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Your Environment. Your Health.

New Approaches and Alternatives for Toxicity Testing

Superfund Research Program

The NIEHS Superfund Research Program (SRP) is hosting a webinar series highlighting research that may be useful as new approaches and methodologies for toxicity testing. This series coincides with recent initiatives found in the U.S. Environmental Protection Agency (EPA) New Draft Strategic Plan to Reduce Animal Testing and the National Toxicology Program (NTP) Strategic Roadmap for Establishing New Approaches to Evaluate the Safety of Chemicals and Medical Products in the United States.

We would like to thank the following members of the Risk e-Learning committee for their help in developing the Risk e-Learning sessions: Marcy Card, Warren Casey, Nicole Kleinstreuer, Jesse Kneeland, Lingamanaidu Ravichandran, James Rice, and Daniel Shaughnessy.

Session I - Toxicity Testing Strategies and Model Systems
May 14, 2018 • 1:00 – 3:00 p.m. EDT

For more information, visit EPA's CLU-IN Training & Events webpage.

In the first session, speakers provided an overview of toxicity testing strategies to advance the use of 21st-century science in chemical safety evaluation. Speakers also described the pros and cons of model systems, such as zebrafish and cell-based assays, in hazard identification.

Presenters:

  • Nicole Kleinstreuer, Ph.D., deputy director, NTP Interagency Center for the Evaluation of Alternative Toxicological Methods
  • Lisa Truong, Ph.D., assistant professor of environmental and molecular toxicology, Oregon State University
  • April Rodd, Ph.D., postdoctoral researcher, Brown University

Moderators:

  • William Suk, Ph.D., director, Superfund Research Program
  • Heather Henry, Ph.D., health scientist administrator, Superfund Research Program

Nicole Kleinstreuer, Ph.D., deputy director of the NTP Interagency Center for the Evaluation of Alternative Toxicological Methods (NICEATM), discussed the NTP Strategic Roadmap for incorporating new human-relevant approaches into safety testing of chemicals and medical products in the United States. The Interagency Coordinating Committee for the Validation of Alternative Methods (ICCVAM), consisting of representatives from 16 federal agencies, recently developed and published the strategic roadmap with input from a broad range of stakeholder groups. The successful implementation of the roadmap will require coordinated efforts that address three strategic goals: (1) connecting end users with developers of new approach methodologies; (2) fostering the use of efficient, flexible, and robust practices to establish confidence in new methods; and (3) encouraging the adoption and use of new methods and approaches by federal agencies and regulated industries.

Lisa Truong, Ph.D., assistant professor of environmental and molecular toxicology at Oregon State University (OSU) and deputy director of the Sinnhuber Aquatic Research Laboratory, discussed the use of zebrafish for toxicity testing and its ability to help advance 21st-century science. She presented a systematic evaluation of a large polycyclic aromatic hydrocarbon (PAH) library and explored potential long-lasting behavior effects from developmental exposure to PAHs. Additionally, she described transgenerational behavioral effects observed in animals exposed to benzo[a]pyrene.

April Rodd, Ph.D., a postdoctoral researcher at Brown University and a former Brown SRP Center trainee, discussed how some of the innovative techniques developed for alternative toxicity testing platforms can be applied to aquatic toxicology. This presentation focused on 3D cell culture techniques and how they can be applied to build a fish liver microtissue that bridges traditional in vitro techniques and the complexity of whole animal exposures. She described the fish liver microtissues and how they can be used to study a model contaminant, benzo[a]pyrene.

SRP Director William Suk, Ph.D., welcomed participants and provided a short introduction to the series.

Session II - Tools for Assessing Exposure and Toxicity
May 23, 2018 • 1:00 – 3:00 p.m. EDT

To register, visit EPA's CLU-IN Training & Events webpage.

Assessing environmental exposure and identifying health hazards are both important aspects of chemical safety evaluation, and rapid screening tools may be used to improve our understanding of both aspects. In the second session, speakers will discuss tailoring read-across methodology to address chemical evaluation challenges, explore analysis of environmental toxicants in the environment, and highlight genetic screening tools to examine mechanisms of toxicity.

Presenters:

  • James W. Rice, Ph.D., senior environmental scientist, Gradient
  • Erin Baker, Ph.D., bioanalytical chemist, Pacific Northwest National Laboratory
  • Chris Vulpe, M.D., Ph.D., professor, University of Florida

Moderator:

  • Brittany Trottier, health specialist, Superfund Research Program

James W. Rice, Ph.D., a senior environmental scientist at Gradient and a former Brown University SRP Center trainee, will discuss chemical safety evaluation challenges of the Lautenberg Chemical Safety Act (LCSA) and potential ways to address these challenges. LCSA joins an array of regulatory schemes that require substantial data on chemical health hazard prior to chemical registration and sale. There are consumer product manufacturers, however, for whom product evaluation and associated chemical safety fall outside the scope of these large chemical registration programs but who are interested in specific health endpoints related to use of their products or proposed products. In response, Rice and colleagues have developed and validated a read-across framework aimed at filling dermal sensitization and irritation data gaps. The framework quantifies structural similarity between proposed surrogates and target chemicals and shows an expected common mode of action via structural alerts and relevant chemical properties.

Erin Baker, Ph.D., a bioanalytical chemist at the Pacific Northwest National Laboratory and an Oregon State University SRP Center grantee, will discuss novel approaches to rapid analysis of environmental samples. Surveillance of chemical exposure requires analytical platforms offering rapid measurements, high sensitivity, efficient separations, wide dynamic ranges, and applicability to a broad chemical space. Baker and colleagues have developed a platform and pipeline that meets these needs by combining solid phase extractions with ion mobility spectrometry and mass spectrometry (SPE-IMS-MS). This exposomics approach overcomes many challenges for large-scale exposure assessments and is a viable way of screening environmental conditions and patient cohorts for insight into human exposure and disease mechanisms.

Chris Vulpe, M.D., Ph.D., a professor at the University of Florida's Center for Environmental and Human Toxicology, will describe his work on the application of CRISPR-Cas9 genome-editing tools in the evaluation of chemical hazards. An ongoing revolution in gene-editing capabilities is enabling new approaches to assess the biological effects of chemical exposure. The interrogation of the functional role of genes in response to a chemical through CRISPR-Cas9 targeting provides a new and potentially transformative approach to chemical hazard assessment.

Session III - Modernizing Safety Testing
May 31, 2018 • 1:00 – 3:00 p.m. EDT

To register, visit EPA's CLU-IN Training & Events webpage.

In the third session, presenters will discuss new and emerging strategies for chemical safety evaluation. This will include new and emerging in vivo, in vitro, and in silico models to address population variability and how in vitro high-throughput assays can provide useful information for hazard assessment of complex mixtures.

Presenters:

  • William Suk, Ph.D., director, Superfund Research Program
  • Weihsueh Chiu, Ph.D., professor and Decision Science Core leader, Texas A&M SRP Center
  • Michael DeVito, Ph.D., acting chief, National Toxicology Program Laboratory

Moderator:

  • Michelle Heacock, Ph.D., health scientist administrator, Superfund Research Program

William Suk, Ph.D., director of the SRP, will describe other SRP efforts to address the complex challenges posed by hazardous pollutants and mixtures of chemicals. The SRP is well-positioned to lead the way in the use of 21st-century science to protect human health. This includes development of rapid tools to evaluate hazard, exposure, and environmental fate, as well as approaches to integrate these methods to evaluate risk.

Weihsueh Chiu, Ph.D., leader of the Texas A&M SRP Center's Decision Science Core, will discuss new and alternative approaches to addressing human variability and susceptibility. Characterizing population variability, including identifying susceptible populations and quantifying their increased susceptibility, is an important aspect of chemical risk assessment — but one that is challenging with traditional experimental models and risk assessment methods. This presentation will discuss some new and emerging in vivo, in vitro, and in silico models to address population variability and advance human health hazard and dose-response assessments. A number of case studies providing proof of principle, as well as some key challenges, will be highlighted.

Michael DeVito, Ph.D., acting chief of the National Toxicology Program Laboratory, will discuss evaluation of mixtures in Tox21. Traditional testing methods alone cannot provide the answers to the challenges in understanding potential effects of mixtures. Both component-based approaches and whole mixture approaches have been employed in Tox21. Using these high-throughput screening (HTS) approaches, they have evaluated 69 mixtures of 18 estrogen and androgen receptor agonists. The 18 chemicals range from highly efficacious and potent to negative in the different assays. The mixtures ranged from binary to all 18 chemicals at a variety of mixing ratios. The HTS approach allowed for the evaluation of dose addition under a broad range of mixing ratios and chemicals. Dose addition models consistently provided adequate fits to the data. These data demonstrate the advantage of the HTS approach to mixtures toxicology.

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