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Flutamide, which has antiandrogenic properties, was administered to pregnant rats, and effects on male offspring were examined. Crj: CD (SD) IGS (SPF) females were administered flutamide (0.15, 0.6, 2.5, 10.0, 100 mg/kg, p.o.) from gestation Day 14 to post parturition Day 3. The number of pups, body weights, clinical features, anogenital distance (AGD), nipple retention, testicular descent, and urogenital malformation in F1 males were examined. Hormone measurement, necropsy and histopathological examination were carried out at post-neonatal Day 4 (PND 4) and PND 60. Sperm analysis was also carried out at PND 60. Decrease in body weight was seen in the 100 mg/kg group and the AGD was decreased at 2.5 mg/kg and above. Retention of nipples, hypospadia, vaginal pouches, penis malformation, unilateral ectopic testis, and decrease of organ weights (prostate, seminal vesicles, levator ani muscle plus bulbocavernosus muscle, testis) were observed at 10 mg/kg and above. Testicular testosterone (T) was increased significantly with 100 mg/kg at PND 4 and tendencies for increase were observed in serum T, LH and FSH at 10 mg/kg and more at the same time point. In contrast, elevated levels of LH and FSH were seen with 100 mg/kg at PND 60. Histopathological examination revealed defects or hypoplastic changes of genital organs (> or = 10 mg/kg), squamous metaplasia (10 mg/kg) or mucification (100 mg/kg) of the urethral diverticulum epithelium and inflammation of genital organs (100 mg/kg). Though only undescended testes lacked spermatogenesis at 10 mg/kg, atrophic change of seminiferous tubules and azoospermia were observed in the 100 mg/kg group, despite testicular descent. Perinatal administration of flutamide affected F1 male rats at 2.5 mg/kg and above. In addition to urogenital malformation, 100 mg/kg flutamide caused high LH and FSH levels at PND 60. This study indicates that the most sensitive parameter is AGD, whereby reduction was observed at 2.5 mg/kg. A clear no-effect level (NOEL: 0.6 mg/kg) was obtained in this perinatal study of an antiandrogenic chemical.

Abstract:The modifying effects of carrageenan administration on colonic carcinogenesis were investigated in male F344/DuCrj rats subcutaneously injected with 1,2-dimethylhydrazine dihydrochloride (DMH) 4 times at weekly intervals. Starting one week after the final injection of DMH, the rats were given carrageenan at dietary levels of 0, 1.25, 2.50, or 5.0% until week 36. Animals given cholic acid at a dietary level of 0.2%, served as a reference group. All rats were killed at the end of week 36, and the colons were carefully examined for preneoplastic and neoplastic lesions. No treatment related changes in clinical signs and body weights were found. Detailed histopathological examination did not demonstrate any enhancement by carrageenan of carcinogenesis with regard to the incidence of lesions in the colon. The results thus demonstrate that carrageenan does not possess any promoting activity at the highest dietary level of 5.0% for colorectal carcinogenesis under the present experimental conditions. (J Toxicol Pathol 2001; 14: 37-43)

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