RESUMEN
Chromium picolinate monohydrate (CPM) is a synthetic compound heavily marketed to consumers in the United States for use as a dietary supplement for muscle building and weight loss. The National Toxicology Program (NTP) tested the toxicity of this compound based on the potential for widespread consumer exposure and lack of information about its toxicity. Groups of 10 male and 10 female F344/N rats and B6C3F(1) mice were exposed to 0, 80, 240, 2000, 10,000, or 50,000 ppm CPM in feed for 13 weeks. CPM administration produced no effect on body weight gain or survival of rats or mice. Organ weights and organ/body weight ratios in exposed animals were generally unaffected by CPM. No compound-related changes in hematology and clinical chemistry parameters were observed. There were no histopathological lesions attributed to CPM in rats or mice.
Asunto(s)
Composición Corporal/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Quelantes del Hierro/toxicidad , Ácidos Picolínicos/toxicidad , Administración Oral , Animales , Relación Dosis-Respuesta a Droga , Ingestión de Alimentos/efectos de los fármacos , Estro/efectos de los fármacos , Femenino , Quelantes del Hierro/farmacocinética , Quelantes del Hierro/farmacología , Masculino , Ratones , Ratones Endogámicos , Tamaño de los Órganos/efectos de los fármacos , Ácidos Picolínicos/farmacocinética , Ácidos Picolínicos/farmacología , Distribución Aleatoria , Ratas , Ratas Endogámicas F344 , Espermatozoides/efectos de los fármacos , Análisis de Supervivencia , Distribución Tisular , Pruebas de Toxicidad CrónicaRESUMEN
The toxicologic and carcinogenic potential of naphthalene was studied by exposing groups of 49 male and 49 female F344 rats to atmospheres containing 0, 10, 30, or 60 ppm of the chemical for 6 h daily, 5 days/wk for 2 yr. Mean body weights of exposed groups of male rats were less than for the control group throughout most of the study. Mean body weights of exposed female rats were generally similar to those of controls. Survival of exposed and control rats was similar. Under the conditions of this 2-yr inhalation study, naphthalene was carcinogenic to male and female F344/N rats, causing increased incidences of respiratory epithelial adenoma (males: control, 0%; low dose, 12%, mid dose, 17%; high dose, 31%; females: 0%; 0%; 8%; 4%) and olfactory epithelial neuroblastoma (males: control, 0%; low dose, 0%; mid dose, 8%; high dose, 6%; females: 0; 4%; 6%; 24%) of the nose. In both sexes of rats, exposure to naphthalene also caused significant increases in the incidences of nasal lesions including hyperplasia, atrophy, chronic inflammation, and hyaline degeneration of the olfactory epithelium and hyperplasia; squamous metaplasia, hyaline degeneration, and goblet-cell hyperplasia of the respiratory epithelium; and glandular hyperplasia and squamous metaplasia.
Asunto(s)
Naftalenos/toxicidad , Neoplasias Nasales/inducido químicamente , Administración por Inhalación , Animales , Sistema Enzimático del Citocromo P-450/fisiología , Femenino , Pulmón/efectos de los fármacos , Pulmón/patología , Masculino , Naftalenos/administración & dosificación , Naftalenos/metabolismo , Nariz/efectos de los fármacos , Nariz/patología , Neoplasias Nasales/patología , Ratas , Ratas Endogámicas F344 , Especificidad de la Especie , VolatilizaciónRESUMEN
Methyleugenol, a food flavor and fragrance agent, was tested for toxicity in male and female F344/N rats and B6C3F1 mice. Groups of 10 males and 10 females per sex per species were administered 0, 10, 30, 100, 300 or 1000 mg methyleugenol/kg body weight in 0.5% aqueous methylcellulose by gavage, 5 days per week for 14 weeks. Additional groups of rats and mice of each sex were dosed similarly and used for hematology and clinical chemistry studies. Groups of 10 male and 10 female rats and mice received the vehicle by gavage on the same dosing schedule and served as vehicle controls. For serum gastrin, gastric pH and cell proliferation studies groups of 10 female rats were given 0, 37, 75 or 150 mg/kg, once daily 5 days per week for 30 or 90 days or 300 or 1000 mg/kg for 30 days; male mice were given 0, 9, 18.5, 37, 75, 150 or 300 mg/kg for 30 or 90 days. For the gastrin, pH and cell proliferation studies, groups of 10 female rats and 10 male mice were given the vehicle for 30 or 90 days and served as controls. Methyleugenol administration to rats induced erythrocyte microcytosis and thrombocytosis in male and female rats. It also caused an increase in serum alanine aminotransferase and sorbitol dehydrogenase activities and bile acid concentration, suggesting hepatocellular injury, cholestasis or altered hepatic function. Additionally, methyleugenol induced hypoproteinemia and hypoalbuminemia, evidenced by decreased total protein and albumin concentrations in both male and female rats, suggesting in inefficiency of dietary protein utilization due to methyleugenol-induced toxic effects on the liver and glandular stomach of rats and mice. The increase in gastrin and gastric pH of rats and mice given methyleugenol suggests that gastrin feedback was impaired and resulted in conditions not conducive to protein digestion. In rats, methyleugenol caused an increase in the incidences of hepatocyte cytologic alteration, cytomegaly, Kupffer cell pigmentation, mixed foci of cellular alteration and bile duct hyperplasia of the liver and atrophy and chronic inflammation of the mucosa of the glandular stomach. In mice, it caused an increase in the incidence of cytologic alteration, necrosis, bile duct hyperplasia and subacute inflammation of the liver and atrophy, degeneration, necrosis, edema, mitotic alteration, and cystic glands of the fundic region of the glandular stomach. The increased incidences of adrenal gland cortical hypertrophy and/or cytoplasmic alteration in the submandibular salivary glands, adrenal glands, testis and uterus of rats were considered secondary to the chemical-related effects observed in the liver and glandular stomach. Based on mortality, body weight gain, clinical chemistry and gross and microscopic evaluation of tissues of rats and mice, the no-observed-effect level (NOEL) of methyleugenol for both species was estimated at 10 mg/kg.
Asunto(s)
Eugenol/toxicidad , Mucosa Gástrica/efectos de los fármacos , Hígado/efectos de los fármacos , Mutágenos/toxicidad , Alanina Transaminasa/sangre , Animales , Peso Corporal , División Celular/efectos de los fármacos , Pruebas Inmunológicas de Citotoxicidad , Relación Dosis-Respuesta a Droga , Eritrocitos , Eugenol/análogos & derivados , Femenino , Mucosa Gástrica/metabolismo , Mucosa Gástrica/patología , Gastrinas/sangre , Concentración de Iones de Hidrógeno , L-Iditol 2-Deshidrogenasa/metabolismo , Hígado/enzimología , Hígado/patología , Masculino , Ratones , Tamaño de los Órganos/efectos de los fármacos , Especificidad de Órganos , Ratas , Ratas Endogámicas F344 , TrombocitosisRESUMEN
Methyleugenol (MEG) was tested for toxicity/carcinogenicity in a 2-yr carcinogenesis bioassay because of its widespread use in a variety of foods, beverages, and cosmetics as well as its structural resemblance to the known carcinogen safrole. F344/N rats and B6C3F(1) mice (50 animals/sex/dose group) were given MEG suspended in 0.5% methylcellulose by gavage at doses of 37, 75, or 150 mg/kg/day for 2 yr. Control groups (60 rats/sex and 50 mice/sex) received only the vehicle. A stop-exposure group of 60 rats/sex received 300 mg/kg/day by gavage for 53 weeks followed by the vehicle only for the remaining 52 weeks of the study. A special study group (10 animals/sex/species/dose group) were used for toxicokinetic studies. All male rats given 150 and 300 mg/kg/day died before the end of the study; survival of female rats given 150 mg/kg/day and all treated female mice was decreased. Mean body weights of treated male and female rats and mice were decreased when compared to control. Area under the curve results indicated that greater than dose proportional increases in plasma MEG occurred for male 150 and 300 mg/kg/day group rats (6 and 12 month) and male 150 mg/kg/day mice (12 month). Target organs included the liver, glandular stomach, forestomach (female rats) and kidney, mammary gland, and subcutaneous tissue (male rats). Liver neoplasms occurred in all dose groups of rats and mice and included hepatoadenoma, hepatocarcinoma, hepatocholangioma (rats only), hepatocholangiocarcinoma, and hepatoblastoma (mice only). Nonneoplastic liver lesions included eosinophilic and mixed cell foci (rats only), hypertrophy, oval cell hyperplasia, cystic degeneration (rats only), and bile duct hyperplasia. Mice also exhibited necrosis, hematopoietic cell proliferation, and hemosiderin pigmentation. Glandular stomach lesions in rats and mice included benign and malignant neuroendocrine tumors, neuroendocrine cell hyperplasia, and atrophy and in mice included glandular ectasia/chronic active inflammation. In female rats, the forestomach showed a positive trend in the incidences of squamous cell papilloma or carcinoma (combined). Male rats also exhibited kidney (renal tubule hyperplasia, nephropathy, and adenomacarcinoma), mammary gland (fibroadenoma), and subcutaneous tissue (fibroma, fibrosarcoma) lesions. Male rats also exhibited malignant mesotheliomas and splenic fibrosis. These data demonstrate that MEG is a multisite, multispecies carcinogen.
Asunto(s)
Carcinógenos/toxicidad , Eugenol/análogos & derivados , Animales , Peso Corporal , Pruebas de Carcinogenicidad , Eugenol/toxicidad , Femenino , Masculino , Ratones , Ratones Endogámicos , Ratas , Ratas Endogámicas F344RESUMEN
The influence of supplemental glycine on benzyl acetate (BA; a compound metabolized via the hippurate pathway)-induced toxicity was investigated. Groups of male F344 rats were fed NIH-07 diet containing 0, 20,000, 35,000, or 50,000 ppm BA for up to 28 days. Two additional groups were fed NIH-07 diet with 50,000 ppm BA and 27,000 ppm glycine or 50,000 ppm BA 32,000 ppm L-alanine; supplemental glycine and L-alanine were equimolar. The L-alanine group served as an amino nitrogen control. A third group was fed NIH-07 diet with 32,000 ppm L-alanine and served as an untreated isonitrogenous control BA caused increase in mortality, body weight loss, the incidence of abnormal neurobehavioral signs such as ataxia and convulsions, along with astrocyte hypertrophy and neuronal necrosis in the cerebellum, hippocampus, and pyriform cortex of the brain. These effects were reduced significantly by supplementation with glycine but not with L-alanine. These results suggest that the neurodegeneration induced by BA is mediated by a depletion of the glycine pool and the subsequent excitotoxicity.
Asunto(s)
Compuestos de Bencilo/efectos adversos , Glicina/farmacología , Enfermedades Neurodegenerativas/prevención & control , Contaminantes Ocupacionales del Aire/efectos adversos , Animales , Ataxia/inducido químicamente , Ataxia/prevención & control , Encéfalo/efectos de los fármacos , Encéfalo/patología , Suplementos Dietéticos , Relación Dosis-Respuesta a Droga , Glicina/administración & dosificación , Hipertrofia/inducido químicamente , Hipertrofia/prevención & control , Masculino , Necrosis , Enfermedades Neurodegenerativas/inducido químicamente , Enfermedades Neurodegenerativas/mortalidad , Enfermedades Neurodegenerativas/patología , Tamaño de los Órganos/efectos de los fármacos , Ratas , Ratas Endogámicas F344 , Convulsiones/inducido químicamente , Convulsiones/prevención & control , Tasa de Supervivencia , Pérdida de Peso/efectos de los fármacosRESUMEN
Isobutyraldehyde (a chemical structurally related to formaldehyde and used as a flavoring agent) was studied for toxicity and carcinogenicity by exposing male and female F344/N rats and B6C3F1 mice. Animals were exposed to isobutyraldehyde vapors 6 h per day, 5 days per week for up to 13 weeks or 2 years. In the 13-week studies, groups of 10 male and 10 female F344/N rats and B6C3F1 mice were exposed to concentrations of 0, 500, 1000, 2000, 4000, or 8000 ppm. Chemical-related body weight depression and deaths occurred in rats and mice exposed to 4000 and 8000 ppm. Necrosis of the epithelium accompanied with acute inflammatory reaction was observed in the nasal turbinate, larynx, and trachea of rats exposed to 8000 ppm. Exposure of rats to 4000 ppm resulted in metaplasia of the nasal respiratory epithelium, inflammation, degeneration of the olfactory epithelium, and osteodystrophy of the nasal turbinate bone. In the 13-week mouse study, exposure to 8000 ppm or 4000 ppm resulted in necrosis of the epithelium lining of the nasal turbinates. Osteodystrophy of the nasal turbinate bone and squamous metaplasia of the nasal respiratory epithelium were noted in mice exposed 4000 ppm. Degeneration of the olfactory epithelium was noted in males exposed 2000 ppm and in females exposed to 4000 ppm. In the 2-year studies, groups of 50 male and 50 male F344/N rats and B6C3F1 were exposed to concentrations isobutyraldehyde vapors of 0, 500, 1000, or 2000 ppm 6 h per day, 5 days per week. There were no differences in survival rates or mean body weights between exposed groups and control rats. Survival of male mice exposed to 2000 ppm and mean body weights of female mice exposed to 1000 or 2000 ppm were lower than those of the of the controls. No increase in neoplasm incidence was observed in rats and mice in the 2-year studies that could be attributed to isobutyraldehyde exposure. Chemical-related nonneoplastic lesions were limited to the nose of rats and mice. They included squamous metaplasia of the respiratory epithelium (rats), suppurative inflammation (rats), and olfactory epithelial degeneration (rats and mice) at 1000 and 2000 ppm.
Asunto(s)
Aldehídos/toxicidad , Sistema Respiratorio/efectos de los fármacos , Aldehídos/administración & dosificación , Animales , Peso Corporal/efectos de los fármacos , Pruebas de Carcinogenicidad , Relación Dosis-Respuesta a Droga , Femenino , Exposición por Inhalación , Masculino , Metaplasia , Ratones , Ratones Endogámicos , Ratas , Ratas Endogámicas F344 , Sistema Respiratorio/patologíaRESUMEN
Salicylazosulfapyridine (SASP), which has been in clinical use for over 50 years, was reported by the National Toxicology Program to increase rat (F344 strain) urinary bladder and mouse (B6C3F1 hybrid) liver tumours under ad libitum (AL) feeding conditions, while under a feed restriction (FR) regimen, these tumours were not increased. The present investigations were undertaken to assess the implications of these results for the safety of SASP in humans. SASP and its 2 major metabolites, 5-aminosalicylic acid (ASA) and sulfapyridine (SP) were tested for in vivo induction of micronuclei in mouse bone marrow cells with or without prefolic treatment and for in vivo formation of DNA adducts in rat and mouse liver and urinary bladder. None exhibited mutagenicity or DNA reactivity. SASP and SP have induced sister chromatid exchanges and micronuclei (MN) in cultured human lymphocytes in the absence of liver activation enzymes and in B6C3F1 mice (but not in rats) MN in bone marrow and peripheral RBC. Treatment with folate reduces the frequency of MN. Perhaps the short (28 days) RBC lifespan in mouse underlies the sensitivity of this species. Thus, SASP without folate supplementation is an aneuploidogen. In a 2-year study in AL fed SASP-treated (high dose 337.5 mg/kg) rats, urinary pH was increased and urinary specific gravity was reduced at 60 weeks. At the end, this SASP group showed urothelial hyperplasia and papillomas in the urinary bladders of male rats primarily. In the FR high dose SASP group, the hyperplasia was reduced from 82% to 14%. At the end of 2 years, the incidence of multi-organ leukemia was reduced in both AL and FR high dose SASP groups. Thus, SASP caused intraluminal bladder changes in the rat (especially males) consisting of chronic urothelial stimulation, concretions, hyperplasia which resulted in neoplasia. In the mouse, because of species differences in liver ratios (mouse > rat) and, increasing (3 times higher) liver perfusion in the mouse, compared to the rat, there was hepatocellular toxicity and resulting preneoplasia and neoplasia within 2 years. These findings occurred in all AL SASP groups (flat curve without dose response); but were reduced under FR conditions. In this species, the multiorgan lymphoma incidence was reduced in both AL and FR high dose SASP groups. Thus, SASP and its major metabolites are not genotoxic. Folate deficiency associated with SASP administration is probably responsible for aneuploidy in lymphocytes and erythrocytes. SASP does not induce neoplasia directly in either livers, urinary bladders or other organs. Accordingly, SASP is judged to pose no carcinogenic risk to humans.
Asunto(s)
Antiinflamatorios/toxicidad , Médula Ósea/efectos de los fármacos , Hígado/efectos de los fármacos , Sulfasalazina/toxicidad , Vejiga Urinaria/efectos de los fármacos , Ácidos Aminosalicílicos/farmacocinética , Ácidos Aminosalicílicos/toxicidad , Animales , Antiinfecciosos/farmacocinética , Antiinfecciosos/toxicidad , Antiinflamatorios/farmacocinética , Pruebas de Carcinogenicidad , Aductos de ADN/efectos de los fármacos , Femenino , Ácido Fólico/farmacología , Masculino , Mesalamina , Ratones , Micronúcleos con Defecto Cromosómico/efectos de los fármacos , Pruebas de Mutagenicidad , Ratas , Ratas Sprague-Dawley , Medición de Riesgo , Sulfapiridina/farmacocinética , Sulfapiridina/toxicidad , Sulfasalazina/farmacocinéticaRESUMEN
Studies were undertaken to compare outcomes when four chemicals were evaluated under typical NTP bioassay conditions as well as by protocols employing dietary restriction. Four chemicals, using three different routes of exposure (in utero [accomplished by feeding the dam dosed feed], dosed feed, and gavage) were used to 1) evaluate the effect of diet restriction on the sensitivity of the bioassay toward chemically-induced chronic toxicity and carcinogenicity; and 2) evaluate the effect of weight-matched control groups on the sensitivity of the bioassays. Control and chemical exposed F344 rats and B6C3F1 mice (50-60/group) were fed NIH-07 diet either ad libitum or at restricted levels such that body weights were approximately 80% of ad libitum control weights. The dietary restricted groups were either sacrificed at the end of two or 3-years. Results consistently show that feed restriction decreased the incidence of neoplastic and non-neoplastic lesions at a variety of anatomic sites in both control and chemical exposed animals. Furthermore, the sensitivity of the bioassay to detect chemical carcinogenic response were altered by dietary restriction: three of the four chemicals were found to increase the incidence of neoplastic lesions at four sites when evaluated under standard ad libitum conditions for 104 weeks. When unexposed and exposed groups were both subjected to dietary restriction, none of these 4 sites were detected as a target for carcinogenesis after two or three years. Rather, two different sites of carcinogenesis were detected. When the top dosed ad libitum fed animals were compared against their weight-matched control groups, a total of 10 sites were identified as targets for carcinogenesis. These included all four sites identified under the ad libitum protocol, both sites identified under the feed restricted protocol, and an additional four sites that were not identified under the other two protocols. These studies show that dietary restriction of all animals can be expected of decrease the sensitivity of carcinogenesis bioassays. However, restricting only unexposed groups (weight matching) of control for non-specific weight loss in chemical exposed groups yielded the most sensitivity among our comparisons.
Asunto(s)
Pruebas de Carcinogenicidad/métodos , Privación de Alimentos , Animales , Peso Corporal/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ingestión de Alimentos , Femenino , Hidroquinonas/administración & dosificación , Hidroquinonas/toxicidad , Intubación Gastrointestinal , Masculino , Ratones , Ratones Endogámicos C57BL , Ácidos Ftálicos/administración & dosificación , Ácidos Ftálicos/toxicidad , Ratas , Ratas Endogámicas F344 , Escopolamina/administración & dosificación , Escopolamina/toxicidad , Sensibilidad y Especificidad , Sulfasalazina/administración & dosificación , Sulfasalazina/toxicidadRESUMEN
2,3-Dibromo-1-propanol is a metabolite of the flame retardant tris(2,3-dibromopropyl) phosphate, previously shown to be a mutagen and carcinogen in experimental animals. Toxicology and carcinogenesis studies of 2,3-dibromo-1-propanol were conducted by applying the chemical in 95% ethanol to the interscapular skin of male and female F344/N rats and B6C3F1 mice 5 days a week for 13 weeks in the prechronic study and 48-55 weeks (rats) or 36-42 weeks (mice) in the carcinogenicity study. In the 13-week study, 10 rats and 10 mice of each sex received doses of 0, 44, 88, 177, 375, or 750 mg/kg. Deaths associated with chemical application occurred only in the high-dose (750 mg/kg) male mice. Chemical-related lesions were seen in the kidney of male rats, liver of female rats, and liver and lung of both sexes of mice. Based on the toxicity observed in the 13-week study, 50 rats of each sex received doses of 0, 188, or 375 mg/kg and 50 mice of each sex received 0, 88, or 177 mg/kg in the carcinogenicity study. The planned 2-year study was terminated early because of reduced survival of rats related to chemical-induced neoplasia and because of the appearance of antibodies to lymphocytic choriomeningitis virus in sentinel mice. Nearly all dosed rats had malignant neoplasms at one or more sites, while only one control male and one control female had malignant neoplasms. In rats, neoplasms induced by 2,3-dibromo-1-propanol occurred in the skin, nasal mucosa, Zymbal's gland, oral mucosa, esophagus, forestomach, intestines, liver, kidney, mammary gland (females), clitoral gland (females), spleen (males), and mesothelium (males). In mice, chemical-induced neoplasms occurred in the skin, forestomach, liver (males), and lung (males).
Asunto(s)
Pruebas de Carcinogenicidad , Neoplasias Experimentales/inducido químicamente , Propanoles , 1-Propanol/administración & dosificación , 1-Propanol/toxicidad , Administración Cutánea , Animales , Femenino , Neoplasias Gastrointestinales/inducido químicamente , Masculino , Ratones , Ratones Endogámicos , Ratas , Ratas Endogámicas F344 , Neoplasias Cutáneas/inducido químicamenteRESUMEN
The modulatory effects of caloric intake on the rate and extent of both spontaneous and induced disease incidence is well known, but the significance of these effects in the interpretation of testing data has only recently become appreciated. This is especially true relative to the impact of caloric intake on both survival and background incidence for common tumors. In order to enhance the health and survival of animals ongoing chronic toxicity testing it has been suggested that such tests should restrict food consumption. Although this restriction will result in increasing survival of the test animals, it may also effect the expression of toxicity by altering agent metabolism and disease progression. Focus in this symposium is on the necessity to control dietary consumption in toxicity tests (dietary control), and if such a need does exist to what level of consumption should be diet be focused (caloric restriction).
Asunto(s)
Bioensayo/métodos , Ingestión de Energía/fisiología , Enzimas/metabolismo , Pruebas de Toxicidad/métodos , Animales , Peso Corporal , Evaluación Preclínica de Medicamentos , Humanos , Ratones , Ratas , Ratas Sprague-Dawley , Sensibilidad y EspecificidadRESUMEN
Isobutyl nitrite (IBN) is a volatile liquid that has become increasingly popular as an inhaled recreational drug. To investigate short-term toxic effects and establish exposure parameters for chronic inhalation studies, F344/N rats and B6C3F1 mice were exposed to IBN vapors on a 6 hr/day + t90, 5 days/week schedule. Twelve exposures were administered at concentrations of 0, 100, 200, 400, 600, and 800 ppm IBN. This exposure series resulted in mortality in rats exposed to greater than or equal to 600 ppm and mice exposed to 800 ppm. Animals exposed at the lower concentrations developed hyperplasia of the bronchiolar and nasal turbinate epithelium (rats and mice) and lymphocytic atrophy in the spleen and thymus (mice). Longer term, 13-week, subchronic exposures were conducted at concentrations of 0, 10, 25, 75, 150, and 300 ppm IBN. Exposure to 300 ppm IBN reduced the body weight gains in both sexes of rats and in female mice. IBN-related clinical pathology changes included reduced RBC counts accompanied by moderate increases in mean corpuscular volume and reticulocyte counts, increased WBC counts, and mildly increased methemoglobin concentration. Bone marrow hyperplasia was observed in all groups of IBN-exposed rats, while in mice only females at greater than or equal to 150 ppm IBN displayed this change. Excessive splenic pulp hematopoiesis was noted in mice at all IBN exposure levels.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Butanos/toxicidad , Drogas Ilícitas/toxicidad , Nitratos/toxicidad , Administración por Inhalación , Animales , Peso Corporal/efectos de los fármacos , Médula Ósea/efectos de los fármacos , Médula Ósea/patología , Butanos/administración & dosificación , Epitelio/efectos de los fármacos , Epitelio/patología , Femenino , Hematología , Hematopoyesis/efectos de los fármacos , Hiperplasia , Pulmón/efectos de los fármacos , Pulmón/patología , Masculino , Ratones , Mucosa Nasal/efectos de los fármacos , Mucosa Nasal/patología , Nitratos/administración & dosificación , Ratas , Ratas Endogámicas F344 , Especificidad de la EspecieRESUMEN
Groups of 20 rats and 20 mice of each sex were administered monochloroacetic acid (MCAA) once daily, 5 days per week, in water by gavage for up to 13 weeks. Doses used were 0, 30, 60, 90, 120, or 150 mg/kg for rats and 0, 25, 50, 100, 150, or 200 mg/kg for mice. Compound-related deaths occurred at the four highest dose levels in rats and at the highest dose level in mice. Mean body weights of treated groups of rats and mice surviving until the end of the study were similar to those of the controls. A dose-related increase in blood urea nitrogen, alanine aminotransferase, aspartate aminotransferase, as well as a dose-related increase in the relative liver and kidney weights was observed in rats but not in mice. A dose-related increase in the incidence and severity of cardiomyopathy occurred in rats. This lesion may be related to the inhibition of heart mitochondrial aconitase activity. No compound-related lesions were observed in mice. The results of this study indicate that F344 rats are more sensitive than B6C3F1 mice; sexes within the species were equally sensitive. The no-observable-effect level was estimated as 30 mg MCAA/kg body weight for rats and 100 mg MCAA/kg body weight for mice.
Asunto(s)
Acetatos/toxicidad , Carcinógenos/toxicidad , Aconitato Hidratasa/antagonistas & inhibidores , Aconitato Hidratasa/metabolismo , Animales , Peso Corporal/efectos de los fármacos , Cardiomiopatías/inducido químicamente , Cardiomiopatías/patología , Femenino , Riñón/efectos de los fármacos , Riñón/patología , Hígado/efectos de los fármacos , Hígado/patología , Masculino , Ratones , Mitocondrias Cardíacas/efectos de los fármacos , Mitocondrias Cardíacas/enzimología , Tamaño de los Órganos/efectos de los fármacos , Ratas , Ratas Endogámicas F344RESUMEN
Two-year toxicity and carcinogenicity studies of oxytetracycline hydrochloride and tetracycline hydrochloride, two structurally similar and widely used antibiotics, were performed in F344/N rats and B6C3F1 mice. Rats and mice were continuously exposed via their diet to the following levels of antibiotic: oxytetracycline HCl--rats 0, 25,000, or 50,000 ppm; mice 0,6,300, or 12,500 ppm; tetracycline HCl--rats and mice 0, 12,500, or 25,000 ppm. On a milligram per kilogram of body weight basis these exposures represent doses that are 20 to 140 times daily human therapeutic doses. Dose-related increased survival was noted among oxytetracycline-treated male rats and tetracycline-treated female rats and male mice, while treatment-related reduced body weight gain occurred in oxytetracycline- and tetracycline-treated mice. Microscopic changes included fatty metamorphosis and focal cellular change in livers of oxytetracycline-treated male rats and basophilic cytoplasmic and clear cell change in livers of tetracycline-treated male rats. The only neoplastic changes were a marginally increased trend in pheochromocytoma of the adrenal medulla (equivocal evidence only) among oxytetracycline-exposed male rats (12/50 controls, 19/50 low dose, 24/50 high dose) and an increased incidence of pituitary adenoma or adenocarcinoma among high-dose oxytetracycline-treated female rats (20/50 controls, 32/50 high dose). Although oxytetracycline and tetracycline appeared to increase the incidence of pituitary hyperplasia in high-dose male and female rats, respectively, the total incidence of proliferative changes (hyperplasia, adenoma, and adenocarcinoma) was not affected by antibiotic exposure. The results from these studies therefore support the notion that neither antibiotic is carcinogenic in rodents. There were several negative trends suggesting possible protective effects by both these tetracycline analogs against certain spontaneous neoplastic and non-neoplastic changes.
Asunto(s)
Carcinógenos/toxicidad , Oxitetraciclina/toxicidad , Tetraciclina/toxicidad , Animales , Anticarcinógenos/farmacología , Peso Corporal/efectos de los fármacos , Ingestión de Alimentos/efectos de los fármacos , Femenino , Masculino , Ratones , Ratones Endogámicos , Neoplasias Experimentales/inducido químicamente , Neoplasias Experimentales/prevención & control , Ratas , Ratas Endogámicas F344RESUMEN
The subchronic toxicity of N,N-dimethylaniline (DMA) was studied by administration in corn oil by gavage at doses of 31.25, 62.5, 125, 250, 20, or 500 mg/kg body weight to groups of 10 male and 10 female F344 rats and B6C3F1 mice 5 d per week for 13 wk. No compound-related mortality was noted in either rats or mice. Significant decrease in body weight gain was observed in male rats at 250 and 500 mg/kg. The body weight gain of female rats and female mice was not adversely affected by the treatment. Clinical signs of toxicity (cyanosis and decrease in motor activity) occurred in both species and sexes in a dose-dependent fashion. Splenomegaly was observed in all treated groups of rats and mice, with the severity being dose-related. Microscopic examination revealed the presence of hemosiderin in the spleen, liver, testes, and kidney of treated rats and mice. Bone marrow hyperplasia and increased hematopoiesis in the spleen occurred in treated rats, and hematopoiesis was increased in the spleen and liver of treated mice. The severity of these lesions was dose-related. A no-observable-effect for mice was estimated at 31.25 mg/kg; however, a no-effect level was not reached in rats in this study. This suggests that rats are more sensitive than mice to the toxic effect of DMA.
Asunto(s)
Compuestos de Anilina/toxicidad , Riñón/efectos de los fármacos , Bazo/efectos de los fármacos , Compuestos de Anilina/administración & dosificación , Animales , Médula Ósea/patología , Relación Dosis-Respuesta a Droga , Femenino , Riñón/patología , Hígado/efectos de los fármacos , Hígado/patología , Masculino , Ratones , Ratas , Ratas Endogámicas F344 , Bazo/patología , Esplenomegalia , Aumento de Peso/efectos de los fármacosRESUMEN
This study was designed to investigate the toxicity of intravenously administered alpha-tocopherol, alpha-tocopheryl acetate, and a polysorbate vehicle similar to that used in a commercial preparation of alpha-tocopheryl acetate intended for intravenous administration. Cesarean-delivered newborn rabbits fed intravenously were administered 100 mg of either alpha-tocopherol or alpha-tocopheryl acetate in a polysorbate vehicle, or the vehicle only, or no treatment for 6 or 7 days. Two intravenous diets were employed which differed in nutritional content and were termed low energy (LE) and high energy (HE). High concentrations of alpha-tocopherol were present in the tissues of all pups that received either treatment with alpha-tocopherol or alpha-tocopheryl acetate in the polysorbate vehicle, irrespective of the nutritional regimen. Pups in all treatment and control groups which received the LE diet had hepatic centrilobular degeneration, necrosis and pigment accumulation, which was attributed to malnutrition. No additional toxicities could be attributed to the vitamin E or polysorbate treatments. Administration of the HE diet eliminated the nutrition-related centrilobular degeneration, and revealed treatment-related liver changes. HE pups treated with alpha-tocopheryl acetate in the polysorbate vehicle had microscopic evidence of mild bile stasis and had elevated serum bilirubin. Minimal lipidosis or fatty change in the liver was observed only in alpha-tocopherol and alpha-tocopheryl acetate-treated pups. Lipidosis in the spleen was moderate in the alpha-tocopherol group and minimal in the alpha-tocopheryl acetate group. Lipidosis also occurred in the adrenal gland primarily in the alpha-tocopheryl acetate group.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Animales Recién Nacidos/metabolismo , Vitamina E/toxicidad , Animales , Bilirrubina/sangre , Enzimas/sangre , Inyecciones Intravenosas , Nutrición Parenteral Total , Polisorbatos/metabolismo , Conejos , Vitamina E/administración & dosificaciónRESUMEN
Two-week repeated-dose and 13-week subchronic studies of HCBD were conducted in B6C3F1 mice. Groups of five mice/sex received 0, 30, 100, 300, 1,000, or 3,000 ppm HCBD in feed for 15 days. Toxic responses, primarily in the higher dose groups, included abnormal clinical signs (lethargy, hunched posture, rough coat, sensitivity to light, and/or incoordination), mortality (all mice in the top two dose groups died by day 7), body and organ weight depression, and gross and histopathological changes. The most prevalent microscopic lesion, seen in all HCBD-treated mice of both sexes, was renal tubular cell necrosis and/or regeneration. Regeneration was seen only in the lower dose groups. Thirteen-week studies were conducted in which groups of 10 mice/sex received 0, 1, 3, 10, 30, or 100 ppm HCBD in feed. No treatment-related clinical signs or mortality were observed. Body weight gain was reduced in the 30- and 100-ppm males (-49 and -56, respectively), and the 100-ppm females (-47). Significant reduction in kidney weights was seen in the 30- and 100-ppm males and 100-ppm females. A treatment-related increase in tubular cell regeneration in the renal cortex occurred in both male and female mice. This lesion was characterized by an increase both in number and basophilic staining intensity of the tubular epithelial cells. Regeneration was seen in the outer stripe of the outer medulla and extended into the medullary rays (pars recta); severity increased with dose. Female mice were more susceptible to the toxicity of HCBD than male mice. Although no adverse effects were observed at the 10-ppm level for male mice in the subchronic study, the regenerative lesion was present in female mice at 1 ppm, the lowest dose administered.
Asunto(s)
Butadienos/toxicidad , Dieta , Animales , Butadienos/administración & dosificación , Contaminantes Ambientales/toxicidad , Epitelio/patología , Femenino , Riñón/patología , Enfermedades Renales/inducido químicamente , Enfermedades Renales/patología , Enfermedades Renales/fisiopatología , Túbulos Renales/patología , Túbulos Renales/fisiopatología , Masculino , Ratones , Ratones Endogámicos C3H , Ratones Endogámicos C57BL , Necrosis , Tamaño de los Órganos , Regeneración , Caracteres SexualesRESUMEN
Thirteen-week toxicity studies were conducted in groups of 10 F344 rats and B6C3F1 mice of each sex fed roxarsone at 0, 50, 100, 200, 400, or 800 ppm in the diet. Arsenic levels in blood, urine, kidneys, and liver of rats were measured in additional animals of each sex dosed with 100 or 400 ppm roxarsone. Compound-related mortality occurred in both sexes of rats at 800 ppm and mice at 800 and 400 ppm. Significant body weight gain depression occurred in both sexes of rats at 200, 400, and 800 ppm and mice at 800 ppm. Clinical signs of toxicity (trembling, ataxia, and pale skin) were seen primarily in rats and mice at 800 ppm. Lesions associated with roxarsone administration were noted only in the kidney of rats and were characterized by tubular necrosis and mineralization at the corticomedullary junction. Arsenic levels in urine, blood, liver, and kidneys increased over time and were directly proportional to the level of roxarsone in feed. These levels were greater than 6 times higher in rats than in mice and were about 2 time higher in males than in females. The no-observable-effect level for roxarsone toxicity was estimated at 100 ppm for rats and 200 ppm for mice. No hematology or clinical chemistry effects were found in rats or mice of either sex.
Asunto(s)
Intoxicación por Arsénico , Arsénico/metabolismo , Riñón/efectos de los fármacos , Hígado/efectos de los fármacos , Roxarsona/toxicidad , Animales , Peso Corporal/efectos de los fármacos , Dieta , Relación Dosis-Respuesta a Droga , Ingestión de Alimentos , Femenino , Riñón/patología , Corteza Renal/patología , Médula Renal/patología , Hígado/metabolismo , Masculino , Ratones , Ratones Endogámicos , Ratas , Ratas Endogámicas F344 , Roxarsona/administración & dosificación , Factores Sexuales , Especificidad de la EspecieRESUMEN
Toxicity and carcinogenicity studies of rotenone were conducted in F344/N rats and B6C3F1 mice. Groups of 50 rats and 50 mice of each sex were given rotenone in their diet for up to 103 weeks. The doses were 0, 38, and 75 ppm for rats and 0, 600, and 1,200 ppm for mice. Reduction in body weight gain occurred in male and female mice given rotenone. No effects on survival were observed for rats of either sex or female mice. Survival of male mice at 1,200 ppm was significantly greater than that of controls (47/50 vs. 29/50). There were no observed nonneoplastic effects due to rotenone, and for male and female mice no neoplasms were induced by rotenone. Parathyroid adenomas occurred at a higher incidence (4/44) in male rats at 75 ppm than in the controls (1/41). Because these tumors are rare (historical rate in NTP studies is 0.3%), the increase in the incidence of these benign tumors may have been related to rotenone administration. Hepatocellular neoplasms were reduced (p less than 0.01) in males receiving 1,200 ppm 1/50 relative to controls 12/47. Because this low rate of liver tumors is unusual in male B6C3F1 mice, this decrease was considered to be related to rotenone administration.
Asunto(s)
Carcinógenos , Rotenona/toxicidad , Animales , Peso Corporal/efectos de los fármacos , Dieta , Ingestión de Alimentos/efectos de los fármacos , Femenino , Masculino , Ratones , Ratones Endogámicos , Neoplasias de las Paratiroides/inducido químicamente , Neoplasias de las Paratiroides/patología , Ratas , Ratas Endogámicas F344 , Rotenona/administración & dosificación , Factores Sexuales , Neoplasias de los Tejidos Blandos/inducido químicamente , Neoplasias de los Tejidos Blandos/patología , Factores de TiempoRESUMEN
Chronic toxicity and carcinogenicity studies were conducted on D-mannitol and propyl gallate in F344 rats and B6C3F1 mice. Groups of 50 rats and 50 mice of each sex were maintained on diets containing either 0, 2.5 or 5.0% D-mannitol or 0, 0.6 or 1.2% propyl gallate for 103 wk. D-Mannitol had no effect on survival or mean body weight of rats and mice, and feed consumption was approximately the same in control and treated groups in each species. Gastric fundal gland dilation occurred at a higher incidence in treated female rats than in controls. A mild nephrosis characterized by focal vacuolization of the renal tubular epithelium was observed in an increased incidence in treated mice. No significant increase in tumour incidence was observed in any of the treated groups in comparison with the corresponding controls. Survival of rats and mice given propyl gallate was similar to that of the controls. Mean body weights were lower in chemically exposed animals, and more so for females. Male rats exposed to propyl gallate showed an increased incidence of hepatic cytoplasmic vacuolization and suppurative inflammation of the prostate gland. Tumours of the preputial gland, islet-cell tumours of the pancreas, and phaeochromocytoma of the adrenal gland occurred at a significantly (P less than 0.05) higher incidence in the low-dose male rats. Malignant lymphoma occurred with a positive trend in male mice (control 1/50, low dose 3/49 and high dose 8/50), and the incidence in the high-dose group was significantly (P less than 0.05) higher than in the control group. However, since the incidence in the control group was much less than the historical control rate (36/398 or 9%) in this laboratory, this apparent increase was not considered to be related to propyl gallate administration. Under the conditions of these studies, neither D-mannitol nor propyl gallate was considered to be carcinogenic to F344 rats or B6C3F1 mice of either sex.
Asunto(s)
Carcinógenos , Ácido Gálico/análogos & derivados , Manitol/toxicidad , Mutágenos , Neoplasias/inducido químicamente , Galato de Propilo/toxicidad , Administración Oral , Animales , Peso Corporal/efectos de los fármacos , Femenino , Masculino , Ratones , Ratas , Ratas Endogámicas F344RESUMEN
A 13-wk study was conducted by administering d-alpha-tocopheryl acetate (vitamin E) in corn oil by gavage to groups of ten male and ten female Fischer 344 rats at doses of 0, 125, 500 or 2000 mg/kg body weight daily for 13 wk. The dose of corn oil given was 3.5 ml/kg. Additional groups of ten males and ten females were included and served as untreated controls. Deaths occurred only in males at 2000 mg/kg. Vitamin E dosing had no effect on body weight or food consumption. The liver-to-body weight ratio of females at 2000 mg/kg was significantly increased. In males, high levels of vitamin E (2000 mg/kg) caused prolongation of both prothrombin and activated partial thromboplastin (APTT) times, reticulocytosis and a decrease in haematocrit values and haemoglobin concentrations. APTT was also lengthened in females at this dose level. High levels (2000 mg/kg) caused haemorrhagic diathesis in both males and females and increased medullary erythropoiesis in the spleen of one male. Vitamin E at all doses tested caused interstitial inflammation and adenomatous hyperplasia of the lung. The above findings indicate that vitamin E administration in excessive amounts is potentially toxic.