SolventsandVapors

(VolatileOrganicCompounds)有機溶劑的特性

溶解性

脂溶性（可溶解脂肪）愈強，去脂效能愈佳，對皮膚和神經系統的傷害也愈大可燃性

可燃性高者作燃料，不可燃者則作滅火劑。揮發性

蒸氣壓愈高，揮發性愈強，空氣中有機溶劑的濃度愈大，愈多經由呼吸道吸入人體。化學結構

一般而言，結構相似者毒性可能相近，例如鹵化有機溶劑（四氯甲烷，三氯乙烯，四氯乙烯等），對肝皆具毒性。也可能差很多，2,4-diaminotoluene(livertumor)/2,6-diaminotoluene(not)Themaindeterminantsofasolvent’sinherenttoxicity

thenumberofcarbonatomlipophilicityvolatilitywhetheritissaturatedorhasdoubleortriple bondsbetweenadjacentcarbonatomsitsconfiguration(straightchain,branchchain,or cyclic)thepresenceoffunctionalgroupsex.Amides/amines-potentsensitizeraldehyde-irritatingRouteofExposurePrimaryrouteRespiratoryRelatedtovolatilityofsolventLipidsolubilityMACSecondaryrouteSkinIngestion(accident)Sourcesofexposure

Dailyactivity-workplace,gasstation,smoking,household,etc.Solventabuse-produceeuphoria,delusions,sedationandvisualandauditoryhallucinationEnvironmentalcontaminationmajorvolatileorganicsolvents(VOCs)OccupationalStandards:TWAThetime-weightedaverageisthetime-weightedaverageconcentrationforanormal8-hourworkdayor40-hourworkweek,towhichnearlyallworkersmayberepeatedlyexposed,dayafterday,withoutadverseeffect.

Asshowninthefigure,timeweightedaveragespermitexcursionsabovethelimitprovidedthattheyarecompensatedbyequivalentexcursionsbelowthelimitduringtheworkweekTWAToillustratetheTWAformula,assumethatasubstancehasan8-hourtime-weightedaveragePELof100ppm.Assumethatanemployeeissubjecttothefollowingexposure:

Twohoursexposureat150ppm

Twohoursexposureat75ppm

Fourhoursexposureat50ppm.Substitutingthisinformationintheformula,wehave:TWA=(150)(2)+(75)(2)+(50)(4)=81.25ppm

8Since81.25ppmislessthan100ppm,the8-hourtime-weightedaveragelimit,theexposureisacceptableShort-TermExposureLimit(TLV-STEL)themaximumconcentrationtowhichworkerscanbeexposedcontinuouslyforashortperiodoftime(15-minute)withoutsufferingfromirritation,chronicorirreversibletissuechange,ornarcosisofsufficientdegreetoincreaseaccidentproneness,impairself-rescue,ormateriallyreduceworkefficiency.

Ceiling(TLV-C)Ceiling(TLV-C)istheconcentrationthatshouldnotbeexceededeveninstantaneously.Forsomesubstances,forexampleirritantgases,onlytheTLV-ceilingmayberelevant.GeneralAcuteToxicEffects

CNSdepressionHighlevelexposure中樞神經麻醉效果，例如乙醚麻醉 一般而言，碳鏈愈長，含雙鍵、鹵素基（氯、溴、氟等）的溶劑中樞效果愈強。臨床上，暴露的人會頭暈、頭痛、噁心、嘔吐、嗜睡，平衡失調，像醉酒一般，除了影響健康外，勞工甚易發生工作意外。工作場所中常存在多種溶劑或混合物，彼此加強作用，危害比單一物質更大。

-Subanestheticdose behavioraltoxicityDermalandmucousirritationSolvent-inducedchronicencephalopathy(CSE)Nonspecificsymptoms(headache,fatigue,sleepdisorders)withorwithoutchangesinneuropsychologicaldysfunctionTypeISymptomsonlyType2ASustainedpersonalityormoodchangeType2BImpairmentinintellectualfunctionType3Dementia刺激性或過敏性皮膚炎

有機溶劑具去脂性，能溶解皮膚表面油脂，引起皮膚炎。暴露濃度愈高，時間愈長，或溶劑封閉在手套內無法揮發，造成的傷害愈大。在工廠內有一個動作十分容易傷害皮膚，即是用溶劑來洗手，去除污垢。殊不知長期下來，油脂儘失，往往引起刺激性或過敏性皮膚炎。

皮膚炎的臨床表現分急慢性兩種，急性呈紅，腫，慢性呈乾，裂的濕疹樣變化。Biomarkersofsolvents

Measurementsofbloodorurinelevelsofchemicalsfollowingexposure(nothighlyspecific)CharacterizationandquantitationofuniquemetabolitesinbodyfluidsMeasurementofcovalentbindingofreactivemetabolitestoproteins,lipids,ornucleicacidsChemicallyrelatedandspecificformsofchromosomedamageMetabolismMetabolicinactivation(detoxification)

tolueneMetabolicactivation(bioactivation)

benzeneP450isozymesexhibitspecies-,substrate-,andregion-selectivityCYP2E1(1)2E1activeinbothhepaticandnon-hepatictissuessubstratepreference--mainlyforsimplealiphaticcompounds(‘solvents’)oxidizessmallstraight-chainorbranched-chaincompounds(norings)alcohols(methanol,ethanol),acetoneandketonebodies,short-chainfattyacidschlorinatedsolvents--chloroform,trichloroethylene(TCE),carbontetrachloride,etc.oxidizesbenzene(singleunsubstitutedaromaticring)CYP2E1(2)Bioactivationaliphaticepoxidesandaldehydesarereactivemetabolites(liverdamage)benzeneepoxide(myelotoxicity)-->bonemarrowcelldamage-->leukemiaslightlyinduciblebysmallaliphaticcompounds/alsoprolongsenzymeactivity‘EtOH-inducibleP450’(ethanol)-->2-5xincreaseCYP2E1levelsMetabolitesGenerationofbiologicreactiveintermediates a.Inactivatedbyglutathione,ascorbicacidandothercellularantioxidants b.covalentbindtocellularmacromolecules→inactivationofreceptorsandspecificproteins,damagetocellmembranes,orinitiationofmutagenicreactionsc.Metabolicsaturation-detoxicationpathway →bioactivationpathwayGenerationofreactiveoxygenspecies-freeradical,ROSP450inducersandinhibitorsInducers-ethanol,acetone,ketones,PAH, certaindrugs(phenobarbital,phenytoin, diazepam,rifampicin),smokingInhibitors-disulfiram,3-amino-1,2,4-triazole,severalconstituentsoffoods(diallylsulfide,dihydrocapsaicin,phenylethylisothiocyanate)Suicideinhibitors 1,2-dichloroethylenevs.CYP2E1AlkanesandAlkenesCarbonchainsSimpleStraightorbranchedGenerallyhighlyvolatileandlipophilicExamplesPentane,hexane,octanePaintthinners,enamels,varnishesAlkanesandAlkenesSolubilizeoremulsifyfatsRespiratoryEffectsIrritation/swellingofmucousmembranesBronchoconstrictionPulmonaryedemaCNSAnesthesiaandnarcosisSkinIrritationandswellingHalogenatedHydrocarbonsGeneralStructure–HofhydrocarbonreplacedbyF,Cl,Br,INames–Halogennamedassubstituentgroup F–fluoro Cl-chloro Br-bromo I-iodo–Examples:?dichloromethane=CH2Cl2?1,2-dibromoethane=CH2Br-CH2BrHalogenatedHydrocarbonsChloroform,dichloromethane,carbontetrachlorideHeptatoxicity-fattyliverandnecrosis↑numbersofhalogens,size,easeofhomolyticcleavage→↑toxicityDichloromethane

(methylenechloride)SolventforremovingpaintordegreasingRemovalofcaffeinefromcoffeeToxiceffectsCNSdepressionMetabolizedtoCOhypoxiaChloroformEarliestanestheticsAcuteeffectsAnesthesia,cardiacarrhythmiasChroniceffectsLiverdamageMetabolismtoreactivemetabolitePhosgene

Centrilobularnecrosis,fattyliverKidneydamageCarbonTetrachlorideUsesSolvent,cleaningagent,fireextinguisherAntihelminthicforhumansExposureOccupationalFoundingroundwaterandwastesitesCarbonTetrachlorideToxicityHepatotoxicFormsreactivemetabolitesCentrilobularnecrosis,fattyliver2E1InhibitmicrosomalATPaseactivitywithinminutesSinglecellnecrosis5-6hrMaximalcentrolobularnecrosis24-48hCYP2E1inhibitorscanpreventCCl4toxicityTCEhasmultipleeffects:Severalformsofcancer.neurotoxicity,immunotoxicity,developmentaltoxicity,livertoxicity,kidneytoxicity,andendocrineeffects.TCEactsthroughmultiplemetabolitesandmetabolicpathways: CYP450metabolitesincludeTCA,DCA. GSTmetabolitesincludeDCVC..TCEactsthroughmultiplemodesofaction.Trichloroethylene(TCE)KidneytumorsDCVCisbioactivatedinproximaltubularcellstoreactivethiolS-(1,2-dichlorovinyl)thiolLivertumorsExpressionofCYP2E1inthehepatocytesTCAandDCALungcancerChloralhydrateaccumulationinClaracellsTetrachloroethylenewidelyusedfordry-cleaningfabricsandmetaldegreasingoperationsliver,kidney,andcentralnervoussystem(CNS)fromacuteandchronicinhalationexposuretotetrachloroethyleneprobablycarcinogenictohumansAlcoholsEthylalcoholSolvent,intoxicatingbeverageOccupationalexposureminorToxiceffectsCNSdepressionDisruptcellmembraneBlockNMDAreceptorsFetalalcoholsyndromeHepatotoxicMetabolismtoacetaldehydeROSMalnutritionPossiblemechanismsofalcohol↑membranefluidity→displacementofmembraneenzymeandalterationthefunctionofmembrane,thereticularactivatingsystemismostsensitive

blocktheNMDAreceptorinterferewithATP-gatedionchannelMethanolSolventIndustrialexposureToxicityPermanentblindnessDamagesretinaandopticnerveMetabolizedtoformicacidAccumulatesintissues

CO2+H2OFormicacidFormaldehydeMethanolTetrahydrofolateAlcoholdehydrogenaseAldehydedehydrogenaseMethanolintoxicationNeurologicsymptoms:headachedizzinessamnesiarestlessnessacutemanialethargyconfusioncomaconvulsionsOPHTHALMOLOGICTOXICITYTarget-retina-opticdiskandopticnerveOccurwhenserumpHdropsbelow7.2LowpHintracellularconcentrationofformateImprovementofvisionwithcorrectionofacidosis,becauseformatemovesoutofthecellFormateisaninhibitorofcytochromeoxidase,whichcouldinhibitATPformationintheopticnerveTreatment

EthanoltherapyHemodialysiseffectivelyremovesmethanolanditstoxicmetabolites4-methylpyrazole(4-MP)“Fomepizole”:amorepotentinhibitorofalcoholdehyrogenaseFolatetherapySodiumbicarbonateEthyleneGlycolUsesHeatexchangers,antifreeze,hydraulicfluid,industrialsolventsExposureVaporormistGroundwaterAccidentalTreatment–thesameasmethanolAromaticHydrocarbonsBenzene,tolueneandxyleneMostcommonaromatichydrocarbonsfoundinpetroleumHighvolatilityLowwatersolubilityPrioritypollutantsBenzeneUsesPetroleumindustryStartingmaterialinchemicalsynthesisExposurePrimarilyworkplaceInhalationofbenzenevaporsSkinabsorptionBenzeneToxicityMechanism(Chronic)ConversionofbenzenetoreactivemetaboliteBenzeneoxideQuinones,semiquinonesInitialreactionsLiverFinalreactionsBonemarrowCovalentlybindtoDNA,RNAandproteinsROSTolueneandXyleneUsesSynthesisofresins,plastics,gasolineadditivesPaints,thinners,glues,cleaningagentsExposureLowlevelIndustrialworkers,gasstationattendantsToluenemorelipophilicthanbenzeneTolueneandXyleneToxicityAcuteCentralnervoussystemDepression,narcosisGastrointestinaldisturbancesChronicImpairedcognition,reactiontimesHearinglossPossiblemechanismofCNSeffectsoftolueneChangemembranefluidity alteringintracellularcommunicationPartitionintohydrophobicregionsofproteinsalteringmembrane–boundenzymeactivityand/orreceptoractivityNeurotransmitterEnhanceGABAAreceptorAttenuateNMDAreceptor,nicotinicreceptorActivatedopaminesystemsPolycyclicAromaticHydrocarbons(PAHs)TwoormorefusedaromaticringsLargegroupofchemical