Predicting points of departure for risk assessment based on in vitro cytotoxicity data and physiologically based kinetic (PBK) modeling: The case of kidney toxicity induced by aristolochic acid I. (June 2016)

• Record Type: Journal Article
• Authors: Abdullah, Rozaini; Alhusainy, Wasma; Woutersen, Jasper; Rietjens, Ivonne M.C.M.; Punt, Ans
• Is Part Of: Food and chemical toxicology. Volume 92(2016)
• Page Start: 104
• Page End: 116
• Publication Date: 2016-06
• Subjects: Physiologically based kinetic (PBK) model -- Aristolochic acid I (AAI) -- Kidney toxicity -- In vitro-in vivo extrapolation -- Risk assessment -- Physiologically based pharmacokinetic (PBPK) model; AA aristolochic acid -- AAI aristolochic acid I -- AAII aristolochic acid II -- AAIa aristolochic acid Ia -- ADI acceptable daily intake -- AAN Aristolochic Acid Nephropathy -- AUC area under the curve -- BMCL 95% lower confidence limit of the benchmark concentration -- BMDL 95% lower confidence limit of the benchmark dose -- Cmax maximum concentration -- LOAEL lowest observed adverse effect level -- NOAEL no observed adverse effect level -- PBK Physiologically based kinetic -- PODs points of departure -- TDI tolerable daily intake; Toxicology -- Periodicals; Food poisoning -- Periodicals; Food Poisoning -- Periodicals; Toxicology -- Periodicals; Toxicologie -- Périodiques; Intoxications alimentaires -- Périodiques; Food poisoning; Toxicology; Periodicals; Electronic journals; 615.9
• DOI: 10.1016/j.fct.2016.03.017
• Languages: English
• ISSNs: 0278-6915

Abstract

Abstract: Aristolochic acids are naturally occurring nephrotoxins. This study aims to investigate whether physiologically based kinetic (PBK) model-based reverse dosimetry could convert in vitro concentration-response curves of aristolochic acid I (AAI) to in vivo dose response-curves for nephrotoxicity in rat, mouse and human. To achieve this extrapolation, PBK models were developed for AAI in these different species. Subsequently, concentration-response curves obtained from in vitro cytotoxicity models were translated to in vivo dose–response curves using PBK model-based reverse dosimetry. From the predicted in vivo dose–response curves, points of departure (PODs) for risk assessment could be derived. The PBK models elucidated species differences in the kinetics of AAI with the overall catalytic efficiency for metabolic conversion of AAI to aristolochic acid Ia (AAIa) being 2-fold higher for rat and 64-fold higher for mouse than human. Results show that the predicted PODs generally fall within the range of PODs derived from the available in vivo studies. This study provides proof of principle for a new method to predict a POD for in vivo nephrotoxicity by integrating in vitro toxicity testing with in silico PBK model-based reverse dosimetry. Highlights: PBK models were developed for AAI in rat, mouse and human based on in vitro kinetic data. Concentration–response curves for AAI cytotoxicity were obtained with the MTT assay. PBK-based reverse dosimetry defined in vivo dose response curves for kidney toxicity of AAI. The predicted in vivo data could be used to define a POD for risk assessment of AAI. The approach provides a non-animal testing strategy for predicting PODs in risk assessment.