Simulating Microdosimetry in a Virtual Hepatic Lobule 英文参考文献.docVIP

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Simulating Microdosimetry in a Virtual Hepatic Lobule 英文参考文献.doc

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Simulating Microdosimetry in a Virtual Hepatic Lobule 英文参考文献

SimulatingMicrodosimetryinaVirtualHepaticLobule JohnWambaugh*,ImranShah NationalCenterforComputationalToxicology,OfficeofResearchandDevelopment,U.S.EnvironmentalProtectionAgency,ResearchTrianglePark,NorthCarolina,United StatesofAmerica Abstract The liver plays a key role in removing harmful chemicals from the body and is therefore often the first tissue to suffer potentiallyadverseconsequences.Toprotectpublichealthitisnecessarytoquantitativelyestimatetheriskoflong-term lowdose exposuretoenvironmentalpollutants. Animaltestingis theprimarytoolforextrapolating humanrisk butitis fraughtwithuncertainty,necessitatingnovelalternativeapproaches.Ourgoalistointegrateinvitroliverexperimentswith agent-based cellular models to simulate a spatially extended hepatic lobule. Here we describe a graphical model of the sinusoidal network that efficiently simulates portal to centrilobular mass transfer in the hepatic lobule. We analyzed the effectsofvasculartopologyandmetabolismonthecell-leveldistributionfollowingoralexposuretochemicals.Thespatial distribution of metabolically inactive chemicals was similar across different vascular networks and a baseline well-mixed compartment.Whenchemicalswererapidlymetabolized,concentrationheterogeneityoftheparentcompoundincreased across the vascular network. As a result, our spatially extended lobule generated greater variability in dose-dependent cellularresponses,inthiscaseapoptosis,thanwereobservedintheclassicalwell-mixedliverorinaparalleltubesmodel. Themass-balancedgraphicalapproachtomodelingthehepaticlobuleiscomputationallyefficientforsimulatinglong-term exposure,modularforincorporatingcomplexcellularinteractions,andflexiblefordealingwithevolvingtissues. Citation:WambaughJ,ShahI(2010)SimulatingMicrodosimetryinaVirtualHepaticLobule.PLoSComputBiol6(4):e1000756.doi:10.1371/journal.pcbi.1000756 Editor:DanielA.Beard,MedicalCollegeofWisconsin,UnitedStatesofAmerica ReceivedNovember22,2009;AcceptedMarch23,2010;PublishedApril22,2010 Thisisanopen