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R Preussmann

Publications and source records attributed to R Preussmann.

At least 91 records · Page 5Linked to original sources
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↗
PubMed1986

Formation of N-nitrosoiminodialkanoic acids and their unsuitability as biological monitors for endogenous nitrosation of dipeptides.

Nitrosation of dipeptides which do not contain imino acids leads to rearrangement and the formation of N-nitrosoiminodialkanoic acids. The optimum conditions for the nitrosation of dipeptides in buffer solutions occur at pH 2.0 (0.8-3.2% yield) and are not significantly catalysed by thiocyanate. In vitro nitrosation in gastric juice resulted in a lower yield. It was demonstrated that under normal gastric conditions, a maximum yield of 0.1 mumol total N-nitrosoiminodialkanoic acids/0.1 mol dipeptide would occur, 0.1 mol representing a typical dietary intake of dipeptide. This corresponds to a total concentration of approximately 20 micrograms/l N-nitrosoiminodialkanoic acids over a 24 h period. However, this figure may be significantly altered due to the fluctuation of nitrosation catalysts and inhibitors in gastric juice. Further studies showed that N-nitrosoiminodialkanoic acids are quantitatively excreted in urine when fed by gavage to rats. However, co-administration of the precursor dipeptide and nitrite resulted in negligible in vivo formation. The presence of N-nitrosoiminodialkanoic acids in normal human urine was not detected. Thus it was concluded that the monitoring of N-nitrosoiminodialkanoic acids in human urine is not a suitable method for biological monitoring of the endogenous nitrosation of dipeptides.

Animals↗
PubMed1986

Carcinogenicity of nitrosoureas in humans.

Literature on secondary tumours developing after cancer chemotherapy with nitrosoureas is reviewed. Many case studies show that combination treatments including BCNU and CCNU give rise predominantly to acute leukaemia within an average latent period of about 40 months. However, because other, potentially carcinogenic alkylating agents may be administered during treatment, no direct causal association with nitrosoureas can be made on the basis of these studies. A large case-control study by Boice et al. (1983), however, provides strong evidence of a causal relationship between the induction of acute nonlymphocytic leukaemia (ANLL) and treatment with methyl-CCNU. Among 2067 patients treated with methyl-CCNU and 5-fluorouracil as adjuvant chemotherapy after surgery for gastrointestinal cancers, nine cases of ANLL were observed, whereas 0.71 were expected; the relative risk was 15.9. The results are discussed and are interpreted as providing evidence for the carcinogenicity of methyl-CCNU to humans. They are therefore consistent with other epidemiological data on the carcinogenicity of N-nitroso compounds to man.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1985

Fluoro-substituted N-nitrosamines. 7. Non-genotoxic N-nitroso-bis(2,2,2-trifluoroethyl)amine and N-nitroso-bis(2,2,3,3,4,4,4-heptafluorobutyl)amine: binding to cytochrome P-450, acidity of alpha-protons and pharmacokinetic investigations.

The biologically inactive fluorinated nitrosamines N-nitroso-bis(2,2,2-trifluoroethyl)amine (NDEA-F6) and N-nitroso-bis-(2,2,3,3,4,4,4-heptafluorobutyl)amine (NDBA-F14) were investigated for binding affinity to cytochrome P-450 and for ease of alkali-induced proton abstraction at the alpha-C atom, in comparison with biologically active analogues (N-nitroso-diethylamine, NDEA; N-nitroso-2,2,2-trifluoroethylethylamine, NDEA-F3; N-nitrosodibutylamine, NDBA; N-nitroso-4,4,4-trifluorobutylbutylamine, NDBA-F3; N-nitroso-bis(4,4,4-trifluorobutyl)amine, NDBA-F6). Binding to cytochrome P-450 was studied by spectroscopic measurements (optical difference spectra with microsomal fractions); base-catalyzed deuterium exchange of alpha-hydrogen atoms was followed by 1H n.m.r. measurements. Additionally the excretion of NDEA-F6 and NDBA-F14 in expired air, urine and faeces was studied after oral application to the rat. Compared with the biologically active nitrosamine analogues, NDEA-F6 and NDBA-F14 showed higher binding affinity to cytochrome P-450. N.m.r. spectroscopy showed that NDEA-F6, NDBA-F14 and NDEA-F3 (at the fluorinated alkyl chain) were rapidly deprotonated at the alpha-C-position in sodium perdeutero methylate, in contrast to the other analogues tested. In vivo, NDEA-F6 and NDBA-F14 were excreted unchanged, mainly via exhalation. The biological inactivity of NDEA-F6 and NDBA-F14, together with the observed blocking of their microsomal activation can be reconciled with the experimental findings which indicate that homolytic alpha-C-H bond fission is more likely to be involved in alpha-C-hydroxylation of dialkylnitrosamines, than alpha-proton abstraction.

Animals↗
PubMed1985

Fluoro-substituted N-nitrosamines. 8. N-Nitrosodibutylamine and omega-fluorinated analogues: in vivo metabolism in relation to the induction of urinary bladder cancer in the rat.

Urinary excretion of N-nitrosodibutylamine (NDBA) and of two omega-fluorinated analogues [N-nitroso-4,4,4-trifluorobutyl-butylamine, NDBA-F3; N-nitroso-bis(4,4,4-trifluorobutyl)-amine, NDBA-F6] was studied in male Sprague-Dawley (SD) rats. After oral application of equimolar doses (0.44 and 1.32 mmol/kg body wt.) urines were collected (48 h) and analyzed for parent compounds, and for nitrosamine metabolites by gas chromatography/Thermal Energy Analyzer (GC/TEA) and gas chromatography/mass spectrometry (GC/MS). After administration of NDBA the known major metabolites N-nitroso-3- hydroxybutylbutylamine (3-OH-NDBA) and N-nitroso-3-carboxypropylbutylamine (BCPN) were excreted in urine. After application of the omega-fluorinated analogue NDBA-F6, however, urinary and biliary nitrosamine metabolites were detected only in trace amounts. This finding demonstrates a strong inhibitory effect of fluorine substitution on oxidations at omega, (omega-1) and beta-positions. Confirmation of this inhibitory effect of omega-fluorine substitution is given from the excretion profiles of NDBA-F3 which shows metabolic oxidations only at the nonfluorinated chain: N-nitroso-3-hydroxybutyl-4,4,4-trifluorobutylamine (3-OH-NDBA-F3) and N-nitroso-3-carboxypropyl-4,4,4-trifluorobutylamine (BCPN-F3) were excreted as main metabolites. Our results on metabolism together with the available data on carcinogenicity of the compounds in the rat strongly support the hypothesis that omega-oxidation of one butyl-chain is a prerequisite for the induction of urinary bladder tumors with NDBA. For the induction of liver tumors, alpha-C-hydroxylation appears to be the crucial event.

Animals↗
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

Carcinogenic N-nitroso compounds and their environmental significance.

A short review is given on the potent and organ-specific carcinogenic effects of N-nitroso compounds. Like many other chemical carcinogens, nitrosamino compounds require activation in vivo via enzymatic alpha-hydroxylation to form alkylating agents as ultimate carcinogens. Since no epidemiological data in man are available, extrapolation of animal data to man are important as well as dose-response studies in risk evaluations. Important aspects of these problems are presented. Finally the environmental impact of N-nitroso compounds is summarized.

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

The carcinogenic effect of bis-(2-oxopropyl)-nitrosamine on Sprague-Dawley rats.

Sprague-Dawley rats received subcutaneous injections of bis-2-oxopropyl)-nitrosamine (BOPN) once weekly for life. The animals developed mainly papillomas and squamous cell carcinomas of the nasal cavity, follicle cell carcinomas of the thyroid gland and papillomas and transitional cell carcinomas of renal pelvis, ureter and urinary bladder. The tumour incidence was 100% in all the 3 treated groups. Survival time, tumour latency and multiplicity showed dose dependency.

Animals↗
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↗
PubMed1984

Effects of fluorination on in-vitro metabolism and biological activity of N-nitrosodialkylamines.

Substitution of N-nitrosodialkylamines with fluorine at specific sites inhibits oxidative metabolism at the respective carbon atoms. The results of in-vitro metabolism studies with N-nitrosodiethylamine (NDEA), N-nitrosodibutylamine (NDBA) and their fluorinated analogues, N-nitroso-2,2,2-trifluoroethyl-ethylamine (NDEA-F3), N-nitroso-bis(2,2,2-trifluoroethyl)amine (NDEA-F6), N-nitroso-4,4,4-trifluorobutyl-butylamine (NDBA-F3), N-nitroso-bis(4,4,4-trifluo-robutyl)amine (NDBA-F6) and N-nitroso-bis(2,2,3,3,4,4,4-heptafluorobutyl)amine (NDBA-F14), showed effects of fluorination on biotransformation which can explain results of carcinogenicity and mutagenicity experiments; NDEA-F6 and NDBA-F14 were practically not metabolized by microsomal fractions, even though no decrease in binding affinity to cytochrome P450 was observed. Both compounds were not biologically active and were exhaled unchanged in high proportions after oral administration to the rat. Biologically active analogues, NDEA, NDBA, NDBA-F3 and NDBA-F6, were found to be dealkylated at the unfluorinated alkyl chains and, to a lesser extent, at the omega-fluorinated alkyl chains. Detection of corresponding alcohols as hydrolysis products confirmed the generation of electrophilic intermediates by alpha-C-hydroxylation. However, trifluorethanol was detected only in very small proportions from dealkylation of NDEA-F3, although dealkylation occurred almost exclusively at the unfluorinated site.

Animals↗
PubMed1984

Biological monitoring in the metal working industry.

N-Nitrosodiethanolamine (NDELA) is a strong carcinogen in animal experiments. Its occurrence in cutting and grinding fluids represents a major risk for workers who come into contact with those compounds. But until now it was not possible to describe the extent of N-nitrosodiethanolamine exposure at the workplace. Since 60-90% of N-nitrosodiethanolamine given by oral, intravenous, epicutaneous or intratracheal application in rat experiments is excreted unchanged in the urine, N-nitrosodiethanolamine should be found in the urine of workers in the metal working industry. Analyses of grinding fluids containing di- and triethanolamine in combination with up to 30% nitrite showed concentrations of up to 593 mg/kg N-nitrosodiethanolamine in the original, concentrated fluid and up to 90 mg/kg in ready-to-use emulsions. In preliminary investigations, it was also found in the urines of metal grinders: of 264 urines analysed, 166 showed positive results (greater than 0.5 micrograms/kg) with levels up to 103 micrograms/kg N-nitrosodiethanolamine. These results indicate that workers' exposure to NDELA can be monitored by urine analysis.

Air Pollutants, Occupational↗
PubMed1983

Nitrosamine metabolism in kwashiorkor rats.

The in vitro metabolism of nitrosodimethylamine (NDMA) was studied in liver tissue obtained from male weanling kwashiorkor wistar rats. The elimination of this compound and that of nitrosomorpholine (NMOR) from the blood, after a single intravenous dose, was also investigated. N-demethylase activity in liver microsomes of the test animals was not significantly different from that of the controls although the activity of this enzyme per gram wet liver tissue was considerably reduced in the model animals. On the other hand, the glutathione (GSH) content in liver cytosol of the kwashiorkor animals was much higher than that of the controls. The elimination of NDMA and NMOR from the blood of the experimental animals over 8 hr following i.v. administration of the carcinogens, showed that the clearance rate of each nitrosamine was significantly lower in the kwashiorkor rats.

Animals↗
PubMed1983

Carcinogenic effect of nitrosomorpholine administered in the drinking water to Syrian golden hamsters.

The long term carcinogenic effect of nitrosomorpholine (NM) was tested in Syrian golden hamsters (Mesocricetus auratus W.). Groups of 30 females and 30 males were given 0.010%, 0.005% and 0.001% NM in their drinking water. The animals developed neoplasms in the larynx, and trachea (papillary polyps, papillomas and epidermoid carcinomas) and in the liver (hepatocellular adenomas and carcinomas). In addition to these, cholangiocellular and endothelial liver tumours were observed. The overall tumour frequency was dose dependent.

Animals↗