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

摘要 评估与纳米材料暴露相关风险的重要组成部分包括了解纳米材料的吸收、分布和消除; acfion的模式;以及纳米颗粒作用的药效学。妊娠和哺乳是生理状态，其中纳米材料的分布和影响尚未得到广泛研究。本计画将探讨不同大小及电荷性质之奈米粒子之吸收、分布、代谢及排泄。 将在雌性大鼠和小鼠、妊娠大鼠和小鼠以及哺乳期大鼠和小鼠中使用富勒烯060和多壁碳纳米管形式进行调查。纳米颗粒将由RTI合成和表征核心均匀标记碳-14，以进行这些研究。使用三种不同 雌性大鼠和小鼠的给药途径（口咽抽吸、经口灌胃和静脉内[i. v.]注射）将提供关于纳米颗粒的摄取和分布过程的信息。 在怀孕的不同时间通过静脉注射将标记的纳米颗粒给予怀孕的大鼠和小鼠将提供关于纳米颗粒穿过胎盘并导致胎儿暴露的能力的信息。类似地，对哺乳期大鼠和小鼠静脉注射将能够评估纳米颗粒分泌到乳汁中，导致后代暴露。放射性标记物质平衡的测定 在给药后30天内的5个时间点，在尿液、粪便、血液组织和尸体中检测纳米颗粒的含量，将增强对纳米颗粒在体内长期命运的理解。定量全身放射自显影将能够详细表征纳米颗粒的分布。用透射电子显微镜检查组织样品将提供关于以下的亚细胞定位的信息： 纳米材料。将通过测量动脉血管反应性、血压和心脏超声，在非妊娠和妊娠（仅静脉注射）啮齿动物中研究通过口咽抽吸和静脉注射给药暴露于碳纳米材料的影响。炎症（细胞因子）、生殖和发育（激素）以及氧化应激（8-羟基脱氧鸟苷; 8-羟基脱氧鸟苷）的标志物的测定。 OHDG）将进行。从项目2中获得的数据将用于开发项目3中构建的基于生理学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.