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Biomedical subjects

R Preussmann

Publications and source records attributed to R Preussmann.

At least 145 records · Page 8Linked to original sources
PubMed1979

Carcinogenic N-nitrosodimethylamine as a contamination in drugs containing 4-dimethylamino-2,3-dimethyl-1-phenyl-3-pyrazolin-5-one (amidopyrine, aminophenazone).

A total of 68 commercially available drugs containing amidopyrine were investigated for contamination with the strong carcinogen N-nitrosodimethylamine (NDMA). All samples contained varying amounts of NDMA. About half of the drugs contained 1--10 micrograms/kg, 40% contained 11--50 micrograms/kg, 7% contained 51--10 micrograms/kg and one sample had 370 micrograms/kg. NDMA-contents in batches of pure amidopyrine that had been utilized for preparation of drugs were higher than those in the respective drugs: about one-third was in the range of 20--50 micrograms/kg, one-third had 51--100 micrograms/kg, and one-third was above 100 micrograms/kg. There was, however, no correlation between NDMA-contents of batches of the pure substance and NDMA-contents of the drugs prepared from these batched. NDMA concentrations in the samples were inhomogenously distributed. It could be demonstrated that amidopyrine in substance reacts extremely rapidly with nitrogen oxides from the air to form NDMA. Ascorbic acid, which prevents nitrosamine formation in aqueous-acidic solution, under these conditions had no protective effect.

Aminopyrine↗
PubMed1979

Carcinogenicity and mutagenicity testing of three isomeric N-nitroso-N-methylaminopyridines in rats.

Three isomeric N-nitroso-N-methylaminopyridines (NMPY's) were investigated for their carcinogenic activity in BD VI rats following chronic oral administration and for their mutagenic properties in the Ames assay. On the basis of postulated reaction mechanisms, it was expected that 3-NMPY would react differently than 2- and 4-NMPY, but the outcome of both carcinogenicity and mutagenicity assays did not show this. 2-NMPY induced tumors of the esophagus and possibly also of the liver; 3- and 4-NMPY had no activity as carcinogens under the experimental conditions used. Similarly, high concentrations of 2-NMPY showed mutagenic activity toward Salmonella typhimurium TA100, whereas 3- and 4-NMPY did not have such an effect.

Aminopyridines↗
PubMed1978

Induction of gastric tumors in BD-VI rats by single application of N-methyl-N'-nitro-N-nitrosoguanidine in dimethylsulfoxide (DMSO).

The oral acute LD50 of N-Methyl-N'-Nitro-N-Nitrosoguanidine (MNNG) in a 10% aqueous solution of dimethylsulfoxide (DMSO) amounted to approximately 90 mg/kg. After single oral application of 50 mg/kg (group I), 75 mg/kg (group II) and 100 mg/kg (group III) of MNNG in a 10% aqueous solution of DMSO, generalized papillomatoses of the forestomach were found in all BD-VI rats after a test period of 500 days. Squamous cell carcinomas could be detected in 7/24 (21%) rats in group I, in 12/26 (46%) in group II and in 7/23 (30%) in group III). Benign adenomatous dysplasia of the glandular stomach was diagnosed in 2 rats (8%) of group I, in 1 animal (4%) of group II and in 12 rats (52%) of group III. Adenocarcinomas of the glandular stomach were induced in 1 animal (4%) of both group I and II and in 8 rats (35%) of group III. 20--30% of the animals treated with MNNG also showed degenerative cystic alterations in the liver with bile-duct proliferation.

Animals↗
PubMed1978

Toxicological aspects of food safety - carcinogenicity and mutagenicity.

One major problem in the evaluation of potential carcinogenic food additives and contaminants is that of thresholds or, better, of "no-adverse-effect-levels". Arguments in favour of the postulated "irreversibility" of carcinogenic effects are based on dose-response studies, single-dose and multi-generation experiments as well as on the concept of somatic mutation as the first steps in carcinogenesis with subsequent transmittance of induced defects during cell replication. The problem of extrapolation of results of animal experiments using high doses to low exposure and low incidences in man is not yet solved satisfactorily. Possible practical consequences include zero-tolerance, acceptable thresholds at low risk and safety factors. Acceptable intakes never should be considered constants but should be changeable as soon as new facts in regard to the safety evaluation are available. Several systems of short-term tests as screening methods are based on mutagenicity tests and offer many advantages. Their critical evaluation is of utmost importance. Examples of some relevant problems to be discussed include nitrosamines in food products and their formation from ingested precursors; the migration of vinyl chloride from PVC food packing material; the occurrence of low levels of chloroform in drinking water.

Animals↗
PubMed1978

Carcinogenicity of N-nitrosoephedrine in rats.

N-nitrosoephedrine was administered orally to 32 male Srague--Dawley rats at doses of 120 mg/kg body wt. twice weekly. Of the treated animals, 50% died with preneoplastic and malignant lesions mainly in the liver, lung and forestomach. The median time of death of tumor bearing animals was 522 days after the beginning of the experiment. The observation of hyperkeratosis, papillomas, and 1 squamous cell carcinoma of the forestomach suggests that the compound not only exhibits systemic effects but is probably also a weak local carcinogen.

Administration, Oral↗
PubMed1978

Urinary excretion of N-nitrosodiethanolamine administered orally to rats.

N-Nitrosodiethanolamine (NDE1A) was administered by gavage to male rats in single doses of 1000, 500 and 100 mg/kg body wt. More than 70% of a given dose was excreted unchanged in the urine, essentially within the first 24 h after exposure. This high excretion rate might explain the relatively low carcinogenic potential of NDE1A, and also offers a possible method of monitoring exposure to this compound under occupational and/or environmental conditions.

Administration, Oral↗
PubMed1978

[Environmental carcinogens: mechanisms of action and occurrence. Some aspects (author's transl)].

New aspects on the mechanism of action of known environmental carcinogens are described. These compounds are not active as such, but are bioactivated in the mammalian metabolism via chemically reactive intermediates to electrophilic reactants, forming with information-bearing biopolymeres covalent bonds. This change in the genetic code is in agreement with the mutation hypothesis of carcinogenesis. Aflatoxin B1, N-nitroso compounds and benzo(a)pyrene are taken as examples. "Threshold levels", e.g. no-effect-levels derived from animal experiments with all their inherent limitations, are compared with data from human exposure to benzo(a)pyren, aflatoxine, N-nitroso compounds and vinyl chloride. The difficulties of such risk evaluations are discussed.

Aflatoxins↗
PubMed1978

Volatile and non-volatile N-nitroso compounds in foods and other environmental media.

A further series of cured meat products (meat loaf, liver loaf, bologna) has been investigated for their nitrosamine contents before and after frying. Contents in general were in the low microgram/kg range. An extensive study of nitrosamine contents of various types of cheese has been terminated. Although 45% of all samples showed indications of nitrosamine content, only 12% had concentrations of greater than 1 microgram/kg (1-6 microgram/kg); NDMA was more often found in hard and in soft cheese, than in other types. Analytical grade dichloromethane and chloroform have been found to contain N-nitrosomorpholine in concentrations of 2-376 microgram/kg (27-40% of the samples). The origin of the contamination is not known at present. A survey of the nitrosamine content of animal diets showed that 80% of all samples had contents of greater than 1 microgram/kg. NDMA (up to 79 microgram/kg) and NPYR (up to 26 microgram/kg) were most often found. There are indications that fish meal is the main source of contamination. Drugs containing amidopyrine (AP) have invariably been found to contain NDMA. Concentrations varied within wide limits (less than 10 microgram/kg - 371 microgram/kg). No correlation has been found between samples of pure AP and NDMA contents of drugs in which pure AP had been incorporated. Also, strong variations in NDMA contents have been found within individual batches, probably caused by the high reactivity of AP towards nitrogen oxides. The determination of N-nitroso-3-hydroxypyrrolidine has been further improved and a further series of food analyses for contents of this nitrosamine has been carried out. About 30% of the samples were positive with contents below or near 10 microgram/kg. An analytical method for determination of N-nitrosamino acids has been worked out. The method consists of a series of extraction, liquid/liquid distribution and chromatography steps; N-nitrosoamino acids are finally determined, after trimethylsilylation, with a TEA detector. First results on the occurrence of these compounds in various cured meat products are reported.

Animal Feed↗
PubMed1977

Occurrence of volatile N-nitrosamines in animal diets.

46 samples of commercially available diets for experimental animals have been analysed for their content of volatile N-nitrosamines by use of a nitrosamine-specific detection method (TEA-detector). 80% of all analysed samples were positive for N-nitrosodimethylamine with a maximum content of 79 ppb (microgram/kg) found in one sample. 59% of the samples were positive for N-nitrosopyrrolidine with 26 ppb as highest content. In 3 samples trace quantities (less than 1 ppb) of N-nitrosodiethylamine were found, one sample contained N-nitrosopiperidine (4 ppb).

Animal Feed↗
PubMed1977

Carcinogenicity of N-nitrosopyrrolidine: dose-response study in rats.

Results from a dose-response study in rats are reported, in which daily oral doses of 10, 3, 1, and 0.3 mg/kg bodyweight/day respectively were administered. The three highest dose levels resulted in incidences of liver cancer of 46, 84, and 32% respectively. In the lowest dose group (0.3 mg/kg/day) no statistically significant increase in tumor rate compared to untreated controls was found.

Animals↗
PubMed1976

Selective detection of N-nitrosamines by gas chromatography using a modified microelectrolytic conductivity detector in the pyrolytic mode.

The pyrolysis of nitrosamines in a modified Hall microelectrolytic conductivity system provides the basis for a highly selective and sensitive determination method. Under the conditions specified, the response of this detector system to nitrosamines is at least 10(7) times greater than that for n-hexane. The influence of several operational parameters on the response of the detector to nitrosamines was studied. For open-chain nitrosamines, the detection limit is 50 pg and the response is linear up to at least 200 ng.

Chromatography, Gas↗
PubMed1976

[Differing carcinogenic activity in BD-rats of 1-phenyl- and 1-(pyridyl-3)-3,3-diethyltriazene after single doses on 1., 10. or 30. day of life (author's transl)].

1-Phenyl- and 1-(pyridyl-3)-3,3-diethyltriazene have been investigated for carcinogenic effects in BD-rats after subcutaneous injection of a single dose of 50 mg of the compounds on day 1, 10, or 30 of life. The phenyl derivative showed a lower carcinogenic activity in comparison with the pyridyltriazene. Predominantly neurogenic tumors were observed. These were seen much more on treatment on day 1 or 10 of life than on treatment on day 30. The results confirm that the nervous system of rats is a target organ predominantly during early postnatal life.

Age Factors↗