[Effects of mesalazine on liver carcinogenesis in medium-term bioassay using rats].

A two stage carcinogenesis promotion test using phenobarbital (PB) as a positive control was performed on mesalazine in rats (F344,male). Pathological and immunohistological examinations were performed to examine the cell damage and proliferation in the liver and kidneys. As the initiation treatment, groups 1,2,3 and 5 were administered 300 mg/kg diethylnitrosamine (DEN)dissolved in 0.9% physiological saline, and group 4 was administered 5 ml/kg 0.9% physiological saline once intraperitoneally. Then group 1 was orally administered a water solution (5 ml/kg) containing 0.5% CMC-Na, and groups 2,3 and 4 similar water solution but containing 150, 300 and 300 mg/kg mesalazine, respectively. Group 5 was administered 0.05% PB mixed in feed from weeks 2 to 8. Partial (2/3) hepatectomy was performed in all 5 groups at week 3 after DEN administration. NO clear differences between the groups were observed in general conditions, body weight or amount of food consumption. The number or area-size of hepatic GST-P positive altered cell foci revealed no significant differences between groups 1,2 and 3, but a significant increase in number and area-size was observed in group 5. No GST-P positive cell foci were detected in group 4. The number of altered cell foci (H.E. staining) in the DENgroups administered mesalazine was the same as that in group 1. Thus, mesalazine did not promote hepatocarcinogenesis in the present experimental system. Statistically insignificant appearances of basophilic and acidophilic changes were observed in the renal tubular epithelium and mineral deposits in the renal papillary region and cortical margin region. The PCNA labeling rate was significantly lower in group 4, corresponding with the histological finding showing no proliferation of the renal tubular epithelium. Judging from the above test results, mesalazine was likely to show neither a promotion effect on the initiation induced by DEN nor cell proliferative activity on the kidneys by administration for this experimental period.

Mortality, body weight, food and water consumption, and clinical signs in Slc: B6C3F1 (C57BL/6 x C3H) mice utilized in chronic toxicity and carcinogenicity studies.

In vivo historical control data for Slc: B6C3F1 mice, including mortality, body weight, food and water consumption, and clinical signs and which were obtained from long-term toxicity and carcinogenicity studies (11 male and 12 female studies) conducted at the Biosafety Research Center, Foods, Drugs and Pesticides, (An-Pyo Center) during the last five years are presented. Mean survival at 83 and 109 weeks of age was 96.4% (min: 94.0%, max: 100%) and 79.0% (min: 74.0%, max: 86.0%) in males and 98.7% (min: 96.0%, max: 100%) and 81.7% (min: 70.0%, max: 90.0%) in females, respectively. The maximum mean body weight of males and females was 45.1 +/- 3.1 g (mean +/- S.D.) and 39.2 +/- 4.1 g, respectively. Male mice attained their maximum body weight at 72.7 +/- 4.3 weeks of age and females at 76.2 +/- 5.9 weeks of age. Clinical symptoms increased with age, particularly after week 84, and included: wasting, piloerection and palpable abdominal masses. Hypothermia and auricular pallor were common findings in moribund animals from week 79 to 104 of the studies. The use of in-house, historical control data can prove invaluable in the evaluation and interpretation of experimental results, especially in long-term and life-time studies.

Mortality, body weight, food and water consumption, and clinical signs in F344/DuCrj rats in studies of chronic toxicity and carcinogenicity.

In vivo historical control data, including mortality, body weight, food and water consumption, and clinical signs in F344/DuCrj rats were obtained from 11 long-term toxicity and carcinogenicity studies conducted at the Biosafety Research Center, Foods, Drugs and Pesticides, (An-Pyo Center) during the last five years. Survival at 109 weeks of age was 80.2% (min: 74%, max: 90%) in males and 80.5% (min: 72%, max: 92%) in females. The maximum mean body weights of males and females were 443.3 +/- 15.8 g (mean +/- S. D.) and 295.7 +/- 13.3 g respectively. Male rats attained their maximum body weight at 82.6 +/- 5.3 weeks of age, the females at 103.5 +/- 2.5 weeks of age. Clinical symptoms increased with age, particularly after 84 weeks of age, and included: wasting, piloerection, palpable subcutaneous and abdominal masses, and decreased spontaneous movement. Lowered body temperature and auricular pallor occurred commonly in moribund animals. The nature and grade of toxicity in the treated animals were generally disclosed by comparing with the behavior and signs in the control animals. The use of in-house, historical control data can be useful in subsequent evaluations of chronic toxicity and carcinogenicity studies.