Biomedical subjects

R M Kovatch

Publications and source records attributed to R M Kovatch.

At least 55 records · Page 3Linked to original sources

PubMed1988

Inhibitory effect of zinc on nickel subsulfide carcinogenesis in Fischer rats.

The effects of zinc oxide (ZnO) and zinc acetate (ZnAcet) administered i.m. together with nickel subsulfide (Ni3S2), a potent muscle carcinogen, were observed over 66 weeks in male F344/NCr rats. The rats (20/group) received a single injection of 2.5 mg Ni3S2 (equal to 31 mumol Ni) alone or combined with different molar proportions of ZnO or ZnAcet (8-60 mumol Zn) into both thighs. One more group of rats given i.m. Ni3S2 received s.c. ZnO (60 mumol Zn) at the nape of the neck. Control rats were treated with i.m. ZnO (60 mumol Zn) or the injection vehicle, water. In rats given Ni3S2 alone the incidence of local tumors reached 100% in 40 weeks. In rats treated locally with Ni3S2 + ZnO or ZnAcet, the tumor incidence at week 40 was only 40-60%; it reached 85-100% in 66 weeks, with no significant differences among the treatments. Treatment with i.m. Ni3S2 + s.c. ZnO resulted in 100% muscle tumors at week 58. One local tumor was found in rats given ZnO alone and none in the water injected animals. Statistical analysis revealed highly significant differences in the tumor occurrence rates between rats treated with Ni3S2 alone and rats treated with Ni3S2 combined with ZnO or ZnAcet, whereas the final tumor incidences at week 66 were not different. The first tumors were found at weeks 24-31 regardless of the treatment. Hence, administration of zinc slows the carcinogenic process induced by nickel. This effect has a systemic character and is produced by both water-soluble and insoluble zinc compounds despite their different retention times in the muscle. The half-lives of ZnO and ZnAcet in the muscle were approx. 24 days and 2.5 days, respectively; that of Ni3S2 was 21 days. Zinc in either form exerted no apparent influence upon the retention of nickel at the injection site and did not significantly affect the early local cellular reactions to nickel.

Acetates↗

PubMed1988

Strain comparison of systemic N-nitrosohexamethyleneimine carcinogenesis in BALB/c, SENCAR and CD-1 mice.

SENCAR mice have been selectively bred for hypersusceptibility to 2-stage chemical skin carcinogenesis. In this study the relative susceptibilities of SENCAR, BALB/c and CD-1 mice to systemic carcinogenesis by N-nitrosohexamethyleneimine (NHEX) were examined. NHEX was administered twice weekly (1 mg/mouse) in corn oil by gavage for 30 weeks. NHEX caused primarily liver and lung tumors in all 3 strains of mice. Hemangiosarcomas (but not other liver tumors) were more common in CD-1 mice than BALB/c or SENCAR mice. Lung tumors (adenomas and adenocarcinomas) and forestomach tumors (squamous carcinomas) were more common in SENCAR mice than BALB/c or CD-1 mice. Survival was better in SENCAR mice dosed with NHEX than in the other 2 strains. These results indicate that SENCAR mice are not unusually sensitive to liver carcinogenesis by NHEX, but are relatively sensitive to tumorigenesis in 2 epithelial tissues, lung and forestomach.

Animals↗

PubMed1988

Carcinogenesis by nitroso-2-hydroxyethylurea in splenectomized hamsters.

Several nitrosoalkylureas tested for carcinogenic activity in Syrian hamsters have as their main effect the induction of hemangiosarcomas of the spleen, many of which appear to metastasize to the liver. To investigate whether any of these lesions in the liver might not be metastases, a group of female Syrian hamsters was surgically splenectomized and treated with nitroso-2-hydroxyethylurea (NHEU) dissolved in corn oil/ethyl acetate once a week for 22 weeks. The animals survived much longer (median 45 weeks) than a comparable group of unsplenectomized female hamsters given identical treatment (median 24 weeks). The absence of hemangiosarcomas of the liver in the splenectomized hamsters showed that the presumed metastases seen in intact animals were, in fact, just that. A second interesting conclusion is that the compound did not produce a concomitant increase in tumors of other types.

Animals↗

PubMed1988

Dose-response study with N-nitrosomorpholine in drinking water of F-344 rats.

A dose-response study in carcinogenesis was carried out with N-nitrosomorpholine in female F344 rats. The compound was administered in drinking water, which was supplied in controlled amounts of 20 ml per day per rat, 5 days a wk. At the two highest dose rates, 100 mg/liter and 40 mg/liter, treatment lasted 25 and 40 wk, respectively. At the other dose rates, which differed by a factor of 2.5, treatment lasted 50 or 100 wk. The average total dose received by each rat ranged from 250 mg to 0.7 mg. There were 100 animals per group at the lowest dose rates and 24 animals per group at the highest dose rates. Total doses of nitrosomorpholine above approximately 30 mg per rat caused a statistically significant decrease in survival, but at lower doses survival was similar to that of untreated controls. In nearly all of the treated groups there was a statistically significant increase in the incidence of benign or malignant hepatocellular neoplasms, with a highly significant dose-related trend. At the higher doses there was a significant incidence of hemangiosarcomas of the liver. Both hepatocellular carcinomas and hemangiosarcomas metastasized to the lungs and other organs. At the highest doses there was a significant incidence of neoplasms of the tongue and esophagus, which were rarely seen at the lower doses. The results suggest that even the lowest dose of nitrosomorpholine received by the rats, 0.7 mg or approximately 3 mg/kg body weight, was not a no-effect dose during the 2-yr lifetime of a rat. Probit analysis of the results indicate a dose estimated to cause tumors in 50% of the population of 25 mg nitrosomorpholine for liver neoplasms.

Animals↗

PubMed1988

Carcinogenesis and nucleic acid alkylation by some oxygenated nitrosamines in rats and hamsters.

A comparison has been made of the carcinogenic effects of nitroso-2,6-dimethylmorpholine and several hydroxylated acyclic nitrosodialkylamines derived from it or related to it in rats and Syrian hamsters. In rats nitrosodimethylmorpholine was the most potent, inducing mainly esophageal tumors. Nitrosodiethanolamine was the weakest of the five nitrosamines in both rats and hamsters. Tumors of the pancreas ducts were induced by four of the five compounds, but only in hamsters, and esophageal tumors appeared only in rats. Most of the nitrosamines induced tumors of liver and lung in both rats and hamsters. A study of alkylation of nucleic acids of the liver following treatment of rats and hamsters with the radiolabeled nitrosamines showed that nitrosodiethanolamine alkylated liver nucleic acids in rats to only a very small extent. The other four nitrosamines all gave rise to 7-methylation and O6-methylation of guanine residues in DNA of hamster liver and all but nitrosodimethylmorpholine in rat liver DNA, which corresponded quite well with the induction of liver tumors in the two species. Quantitatively, however, there was not a good correlation between liver DNA alkylation and the potency of the nitrosamine in inducing tumors.

Administration, Oral↗

PubMed1988

Effects of feminization of male F344 rats on induction of tumors and on nucleic acid alkylation by nitrosobis-(2-oxopropyl)amine.

Groups of male and female F344 rats were treated twice weekly by gavage with 2.5 mg of nitrosobis-(2-oxopropyl)amine (BOP) for 35 weeks. Additional groups given the same treatment were male rats castrated at birth, male rats bearing an implant of a pellet containing estradiol and castrated male rats bearing an estradiol pellet. Most rats died with tumors related to the treatment; intact male rats survived the least well of the five groups. Most rats in all groups had alveolar/bronchiolar neoplasms of the lung. Many of the male rats also had follicular cell neoplasms of the thyroid and transitional cell neoplasms of the urinary bladder and kidney pelvis; there were no liver tumors in intact male rats. Almost all female rats and castrated male rats had liver neoplasms, including hepatocellular, cholangiocellular and hemangiosarcomatous neoplasms, but few neoplasms of the thyroid, kidney or bladder. The male rats feminized with estradiol, intact or castrated, had liver neoplasms, mainly cholangiocellular, and also neoplasms of the thyroid. Two rats of each of the five groups were treated at 20 weeks of age with [14C]BOP. As measured by respiration of 14CO2, metabolism of BOP was faster in the two groups of male rats with the estradiol implant than in the other groups. DNA and RNA of the liver were isolated 6 h after treatment. The extent of methylation of liver DNA as 7-methylguanine and O6-methylguanine was higher in the females and in the feminized males than in the intact male rats, but when normalized to the dose of nitrosamine per unit body weight there was little difference among the five groups.

Alkylation↗

PubMed1988

Carcinogenesis in rats by cyclic N-nitrosamines containing sulphur.

The effects of chronic exposure to three sulphur-containing heterocyclic N-nitrosamines were determined after repeated oral administration to female Fischer 344 rats. Nitrosothiazolidine did not significantly affect the survival of the rats or the incidence of tumours at a total dose of 3.5 mmol. Nitrosodithiazine, an analogue of nitrosothiazolidine which contains an extra sulphur atom inserted between the carbons of its CH2-CH2 moiety, produced only three tumours (two of the nasal mucosa) in a group of 20 rats at a total dose of 1.75 mmol/rat. Nitrosothialdine, the all-cis 2,4,6-trimethyl analogue of nitrosodithiazine, was a potent carcinogen that significantly shortened the lifespan and produced oesophageal tumours in 70% of treated rats as well as numerous tumours of the tongue and liver; this outcome was unexpected because alpha-methyl substitution in other heterocyclic nitrosamines usually reduces or eliminates tumorigenicity. The results extend the data base on the carcinogenic activity of molecules containing both divalent sulphur and the nitrosamino function. The lack of significant carcinogenicity of nitrosothiazolidine in this study suggests that its presence in the human food supply presents a relatively minor risk.

Animals↗

PubMed1988

N-nitrosocimetidine as a modifier of chemically-initiated tumors in mice.

N-Nitrosocimetidine (NCM) is a nitrosation product of cimetidine, a commonly-prescribed pharmaceutical agent. In spite of its known genotoxicity, NCM has failed to cause tumors in assays with rats and mice, but has given indications of enhancing or suppressive effects on tumor development. This possibility was tested by administering NCM topically to the skin or in the drinking water to mice in which tumors had been initiated by treatment with chemical carcinogens. Sencar mouse skin papillomas initiated by 7,12-dimethylbenzanthracene (DMBA) and promoted by 12-O-decanoylphorbol-13-acetate (TPA), progressed more rapidly to carcinoma on mice given treatment during stage 3 (after TPA) with NCM (1 mg/week) or N-methyl-N'-nitro-N-nitrosoguanidine (MNNG, 120 micrograms/week) [corrected] than on stage 3 acetone controls. Oral NCM (1 g/l drinking water) did not have this effect but rather suppressed development of keratoacanthomas, as did stage 3 MNNG or TPA. Primary lung tumors initiated in BALB/c mice by i.p. injection of urethane; and tumors of forestomach, lung, mammary, lymphoid and skin tissues caused in (C57BL/6 X DBA/2)F1 mice by oral DMBA were not markedly affected by NCM given in drinking water (1000-1800 ppm) until 14-16 months of age. These results confirm NCM's general lack of activity as an in vivo toxicant, but show that under certain circumstances it may enhance or suppress tumor development.

9,10-Dimethyl-1,2-benzanthracene↗

PubMed1988

Carcinogenesis by nitrosohydroxyethylurea and nitrosomethoxyethylurea in F344 rats.

Nitroso-2-hydroxyethylurea and its methyl ether, nitroso-2-methoxyethylurea, were administered to male and female rats by gavage, each at two dose rates. The highest dose rate of nitrosohydroxyethylurea was 14 mg twice a week for 18 weeks, which led to death of all animals by week 34 with a variety of neoplasms, which have been observed in earlier experiments at lower doses, and included those in lung, colon, thyroid, forestomach, tongue, duodenum, jejunum, Zymbal's gland, thymus and mammary gland adenocarcinomas. At a dose 10 times smaller, the animals survived much longer, but the distribution of tumors was similar, except that there were few of the duodenum and jejunum. At an equimolar dose of nitrosomethoxyethylurea (1.6 mg, twice a week), the pattern of tumors was similar to that seen with nitrosohydroxyethylurea, including the absence of tumors in the duodenum and jejunum, although there were tumors of the colon. The rats treated with the methyl ether died earlier than those given nitrosohydroxyethylurea, indicating a greater potency of the former. At a dose of 3.2 mg twice a week, nitrosomethoxyethylurea produced the same pattern of tumors as the lower dose, but the animals died earlier. In all groups, there were more lung tumors in males than in females, and this was true to a lesser extent of the colon. The main effect of methylation of the hydroxyl group in nitrosohydroxyethylurea was to increase the potency of the carcinogen, but there was no effect on the target organ specificity of the nitrosourea.

Animals↗

PubMed1988

The induction of bladder tumors in F344 rats by intravesicular administration of some nitrosamines.

Three nitrosamines, metabolically related and formed in vivo from the bladder carcinogen nitrosomethyl-n-octylamine, were administered to groups of 12 female F344 rats by intraurethral instillation twice a week for 30 weeks. All three compounds induced tumors in the urinary bladder. Nitrosomethyl-2-oxopropylamine at 10 mg/ml was the most potent, causing death of half of the animals with tumors at 43 weeks, following a total dose of 1.0 mmol; most of the rats also had tumors of the nasal mucosa, and there were some tumors of the kidney and kidney pelvis. Nitrosomethyl-2-hydroxypropylamine at 10 mg/ml (total dose 1.0 mmol) was much less effective, the median week of death being 83 weeks. In addition to bladder tumors, this group had tumors of the nasal mucosa, esophagus, and kidney. Nitrosomethyl-3-carboxypropylamine at 75 mg/ml and a total dose of 6.2 mmol per rat induced a high incidence of bladder tumors and tumors of the kidney pelvis, but not tumors of the nasal mucosa; the median week of death for this group was 55 weeks. It is concluded that nitrosomethyl-n-alkylamines that induce bladder tumors by oral administration to rats are metabolized to nitrosomethyl-3-carboxypropylamine, which is excreted in the urine and further metabolized to nitrosomethyl-2-oxopropylamine, the proximate bladder carcinogen.

Administration, Intravesical↗

PubMed1987

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↗

PubMed1987

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↗

PubMed1986

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↗

PubMed1986

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↗

PubMed1986

Naturally occurring nonneoplastic histopathological lesions in the female SENCAR mouse.

Lesions that were considered naturally occurring were surveyed in female SENCAR mice used in short-term bioassays. These lesions were encountered in selected target organs and in organs and tissues with gross lesions encountered at necropsy. The genitourinary system was the most frequent site for lesions; cystic ovaries, cystic endometrial hyperplasia, and glomerulonephritis were commonly encountered in this system.

Animals↗

PubMed1986

Gross and microscopic lesions in the female SENCAR mouse skin and lung in tumor initiation and promotion studies.

The skin and lung tissues from SENCAR mice used as part of the Environmental Protection Agency's (EPA's) Carcinogenesis Testing Matrix were examined. This study included SENCAR mice used in three different short-term bioassay protocols in which the skin papilloma assay was used to identify initiators, promoters, and complete carcinogens. Also included were the pathology findings from SENCAR mice used in the combined bioassay in which the skin assay and the lung adenoma assay were conducted simultaneously. The gross and microscopic features of treatment-associated and spontaneous lesions of the skin and lung of the SENCAR mouse used in these studies are defined and the lesions most commonly observed are described. Generally, gross observations and microscopic findings in both the skin and lung tissues were poorly correlated. Although there are several definite criteria on which gross interpretations of the various skin and lung lesions can be made, with the exception of pedunculated squamous cell papillomas and the classic squamous cell carcinomas, the various lesion types had a wide variety of clinical presentations that severely compromised the accuracy of gross diagnosis. Further, in the case of benign skin neoplasms, malignant transformation of these tumors most often occurred at the base of the lesion and was initially hidden from gross observation. As a result, approximately 50% of the neoplasms interpreted clinically as benign tumors (papillomas and keratoacanthomas) were actually malignant neoplasms. Moreover, many lesions determined grossly to be nontumorous were in fact found to be neoplastic when examined microscopically. The SENCAR mouse was found to be more responsive in the lung adenoma assay than other strains examined with exception of the Strain A. Although accurate interpretation of the lung lesions in the SENCAR was compromised by nonneoplastic treatment-associated and/or spontaneous lesions, the feasibility of using the SENCAR skin and lung as target tissues in two-stage combined carcinogenesis studies merits further consideration.

Animals↗

PubMed1986

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↗

PubMed1986

Chronic toxicity study of cyclohexanone in rats and mice.

A 2-year chronic toxicity assay of cyclohexanone (CAS: 108-94-1) was conducted in F344 rats and (C57BL/6 X C3H)F1 mice by administering a solution of cyclohexanone in drinking water. Two concentrations were given to rats, 6,500 and 3,300 ppm (wt/vol). Male mice received 13,000 and 6,500 ppm, while female mice were given three concentrations, 25,000, 13,000, and 6,500 ppm. Each treatment group consisted of 50 or 52 male and 50 or 52 female rats or mice, except 47 male mice treated with the highest dose and 41 female mice treated with the highest dose, and there was a group of untreated controls of each species. Survival and weight gain were similar to those of controls at the lowest cyclohexanone dose in both sexes of both species, but weight gain was depressed at all of the higher doses. Survival was good (greater than 80% at 90 wk) in all groups except in female mice at the 2 highest doses; at 25,000 ppm of cyclohexanone, only 50% of mice lived beyond 1 year. Most of the neoplasms in the treated groups did not differ significantly in number from those in the controls. Male rats receiving 3,300 ppm cyclohexanone had a 13% incidence of adrenal cortex adenomas (7 animals) compared with an incidence of 2% in controls; the incidence of this neoplasm did not increase in the male rats receiving 6,500 ppm or in the female rats given either dose. The mice had a statistically significant increase in incidence of lymphomas-leukemias among the females given 6,500 ppm, but not among the groups given higher doses of cyclohexanone. Male mice given 6,500 ppm cyclohexanone showed an increased incidence of hepatocellular adenomas and carcinomas, 50% versus 32.5% in controls, but the incidence of these neoplasms was only 37% in the male mice given 13,000 ppm cyclohexanone. The incidence of lymphomas in male mice and of hepatocellular neoplasms in female mice given cyclohexanone did not differ from that in the controls. The evidence for carcinogenic activity of cyclohexanone is marginal and the effect, if any, is weak.

Adenoma↗