Prediction of in vivo developmental toxicity of all-trans-retinoic acid based on in vitro toxicity data and in silico physiologically based kinetic modeling

Abstract

values [lower limit of the 95 % confidence interval on the BMD at which a benchmark response equivalent to a 10 % effect size (BMR 10 ) is reached (BMD 10 )] for rat were compared with BMDL 10 values derived from in vivo developmental toxicity data in rats reported in the literature. The results show that the BMDL 10 values from predicted dose-response data differ about sixfold from the BMDL 10 values obtained from in vivo data, pointing at the feasibility of using a combined in vitro-in silico approach for defining a point of departure for toxicological risk assessment. KeywordsIn vitro-in vivo extrapolation · Developmental toxicity · All-trans-retinoic acid · Physiologically based kinetic modeling · Reverse dosimetry · Solid phase microextraction In order to use toxicity data obtained from in vitro assays for risk assessment, in vitro concentration-response data need to be translated into in vivo dose-response data that are needed to obtain points of departure for risk assessment, like a benchmark dose (BMD). In the present study, we translated in vitro concentration-response data of the retinoid all-trans-retinoic acid (ATRA), obtained in the differentiation assay of the embryonic stem cell test, into in vivo dose-response data using a physiologically based kinetic model for rat and human that is mainly based on kinetic model parameter values derived using in vitro techniques. The predicted in vivo dose-response data were used for BMD modeling, and the obtained BMDL 10 AbbreviationsElectronic supplementary material The online version of this article

Physiologically based kinetic modeling of hesperidin metabolism and its use to predict in vivo effective doses in humans

“…PBK‐based reverse dosimetry was carried out to convert in vitro effect concentrations to predicted in vivo dose levels of hesperidin based on the methods described by Louisse et al. and Strikwold et al. .…”

Integrating in vitro data and physiologically based kinetic (PBK) modelling to assess the in vivo potential developmental toxicity of a series of phenols

“…In previous studies it was demonstrated that PBK-based reverse dosimetry converting in vitro concentration–response values to in vivo dose–response data could successfully be applied to predict a PoD for phenol (Strikwold et al 2013), for all-trans-retinoic-acid (Louisse et al 2015) and for some glycol-ethers (Louisse et al 2010). The aim of the present study was to investigate whether PBK-based reverse dosimetry could be used to translate in vitro embryotoxicity data obtained with the EST for a series of phenols (Strikwold et al 2012) to in vivo developmental toxic potency values for the rat, using only in silico- and in vitro-derived (kinetic) parameters and data from the literature, and whether this approach could overcome differences in in vitro and in vivo relative potencies of different phenolic congeners observed by Strikwold et al (2012).…”

“…Combining in vitro toxicity data with physiologically based kinetic (PBK) modelling applying reverse dosimetry has recently been shown to provide a promising approach to extrapolate in vitro concentration–response curves to in vivo dose–response curves from which points of departure (PoDs) for the risk assessment of chemicals can be derived (Louisse et al 2010, 2015; Strikwold et al 2013). In this way kinetic differences between the vitro and in vivo situation can be taken into account and in vivo dose–response curves suitable for deriving a PoD for risk assessment can be obtained based on in vitro data.…”

Regulation of IgA Class Switch Recombination in Immunoglobulin A Nephropathy: Retinoic Acid Signaling and BATF

“…In our study, ATRA (500 μg/kg body weight) treatment was given to IgAN rat models for 8 weeks, and no evidence of kidney functional damage was observed during the entire study period. In fact, dose-response data for ATRA in rats revealed that developmental toxicity was the main side effect [50] . Because of high lipophilicity, ATRA is thought to be responsible for the slow dissolution and low bioavailability following oral administration [51] , so ATRA (500 μg/kg body weight) was dosed intraperitoneally.…”