Environmental Factor, March 2007, National Institute of Environmental Health Sciences
LPC/ LMT Guest Lecturer on Genomics and Risk Assessment
By Eddy Ball
Guest Lecturer Rusty Thomas, Ph.D., spoke to a standing-room-only audience of NIEHS scientists on January 25 in F-193. The talk, sponsored jointly by the Laboratory of Pharmacology and Chemistry (LPC) and the Laboratory of Molecular Toxicology (LMT), addressed an important question, "Chemical Risk Assessment Improvement: Can Genomic Tools Provide More Power?"
Thomas is the Director of the Functional Genomics Research Program and the Gene Expression Core at The Hamner Institutes for Health Sciences in Research Triangle Park. NIEHS Director of the Office of Risk Assessment Research Chris Portier, Ph.D., sponsored the lecture.
In his talk, Thomas reported on The Hamner Institute's progress in using genomic tools to assess health risks from chemical exposure. "Both the risk assessment community and the toxicology community have really been struggling over the past few years with how to apply these new tools...," he explained, "and how to get the most out of them in terms of hazard identification, dose response assessment and trying to predict some of the more complex endpoints that we see after chemical exposure." In response to these challenges, the American Chemistry Council funded a series of projects to examine how best to apply genomic tools to environmental health and risk assessment.
The process of chemical risk assessment can be broken down into a series of steps that include hazard identification and dose response assessment. In the first project, Thomas looked to apply genomic tools to the hazard identification step. Part of the hazard identification stage involves determining which chemicals pose significant risks of causing long-term health effects, such as cancer.
Thomas explained that, currently, the National Toxicology Program (NTP) rodent cancer bioassay is considered by most toxicologists the gold standard for assessing the carcinogenic potential of chemical agents, but each rodent cancer bioassay is extremely expensive, costing from two to four million dollars per chemical.
Because of the cost and the length of time involved, investigators have been able to test only about 1,500 of the over 80,000 chemicals on the Environmental Protection Agency's Toxic Substance Control Act inventory.
In his studies, Thomas attempted to identify genomic biomarkers that could predict mouse lung tumor formation in a two-year rodent cancer bioassay after a 90-day exposure. Thomas exposed mice to a diverse set of 13 chemicals previously tested by the NTP. These chemicals included seven lung carcinogens and six non-carcinogens. Thomas was able to predict lung tumor formation with an overall accuracy of nearly 94 percent using gene expression changes in a select group of informative genes. This study suggested that it is possible to predict the long-term health effects of a chemical using the gene expression changes following a short-term exposure.
In the second project, Thomas applied genomic tools in order to understand better the underlying signaling pathways involved in the toxicologic response, using cell-based screens to identify novel modulators of selected signaling pathways. By first constructing luciferase or fluorescent protein reporters to indicate when a particular pathway is turned on, Thomas was able to specify the novel modulators involved. Robotic systems individually screened thousands of full-length genes and small interfering (si) RNA duplexes to identify which genes, when over-expressed or knocked-out inside the cell, alter the signaling of the pathway of interest.
By identifying these novel modulators and performing additional follow-up studies, Thomas is seeking to determine what molecular targets may be involved in the pathway, the overall logic of the cell signaling network, the potential shape of the dose-response curve and the degree to which this response is conserved across species. The Hamner Institute maintains a full-length gene library that contains approximately 15,000 genes and a large inhibitory RNA library that contains synthetic siRNA duplexes that target the known kinases, phosphatases and G-protein coupled receptors.
In the conclusion to his talk, Thomas readily conceded that his work is still in its infancy and that he has yet to fully answer the question posed in the title of his lecture. However, Thomas has seen enough promising data in his preliminary studies to keep working toward his goal - integrating genomic tools into toxicology and chemical risk assessment.