Assessment of the risk of formation of carcinogenic N-nitroso compounds from dietary precursors in the stomach

Abstract

Summary-A Iiterature review has shown that the daily intakes of various N -nitroso-precursor classes in a typical European diet span five orders of magnitude. Amides in the form of protein, and guanidines in the form of creatine and creatinine, are the nitrosatable groups found most abundantly in the diet, approaching Ievels of 100 g/day and 1 gjday, respectively. Approximately 100 mg of primary amines and amino acids are consumed daily, whereas aryl amines, secondary amines and ureas appear to lie in the 1-10 mg range. The ease of nitrosation of each precursor was estimated, the reactivities being found to span seven orders of magnitude, with ureas at the top and amines at the bottom of the scale. From this infonnation and an assessment of the carcinogenicity of the resulting N-nitroso derivatives, the potential health risk due to gastric in vivo nitrosation was calculated. The combined effects of these risk variables were analysed using a simple mathematical model: Risk = [daily intake of precursor] x [gastric concen· tration of nitrite]" x [nitrosatability rate constant} x [carcinogenicity of derivative]. The risk estimates for the various dietary components spanned nine orders of magnitude. Dietary ureas and aromatic amines combined with a high nitrite burden could pose as great a risk as the intake of preformed dimethylnitrosamine in the diet. In contrast, the risk posed by the in vivo nitrosation of primary and secondary amines is probably negligib1y small. The risk contribution by amides (including protein), guanidines and primary amino acids is intermediate between these two extremes. Thus three priorities for future work are a comprehensive study of the sources and Ievels of arylamines and ureas in the diet, determination of the carcinogenic potencies of key nitrosated products to replace the necessarily vague categories used so far, and the development of short-term in situ tests for studying the alkylating power or genotoxicity of N-nitroso compounds too unstable for inclusion in long-term studies.

Generation of an endogenous DNA-methylating agent by nitrosation in Escherichia coli

“…MU added with NaNO 2 was also more mutagenic than NaNO 2 alone (Fig. 4B), although to a lesser extent than MA and NaNO 2 , which agrees with MU being less nitrosatable than MA (42). These observations suggest that nitrosation of MA or MU by NaNO 2 to generate mutagenic monomethylnitrosamine or MNU, respectively, was occurring on the agar plates.…”

Generation of an endogenous DNA-methylating agent by nitrosation in Escherichia coli

“…MU added with NaNO 2 was also more mutagenic than NaNO 2 alone (Fig. 4B), although to a lesser extent than MA and NaNO 2 , which agrees with MU being less nitrosatable than MA (42). These observations suggest that nitrosation of MA or MU by NaNO 2 to generate mutagenic monomethylnitrosamine or MNU, respectively, was occurring on the agar plates.…”

Urinary excretion of 3-methyladenine after consumption of fish containing high levels of dimethylamine

“…that is rich in dimethylamine is insignificant with respect to levels of NDMA pre-formed in the diet (22). A similar Increase in 3-MeAde excretion following exposure to methylating agents was achieved by measuring the 3-MeAde conclusion was drawn by Shephard et al (43). However, animal studies have shown that sufficient endogenous nitrosation of levels in urine of a subject from a study previously reported by Prevost and Shuker, on the influence of cigarette smoking aminopyrine occurs to permit the detection of 7-methylguanine DNA adducts excreted in urine (44).…”

Presence of the CarcinogenN′-Nitrosonornicotine in Saliva of E-cigarette Users

“…Endogenous formation of N -nitrosamines has been convincingly demonstrated in humans. ,− In this study, we report for the first time that NNNa potent oral and esophageal carcinogenis formed endogenously in e-cigarette users. Sixteen out of 20 e-cigarette users analyzed here had quantifiable levels of NNN in their saliva, with the distribution of salivary NNN levels substantially overlapping between e-cigarette users and smokers (Figure ).…”

Generation of an endogenous DNA-methylating agent by nitrosation in Escherichia coli

“…MU added with NaNO 2 was also more mutagenic than NaNO 2 alone (Fig. 4B), although to a lesser extent than MA and NaNO 2 , which agrees with MU being less nitrosatable than MA (42). These observations suggest that nitrosation of MA or MU by NaNO 2 to generate mutagenic monomethylnitrosamine or MNU, respectively, was occurring on the agar plates.…”

Urinary excretion of 3-methyladenine after consumption of fish containing high levels of dimethylamine

“…that is rich in dimethylamine is insignificant with respect to levels of NDMA pre-formed in the diet (22). A similar Increase in 3-MeAde excretion following exposure to methylating agents was achieved by measuring the 3-MeAde conclusion was drawn by Shephard et al (43). However, animal studies have shown that sufficient endogenous nitrosation of levels in urine of a subject from a study previously reported by Prevost and Shuker, on the influence of cigarette smoking aminopyrine occurs to permit the detection of 7-methylguanine DNA adducts excreted in urine (44).…”

Presence of the CarcinogenN′-Nitrosonornicotine in Saliva of E-cigarette Users

“…Endogenous formation of N -nitrosamines has been convincingly demonstrated in humans. ,− In this study, we report for the first time that NNNa potent oral and esophageal carcinogenis formed endogenously in e-cigarette users. Sixteen out of 20 e-cigarette users analyzed here had quantifiable levels of NNN in their saliva, with the distribution of salivary NNN levels substantially overlapping between e-cigarette users and smokers (Figure ).…”

Generation of an endogenous DNA-methylating agent by nitrosation in Escherichia coli

“…MU added with NaNO 2 was also more mutagenic than NaNO 2 alone (Fig. 4B), although to a lesser extent than MA and NaNO 2 , which agrees with MU being less nitrosatable than MA (42). These observations suggest that nitrosation of MA or MU by NaNO 2 to generate mutagenic monomethylnitrosamine or MNU, respectively, was occurring on the agar plates.…”

Urinary excretion of 3-methyladenine after consumption of fish containing high levels of dimethylamine

“…that is rich in dimethylamine is insignificant with respect to levels of NDMA pre-formed in the diet (22). A similar Increase in 3-MeAde excretion following exposure to methylating agents was achieved by measuring the 3-MeAde conclusion was drawn by Shephard et al (43). However, animal studies have shown that sufficient endogenous nitrosation of levels in urine of a subject from a study previously reported by Prevost and Shuker, on the influence of cigarette smoking aminopyrine occurs to permit the detection of 7-methylguanine DNA adducts excreted in urine (44).…”

Presence of the CarcinogenN′-Nitrosonornicotine in Saliva of E-cigarette Users

“…Endogenous formation of N -nitrosamines has been convincingly demonstrated in humans. ,− In this study, we report for the first time that NNNa potent oral and esophageal carcinogenis formed endogenously in e-cigarette users. Sixteen out of 20 e-cigarette users analyzed here had quantifiable levels of NNN in their saliva, with the distribution of salivary NNN levels substantially overlapping between e-cigarette users and smokers (Figure ).…”