Project 7: Assessment of Toxicity and Risk of Inhaled Environmental PCB Mixtures

项目7：吸入环境PCB混合物的毒性和风险评估

• 批准号: 8919616
• 负责人: Peter S Thorne
• 金额: $ 25.39万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-12 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8919616
• 关键词: Address; Adult; Adverse effects; Advisory Committees; Affect; Air; Animals; Biological; Biological Markers; Blood; Body Burden; Breathing; Cell physiology; Chicago; Child; Collaborations; Control Animal; Data; Data Collection; Development; Dose; Evaluation; Excretory function; Exposure to; Fetus; Generations; Goals; Grant; Health; Histopathology; Hour; Human; Immune; Indoor environment; Inflammation; Inhalation Exposure; Inhalation Toxicology; Injection of therapeutic agent; Inorganic Sulfates; Iowa; Knowledge; Label; Lung; Measurement; Metabolism; Methodology; Methods; Modeling; Molecular; Mus; National Institute of Environmental Health Sciences; Neurologic; New York City; No-Observed-Adverse-Effect Level; Nose; Oral Administration; Outcome; Outcome Measure; Oxidative Stress; Pathway interactions; Pentas; Perinatal; Polychlorinated Biphenyls; Predisposition; Pregnancy; Process; Publications; Publishing; Radiolabeled; Rattus; Reporting; Research; Research Design; Research Project Grants; Risk; Risk Assessment; Rodent; Schools; Seminal; Services; Source; Superfund; System; Testing; Thyroid Hormones; Time; Tissues; Toxic effect; Toxicokinetics; Toxicology; Uncertainty; Unspecified or Sulfate Ion Sulfates; Weight Gain; Work; absorption; adverse outcome; animal data; base; cytotoxicity; diphenyl; exposed human population; fundamental research; genotoxicity; human data; in utero; in vivo; innovation; insight; neurotoxicity; novel strategies; prenatal; prenatal exposure; programs; pup; radiotracer; remediation; reproductive; research and development; research study; response; vapor

PROJECT SUMMARY The potential hazardous effects of inhalation exposure to semi-volatile PCBs in ambient and indoor environ- ments have caused growing concern and demonstrated the need for research in inhalation toxicology of airborne PCBs. The paucity of data on metabolism, excretion, and dose-specific toxicologic effects has been the main barrier to meaningful human health risk assessment of inhaled PCBs, especially of the non-legacy, semi-volatile PCBs. In this grant cycle, the former Inhalation Toxicology Core is elevated to project status in recognition of the formative and highly innovative research this group has performed. Project 7 is highly integrated with other projects and cores of the Iowa Superfund Research Program (isrp) and will continue to provide tissues, blood and excreta from inhalation-exposed animals and controls. As a project, this research team will expand the body of knowledge on inhaled PCBs using innovative exposure systems and methodol- ogy developed in the last cycle. We will conduct studies to identify adverse outcome pathways (AOPs) for inhaled environmentally-relevant PCB mixtures and identify both the no observed adverse effect level (NOAEL) and the lowest observed adverse effect level (LOAEL). We will test multiple dose levels using a congener profile that we have demonstrated represents the Chicago airshed. The study will, for the first time, reduce uncertainties in the inhalation reference concentration (RfC) for risk assessment and present an extensive dose-dependent evaluation of AOPs. Adverse outcomes measured in adult rats and mice will be further investigated in prenatal exposure studies, recognizing the enhanced susceptibility of pregnancy and the developing fetus. In addition, collaboration with other projects of the isrp will provide mechanistic insights on how molecular and cellular processes respond in those pathways. Over the past 5 years, our publications have begun to fill what was a near total void on the biological fate of inhaled PCBs. We will continue to elucidate the absorption, distribution, metabolism and excretion (ADME) of predominant airborne PCBs using 14C-labelled congeners. Our central hypothesis is that even though inhaled environmental PCBs are susceptible to relatively fast elimination, inhalation exposure to rodents at current human equivalent concentrations will result in adverse health effects and measureable toxicity. Three specific aims will be addressed: AIM 1) Conduct inhalation studies using our Chicago Air Mixture (CAM+) to identify adverse outcome pathways and derive in vivo data for an integrated risk assessment; AIM 2) Conduct ADME toxicology studies with lung exposure to radiolabelled tetra- and penta- chlorobiphenyls to provide data for toxicokinetic modeling; and AIM 3) Investigate developmental, immune and neurologic toxicity after prenatal inhalation exposure to airborne PCBs (CAM+) at the LOAEL. The research proposed herein will significantly advance the understanding of the dose-specific toxicity of inhaled PCB mixtures and the operative AOPs and thus will facilitate the establishment of an integrated risk assessment for inhalation exposure to environmental PCBs.

项目摘要 吸入暴露于大气和室内环境中的半挥发性多氯联苯的潜在危害影响 的吸入毒理学研究的必要性， 空气中的PCB缺乏关于代谢、排泄和剂量特异性毒理学效应的数据， 对吸入性多氯联苯进行有意义的人类健康风险评估的主要障碍，特别是对非传统的多氯联苯， 半挥发性多氯联苯在本资助周期中，前吸入毒理学核心项目在 对该小组所进行的形成性和高度创新性研究的认可。项目7高度 与爱荷华州超级基金研究计划（isrp）的其他项目和核心相结合，并将继续 提供吸入暴露动物和对照动物的组织、血液和排泄物。作为一个项目，这项研究 该小组将扩大知识体系的吸入多氯联苯使用创新的暴露系统和methodol- ogy在上一个周期中发展起来。我们将进行研究，以确定不良后果途径（AOP）， 吸入环境相关的多氯联苯混合物，并确定无明显不良影响水平（NOAEL） 最低可见不良反应水平（LOAEL）。我们将使用同类物测试多个剂量水平 我们所演示的剖面代表了芝加哥的气棚。这项研究将首次减少 风险评估的吸入参考浓度（RfC）的不确定性， AOPs的剂量依赖性评价。在成年大鼠和小鼠中测量的不良结果将进一步 在产前暴露研究中进行了调查，认识到怀孕的易感性增强， 发育中的胎儿此外，与isrp的其他项目的合作将提供以下方面的机制见解 分子和细胞过程如何在这些通路中反应。在过去的五年里，我们的出版物 开始填补吸入多氯联苯的生物命运的几乎完全空白。我们会继续阐释 使用14 C标记的多氯联苯的吸收、分布、代谢和排泄（ADME） 同源物。我们的中心假设是，即使吸入环境中的多氯联苯容易受到 相对快速消除，在当前人体等效浓度下吸入接触啮齿动物 会对健康造成不良影响并产生可测量的毒性。将讨论三个具体目标： 1)使用我们的芝加哥空气混合物（CAM+）进行吸入研究，以确定不良结局途径， 获得用于综合风险评估的体内数据; AIM 2）使用肺进行ADME毒理学研究 暴露于放射性标记的四氯联苯和五氯联苯，为毒代动力学建模提供数据;以及AIM 3)研究产前吸入暴露于空气中的有毒物质后的发育、免疫和神经毒性 多氯联苯（CAM+）的最低可见有害效应水平。本文提出的研究将大大促进对 吸入多氯联苯混合物的剂量特异性毒性和有效的AOPs，因此将有助于建立 对吸入接触环境中的多氯联苯进行综合风险评估。