title: Comparing rat and rabbit embryo-fetal developmental toxicity data for 379 pharmaceuticals: on systemic dose and developmental effects.
abstract: A database of embryo-fetal developmental toxicity (EFDT) studies of 379 pharmaceutical compounds in rat and rabbit was analyzed for species differences based on toxicokinetic parameters of area under the curve (AUC) and maximum concentration (Cmax) at the developmental lowest adverse effect level (dLOAEL). For the vast majority of cases (83% based on AUC of n = 283), dLOAELs in rats and rabbits were within the same order of magnitude (less than 10-fold different) when compared based on available data on AUC and Cmaxexposures. For 13.5% of the compounds the rabbit was more sensitive and for 3.5% of compounds the rat was more sensitive when compared based on AUC exposures. For 12% of the compounds the rabbit was more sensitive and for 1.3% of compounds the rat was more sensitive based on Cmaxexposures. When evaluated based on human equivalent dose (HED) conversion using standard factors, the rat and rabbit were equally sensitive. The relative extent of embryo-fetal toxicity in the presence of maternal toxicity was not different between species. Overall effect severity incidences were distributed similarly in rat and rabbit studies. Individual rat and rabbit strains did not show a different general distribution of systemic exposure LOAELs as compared to all strains combined for each species. There were no apparent species differences in the occurrence of embryo-fetal variations. Based on power of detection and given differences in the nature of developmental effects between rat and rabbit study outcomes for individual compounds, EFDT studies in two species have added value over single studies.
authors: a Centre for Health Protection, National Institute for Public Health and the Environment (RIVM) , Bilthoven , The Netherlands.|b Medicines Evaluation Board , Utrecht , The Netherlands.|c Innovative Testing in Life Sciences and Chemistry , University of Applied Sciences Utrecht (HU) , Utrecht , The Netherlands.
authors: Peter T
authors: PT
authors: Theunissen
authors: d Federal Agency for Medicines and Health Products , Brussels , Belgium.
authors: Sonia
authors: S
authors: Beken
authors: e Sanofi U.S. Inc , Bridgewater , NJ , USA.
authors: Bruce
authors: B
authors: Beyer
authors: f Lilly Research Laboratories, Lilly Corporate Center , Indianapolis , IN , USA.
authors: William J
authors: WJ
authors: Breslin
authors: g Pfizer Worldwide Research & Development , Groton , CT , USA.
authors: Gregg D
authors: GD
authors: Cappon
authors: h ILSI-Health and Environmental Sciences Institute , Washington , DC , USA.
authors: Connie L
authors: CL
authors: Chen
authors: i Covance Laboratories Inc , Greenfield , IN , USA.
authors: Gary
authors: G
authors: Chmielewski
authors: j Preclinical Development & Safety , Beerse , Belgium.
authors: Luc
authors: L
authors: de Schaepdrijver
authors: k AbbVie Inc , North Chicago , IL , USA.
authors: Brian
authors: B
authors: Enright
authors: l ExxonMobil Biomedical Sciences, Inc , Annandale , NJ , USA.
authors: Jennifer E
authors: JE
authors: Foreman
authors: m US Food & Drug Administration , Silver Spring , MD , USA.
authors: Wafa
authors: W
authors: Harrouk
authors: n Takeda Pharmaceutical Company , Deerfield , IL , USA.
authors: Kok-Wah
authors: KW
authors: Hew
authors: o Preclinical Services , Charles-River Laboratories , Horsham , PA , USA.
authors: Alan M
authors: AM
authors: Hoberman
authors: p Celgene Corporation , Summit , NJ , USA.
authors: Julia
authors: J
authors: Y Hui
authors: q US Environmental Protection Agency, National Center for Computational Toxicology , Research Triangle Park , NC , USA.
authors: Thomas B
authors: TB
authors: Knudsen
authors: r Safety Assessment , GlaxoSmithKline , King of Prussia , PA , USA.
authors: Susan B
authors: SB
authors: Laffan
authors: s National Center for Environmental Assessment, US Environmental Protection Agency , Washington , DC , USA.
authors: Susan L
authors: SL
authors: Makris
authors: q US Environmental Protection Agency, National Center for Computational Toxicology , Research Triangle Park , NC , USA.
authors: Matthew
authors: M
authors: Martin
authors: t Drug Safety Evaluation , Bristol-Myers Squibb , New Brunswick , NJ , USA.
authors: Mary Ellen
authors: ME
authors: McNerney
authors: b Medicines Evaluation Board , Utrecht , The Netherlands.
authors: Christine L
authors: CL
authors: Siezen
authors: r Safety Assessment , GlaxoSmithKline , King of Prussia , PA , USA.
authors: Dinesh J
authors: DJ
authors: Stanislaus
authors: u Drug Safety & Metabolism , AstraZeneca , Macclesfield , UK.
authors: Jane
authors: J
authors: Stewart
authors: t Drug Safety Evaluation , Bristol-Myers Squibb , New Brunswick , NJ , USA.
authors: Kary E
authors: KE
authors: Thompson
authors: k AbbVie Inc , North Chicago , IL , USA.
authors: Belen
authors: B
authors: Tornesi
authors: a Centre for Health Protection, National Institute for Public Health and the Environment (RIVM) , Bilthoven , The Netherlands.|b Medicines Evaluation Board , Utrecht , The Netherlands.
authors: Jan Willem
authors: JW
authors: Van der Laan
authors: v Covance Preclinical Services GmbH , Muenster , Germany.
authors: Gerhard F
authors: GF
authors: Weinbauer
authors: w Merck Research Laboratories , Upper Gwynedd , PA , USA.
authors: Sandra
authors: S
authors: Wood
authors: a Centre for Health Protection, National Institute for Public Health and the Environment (RIVM) , Bilthoven , The Netherlands.|x Faculty of Veterinary Sciences , Institute for Risk Assessment Sciences, Utrecht University , Utrecht , The Netherlands.
authors: Aldert H
authors: AH
authors: Piersma
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D064420:Drug-Related Side Effects and Adverse Reactions; D004622:Embryo, Mammalian / Q000187:drug effects / Q000502:physiology*; D047108:Embryonic Development / Q000187:drug effects*; D004364:Pharmaceutical Preparations; D011817:Rabbits; D051381:Rats
chemical_list: D004364:Pharmaceutical Preparations
keywords: Cross-species evaluation; embryo-fetal developmental toxicity in rat and rabbit; human equivalent dose comparison; pharmaceutical testing; strain differences; systemic dose-based comparison