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PubMed1977

Damage and repair of DNA in urinary bladder epithelium of rats treated with N-butyl-N-(4-hydroxybutyl) nitrosamine.

N-Butyl-N-(4-hydroxybutyl) nitrosamine (BBN), which selectively induced urinary bladder tumors in several experimental animal species, was found to cause damage of DNA in the bladder epithelium. Wistar strain rats were given 100 mg/kg of BBN intravesically and killed after 2, 6, 12, 24, or 48 hr. DNA damage was examined by measuring the change in sedimentation pattern in an alkaline sucrose gradient. Amount of DNA in each fraction was determined by fluorescence spectrophotometry. At 2 hr, the sedimentation profile shifted from heavier (No 15, control peak) to lighter (Nos. 2 approximately 4) fractions, and the maximum effect appeared at 6 hr as a single peak in the lighter fractions. At 12 hr, damaged DNA was in the process of repair as two peaks were present, one light and one heavy. At 48 hr, the sedimentation profile showed a single peak identical with that of controls indicating complete repair of DNA.

Animals↗
PubMed1981

Nitrosamine-induced transplantable pancreatic ductal adenocarcinoma in inbred Syrian hamsters.

A pancreatic ductal carcinoma, designated CBP, was established as a transplantable tumor line in the CB/SsLak inbred strain of Syrian golden hamsters. The tumor, a primary one induced by chronic administration of the nitrosamine N-nitro-bis(2-hydroxyproyl) amine, is a well-differentiated adenocarcinoma that can be propagated by transplantation in syngeneic hamsters. It grows poorly in other hamster strains. The CBP tumor develops in a predictable quantitative manner and metastasizes to regional lymph nodes. Excision of primary transplanted tumor nodules leads to immunity against subsequent secondary tumor challenges. The CBP tumor appears to be a suitable model for biologic and immunologic studies of pancreatic carcinoma in the syrian hamster.

Animals↗
PubMed1984

Use of aquarium fish, Danio rerio and Poecilia reticulata, as test species for evaluation of nitrosamine carcinogenicity.

The carcinogenic effects of various doses of dimethylnitrosamine (DMNA), diethylnitrosamine (DENA), and nitrosomorpholine (NM), as well as the results of varying temperature and length of exposure to these carcinogens, were studied in short-term (20-21 wk) experiments in aquarium fish (820 Danio rerio and 944 Poecilia reticulata). All nitroso compounds induced liver tumors (hepatocellular carcinomas and adenomas, cholangiomas, and cholangiocarcinomas) and esophageal papillomas. Exposure to NM also induced intestinal adenocarcinomas in D. rerio. At a conventional temperature (22 degrees +/- 1 degree C), tumors were induced in 76% of the D. rerio in an average of 13.8 weeks following an initial 8-week exposure to 100 ppm DMNA and in 22% of P. reticulata in an average of 10.9 weeks. The DENA exposure resulted in tumors in 61.5% of Danio by 15 weeks and in 29% of Poecilia in 15.5 weeks. Under the same conditions, 500 ppm NM induced tumors in 78% of the zebra fish in 15.6 weeks and in 75% of the guppies after 12.3 weeks. When exposure time was shortened to 2 weeks, the dosage was decreased, or if the temperature was reduced to 17 degrees +/- 1 degree C, the tumor incidence dropped and the latency increased. An increase in temperature to 27 degrees +/- 1 degree C resulted in a 72-89% tumor incidence and shortened the latency to 11.3-14.1 weeks. Thus the modulation of our experimental conditions to maximize tumor incidence and minimize mean latency permitted the use of the aquarium fish D. rerio and P. reticulata for the screening of carcinogenic nitrosamines.

Animals↗
PubMed1984

Dose-related induction of lung, thyroid and kidney tumors by N-bis(2-hydroxypropyl)nitrosamine given orally to F344 rats.

The organotropic effect of orally administered N-bis(2-hydroxypropyl)nitrosamine (DHPN) in male F344 rats was studied with respect to total dosage and length of observation period. DHPN was given at 5 dosages, a single intragastric intubation of 800 mg/kg body weight, or administration as a 0.2% solution in the drinking water for 4, 7, 14 or 21 days. Animals were killed at weeks 32, 40 and 48. Tumors were induced in the lung, thyroid, kidney and urinary bladder. High tumor incidence was demonstrated in the lung and thyroid. Dose-related increases in overall tumor incidences in these 4 organs were clearly shown but time-related increases at the 3 sacrifice time points were not clear. Histologically, the tumors were adenoma and adenocarcinoma of the lung and thyroid, renal cell tumor, nephroblastoma and transitional cell tumor of the kidney, and transitional cell papilloma of the urinary bladder.

Administration, Oral↗
PubMed1984

Summation and synergism in the promotion of urinary bladder carcinogenesis initiated by N-butyl-N-(4-hydroxybutyl)-nitrosamine in F344 rats.

Summation and synergism in the effects of three tumor promoters on urinary bladder carcinogenesis initiated by a 4-week treatment with 0.05% N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) in male F344 rats were examined. In experiment 1, the sequential administration of sodium saccharin (SS, 5.0%), DL-tryptophan (Tr, 2.0%) and sodium L-ascorbate (SA, 5.0%) in the diet, each for 10 weeks, significantly increased the incidence and the number of bladder tumors over that observed after SS alone or SS followed by Tr. In experiment 2, the simultaneous dietary administration of 2.5% SA, 1.0% butylated hydroxyanisole and 0.01% allopurinol for 32 weeks significantly increased the yield of bladder tumors. Paired combinations of promoters or each of the promoters administered alone were associated with a less pronounced promotive effect than when all three were combined. Thus, it is evident from the results of the present investigation that whatever the mechanisms underlying promotion by the different agents, they are capable of working in an additive fashion, under conditions of summation (consecutive administration) or synergism (simultaneous administration).

Allopurinol↗
PubMed1984

[Cancer of the esophagus induced in the Wistar rat by ethyl-N-butyl-nitrosamine].

OEsophageal papillomas and carcinomas have been induced in Wistar rats using Ethyl-N-Butyl-Nitrosamine. None of those lesions were observed in a previous experiment on the same rats strains, with ethanol and apple brandy. Experimentally induced tumours in the rat are different from oesophageal cancers and associated mucous lesions in man. Both upper digestive mucosae are only similar in regards to their response to carcinogens.

Animals↗
PubMed1984

N-nitrosamine analysis in foods: N-nitrosoamino acids by high-performance liquid chromatography/thermal energy analysis and total N-nitroso compounds by chemical denitrosation/thermal energy analysis.

The total N-nitroso content of foods can be measured by chemical denitrosation and chemiluminescent detection of the eliminated nitric oxide. Appropriate procedures substantially reduce the 'system response' to the denitrosating agent, so that N-nitroso group contents down to 10 micrograms/kg can be measured on a one-gram sample. Using N-nitrosamine standards added to beer, the coefficients of variation are approximately 10% and 5% at N-nitroso contents of 19 and 94 micrograms/kg, respectively. In cured meats, the coefficient of variation for unidentified N-nitroso compounds is 26% for a 0.3-g sample containing 600 micrograms/kg. Some interference from non-nitroso compounds is possible, but, in some commodities at least, these interfering compounds are not detectable. Conditions have been established that allow measurement of N-nitrosoamino acids in foods using a high-pressure liquid chromatograph interfaced to a Thermal Energy Analyzer, without the need for prior derivatization. After extraction of lipids with hexane, nitrosoamino acids are extracted with ethyl acetate and subjected to appropriate clean-up stages prior to high pressure liquid chromatography on Microbondapak CN with a hexane:ethanol:acetic acid mobile phase and Thermal Energy Analyzer detection. Recoveries from cured meat are in the 55-75% range for N-nitrososarcosine, N-nitrosoproline and N-nitrosohydroxyproline; elution is complete within seven minutes.

Amino Acids↗
PubMed1984

In-vivo nitrosation of amines in mice by inhaled nitrogen dioxide and inhibition of biosynthesis of N-nitrosamines.

Inhalation of nitrogen dioxide (NO2) by mice administered orally morpholine (MOR) or dimethylamine (DMA) resulted in the biosynthesis of N-nitrosomorpholine (NMOR) or N-nitrosodimethylamine (NDMA), respectively, as determined by the analysis of frozen whole-mouse powder, using gas chromatography with a Thermal Energy Analyzer detector. Significant levels of NMOR were detected following exposure of mice to 0.38 mg/m3 NO2 for 0.5 h (26 ng NMOR/mouse) and there was a two-fold increase when NO2 exposure was extended to 4 h. NMOR levels also increased in a time-dependent manner at 28.4 and 47.3 mg/m3 NO2 exposure levels, reaching a maximum of 450 and 725 ng NMOR/mouse, respectively, at 4 h. Oral administration of sodium ascorbate (50-250 mg), ammonium sulfamate (50-100 mg) or DL-alpha-tocopherol (67-167 mg) immediately after MOR or DMA, but prior to NO2 exposure, significantly inhibited both NMOR and NDMA biosynthesis, sulfamate being the most effective (greater than 90% NMOR and NDMA inhibition), followed by ascorbate (83-90% NMOR and 58-90% NDMA inhibition) and alpha-tocopherol (22-42% NMOR and 46-69% NDMA inhibition). Low levels of NDMA were found in untreated control mice (less than 13 ng/mouse) and in most samples of commercially obtained animal feed (10-15 micrograms/kg); NMOR, however, was not detectable or was detected in negligible amounts in these cases. Various control experiments indicated that most of the recovered nitrosamine resulted from in-vivo nitrosation in mice, with only up to 1-2% of NMOR and approximately 10% of NDMA yields being attributed to artefact formation, possibly during work-up of the mouse-powder samples.

Animals↗
PubMed1984

Further factors influencing N-nitrosamine formation in bacon.

The possible relationship of unsaturated fatty acids in adipose tissue to the formation of N-nitrosamines in bacon was evaluated by trials in which pigs were fed regular (control), tallow-, coconut fat- and corn oil-supplemented diets. Bacon prepared from pigs fed corn oil-supplemented diets contained significantly higher levels of N-nitrosopyrrolidine and N-nitrosodimethylamine than did control bacon samples; however, bacon produced from pigs fed a coconut fat-supplemented diet contained significantly lower levels of N-nitrosopyrrolidine. Fatty acid analyses of the adipose tissue of the bacon samples indicated that N-nitrosopyrrolidine levels in bacon correlated well with the degree of unsaturation of the adipose tissue. N-nitrosothiazolidine was detected in both brine-cured and dry-cured bacon at levels generally below 4 micrograms/kg. However, its formation was greatly reduced by the inclusion of alpha-tocopherol in the cure. The role of woodsmoke in N-nitrosothiazolidine formation in bacon is discussed.

Adipose Tissue↗
PubMed1984

Formation of nitrosamines in non-ionic and anionic emulsions in the presence and absence of inhibitors.

Nitrosation of water-soluble (diethanolamine) and oil-soluble (dodecylmethylamine and dicyclohexylamine) amines in the absence and presence of inhibitors in model anionic and non-ionic emulsions was studied. Nitrosation of diethanolamine occurred at similar rates in non-ionic and anionic emulsions. Surprisingly, dodecylmethylamine and dicyclohexylamine were readily nitrosated in non-ionic emulsions, but not in anionic emulsions. Sodium bisulfite and ascorbyl palmitate were effective inhibitors, but the activity of ascorbic acid was lower. Considerably less effective were potassium sorbate, alpha-tocopherol and butylated hydroxyanisole. The results of this study will help formulators of emulsion products to minimize N-nitrosamine contamination.

Cyclohexylamines↗
PubMed1984

Role of the respiratory system in metabolism of N-nitrosamines after simultaneous application of disulfiram.

Subsequent to modification of N-nitrosamine metabolism by disulfiram, mucus-producing cells and Clara cells in the respiratory tract are involved increasingly in detoxification as well as in bioactivation of N-nitroso-N-methylbenzylamine and N-nitrosodibutylamine. Overtaxing of these cells or local concentration of antigenic metabolites leads to cytolytic defects in tracheal, bronchial and bronchiolar epithelium, in addition to toxic degenerative lesions. The resulting continuous stimulation of proliferation leads to basal-cell hyperplasia, squamous-cell metaplasia and squamous papillomas. In areas with insufficient differentiation, due to cell proliferation, there is an increased probability that focal mutation, subsequent to alkylation of purine bases, will be passed from one cell generation to the next, with subsequent formation of tumours in the bronchiolo-alveolar region.

Animals↗
PubMed1984

Promoting effect of phenobarbital on N-bis (2-hydroxypropyl)nitrosamine thyroid tumorigenesis in rats. Effect of varying duration of exposure to phenobarbital.

Male Wistar rats were injected subcutaneously with a single dose of 280 mg N-bis(2-hydroxypropyl)nitrosamine (DHPN) per 100 g body weight and then given a diet containing 500 mg/kg phenobarbital (PB) for 6, 12 and 19 weeks. Exposure to PB for 12 or 19 weeks enhanced the development of thyroid tumours in rats treated with DHPN. The incidences of thyroid tumours at the end of the experiment were 87% in rats given DHPN and then PB for 19 weeks, 83% in rats given DHPN and then PB for 12 weeks, 42% in rats given DHPN and then PB for 6 weeks, and 37% in rats given DHPN. The incidence of thyroid cancer was 12% in rats given DHPN and then PB for 19 weeks. The total numbers of thyroid tumours were: 241 in rats given DHPN and then PB for 19 weeks, 125 in rats given DHPN and then PB for 12 weeks, 65 in rats given DHPN and then PB for 6 weeks, and 23 in rats given DHPN alone. The total numbers of thyroid tumours were proportional to the period of exposure to PB.

Animals↗
PubMed1984

Monitoring endogenous nitrosamine formation in man.

Results from animal experiments and studies in human subjects indicated that the amount of nitrosoproline (NPRO) excreted in the 24-h urine, following ingestion of precursors, is an index for the rate of endogenous nitrosation; this method was found to be sensitive, reproducible and could be satisfactorily applied to human subjects in clinical and field studies. N-Nitrosothiazolidine 4-carboxylic acid (NTCA) and its 2-methyl derivative (NMTCA) were also identified in the urine of human subjects. As the respective amino precursors (thiazolidine 4-carboxylic acids) can be formed by reaction of formaldehyde or acetaldehyde with cysteine, measurement of NTCA and NMTCA in urine may provide a further index for endogenous nitrosation in the human body and may also allow monitoring of exposure of human subjects to aldehydes, nitrate and nitrite. The yield of nitroso compounds formed endogenously in the human body was shown to be linked to the intake of precursors, but several inhibitors and catalysts, either as pure substances or occurring in complex mixtures, were shown to modify the nitrosation reaction in vivo. In particular, ingestion of ascorbic acid after nitrate-rich meals was efficient in lowering human exposure to endogenously formed N-nitroso compounds. A dose-response relationship was established for the formation of NPRO in rats in vivo, after concurrent administration of various concentrations of the precursors, L-proline and sodium nitrite. The logarithm of the amount of NPRO formed was found to be proportional to the logarithm of the product of the proline dose and the square of the nitrite dose. On the basis of these results, a kinetic model was formulated allowing the estimation of the daily precursor dose quantity, ([amine][nitrite]2), required to give 50% tumour incidence in rats after two years of feeding. The potential application of this model, for the estimation of carcinogenic risk from endogenously formed N-nitrosamines in humans, is discussed. Our results demonstrate unequivocally the endogenous formation of N-nitroso compounds in the human body, the significance of which in human carcinogenesis remains to be established.

Animals↗
PubMed1984

4,4'-Diaminodiphenylmethane: promoting effect on the development of thyroid tumors in rats treated with N-bis(2-hydroxypropyl)nitrosamine.

4,4'-Diaminodiphenylmethane (4,4'-methylenedianiline) (DDPM) promoted the development of thyroid tumors in rats treated with a subeffective dose of N-bis(2-hydroxypropyl)nitrosamine (2,2'-dihydroxy-N-nitrosodipropylamine) (DHPN) for thyroid tumorigenesis. Male inbred W rats were given a single ip injection of 280 mg DHPN/100 g body weight and fed diets with or without 1,000 ppm DDPM. Thyroid tumor incidences at the end of week 20 of the experiment were 90% (19/21) in rats given DHPN and then DDPM and 28% (6/21) in rats given DHPN alone. The incidence of thyroid cancers was 9.5% (2/21) in rats first given DHPN and then DDPM. Untreated rats and rats given DDPM alone had no thyroid tumors after 20 weeks. Incidences of kidney tumors were 38% (8/21) in rats given DHPN and then DDPM and 28% (6/21) in rats given DHPN alone. No tumors were found in the kidneys and lungs of rats given DDPM alone and in those of control rats. Treatment with DDPM alone slightly but not significantly decreased the serum concentrations of thyroxine and triiodothyronine; treatment with DHPN plus DDPM had no such effect.

Aniline Compounds↗
PubMed1983

Single-cell origin of bladder cancer induced by N-butyl-N-(4-hydroxybutyl) nitrosamine in mice with cellular mosaicism.

The single-cell origin of bladder cancer was established in mice with cellular mosaicism for phosphoglycerate kinase (PGK). Administration of N-butyl-N-(4-hydroxybutyl)nitrosamine in the drinking water resulted in development of large, solitary, infiltrating bladder carcinomas. On electrophoresis, PGK from all the cancer tissues examined gave only a single spot.

Animals↗
PubMed1983

Cataracts in rats given a bladder carcinogen, N-butyl-N-(4-hydroxybutyl)-nitrosamine.

Cataracts were incidentally found at week 30 in six out of 65 female Wistar rats given a urinary bladder carcinogen, N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) in a 0.05% solution in drinking water for 8 weeks and then treated with mitomycin C, a retinoid or a combination of both. No cataracts were found in 12 control rats given no carcinogen. Although the difference in the incidence was not significant statistically, the present finding suggests the possibility that administration of BBN induces or facilitates the development of cataracts.

Animals↗
PubMed1984

Possible mechanistic roles of anatomical and functional vascular changes in rat urinary bladder carcinogenesis induced by N-butyl-N-(4-hydroxybutyl)nitrosamine.

Anatomical and functional vascular changes during rat urinary bladder carcinogenesis were studied by scanning electron microscopy of vascular casts, transmission electron microscopy of bladder capillaries, and fractional distributions of 51Cr-erythrocytes, 125I-human serum albumin, and 86RbCl which were used to determine vascular volume, permeability, and perfusion. Histopathological changes and focal capillary changes in vascular casts were measured quantitatively by an image analyzer. Male Wistar rats received 0.05% N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) in their drinking water for 8 weeks and were then maintained on tap water without BBN for an additional 32 weeks. Simple hyperplasia was first seen at Week 2. The percentage of the area of hyperplastic epithelium increased to about 95% by Week 8 and then decreased to 4 to 6% at Weeks 20 or 40. Papillary or nodular hyperplasia was first seen at Week 6. The percentage of the area of papillary or nodular hyperplasia increased with time to 31.0% at Week 40. Papillary transitional-cell carcinomas were found from Week 20, increasing with time, and their incidence was 100% after Week 35. Vascular cast diameters of normal-looking capillaries were larger during than after BBN treatment. Type 3 vascular proliferations were found beneath papillary or nodular hyperplasia and cancer. Capillaries beneath simple hyperplasia and type 3 capillaries beneath capillary or nodular hyperplasia and cancers were fenestrated and dilated. Changes in vascular volume were independent of changes in permeability and perfusion. Best-fit curve analyses showed the maximum vascular volume at 8 weeks and minimum at 25 weeks, and the permeability maxima at 4 and 25 weeks with minima at 15 and 32 weeks. While 86Rb values correlated 125I values (r = 0.58), they were unstable in intermediate time periods. Changes of vascular volume were coincident initially with increased areas of dilated capillaries beneath simple hyperplasia and later with areas of type 3 capillary proliferation beneath papillary or nodular hyperplasia and cancer. Changes of vascular permeability were related to inflammation indices throughout the study. Increases in permeability were coincident with fenestrated capillaries beneath simple hyperplasia in early stages, and subsequently with fenestrated type 3 capillaries beneath papillary or nodular hyperplasia and cancer. BBN appears to cause alterations in vascular volume via induction of capillary dilation and also possibly by enhancing the responsiveness of host endothelium to angiogenic stimulation from neoplastic or preneoplastic tissues.

Analysis of Variance↗