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Probabilistic risk assessment of gold nanoparticles after intravenous administration by integrating in vitro and in vivo toxicity with physiologically based pharmacokinetic modeling
Nanotoxicology ( IF 5 ) Pub Date : 2018-04-14 , DOI: 10.1080/17435390.2018.1459922
Yi-Hsien Cheng 1 , Jim E. Riviere 1 , Nancy A. Monteiro-Riviere 2 , Zhoumeng Lin 1
Affiliation  

This study aimed to conduct an integrated and probabilistic risk assessment of gold nanoparticles (AuNPs) based on recently published in vitro and in vivo toxicity studies coupled to a physiologically based pharmacokinetic (PBPK) model. Dose–response relationships were characterized based on cell viability assays in various human cell types. A previously well-validated human PBPK model for AuNPs was applied to quantify internal concentrations in liver, kidney, skin, and venous plasma. By applying a Bayesian-based probabilistic risk assessment approach incorporating Monte Carlo simulation, probable human cell death fractions were characterized. Additionally, we implemented in vitro to in vivo and animal-to-human extrapolation approaches to independently estimate external exposure levels of AuNPs that cause minimal toxicity. Our results suggest that under the highest dosing level employed in existing animal studies (worst-case scenario), AuNPs coated with branched polyethylenimine (BPEI) would likely induce ∼90–100% cellular death, implying high cytotoxicity compared to <10% cell death induced by low-to-medium animal dosing levels, which are commonly used in animal studies. The estimated human equivalent doses associated with 5% cell death in liver and kidney were around 1 and 3 mg/kg, respectively. Based on points of departure reported in animal studies, the human equivalent dose estimates associated with gene expression changes and tissue cell apoptosis in liver were 0.005 and 0.5 mg/kg, respectively. Our analyzes provide insights into safety evaluation, risk prediction, and point of departure estimation of AuNP exposure for humans and illustrate an approach that could be applied to other NPs when sufficient data are available.

中文翻译:

通过将体外体内毒性与基于生理的药代动力学模型相结合静脉内给药后金纳米颗粒的概率风险评估

这项研究旨在基于最近发表的体外体内毒性研究以及基于生理学的药代动力学(PBPK)模型进行金纳米颗粒(AuNPs)的综合和概率风险评估。基于各种人类细胞类型中的细胞活力测定,对剂量-反应关系进行了表征。应用先前经过充分验证的AuNP的人PBPK模型来量化肝脏,肾脏,皮肤和静脉血浆中的内部浓度。通过应用结合了蒙特卡洛模拟的基于贝叶斯的概率风险评估方法,对可能的人类细胞死亡分数进行了表征。此外,我们在体外体内都实施以及动物对人的外推方法来独立地估计引起最小毒性的AuNPs的外部暴露水平。我们的结果表明,在现有动物研究中使用的最高剂量水平(最坏的情况)下,涂有支化聚乙烯亚胺(BPEI)的AuNPs可能会引起约90–100%的细胞死亡,这意味着与低于10%的细胞死亡相比,具有较高的细胞毒性。由动物研究中常用的中低剂量引起。与肝和肾中5%细胞死亡相关的估计人当量剂量分别约为1和3 mg / kg。根据动物研究中报道的出发点,与肝脏中基因表达变化和组织细胞凋亡相关的人体等效剂量估计分别为0.005和0.5 mg / kg。
更新日期:2018-06-06
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