在体外和计算方法来预测发育性毒性:将PBPK模型与基于细胞的测定集成
Marjory Moreau1, Todor Antonijevic1, John Carter Hall1
1ScitoVation, LLC, Research Triangle Park, NC 27713, USA.
Toxicology and applied pharmacology
|June 6, 2025
概括
这项研究将新的体外方法与药理动力学建模相结合,以预测化学发育毒性. 这些方法为人类健康风险评估提供了量化,无动物的替代方案.
科学领域:
- 毒理学和化学安全评估
- 生殖和发育毒理学
- 新方法方法论 (NAMs)
背景情况:
- 化学品安全评估领域正在从动物试验转向新方法方法 (NAMs).
- 现有的体外测试方法缺乏人体健康风险评估的定量框架.
- 将体外试验结果与人类暴露水平联系起来仍然是公共卫生风险评估的挑战.
研究的目的:
- 用产前发育毒性试验量化预测发育毒性值.
- 评估体外测试对9种生殖毒素和1种非育原性毒素的预测能力.
- 建立量化框架,将体外数据与人体等效剂量 (HED) 联系起来.
主要方法:
- 使用了三级生理学基础的药理动力学 (PBPK) 模型.
- 从ReproTracker,Stemina DevTOX quickPredictTM和发育神经毒性 (DNT) 电池测定中翻译成HEDs的体外度.
- 将体外衍生HED与基于动物研究的HED (LOAEL) 和人类暴露数据进行比较.
主要成果:
- 证明将PBPK建模与特定的体外测试 (Reprotracker,Stemina DevTOX quickPredictTM,DNT) 结合在一起可以定量预测发育性毒性.
- 开发的框架成功地将体外发现转化为相当于人体剂量的风险评估.
- 这项研究为开发性毒性评估提供了动物试验的可行替代方案.
结论:
- 结合PBPK建模与体外测试的整合有助于进步无动物发育毒性评估.
- 这种方法提高了化学品安全评估对人类的相关性.
- 需要对发育性毒性机制和计算翻译方法进行进一步的研究,以进行可靠的人类风险评估.
相关概念视频
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01:12Analysis of Population Pharmacokinetic Data
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01:07Physiological Pharmacokinetic Models: Incorporating Hepatic Transporter-Mediated Clearance
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01:26Pharmacokinetic Models: Comparison and Selection Criterion
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01:23Toxicity Testing in Animals
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