PDF(Pubmed)
Abstract：
Physiologically based kinetic models facilitate the safety assessment of inhaled engineered nanomaterials (ENMs). To develop these models, high quality datasets on well-characterized ENMs are needed. However, there are at present, several data gaps in the systemic availability of poorly soluble particles after inhalation. The aim of the present study was therefore to acquire two comparable datasets to parametrize a physiologically-based kinetic model.
Rats were exposed to cerium dioxide (CeO2, 28.4 ± 10.4 nm) and titanium dioxide (TiO2, 21.6 ± 1.5 nm) ENMs in a single nose-only exposure to 20 mg/m3 or a repeated exposure of 2 × 5 days to 5 mg/m3. Different dose levels were obtained by varying the exposure time for 30 min, 2 or 6 h per day. The content of cerium or titanium in three compartments of the lung (tissue, epithelial lining fluid and freely moving cells), mediastinal lymph nodes, liver, spleen, kidney, blood and excreta was measured by Inductively Coupled Plasma-Mass Spectrometry (ICP-MS) at various time points post-exposure. As biodistribution is best studied at sub-toxic dose levels, lactate dehydrogenase (LDH), total protein, total cell numbers and differential cell counts were determined in bronchoalveolar lavage fluid (BALF).
Although similar lung deposited doses were obtained for both materials, exposure to CeO2 induced persistent inflammation indicated by neutrophil granulocytes influx and exhibited an increased lung elimination half-time, while exposure to TiO2 did not. The lavaged lung tissue contained the highest metal concentration compared to the lavage fluid and cells in the lavage fluid for both materials. Increased cerium concentrations above control levels in secondary organs such as lymph nodes, liver, spleen, kidney, urine and faeces were detected, while for titanium this was found in lymph nodes and liver after repeated exposure and in blood and faeces after a single exposure.
We have provided insight in the distribution kinetics of these two ENMs based on experimental data and modelling. The study design allows extrapolation at different dose-levels and study durations. Despite equal dose levels of both ENMs, we observed different distribution patterns, that, in part may be explained by subtle differences in biological responses in the lung.
Rats were exposed to cerium dioxide (CeO2, 28.4 ± 10.4 nm) and titanium dioxide (TiO2, 21.6 ± 1.5 nm) ENMs in a single nose-only exposure to 20 mg/m3 or a repeated exposure of 2 × 5 days to 5 mg/m3. Different dose levels were obtained by varying the exposure time for 30 min, 2 or 6 h per day. The content of cerium or titanium in three compartments of the lung (tissue, epithelial lining fluid and freely moving cells), mediastinal lymph nodes, liver, spleen, kidney, blood and excreta was measured by Inductively Coupled Plasma-Mass Spectrometry (ICP-MS) at various time points post-exposure. As biodistribution is best studied at sub-toxic dose levels, lactate dehydrogenase (LDH), total protein, total cell numbers and differential cell counts were determined in bronchoalveolar lavage fluid (BALF).
Although similar lung deposited doses were obtained for both materials, exposure to CeO2 induced persistent inflammation indicated by neutrophil granulocytes influx and exhibited an increased lung elimination half-time, while exposure to TiO2 did not. The lavaged lung tissue contained the highest metal concentration compared to the lavage fluid and cells in the lavage fluid for both materials. Increased cerium concentrations above control levels in secondary organs such as lymph nodes, liver, spleen, kidney, urine and faeces were detected, while for titanium this was found in lymph nodes and liver after repeated exposure and in blood and faeces after a single exposure.
We have provided insight in the distribution kinetics of these two ENMs based on experimental data and modelling. The study design allows extrapolation at different dose-levels and study durations. Despite equal dose levels of both ENMs, we observed different distribution patterns, that, in part may be explained by subtle differences in biological responses in the lung.
摘要：
背景：基于生理的动力学模型有助于吸入工程纳米材料（ENM）的安全性评估。为了开发这些模型，需要关于特征良好的ENM的高质量数据集。然而,目前有,吸入后难溶颗粒的全身可用性存在几个数据空白。因此，本研究的目的是获取两个可比较的数据集以参数化基于生理的动力学模型。
方法：将大鼠暴露于二氧化铈（CeO2，28.4±10.4nm）和二氧化钛（TiO2，21.6±1.5nm）ENM，单次暴露于20mg/m3或2×5天重复暴露于5mg/m3。通过改变暴露时间30分钟获得不同的剂量水平，每天2或6小时。肺三个隔室中铈或钛的含量(组织，上皮衬里液和自由移动的细胞)，纵隔淋巴结，肝脏,脾,脾肾,在暴露后的各个时间点，通过电感耦合等离子体质谱法（ICP-MS）测量血液和排泄物。由于生物分布最好在亚毒性剂量水平进行研究，乳酸脱氢酶（LDH），总蛋白质，在支气管肺泡灌洗液(BALF)中测定总细胞数和差异细胞计数.
结果：尽管两种材料的肺沉积剂量相似，暴露于CeO2诱导的持续性炎症表现为中性粒细胞粒细胞流入，并表现出增加的肺消除半衰期，而暴露于TiO2没有。与两种材料的灌洗液和灌洗液中的细胞相比，灌洗的肺组织含有最高的金属浓度。在淋巴结等次级器官中，铈浓度高于对照水平，肝脏,脾,脾肾,检测到尿液和粪便，而对于钛，在反复暴露后的淋巴结和肝脏中以及单次暴露后的血液和粪便中都发现了这种情况。
结论：我们基于实验数据和建模提供了对这两种ENM分布动力学的见解。研究设计允许在不同的剂量水平和研究持续时间下外推。尽管两种ENM的剂量水平相等，我们观察到不同的分布模式，That,部分原因可能是肺部生物反应的细微差异。
方法：将大鼠暴露于二氧化铈（CeO2，28.4±10.4nm）和二氧化钛（TiO2，21.6±1.5nm）ENM，单次暴露于20mg/m3或2×5天重复暴露于5mg/m3。通过改变暴露时间30分钟获得不同的剂量水平，每天2或6小时。肺三个隔室中铈或钛的含量(组织，上皮衬里液和自由移动的细胞)，纵隔淋巴结，肝脏,脾,脾肾,在暴露后的各个时间点，通过电感耦合等离子体质谱法（ICP-MS）测量血液和排泄物。由于生物分布最好在亚毒性剂量水平进行研究，乳酸脱氢酶（LDH），总蛋白质，在支气管肺泡灌洗液(BALF)中测定总细胞数和差异细胞计数.
结果：尽管两种材料的肺沉积剂量相似，暴露于CeO2诱导的持续性炎症表现为中性粒细胞粒细胞流入，并表现出增加的肺消除半衰期，而暴露于TiO2没有。与两种材料的灌洗液和灌洗液中的细胞相比，灌洗的肺组织含有最高的金属浓度。在淋巴结等次级器官中，铈浓度高于对照水平，肝脏,脾,脾肾,检测到尿液和粪便，而对于钛，在反复暴露后的淋巴结和肝脏中以及单次暴露后的血液和粪便中都发现了这种情况。
结论：我们基于实验数据和建模提供了对这两种ENM分布动力学的见解。研究设计允许在不同的剂量水平和研究持续时间下外推。尽管两种ENM的剂量水平相等，我们观察到不同的分布模式，That,部分原因可能是肺部生物反应的细微差异。
