Two major areas of emerging research and policy relevant to -omics, bioinformatics, and computational toxicology are their applications in drug product development and safety, and in predictive toxicology for the hazard and risk assessment of chemicals, pesticides, and consumer products.
The US FDA's Critical Path Initiative was devised to stimulate scientific innovation in the development and evaluation of FDA-regulated products (drugs, biologicals, medical devices). The Critical Path Opportunities List provides "examples of how new scientific discoveries—in fields such as genomics and proteomics, imaging, and bioinformatics—could be applied during medical product development to improve the accuracy of the tests used to predict the safety and efficacy of investigational medical products."
The FDA's National Center for Toxicological Research (NCTR) has a Center for Toxicoinformatics, the objectives of which are to:
- Conduct research in bioinformatics and chemoinformatics
- Develop and coordinate informatics capabilities within NCTR, the FDA, and the toxicology community
- Develop methods for analysis and integration of omics databases for knowledge discovery and the study of mechanisms of toxicity
The FDA is collaborating with pharmaceutical companies to devise liver toxicogenomic approaches for screening drugs candidates in preclinical studies. Challenges encountered with toxicogenomics approaches include the limited experience with this technology, the limited correlation between the induced RNAs and the protein response, the limited robustness of the protocols, and the limited reproducibility of these systems.
Seven pharmaceutical companies are working together as a consortium and consulting with the FDA to develop toxicogenomic tests to predict human liver toxicity and other side effects from drugs (Reinberg, 2007). The consortium is identifying genetic markers or variations in human DNA that indicate drug-induced adverse effects such as liver toxicity. These markers can then be developed into genetic tests to determine a person's specific risk before taking a drug, a new development known as personalized safety (echoing the field of personalized medicine). The findings will be public domain, so that all companies can use the results in developing safer drugs.
Another approach, cellular phenotyping, is being developed to analyze gene function and drug action at the cellular level. DNA microarrays have been successful in mapping changes in gene expression. Cellular phenotyping extends this technology to evaluating changes in the cell at the level of protein expression by using RNA interference (RNAi) to study genome-scale loss-of-function. Cenix Bioscience has developed a proteome-level profiling technique based on "broad, quantitative surveys of protein levels in RNAi- and drug-treated cells using antibody-independent, mass spectrometry-based analyses." Another RNAi approach in cells based on antibody detection was used to develop a high-throughput assay to define signaling pathway regulation (Friedman & Perrimon, 2006).
The US EPA has several programs in place for the development and assessment of omics, bioinformatics, and computational biology data and tools for regulatory applications. The EPA's Interim Policy on Genomics (2002) states that genomics data may be submitted to the EPA for consideration in the decision-making process, but that these data alone are not sufficient. The document Potential Implications of Genomics for Regulatory and Risk Assessment Applications at EPA was developed by the EPA's Genomics Task Force in 2003-04 to stimulate discussion on the implications of genomics technologies to EPA programs and policies. In 2007, the draft Interim Guidance for Microarray-Based Assays was released for comment, and provides recommendations for quality assessment parameters, data assessment approaches, and the type of DNA microarray data that can be submitted as well as its management and storage.
The EPA developed a strategy document in 2003 to describe the agency's Computational Toxicology Research Program (CTRP), which defined computational toxicology as "the integration of modern computing and information technology, with molecular biology and chemistry to improve risk assessment and prioritization of data requirements of chemicals by the Agency." Objectives of this program are:
- "EPA risk assessors use improved methods and tools to better understand and describe linkages across the source to outcome paradigm"
- "EPA Program Offices use advanced hazard characterization tools to prioritize and screen chemicals for toxicological evaluation"
- "EPA risk assessors and regulators use new models based on the latest science to reduce uncertainties in dose-response assessment, cross-species extrapolation, and quantitative risk assessment"
The US EPA's National Center for Computational Toxicology sponsored an International Science Forum on Computational Toxicology in May 2007. This meeting brought together researchers and risk assessors for about 50 presentations on cutting edge research, computational tools, and their applications in hazard and risk assessment for environmental chemicals.
The US EPA's Toxcast™ Program was developed to prioritize chemicals for further evaluation of their potential toxicity using "state-of-the-art high-throughput screening (HTS), toxicogenomics, and computational chemistry tools...with elements specific to environmental toxicology."
Additional information on emerging research, methods, and policies pertaining to -omics, bioinformatics, and computational biology will be provided on AltTox.org in the future; please check back again.
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