Dosimetric principles for extrapolating results of rat inhalation studies to humans, using an inhaled Ni compound as an example.
Dosimetric principles for extrapolating results of rat inhalation studies to humans, using an inhaled Ni compound as an example.
复制标题
以吸入镍化合物为例，将大鼠吸入研究结果外推至人类的剂量测定原理。
DOI：
10.1097/00004032-198907001-00027
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发表时间：
1989
期刊：
影响因子：
2.2
通讯作者：
Oberdörster,G
中科院分区：
文献类型：
--
作者：
Oberdörster,G
吸入物质的剂量效应关系因吸入剂量、沉积剂量和保留剂量之间的相互关系而变得复杂。沉积和保留剂量对于评价剂量效应关系最为重要;然而，吸入剂量和接触浓度并不代表靶部位的实际剂量，因此被广泛用于这一目的。为了将动物吸入研究的结果外推至人类，在计算呼吸道的人类等效剂量和估计人类等效接触浓度时必须考虑几个因素。这些因素包括鼻咽、气管支气管和肺泡区域的单独沉积，包括总区域沉积和单位表面积沉积剂量。呼吸道的预测颗粒沉积模型可用于计算这些。保留剂量是考虑呼吸道保留并确定呼吸道长期剂量的另一个因素。在大鼠吸入研究中，暴露于Ni 3 S2（浓度为970 μg m− 3;持续时间为78周;暴露时间为6 hd− 1，5 d wk− 1）导致支气管和肺泡肿瘤。根据上述剂量因素对大鼠数据进行外推建模，并假设Ni 3S 2的肺滞留条件不同，大鼠的半衰期为36 d，人的半衰期为103 d。模型计算表明，沉积表面积剂量是大于气管支气管比肺区域在大鼠和人。保留剂量每克肺在大鼠比在人在静息条件下。如果以每平方厘米肺泡表面积的保留剂量为基础，则人体的等效接触浓度将低于大鼠。然而，当考虑到气管支气管表面积剂量时，人的吸入当量浓度可能要高得多。应选择呼吸道最敏感的区域-例如，在诱发肿瘤方面-来估算人体等效接触量。
Dose-effect relationships of inhaled substances are complicated by the interrelationship between inhaled dose, deposited dose, and retained dose. Deposited and retained doses are most important for evaluating dose-effect relations; however, inhaled dose and exposure concentration that are not representative of the actual dose to target sites are widely used for this purpose. For extrapolating results of animal inhalation studies to humans, several factors have to be considered for calculating a human equivalent dose to the respiratory tract and for estimating a human equivalent exposure concentration. Among these factors are separate deposition in nasopharyngeal, tracheobronchial, and alveolar regions, both total regional deposition and deposited dose per unit surface area. Predictive particle deposition models for the respiratory tract can be used for calculating these. The retained dose is another factor that takes into account respiratory tract retention and determines the long-term dose to the respiratory tract. A rat inhalation study using Ni 3 S 2 exposure (concentration, 970 μg m− 3; duration, 78 wk; exposure, 6 hd− 1, 5 d wk− 1) resulted in bronchogenic and alveologenic tumors. Extrapolation modeling of rat data was performed based on dose factors discussed above, and assuming different conditions of pulmonary retention for Ni 3 S 2 with half-times of 36 d for rats and 103 d for humans. Model calculations showed that deposited surface area dose was greater for the tracheobronchial than for the pulmonary region in both rat and man. The retained dose per gram of lung was greater in rat than in man under resting conditions. An equivalent exposure concentration would be lower in humans than in the rat if it is based on the retained dose expressed per square centimeter of alveolar surface area. However, inhaled equivalent concentration in man can be considerably higher when the tracheobronchial surface area dose is considered. The most sensitive region of the respiratory tract-for example, with regard to tumor induction-should be selected for estimating human equivalent exposure.