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PBPK Models, BBDR Models, and Virtual Tissues: How Will They Contribute to the Use of Toxicity Pathways in Risk Assessment?
Citation:
CONOLLY, R., I. A. SHAH, AND T. B. KNUDSEN. PBPK Models, BBDR Models, and Virtual Tissues: How Will They Contribute to the Use of Toxicity Pathways in Risk Assessment? Presented at Symposium on Toxicity Pathway-Based Risk Assessment, Washington, DC, May 11 - 13, 2009.
Impact/Purpose:
This enhanced capability will help to identify (1) the doses or concentrations for in vitro studies that correspond to realistic levels of exposure in vivo, (2) relevant descriptions of the tissue dose-endpoint response continuum, and (3) will contribute to pathway-based assessment of specific biological processes and toxicities.
Description:
Accuracy in risk assessment, which is desirable in order to ensure protection of the public health while avoiding over-regulation of economically-important substances, requires quantitatively accurate, in vivo descriptions of dose-response and time-course behaviors. This level of detailed characterization is desirable when substances are economically-important or environmentally persistent. The NAS toxicity testing report emphasizes in vitro studies, with bioinformatics and systems modeling approaches used to predict in vivo behavior. PBPK and BBDR models and virtual tissues (VT) will all be important in these extrapolations. PBPK models describe the relationship between external exposure and target site dose. BBDR models extend PBPK models to include the linkage between target site dose, key events and endpoint effect. These mathematical models typically have compartments that correspond to whole tissues (e.g. liver, kidney, lung) and typically contain limited tissue-specific data. VT models such as EPA’s v-LiverTM and v-EmbryoTM projects are computational models that will encode sufficient biological information to support significant predictive capabilities, with higher-level behaviors emerging from the structures encoded at more fundamental levels of organization. PPBK, BBDR and VT models are thus complementary to one another, with each having the ability to facilitate the interpretation of in vitro data with respect to in vivo significance and predicting dosimetry at finer levels of biological detail. This enhanced capability will help to identify (1) the doses or concentrations for in vitro studies that correspond to realistic levels of exposure in vivo, (2) relevant descriptions of the tissue dose-endpoint response continuum, and (3) will contribute to pathway-based assessment of specific biological processes and toxicities.
URLs/Downloads:
PBPK Models, BBDR Models, and Virtual Tissues: How Will They Contribute to the Use of Toxicity Pathways in Risk Assessment? (PDF, NA pp, 11 KB, about PDF)PBPK Models, BBDR Models, and Virtual Tissues: How Will They Contribute to the Use of Toxicity Pathways in Risk Assessment? (poster) (PDF, NA pp, 197 KB, about PDF)