Hepatic and Renal Toxicity of Gardenia Yellow: Repeated-Dose Assessment and Human Oral Equivalent Dose Prediction via IVIVE Yue-Fei Lai, Fei-Fei Xu, Wei-Liang Wu, Yi-Ping Xu, Xiao-Dan Wang, Rui-Li Xie, Jia-Liang Pan, Zhi-Ni He, Jia Song, Zi-Yin Li, Lei Zhang, Xing-Fen Yang Journal of Agricultural and Food Chemistry, 2025 Gardenia yellow, an edible pigment derived from Gardenia jasminoides, has wide food applications; however, its safety profile is insufficiently defined. In this study, we characterized the composition of gardenia yellow and simulated its gastrointestinal digestion, absorption, and metabolism using an in vitro gastrointestinal model. Its hepatotoxicity and nephrotoxicity were assessed using the HepaRG and RPTEC/TERT1 cell lines via cellular viability, oxidative stress, and mitochondrial dysfunction assays. Its lowest effective concentration (LEC), determined after 14 days of repeated exposure, was used to estimate its oral equivalent dose (OED) via the in vitro-to-in vivo extrapolation (IVIVE) method. Crocin, the primary bioactive component of gardenia yellow (44.96%), exhibited 4.68 ± 1.00% oral bioavailability and was biotransformed to crocetin (30.47 ± 1.95%) in the colon. Crocetin induced oxidative stress and mitochondrial dysfunction in hepatic and renal cells. The predicted oral equivalent dose for gardenia yellow (1.43 g/(kg·bw·day)) exceeded the typical Chinese dietary exposure, indicating a favorable safety margin.
Fish Physiologically Based Toxicokinetic Modeling Approach for In Vitro-In Vivo and Cross-Species Extrapolation of Endocrine-Disrupting Chemicals in Risk Assessment Ruili Xie, Yiping Xu, Mei Ma, Zijian Wang Environmental Science and Technology, 2024 High-throughput in vitro assays combined with in vitro-in vivo extrapolation (IVIVE) leverage in vitro responses to predict the corresponding in vivo exposures and thresholds of concern. The integrated approach is also expected to offer the potential for efficient tools to provide estimates of chemical toxicity to various wildlife species instead of animal testing. However, developing fish physiologically based toxicokinetic (PBTK) models for IVIVE in ecological applications is challenging, especially for plausible estimation of an internal effective dose, such as fish equivalent concentration (FEC). Here, a fish PBTK model linked with the IVIVE approach was established, with parameter optimization of chemical unbound fraction, pH-dependent ionization and hepatic clearance, and integration of temperature effect and growth dilution. The fish PBTK-IVIVE approach provides not only a more precise estimation of tissue-specific concentrations but also a reasonable approximation of FEC targeting the estrogenic potency of endocrine-disrupting chemicals. Both predictions were compared with in vivo data and were accurate for most indissociable/dissociable chemicals. Furthermore, the model can help determine cross-species variability and sensitivity among the five fish species. Using the available IVIVE-derived FEC with target pathways is helpful to develop predicted no-effect concentration for chemicals with similar mode of action and support screening-level ecological risk assessment.
