Linakis Matthew W, Clewell Rebecca A, Campbell Jerry, Gentry P Robinan, Clewell Harvey J
Ramboll Americas Engineering Solutions, Inc., Raleigh, NC, USA.
21st Century Tox Consulting, LLC, Chapel Hill, NC, USA.
ALTEX. 2025 May 28. doi: 10.14573/altex.2406281.
New approach methodologies (NAMs) are rapidly being developed to help improve the speed of risk assessment and reduce the use of animals. In vitro to in vivo extrapolation (IVIVE) is necessary to translate NAM data to human exposures. While past IVIVE efforts have demonstrated impressive success, several specialized scenarios exist where current IVIVE methods have not been tested, including pregnancy and developmental toxicity. To that end, this investigation proposes a preliminary IVIVE workflow for identification of potential developmental toxicants. Readily available in vitro and in vivo data with developmental toxicity endpoints were aggregated from the US Environmental Protection Agency's CompTox Chemicals Dashboard. In vitro distribution models (i.e. Armitage model) and both generic (httk) and bespoke physiologically-based pharmacokinetic (PBPK) models were used to estimate exposures from blood concentrations associated with in vitro bioactivity (reverse dosimetry) and NAM-based bioactive doses were compared to in vivo endpoints (LOAELs) where available. Based on literature sources, this method identified chemicals as a high, medium, or low priority for follow-up as a developmental toxicant. Of the 23 chemicals with in vitro developmental toxicity assays, 7 had a NAM-based human oral equivalent dose (hOED) that was lower for developmental assays than for all available assays, indicating that the use of all in vitro data to derive a hOED would generally provide the most conservative approach. Potential data streams and refinements for improvement of the IVIVE workflow are also discussed.
新方法学（NAMs）正在迅速发展，以帮助提高风险评估的速度并减少动物的使用。体外到体内外推法（IVIVE）对于将NAM数据转化为人体暴露情况是必要的。虽然过去的IVIVE工作已取得显著成功，但仍存在一些当前IVIVE方法未经过测试的特殊情况，包括妊娠和发育毒性。为此，本研究提出了一种用于识别潜在发育毒物的初步IVIVE工作流程。从美国环境保护局的综合毒性化学物质仪表板汇总了具有发育毒性终点的现成体外和体内数据。使用体外分布模型（即阿米蒂奇模型）以及通用（httk）和定制的基于生理的药代动力学（PBPK）模型，根据与体外生物活性相关的血药浓度估算暴露情况（反向剂量测定），并将基于NAM的生物活性剂量与可用的体内终点（最低观察到有害作用水平）进行比较。根据文献来源，该方法将化学物质确定为作为发育毒物进行后续研究的高、中或低优先级。在进行了体外发育毒性试验的23种化学物质中，有7种基于NAM的人体口服等效剂量（hOED）在发育试验中低于所有可用试验，这表明使用所有体外数据得出hOED通常会提供最保守的方法。还讨论了用于改进IVIVE工作流程的潜在数据流和改进措施。
