评估解剖学和生理学变异对使用PBPK模型的人类等效剂量的影响
Celia M Schacht1, Annabel E Meade2, Amanda S Bernstein1,3
1Center for Public Health and Environmental Assessment, Office of Research and Development, U.S. Environmental Protection Agency, Durham, North Carolina 27711, USA.
概括
化学药理动学的人类变异性是风险评估的关键. 这项研究表明,假设模型参数的标准分布形状可以导致不准确的人类等效剂量 (HED) 估计,特别是极端百分位数.
科学领域:
- 毒理学和环境健康
- 药理动力学和生理基础的药理动力学 (PBPK) 建模.
背景情况:
- 在化学风险评估中,人体解剖学和生理学变异性至关重要.
- 建议进行概率风险评估和分布调整因子,以应对不确定性和可变性,包括药理动力学差异.
- 当前的做法往往依赖于方便的,未经验证的假设,关于调整因子和人体等效剂量 (HED) 的分配形式.
研究的目的:
- 为了调查从生理学基础的药代动力学 (PBPK) 模型中得出的人体等剂量 (HED) 是否被逻辑正常分布.
- 确定不同输入参数分布形状对HED的影响,特别是它们的中心趋势和极端百分位.
- 评估化学风险评估的PBPK建模中关于参数分布形式的概括假设的准确性.
主要方法:
- 用于二甲 (DCM) 和的PBPK模型,包括不确定性和可变性.
- 从各种分布类型中随机抽取PBPK模型参数,以表示人类的可变性.
- 进行反向剂量计,以计算每个参数集的动物出发点的HED.
主要成果:
- 输入参数的分布形状显著影响了计算HED的中心趋势和极端百分位数.
- 来自PBPK模型的HED不是一致的lognormal,这与常见的假设相矛盾.
- 当使用参数分布的概括假设时,观察到极端HED百分位数的不准确估计.
结论:
- 人类可变性的可衡量属性需要在化学风险评估中更加仔细地考虑.
- 关于PBPK模型参数分布形状的概括假设可能导致不准确的HED估计.
- 输入参数的分布选择对PBPK模型输出的可靠性产生了重大影响,特别是在评估高风险暴露场景时.
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