ICH遗传毒性指导原则S2(R1)修订要点及相关背景介绍

ChineseJournalofNewDrugs20132221462013222国家“十二五”重大专项基金资助项目(2012ZX09505-001-003)张铭，男，硕士研究生，毒理学专业。联系电话:[phone]，E-mail:[e-mail]。黄芳华，女，从事新药审评工作。联系电话:[phone]，E-mail:[e-mail]。··ICHS2R11211212012032100038ICHS2R1201111。S2R1。ICHS2R1R968A1003－3734201302－0146－05MajorrevisionpointsandbackgroundintroductionofICHguidanceongenotoxicitytestS2R1ZHANGMing1HUANGFang-hua2ZHOUChang-hui1CHANGYan1WANGQing-li21ChinaStateInstituteofPharmaceuticalIndustryNationalShanghaiCenterforNewDrugSafetyEvaluation＆ResearchShanghai201203China2CenterforDrugEvaluationStateFoodandDrugAdministrationBeijing100038ChinaAbstractICHguidanceongenotoxicitytestS2R1wasissuedinNovember2011whichisareferenceforChinesegenetictoxicologyresearchers．ThemajorrevisionpointsoftheS2R1andsomenewmethodsandtechniqueswerereviewedinthisarticle．KeywordsgenotoxicityassayICHS2R1majorrevisionpoints19951997InternationalConferenceonHarmoniza-tionofTechnicalRequirementsforRegistrationofPhar-maceuticalsforHumanUseICHS2AGuidanceonSpecificAspectsofRegu-latoryGenotoxicityTestsforPharmaceuticals、S2BGenotoxicityAStandardBatteryforGenotoxicityTestingforPharmaceuticalsOECDOrganizationforEconomicCo-operationandDevelopment10。、、。。Kirkland1－2MutationResearch2。ICH20066、201111ICHICH、、。。ChineseJournalofNewDrugs20132221472013222。1ICHS2R1S2AS2B。2S2R132。①。②tk。③。①。②/。33．1AmesAmes2070、、、。Gatehouse1994mutationresearchAmes。OECD1997Ames。。。Ames。3．23．2．1。10mmol·L－15mg·mL－11mmol·L－10．5mg·mL－1。200。。。S2B50%。。Greenwood4DNA。DNA。S2R150%。MLA80%～90%20%～10%。3．2．22007ECVAMEuropeanCentrefortheValidationofAlternativeMethodsCorvi5。。OECD20106TG487OECD。3．2．3。。。44．1。ICH。ChineseJournalofNewDrugs20132221482013222、。4．1．12070、。、。7－920000/。FDA。10－13。S2R1。4．1．2、。14－16。6201222012830OECD20129。4．1．317。BigBlueMutaMouse。OECD20117TG488。。4．1．4、DNADNA。。。Pig-aPig-a＜5×10－618＜100μL、、。19OECD。/Pig-a“”。4．22006FDA20。2009IWGTInternationalWorkshoponGenotox-icityTesting21。S2R13R。。S2R1。、UDSOECDChineseJournalofNewDrugs20132221492013222OECD、、OECD。24～48h2～6h。3d0～24h。OECD3d0～40h。4．3。。。GLP。5ICHOECD、。。。1KIRKLANDDAARDEMAMHENDERSONLetal．Evalua-tionoftheabilityofabatteryofthreeinvitrogenotoxicityteststodiscriminaterodentcarcinogensandnon-carcinogens．I．Sensitiv-ityspecificityandrelativepredictivityJ．MutatRes20055841－21－256．2KIRKLANDDAARDEMAMMULLERLetal．Evaluationoftheabilityofabatteryofthreeinvitrogenotoxicityteststodis-criminaterodentcarcinogensandnon-carcinogensII．Furthera-nalysisofmammaliancellresultsrelativepredictivityandtumourprofilesJ．MutatRes2006608129－42．3ICH．GuidanceongenotoxicitytestinganddatainterpretationforpharmaceuticalsintendedforhumanuseEB/OL．2011－11－09．http//．ich．org/products/guidelines/safety/article/safety-guidelines．html．4GREENWOODSKHILLRBSUNJTetal．Populationdou-blingAsimpleandmoreaccurateestimationofcellgrowthsup-pressionintheinvitroassayforchromosomalaberrationsthatre-ducesirrelevantpositiveresultsJ．EnvironMolMutagen200443136－44．5CORVIRALBERTINISHARTUNGTetal．ECVAMRetro-spectivevalidationoftheinvitromicronucleustestMNTJ．Mutagenesis2008234271－283．6OECD．TestGuideline487Invitromammaliancellmicronucle-ustestEB/OL．2010－07－23．http//．oecd．org．7DERTINGERSDBISHOPMEMCNAMEEJPetal．Flowcy-tometricanalysisofmicronucleiinperipheralbloodreticulocytesI．Intra-andinter-laboratorycomparisonwithmicroscopicscoringJ．ToxicolSci200694183－91．8MACGREGORJTBISHOPMEMCNAMEEJPetal．Flowcytometricanalysisofmicronucleiinperipheralbloodreticulo-cytesII．AnefficientmethodofmonitoringchromosomaldamageintheratJ．ToxicolSci200694192－107．9HAYASHIMMACGREGORJTGATEHOUSEDGetal．Invivorodenterythrocytemicronucleusassay．II．SomeaspectsofprotocoldesignincludingrepeatedtreatmentsintegrationwithtoxicitytestingandautomatedscoringJ．EnvironMolMuta-gen2000353234－252．10WAKATAAMIYAMAEYSATOSetal．Evaluationoftheratmicronucleustestwithbonemarrowandperipheralbloodsummaryofthe9thcollaborativestudybyCSGMT/JEMS．MMSJ．EnvironMolMutagen199832184－100．11HAMADAS．SUTOUSMORITATetal．Evaluationoftherodentmicronucleusassaybya28-daytreatmentprotocolsum-maryofthe13thcollaborativestudybythecollaborativestudygroupforthemicronucleustestCSGMT/Environmentalmuta-gensocietyofJapanJEMS-mammalianmutagenicitystudygroupMMSJ．EnvironMolMutagen200137293－110．12HAYASHIMMACGREGORJTGATEHOUSEDGetal．Invivoerythrocytemicronucleusassay．III．Validationandregulato-ryacceptanceofautomatedscoringandtheuseofratperipheralbloodreticulocyteswithdiscussionofnon-hematopoietictargetcellsandasingledose-levellimittestJ．MutatRes2007627110－30．182ChineseJournalofNewDrugs201322218220132226BAROLIBENNASMGLOFFREDOFetal．Penetrationofmetallicnanoparticlesinhumanfull-thicknessskinJ．JInvestDermatol200712771701－1712．7SHEIHETALCHANDRAPBATHEJAPetal．Tyrosined-erivednanospheresforenhancedtopicalskinpenetrationJ．IntJPharm20083501－2312－319．8KIMKPARKDSLUHMetal．AtaperedhollowmetallicmicroneedlearrayusingbacksideexposureofSU-8J．JMicro-mechanicsMicroengineering2004144597－603．9TAKAYAMYOSHIKAZUTTAKAHIROKetal．SugarMi-croNeedlesasTransdermicDrugDeliverySystemJ．Biomedic-alMicrodevices200573185－188．10ITOYHAGIWARAEJSAEKIAetal．Feasibilit