By National Research Council, Division on Earth and Life Studies, Board on Environmental Studies and Toxicology, Standing Committee on Risk Analysis Issues and Reviews, Ellen Mantus
In 2007, the nationwide examine Council predicted a brand new paradigm during which biologically vital perturbations in key toxicity pathways will be evaluated with new tools in molecular biology, bioinformatics, computational toxicology, and a entire array of in vitro checks dependent totally on human biology. even though a few thought of the imaginative and prescient too confident with recognize to the promise of the hot technological know-how, not anyone can deny revolution in toxicity trying out is less than approach. New methods are being constructed, and information are being generated. therefore, the U.S. Environmental safety organisation (EPA) expects a wide inflow of knowledge that might must be evaluated. EPA is also confronted with tens of hundreds of thousands of chemical compounds on which toxicity details is incomplete and rising chemical compounds and components that might desire possibility review and attainable law. as a result, the corporation requested the nationwide study Council to convene a symposium to stimulate dialogue at the program of the recent ways and knowledge in possibility overview. The symposium used to be hung on could 11-13, 2009, in Washington, DC, and incorporated shows and dialogue classes on pathway-based techniques for threat identity, purposes of latest methods to mode-of-action analyses, the demanding situations to and possibilities for threat review within the altering paradigm, and destiny instructions.
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Additional info for Toxicity Pathway-Based Risk Assessment: Preparing for Paradigm Change: A Symposium Summary
Bucher stated that toxicity pathways are the contents of the “black boxes” described by the modes of action and that key toxicity pathways will be identified with the help of toxicogenomic data and genetic-association studies that examine relationships between genetic alterations and human diseases. He contrasted toxicity pathways and mode of action: mode of action accommodates a less-than-complete mechanistic understanding, allows and requires considerable human judgment, and provides for conceptual cross-species extrapolation; toxicity pathways accommodate unbiased discovery, can provide integrated dose-response information, may allow more precise mechanistic “binning,” and can reveal a spectrum of responses.
Dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin [TCDD]) is a contaminant of Agent Orange—a herbicide used during the Vietnam War—that has been linked with numerous health effects. Some effects are characterized as antiproliferative, such as the antiestrogenic, antiandrogenic, and immunosuppressive effects; others are proliferative, such as cancer; and the remainder are characterized as effects on differentiation and development, such as birth defects. The effects of dioxin are primarily receptor-dependent.
Thomas concluded that pathway-based transcriptomic dose-response data can provide insights into the mode of action. In the third example, Thomas provided suggestions for using genomics data to conduct risk assessments. If the mode of action is known, transcriptional benchmark dose lower confidence limit (BMDL) values could be derived on the basis of responses in key pathways and the values could be used in the risk assessment. If the mode of action is not known, the challenge is to discriminate between “adverse” and “adaptive” changes.
Toxicity Pathway-Based Risk Assessment: Preparing for Paradigm Change: A Symposium Summary by National Research Council, Division on Earth and Life Studies, Board on Environmental Studies and Toxicology, Standing Committee on Risk Analysis Issues and Reviews, Ellen Mantus