构建和评估一个开源数据库,用于对工业化学品的选定类别的基于呼吸的生理基动力学建模
Shigechika Yamamoto1, Kikuo Yoshida1, Mariko Matsumoto1
1Division of Risk Assessment, Center for Biological Safety and Research, National Institute of Health Sciences.
The Journal of toxicological sciences
|February 2, 2025
概括
开发基于生理学动力学 (PBK) 参数的预测模型对于化学风险评估至关重要. 这项研究创建了一个数据库,并推导出定量关系来估计这些基本的PBK值.
科学领域:
- 毒理学 毒理学 毒理学
- 计算化学的计算化学
- 药理动力学 药理动力学
背景情况:
- 基于生理学的动力学 (PBK) 模型对于预测组织中的化学度至关重要.
- 获得PBK建模的化学特异实证参数是一个重大挑战.
- 对于这些参数的预测方法是必要的,以推进毒动力学研究.
研究的目的:
- 为大约200种人类和动物工业化学品开发PBK参数数据库.
- 建立定量关系,以预测分配系数和代谢参数.
- 提高化学风险评估PBK模型的准确性和适用性.
主要方法:
- 编制了200种化学品的PBK参数数据库.
- 根据分子间相互作用将化学物质分为不同类别.
- 分割系数和物理化学性质之间的导数定量关系.
- 利用多重回归分析将代谢参数 (Vmax,Km) 与分子碎片相关联.
主要成果:
- 开发了血液/空气和组织/血液分区系数的预测模型,具有较高的确定系数 (例如,在IIA类人类中,对日志 (血液/空气) 0.88).
- 在不同化学品类别和物种中成功应用了预测方法.
- 使用分子碎片分析预测代谢参数 (Vmax,Km) 的良好相关性.
- 通过预测在定义的适用性领域内测试化学品接近报告值的值来验证模型.
结论:
- 开发的定量结构与属性关系 (QSPR) 模型有效预测PBK参数.
- 这种方法改善了化学度的估计,并支持毒性动力学评估.
- 该方法适用于已确定的领域内的更广泛的化学品,有助于对未经研究的化合物的风险评估.
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