ISDD: A computational model of particle sedimentation, diffusion and target cell dosimetry for in vitro toxicity studies.
ISDD: A computational model of particle sedimentation, diffusion and target cell dosimetry for in vitro toxicity studies.
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DOI：
10.1186/1743-8977-7-36
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发表时间：
2010-11-30
影响因子：
10
通讯作者：
Teeguarden JG
中科院分区：
文献类型：
--
作者：
Hinderliter PM;Minard KR;Orr G;Chrisler WB;Thrall BD;Pounds JG;Teeguarden JG
直接测量细胞剂量的困难是将靶组织剂量测定应用于纳米颗粒和微粒毒性评估的一个重大障碍，特别是对于体外系统而言。因此，在纳米颗粒的剂量测定和危害评估中，靶组织范式在很大程度上被忽视，人们更倾向于使用暴露指标（例如，微克颗粒/毫升培养基、颗粒表面积/毫升、颗粒数量/毫升）。我们已经为非相互作用的球形颗粒及其在单层细胞培养系统中的聚集体开发了一个溶液颗粒动力学（沉降、扩散）和剂量测定的计算模型。颗粒向细胞的传输是通过同时求解斯托克斯定律（沉降）和斯托克斯 - 爱因斯坦方程（扩散）来计算的。
体外沉降、扩散和剂量测定模型（ISDD）针对多种尺寸的聚苯乙烯球（20 - 1100纳米）、35纳米无定形二氧化硅以及30纳米氧化铁颗粒的大聚集体的测量传输速率或细胞剂量进行了测试。总体而言，在不调整任何参数的情况下，模型预测的细胞剂量与实验数据非常吻合，差异从低至5%到高达3倍不等，但在大多数情况下约为2倍，处于测量系统的精度范围内。通过应用该模型，我们概括了颗粒大小、颗粒密度、聚集状态和聚集体特征对体外靶细胞剂量测定的影响。
我们的结果证实了我们的假设，即对于基于液体的体外系统，所有颗粒的剂量率和靶细胞剂量并不相等；它们可能有显著差异，这与在剂量 - 响应评估中使用基于质量的培养基浓度作为暴露指标时所隐含的剂量等效性假设形成直接对比。基于微克/毫升的等效名义培养基浓度暴露与基于颗粒表面积或数量的靶细胞剂量之间的差异可高达3到6个数量级。因此，在利用基于质量的暴露指标进行的体外危害评估中，当认为颗粒数量或表面积的靶细胞剂量驱动响应时，本身就存在很高的误差。体外纳米毒理学研究中颗粒剂量测定的金标准应该是对所研究颗粒的细胞含量进行直接实验测量。然而，在这种测量不切实际、不可行的情况下，以及在这种测量变得普遍之前，像ISDD这样的颗粒剂量测定模型提供了一种有价值的、可立即使用的替代方法，并最终可作为这种测量的辅助手段。
The difficulty of directly measuring cellular dose is a significant obstacle to application of target tissue dosimetry for nanoparticle and microparticle toxicity assessment, particularly for in vitro systems. As a consequence, the target tissue paradigm for dosimetry and hazard assessment of nanoparticles has largely been ignored in favor of using metrics of exposure (e.g. μg particle/mL culture medium, particle surface area/mL, particle number/mL). We have developed a computational model of solution particokinetics (sedimentation, diffusion) and dosimetry for non-interacting spherical particles and their agglomerates in monolayer cell culture systems. Particle transport to cells is calculated by simultaneous solution of Stokes Law (sedimentation) and the Stokes-Einstein equation (diffusion). The In vitro Sedimentation, Diffusion and Dosimetry model (ISDD) was tested against measured transport rates or cellular doses for multiple sizes of polystyrene spheres (20-1100 nm), 35 nm amorphous silica, and large agglomerates of 30 nm iron oxide particles. Overall, without adjusting any parameters, model predicted cellular doses were in close agreement with the experimental data, differing from as little as 5% to as much as three-fold, but in most cases approximately two-fold, within the limits of the accuracy of the measurement systems. Applying the model, we generalize the effects of particle size, particle density, agglomeration state and agglomerate characteristics on target cell dosimetry in vitro. Our results confirm our hypothesis that for liquid-based in vitro systems, the dose-rates and target cell doses for all particles are not equal; they can vary significantly, in direct contrast to the assumption of dose-equivalency implicit in the use of mass-based media concentrations as metrics of exposure for dose-response assessment. The difference between equivalent nominal media concentration exposures on a μg/mL basis and target cell doses on a particle surface area or number basis can be as high as three to six orders of magnitude. As a consequence, in vitro hazard assessments utilizing mass-based exposure metrics have inherently high errors where particle number or surface areas target cells doses are believed to drive response. The gold standard for particle dosimetry for in vitro nanotoxicology studies should be direct experimental measurement of the cellular content of the studied particle. However, where such measurements are impractical, unfeasible, and before such measurements become common, particle dosimetry models such as ISDD provide a valuable, immediately useful alternative, and eventually, an adjunct to such measurements.
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影响因子：
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