Combined Exposures and Mixtures Research Program

组合暴露和混合物研究计划

• 批准号: 10914582
• 负责人: Cynthia Rider
• 金额: $ 176.93万
• 依托单位: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10914582
• 关键词: Address; Animals; Area; Aromatic Polycyclic Hydrocarbons; Biological Assay; Botanicals; Cells; Chemical Actions; Chemicals; Communities; Community of Practice; Complex; Complex Mixtures; Data; Data Analyses; Decision Making; Dose; Drug Kinetics; Evaluation; Exposure to; Foundations; Fractionation; Future; Garcinia cambogia; Goals; Human; In Vitro; Individual; Joints; Learning; Methods; Modeling; Pathway interactions; Poly-fluoroalkyl substances; Public Health; Research; Risk; Risk Assessment; Safety; Structure; Systems Biology; Testing; Toxic effect; Toxicology; Translating; Uncertainty; Valerian; Work; adverse outcome; dietary supplements; hazard; in silico; predictive modeling; programs; public-private partnership; response; stressor; tool

Our current work focuses on evaluating hypotheses related to the joint action of chemicals and nonchemical stressors. Our work on defined mixtures will strengthen our ability to predict the effects of mixtures based on data from individual constituents. The goal of our studies on defined mixtures (e.g., polycyclic aromatic hydrocarbons, per- and polyfluoroalkyl substances) is to decrease the uncertainty involved in component-based risk assessment by conducting hypothesis-driven research on the current assumptions (e.g., dose addition for estimating cumulative effects of like-acting chemicals, lack of interactions among chemicals within a class). Our work on defined mixtures approaches leverages the toxicological data that already exist for single chemicals to estimate effects of mixtures. The defined mixtures projects will be used to develop statistical tools and refine predictive modeling approaches used to evaluate the risk associated with exposure to mixtures. Future work will further build on this foundation by addressing combinations of chemical and nonchemical stressors. Work in this portfolio is conducted using both animal and human cell-based models with a focus on translating findings to real-world exposure scenarios. Another goal of our mixtures work is to expand the availability and translatability of whole mixtures hazard data. We are currently evaluating the toxicity of complex botanical extracts that are common dietary supplement ingredients (e.g., valerian, Garcinia cambogia). We are also refining methods to evaluate sufficient similarity of complex mixtures, which are used to determine when findings from a tested substance can be extrapolated to related substances with variable composition. In addition, we are developing methods for bioassay guided fractionation and polypharmacokinetics, which can allow for identification of bioactive constituents within complex mixtures. Finally, our current work is aimed at developing collaborative communities of experts to inform current and future mixtures research. We are actively contributing to the Botanical Safety Consortium, a public-private partnership that is working on expanding the in silico and in vitro toolbox available for evaluating the toxicity of complex botanical ingredients (https://botanicalsafetyconsortium.org/). In addition, we are developing a Community of Practice for Mixtures that will engage diverse federal and state partners, including risk analysts and regulatory stakeholders. This effort will provide an active forum for reviewing data generated through the CEM portfolio, learning about complementary research being conducted by other agencies, and providing advice on critical areas of research that will be most useful for public health decision-making.

我们目前的工作着重于评估与化学物质和非化学应激源联合作用有关的假设。我们在定义的混合物上的工作将增强我们基于各个成分数据的数据来预测混合物影响的能力。我们对定义混合物的研究（例如，多环芳烃，每个和多氟烷基物质）的目的是减少基于组件的风险评估所涉及的不确定性，通过对当前假设进行假设驱动的研究研究（例如，估算累积累积化学效应的化学效果，都在化学上的累积效应中，相互作用中的化学效果）在化学效果中，而在化学上的累积效应中，则是在化学效果中的累积效应。我们在定义的混合物上的工作利用了单个化学物质已经存在的毒理学数据来估计混合物的影响。定义的混合物项目将用于开发统计工具，并完善用于评估与混合物相关的风险的预测建模方法。未来的工作将通过解决化学和非化学压力源的组合来进一步以此为基础。该投资组合中的工作是使用动物和人类细胞模型进行的，重点是将发现转化为现实世界的暴露场景。 混合物工作的另一个目标是扩大整个混合物危险数据的可用性和转换性。我们目前正在评估常见的饮食补充剂成分（例如，valerian，柬埔寨藤黄）的复杂植物提取物的毒性。我们还精炼了评估复杂混合物的足够相似性的方法，这些方法用于确定何时可以将来自测试物质的发现何时推断到具有可变组成的相关物质。此外，我们正在开发生物测定指导分级和多疗法的方法，这可以识别复杂混合物中的生物活性成分。 最后，我们目前的工作旨在发展专家的协作社区，以告知当前和未来的混合研究。我们正在积极贡献植物安全联盟，这是一种公私合作伙伴关系，正在努力扩展用于评估复杂植物成分的毒性（https://botanicalsafetyconsortium.org/）的硅和体外工具箱。此外，我们正在为混合物开发一个实践社区，该社区将吸引各种联邦和州合作伙伴，包括风险分析师和监管利益相关者。这项工作将提供一个活跃的论坛，用于审查通过CEM投资组合生成的数据，了解其他机构正在进行的补充研究，并就关键研究领域提供建议，这对于公共卫生决策最有用。

项目成果

A geospatial modeling approach to quantifying the risk of exposure to environmental chemical mixtures via a common molecular target.

• DOI: 10.1016/j.scitotenv.2022.158905
• 发表时间: 2023-01-10
• 期刊: SCIENCE OF THE TOTAL ENVIRONMENT
• 影响因子: 9.8
• 作者: Eccles, Kristin M.;Karmaus, Agnes L.;Kleinstreuer, Nicole C.;Parham, Fred;Rider, Cynthia, V;Wambaugh, John F.;Messier, Kyle P.
• 通讯作者: Messier, Kyle P.

Working with the natural complexity: Selection and characterization of black cohosh root extract for use in toxicology testing.

• DOI: 10.1016/j.fct.2021.112769
• 发表时间: 2022-03
• 期刊: FOOD AND CHEMICAL TOXICOLOGY
• 影响因子: 4.3
• 作者: Waidyanatha, Suramya;Cristy, Tim;Pierfelice, Jessica;Andre, Jon C.;Burback, Brian;Mutlu, Esra
• 通讯作者: Mutlu, Esra

The Botanical Safety Consortium: A public-private partnership to enhance the botanical safety toolkit.

植物安全联盟：旨在增强植物安全工具包的公私合作伙伴关系。

• DOI: 10.1016/j.yrtph.2021.105090
• 发表时间: 2022
• 期刊: Regulatory toxicology and pharmacology : RTP
• 作者: Mitchell,ConstanceA;Dever,JosephT;Gafner,Stefan;Griffiths,JamesC;Marsman,DanielS;Rider,Cynthia;Welch,Cara;Embry,MichelleR
• 通讯作者: Embry,MichelleR

Plant vs. Kidney: Evaluating Nephrotoxicity of Botanicals with the Latest Toxicological Tools.

植物与肾脏：使用最新毒理学工具评估植物的肾毒性。

• DOI: 10.1016/j.cotox.2022.100371
• 发表时间: 2022
• 期刊: Current opinion in toxicology
• 影响因子: 4.6
• 作者: Pearson,Adam;Gafner,Stefan;Rider,CynthiaV;Embry,Michelle;Ferguson,StephenS;Mitchell,ConstanceA
• 通讯作者: Mitchell,ConstanceA

Correction to: Comparison of phytochemical composition of G. biloba extracts using a combination of non-targeted and targeted analytical approaches.

更正：使用非靶向和靶向分析方法相结合对银杏提取物的植物化学成分进行比较。

• DOI: 10.1007/s00216-021-03594-z
• 发表时间: 2021
• 期刊: Analytical and bioanalytical chemistry
• 影响因子: 4.3
• 作者: Collins,BradleyJ;Kerns,SeasonP;Aillon,Kristin;Mueller,Geoffrey;Rider,CynthiaV;DeRose,EugeneF;London,RobertE;Harnly,JamesM;Waidyanatha,Suramya
• 通讯作者: Waidyanatha,Suramya