生物钟基因研究进展

IntroductiontoToxicologyChapter11Toxicology-Chaper11/29ThestudyoftheadverseeffectsofchemicalsonlivingorganismsandtheunderlyingmechanismsToxicology2Toxicology-Chaper12/29Likemedicine,toxicologyisbothascienceandanart.Thescienceoftoxicologyisdefinedastheobservationalanddata-gatheringphase,whereastheartoftoxicologyconsistsoftheutilizationofthedatatopredictoutcomesofexposureinhumanandanimalpopulation.Toxicology3Toxicology-Chaper13/29HistoryofToxicologyAntiquity:Eberspapyrus(1500B.C.),BenChaoGongMu(Mingdynasty)Middleages:Renaissance-PoisonsandTheirAntidotes(1198),arsenic-containingproductsAgeofenlightenment:Parcelsus(1493-1548)“Allsubstancesarepoisons;thereisnonewhichisnotapoison.Therightdosedifferentiatesapoisonfromaremedy.”4Toxicology-Chaper14/29HistoryofToxicologyAgeofenlightenment:Orfila(1787-1853)–thefirsttoxicologisttouseautopsymaterialandchemicalanalysissystematicallyaslegalproofofpoisoning.OswaldSchmiedeberg(1838-1921)–thefirsttoxicologisttotrain120studentswholaterpopulatedthemostimportantlaboratoriesofpharmacologyandtoxicologythroughouttheworld.5Toxicology-Chaper15/29HistoryofToxicologyMordentoxicology:1900-Developmentofearlyadvancesinanalyticmethods:heavymetalsEarlymechanisticstudies:drugs,plantsIntroductionofnewtoxicantsandantidotes:nitriteandthiosulfateforcyanide;DDT(1944);organophophoruscompounds(1952)Developmentofnewbranches6Toxicology-Chaper16/297Toxicology-Chaper17/29HistoryofToxicologyTheSilentSpring(RachelCarson,1962)“Theearth’svegetationisapartofaweboflifeinwhichthereareintimateandessentialrelationsbetweenplantsandtheearth,betweenplantsandotherplants,betweenplantsandanimals.Sometimeswehavenootherchoicebuttodisturbtheserelationships,butweshoulddosothoughtfully,withfullawarenessthatwhatwedomayhaveconsequencesremoteintimeandplace.”8Toxicology-Chaper18/29Threeerasofdevelopmentofexperimentaltoxicology9Toxicology-Chaper19/29ToxicologyBranchAccordingtoobjectofstudy:AnimalToxicologyHumanToxicologyPlantToxicologyInsectToxicologyLivestockToxicology10Toxicology-Chaper110/29ToxicologyBranchAccordingtofieldofstudy:EnvironmentalToxicologyFoodToxicologyOccupationalToxicologyClinicalToxicologyForensicToxicologyAnalyticToxicology11Toxicology-Chaper111/29ToxicologyBranchAccordingtotargetorganofstudy:LiverToxicologyKidneyToxicologyNeurotoxicologyImmunotoxicologyProductiveToxicologyHemotoxicolgy12Toxicology-Chaper112/29ToxicologyBranchAccordingtomechanismofstudy:CellularToxicologyMolecularToxicologyMembraneToxicologyBiochemicalToxicologyGeneticToxicology13Toxicology-Chaper113/29ToxicologyBranchAccordingtoareaofstudy:DescriptiveToxicologyMechanisticToxicologyRegulatoryToxicology14Toxicology-Chaper114/2915Toxicology-Chaper115/29MainAreasofToxicologyStudyDescriptiveToxicology:Totesttoxicityinexperimentalanimalstoprovideimportantcluestoachemical’smechanismofaction.Toyieldinformationthatcanbeusedtoevaluaterisksposedtohumansandtheenvironment.16Toxicology-Chaper116/29MainAreasofToxicologyStudyMechanisticToxicology:Toidentifyandunderstandthecellular,biochemicalandmolecularmechanismsbywhichchemicalsexerttoxiceffectsonlivingorganisms.Todesignandproducesaferalternativechemicalsfortherapyofpoisoningandtreatmentofdiseases.17Toxicology-Chaper117/29MainAreasofToxicologyStudyRegulatoryToxicology:Toperformtheriskassessmentofapotentialhazardtothehumanhealthandtheecosystem.Toestablishstandardsfortheamountofchemicalspermittedinambientair,industrialatmosphere,anddrinkingwater.18Toxicology-Chaper118/29SpectrumofToxicDoseAmongchemicalsthereisawidespectrumofdosesneededtoproducedeleteriouseffects,seriousinjury,ordeath.However,themeasuresofacutelethalitysuchasLD50maynotaccuratelyreflectthefullspectrumoftoxicityassociatedwithexposure,e.g.,carcinogenicorteratogeniceffects.19Toxicology-Chaper119/2920Toxicology-Chaper120/29SpectrumofUndesiredEffects(1)AllergicreactionsChemicalallergyisanimmunologicallymediatedadversereactiontoachemicalandisdose-relatedforagivenindividual.Theincidenceofallergicasthmahasincreasedsubstantiallyinrecentyears.21Toxicology-Chaper121/29SpectrumofUndesiredEffects(2)IdiosyncraticreactionsReferringtoageneticallydeterminedabnormalreactivitytoachemical,i.g.,extremesensitivetolowdosesorextremeinsensitivetohighdoses.Examplesofchemicalidiosyncrasyincludeexposurestosuccinylcholineandmethemoglobin-inducingchemicals.22Toxicology-Chaper122/29SpectrumofUndesiredEffects(3)ImmediateversusdelayedtoxicityMostchemicalsproduceimmediatetoxiceffectsbutnotdelayedeffects.Delayedtoxicitycanbeseenincarcinogenicchemicals(years)andorganophosphoruspesticides(weeks)suchasTOCPtoinhibittheneuropathytargetesterase(NTE).23Toxicology-Chaper123/29SpectrumofUndesiredEffects(4)ReversibleversusirreversibletoxiceffectsTheabilityofexposedtissuetoregeneratelargelydetermineswheretheeffectsisreversibleorirreversible.Carcinogenicandteratogeniceffectsareusuallyconsideredirreversibletoxiceffectsoncetheyoccur.24Toxicology-Chaper124/29SpectrumofUndesiredEffects(5)LocalversussystemictoxicityLocaleffectsoccuratthesiteoffirstcontactofchemicals,e.g.,ingestionofcausticsubstancesorinhalationofirritantmaterials.Systemiceffectsrequireabsorptionanddistributionofatoxicantfromitsentrypointtoadistantsitetoproducedamages,someoftheaffectedorgansarereferredtoasthetargetorgansofaparticularchemical.25Toxicology-Chaper125/29Overview

of

Toxicology

StudyXenobioticTargetOrganismCommunity/PopulationEcosystemAbsorptionTargetTissueTargetCellExposureDistributionMetabolismClassicalToxicologyXenobioticMembrane

TransportOrganismToxicityTissueToxicityRegulatoryToxicologyExcretionEpidemiology/EnvironmentalToxicologyTargetMoleculeCellularandMolecularEventsCellularToxicityMolecularandCellularToxicologyGeneticSusceptibilityBiomarkersRiskassessmentMechanismsandtreatmentoftoxicityRiskcharacterizationBiologyResponseMetabolism26Toxicology-Chaper126/29InformationResourceofToxicology,HazardousChemicals,andtheEnvironmentChemicalInformationIdentifychemical,itssynonyms,andCASnumber

findchemicalstructure,chemicalsurrogatebasedonstructuresimilarity.Canbesearchedbyusingachemicalname,CASNumber,molecularformula,ormolecularweight

/(ChemID)