Use of the rabbit in teratogenicity studies

Abstract

The advantages of using the rabbit in teratologic studies are enumerated, and a technique for their use is reported in which preexperimental care, induction of ovulation, artificial insemination, administration of test compound, and examination of the fetuses are described. With these methods the conception rate in Dutch-Belted rabbits was 82.4%, and the average number of corpora lutea, implantation sites, and litter size were similar to those reported for natural matings. A total of 1186 rabbit fetuses from eight different teratogenicity studies was examined for morphologic abnormalities. The incidence and type of abnormalities in both control and treated groups were similar, indicating that these compounds were not teratogenic in the rabbit. A total of 881 fetuses was examined for skeletal defects. Extra ribs occurred in 35.4% of the fetuses. The fifth sternebra was missing or atrophic 23.7% of the time, and the second sternebra was similarly affected 2.5% of the time. Other sternebrae were missing or atrophic less than 1% of the time. Missing and/or atrophic sternebrae occurred in 25.8% of the fetuses. Bipartite and/or asymmetrical sternebrae occurred in 1.7% of the fetuses, and fused sternebrae occurred in 1.5%. One fetus had fused fourth and fifth ribs, another had the right half of two vertebral bodies fused. No visceral abnormalities were detected in 305 fetuses that were sectioned. Bipartite, asymmetrical, and fused sternebrae, although occurring infrequently, sometimes affected more than one kit in the same litter. Because of this, caution is required in interpreting such variations as drug-induced changes, even when several occur in a particular dose group. Such an occurrence can happen by chance alone. A review of available data indicated that neither thalidomide nor a corticosteroid (16-methyleneprednisolone) increased the incidence of these types of sternal variations. It is, therefore, concluded that if a drug is to be considered teratogenic in the rabbit, it should produce a dose-related incidence and pattern of malformations different than the normally expected variations described in this report.