toxicology

Which Ounces of Prevention? Predictive Toxicology Using Organotypic Models

By Shane Hutson

VPROMPT team members (left-to-right) Shane Hutson, Dmitry Markov, John Wikswo and Lisa McCawley. Photo courtesy of Vanessa Allwardt.

VPROMPT team members (left-to-right) Shane Hutson, Dmitry Markov, John Wikswo and Lisa McCawley. Photo courtesy of Vanessa Allwardt.

Everyone knows that “an ounce of prevention is worth a pound of cure,” but think about that saying’s application to environmental chemical exposure. There are tens of thousands of chemicals in common use. If we don’t prioritize that list, it quickly adds up to a few tons of prevention.

There is no doubt that prevention is the best medicine when you know exactly what needs to be prevented, but how do we know? How do we predict which chemicals are toxic – and at which exposure levels? Those questions are why I became involved in toxicology research.

For 40+ years, the gold standard for those questions has been expensive, time consuming, animal-based (primarily mice and rats) laboratory exposure studies where results are not clearly predictive of effects in humans. Are we stuck with such studies? A large number of scientists are working to answer that question with “No, we can do better.”

I became involved in this effort during a year at EPA’s National Center for Computational Toxicology. My interests lie in developmental toxicity – understanding how chemical exposures affect the developing fetus – so I worked with EPA researchers on the Virtual Embryo Project to build computational models of specific developmental events and how they go awry during chemical exposure. When combined with high-throughput screening efforts such as ToxCast, computational models do have some predictive ability. But we still have a lot to learn.

That brings me to my current efforts. I’ve teamed up with a talented group of colleagues at Vanderbilt and the University of Pittsburgh to found VPROMPT – Vanderbilt-Pittsburgh Resource for Organotypic Models for Predictive Toxicology.

The word “models” pops up again here, but these are not computational. VPROMPT is using diverse expertise in biology, chemistry, physics and engineering to grow “models” that are three dimensional assemblies of multiple human cell types in carefully perfused microfluidic chambers. Such models are designed to be “organotypic,” that is, matching the microenvironment that cells experience in a living organ. This will enable our model to more closely mimic human responses to chemical exposure.

Our plans focus on developmental toxicity with models for liver, mammary gland, developing limb, and fetal membrane. The latter is a key model for investigating chemicals’ links to preterm birth.

VPROMPT is just getting started. We have lots to do in terms of engineering, fabricating and validating our models, but we also have high hopes for their predictivity. Will they help us make sure we only need that reasonable ounce of prevention? Stay tuned and let’s see where the science takes us!

About the Author: Shane Hutson is an Associate Professor of Physics at Vanderbilt University and Deputy Director of the Vanderbilt Institute for Integrative Biosystems Research & Education.

Editor's Note: The opinions expressed here are those of the author. They do not reflect EPA policy, endorsement, or action.

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Globally Linking Scientific Knowledge through the Adverse Outcome Pathways Wiki

By Steve Edwards, Ph.D.

I am thrilled to announce that on September 25th, we and our partners released the online Adverse Outcome Pathway (AOP) Wiki—an interactive, virtual encyclopedia for the development and evaluation of adverse outcome pathways.

An AOP is a conceptual framework that shows what is known about the “pathways,” or links between a chemical and how it: interacts with a biological process, initiates direct changes on a molecular level, and leads to an environmental and human health risk, or “adverse outcome.”

It is important for us to understand and map AOPs in order to incorporate toxicological data into chemical risk assessments and regulatory decision-making.

Our goal for the AOP Wiki was to create an easy-to-use tool that will stimulate, capture, and use crowd-sourced knowledge from the scientific community. Using the Wiki’s user-friendly interface and standardization guidance, we have created a tool to allow scientists from all industries and disciplines to develop, evaluate, and use adverse outcome pathways.

All AOPs within the wiki are constructed using guidance from two reports of the Organization for Economic Co-operation and Development’s (OECD) Extended Advisory Group on Molecular Screening and Toxicogenomics (Guidance on Developing and Assessing Adverse Outcome Pathways and the AOP Developers’ User Handbook). What I find particularly helpful about the guidance and wiki design is that it provides a user-friendly experience with consistent terminology and useful widgets for navigation and development. This way AOP developers and other users without extensive experience with Wiki language can take full advantage of the available information.

AOP Knowledge Base

AOP Knowledge Base

Our Wiki is the first publicly released module of the larger AOP Knowledge Base (AOP KB). This international collaboration will provide a consolidated, comprehensive knowledge base on how chemicals can induce adverse effects. Through quality user engagement, we want the knowledge base to evolve and become the focal point for AOP development and dissemination. Our next step is to integrate the wiki with the other AOP KB modules in development:

  • AOP Xplorer
    A graphic computer module that will allow scientists worldwide to create graphics that highlight how several different AOPs might interconnect and adversely affect the same biological system. (Expected release later this year.)
  • Intermediate Effects Database
    Will host chemical-related data derived from non-traditional methods.
  • Effectopedia
    Will bring together scientists and studies from different disciplines to share data about different species and biological organization, chemical exposure routes and durations, and much more.

With these tools, we are taking strides toward connectingthe sequence of events that unfold after chemical interaction sparks changes on the molecular level of a biological system, and cascades on until an adverse health outcome. The Advanced Outcome Pathway Wiki is a collaborative effort of the EPA, the OECD, the international scientific community, the European Joint Research Center, and the U.S. Army Corp of Engineers. For more information on this project, please see our fact sheet.

About the Author: EPA systems biologist Stephen Edwards is developing a framework to improve the scientific underpinnings of the Agency’s human and ecological risk assessments. He serves as a senior Agency advisor on the development of predictive toxicology models of disease using genomics, proteomics, and metabolomics.

Editor's Note: The opinions expressed here are those of the author. They do not reflect EPA policy, endorsement, or action.

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Education Outreach: Fun for All!

By Maureen Gwinn, Ph.D., DABT

Since 2007, the Girl Scouts Council Nation’s Capital Chapter has organized a Girl Scout Science Day to give local Girl Scouts an opportunity to learn more about science in a fun and friendly environment. 

I first became involved as a friend of the troop leader in charge of the event.  She and I would work on ideas, adapt experimental protocols and talk our science friends into volunteering at the event. 

EPA's Maureen Gwinn: "I enjoy every opportunity I have to encourage kids to have fun with science."

From the beginning, experiments have been led by Cadette or Senior Girl Scouts with the assistance of volunteers, including troop ‘moms’ and ‘dads’ and area scientists. We have hands-on experiments that address concepts of chemistry, microbiology, genetics, and toxicology.  We have had discussions related to what goes into your personal hygiene products, why DNA is unique to each of us, and how forensic science can help to solve a crime.

The Cadette and Senior Girl Scouts running the experiments at a recent event were the 4th graders who participated five years ago.  It has been a pleasure to see these girls not only learn the scientific concepts well enough to teach them to the new Brownie and Junior Girl Scouts, but to watch them take on more responsibility for the event itself.  Through my involvement in this event, I have been privileged to watch those young, giggly ten-year-old girls turn into responsible young ladies – that still giggle, but do so while teaching or setting up for the next group of girls. 

This event inspired me to volunteer in education outreach at other events, including the Society of Toxicology Annual meeting, EPA’s Earth Day celebrations, and the USA Science & Engineering Festival

Volunteering in education outreach was not something I had considered in the past, but after participating in the Girl Scout Science Day for the past five years, I enjoy every opportunity I have to encourage kids to have fun with science, to ask questions about how things work, and to work together to solve scientific problems. 

The Society of Toxicology Education Committee has ways to help support these types of opportunities, and for K-12 in particular we are putting together a website of ideas, experiments, and how-to’s to get you started in the new year. 

Are you interested in getting involved in education outreach, but don’t know where to start? Or are you already involved and have some tips or favorite resources to share? Please post your questions or suggestions in the comments section below so we can join forces.

The impact these events have on the kids is worth the effort. 

About the Author:  Maureen Gwinn is a biologist in EPA’s National Center for Environmental Assessment and works as an Associate National Program Director for Sustainable and Healthy Communities.  She is currently serving in her final year as the K-12 Subcommittee Chair for the Society of Toxicology and is always looking for ideas for scientific outreach.

Editor's Note: The opinions expressed here are those of the author. They do not reflect EPA policy, endorsement, or action.

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