ABSORPTION AND TRANSPORT OF TOXICANTS

有毒物质的吸收和运输

• 批准号: 3840552
• 负责人: FRANK E GUTHRIE
• 金额: --
• 依托单位: NORTH CAROLINA STATE UNIVERSITY RALEIGH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3840552
• 关键词: agriculture worker; autoradiography; bioenergetics; chemical hypersensitivity; detoxification; drug administration routes; drug delivery systems; electron microscopy; environmental contamination; environmental toxicology; herbicides; high performance liquid chromatography; human tissue; insecticide biological effect; laboratory mouse; laboratory rat; lindane; membrane permeability; microcirculation; occupational hazard; paraquat; parathion; pesticide biological effect; pyrethroid; radiotracer; skin absorption; skin circulation; skin irritation /irritant; skin pharmacology; swine; thin layer chromatography; toxicant screening; toxin metabolism

The purpose of this project is to investigate the toxicokinetics of pesticide percutaneous absorption and biotransformation using established in vitro techniques with mice and human skin as well as a novel isolated perfused porcine skin flap (IPPSF) preparation. This model system is ideally suited to study these phenomenon because it is an isolated perfused tissue model which has an intact and viable epidermis in association with a functional microcirculation. This project will focus on studying the cutaneous biotransformation of pesticides using static and flow- through in vitro diffusion cell chambers and the IPPSF. This area has not received attention in the past. Using the IPPSF, the effects of altered epidermal bioenergetics, microcirculation and inhibition/induction on cutaneous biotransformation will be investigated. A strategy will be developed using deconvolution pharmacokinetic models for integrating the absorption profiles from the IPPSf into in vivo toxicokinetic models. In addition to studying the rate and extent of pesticide penetration and metabolism in these in vitro systems, the effect of anatomical site of application will be addressed in vivo in rats and pigs. Finally, the direct cutaneous toxicity of pesticides will be examined in the IPPSF since the skin may serve as a target organ in addition to being a portal of entry. Since the skin is the primary route of exposure to the systemic circulation for a number of toxicologically significant pesticides, a full characterization of their absorption profile and pattern of cutaneous biotransformation is essential before a rational strategy for risk- assessment can be formulated.

该项目的目的是调查Texicokinetics 使用农药经皮的吸收和生物转化 还用小鼠和人类皮肤建立了体外技术 作为一种新型孤立的灌注猪皮皮瓣（IPPSF）制剂。 该模型系统非常适合研究这些现象 因为它是一个孤立的灌注组织模型，具有完整的 与功能性相关的表皮和可行的表皮 微循环。 该项目将着重于研究 使用静态和流动 - 通过体外扩散细胞腔和IPPSF。 这个区域 过去没有受到关注。 使用IPPSF， 表皮生物能量改变，微循环和改变的影响 对皮肤生物转化的抑制/诱导将是 调查。 将使用反卷积制定策略 药代动力学模型，用于整合来自 IPPSF进入体内毒性模型。 此外 研究农药渗透的速度和程度 这些体外系统的代谢，解剖部位的作用 在大鼠和猪中，将在体内解决施用。 最后，农药的直接皮肤毒性将是 在IPPSF中检查，因为皮肤可以用作目标器官 除了进入门户。 由于皮肤是 一个数字的主要接触系统循环的途径 具有毒性意义的农药，完整的特征 它们的吸收曲线和皮肤的模式 生物转化在风险的合理策略之前至关重要 - 可以制定评估。