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2007 CompTox Forum
Abstract - Towards the Virtual Human: Development of Three Dimensional Organ Models for Human Health Risk Assessment
Richard A. Corley, Ph.D.
Laboratory Fellow
Pacific Northwest National Laboratory
902 Battelle Boulevard, P.O. Box 999 MSIN P7 59, Richland, WA 99352
Phone: 509-376-8462
E-mail: rick.corley@pnl.gov
For the past two decades, biologically based dosimetry modeling has gained increased acceptance and use in the toxicology and risk assessment communities. With the tremendous growth in systems biology research, quantitative modeling of biological processes and the interactions between chemicals or drugs with cellular systems are now the subjects of intense research. However, to ultimately impact human health risk assessments, the advancements in modeling cellular responses must be integrated with whole organ and whole body models to relate exposures with internal target cell dose. Thus, for many applications, biologically based dose-response models must eventually address the reality that tissues and organs are spatially organized complexes of multiple cell types which can vary greatly across species, gender, stage of development or disease status. A classic example is the tremendous differences in architecture and thus responses of the respiratory systems of laboratory animals and humans to a variety of gases, vapors or airborne particulates. Fortunately, important technological advancements are taking place by collaborations between multiple scientific disciplines that are not normally associated with toxicology. These advances will greatly improve our ability to quantitatively describe the 3D structure and function of whole organ systems at unprecedented levels of detail and at a much more rapid pace than ever before. In our laboratory and the laboratories of several collaborators, a team of physicists, mathematicians, bioengineers, chemists, and biologists have been exploiting these advances to develop and validate 3D computational models of several organ systems of laboratory animals and humans. Our main area of emphasis has been with the respiratory system where we have built upon the work of Kimbell, Martonen, Tahwai, Plopper, Harkema, and other pioneers to develop 3D models of the respiratory tracts of rats, mice, rabbits, monkeys, and humans. To do so, we have developed magnetic resonance imaging approaches for elucidating the architecture and tissue mechanics of respiratory airways under both normal and disease conditions, image processing tools for feature recognition and analysis, meshing algorithms and codes for computational fluid dynamics simulations of airflows, and Lagrangian particle tracking codes for particle or drug delivery. Imaging and mass spectrometry approaches have also proven useful for validating localized airflows and gas, vapor, and particle dosimetry simulations. We have also begun development of a multi-scale computational model of the heart that will eventually link cardiovascular with respiratory function. For both organ systems, part of the effort involves the organization and distribution of cell phenotypes, and eventually cell-specific genomic, proteomic and metabolic data, into a geometric atlas to elucidate the spatial connection among disease states, cellular pathways, and environmental exposures. Although many technical challenges remain, extending the organ-specific models to the cellular level will provide a framework for incorporating advances in systems biology and facilitate our quantitative understanding of environment-disease interactions. Likewise, integrating models across organs holds the promise for taking systems biology to a new level, the whole body, where arguably it belongs. Supported by NHLBI RO1 HL073598-01; NIEHS P01 ES011617; Arysta Life Sciences; DOE LDRD; Battelle IR&D.