Combined Exposures and Mixtures Research: An Enduring NIEHS Priority

Abstract

Background: The National Institute of Environmental Health Sciences (NIEHS) continues to prioritize research to better understand the health effects resulting from exposure to mixtures of chemical and nonchemical stressors. Mixtures research activities over the last decade were informed by expert input during the development and deliberations of the 2011 NIEHS Workshop "Advancing Research on Mixtures: New Perspectives and Approaches for Predicting Adverse Human Health Effects." NIEHS mixtures research efforts since then have focused on key themes including a) prioritizing mixtures for study, b) translating mixtures data from in vitro and in vivo studies, c) developing cross-disciplinary collaborations, d) informing component-based and whole-mixture assessment approaches, e) developing sufficient similarity methods to compare across complex mixtures, f) using systems-based approaches to evaluate mixtures, and g) focusing on management and integration of mixtures-related data.

Objectives: We aimed to describe NIEHS driven research on mixtures and combined exposures over the last decade and present areas for future attention.

Results: Intramural and extramural mixtures research projects have incorporated a diverse array of chemicals (e.g., polycyclic aromatic hydrocarbons, botanicals, personal care products, wildfire emissions) and nonchemical stressors (e.g., socioeconomic factors, social adversity) and have focused on many diseases (e.g., breast cancer, atherosclerosis, immune disruption). We have made significant progress in certain areas, such as developing statistical methods for evaluating multiple chemical associations in epidemiology and building translational mixtures projects that include both in vitro and in vivo models.

Discussion: Moving forward, additional work is needed to improve mixtures data integration, elucidate interactions between chemical and nonchemical stressors, and resolve the geospatial and temporal nature of mixture exposures. Continued mixtures research will be critical to informing cumulative impact assessments and addressing complex challenges, such as environmental justice and climate change. https://doi.org/10.1289/EHP14340.

Figure 1.

Approaches to mixtures research. Mixtures research can be “bottom-up” by reducing real-world mixtures to components (i.e., individual chemicals) and using additivity models to predict mixture effects or “top down” wherein complex whole mixtures related to the real-world exposure are evaluated. Whole mixtures can be variable, and approaches that compare across related mixtures are needed to ensure that data generated on one whole mixture can be used to estimate the risk associated with sufficiently similar data-poor mixtures. Both bottom-up and top-down approaches aim to inform intervention and exposure mitigation strategies to improve public health.

Figure 2.

Cumulative risk assessment options adapted from the 2000 US Environmental Protection Agency Supplementary Guidance for Conducting Health Risk Assessment of Chemical Mixtures. Based on data availability, risk assessments can be conducted using data from the whole mixture of interest, data from a sufficiently similar mixture(s), or data from known mixture constituents.