Advancing research on environmental mixtures
Humans are exposed to numerous external/environmental chemicals from diverse sources throughout their lifetimes. NIEHS and the NIEHS Superfund Basic Research and Training Program (SRP) have supported research over three decades to understand the implications of these chemical mixtures.
SRP-funded researchers are providing a foundation of knowledge on issues related to mixtures, including human health and ecological assessments, remediation approaches, sampling technologies, fate and transport modeling, and other mathematical and statistical approaches.
Goal 4 of the NIEHS Strategic Plan focuses on understanding human health effects associated with combined environmental exposures. SRP has contributed to Goal 4 objectives to define the state of the science and identify critical knowledge gaps through workshops, initiatives, and funding opportunities. For example, SRP was instrumental in 2011 and 2015 mixtures workshops that brought together experts in diverse fields to prioritize research goals.
Understanding how mixtures behave in environmental and biological systems
Components of complex mixtures may interact with each other in unexpected ways. These interactions can change the way individual components of a mixture behave in environmental and biological systems. SRP researchers are developing novel computational, analytical, and experimental approaches critical to advancing mixtures research.
SRP-funded grantees are learning how mixtures are transported in water, air, and soil. For example, researchers led by Kate Scow, Ph.D., at the University of California (UC) Davis SRP Center developed a kinetics-based reactive transport model to predict fate and transport processes of ethanol-blended fuel in groundwater. A team led by Eric Suuberg, Ph.D., from the Brown University SRP Center, characterized thermochemical and vapor pressure behavior of anthracene and brominated anthracene mixtures in indoor air.
Others are using unique experimental approaches to better represent environmentally realistic conditions. For example, researchers from the Colorado School of Mines have designed small-scale field and mesocosm experiments to better test physical and chemical stressors on fish communities in streams. Mesocosm experiments are conducted in enclosures in the environment so they incorporate natural variation but can be done under more controlled conditions than field studies. Their work illustrates how small-scale tests can be used to complement large-scale field studies.
SRP researchers are developing new ways to reliably measure and analyze mixtures in environmental and biological samples to understand how chemicals interact. A team at the UC Davis SRP Center developed an approach to measure chemical metabolites in complex mixtures using heteronuclear single quantum coherence spectroscopy. This automated method provides more information about the wide range of metabolites in biological samples. Understanding the collection of all metabolites in the body, or the metabolome, provides information about how a chemical or a mixture of chemicals may lead to physiological changes and health effects. They also analyzed water samples using multiple separation techniques to obtain a comprehensive profile of the chemical contaminants in the samples.
New statistical and mathematical approaches are also needed. Tom Webster, Ph.D., and other investigators at the Boston University (BU) SRP Center have proposed and evaluated a new statistical approach, called generalized concentration addition (GCA), to evaluate the effects of chemical mixtures and chemical and non-chemical stressors.
The team provided evidence that GCA outperforms three traditional mathematical models when predicting experimental responses to mixtures at higher exposure concentrations. In addition, researchers at the University of Kentucky SRP Center created an online, open-sourced statistical application to help other investigators analyze complex mixtures data.
Understanding biological mechanisms of mixtures with cells and animal models
Interactions between mixtures components and chemicals within the human body may alter how a disease is initiated or progresses. Scientists use studies in cells and other organisms to examine how exposure to mixtures may affect changes in DNA and proteins. These studies help us understand how real-life exposures impact biological mechanisms that may lead to disease.
For example, BU SRP Center investigators reported that semi-volatile compounds and chemical mixtures common in house dust are possible PPARγ1 agonists in cell culture systems. Activation of PPARγ, which regulates gene expression of fat cells, may be a key mechanistic factor for obesity. Researchers at the Louisiana State University (LSU) SRP Center led by Stephania Cormier, Ph.D., found that neonatal exposure to environmentally persistent free radicals (EPFRs) suppresses the adaptive immune response and results in increased influenza disease severity.
Researchers from the Oregon State University (OSU) SRP Center have developed an approach for classifying the carcinogenic potential of polycyclic aromatic hydrocarbon (PAH) mixtures. The pathway-based approach uses previous data about the mechanisms of PAHs to predict PAH potency and interactions with other chemicals. By integrating data about PAHs across several biological processes, they are using short-term studies about the effects of PAH mixtures to predict long-term carcinogenic potential.
Characterizing exposure and evaluating health outcomes of mixtures in human populations
Studying human populations over time helps researchers understand how exposures to harmful pollutants and other factors influence disease. SRP researchers are conducting studies to better understand environmentally relevant exposures to mixtures and potential health outcomes in humans.
For example, OSU SRP Center researchers led by Kim Anderson, Ph.D., have developed simple, wearable silicone wristbands to capture and measure a large number of diverse compounds at environmentally relevant concentrations. The wristbands have been implemented successfully to study the link between flame retardant exposure and social behaviors in children. In this study, researchers found that children with higher flame retardant exposures were more likely to exhibit poorer social skills that play an important role in a child's ability to succeed academically and socially.
In addition to characterizing personal exposure to mixtures, SRP researchers are studying the molecular mechanisms by which exposure to mixtures can result in adverse health outcomes. For example, researchers at the Northeastern University SRP Center have established a large pregnancy cohort in Puerto Rico to study the relationship between hazardous waste contamination and pre-term birth. The team reported that exposure to bisphenol A, parabens, and triclosan during pregnancy may be related to oxidative stress and inflammation, which may influence birth outcomes. The team also reported that urinary phthalate metabolites are associated with altered maternal serum thyroid and sex hormone levels. This work provided important insight to inform subsequent epidemiological studies and intervention strategies related to phenols and parabens.
SRP researchers have also developed a new epidemiological approach for examining the risk of exposure to mixtures. Using National Health and Nutrition Examination Survey data, researchers from the Northeastern SRP Center developed the environmental risk score, which is a promising tool for characterizing disease risk from multi-pollutant exposures.
Remediation approaches for mixtures
SRP researchers also are working to reduce exposure to mixtures by developing innovative remediation strategies. For example, the team from the Brown University SRP Center developed a cyclic electrowinning/precipitation system capable of removing heavy metal mixtures from water. Similarly, researchers from the Northeastern SRP Center reported a modified electrocoagulation process that is better at removing certain contaminants and mixtures of contaminants from wastewater and groundwater than traditional approaches. In addition, UC Davis SRP Center investigators have shown that biochar can be added to minimize the mobility of mixtures of pharmaceutical compounds, heavy metals, and herbicides in biosolids.
Moving mixtures research forward
Despite this incredible progress in mixtures research, many challenges remain. Traditional statistical approaches of single chemicals on health outcomes are not well-suited to studying mixtures, highlighting the need for novel approaches to address this complex problem. More research is also needed to determine which components of mixtures contribute to toxicity and how chemicals interact with each other to contribute to human disease.
In addition to innovative research, SRP grantees are contributing to scientific reviews of the available literature that help to highlight research needs and data gaps. SRP-funded researchers have published reviews related to assessing the health risks of exposure to PAH mixtures, statistical strategies for assessing health risk from mixtures exposures, and the unique challenges epidemiologists face with chemical mixtures and approaches to address these challenges.