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R R Maronpot

Publications and source records attributed to R R Maronpot.

At least 145 records · Page 8Linked to original sources
PubMed1987

A method to quantitate the relative initiating and promoting potencies of hepatocarcinogenic agents in their dose-response relationships to altered hepatic foci.

The relative response to various initiating doses of diethylnitrosamine (DEN) and dimethylbenz[a]anthracene of the induction of numbers and size (vol. % of liver) of altered hepatic foci (AHF) in livers of adult female rats of the Sprague-Dawley and Fischer 344 (F-344) strains was studied by methods of quantitative stereology in the presence and absence of the promoting agent, phenobarbital (PB, 0.05% in the diet). In all cases, a relatively linear response with dose, even at the lowest doses employed, was obtained except for the numbers of AHF at the highest dose of DEN (30 mg/kg), which was not significantly different from that at a dose of 10 mg/kg in F-344 female rats. Similar dose-response data were obtained at various doses of two promoting agents effective in hepatocarcinogenesis, PB and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), in livers of F-344 female rats following initiation with DEN (10 mg/kg) 24 h post-70% hepatectomy. The response to these agents exhibited threshold levels below which no increase in number or vol. % of liver of AHF was noted in comparison with that in livers of animals not treated with the promoting agents. At several subthreshold doses of both PB and TCDD an inhibition of AHF formation and growth (measured as vol. % of liver) was observed. Based on quantitative stereologic calculations, parameters for the estimation for the relative potency of chemicals as initiating or promoting agents have been established. These are defined as: initiation index = no. of foci induced X liver-1 X [mmol/kg body wt]-1 and promotion index = Vf/Vc X mmol-1 X weeks-1, where Vf is the total volume fraction (%) occupied by AHF in the livers of rats treated with the test agent and Vc is the total volume of AHF in control animals which have only been initiated. These parameters were calculated for a number of agents based on data published in the literature and from those reported herein. Neither parameter varied significantly with the dose of the initiating agent based on the data in this paper. The range of promotion indices extended over more than eight orders of magnitude, whereas that of initiation indices was much less variable. Such parameters may be useful as quantitative estimates of the potency of hepatocarcinogenic agents, such values having potential application to risk estimations.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1987

Spontaneous tumors of the meninges in rats.

Histologic brain sections from 107 rats reported to have granular cell tumors or meningiomas in 2-year carcinogenicity studies conducted by the National Toxicology Program (NTP) or the National Cancer Institute (NCI) were reexamined microscopically. There were 62 rats with granular cell tumors, 26 with benign meningiomas, and 19 with meningeal sarcomas. Granular cell tumors were compatible with previous descriptions of this tumor. Meningeal sarcomas were subclassified into nine spindle cell sarcomas and ten fibrosarcomas. Among the rats with benign meningiomas, five were typical meningiomas (three fibroblastic meningiomas, and two meningothelial meningiomas) and 21 were meningothelial meningiomas containing cells with granules identical to those in granular cell tumors. There was a transition from epithelial-like cells of the meningothelial meningiomas to granular cells in these 21 cases. Based upon anatomic location, cytomorphologic similarities, and the occurrence of transitional or mixed forms of meningothelial meningiomas and granular cell tumors, it is suggested that these two tumors are related and may both originate from a common progenitor meningothelial arachnoid cell.

Animals↗
PubMed1987

Ovarian toxicity and carcinogenicity in eight recent National Toxicology Program studies.

Ovarian toxicity and/or carcinogenicity has been documented for at least eight chemicals recently tested in National Toxicity Program prechronic and chronic rodent studies. The chemicals that yielded treatment-related ovarian lesions were 1,3-butadiene, 4-vinylcyclohexene, vinylcyclohexene deipoxide, nitrofurantoin, nitrofurazone, benzene, delta-9-tetrahydrocannabinol, and tricresylphosphate. Typical nonneoplastic ovarian changes included hypoplasia, atrophy, follicular necrosis, and tubular hyperplasia. The most commonly observed treatment-related neoplasms were granulosa cell tumors and benign mixed tumors. A relationship between antecedent ovarian hypoplasia, atrophy, and hyperplasia and subsequent ovarian neoplasia is supported by some of these National Toxicology Program studies. Pathologic changes in other tissues such as the adrenal glands and uterus were associated with the treatment-related ovarian changes.

Animals↗
PubMed1987

The role of oncogenes in chemical carcinogenesis.

Proto-oncogenes are cellular genes that are expressed during normal growth and developmental processes. Altered versions of normal proto-oncogenes have been implicated in the development of human neoplasia. In this report, we show the detection of activated proto-oncogenes in various spontaneous and chemically induced rodent tumors. The majority of activated proto-oncogenes found in these tumors are members of the ras gene family and have been activated by a point mutation. Characterization of the activating mutation may be useful in determining whether this proto-oncogene was activated by direct interaction of the chemical with the DNA. Comparison of activating lesions in spontaneous versus chemically induced tumors should be helpful in determining whether the chemical acts via a genotoxic or a nongenotoxic mechanism. All of this information may be helpful in the assessment of potential carcinogenic hazards of human exposure to chemicals.

Animals↗
PubMed1987

Quantitation of silica-induced type II cell hyperplasia by using alkaline phosphatase histochemistry in glycol methacrylate embedded lung.

A light microscopic technique based on alkaline phosphatase histochemistry was developed to specifically quantitate Type II cells in the intact rat lung. Lungs were fixed in 4% neutral-buffered formalin containing 0.25 M sucrose and embedded in glycol methacrylate. Two micron thick sections were mounted on glass microscope slides. Alkaline phosphatase activity was localized by using naphthol AS-BI phosphate as substrate in 0.125 M 2-amino-2-methyl-1-propanol buffer containing 0.625 mM MgCl2 (pH 8.9). Sections were counterstained with Harris hematoxylin. Type II cells were the only cell type in the alveolar region containing alkaline phosphatase activity, an observation that was confirmed by using electron microscopic histochemistry. By combining the alkaline phosphatase staining technique with standard morphometric procedures, the proliferative response to a single intratracheal dose of 10 mg silica was followed as a function of time. Type II cells were significantly increased at all time points examined. Twenty eight days following silica, Type II cells had increased to (252 +/- 16) X 10(6) cells per set of lungs compared to a control value of (141 +/- 32) X 16(6) cells. The method presented is a simple and rapid technique for examining Type II cell population kinetics.

Alkaline Phosphatase↗
PubMed1987

Biochemical markers for Fischer rat leukemia in a cell transplant model.

Cellular glucose-metabolizing enzymes and acetylcholinesterase (AChE) have been utilized as biochemical markers of mononuclear cell (MNC) leukemia maintained by serial cell transplantation in F344 rats. We have evaluated the sensitivity and reproducibility of these tumor markers in comparison to other diagnostic criteria of leukemia. Weanling rats were injected with 2 X 10(7) leukemic spleen MNC and sampled at 6, 35, 63, and 83 days. At 6 days, the glycolytic enzyme activities from spleen that decreased were believed to be residual activity from injected leukemic MNC. Glycolytic enzyme activities in spleen MNC were normal at 35 days and no changes in blood MNC enzyme activity occurred at 6 days or 35 days. At 63 days, prior to clinical evidence of leukemia, glucose-metabolizing enzymes from spleen MNC changed, and there were decreases in AChE from both blood and spleen MNC that progressively decreased at 83 days, when there was depressed body weight, splenomegaly, elevated WBC, depressed RBC, hypoglycemia, hyperbilirubinemia, and elevated serum enzyme levels. Separation of leukemic MNC from blood and spleen enhances sensitivity of cellular enzyme responses and provides a reproducible model to study biochemical markers correlated with severity of leukemia.

Acetylcholinesterase↗
PubMed1986

Ethyl acrylate-induced gastric toxicity. III. Development and recovery of lesions.

Rats receiving 14 daily gavage doses of 100 or 200 mg/kg ethyl acrylate (EtAc) and killed at varying times following the end of dosing exhibited dose-dependent lesions and recovery from lesions in the forestomach. The glandular stomach which was previously shown to be affected by acute exposure to EtAc appeared to have adapted to resist EtAc toxicity with repeat exposure and appeared normal in all animals. Adaptation of the forestomach was characterized by increased papillomatous thickening with dose. Lesions observed in acute exposure to EtAc were still present with repeat dosing and were more pronounced at the high dose. Forestomachs of rats which received 100 mg/kg EtAc for 14 days were recovered to normal within 2 weeks following the last dose. Forestomachs of rats receiving 200 mg/kg EtAc still exhibited numerous lesions 2 weeks following the last dose, and mucosal hyperplasia was present in the forestomachs at 4 weeks postexposure. Two lesions, submucosal fibrosis and foreign body reaction, became more prevalent in high-dose animals with time. Foreign body reaction, which was present in all animals 4 weeks postexposure, appeared to have resulted from entrapment of hair and/or feed particles in forestomach lesions in the course of healing. It is speculated that the increased cell proliferation and the induced foreign body reactions may contribute to the previously demonstrated carcinogenic effect of EtAc on the rat forestomach.

Acrylates↗
PubMed1986

Regression of methyl bromide-induced forestomach lesions in the rat.

There is continuing concern about the role of irritation in cancer development. Methyl bromide, a widely used fumigant and known irritant reported to cause forestomach carcinomas in rats, was dissolved in peanut oil and given by gavage at 50 mg/kg body wt to Wistar rats five times per week for 13 to 25 weeks. Starting at Week 13, methyl bromide administration was discontinued for half of the methyl bromide-treated rats (stop treatment group). After that, rats from both the continuous treatment and stop treatment groups were terminated at 4-week intervals to follow the progression of the stomach lesions. Forestomach lesions were not found in control rats receiving peanut oil and killed at 13 or 25 weeks. At 13 weeks the forestomachs from rats receiving methyl bromide were contracted and adherent to the liver and spleen. Inflammation, acanthosis, fibrosis, and a high incidence of pseudoepitheliomatous hyperplasia were found microscopically in treated animals. At 25 weeks, 100% of the rats receiving methyl bromide continuously had hyperplastic lesions of the forestomach which were more severe than those at 13 weeks. Evidence of malignancy was seen in one rat and the lesion was considered a very early carcinoma. In the stop treatment group that received methyl bromide for 13 weeks, there was regression of the stomach lesions, but at the 12-week final sacrifice, adhesions, fibrosis, and mild acanthosis remained. This study illustrates the need for regression experiments for complex forestomach lesions in rodents, especially when an irritating chemical is given by gavage.

Administration, Oral↗
PubMed1986

Chronic toxicity and oncogenicity studies of ethylene glycol in rats and mice.

These studies were performed to assess the chronic toxicity and oncogenicity of ethylene glycol (EG) in rats and mice. Groups of 130 Fischer 344 rats and 80 CD-1 mice per sex were fed diets yielding approximate dosages of 1.0, 0.2, or 0.04 g/kg/day of EG. Two separate control groups in each study received no EG. Mortality rate was increased in high-dose male rats all of which died by 475 days. The following effects were also observed in high dose male rats: reduced body weight gain, increased water intake, increased blood urea nitrogen and creatinine, reduced erythrocyte count, reduced hematocrit and hemoglobin, increased neutrophil count, increased urine volume, reduced specific gravity and pH. Urinary calcium oxalate crystals and increased kidney weight were seen in all high-dose rats. Uric acid crystals were seen in the urine of high-dose female rats at 18 and 24 months. Histopathologic changes in high-dose male rats included tubular cell hyperplasia, tubular dilation, peritubular nephritis, parathyroid hyperplasia, and generalized soft tissue mineralization. Fatty change of the liver was seen in high- and intermediate-dose female rats. No clinical signs, or gross or microscopic evidence of toxicity was seen in mice at the dosages used. Water intake and clinical pathologic parameters were not measured in the mouse study. In these studies there was no evidence of an oncogenic effect of EG in rodents.

Animals↗
PubMed1986

Three-generation reproduction and dominant lethal mutagenesis studies of ethylene glycol in the rat.

To assess the possible effects of ethylene glycol (EG) on reproductive performance and mutagenesis, three-generation reproduction and dominant lethal mutagenesis studies were performed in the Fischer 344 rat. EG was included in the diet at approximate dosages of 1.0, 0.2, and 0.04 g/kg/day during three generations of reproduction. Each generation was bred once. In a dominant lethal mutagenesis study, the F2 males from the reproduction study were bred to three consecutive lots of untreated females at weekly intervals. Concomitantly, another group of untreated F2 males that received a single ip injection of 0.50 mg/kg triethylenemelamine (TEM) were bred similarly to serve as a positive control group. No evidence of reduced fertility or increased fetal death was observed in any of the groups receiving EG. Dominant lethal effects in the TEM group confirmed the susceptibility of the rats to a known mutagen. In conclusion, there were no reproductive or dominant lethal effects associated with the inclusion of as much as 1.0 g/kg/day of EG in the diet.

Animals↗
PubMed1986

Frequency, size and location of brain tumours in F-344 rats chronically exposed to ethylene oxide.

Increased frequencies of primary brain tumours were seen in male and female F-344 rats exposed to 100 or 33 ppm ethylene oxide (EO) vapour (for 6 hr daily on 5 days/wk for up to 2 yr) but no such increase was seen in rats similarly exposed to 10 ppm EO. The tumours that were seen (glial-cell tumours, granular-cell tumours and malignant reticuloses) were similar in appearance to those that develop spontaneously in F-344 rats, but the tumours associated with EO exposure at levels of 100 or 33 ppm were larger, and in at least six cases were thought to be the primary cause of death. Only two of the 23 tumours seen microscopically were detected by gross examination at necropsy, and brain weights were of minimal value in predicting the presence of tumours. Only three animals demonstrated abnormal neurological signs. These findings point to the need for thorough microscopic examination of the brains of rodents in chronic studies.

Age Factors↗
PubMed1986

Toxicity of formaldehyde vapor in B6C3F1 mice exposed for 13 weeks.

Groups of 10 male and 10 female B6C3F1 mice were exposed to 0, 2, 4, 10, 20, or 40 ppm of formaldehyde vapor 6 h/day, 5 days/week for 13 weeks. Clinical abnormalities (dyspnea, listlessness, and hunched posture), significant mortality, and body weight loss were observed in the 40 ppm groups. Pathologic changes were observed in the nose, larynx, trachea, and bronchi of treated males and females and in the uterus and ovaries of treated females. Squamous metaplasia and inflammation were present in the nasal tissues of male and female mice in the 10, 20, and 40 ppm groups and in the larynx of males and females in the 20 and 40 ppm groups. The trachea had squamous metaplasia and hyperplasia of the epithelium in addition to submucosal fibrosis and inflammation in the 20 and 40 ppm groups. In some mice, epithelial-lined, irregular connective tissue bands spanned the tracheal lumen. Metaplasia of the bronchial epithelium was confined to the 40 ppm exposure groups. These effects on the respiratory system were more prevalent in male than in female mice. Hypoplasia of the uterus and ovaries, probably secondary to body weight loss, was confined to the 40 ppm exposure group. In conclusion, 13-week inhalation exposures of B6C3F1 mice to 10, 20, and 40 ppm of formaldehyde vapor induced histologic lesions in the upper respiratory system and concentrations of 40 ppm were lethal to those mice.

Animals↗
PubMed1986

Association of chemically induced forestomach cell proliferation and carcinogenesis.

A number of chemicals have been shown to cause malignant neoplasms in the forestomach of Fischer 344 rats when administered chronically by gavage. The present study was designed to identify early forestomach lesions following 2-week repeated gavage administration of some of these forestomach carcinogens. In this manner, we attempted to examine the hypothesis that early cell proliferation is associated with repetitive gavage administration of these chemicals. Groups of 8 or more male F344 rats received 1 of 6 reported forestomach carcinogens (ethyl acrylate (EtAc), diglycidyl resorcinol ether(DGRE), 1,2-dibromoethane (DBE), 1,2-dibromo-3-chloro-propane (DBCP), 1-chloro-2-methylpropene (dimethylvinyl chloride, DMVC) and 3-chloro-2-methylpropene (CMP)), 1 of 2 structurally related chemicals (methyl methacrylate (MMA) and dichloroethane (DCE)) which were negative in chronic carcinogenicity studies or the vehicle (corn oil) alone 5 days/week for 2 weeks. Histopathologic examination of forestomachs of rats killed 24 h after the last dose indicated no significant difference in the incidence or severity of epithelial cell proliferation in the rat forestomach between the vehicle control group and the 2 negative control groups. In contrast, the incidence and severity of epithelial cell proliferation of the rat forestomach in every group treated with a forestomach carcinogen was significantly higher than the incidence in the vehicle or negative control groups. These results suggest that early epithelial cell proliferation of the forestomach may be associated with at least some chemicals that induce forestomach neoplasia following chronic administration by gavage.

Animals↗
PubMed1986

Detection and identification of activated oncogenes in spontaneously occurring benign and malignant hepatocellular tumors of the B6C3F1 mouse.

Species- and strain-specific spontaneously occurring tumors have been observed in rodents maintained under normal laboratory conditions. Elucidation of the molecular mechanisms associated with the development of these spontaneous tumors may provide a better understanding of tumor development associated with exposure to chemical carcinogens. In view of the high frequencies of oncogene activation shown in rodent tumors induced by known chemical carcinogens, we have investigated oncogene activation in spontaneous tumors of the B6C3F1 mouse and Fischer 344/N rat by DNA transfection techniques. A marked difference in the presence of activated oncogenes in spontaneous rat tumors versus spontaneous mouse liver tumors was observed in this study. All rat tumors tested failed to yield activated oncogenes (0/29), whereas 30% (3/10) of mouse hepatocellular adenomas and 77% (10/13) of hepatocellular carcinomas scored positive by DNA transfection. These transforming genes were identified as an activated Ha-ras gene in all the adenoma transfectants and in 8 of the 10 carcinoma transfectants. The two remaining hepatocellular carcinomas contained transforming genes that appear not to be members of the known ras gene family. The B6C3F1 mouse liver system might provide a very sensitive assay not only for assessing the potential of a chemical to activate a cellular proto-oncogene, but also for detecting various classes of proto-oncogenes that are susceptible to mutational activation.

Adenoma↗
PubMed1986

National Toxicology Program nomenclature for hepatoproliferative lesions of rats.

Diagnostic criteria for hepatoproliferative lesions of Fischer 344 rats are presented to permit more complete categorization of the spectrum of lesions observed in two-year chemical carcinogenicity studies. A nomenclature recently adopted by the National Toxicology Program differs from previous classification schemes in that hepatocellular hyperplasia and hepatocellular adenoma are to be used for lesions which were previously combined under the diagnosis of neoplastic nodule. The term hyperplasia is reserved for proliferative lesions that are perceived to be secondary, nonneoplastic responses to degenerative changes in the liver. Foci of cellular alteration, hepatocellular adenoma, and hepatocellular carcinoma are believed to represent a spectrum of changes that comprise the natural history of neoplasia. This change in nomenclature was made subsequent to a peer review of representative hepatoproliferative lesions from two-year carcinogenicity studies. The revised nomenclature is consistent with traditional pathologic diagnoses for proliferative lesions in other epithelial tissues and should facilitate the interpretation of conventional toxicity and carcinogenicity studies in rats. Morphologic features of other selected rat liver lesions are also presented.

Animals↗
PubMed1986

Strain A mouse pulmonary tumor test results for chemicals previously tested in the National Cancer Institute carcinogenicity tests.

Sixty-five chemicals were coded and examined for their ability to induce lung tumors in strain A/St (laboratory A) or strain A/J (laboratory B) mice. Thirty-five chemicals were tested in laboratory A only, 6 in laboratory B only, and 24 in both laboratories. Two-year carcinogenicity test results as well as genotoxicity test data are available for most of these chemicals. There was poor interlaboratory agreement in strain A test results for the 24 chemicals tested in both laboratories. In addition, there was poor agreement between strain A test results from either laboratory and 2-year carcinogenicity test results or genotoxicity results. Possible explanations for these findings include selection of a large number of aromatic amines in the group of chemicals submitted for strain A testing, differences in strain A testing protocols and in statistical analysis of results from the two laboratories, low sensitivity of the strain A/St mice used in this particular study, and general problems inherent in comparing any relatively short-term animal tumor model with 2-year carcinogenicity tests. Since there is no absolute reference for carcinogenicity, no one test system is better than another. Carcinogenicity test data are relevant only to the test model employed.

Animals↗
PubMed1986

Forestomach ulcers in Crj:B6C3 (C57BL/6NCrj x C3H/HeNCrj) F1 mice.

An unusually high incidence of forestomach ulcers was observed in a mouse strain that is used frequently for long-term toxicology studies. Examination of 98 untreated male and 98 untreated female B6C3F1 hybrid mice, the majority of which were between 105 and 113 weeks of age, revealed forestomach ulcers in 52% of the males and 54% of the females. Glandular stomach ulcers were uncommon, being found in only four female mice. The incidence of the ulcers increased with age. The etiology of the lesion is unknown.

Animals↗