Using physiologically based pharmacokinetic (PBPK) modeling for dietary risk assessment of titanium dioxide (TiO2) nanoparticles
Using physiologically based pharmacokinetic (PBPK) modeling for dietary risk assessment of titanium dioxide (TiO2) nanoparticles
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DOI：
10.3109/17435390.2014.940404
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发表时间：
2015-05-01
期刊：
影响因子：
5
通讯作者：
Hungerbuhler, Konrad
中科院分区：
文献类型：
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作者：
Bachler, Gerald;von Goetz, Natalie;Hungerbuhler, Konrad
纳米二氧化钛颗粒（nano-TiO 2）可以在大量食品和消费品中发现，例如化妆品和牙膏，因此，消费者通过多种来源接触，可能涉及不同的接触途径。为了确定纳米二氧化钛颗粒的处置，采取了基于生理的药代动力学（PBPK）模型的开发。高度优先考虑限制参数的数量，以匹配基础数据点的数量（从而避免过度参数化），但仍然反映了有关纳米TiO 2毒理学的可用机制信息。为此，基于纳米TiO 2穿过器官毛细血管壁和在单核吞噬细胞系统（MPS）中被吞噬的能力，对纳米TiO 2的生物分布进行建模。通过比较模拟器官水平与独立体内研究的实验评估器官水平来评估模型的预测能力。我们的PBPK模型的结果表明：（1）在15 - 150 nm的PBPK模型的应用范围内，颗粒的大小和晶体结构对生物分布的影响较小;（2）在高内部暴露下，颗粒在体内聚集，随后被MPS中的巨噬细胞吸收。此外，我们还给出了一个例子，如何PBPK模型可能用于风险评估。为此，计算了德国人群的纳米TiO 2每日膳食摄入量。然后使用PBPK模型将这种慢性外部暴露转换为每个器官的内部钛水平。
Nano-sized titanium dioxide particles (nano-TiO2) can be found in a large number of foods and consumer products, such as cosmetics and toothpaste, thus, consumer exposure occurs via multiple sources, possibly involving different exposure routes. In order to determine the disposition of nano-TiO2 particles that are taken up, a physiologically based pharmacokinetic (PBPK) model was developed. High priority was placed on limiting the number of parameters to match the number of underlying data points (hence to avoid overparameterization), but still reflecting available mechanistic information on the toxicokinetics of nano-TiO2. To this end, the biodistribution of nano-TiO2 was modeled based on their ability to cross the capillary wall of the organs and to be phagocytosed in the mononuclear phagocyte system (MPS). The model's predictive power was evaluated by comparing simulated organ levels to experimentally assessed organ levels of independent in vivo studies. The results of our PBPK model indicate that: (1) within the application domain of the PBPK model from 15 to 150 nm, the size and crystalline structure of the particles had a minor influence on the biodistribution; and (2) at high internal exposure the particles agglomerate in vivo and are subsequently taken up by macrophages in the MPS. Furthermore, we also give an example on how the PBPK model may be used for risk assessment. For this purpose, the daily dietary intake of nano-TiO2 was calculated for the German population. The PBPK model was then used to convert this chronic external exposure into internal titanium levels for each organ.