TOXIC INTERACTIONS OF POLYCYCLIC AND HALOGENATED AROMATIC HYDROCARBONS

马塞纳超级基金网站受到两种多环芳烃的污染 碳氢化合物(PAHs)和卤代芳香烃(HAHS)， 包括多氯联苯和多氯联苯 二苯并二恶英(PCDDs)和呋喃(PCDF)。长期致癌物质 多环芳烃的潜力和微粒体酶的短期诱导和 HAHS的免疫抑制作用是有据可查的。然而， 同时接触这两类苯系物对健康的影响 化合物还没有被调查过。这就是这个项目的目标 为了确定多环芳烃与HAHS毒性相互作用的程度， 本网站代表通过使用两个成熟的动物模型 每一类的毒性终点，微粒体酶的诱导和 免疫抑制，两者都是由胞浆中的AH受体介导的 (AHR)。反应性C57BL/6(ahb/b)小鼠对PAH和HAH的敏感性 毒性将与无反应的同源基因C57BL/6进行比较 (ahd/d)小鼠(别名B6.D2)以确定AhR在推测的 PAHs和HAHS的交互毒性。这种方法将补充 本计划中的其他项目，主要是分析性或 专注于非AhR介导的健康影响。这项工作将 进一步加深对三氯甲烷复杂混合物毒理学的理解 并将大幅改进风险评估技术 该场地及类似场地均受到多环芳烃和HAHS的污染。 基于已知的PAHs和HAHS的作用机制 目前在现场，我们提出：1)之间存在互动 在这个位置存在两类化合物，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 相互作用显著改变了HAHS的毒性当量因子， 用于风险评估，以及4)在多大程度上 相互作用的发生取决于暴露的发育阶段 (产前、围产期、青壮年、晚年)。 具体目标1：调查有毒物质相互作用的可能性 在Massena超级基金网站和HAHS发现具有代表性的PAHs和HAHS 确定多环芳烃与HAH毒性相互作用的水平。这个 将对暴露动力学进行调查，以确定 暴露于PAHs和HAHS的有毒后遗症的顺序。 具体目标2：建立有反应和无反应菌株 小鼠可作为研究多环芳烃和多环芳烃相互作用的模型。 哈哈斯。 具体目标3：确定已确定的 HAH异构体和同系物的混合物，代表这一超级基金 场地，有和没有伴随的多环芳烃暴露。 具体目标4：确定动物处于哪个发育阶段 对PAHs和HAHS的交互作用很敏感。

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.