2021 FDA Science Forum
In Vitro-to-In Vivo Extrapolation (IVIVE) for Liver Safety Assessment of Anthraquinones
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Contributing OfficeCenter for Food Safety and Applied Nutrition
Abstract
Anthraquinones are found in a variety of consumer products such as foods, dietary supplements and traditional Chinese medicines. Along with their widespread use, potential safety concerns have emerged including liver toxicity. Due to a lack of toxicokinetic and liver toxicity data for anthraquinones in animals and humans, there is a need to conduct time- and cost-effective safety assessment to prioritize and select anthraquinones for more in-depth studies. In vitro-to-in vivo extrapolation could bridge between in vitro toxicity and an in vivo dose that causes toxic effects therefore enabling rapid and effective safety evaluation. Here, a combined in vitro cytotoxicity and in silico reverse dosimetry approach was adopted to evaluate the potential human liver toxicity of 16 anthraquinones and derivatives. First, cytotoxicity (EC50) in two human liver cell lines (HepG2/C3A and HuH-7) was measured under two conditions (single and repeated dosing, 72 hrs). Second, toxic doses (Dtox) required to yield plasma steady-state concentrations (Css) equal to in vitro EC50 values were predicted by reverse dosimetry simulation using a PBPK model. Finally, Dtox was compared to literature-derived estimated daily intake (EDI) of anthraquinones to assess liver safety. Among the 16 anthraquinones, rhein was identified as a potential hepatotoxicant due to a combination of cytotoxicity, plasma concentration, and daily intake level. These in vitro and in silico findings provide preliminary data and guidance for further animal and clinical studies to confirm liver toxicity of anthraquinones.
