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PubMed1983

Safe disposal of carcinogenic nitrosamines.

A simple one-step procedure for chemically degrading nitrosamine residues generated in the research laboratory is described. Treatment with aluminum-nickel alloy powder and aqueous alkali rapidly reduced all 11 nitrosamines studied to the corresponding amines. Hydrazines were produced as transitory intermediates, but these potential carcinogens were also easily reduced under the conditions employed, and no products except amines, ammonia, and, in some cases, alcohols were detected in the final reaction mixtures. Reduction proceeded smoothly in every other solvent system tested, except that reactions in acetone or dichloromethane solution were sometimes slow, incomplete, and/or led to unidentified products; therefore, we cannot recommend the procedure for use in these solvents. Otherwise, the method was efficient, reliable, and inexpensive and has been recommended as one of the preferred means of degrading potentially carcinogenic nitrosamines to innocuous products. Details of its application to some decontamination and disposal problems commonly encountered in the research laboratory are provided. Data illustrating this procedure's advantages over six other reducing systems are also presented.

Chemical Phenomena↗
PubMed1987

Influence of disulfiram on the metabolism of the urinary bladder carcinogen N-butyl-N-(4-hydroxybutyl)nitrosamine in the rat.

The effect of feeding disulfiram (DSF) to rats on the metabolism of N-butyl-N-(4-hydroxybutyl)nitrosamine (BHBN) was examined in order to study the mechanism by which DSF inhibits bladder cancer induction by BHBN. After 2 weeks of feeding 0.5% DSF in the diet, animals were given [14C]BHBN (25 mg/kg) and the urine and expired CO2 were collected for 8 h. Radioactivity in expired air was very low, but DSF caused a significant reduction in expired 14CO2 (control 1.0% of dose; DSF 0.6%), presumably by inhibition of alpha-hydroxylation pathways. There was no difference in the excretion of total urinary radioactivity (control 84%; DSF 85%). Urine was analyzed by h.p.l.c. for BHBN, N-butyl-N-(3-carboxypropyl)nitrosamine (BCPN), N-butyl-N-2-hydroxy-3-carboxypropyl)nitrosamine (BHCPN) and N-butyl-N-carboxymethylnitrosamine (BCMN). DSF did not alter the urinary excretion of BCPN (control 64% of dose; DSF 61%), whereas BHCPN excretion was increased (control 11% of dose; DSF 22%) and urinary levels of BCMN were decreased (control 10% of dose; DSF 4%). The metabolism of BHBN was also studied in isolated hepatocytes from control and DSF-fed rats. Hepatocytes were incubated in Liebovitz's L-15 medium containing 0.5 mM [14C]BHBN and aliquots of the medium were removed for h.p.l.c. analysis at 0.5, 1, 2 and 4 h. Metabolic rates are expressed as mumol/h/5 million cells. There was no difference in the overall rate of metabolism of BHBN in control and DSF-fed rats. BHBN was very rapidly oxidized to BCPN and the rate was not affected by DSF treatment (control 1.82; DSF 1.76). The rate of accumulation of BHCPN was increased 3.5-fold in the DSF-fed rats (control 0.06; DSF 0.21) and BCMN could not be detected. Taken together, these data show that (i) DSF may inhibit the low extent of alpha-hydroxylation of BHBN or BCPN; (ii) DSF does not inhibit the rapid oxidation of BHBN to BCPN and (iii) DSF appears to inhibit the metabolism of BHCPN.

Animals↗
PubMed1988

Theoretical model for predicting rates of nitrosamine and nitrosamide formation in the human stomach.

A mathematical model has been developed to estimate the rates of formation of nitrosamines and nitrosamides in the human stomach, under a variety of physiological and environmental conditions. The model combines a detailed description of the kinetics of N-nitrosation with mass balance equations which account for gastric emptying, dilution and absorption. The simulations were based on a typical schedule of dietary inputs, and included variations in gastric pH and in the volume of the stomach contents over a 24-h period. Consideration of these transient phenomena allowed a distinction to be made between amines or amides present in the diet and in gastric or salivary secretions. A comparison of the theoretical results with available data on the nitrosation of proline suggests that the model accurately predicts gastric rates of nitrosamine formation under control conditions, and correctly represents the strong catalytic effects of thiocyanate and the inhibitory effects of ascorbic acid or ascorbate ion. The results further suggest that nitrosoproline (NPro) excretion is not an accurate index of gastric nitrosation under physiological (low-dose) conditions, even when corrections are made for dietary intake of NPro. The predicted rates of formation of N-nitrosodimethylamine (NDMA), even for a diet high in dimethylamine, were found to be a factor of approximately 10(2) to 10(3) lower than published estimates of the dietary exposure to preformed NDMA. Thus, these findings do not support the hypothesis that gastric formation of NDMA from dietary dimethylamine poses a serious additional health risk. The results are presented in a graphical and tabular form which makes it possible to readily estimate the rates of formation of other nitrosamines or nitrosamides in the stomach, under various assumed conditions.

Ascorbic Acid↗
PubMed1993

Multiresidue recovery at PPB levels of 10 nitrosamines from frankfurters by supercritical fluid extraction.

The design of a laboratory-assembled supercritical fluid extractor is described for the efficient recovery of volatile nitrosamines from a common-cured meat product, frankfurters. The principal feature of the apparatus was a newly designed restrictor-collector interface where a commercial solid-phase extraction cartridge was directly attached to the micrometering valve. This reduced the path length between the discharge tube and the 1 g silica gel sorbent bed. The elapsed time for each 2.5 g sample extraction with supercritical CO2 was 17 min. The nitrosamines were separated and detected using a gas-chromatographic chemiluminescence (Thermal Energy Analyzer, Thermedics, Inc.; Woburn, MA) system. Recovery of 10 volatile aliphatic and alicyclic nitrosamines from frankfurters, fortified at the 20 ppb level, ranged from 84.3 to 104.8% with relative standard deviation of 2.34 to 6.13%.

Carbon Dioxide↗
PubMedDate not supplied

Identification and quantitation of N-nitrosamines in human postmortem organs.

A gas-liquid chromatographic method for quantitative determination of six volatile N-nitrosamines in human postmortem organs (brain, liver, kidneys, and pancreas) is described. This method, which is highly sensitive and selective, makes use of two different detectors, i.e., the electron capture detector (ECD) and the thermal energy analyzer (TEA). The mean absolute percentage recoveries of N-nitrosodimethylamine (NDMA), N-nitrosodiethylamine (NDEA), N-nitrosodipropylamine (NDPA), N-nitrosodibutylamine (NDBA), N-nitrosodipropylamine (NDPA, N-nitrosodibutylamine (NDBA), N-nitrosopiperidine (NPIP), and N-nitrosopyrrolidine (NPY) were 54.7, 80.0, 79.6, 72.5, 75.5, and 79.6, respectively. N-Nitrosamines in the organ extracts were converted to their corresponding N-nitramine analogs by pertrifluoroacetic acid oxidation. These derivatives were purified by adsorption chromatography on basic alumina and then analyzed by ECD. N-Nitrosamines were analyzed without derivatization in the organ extracts with the TEA detector. The described method did not cause artifactual formation of N-nitrosomethyl-N-butylamine (NMBA) when methyl-N-butylamine was used as an internal marker of nitrosation. NDMA was found in all the organs examined, whereas NDPA was only detected in the liver of one in four subjects. NDMA was found in all brain samples, indicating that it crosses the blood-brain barrier.

Aged↗
PubMed1978

Nitrosamine formation in human saliva.

Nitrosamines formed when secondary amines were added to normal human saliva. Fractionation of saliva into cells and supernatant showed that factors that accelerated and retarded the nitrosation reaction were both present. Acidification of saliva greatly increased the nitrosamine yield, but differences in nitrosamine yield among saliva fractions were still observable.

Bacteria↗
PubMed1978

Tobacco-specific nitrosamines: formation from nicotine in vitro and during tobacco curing and carcinogenicity in strain A mice.

The formation of tobacco-specific nitrosamines from the major tobacco alkaloid nicotine was examined. Detached leaf tobacco was fed either [2'-14C]nicotine or [2'-14C]nornicotine and air cured. The cured leaf was then analyzed for [2'-14C]N'-nitrosonornicotine ([2'-14C]NNN). The yield of [2'-14C]NNN was 0.007% from nornicotine and 0.009% from nicotine. Because the ratio of nicotine to nornicotine in conventional nicotine-type tobacco is 20-100:1, nicotine is considered to be the major precursor for the carcinogen NNN in tobacco. The formation of other nitrosamines from nicotine in vitro was then studied. Reaction of nicotine with NaNO2 gave rise to NNN, as well as to two other nitrosamines, 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and 4-(N-methyl-N-nitrosamino)-4-(3-pyridyl)butanal (NNA). Analysis of market products revealed the presence of NNK (0.6-24 microgram/g) in chewing tobacco and snuff. The tumorigenic activity of NNN, NNK, and NNA in strain A mice was studied. NNK induced more lung adenomas per mouse than did NNN, whereas NNA was less active than NNN. In addition, two cases of undifferentiated carcinoma of the salivary glands occurred in the NNN experimental groups.

Adenoma↗
PubMed2001

Lack of change in the levels of liver and kidney cytochrome P-450 isozymes in p53+/- knockout mice treated with N-butyl-N-(4-hydroxybutyl)nitrosamine.

We have previously shown that p53(+/-) knockout mice are highly sensitive to urinary bladder carcinogenesis induced by N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) in spite of a lack of effects of p53 heterozygosity on N-butyl-N-(3-carboxypropyl)nitrosamine (BCPN) excretion in urine. To determine the influence of p53 deficiency on in vitro formation of BCPN, mutagenicity of BBN and BCPN and levels of several cytochrome P450 (CYP) isozymes, groups of five p53(+/-) knockout and wild-type mice (littermates), as well as animals of the C57BL/6 parental strain, were administered 0.025% BBN in their drinking water for 4 weeks. The livers and kidneys were then used for analyses of BBN metabolism, western immunoblotting and Ames liquid incubation. BBN treatment caused a slight decrease in BCPN formation in the livers of C57BL/6 mice, but there was no significant difference between p53 knockout, wild-type and C57BL/6 mice. In kidney BCPN formation in p53 knockout mice was 33-46% less than that in their wild-type counterparts. Using anti-rat CYP antibodies, CYP1A2, 2B9/10, 2E1 and 3A11/13 were constitutively detected in liver microsomes and CYP2E1 and 3A11/13 in the kidney. Densitometric determination of these CYP proteins revealed no significant variation in levels detected in both tissues among the four groups of mice. BBN and BCPN were not mutagenic for Salmonella typhimurium TA100 in either the absence or presence of liver S9 from untreated mice and rats and from p53 knockout mice treated with BBN. In conclusion, p53 deficiency and BBN had no enhancing effects on metabolism of BBN to BCPN and expression of the CYP isozymes typically responsible for activation of environmental carcinogens, including both of the N-nitrosamines tested, and their mutagenicity, indicating that the high susceptibility of p53(+/-) knockout mice is not attributable to metabolic activation in liver and kidney by CYP isozymes or urinary excretion of BCPN.

Animals↗
PubMed1995

Nitrosamine intake and gastric cancer risk.

The association between intake of N-nitrosodimethylamine (NDMA), the most commonly occurring of the volatile nitrosamines derived from foods, and gastric cancer risk has been investigated using data from a case-control study conducted in Northern Italy between 1985 and 1993, including 746 incident cases of gastric cancer and 2,053 controls admitted to hospital for acute, non-neoplastic and non-digestive tract diseases, not related to long-term modifications of diet. Information was collected on frequency of consumption of 29 food items, including selected sources of NDMA. Compared with subjects in the lowest tertile of NDMA intake, the odds ratios (ORs) were 1.1 in the intermediate and 1.6 in the highest tertile of intake. These estimates were not appreciably modified after allowance for total energy intake, other major dietary and non-dietary correlates of gastric cancer, and estimated intake of nitrite and nitrate: the multivariate OR for the highest NDMA intake tertile was 1.4 (95% CI 1.1-1.7). The association was consistent across strata of sex and age, but somewhat stronger in males and in subjects below age 60 (OR in the highest tertile, 1.8). Limitations of exposure assessment and absence of information on other N-nitrosamines preclude, however, any definite assessment of the possible role of exogenous N-nitrosamines in gastric carcinogenesis.

Adult↗
PubMed1995

Effect of bifidobacteria on nitrites and nitrosamines.

The effects of six different bifidobacteria strains were studied on two procarcinogens: nitrite and nitrosamines. Growth of bifidobacteria was not affected by nitrite concentrations below 50 mumol l-1. At nitrite concentrations greater than 2000 mumol l-1, total growth inhibition was observed. Nitrite elimination by a non-enzymic mechanism was noted for six strains of bifidobacteria. Acids produced by the bacteria seem to be involved in nitrite elimination. Nitrosamines tested had no effect on growth of bifidobacteria. Only one strain (Bifidobacterium longum BB 536) was able to metabolize nitrosamines by an intracellular mechanism.

Bifidobacterium↗
PubMed1976

N-Nitrosamine formation by cultures of several microorganisms.

Of 38 pure cultures of microorganisms tested, only one, Pseudomonas stutzeri, was capable of forming dimethylnitrosamine from dimethylamine and nitrite during growth. Resting cells of P. stutzeri, Cryptococcus terreus, Escherichia coli, and Xanthomonas campestris formed dimethylnitrosamine, although no nitrosamine was found in growing cultures of the latter three organisms. No nitrosamine was produced by either growing cultures or resting-cell suspensions of Pseudomonas fragi or Proteus mirabilis. Boiled cells of P. stutzeri, but not those of C. terreus, E. coli, and X. campestris, formed dimethylnitrosamine, and this nitrosamine was also produced by extracts of E. coli cells at pH 5.0.

Bacteria↗
PubMed1980

Daily dietary intakes of nitrate, nitrite and volative N-nitrosamines in the Netherlands using the duplicate portion sampling technique.

In total, 201 duplicates of all foods and drinks sampled by adult volunteers during a 24-hour sampling period have been analyzed for nitrate, nitrite and volatile N-nitrosamines. For nitrate the mean daily intake was equivalent to 179 mg of potassium nitrate per 24 h, for nitrite this intake was equivalent to 4.2 mg of sodium nitrite per 24 h. The best estimate for the total daily fraction of salivary nitrite originating from dietary nitrate has been calculated as 6.3 mol%/24 h. For N-nitrosodimethylamine the mean daily intake was 0.38 microgram/24 h. The most important source of this nitrosamine contributing to the daily dietary intake was shown to be beer, which contributes 71% of the intake of an average consumer. Finally, attention has been drawn to the identification of N-nitroso-5-methyl-1,1-oxazolidine as an environmental nitrosamine present as an impurity in cutting fluids.

Beer↗
PubMed2000

Synthesis and properties of novel bifunctional nitrosamines with omega-chloroalkyl groups.

Novel N-nitroso-N-(acetoxymethyl)-omega-chloroalkylamines were synthesized and their chemical and biological properties were evaluated. The nitrosamines were expected to decompose through omega-chloroalkyldiazohydroxides in aqueous solution, and then to alkylate various cellular macromolecules. N-Nitroso-N-(acetoxymethyl)-2-chloroethylamine rapidly decomposed in aqueous solution, and the reaction rate was apparently independent of the pH of the solution. On the other hand, the rate of decomposition of chloropropyl and chlorobutyl homologs was pH-dependent, and increased in alkaline solution. When mutagenicity was assayed in Salmonella typhimurium TA1535 and TA92 for preliminary evaluation, all three compounds were directly mutagenic. The mutagenicity in Salmonella typhimurium TA1535, which can detect base-pair change mutation, clearly showed that these compounds induced DNA alkylation in vivo. The increase of alkyl chain length in chloroalkyl compounds increased the mutagenic activity, and the activities were stronger than those of the corresponding simple alpha-acetoxy nitrosamines lacking a chloro group, N-nitroso-N-(acetoxymethyl)alkylamines. Furthermore, the positive result in TA92 suggested that chlorinated nitrosamines cross-linked DNA like antitumor chloroethylnitrosoureas and that they are expected to be new lead compounds for antitumor agents.

Alkylation↗
PubMed1998

Volatile N-nitrosamine formation after intake of nitrate at the ADI level in combination with an amine-rich diet.

Formation of nitrite from ingested nitrate can result in several adverse health effects and implies a genotoxic risk as a consequence of endogenous formation of carcinogenic N-nitroso compounds. We studied the formation of volatile N-nitrosamines after intake of nitrate at the acceptable daily intake (ADI) level in combination with a fish meal rich in amines as nitrosatable precursors. Twenty-five volunteers consumed this meal during 7 consecutive days; a diet low in nitrate was consumed during 1 week before and 1 week after the test week. Nitrate intake at the ADI level resulted in a significant rise in mean salivary nitrate and nitrite concentrations. Mean urinary nitrate excretion increased from 76 mg/24 hr in the first control week to 194 and 165 mg/24 hr in the test week, followed by a decline to 77 mg/24 hr in the second control week. The urine samples were analyzed for volatile N-nitrosamines, and both N-nitrosodimethylamine (NDMA) and N-nitrosopiperidine (NPIP) were detected in the samples. Mean urinary NDMA excretion significantly increased from 287 ng/24 hr in the control week to 871 and 640 ng/24 hr in the test week and declined to 383 ng/24 hr in the second control week. Excretion of NPIP was not directly related to the nitrate intake and composition of the diet. Nitrate excretion and NDMA excretion were significantly correlated, as well as salivary nitrate and nitrite concentration and NDMA excretion. We conclude that nitrate intake at the ADI level in combination with a fish meal containing nitrosatable precursors increases NDMA excretion in urine and thus demonstrates increased formation of carcinogenic N-nitrosamines.

Adolescent↗
PubMed1976

[Nitrosamines. Review].

Nitrosamines are an extremely carcinogenic class of compounds. The hasard, bound with the occurrence of this compounds in the food and the possibility to be formed in vivo, during the digestion, justifies the current works. The authors quoting numerous works on different laboratory's animals, remind the toxicity. and carcinogenicity of this compounds. The metabolism is also discussed. The N-nitroso, compounds may be formed in food from the presence of the precursors (nitrite or nitrate, amines and amino-acides). The synthesis takes place during the technological processes, the storage and the house cooking. Today, the marginal effect dose is estimated as 10 mug/kg of daily food. The carcinogenicity has not been demonstrated in human, but is strongly suspected. The amount of N-nitroso compounds in human food is generally low. Many factors can influence the reaction; it is inversely related to the basicity of secondary amine and optimum pH is around pH 4. A lot of compounds such as sodium ascorbate inhibit the synthesis in food. A number of recent reports using reliable methodology have identified nitrosamines at the lower part per billion level. Dimethyl-nitrosamines occurs, very sporadically in a number of cooked meat samples. The nitrosopyrrolidine appears frequently in fried but not in uncooked products. The nitrosopiperidine seems to be bind with the presence of pepper in food. Finally the presence of nitrosamides (nitrososarcosine) and nitrosoaminoacides (nitrosoproline, nitrosohydroxy-proline) is being quested. The N-nitroso compounds may be synthetized in vivo during the digestion at the acide medium of the stomach or by bacterial action during the transit in the gut...

Amino Acids↗
PubMed2001

The bacterial flora and the changes of the N-nitrosamine concentration in the operated stomach.

The studies included 170 patients (103 men and 67 women) aged 23 to 66 years, operated on because of an ulcerous disease. Depending on the method of surgical treatment patients were divided into 5 groups (those after gastric resection with Rydygier's method, after resection with the Billroth II method, after trunk vagotomy with pyloroplasty, after highly selective vagotomy, and after gastro-enterostomy). In all patients a qualitative estimation of the nitrate-reducing bacteria was carried out, as well as a chromatographic test of the selected N-nitrosamine concentration in the gastric juice. It was shown that the changes in the quantity of the nitrate-reducing bacteria and in the N-nitrosamine concentration depended on the type of surgical intervention conducted. The largest mean content of nitrate-reducing bacteria and the highest average N-nitrosamine concentration were confirmed in the gastric juice of patients after gastroenterostomy and after gastric resection with the Billroth II method, and the lowest values--in patients after highly selective vagotomy.

Adult↗
PubMed1992

Volatile N-nitrosamines in salted fish samples from high- and low-risk areas for NPC in China.

Four carcinogenic volatile nitrosamines (N-dimethylnitrosamine, NDMA; N-diethylnitrosamine, NDEA; N-nitrosopyrroline, NPYR; and N-nirosopiperilidine, NPIP) were screened in twenty specimens of salted fish collected from areas in China with different nasopharyngeal carcinoma (NPC) mortality rates. The highest NDMA, NDEA and total N-nitrosamine contents (322.92, 50.27 and 373.19 micrograms/kg, respectively) were found in the samples from Sihui, one of the areas with highest NPC mortality. The lowest contents (12.64, 7.65 and 20.29 micrograms/kg, respectively) were seen in the samples from Shanghai, the area with the lowest mortality from NPC in the study. These results confirm that there are appreciable levels of nitrosamines in the salted fishes consumed by residents in high-risk areas of NPC in China.

Animals↗
PubMed1992

Nitrosamine-induced lung carcinogenesis and Ca2+/calmodulin antagonists.

This review summarizes recent data which implicate cell membrane receptors and their associated signal transduction pathways as molecular targets of tobacco-related lung carcinogenesis as well as therapy of such cancers. It is shown that the two nitrosamines N-nitrosodiethylamine and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone bind to nicotinic cholinergic receptors in hamster lung. Binding of the nitrosamines as well as nicotine to this receptor stimulates proliferation of human lung carcinoid cells in vitro. These data suggest chronic stimulation of nicotinic receptors by nicotine and nitrosamines in smokers as one of the molecular events responsible for stimulation of neuroendocrine cell proliferation and ultimately the development of lung tumors with neuroendocrine differentiation. On the other hand, a selective antiproliferative effect of the dihydropyridine derivative B859-35 on neuroendocrine lung tumor cells in vivo and in vitro suggests the potential use of such agents as cancer therapeutics. The demonstrated inhibition of Ca2+/calmodulin and protein kinase C by B859-35 as reported in other in vitro systems suggests interference with such elements of signal transduction pathways as the molecular mechanism of the observed antiproliferative effects.

Animals↗