RECEPTOR INTERACTION FOR TCDD & ITS STRUCTURAL ANALOGS-S

我们研究方法的主要特点是整合来自多个层面的数据，以解决在受体介导的毒物风险评估中造成不确定性的知识差距。这些研究主要集中在二恶英及其结构类似物作为典型的受体介导的毒物。二恶英类化合物是普遍存在的环境污染物，它们在环境中的持久性、亲油性和随后通过食物链积累的生物，导致人类长期接触二恶英。虽然二恶英已被归类为已知的人类致癌物质，但对于每天接触这些化合物对人类健康构成的潜在风险仍存在相当大的争议。我们相信，当从动物模型、细胞系统和人类研究中获得相关数据，并将数据转化为允许以科学可信的方式扩展数据的风险评估模型时，科学基础是最强大的。本研究的具体目标是(1)确定二恶英效应(基因表达、激素变化和细胞效应)在雌性SD大鼠体内的剂量反应形状，这是世界上几乎所有监管机构用来评估二恶英-S对人类风险的动物模型。这些研究主要集中在肝脏、肺、甲状腺和生殖道，这些都是二恶英的靶组织。(2)与生物数学家合作，根据组织剂量学、与芳香烃受体(AHR)的结合、关键靶基因表达的变化、靶细胞的生长特征和不良健康后果，开发基于生物的二恶英剂量反应模型(3)比较细胞系统、啮齿动物和人类对二恶英的反应，以确定用于评估暴露于二恶英及其结构类似物的人类风险的实验模型的相关性。人体样本从代表环境、意外和高水平职业接触二恶英的人群中获得(4)，通过整合关于生物半衰期、基因表达变化、人类和不良健康后果的信息，确定人类对二恶英反应的个体间差异的大小。这些研究试图确定敏感的亚群，并制定战略，以取代估计人群中预期风险范围的默认方法。

The dominating feature of our research approach is to integrate data from a number of levels to address knowledge gaps that create uncertainty in risk assessment for receptor-mediated toxicants. These studies focus primarily on dioxin and its structural analogs as a prototypical receptor-mediated toxicant. Dioxin-like compounds are ubiquitous environmental contaminants and their persistence in the environment, their lipophilicity and subsequent bioaccumulation through the food chain, results in chronic human exposure. While dioxin has been classified as a known human carcinogen, considerable controversy exists over the potential human health risk posed by daily exposure to these compounds. It is our belief that the science foundation is strongest when relevant data is available from animal models, cell systems, and human studies, and when data are translated into risk assessment models that permit extensions of the data in a scientifically credible way. Specific objectives of this research is (1) To determine the shape of the dose response for dioxin's effects (gene expression, hormonal changes and cellular effects) in the female Sprague-Dawley rat which is the animal model used by virtually all regulatory agencies in the world to estimate dioxin?s risks to humans. These studies focus on liver, lung, thyroid and reproductive tract which are target tissues for dioxin. (2) To collaborate with biomathematicians to develop biologically based dose response models for dioxin based on tissue dosimetry, binding to the aryl hydrocarbon receptor (AHR), changes in expression of critical target genes, growth characteristics of target cells and adverse health outcomes (3) To compare responses to dioxins in cell systems, rodents and humans in order to determine the relevance of experimental models for estimating human risks from exposure to dioxin and its structural analogs. Human samples are obtained from populations representing environmental, accidental, and high-level occupational exposure to dioxins(4) To determine the magnitude of interindividual variation in human responses to dioxin by integrating information on biological half lives, changes in gene expression, human and adverse health outcomes. These studies attempt to identify sensitive subpopulations and also to develop strategies for replacing default methods for estimating the range of expected risks in the population.