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Comparison of rat and rabbit embryo-fetal developmental toxicity data for 379 pharmaceuticals: on the nature and severity of developmental effects (Critical Reviews in Toxicology)
Citation:
Theunissen, P., S. Beken, B. Beyer, W. Breslin, G. Cappon, C. Chen, G. Chmielewski, L. De Schaepdrijver, B. Enright, J. Foreman, W. Harrouk, K. Hew, A. Hoberman, J. Hui, TB Knudsen, S. Laffan, S Makris, M Martin, M. McNerney, C. Siezen, D. Stanislaus, J. Stewart, K. Thompson, B. Tornesi, G. Weinbauer, S. Wood, J. Van der Laan, AND A. Piersma. Comparison of rat and rabbit embryo-fetal developmental toxicity data for 379 pharmaceuticals: on the nature and severity of developmental effects (Critical Reviews in Toxicology) . CRITICAL REVIEWS IN TOXICOLOGY. CRC Press LLC, Boca Raton, FL, , 1-11, (2016).
Impact/Purpose:
Report from ILI-HESI-DART workgroup . Study tries to address the question of whether under some conditions EFDT testing could be limited to one species, or whether the need for testing in a second species could be decided on a case by case basis. The current analysis based on the nature and severity of EFDT suggests that in general both species are equally sensitive on the basis of an overall EFDT LOAEL comparison, but selective toxicity in one species is not uncommon.
Description:
Regulatory non-clinical safety testing of human pharmaceutical compounds typically requires embryo fetal developmental toxicity (EFDT) testing in two species, (one rodent and one non-rodent, usually the rat and the rabbit). The question has been raised whether under some conditions EFDT testing could be limited to one species, or whether the need for testing in a second species could be decided on a case by case basis. As part of an RIVM/CBG-MEB/HESI/US EPA consortium initiative, we built and queried a database of 379 EFDT studies conducted for marketed and non-marketed pharmaceutical compounds. The animal models (rat and rabbit) were assessed for their potential for adverse developmental and maternal outcomes. The database was analyzed for the prevalence of EFDT incidence and the nature and severity of adverse findings in the two species. Some manifestation of EFDT in either one or both species (rat and rabbit) was demonstrated for 282 compounds (74%), and EFDT was detected in only one species (rat or rabbit) in almost a third (31%, 118 compounds), with approximately 58% rat and 42% rabbit studies identifying an EFDT signal among the 379 compounds tested. For 24 compounds (6%), fetal malformations were observed in one species (rat or rabbit) in the absence of any EFDT in the second species. In general, growth retardation, fetal variations, and malformations were more prominent in the rat, whereas embryo-fetal death was observed more often in the rabbit. Discordance across animal species may be attributed to factors such as maternal toxicity, study design differences, pharmacokinetic differences, and pharmacologic relevance of species. Discussion of the implications of these findings for EFDT testing strategies of pharmaceuticals awaits an accompanying study considering systemic exposure comparison between species. The current analysis based on the nature and severity of EFDT suggests that in general both species are equally sensitive on the basis of an overall EFDT LOAEL comparison, but selective toxicity in one species is not uncommon. Also, there appear to be species differences in the prevalence of various manifestations of EFDT (i.e., embryo-fetal death, growth retardation and dysmorphogenesis) between rat and rabbit, suggesting that the use of both species has a higher probability of detecting developmental toxicants than either one alone.
