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Long-Term Goal 1-11: Research Description
Back to Long-Term Goal 1 (LTG 1):
Research Descriptions and Posters
Title: Systems Biology and Toxicity Testing in the Twenty-first Century
Presenters: Stephen Edwards (NHEERL) and Jerry Blancato (NCCT)
Contributors: Michael DeVito (NHEERL), Hisham El-Masri (NHEERL), Imran Shah (NCCT), Rory Conolly (NCCT), Tox21 MOU Participants (NCCT, NHEERL), Integrated Toxicology Working Group (NHEERL)
Science Questions:
- How do we measure, model, and predict the key attributes of the MOA that could impact risk assessment?
- How do we get better and more detailed understanding of MOA at various scales and address the associated uncertainty in a shorter time frame than traditional methods have allowed?
- How do we incorporate in vitro data into future toxicity testing in a way that will support risk assessment?
- How can 'omics' approaches be used in the context of quantitative risk assessments?
The Research:
The overall goals of the ORD systems biology efforts are to incorporate data regarding mode of action (MOA) into quantitative models for predicting risk and to apply new technologies for genome-wide measurements to elucidate and evaluate the MOA. This effort addresses many of the issues raised in the 2007 NRC report on toxicity testing in the 21st century (NRC 2007). In response to this report, the EPA has entered into a memorandum of understanding (Collins, Gray et al. 2008) with the National Human Genome Research Institute and the National Toxicology Program to jointly pursue ways to incorporate high throughput methods into hazard identification and risk assessment. In collaboration with these organizations, ORD researchers are coordinating animal, human, and in vitro studies with computational methods for data analysis and modeling to establish a path forward. Five major strategic goals have been defined (FTTW 2008):
1. Toxicity pathway identification and assay development
2. Chemical prioritization
3. Toxicity pathway knowledgebases
4. Virtual tissues, organs, and systems: linking exposure, dosimetry, and response
5. Human evaluation and quantitative risk assessment.
For implementation, human health research within ORD, augmented by direct computational toxicology (Kavlock, Ankley et al. 2008) support for the NCCT, can be categorized as four main efforts all of which are supported by and contribute to toxicity pathway knowledgebases.
1. Toxicity pathway identification
2. Toxicity pathway interrogation for chemical prioritization and hazard identification
3. Development of virtual tissue models
4. Targeted testing and mode of action based risk assessment
There is heavy emphasis on toxicity pathway identification and interrogation as part of the NCCT Toxcast program, and the human health effort proposed here will seek to complement that NCCT effort by identifying key toxicity pathways associated with the mode of action for classes of chemicals of key regulatory importance. The human health projects will also seek to support the development of virtual tissues by generating the data required for defining the key parameters of these models as described in poster 01-12. To enable the use of toxicity pathway-based models in risk assessment, a research effort which quantitatively relates the in vitro toxicity pathway assays to in vivo apical endpoints is required. To this end, biologically-based dose-response models as described in poster 01-13 are being developed which use toxicity pathways as key events in the proposed mode of action. A targeted testing program is being initiated where in vivo laboratory animal and human data will be generated for key chemical classes to establish the quantitative relationship between in vitro toxicity pathway assay results and the in vivo parameter values. Finally, the usefulness of "Omics" technologies for defining and evaluating the mode of action and facilitating the development of quantitative models for that mode of action (Edwards and Preston 2008) is being tested in conjunction with all other efforts in this research area.
Impact and Outcomes:
- This research effort will integrate computational modeling and data generation to support the development of quantitative models for use in risk assessment.
- Toxicity pathways linked to key events in the mode of action for selected environmental chemicals will be defined. The assays associated with these pathways would then be available for use in Toxcast and Tox21 (Collins, Gray et al. 2008) screening.
- Predictions from Toxcast and Tox21 screening will be evaluated using secondary in vitro assays as well as in vivo studies in laboratory animals and humans.
- An implementation plan for toxicity pathway-based risk assessment within ORD will be developed and work initiated under that plan.
Key Products:
Collins, F. S., G. M. Gray, et al. (2008). "Toxicology. Transforming environmental health protection." Science 319(5865): 906-907.
Edwards, S. W. and R. J. Preston (2008). "Systems Biology and Mode of Action Based Risk Assessment." Toxicol Sci 106(2): 312-318.
Kavlock, R. J., G. Ankley, et al. (2008). "Computational toxicology--a state of the science mini review." Toxicol Sci 103(1): 14-27.
NRC (2007). "Toxicity Testing in the Twenty-first Century: A Vision and a Strategy."
Future of Toxicity Testing Workgroup (FTTW), Science Policy Council (2008). "Draft Strategic Plan for the Future of Toxicity Testing and Risk Assessment at the U.S. Environmental Protection Agency", U.S. EPA white paper currently under review.