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.

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.