RECEPTOR INTERACTION FOR TCDD & ITS STRUCTURAL ANALOGS-S

我们的研究方法的主要特点是从多个层面整合数据，以解决知识差距，创造受体介导的毒物风险评估的不确定性。 这些研究主要集中在二恶英及其结构类似物作为一个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，其在环境中的持久性、亲脂性和随后通过食物链的生物累积性导致人类长期接触。虽然二恶英已被列为已知的人类致癌物，但对于每日接触这些化合物对人类健康构成的潜在风险存在相当大的争议。 我们认为，当相关数据来自动物模型、细胞系统和人类研究时，当数据转化为风险评估模型，允许以科学可信的方式扩展数据时，科学基础是最强大的。 这项研究的具体目标是：（1）确定二恶英对雌性Sprague-Dawley大鼠的影响（基因表达、激素变化和细胞效应）的剂量反应形式，这是世界上几乎所有管理机构用来估计二恶英的动物模型。对人类的风险。 这些研究集中在肝脏、肺、甲状腺和生殖道等二恶英的靶组织。 (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，开发基于生物学的二恶英剂量反应模型（3）比较细胞系统对二恶英的反应，啮齿动物和人类，以确定实验模型的相关性，估计人类接触二恶英及其结构类似物的风险。 从环境、意外和高水平职业暴露于二恶英的人群中获得人类样本（4）通过整合生物半衰期、基因表达变化、人类和不良健康后果等信息，确定人类对二恶英反应的个体间差异程度。 这些研究试图确定敏感的亚群，并制定策略，以取代默认的方法来估计人群中的预期风险范围。

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.