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

Abstract

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.

Protocols for the Evaluation of Neurodevelopmental Alterations in Rabbit Models In Vitro and In Vivo

“…In this case, the recommendation of the OECD TG 426 is that the study is conducted in the species increasing the concern, but so far this could not be completely carried out if the concern was raised in rabbits because there were no protocols available. Some specific examples of compounds displaying structuraldevelopmental neurotoxicity in rabbits and not in rats have already been identified (Theunissen et al, 2016;Teixidó et al, 2018). Unfortunately, one of the studies is based on a coded dataset that did not reveal the identity of the compounds showing species differences, but the identified substances (and the adverse neurodevelopmental effect) were: 10224 (small or absent cerebrum), 10330 (enlarged cerebral ventricle), and tafluprost (cranial and spinal malformations).…”

“…The adaptation of protocols regularly used to evaluate developmental neurotoxicity in rats to rabbits could be useful in specific cases where the rabbit could mimic human conditions better than the rat, especially if it is taken into account that the OECD TG 426 indicates that if there is an earlier test raising concerns on developmental neurotoxicity the species/strain that raised this concern should be considered for the developmental neurotoxicity assay instead of the rat (OECD, 2007). From several review articles comparing the effects of test compounds in the OECD TG 414 performed in rats and rabbits, it has been demonstrated that there is an overlap of detectable effects in these species (Theunissen et al, 2016;Theunissen et al, 2017;Teixidó et al, 2018). However, there is a significant proportion of compounds with embryo-fetal developmental toxicity only detected in one of both species.…”

“…However, there is a significant proportion of compounds with embryo-fetal developmental toxicity only detected in one of both species. The proportion of chemicals or drugs whose developmental toxic potential was only described in rabbits and not in rats was around 13% in several large-scale comparative studies (Theunissen et al, 2016;Theunissen et al, 2017;Teixidó et al, 2018). For all these reasons, it is plausible that the rabbit species becomes relevant for the evaluation of developmental neurotoxicity in particular cases.…”

Head skeleton malformations in zebrafish (Danio rerio) to assess adverse effects of mixtures of compounds

“…However, these few observations may be too limited as a basis for inclusion in the mammalian CAG skeletal malformations. CAG membership may also be questioned when developmental toxicity is secondory to maternal toxicity (Teixido et al 2018), which may be the case with the dithiocarbamates, where skeletal variants were induced with maneb in CD1 mice and in Sprague–Dawley rats at a high dose overlapping with maternal toxicity (Beck 1990; Kapp et al 1991). …”

Grouping of chemicals into mode of action classes by automated effect pattern analysis using the zebrafish embryo toxicity test

“…To include an estimation of the specificity of the responses the comparative analysis was related to mortality and unspecific hydrophobicity-driven baseline toxicity. Twenty-five chemicals with known developmental toxicity and different (pharmacological) MoA were selected based on previous published studies (Teixidó et al 2018 , 2019 ). We hypothesized that by application of standard supervised and non-supervised descriptive statistical techniques on zebrafish embryo effect patterns chemicals can be grouped according to their MoA.…”