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Your Environment. Your Health.

June 2018

Superfund Research Program Science Digest
Balancing Scientific Excellence with Research Relevance

Features

"21st Century Science" Could Revolutionize Toxicity Testing, Improve Human Health

Pipetting

To better protect and improve public health, federal agencies and partners are exploring new ways to evaluate chemical safety. These approaches, which include cell-based methods, chemical tests, and computational modeling that considers chemical structure, aim to replace or reduce the use of animal models and generate findings that are more relevant to humans.

Scientists conduct toxicity testing to identify potential hazards from a chemical and to characterize the relationship between the level of exposure and the risk of health effects. Many current approaches are expensive, time-consuming, and may require traditional toxicity tests in animals, such as mouse studies. In addition, better methods of assessing how chemicals move through the environment and the risks of exposure to humans and other organisms are sorely needed.

This feature provides examples of methods and tools developed by Superfund Research Program (SRP) grantees to expedite the use of 21st century science, which complements the federal Toxicology in the 21st Century initiative, known as Tox21. These alternative approaches, which include methods to predict the toxicity of a chemical based on its structure, cell-based assays to assess toxicity potential, and computational modeling, generate information that can be useful in understanding exposure and potential health effects.

New methods to predict the toxicity of chemicals

SRP-funded researchers are developing new ways to identify hazards and evaluate chemical safety. These approaches help us understand how humans are exposed to chemicals, how these chemicals might interact in the body, and how differences between humans play a role.

Chemical-specific compound networks and a control network
At Boston University, liver samples are used to infer chemical-specific compound networks and a control network. Network structures are evaluated for similarities to identify groups of compounds. Groups of tightly connected genes both in the control network and in compound aggregate networks are identified and compared across conditions. (Image from Mulas et al.)

  • At the Boston University SRP Center, researchers led by Stefano Monti, Ph.D., developed a computational pipeline to construct chemical networks. They have shown that by grouping chemicals based on the similarity of their associated networks, they can identify groups of chemicals or drugs with similar functions and similar profiles that may damage genes and lead to cancer. These networks also can point to the main molecular pathways triggered by specific chemicals.

  • Texas A&M University (TAMU) SRP Center grantees working at the Pacific Northwest National Laboratory have developed a novel platform that can rapidly and automatically analyze environmental samples. According to the researchers, led by Erin Baker, Ph.D., this approach is a viable way to screen for chemicals in the environment and in biological samples to give insight into human exposure and disease mechanisms.

  • Led by Forest White, Ph.D., researchers at the Massachusetts Institute of Technology (MIT) SRP Center are using a systems toxicology approach to assess the systemic, molecular network, and cellular effects of environmental contaminants, with a focus on nitrosamines and polycyclic aromatic hydrocarbons (PAHs). The researchers are quantifying different cell responses to the chemicals and integrating these datasets to identify molecular-level responses to exposures.

  • Proteome-wide interactions of chemcials and their effects

    UC Berkeley SRP Center researchers are developing technologies to assess the direct proteome-wide interactions of chemicals, which can affect downstream transcriptional, signaling, and metabolic pathways that lead to toxicity.
    (Photo courtesy of Daniel Nomura)

  • Using a platform to map the reactivity of environmental chemicals across all the proteins in the body may uncover new ways that environmental chemicals interact in humans, according to researchers at the University of California (UC) Berkeley SRP Center. Led by Daniel Nomura, Ph.D., researchers are using reactivity-based strategies to mine for distinct sets of proteins that may be particularly sensitive to environmental chemicals, which could inform how molecules interact in the body and how they might be linked to chemical toxicity.

  • Using cell-based data, TAMU SRP Center grantees led by Ivan Rusyn, Ph.D., developed a computational approach to estimate differences in susceptibility to chemicals based on population variability, or the genetic differences normally found from person to person within a population. Rusyn's lab is exploring a number of population-based models to address population variability.

Alternative models and assays to classify potential health hazards

Several SRP grantees are using zebrafish to advance the use of 21st-century science in toxicity testing.

Zebrafish

School of adult zebrafish
(Photo courtesy of Robert Tanguay)

  • A newly developed panel of zebrafish genes can be combined with a rapid testing platform to identify chemicals that induce oxidative stress, according to researchers led by Evan Gallagher, Ph.D., at the University of Washington (UW) SRP Center. The method, optimized for use on larval zebrafish, is cost-effective and can be performed more quickly and with less tissue than conventional methods.

  • Researchers led by Robert Tanguay, Ph.D., at the Oregon State University SRP Center use zebrafish to define the toxicity of complex PAH mixtures. According to the researchers, the zebrafish model is uniquely suited to link biochemical, genetic, and cellular changes to observations at the structural, functional, and behavioral level in a high-throughput format.

  • Heather Stapleton, Ph.D., and her team at the Duke University SRP Center, demonstrated that polybrominated diphenyl ethers (PBDEs) and halogenated phenolic compounds can bind proteins that regulate thyroid hormones and bone development. This binding was very similar in both humans and zebrafish, demonstrating the utility of using zebrafish as a model to understand potential human health hazards.

Other SRP grantees are developing tests using cells and antibodies to screen for hazardous chemicals in the environment and in human samples.

Alpaca
Alpaca housed at UC Davis. The VHH genes are isolated from blood samples, which are used to produce VHH antibodies that can detect various environmental chemicals. (Photo from Bever et al.)

  • Researchers led by TAMU SRP Center grantee Michael Mancini, Ph.D., at the Baylor College of Medicine, are developing rapid imaging platforms and custom automated Web-based image analysis and reporting tools to identify the presence of endocrine disrupting chemicals in complex chemical mixtures. The researchers aim to develop cost-effective tools that can be used to quickly assess the risks to human health during natural and man-made environmental emergencies.

  • Researchers at UC Davis, led by Candace Bever, Ph.D., are using VHH antibodies, or binding fragments of antibodies, to develop immunoassays to detect coumarin rodenticides, polychlorinated biphenyls (PCBs), pesticides, and other compounds and degradation products. These immunoassays, which use VHH antibodies isolated from alpacas, are characterized by their speed, sensitivity, high throughput, and low cost.

New approaches to understand fate and transport

Understanding how chemicals migrate through and interact with the environment is important for assessing potential human exposure and toxicity. SRP grantees are developing a variety of tools to improve our understanding of the environmental fate and transport of contaminants.

Kelly Pennell, Leigh Friguglietti, and Jennifer Ames

The University of Kentucky's Pennell, left, demonstrates the use of a pressure meter to take field measurements with Leigh Friguglietti, center, and Jennifer Ames, right, from the Boston University SRP Center.
(Photo courtesy of Kelly Pennell)

  • Scientists from the Brown University SRP Center led by Eric Suuberg, Ph.D., developed process models to predict vapor concentrations that enter indoor environments, a step toward providing a simpler, accurate screening method to determine whether chemicals in underground sources are seeping into buildings and contaminating indoor air. At the University of Kentucky SRP Center, researchers led by Kelly Pennell, Ph.D., in partnership with Brown and Boston University SRP Center researchers, have incorporated multiple lines of evidence, including soil gas measurements and a 3D model, to better evaluate exposure risks from vapor intrusion into homes and buildings.

  • As part of the MIT SRP Center, researchers led by Jesse Kroll, Ph.D., are developing a new method, called spatio-temporal pollutant tracking, to assess the pathways that transport PAHs in the atmosphere. In the atmosphere, pollutants can be quickly transported and transformed, potentially creating products of lower or higher toxicity than the original compound. To better understand these processes, MIT's approach integrates state-of-the-art sensors, pollutant laboratory studies, and modeling of contaminant chemistry to predict pollutant concentrations and fate.

  • Researchers led by Staci Simonich, Ph.D., at Oregon State University are identifying toxic products in complex environmental mixtures using an integrated framework that incorporates complementary instrumental techniques, computational chemistry, and toxicity analysis. By developing these tools to rapidly screen for toxicity, researchers are helping to focus efforts on chemicals that may pose risks to humans and the environment.

  • University of Rhode Island SRP Center researchers are using novel statistical methods to fingerprint poly- and perfluoroalkyl substances (PFASs) measured in fish and drinking water around a contaminated site. The researchers, led by Elsie Sunderland, Ph.D., are comparing PFAS profiles in drinking water to those from wastewater to identify exposures originating from the contaminated site.

  • University of Pennsylvania SRP Center researchers are identifying how asbestos forms aggregates and moves through groundwater. Recent findings indicate that the diffusion rates of asbestos, as well as a wide range of natural particles, can be predicted by taking the specific particle shape into account.

New tools to study ecotoxicology

Several SRP grantees are working to understand ecotoxicology, the study of how contaminants harm the environment and other organisms.

Immunofluorescence detecting expression of Cyp1a protein

The Brown SRP Center fish microtissue was tested using benzo(a)pyrene (BaP), a well-characterized contaminant. After exposure to BaP, researchers used immunofluorescence to detect expression of Cyp1a protein, a biological marker of toxicant exposure and cellular response.
(Photo courtesy of April Rodd)

  • Researchers at the Brown University SRP Center have developed a new 3D liver cell model that can be used to screen chemicals for toxicity in fish. The new model, developed by April Rodd, Ph.D., under the guidance of Agnes Kane, Ph.D., uses fish liver cells cultured to form 3D microtissue to test the effects of liver toxicants after single or repeated exposures. Compared to a single layer of cells often used in toxicology, 3D liver microtissues live longer and are better differentiated, meaning they act more like real livers and can better predict the response of fish.

  • Researchers explored the complex genetics involved in how Atlantic killifish have rapidly evolved to tolerate normally lethal levels of environmental contaminants in polluted East Coast estuaries. Mark Hahn, Ph.D., and Sibel Karchner, Ph.D., who were involved in the study, have been studying killifish resistant to contamination in New Bedford Harbor since 1995 as part of the Boston University SRP Center. Their findings may provide new information about the mechanisms of environmental chemical toxicity in both animals and humans.

  • A research team led by Evan Gallagher, Ph.D., at the University of Washington is using approaches that integrate molecular, biochemical, physiological, and behavioral endpoints to investigate how exposure to metals such as cadmium may impact regional survival of fish. Cadmium and copper exposure has been shown to lead to damage to the olfactory system of fish. Their work to examine markers of oxidative stress in salmon may have implications for both human and ecological health.