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Acute,subchronic,andchronictoxicityofachemicalcompoundcanAcute,subchronic,andchronictoxicityofachemicalcompoundcanbeevaluatedbyfivebasic?????Animaltestswithhigherorganisms(invivo)Testswithlowerorganisms(invivo)Testswithcellcultures(inComputercalculations(inEpidemiologicalHumanEpidemiologicalHumanexposuretoachemicalcompoundcan??Incidentalviaenvironment,occupation,orIntentional,forexample,withadrugorafoodEpidemiologicalStudyEpidemiologicalStudy?????AnalyticresearchEpidemiological––health-relatedstatesor?????Epidemiological––health-relatedstatesor????????GroupsofaffectedCauseofdeathResponsetoProvisionanduseofhealth–?????–inspecified???IdentifiableExamplesofspecificpopulationsPreciselydefinednumbersEpidemiologicalstudiescanbeclassifiedintofourCohortEpidemiologicalstudiescanbeclassifiedintofourCohortstudies（群體研究）duringwhichtheexposedindividualsareprospectivelyinvigilated??Clinicalstudiesofexposedindividualswhohaveanestablisheddiseasearecomparedwithcontrolsubjectsnothavingthis??IncidentalexposureCross-sectionalstudies（橫向研究）wherethespreadofthediseaseintheexposedgroupisstudied??PopulationEcologicalstudies（生態(tài)研究）,wheretheincidenceofdiseaseinacertaingeographicareainwhichtheexposuretotoxicantishighlyprobableiscomparedwiththeincidenceinanotherareapositivelyfreeofthis??FoodtoxicologicalAnimalMostoftheAnimalMostoftheknowledgeconcerningthetoxicityofasubstanceisobtainedfromanimalstudies.Thisinformation?Fortheriskassessmentandsafetyevaluationofadrugbeforethehuman?Forestimationofno-observedadverseeffect(NOAEL)valuesoffoodadditivesbeforetakeinto?ForriskassessmentofvariouschemicalsusedinindustryandintheGeneralprinciples:toGeneralprinciples:tofollowprinciplesofcareand??guidelinesandlawsandgovernment?USDA,theAnimalWelfareTwobasicTwobasicaxiomsindesigninganimalTheadverseeffectofatoxicantcanin“principle”beextrapolatedfromanimalstohumansSamedosageinmg/kgbw(humansare10timessensitivethanThebodyareaandtheunitForcalculationofbodyarea,WhereKisaspecies-specificfactor(9forrat,10.6forhumans),wisthebodyweightofthelaboratoryanimalinkgToTominimizethenumberofnecessarylaboratoryItisnecessarytohave30000laboratoryanimalstodetectcancerwithanincidenceof0.01%Therefore,hightoxicantdosesandextrapolationtosmalldosesareusedforthehumanriskassessmentoftoxicantinsmallanimalEquivalentToxicDosesfor4Animal2EquivalentToxicDosesfor4Animal2laboratoryanimalsandlaboratoryanimalsandextrapolationtoManytoxicantsarecapableofcausingseriousharmtoanorganism,notproducinganyadverseeffectAnimalsvs.AnimalsaresensitivetoPlantsaresensitivetoAnimalsvs.AnimalsaresensitivetoPlantsaresensitivetoNervous//Bloodand//Cell/ThevariabilityofThevariabilityoftoxicresponsecanbecauseddifferencesinthefunctioningofthebiochemicalpathwayofsulfonamides磺胺類resemblep-aminobenzoicacid(對基苯甲酸t(yī)heprecursoroffolicacid,soantagonizesynthesisoffolicacidinMostimportantdifferencesbetweenHumansandthewidelyusedlaboratoryanimalratAnatomical（解剖結(jié)構(gòu)Fastmultiplication（快速倍增ShortMostimportantdifferencesbetweenHumansandthewidelyusedlaboratoryanimalratAnatomical（解剖結(jié)構(gòu)Fastmultiplication（快速倍增ShortThecaseofAbsenceofthevomitingreflex（嘔吐反射DifferentneedsforvitaminandmineralsindependenceofascorbicacidinfoodNocturnalwayoflife（夜間生活方式Controlled/humidityinthecaseoftestInterstraindifferencesingenesisofspontaneoustumorsLiving Genetic Multiparous（多產(chǎn)的 Formationofα2γ-globulinin（球蛋白Drydiet Shortgestation/lactation(孕/哺乳期短 Presenceofudder（乳腺的存在Body Absenceofgallbladder（膽囊ThestructureofThestructureofanimaltoxicologicaltests?ThebiochemicalpropertiesoftheparticularOnitssupposedendOn??ThelaboratoryanimalsThelaboratoryanimalswereselectedbased??ThetypeofOnthepreliminaryinformationaboutthetoxicityofthecompoundtobetestedOntheethicalandfinancial?Inthestartingphaseofananimaltest,theapproximatetoxicitylevelInthestartingphaseofananimaltest,theapproximatetoxicitylevelofthetoxicdoseofacompoundshouldbedetermined.Usuallyacute/subchronic(28-or96-days),chronic(lifelong)testvitrotestsareAccordingtotheirAccordingtotheirsource,thetestanimalscandividedintothree?AnimalsobtainedfromwildpopulationoropencoloniesAnimalsderivedfromclosedAnimalsstemmingfromcoloniesobtainedbyCaesareansectionorembryotransplantation??Organism-independentfactorsinfluencingcompoundOrganism-independentfactorsinfluencingcompoundtoxicityThefollowingmaterialsisusableforestimationhumantoxicityofaparticularcompoundinaparticularsituation:???????DependenceonspeciesGeneticvariabilitiesGenericvariabilities（類屬差異）:DependenceonageDietaryconditionsHealthconditionsSimultaneouscontactwithseveralCellculturepreliminaryassessmentCellculturepreliminaryassessmentofits???UnscheduledDNAsynthesisUnscheduledDNAsynthesis?DNA DNAUnscheduledDNAsynthesis?DNA DNAdistinctfromthesemi-conservativereplicationofDNAwhichisconfinedtotheS-phaseoftheeukaryoticcellcycle(G1,S,G2andMphases).Detectedbyanelevatedincorporationof[3H]-thymidineintotheDNAofculturedmammaliancellsduringtherepairofdamage.Thiscanbedetectedbyautoradiographyassociatedwithimageanalysis.BlockthecellcycleatG1phase,andinhibitthesemi-conservativebysomechemicals,suchashydroxyurea(羥基脲),thenexposethecellsto??[3H]-incorporatedduringUDSintothosecellsthatarenotsemi-replicating?replicationwithsemi-conservativeIfautoradiographyistomonitorthisprocess,S-phasecellswhicharesemi-?replicationwithsemi-conservativeIfautoradiographyistomonitorthisprocess,S-phasecellswhicharesemi-fromtheanalysisduetotheirheavylabellingThemeasureofradiolabelledthymidineincorporated? semi-replicationinthecellSalmonellaTyphimuriumstrainsmutatedinofhistidinesynthesisauxotrophic營養(yǎng)缺陷型)mutants,i.e.theyrequirehistidineforgrowth.Themethodteststhecapabilityofthetestedsubstanceincreatingmutationsthatresultinareversionbacktoa"prototrophic"state,sothatthecellscangrowonahistidine-freeAmesAmesGiemsaGiemsa????SisterchromatidMitosisanaphase（有絲分裂后期T(darkblue)（溴脫氧尿嘧啶核苷(light4-5SCEsperchromosomepairpermitosisisnormal,while14-100SCEsisabnormalandpresentsadangertothe?Metaphasespreadofacelllineshowingaringchromosome(R)andseveralSCEs,someofwhichareindicatedbyarrows.ComputerQSAR(quantitativestructure-activityComputerQSAR(quantitativestructure-activityquantifyingvariouselectronic,geometric,orstericpropertiesofamoleculearecomputedandusedtodevelopaQSAR電性參數(shù)、立體參數(shù)、幾何參數(shù)、BasedontoxicityBasedontoxicityAcutetoxicityChronictoxicityAcutetoxicityAcutetoxicityTheconventionalLD50testwasfinallycancelledendof2002.Thefollowingalternativeanimaltestsofacutetoxicityhavebeendeveloped:???FixeddoseprocedureAcutetoxicclass(ATC)methodProposedin1984Proposedin1984bytheBritishToxicologySociety,itisamethodtoassessasubstance'sacuteoralToidentifyadosethatproducesclearsignsoftoxicitybutnomortality.Givenatoneofthefourfixed-doselevels(5,50,500,and2000mg/kg)tofivemaleandfivefemalerats.Ifmortalityoccurs,retestingatalowerdoselevelisnecessary(exceptiftheoriginaldoseis5mg/kg).Ifnosignsoftoxicityoccur,itisnecessarytoretestatahigherdoselevel.In1992,thistestwasproposedasanalternativetotheLD50testbyOECD.ProposedbytheGermanProposedbytheGermanFederalHealthAdoptedin1996asanofficialtestguidelineoftheOECDandtheEuropeanUnion6levels:<1mg/kg,1-50mg/kg,51-500mg/kg,5000mg/kg,5001-15000mg/kg,>150003animalsofeachsexforeachProbitmodel(maximumlikelihoodArchToxicol.1992;66(7):455-ALTEX.1999;16(3):129-Limittest:startatLimittes