Citation:

Cappon, G., P. Theunissen, S. Beken, B. Beyer, W. Breslin, C. Chen, G. Chmielewski, L. De Schaepdrijver, B. Enright, J. Foreman, W. Harrouk, K. Hew, A. Hoberman, J. Hui, A. Jacobs, T. Knudsen, S. Laffan, S. Makris, M. Martin, M. McNerney, D. Stanislaus, J. Stewart, K. Thompson, B. Tornesi, J. Van der Laan, G. Weinbauer, 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. Taylor & Francis Group, London, Uk, 46(10):900-910, (2016). https://doi.org/10.1080/10408444.2016.1224807

Impact/Purpose:

This project is an activity of the ILSI/HESI Developmental and Reproductive Toxicity (DART) Committee. It follows up on the conclusions of 2 publications by Theunissen et al (2016), which had reviewed developmental toxicity data in rats and rabbits submitted to regulatory agencies in the US and EU for pharmaceutical products. Neither the rat nor the rabbit were found to be more sensitive than the other in detecting or characterizing developmental toxicity. The results of this project do not alter the way EPA views or uses DART data in risk assessment.

Description:

A retrospective review of results from more than 800 embryo-fetal development (EFD) studies with 379 pharmaceutical compounds was performed to compare the utility of rats and rabbits for the detection of developmental toxicity of small molecule pharmaceuticals. A major advantage of this survey over previous similar evaluations was the inclusion of pharmacokinetic information. This project was initiated to test the hypothesis whether it might be possible to limit EFDT (embryo-fetal developmental toxicity) testing to a single species – at the least for some compound classes. The concordance of data between rats and rabbits for the presence or absence of severe manifestations of developmental toxicity (i.e., malformations and/or embryo-fetal death) was 77% for malformation and 67% for malformation and/or embryo-fetal death combined; indicating that rats and rabbits were not equivalent for hazard identification. Rats and rabbits had similar overall susceptibility to compound-induced malformation, with 22% and 21% of compounds causing malformations in rats and rabbits, respectively, but rabbits were more susceptible to embryo-fetal death. Of the 30 compounds that caused malformations in both species and had exposure information, rabbits were more sensitive than rats based on maternal AUC exposure at the dose causing malformations for 80% of the compounds, and for 30% of the compounds this difference in AUC exposure was greater than 10-fold. Because of the dissimilarities in the observed response between the two species a presupposed preference for one species over the other based on existing knowledge of developmental testing in two species could not be established for small molecule pharmaceuticals. However, there are cases where a single species may sufficiently identify the developmental toxicity risk and justify a deviation from the default two species testing paradigm for human risk assessment.

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