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PubMedDate not supplied

Volatile N-nitrosamines in mainstream cigarette smoke: occurrence and formation.

Analytical data is presented for the occurrence of the three major volatile N-nitrosamines in cigarette tobacco and mainstream smoke, namely N-nitrosodimethylamine (NDMA),- N-nitrosoethylmethylamine (NEMA) and N-nitrosopyrrolidine (NPYR) as well as for the occurrence of the corresponding precursor amines and non-volatile N-nitrosamino acids in tobacco. Experimental studies using the C20 reference cigarette show that NPYR present in mainstream smoke results from direct transfer of preformed NPYR (ca. 1.5%), decarboxylation of N-nitrosoproline in tobacco (ca. 10%), pyrolytic nitrosation of pyrrolidine in tobacco (ca. 37%) and concerted decarboxylation/nitrosation of proline (ca. 52%) during tobacco pyrolysis.

Chromatography, Gas↗
PubMed1982

Effect of partial cystectomy on the induction of pre-neoplastic lesions in rat bladder initiated with N-butyl-N-(4-hydroxybutyl)nitrosamine followed by bladder carcinogens and promoters.

The effect of partial cystectomy on the occurrence of pre-neoplastic lesions, papillary or nodular hyperplasia (PN hyperplasia), of the bladder in male F344 rats was studied in an experiment in which bladder carcinogens and promoters were given to the rats after initiation with BBN. The bladder carcinogens tested were N-ethyl-N-(4-hydroxybutyl)nitrosamine (EHBN) and N-4[4-(5-nitro-2-furyl)-2-thiazolyl]formamide (FANFT) and the bladder promoters were sodium saccharin, sodium cyclamate, and DL-tryptophan. Partial cystectomy significantly decreased the occurrence of PN hyperplasia in rats treated with EHBN and tended to inhibit that in rats given saccharin or tryptophan. Thus partial cystectomy inhibited rather than enhanced the induction of PN hyperplasia.

Animals↗
PubMed1978

Carcinogenicity of acetoxymethyl-methyl-nitrosamine after subcutaneous, intravenous and intrarectal applications in rats.

In comparison to the known carcinogenic properties of Acetoxymethyl-Methyl-Nitrosamine (AMMN) after oral or intraperitoneal application the dimethylnitrosamine derivative was tested by subcutaneous, intravenous and intrarectal route in male Sprague-Dawley or Wistar rats. AMMN proved to be primarily a locally acting carcinogen. However, a second mode of action is indicated by systemic carcinogenic properties found after i.v. and s.c. applications. The lung and heart, and to a less extent the kidney and earduct were found as target organs of distant carcinogenic response.

Adenocarcinoma↗
PubMed1976

Stages of transformation in the development of N-butyl-N-(4-hydroxybutyl)-nitrosamine-induced transitional cell carcinomas in the urinary bladder of rats.

The histogenesis of papillary and nonpapillary transitional cell carcinomas were studied morphologically and autoradiographically in 177 female Wistar rats after oral application of N-butyl-N-(4-hydroxybutyl)-nitrosamine with varying exposure and induction times. By far the largest proportion of carcinomas developed by a malignant transformation of preexisting papillomas or their precursors, the papillary hyperplasias. The transition into a focally malignant growth did not take place abruptly, but occurred stepwise through different successive stages of transformation, each having its own distinct morphological character. The first stage consisted of a focal, sharpely defined cellular atypia. In a further stage carcinomata in situ developed out of the atypical foci and progressed finally in a last stage of transformation into a circumscript infiltrative growth. The successive development of each stage occurred independent of any further carcinogen application after transformation was initiated at the molecular level. The number of papillomas with transformation stages increased with a lengthening of the exposure and induction time. 74.4% of all the registered papillomas had been transformed. Consequently papillomas must be considered potentially highly malignant. The 3H-TdR index was 4.2 times higher in atypical urothelial areas (7.6%) and 7.5 times higher in carcinomata in situ (14.3%) than in the surrounding papillomatous structures which appeared light microscopically benign. The latter demonstrated a rather constant 3H-TdR index, whether they bordered on atypical foci (1.8%) or carcinomata in situ (1.9%). The length of exposure and induction time exercised no significant influence on the degree of proliferative activity. The development of transitional cell carcinomas from a primary carcinoma in situ (intraurothelial carcinoma) played a much less significant role.

Animals↗
PubMed1977

Transplacental effect of nitrosamines in Syrian hamsters. IV. Metabolites of dipropyl- and dibutylnitrosamine.

The present investigations showed that assumed and established metabolites of dipropylnitrosamine and dibutylnitrosamine reach the Syrian hamster fetus after subcutaneous (s.c.) treatment of their mothers (at day 14 of gestation). The compounds [2-hydroxypropylpropylnitrosamine, HPPN; 2-oxopropylpropylnitrosamine, OPPN; methylpropylnitrosamine, MPN; N-nitrosobis(2-hydroxypropyl)amine, BHP; and 4-hydroxybutylbutylnitrosamine, HBBN] were still present in the examined tissue (maternal blood, placenta, fetus, amniotic fluid) 4--6 h after s.c. injection. The overall incidence of transplacentally induced tumors was lower in the F1- than in the P-generation and comparatively longer latencies were also observed in the F1- generation. However, in some groups low incidences were found of tumors which did not occur in the mothers (i.e., nasal cavities: BHP, HBBN; trachea: HBBN; lungs: HPPN, BHP, HBBN; liver: OPN, MPN, BHP, HBBN). Compared to exposure at early gestation, the transplacental carcinogenic effect increased at day 14 of gestation. Neoplasms originating in other organs were not associated with a transplacental effect of the examined nitrosamines.

Amniotic Fluid↗
PubMed1987

Expression and inducibility of drug-metabolizing enzymes in preneoplastic and neoplastic lesions of rat liver during nitrosamine-induced hepatocarcinogenesis.

The expression, inducibility, and regulation of four different cytochrome (cyt.) P-450 isoenzymes (PB1, PB2, MC1, and MC2) NADPH-cytochrome P-450 reductase, the glutathione transferases (GSTs) B and C and microsomal epoxide hydrolase (mEHb) have been studied during nitrosamine-induced hepatocarcinogenesis using immunohistochemical techniques. The investigations revealed basic differences in the expression of the individual drug metabolizing enzymes in the course of neoplastic development. While the two GSTs and mEHb were increased in all preneoplastic and benign neoplastic lesions, the levels of the distinct cyt. P-450 isoenzymes were characteristically different from each other. Following initial changes in the expression of these enzymes in early preneoplastic lesions (i.e., increase of cyt. P-450 PB1 versus slight decrease of the other cyt. P-450 isoenzymes), a continuous reduction of all cyt. P-450 isoenzymes was observed during the further course of hepatocarcinogenesis. In progressed neoplastic nodules, all cyt. P-450-isoenzymes and NADPH cyt. P-450 reductase were decreased to varying extents. Treatment of animals with inducers of the monooxygenase system, such as phenobarbital, 3-methylcholanthrene and polychlorinated biphenyls, led to a rather heterogenous pattern of enzyme alterations in preneoplastic and neoplastic lesions. Following administration of phenobarbital, some islets responded to the same degree as the surrounding tissue, others were less or not at all inducible and a few of the lesions showed a prominent increase in cyt. P-450 PB2 and NADPH-cyt. P-450 reductase levels. The interesting finding that these two enzymes always showed concurrent changes may be indicative of a common regulation.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Triphosphatases↗
PubMed1975

Focal loss of alkaline phosphatase and increase of proliferation in preneoplastic areas of the rat urothelium after administration of n-butyl-n-(4-hydroxybutyl)-nitrosamine and n-[4-(5-nitro-2-furyl)-2-thiazolyl] formamide.

Development of tumours of the urinarY bladder was studied in 59 Male and female Sprague-Dawley and Wistar rats with combined enzyme-histochemical and autoradiographic methods after oral application of n-butyl-n-(4-hydroxybutyl)-nitrosamine (BBN) and n-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide (FANFT). as the first carcinogenic lesion detectable by light-microscopy a focal, sharply defined irreversible loss of alkaline phosphatase activity was consistently demonstrated in the urothelium, which appeared normal histologically and cytologically. In about 2/3 of the cases, NADH-diaphorase activity was markedly reduced in identical regions. The enzyme-deficient areas are to be considered as preneoplastic, because papillomas and carcinomas developed from them through different stages of hyperplasia. As a rule, these also were characterized by total loss of alkaline phosphatase activity and attenuation of the NADH-diaphorase in all parts or circumscribed areas. Autoradiographically 3H-thymidine-labelling index revealed a 43.2-fold (BBN) and 22.6-fold (FANFT) increase, respectively, in the enzyme-deficient areas, as compared with the surrounding emzyme-containing urothelium. After 54 hrs of continous labelling, there was a mean 3H-thymidine-labelling index of 54.9% in the enzyme-negative regions. The physiological mode of regeneration was no longer maintained in the areas of enzyme deficiency as there was an increased proliferation of suprabasal cells. Areas of papillomas that showed a marked attention of NADH-diaphorase had a 3H-thymidine-labelling index 4.5 (BBN) and 3.1 (FANFT) greater than the surrounding areas with preserved enzyme activity. Since loss of alkaline phosphatase activity occurs regulary and consistently after application of carcinogens with chemically different structures it appears to indicate the initial phase of tumor development in the urinary bladder of the rat.

Administration, Oral↗
PubMed1977

Morphology, classification and histogenesis of N-butyl-N-(4-hydroxybutyl)-nitrosamine-induced carcinomas in the urinary bladder of rats.

The aim of the experiments was to determine whether the various types of carcinomas found in the human urinary bladder were reproducible in animals. We added n-butyl-n-(4-hydroxybutyl)-nitrosamine at a dose of 20 mg/kg/day to the drinking water of 177 female Wistar rats for a period of 40 to 150 days. After a total experimental time of between 150 and 250 days the animals were sacrified. The spectrum of carcinomas induced, includes all the types known to occur in man. The various tumor types occurred with the same frequency as in man and exhibited the same growth patterns. Variously differentiated papillary and non-papillary transitional cell carcinomas comprised 88.8% of tumors registered. 5.1% were keratinized and nonkeratinized squamous cell carcinomas, 2.2% adenocarcinomas. 1.1% were undifferentiated carcinomas and 2.8% were carcinomas of the mixed type with squamous cell and transitional cell differentiation. Histogenetically adenocarcinomas were found to originate from glandular metaplasia and squamous cell carcinomas from squamous metaplasia within completely developed transitional cell carcinomas. Furthermore it was possible to induce proliferative lesions such as von Brunn's nests, cystitis cystica and cystitis glandularis. However, we found no clues to substantiate the development of adenocarcinomas from these proliferative lesions, or for that matter squamous cell carcinomas from squamous metaplasia of the otherwise unchanged urothelium. The present experimental model seems particulary suited for the search of further information regarding the development of tumors in the human bladder.

Adenocarcinoma↗
PubMed1977

Transplacental effects of nitrosamines in Syrian hamsters. III. Dimethyl- and dipropylnitrosamine.

The aliphatic nitrosamines dimethylnitrosamine (DMN), diethylnitrosamine (DEN), dipropylnitrosamine (DPN), and dibutylnitrosamine (DBN) reached fetal tissue in quantitatively measurable amounts after subcutaneous administration to pregnant Syrian hamsters. The compounds were present for at least 2 h in maternal blood, placenta, fetus, and amniotic fluid; DBN was still measurable after 6 h. Only a weak or borderline transplacental effect was seen when incidences and latencies of neoplasms in the respiratory and digestive tracts of the F1-generation were compared with those of the P-generation after exposure to a single dose of DMN or DPN. However, some tumor types occurred at relatively high rates in the young, but were seen only occcasionally in their mothers or in this hamster colony in general.

Amniotic Fluid↗
PubMed1984

Species differences in nitrosamine carcinogenesis.

The carcinogenic action of approximately 50 N-nitroso compounds, nitrosamines, and nitrosoalkylamides has been compared in rats and in Syrian golden hamsters. The compounds were administered PO, as far as possible at comparable dose rates. The relative potencies of the treatments were assessed mainly by the time to death of the animals with tumors. The esophagus and other parts of the upper gastrointestinal tract were the most common sites for tumor induction in rats, but the esophagus was hardly ever affected in hamsters, although several compounds induced tumors of the forestomach in both rats and hamsters. No conclusion could be drawn about the relative susceptibility of the rat and hamster to these N-nitroso compounds, which varied with different compounds. Few generalizations can be made about these results, although it appeared that the 2-hydroxypropyl group was usually necessary for the induction of pancreas tumors in hamsters.

Alkylation↗
PubMed1984

Dose-response study of urinary bladder carcinogenesis in rats by N-butyl-N-(4-hydroxybutyl)nitrosamine.

A dose-response study was carried out in male F344 rats with a specific urinary bladder carcinogen, N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN), which was administered as a solution in drinking water for up to 112 weeks. BBN was given in four different concentrations, 50, 10, 5, and 1 ppm, to groups of 30 rats. The highest dose induced urinary bladder cancer in all rats treated by week 91, decreasing yields being associated with lower dose levels: an incidence of 76.7% was observed with 10 ppm, followed by 20.0% with 5 ppm. The lowest dose (1 ppm) only induced two cases of papilloma (6.9%).

Animals↗
PubMed1986

Strain differences in mice with invasive bladder carcinomas induced by N-butyl-N-(4-hydroxybutyl)nitrosamine.

Papillary superficial and nonpapillary invasive bladder carcinomas of humans are two disease entities exhibiting completely different biological behavior. Studies were performed on the susceptibilities of various strains of mice to induction of bladder carcinomas by N-butyl-N-(4-hydroxybutyl)nitrosamine (BHBN), and the type of carcinomas that developed. BHBN at concentrations of 0.05% and 0.01% in drinking water was given to female mice of strains A/Jax, AKR/Jax, C3H/He, DBA/2, and C57BL/6 for 22 weeks. The incidence of nonpapillary invasive bladder carcinomas in these strains was 40%, 100%, 100%, 89%, and 89%, respectively, in groups treated with 0.05% BHBN and 30%, 60%, 60%, 90%, and 40%, respectively, in groups treated with 0.01% BHBN. At both levels BHBN and in all strains the bladder carcinomas induced were of the nonpapillary invasive type.

Animals↗
PubMed1986

Promoting effect of sodium chloride in 2-stage urinary bladder carcinogenesis in rats initiated by N-butyl-N-(4-hydroxybutyl)nitrosamine.

The promoting effect of sodium chloride (NaCl) in 2-stage urinary bladder carcinogenesis in F344 rats initiated by 2 doses of N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) was investigated. The incidences of PN hyperplasia were significantly higher in rats initiated with 0.01 or 0.05% BBN when they were given diet containing 10% NaCl for 32 weeks than when they were given control diet. The incidence of papilloma in rats given 0.05% BBN followed by diet containing 10% or 5% NaCl tended to be higher than that in control rats. The urine of rats given diet containing NaCl was larger in volume and had lower osmolality than that of controls. The total urinary sodium and chloride contents were also increased, whereas those of potassium and phosphorus were decreased. No calculus formation or crystalluria was observed. These data suggest that excess intake of sodium as NaCl has a weak promoting effect in 2-stage urinary bladder carcinogenesis.

Animals↗
PubMed1978

The change in carcinogenic effectiveness of some cyclic nitrosamines at different doses.

The carcinogenic effectiveness in rats of three cyclic nitrosamines administered at two doses separated by a factor of five has been studied. All three compounds showed a response at the lower dose quite different from that at the higher dose. One, 2,6-dimethyl-dinitrosopiperazine, was only a little less effective at the lower dose than at the higher dose, giving 100% nasal turbinate tumors, but only 33% esophageal tumors, compared with 100% esophageal tumors at the higher dose. 3,4-Dichloronitrosopiperidine gave 100% incidence of esophageal tumors at the higher dose. At the lower dose, survival of the rats was very much better, some living 80 weeks, and, in addition to the esophagus, there were tumors of several organs including forestomach, tongue, and nasal turbinates. On the other hand, 2,6-dimethylnitrosomorpholine was a very much weaker carcinogen at the lower than at the higher dose, only six animals dying with tumors, compared with 100% incidence at the higher dose. However, the pattern of mortality of rats given the lower dose of dimethylnitrosomorpholine was similar to that of rats given the lower dose of dichloronitrosopiperidine.

Animals↗
PubMed1983

Pancreatic secretory abnormalities precede appearance of tumors of the pancreas in hamsters treated with bis-(2-oxopropyl)-N-nitrosamine.

The possibility that pancreatic secretory abnormalities might precede the appearance of pancreatic neoplasms and thus provide clues to early detection of this malignancy has been investigated in an animal model. Syrian golden hamsters were treated with bis-(2-oxopropyl)-N-nitrosamine on two successive weeks (2 mg/100 g body weight/week). Pancreatic secretions from treated and untreated control animals were studied at approximately monthly intervals. The animals were anesthetized, their pancreatic ducts cannulated, and basal pancreatic juice collected for 30 min. Pancreatic secretion was then stimulated by sequential intravenous injection of secretin (50 ng/100 g) and C-terminal octapeptide of cholecystokinin (4 ng/100 g) 1 hr later. Four consecutive 15-min collections of fluid were made following secretin stimulation and four additional collections after CCK administration. Each collection was examined for volume, total protein, trypsin, chymotrypsin, elastase, arylsulfatase, beta-D-glucuronidase, alpha-D-glucosidase, and leucine naphthylamidase. In addition two trypsinogen variants present in pancreatic secretions were determined. The pancreas and other organs were removed and examined histologically at the end of each experiment. Cytological atypia appeared 3 months, ductal hyperplasia 4 months, and pancreatic neoplasms 6 months after the last injection of carcinogen. Striking decreases in flow rate and output of trypsin and chymotrypsin were observed several months prior to the appearance of histologically recognizable pancreatic tumors. By contrast, output of beta-D-glucuronidase and alpha-D-glucosidase in pancreatic juice increased markedly in the last 2 months preceding the emergence of neoplasms. The diagnostic significance of these premalignant abnormalities is illustrated most dramatically in the form of ratios of lysosomal to digestive enzymes, such as beta-D-glucuronidase-trypsin or alpha-D-glucosidase-chymotrypsin. Highly significant increases in these ratios were observed consistently, not only in hamsters with pancreatic neoplasms, but also in animals with preneoplastic lesions (ductular hyperplasia) which preceded malignancies by about 2 months.

Age Factors↗
PubMed1990

Tobacco-specific nitrosamines in Canadian cigarettes.

Twenty-five brands of Canadian commercial cigarettes were analyzed for tobacco-specific nitrosamines (TSNA) in tobacco and in mainstream smoke as well as for nitrate in tobacco. Preformed N'-nitrosonor-nicotine (NNN) in the tobacco ranged from 265 ng to 979 ng/cigarette, preformed 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) ranged from 465 ng to 878 ng/cigarette. The mainstream smoke concentration for NNN was between 5 ng and 39 ng/cigarette and for NNK between 5 ng and 97 Ng/cigarette. The nitrate levels were between 0.3 mg and 3.4 mg/cigarette. The NNK levels in tobacco and in mainstream smoke were higher than the NNN levels, which is typical for Virginia-type cigarettes. Based upon the average mainstream smoke concentration of the three most popular Canadian cigarette brands, an average TSNA delivery for 20 cigarettes of 0.7 micrograms NNN and 1.7 micrograms NNK can be calculated, which is less than the average for West German cigarettes. The results of this investigation demonstrate that there seems to be a good correlation between the TSNA and tar deliveries in mainstream smoke. However, no correlation between the level of preformed TSNA in tobacco and the tar delivery in mainstream smoke could be observed. It is demonstrated that the good correlation between the tar and TSNA deliveries in mainstream smoke can only be attributed to the unusual good correlation between the tar delivery and the ventilation ratio. For the cigarettes investigated, which seemed to be Virginia-type cigarettes, with few exceptions, the ventilation ratio had a much higher influence on the mainstream smoke concentration than the level of preformed TSNA in tobacco.

Canada↗
PubMed1990

N-nitrosamines in gastric juice of patients with gastric ulcer before and during treatment with histamine H2-receptor antagonists.

The clinical implications of N-nitrosamines (NAs) were studied by analyzing their concentration in the gastric juice of 72 healthy subjects and 279 patients with gastric ulcer before and during treatment with histamine H2-receptor antagonists. NAs were measured by combined gas chromatography and thermal energy analyzer. The detection ratios of N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA) in the patients were 35.3% and 34.6%, respectively, which were significantly higher than the corresponding values in healthy subjects (19.4% and 16.7%, P less than 0.01). Analysis among the patients showed that this trend was mainly due to higher values in patients who were given histamine H2-receptor antagonists, as their detection ratios increased to 40.2% (NDMA) and 39.9% (NDEA). Patients without histamine H2-receptor antagonists showed moderate increases of detection ratios (NDMA; 24.2% NDEA; 22.6%) compared with healthy controls. The differences in these values between those receiving and not receiving histamine H2-receptor antagonists were statistically significant (P less than 0.01). The maximum concentrations of NDMA and NDEA were 7.9 and 9.8 ng/ml in patients, and 1.2 and 1.3 ng/ml in healthy subjects (the difference between the 2 groups P less than 0.02). These results indicated that patients with gastric ulcer had higher detection ratios and concentrations of NDMA and NDEA in gastric juice and that, while significant increases occurred during treatment with histamine H2-receptor antagonists, the extent of increase was below toxic or experimental carcinogenic levels.

Adult↗