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B Spiegelhalder

Publications and source records attributed to B Spiegelhalder.

At least 91 records · Page 5Linked to original sources
PubMed1988

The occurrence of tobacco-specific nitrosamines in oral tobacco products and their potential formation under simulated gastric conditions.

The levels of the tobacco-specific nitrosamines: N-nitrosoanabasine, N-nitrosoanatabine, N-nitrosonornicotine and 4-(N-nitrosomethylamino)-1-(3-pyridyl)-1-butanone in a variety of chewing tobaccos, oral snuffs, masheri and zarda samples were determined. The potential endogenous formation of tobacco-specific nitrosamines was estimated by incubation of tobacco samples at pH 2.0 for 1 hr at 37 degrees C and over the pH range 1.0 to 5.5 under conditions simulating the normal fasting stomach, with a constant nitrite concentration of 25 microM. Under the simulated gastric conditions, N-nitrosoanabasine, N-nitrosoanatabine and N-nitrosonornicotine were formed, and maximum formation of these tobacco-specific nitrosamines occurred at pH 2.5. Nicotine, the major alkaloid present in tobacco and precursor to N-nitrosonornicotine and 4-(N-nitrosomethylamino)-1-(3-pyridyl)-1-butanone, was not nitrosated. The formation of N-nitrosonornicotine resulted from nitrosation of nornicotine, another alkaloid also present in tobacco. Under the acidic simulated gastric conditions, slight decomposition of 4-(N-nitrosomethyl-amino)-1-(3-pyridyl)-1-butanone via transnitrosation was observed.

Carcinogens↗
PubMed1988

The initiator tRNA acceptance assay as a short-term test for carcinogens. 2. Results with ten compounds selected by the International Programme on Chemical Safety for the evaluation of short-term tests for carcinogens.

Eight carcinogenic and two non-carcinogenic compounds that are difficult to detect by short-term tests (acrylonitrile, benzene, benzoin, caprolactam, diethylhexylphtalate, diethylstilbestrol, hexamethylphosphoramide, phenobarbital, safrole and o-toluidine) were tested independently in Prague and in Heidelberg by the newly developed initiator tRNA acceptance assay. Seven out of eight tested carcinogens gave a positive response in this assay, only safrole showed a false negativity in both laboratories. Both non-carcinogenic compounds, benzoin and caprolactam, exhibited no activity. An absolute qualitative agreement was found with all compounds tested between the results of both laboratories. With the exception only of phenobarbital (intermediate activity in Prague and low in Heidelberg) the quantitative results obtained in both laboratories were comparable. The initiator tRNA acceptance assay thus appears to be a reliable short-term test for carcinogenicity with good reproducibility.

Carcinogens↗
PubMed1988

The initiator tRNA acceptance assay as a short-term test for carcinogens. 3. Results with 69 N-nitroso compounds.

The activity of 69 carcinogenic and non-carcinogenic N-nitroso compounds was tested by the recently developed initiator tRNA acceptance assay for carcinogens. Of 51 carcinogens tested, 50 were active in the assay. Only N-nitrosopropylpropanolamine showed a false negativity. Eleven out of 14 tested non-carcinogenic compounds were not active in the assay, nitrosoethyl-tert-butylamine and nitrosoprolineethylester were positive. As calculated from these data, the sensitivity of the assay was 98.0%, specificity 84.6%, accuracy 95.4% and predictive value 94.4%. Comparison of relative carcinogenicities in animal bioassays with quantitative results (% stimulation of initiator tRNA charging) of the short-term test showed a good correlation for non-carcinogenic compounds and strong carcinogens. However, carcinogens of low and median potency could not be easily distinguished. A good correlation was obtained for three isomer N-nitrosomethylaminopyridines between the TD50-value and activity in the tRNA acceptance assay. The initiator tRNA acceptance assay thus seems preferable for recognizing and classifying carcinogenic and non-carcinogenic N-nitroso compounds than any other individual short-term test for carcinogenicity.

Animals↗
PubMed1988

Transnitrosating activity of N-nitroso-N-methyl-p-toluenesulfonamide in rats and human gastric juice.

N-nitroso-N-methyl-p-toluenesulfonamide (NMTS, diazald, CAS 80-11-5) is a widely used compound for laboratory production of diazomethane. The present results showed that the noncarcinogenic NMTS reacts as a transnitrosating agent with amino nitrogen of secondary amines and amide both in vitro (human gastric juice) and in vivo (rats) to yield N-nitroso compounds. Since all compounds formed (NMOR, NDMA, NPIP, NPZ, NMU) are known animal carcinogens, caution should be taken by users handling NMTS.

Amides↗
PubMed1987

Some aspects of cytochrome P450-dependent denitrosation of N-nitrosamines.

The present paper deals with three aspects of cytochrome P450-dependent denitrosation of N-nitrosamines. (1) Nitrate was found in addition to nitrite as a metabolic product of the denitrosation reaction when N-nitrosamines were incubated with a microsomal system. This could also be shown when nitric oxide was added to the microsomes. (2) In order to determine the amount of denitrosation in vivo, the nitroso group of N-nitroso-N-methylaniline was labelled with the 15N isotope and administered to rats; then, the concentrations of 15N-nitrate and 15-N-nitrite in the urine were quantified by measuring the reaction of nitrate and benzene to nitrobenzene. It is estimated from these data that about 33% of the applied dose of 15N-nitroso-N-methylaniline is denitrosated in vivo. (3) Although N-nitrosodiphenylamine (NDPhA) has been classified as a noncarcinogen, recent long-term and short-term studies have cast some doubt. In order to evaluate the mechanism by which NDPhA exerts its possible genetoxic effects, its metabolism was studied in vitro, and NDPhA and its metabolites were tested for induction of DNA single-strand breaks in rat hepatocytes and in Chinese hamster V79 cells. One metabolite was identified as diphenylamine; others were suspected to be the 4-hydroxylated derivative and its corresponding quinoneimine. NDPhA caused DNA damage in rat hepatocytes but not in V79 cells. Diphenylamine also gave negative results in V79 cells, but its putative metabolite, diphenylhydroxylamine, induced a significant increase in DNA single-strand breaks.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Exhalation of N-nitrosoethylvinylamine after application of N-nitrosodiethylamine to Sprague-Dawley rats.

Our method of endotracheal intubation makes it possible to collect exhaled air directly from the respiratory tract, thus eliminating the possibility of artefact formation and decomposition of metabolites. N-Nitrosodiethylamine (NDEA) has been postulated as a precursor of N-nitrosoethylvinylamine (NEVA), however, NEVA has not been detected as a metabolite of NDEA. Following endotracheal intubation and intravenous application of 550 micrograms NDEA to Sprague-Dawley rats, appreciable amounts of NEVA and unaltered NDEA were found in exhaled air. Further confirmation that NEVA is a metabolite of NDEA was obtained when, after eliminating oxidative decomposition of the nitrosamine with disulfiram in an enzyme inhibition assay, pretreated rats exhaled only traces of NEVA. Such findings could be informative with respect to the organotropism of nitrosamine carcinogenesis.

Animals↗
PubMed1987

Prevention of exposure to N-nitrosamines in the rubber industry: new vulcanization accelerators based on 'safe' amines.

Introduction of 'safe' amino components into traditional accelerator molecules could be an effective measure to prevent formation of carcinogenic N-nitroso compounds during rubber production. About 20 new derivatives of the dithiocarbamate and sulfenamide class, based on 'safe' amines, were synthesized and shown to be suitable for industrial application. Some of the corresponding N-nitrosamines were prepared and investigated for mutagenicity in Salmonella typhimurium TA1535. No or weak mutagenic potential was observed in most cases. The nitrosatability of five sulfenamides derived from 'safe' amines was determined and found to be substantially lower than that of a commercial sulfenamide accelerator tested under identical conditions.

Animals↗
PubMed1987

Nitrosamine measurements in ambient air of an industrial area in Austria.

The area of Linz (Oberösterreich) is the most heavily polluted region in Austria, due to its chemical and steel industry. In 1981, a survey of volatile nitrosamines in ambient air performed by a local laboratory revealed levels of up to 5.45 micrograms/m3. This instigated the setting up of a systematic nitrosamine monitoring programme from February 1983 to May 1984, during which the validity of the analytical procedures was determined. A total of 363 air samples was collected over 200 days at 16 different locations in and around Linz. About 6% of the samples showed low nitrosamine contamination, with levels between 0.01 and 0.04 microgram/m3 of N-nitrosodimethylamine (NDMA), N-nitrosodiethylamine (NDEA), and N-nitrosomorpholine (NMOR). The lower limit of detection was 0.005 microgram/m3. It was not possible to confirm these low concentrations by high-resolution mass spectrometry. In some samples, thermal energy analyser-responsive material was observed, which may be due to the occurrence of C-nitro compounds.

Air Pollution↗
PubMed1987

Mutagenicity and carcinogenicity of masheri, a pyrolysed tobacco product, and its content of tobacco-specific nitrosamines.

Masheri, an indigenous pyrolysed tobacco product in India, was studied for its chemical, mutagenic and carcinogenic profile. Masheri extract was found to be rich in N-nitrosamines and polycyclic aromatic hydrocarbons. It was highly mutagenic in the presence of an exogenous metabolic system in the Ames test and in the micronucleus test, in a dose-dependent manner. It also induced 8-azaguanine-resistant mutants in Chinese hamster V79 cells. On skin painting, it showed a weak carcinogenic effect in Swiss nude mice. The saliva of masheri users showed high levels of N'-nitrosonornicotine (NNN; 14-43 ppb) and N-nitrosopyrrolidine (NPYR; 2.2-8.3 ppb). Thus, this widespread habit, predominant among women, could be an additive risk factor in the high incidence of oropharyngeal cancer prevalent in India.

Adult↗
PubMed1987

N-nitrosodiethanolamine excretion in metal grinders.

Grinding fluids usually contain ethanolamines and nitrite as anticorrosive agents; these are known precursors of N-nitrosodiethanolamine (NDELA). In a preliminary study, it was demonstrated that workers' exposure to NDELA can be monitored by urine analysis. In order to estimate total daily exposure, 12 workers in a grinding shop were investigated by a three-step biological monitoring programme, giving the following results: (1) after exposure-free weekends, no NDELA was found in urine; (ii) urine collected during working shifts contained NDELA in up to microgram/kg concentrations; (iii) total daily NDELA excretion in 24-h urines was up to 40 micrograms; (iv) the amount of excreted NDELA correlated with the amount of NDELA contamination in the grinding fluid; (v) NDELA seems to be accumulated in the body during the week; (vi) other workers in machine shops, like maintenance and transport workers, are also heavily exposed to NDELA.

Diethylnitrosamine↗
PubMed1986

N-nitrosamines in the saliva of tobacco chewers or masheri users.

Saliva was collected from men and women who were habitual chewers of tobacco (with lime or betel quid) and from women who used masheri. The saliva was analysed for tobacco-specific nitrosamines (TSNAs). TSNAs were detected in the saliva of all tobacco users, but within each habit group there were wide variations between donors in salivary nitrosamine levels. TSNA levels in the saliva from men and women chewing betel quid and tobacco were similar, although women used less tobacco for chewing. The saliva of men who chewed tobacco with lime contained higher levels of TSNAs than did that of men who chewed betel quid with tobacco.

Adult↗
PubMed1985

In vivo nitrosation of amidopyrine in humans: use of 'ethanol effect' for biological monitoring of N-nitrosodimethylamine in urine.

Under normal conditions a possible N-nitrosodimethylamine formation in vivo cannot directly be monitored in urine due to high metabolic conversion rate (greater than 99.9%). Own experiments showed an increased excretion rate (up to 2.4%) if ethanol was administered simultaneously. This model was used for monitoring experiments with respect to in vivo formation of N-nitrosodimethylamine. Amidopyrine, as a compound which is easily nitrosated, was administered (single oral dose of 500 mg) to volunteers. Under the influence of 20-30 g ethanol it was possible to detect N-nitrosodimethylamine in urine. From negative control experiments it must be concluded that this appearance of N-nitrosodimethylamine derives from in vivo nitrosation of the drug. The amount excreted in urine varied between 0.5 and 10 micrograms N-nitrosodimethylamine within 8 h and seemed to be influenced by salivary nitrite concentrations which ranged from 5 to 220 p.p.m. NO-2. In comparison with earlier excretion studies in humans it can be assumed that only 1-2% of the originally formed nitrosamine was found in urine. To our knowledge this is the first time that in vivo formation of N-nitrosodimethylamine was directly shown to occur in humans.

Aminopyrine↗
PubMed1984

Effects of disulfiram on the metabolism of nitrosodiethylamine during liver carcinogenesis.

We have studied the effects of disulfiram (DSF) administration on the metabolism of nitrosodiethylamine (NDEA) in rats during acute and chronic administration. DSF was found to have the following effects during the course of carcinogenesis: (a) marked decrease in the exhalation of 14CO2 derived from 14C-NDEA; (b) reduction of the total levels of DNA and RNA ethylation in the liver. In acute experiments DSF caused an increase in the amount of NDEA in organs and in the urine. We suggest that inhibition of NDEA biotransformation and the subsequent decrease in the total level of DNA ethylation may prevent specific chemical interactions relevant to carcinogenesis.

Alkylation↗
PubMed1984

Contamination of toiletries and cosmetic products with volatile and nonvolatile N-nitroso carcinogens.

Commercially available cosmetics and toiletries were analyzed for contamination with volatile and nonvolatile N-nitrosamines. Of a total of 145 samples analyzed 50 were found to contain N-nitrosodimethylamine (max. value found 24 micrograms/kg), 26 samples were contaminated with N-nitrosomorpholine (max. value found 640 micrograms/kg), and 25 samples contained N-nitrosodiethanolamine, a non-volatile carcinogen (max. value found 1400 micrograms/kg). These results are discussed and compared with other published data on NDE1A in cosmetics, with reference to potential human exposure and to possible preventive measures.

Carcinogens↗
PubMed1984

Urinary excretion of N-nitrosodimethylamine in rats after Thalamonal narcosis.

Urinary excretion of N-nitrosodimethylamine (NDMA) in Sprague--Dawley rats was investigated after oral administration and inhalation of NDMA and concomitant narcosis by Thalamonal and diethyl ether. While ether anesthesia induced a 4-fold increase in the excretion rate, there was a drastic reduction (about 20-fold) in the amount of NDMA excreted after narcosis by Thalamonal.

Anesthetics↗
PubMed1984

Denitrosation of diphenylnitrosamine in vivo.

A single dose of diphenylnitrosamine (NDphA) was applied orally or intraperitoneally (i.p.) to rats. The urine was sampled and analysed for nitrite/nitrate by ion chromatography and for diphenylamine (DphA) plus hydroxydiphenylamine by gas chromatography. The major metabolite was nitrate. Nitrite and DphA were found in minor amounts. In a somewhat higher concentration, a monohydroxylated DphA was detected. It is concluded that NDphA is denitrosated to nitric oxide (NO) and DphA in the organism and that NO is then converted into nitrite and nitrate.

Administration, Oral↗
PubMed1984

In-vivo formation of N-nitrosodimethylamine in humans after amidopyrine intake.

Several authors have described the occurrence of N-nitrosodimethylamine (NDMA) in body fluids (e.g., blood and urine) and have interpreted this finding as an indication of endogenous formation of NDMA. Controlled excretion studies as well as careful control of artefacts showed, however, that, under normal conditions, NDMA formation in vivo cannot be monitored directly in urine due to a high metabolic conversion rate (more than 99.9%). Our own experiments showed an increased excretion rate (up to 2.4%) when ethanol was administered simultaneously. This model was used in experiments to monitor in-vivo formation of NDMA. Amidopyrine, a compound that is easily nitrosated, was administered as a single oral dose of 500 mg to volunteers. With ingestion of 20-30 g ethanol NDMA could be detected in urine. Negative control experiments indicate that the appearance of NDMA in urine derives from in-vivo nitrosation of the drug. Between 0.5 and 10 micrograms NDMA were excreted within 8 h, and excretion was influenced by salivary nitrite concentrations, which ranged from 5-220 mg/L. By comparison with our earlier excretion studies in humans, it can be assumed that only 1-2% of endogenously formed N-nitrosamine was found in urine. To our knowledge, this is the first time that in-vivo formation of NDMA has been shown directly to occur in humans.

Aminopyrine↗