Comparing rat and rabbit embryo-fetal developmental toxicity data for 379 pharmaceuticals: on systemic dose and developmental effects.

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 Cmax exposures. 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 Cmax exposures. 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.

Comparison of rat and rabbit embryo-fetal developmental toxicity data for 379 pharmaceuticals: on the nature and severity of developmental effects.

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.

Numeric Estimates of Teratogenic Severity from Embryo-Fetal Developmental Toxicity Studies.

A developing organism exposed to a toxicant will have a response that ranges from none to severe (i.e., death or malformation). The response at a given dosage may be termed teratogenic (or developmental toxic) severity and is dependent on exposure conditions. Prenatal/embryo-fetal developmental (EFD) toxicity studies in rodents and rabbits are the most consistent and definitive assessments of teratogenic severity, and teratogenesis screening assays are best validated against their results. A formula is presented that estimates teratogenic severity for each group, including control, within an EFD study. The developmental components include embryonic/fetal death, malformations, variations, and mean fetal weight. The contribution of maternal toxicity is included with multiplication factors to adjust for the extent of mortality, maternal body weight change, and other parameters deemed important. The derivation of the formula to calculate teratogenic severity is described. Various EFD data sets from the literature are presented to highlight considerations to the calculation of the various components of the formula. Each score is compared to the concurrent control group to obtain a relative teratogenic severity. The limited studies presented suggest relative scores of two- to

Embryo-fetal developmental toxicity and toxicokinetics of loxoprofen tromethamine intravenously administered to pregnant rats.

BACKGROUND: Loxoprofen tromethamine is a novel structural compound related to loxoprofen. It has been used for the treatment of pain and inflammation. However, the embryo-fetal developmental toxicity (EFDT) of loxoprofen tromethamine has not been evaluated in detail in vivo. This study investigated the EFDT and toxicokinetics of loxoprofen tromethamine in rats. METHODS: The aim of this study was to investigate the potential reproductive toxicity on embryo-fetal development of loxoprofen tromethamine (0, 1, 3, and 10 mg/kg/day) and sodium cyclophosphamide (CP) (2.8 mg/kg/day) administered by intravenous injection to pregnant rats during gestation days (GDs) 6-15. Pregnant rats were euthanized on GD20. The numbers of live/dead fetuses, resorptions, implantations, and corpora lutea, gravid uterus mass, placenta mass, fetal gender ratios, body weight, and skeletal development were evaluated. In a concomitant toxicokinetic (TK) study (10 pregnant rats per group), plasma TK parameters and the tissue distribution of loxoprofen tromethamine were tested. RESULTS: On GD20, rats were anesthetized and dissected by caesarean section. The appearance, internal organs, gravid uterus weight, embryo implantation number, and implantation loss rate in maternal rats of each group did not reveal any lesions. In fetuses, there were no significant differences in the fetus weight, embryo resorption number, stillbirth number, or fetal visceral examination in all test groups compared to the negative control group. However, in the high-dose group, the fetuses showed significant differences in the anomalies of the bones compared to the negative control group. The TK study showed that in the dose range of 1-10 mg/kg, the Cmax and AUC(0-t) of loxoprofen tromethamine in animals after the first administration increased proportionally to the dose, showing linear kinetic characteristics; after the last administration, the Cmax and AUC(0-t) increased disproportionately to the dose, showing nonlinear kinetic characteristics. The results of tissue distribution show that loxoprofen tromethamine was mainly distributed in the placenta and lung after the intravenous administration to pregnant rats; the content in the liver was lower and increased sharply in the heart with increasing doses; the content in all tissues was lower than that in the plasma. Loxoprofen tromethamine in fetal tissues and organs was mainly distributed in fetal lungs, liver and heart, and the lowest content was in amniotic fluid. CONCLUSIONS: In conclusion, the no-observed-adverse-effect level (NOAEL) and lowest-observed-adverse-effect level (LOAEL) of loxoprofen tromethamine were considered to be 1 and 10 mg/kg/day, respectively.

Species-specific developmental toxicity in rats and rabbits: Generation of a reference compound list for development of alternative testing approaches.

For regulatory information requirements, developmental toxicity testing is often conducted in two mammalian species. In order to provide a set of reference compounds that could be used to explore alternative approaches to supersede testing in a second species, a retrospective data analysis was conducted. The aim was to identify compounds for which species sensitivity differences between rats and rabbits are not caused by maternal toxicity or toxicokinetic differences. A total of 330 compounds were analysed and classified according to their species-specific differences. A lack of concordance between rat and rabbit was observed in 24% of the compounds, of which 10% were found to be selective developmental toxicants in one of the species. In contrast to previously published analyses the presented comparison is based entirely on publically data allowing validating and comparing alternative approaches for developmental toxicity testing. Furthermore, this list could be useful to identify mechanisms leading to species differences.