Advancing chemical risk assessment through development, validation and integration of high throughput mechanistic in vitro data

项目摘要/摘要 尽管合成化学品在消费品中的使用已有一个多世纪的历史，但它们的使用 迅速增长，我们无法对它们进行监管，以危害人类健康。令人担忧的是，大多数 这些化学品没有对人类健康的潜在毒性进行评估。我们所知的更少 关于它们的发育和生殖毒性，即使是那些经常在母体中检测到的 以及孕期脆弱生命阶段的脐带血清。人们迫切需要这本小说 生成有针对性的环境化学品发育和生殖毒性数据 怀孕期间已知的暴露情况，以及系统地解释这些数据的可靠方法 支持基于证据的政策和决策。这项拟议项目的长期目标是 利用既定的系统审查方法来确定关注的环境化学品 极有可能导致发育或生殖毒性的人类接触以及 找出数据差距，重点关注高通量筛选工作。我们的中心假设是 毒理学反应是由外源化学物质和生物分子之间的相互作用驱动的。 目标和高通量筛查可以被用来预测对人类健康的有害影响， 特别注重发展和生殖健康的终点。为了测试这一点，这项提议 该项目将涉及三个具体目标：1)建立全面的数字知识库 发展/生殖健康终点和利用结果来验证体外存在的 机械性分析；2)评估和验证优先化学小组的生殖毒性 建立HTS检测(酵母菌和线虫)；以及3)评估和验证优先化学物质 使用已建立的体外人类胚胎干细胞的发育毒性小组 差异化模型。总体而言，这些目标将实现利用和整合的目标 从数千项已发表的研究中得出的科学发现，这些研究的主题是发育和 以全面和系统的方式促进生殖健康 进行系统审查和化学品评估，其规模在实地迄今是不可能的 环境健康的问题。它还将利用新的方法产生新的科学数据 旨在填补现有研究差距并评估动物- 预测对人类健康不利影响的替代测试模型。最终，这个拟议的项目 将提供关键的洞察力，以加速并增强评估关系的能力 环境化学品暴露与人类发育和生殖之间的关系 健康结果。

Project Summary/Abstract Although synthetic chemicals have been used in consumer products for over a century, their use has rapidly outgrown our ability to regulate them for human health harm. Concerningly, the majority of these chemicals are not evaluated for potential toxicities towards human health. Even less is known about their developmental and reproductive toxicities, even for those routinely detected in maternal and umbilical cord sera during the vulnerable life-stage of pregnancy. There is a dire need for the novel generation of targeted developmental and reproductive toxicity data for environmental chemicals with known exposures during pregnancy, as well as robust methods to systematically interpret these data to support evidence-based policy- and decision-making. The long-term goal of this proposed project is to utilize established systematic review approaches to identify environmental chemicals of concern for human exposure with significant potential to cause developmental or reproductive toxicities and identify data gaps to focus high-throughput screening efforts. Our central hypothesis is that toxicological responses are driven by interactions between exogenous chemicals and biomolecular targets and that high throughput screening can be leveraged to predict harmful human health effects, specifically focusing on developmental and reproductive health endpoints. To test this, this proposed project will involve three Specific Aims: 1) Establish a digital knowledge base of comprehensive developmental/reproductive health endpoints and leverage results to validate existing in vitro mechanistic assays; 2) Assess and validate a prioritized chemical panel for reproductive toxicity using established HTS assays (yeast and C. elegans); and 3) Assess and validate a prioritized chemical panel for developmental toxicity using established in vitro human embryonic stem cell differentiation models. Collectively, these aims will achieve the goals of leveraging and integrating scientific findings from thousands of published studies on the topic of developmental and reproductive health in a comprehensive and systematic manner that will stimulate the rapid conduct of systematic reviews and chemical assessments on a scale not possible to date in the field of environmental health. It will also generate novel scientific data utilizing new approach methodologies targeted to fulfill existing research gaps and evaluate the relevance of animal- alternative test models for predicting adverse human health effects. Ultimately, this proposed project will provide critical insight that will accelerate and enhance the ability to assess relationships between environmental chemical exposures and human developmental and reproductive health outcomes.