Comprehensive toxicity study of safrole using a medium-term animal model with gpt delta rats.

In order to investigate a medium-term animal model using reporter gene transgenic rodents in which general toxicity, genotoxicity and carcinogenicity are evaluated, F344 gpt delta rats were given a diet containing 0.1% and 0.5% (a carcinogenic dose) safrole for 13 weeks. Serum biochemistry and histopathological examinations revealed overt hepatotoxicity of safrole, in line with previous reports. In the current study, safrole treatment possibly resulted in renal toxicity in male rats. In the in vivo mutation assays, an increase or a tendency to increase of the gpt mutant frequencies (MFs) was observed in both sexes at the carcinogenic dose. The number and area of foci of glutathione S-transferase placental form (GST-P) positive hepatocytes, ratio of proliferating cell nuclear antigen (PCNA)-positive hepatocytes and 8-hydroxydeoxyguanosine (8-OHdG) levels in liver DNA were significantly increased in both sexes of the 0.5% group. The overall data suggested that the present model might be a promising candidate for investigating comprehensive toxicities of the agents. In addition, data demonstrating the base modification and cell proliferation due to exposure to safrole could contribute to understanding safrole-induced hepatocarcinogenesis, which imply expanding in application of this model.

Effects of equine herpesvirus-9 infection in pregnant mice and hamsters.

The pathogenicity of equine herpesvirus (EHV)-9, a new neurotropic equine herpesvirus isolated from gazelles, was assessed in pregnant rodents (mice and hamsters) following intranasal inoculation. The pregnant female mice and hamsters were inoculated with EHV-9 in the early or late trimesters. The inoculated animals exhibited mild to severe neurological signs and gave birth to dead or undersized fetuses. All three mice and four hamsters inoculated in the first trimester had varying degrees of placental abnormality, characterized by markedly dilated maternal blood sinusoids, atrophy of the trophoblast cells and necrosis of the middle layer of the trophoblast. There was also endometrial blood vessel congestion and necrosis and disorganization of the fetal capillaries in the mice and hamsters inoculated in the last trimester. EHV-9 antigen was detected in the brain of dams and the lungs of the fetuses and in the middle of the trophoblast layer of the placenta in hamsters inoculated in the first trimester. The placental lesions were milder in mice than in the hamsters. The mice and hamsters inoculated in the last trimester had more prominent lesions than the animals inoculated in the first trimester. These results suggest that EHV-9 can cause the death of the fetus or abortion and that these events may be secondary to placental vascular compromise.

Study on the infectivity of equine herpesvirus 9 (EHV-9) by different routes of inoculation in hamsters.

The infectivity and pathology of equine herpesvirus 9 (EHV-9), a new neurotropic equine herpesvirus isolated from gazelles, was studied in hamsters experimentally infected via nasal, ocular, oral, intravenous (IV), or peritoneal routes. Clinically, all animals inoculated by the nasal route and ~25% inoculated by the oral and peritoneal routes showed neurological signs on days 3, 6, and 9 postinoculation (PI), respectively. Neurological signs were not observed in animals administered EHV-9 by the IV and ocular routes. With the exception of animals administered EHV-9 by the IV route, all infected animals had lymphocytic meningoencephalitis. Although there were a number of differences in the severity and distribution of the lesions depending on the route of inoculation, the basic features of lymphocytic meningoencephalitis caused by EHV-9 were common. Lesions consisted of neuronal necrosis, perivascular aggregates of lymphocytes, plasma cells, and neutrophils, gliosis, intranuclear inclusion bodies, and diffuse lymphocytic infiltrates in the meninges. Viral antigen was detected in degenerated neurons in infected animals inoculated by the nasal, ocular, oral, and peritoneal routes. The distribution of EHV-9 antigen was somewhat dependent on inoculation route. There were no microscopic abnormalities or viral antigen in animals treated by the IV route. This study provides new data about experimental EHV-9 infection in hamsters through routes other than the IV route. These results suggest that in the animals infected by the oral, ocular, and peritoneal routes, EHV-9 might travel to the brain through nerves, other than by the olfactory route, after initial propagation at the site of viral entry.

Investigation of carcinogenicity for levamisole administered in the diet to F344 rats.

A two year carcinogenicity study of anthelmintic drug levamisole (LV) was performed using 50 male and 50 female F344 rats at dietary drug concentrations of 0, 60, or 300 ppm. The daily intakes of LV were calculated to be 2.6, 12.9 mg/kg b.w./day for males and 2.9, 14.1mg/kg b.w./day for females, respectively. No significant differences in general condition and survival rate (82%, 74%, 80% in males and 84%, 84%, 84% in females, respectively) were observed. In the 300 ppm group, suppression of body weight gain was observed from the onset of treatment and reduction in final body weights was 6% in males and 11% in females. Significant increases in the absolute and/or relative weights of the lungs, heart, spleen, liver, kidneys, and adrenals were observed in males and/or females treated with 300 ppm. Some of high incidences neoplasms were observed, and there were also tendencies to increase for mammary gland fibroma and thoracic/abdominal cavity mesothelioma in males. However, there were no significant inter-group differences in incidences, histopathological types or differences compared with historical control data. Thus, it was concluded that LV was not carcinogenic to male and female F344 rats under the experimental conditions.