毒理学基础-讲稿

毒理学基础毒理学基础第一部分毒理学总论第一章绪论毒理学概述毒理学简史毒理学方法毒理学应用毒理学展望2第二章毒理学基本概念毒物和毒效应剂量和剂量反应关系结构-活性关系时间-反应关系选择毒性、靶器官和高危险人群毒理学的研究方法毒性参数和安全限值3第三章化学度物在体内的生物转运与生物转化化学毒物在体内的生物转运化学毒物在体内的生物转化毒物动力学4第四章毒作用机制毒物的ADME过程与靶器官靶分子的反应细胞调节功能障碍修复障碍毒物作用的表观遗传机制5第五章毒作用影响因素化学物因素机体因素暴露因素环境因素化学物的联合作用6毒理学动物实验基础（补）实验动物动物实验7第六章外源化学物的一般毒性作用概述急性毒性作用局部毒性作用短期、亚慢性和慢性毒性作用8第七章外源化学物致突变作用第八章外源化学物致癌作用第九章发育毒性与致畸作用第十章毒理基因组学与系统毒理学（自学）第十一章管理毒理学安全性评价危险度评价9第二部分毒理学各论

(不在教学计划内）纳米毒理学放射毒理学血液免疫生殖神经和行为呼吸肝脏肾脏心血管皮肤毒理学网络信息资源10毒理学基础BasicPrinciplesandMethodsofToxicology

PartOneThePandectofToxicologyChapterOneIntroductionofToxicologyChapterTwoBasicConceptsofToxicology第一部分毒理学总论第一章绪论（2学时）

第二章毒理学基本概念（2学时）11ChapterOne

Introduction

ofToxicology

SectionOneOverviewofToxicologyDefinitionofToxicology(whatisToxicology?)Thetraditionaldefinitionoftoxicology:1."thescienceofpoisons."

2.“Thestudyoftheadverseeffectsof

xenobioticsonlivingorganisms.”12DefinitionofToxicology

Themoredescriptivedefinitionoftoxicology

"thestudyoftheadverseeffectsofchemicals,physicalorbiologicalagentsonlivingorganisms,andthemechanismsofsucheffects,safetyevaluationandriskanalysis(evaluation).

---BasisofToxicology5thEdition13DefinitionofToxicology“Toxicologyisthestudyoftheadverseeffectsofchemical,

physicalorbiologicalagentson

livingorganismsandtheecosystem,includingthepreventionandameliorationofsuchadverseeffects.”

SOT:SocietyofToxicology

14

卫生毒理学（hygienetoxicology，

preventivetoxicology）

是利用毒理学的概念和方法，从预防医学角度出发，研究人类生活和生产活动中可能接触的外来化合物对机体的生物学作用，特别是损害作用及其机理的科学。

任务：

☻对化学物进行安全性评价

☻研究机体与化学物相互作用的规律(亦即中毒机理的研究）

☻为制订卫生标准提供毒理学依据

DefinitionofToxicology15Xenobiotic

Definition1.Strictly,anysubstanceinteractingwithanorganismthatisnotanaturalcomponentofthatorganism.

2.Man-madecompoundswithchemicalstructuresforeigntoagivenorganism.Synonym:exogenous/foreignsubstance/compound

16XenobioticXenobiotic

isthegeneraltermthatisusedfora

foreign

substancetakenintothebody.

Itis

derivedfromtheGreekterm“xeno”which

means"foreigner."

Xenobioticsmayproducebeneficialeffects

(suchasapharmaceuticals)ortheymaybe

toxic(suchaslead).

17Exposure

SourcesofExposuretochemicals:EnvironmentalOccupationalTherapeuticDietaryAccidentalDeliberate18Exposure

RoutesofExposureTheROUTE(site)ofexposureisanimportantdeterminantoftheultimateDOSE–differentroutesmayresultindifferentratesofabsorption.Dermal(skin)Inhalation(lung)Oral(GI)Injection19ToxicologyWhatistoxicology?Thestudyoftheeffectsofpoisons.Poisonoussubstancesareproducedbyplants,animals,orbacteria.

Phytotoxins Zootoxins Bacteriotoxins

Toxicant-thespecificpoisonouschemical.

Xenobiotic-man-madesubstanceand/orproducedbybutnotnormallyfoundinthebody.20ToxicologyAffectsUsEveryday/CaliforniaWantstoServeaWarningWithFries(NYTimes,Sept21,2005)Fish-mercuryriskunderestimated(CNN.com,Apr12,2001)EphedraBan:WhatTookSoLong?(CBSN,Dec30,2003)Acrylamide21©APPhoto/AlexanderZemlianichenko©APPhoto/AnatolyMedzyk

ViktorYushchenko:presidentofUkraine

poisonedbyDioxinToxicologyAffectsUsEveryday22

Melaminemilkpowder(China)ToxicologyAffectsUsEveryday23Melamineisachemicaltoproduce：

So,Melamineisapoisontohumanbody.

24WhyMelaminediscoverinMilkPowder?Milkpowderisproducedbymilk,themostimportantofmilkingredientisprotein.MelamineandproteinalsohavethesameN25Toreducetheconsumptionofmilk,produceraddedMelaminetocutcost,

MelamineisnoteasytotasteanddiscoverandlookssimilartoMilkpowder.26Howcomelatelydiscovered?Year2007,manypetswasdeadafterhadtheMadeinChinaPetFoodsandUSAdiscoveredthecontentofMelamineingredientinsidethepetsfood.

27Year2008,ManycaseswerefoundthatChina’sbabyhavingmostcasesofKidneyproblemsandthecasesstillincreasing.Year2008Aug,China’sauthoritydiscoveredthebelowfavoritesbrandofmilkpowdercontentsMelamine

28Whyitharmfultohuman?AfterconsumptionofMelamineintohumanbody,itwilltransfertoKidneystone.29

<>30

WhatDoToxicologistsDo?MostToxicologistsworktodevelopaMECHANISTICunderstandingofhowchemicalsaffectlivingsystemsDevelopsaferchemicalproductsDevelopsaferdrugs&medicinesDeterminerisksforchemicalexposuresDeveloptreatmentsforchemical

exposuresEnsureasafefoodsupplyForensics31ToxicologyisanappliedsciencewithmanyareasofspecializationImagesfromGray’sAnatomyImagefromMolecularCellBiologyImagesfrom32Whataremajorareasofspecialization

intoxicology?Descriptivetoxicology(testing)Mechanistictoxicology(basicbiologyandchemistry)Regulatorytoxicology(rulemakingandcomplianceandriskassessmentbymodeling)

33A.DescriptiveToxicologyTypicallyinvolvestoxicitytestingBroadspectrumofresponsesreflectstoxicityMortalityGrowthinhibitionReproductiveimpairmentIncreaseincancerincidence

34B.MechanisticToxicologyFocusesonhowChemicalproducesanadverseeffectBiologicalsystemprotects

itselfagainstadverseeffectInvolvesCellularandMolecularBiologyBiochemistry,oftenxenobioticmetabolism35

Chemicalresearchintoxicologyusually

investigatesmetabolictransformationsof

drugsorpotentiallyhazardouschemicals

Howpersistentisachemicalinthebody?Dotestanimalsreflecthumansorother

speciesofconcern?Aremetabolicproductstoxic?36机制毒理学的作用1.证实与人类直接相关的实验动物中所观察到的损害作用。2.验证可能与人类无关的发生于实验动物中的有害效应。(排除实验动物有害反应发生于人类的可能性）3.设计和生产较为安全的化学物以及合理治疗化学中毒和临床疾病。4.人和动物毒性反应差异、保护遗传易感、个体化预防治疗5.促进生理学、药理学细胞生物学和生物化学等基础学科的发展。37C.RegulatoryToxicologySettingrulesandassuringcomplianceProductsregistrationAllowableconcentrationsinfoodorenvironmentalmediaTechnicalandlegalissuesmayrequirenegotiationandgatheringofnewinformation根据描述、机制毒理学的研究资料进行科学决策，协助政府部门制定相关法规、条例和管理措施并使之付诸实施，以确保化学品、食品、药品等进入市场足够安全，以保证人民群众身心健康。（如卫生标准的制定）38RiskAssessmentMathematicalmodelingprocessthatyieldsestimateforsafeorallowablechemicalconcentrationsHazardidentificationDose-responseassessmentExposurecharacterizationRiskassessmentRiskcharacterization39Stageofgermination2700B.C.-Chinesejournals:showintextbookplantandfishpoisons

1900-1200B.C.-Egyptiandocumentsthathaddirectionsforcollection,preparation,andadministrationofmorethan800medicinalandpoisonousrecipes.

800B.C.-India-Hindumedicineincludesnotesonpoisonsandantidotes.Section2BrifeHistoryofToxicology40BrifeHistoryofToxicology50-100A.D.-Greekphysiciansclassifiedover600plant,animal,andmineralpoisons.50-400A.D.-RomansusedpoisonsforexecutionsandassassinationsThephilosopher,Socrates,wasexecuted

usinghemlockforteachingradicalideastoyouths.41BriefhistoryofToxicologyFormativeperiod

Avicenna(A.D.980-1036)Islamicauthorityon

poisonsandantidotes.1200A.D.-SpanishrabbiMaimonideswrotefirst-aidbookforpoisonings:

PoisonsandTheirAntidotes42SwissphysicianParacelsus(1493-1541)“Allsubstancesarepoisons:thereisnonewhichisnotapoison.Therightdosedifferentiatesapoisonfromaremedy.”

HistoryofToxicology43TheDoseMakesthePoisonThemainideaofParacelsus:Anapparentlynontoxicchemicalcanbetoxicathighdoses.(Toomuchofagoodthingcanbebad).Highlytoxicchemicalscanbelifesavingwhengiveninappropriatedoses.(Poisonsarenotharmfulatasufficientlylowdose).44

describing"asthma"inbakers,

miners,farmers,gilders,tinsmiths,glass-workers,tanners,millers,grain-sifters,stonecutters,ragmen,runners,riders,porters,&professors.Ramazzinioutlinedhealthhazardsofthedusts,fumes,orgasesthatsuchworkersinhaled.Thebakersandhorserider-sdescribedbyRamazziniwouldtodayprobablybediagnosedassufferingfromallergen-inducedasthma.Thelungdisea-sessufferedbymostoftheotherworkerswouldnowbeclas-sifiedas"pneumoconiosis,"agroupofdust-relatedchronicdiseases.

Italianphysician

Ramazzini(1713)published

“DeMorbisArtificum”

(DiseasesofWorkers)

HistoryofToxicology45

Spanishphysician

Orfila(1815)establishedtoxicologyasadistinctscientificdiscipline.“thefatherofmoderntoxicology.”HistoryofToxicology46DevelopmentStage20thCentury

PaulEhrlich

–developedstainingprocedurestoobservecellandtissuesandpioneeredtheunder-standingofhowtoxicantsinfluencelivingorganis-ms.HistoryofToxicology4720thCentury

RachelCarson-alarmedpublic

aboutdangersofpesticides

intheenvironment.HistoryofToxicology48国内外毒理学相关机构FDA:FoodandDrugAdministrationEPA:EnvironmentalProtectionAgencySOT:SocietyofToxicologyIUTOX:InternationalUnionofToxicologyIAEMS:InternationalAssociationofEnvironmental

mutagen

Societies

CSTChineseSocietyofToxicologyCEM:ChineseEnvironmentalMutagenSociety

49Section3

MethodsandTypesof

ToxicologicalstueiesInvivomethods体内试验Invitromethods体外试验Epidemiologicalstudies流行病学研究Clinical(human)exposurestudies临床研究Accidentalacutepoisonings事故性急性中毒50研究方法流行病学研