Role of N-nitroso compounds (NOC) and N-nitrosation in etiology of gastric, esophageal, nasopharyngeal and bladder cancer and contribution to cancer of known exposures to NOC.

Formation of N-nitroso compounds: chemistry, kinetics, and in vivo occurrence.

The Seventh-Day Adventist population abstains from smoking and drinking; about 50% follow a lacto-ovo-vegetarian diet; and most avoid the use of coffee, tea, hot condiments, and spices. Existing data on cancer mortality in Seventh-Day Adventists clearly document mortality rates that are 50 to 70% of general population rates for most cancer sites that are unrelated to smoking and drinking. Several approaches to determining whether this reduced risk is due to the unique Seventh-Day Adventist life-style or selective factors related to who choses to become and remain a Seventh-Day Adventist are described. A comparison of the mortality experience of Seventh-Day Adventist and non-Seventh-Day Adventist physicians shows equal cancer mortality, which is consistent with the hypothesis that the apparent reduced risk of cancer death in all Adventists may be due to selective factors. However, the results of a small case-control study of colon and breast cancer among Adventists show statistically significant relative risks for colon cancer of 2.8 for past use of meat. For current food use, the significant relative risks are 2.3 for beef, 2.7 for lamb, and 2.1 for a combined group og highly saturated fat foods. This strongly suggests that the lacto-ovo-vegetarian diet may protect against colon cancer. However, the evidence linking diet to breast cancer is less clear. Because of the marked variability in dietary habits within the Seventh-Day Adventist population, they will be a productive group for further study of diet and cancer.

https://cancerres.aacrjournals.org/content/canres/35/11_Part_2/3513.full.pdf

Role of Life-style and Dietary Habits in Risk of Cancer among Seventh-Day Adventists

The preceding paper described our numerical index of carcinogenic potency, the TD50 and the statistical procedures adopted for estimating it from experimental data. This paper presents the Carcinogenic Potency Database, which includes results of about 3000 long-term, chronic experiments of 770 test compounds. Part II is a discussion of the sources of our data, the rationale for the inclusion of particular experiments and particular target sites, and the conventions adopted in summarizing the literature. Part III is a guide to the plot of results presented in Part IV. A number of appendices are provided to facilitate use of the database. The plot includes information about chronic cancer tests in mammals, such as dose and other aspects of experimental protocol, histopathology and tumor incidence, TD50 and its statistical significance, dose response, author's opinion and literature reference. The plot readily permits comparisons of carcinogenic potency and many other aspects of cancer tests; it also provides quantitative information about negative tests. The range of carcinogenic potency is over 10 million-fold.

A carcinogenic potency database of the standardized results of animal bioassays

Problem statement: Spoilage of food products is due to chemical, enzymatic or microbial activities One-fourth of the world’s food supply and 30% of landed fish are lost through microbial activity alone. With the ever growing world population and the need to store and transport the food from one place to another where it is needed, food preservation becomes necessary in order to increase its shelf life and maintain its nutritional value, texture and flavor. The freshness and quality of fish have always gained the attention by Food Regulatory Agencies and Food Processing Industry. Proper handling, pretreatment and preservation techniques can improve the quality fish and fish products and increase their shelf life. Methodology: Historically salting, drying, smoking, fermentation and canning were the methods to prevent fish spoilage and extend its shelf life. In response to consumer demand for texture, appearance and taste, new methods were developed including: Cooling, freezing and chemical preservation. A comprehensive review of the literature on the subject of fish spoilage and modern preservation techniques was carried out. Conclusion: Fish spoilage results from three basic mechanisms: Enzymatic autolysis, oxidation, microbial growth. Low temperature storage and chemical techniques for controlling water activity, enzymatic, oxidative and microbial spoilage are the most common in the industry today. A process involving the addition of an EDTA (1 mM)-TBHQ (0.02%) combination and ascorbic acid and storage at refrigerated temperatures (5°C) in darkness can be the most positive for controlling the spoilage of fish and fish product. The suggested process would address antimicrobial activity as well as destructive oxidation of the desired lipids and fats. However, more efforts are required to understand the role of proximate composition of fish, post harvest history, environmental conditions, initial microbial load, type and nature of bacteria and their interaction in order to optimize the shelf-life of fish.

/pdf/fish-spoilage-mechanisms-and-preservation-techniques-review-4ka5l2iokh.pdf

Fish Spoilage Mechanisms and Preservation Techniques: Review

The formation of carcinogenic N-nitroso compounds by the chemical reaction between nitrous acid and oxytetracycline, morpholine, piperazine, N-methylaniline, methylurea, and (in some experiments) dimethylamine was blocked by ascorbic acid. The extent of blocking depended on the compound nitrosated and on the experimental conditions. Urea and ammonium sulfamate were less effective as blocking agents. The possibility of in vivo formation of carcinogenic N-nitroso compounds from drugs could be lessened by the combination of such drugs with the ascorbic acid.

http://science.sciencemag.org/content/sci/177/4043/65.full.pdf

Ascorbate-Nitrite Reaction: Possible Means of Blocking the Formation of Carcinogenic N-Nitroso Compounds

Six nitrosamides [ethylnitrosourea (ENU), 2-hydroxyethylnitrosourea (HENU), carboxymethylnitrosourea, 1-nitroso-5,6-dihydrouracil (NDHU), 1-nitrosohydantoin, and N-methyl-N-nitrosobenzamide (MNB)] and ethylnitrosocyanamide (ENC) were administered chronically in sodium citrate-buffered drinking water to MRC Wistar rats. ENU induced tumors of the reticuloendothelial system (RES) (50% incidence), mammary glands, and large intestine. NDHU in drinking water produced hepatocellular carcinomas (96% incidence), but NDHU injected ip caused mostly tumors at the injection sites (54% incidence). HENU produced bone tumors (38% incidence) and RES tumors (28% incidence). ENC produced nasal cavity tumors (36% incidence). Papillomas and/or carcinomas of the forestomach, tongue, and pharynx were induced by most of the compounds, with the highest incidence in the forestomach (47% for MNB); these tumors were attributed to local action when the compounds were ingested. Carcinogenicity was not quantitatively correlated with direct mutagenicity for Salmonella typhimurium TA1535.

Carcinogenicity Test of Six Nitrosamides and a Nitrosocyanamide Administered Orally to Rats

The initial rate of nitrosation of aminopyrine (AP, Pyramidon) to give dimethyl nitrosamine (DMN) showed maxima at pH 20 and 31 At pH 2, initial rate was proportional to nitrite concentration squared down to 6 mM, below which it decreased rapidly The rate was independent of AP concentration at pH 2 but proportional to AP concentration at pH 05, indicating that nitrous anhydride formation was rate-limiting at pH 2 DMN was detected after 5 seconds reaction under “normal” conditions The stoichiometric rate constant at pH 2 and 0° was 80 M−2 sec−1, higher than that for all secondary amines previously studied, except N-methylaniline In addition to the “initial reaction”, a second slow reaction giving DMN was observed When 20 mM AP was reacted for 1 hr with 25–100 μM nitrite at 37°, >90% of the nitrite reacted to give DMN Ascorbate blocked DMN formation from AP efficiently under various conditions We confirmed Bockmuhl's finding that the other main product of AP nitrosation is 1-diketo-butyryl-1-phenyl-2-methyl-2-nitrosohydrazide hydrate (DPMN) The unusual ease of reaction is attributed to the enamine structure of AP The possibility of intragastric nitrosation of AP is considered to present a hazard to people ingesting this analgesic drug, which is widely used in Europe

Kinetics of the nitrosation of aminopyrine to give dimethylnitrosamine

The transplacental carcinogenic effects of dibutylnitrosamine (DBN) and nitrosohexamethyleneimine (N-6-MI) were examined in Syrian hamsters. A proportion of both substances reached the fetal tissue unaltered. No macroscopic malformations were observed in the offspring; however, postnatal mortality was high. Respiratory tumours were found upon histologie examination of surviving animals. Single doses of 30 mg/kg body weight (b.w.) DBN and 2 doses of 10 mg/kg b.w. N-6-MI did not induce tumours in the P-generation, but led to a low tumour incidence in the F1-generation (DBN, 7.0%; N-6-MI, 2.0%). Treatment for up to eight days during the second half of pregnancy led to a higher tumour incidence in the P-generation (DBN, 22%; N-6-MI, 20%), than in the F1-regeneration (DBN, 6.0%; N-6-MI, 10%).

Transplacental effects of nitrosamines in Syrian hamsters: I. Dibutylnitrosamine and nitrosohexamethyleneimine.

Oxidation at the beta carbon occurred in metabolism of di-n-propylnitrosamine (DPN), previously shown to be carcinogenic for animals. When 2,2'-dimethyldipropylnitrosamine (DMDPN) was injected sc once a week for life into male and female Syrian hamsters at levels of 500, 250, 125, and 62.5 mg/kg body weight, it induced neoplasms in the nasal cavities, larynx, trachea, and stem bronchi. Since the presence of a methyl group on the beta carbon suggested that DMDPN could not undergo beta oxidation, the carcinogenicity of DPN for these portions of the respiratory tract was probably unrelated to beta oxidation, though earlier experiments had indicated the possibility of this mechanism. Because DMDPN failed to induce neoplasms in other organs, the carcinogenicity of DPN or its beta metabolites for the lungs, liver, pancreas, and kidneys was not explained by this experiment.

Michael Eagen

Papers

Ascorbate-Nitrite Reaction: Possible Means of Blocking the Formation of Carcinogenic N-Nitroso Compounds

Carcinogenicity Test of Six Nitrosamides and a Nitrosocyanamide Administered Orally to Rats

Kinetics of the nitrosation of aminopyrine to give dimethylnitrosamine

Transplacental effects of nitrosamines in Syrian hamsters: I. Dibutylnitrosamine and nitrosohexamethyleneimine.

Carcinogenic ERect of 2,2′-Dimethyldipropylnitrosamine in Syrian Hamsters