绿色化学：第四章 设计更加安全化学品的应用

Applicationof

DesigningSaferChemicals

Chapter4第四章设计更加安全化学品的应用

4.1IsostericReplacementofCarbonwithSiliconintheDesignofSaferChemicals4.2DesigningBiodegradableChemicals

4.3DesigningAquaticallySaferChemicals4.1IsostericReplacementofCarbonwithSilicon(用硅对碳进行等电排置换)intheDesignofSaferChemicalsSilicon

isanIsostereof

CarbonDifferencesbetweenSiliconcompoundsandCarboncompounds

ThedegradationandoxidativemetabolismoforganicsiliconcompoundsExamplesofisostericreplacementofcarbonwithsilicon4.1.1SiliconisanIsostericatomofCarbon

CommonFeaturesofSiliconandCarbongroupedincolumn4AofthePeriodicTablehavingmanychemicalsimilarities：

tetravalent,tetrahedral,andformstablebondswithcarbon.金刚石碳化硅Organicderivativesinwhichcarbonisreplacedbysilicongenerallyhavenointrinsictoxicity,incontrastwiththeotherGroup4Aelementsgermanium,

tin,andlead.Fromatoxicityperspective,siliconistheonlyGroup4Aelementthatisasuitablereplacementforcarbon.Inaddition,siliconisanabundant,inexpensiveelementandonethatisavailableinavarietyofforms.organicsiliconcompoundsisquiteinstable,fortheSi-Oissostrungthatorganicsiliconcompoundsareeasilyoxidatedafterexposedinenvironment.Acetylcholine(乙酰胆碱)Urethane(尿烷)Muscarinic

Antagonistis（蝇覃碱拮抗剂）Example1ONH2NOCH3SiONH2OOOUrethanesareneutralanalogsoftheneuro-transmitteracetylcholine,andwerefoundtobeantagonists(拮抗药)ofthelatter.Interestingly,silanewasmuchlesstoxictomicethanUrethane(carbon)withidenticaldose-responsecurves,andexhibitedmusclerelaxantproperties.CarbamateSiliconsubstitutedIsostereofcarbamate

(Similarinsecticidaleffect,moredegradable,lesstoxictohumanandenvironment)

Example2Carbamateinsecticideanditssiliconanalogwerefoundtohavesimilartoxicitytothehousefly.ONHCH3OONHCH3OSiONHCH3OONHCH3OSiDoublebondstosilicon,andthree-memberedringscontainingsilicon,areunstabletoairandmoisture

Singlebondsfromsilicontoheteroatomssuchasnitrogenandoxygenarestrongbutcanhydrolyzereadily.

4.1.2DifferencesbetweenSiliconandCarbonCompounds

Thesilicon-hydrogenbondismorepolarizedthanthecarbon-hydrogenbond.Polarization:Si－H>C－HIncontrasttothecarboncase,increasingthenumberofhydrogenonasiliconincreasestheeaseofoxidation,andtheparentsilane(SiH4)ispyrophoric(发火的、生火的).

[SiH2－CH2－CH2－SiH2－CH2－SiH2－CH2]n

Polyvinylsilane:Stable

ananalogofpolyethylenethatisrichinSiH2groupshasrecentlybeenreportedtobeairstableH2C=CH2Ethylene:StableH2Si=CH2vinylsilane:unstable

[CH2CH2CH2CH2CH2CH2]nPolyethylene:Stable

Forasubtledifferenceinatomicsizeexistsforsiliconandcarbon,Importantdifferencesinchemicalreactivityalsoexist.Whensiliconisproximal(最接近的)tounsaturation,asinavinylorallyl

silane,thecompoundsarestable,butunliketheircarbonanalogstheyaresubjecttoacidcatalyzedsilicon-carbonbondcleavage

BreakingofC－SibondiseasyHereinliesapotentialavenueforthedesignofenvironmentallydegradableproducts.4.1.3ThedegradationandoxidativemetabolismoforganicsiliconcompoundAnimportantcomponentofdesigningsaferchemicalsispredictingtheirenvironmentfate,andbothabioticdegradation（非生物降解）andbiologicaloxidationcanplayarole.IsostericsubstitutionofcarbonwithsiliconinmanycasesmayenhanceabioticdegradationandbiologicaloxidationCurrentlythemajorenvironmentalsourceoforganosilaneis

siliconepolymer

（聚硅酮）(siloxanes),primarilypolymersof1,1-dimethyl

silanediol.

HODepolymerizesinthepresenceofwaterandsoiltosilicatesfinallyAbioticDegradation

Furthermorelabelingstudieshaveshownthatthe

methylgroups

canbephoto-chemicallycleavedfromthesilicon,withthefinalproductbeingthenaturallyoccurring

silicates.

BiologicalOxidationEarlystudiesofmicrobialgrowthinthepresenceofpermethyl

siloxanes（硅氧烷）

suggestedthat

biologicalcleavageofsilicon-carbonbonds

couldoccurMorerecentworkhasshownthat

microorganismscanutilizedimethy

siloxanes

asasourceofcarbon,andsoilincubationof14Clabeledsiloxaneshasbeenfoundto

release14CO2

PioneeringworkbyFessendenonthemetabolismoforganosilanesby

mammalsfoundthat

phenylandalkylsilanes

wereoxidizedverymuchlike

theircarbonanalogs.

Anotabledifference,however,was

foundfordimethyl

phenylsilane

inwhich

thesilicon-hydrogenbondwasrapidlyoxidizedinvivo

Example1：SilaneAnalogsofDDTExample2：OrganosilaneFungicides4.1.4ExamplesfortheDesignofSaferChemicalsUsingSiliconSubstitutionforCarbonSilaneAnalogsofDDTDespitetherelativesafetyofDDTtomammals,itstoxicitytootherspeciesandenvironmentalpersistenceledtotheban(被禁止)ofthisimportantpesticide.InanearlyefforttodesignamorebenignversionofDDT,anumberofsilaneanalogssuchastheDDDanalogwerepreparedwiththeanticipationthatthesewouldbelessenvironmentallypersistent.

SilaneAnalogsofDDTThepresenceofthereadilyoxidizedsilicon-hydrogenbondwouldhavebeenonesourceofinstability,bothenvironmentallyandinvivo.SilaneAnalogsofDDTOrganosilaneFungicidesAsanovelentryintotheclassoftriazole（三唑）fungicides（防真菌剂）Mebergandcoworkerspreparedaseriesofsilaneanalogs.Oneofthese,flusilazole（氟苯代硅三唑）provedtobeahighlyeffectivecropfungicide（谷类防真菌）andisnowamajorcommercialproduct.Compoundflusilazoleisaninhibitorofsterol（甾醇）biosynthesis,similartoothertriazolefungicides.Thepropertiesofthiscompoundresponsibleforitsfieldperformance,includingvolatility,solubility,andmovementwithinplants,havebeendescribed.OrganosilaneFungicidesTheprimarymetaboliteofflusilazoleisthesilanol,resultingfromcleavageofthetriazole-substitutedmethylgroupfromsilicon.

Presumablysilanolhaslittleornobiologicalactivity,andthehigheroxidationlevelsilanolwillenhancetherateofitsfurtherdegradation(relativetoflusilazole).Flusilazoleisanexcellentexampleofthecommercialpotentialforbiologicallyactiveorganosilanes.Flusilazole

（氟苯代硅三唑）MetabolismUsage：

cropfungicide

4.2DesigningBiodegradableChemicalsExamplesofDesigningBiodegradableChemicalsTheMicrobialBasisofBiodegradation

ChemicalStructureandBiodegradability

GroupContributionMethodforPredictingBiodegradability

Chemicals:(resistbiodegradation)exertpossibletoxiceffecttobiota，hardlytopredicttheirpotentialtoxiceffect(atthetimeofreleasetotheenvironment).Moreover,somebio-accumulativechemicalsseemsafeaccordingtotoxicitycriteria,buthavechronic(慢性的)orotherunforeseentoxiceffect

Microbialdegradationisthemajorlossmechanismformostorganicchemicalsinaquatic(水的)andterrestrial（陆地）environments,andisthecornerstoneofthemodernwastewatertreatmentplant.4.2.1Themicrobialbasisofbiodegradation

Thekeyroleinbiodegradation:Microorganisms（primarilybacteria细菌andfungi真菌）arebyfarthemostimportantagentsofbiodegradationinnature.Anabundanceofevidenceexiststoshowthatmicroorganismsareresponsibleforthedegradationofmanyorganicchemicalscannotbealteredsignificantlybyhigherorganism.Animals:

excretechemicalsthattheycannotmetabolize;

Plants:

tendtoconvertchemicalsintowaterinsoluble;Microorganisms:

Theeventualmineralizationoforganiccompounds(theirconversiontoinorganicsubstancessuchasCO2andwater)canbeattributedpredominantlytomicrobialdegradation.

Theprocessofbiodegradation1.Anorganiccompoundmustfirstenterthemicrobialcellthroughthecellmembrane.(Thismayoccurbypassivediffusionorwiththeassistanceofspecifictransportsystems)

Especially:foraquaticandterrestrialenvironments——lowlevelsoforganicsubstrateandothernutrients.Forlargepolymericsubstrates:proteins,polysaccharides(多糖),

biodegradatedbyextracellular(细胞外酶)enzymes,

2.Onceinsidethecell,thereactionsthatacompoundmayundergoaredeterminedbyitsmolecularstructure,hundredsoftransformationshavebeendescribedintheliterature,butalmostallcanbeclassifiedbroadlyas：

oxidative;reductive;hydrolytic;conjugativereactions

InadditionThecatabolicpathwaysemployedbymicrobialpopulationsarealsodiverseandvarywiththe

environmentalconditions.

microbialdegradation

strategyisstepwisedegradationtoyieldoneormoreintermediateproductscapableofenteringthecentralpathwaysofmetabolism.Theoverallobjectiveisalwaystoproducecarbonandenergyforgrowth.

Thestrategyofmicrobialdegradation

Naturallyoccurringorganiccompoundsaredegradableviapathwaysthatrepresentevolutionaryadaptationstoprevailingconditions.Daleyhassaid：“…itisreasonabletobelievethateverybiochemicallysynthesizedorganiccompoundisbiodegradable.”4.2.2Relationshipbetweenchemicalstructureandbio-degradabilityThebio-degradabilityofasubstance,whichisoneofthepropertiesofthesubstance,dependsstronglyonitschemicalstructure.Studies,ResearchandEnvironmentalMonitoring:

Smallchangesinmolecularstructurecanevidentlyalterachemical'ssusceptibilitytobiodegradation!Thefollowingmolecularfeaturesgenerallyincrease

resistancetoaerobicbiodegradation

Halides(卤代物）;especiallychlorineandfluorine;Chainbranching（支链物质）,especiallyquaternarycarbon（季碳）andtertiarynitrogen,orextremelybranchingsuchasinsurfactantsderivedfromtri-ortetrapropylene;3.Nitro,nitroso（亚硝基）,azo

（偶氮基）,arylamino

（芳氨基）;

Polycyclicresidues（多环残基）(suchasinpolycyclicaromatichydrocarbons（多环芳香烃）orPAHS（稠环芳烃）),especiallywithmorethanthreefusedrings;Heterocyclicresidues（杂环残基）;e.g.,pyridinerings（吡啶环）;Aliphaticether(C-O-C)bonds（脂肪族醚键）;High-substitutedcompoundismoredifficulttodegradethanlow-substitutedone.

Forthemostpart,thefeatureslistedaboveaffecttheabilityofthecompoundtoserveasaninducerorsubstrate,orboth,ofdegradativeenzymesandcellulartransportsystems.

Thechemicalstructureswhichfavorbiodegradabilitybythepresenceofpotentialsitesofenzymatichydrolysis(e.g.,esters酯,amines胺);bytheintroductionofoxygenintheformofhydroxyl(羟基),aldehydic(醛基)orcarboxylic(羧基)acidgroups;bythepresenceofun-substitutedlinearalkylchains(especially>4carbons)andphenylrings,whichrepresentpossiblesitesforattackbyoxygenases.Lower-substitutedcompoundsThefirststepofbiodegradationissomekindofoxidationreaction.Thesecondfactorisparticularlyimportantbecausethefirststepinthebiodegradationofmanycompounds(e.g.,hydrocarbons)istheenzymaticinsertionofoxygenintothestructure,Andthisstepisalmostalwaysratelimiting.

TheimportanceofinsertingoxygeninthemoleculeMoregenerally,ifthefirstbiodegradativestepissomeformofoxidation,itseemslogicaltoexpectthatbiodegrabilitywillbeenhancedifthesyntheticchemisthasalreadycarriedit(oxygeninserted)outduringmoleculardesign.Thesolubilityandbio-degradabilityThenumberofsubstitutedgroupsattachedtothemainstructureofthemoleculeandtheaqueoussolubilityofthemoleculesaltersignificantlythebiodegradability.

Thepossibleeffectsofsolubilityonbiodegradabilityareasthefollowing：1:Microbialbioavailability(微生物生物利用度)Insolublechemicalstendtopartitiontotheadsorbedstateinactivatedsludge,sedimentsandsoil.Moststudieshaveshownthatthistendstoreducetherateofbiodegradation2：Rateofsolubilization(溶解速度)Moststudieshaveshownthatforsolidwithverylowsolubility,onlythedissolvedordispersedphaseisavailabletomicroorganisms.Therefore,therateofdissolutionofasolidinwatermaycontroltherateofbiodegradation.Manymicroorganismsexcretebiosurfactants(e.g.,rhamnolipids,鼠李糖脂)thatenhancetherateofsolubilizition.

3：LowaqueousconcentrationSomestudieshaveshownthatforchemicalssolubletotheextentofonlyafewmicrogramsperliterorless,thisconcentrationmaybetoolowforoptimalfunction(无法发挥其最佳功能)ofcellularenzymes(细胞酶)ortransportsystems(传输系统).Thusthebiodegradabilityislimited.4.2.3ExamplesofdesigningbiologicallysaferchemicalsExample1Linearalkylbenzenesulfonate（直链烷基苯磺酸,LAS）AsmanufacturedTPBSisactuallyacomplexmixturebutatypicalstructureiscontinueWhatwillhappenwithhighlybranchedhydrocarbons???EnvironmentalproblemTPBSwerefoundtobeincompletelybiodegradedinmunicipalsewagetreatmentsystems(城市污水处理系统）.[TPBS]wasdegradedbyonlyabout50%insewagetreatmentunitsandasaresultexcessivefoamingoccurredinactivatedsludgeaeration(通风)tanks,aswellasinreceivingrivers.

UsinglinearAlkylbenzene

Sulfonates(LAS)toreplaceTPBS:thestructureEventuallymethodsweredevelopedthatpermittedtheeconomicalmanufactureofamoreenvironmentallyacceptableproductLAS,LASsurfactantscouldbecompletelydegradedinmunicipalsewagetreatmentsystemsmorethan50yearsago,Domagkfoundthatthetoxicityofsimplequaternaryammoniumcompounds(QACS)weregreatlyenhancedbythepresenceofalongalkylgroup(长链烷基）.Example2

DialkylQuaternaries（二烷基季铵盐）DialkylQuaternariesAccordingtoCross,66%ofthemarketforQACsisdominatedbythreeclasses,allofwhicharedialkylquaternaries,meaningthathydrophobicity(疏水性)isimpartedtothemoleculebytwolinearalkylchainsintheC9toC17range.1）di-alkyldimethylammoniumsalts（二烷基二甲铵盐）continue2)imidazoliumquaternaryammoniumsalts（咪唑季铵盐）

continue3)ethoxylated

ethan

aminiumquaternaryunmoniumsalts（羟乙基乙铵鎓季铵盐）

UntilrecentlythefabricsoftenermarketwasdominatedbyaQACofthefirsttype,dihydrogenatedtallow(动物脂)dimethylammoniumchloride(DHTDMAC二氢化动物脂二甲基氯化铵)ThelongalkylgroupsinDHTDMACarederivedfrompurifiedanimalfat(tallow),andconsistofamixturechieflyintheC16-C18(tallowfattyacids)range.ThetrueaqueoussolubilityofDHTDMACisexceedinglylow,andthechemicalsorbsstronglytosolidsinwastewatertreatmentandtheenvironment.Removalintreatmentisthereforehigh(>95%),unlikeTPBS,butdoesnotnecessarilyconespondtoultimatebiodegradation.Example3Alkylphenol

Ethoxylates

（烷基酚乙氧基化物）

Alkylphenolethoxylates(APEs),areoneoftwomajorclassesofnonionicsurfactants（非离型表面活性剂）.AgoodexampleofNPEuseinindustryisinprinting.

APEusesaremainlyindustrialandcoverawiderange,includingapplicationsintextileprocessing（织物加工）,emulsionpolymerization,printing,metalcleaning,oilwelldrillingandpapermaking.

Unlikelinearalcoholethoxylates(乙氧基化物，theothermajorclassofnonionicsurfactants),APEsaremostlybranched.

TheenvironmentalrisksassociatedwithAPEsandespeciallyNPEareacomplexandcontentiousissue.continueDebate

Mostattentionhasfocusedonthemono-anddiethoxylated

nonylphenoladductsNP1EO(n=1)andNP2EO(n=2),whichhavebeenreportedtoberelativelystableintermediatesinNPEbiodegradation.NP1E0,NP2E0andnonylphenol（壬基酚）itselfarehighlytoxictoaquaticorganisms,whereastheparentNPEs(thenumberofethoxylategroupsmaybeashighas30-50,but12-14ismoretypical)aremuchlesstoxic.Recentlyaddedtothisisanewcontroversy,asnonylphenol,NP2EOandrelatedcompoundshavebeenreportedtobeestrogenic(雌性激素的)infish.APE%Biodegradation

LinearBranchedC8AEE97146C8APE9：containing9oxy-ethylgroup5149C9APE96525C9APE9：containing9oxy-ethylgroup6530885557336632750621060180~5008975

Table4-1DegradationofAPE4.3Designingaquaticallysafechemicals氧气、碳氢化合物光合作用哺乳动物、鸟和人绿藻微生物水生生物食物链ToxiceffectsofchemicalstoaquaticspeciesChemicalsthataretoxictoaquaticspeciesmaythereforeputanecosystematunreasonableriskofharm,andcanleadtodisruptionofsomefoodchains.Thesurvivalofterrestrialspecies（陆生生物）,includinghumans,isatleastpartiallydependentuponaquaticorganisms.Therearetwogeneraltypesofchemical-inducedlethality（致命性）inaquaticorganisms:non-specific(i.e.,narcosis麻醉性的),andspecific.

Themajorityofchemicalsthataretoxictoaquaticspeciesaretoxicbynarcosis.Non-specificornarcosistoxicityThemechanisticbasisofnarcosistoxicityistheabilityofachemicaltodiffuseacrossthebiologicalmembranesofanaquaticorganism.Onceahighenoughconcentrationisreachedwithinthecellsorincellularmembranes,itcanleadtodeath.

Becausecellularmembraneshaveahigherlipid（脂类）content,theyarereadilypenetratedbynon-polar,lipid-solublechemicals.Chemicalswithonlyanarcoticmodeoftoxicactionrepresentavarietyofchemicalclassesincludingchlorinatedhydrocarbons,alcohols,ethers,ketones,weakorganicacidsandbases,andsimplearomaticnitro-compounds,tonamejustafew.

specificorreactivetoxicity

Incontrasttochemicalsthatareonlytoxicbynarcosis,somechemicalsaretoxictoaquaticorganismsasaresultofachemicalreactionbetweenthechemical(oritsmetabolite)withacriticalcellularmacromolecule.Thechemicalsexhibitexcesstoxicitytothatofnarcosisandistermedspecificorreactivetoxicity.

Forexample,excesstoxicitycanbeexpectedtoresultifachemical(oritsmetabolite)cancovalentlybondtocriticalproteinmolecules(e.g.,enzymes,DNA).Examplesofthetypesofchemicalsarecyanogens(腈),electrophiles.UseofStructure-ActivityRelationshipstoPredictAquaticToxicityModificationofPhysicochemicalPropertiesandStructureModificationofChemicalStructure4.3.1Useofstructure-activityrelationshipstopredictaquatictoxicityInordertoidentifyrisksposedbynewchemicalsforwhichnodataareavailable,andtodosounderthestricttimeconstraintsprescribedbyTSCA,theEPA(环境保护署）basesmanyofitstoxicityassessmentsonstructure-activityrelationships(SARs).WhatisSARs???SARsrefertotheabilityofagroupofanalogouschemicalstoproduceaparticularbiologicaleffect,andtheinfluencethatthestructuraldifferencesbetweenthechemicalshaveonrelativepotencyinproducingthebiologicaleffect.

IntheQSAR(quantitativestructure-activityrelationships)ofaquatictoxicity,somephysicalpropertiesareoftenusedasoctanol-waterpartitioncoefficient(辛醇—水分配系数logP),

water-solubility(水溶性),dissociationconstant(解离常数pKa）,

molecularweight(分子量),PercentAmineNitrogen（胺氮百分数）,etal.(1)Octanol-WaterPartitionCoefficient

（logP或logKo-w）

Theoctanol-waterPartitionCoefficientisatermusedtoexpressasubstance‘slipophilicity(油溶性）.Itisthephysicalchemistrypropertymostfrequentlyusedtoestimatetheaquatictoxicityoforganicchemicals.BecauselogPoftencorrelateswellwithbiologicalactivity.

4.3.2AdjustingthePhysicalChemicalProperties

Forchemicalswhoseaquatictoxicityisduetonarcosistoxicity

Chemistscanreducethepotentialforaquatictoxicitybydesigningchemicalsasbelow:

logP≤2,molecularweight≤200daltons

logP≥8,regardlessofmolecularweight.

TodecreaselogP,polarsubstationssuchascarboxylic,alcoholic,orotherwatersolublegroupscanbeaddedtochemicals.Ontheotherhand,logPcanbeincreasedbyaddinghydrophobicgroupssuchashalogens,phenylrings,andalkylgroups.

(2)WaterSolubility

Asageneralrule,chemicalshavingwatersolubilitylessthan1ppbareessentiallynon-toxictoaquaticspeciesduetolowbioavailability.

Ontheotherhand,chemicalshavinggoodwatersolubilityarenontoxictoaquaticspecies.However,thereisnotaupperlimit.CH3CH2C（OH）(CH3)2

CH3CH2CH2CH2CH2OH

a＋98g/L

ag/L

continue(3)MolecularSizeandWeightIfthenewchemical'smolecularweightisincreased,thechemicalwillbelesstoxictoaquaticorganismswhileholdingallotherfactorsconstant.Atamolecularweightof1000Daltons,uptakewillbenegligiblebecausethechemicalwillnotdiffuseacrosstherespiratorymembranesofaquaticorganisms.Chemicalswithminimumcross-sectiondiametersgreaterthan1nmaretoolargeforpassivediffusionanduptakethroughtherespiratorymembranesofaquaticorganisms.

Neutralphthalocyaninedyes(天然酞菁染料)minimumcross-sectionaldiameters>1nm.lowacuteandchronictoxicitytoaquaticorganismsTheDesignPrinciple*toincreaseminimumcross-sectionaldiameters*toincreasethemoleculeweight(4)IonPairSomechemicalsaltsexistasstrongionpairswhenanionanditscounterionareassociatedstronglywithoneanother.Thesechemicalsdissociateweaklyornotatallinwater.Consequently,mayhavelowwatersolubilitiesandlowaquatictoxicity

Ifasolubleandchargedchemicalcanbeconvertedtoastrongionpairandstillretainitsusefulnessinauseapplication,thentheresultingsubstancewillbelesstoxictoaquaticorganisms.Ifthepesticidescouldbeformulatedwiththecationicsurfactant:anionicsurfactantstrongionpair(assuminga1:1ratio),thenthetoxicityofthesurfactant(s),couldbereducedmorethan100-fold.（5）Zwitterions（两性离子）ZwitterionsaresubstancesthatcontainpositivelyandnegativelychargedgroupsZwitterionsgenerallyhavelowtoxicitytoaquaticorganisms,providedthatthesubstancehasbalancedchargesanddoesnothavesurfactantproperties.酸性蓝1号

（6）ChelationSubstancesthatcanchelatepolyvalentmetalsareoftentoxictoalgae(海藻）insoftwatersituationsbecausetheydeprivethealgaeofessentialnutrientelements,e.g.,Ca2+,Mg2+,orFe2+.Therefore,algaltoxicitycanbereducedifachelatorisboundwithapolyvalentmetalbeforeexposuretoalgaetakesplaceorifthechemicalisreleasedtosurfacewaterswhichhavemoderatetohighhardness.4.3.3MolecularModification1、NarcosisandExcessToxicityExamplesofchemicalsthataretoxicbyspecificmechanismsinclude:electrophiles(亲电性物质）suchasepoxides,alkylhalides,acrylates,andaldehydescertainesters;dinitrobenzenes;andthiols,tonameafew.Theelectrophilicchemicalsmaycombinecovalentlywithnucleophiles（亲核性物质）locatedinreceptorsofintracellularmacro-molecules.Thisbondingresultsinacellularchangethatisdifficulttoreverse,andresultinirreversibletoxicity.

ExcessToxicity

TheaquatictoxicityofachemicalthatistoxicfromaspecificmechanismisusuallyconsiderablygreaterthanthatpredictedforthesubstanceusingaQSARequationdevelopedforchemicals

thataretoxicbynarcosis.ExcessToxicity=TAT－TAP

2.Thetoxicityofchemicalscanbedecreased

bymodification

Thetoxicityofchemicalsthataretoxicbyaspecificmechanismcanbedecreasedbymakingstructuralmodificationsthatstericallyhinderthemsuchthattheycannolongerreachoractwiththeirtargetsites(i.e.,reducingtheirtoxicitytoonlynarcosis).Forexample,ie

stericallyhinderedcyclicaliphaticamineis2