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

项目总结 吸入环境和室内环境中的半挥发性多氯联苯的潜在危险影响- 已引起越来越多的关注，并表明有必要进行吸入毒理学研究。 空气中的多氯联苯。关于新陈代谢、排泄和剂量特定毒理学效应的数据一直很少。 对吸入性多氯联苯，特别是非遗留多氯联苯进行有意义的人类健康风险评估的主要障碍， 半挥发性多氯联苯。在这个赠款周期中，以前的吸入毒理学核心被提升到#年的项目状态 对该小组所进行的形成和高度创新的研究的认可。项目7高度 与爱荷华州超级基金研究方案(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，本研究 该团队将利用创新的暴露系统和方法来扩大关于吸入多氯联苯的知识体系。 OGY是在上一个周期中发展起来的。我们将进行研究，以确定不良后果途径(AOPS) 吸入与环境相关的多氯联苯混合物，并确定未观察到的不良影响水平(NOAEL) 观察到的最低不良反应水平(LOAEL)。我们将使用同类物测试多个剂量水平 我们展示的资料代表了芝加哥机场。这项研究将首次减少 用于风险评估的吸入参考浓度(RFC)的不确定度，并呈现广泛的 AOPS的剂量依赖性评估。在成年大鼠和小鼠身上测量的不良后果将进一步 在产前暴露研究中进行了调查，认识到怀孕和 发育中的胎儿。此外，与ISRP的其他项目的合作将提供关于 分子和细胞过程如何在这些途径中做出反应。在过去的5年里，我们的出版物 开始填补关于吸入多氯联苯的生物命运的几乎全部空白。我们将继续澄清 ~(14)C标记空气中主要多氯联苯的吸收、分布、代谢和排泄(ADME) 同类人。我们的中心假设是，即使吸入的环境中的多氯联苯容易受到 相对较快的消除，吸入暴露于当前人类相当浓度的啮齿动物 将导致不良的健康影响和可测量的毒性。将解决三个具体目标：目标 1)使用我们的芝加哥空气混合物(CAM+)进行吸入研究，以确定不良后果途径和 获取体内数据以进行综合风险评估；目标2)对肺部进行ADME毒理学研究 暴露于放射性标记的四氯联苯和五氯联苯，为毒物动力学模型提供数据；和 3)调查产前吸入空气后的发育、免疫和神经毒性 多氯联苯(CAM+)在LOAEL。本文提出的研究将极大地促进对 吸入的多氯联苯混合物的剂量特异性毒性和操作的AOPS，从而将有助于建立 关于吸入暴露于环境多氯联苯的综合风险评估。

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.