This study describes the development and intercomparison of generic physiologically-based toxicokinetic (PBTK) models for humans comprised of internally consistent one-compartment (1Co-) and multi-compartment (MCo-) implementations (G-PBTK). The G-PBTK models were parameterized for an adult male (70 kg) using common physiological parameters and in vitro biotransformation rate estimates and subsequently evaluated using independent concentration versus time data (n = 6) and total elimination half-lives (n = 15) for diverse organic chemicals. The model performance is acceptable considering the inherent uncertainty in the biotransformation rate data and the absence of model calibration. The G-PBTK model was then applied using hypothetical neutral organics, acidic ionizable organics and basic ionizable organics (IOCs) to identify combinations of partitioning properties and biotransformation rates leading to substantial discrepancies between 1Co- and MCo-PBTK calculations for whole body concentrations and half-lives. The 1Co- and MCo-PBTK model calculations for key toxicokinetic parameters are broadly consistent unless biotransformation is rapid (e.g., half-life less than five days). When half-lives are relatively short, discrepancies are greatest for the neutral organics and least for the acidic IOCs which follows from the estimated volumes of distribution (e.g., VD_SS = 9.6–15.4 L/kg vs 0.3–1.6 L/kg for the neutral and acidic compounds respectively) and the related approach to internal chemical equilibrium. The model intercomparisons demonstrate that 1Co-PBTK models can be applied with confidence to many exposure scenarios, particularly those focused on chronic or repeat exposures and for prioritization and screening-level decision contexts. However, MCo-PBTK models may be necessary in certain contexts, particularly for intermittent, short-term and highly variable exposures. A key recommendation to guide model selection and the development of tiered PBTK modeling frameworks that emerges from this study is the need to harmonize models with respect to parameterization and process descriptions to the greatest extent possible when proceeding from the application of simpler to more complex modeling tools as part of chemical assessment activities.

这项研究描述了针对人类的基于生理的通用毒物动力学（PBTK）模型的开发和相互比较，该模型由内部一致的一室（1Co-）和多室（MCo-）实施（G-PBTK）组成。使用常见的生理参数和体外生物转化率估算值对成年雄性（70 kg）的G-PBTK模型进行参数设置，然后使用独立的浓度对时间数据（n  = 6）和总消除半衰期（n = 15）用于多种有机化学品。考虑到生物转化率数据中固有的不确定性以及缺乏模型校准，模型性能是可以接受的。然后，使用假设的中性有机物，酸性可离子化有机物和碱性可离子化有机物（IOC）来应用G-PBTK模型，以识别分配特性和生物转化率的组合，从而导致1Co-和MCo-PBTK计算的全身浓度和一半之间存在实质性差异-生活。除非生物转化迅速（例如，半衰期少​​于5天），否则关键毒代动力学参数的1Co-和MCo-PBTK模型计算是大致一致的。当半衰期相对较短时，_党卫军 = 9.6–15.4 L / kg，而中性和酸性化合物分别为0.3–1.6 L / kg）和内部化学平衡的相关方法。模型间的比较表明1Co-PBTK模型可以放心地应用于许多暴露场景，尤其是那些侧重于长期或重复暴露以及用于优先级和筛选级别决策环境的模型。但是，在某些情况下可能需要MCo-PBTK模型，尤其是对于间歇性，短期和高度可变的风险敞口。