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Transitional cell carcinoma was induced in the bladders of male Fischer rats by 12 oral doses of the carcinogen N-butyl-N-(4-hydroxybutyl)nitrosamine. Feeding of 13-cis-retinoic acid after completion of carcinogen treatment diminished the number and severity of cancers and other proliferative lesions of the bladder.
Comminuted ham was formulated with different levels of sodium nitrite and nitrate, inoculated with Clostridium botulinum, and pasteurized to an internal temperature of 68.5 C. When added to the meat, nitrite concentrations decreased, and cooking had little effect on them. Nitrite concentrations decreased more rapidly during storage at 27 than at 7 C; however they remained rather constant at formulated levels throughout the experiment at both incubation temperatures. The level of nitrite added to the meat greatly influenced growth and toxin production of C. botulinum. The concentration of nitrite necessary to effect complete inhibition was dependent on the inoculum level. With 90 C. botulinum spores/g of meat, botulinum toxin developed in samples formulated with 150 but not with 200 mug of nitrite per g of meat. At a spore level of 5,000/g, toxin was detected in samples with 400 but not with 500 mug of nitrite per g of the product incubated at 27 C. At lower concentrations of nitrite, growth was retarded at both spore levels. No toxin developed in samples incubated at 7 C. Nitrate showed a statistically significant inhibitory effect at a given nitrite level; however, the effect was insufficient to be of practical value. Analyses for 14 volatile nitrosamines from samples made with varying levels of nitrite and nitrate were negative at a detection level of 0.01 mug of nitrite or nitrate per g of meat.
Carcinogenic N-nitrosamines were tested for their ability to induce lambda in a lysogenic strain of Escherichia coli K-12 (58-161 F+ Dimethylnitrosamine, di-n-propylnitrosamine, methyl-n-propylnitrosamine, and N-nitrosopiperidine were shown to be inducers of prophage.
Administration of methyl(methoxymethyl)nitrosamine to newborn Fischer 344 rats results in the preferential induction of renal tumors arising from the mesenchymal component of the kidney. DNA from a significant proportion of these tumors was capable of transforming NIH/3T3 cells. This report describes the renal tumor model, the detection of two different ras transforming genes in the kidney tumors (the N-ras oncogene in 1 and K-ras oncogene in 10 kidney tumors) and the characterization of DNA sequences specifying the transformed phenotype.
Measurement of N-nitroso compounds in gastric juice by different methods has given conflicting results. In order to resolve this controversy, we have assessed endogenous nitrosation by the independent N-nitrosoproline excretion test in subjects who had previously undergone gastric juice analysis by one of these methods. Ten Polya gastrectomy, 10 pernicious anaemia and nine matched control subjects were fed 380 mg of nitrate in beetroot juice and 500 mg proline. N-nitrosoproline (N-Pro) synthesised intragastrically from these precursors, and quantitatively excreted by the kidneys, was measured in 24 hour urine samples (collection checked by creatinine clearance). N-Pro excretion (mean +/- SEM) was reduced (p less than 0.01) in pernicious anaemia (1.1 +/- 0.8 ng/day) compared with matched control (18.0 +/- 7.2 ng/day), and also tended to be lower (NS) in polya gastrectomy (3.2 +/- 2.3 ng/day). Twenty four hour intragastric pH was monitored on a separate occasion in 23 of the 29 subjects; 13 were hypoacidic (pH greater than 4 greater than 50% of 24 hours) and 10 were acidic. N-Pro yields were reduced (p less than 0.01) in the hypoacidic group (0.9 +/- 0.6 ng/day) compared with the acidic group (17.9 +/- 6.6 ng/day), and N-Pro was negatively associated with mean intragastric pH (tau = -0.53, p = 0.001). We conclude that endogenous synthesis of this specific N-nitroso compound is favoured by low rather than high pH. These results are concordant with those previously reported in gastric juice from the same subjects and suggest that nitrosation is chemically rather than bacterially mediated, contrary to the nitrosamine hypothesis of gastric carcinogenesis.
OBJECTIVE: To develop a method for evaluating the carcinogen delivery of potential reduced exposure products (PREPs) like Advance, a PREP marketed to reduce smokers' exposure to one tobacco specific nitrosamine (TSN), NNK, a potent lung carcinogen. DESIGN, SETTING, AND PARTICIPANTS: Latin square ordered, three condition, outpatient, crossover design with 12 smokers of light or ultra-light cigarettes (15 or more cigarettes/day). In each five day condition, participants either smoked own brand, Advance, or no cigarettes. Also, on the first and last day of each condition, participants smoked one cigarette in the laboratory. MAIN OUTCOME MEASURES: Subject rated measures of tobacco/nicotine withdrawal, expired air carbon monoxide, urine concentrations of cotinine and NNAL (one TSN biomarker), puff volume, duration, number, and interpuff interval. RESULTS: Relative to own brand, Advance produced similar withdrawal suppression, slightly lower carbon monoxide, equivalent cotinine, and 51% lower NNAL concentrations. The lowest cotinine and NNAL concentrations were observed in the no cigarette condition. Participants took fewer puffs when smoking Advance. CONCLUSIONS: Past experience with PREPs that failed to reduce smoking's harm demonstrates the need for clinical methods in PREP evaluation. This study shows how assessing PREP induced changes in withdrawal and exposure to carbon monoxide, nicotine, and carcinogens may help predict PREP harm reduction potential. Adequate withdrawal suppression, slightly lower concentrations of carbon monoxide, and reduction of one TSN biomarker were observed for Advance. In the future, clinical methods like those described here may be valuable for evaluating PREPs before they are marketed publicly.
A monoclonal antibody (MAb) to a rat acetone-inducible and nitrosamine-metabolizing form of microsomal cytochrome P-450, P-450ac, detected a related P-450 in human liver microsomes by both immunoblot and competitive radioimmunoassay. This MAb was also used to immunopurify microsomal cytochromes P-450 from both human liver and acetone-treated rats; these were electrophoretically homogeneous with apparent molecular weights of 56,200 and 53,000 daltons, respectively. The structures of the cytochromes P-450 were compared by peptide mapping and amino-terminal sequence analyses. They differed in their peptide maps but displayed amino-terminal sequence similarity in their first 19 residues. This report thus demonstrates the utility of MAbs to rat cytochromes P-450 for detection, identification and structural characterization of human P-450s.
The results of the systematic survey of food from the German market in regard to the occurrence of volatile nitrosamines are presented. The average daily intake for male persons amount to 1.1 microgram for N-nitrosodimethylamine (NDMA) and 0.1-0.15 microgram for N-nitroso-pyrrolidine (NPYR). About 64% of this total daily intake for NDMA is found in beer, 10% result from cured meat products. The surprising contamination of beer is formed during the drying (kilning) of malt and can be eliminated.
Volatile N-nitrosamines were quantitatively determined in mainstream and sidestream smoke of commercial cigarettes using gas chromatography-thermal energy analysis (GLC-TEA). The smoke was trapped in ascorbic acid solution buffered at pH 4.5 and then extracted with dichloromethane; the organic phase was chromatographed on basic alumina and analyzed by GLC-TEA. The mainstream smoke of 22 different commercial cigarettes from Germany and Switzerland contained between 0.1 and 27 ng dimethylnitrosamine (DMN), 1.5 and 29 ng nitrosopyrrolidine (NPY) and traces of methylethylnitrosamine (MEN). The sidestream smoke of these cigarettes contained between 143 and 415 ng DMN, 3.1 and 27 ng MEN and 28 and 150 ng NPY. In a final experiment we measured the DMN concentration in a sealed experimental chamber as a function of the number of cigarettes smoked and recovered 68-87% of the DMN values found when using the sidestream collection device applied in the other experiments.
Dose-response studies were carried out, principally with dimethylnitrosamine and diethylnitrosamine, in rats. The compounds were given in the drinking water at levels of 33-1,690 ppb, each being given at 15 dose levels. This range of dosage corresponds to approximately 2-1,080 microgram/kg b.w./day for male animals and 3-1,470 microgram/kg b.w./day for females. Subsidiary experiments using mice and hamsters, and also in rats, where the dialkyl compounds were first given on weaning and at 20 weeks of age were also carried out. In each of these experiments 15 dose levels were used. Additional experiments with N-nitrosopyrrolidine and N-nitrosopiperidine were undertaken. The problems encountered in the experimental design and in the execution of the studies are discussed, and the necessity for pilot studies is emphasized. A preliminary consideration of the results are presented. Lowest levels at which carcinogenic responses were observed were 132 ppb for dimethyl- and diethylnitrosamine in male rats after median survival times in excess of 900 days. Hyperplastic nodules of the liver occurred with dimethyl nitrosamine at a level of 2 microgram/kg b.w./day.
Ethanol in amounts equivalent to a man drinking a pint of beer has a dramatic effect on the metabolism and distribution of nitrosamines in rats. It prevents the first pass clearance of dimethylnitrosamine and thus exposes the extrahepatic organs to oral doses of this carcinogen. By selectively inhibiting metabolism in liver and kidney, ethanol increases the amount of diethylnitrosamine activated in the esophagus between 1.8- and 4.6-fold. It is suggested that there may be a link between these observations and the increase in human esophageal cancer which is associated with alcohol consumption.
It has been shown that the occurrence of the preneoplastic lesion, papillary or nodular hyperplasia (PN hyperplasia) in rat urinary bladder induced by carcinogens is correlated with that of cancer. Therefore, the promoting effects of chemicals in two-stage bladder carcinogenesis were judged by measuring their ability to induce PN hyperplasia in rats. Male rats were given N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) for 4 weeks and then one of 16 test chemicals for 32 to 34 weeks. Saccharin, ascorbate, DL-tryptophan, allopurinol, and diphenyl promoted development of PN hyperplasia. The dose-response of the promoters were examined in both sexes of rats by administration of saccharin at doses of 0.04, 0.2, 1.0 and 5.0% for 32 weeks after BBN treatment. The occurrence of PN hyperplasia was significantly increased in the group given 5% saccharin. Dose-response curves showed enhanced hyperplastic responses in both sexes given 0.2 to 5% saccharin. The organ specificities of promoters were studied in rats initiated with BBN or 2-acetylamino-fluorene (2-AAF) followed by phenobarbital or saccharin for 32 weeks. Phenobarbital greatly enhanced hepatocarcinogenesis. Saccharin significantly enhanced the occurrence of both BBN-induced and 2-AAF-induced PN hyperplasia. However, there was no effect of phenobarbital on the urinary bladder or of saccharin on the liver. The rats showed a strain difference in susceptibility of the urinary bladder to saccharin; ACI rats were most susceptible and Sprague Dawley rats were most resistant to saccharin. The membrane potential of superficial epithelial cells in the urinary bladder of rats treated with saccharin was measured with an intracellular microelectrode and found to be higher than that of controls.
This paper describes quantitation of human hemoglobin and DNA adducts of the carcinogenic tobacco-specific nitrosamines 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and N'-nitrosonornicotine (NNN). NNK and NNN are believed to be involved in cancers of the lung, esophagus, oral cavity, and pancreas in people who use tobacco products. The adduct dosimetry method employs GC-MS for quantitation of 4-hydroxy-1-(3-pyridyl)-1-butanone (HPB) released by mild base hydrolysis of hemoglobin or acid hydrolysis of DNA as a biochemical marker of the pyridyloxobutylation metabolic activation pathway. Approximately 22% of smokers (n = 101) had elevated levels of HPB released from hemoglobin (range, 200-1600 fmole/g Hb). Adduct levels in snuff dippers ranged from 200-1800 fmole/g Hb. HPB levels in nonsmokers were generally below the detection limit. Acid hydrolysis of lung and tracheal DNA obtained at autopsy and analysis for released HPB revealed levels ranging up to 50 fmole/mg DNA in smokers; the adduct was not detected in nonsmokers. These findings are consistent with data generated in studies of adduct formation by NNK in rats. The biological significance of the HPB-releasing DNA pyridyloxobutylation pathway was compared to that of the DNA methylation pathway in the A/J mouse. These studies demonstrated that the persistence of O6-methylguanine in lung DNA is critical for tumorigenesis by NNK and that pyridyloxobutylation enhances both persistence of O6-methylguanine and tumorigenesis by acetoxymethylmethylnitrosamine. In the rat, the relative roles of methylation and pyridyloxobutylation in lung tumorigenesis by NNK are not as clearly defined.(ABSTRACT TRUNCATED AT 250 WORDS)
We studied peripheral lymphocyte HPRT variant frequency and endogenous nitrosation in human populations exposed to various nitrate levels in their drinking water. Four test populations of women volunteers were compared. Low and medium tap water nitrate exposure groups (14 and 21 subjects) were using public water supplies with nitrate levels of 0.02 and 17.5 mg/l, respectively. Medium and high well water nitrate exposure groups (6 and 9 subjects) were using private water wells with mean nitrate levels of 25 and 135 mg/l, respectively. Higher nitrate intake by drinking water consumption resulted in a dose-dependent increase in 24-hr urinary nitrate excretion and in increased salivary nitrate and nitrite levels. The mean log variant frequency of peripheral lymphocytes was significantly higher in the medium well water exposure group than in the low and medium tap water exposure groups. An inverse correlation between peripheral lymphocyte labeling index and nitrate concentration of drinking water was observed. Analysis of N-nitrosamine in the urine of 22 subjects by gas chromatography-mass spectrometry revealed the presence of N-nitrosopyrrolidine in 18 subjects. Analysis of the mutagenicity of well water samples showed that a small number of the well water samples were mutagenic in the Ames Salmonella typhimurium test after concentration over XAD-2 resin. In conclusion, consumption of drinking water, especially well water, with high nitrate levels can imply a genotoxic risk for humans as indicated by increased HPRT variant frequencies and by endogenous formation of carcinogenic N-nitroso compounds from nitrate-derived nitrite.
N-Methyl N-benzyl nitrosamine (MBNA), which requires P450-dependant activation to be mutagenic, has been shown to produce squamous cell carcinoma of rat oesophagus. The aim of this study was to determine the effects of tumour induction on hepatic cytochrome P450 (CYP) and phase II enzyme activity. Female Wistar rats were given MBNA (2.5 mg/kg) by gavage, twice weekly for 12 weeks. At the end of 12 weeks they were sacrificed; livers and oesophagi were removed. The activity of hepatic CYP and phase II enzymes was determined by incubation of liver microsomes with appropriate CYP substrates. All rats receiving MBNA developed oesophageal lesions. Hepatic CYP1A2 activity (phenacetin 5 microM) in tumour-bearing rats was significantly decreased to 53% of the controls (p <0.05). CYP2E1 (p-nitrophenol hydroxylase), CYP2D (debrisoquine hydroxylase) and CYP3A (quinine hydroxylase) activity was significantly (p <0.05) reduced. Microsomal UDP-glucuronosyl transferase activity was also found to be markedly decreased while glutathione-S-transferase activity remained almost unchanged. Alteration of the activities of drug metabolising enzymes in rats with chemically induced tumours could be an important factor in determining resistance or susceptibility to xenobiotics and antitumour drugs.
Occupationally induced lung cancer and mesothelioma have long been attributed to asbestos and moreover, several epidemiological studies have indicated a co-carcinogenic effect of cigarette smoking on the incidence of lung cancer in asbestos workers. The aim of the present study was to investigate the co-carcinogenic effects of asbestos and other carcinogens with emphasis placed on determining the effects of cigarette smoking on the incidence of asbestos induced carcinomas. Doses of 15 mg of chrysotile asbestos were administered intratracheally to Wistar rats alone and in conjunction with N-bis(hydroxypropyl)nitrosamine (DHPN) and/or cigarette smoking. DHPN at dose of 1 g/kg/B.W. was injected three times intraperitoneally, and the subject animals were exposed to smoke from 10 cigarettes per day, six days a week, for their entire life span. As a result, lung carcinomas were induced in one out of the 31 rats receiving only asbestos. Lung tumors were induced at a much higher incidence in the groups receiving DHPN alone and in conjunction with asbestos: of the 37 rats treated with DHPN alone 19 (51.4%) developed lung tumors, whereas those receiving asbestos as well showed an incidence of 68.4% (23/38) of carcinomas. The development of lung carcinomas (including adenocarcinomas, epidermoid carcinomas, anaplastic carcinomas, and combined carcinomas) was seen in 8 (21.6%) out of the 37 rats receiving DHPN alone and in 23 (60.5%) out of the 38 rats receiving asbestos as well. The incidence of lung carcinoma was significantly increased in combined treatment with asbestos than DHPN alone. In the group receiving asbestos in combination with cigarette smoke, 4 (13.8%) out of the 29 rats developed lung carcinomas, but these carcinomas were more common than in the group receiving only asbestos. Moreover, in the group administered asbestos, DHPN and smoking combined, lung tumors developed in 18 (62.1%) out of the 29, 15 (51.7%) of which proved to be malignant. Mesothelioma (pleura) was induced in three groups in the following combinations: DHPN plus asbestos, 8/38 (21.1%); smoking plus asbestos, 2/29 (6.9%); and smoking, DHPN and asbestos, 4/29 (13.8%). These tumors were extensively located, that is, on the parietal pleura, visceral pleura, epicardium and diaphragm surface. However, mesothelioma was not induced by asbestos alone nor by DHPN alone. Carcinogenicity of asbestos for pleural tumors was significantly promoted by combined treatment with DHPN to an extent greater than DHPN alone. It should be noted that asbestos plus smoking resulted in a higher incidence of mesothelioma than asbestos alone.(ABSTRACT TRUNCATED AT 400 WORDS)
ICR mice were given four subcutaneous injections of bis(2-oxopropyl)nitrosamine (BOP) 10, 20 and 40 mg/kg body weight, respectively, on day 1, 8, 15 and 22 of age. Animals treated with BOP developed mainly tumors of the lung, liver, nasal cavity, and pancreas. Lung tumors were histologically alveolar cell adenoma or adenocarcinoma at an incidence of 41-100%, hepatocellular adenoma or carcinoma 59-96%, adenoma or adenocarcinoma of the nasal cavity 11-26%, and pancreatic acinar cell adenoma or anaplastic carcinoma 3-7%. No sex difference in response to BOP carcinogen was observed.
The tumorigenesis and cystic lesion by a single intraperitoneal administration (ip) of N-bis (2-hydroxypropyl)nitrosamine (DHPN) for 52 weeks were studied in ddY mice. The amount of DHPN was 1000 mg/kg in group I, 500 mg/kg in group II, 250 mg/kg in group III, 125 mg/kg in group IV and 0 mg/kg in group V. The tumorigenesis of DHPN was found in the lung and liver. However, cystic lesion was observed only in the liver. Lung tumors were adenoma, adenocarcinoma and squamous cell carcinoma. As liver tumors, adenoma, hepatocellular carcinoma, cholangioma and hemangioma were observed only in the mice treated with DHPN. Incidence of cystic lesion in the liver was detected in all groups treated with DHPN. Histologically, cystic lesion of the liver showed four patterns of bile duct-like, sinusoid-like, hepatocyte-like and mixed.