Combined Exposures and Mixtures Research Program

National Institute Of Environmental Health Sciences

Investigators

Linked publications & trials

Abstract

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. Additional work evaluating the joint action of chemicals commonly found at Superfund sites is being conducted in collaboration with the National Center for Advancing Translational Sciences (NCATS). 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. Complex environmental mixtures such as woodsmoke and wildfire smoke are also being evaluated for carcinogenicity under the Report on Carcinogens. Tools developed with botanical ingredients (e.g., sufficient similarity) will be applied to better understand the chemical variability in these smoke related mixtures. Finally, work to better understand the totality of environmental exposures (i.e., exposome) will be conducted through projects using non-targeted chemical analysis to evaluate human samples (e.g., serum). 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 plan to develop 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.