Computational Toxicology

Superfund Research Program

The Superfund Research Program (SRP), in collaboration with the US Environmental Protection Agency's Office of Superfund Remediation and Technology Innovation (OSRTI), presented the Spring/Summer 2009 edition of Risk eLearning: "Computational Toxicology: New Approaches for the 21st Century." This series of online seminars provided an introduction to the key concepts of computational toxicology along with case studies demonstrating the utility of these approaches (e.g. high throughput screening, computer modeling, informatics) to risk assessment.

Session I: An Introduction to Key Concepts and Approaches

Seminar web page and archived recording (http://www.clu-in.org/conf/tio/comptox1_05280 9/)
Presented May 28, 2009; 1:30 - 3:30 pm EDT

• Introduction by Linda Birnbaum Ph.D., Director NIEHS.
• Presenter: Kim Boekelheide (http://biomed.brown.edu/facultydirectory/prof ile.php?id=1100923742) , Professor of Pathology and Laboratory Medicine, SRP-Brown University.
• Presenter: Robert Kavlock (http://www.epa.gov/ncct/biosketches/kavlock_b io.pdf)   , Director of the National Center for Computational Toxicology (NCCT/ORD/USEPA).

Dr. Boekelheide's presentation provided an overview of the 2007 National Academy of Sciences report on the future of toxicity testing (Toxicity Testing in the 21st Century: A Vision and a Strategy (http://dels.nas.edu/dels/rpt_briefs/Toxicity_ Testing_final.pdf)   ). As described in the report, toxicity testing in the future will utilize emerging technologies from the ongoing revolution in understanding biological processes to identify the effects of chemicals on toxicity pathways using in vitro approaches. The interpretation of chemically-induced alterations in toxicity pathways will depend upon sophisticated modeling that extrapolates from the measured dose-response in cell-based systems to human exposure.

Dr. Kavlock's presentation covered the rationale behind EPA's desire to develop more efficient and effective means for assessing the hazards and risks of environmental contaminants. Assisted by use of technology used in drug discovery, we are now able to evaluate the interaction of large numbers of chemicals against multiple biological targets at relatively low expense. The challenges are to ensure that there is coverage of sufficient biological processes, that the systems employ realistic exposure conditions, and that the new toxicology will be as health protective as existing traditional methods.

Session II: Dose Response Modeling

Seminar web page and archived recording (http://www.clu-in.org/conf/tio/comptox2_06240 9/)
Presented June 24, 2009; 1:30 - 3:30 pm EDT

• Moderator: Heather Henry, Ph.D., Program Administrator, Superfund Research Program.
• Presenter: Melvin Andersen (http://www.thehamner.org/translational-resear ch/scientists/melvin-andersen.html) , Ph.D., The Hamner Institutes for Health Sciences.
• Co-Presenters: Norbert Kaminski (http://cit.msu.edu/Faculty/Kaminski.html) , Ph.D., Director, Center for Integrative Toxicology; Professor, Pharmacology and Toxicology, Cell and Molecular Biology Program at Michigan State University, and Rory Conolly (http://www.epa.gov/ncct/biosketches/conolly_b io.pdf)   , Sc.D., Senior Research Biologist, National Center for Computational Toxicology, NCCT/ORD/USEPA.

Regional induction of CYP proteins within the liver by dioxin indicated a switching between basal and fully-induced cells. Some switches in transcriptional states were known for positive feedback controlled synthesis of transcriptional factors (Andersen and Barton, Toxicol. Sci., 48, 38-50, 1999); however, computational tools were not well developed for assessing the networks and dose response characteristics for network activation by transcriptional activation. With support from the Superfund Research Program, scientists in the Computational Core at the Hamner Institutes for Health Sciences developed a course in Computational Systems Biology and Dose Response Modeling to provide instruction on using computational approaches in studying gene transcriptional processes in order to assess likely dose response behaviors for non-linear control processes inherent in biological systems (see The Hamner website (http://www.thehamner.org/education-and-traini ng/current-course-offerings.html) ). The first presentation, by Melvin Andersen, Ph.D. The Hamner Institutes for Health Sciences, provided a background on dioxin induction of proteins in the liver and emphasized the tools that can be applied in assessing the circuitry and dose response for these and other processes.

The second presentation was a joint presentation by Norbert Kaminski, Ph.D., Director, Center for Integrative Toxicology; Professor, Pharmacology and Toxicology Cell and Molecular Biology Program and Rory Conolly, Sc.D., Senior Research Biologist, National Center for Computational Toxicology, NCCT/ORD/USEPA. This presentation provided a case study looking at the effects of dioxins on B cell function. The presenters highlighted their project within their Superfund Research Program grant that focuses on developing a computational description of the molecular signaling by which dioxins impair B cell differentiation and ultimately antibody responses. The presenters gave a background of B cell biology in the context of dioxins and dioxin like compounds and explained that dose-response is a function of biological mechanisms, computational models of these mechanisms improve the efficiency of research and provide the capability for prediction and emphasized the need for quantitative understanding of how TCDD-AhR interacts with AP-1 and other sites in the B cell differentiation program.

Session III: Chemical Prioritization / Rapid Assay Techniques

Seminar web page and archived recording (http://www.clu-in.org/conf/tio/comptox3_07070 9/)
Presented July 7th, 2009; 1:30 - 3:30 pm EDT

• Moderator: Raymond Tice, Ph.D., Chief, Biomolecular Screening Branch NIEHS/NTP.
• Presenter: Ivan Rusyn (http://www.unclineberger.org/research/faculty /displayMember.asp?ID=398) , Ph.D., Associate Professor, Department of Environmental Sciences & Engineering, University of North Carolina at Chapel Hill.
• Presenter: Richard Judson (http://www.epa.gov/ncct/biosketches/judson_bi o.pdf)   , Ph.D., Bioinformatician, National Center for Computational Toxicology, U.S. EPA.

The National Research Council's Toxicology in the 21st Century report is advocating for greater acceptance of the pathway-based toxicity testing conducted mostly in in vitro systems. Recent advances in science and technology do provide unique opportunities to probe normal physiology and disease biology to an unprecedented depth.  Ivan Rusyn, Ph.D., Associate Professor, Department of Environmental Sciences & Engineering, University of North Carolina at Chapel Hill, highlighted the tools and techniques that enable pathway-based toxicity testing and considers the challenges and opportunities that new science brings to the practice of toxicology.

For the second presentation Richard Judson, Ph.D., Bioinformatician, National Center for Computational Toxicology, U.S. EPA, gave an overview of ACToR.  ACToR (Aggregated Computational Toxicology Resource) is a collection of databases collated or developed by the US EPA National Center for Computational Toxicology (NCCT). More than 200 sources of publicly available data on environmental chemicals have been brought together and made searchable by chemical name and other identifiers, and by chemical structure. Data includes chemical structure, physico-chemical values, in vitro assay data and in vivo toxicology data. Chemicals include, but are not limited to, high and medium production volume industrial chemicals, pesticides (active and inert ingredients), and potential ground and drinking water contaminants.

Session IV: Computational Toxicology: ToxCast and the Comparative Toxicogenomics Database (CTD)

Seminar web page and archived recording (http://www.clu-in.org/conf/tio/comptox4_09090 9/)
Presented September 9th, 2009; 2:00 - 4:00 pm EDT

• Moderator: Owen Hughes, Ph.D., NIEHS grantee and President, Eon Corporation (http://eonresearch.com/default.aspx) .
• Presenter: David J. Dix (http://epa.gov/ncct/biosketches/dix_bio.pdf)   , Ph. D., Acting Deputy Director of EPA/ORD's National Center for Computational Toxiclolgy.
• Presenter: Carolyn Mattingly (http://www.maineidea.net/Research/CarolynMatt ingly.html) , Ph.D., NIEHS grantee and Mount Desert Island Biological Laboratory Investigator.

Dr. David J. Dix, Acting Deputy Director of EPA/ORD’s National Center for Computational Toxicology (http://www.epa.gov/ncct/) presented “ToxCast - Screening and Prioritization of Environmental Chemicals Based on Bioactivity Profiling and Predictions of Toxicity.”   The objective of EPA's ToxCast research program is to develop a cost-effective and rapid approach for screening and prioritizing a large number of chemicals for further toxicological testing. Using data from high throughput screening (HTS) bioassays, ToxCast is generating data, constructing databases, building computational models and prioritization tools based on the potential human toxicity of chemicals.  These hazard predictions will provide EPA regulatory programs with science-based information helpful in prioritizing chemicals for more detailed toxicological evaluations, ultimately leading to more intelligent targeted testing.

NIEHS grantee and Mount Desert Island Biological Laboratory investigator, Dr. Carolyn Mattingly, presented “The Comparative Toxicogenomics Database: A resource for predicting chemical-gene-disease networks.”  The etiology of many chronic diseases involves interactions between the environment and genes that modulate biological processes.  The Comparative Toxicogenomics Database (CTD) (http://ctd.mdibl.org) ; promotes understanding about the underlying mechanisms of environmental diseases by providing curated data describing relationships between chemicals, genes/proteins, and human diseases.  Coupled with custom analysis tools, these data provide the foundation for predicting novel chemical-gene-disease networks.

For more information, contact:

Heather Henry (919) 541-5330 (henryh@niehs.nih.gov) or
Justin Crane (919) 794-4702 (cranej2@niehs.nih.gov)