毒理学基础Chapter-1-principle-of-toxicology-英文版

Tox102PrinciplesofToxicologyBasicdefinitionsToxicology-Toxicologist-TheprinciplesoftoxicologyareintegraltotheconceptofriskassessmentRisk/benefitDifferentAreasofToxicologyThreeMainAreasofToxicology:DescriptiveMechanisticRegulatoryMechanisticToxicologycellular,biochemicalandmolecularmechanismsMaydemonstratethataparticularcompoundwillbeunlikelytoeffecthumans(eg.Saccharin)MechanisticToxicologyUsefulfordrugdevelopment.CanclarifywhycertainindividualsmaybeoverlysusceptibletoaparticularagentDescriptiveToxicologyConcerneddirectlywithtoxicitytestingGivesinfoneededtoevaluatepotentialhumanandenvironmentalRegulatoryToxicologyResponsibilities?OtherCategoriesofToxicologyForensicToxClinicalToxEnvironmentalToxSpectrumofToxicDoseDefinitionofapoison:Isthisahelpful“working”definitionParacelsus(1493-1541)PhillippusAureolusTheophrastusBombastusvonHohenheim(1493-1541)Consideredtobethe“FatherofToxicology”Swiss/German/Austrianphysician,scientistandphilosopher“Whatistherethatisnotapoison?Allthingsarepoisonandnothingiswithoutpoison?”HowmayToxicAgentsbeClassified?TargetorgansUseSourceEffectsPhysicalstateChemicalstabilityorreactivityGeneralchemicalstructurePoisoningpotentialMoreDefinitionsToxicantToxinXenobioticTargetorganCharacteristicsofExposureInorderforatoxintohaveaneffectonabiologicalsystem–biotransformation–reachthetargetorgan–Time–DoseRouteandSiteofExposureThemajorroutesofexposuretotoxicchemicalsare:Gastrointestinal(ingestion)Lungs(inhalation)Skin(topical)DurationandFrequencyofExposure4categoriesAcuteSubacuteSubchronicChronic–Exposuretimemaygreatlyeffecttoxicityandtargetorgan(eg.Benzene)–Pharmacokineticsplaysaroleindegreeoftoxicity.Howefficientiselimination?SpectrumofUndesiredEffectsAllergicReactionIdiosyncraticReactionImmediatevs.DelayedToxicityImmediateDelayedLocalvs.SystemicToxicityLocaleffects:initialcontactSystemiceffectsrequireabsorptionanddistributionCanbothoccur?InteractionofChemicalsAdditiveEffectSynergisticEffectPotentiationAntagonism–Functional–Chemical–Dispositional–ReceptorInteractionofChemicalsAdditiveeffectExampleInteractionofChemicalsSynergisticeffectExampleInteractionofChemicalsPotentiationExampleInteractionofChemicalsAntagonism-AntagonisticeffectsmaybehelpfulasantidotesFourtypesofantagonism:–Functional–Chemical–Dispositional–ReceptorAntagonismFunctionalantagonism:ExamplesAntagonismChemicalantagonism(inactivation):ExampleAntagonismDispositional:ExampleAntagonismReceptor:ExampleToleranceToleranceisastateofdecreasedresponsivenesstoatoxiceffectofachemicalresultingfrompriorexposuretothatchemicalortoastructurallyrelatedchemicalDoseResponseDose-responseisacorrelativerelationshipTheresponseischaracterizedbyadose-relatedincreaseintheseverityoftheresponseFig1.EffectsofNBonCaco2andHT-29cellsviabilityasdeterminedbytheMTTassay.CellsweretreatedwithvariousconcentrationsofNBfor24hrs.Significantdecreasesincellviabilitywerenotedfrom200-3200µMinCaco2cells(A).SignificantdecreasesincellviabilitywereobservedinHT-29cellsfrom400-3200µM(B).Cellviabilityresultsareexpressedascellnumber.Eachcontrolandtreatmentgrouphadann=4(p0.05).Theexperimentwasrepeatedintriplicate.QuantalDose-ResponseThedose-responserelationshipthatoccursinapopulationarequantal(allornothing)innature.Eachindividual’sresponseisclassifiedaseithera“responder”ora“non-responder”.InTox,quantaldoseresponseisusedextensively.DeterminationoftheLD50isoftenthefirstexperimentperformedonanewchemicalShapeoftheDose-ResponseCurveEssentialNutrientsHormesisWhatisit?ExampleSpeciesDifferencesToxicitymayvaryfromspeciestospeciesregardlessofproperlyconductedexperimentsIndividualDifferencesinResponseEvenw/inaspecieslargedifferencesmayoccurgeneticpolymorphismsDescriptiveAnimalToxicityTestsMainprinciplesthatunderliealldescriptiveanimaltoxicitytesting:1.2.DescriptiveAnimalToxicityTestsTheeffectsproducedbyacompoundinlabanimals,whenproperlyqualified,areapplicabletohumansDescriptiveAnimalToxicityTestsExposureofexpanimalstotoxicagentsinhighdosesisanecessaryandvalidmethodofdiscoveringpossiblehazardsinhumansDescriptiveAnimalToxicityTests–Acutelethality–Skinandeyeirritation–Sensitization–Subacute(repeateddosestudy)–Subchronic–Chronic–Developmentalandreproductivetoxicity–MutagenicityAcuteLethalityFirsttestLD50RatandmouseAdultmalesandfemales#deadin14dayperiodaretabulatedAcuteLethalityValuegained?–Quantitativeestimateofacutetoxicityforcomparisonwithothersubstances–Identifytargetorgans–Establishreversibility–ProvideadoserangingguideforotherstudiesSkinandEyeIrritationUsuallyperformedinrabbitsDraizeTestSkinirritationisscoredForocularirritation,chemicalisinstilledintheeye.Contra-lateraleyeisusedascontrol.SensitizationGuineapigpreferredspeciesDoneforchemicalswithlikelyskinexpshavedskin,intradermallyorbothMultipleadministrationsover2-4weeks2-3weeksafterlasttreatment,animalischallengedwithanonirritatingconcoftestsubstanceanderythemaisevaluatedAnimalTestingSubacute(repeateddose)–3-4dosesinfeed–10animalspersex(rats)–3