Assessing the Adverse Effects of Environmental Hazards

对潜在环境危害的识别已经超过了制定安全和暴露标准的能力。一个限制是缺乏将各种化合物的环境浓度转化为人类接触和不利影响的工具。直到现在才制定和验证了监测其转归和迁移、人类接触和对人类健康的不利影响的实用方法。本提案涉及后两个问题。该项目的第一个目标是筛选选定的环境污染物对人类胎盘的不利影响。将使用人滋养层细胞的原代细胞培养物来确定来自其他项目的感兴趣化合物是否是通过其体外靶向胎盘细胞的能力确定的更密集研究的候选物。该系统已成功地用于二恶英和溴二氯甲烷，并提供了一个尖锐的方法来评估潜在的胎盘毒物。将根据其他次级项目的结果选择待调查的化合物，在这些次级项目中，人类接触和潜在的不利影响分别得到了记录。第二个目标是通过使用非人灵长类动物模型的体内实验来跟踪体外阳性结果。这些体内研究将证实先前的体外结果，并验证人类相关动物模型中的毒性靶点。第三个和第四个目标是将现有的生物标志物免疫测定适应于自动化平台，并结合Denison博士的项目和分析化学核心开发新的生物标志物测定。新的发育生物标志物，Escherichin和激活素，已被选定的基础上，我们认为需要有一个完整的监测人类生殖健康和这些激素在性腺功能的调节中发挥关键作用。新的算法和数据简化方法也将与核心B一起开发。该项目还将与项目8合作开发新的检测平台，以供未来开发。目前生物标志物测定的自动化将增加通量，降低成本并简化标准化。第五个目标是将现有的生物标志物检测应用于其他超级基金项目中基于人群的人类生殖健康研究。总的来说，该项目连接了大多数其他项目和核心，重点是个人和人口两级的人类生殖健康。

The identification of potential environmental hazards has outpaced the ability to set safety and exposure standards. One limitation has been the lack of tools to translate environmental concentrations of various compounds to human exposures and adverse effects. Only now have practical methods been developed and validated to monitor the fate and transport, human exposure and adverse effects to human health. The present proposal addresses the later two issues. The first objective of this Project will be to screen selected environmental contaminants for adverse effects on the human placenta. A primary cell culture of human trophoblast cells will be used to determine if compounds of interest from other projects are candidates for more intense investigations as determined by their ability to target placenta cells in vitro. This system has been successfully used for dioxin and bromodichloromethane and provides an incisive method for evaluating potential placental toxicants. The compounds to be investigated will be selected based on the results of other subprojects in which human exposures and potential adverse effects, respectively, have been documented. The second objective will follow up the positive in vitro results with in vivo experiments using nonhuman primate animal model. These in vivo studies will confirm the previous in vitro results and verify the target of toxicity in a human-relevant animal model. The third and fourth objectives are to adapt existing biomarker immunoassays to an automated platform and develop new biomarker assays in conjunction with Dr. Denison's project and the analytical chemistry Core. The new biomarkers for development, inhibin and activin, have been selected based on our perceived need to have a complete surveillance of human reproductive health and these hormones play pivotal roles in the regulation of gonadal function. New algorithms and data reduction methods will also be developed in conjunction with Core B. This Project will also collaborate with Project 8 in the development of new assay platforms for future development. The current automation of the biomarker assays will increase throughput, decrease costs and simplify standardization. The fifth objective is to apply existing biomarker assays to population-based studies of human reproductive health in other Superfund Projects. Taken together this project bridges most of the other projects and cores with a focus on human reproductive health at both the individual and population level.