Additive Mixture Effects of Estrogenic Chemicals in Human Cell-Based Assays Can Be Influenced by Inclusion of Chemicals with Differing Effect Profiles 英文参考文献.docVIP

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Additive Mixture Effects of Estrogenic Chemicals in Human Cell-Based Assays Can Be Influenced by Inclusion of Chemicals with Differing Effect Profiles 英文参考文献.doc

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Additive Mixture Effects of Estrogenic Chemicals in Human Cell-Based Assays Can Be Influenced by Inclusion of Chemicals with Differing Effect Profiles 英文参考文献

AdditiveMixtureEffectsofEstrogenicChemicalsin HumanCell-BasedAssaysCanBeInfluencedbyInclusion ofChemicalswithDifferingEffectProfiles RichardMarkEvans*,MartinScholze,AndreasKortenkamp InstitutefortheEnvironment,BrunelUniversity,Uxbridge,Middlesex,UnitedKingdom Abstract Agrowingbodyofexperimentalevidenceindicatesthattheinvitroeffectsofmixturesofestrogenicchemicalscanbewell predictedfromtheestrogenicityoftheircomponentsbytheconcentrationaddition(CA)concept.However,somestudies haveobservedsmalldeviationsfromCA.Factorsaffectingthepresenceorobservationofdeviationscouldinclude:thetype ofchemicaltested;numberofmixturecomponents;mixturedesign;andassaychoice.Wedesignedmixtureexperiments that address these factors, using mixtures with high numbers of components, chemicals from diverse chemical groups, assayswithdifferentinvitroendpointsanddifferentmixturedesignsandratios.Firstly,theeffectsofmixturescomposedof upto17estrogenicchemicalswereexaminedusingestrogenicityassayswithreporter-gene(ERLUX)andcellproliferation (ESCREEN)endpoints.Twomixturedesignswereused: 1)a‘balanced’designwithcomponentspresentinproportionto acommoneffectconcentration(e.g.anEC10)and2)a‘non-balanced’designwithcomponentsinproportiontopotential humantissueconcentrations.Secondly,theindividualandsimultaneousabilityof16potentialmodulatorchemicals(each withminimalestrogenicity)toinfluencetheassayoutcomeproducedbyareferencemixtureofestrogenicchemicalswas examined. Test chemicals included plasticizers, phthalates, metals, PCBs, phytoestrogens, PAHs, heterocyclic amines, antioxidants,UVfilters,musks,PBDEsandparabens.Inallthescenariostested,theCAconceptprovidedagoodprediction ofmixtureeffects.Modulationstudiesrevealedthatchemicalspossessingminimalestrogenicitythemselvescouldreduce (negativelymodulate)theeffectofamixtureofestrogenicchemicals.Whetherthetypeofmodulationweobservedoccurs inpracticemostlikelydependsonthechemicalconcentrationsinvolved,andbetterinformationisrequiredonlikelyhuman tissue concentrations o