title: Comparison of rat and rabbit embryo-fetal developmental toxicity data for 379 pharmaceuticals: on the nature and severity of developmental effects.
abstract: Regulatory non-clinical safety testing of human pharmaceuticals typically requires embryo-fetal developmental toxicity (EFDT) testing in two species (one rodent and one non-rodent). The question has been raised whether under some conditions EFDT testing could be limited to one species, or whether the testing in a second species could be decided on a case-by-case basis. As part of a consortium initiative, we built and queried a database of 379 compounds with EFDT studies (in both rat and rabbit animal models) conducted for marketed and non-marketed pharmaceuticals for their potential for adverse developmental and maternal outcomes, including EFDT incidence and the nature and severity of adverse findings. Manifestation of EFDT in either one or both species was demonstrated for 282 compounds (74%). EFDT was detected in only one species (rat or rabbit) in almost a third (31%, 118 compounds), with 58% (68 compounds) of rat studies and 42% (50 compounds) of rabbit studies identifying an EFDT signal. 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 species may be attributed to factors such as maternal toxicity, study design differences, pharmacokinetic differences, and pharmacologic relevance of species. The current analysis suggests that in general both species are equally sensitive on the basis of an overall EFDT LOAEL comparison, but selective EFDT toxicity in one species is not uncommon. Also, there appear to be species differences in the prevalence of various EFDT manifestations (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.
authors.affiliation: 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.forename: Peter T
authors.initials: PT
authors.lastname: Theunissen
authors.affiliation: d Federal Agency for Medicines and Health Products , Brussels , Belgium.
authors.forename: Sonja
authors.initials: S
authors.lastname: Beken
authors.affiliation: e Sanofi U.S. Inc. Bridgewater , NJ , USA.
authors.forename: Bruce K
authors.initials: BK
authors.lastname: Beyer
authors.affiliation: f Lilly Research Laboratories , Lilly Corporate Center , Indianapolis , IN , USA.
authors.forename: William J
authors.initials: WJ
authors.lastname: Breslin
authors.affiliation: g Pfizer Worldwide Research & Development , Groton , CT , USA.
authors.forename: Gregg D
authors.initials: GD
authors.lastname: Cappon
authors.affiliation: h ILSI-Health and Environmental Sciences Institute , Washington , DC , USA.
authors.forename: Connie L
authors.initials: CL
authors.lastname: Chen
authors.affiliation: i Covance Laboratories Inc , Greenfield , IN , USA.
authors.forename: Gary
authors.initials: G
authors.lastname: Chmielewski
authors.affiliation: j Janssen R&D, Preclinical Development & Safety Beerse , Belgium.
authors.forename: Luc
authors.initials: L
authors.lastname: De Schaepdrijver
authors.affiliation: k AbbVie Inc , North Chicago , IL , USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Enright
authors.affiliation: l ExxonMobil Biomedical Sciences, Inc , Annandale , NJ , USA.
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Foreman
authors.affiliation: m U.S. Food & Drug Administration , Silver Spring , MD , USA.
authors.forename: Wafa
authors.initials: W
authors.lastname: Harrouk
authors.affiliation: n Takeda Pharmaceutical Company , Deerfield , IL , USA.
authors.forename: Kok-Wah
authors.initials: KW
authors.lastname: Hew
authors.affiliation: o Charles-River Laboratories, Preclinical Services , Horsham , PA , USA.
authors.forename: Alan M
authors.initials: AM
authors.lastname: Hoberman
authors.affiliation: p Celgene Corporation , Summit , NJ , USA.
authors.forename: Julia Y
authors.initials: JY
authors.lastname: Hui
authors.affiliation: q U.S. Environmental Protection Agency, National Center for Computational Toxicology, Research Triangle Park , NC , USA.
authors.forename: Thomas B
authors.initials: TB
authors.lastname: Knudsen
authors.affiliation: r Safety Assessment, GlaxoSmithKline , King of Prussia , PA , USA.
authors.forename: Susan B
authors.initials: SB
authors.lastname: Laffan
authors.affiliation: s U.S. Environmental Protection Agency, National Center for Environmental Assessment , Washington , DC , USA.
authors.forename: Susan L
authors.initials: SL
authors.lastname: Makris
authors.affiliation: q U.S. Environmental Protection Agency, National Center for Computational Toxicology, Research Triangle Park , NC , USA.
authors.forename: Matt
authors.initials: M
authors.lastname: Martin
authors.affiliation: t Drug Safety Evaluation, Bristol-Myers Squibb , New Brunswick , NJ , USA.
authors.forename: Mary Ellen
authors.initials: ME
authors.lastname: McNerney
authors.affiliation: b Medicines Evaluation Board , Utrecht , The Netherlands.
authors.forename: Christine L
authors.initials: CL
authors.lastname: Siezen
authors.affiliation: r Safety Assessment, GlaxoSmithKline , King of Prussia , PA , USA.
authors.forename: Dinesh J
authors.initials: DJ
authors.lastname: Stanislaus
authors.affiliation: u Drug Safety & Metabolism, AstraZeneca , Macclesfield , UK.
authors.forename: Jane
authors.initials: J
authors.lastname: Stewart
authors.affiliation: t Drug Safety Evaluation, Bristol-Myers Squibb , New Brunswick , NJ , USA.
authors.forename: Kary E
authors.initials: KE
authors.lastname: Thompson
authors.affiliation: k AbbVie Inc , North Chicago , IL , USA.
authors.forename: Belen
authors.initials: B
authors.lastname: Tornesi
authors.affiliation: 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.forename: Jan Willem
authors.initials: JW
authors.lastname: Van der Laan
authors.affiliation: v Covance Preclinical Services GmbH , Muenster , Germany.
authors.forename: Gerhard F
authors.initials: GF
authors.lastname: Weinbauer
authors.affiliation: w Merck Research Laboratories , Upper Gwynedd , Pennsylvania , USA.
authors.forename: Sandra
authors.initials: S
authors.lastname: Wood
authors.affiliation: a Centre for Health Protection, National Institute for Public Health and the Environment (RIVM) , Bilthoven , The Netherlands.|x Institute for Risk Assessment Sciences, Faculty of Veterinary Sciences , Utrecht University , Utrecht , The Netherlands.
authors.forename: Aldert H
authors.initials: AH
authors.lastname: Piersma
mesh_terms: D000014:Abnormalities, Drug-Induced; D000818:Animals; D047109:Fetal Development / Q000187:drug effects*; D015386:Hazardous Substances / Q000633:toxicity*; D023421:Models, Animal; D009152:Mutagenicity Tests / Q000379:methods*; D011817:Rabbits; D051381:Rats; D013723:Teratogens / Q000633:toxicity*
chemical_list: D015386:Hazardous Substances; D013723:Teratogens
keywords: Pharmaceutical testing; cross-species evaluation; embryo–fetal developmental toxicity; non-clinical