Table_1_Internal Threshold of Toxicological Concern (iTTC): Where We Are Today and What Is Possible in the Near Future.DOCX

The Threshold of Toxicological Concern (TTC) is a risk assessment tool for evaluating low-level exposure to chemicals with limited toxicological data. A next step in the ongoing development of TTC is to extend this concept further so that it can be applied to internal exposures. This refinement of TTC based on plasma concentrations, referred to as internal TTC (iTTC), attempts to convert the chemical-specific external NOAELs (in mg/kg/day) in the TTC database to an estimated internal exposure. A multi-stakeholder collaboration formed, with the aim of establishing an iTTC suitable for human safety risk assessment. Here, we discuss the advances and future directions for the iTTC project, including: (1) results from the systematic literature search for metabolism and pharmacokinetic data for the 1,251 chemicals in the iTTC database; (2) selection of ~350 chemicals that will be included in the final iTTC; (3) an overview of the in vitro caco-2 and in vitro hepatic metabolism studies currently being generated for the iTTC chemicals; (4) demonstrate how PBPK modeling is being utilized to convert a chemical-specific external NOAEL to an internal exposure; (5) perspective on the next steps in the iTTC project.

毒理学关注阈值（Threshold of Toxicological Concern, TTC）是一款用于评估毒理学数据有限的化学品低水平暴露风险的风险评估工具。当前TTC研发进程中的下一步方向，是进一步拓展该概念的适用边界，使其可应用于内暴露评估场景。基于血浆浓度构建的TTC优化方案被称为内暴露毒理学关注阈值（internal TTC, iTTC），其核心目标是将TTC数据库中各化学物的外源性未观察到有害作用水平（单位：mg/kg/天）转换为对应的估算内暴露量。目前已组建多利益相关方协作团队，旨在建立适用于人类健康安全风险评估的iTTC体系。本文将就iTTC项目的研究进展与未来方向展开探讨，具体包括：（1）针对iTTC数据库中1251种化学品的代谢与药代动力学数据开展系统文献检索的研究结果；（2）最终纳入iTTC体系的约350种化学品的遴选流程；（3）当前针对iTTC相关化学品所开展的体外Caco-2细胞试验与体外肝代谢研究的整体概况；（4）阐述如何利用生理药代动力学模型（Physiologically Based Pharmacokinetic Modeling, PBPK）将特定化学物的外源性未观察到有害作用水平转换为内暴露量；（5）关于iTTC项目后续研发步骤的展望。