Project 2 Pharmacokinetics and Pharmacodynamics of C60 and MWCNTs in non-pregnant

摘要 评估与纳米材料接触相关的风险的重要组成部分包括了解纳米材料的摄取、分布和消除；Acfion的模式；以及纳米颗粒效应的药效学。怀孕和哺乳是一种生理状态，纳米材料在其中的分布和作用尚未被广泛研究。本项目将研究几种不同尺寸和电荷性质的纳米粒子的吸收、分布、代谢和排泄。 将使用富勒烯060和多壁碳纳米管的形式在雌性大鼠和小鼠、怀孕大鼠和小鼠以及哺乳期大鼠和小鼠中进行研究。这些纳米粒子将由RTI合成和表征核心统一标记为碳-14，用于进行这些研究。使用三种不同的 雌性大鼠和小鼠的给药途径(口咽吸入、口服和静脉注射)注射)将提供有关纳米颗粒摄取和分布过程的信息。 在怀孕的不同时间静脉注射标记的纳米颗粒给怀孕的大鼠和小鼠，将提供有关纳米颗粒穿过胎盘并导致胎儿暴露的能力的信息。类似地，静脉注射。对哺乳期大鼠和小鼠的注射将能够评估纳米颗粒分泌到乳汁中的情况，从而导致子代接触。放射性标记物质量平衡的测定 在给药后30天内的5个时间点，尿液、粪便、血液组织和身体中的纳米颗粒将提供对纳米颗粒在体内的长期命运的更好的理解。定量全身放射自显影将能够详细描述纳米颗粒的分布。用透射电子显微镜检查组织样本将提供关于亚细胞定位的信息。 纳米材料。口咽部吸入和静脉注射碳纳米材料的影响。将调查未怀孕和怀孕(静脉注射)患者的给药情况。仅限)通过测量动脉血管反应性、血压和心脏超声。炎症(细胞因子)、生殖和发育(激素)和氧化应激(8-羟基脱氧鸟苷；8-羟基脱氧鸟苷；8- OHdG)将被执行。从项目2获得的数据将用于开发项目3中构建的基于生理的药代动力学和药效学模型。

Abstract Important components in estimating risks associated with exposure to nanomaterials include understanding the uptake, distribution, and elimination; the mode of acfion; and the pharmacodynamics of the effects of nanoparticles. Pregnancy and lactation are physiological states in which the distribution and effects of nanomaterials have not been extensively invesfigated. This project will invesfigate the absorption, distribution, metabolism, and excrefion of several nanoparticles with different size and charge properties. Investigations will be conducted with fullerene 060 and forms of multi-walled carbon nanotubes in female rats and mice, pregnant rats and mice, and in lactating rats and mice. The nanoparticles will be carbon-14 uniformly labeled by the RTI Synthesis and Characterization Core for conduct of these studies. Using three different routes of administration in female rats and mice (oropharyngeal aspiration, oral gavage, and intravenous [i.v.] injection) will provide information regarding the uptake and distribution processes for nanoparticles. Administration of the labeled nanoparticles to pregnant rats and mice by i.v, injection at different times in pregnancy will provide information about the ability of the nanoparticles to cross the placenta and result in fetal exposure. Analogously, i.v. administration to lactating rats and mice will enable evaluation ofthe secretion of nanoparticles into milk, resulting in exposure to offspring. The determinafion of the mass balance of radiolabel in urine, feces, blood tissues, and carcass at 5 time points over a period of 30 days following dosing will provide an enhanced understanding of the long-term fate of nanoparticles in the body. Quantitative whole body autoradiography will enable detailed characterization of the distribution of the nanoparticles. Examination of tissue samples with transmission electron microscopy will provide information on the subcellular localization of the nanomaterials. The effects of exposure to the carbon nanomaterials by oropharyngeal aspiration and i.v. administration will be investigated in the non-pregnant and pregnant (i.v. only) rodent by measuring arterial vascular reactivity, blood pressure, and cardiac ultrasound. The determination of markers of inflammation (cytokines), reproduction and development (hormones), and oxidative stress (8-hydroxydeoxyguanosine; 8- OHdG) will be conducted. The data obtained from Project 2 will be used in the development ofthe physiologically based pharmacokinetic and pharmacodynamic models constructed in Project 3.