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Approximately 1 in 113 men and women in the U.S. will be diagnosed with cancer of the stomach during their lifetime according to the National Institute of Cancer. The incidence of gastric cancer (GC) varies greatly depending on ethnicity. Asians, Pacific Islanders, African Americans and Hispanics have the highest mortality rates in the U.S. Research indicates that nitrate consumption increases risk of gastric cancer by converting dietary nitrate to nitrite and then to carcinogenic N-nitroso compounds.
The association between dietary intake of nitrates and GC is somewhat controversial since some scientists propose that nitrates are beneficial to the body and therefore should be classified as nutrients. Dietary nitrates, although precursors for N-nitroso, when consumed with polyphenols and antioxidants may exhibit a protective effect for gastric cancer. Scientists hypothesize that these compounds may inhibit endogenous nitrogenation.
In both Mexico and Korea scientists have explored novel approaches in assessing risk of dietary nitrates in GC. The population-based case-control study in Mexico City reported an approximate 50% reduction in gastric cancer risk among those with high polyphenol intakes of cinnamic acids, secoisolariciresinol and coumestrol. Absolute nitrite intake as well as animal source nitrate and nitrite consumption nearly doubled the GC risk, while high consumption of nitrate from fruits and vegetables was associated with decreased risk of GC. The risk was greatest among those with high animal nitrate intake and low polyphenol intake.
The case-control study in Korea showed that a higher absolute intake of dietary nitrate was not associated with an increased risk for gastric cancer although this risk increased as the nitrate:antioxidant vitamin consumption ratio increased. Authors propose that reducing nitrate intake relative to antioxidant supplementation may be more important that absolute nitrate intake when preventing gastric cancer.
These findings highlight a new dietary approach worthy of exploration in the quest to reducing the risk of GC.
After viewing this presentation, participants will be able to:
Explain the proposed mechanism through which N-nitroso compounds are formed
Describe the mechanism by which antioxidants are thought to protect against gastric cancer
Describe major dietary sources of nitrate, nitrite, antioxidant vitamins and polyphenols thought to affect gastric cancer risk
Describe the current hypotheses regarding the associations between nitrate, nitrite, antioxidant vitamins, polyphenols and gastric cancer
Explain the current hypothesis regarding the nitrate:antioxidant ratio and gastric cancer risk
Critically assess and draw conclusions on the strength of evidence regarding the associations between nitrate, nitrite, antioxidant vitamins, polyphenols and gastric cancer
Describe the latest research promoting both the positive and the negative aspects of nitrates and nitrite on health
Dietary Intake of Polyphenols, Nitrate and Nitrite and Gastric Cancer Risk in Mexico City Hernández-Ramírez RU, Galván-Portillo MV, Ward MH, Agudo A, González CA, Oñate-Ocaña LF, Herrera-Goepfert R, Palma-Coca O, López-Carrillo L. Int J Cancer. 2009 Sep 15;125(6):1424-30.
In Mexico, gastric cancer rates have been increasing, and are the 2 nd leading cause of cancer death (2)
Nitrate and nitrite are precursors for the endogenous formation of N-nitroso compounds (NOC), a known carcinogen in animals (3)
The formation of NOC Certain antioxidants prevent the formation of NOC
Research consistently shows that nitrite consumption increases the risk of gastric cancer (4)
Research evaluating the association of nitrate consumption with gastric cancer is somewhat conflicting ; some studies show no association and some show it decreases risk (5-14)
The major dietary source of nitrate is vegetables. Vegetables also contain antioxidants, which are inhibitors of NOC formation
The major dietary source of nitrite is preserved meats. Preserved meats also contain nitrosatable compounds (amides and amines) , which contribute to the formation of NOC (3)
Introduction to Polyphenols
Polyphenols may play a role in preventing cancer through several mechanisms, including (15):
Inhibiting cell proliferation
Induction of cancer cell apoptosis
Prevention of oxidation
Induction of detoxification enzymes
However, epidemiologic evidence for an inverse association between polyphenols and gastric cancer risk is limited
The objective of this study was to evaluate the individual and joint effects of consumption of polyphenols, nitrate and nitrite on gastric cancer risk
Critique - Introduction
Provided brief background on previous research and the hypothesized mechanisms involving nitrites, nitrates, polyphenols and gastric cancer
A brief summary of the research design and why the research design was selected could have added to the introduction
Population-based case-control study of gastric cancer in Mexico City between Jan 2004 and Dec 2005
263 case patients who met the criteria identified, 257 agreed to participate
For each case, up to 2 controls were matched by age (+/- 5 years) and gender
Structured interviews about participant's sociodemographic characteristics, medical history, lifestyle and dietary patterns
Tests for helicobacter pylori CagA positivity
127-item FFQ developed for the Mexican population and previously validated
Statistical analysis :
Selected dietary and other characteristics were compared between cases and controls using the Mann-Whitney and the x2 tests
Evaluated tertiles of distributions of polyphenols, nitrate and nitrite in relation to gastric cancer risk
Controlled for age, gender, energy, schooling, H. pylori CagA status, chili consumption, salt consumption, and alcohol intake
Critique - Methods
Controlled for multiple confounding variables, including Helicobacter pylori CagA positivity and chili consumption
Separately evaluated animal and plant sources of nitrate
Matched cases and controls
High response rate
Retrospective, case-control study is inherently subject to biases
Only patients from public hospitals included
Cases had significantly more years of schooling, higher prevalence of H. pylori CagA antibodies, higher total energy intake and greater consumption of alcohol, salt and chili than controls
Cases consumed more total nitrite
Also consumed more total nitrate/nitrite from animal sources, but the difference was not statistically significant
Controls consumed more vegetables, total nitrate, nitrite/nitrate from fruits and vegetables, cinnamic acids, total lignans, secoisolariciresinol and coumestrol.
Flavanols and pinoresinol consumption was also greater among controls, but the differences were not significant
Characteristics of the Study Population
Intake of Polyphenols, Nitrate and Nitrite
Increasing consumption of cinnamic acids, secoisolariciresinol, and coumestrol was associated with significant inverse trends in gastric cancer risk (see chart on next slide)
Intakes of flavoniods and lignans did not show significant associations
High consumption of total nitrite and nitrate/nitrite from animal sources was associated with an increased risk of gastric cancer (nitrate: 1.92 OR, p=0.004; nitrite: 1.56 OR, p=0.030)
High consumption of total nitrate and nitrate/nitrite from fruits and vegetables was associated with a decreased risk of gastric cancer (nitrate: 0.62 OR, p=0.038; nitrite: 0.77 OR, p=0.216)
Risk was highest for those with both high nitrite/nitrate intake from animal sources and low polyphenol intake
Inverse Association of Polyphenols and GC
GC Risk by Histological Type
Critique - Results
Data is fully presented in tables and graphs
Retrospective study: unable to determine causality
Relative risk, but not absolute risk, presented
This study’s results show, for the first time, a reduced risk for gastric cancer with higher consumption of polyphenols such as cinnamic acids, secoisolariciresinol, and coumestrol
The results for dietary nitrite being associated with an increased risk of gastric cancer are consistent with the findings of most previous studies
In contrast to most previous studies, however, this study separated animal and plant sources of nitrite/nitrate
Authors asserted that more studies are needed to confirm the associations between intake of specific polyphenols and gastric cancer risk
Dietary sources of polyphenols were also discussed. Boxed in red are those polyphenols found to have a negative association with gastric cancer in this study and the major dietary sources in this Mexican population
Critique - Discussion
Discussion provided little further insight regarding the significance or implications of their findings
Data appears to support the conclusions drawn by the authors, although authors should be careful when drawing conclusions about causality
Limitations of research discussed
Critique - Strength of Evidence
Contributes to growing evidence of nitrites and their positive association with gastric cancer
Provides new evidence of certain polyphenols being linked to a reduced risk of gastric cancer, however further studies needed to strengthen the evidence of this finding
Nitrate Intake Relative to Antioxidant Vitamin Intake Affects Gastric Cancer Risk: A Case-Control Study in Korea Hyun Ja Kim, Sang Sun Lee, Bo Youl Choi and Mi Kyung Kim Nutrition and Cancer, 59(2), 185-191, 2007
Introduction to Nitrates
Gastic Cancer remains the leading type of cancer in Korea as per the nationwide Cancer Registry Program (16)
The metabolites of nitrate are known carcinogens which have led to concern about nitrates in food
Nitrate reduces to Nitrite and is involved in the formation of carcinogenic N -nitroso compounds (17,18)
An ecological study of total nitrate intake in 12 countries revealed a high correlation between nitrate intake and incidence of Gastric Cancer (GC) (19)
Introduction to Antioxidants
Antioxidant vitamins (vitamin C, vitamin E and carotenoids) and phytochemicals from foods protect against GC by inhibiting the intragastric formation of N -nitroso compounds (20-22)
The major source of antioxidant vitamins are fruits and vegetables yet vegetables, particularly leafy vegetables, are also a main source of nitrate! The use of widespread use of nitrogen-based fertilizers may be the cause for accumulation among vegetables. (23)
Although the detrimental effects of nitrates to the carcinogenic process have been suggested, many epidemiological studies on dietary nitrate and GC risk have demonstrated no association. (24-30)
Authors Kim et al. propose that the dietary requirement for antioxidant vitamins increases as intake of nitrates increases
The intake of nitrate relative to antioxidant vitamins rather than absolute intake of nitrate per se affects GC risk
Case-control study of patients of Hanyang University Hospital and Hallym University Hospital in Korea, March 1997 to Nov. 1998
136 cases and 166 controls
Controls were matched by age (+/- 2 years) and gender
Questionnaire included socioeconomic, family history, medical history, smoking, drinking, duration of refrigerator use, vitamin intake and dietary information
Dietitians interviewed patients based on a FFQ recording the average intake and portion size of 109 food items for a 12-month period of 3 years prior to the interview (31)
To avoid bias all patients were interviewed after endoscopic examination yet prior to histological diagnosis. Nitrate/nitrite values were taken from data analyzed in a previous paper since national food composition data do not contain information on nitrate (Kim and Yoon (32)
Total amount of each food intake was divided into 3 groups (<25, 25-75, >75 percentiles) under the criterion of the control group
T-tests for continuous variables and x2 tests for categorical values were compared
Correlations between nitrate and vitamin intake were tested by partial correlation analysis adjusting for age and gender
Factors which exhibited an association with GC in previous studies were adjusted for in a multivariate logistic model. (socioeconomic status, family history of GC, duration of refrigerator use, and H. pylori infection)
Nitrate:antioxidant vitamin consumption ratio for daily consumption was used to assess the effect of the intake of nitrate relative to antioxidant vitamins
Critique - Methods
A unique study since the database to assess daily nitrogen intake in content has only recently been created in Korea
Interviewing the patients prior to diagnosis reduces recall bias during the FFQ interview
Interviews were conducted by trained dietitians
Controlled for socioeconomic status, family history of GC, duration of refrigerator use, and H. pylori infection
Although the 84-item semiquantatative FFQ had been evaluated for validity and reproducibility, the 109-item survey used in this study was not validated for the GC study. Authors concluded that the items were not largely different
Although a novel concept, individual daily nitrate/nitrite intake from foods were estimated based on the nitrate database reported recently by Kim and Yoon rather than a tested and validated national database
Urinary nitrate/nitrite excretion in patients was not assessed
Beta-carotene, vitamin C and folate exhibited a positive correlation with nitrate intake (see figures 1-4)
A higher absolute intake of nitrate was not associated with a greater risk of GC risk. However, as the nitrate:all antioxidant vitamin consumption ratio increased, the GC risk increased. Nitrate:Folate consumption ratio on GC risk exhibited a significant linear trend (OR = 3.37; 95% CI = 1.28-8.78 for high ratio, P=0.021)
Mean daily intake of Korean cabbage kimchi, Korean radish kimchi, and spinach increased significantly as the nitrate intake increased
Mean daily intake of mushrooms and all antioxidant vitamins was significantly higher in the controls than the GC patients
Prevalence of H. pylori infection was significantly higher in the GC patients as compared to the controls
Difference between the mean daily intake of nitrate between the GC and controls was not significant
Correlation Coefficient of Nitrate and Antioxidant Vitamin Intake
GC in Relation to Absolute Nitrate Intake & Nitrate:Antioxidant
Critique - Results
Although a positive correlation between B-carotene and nitrate exists, it appears relatively low according to the correlation coefficient (r = 0.262)
Tables identifying the 6 food groups and odds ratios for GC would have been beneficial to include in the study
Authors did not analyze data between nitrate from meat sources verses vegetable sources
Authors note the limitations of the study in the small sample size and type of design
Since national data on nitrate concentration in food is not available in Korea, the data analyzed by Kim and Yoon was used (33)
Biological data for the effect of different combinations of nitrate and antioxidant vitamin intake on GC risk is not available
The average daily intake of nitrate from foods among the controls was 533.5mg, nearly 2.4 times the acceptable intake levels established by the World Health Organization. These levels are considerably higher than other countries due to the vegetable-centered diet and nitrate-rich leafy greens consumed in Korea.
The detrimental effects of nitrate isolation on GC risk via nitrosamines formation has been suggested although study results are often null. As nitrate intake is probably an index of vegetable intake, the negative association is not surprising. These results may be confounded by the effects of antioxidant vitamins .
Authors here demonstrated that a high absolute intake of nitrate was not associated with increased GC risk . (OR 1.13) This may be due to the fact that antioxidant vitamin intake was not considered as a confounder.
After adjusting for the intake of all antioxidant vitamin, a high intake of nitrate was associated with an increased risk of GC, although not significant (OR = 2.00; 95% CI = 0.59-6.76)
As the nitrate:antioxidant vitamin ratio increased greatly the GC risk increased, particularly with the higher ratio of nitrate:vitamin E (OR = 2.78) and nitrate:folate (OR = 3.37)
Results indicate that a lower intake of nitrate relative to antioxidant vitamins, by inhibiting intragastric formation of N-nitroso compounds, may be a key factor in preventing the incidence of GC. (34-36)
One study suggests that a high consumption of vitamin C and E inhibits the endogenous formation of nitroamines by 80% and 50%
An increased intake of foods containing containing low nitrate and high antioxidant vitamins, such as fruits and nuts, may aid in decreasing the GC risk
To lower the nitrate contents in vegetables, alternative cultivation techniques, storage and cooking may need to be explored
Decreasing the intake of nitrate relative to antioxidant vitamins may be more effective at lowering GC risk verses lowering absolute intake of nitrate or increasing intake of antioxidant vitamins alone
Critique - Discussion
Since this is the first study among Koreans to examine the nitrate:antioxidant vitamin ratio further studies are needed to explore the association with Gastric Cancer risk
Future prospective studies in populations outside Korea are important to pursue
The study provides a novel approach in studying nitrates and gastric cancer risk due to the creation of the nitrate database by Kim and Yoon
There is some controversy among scientists over the evidence for nitrates as a cause of serious disease
Two main health issues are associated with nitrates:
Infant mathaemoglobinemia (which will not be addressed in this report)
Cancers of the GI tract
Approximately 50 epidemiological studies since 1973 have tested the link between nitrates and stomach cancer incidence and mortality in humans.
The Subcommittee on Nitrate and Nitrite Drinking Water concluded in 1995 that no convincing link between nitrate and stomach cancer and mortality has been established.
In 1986 Al-Dabbagh et al., showed no significant difference in cancer incidence between nitrate fertilizer workers and a local control group of factory workers (37)
Nitrates and Research (Powlson et al. 2008)
Environmental Protection Agency has set a Maximum Contaminant Level for nitrate at 44mg/L (equal to 10mg nitrate-nitrogen/L or 10ppm)
The bioavailability of Nitrate is 100%
Nitrogen intake over the years has increased from drinking water and consuming vegetables
Bacteria in the gut and mouth convert nitrate into nitrite which then reacts with hemoglobin to produce methemoglobin.
After consuming about 200g of spinach, the nitrate concentration in saliva may rise to 72mg/L (38)
Some recent studies suggests nitrates benefit cardiovascular health
Hord et al suggest that the blood pressure-lowering effect of the DASH diet may be due to the nitrate-rich vegetables (39)
Another hypothesis presented by Lundberg et al., explains that the content of inorganic nitrate in vegetables and fruit can provide a physiologic substrate for reduction to nitrite and nitric oxide that produce vasodilation, decrease blood pressure and support cardiovascular function . (40)
In 2002, Richardson et al. discovered that the body cells produce nitric oxide from the amino acid L-arginine and that this production is vital to maintain normal blood circulation and protection from infection (41,42)
Nitrate reduced to nitric oxide in the stomach aids in the destruction of swallowed pathogens that cause gastroenteritis (43)
Nirates and nitrites become carcinogenic when nitrite from dietary nitrate reacts with dietary amines to form nitrosamines
Chronic exposure to nitric oxide as a result of chronic inflammation may explain the association between inflammation and cancer
Nitric oxide and NO-synthase are involved in cancer-related angiogensis, apoptosis, cell cycle, invasion and metastasis
Individuals with increased rates of endogenous formation of N-nitroso compounds may be more susceptible to development of GI cancers (45)
… or Harmful?
Because the primary source of nitrates are antioxidant-rich vegetables, a high intake of nitrate from plant sources is likely not associated with increased GC risk
A high intake of nitrites and nitrates from animal sources is likely associated with increased GC risk
A high nitrite/nitrate to antioxidant ratio is probably the worst combo for increasing gastric cancer risk
Certain polyphenols (such as cinnamic acids, secoisolariciresinol, and coumestrol) and antioxidants (such as Vitamin C & E and folate) may have the most benefit on decreasing GC risk, but more research is needed to confirm these findings
Observational studies exploring the nitrogen:antioxidant ratio and gastric cancer
High verses low vegetable-matched studies to assess the effects of nitrate levels in vegetables and health
Systematic review of the biological consequences of dietary nitrate and nitrite consumption
Observational studies examining the link between DASH diet and nitrogen intake with that of cardiovascular health
Prospective studies examining the benefits of vegetable sources of nitrates verses meat sources of nitrates
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