药品中N-二甲基胺的风险表征
D J Paustenbach1, S E Brown2, J J Heywood2
1Paustenbach and Associates, 970 West Broadway, Suite E, Jackson, WY, USA.
概括
药物中的N-二甲基胺 (NDMA) 污染是一个令人担忧的问题. 一种新的基于值的方法表明,允许的每日暴露量 (PDE) 为5800ng/天,可能降低药物NDMA的癌症风险.
科学领域:
- 制药科学 制药科学
- 毒理学 毒理学 毒理学
- 风险评估 风险评估
背景情况:
- 自2018年以来,N-二甲基胺 (NDMA) 已被确定为制药中的污染物.
- 美国食品和药物管理局此前根据动物研究的线性推断,为NDMA设定了96ng/天的可接受摄入量 (AI).
- NDMA被怀疑是动物的突变致癌性致癌物,但未被归类为已知的人类致癌物.
研究的目的:
- 重新评估药品中NDMA可接受的摄入量限制.
- 提出一种基于值的方法来确定NDMA的允许每日暴露量 (PDE).
- 评估与人类药物NDMA暴露相关的肝癌和其他癌症的风险.
主要方法:
- 使用基于值的基准剂量或出发点 (POD) 方法.
- 估计NDMA的适当POD为29,000 ng/kg/天.
- 计算了NDMA的PDE,假设平均体重为50公斤.
主要成果:
- 据估计,NDMA的POD为29,000 ng/kg/天.
- 根据POD和人体平均体重计算出每天5800ng的PDE.
- 人类暴露在每天5800ng以下的NDMA中不太可能增加肝癌风险.
结论:
- 基于值的方法在科学上是合理的,因为可能存在非线性剂量反应,为确定NDMA暴露限值.
- 拟议的PDE为5800ng/天,为药品中的NDMA提供了一个潜在的更安全的极限.
- 目前人类对药品中NDMA的暴露水平不太可能构成显著的癌症风险,特别是肝癌.
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