Chronic studies in rodents of vinyl acetate and compounds related to acrolein.
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1-Propanol↗
Biomedical subjects
W Lijinsky
Publications and source records attributed to W Lijinsky.
Intestinal cancer induced by N-nitroso compounds.
Several N-nitroso compounds induce tumors of the colon, and some induce tumors in other parts of the intestinal tract as well. The nitrosamines that induce colon tumors are beta oxidized n-propyl-nitrosamines. These require metabolic activation, as do 1,2-dimethylhydrazine, azomethane, and azoxymethane, another group of colon carcinogens. Several nitrosoalkylureas induce tumors in rat colons after oral administration, although the monoalkylnitrosoureas are fairly unstable and might not be expected to reach the colon. However, monoalkylnitrosoureas are equally effective with the much more stable dialkylnitrosoureas. Although nitrosomethylurea did not induce colon tumors under these conditions, nitrosoethylurea did, together with nitrosodiethylurea and other nitrosoethylalkylureas. Nitroso-n-butyl-, n-amyl-, n-hexyl-urea, and nitrosohydroxyethylurea also induced colon tumors, but the last, like nitrosoethylurea, also induced tumors of the duodenum and ileum. In most of these experiments male rats were more susceptible to induction of intestinal tumors than female rats. An explanation for the differences between these compounds of similar structure might be found in variations in their ability to alkylate DNA in intestinal cells, or in differences in stability of the alkylated product between the compounds. The physical properties of the compounds might also modulate the process of carcinogenesis, however.
Alkylation↗
Carcinogenesis by nitrosodialkylamines and azoxyalkanes given by gavage to rats and hamsters.
The carcinogenic effects of three nitrosamines, nitrosodimethylamine (NDMA), nitrosodiethylamine (NDEA), and nitrosomethylethylamine (NMEA), and two azoxyalkanes, azoxymethane and azoxyethane, have been compared by administration by gavage of multiple equimolar doses to F344 rats and Syrian golden hamsters. NDMA and azoxymethane were severely toxic to hamsters, requiring the use of lower dose rates. In hamsters, the most commonly observed tumors were hepatocellular, cholangiocellular, and vascular tumors of the liver, but azoxyethane, NMEA, NDMA, and NDEA also induced tumors of the nasal mucosa, and azoxymethane induced tumors of the colon. In hamsters, NDEA and azoxyethane were less potent carcinogens than the corresponding methyl compounds, NDMA and azoxymethane. In contrast, in rats the two ethyl compounds were more potent than the corresponding methyl compounds, and NMEA was intermediate in potency. In rats, all three nitrosamines commonly induced liver tumors, mostly hepatocellular, but few liver tumors were induced by the two azoxyalkanes. Instead, azoxymethane induced colon tumors and azoxyethane induced tumors of the nasal mucosa. When given by gavage, NDMA induced a high incidence of mesenchymal tumors of the kidney and alveolar-bronchiolar tumors of the lungs as well as liver tumors.
Administration, Oral↗
Structure-activity relations in carcinogenesis by N-nitroso compounds.
For a large number of N-nitroso compounds a comparison of their carcinogenic effects in rats and Syrian golden hamsters has been made. Nitrosamines, which require metabolic activation, and nitrosoalkylamides, which do not, produce quite different tumor responses. There are also large differences in the types of tumor induced in rats and in hamsters. In all the studies doses of the various compounds, equimolar to the extent that was possible, are administered orally. Continuous doses (in drinking water or food) often produce a response different from that after administration of the same compound in pulsed doses (by gavage), even though the same total dose is delivered. Continuous doses of nitrosamines are usually more effective than pulsed doses, but with the nitrosoalkylureas, the reverse is more generally the case. Rat and hamster liver is a common target of many nitrosamines, but rarely of nitrosamides. The most common site of tumor induction in rats by N-nitroso compounds is the esophagus, but the hamster esophagus never responds. The pancreas duct of the hamster is a common target of nitrosamines containing a beta-oxygenated propyl group, but pancreas duct tumors are never seen in rats. Nitrosomethyl-n-alkylamines (with an even numbered carbon chain) induce bladder tumors in rats and hamsters. Many nitrosoalkylureas induce tumors of the nervous system in rats, as well as a great variety of other tumors. In hamsters, nitrosoalkylureas give rise only to tumors of the forestomach and spleen, but no tumors of the nervous system. The similar carcinogenic actions of certain groups of N-nitroso compounds can be related to their generation, directly or by metabolism, of similar simple moieties having certain organs as their target.
Animals↗
Relative mutagenic and prophage-inducing effects of mono- and di-alkyl nitrosoureas.
Mutagenic capacity, prophage-inducing ability, and decomposition rates of mono- and di-alkylnitrosoureas with the same alkyl groups were studied in aqueous systems using S. typhimurium strain TA1535 and E. coli strain BR339 (lambda). Slower decomposition rates of nitrosodialkylureas compared with monoalkylnitrosoureas were not reflected in reduced mutagenicity, with the exception of the methylating agents. With the monoalkylnitrosoureas, mutagenicity varied with length of the alkyl chain, and was greatly increased by oxygen substituents. Among the dialkylnitrosoureas, mutagenesis and decomposition rates were dependent on the substitutent in the N-1 position, adjacent to the nitroso group. Prophage induction, on the other hand, was dependent on a substituent in the N-3 position. The results suggested the existence of two distinct mechanisms for DNA damage, one SOS-dependent and the other SOS-independent, by which different dialkylnitrosoureas acted. Neither in vitro assay system was a reasonable model for the carcinogenic activity of these compounds.
Alkylation↗
Tumors in F344 rats by oral administration of 1,3-diethyltriazene.
A group of 20 male F344 rats was given by gavage a solution of 2.5 mg of 1,3-diethyltriazene in 0.2 ml corn oil twice a week for 20 weeks. Diethyltriazene is very unstable in hydroxylic solvents, but when administered in oil by gavage it induced tumors in almost all of the treated animals, 16 of which had neoplasms of the forestomach; 13 of which were carcinomas. In addition 9 rats had adenomas of the nasal mucosa, two had alveolar-bronchiolar adenomas of the lung, one had a carcinoma of the esophagus and one an adenocarcinoma of the ileum. Half of the rats had died by week 56 of the experiment, the first at week 40 and the last at week 73. The induction of tumors at sites distant from the stomach indicate that diethyltriazene is more stable in the body than would be predicted from its chemical behavior. Although diethyltriazene is a protected alkyldiazonium ion, its carcinogenic effects in rats differ from ethylnitrosoureas, which are also ethylating agents.
Administration, Oral↗
DNA methylation in rat tissues by a series of homologous aliphatic nitrosamines ranging from N-nitrosodimethylamine to N-nitrosomethyldodecylamine.
Aliphatic N-nitrosomethylalkylamines exhibit a remarkable organ specificity in rats, the principal targets for tumour induction being liver, oesophagus, urinary bladder and lung. We have determined the extent of DNA methylation in these tissues following a single oral dose (0.1 mmol/kg; 6 h survival) of each of 12 homologues, ranging from N-nitrosodimethylamine (C1) to N-nitrosomethyldodecylamine (C12). Methylpurines (7- and O6-methylguanine) were determined by cation exchange HPLC with fluorescence detection. Highest levels of hepatic DNA methylation were found with N-nitrosodimethylamine (C1) and N-nitrosomethylethylamine (C2), the most potent hepatocarcinogens in this series. Concentrations of methylpurines in liver DNA decreased with increasing chain length for C1-C5. Administration of the higher homologues (C6-C12) caused levels of DNA methylation which by themselves were considered too low to account for their hepatocarcinogenicity. In rat oesophagus, DNA methylation closely paralleled carcinogenicity, the butyl and pentyl derivatives (C4, C5) being most effective. In rat lung, the extent of DNA methylation was generally lower and there was no apparent correlation with carcinogenicity. Methylation of kidney DNA also decreased with increasing chain length and was only detectable for C1-C5. In urinary bladder DNA, methylpurines were below or close to the limit of detection. It is concluded that the initiation of malignant transformation by DNA methylation alone (through hydroxylation at the methylene alpha-carbon) could be operative for C1 in kidney and lung, for C1 and C2 in liver, and C3-C5 in oesophagus. For the higher homologues, the extent of DNA methylation seems insufficient to explain the complex pattern of tissue specificity, suggesting that DNA modification other than, or in addition to, methylation may be responsible.
Animals↗
Chronic carcinogenesis studies of acrolein and related compounds.
Acrolein and two of its more stable derivatives, the oxime and the diethylacetal, and the related allyl alcohol were given in drinking water to groups of 20 male and 20 female F344 rats at doses close to the maximum that could be tolerated by the animals, for most of their lifetime. Acetaldoxime served as a control for the hydroxylamine derivative of acrolein. Most of the tumors were common in untreated rats of this strain. Only adenomas of the adrenal cortex in females were more numerous than in untreated controls. Acrolein itself was too toxic to hamsters to conduct a carcinogenesis study. Acrolein oxime, acrolein diethylacetal and allyl alcohol were all quite toxic to hamsters, but 2 mg per week by gavage was tolerated by groups of 20 male Syrian hamsters. There was a small number of tumors of the pancreatic ducts and of the forestomach in the treated hamsters, but the incidence was not statistically significant.
1-Propanol↗
Pathologic effects of chronic administration of hydrochlorothiazide, with and without sodium nitrite, to F344 rats.
The diuretic drug hydrochlorothiazide was administered to 24 male and 24 female F344 rats as a mixture of 0.1% in powdered food. A parallel group of the same size was given 0.1% hydrochlorothiazide plus 0.2% sodium nitrite in the food. A third group received 0.2% sodium nitrite in the food and there was a similar group of untreated controls. The treatments were well tolerated and there was no significant life shortening. A majority of the rats given hydrochlorothiazide, with or without nitrite, developed chronic progressive nephropathy, which was more severe in males than in females. Associated with this were diffuse parathyroid hyperplasia in both groups receiving the drug, also more severe in males than in females, and parallel increases in lesions of the blood vessels (mural thrombosis of the heart and polyarteritis). The few adenomas of the parathyroid and tubular cell adenomas of the kidney in rats ingesting hydrochlorothiazide were not statistically significant.
Animals↗
A comparison of in vivo and in vitro metabolites of the H1-antagonist N,N-dimethyl-N'-2-pyridyl-N'-(2-thienylmethyl)-1,2-ethanediamine (methapyrilene) in the rat.
1. The H1-antagonist N,N-dimethyl-N'-2-pyridyl-N'-(2-thienylmethyl)-1,2-ethanediamine (methapyrilene) is carcinogenic in rats. 2. The compound, which is inactive in short-term tests and does not bind to DNA, has been classified as a non-genotoxic carcinogen. 3. Studies have been made in vitro and in vivo in F344 and Sprague-Dawley rats. New metabolites included N-(N',N'-dimethylaminoethyl)-2-aminopyridine and the corresponding N'-oxide, a derivative in which methapyrilene is hydroxylated on the 5-position of the pyridine ring, 2-(N',N'-dimethylamino)-N-2'-pyridylacetamide, N-(2-pyridyl)-N-2"-thienylmethyl)aminoacetaldehyde, and 2-hydroxymethylthiophene. 4. Both strains of rat metabolize methapyrilene to reactive species which may be of importance in the carcinogenic process.
Aminopyridines↗
Metabolism and cellular interactions of N-nitrosodiethanolamine.
N-Nitrosodiethanolamine (NDELA) labelled with 14C at the alpha carbon was administered by gavage to adult male Fischer 344 rats at various doses ranging from 0.6 to 100 mg per rat. The proportion of the dose excreted as 14CO2 was small, ranging from 0.27% at the lowest dose to 0.83% at the highest in 24 h. At all doses, approximately 95% of the dose of radioactivity (most of which was NDELA) appeared in the urine within 24 h, but the proportion of metabolites increased from 7% to 14% from the lowest to the highest dose. The specific activity of the nucleic acids isolated from the liver of rats given 100 mg and 100 microCi of NDELA was very low and was the same at 6 h and 24 h after treatment (70 dpm/mg DNA, 92-95 dpm/mg RNA). N7-(2-Hydroxyethyl)guanine and O6-(2-hydroxyethyl)-guanine were tentatively identified in the hydrolysates of the nucleic acids, comprising 10% and 4%, respectively, of the DNA radioactivity; there was no difference between the amounts found 6 h and 24 h after NDELA treatment. In addition to NDELA, four components were separated from rat urine, and two were identified. One is the glucuronide of NDELA, the other is N-nitroso-N-(2-hydroxyethyl)carboxymethylamine. Neither nitroso-2-hydroxymorpholine nor a sulfate of NDELA was detected.
Animals↗
Organ specificity, metabolism and reaction with DNA of aliphatic nitrosomethylalkylamines.
Aliphatic nitrosomethylalkylamines are carcinogens with a remarkable organ specificity in rats, the principal targets being liver, oesophagus and bladder. We have determined the extent of DNA methylation in these tissues following a single oral dose (0.1 mmol/kg; 6-h survival) of each of 12 homologues, ranging from N-nitrosodimethylamine (NDMA, C1) to N-nitrosomethyldodecylamine (C12). Methylpurines (7- and O6-methylguanine; 7-meGua and O6-meGua) were determined by cation-exchange high-performance liquid chromatography with fluorescence detection. Highest levels of hepatic DNA methylation were found with NDMA (C1) and N-nitrosoethylmethylamine (NEMA, C2), the most potent hepatocarcinogens in this series. Concentrations of methylpurines in liver DNA decreased with increasing chain length from C1 to C5. Administration of the higher homologues (C6-C12) caused levels of DNA methylation which by themselves were considered too low to account for their hepatocarcinogenicity. In rat oesophagus, DNA methylation closely paralleled carcinogenicity, the most effective agents being the butyl and pentyl derivatives (C4 and C5). Levels of DNA methylation in bladder epithelium were close to the limit of detection (C6,C9,C10,C12) and there was no apparent correlation with carcinogenicity. It is concluded that initiation of malignant transformation by DNA methylation alone (through hydroxylation of the nitrosamine at the methylene alpha-carbon) could be operative for C1-C5. For the higher homologues, this type of DNA modification is insufficient to explain the complex pattern of tissue specificity.
Animals↗
Carcinogenicity studies of some analogs of the carcinogen methapyrilene in F344 rats.
Four antihistaminic drugs similar in structure to the rat liver carcinogen methapyrilene were administered to comparable groups of male and female F344 rats in their drinking water for most of their lifetime (80-108 weeks). The concentrations were 0.1% or 0.05% and the total doses received by the animals were comparable with that of methapyrilene which induced 100% incidence of liver neoplasms. No increase in incidence of liver neoplasms was observed after treatment with any of the four compounds, thenyldiamine, chlorothen, methafurylene, or methaphenilene, although each differed structurally from methapyrilene only in one atom or one position of substitution. There were a few animals with neoplasms not usually found in untreated F344 rats, but none of these was found in statistically significant numbers. These results suggest that none of the four analogs of methapyrilene was carcinogenic under the conditions of this study, and that the property of inducing liver neoplasms in rats was confined to the intact methapyrilene molecule.
Aminopyridines↗
Carcinogenesis in F-344 rats induced by nitrosohydroxyalkyl-chloroethylureas.
The two isomeric N-nitroso derivatives of 1-chloroethyl-3-(2-hydroxyethyl)-urea and of 1-chloroethyl-3-(2-hydroxypropyl)-urea were prepared and isolated. They were given by gavage in ethyl acetate/corn oil to groups of 20 male and female F-344 rats. The two nitroso-1-chloroethyl compounds were nephrotoxic and most animals died within 20 weeks; no neoplasms were seen in any of these animals. Nitroso-1-hydroxyethyl-3-chloroethylurea was given at 2 concentrations, 21 and 10.5 mg/ml; in both groups almost all animals died with neoplasms related to the treatment. These included hepatocellular and cholangiocellular neoplasms of the liver; many of the former metastasized. Many rats also had tubular cell neoplasms in the kidney. Nitroso-1-(2-hydroxypropyl)-3-chloroethylurea was a less potent carcinogen at equimolar doses, inducing fewer liver neoplasms than the nitrosohydroxyethyl analog and only few kidney neoplasms. Both of these carcinogens were less effective in female rats than in males, although the females, which were smaller, received a higher dose per unit body weight. The spectrum of neoplasms induced by the nitrosohydroxyalkyl-chloroethylureas was quite different from that induced by equimolar doses of each corresponding nitrosohydroxyalkylurea, neither of which induced neoplasms of the liver, although they were potent inducers of neoplasms in other organs.
Animals↗
Deuterium isotope effects in carcinogenesis by N-nitroso compounds.
A number of N-nitroso compounds and an azoxyalkane have been labeled with deuterium in various positions and have been administered to rats, hamsters, or mice in parallel with the unlabeled compounds. The treatments with the labeled and analogous unlabeled compounds were equimolar and for the same time. Mortality rates from tumors and tumor incidences were compared between deuterium-labeled and the unlabeled analogs. In many cases more than one dose level was used for the comparisons. An increased rate of mortality from tumors or an increased incidence of induced tumors was considered an index of increased potency of one treatment compared with the other. Using these criteria deuterium in the alpha positions of nitrosodimethylamine, nitrosomorpholine, nitrosoheptamethyleneimine, and nitrosoazetidine reduced carcinogenic potency compared with the unlabeled compounds. This indicated that cleavage of a carbon-hydrogen bond in the alpha position was a rate-limiting step in carcinogenesis by these nitrosamines. In both nitrosomethylethylamine and nitroso-2,6-dimethylmorpholine, the presence of deuterium at different positions increased or decreased carcinogenic potency, suggesting that competition for oxidation between these sites might be the determining factor in activation of the molecule. This also applied to nitrosomethyl-n-butylamine and nitrosomethyl-phenylethylamine with deuterium at the methyl group or at the alpha carbon of the butyl or phenylethyl groups, and to azoxymethane with deuterium in the 1-methyl or 4-methyl group. In nitrosomethylcyclohexylamine, nitrosomethyl-n-dodecylamine, and dinitroso-2,6-dimethylpiperazine there was no detectable effect of deuterium on carcinogenic potency, suggesting that the conditions did not provide sufficient sensitivity for detection of an isotope effect, or that oxidation at the alpha carbon was not a rate-limiting step in carcinogenesis by these molecules.
Alkylation↗
Nitrosamines and nitrosamine precursors in foods from Linxian, China, a high incidence area for esophageal cancer.
Nitrosamines and precursor secondary amines were assayed in foods from families in four villages of the esophageal cancer high incidence area of Linxian, Henan Province, People's Republic of China. Amines (as tosylamides) and nitrosamines were readily detected at p.p.m. and p.p.b. levels, respectively, in all samples. In this small preliminary survey (25 families, four villages), however, there were no strong correlation between the levels of the carcinogenic nitrosamines or the precursor secondary amines with the incidence of esophageal cancer in the individual families. The success of the analytical procedures suggests that a more extensive study is warranted.
Amines↗
The effect of age on susceptibility of rats to carcinogenesis by two nitrosamines.
The carcinogenic effects of identical doses of two carcinogenic nitrosamines each given to young (8-week-old) and old (54- or 65-week-old) F344 rats were compared. The two compounds were nitrosomorpholine, which was given in drinking water to females, and nitrosobis(2-oxopropyl)amine (BOP), which was given to males by gavage in oil. In both old (54 weeks) and young rats nitrosomorpholine at 100 mg/liter induced hepatocellular neoplasms in the liver of almost all rats, but the rate at which the neoplasms killed the animals was much slower in the old than in the young rats, and by this measure of potency the old rats given 100 mg/liter resembled young rats given 40 mg/liter. BOP administered at two dose rates, 2.5 mg twice a week for 35 weeks, and 6 mg twice a week for 29 weeks, induced neoplasms of the lung and of follicular cells in the thyroid and transitional cell neoplasms of the bladder and kidney pelvis in almost all animals when treatment began at 8 weeks, but many fewer, or none, of these neoplasms in male rats whose treatment began at 65 weeks. Instead, the old male rats developed hepatocellular neoplasms in the liver, none of which were seen in the young rats treated with BOP. There was no significant difference in mortality rate between young and old rats which would account for these differences in BOP-treated rats.
Age Factors↗
Chronic bioassay of benzyl chloride in F344 rats and (C57BL/6J x BALB/c)F1 mice.
Benzyl chloride was administered to groups of 52 male and 52 female F344 rats and (C57BL/6J x BALB/c)F1 mice at two dose levels by gavage in corn oil three times a week for 2 years. Survivors were sacrificed a few weeks later and examined histopathologically. On the basis of a subchronic study at a range of doses, the doses of benzyl chloride in the chronic study were 100 and 50 mg/kg body weight for mice and 30 and 15 mg/kg body weight for rats. In mice of both sexes there was a high and statistically significant incidence of carcinomas and papillomas of the forestomach. In the livers of male mice, but not of females, there was a significantly increased incidence of hepatocellular neoplasms at the low dose but not at the maximally tolerated dose (MTD). In rats the only neoplasms showing a statistically significant increase compared with controls were C-cell neoplasms of the thyroid gland in females. A significant incidence of neoplasms was not found in the forestomachs of F344 rats, but it is possible that true MTD was not used for rats.
Animals↗