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Pages 1-10

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From page 1...
... As a result, the Human Genome Project and the technologic innovations and computational tools that it spawned are having profound effects on biologic research and understanding. The application of these technologies to toxicology has ushered in an era when genotypes and toxicant-induced genome expression, protein, and metabolite patterns can be used to screen compounds for hazard identification, to monitor individuals' exposure to toxicants, to track cellular responses to different doses, to assess mechanisms of action, and to predict individual variability in sensitivity to toxicants.
From page 2...
... , to examine the potential impacts of toxicogenomic technologies on predictive toxicology. NIEHS has invested significant resources in toxicogenomic research through establishment of the National Center for Toxicogenomics, funding of the National Toxicogenomics Research Consortium, development of the Chemical Effects in Biological Systems database for toxicogenomic data, and other collaborative ventures.
From page 3...
... Studies supporting each of these putative applications were then critically evaluated to define limitations, to enumerate remaining challenges, and to propose viable solutions whenever possible. Finally, the committee outlined realistic expectations of how these applications can be validated and how they can be used in risk assessment.
From page 4...
... develop and expand research programs dedicated to integrating toxicogenomics into challenging risk assessment problems, including the development of partnerships between the public and private sectors. Need for a Human Toxicogenomics Initiative Several themes emerged throughout evaluation of the different applications discussed below, including the need for more data, the need to broaden data collection, the need for a public database to facilitate sharing and use of the volumes of data, and the need for tools to mine this database to extract biologic knowledge.
From page 5...
... The information generated from toxicogenomic experiments is on a scale vastly exceeding DNA sequencing efforts like the Human Genome Project. The heft of these outputs, consisting of multidimensional datasets that include genotype, gene expression, metabolite, and protein information; design factors such as dose, time, and species information; and information on toxicologic effects warrant the creation of a public database.
From page 6...
... The resulting publicly accessible HTGI data resource would strengthen the utility of toxicogenomic technologies in toxicity assessment and thus enable more accurate prediction of health risks associated with existing and newly developed compounds and formulations. SPECIFIC APPLICATIONS OF TOXICOGENOMICS To address the expectation that toxicogenomics will revolutionize predictive toxicology, the committee explored several proposed applications of toxicogenomics, including hazard screening, the study of toxicologic mechanisms of action, exposure assessment, and characterizing variability in susceptibility.
From page 7...
... The process of creating such a database could be accelerated by addressing proprietary and legal hurdles so at least some of the toxicogenomic data currently in private databases could be made available, and by integrating toxicogenomic assays into ongoing chemical screening and testing initiatives such as those conducted by the National Toxicology Program. In addition, regulatory agencies should continue to develop and refine guidance documents for their staff on interpreting toxicogenomic data.
From page 8...
... In addition, by providing molecular level comparisons between humans and other species, toxicogenomics may assist in identifying those animal species and strains that are most relevant for specific assays. Toxicogenomics should continue to be used to study differences in toxicant responses between animal models and humans, and genotyped and genetically altered animal model strains should continue to be used as experimental tools to better extrapolate results from animal tests to human health.
From page 9...
... It is unlikely that toxicogenomic signatures will be able to decipher all interactions among complex mixtures, but it should be possible to use mechanism-of-action data to design informative toxicogenomic experiments, including screening chemicals for potential points of biologic conversion (overlap) such as shared activation and detoxification pathways, enhancing identification and exploration of potential interactions, and moving beyond empirical experiments.
From page 10...
... CONCLUSIONS In summary, toxicogenomic technologies present a set of powerful tools for transforming current observation-based approaches into predictive science, thereby enhancing risk assessment and public health decision making. To leverage this potential will require more concerted efforts to generate data, make multiple uses of existing data sources, and develop tools to study data in new ways.


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