancer. 2018; 143(1)DOI
73. Zeegers MP, Selen REM, Kleinjans JCS, Goldbohm RA, Brandt PA. Nitrate intake does not influence bladder cancer risk: the Netherlands cohort study. Environmental Health Perspectives. 2006; 114(10)DOI
74. Espejo-Herrera N, Cantor KP, Malats N, Silverman DT, Tardón A, García-Closas R, Serra C, Kogevinas M, Villanueva CM. Nitrate in drinking water and bladder cancer risk in Spain. Environmental Research. 2015; 137DOI
75. Jones PA, Issa JJ, Baylin S. Targeting the cancer epigenome for therapy. Nature Reviews. Genetics. 2016; 17(10)DOI
76. Ebrahimifar M, Nili-Ahmadabadi A, Akbarzadeh A, Shahemabadi HE, Hasanzadegan M, Moradi-Sardareh H, Madadizadeh H, Rezaee-Diyan J. Preparation, Characterization and Cytotoxic Effects of Pegylated Nanoliposomal Containing Carboplatin on Ovarian Cancer Cell Lines. Indian journal of clinical biochemistry: IJCB. 2017; 32(2)DOI
77. Albouy-Llaty M, Limousi F, Carles C, Dupuis A, Rabouan S, Migeot V. Association between Exposure to Endocrine Disruptors in Drinking Water and Preterm Birth, Taking Neighborhood Deprivation into Account: A Historic Cohort Study. International Journal of Environmental Research and Public Health. 2016; 13(8)DOI
78. Inoue-Choi M, Ward MH, Cerhan JR, Weyer PJ, Anderson KE, Robien K. Interaction of nitrate and folate on the risk of breast cancer among postmenopausal women. Nutrition and Cancer. 2012; 64(5)DOI
79. Espejo-Herrera N, Gracia-Lavedan E, Pollan M, Aragonés N, Boldo E, Perez-Gomez B, Altzibar JM, et al. Ingested Nitrate and Breast Cancer in the Spanish Multicase-Control Study on Cancer (MCC-Spain). Environmental Health Perspectives. 2016; 124(7)DOI
80. Kanaani L, Javadi I, Ebrahimifar M, Ebrahimi Shahmabadi H, Akbarzadeh Khiyav A, Mehrdiba T. Effects of Cisplatin-Loaded Niosomal Nanoparticleson BT-20 Human Breast Carcinoma Cells. Asian Pacific journal of cancer prevention: APJCP. 2017; 18(2)DOI
81. Amiri B, Ebrahimi-Far M, Saffari Z, Akbarzadeh A, Soleimani E, Chiani M. Preparation, Characterization and Cytotoxicity of Silibinin- Containing Nanoniosomes in T47D Human Breast Carcinoma Cells. Asian Pacific journal of cancer prevention: APJCP. 2016; 17(8)
82. kbarzadeh I, Shayan M. Preparation, optimization and in-vitro evaluation of curcumin- loaded niosome@ calcium alginate nanocarrier as a new approach for breast cancer treatment. Biology. 2021; 10(3):173.
83. Akbarzadeh I, Poor AS. Gingerol/letrozole-loaded mesoporous silica nanoparticles for breast cancer therapy: In-silico and in-vitro studies. Microporous and Mesoporous Materials. 2022; 337:111919.
84. Moghtaderi M, Sedaghatnia K, Bourbour M, Fatemizadeh M, Salehi Moghaddam Z, Hejabi F, Heidari F, Quazi S, Farasati Far B. Niosomes: a novel targeted drug delivery system for cancer. Medical Oncology (Northwood, London, England). 2022; 39(12)DOI
85. Inoue-Choi M, Jones RR, Anderson KE, Cantor KP, Cerhan JR, Krasner S, Robien K, Weyer PJ, Ward MH. Nitrate and nitrite ingestion and risk of ovarian cancer among postmenopausal women in Iowa. International Journal of Cancer. 2015; 137(1)DOI
86. Holtby CE, et al. www. mdpi. com/journal/ijerph Article A Population-Based Case-Control Study of Drinking-Water Nitrate and Congenital Anomalies Using Geographic Information Systems (GIS) to Develop Individual-Level Exposure Estimates. 2014.
87. Brender JD, Weyer PJ, Romitti PA, Mohanty BP, Shinde MU, Vuong AM, Sharkey JR, et al. Prenatal nitrate intake from drinking water and selected birth defects in offspring of participants in the national birth defects prevention study. Environmental Health Perspectives. 2013; 121(9)DOI
88. Weyer PJ, Brender JD, Romitti PA, Kantamneni JR, Crawford D, Sharkey JR, Shinde M, Horel SA, Vuong AM, Langlois PH. Assessing bottled water nitrate concentrations to evaluate total drinking water nitrate exposure and risk of birth defects. Journal of Water and Health. 2014; 12(4)DOI
89. Migeot V., Albouy-Llaty M., Carles C., Limousi F., Strezlec S., Dupuis A., Rabouan S.. Drinking-water exposure to a mixture of nitrate and low-dose atrazine metabolites and small-for-gestational age (SGA) babies: a historic cohort study. Environmental Research. 2013; 122DOI
90. Ward MH, Kilfoy BA, Weyer PJ, Anderson KE, Folsom AR, Cerhan JR. Nitrate intake and the risk of thyroid cancer and thyroid disease. Epidemiology (Cambridge, Mass.). 2010; 21(3)DOI
91. Ward MH, Heineman EF, Markin RS, Weisenburger DD. Adenocarcinoma of the stomach and esophagus and drinking water and dietary sources of nitrate and nitrite. International Journal of Occupational and Environmental Health. 2008; 14(3)DOI
92. Joyce SJ, Cook A, Newnham J, Brenters M, Ferguson C, Weinstein P. Water disinfection by-products and pre-labor rupture of membranes. American Journal of Epidemiology. 2008; 168(5)DOI
93. Winchester PD, Huskins J, Ying J. Agrichemicals in surface water and birth defects in the United States. Acta Paediatrica (Oslo, Norway: 1992). 2009; 98(4)DOI
94. Waller SA, Paul K, Peterson SE, Hitti JE. Agricultural-related chemical exposures, season of conception, and risk of gastroschisis in Washington State. American Journal of Obstetrics and Gynecology. 2010; 202(3)DOI
95. Lundberg JO, Carlström M, Larsen FJ, Weitzberg E. Roles of dietary inorganic nitrate in cardiovascular health and disease. Cardiovascular Research. 2011; 89(3)DOI
96. Ebrahimifar M, Hasanzadegan Roudsari M, Kazemi SM, Ebrahimi Shahmabadi H, Kanaani L, Alavi SA, Izadi Vasfi M. Enhancing Effects of Curcumin on Cytotoxicity of Paclitaxel, Methotrexate and Vincristine in Gastric Cancer Cells. Asian Pacific journal of cancer prevention: APJCP. 2017; 18(1)DOI
97. Gatseva PD, Argirova MD. Iodine status and goitre prevalence in nitrate-exposed schoolchildren living in rural Bulgaria. Public Health. 2008; 122(5)DOI
98. Mattix KD, Winchester PD, Scherer LRT. Incidence of abdominal wall defects is related to surface water atrazine and nitrate levels. Journal of Pediatric Surgery. 2007; 42(6)DOI
99. Ward MH, Cerhan JR, Colt JS, Hartge P. Risk of non-Hodgkin lymphoma and nitrate and nitrite from drinking water and diet. Epidemiology (Cambridge, Mass.). 2006; 17(4)DOI
100. Ward MH, Rusiecki JA, Lynch CF, Cantor KP. Nitrate in public water supplies and the risk of renal cell carcinoma. Cancer causes & control: CCC. 2007; 18(10)DOI
101. Mueller T, Regele H, Posch M, Marszalek M, Schwarz C, Pichlhoefer B, Arbeiter K, Aufricht C. HSP-72 expression in pre-transplant donor kidney biopsies and post-transplant outcome. Transplantation. 2004; 78(2)DOI
102. Karanasios K. A., Vasiliadou I. A., Pavlou S., Vayenas D. V.. Hydrogenotrophic denitrification of potable water: a review. Journal of Hazardous Materials. 2010; 180(1-3)DOI
103. Seitzinger S. P., Mayorga E., Bouwman A. F., Kroeze C., Beusen A. H. W., Billen G., Van Drecht G., Dumont E., Fekete B. M., Garnier J., Harrison J. A.. Global river nutrient export: A scenario analysis of past and future trends. Global Biogeochemical Cycles. 2010; 24(4)DOI
104. Chintala R, Mollinedo J, Schumacher T, Schneider S, Malo D, Clay D, Kumar S, Gulbrandson D. Nitrate Sorption and Desorption in Biochars from Fast Pyrolysis. Microporous and Mesoporous Materials. 2013; 179DOI
105. Weigelhofer G, Hein T. Efficiency and detrimental side effects of denitrifying bioreactors for nitrate reduction in drainage water. Environmental Science and Pollution Research International. 2015; 22(17)DOI
106. Hatamian Zarmi A, Shojaosadati S, Vasheghani-Farahani E, Hosseinkhani S, Emamzadeh A. Extensive biodegradation of highly chlorinated biphenyl and Aroclor 1242 by Pseudomonas aeruginosa TMU56 isolated from contaminated soils. International Biodeterioration & Biodegradation. 2009; 63DOI
107. Rezvani F, Sarrafzadeh M, Ebrahimi S, Oh H. Nitrate removal from drinking water with a focus on biological methods: a review. Environmental Science and Pollution Research International. 2019; 26(2)DOI
108. Schoeman J, Steyn A. Nitrate removal with reverse osmosis in a rural area in South Africa. Desalination. 2003; 155(1):15-26.
109. Cliford D, Liu X. Ion exchange for nitrate removal. Journal‐American Water Works Association. 1993; 85(4):135-143.
110. Szpyrkowicz L., Daniele S., Radaelli M, Specchia S. Removal of NO3− from water by electrochemical reduction in different reactor configurations. Applied Catalysis B Environmental. 2006; 66DOI
111. Hell F., Lahnsteiner J., Frischherz H., Baumgartner G.. Experience with full-scale electrodialysis for nitrate and hardness removal. Desalination. 1998; 117(1)DOI
112. Batista J, Levec J. Catalytic denitrification: Direct and indirect removal of nitrates from potable water. Catalysis Today - CATAL TODAY. 2001; 66DOI
113. Bhatnagar A, Sillanpää M. A review of emerging adsorbents for nitrate removal from water. Chemical Engineering Journal. 2011; 168DOI
114. Choi J, Maruthamuthu S, Lee H, Ha T, Bae J. Nitrate removal by electro-bioremediation technology in Korean soil. Journal of Hazardous Materials. 2009; 168(2-3)DOI
115. Pous N, Puig S, Coma M, Balaguer MD, Colprim J. Bioremediation of nitrate-polluted groundwater in a microbial fuel cell. Journal of Chemical Technology & Biotechnology. 2013; 88(9)DOI
116. Castro-Rodríguez V, García-Gutiérrez A, Canales J, Cañas RA, Kirby EG, Avila C, Cánovas FM. Poplar trees for phytoremediation of high levels of nitrate and applications in bioenergy. Plant Biotechnology Journal. 2016; 14(1)DOI
117. Azaripa H, et al. Vermiremediation of microelements and soluble salts in sewage sludge by earthworms. Inter. J. Curr. Res. 2013; 5(12):3628-3632..
118. Apseloff G.. Therapeutic uses of gallium nitrate: past, present, and future. American Journal of Therapeutics. 1999; 6(6)DOI
119. Parker J. D., Parker J. O.. Nitrate therapy for stable angina pectoris. The New England Journal of Medicine. 1998; 338(8)DOI
120. Franciosa J. A., Nordstrom L. A., Cohn J. N.. Nitrate therapy for congestive heart failure. JAMA. 1978; 240(5)
121. Peng Yubo, Li Yanfang, Chen Mengmeng, Song Junying, Jiang Zhili, Shi Shutian. High-dose nitrate therapy recovers the expression of subtypes α1 and β-adrenoceptors and Ang II receptors of the renal cortex in rats with myocardial infarction-induced heart failures. BMC Cardiovascular Disorders. 2020; 20(1)DOI
122. Bashir NZ, Caratela N. Silver nitrate in the management of recurrent aphthous stomatitis: A systematic review and meta-analysis. Journal of Oral and Maxillofacial Surgery. Medicine, and Pathology. 2021; 33(2):196-203.
123. Blekkenhorst LC, Bondonno CP, Lewis JR, Devine A, Woodman RJ, Croft KD, Lim WH, Wong G, Beilin LJ, Prince RJ, Hodgson JM. Association of dietary nitrate with atherosclerotic vascular disease mortality: a prospective cohort study of older adult women. The American Journal of Clinical Nutrition. 2017; 106(1)DOI
124. Webb AJ, Patel N, Loukogeorgakis S, Okorie M, Aboud Z, Misra S, Rashid R, Miall P, et al. Acute blood pressure lowering, vasoprotective, and antiplatelet properties of dietary nitrate via bioconversion to nitrite. Hypertension (Dallas, Tex.: 1979). 2008; 51(3)DOI
125. Larsen FJ, Ekblom B, Sahlin K, Lundberg JO, Weitzberg E. Effects of dietary nitrate on blood pressure in healthy volunteers. The New England Journal of Medicine. 2006; 355(26)DOI
126. Nossaman VE, Nossaman BD, Kadowitz PJ. Nitrates and nitrites in the treatment of ischemic cardiac disease. Cardiology in Review. 2010; 18(4)DOI
127. Chen C. F., Yeh S. U., Chien C. T., Wu M. S.. Renal response during acute unilateral ureteral obstruction in rats. Neurourology and Urodynamics. 2001; 20(1)DOI
128. Dong Y. L., Gangula P. R., Fang L., Wimalawansa S. J., Yallampalli C.. Uterine relaxation responses to calcitonin gene-related peptide and calcitonin gene-related peptide receptors decreased during labor in rats. American Journal of Obstetrics and Gynecology. 1998; 179(2)DOI
129. Facchinetti F., Neri I., Genazzani A. R.. L-arginine infusion reduces preterm uterine contractions. Journal of Perinatal Medicine. 1996; 24(3)DOI
130. Yallampalli C., Garfield R. E., Byam-Smith M.. Nitric oxide inhibits uterine contractility during pregnancy but not during delivery. Endocrinology. 1993; 133(4)DOI
131. Gilchrist M, Benjamin N. Potential Benefit of Inorganic Nitrate in Acute Kidney Injury and Renal Cell Cancer. Medicine and Science in Sports and Exercise. 2015; 47(7)DOI
132. Gilchrist M, Benjamin N. Potential Benefit of Inorganic Nitrate in Acute Kidney Injury and Renal Cell Cancer. Medicine and science in sports and exercise. 2015; 47(7)DOI