[Toxicity studies of VP 16-213 (V)--Intravenous three-month toxicity in rats]

VP 16-213 (etoposide, abbr. to VP), an oncostatic drug, was administered intravenously to Crj : CD (Sprague-Dawley) rats of both sexes at dose levels of 0.05, 0.15, 0.5 and 1.5 mg/kg/day for three months with the object of examining its toxicity and the reversibility of toxic effects. For the purpose of comparison, vincristine (abbr. to VCR) was administered in the same manner at a dose level of 0.02 mg/kg/day. The summarized results obtained are as follows: VP 1.5 mg/kg brought anemia as well as suppression of body weight increase and food intake, and 0.5 and 1.5 mg/kg increased water consumption. However, no drug-related deaths occurred. VP 0.5 and 1.5 mg/kg predominantly decreased red blood cell count and white blood cell count accompanied with lowered lymphocyte fraction which was agreeable to the findings on bone marrow. VP 1.5 mg/kg increased platelet count. VP 1.5 mg/kg lowered total serum protein content and elevated A/G ratio. VP 0.15 mg/kg and higher decreased testicular weight; 0.5 and 1.5 mg/kg brought thymic atrophy, suppression of spermatogenesis, tubular atrophy and hydropic change in testis. VP 1.5 mg/kg induced decrease of sperms in number and appearance of giant cells in epididymis. Above-described changes excluding the findings on testis and epididymis were shown to be generally reversible. Most of the findings for a reference drug, VCR, were qualitatively comparable to those for VP. Based on these results, the non-effect dose level of VP under the present experimental condition was estimated to be 0.05 mg/kg/day against male rats and 0.15 mg/kg/day against female rats.