Biomedical subjects

M D Reuber

Publications and source records attributed to M D Reuber.

At least 37 records · Page 2Linked to original sources

PubMed1983

Induction of tumors of the esophagus in rats by nitrosomethylalkylamines.

The carcinogenic effectiveness of nitrosomethyl-n-butylamine,-n-hexylamine and -n-heptylamine was compared by administration to F344 rats at various concentrations in drinking water and by gavage in oil. Nitrosomethylbutylamine induced only tumors of the upper gastrointestinal tract, and was very toxic. Nitrosomethylhexylamine was less toxic and induced tumors of the liver and lung, as well as those the upper GI tract, when given by gavage, but only tumors of the GI tract when given in drinking water. In contrast, nitrosomethylheptylamine induced tumors of the liver and lung when given in drinking water or by gavage, but there were tumors of the esophagus only in those rats treated via the drinking water. As measured by the dose needed to produce a given carcinogenic effect, nitrosomethylheptylamine was a weaker carcinogen than the other two nitrosamines, but was not inactive as has been reported previously.

Animals↗

PubMed1983

Analysis and interpretation of data from carcinogenicity and toxicity studies in animals.

Many chemicals are being tested for carcinogenicity and toxicity in animals. Reports are submitted to government agencies in order to evaluate the safety of chemicals. Personnel generally are not trained to carry out such evaluations. There is no particular system that is being used in these evaluations. The purpose of this paper is to describe a system for the evaluation of carcinogenicity and toxicity studies developed over the past several years.

Animals↗

PubMed1983

Carcinogenesis by combinations of N-nitroso compounds in rats.

Five N-nitroso compounds were administered individually or in various combinations to groups of 20 female F344 rats to examine possible additive or synergistic effects on mortality rate and the induction of tumours. Combination of the oesophageal carcinogen dinitroso-2,6-dimethylpiperazine with nitrosodiethylamine, which also induces oesophageal tumours, or with nitrosoethylmethylamine, which induces liver tumours, did not appear to increase tumour incidence. Similarly, combination of nitrosodiethylamine with the bladder carcinogen nitrosomethyldodecylamine did not increase the formation of either bladder or oesophageal tumours compared with the effects of either compound alone, although an additive effect was suggested by a higher incidence of liver tumours after the combined treatment than after treatment with either compound alone. Nitrosomethylurethane, which induces tumours of the forestomach in rats, appeared to enhance the effectiveness of nitrosoethylmethylamine and dinitroso-2,6-dimethylpiperazine in inducing tumours of the oesophagus, and increased the rate of death. Nitrosomethylurethane given, at a somewhat higher dose, in combination with both of these compounds increased the incidence of oesophageal tumours even when the treatment lasted only 4 wk. This evidence suggests that additive or synergistic effects of combinations of N-nitroso compounds at low dose rates can be demonstrated in small groups of rats.

Animals↗

PubMed1983

Carcinogenesis in Fischer rats by nitrosodipropylamine, nitrosodibutylamine and nitrosobis(2-oxopropyl)amine given by gavage.

Nitrosodi-n-propylamine, nitrosodi-n-butylamine and the ketone nitrosobis(2-oxopropyl)amine were administered by gavage to F344 rats at doses of 1 and 2 mmol for 30 weeks. The higher level of nitrosodipropylamine led to death of all the animals with carcinomas of the liver, nasal cavity and esophagus by the 40th week. At the lower level the rats died of these tumors but survived to week 60. In contrast, 1 mmol of nitrosobis(2-oxopropyl)amine did not cause death of all the animals until week 95, and fewer than half of them had liver carcinomas; none had tumors of the esophagus or nasal cavity. Nitrosodi-n-butylamine was a much weaker carcinogen than nitrosodipropylamine, since 80% of the rats given 2 mmol survived until week 83. Although, with this compound, the lifespan of the rats was not greatly shortened, a large variety of tumors was induced; about 60% of the animals had liver carcinomas, 50% forestomach carcinomas and 35% transitional cell carcinomas of the urinary bladder.

Animals↗

PubMed1983

The effect of substituents in the aromatic ring on carcinogenicity of N-nitrosomethylaniline in F344 rats.

N-Nitroso-N-methylaniline (NMA) and N-nitroso-N-methyl-4-fluoroaniline (p-F-NMA), both non-mutagenic in Salmonella typhimurium and N-nitroso-N-methyl-4-nitroaniline (p-NO2-NMA), a potent mutagen, were tested for carcinogenicity in F344 rats. NMA was shown to induce a high level of tumors in the upper gastrointestinal tract, particularly in the esophagus. Male rats treated with NMA died with tumors at a slightly higher rate than females, although the final tumor yield was the same. Most of the rats treated with p-F-NMA also developed tumors of the esophagus, but they died less rapidly than the NMA treated rats, indicating that p-F-NMA is a slightly weaker carcinogen than NMA. The powerful, directly acting mutagen, p-NO2-NMA did not appear to induce tumors at all since its tumor spectrum was essentially identical to that of the untreated control rats. Thus, the carcinogenic activities of NMA and its substituted analogs do not appear to correlate with bacterial mutagenesis assays. Additionally, NMA, p-F-NMA and N-nitroso-N-methyl-4-bromoaniline, the last a strong mutagen in S. typhimurium, were shown not to induce sister chromatid exchanges in CHO cells and in a clone of a CHO:liver cell hybrid which had previously been shown to be sensitive to chemical agents which require metabolic activation.

Aflatoxin B1↗

PubMed1983

Carcinogenicity of methylated nitrosopiperazines in rats and hamsters.

A comparison has been made of the carcinogenic activities of dinitroso-2,6-dimethylpiperazine (Me2DNP) and nitroso-3-4,5-trimethylpiperazine (Me3NP) in F344 rats and Syrian golden hamsters. The compounds were administered in drinking water to the rats and by gavage to the hamsters, at similar dose rates. As measured by the increased rate of mortality from tumors induced, Me2DNP was a more potent carcinogen in rats than Me3NP; Me2DNP induced mainly esophageal tumors, while Me3NP induced tumors of the nasal cavity, but no esophageal tumors. In contrast, in Syrian hamsters, by the same criterion, Me3NP was at least as potent as Me2DNP. Me3NP was more potent in hamsters than Me2DNP as measured by the number and multiplicity of tumors induced. The most numerous tumors induced by both compounds in hamsters were papillomas of the forestomach, but in addition Me3NP induced a high incidence of lung tumors. A small number of hamsters treated with either compound had liver angiosarcomas. Two hamsters given Me3NP had papillomas of the esophagus, a highly unusual tumor in Syrian hamsters.

Animals↗

PubMed1983

Carcinogenesis in F344 rats by N-nitrosomethyl-n-propylamine derivatives.

The carcinogenicity of N-nitrosomethyl-n-propylamine and five of its derivatives, including N-nitrosomethyl-n-butylamine, was compared by oral administration of the compounds to inbred F344 rats. N-Nitromethyl-n-propylamine and N-nitrosomethyl-n-butylamine given in drinking water induced tumors of the upper gastrointestinal tract, mainly carcinomas of the esophagus, and appeared to be of comparable potency. N-Nitrosomethyl(2-hydroxypropyl)amine also mainly induced esophageal carcinomas (100% incidence) and lung tumors, whereas N-nitrosomethyl(2,3-dihydroxypropyl)amine mainly induced nasal cavity tumors and gave rise to a high incidence of esophageal tumors; however, it appeared to be less potent than the monohydroxy compound. N-Nitrosomethyl(2-oxopropyl)amine, the ketone corresponding to N-nitrosomethyl(2-hydroxypropyl)amine, was a more potent carcinogen than the latter at comparable doses in drinking water and gave rise to a high incidence of esophageal tumors and tumors of the trachea; female rats had a high incidence (15/20) of angiosarcomas of the liver, but only 2 male rats died with this tumor. When N-nitrosomethyl(2-oxopropyl)amine was administered at a lower dose in drinking water or at the same dose given by gavage, the incidence of esophageal tumors was lower and there were fewer carcinomas. After administration of large doses in drinking water to male and female rats, N-nitrosomethyl(3-carboxypropyl)amine, a urinary metabolite of several N-nitrosomethyl-n-alkylamines that induce tumors of the urinary bladder in rats, gave rise to a high incidence of transitional cell carcinomas of the bladder. The time to death of animals with these tumors was long, and there were few other tumors.

Administration, Oral↗

PubMed1983

Carcinogenicity of hydroxylated alkylnitrosoureas and of nitrosooxazolidones by mouse skin painting and by gavage in rats.

The carcinogenic effectiveness of a number of nitrosoalkylamides related to nitrosoethylurea and nitroso-n-propylurea has been compared by topical application to Swiss mice and by intragastric administration to F344 rats. Nitrosohydroxyethylurea and the related cyclic nitrosamide, nitrosooxazolidone, were as potent as nitrosoethylurea as skin carcinogens, although the latter was a much weaker mutagen to Salmonella. When administered p.o., nitrosooxazolidone induced mainly forestomach tumors in rats, while nitrosohydroxyethylurea was very broadly acting, inducing neoplasms of the lung, forestomach, glandular stomach, colon, duodenum, and bone (osteogenic sarcomas). Nitroso-2-hydroxypropylurea, nitroso-3-hydroxypropylurea, and nitroso-5-methyloxazolidone were all much more potent carcinogens on mouse skin than was nitroso-n-propylurea, nitroso-5-methyloxazolidone being somewhat less effective than the nitrosoureas; the mutagenicity to Salmonella seemed not to be quantitatively related to carcinogenicity. Nitroso-5-methyloxazolidone given p.o. to rats induced mainly forestomach neoplasms and a few neoplasms of the duodenum, whereas similar treatment of rats with nitroso-2-hydroxypropylurea induced a high incidence of neoplasms of the thymus, some of the forestomach, and few at any other site.

Administration, Topical↗

PubMed1982

Dose-response studies with nitroso-1,2,3,6-tetrahydropyridine and dinitrosohomopiperazine in F344 rats.

Dose-response studies were carried out on female F344 rats with two carcinogenic cyclic nitrosamines, nitroso-1,2,3,6-tetrahydropyridine (NTHP) and dinitrosohomopiperazine (DNHP). Groups of 20 rats were given the nitrosamines in drinking water solution, at concentrations ranging from 100 to 1 mg/liter of the former and 110 to 1.1 mg/liter of the latter, each lower dose being 40% of the dose above it. The lengths of treatment were 25 or 30 weeks at the higher concentrations, and were extended to most of the lifespan at the lower concentrations. The mortality rate of the animals with induced tumors of the upper gastrointestinal tract (and liver in the case of the highest dose of NTHP), decreased with lower doses at the higher concentrations. At the lower concentrations there was little effect on mortality rate, compared with untreated controls, but there were a number of rats with induced tumors of the upper GI tract and the incidence of these tumors increased with increasing dose of nitrosamine. Of the doses given, only the lowest dose of DNHP given for the shortest time was without significant carcinogenic effect. The relationship between dose of nitrosamine and carcinogenic potency, as measured by mortality rate, was linear over part of the range, but not at lower doses. The slopes of these dose responses differed between NTHP- and DNHP-treated animals, suggesting that the mechanisms of carcinogenesis by these two compounds are not identical.

Animals↗

PubMed1982

Studies of a deuterium isotope effect in carcinogenesis by N-nitroso-N-alkylurethanes in rats.

Nitroso-N-methylurethane and nitroso-N-ethylurethane were administered to groups of 20 female F344 rats in corn oil solution by gavage. Each rat received once a week 0.2 ml of solution containing 7 mg/ml or 1.75 mg/ml of the methyl compound or 8 mg/ml or 2 mg/ml of the ethyl compound for 20 weeks. In parallel with these treatments additional groups of rats were given equimolar dose of nitrosomethylurethane and nitrosoethylurethane fully labeled with deuterium in the N-alkyl groups. All animals were allowed to die naturally. The total doses received by the rats were 0.2 mmol at the higher concentration and 0.05 mmol at the lower concentration. Almost all of the treated rats died with papillomas and carcinomas of the forestomach (non-glandular stomach), and the other induced tumors of significance were carcinomas and papillomas of the esophagus in rats given the 7 mg/ml dose of nitrosomethylurethane, both labeled and unlabeled. There was no significant difference in tumor incidence or rate of mortality from tumors that would indicate a difference in carcinogenic effectiveness between the nitrosoalkylurethanes and their deuterium-labeled counterparts. Apart from the esophageal tumors induced only by nitrosomethylurethane at the higher dose, there was no significant difference in carcinogenic effectiveness between the methyl and ethyl nitrosourethanes.

Animals↗

PubMed1982

Contrasting carcinogenic effects of nitroso-2,6-dimethylmorpholine given by gavage to F344 rats and Syrian golden hamsters.

Nitroso-2,6-dimethylmorpholine (Me2NM) has been given by gavage to F344 rats of both sexes and to male Syrian hamsters at similar doses. The rats died more rapidly from the tumors induced than did the hamsters, the males being more susceptible than the females. The rats developed mainly carcinomas and papillomas of the esophagus, whereas the hamsters died with angiosarcomas of the liver, ductal adenocarcinomas of the pancreas, adenocarcinomas of the lung and olfactory adenocarcinomas of the nasal cavity. It was notable that, with the exception of a few lung tumors in the rat, none of the tumors found in the hamster were induced by Me2NM in the rat, and no esophageal tumors were seen in the hamsters.

Animals↗

PubMed1982

Dose-response studies in carcinogenesis by nitroso-N-methyl-N-(2-phenyl)ethylamine in rats and the effects of deuterium substitution.

A dose-response study of the carcinogenicity of nitroso-N-methyl-N-(2-phenyl)ethylamine was carried out in male Fischer 344 rats. The compound was given in drinking water at concentrations of 115, 28, 9.5, 3.2, 1.1 and 0.4 mg/litre. The highest concentration proved toxic leading to the early death of several animals; the remainder of this group were treated for 21 wk. All of the other concentrations were given for 33 wk, except the 28 mg/litre treatment which ceased at 30 wk. An additional group of rats was given 0.4 mg/litre for 104 wk. In all groups of animals, except those in the high-dose group that died early and those given 0.4 mg/litre for 33 wk, 50% or more of the animals had tumours of the oesophagus or forestomach or both when they died. In several groups the number of rats with these tumours approached 100%. The total dose of carcinogen received by the rats in the lowest dose group was 1.3 mg and 45% of them had tumours of the upper gastro-intestinal tract. The effect on carcinogenicity of labelling the nitrosamine with deuterium in either the methyl group or the alpha-methylene of the phenylethyl group was determined by treating groups of rats with equimolar concentrations of the deuterium-labelled and unlabelled nitrosamine. A very significant increase in carcinogenic effectiveness was observed with the compound containing deuterium in the alpha-methylene of the phenylethyl group, suggesting that methylation might not be the important event in carcinogenesis by this compound in rats.

Animals↗

PubMed1982

Comparative carcinogenesis by nitrosomorpholines, nitrosooxazolidines and nitrosotetrahydrooxazine in rats.

A comparison was made of the carcinogenic effectiveness of some cyclic nitrosamines containing oxygen in the ring. The compounds were administered to F344 rats at approximately equimolar concentrations in drinking water. Nitrosomorpholine, nitroso-1,3-oxazolidine and nitrosotetrahydro-1,3-oxazine were of similar potency and gave rise to hepatocellular carcinomas and angiosarcomas of the liver in almost 100% of treated rats. Methyl substitution at the beta position of nitrosomorpholine increased the potency, but retained the main target organ as the liver, while methyl substitution at both beta positions resulted in a further increase in potency, but elimination of the liver as a target and with the main site of tumor induction the upper gastrointestinal tract. In contrast, methyl substitution in the beta position of nitrosooxazolidine resulted in a decrease in carcinogenic potency, but with 100% incidence of liver tumors, but relatively few angiosarcomas. A methyl group at the 2-position of nitrosooxazolidine also reduced carcinogenic potency, all of the animals dying with liver tumors, but few angiosarcomas, but the change was no larger than that produced by the presence of methyl at the 5-position (beta).

Animals↗

PubMed1982

Esophageal carcinogenesis in F344 rats by nitrosomethylethylamines substituted in the ethyl group.

The carcinogenic activity in male F344 rats of five nitrosomethylalkylamines related to nitrosomethylethylamine has been examined. All rats were tested by administration of controlled doses of the compounds in the drinking water. Nitrosomethylbenzylamine was the most potent carcinogen of the five, causing death of most animals with tumors of the upper gastrointestinal tract (mainly the esophagus) within 6 months after a total dose of 0.2 mmol. The remaining compounds, all of which can be considered true derivatives of nitrosomethylethylamine, were less potent than nitrosomethylbenzylamine but also induced a high incidence of tumors of the esophagus. Nitrosomethyl-2-phenylethylamine and nitrosomethylneopentylamine were of comparable potency, while nitrosomethyltrifluoroethylamine was considerably less potent, as measured by the time to death with esophageal tumors. Deuterium-labeled nitrosomethylethylamine, in which deuterium replaces hydrogen on the beta-carbon atom of nitrosomethylethylamine, induced a high incidence of esophageal tumors as well as liver tumors after administration of identical doses. Reactions on the beta-carbon atom of nitrosomethylethylamine might be important as well as oxidation at the alpha-carbon atoms in determining carcinogenic effects.

Animals↗

PubMed1982

Carcinogenesis by isomers of N-nitroso-3,5-dimethylpiperidine.

The cis- and trans-isomers of N-nitroso-3,5-dimethylpiperidine were administered separately in drinking water solution to groups of 20 female F344 rats for 50 weeks. The concentrations of the solutions were 0.72 m M for the cis-isomer and 0.14 mM for the trans-isomer. In both groups the animals died with tumors of the upper gastrointestinal (GI) tract, mainly carcinomas of the esophagus, at about the same time. A third group of animals was given a mixture of the two isomers in the ratio of 5 cis:1 trans, and these animals died more rapidly with the same upper GI tumors. The trans-isomer appeared to be a more potent carcinogen than the cis-isomer. The 3,5-dimethyl derivative is a less potent carcinogen than nitrosopiperidine.

Animals↗

PubMed1982

Dose-response studies with nitrosoheptamethyleneimine and its alpha-deuterium-labeled derivative in F344 rats.

A dose-response study of the carcinogenicity of nitrosoheptamethyleneimine (N-HEP) in inbred F344 male and female rats was performed by administration of the nitrosamine at several concentrations in drinking water to groups of 20 rats. The concentrations differed by a factor of nearly 2.5 and ranged from 1.0 to 100 mg/liter. The duration of treatment was 13, 25, 50, or 100 weeks, after which the animals were allowed to die naturally of tumors induced. In most treated groups the incidence of tumors of the upper gastrointestinal tract approached 100%. However, at the higher doses there was an inverse relationship between total dose and survival time of the rats. Matched treatment of groups of rat with N-HEP labeled with deuterium in the alpha positions resulted in longer survival. The slower action of the deuterium-labeled compound, as measured by a lower rate of death from tumors, suggests that cleavage of a carbon-hydrogen bond at an alpha position is a rate-limiting step in carcinogenesis by N-HEP in rats.

Animals↗

PubMed1982

Transnitrosation by nitrosamines in vivo.

The significance of in vivo transnitrosation in carcinogenesis by the nitrosamines formed was studied by feeding mixtures of morpholine and nitrosamines to rats for most of their lifespan. In some groups, a transnitrosation catalyst (sodium thiocyanate) was fed simultaneously. None of the four nitrosamines induced a significant number of liver tumours when fed singly, although nitrosophenylbenzylamine induced tumours of the spleen and upper gastrointestinal tract and nitroso-N-methylpiperazine induced tumours of the nasal cavity. Nitrosoproline taken with morpholine did not give rise to tumours, except when given in combination with sodium thiocyanate, which gave rise to an even higher frequency of hepatic tumours when given alone. Nitrosohydroxyproline with morpholine induced liver carcinomas in 3 of 20 rats and in 9 of 20 rats in the presence of sodium thiocyanate. Rats given nitrosophenylbenzylamine plus morpholine lived less than 2 years and 4 of them had liver tumours. Most rats treated with nitrosomethylpiperazine died within a year, because of the tumours induced; the combination with morpholine hydrochloride led to the formation of liver carcinomas in 2 of 20 rats and in 5 of 20 when thiocyanate was given.

Animals↗

PubMed1981

The role of toxicity in the carcinogenicity of endosulfan.

Two studies have been undertaken on the toxicity and carcinogenicity of endosulfan, a chlorinated cyclodiene - the NCI Endosulfan Rat Study and the NCI Endosulfan Mouse Study. Histological sections have been examined and the results of this review are based on my diagnoses. Endosulfan is highly toxic for male and female osborne-Mendel rats, particularly for male rats. The chemical causes interstitial fibrosis or acute tubular necrosis of the kidney and death. These lesions, as well as atrophy of the testes, polyarteritis, parathyroid hyperplasia, osteitis fibrosis of bone, and abscesses of the lung, interfere with the health of the animals and with the development of neoplasms. Endosulfan, even though it is extremely toxic, is carcinogenic for male and female Osborne-Mendel rats. The chemical induced malignant neoplasms at all sites in male and female rats and the endocrine organs in male rats. Rats of both sexes developed lymphosarcomas, and female rats had neoplasms of the reproductive system. Endosulfan is also carcinogenic for the liver of female mice.

Animals↗