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High-throughput PBPK and Microdosimetry: Cell-level Exposures in a Virtual Tissue Context (WC9)
Citation:
Wambaugh, J. High-throughput PBPK and Microdosimetry: Cell-level Exposures in a Virtual Tissue Context (WC9). Presented at 9th World Congress on Alternatives to Animal Testing, Prague, CZECH REPUBLIC, August 24 - 29, 2014. https://doi.org/10.23645/epacomptox.5082448
Impact/Purpose:
Abstract to be presented at the 9th World Congress on Alternatives to Animal Testing Prague Czechoslovakia, August 26, 2014
Description:
Toxicokinetic (TK) models can determine whether chemical exposures produce potentially hazardous tissue concentrations. Tissue microdosimetry TK models relate whole-body chemical exposures to cell-scale concentrations. As a proof of concept, we approximated the micro-anatomic architecture of the hepatic lobule with a discrete topology by a graphical model that can be connected to a chemical-specific physiologically-based TK (PBTK) model. The development of traditional PBTK models is time and resource intensive. Successful methods have been developed for pharmaceutical compounds to determine TK from limited in vitro measurements and chemical structure-derived property predictions. These high throughput (HT) TK methods provide a more rapid and less resource–intensive alternative to traditional TK model development. We have augmented these in vitro data with chemical structure-based descriptors and mechanistic tissue partitioning models to construct HTPBPK models for over three hundred environmental and pharmaceutical chemicals. When evaluated with human in vivo data for 74 chemicals we find that we can generally predict when HTPBPK models will perform well, and when more complicated effects (e.g., transporters) impact HTPBPK assumptions. For those chemicals where the assumptions that allow HTPBPK models are appropriate, virtual tissue simulation of quantitative chemical-specific effects is possible. This abstract does not necessarily reflect Agency policy.
URLs/Downloads:
DOI: High-throughput PBPK and Microdosimetry: Cell-level Exposures in a Virtual Tissue Context (WC9)
WC9-THEMEI-1-VIRTUALTISSUES-WAMBAUGH-043014 ABSTRACT.PDF (PDF, NA pp, 62.359 KB, about PDF)
WC9 - WAMBAUGH - PBPK AND MICRODOSIMETRY.PDF (PDF, NA pp, 2314.88 KB, about PDF)