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.

项目总结/摘要 尽管合成化学品已经用于消费品超过世纪，但是它们的使用 迅速超出了我们对它们对人类健康危害的监管能力。令人担忧的是，大多数 没有评估这些化学品对人类健康的潜在毒性。我们知道的就更少了 关于它们的发育和生殖毒性，即使是那些在母体中常规检测到的， 和脐带血清中的一种。对这部小说有迫切的需要 生成环境化学品的目标发育和生殖毒性数据， 怀孕期间已知的暴露，以及系统地解释这些数据的可靠方法， 支持循证决策。本项目的长期目标是 利用既定的系统审查办法，查明引起关注的环境化学品， 人类接触有可能导致发育或生殖毒性， 确定数据差距，以集中高通量筛选工作。我们的核心假设是， 毒理学反应是由外源性化学物质和生物分子之间的相互作用驱动的。 靶点和高通量筛选可以用来预测有害的人类健康影响， 特别侧重于发育和生殖健康终点。为了验证这一点， 该项目将涉及三个具体目标：1）建立一个全面的数字知识库 发育/生殖健康终点，并利用结果来验证现有的体外 机制分析; 2）评估和验证一个优先化学品小组的生殖毒性，使用 建立的HTS测定（酵母和C. elegans）;以及3）评估和验证优先化学品 使用已建立的体外人胚胎干细胞的发育毒性试验组 差异化模型总的来说，这些目标将实现利用和整合的目标 科学发现从数以千计的已发表的研究主题的发展和 生殖健康的全面和系统的方式，将刺激迅速 以迄今为止在实地无法实现的规模进行系统审查和化学品评估 环境健康。它还将利用新方法生成新的科学数据 旨在填补现有研究空白和评估动物相关性的方法， 用于预测对人类健康不利影响的替代测试模型。最终，这个项目 将提供关键的洞察力，这将加速和提高评估关系的能力 环境化学品暴露与人类发育和生殖之间的关系 健康成果。