TOXIC INTERACTIONS OF POLYCYCLIC AND HALOGENATED AROMATIC HYDROCARBONS

多环和卤代芳烃的毒性相互作用

• 批准号: 3840819
• 负责人: JAY B SILKWORTH
• 金额: --
• 依托单位: STATE UNIVERSITY OF NEW YORK AT ALBANY
• 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/3840819
• 关键词: aging; artificial immunosuppression; benzopyrenes; biological models; carbopolycyclic compound; chemical structure function; cytochrome P450; dioxins; embryo /fetus toxicology; environmental contamination; environmental toxicology; enzyme induction /repression; genetic strain; halobiphenyl /halotriphenyl compound; high performance liquid chromatography; humoral immunity; immunization; immunologic assay /test; immunotoxicity; industrial waste; juvenile animal; laboratory mouse; mature animal; microsomes; perinatal; polychlorodibenzofuran; receptor; toxicant interaction; toxin metabolism; waste disposal

The Massena Superfund Site is contaminated with both polycyclic aromatic hydrocarbons (PAHs) and halogenated aromatic hydrocarbons (HAHs), which include the polychlorinated biphenyls (PCBs) and the polychlorinated dibenzo-dioxins (PCDDs) and -furans (PCDFs). The long-term carcinogenic potential of the PAHs and the short-term microsomal enzyme inductive and immunosuppressive effects of the HAHs are well-documented. However, the health effects associated with simultaneous exposure to both classes of compounds have not been investigated. It is the objective of this project to determine the extent to which PAHs interact with the toxicity of HAHs, representative of this site, by using two well-established animal model toxic endpoints of each class, microsomal enzyme induction and immunosuppression, both of which are mediated by the cytosolic Ah receptor (AhR). The sensitivity of responsive C57BL/6 (Ahb/b) mice to PAH and HAH toxicity will be compared with that of non-responsive congenic C57BL/6 (Ahd/d) mice (alias B6.D2) to determine role of the AhR in the putative interactive toxicity of PAHs and HAHs. This approach will complement the other projects in this program which are primarily analytical or concentrate on health effects which are not AhR-mediated. This work will further our understanding of the toxicology of complex mixtures of xenobiotics and will substantially improve risk assessment technology at this site and similar sites contaminated by both PAHs and HAHs. Based on the known mechanisms of action of both the PAHs and the HAHs present at the site, we propose that: 1) there is interaction between the two classes of compounds present at this site, 2) the levels of interaction can be investigated using established animal models, 3) the putative interaction significantly alters the toxic equivalency factors for HAHs, which are used in risk assessment, and 4) the extent to which the interaction occurs is dependent on the developmental stage of exposure (prenatal, perinatal, young adult, late adult). Specific Aim 1: Investigate the potential for toxic interaction between representative PAHs and HAHs found at the Massena Superfund site and establish the levels at which PAHs interact with HAH toxicity. The kinetics of exposure will be investigated to determine the significance of the sequence of exposure to PAHs and HAHs to the toxic sequelae. Specific Aim 2: Establish that responsive and non-responsive strains of mice can be used as a model to investigate the interactions of PAHs and HAHs. Specific Aim 3: Determine the toxic equivalency factors (TEFs) of defined mixtures of HAH isomers and congeners, representative of this superfund site, with and without concomitant exposure to PAHs. Specific Aim 4: Establish at which developmental stage the animal is most sensitive to the interactive effects of PAHs and HAHs.

马塞纳超级基金场地受到多环芳烃和 碳氢化合物（PAHs）和卤代芳烃（HAHs）， 包括多氯联苯（PCBs）和 二苯并二恶英（PCDDs）和呋喃（PCDFs）。 长期致癌 潜在的多环芳烃和短期微粒体酶诱导和 HAH的免疫抑制作用已被充分证明。 但 与同时接触这两类药物有关的健康影响 化合物尚未研究。 本项目的目标是 为了确定多环芳烃与多环芳烃毒性相互作用的程度， 通过使用两种成熟的动物模型， 每类毒性终点、微粒体酶诱导和 免疫抑制，两者均由胞质Ah受体介导 （AhR）。 C57 BL/6（AhB/B）小鼠对PAH和HAH的敏感性 毒性将与无反应的同类C57 BL/6进行比较 (Ahd/d）小鼠（别名B6.D2），以确定AhR在推定的免疫应答中的作用。 多环芳烃和多环芳烃的相互毒性。 这种做法将补充 该计划中的其他项目主要是分析或 集中于非AhR介导的健康影响。 这项工作将 进一步了解复杂混合物的毒理学， 并将大大提高风险评估技术， 这个网站和类似的网站污染的多环芳烃和多环芳烃。 根据多环芳烃和多环芳烃的已知作用机制， 目前在现场，我们提出：1）有相互作用之间的 存在于该位点的两类化合物，2）相互作用的水平 可以使用已建立的动物模型进行研究，3）假定的 相互作用显著改变了HAH的毒性当量因子， 用于风险评估的程度，以及4） 相互作用的发生取决于暴露的发育阶段 （产前、围产期、年轻成人、晚期成人）。 具体目标1：研究以下物质之间毒性相互作用的可能性： 在马塞纳超级基金现场发现的代表性多环芳烃和多环芳烃， 确定多环芳烃与HAH毒性相互作用的水平。 的 将研究暴露的动力学，以确定 多环芳烃和多环芳烃的暴露顺序对毒性后遗症的影响。 具体目标2：确定响应和非响应菌株 小鼠可用作研究多环芳烃和 哈。 具体目标3：确定定义的毒性当量因子（TEF） HAH异构体和同源物的混合物，这一超级基金的代表 地点，有和没有伴随暴露于多环芳烃。 具体目标4：确定动物在哪个发育阶段 对多环芳烃和多环芳烃的交互作用敏感。