毒理學(xué)基礎(chǔ)-講稿

毒理學(xué)基礎(chǔ)毒理學(xué)基礎(chǔ)第一部分毒理學(xué)總論第一章緒論毒理學(xué)概述毒理學(xué)簡史毒理學(xué)方法毒理學(xué)應(yīng)用毒理學(xué)展望2第二章毒理學(xué)基本概念毒物和毒效應(yīng)劑量和劑量反應(yīng)關(guān)系結(jié)構(gòu)-活性關(guān)系時(shí)間-反應(yīng)關(guān)系選擇毒性、靶器官和高危險(xiǎn)人群毒理學(xué)的研究方法毒性參數(shù)和安全限值3第三章化學(xué)度物在體內(nèi)的生物轉(zhuǎn)運(yùn)與生物轉(zhuǎn)化化學(xué)毒物在體內(nèi)的生物轉(zhuǎn)運(yùn)化學(xué)毒物在體內(nèi)的生物轉(zhuǎn)化毒物動力學(xué)4第四章毒作用機(jī)制毒物的ADME過程與靶器官靶分子的反應(yīng)細(xì)胞調(diào)節(jié)功能障礙修復(fù)障礙毒物作用的表觀遺傳機(jī)制5第五章毒作用影響因素化學(xué)物因素機(jī)體因素暴露因素環(huán)境因素化學(xué)物的聯(lián)合作用6毒理學(xué)動物實(shí)驗(yàn)基礎(chǔ)（補(bǔ)）實(shí)驗(yàn)動物動物實(shí)驗(yàn)7第六章外源化學(xué)物的一般毒性作用概述急性毒性作用局部毒性作用短期、亞慢性和慢性毒性作用8第七章外源化學(xué)物致突變作用第八章外源化學(xué)物致癌作用第九章發(fā)育毒性與致畸作用第十章毒理基因組學(xué)與系統(tǒng)毒理學(xué)（自學(xué)）第十一章管理毒理學(xué)安全性評價(jià)危險(xiǎn)度評價(jià)9第二部分毒理學(xué)各論

(不在教學(xué)計(jì)劃內(nèi)）納米毒理學(xué)放射毒理學(xué)血液免疫生殖神經(jīng)和行為呼吸肝臟腎臟心血管皮膚毒理學(xué)網(wǎng)絡(luò)信息資源10毒理學(xué)基礎(chǔ)BasicPrinciplesandMethodsofToxicology

PartOneThePandectofToxicologyChapterOneIntroductionofToxicologyChapterTwoBasicConceptsofToxicology第一部分毒理學(xué)總論第一章緒論（2學(xué)時(shí)）

第二章毒理學(xué)基本概念（2學(xué)時(shí)）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

衛(wèi)生毒理學(xué)（hygienetoxicology，

preventivetoxicology）

是利用毒理學(xué)的概念和方法，從預(yù)防醫(yī)學(xué)角度出發(fā)，研究人類生活和生產(chǎn)活動中可能接觸的外來化合物對機(jī)體的生物學(xué)作用，特別是損害作用及其機(jī)理的科學(xué)。

任務(wù)：

?對化學(xué)物進(jìn)行安全性評價(jià)

?研究機(jī)體與化學(xué)物相互作用的規(guī)律(亦即中毒機(jī)理的研究）

?為制訂衛(wèi)生標(biāo)準(zhǔn)提供毒理學(xué)依據(jù)

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機(jī)制毒理學(xué)的作用1.證實(shí)與人類直接相關(guān)的實(shí)驗(yàn)動物中所觀察到的損害作用。2.驗(yàn)證可能與人類無關(guān)的發(fā)生于實(shí)驗(yàn)動物中的有害效應(yīng)。(排除實(shí)驗(yàn)動物有害反應(yīng)發(fā)生于人類的可能性）3.設(shè)計(jì)和生產(chǎn)較為安全的化學(xué)物以及合理治療化學(xué)中毒和臨床疾病。4.人和動物毒性反應(yīng)差異、保護(hù)遺傳易感、個(gè)體化預(yù)防治療5.促進(jìn)生理學(xué)、藥理學(xué)細(xì)胞生物學(xué)和生物化學(xué)等基礎(chǔ)學(xué)科的發(fā)展。37C.RegulatoryToxicologySettingrulesandassuringcomplianceProductsregistrationAllowableconcentrationsinfoodorenvironmentalmediaTechnicalandlegalissuesmayrequirenegotiationandgatheringofnewinformation根據(jù)描述、機(jī)制毒理學(xué)的研究資料進(jìn)行科學(xué)決策，協(xié)助政府部門制定相關(guān)法規(guī)、條例和管理措施并使之付諸實(shí)施，以確?；瘜W(xué)品、食品、藥品等進(jìn)入市場足夠安全，以保證人民群眾身心健康。（如衛(wèi)生標(biāo)準(zhǔn)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國內(nèi)外毒理學(xué)相關(guān)機(jī)構(gòu)FDA:FoodandDrugAdministrationEPA:EnvironmentalProtectionAgencySOT:SocietyofToxicologyIUTOX:InternationalUnionofToxicologyIAEMS:InternationalAssociationofEnvironmental

mutagen

Societies

CSTChineseSocietyofToxicologyCEM:ChineseEnvironmentalMutagenSociety

49Section3

MethodsandTypesof

ToxicologicalstueiesInvivomethods體內(nèi)試驗(yàn)Invitromethods體外試驗(yàn)Epidemiologicalstudies流行病學(xué)研究Clinical(human)exposurestudies臨床研究Accidentalacutepoisonings事故性急性中毒50研究方法流行病學(xué)研