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PubMed1978

Chemical studies on tobacco smoke LVI. Tobacco specific nitrosamines: origins, carcinogenicity and metabolism.

Tobacco contains specific carcinogenic nitrosamines which are derived from nicotine. These compounds may be among the causative agents for the various cancers (lung, oral cavity, oesophagus, bladder and pancreas) which are associated with tobacco usage. The major tobacco specific nitrosamine is N'-nitrosonornicotine (NNN), which has been detected in both unburned tobacco (0.3-90.6 ppm) and cigarette mainstream smoke (137-238 ng/cig.). Studies with labelled precursors showed that the major source of NNN formed during curing of tobacco was nicotine, rather than nornicotine. The transfer rate of NNN from tobacco to mainstream smoke was 11.3%; about half the NNN present in smoke therefore originated from tobacco, with the remainder being formed during smoking. Model studies of the reaction of nicotine and nitrite showed that, in addition to NNN, two other nitrosamines, 4-(N-methyl-N-nitrosamino)-4-(3-pyridyl)-1-butanal (NNA) and 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK) were formed. Analysis of tobacco revealed the presence of NNK in chewing tobacco and snuff (0.6-2.4 ppm). A comparative bioassay of NNN, NNK and NNA in strain A mice indicated that NNK was more tumorigenic than NNN and that NNA was inactive. NNN, which had previously been shown to induce oesophageal and nasal cavity tumours in rats, also was a moderately active carcinogen in the Syrian golden hamster, giving tracheal tumours. A study of the metabolism of cyclic nitrosamines was initiated. Metabolic alpha-hydroxylation of nitrosopyrrolidine, which is thought to be the critical step in activation of this compound, was demonstrated by detection in vitro and in vivo of 2-hydroxytetrahydrofuran, which was the product of decomposition of alpha-hydroxynitrosopyrrolidine. The metabolism of the related cyclic nitrosamine, NNN, is currently under investigation, with emphasis on metabolites resulting from alpha- and beta-hydroxylation. These analytical and metabolic studies are intended to clarify the possible relationship of tobacco-specific nitrosamines and site-specific cancers in tobacco users.

Anabasine↗
PubMed1983

Species variations in the metabolism of N-butyl-N-(4-hydroxybutyl) nitrosamine and related compounds in relation to urinary bladder carcinogenesis.

Species variations in response to urinary bladder carcinogens, N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN), N-ethyl-N-(4-hydroxybutyl)nitrosamine (EHBN), and N,N-dibutylnitrosamine (DBN), were investigated in several animal species from the metabolic point of view. Since N-butyl-N-(3-carboxypropyl) nitrosamine (BCPN) and N-ethyl-N-(3-carboxypropyl) nitrosamine (ECPN) had been found to be the principal urinary metabolites which are responsible for the induction of bladder tumors by BBN or DBN and EHBN, respectively, in rats, acidic urinary metabolites with the N-nitroso moiety were isolated and determined by a colorimetric method after oral administration of these nitrosamines to rats, mice, hamsters, guinea pigs, and dogs. Qualitatively almost no species differences were observed among these animals in regard to the urinary metabolites except in the case of mice, in which the glycine conjugate of BCPN was isolated from the urine and identified as the principal metabolite of BBN and DBN. However, appreciable quantitative differences in the urinary excretion of BCPN or ECPN were found among these animal species, indicating that the differences in the susceptibilities of different animal species to urinary bladder carcinogenesis induced by BBN, DBN and EHBN may be closely related to the different extents of urinary excretion of the active metabolites of these nitrosamines.

Animals↗
PubMed1983

Drug interactions. II. Formation of nitrosamines from therapeutic drugs. Properties and kinetics of the formation of N-nitrosopropranolol from nitrite and the secondary amine propranolol hydrochloride.

In the presence of hydrochloric acid, nitrosamines may be generated from amines and nitrite. Most nitrosamines are carcinogens and many commonly used drugs contain potentially nitrosatable amine groups. Beta-adrenergic blockers, which have such amine groups, are widely prescribed and are often ingested for the lifetime of the patients, but their safety with respect to the intragastric formation of nitrosamines has not been established. The studies in this and the following report were designed to assess the potential risk posed by the endogenous formation of a nitrosamine in the stomach to individuals receiving longterm treatment with propranolol hydrochloride. The putative nitrosamine, N-nitrosopropranolol (NNP), was synthesized and its stability was examined under various experimental conditions. A high-pressure liquid chromatographic method was developed which detects a minimum of 7 X 10(-11) mol of NNP in the presence of large quantities of unreacted drug. Preparations of propranolol hydrochloride were found to contain several non-nitrosamine contaminants, which were removed before kinetic studies. At 37 degrees C, in solutions of HCl within the pH range found in the stomach, the optimum pH for the formation of NNP was 3. The yield of NNP increased linearly as incubation time and concentration of propranolol increased and exponentially as the concentration of nitrite was raised. Under optimal conditions in hydrochloric acid, the minimum concentration of nitrite required for the production of detectable amounts of NNP was 10(-5) M.

Chemical Phenomena↗
PubMed1980

A sensitive hepatocyte-mediated assay for the metabolism of nitrosamines to mutagens for mammalian cells.

A sensitive cell-mediated assay has been developed for testing mutagenesis in Chinese hamster V79 cells by carcinogenic nitrosamines. Mutations were characterized by resistance to ouabain and 6-thioguanine. Since V79 cells do not metabolize nitrosamines, mutagenesis in the V79 cells was tested in the presence of primary hepatocytes capable of metabolizing nitrosamines. The hepatocytes were isolated after collagenase and hyaluronidase digestion of liver slices. All seven liver carcinogens of the nine tested nitrosamines exhibited a mutagenic response in this cell-mediated assay. The potent liver carcinogens nitrosodimethylamine, nitrosodiethylamine, nitrosoethylmethylamine, and nitrosodipropylamine could be detected with doses as low as 1 muM. The noncarcinogenic nitrosodiphenylamine was not mutagenic. Nitrosomethoxymethylamine was the only nitrosamine that exhibited mutagenic activity in the absence of hepatocytes, and this activity was diminished in the presence of hepatocytes. It is suggested that the use of hepatocytes prepared by the slicing method for carcinogen metabolism and mutable V79 cells offers a highly sensitive assay for determining the mutagenic potential of carcinogenic nitrosamines and probably of other classes of hazardous chemicals occurring in the environment.

Animals↗
PubMed1980

Formation and chemistry of alpha- and beta-oxidized nitrosamines.

Nitrosamines, in general, require metabolic transformation to produce electrophilic metabolites. These interact with cellular nucleophiles to initiate the chain of events culminating in tumour initiation. The enzymatic hydroxylation of the alpha-carbon of nitrosamines has long been held to be an important process in the formation of carcinogenic metabolites. The present work suggests, however, that there may be other processes which also result in the formation of electrophilic species. These include: (1) beta-hydroxylation, followed by appropriate conjugation, which results in the formation of electrophilic oxadiazolium ions. (2) O-alkylation of nitrosamines, which has the effect of labilizing the alkyl groups attached to the nitrogen toward nucleophilic substitution. (3) The formation of alpha, beta-unsaturated nitrosamine (N-nitrosoenamines), which are highly reactive species that can be readily transformed to alpha-hydroxylated nitrosamines by acid-catalyzed hydration. N-nitrosoenamines also react directly with a variety of nucleophilic reagents. The isomerization of beta, gamma-unsaturated nitrosamines to the alpha, beta-unsaturated isomers has been demonstrated to occur in vivo.

Alkylation↗
PubMed1980

Metabolic fate of N-butyl-N-(4-hydroxybutyl)nitrosamine in the rat.

The metabolic fate of N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) was studied in the rat, to investigate the possibility of a relationship between urinary metabolites and organotropic carcinogenicity to the urinary bladder of this N-nitrosamine. The principal urinary metabolite of BBN was identified as N-butyl-N-(3-carboxypropyl)nitrosamine (BCPN). Several minor metabolites characterized were transformation products of BCPN formed by beta-oxidation according to the Knoop mechanism, i.e., N-butyl-N-(2-hydroxy-3-carboxy-propyl)nitrosamine, N-butyl-N-(carboxymethyl)nitrosamine and N-butyl-N-(2-oxopropyl)nitrosamine; glucuronic acid conjugates of BBN and BCPN were also detected. No BBN was detected in the urine. A possible correlation of the urinary excretion of BCPN with selective induction of bladder tumors by BBN in rats is discussed in relation to the carcinogenic action of BCPN.

Animals↗
PubMed2002

Influence of UV radiation and nitrosamines on the induction of mycotoxins synthesis by nontoxigenic moulds isolated from feed samples.

The effects of UV radiation and nitrosamines on the induction of mycotoxin biosynthesis by some nontoxigenic moulds isolated from feed samples collected from Egypt and Poland was investigated. Nontoxigenic strains of Aspergillus flavus P-63, A. niger EN-200 and A. ochraceus P-157 synthesized mycotoxins (aflatoxins and ochratoxin, A) after exposure to near UV radiation for 120-210 min. Nitrosamines (DMNA and DENA) at 30 up to 1000 ppm induced the synthesis of aflatoxins by nontoxigenic species of A. flavus ES-255 and P-63 and A. niger EN 200. Near-UV radiation and nitrosamines had no influence on the induction of mycotoxin synthesis by Penicillium and Fusarium isolates. All nontoxigenic strains of Aspergilli which synthesized aflatoxins in the presence of 1000 ppm nitrosamines, also synthesized continuously aflatoxins during the next fifteen generations. Near-UV radiation and nitrosamines had a mutagenic effect on the induction of mycotoxins synthesis by nontoxigenic moulds.

Aspergillus↗
PubMed1978

Mass spectrometry of N-nitrosamines.

The preparation of a series of N-nitrosamines for carcinogenicity studies presented an opportunity to study mass spectral fragmentation schemes in detail. Condensed spectra are listed for 146 N-nitrosamines of widely differing structures, including nitroso derivatives of commercial drugs and insecticides. Aliphatic nitrosamines were generally characterized by molecular ions and loss of OH. Subsequent fragmentation via alpha-cleavage is similar to that of aliphatic amines. The loss of OH is believed to result in a cyclic ion. Subsituted aliphatic nitrosamines varied in fragmentation schemes with structure and position of the substitutent groups. However, most showed alpha-cleavage at some point in fragmentation. When substituted with aromatic groups prominent peaks due to the aromatic moiety were observed. The alicyclic nitrosamines showed losses of NO, NOH and OH and subsequent alpha-cleavages. Nitrosamides were characterized by rupture of the carbonyl to nitrogen bond. Spectra of substituted ureas usually showed charge retention by the carbonyl fragment, while carbamate esters showed ions from both fragments.

Carcinogens↗
PubMed2005

Migration of nitrosamines from rubber products--are balloons and condoms harmful to the human health?

Studies performed in 2001 and 2003 surveyed the release of carcinogenic nitrosamines and nitrosatable substances from rubber toy balloons by extraction with artificial saliva and gas chromatography-thermal energy analysis (GC-TEA). 81% of the 16 in 2001 sampled balloons and 93% of the 14 in 2003 sampled balloons released nitrosamines above the recommended level in Germany of 10 mug per kg material. Furthermore, 32 rubber condom samples collected in 2004 from the German market were surveyed for nitrosamines by determining the amount migrating into an artificial sweat test solution. The levels released from condoms varied from < 10 to 660 mug per kg material (i. e., up to 1.4 mug nitrosamines per condom). In a model calculation, not considering the differences that may exist in the resorption rate, we have calculated that the exposure from condoms may exceed the exposure from food 1.5-3 fold. To our knowledge so far no legal binding legislation exists worldwide concerning nitrosamine migration from toy balloons or condoms.

Carcinogens↗
PubMed1990

N-nitrosamino phosphates are unlikely transport forms for activated nitrosamines.

Some of the target organs for nitrosamine carcinogenicity have a low activating capacity but many carcinogenic nitrosamines can be activated in the liver. Conjugates, such as phosphates, are chemically accessible reaction products of 1-OH-nitrosamines, and are either potential detoxication products or potential transport forms for activated nitrosamines. 14C-labeled 1-(N-ethyl-N-nitrosamino)ethyl phosphate was tested for its ability to enter primary rat hepatocytes but no uptake was detectable. No uptake was observable into fibroblasts and human leukocytes. N-Nitrosomethylbenzylamine is efficiently 1-C-hydroxylated by hepatocytes but the corresponding 1-C-phosphate was detectable neither in the cells nor in the surrounding medium. N-Nitrosamino-1-phosphates, unlike 1-glucuronides, therefore, do not seem to be important for nitrosamine toxicokinetics.

Animals↗
PubMed1978

Inhibition of rat hepatic dimethylnitrosamine demethylase by cyclic and acyclic nitrosamines and secondary amines.

Inhibition of hepatic dimethylnitrosamine (DMN) metabolism by a variety of cyclic and acyclic nitrosamines was demonstrated. Nitrosoproline, a noncarcinogenic nitrosamine, behaved differently from the carcinogenic nitrosamines as an inhibitor for DMN-demethylase. Secondary amines corresponding to the nitrosamines inhibited DMN-demethylase in a manner similar to the nitrosamines.

Animals↗
PubMed1988

Carcinogenesis and nucleic acid alkylation by some oxygenated nitrosamines in rats and hamsters.

A comparison has been made of the carcinogenic effects of nitroso-2,6-dimethylmorpholine and several hydroxylated acyclic nitrosodialkylamines derived from it or related to it in rats and Syrian hamsters. In rats nitrosodimethylmorpholine was the most potent, inducing mainly esophageal tumors. Nitrosodiethanolamine was the weakest of the five nitrosamines in both rats and hamsters. Tumors of the pancreas ducts were induced by four of the five compounds, but only in hamsters, and esophageal tumors appeared only in rats. Most of the nitrosamines induced tumors of liver and lung in both rats and hamsters. A study of alkylation of nucleic acids of the liver following treatment of rats and hamsters with the radiolabeled nitrosamines showed that nitrosodiethanolamine alkylated liver nucleic acids in rats to only a very small extent. The other four nitrosamines all gave rise to 7-methylation and O6-methylation of guanine residues in DNA of hamster liver and all but nitrosodimethylmorpholine in rat liver DNA, which corresponded quite well with the induction of liver tumors in the two species. Quantitatively, however, there was not a good correlation between liver DNA alkylation and the potency of the nitrosamine in inducing tumors.

Administration, Oral↗
PubMed1990

Nitrosamines as potential environmental carcinogens in man.

Nitrosamines are ubiquitous in our environment and diet. Many nitroso compounds are carcinogenic in animals and most probably in man. Nitrosamines are formed from the reaction of nitrite with primary, secondary, or tertiary amines in an acid medium. Nitrate should be considered as a nitrosating agent because it can be converted to nitrite by microbial action. Many aliphatic and nitrogen-containing heterocyclic compounds can be nitrosated to form carcinogenic substances. The occurrence in food and in some drugs of several nitrosamines or their nitrosatable precursors is described. Several tobacco-specific nitrosamines have been considered as possible causative agents for human cancer. Nitrosamines may be implicated in the induction of certain human gastric cancers.

Animals↗
PubMed1976

Comparative mutagenicity of N-nitrosamines in a semi-solid and in a liquid incubation system in the presence of rat or human tissue fractions.

The rat liver microsome-mediated mutagenicities of a series of N-nitrosodialkylamines and heterocyclic N-nitrosamines were determined in a liquid incubation system using Salmonella typhimurium TA1530. The influence on mutation frequency of the concentration of co-factors for mixed-function oxidase and composition and molarity of the buffer was investigated, using N-nitrosomorpholine as substrate. The mutagenicity of the N-nitroso compounds in the liquid incubation system under optimal reaction conditions at equimolar concentration was compared quantitatively with that obtained in a soft-agar incorporation assay. N-Nitrosodi-n-pentylamine and N-nitrosodi-n-butylamine showed no enzyme-mediated mutagenicity in the liquid incubation system, and metabolically activated N-nitroso-dimethylamine and N-nitroso-diethylamine showed negligible mutagenic activity in the soft-agar assays. In contrast with these results with the N-nitrosodialkylamines, the mutagenic effects of heterocyclic N-nitrosamines were similar in the liquid incubation system and in soft-agar incorporation assays. The heterocyclic N-nitrosamines showed rat-liver microsome-mediated mutagenicity in the following descending order: N-nitrosomorpholine greater than N-nitrosopyrrolidine greater than N-nitrosopiperidine greater than N-nitroso-N'-methylpiperazine. Seven human liver specimens converted all heterocyclic N-nitrosamines into mutagens; this activity was similar to that of rat liver, except that for N-nitroso-N'-methylpiperazine, fractions from three human liver biopsies were three to 30 times more active than those from untreated rats. The specific reversion of S. typhimurium TA1530 to histidine prototrophy provides experimental evidence that all the N-nitrosamines studied were converted by liver microsomal enzymes into monofunctional alkylating agents.

Animals↗
PubMed1986

Mutagenic activity and structure-activity relationships of short-chain dialkyl N-nitrosamines in a hamster hepatocyte V79 cell-mediated system.

A series of 19 short chain dialkyl N-nitrosamines was studied for mutagenic activity in an uninduced hamster hepatocyte V79 cell-mediated mutagenesis system. Ouabain was used as the selective agent to quantitatively analyze for chemically induced mutants. None of the nitrosamines was mutagenic in the absence of hamster hepatocyte activation. The relative mutagenic activities of the nitrosamines at an equimolar dose are presented. The results of the study indicated that: increasing alkyl chain length decreased mutagenic activity; oxidation of the 2-carbon position to a carbonyl group increased the mutagenic activity of symmetrical and asymmetrical nitrosamines, whereas oxidation to a hydroxyl group only increased the mutagenic activity of the asymmetrical nitrosamines tested; and the carbon position at which oxidation occurred was important in determining mutagenic activity. The relationships between structure, metabolic activation, and mechanisms of mutagenic activity are discussed.

Animals↗
PubMed1993

The need for regulation of carcinogenic N-nitrosamines in oral snuff.

Oral snuff is carcinogenic to humans and laboratory animals. The major carcinogenic agents in snuff are the N-nitrosamines, especially the tobacco-specific N-nitrosamines. During the past decade, a gradual reduction of the levels of carcinogenic N-nitrosamines was observed in the leading snuff brands in the USA and in Sweden. However, in 1990 a newly introduced snuff brand in the USA contained the highest concentration of carcinogenic N-nitrosamines ever to be determined in a commercial tobacco product. The elevated pH and relatively high levels of nitrite in this snuff favoured the formation of N-nitrosamines. 2 yr after the product first appeared, it was replaced by a new preparation of snuff under the same brand name, and, according to chemical analyses, this material would be expected to have about the same carcinogenic potential as the leading snuff products. The interdependence of the formulation and manner of preparation of snuff products with their carcinogenic potential emphasizes the need for regulation and control of the harmful substances in smokeless tobacco, especially in view of the trend of increasing consumption of snuff.

Carcinogens↗
PubMed1988

Occupational exposure to volatile nitrosamines in foundries using the "Ashland" core-making process.

Eight foundries using the "Ashland" process for the production of cores were surveyed to assess the occupational exposure to carcinogenic volatile nitrosamines. Personal and area samples were collected by means of artifact-free cartridges during the core-making and the molding/casting/shake-out operations. Analyses were carried out with gas chromatography/Hall detector and gas chromatography/TEA (thermal energy analyzer) for validation. The core-making workshops had the highest concentration for at least two nitrosamines, N-nitrosodimethylamine (NDMA) and N-nitrosoethylmethylamine (NEMA), but the levels of NDMA never exceeded 0.35 microgram/m3 with an arithmetic mean between 0.23 and 0.02 microgram/m3. In a number of samplings, two other peaks, both on TEA and Hall detector, could not be identified. The foundries per se (molding/casting/shake-out) had lower nitrosamine levels (CNDMAmax = 0.15 microgram/m3, CNDMA less than 0.03 microgram/m3). For the first time NEMA was identified as an industrial contaminant in foundries but its concentration was always lower than that of NDMA. The nitrosamines found were presumably produced from dimethylethylamine (DMEA). Industries producing or using tertiary or secondary amines should be controlled for their possible nitrosamine contamination.

Air Pollutants, Occupational↗
PubMed1984

Chromatographic investigations of the configurational and geometrical isomerism of allylic N-terpenyl-N-hydroxyethyl-nitrosamines.

A preparative adsorption column chromatographic method is reported for the separation of cis and trans geometrical isomers of two types of N-nitrosamines derived from allylic terpenyl ethanolamines (experimental fish toxicants). Column eluates were monitored by gas chromatography in which a Carbowax 20M stationary phase was used. Further separation of E and Z configurational isomers was achieved by reversed-phase and normal-phase high-performance liquid chromatography. In the reversed-phase high-performance liquid chromatography system (acetonitrile-water), the 6',7'-acetylenic nitrosamines ( NMOA ) were efficiently resolved by using an argentous (AgNO3) mobile phase, whereas the presence of sodium alkanesulfonate in the aqueous acetonitrile mobile phase favored the base-line resolution of the 6',7'-olefinic nitrosamines ( NDOA ). For normal-phase separation on a silica column, addition of tetrahydrofuran to the mobile phase (methylene chloride-2-propanol) resulted in a varying degree of improvement in peak resolution (R) and column selectivity (alpha). Effects of temperature on the chromatographic behavior of the nitrosamine components are described. The high-performance liquid chromatographic separation method has proved to be applicable for the trace analysis of the title nitrosamines in organic tissues by way of thermal energy analysis.

Chromatography, Gas↗