Abstract
Aristolochic acid I (AAI) is a well‐known genotoxic kidney carcinogen. Metabolic conversion of AAI into the DNA‐reactive aristolactam‐nitrenium ion is involved in the mode of action of tumor formation. This study aims to predict in vivo AAI‐DNA adduct formation in the kidney of rat, mouse and human by translating the in vitro concentration‐response curves for AAI‐DNA adduct formation to the in vivo situation using physiologically based kinetic (PBK) modeling‐based reverse dosimetry. DNA adduct formation in kidney proximal tubular LLC‐PK1 cells exposed to AAI was quantified by liquid chromatography‐electrospray ionization‐tandem mass spectrometry. Subsequently, the in vitro concentration‐response curves were converted to predicted in vivo dose‐response curves in rat, mouse and human kidney using PBK models. Results obtained revealed a dose‐dependent increase in AAI‐DNA adduct formation in the rat, mouse and human kidney and the predicted DNA adduct levels were generally within an order of magnitude compared with values reported in the literature. It is concluded that the combined in vitro PBK modeling approach provides a novel way to define in vivo dose‐response curves for kidney DNA adduct formation in rat, mouse and human and contributes to the reduction, refinement and replacement of animal testing.
Highlights
The development of science-based nonanimal testing strategies in the safety assessment of chemicals in humans is an important challenge
A novel alternative testing strategy that can be used to solve this discrepancy between in vitro and in vivo data involves the translation of in vitro concentrationresponse curves to in vivo dose-response curves using physiologically based kinetic (PBK) modeling-based reverse dosimetry
We translated in vitro concentration-response curves for cytotoxicity of aristolochic acid I (AAI) in LLC-PK1 or MDCK cells to in vivo dose-response curves for kidney toxicity from which we derived BMDL10 values that can be used as points of departure for risk assessment (Abdullah et al, 2016)
Summary
The development of science-based nonanimal testing strategies in the safety assessment of chemicals in humans is an important challenge Current efforts in this area focus on the development and use of in vitro alternative testing strategies using cells in culture resulting in concentration-response curves. 1999; Louisse et al, 2010; Suparmi et al, 2019) By using this integrated in vitro-in silico approach, in vivo dose-response levels and points of departure for risk assessment can be defined based on in vitro concentration-response curves. We translated in vitro concentration-response curves for cytotoxicity of aristolochic acid I (AAI) in LLC-PK1 or MDCK cells to in vivo dose-response curves for kidney toxicity from which we derived BMDL10 values (benchmark dose 10% lower confidence limit) that can be used as points of departure for risk assessment (Abdullah et al, 2016). Human studies on AA kidney DNA adduct formation in patients with AA nephropathy (AAN) are available (Bieler et al, 1997; Nortier et al, 2000), enabling validation of the predictions made
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