van Tongeren Tessa C A, Carmichael Paul L, Rietjens Ivonne M C M, Li Hequn
Division of Toxicology, Wageningen University and Research, Wageningen, Netherlands.
Unilever Safety and Environmental Assurance Centre, Sharnbrook, United Kingdom.
Front Toxicol. 2022 Jun 2;4:881235. doi: 10.3389/ftox.2022.881235. eCollection 2022.
In next generation risk assessment (NGRA), non-animal approaches are used to quantify the chemical concentrations required to trigger bioactivity responses, in order to assure safe levels of human exposure. A limitation of many bioactivity assays, which are used in an NGRA context as new approach methodologies (NAMs), is that toxicokinetics, including biotransformation, are not adequately captured. The present study aimed to include, as a proof of principle, the bioactivity of the metabolite hydroxyflutamide (HF) in an NGRA approach to evaluate the safety of the anti-androgen flutamide (FLU), using the AR-CALUX assay to derive the NAM point of departure (PoD). The NGRA approach applied also included PBK modelling-facilitated quantitative to extrapolation (QIVIVE). The PBK model describing FLU and HF kinetics in humans was developed using GastroPlus™ and validated against human pharmacokinetic data. PBK model-facilitated QIVIVE was performed to translate the AR-CALUX derived concentration-response data to a corresponding dose-response curve for the anti-androgenicity of FLU, excluding and including the activity of HF (-HF and +HF, respectively). The benchmark dose 5% lower confidence limits (BMDL) derived from the predicted dose-response curves for FLU, revealed a 440-fold lower BMDL when taking the bioactivity of HF into account. Subsequent comparison of the predicted BMDL values to the human therapeutic doses and historical animal derived PoDs, revealed that PBK modelling-facilitated QIVIVE that includes the bioactivity of the active metabolite is protective and provides a more appropriate PoD to assure human safety NGRA, whereas excluding this would potentially result in an underestimation of the risk of FLU exposure in humans.
在下一代风险评估（NGRA）中，非动物方法被用于量化引发生物活性反应所需的化学物质浓度，以确保人类接触的安全水平。许多在NGRA背景下用作新方法学（NAMs）的生物活性测定的一个局限性在于，包括生物转化在内的毒代动力学没有得到充分体现。本研究旨在作为原理验证，将代谢物羟基氟他胺（HF）的生物活性纳入NGRA方法中，以评估抗雄激素药物氟他胺（FLU）的安全性，使用AR-CALUX测定法得出NAM的起始点（PoD）。所应用的NGRA方法还包括基于生理药代动力学（PBK）模型的定量外推（QIVIVE）。使用GastroPlus™开发了描述人类体内氟他胺和羟基氟他胺动力学的PBK模型，并根据人类药代动力学数据进行了验证。进行了基于PBK模型的QIVIVE，以将AR-CALUX得出的浓度-反应数据转化为氟他胺抗雄激素作用的相应剂量-反应曲线，分别排除和纳入羟基氟他胺的活性（分别为-HF和+HF）。从预测的氟他胺剂量-反应曲线得出的基准剂量5%置信下限（BMDL）显示，考虑到羟基氟他胺的生物活性时，BMDL降低了440倍。随后将预测的BMDL值与人类治疗剂量和历史动物得出的PoD进行比较，结果表明，纳入活性代谢物生物活性的基于PBK模型的QIVIVE具有保护作用，并为确保人类安全的NGRA提供了更合适的PoD，而排除这一点可能会导致低估人类接触氟他胺的风险。
