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Biomedical subjects

B Spiegelhalder

Publications and source records attributed to B Spiegelhalder.

At least 73 records · Page 4Linked to original sources

Subcellular fractions of rat organs contain nitroreductases which reduce N-nitrodimethylamine to N-nitrosodimethylamine.

The nasal carcinogen N-nitrodimethylamine was reduced to its N-nitroso analogue N-nitrosodimethylamine in vivo. Liver-soluble fraction and brain mitochondria contained enzymes capable of reducing this compound. The activity was only partly inhibited by oxygen; NADPH and NADH served as cosubstrates. N-Nitromethylamine is also carcinogenic and was reduced by liver cytoplasm to a protein binding species (methyldiazohydroxide?).

Animals↗

Tobacco-specific nitrosamines in commercial cigarettes: possibilities for reducing exposure.

Tobacco-specific nitrosamines (TSNA) are powerful carcinogens found in tobacco and tobacco smoke in relatively high concentrations. Tar delivery, which is generally accepted as an index for the carcinogenic potential of cigarette smoke, must be declared in most European countries. In this investigation of more than 170 types of commercial cigarettes from several European countries and the USA, no correlation was observed between tar delivery and mainstream smoke concentration of N'-nitrosonornicotine (NNN) and 4-(N-nitrosomethylamino)-1-(3-pyridyl)-1-butanone (NNK). Therefore, although crucial, tar delivery alone is not a sufficient index for the carcinogenic potential of cigarette smoke. It is proposed that TSNA concentrations be determined for characterization of the carcinogenic potential of cigarettes with low and ultra-low tar yields and that these be declared by an additional and adequate parameter. The mainstream smoke concentrations of NNN and NNK are given by the amounts of preformed compounds in tobacco, which is dependent on the nitrate content of the tobacco and the tobacco type. A further important determinant of the exposure of smokers to TSNA is the total volume drawn through a cigarette while smoking, which is dependent on puff volume and puff frequency and which directly influences TSNA transfer. Smokers inhale higher volumes when smoking low-nicotine cigarettes, so that low NNN:nicotine and NNK:nicotine ratios result in decreased exposure to TSNA. Reduction of exposure to TSNA can be achieved by selecting tobaccos with low levels of preformed TSNA (low nitrate content, small amounts of burley tobaccos and stems) and by manufacturing cigarettes with low NNN:nicotine and NNK:nicotine ratios.

Carcinogens↗

New sulfenamide accelerators derived from 'safe' amines for the rubber and tyre industry.

A reduction of the high exposures to N-nitrosamines in the rubber and tyre industry is possible using the concept of 'safe' amines, in which vulcanization accelerators contain amine moieties that are both difficult to nitrosate and, on nitrosation, yield noncarcinogenic N-nitroso compounds. The toxicological and technological properties of more than 50 benzothiazole sulfenamides derived from 'safe' amines have been evaluated. Some of the new compounds show excellent vulcanization properties and seem suitable as replacements for traditional accelerators in this class of compounds.

Benzothiazoles↗

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↗

An oestradiol-linked nitrosourea and site-directed chemotherapy in mammary carcinoma.

The half-life, peak concentration, peak accumulation and tissue availability of the DNA-crosslinking nitrosourea 1-(2-chloroethyl)-1-nitrosocarbamoyl-L-alanine (CNC-alanine) and its oestradiol-linked derivate (CNC-alanine-oestradiol-17-ester) were studied in liver, lung, spleen, uterus and mammary carcinomas in female Sprague-Dawley rats with chemically induced mammary carcinomas. Compared with CNC-alanine, the ester had a longer half-life, higher peak concentration, increased peak accumulation and enhanced tissue availability in all tissues. In oestradiol receptor positive mammary carcinomas, the oestradiol-linked drug showed a 2 times higher peak concentration, a 5 times longer half-life, a 10 times increased peak accumulation and a 20 times greater tissue availability compared with CNC-alanine. Oestradiol-linked nitrosoureas may offer new perspectives for site-directed chemotherapy of oestradiol receptor positive breast cancer.

Alanine↗

Inhalation carcinogenesis of N-nitrosomorpholine (NMOR) in rats and hamsters.

N-Nitrosomorpholine (NMOR) is a potent liver carcinogen in rats when administered orally. NMOR was found in the atmosphere at working places in the rubber industry in concentrations up to several hundred micrograms/m3. It can be assumed that NMOR inhalation may play a role in human carcinogenesis. Therefore an inhalation study was carried out to evaluate the carcinogenic potency of NMOR vapors in rats and hamsters. The concentration of volatile NMOR in the inhalation chamber was continuously determined with a Thermal Energy Analyzer. The rats received 29 administrations (4th/day, 5 days/week; mean inhaled daily dose: 130 micrograms/animal; total dose: 15 mg/kg bodyweight). The hamsters inhaled a total of 38 mg/kg of NMOR (21 applications, daily dose 260 micrograms/animal). In rats 4 carcinomas and 5 neoplastic nodules of the liver, 1 neuroblastoma and 1 mucoepidermoidal carcinoma of the nose, and 1 carcinoma of the thyroid gland were induced. In treated hamsters 4 carcinomas of the liver, 2 neurogenic sarcomas of the nasal region, and 5 papillomas of the trachea were found. None of these tumors were observed in control rats and control hamsters.

Administration, Inhalation↗

Investigations on the origin of tobacco-specific nitrosamines in mainstream smoke of cigarettes.

The origin of tobacco-specific nitrosamines (TSNA) in mainstream smoke and the possible contribution of synthesis during the smoking procedure was investigated. Addition of the nitrosamine precursors nitrate and nicotine to the tobacco prior to smoking did not change the mainstream smoke concentrations of N'-nitrosonornicotine (NNN) and 4-(methyl-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK), whereas the mainstream smoke concentration of N'-nitrosoanabasine (NAB) and N'-nitrosoanatabine (NAT) increased after spiking the cigarettes with nitrate. Data for TSNA in tobacco and in mainstream smoke and for nitrate in tobacco of commercial cigarettes of the West German market, taken from previous investigations, were used to calculate the mainstream smoke/tobacco ratios for NNN and NNK. These ratios were corrected for ventilation and cigarette length. It is shown that the ratios are constant and neither depend on the nicotine level nor on the nitrate level of the tobacco except for NNK in the nitrate rich dark tobacco type cigarettes. For nonfilter cigarettes the transfer rates of NNN and NNK which had been corrected for ventilation and cigarette length amounted to 23 or 34% respectively. For filter cigarettes a transfer rate of 13% for NNN and 23% for NNK was calculated. Furthermore it is shown that the mainstream smoke/tobacco ratios for NNN and NNK are constant over the whole length of the cigarettes except for NNK in dark tobacco type cigarettes. The results of this investigation indicate that pyrosynthesis of NNN does not occur and that it is very unlikely for NNK at least for lower nitrate levels. Thus with few exceptions the TSNA burden of smokers is predominantly influenced by the amount of preformed NNN and NNK in tobacco.

Carcinogens↗

A new comprehensive technique of catheterisation, blood sampling, sample preparation and sample analysis by means of high-pressure liquid chromatography for pharmacokinetic studies with estradiol-linked nitrosoureas and their metabolites.

Estradiol-linked nitrosoureas are offering new perspectives in the antineoplastic chemotherapy of estradiol-receptor positive mammary carcinomas. In such a molecule estradiol has the function of a carrier which brings about a specific accumulation of the anticancer drug in estradiol-receptor containing tumor cells. However, there is only little knowledge about the pharmacokinetic behavior of this new group of anticancer agents. For that reason a new comprehensive technique of catheterisation, blood sampling, sample preparation and sample analysis with high-pressure liquid chromatography (HPLC) for preclinical pharmacokinetic studies with estradiol-linked nitrosoureas and their metabolites has been developed. N-(2-Chloroethyl)-N-nitroso-carbamoyl-L-alanine-estradiol-17-ester (CNC-alanine-estradiol-17-ester) and N-(2-chloroethyl)-N-nitroso-carbamoyl-L-alanine (CNC-alanine) were used as test compounds. The drugs were tested in female Sprague-Dawley rats with chemically induced mammary carcinomas. The laboratory animals were supplied with two catheters prior to the pharmacokinetic experiments. The blood samples were drawn from the vena cava catheter after the drug had been applied through a vena jugularis catheter. The compounds were extracted from plasma with C18 silicagel reversed phase cartridges. The clean-up technique delivered clear samples only slightly contaminated with the biological matrix. The recovery from plasma was 75 +/- 5% for the hormone-linked CNC-alanine-estradiol-17-ester and 70 +/- 5% for the unlinked CNC-alanine. The analysis was carried out by means of HPLC.(ABSTRACT TRUNCATED AT 250 WORDS)

Alanine↗

Tobacco-specific nitrosamines in European and USA cigarettes.

More than 170 types of commercial cigarettes from several European countries and the USA were analyzed for tobacco-specific nitrosamines (TSNA) in tobacco and mainstream smoke as well as for nitrate in tobacco. The cigarettes included filter and nonfilter cigarettes with different tar and nicotine yields. The observed range for N'-nitrosonornicotine (NNN) was from 4 to 1353 ng/cigarette in mainstream smoke and from 45 to 12454 ng/cigarette in tobacco. For 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) the values were between not detected (less than 4 ng/cigarette) and 1749 ng/cigarette in mainstream smoke and between not detected (less than 50 ng/cigarette) and 10745 ng/cigarette in tobacco. Nitrate levels ranged from 0.6 to 19.4 mg/cigarette. The TSNA levels for the cigarettes from the different countries investigated were in a similar range with the exception of few individual brands. The results demonstrated that there is no correlation between TSNA and tar deliveries in mainstream smoke. The TSNA deliveries in mainstream smoke depend on the amount or preformed TSNA in the actual tobacco composition, which is influenced by the nitrate level of the tobacco and the tobacco type. According to these results the tar delivery, although crucial, is not a sufficient index for the biological activity and the carcinogenic potential of cigarette smoke. Reduction of TSNA exposure can be achieved by selecting tobaccos with low levels of preformed TSNA in tobacco, which means a low nitrate content and reduction of the amount of Burley tobaccos and stems in blended cigarettes.

Chromatography, Gas↗

New estradiol-linked nitrosoureas: can the pharmacokinetic properties help to explain the pharmacodynamic activities?

The pharmacokinetics of 1-(2-chloroethyl)-1-nitrosocarbamoyl-L-alanine-estradiol-17-ester (CNC-alanine-estradiol-17-ester) a new estradiol-linked anticancer drug and the unlinked DNA-crosslinking agent 1-(2-chloroethyl)-1-nitrosocarbamoyl-L-alanine (CNC-alanine) have been studied in methylnitrosourea-induced female Sprague-Dawley rats after equimolar intravenous and oral administration. In comparison with the unlinked single agent, the CNC-alanine-estradiol-17-ester showed a 3-fold longer halflife in plasma and a three times larger volume of distribution. The distribution after intravenous administration was nearly three times faster. The absorption after peroral administration was likewise two times faster. The bioavailability of the estradiol-linked drug was determined to be 52%. After application of CNC-alanine-estradiol-17-ester the cytostatic metabolite CNC-alanine was found, indicating the cleavage of the ester bond. CNC-alanine generated from CNC-alanine-estradiol-17-ester showed a 50% longer halflife than when applied directly. The results indicate that linking 2-chloroethyl-nitrosoureas to estradiol can result in new anticancer agents with modified properties in comparison to the unlinked single agent. The higher antineoplastic activity of the hormone-linked drug can mainly be attributed to differences in the pharmacokinetic behaviour.

Administration, Oral↗

Trapping of reactive intermediates from the nitrosation of primary amines by a new type of scavenger reagent.

N-Methyl-N-nitrosoethanolamine has been used as a scavenger reagent for the in vitro detection of unstable alkylating intermediates. The nucleophilic hydroxy group of the scavenger reagent binds with electrophiles to yield chemically stable ethers, which are analysed using gas-liquid chromatography with the highly sensitive and specific chemiluminescence detector, the thermal energy analyser. In contrast to other test systems for the in vitro detection of alkylating species, non-physiological reaction conditions are avoided and direct conclusions on the structure of the reaction products can be drawn. This test system is shown to be effective for investigating the alkylating capacity of primary amines on nitrosation. From methylamine to butylamine the yield of alkylated scavenger is low, decreasing with elongation of the carbon chain. In contrast, nitrosation of aniline, benzylamine or phenylethylamine leads to much greater yields of alkylated scavenger. These compounds should therefore be included in risk assessment of endogenous nitrosation of primary amine precursors.

Alkylation↗

A sensitive analytical procedure for the detection of N-nitrosamides via their alkylating activity.

Based on a method for trapping direct-alkylating intermediates with scavenger reagents possessing a nucleophilic side-chain and an N-nitroso group as a marker, a sensitive test system for the detection of N-nitrosamides and related compounds has been developed. N-Nitroso-N-tert-butylglycine is an effective scavenger reagent for this purpose. It reacts readily with diazoalkanes released from N-nitrosamides on treatment with alkali to form the corresponding esters which are analysed by gas-liquid chromatography using a thermal energy analyser. The method is easy to perform and specific for N-nitroso compounds that decompose to non-polar diazoalkanes on treatment with alkali. A determination limit of 2 ng solids/sample was established for methylated NTBG formed from N-methyl-N-nitro-sourea following treatment with alkali.

Alkylation↗

Effect of long-term inhalation of N-nitroso-dimethylamine (NDMA) and SO2/NOx in rats.

This report focusses on preliminary results of a long-term inhalation assay with N-nitroso-dimethylamine (NDMA) at low concentrations. Chronic inhalation of 1 ppm of NDMA (4 h/day, 5 days/week) was found to be toxic in rats and diminished life expectancy by about 8 months compared to the control group. Mostly tumors of the nasal region (25/36) were observed. Inhalation of 0.2 ppm of NDMA lead to a high tumor yield in rats (20/36). At a concentration of 0.04 ppm (= 0.12 mg/m3 in air) 3 tumors of the nasal region have been found until now. In addition, a combined inhalation study of other air pollutants SO2 or NOx together with NDMA at the 0.2 ppm level is being performed. Tumors of the nasal region have been observed in the groups with SO2 + NDMA and NOx + NDMA as well as with NDMA alone. Differences in tumor response of the groups treated with NDMA alone or in combination with SO2/NOx cannot be assessed yet. The additional treatment with the air pollutants SO2 or NOx has not affected the body weight gain or any other observable parameters of the life quality of the rats.

Administration, Inhalation↗

Tobacco-specific nitrosamines in mainstream smoke of West German cigarettes--tar alone is not a sufficient index for the carcinogenic potential of cigarette smoke.

Fifty-five types of commercial cigarettes on the West German market were analyzed for tobacco-specific nitrosamines (TSNA) in mainstream smoke. The cigarettes included filter and nonfilter cigarettes with very high, high, medium, low and ultra-low tar and nicotine yields. The observed range for N'-nitrosonornicotine was from 5 to 625 ng/cigarette and for 4-(methylnitrosoamino)-1-(3-pyridyl)-1-butanone from not detected (less than 4 ng/cigarette) to 432 ng/cigarette. The highest TSNA values were obtained for nonfilter cigarettes made of dark tobaccos and the lowest values for nonfilter Oriental-type cigarettes. Relatively high TSNA yields were also observed in filter cigarettes with moderate and lower tar deliveries. The results demonstrated that there is no correlation between TSNA and tar deliveries in mainstrain smoke. The TSNA deliveries in mainstream smoke depended on the actual tobacco composition. According to these results the tar delivery, although crucial, is not a sufficient index for the biological activity and the carcinogenic potential of cigarette smoke.

Filtration↗

Urinary excretion of nitrate, nitrite and N-nitroso compounds in Schistosomiasis and bilharzia bladder cancer patients.

Saliva and 24-h urine samples were collected from male Schistosomiasis (bilharzia) patients with S. haematobium infection and possible concurrent S. mansoni infection without diagnosed bladder cancer (n = 27), bilharzia patients with diagnosed bladder cancer (n = 23) as well as a comparative control group (n = 27) of healthy Egyptian volunteers with no current bilharzia infection and/or bacterial urinary tract infections from the Nile Delta area of Egypt. Saliva samples were analysed for the presence of nitrate and nitrite; urine samples were analysed for the presence of nitrate, nitrite, volatile and non-volatile N-nitroso compounds. Bilharzia patients prior to, and after, diagnosed bladder cancer regularly excreted free nitrite as well as volatile nitrosamines (N-nitrosodimethylamine, N-nitrosodiethylamine, N-nitrosopiperidine and N-nitrosopyrrolidine) in addition to which elevated concentrations of non-volatile N-nitrosamino acids (N-nitrosoproline, N-nitrososarcosine, N-nitrosothiazolidine-4-carboxylic acid and its 2-methyl derivative) were also present. Total urinary excretion of volatile N-nitroso compounds (0.32 +/- 0.64 micrograms/day; mean +/- SD) and non-volatile N-nitroso compounds (31.20 +/- 22.07 micrograms/day) was observed in the Egyptian control group. Significantly higher concentrations were found in bilharzia patients: 3.47 +/- 6.42 (P less than 0.05) and 62.91 +/- 21.96 (P less than 0.05); as well as in bilharzia patients with diagnosed bladder cancer: 1.71 +/- 1.96 (P less than 0.02) and 44.94 +/- 7.31 respectively. Free nitrite was found in the urine of two volunteers in the Egyptian control group (1.7 and 3.0 micrograms/day), urinary nitrite was significantly increased in bilharzia patients (5.18 +/- 9.11 micrograms/day, P less than 0.02) and in bladder cancer patients (1.75 +/- 2.81 micrograms/day, P less than 0.05). Nitrate concentrations were elevated from 139.3 +/- 82.2 in the control group to 143.6 +/- 136.3 and 175 +/- 190 in the bilharzia and bladder cancer groups respectively. These results indicate that significant in vivo formation of nitrite and volatile N-nitroso compounds occurs in the urinary bladder of bilharzia patients and this may be an oetiological factor in the induction of bilharzial bladder cancer associated with S. haematobium infection.

Adult↗

Influence of smoking parameters on the delivery of tobacco-specific nitrosamines in cigarette smoke--a contribution to relative risk evaluation.

The influence of the smoking parameters (puff profile, puff duration, puff volume, puff frequency) on the delivery of tobacco-specific nitrosamines (TSNAs) in mainstream smoke was investigated for six different cigarette brands, including filter cigarettes with very low to medium smoke yields and non-filter cigarettes with high and very high smoke yields. The puff profile did not influence the TSNA yields. The puff duration also had no remarkable influence on the TSNA delivery with the exception of a non-filter cigarette made of dark tobaccos. The puff volume and the puff frequency significantly influenced the TSNA yields. Increasing puff volume and frequency resulted in increasing TSNA values. The total volume drawn through a cigarette was calculated. The dependency of the TSNA delivery on the total volume was almost linear at least up to a total volume of approximately 500 ml/cigarette. The TSNA yield was the same for the same total volume no matter whether the total volume was due to a changing puff volume or a changing puff frequency. The total volume drawn through a cigarette is the main responsible factor for the TSNA delivery in mainstream smoke. Total volume data from smokers of low- and medium-tar cigarettes are used to calculate TSNA intake. The different smoking behaviour observed for smokers of low-tar and low-nicotine cigarettes as compared to standard smoking conditions is discussed with respect to the TSNA dependency on smoke parameters.

Humans↗

Preformed tobacco-specific nitrosamines in tobacco--role of nitrate and influence of tobacco type.

Fifty-five types of commercial cigarettes on the open market in the FRG and several samples of pure tobacco types were analyzed for preformed tobacco-specific nitrosamines (TSNA) and nitrate in the tobacco. For the cigarette tobaccos the observed range for N'-nitrosonornicotine (NNN) was 50-5316 ng/cigarette and for 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) from not detected (less than 50 ng/cigarette) to 1120 ng/cigarette. Nitrate levels ranged from 0.6 to 14.4 mg/cigarette. The highest TSNA values were obtained for cigarettes made of dark tobaccos and the lowest for Oriental type cigarettes. The results demonstrated that there is a correlation between TSNA and nitrate levels. The tobacco type is another important influencing factor, especially for NNK. In Virginia tobaccos unexpectedly high NNK values were observed. For the samples of the pure tobacco types, NNN levels ranged from 20 to 8850 p.p.b. and NNK levels from not detected (less than 50 p.p.b.) to 1400 p.p.b. The observed range for nitrate was from traces (less than 0.005%) to 4.1%. Pure Oriental tobaccos which are low in nitrate showed the lowest TSNA concentrations. In the high nitrate Burley tobaccos the highest TSNA concentrations could be determined. Virginia tobaccos which show a low nitrate content are low in NNN but rather high NNK concentrations were found. The results from these pure tobacco types demonstrate that the nitrate content of the tobacco has a great influence on the TSNA level. However, Virginia tobaccos show higher NNK concentrations than expected according to their low nitrate content.

Chromatography, Gas↗

Environmental exposure to preformed nitroso compounds.

In the human environment, nitrosatable amine precursors to N-nitroso compounds and nitrosating species such as nitrite and oxides of nitrogen are abundant. As a result, the formation of N-nitroso compounds and human exposure to these compounds show a rather complex pattern. The largest known human exposures to exogenous N-nitrosamines occur in the work place. This is particularly evident in the rubber and tyre manufacturing industry and in metal cutting and grinding shops. Nearly all industries which are concerned with the production and/or use of amines have a related nitrosamine problem. Outside the industrial environment, commodities such as cosmetics, pharmaceuticals, rubber and household products, which are either prepared from amines or contain high concentrations of amino compounds, may be subject to contamination by low concentrations of N-nitroso compounds. This contamination may result from the use of contaminated starting materials, in particular amines, or from the formation of N-nitroso compounds during manufacturing processes. A similar problem exists with agricultural chemicals. As our knowledge of the occurrence and formation of N-nitroso compounds in the environment increases, preventive measures can be introduced, particularly in manufacturing industries, to reduce the levels of human exposure to nitrosamines in the work place and to protect the consumer from nitrosamine exposure from household commodities.

Air Pollution↗