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

通过开发、验证和整合高通量机械体外数据推进化学风险评估

• 批准号: 10514512
• 负责人: Juleen Lam
• 金额: $ 46.23万
• 依托单位: CALIFORNIA STATE UNIVERSITY HAYWARD
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-16 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10514512
• 关键词: Address; Affect; Animal Testing Alternatives; Animals; Biological Assay; Caenorhabditis elegans; Chemicals; Child; Congenital Abnormality; Data; Data Set; Databases; Decision Making; Development; Developmental Process; Environment; Environmental Health; Exposure to; Generations; Germ Cells; Goals; Health; Human; Impairment; In Vitro; Industrialization; Infertility; Knowledge; Life; Link; Literature; Live Birth; Measures; Methodology; Methods; Modeling; Occupations; Organogenesis; Outcome; Pesticides; Phenols; Policy Making; Pregnancy; Pregnant Women; Public Health; Publishing; Reproductive Health; Research; Research Methodology; Risk Assessment; Role; Source; Standardization; Structural Congenital Anomalies; Students; Testing; Toxic effect; Toxicology; Translating; Umbilical cord structure; United States; Universities; Validation; Woman; Yeasts; base; consumer product; developmental toxicity; digital; economic cost; environmental chemical; environmental chemical exposure; epidemiologic data; evidence base; experience; exposed human population; hazard; health data; high throughput screening; human embryonic stem cell; in vitro Assay; in vitro Bioassay; in vivo; insight; interoperability; knowledge base; novel; novel strategies; phthalates; polybrominated diphenyl ether; predictive modeling; predictive test; pregnant; prenatal exposure; reproductive; reproductive outcome; reproductive toxicity; response; screening; societal costs; stem cell differentiation; systematic review; undergraduate student; virtual

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.

项目摘要/摘要 尽管合成化学品已在消费产品中使用了一个多世纪，但它们的使用已有 我们迅速超越了我们规范它们对人类健康危害的能力。关于大多数 这些化学物质尚未评估对人类健康的潜在毒性。甚至更少知道 关于它们的发育和生殖毒性，即使对于在母亲中经常检测到的人 和脐带血清在怀孕的脆弱生命阶段。小说迫切需要 生成针对环境化学物质的有针对性的发育和生殖毒性数据 怀孕期间已知的暴露，以及可系统地将这些数据解释为 支持基于证据的政策和决策。这个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 人类暴露具有引起发育或生殖毒性的巨大潜力， 确定数据差距以集中高通量筛选工作。我们的中心假设是 毒理学反应是由外源化学物质与生物分子之间的相互作用驱动的 目标和高吞吐量筛查可以利用以预测有害的人类健康影响， 特别专注于发展和生殖健康终点。为了测试这一点，这提出了 项目将涉及三个具体目标：1）建立全面的数字知识基础 发展/生殖健康终点并利用结果来验证现有的体外 机械测定； 2）评估和验证使用优先的化学面板使用使用 已建立的HTS测定法（酵母和秀丽隐杆线虫）； 3）评估和验证优先的化学品 使用已建立的体外人类胚胎干细胞的发育毒性面板 分化模型。总的来说，这些目标将实现利用和整合的目标 成千上万的关于发展和发展的研究的科学发现 以全面而系统的方式生殖健康，将刺激快速 在现场不可能的规模进行系统评价和化学评估的进行 环境健康。它还将利用新方法生成新颖的科学数据 旨在满足现有研究差距的方法论，并评估动物的相关性 预测不良人类健康影响的替代测试模型。最终，这个建议的项目 将提供关键的见解，以加速和增强评估关系的能力 在环境化学暴露与人类发育和生殖之间 健康结果。