Precursors Of N-nitroso Compounds Research Articles

Reduction in biogenic amines in douchi fermented by probiotic bacteria.

Ecology studies showed that esophageal and gastric cancers are directly correlated with the consumption of processed foods. The carcinogenicity of traditional Chinese fermented foods such as douchi (fermented black beans or fermented black soybeans) is due to the presence of carcinogenic N-nitroso compounds, which are derived from biogenic amines. Among the various biogenic amines that can act as precursors of N-nitroso compounds, histamine and tyramine are considered to be the most toxic and are of public health concern when present in food. We have examined some douchi products on the market, and significant amounts of histamine and tyramine were found. The use of fermentation starters generated by subculturing fermented products with unknown microbiota would induce the risk of biogenic amines. As the microbiota used in fermentation is a crucial factor in determining the biogenic amines of fermented food, it is hypothesized that the possible harmful effects of douchi can be minimized through the use of fermentation starters composed of probiotic bacteria. This is the first study to investigate the potential of using probiotic bacteria in manufacturing douchi. Lactobacillus rhamnosus GG (LGG), Lactobacillus casei Shirota (LcS) and Escherichia coli Nissle 1917 (EcN) were used to ferment black beans in this study, and no tyramine was detected in black bean samples incubated with these three strains anaerobically at 37°C or 20°C. The starter culture strains, temperature and presence of oxygen during the incubation period were found to be critical to the generation of biogenic amines. The findings of this study can provide evidence-based insights and warrant further investigations on the potential of reducing the harmful compounds in food fermented with probiotic bacteria as well as the sensory evaluation of douchi fermented with probiotic bacteria.

Ingested Nitrate and Nitrite and Bladder Cancer in Northern New England.

N-nitroso compounds are hypothesized human bladder carcinogens. We investigated ingestion of N-nitroso compound precursors nitrate and nitrite from drinking water and diet and bladder cancer in the New England Bladder Cancer Study. Using historical nitrate measurements for public water supplies and measured and modeled values for private wells, as well as self-reported water intake, we estimated average nitrate concentrations (mg/L NO3-N) and average daily nitrate intake (mg/d) from 1970 to diagnosis/reference date (987 cases and 1,180 controls). We estimated overall and source-specific dietary nitrate and nitrite intakes using a food frequency questionnaire (1,037 cases and 1,225 controls). We used unconditional logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI). We evaluated interactions with factors that may affect N-nitroso compound formation (i.e., red meat, vitamin C, smoking), and with water intake. Average drinking water nitrate concentration above the 95th percentile (>2.07 mg/L) compared with the lowest quartile (≤0.21 mg/L) was associated with bladder cancer (OR = 1.5, 95% CI = 0.97, 2.3; P trend = 0.01); the association was similar for average daily drinking water nitrate intake. We observed positive associations for dietary nitrate and nitrite intakes from processed meat (highest versus lowest quintile OR for nitrate = 1.4, 95% CI = 1.0, 2.0; P trend = 0.04; OR for nitrite = 1.5, 95% CI = 1.0, 2.1; P trend = 0.04, respectively), but not other dietary sources. We observed positive interactions between drinking water nitrate and red meat (P-interaction 0.05) and processed red meat (0.07). Our results suggest the importance of both drinking water and dietary nitrate sources as risk factors for bladder cancer.

Ingested nitrate and nitrite and bladder cancer in Northern New England

OPS 36: Health effects of dietary exposures, Room 210, Floor 2, August 27, 2019, 4:30 PM - 5:30 PM Background/Aim: N-nitroso compounds (NOCs) are hypothesized human bladder carcinogens. Nitrate and nitrite are NOC precursors; sources include contaminated drinking water and diet. We examined nitrate and nitrite ingestion and bladder cancer risk in the New England Bladder Cancer Study, a population-based case-control study in Maine, New Hampshire, and Vermont. Methods: Using historical nitrate measurements for public water supplies, measured and modeled values for private wells and self-reported water intake, we estimated average nitrate concentrations (NO3-N mg/L) and average daily nitrate intake (mg/day) from 1970 to diagnosis/reference date for 987 cases and 1180 controls. We also estimated source-specific (animal, plant, processed meat) dietary nitrate and nitrite intakes using a food frequency questionnaire (1037 cases and 1225 controls). We used unconditional logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI) adjusting for age, gender, smoking, disinfection by-products, and other factors. We evaluated interactions with factors affecting NOC formation (i.e., red and processed meat, vitamin C, smoking). Results: Average drinking water nitrate concentration above the 95th percentile (>2.07 mg/L) compared with the lowest quartile (<=0.21 mg/L) was associated with bladder cancer risk (OR=1.50, CI: 0.97-2.32; p-trend=0.01); the association was similar for average drinking water nitrate intake. We observed positive associations for dietary nitrate and nitrite intakes from processed meat (highest vs. lowest quintile OR=1.42, CI: 1.01-1.98; p-trend=0.04; OR=1.48, CI: 1.04-2.09; p-trend=0.04, respectively), but no trends for other sources. Risk was highest among those with >2.07 mg/L NO3-N and >median red or processed meat intake vs <0.21 mg/L NO3-N/< median intakes (OR=2.61, CI: 1.33-5.11 and OR=3.47 CI: 1.75-6.87; p-interaction=0.05 and 0.07, respectively). We observed no interaction with vitamin C or smoking. Conclusions: Our results suggest the importance of both drinking water and dietary nitrate sources as risk factors for bladder cancer especially among those with high red or processed meat intake

Re-Examination of the Esophageal Squamous Cell Carcinoma Model in Rats Induced by N-Nitrososarcosine Ethyl Ester Precursors.

Studies of the molecular mechanisms of esophageal cancer development have to be carried out on sufficient amount of tumor material, obtained under conditions of controlled exposure to carcinogenic factors. Esophageal cancer models on laboratory animals serve an indispensable source of this material. One of these models is esophageal cancer induction in rats by N-nitroso compound precursors. Despite adequate reproduction of human esophageal cancer, this model in fact has not been used since the 1990ies. Re-examination of esophageal cancer model, induced by N-nitrososarcosine ethyl ester precursors, is carried out and its efficiency in induction of squamous cell carcinoma is confirmed.

Ingested nitrate and nitrite, disinfection by-products, and pancreatic cancer risk in postmenopausal women.

Nitrate and nitrite are precursors of N-nitroso compounds (NOC), probable human carcinogens that cause pancreatic tumors in animals. Disinfection by-products (DBP) exposures have also been linked with digestive system cancers, but few studies have evaluated relationships with pancreatic cancer. We investigated the association of pancreatic cancer with these drinking water contaminants and dietary nitrate/nitrite in a cohort of postmenopausal women in Iowa (1986-2011). We used historical monitoring and treatment data to estimate levels of long-term average nitrate and total trihalomethanes (TTHM; the sum of the most prevalent DBP class) and the duration exceeding one-half the maximum contaminant level (>½ MCL; 5 mg/L nitrate-nitrogen, 40 µg/L TTHM) among participants on public water supplies (PWS) >10 years. We estimated dietary nitrate and nitrite intakes using a food frequency questionnaire. We computed hazard ratios (HR) and 95% confidence intervals (CI) using Cox regression and evaluated nitrate interactions with smoking and vitamin C intake. We identified 313 cases among 34,242 women, including 152 with >10 years PWS use (N = 15,710). Multivariable models of average nitrate showed no association with pancreatic cancer (HRp95vs. Q1 = 1.16, 95% CI: 0.51-2.64). Associations with average TTHM levels were also null (HRQ4vs. Q1 = 0.70, 95% CI:0.42-1.18). We observed no trend with increasing years of exposure to either contaminant at levels >½ MCL. Positive associations were suggested in the highest dietary nitrite intake from processed meat (HRp95vs. Q1 = 1.66, 95% CI 1.00-2.75;ptrend = 0.05). We found no interactions of nitrate with known modifiers of endogenous NOC formation. Our results suggest that nitrite intake from processed meat may be a risk factor for pancreatic cancer.

Dietary sources of N-nitroso compounds and bladder cancer risk: findings from the Los Angeles bladder cancer study.

N-Nitroso compounds (NOCs) have been proposed as possible bladder carcinogens. The main sources of exogenous exposure to NOCs are cigarette smoke and diet, particularly processed (i.e., nitrite-treated) meats. Perhaps more importantly, NOCs can be formed endogenously from dietary precursors such as nitrate, nitrite and amines. Heme has been shown to increase endogenous nitrosation. We examined the role of dietary sources of NOCs and NOC precursors as potential bladder cancer risk factors using data from the Los Angeles Bladder Cancer Study, a population-based case-control study. Dietary and demographic information was collected from 1,660 bladder cancer cases and 1,586 controls via a structured questionnaire. Intake of liver and of salami/pastrami/corned beef, were both statistically significantly associated with risk of bladder cancer in this study, particularly among nonsmokers. Heme intake was also statistically significantly associated with risk of bladder cancer among nonsmokers only. When considering NOC precursors, risk was consistently higher among subjects with concurrent high intake of nitrate and high intake of the different meats (sources of amines and nitrosamines). Results of this study are consistent with a role of dietary sources of NOC precursors from processed meats in bladder cancer risk, suggesting consumption of meats with high amine and heme content such as salami and liver as a risk factor for bladder cancer. In addition, any effect of consuming these meats may be greater when accompanied by high nitrate intake.

Abstract 149: Dietary intake of nitrate and nitrite, nitrate in drinking water, and ovarian cancer risk among postmenopausal women in Iowa.

Abstract Background: Nitrate and nitrite are precursors of N-nitroso compounds, known animal and human carcinogens. Nitrate and nitrite are common in foods, such as vegetables and processed meats, and nitrate is a contaminant of drinking water. We previously reported an increased ovarian cancer risk associated with higher nitrate intake in public water supplies in the Iowa Women's Health Study. Here, we report results based on an additional 12 years of follow-up and we present results for dietary nitrate and nitrite intake. Methods: Among 28,555 postmenopausal women aged 55–69 y at baseline, we identified 315 incident epithelial ovarian cancers between 1986 and 2010. Dietary nitrate and nitrite intakes were assessed using a food frequency questionnaire at baseline. Information on drinking water source was obtained in 1989. Nitrate-nitrogen (NO3-N) levels in public water supplies (average level 1955-1988) and water sources (finished surface or ground water) were from a database of monitoring data for Iowa water utilities. Cox proportional hazards regression generated hazard ratios (HR) and 95% confidence intervals (CI). Because disinfection by-products (DBP) are higher in surface water and have been associated with increased risk for certain cancers, we determined whether the association between nitrate intake from drinking water and ovarian cancer risk differed by water source. Results: Neither total dietary nitrate nor nitrite intake was associated with ovarian cancer risk after adjusting for age, energy intake, family history of ovarian cancer, number of live births, and history of unilateral oophorectomy. Nitrate and nitrite intakes from animal or plant sources, or processed meats were not associated with ovarian cancer risk. Among women who drank public water, we observed an increased risk for ovarian cancer with higher average levels of NO3-N (ptrend=0.004). Compared with women in the lowest quartile of NO3-N levels (&amp;lt;0.36 mg/L), risk was 1.81 (95% CI=1.08-3.05) and 2.02 (95% CI=1.21-3.36) times higher in the third (1.0-2.5 mg/L) and fourth (&amp;gt;2.5 mg/L) quartiles, respectively. Ovarian cancer risk among private well water drinkers was elevated (HR=1.52, 95% CI=0.91-2.53) but not statistically significantly different from the referent group. When stratified by water source, the positive association between NO3-N levels in public water and ovarian cancer risk was confined to women who drank water from surface sources (ptrend=0.007; pinteraction=0.04). Conclusions: Dietary nitrate or nitrite intake was not associated with ovarian cancer risk. Our findings for nitrate intake from public water supplies suggest that nitrate intake from drinking water may increase ovarian cancer risk, particularly in the likely presence of other contaminants found in surface water. Further evaluation of DBP and other water contaminant levels on ovarian cancer risk in this population is warranted. Citation Format: Maki Inoue-Choi, Kristin E. Anderson, James R. Cerhan, Peter J. Weyer, Mary H. Ward. Dietary intake of nitrate and nitrite, nitrate in drinking water, and ovarian cancer risk among postmenopausal women in Iowa. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 149. doi:10.1158/1538-7445.AM2013-149

Dietary intake of nitrate and nitrite and risk of renal cell carcinoma in the NIH-AARP Diet and Health Study.

Background:Nitrate and nitrite are present in many foods and are precursors of N-nitroso compounds, known animal carcinogens and potential human carcinogens. We prospectively investigated the association between nitrate and nitrite intake from dietary sources and risk of renal cell carcinoma (RCC) overall and clear cell and papillary histological subtypes in the NIH-AARP Diet and Health Study.Methods:Nitrate and nitrite intakes were estimated from a 124-item food frequency questionnaire. Over a mean follow-up of 9 years, we identified 1816 RCC cases (n=498, clear cell; n=115, papillary cell) among 491 841 participants. Cox proportional hazard regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs).Results:Individuals in the highest quintile of nitrite intake from animal sources compared with those in the lowest quintile, had an increased risk of total RCC and clear cell subtype (HR=1.28, 95% CI, 1.10–1.49 and HR=1.68, 95% CI, 1.25–2.27, respectively). Nitrite from processed meats and other animal sources were associated with increased clear cell adenocarcinoma risk (HR=1.33, 95% CI, 1.01–1.76 and HR=1.78, 95% CI, 1.34–2.36, respectively). We found no association for nitrite intake from plant sources or nitrate intake overall.Conclusion:Our findings suggest that nitrite from animal sources may increase the risk of RCC, particularly clear cell adenocarcinomas.

Abstract A97: Dietary nitrosamines, genetic variation in DNA repair and metabolism genes, and bladder cancer risk in the Los Angeles Bladder Cancer Study

Abstract Background: N-nitroso compounds (NOCs) can cause direct DNA damage and are known to induce a wide range of tumors, including tumors of the bladder in animal models. Humans are exogenously exposed to NOCs via diet, in particular processed meats, and cigarette smoke. However, NOCs, such as the carcinogen N-nitrosodimethylamine (NDMA), can also be formed endogenously from their dietary precursors: nitrates, nitrites and amines. The heme found in red meat is a potent stimulator of this endogenous formation. Our previous findings from the Los Angeles Bladder Cancer Study show that intake of meats with concurrent high amine and heme content, such as salami and liver, are associated with an increased risk of bladder cancer. Once NOCs are formed, they need to be activated metabolically by cytochrome P450 enzymes into electrophilic intermediates to exert a carcinogenic effect. These intermediates then react with DNA to form bulky adducts which, if not repaired, can lead to DNA instability and ultimately DNA damage. These reactive intermediates can also undergo metabolism by glutathione S-transferases (GSTs), which results in their detoxification. Multiple DNA repair pathways are available to correct NOC-induced damage. Methods: We examined the role of dietary sources of NOCs and NOC precursors in conjunction with variation in genes involved in NOC metabolism and DNA repair in the risk of bladder cancer using 355 bladder cancer cases and 409 controls from the Los Angeles Bladder Cancer Study, a population-based case-control study. We tested each of 627 SNPs in 27 genes involved in NOC metabolism and DNA repair for effect modification of exposure to different dietary sources of NOCs and NOC precursors. Multiple testing was accounted for using a global Bonferroni correction, across all SNPs combined, and also at the gene and pathway levels. Results: A polymorphism in the base excision repair gene hOGG1 (Ser326Cys; rs1052133) was shown to modify the effect of intake of high amine and heme content meats with a globally corrected p-value of 0.014 (crude p-value = 3.7 x 10-5). We found that the previously identified positive association between intake of high amine and heme content meat intake and bladder risk was restricted to individuals carrying one or more copies of the hOGG1 codon 326 Cys allele, which has been reported to reduce OGG1 protein activity. Conclusion: Results of this study build upon our previous findings that consumption of meats with high amine and heme content, such as salami and liver, are potential risk factors for bladder cancer. Our current finding of modification of this association by a DNA repair variant supports a role for endogenous dietary nitrosamines in bladder carcinogenesis. Citation Format: Chelsea E. Catsburg, Roman Corral, Juan Pablo Lewinger, Amit D. Joshi, Manuela Gago-Dominguez, Jian-Min Yuan, Victoria K. Cortessis, Malcolm C. Pike, Mariana C. Stern. Dietary nitrosamines, genetic variation in DNA repair and metabolism genes, and bladder cancer risk in the Los Angeles Bladder Cancer Study. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr A97.

Dietary nitrate and nitrite intake and risk of non-Hodgkin lymphoma

Although established risk factors such as immunodeficiency and viral infections may be responsible for a portion of cases of non-Hodgkin lymphoma (NHL), the vast majority of cases of NHL remain unexplained. The role of dietary nitrate and nitrite in NHL risk is of interest since they are precursors of N-nitroso compounds, and nitrosoureas have been shown to induce B- and T-cell lymphomas in animal studies. However, few studies have evaluated the potential association between consumption of nitrate and nitrite and NHL by subtype or chromosomal translocation status, and the results of these studies have been inconsistent. We estimated the dietary intake of nitrate and nitrite using a food frequency questionnaire in a population-based, case–control study of 348 cases and 470 controls conducted in Nebraska in 1999–2002. A non-significant excess risk of NHL was found among women who reported an intake of nitrite in the highest quartile compared to the lowest quartile (odds ratio [OR] = 1.6; 95% confidence interval [CI]: 0.8–2.9), particularly nitrite from animal sources (OR = 1.9; 95% CI: 1.0–3.4). No significant associations were observed for nitrate or nitrite by NHL subtype. Although there were some increases in risk that support the N-nitroso hypothesis, they were not significant and do not confer strong evidence of an association.

Epithelial ovarian cancer and exposure to dietary nitrate and nitrite in the NIH-AARP Diet and Health Study

Ovarian cancer is a leading cause of cancer death among women in the United States and it has the highest mortality rate of all gynecologic cancers. Internationally, there is a five-fold variation in incidence and mortality of ovarian cancer, which suggests a role for environmental factors, including diet. Nitrate and nitrite are found in various food items and they are precursors of N-nitroso compounds, which are known carcinogens in animal models. We evaluated dietary nitrate and nitrite intake and epithelial ovarian cancer in the National Institutes of Health (NIH)-AARP Diet and Health Study, including 151 316 women aged 50-71 years at the time of the baseline questionnaire in 1995-1996. The nitrate and nitrite intake was assessed using a 124-item validated food frequency questionnaire. Through 31 December 2006, 709 incident epithelial ovarian cancer cases with complete dietary information were identified. Using Cox proportional hazards regression to estimate hazard ratios and 95% confidence intervals (CIs), women in the highest intake quintile of dietary nitrate had a 31% increased risk (95% CI: 1.01-1.68) of epithelial ovarian cancer, compared with those in the lowest intake quintile. Although there was no association for total dietary nitrite, those in the highest intake category of animal sources of nitrite had a 34% increased risk (95% CI: 1.05-1.69) of ovarian cancer. There were no clear differences in risk by histologic subtype of ovarian cancer. Our findings suggest that a role of dietary nitrate and nitrite in ovarian cancer risk should be followed in other large cohort studies.

Pancreatic cancer and exposure to dietary nitrate and nitrite in the NIH-AARP Diet and Health Study.

Nitrate and nitrite are precursors of N-nitroso compounds, which induce tumors of the pancreas in animals. The authors evaluated the relation of dietary nitrate and nitrite to pancreatic cancer risk in the NIH-AARP Diet and Health Study. Nitrate and nitrite intakes were assessed at baseline using a 124-item food frequency questionnaire. During approximately 10 years of follow-up between 1995 and 2006, 1,728 incident pancreatic cancer cases were identified. There was no association between total nitrate or nitrite intake and pancreatic cancer in men or women. However, men in the highest quintile of summed nitrate/nitrite intake from processed meat had a nonsignificantly elevated risk of pancreatic cancer (hazard ratio = 1.18, 95% confidence interval: 0.95, 1.47; P-trend = 0.11). The authors observed a stronger increase in risk among men for nitrate/nitrite intake from processed meat at ages 12-13 years (highest quintile vs. lowest: hazard ratio = 1.32, 95% confidence interval: 0.99, 1.76; P-trend = 0.11), though the relation did not achieve statistical significance. The authors found no associations between adult or adolescent nitrate or nitrite intake from processed meats and pancreatic cancer among women. These results provide modest evidence that processed meat sources of dietary nitrate and nitrite may be associated with pancreatic cancer among men and provide no support for the hypothesis in women.

Dietary intake of polyphenols, nitrate and nitrite and gastric cancer risk in Mexico City

N-nitroso compounds (NOC) are potent animal carcinogens and potential human carcinogens. The primary source of exposure for most individuals may be endogenous formation, a process that can be inhibited by dietary polyphenols. To estimate the risk of gastric cancer (GC) in relation to the individual and combined consumption of polyphenols and NOC precursors (nitrate and nitrite), a population-based case-control study was carried out in Mexico City from 2004 to 2005 including 257 histologically confirmed GC cases and 478 controls. Intake of polyphenols, nitrate and nitrite were estimated using a food frequency questionnaire. High intakes of cinnamic acids, secoisolariciresinol and coumestrol were associated with an approximately 50% reduction in GC risk. A high intake of total nitrite as well as nitrate and nitrite from animal sources doubled the GC risk. Odds ratios around 2-fold were observed among individuals with both low intake of cinnamic acids, secoisolariciresinol or coumestrol and high intake of animal-derived nitrate or nitrite, compared to high intake of the polyphenols and low animal nitrate or nitrite intake, respectively. Results were similar for both the intestinal and diffuse types of GC. Our results show, for the first time, a protective effect for GC because of higher intake of cinnamic acids, secoisolariciresinol and coumestrol, and suggest that these polyphenols reduce GC risk through inhibition of endogenous nitrosation. The main sources of these polyphenols were pears, mangos and beans for cinnamic acids; beans, carrots and squash for secoisolariciresinol and legumes for coumestrol.

Adenocarcinoma of the Stomach and Esophagus and Drinking Water and Dietary Sources of Nitrate and Nitrite

We conducted a population-based case-control study of adenocarcinoma of the stomach and esophagus in Nebraska, U.S.A. Nitrate concentrations in public drinking water supplies were linked to residential water source histories. Among those using private wells at the time of the interview, we measured nitrate levels in water samples from wells. Dietary nitrate and nitrite were estimated from a food-frequency questionnaire. Among those who primarily used public water supplies (79 distal stomach, 84 esophagus, 321 controls), average nitrate levels were not associated with risk (highest versus lowest quartile: stomach OR=1.2, 95% CI [0.5-2.7]; esophagus OR=1.3, 95% CI [0.6-3.1]). We observed the highest ORs for distal stomach cancer among those with higher water nitrate ingestion and higher intake of processed meat compared with low intakes of both; however, the test for positive interaction was not significant (p=0.213). We did not observe this pattern for esophagus cancer. Increasing intake of nitrate and nitrite from animal sources was associated with elevated ORs for stomach cancer and with a significant positive trend in risk of esophagus cancer (P-trend=0.325 and 0.015, respectively). Larger studies with higher exposures to drinking water sources of nitrate are warranted to further evaluate N-nitroso compound precursors as risk factors for these cancers.

Processed meat intake, CYP2A6 activity and risk of colorectal adenoma

Red and processed meat intake is associated with increased risks of both colorectal adenoma and cancer. Processed meats contain nitrate and nitrite, precursors of N-nitroso compounds (NOCs); furthermore, meats cooked at high temperatures contain heterocyclic amines (HCAs) and polycyclic aromatic hydrocarbons (PAHs). Specific NOC, HCA and PAH are mutagens and animal carcinogens. We conducted a case-control study of 146 cases of colorectal adenoma, diagnosed at sigmoidoscopy or colonoscopy, and 228 polyp-free controls. We calculated odds ratios (ORs) [and 95% confidence intervals (CIs)] and found a 2-fold increased risk in the highest, compared with the lowest, quartile of processed meat intake (95% CI = 1.0-4.0). We estimated nitrate and nitrite intake from meat using published data from the literature as well as from actual measurements of meats analyzed recently. We evaluated the interaction of processed meat and nitrate plus nitrite intake with CYP2A6 activity, an enzyme able to metabolize some NOC to their carcinogenic form. Results for both methods of estimating nitrate and nitrite intake were similar; compared with the lowest, the highest quartile based on measured values was associated with a 2-fold elevated risk (95% CI = 1.0-3.9). Adjustment for the HCA 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) attenuated the association (OR = 1.6, 95% CI = 0.8-3.2), but other HCA and PAH had minimal effect. Higher CYP2A6 activity was not associated with risk and there was no evidence of an interaction of CYP2A6 activity with nitrate and nitrite intake. Our results suggest that nitrite and nitrate intake from processed meat intake increases the risk of colorectal adenoma after accounting for HCA and PAH.

Comparative Analysis of Tobacco-Specific Nitrosamines and Total N-Nitroso Compounds in Moldovan Cigarette Tobacco

While previous studies have evaluated levels of tobacco-specific nitrosamines (TSNA) and total N-nitroso compounds (NOC) in tobacco, there are no reports in the literature on TSNA and total NOC in the same tobacco products. We compared levels of TSNA, total NOC, and NOC precursors (NOCP) in tobacco of cigarettes purchased in Moldova and in some tobacco types commonly used for the manufacturing of Moldovan cigarettes. Cigarette tobaccos included those from non-Moldovan, traditional Moldovan, and blended Moldovan cigarettes. The results demonstrate that tobacco of non-Moldovan cigarettes contains higher TSNA and NOC levels (mean, 16 and 63 nmol/g tobacco, n = 6) than that of Moldovan cigarettes (mean, 5 and 23 nmol/g tobacco, n = 25). TSNA and NOC levels were also generally higher in tobacco of blended than in traditional Moldovan cigarettes. NOCP levels in Moldovan and non-Moldovan cigarette tobacco were similar as follows: 29000 +/- 30000 and 33000 +/- 28000 nmol/g tobacco (mean +/- SD). Total NOC were strongly correlated with total TSNA levels (r = 0.66; P < 0.0001). These findings demonstrate that current technologies involved in the manufacture of some blended cigarettes create conditions that favor N-nitrosation of alkaloids and other tobacco constituents.

N-Nitroso Compound Precursors in some Nigerian Forage Crops

Primary and secondary amine contents of some dried Nigerian forages were analyzed as their sulphonamides by gas chromatography interfaced with a chemiluminescence detector-Thermal Energy Analyzer modified for use in nitrogen mode. Both nitrate and nitrite were analyzed spectrophotometrically using an automated dual channel continuous flow nitrate-nitrate analyzer as nitrite following cadmium reduction of nitrate to nitrite and diazotization of nitrite with sulphanilamide, and coupling with N-(1-naphythyl) ethylenediamine. Secondary amines detected in the forage were diethylamine, dimethylamine, methylbenzylamine, piperidine, methylamine, while primary amines found include n-butylamine, ethylamine, methylamine, isopentylamine and propylamine. Total secondary amines were highest in Urena lobeta (92.7 ppm), but lowest in Dichrostachys cinera (5.6 ppm), while total primary amines were also highest in Urena lobeta (94.7ppm) but lowest in Rottboellia exaltata (8.4 ppm). Only trace amounts of nitrite were detectable in some samples. The toxicological relevance of these findings are discussed with respect to potential endogenous formation of hepatotoxic, mutagenic and carcinogenic n-nitroso compounds in animals, and the consequences of this phenomenon on animal health and production. Keywords: N-nitroso precursors, forages, Nigeria Trop. Vet. Vol. 21 (2) 1-8 (2003)

Total N-Nitroso Compounds and Their Precursors in Hot Dogs and in the Gastrointestinal Tract and Feces of Rats and Mice: Possible Etiologic Agents for Colon Cancer

We review evidence that red and processed meat are causes of colon cancer and that processed meat is a risk factor for childhood cancer and type 2 diabetes. Associations could be due to N-nitroso compounds (NOCs) derived from nitrosation of NOC precursors (NOCPs). We review our survey of total NOC and NOCP content of foods. Only rapidly nitrosated amines, including a glycosyl amino acid, were efficiently determined as NOCPs. NOCPs in hot dogs and rat feces were partly purified by adsorption-desorption and HPLC. After nitrosation, purified hot dog fractions were directly mutagenic in Ames test. The main NOCPs in these materials may be N-glycosyl amino acids and peptides. NOC levels in rat gastrointestinal tract rose steadily from stomach to feces. NOCP levels showed similar trend but with sharp increases from stomach to duodenum. One day after Min and C57BL/6J mice were fed 4% dextran sulfate sodium to induce acute colitis, fecal NOC levels increased 1.9-fold compared with untreated mice (P < 0.05). For 7 d Swiss mice received semipurified diet, 180 g beef-pork hot dogs mixed with 820 g diet or 180 g sautéed beef mixed with 820 g diet. Fecal NOC outputs on day 7 were 3.7-5.0 (hot dog) and 2.0-2.9 (beef) times those for control groups (P < 0.002 for combined groups), perhaps reflecting higher dietary NOC intakes. Feeding a similar hot dog mixture to mice did not affect normal 7-methyldeoxyguanosine level in colonic mucosal DNA. Overall, results support the hypothesis that colonic NOCs are a cause of colon cancer.

Chemopreventive effects of S-methylcysteine on rat hepatocarcinogenesis induced by concurrent administration of sodium nitrite and morpholine

The aim of the present study was to examine the chemopreventive efficacy of S-methylcysteine (SMC) on rat hepatocarcinogenesis induced by concurrent administration of sodium nitrite (NaNO2) and morpholine (Mor) using a medium-term rat liver carcinogenesis bioassay (Ito test). Administration of SMC caused significant reduction in the areas of glutathione S-transferase placental form positive foci along with a significant decrease of hepatocyte 5-bromo-2′-deoxyuridine (BrdU) labeling indices. These results demonstrated potent chemopreventive effects of SMC against hepatocarcinogenesis due to concurrent administration of Mor and NaNO2. SMC could thus be an effective chemopreventive agent for decreasing the risk of carcinogenicity from environmental precursors of N-nitroso compounds.

Progress of gastric cancer etiology: N-nitrosamides 1999s.

Stomach carcinoma is still the leading cause of cancer death in China and the second one in the world. Its possible causes include: (1) chemical factors such as intragastric formation of N-nitroso compounds (NOC) and high salt intake; (2) biological factors such as infection of Helicobacter pylori and biotoxins intake; and (3) nutritional factors such as deficiency of vitamin C, selenium, and other antioxidants. Nitrogenous precursors of NOC, e.g. alkylamines, alkylur eas, alkylguanidines, and alkylamides, occur widely in nature and potential nitrosating agents, e.g., nitrite (NO2-) and NOx (the gaseous oxides of nitrogen) are similarly widespread. Relationship between exposure to NOC and causes of human cancer was investigated extensively ten years ago. Resu lts indicated that the exposures of NOC might contribute to the occurrences of m alignancy in the upper digestive tracts including stomachs. It was also observed that both high salt intake and deficiency of some micronutrients enhanced NOC- induced carcinogenicity. Recent studies show that infection of H. pylori can lead to atrophic gastritis and achlorhydria, and promote endogenous formation of NOC indirectly[1]. Much attention has been paid to stomach cancer and NOC regarding the characterization of natural N-nitrosamides in human environment in the 1990s. N-nitrosamides, one kind of direct-acting NOC, can be synthesized endogenously in stomach lumens and damaged DNA of gastric mucosal epithelium in situ. Most of epidemiological investigations showed that the occurrence of stomach cancers was correlated positively with exposure levels of nitrosating agents and ni trogenous precursors of NOC[2]. Laboratory synthesized N-nitrosamides are strong animal stomach carcinogens. Intragastric N-nitrosamide formation may play an important role in the etiology of gastric carcinomas[3]. However, most N-nitrosamides are chemically reactive, thermal, photo, and alkali-labile compounds. It is very difficult to detect N-nitrosamid es in human environments chemically. Little was known about the existence of n atu ral N-nitrosamides before the 1980s because of lack of a convenient sensi tive method to detect them precisely[4]. Several progresses have been ma de on the study of N-nitrosamides in the past ten years, including setup of detection meth ods for trace N-nitrosamides in the early 1990s[5,6] resulting in recent discovery of natural N-nitrosoureas in human environments[7-9]. This article will present and discuss results of studies on stomach cancer and N-nitrosamides in the past decade.