RESUMEN
To investigate the toxicity and carcinogenic potential of indole-3-carbinol (I3C), the National Toxicology Program has conducted 13-week subchronic studies in Fisher 344 rats and B6C3F1 mice, and chronic 2-year bioassays in Sprague-Dawley rats and B6C3F1 mice. While the chronic study results are not yet available, subchronic study results and short-term special evaluations of interim sacrifices in the 2-year rat bioassay are presented. F344 rats were orally gavaged ≤300 mg I3C/kg body weight 5 days a week for 13 weeks. Rats treated with ≥150 mg/kg demonstrated a dose-related dilation of lymphatics (lymphangiectasis) of the duodenum, jejunum, and mesenteric lymph nodes. Material within dilated lacteals stained positively for Oil Red O and Sudan Black, consistent with lipid. Electron microscopic evaluation confirmed extracellular lipid accumulation within the villar lamina propria, lacteals, and within villar macrophages. Analyses of hepatic and pulmonary CYP1A enzymes demonstrated dose-dependent I3C induction of CYP1A1 and 1A2. B6C3F1 mice orally gavaged ≤250 mg I3C/kg body weight did not demonstrate histopathological changes; however, hepatic CYP induction was similar to that in rats. The histopathologic changes of intestinal lymphangiectasis and lipidosis in this study share similarities with intestinal lymphangiectasia as observed in humans and dogs. However, the resultant clinical spectrum of protein-losing enteropathy was not present.
Asunto(s)
Indoles/toxicidad , Lipidosis/inducido químicamente , Linfangiectasia Intestinal/inducido químicamente , Administración Oral , Animales , Peso Corporal/efectos de los fármacos , Citocromo P-450 CYP1A1/metabolismo , Citocromo P-450 CYP1A2/metabolismo , Femenino , Histocitoquímica , Indoles/administración & dosificación , Intestino Delgado/efectos de los fármacos , Intestino Delgado/metabolismo , Intestino Delgado/patología , Lipidosis/metabolismo , Lipidosis/patología , Hígado/efectos de los fármacos , Hígado/enzimología , Hígado/metabolismo , Pulmón/efectos de los fármacos , Pulmón/enzimología , Pulmón/metabolismo , Ganglios Linfáticos/efectos de los fármacos , Ganglios Linfáticos/metabolismo , Ganglios Linfáticos/patología , Linfangiectasia Intestinal/metabolismo , Linfangiectasia Intestinal/patología , Masculino , Ratones , Ratas , Ratas Endogámicas F344 , Ratas Sprague-Dawley , Pruebas de Toxicidad Crónica , Pruebas de Toxicidad SubcrónicaRESUMEN
The heart is increasingly recognized as a target for toxicity. As studies in laboratory rodents are commonly used to investigate the potential toxicity of various agents, the identification and characterization of lesions of cardiotoxicity is of utmost importance. Although morphologic criteria have been established for degenerative myocardial lesions in rats and mice, differentiation of spontaneously occurring lesions from toxin-induced or toxin-related lesions remains difficult. A retrospective light microscopic evaluation was performed on the hearts of F344 rats and B6C3F(1) mice from National Toxicology Program (NTP) studies of six chemicals identified in the NTP database in which treatment-induced myocardial toxicity was present. Two previously defined myocardial lesions were observed: "cardiomyopathy" that occurred spontaneously or as a treatment-related effect and "myocardial degeneration" that occurred as a treatment-related effect. Both lesions consisted of the same basic elements, beginning with myofiber degeneration and necrosis, with varying amounts of inflammation, interstitial cell proliferation, and eventual fibrosis. This observation is indicative of the heart's limited repertoire of responses to myocardial injury, regardless of the nature of the inciting agent. A prominent differentiating factor between spontaneous and treatment-induced lesions was distribution and lesion onset. Once the respective lesions had undergone fibrosis, however, they generally appeared morphologically indistinguishable.
Asunto(s)
Cardiomiopatías/inducido químicamente , Cardiotoxinas/toxicidad , Corazón/efectos de los fármacos , Miocardio/patología , Miocitos Cardíacos/efectos de los fármacos , Pruebas de Toxicidad/métodos , Animales , Investigación Biomédica , Cardiomiopatías/metabolismo , Cardiomiopatías/patología , Programas de Gobierno , Histocitoquímica , Ratones , Microscopía , Miocardio/metabolismo , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Oximetolona/toxicidad , Ratas , Ratas Endogámicas F344 , Estudios Retrospectivos , Pruebas de Toxicidad/normas , Estados Unidos , United States Dept. of Health and Human Services , Uretano/toxicidad , Vacuolas/efectos de los fármacosRESUMEN
Exposure to dioxin and dioxin-like compounds (DLCs) has been connected to the induction of chloracne in humans and animals. 3,3',4,4'-Tetrachloroazobenzene (TCAB) is an environmental contaminant that induces chloracne in humans. TCAB has been studied only to a limited extent in laboratory animals. While performing a 2-year gavage study in B6C3F1 mice to evaluate the toxic and carcinogenic effects of TCAB, we also explored potential chloracnegenic properties. Groups of 50 male and 50 female B6C3F1 mice were exposed by gavage to TCAB at dose levels of 0, 3, 10 and 30 mg/kg for 5 days a week for 2 years. The animals developed treatment-related gross inflammatory skin lesions, which were characterized histologically by inflammation, fibrosis, hyperplasia, and ulcers. Additionally, many of the animals developed follicular dilatation and sebaceous gland atrophy, consistent with chloracne-like lesions. This current 2-year study supports recently published papers showing susceptibility to chloracne in mouse strains other than hairless mice. The chloracne-like lesions were not clinically evident; therefore, our study highlights the need for careful examination of the skin in order to identify subtle lesions consistent with chloracne-like changes in rodents exposed to dioxin and DLCs. Since previous short-term studies did not demonstrate any skin lesions, we suggest that reliable assessment of all safety issues involving dioxin and DLCs requires evaluation following chronic exposure. Such studies in animal models will help to elucidate the mechanisms of dioxin-related health hazards.
Asunto(s)
Compuestos Azo/toxicidad , Cloracné/patología , Clorobencenos/toxicidad , Dermatitis por Contacto/patología , Piel/patología , Animales , Femenino , Intubación Gastrointestinal , Masculino , Ratones , Ratones Endogámicos , Caracteres Sexuales , Análisis de SupervivenciaRESUMEN
Induction of heart disease can be related to exposure to a number of agents, including environmental chemicals. Studies with laboratory rodents are commonly used to identify cardiotoxic agents and to investigate mechanisms of toxicity. This study was conducted to characterize spontaneous and chemically-induced rodent heart lesions. A retrospective light-microscopic evaluation was performed on the hearts of F344 rats and B6C3F1 mice from National Toxicology Program studies of six chemicals in which chemically-induced myocardial toxicity was present: oxymetholone, monochloroacetic acid, 3,3'-4,4'- tetrachoroazoxybenzene, diethanolamine, urethane, and methyl bromide. Two myocardial lesions were observed: cardiomyopathy (multifocal myofiber degeneration that could occur spontaneously or as a treatment effect) and degeneration (diffuse myofiber degeneration that was clearly related to treatment). Oxymetholone produced cardiotoxicity that was apparent as an increase in the incidence and average severity of cardiomyopathy. The remaining five chemicals produced degeneration, which appeared morphologically similar with each of the chemicals. Based on available information concerning possible mechanisms by which each of these chemicals may induce cardiotoxicity, this evaluation indicated it may be possible to place the chemicals into two main categories: (1) those that primarily affected the coronary vasculature with secondary effects on the myocardium (oxymetholone), and (2) those that had a direct toxic effect on the myocardial cells (the remaining five chemicals). Beyond this, however, light-microscopic findings did not indicate any specific mechanisms. Additional morphologic evaluations, such as electron microscopy or special histochemical or immunostains, may help identify specific subcellular sites of toxic damage, which in turn can indicate appropriate types of molecular mechanistic studies.
Asunto(s)
Modelos Animales de Enfermedad , Contaminantes Ambientales/toxicidad , Cardiopatías/inducido químicamente , Cardiopatías/patología , Acetatos/toxicidad , Animales , Bases de Datos Factuales , Etanolaminas/toxicidad , Femenino , Fibrosis , Hidrocarburos Bromados/toxicidad , Masculino , Ratones , Ratones Endogámicos , Fibras Musculares Esqueléticas/patología , Miocardio/patología , Oximetolona/toxicidad , Dibenzodioxinas Policloradas/toxicidad , Conejos , Ratas , Ratas Endogámicas F344 , Factores de Tiempo , Uretano/toxicidadRESUMEN
We report that an environmental agent, bis(2-chloroethoxy)methane (CEM), caused cardiac toxicity in male and female F344 rats and B6C3F1 mice exposed to the chemical by dermal administration at doses of 0, 50, 100, 200, 400 or 600 mg/kg 5 days a week for up to 14 weeks. Treatment-related deaths occurred in 10/10 male and 10/10 female rats at 600 mg/kg, in 2/10 female rats at 400 mg/kg, and in 3/10 female mice at 600 mg/kg. The heart lesions were more severe in rats than mice, and more severe in females than males. In rats, the no-observed-adverse-effect level (NOAEL) for the heart lesions was 200 mg/kg for males and 100 mg/kg for females; in mice, it was more than 600 mg/kg for males and 200 mg/kg for females. Multifocal, widespread vacuolization of the myocytes comprised the main morphological feature of the lesions, and only in rats was it accompanied by mononuclear cell infiltration, myocytic necrosis and atrial thrombosis. Hearts from male rats were immunohistochemically stained for troponin T (cTnT) protein. Loss of cytoplasmic cTnT correlated with histopathological damage only in the 600 mg/kg animals. CEM is metabolized to thiodiglycolic acid, a chemical that causes mitochondrial dysfunction. It is hypothesized that mitochondrial damage leads to the heart toxicity from bis(2-chloroethoxy)methane.
Asunto(s)
Éteres de Etila/toxicidad , Miocardio/patología , Solventes/toxicidad , Animales , Relación Dosis-Respuesta a Droga , Femenino , Inmunohistoquímica , Inflamación/inducido químicamente , Inflamación/patología , Masculino , Ratones , Mitocondrias/efectos de los fármacos , Mitocondrias/patología , Ratas , Factores Sexuales , Especificidad de la Especie , Troponina T/efectos de los fármacosRESUMEN
BACKGROUND: In-stent restenosis is caused by neointimal hyperplasia. Sirolimus (rapamycin; Wyeth Research, Radnor, Pennsylvania, USA) inhibits vascular smooth muscle cell proliferation and we evaluated the efficacy of sirolimus in reducing neointimal formation in a rabbit iliac model and in-vivo pharmacokinetics in the porcine coronary model. DESIGN: Randomized, blinded, prospective animal study. METHODS: Bilateral rabbit iliac artery stent implantation was performed using crossflex stents (Cordis Corporation, Warren, New Jersey, USA) coated with sirolimus incorporated in a nonerodable polymer. Arteries were randomized to one of four stent groups: uncoated stents (n = 8); polymer control stents (n = 10); low-dose sirolimus-eluting stents (n = 9); and high-dose sirolimus-eluting stents (n = 10). Histomorphometry was performed at 28 days. Arterial tissue and stents were retrieved at 8, 14 and 28 days and blood samples were obtained daily during the first week. RESULTS: Treatment with low-dose sirolimus was associated with a 23% (P = NS) reduction in neointimal area and treatment with high-dose sirolimus with a 45% (P < 0.05) reduction. Sustained drug release from the stent and prolonged intramural arterial deposition were confirmed for up to 28 days. No detectable sirolimus was found in the blood after 2 days. CONCLUSION: Controlled-release local delivery of a cell-cycle inhibitor from a nonerodable polymer-coated stent reduced neointimal formation in rabbit iliac arteries in a dose-dependent manner and represents a promising strategy for preventing restenosis.