Combined Exposures and Mixtures Research Program

National Institute Of Environmental Health Sciences

Investigators

Linked publications, trials & patents

Abstract

Our work on defined mixtures strengthens our ability to predict the effects of mixtures on the basis of their individual constituents. It will also contribute to decreasing 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. It is anticipated that the lessons learned, and statistical tools developed during these projects, will be useful in projects under other strategic focus areas that involve environmental mixtures (e.g., per- and polyfluoroalkyl substances, phthalates, and flame retardants) as well as combination pharmaceuticals (e.g., human immunodeficiency virus (HIV) therapeutics). Future work will further build on this foundation by addressing combinations of chemical and nonchemical stressors. DNTP is currently applying the concept of sufficient similarity of complex mixtures to its test article selection process for botanicals; further development of methods to evaluate sufficient similarity will also be a critical contribution in interpreting data generated from other complex mixture projects. For example, sufficient similarity approaches allow for better definition of when we can extrapolate findings from a tested substance to related substances with variable composition, whereas bioassay guided fractionation and polypharmacokinetics can allow for identification of the bioactive constituent(s). These projects will improve our ability to translate animal study findings from complex mixture exposures to better understand their human relevance. The use of Adverse Outcome Pathway (AOP) networks to provide a framework for mechanistic data and generate testable hypotheses regarding the joint action of combined exposures represents the leading edge of mixtures research. The DNTP is currently developing projects to evaluate the AOP network approach. In addition, we are exploring combinations of chemical and nonchemical stressors to better recapitulate real-world human exposures. Innovative methods for simulating nonchemical stressors in model organisms will advance testing capabilities at DNTP and allow us to begin addressing important environmental justice issues related to unequal environmental and psychosocial burdens in vulnerable populations. DNTP has the resources required to evaluate both individual components and whole mixtures using cutting-edge chemical characterization tools, in vitro assays, and in vivo studies. We have mixtures research experts within DNTP and at the National Institute of Environmental Health Sciences (NIEHS) (Division of Intramural Research and Division of Extramural Research and Training) in complementary disciplines (e.g., statistics, epidemiology) who share ideas and develop collaborations through quarterly meetings of the trans-NIEHS Combined Exposures/Mixtures Working Group. We regularly engage with our federal partners and other stakeholders to design studies that address current mixtures of concern, provide data useful in the risk assessment of mixtures, and refine predictive methods for mixtures evaluation.