Teratologic studies on the Himalayan rabbit: new aspects of thalidomide-induced teratogenesis

The aim of our study was to determine the period of maximum sensitivity for the induction of characteristic malformations with thalidomide (TH) in Himalayan rabbits. TH was administered orally in different doses (50, 100, 150 and 200 mg/kg) four times at 24-h intervals starting at 192 h of gestation. The malformations affected various organs: renal defects (dysplasia) and limb anomalies (dysmelia)--which had never occurred spontaneously in this strain--appeared as dose-dependent effects of the drug. By administering single doses of TH (200 and 300 mg/kg body wt) between hours 192 and 264 of gestation, we discovered the different periods of maximum sensitivity for induction of renal dysplasia (clearly prior to the 220th h of gestation) and dysmelia (between hours 230 and 240 of gestation). The types of limb malformations that we observed in the rabbit were identical to those produced in man following the intake of TH. Three doses of TH (300 mg/kg each) given between hours 222 and 228 of gestation produced characteristic limb malformations in 9 of 11 litters treated. These results make it possible to conduct in vivo experiments on a readily available laboratory animal with minor drug exposure of the gravid dam and under avoidance of toxic side effects.