第一节设计安全无毒化学品的一般原则

Chapter3

DesigningSaferChemicalsGeneralPrinciplesforDesigningSaferChemicalsMethodsforDesigningSaferChemicalsChapter3DesigningSaferChemicals3.1GeneralPrinciplesforDesigningSaferChemicals

3.1.1GeneralPrinciplesforDesigningSaferChemicalsTwomainwaystoavoidHazardandToxicity:

1：makeitnotpossibletoenterthebody,2：makeitnotpossibletoaffectthebio-chemicalandphysiologicalprocesses(生物化学和生理过程)hazardously.tohumanbeings,toenvironment

Directhazard&IndirecthazardGeneralPrinciplesforDesigningSaferChemicalsExternalconsiderations：

Reductionofexposureoraccessibility

减少化学品与生物机体接触的可能性Internalconsiderations：

Preventionoftoxiceffects

预防化学品的毒性Theyrefertothereductionofexposurebydesigningchemicalstoimprovetheimportantphysicalandchemicalpropertiesrelatedtoenvironmentaldistributionandtheup-takeofthechemicalsbymanandotherlivingorganisms.Externalconsiderations：GeneralPrinciplesforDesigningSaferChemicalsExternalconsiderations:

ReductionofexposureoraccessibilityA.Propertiesrelatedtoenvironmentaldistribution/dispersion

1.Volatility/density/meltingpoint2.Watersolubility3.Persistence/biodegradation(生物降解性)a.oxidation,b.hydrolysis,c.microbialdegradation（微生物降解性）

4.Conversiontobiologicallyactivesubstances5.ConversiontobiologicallyinactivesubstancesB.Propertiesrelatedtouptakebyorganisms

1.Volatility（挥发性）

2.Lipophilicity（亲油性）

3.Molecularsize4.Degradation（降解性）

a.hydrolysis（水解）,b.EffectofpH,c.susceptibilitytodigestiveenzymes

（敏感性）（消化酶）Externalconsiderations:

ReductionofexposureoraccessibilityStructuraldesignsorredesigns:

increasedegradationrates,reducevolatility（挥发性）,reducepersistencetimeintheenvironmentandpossibilityofconversiontobiologicallyactivesubstancesintheenvironment.ExternalconsiderationsMoleculardesigns:

reduceorimpede（妨碍）absorptionbyman,animalsandaquaticlife（水生生物）.Externalconsiderations:

ReductionofexposureoraccessibilityBio-accumulation（生物聚集）or

Bio-magnification（生物放大）:Itreferstotheincreaseoftissueconcentrationofachemicalasitprogressesupthefoodchain.生物放大：指食物链向上一级进展，化学物质在组织中的浓度增大的现象。Externalconsiderations:

ReductionofexposureoraccessibilityCertainchemicals,forexamplechlorinatedpesticidesandotherchlorinatedhydrocarbons,willbestoredinthetissues(组织)ofawiderangeoflivingorganismsandmayaccumulatetotoxiclevel(致毒水平).Thisphenomenonisexacerbated(恶化)bythefactthatthelowerformsoflifeortheorganismatlowertrophic(营养的)stagesaresubsequentlyconsumedasfoodbyfish,mammalsandbirds.Thesespeciesinturnmaybeconsumedbyhuman.Externalconsiderations:

Bio-magnification

FoodchainHence,thesubstancesofconcernsmaybothbio-accumulateinlowerlifeformsandbio-magnifyorincreasetheirconcentrationinhigherlifeformsbyordersofmagnitudeastheyaccumulateandmigrateupthefoodchain.

毒物可在低级生命形式中聚集，并会随着食物链在更高一级的生命形式中被生物放大到更大的数量级，如此由低级生命形式传递到更高级的生命形式。Externalconsiderations:Reductionofexposure

oraccessibility

D.Reduction/eliminationofimpurities

1.Generationofimpuritiesofdifferentchemicalclasses（不同化学类别的不纯物）

2.Presenceoftoxichomologs（同系物）

3.Presenceofgeometric,conformationalorstereoisomers(几何、构象及光学异构体)Externalconsiderations:

ReductionofexposureoraccessibilityTheygenerallyincludeapproachesusingmolecularmanipulationsto:

Facilitatebio-detoxication(生物解毒性)AvoiddirecttoxicityAvoidindirectbio-toxicityorbio-activationInternalconsiderations:Preventionoftoxiceffects(预防毒性)Internalconsiderations-Prevention

oftoxiceffectsA.Facilitationofde-toxication（促进生物解毒性）

1.Facilitationofexcretion（排泄）

a.selectionofhydrophilic(亲水的)compoundsb.facilitationofconjugation/acetylation(乙酰化)conjugatedwith:glucuronicacid(葡萄糖醛酸)sulfate(硫酸盐),aminoacidtoaccelerateurinary（泌尿器的）orbiliary(胆汁的)excretionc.otherconsiderations

2.

Facilitationofbiodegradation(可生物降解性)

a.oxidation；b.reduction；c.hydrolysisB.Avoidanceofdirecttoxication

1.Selectionofnon-toxicchemicalclassesorparentcompounds2.Selectionofnon-toxicfunctionalgroups

a.avoidanceoftoxicgroups;b.plannedbiochemicaleliminationoftoxicstructurethroughthenormalmetabolism(新陈代谢)oftheorganismorstrategicmolecularrelocationofthetoxicgroups;c.structuralblockingoftoxicgroups;d.alternatemolecularsitesfortoxicgroups.

Internalconsiderations-Prevention

oftoxiceffectsIndirectbiotoxication—bioactivationItdescribesthecircumstanceswhereachemicalisnottoxicinitsoriginalstructuralformbutbecomestoxicafterinvivotransformationtoatoxicmetabolite

（代谢物）.Bioactivationrepresentsacharacteristicmechanismforthetoxicityofmanycarcinogenic(致癌的),mutagenic（诱变的）,andteratogenic（畸胎的）chemicals.Internalconsiderations-Prevention

oftoxiceffectsC.Avoidanceofindirectbiotoxication(bioactivation)1.Avoidingchemicalswithknownactivationroutes

a.highlyelectrophilicornucleophilicgroupsb.unsaturatedbondsc.otherstructuralfeatures2.Structuralblockingofbioactivation

IncorporationofstructuralmodificationsthatpreventbioactivationInternalconsiderations-Prevention

oftoxiceffectsOpportunitiesforthesyntheticchemistBoththeexternalandinternalconsiderationsprovideawiderangeofopportunitiesandapproachestothesyntheticchemistfordesigningchemicalstructuresthatreduceoreliminatethetoxicityofindustrialandcommercialchemicals.Theopportunitiesandapproachesareexpandedfurtherbythepossibilityoffactoringmorethanoneapproachintothemoleculardesign.e.g.bothpropertiesthatreduceexposureandoneormorepropertiesthatfacilitateexcretion（排泄）ormetabolic（代谢）deactivation.Theeffectiveharmonization（一致）ofthesafetyconsiderationsandofcomplexlivingorganismswiththeefficacyconsiderationsofchemicalstructuresforindustrialandcommercialpurposesisexpectedtoachieve.Delicate（精巧的）balancebetweensafetyandefficacy.Dataandinformationonthestructure-biologicalactivityrelationshipofthesesamechemicalsatmolecularlevel.Opportunitiesforthesyntheticchemist3.1.2.Buildingthefoundationfordesigningsaferchemicals

AcademiaIndustry

Tobringaboutauniversalpracticeofthedesignofsaferchemicals,substantialchangesmusttakeplaceinbothacademiaandindustry

1、Increasedawarenessoftheconceptofdesigningsaferchemicals2、Establishingthescientific,technical,andeconomiccredibilityoftheconcept3、Effectingasharperfocusonchemicalsofconcern4、GreateremphasisonmechanisticandSARresearchintoxicity5、Revisionintheconceptsandpracticeinchemicaleducation6、Majorparticipationbythechemicalindustry3.1.2.Buildingthefoundationfordesigningsaferchemicals1.Awarenessoftheconcept

Strictenvironmentalcontrol：

alreadybuttheoriginoftheenvironmentalpollutionhasnotyetbeenunderstood.

Greenchemistry:Scientificactivitiesandeducationalactivitieshavebeencarriedout,however,vague(含糊的)orblurred（模糊不清的）understandingorevenmisunderstandingsstillgenerallyexistinbothacademiaandindustryaswellasotherarea.Themedia:misleadingreportsstillexistandwhatisreallyneededdoesnotappear.Industry:Althoughsomeideasareaccepted,itisfarfrompractice.2.Scientificandeconomiccredibility3.Focusonchemicalsofconcern4.MechanistictoxicologicalresearchResearchintoxicologymustshiftitsemphasistomechanisticresearch,orbasicunderstandingofhowaspecificchemicalorchemicalclassexertsitstoxicologicaleffectonlivingorganismsatthemolecularlevel.Itisonlywiththeaccumulationofsubstantialdataandinformationofthisnaturethattheexistingprinciplesandconceptsofstructure-activityrelationship(SAR)canbedevelopedfurther.TheSARofachemicalmayinvolveoneormorefunctionalgroups,theparentscompoundsoracombinationoffunctionalgroupsandtheparentchemicalorchemicalclass.Theelucidationoftoxicologicalmechanismsonachemicalspecificorclassspecificbasisandthesystematiccompilationofthisdatawillprovidethenecessaryfoundationandguidanceforthemolecularmanipulationbysyntheticchemiststodevelopsaferchemicals.4.MechanistictoxicologicalresearchTostimulateinterestandprovideacademiawiththemeanstoundertakemorebasicresearchintoxicology,theappropriateinstitutionsmustaccepttheconceptandactivelyparticipatebymakingfundsavailableinthisspecificareaofresearch.Withoutfinancialsupportforconductofmorebasicmechanisticresearch,theopportunitiesfornew,creativemolecularstructuresthatarebothefficatiousandsafewillbeseverelylimited.4.Mechanistictoxicologicalresearch5.RevisionofchemicaleducationTherevisionoftheexistingconceptsandpracticesofchemicaleducationatbothundergraduateandgraduatelevelisneeded.SeparatedmodeofeducationtraditionallyAlthoughthefunctionofdesigningsaferchemicalscanbeaccomplishedthroughmulti-disciplinarycollaborationamongchemists,toxicologists,pharmacologists,bio-chemistsandothers,itisbelievedthatindividualswithacombinedknowledgeofchemicalstructure,industrialapplicationandbiologicalactivityatthemolecularlevelwillperformmoreefficientlyandeffectively.

Toprovideadequatetrainingofsyntheticchemistsinterestedindesigningsaferchemicalsanddestinedforcareersinbothacademiaandindustry,itisbelievedthatnewcurricula(课程)shouldbedevelopedtoprovidefirmgroundingsinbiochemistry,pharmacologyandtoxicology.(药理学)(毒物学)5.RevisionofchemicaleducationAtthegraduatelevelthismaybebestaccomplishedthroughjointappointmentsandmulti-disciplinarygraduatecommitteescomprisedoftheappropriatefieldsofstudytooverseecurricula(课程)andgraduateresearcheffortsdirectlyrelatedtothechemistry/biologyrelationshipsinvolvedindesigningsaferchemicals.5.RevisionofchemicaleducationIndustrialefficacyofchemicalsIndustrialsynthesischemist

Traditional

IndustrialeducationalmodeMedicalandpesticidechemistsPharmacological,Biochemical,Toxicologicaleffects(SAR）TraditionalPharmacologicaleducationalmodeNewhybridGreenchemistAcomparisonofthetraditionaleducationalmodeandthenewmodeneededforcultivationofhybridchemist5.RevisionofchemicaleducationThenewhybridsyntheticchemistwillevolvefromthecurrentsubspecialitiesinsyntheticchemistry.Thenewhybridchemistorthetoxicologicalchemistorsimplygreenchemistmustconsiderboththefunctionofthechemicalinitsindustrialorcommercialapplicationanditstoxicologicaleffectsinhumansandtheenvironment.Inmostrespectsachievingthedelicatebalancebetweensafetyandefficacywillundoubtedlyprovetobethemostdifficultandchallengingeffortinthehistoryofsyntheticchemistry.However,withtheappropriateresolveandfocus,thedevelopmentofsuchchemicalscanbeachieved.6.ChemicalindustryinvolvementsMajorsupportandparticipationbythechemicalindustryisessential.Industrymusttakestepstoincreasetheawarenessoftheconceptamongitsscientistsandmanagement.Industrymustencourageitspeopletoapproachtheconceptwithopenmindsandtocarefullyevaluateitspotentialintermsofeconomicandtechnicalfeasibility.3.2.Techniques

indesigningofsaferchemicals

3.2.1毒理学分析及相关分子设计3.2.2利用构效关系设计安全的化学品3.2.3利用基团贡献法构筑构效关系3.2.4利用等电排置换设计更加安全的化学品3.2.5“软”化学设计3.2.6用另一类有相同功效而无毒的物质替代有毒有害物质3.2.7消除有毒辅助物品的使用Techniquesindesigningofsaferchemicals3.2.1UnderstandingofthebasictoxicityandcorrespondingmoleculardesignToreducethetoxicityofachemicalsubstanceortomakeasaferchemicalthanasimilarchemicalsubstance,anunderstandingofthebasictoxicityisrequired.

TechniquesindesigningofsaferchemicalsOncetoxicityisunderstood,strategicstructuralmodificationscanbemadethatdirectlyorindirectlyattenuate(削弱)toxicitybutdonotreducethecommercialusefulnessofthechemical.Thereareseveralapproachesthatprovidetheframeworkformolecularmodificationneededfortherationaldesignofsaferchemicals.TechniquesindesigningofsaferchemicalsToxicologicalmechanism

structuralmodificationsofthemolecule1、ReducingAbsorption2、Useoftoxicmechanismtoeliminatetoxicity3、Useofstructure-activity(toxicity)relationships4、Useofisostericreplacement（等电排置换）5、Useofretrometabolic(后代谢)(softchemical软化学)design6、Identificationofequallyefficacious,lesstoxicchemicalsubstitutes7、EliminationoftheneedforassociatedtoxicsubstancesTechniquesindesigningofsaferchemicals3.2.1.1ToxicityofchemicalsTherearethreefundamentalrequirementsforchemicaltoxicity(致毒三要素):1.Exposuretothechemicalsubstance(接触致毒)2.Bio-availability(生物吸收致毒)3.Intrinsictoxicity(固有毒性)Exposuretothechemicalsubstance:Thecontactofthesubstancewiththeskin,mouthornostrils(鼻孔)AspectsofchemicaltoxicityBio-availability:Theabilityofasubstancetobeabsorbedintoanddistributedwithinalivingorganism(e.g.,humans,fish)toareaswheretoxiceffectsareexertedandisafunctionofthetoxicokineticsofthesubstance.

Toxicokinetics(毒性动力学相):theinterrelationship(内在关系)ofabsorption,distribution,metabolismandexcretion.AspectsofchemicaltoxicityAspectsofchemicaltoxicityIntrinsictoxicity:Theabilityofasubstancetocauseanalterationinnormalcellularbiochemistryandphysiologyfollowingabsorption.AspectsofchemicaltoxicityToxicophore(毒性载体):aparticularstructuralportionofthesubstancetowhichthetoxicityisgenerallyattributed.Toxicogenic(产毒结构):Somesubstancescontainstructuralfeaturesthatarenotdirectlytoxicbutundergometabolicconversion(bioactivation)toyieldatoxicophore.Thesestructuralfeaturesaretoxicogenic(产毒的),inthattheyyieldatoxicophoresubsequenttometabolism.

毒性动力学相：化学品在生命机体内吸收、分布、代谢和排泄的内在关系。毒性动态学相：化学品毒性载体与生物分子活性位的致毒相互作用。AspectsofchemicaltoxicityAspectsofchemicaltoxicityExposureAbsorptionDistributionMetabolismExcretionChemicalandbiomolecularinteractionintargettissueToxiceffect毒性动力学相毒性动态学相1：AbsorptionItreferstotheentranceofthesubstanceintothebloodstreamfromthesiteofexposure.Forasubstancetobeabsorbedandbecomebio-available,themoleculesofthesubstancemust

passthrough

numerouscellularmembranes

andenterthebloodstream

(whichismostlyaqueous)

wheretheyarecirculatedthroughoutthebody,andagain

cross

manycellularmembranes

togainentranceintothecellsoforgansandtissues.Thismeansthatthesubstancemusthavethenecessaryphysicochemicalpropertiesthatenablethemoleculescomprisingthesubstancetoreachtheirfreemolecularform,crossbiologicalmembranesandentertheblood.1：Absorption1：AbsorptionPhysicochemicalandbiologicalfactors

influencingmembranepermeationandabsorptionPhysicochemicalfactorsMolecularsize,molecularweight,dissociationconstant,aqueoussolubility,lipophilicity:(octanol/waterpartitioncoefficient,i.e.,logP),physicalstate(solid,liquid,gas),particlesize.1:AbsorptionAnatomical（解剖的）andbiologicalfactorsarealsoimportantinabsorption.Theseincludesurfacearea,thicknessofthemembranebarrier,andbloodflow.BiologicalfactorsPhysicochemicalandbiologicalfactors

influencingmembranepermeationandabsorptionForsolid,particlesizealsoaffectstherateofdissolutionandthus,overallabsorption.Thesmallertheparticlesize,thelargerthesurfaceareaandthefasterthedissolutionandabsorptionofthesubstance.Largerparticlesizemeanslesssurfaceareaandthereforeaslowerdissolutioninthegastricfluids,andslowerorevenlessabsorption.Thefunctionofthelung:exchangeoxygenforcarbondioxide.Thecontinuous,repetitivebreathingoftheairwaysfromthetrachea(支气管)totheterminalalveoli(肺气泡)(wheregasexchangetakesplace)createanenormoussurfacearea.Thelungsalsoreceive100%ofthebloodpumpedfromtheheart.Thethicknessofthealveolicellularmembrane(theabsorptionbarrierofthelung)isonly0.2~0.4μm.

AbsorptionfromlungAbsorptionfromthelungTheseanatomical(解剖学)andphysiologicalcharacteristicsofthelungenabletherapidandefficientabsorptionofoxygenandfavortheabsorptionofothersubstancesaswell.Becausethecellularmembranesofthealveoli(肺气泡)areverythin(0.2∼0.4µm),sothatthedistanceasubstancehastotraverseisveryshort.Chemicalsabsorbedthroughthelungcanenterthefloodwithinseconds.Infact,watersolubility,ratherthanlipidsolubility,isthemoreimportantfactor.AbsorptionfromthelungSkin(Dermal)Absorption

Forchemicalstobeabsorbedfromtheskin,theymustpassthroughthe7celllayersoftheepidermisbeforeenteringthebloodandlymphcapillaries(毛细血管)inthedermis(皮肤).Thisabsorptionbarrierrangesfrom100to1000μm.Theratedeterminingstepisdiffusionthroughthestratumcormeum(hornylayer,角质层),whichistheuppermostlayeroftheepidermis.Passagethroughthe6otherlayerismuchmorerapid.Skin(Dermal)Absorption

Substancesthatareliquidintheirneat(纯的)formtendtobeabsorbedmorereadilythansolid,becauseliquidscovermoredermalsurfaceareaandarenearertotheirfreemolecularstatethanaresolid.Solidwithhighermeltingpoints(>125℃)andsubstances(particularlysolids)thatareionicorhighlypolararegenerallynotwellabsorbedfromtheskin.Substanceswithgreaterlipophilicity(油溶性)(higherlogP)areabsorbedmorereadilyfromtheskinthanarelesslipophilicsubstances.Skin(Dermal)AbsorptionSkin(Dermal)AbsorptionHighlylipophilicsubstances(logP>5),however,canpassthroughthestratumcormeumbutaregenerallytoowaterinsolubletopassthroughtheremaininglayersandenterthebloodstream.Thesesubstancesarepoorlyabsorbedfromtheskin.2：DistributionWhereasubstanceisdistributed?

(1)largelydependentuponitsPhysicochemicalCharacteristics

lipophilicsubstances:enterthebrainabilitytocombinewithplasmaproteins(血浆蛋白质),abilitytoaccumulateinfattytissues(脂肪组织),etc.

(2)TargetOrgansofaparticularsubstance

Thetoxicityofasubstanceisusuallyelicitedinonlyoneortwoorgans.ThesesitesarereferredtoastheTARGETORGANSofaparticularsubstance.

2：Distribution3：Metabolism（代谢）Thebodyhastheabilitytodistinguishbetweennon-foodchemicalandnutritionalsubstances.nutritionalsubstances→non-nutritionalsubstancesnon-nutritionalsubstances:thebodywilltrytoeliminateasquicklyaspossible.urine(尿)andfeces(粪):requiresgreaterwatersolubilityThebodyhasenzyme-mediatedmechanismsforconvertingsubstancesintomorewatersolublesubstancesthatareeasiertoexcrete.(metabolismorbiotransformation）

3：MetabolismThepurposeofmetabolism:Detoxication:adefensemechanismtoconvertpotentiallytoxicchemicalsubstancestoothersubstances(metabolites)thatarereadilyexcreted.Thechemicalreactionsinvolvephase-Ⅰreactions(I期反应)phase-Ⅱreactions(II期反应)Phase-IreactionsPhase-Ireactions

convertthechemicalsubstancesintoamorepolarmetabolitebyoxidation,reduction,hydrolysisreactionstointroduceoreliminatethe-OH、-CH3、-NH2、-SHgroups.

Phase-IIReactionsPhase-IIreactionsinvolvecoupling(conjugation)ofthechemicalsubstanceoritspolar(Phase-I)metabolitewithanendogenous(内生的)substratesuchasglucuronate(葡萄糖酸),sulfate,acetate,oranaminoacid,tofurtherincreasewatersolubilityandpromoteexcretion.

Reactiontypeofmetabolism:oxidationcatalyzedbythecytochrome(细胞色素)P450,Phase-I.P450foundin1958,coordinatedwithCO:λmax=450nmMetabolism转化类型转化反应通式1．氧化脂肪族羟化芳香族羟化

N去烷基

O去烷基醛类氧化R→ROHAr→ArOHR1―N(CH3)―R2→R1―NH―R2

R―O―CH3→ROHR―CH2OH→RCHORCHO→RCOOH司可巴比妥,苯妥英,地西泮,可待因,氯丙嗪,对硫磷,氟烷,苯并芘(致癌物)2．还原硝基还原偶氮还原醛类还原ArNO2→ArNH2Ar1―N=N―Ar2→Ar1NH2+Ar2NH2RCHO→RCH2OH乙醇,乙醛,肾上腺素,组胺,茶碱,氯硝西泮,百浪多息,水合氯醛,纳洛酮,3．水解酰胺键水解酯键水解R1―CONH―R2→R1COOH+R2NH2

R1COOR2→R1COOH+R2OH利多卡因,普鲁卡因胺,乙酰胆碱,普鲁卡因4．结合葡萄糖醛酸结合乙酰化载体：UDP-葡萄糖醛酸载体：乙酰辅酶A氯霉素,吗啡,异烟肼MetabolismNote:Metabolismofcertainchemicalsubstancesdoesnotresultindetoxication.Infact,itisthemetabolitesofmanytoxicchemicalsubstancesthat,ironically,areresponsibleforthetoxicity.Whatdoesthisrefertoas???

Bio-activationAspectsofchemicaltoxicityExposureAbsorptionDistributionMetabolismExcretionChemicalandbiomolecularinteractionintargettissueToxiceffect毒性动力学相毒性动态学相4：Toxicodynamics(毒物动态学)Thetoxicodynamicphasecomprisestheprocessesinvolvedinthemolecularinteractionbetweenthetoxicsubstanceanditsbio-molecularsitesofactionandtheresultantsequenceofbiochemicalandbiophysicaleventsthatfinallyresultintheobservedtoxiceffect.4：ToxicodynamicsIngeneral,atoxicsubstanceexertsitstoxicitybytheinteractionofaparticularportionofthemoleculeorametabolitethereofwithacellularmacromolecule(enzymes,nucleiacids,orprotein,tonamejustafew),whichdisruptsnormalbiochemicalfunctionofthemacromoleculeandultimatelyresultsinthetoxicity.Theparticularportioniscalledas???Toxicophore(毒性载体)5:ExcretionSubstancesareeliminatedfromthebodybyurine(尿),feces(粪),orbreath,bile(胆汁)duct(排泄管).Thekidney(肾)andbileducteliminatepolar(morewatersoluble)substancesmoreefficientlythansubstanceswithhighlipidsolubility.Thekidneyisthemostimportantorganforeliminatingsubstancesortheirmetablites（代谢物)fromthebody.5:ExcretionAspectofchemicaltoxicityExposure

Absorption,Distribution,Metabolism,ExcretionExposurephase

ToxicokineticphaseChemical-biologicalInteractionintargettissuesToxicodynamicsToxicEffect

3.2.1.2

ReduceabsorptionbyMolecularmodification

ReducingabsorptionfromthelungLessvolatilelowvaporpressurehigherboilingpointLowwatersolubilityHighmeltingpoint(>150℃)Particlesize:>5µmReducingAbsorptionFromtheSkinTobesolidTobepolarorionizedsodiumsaltofanacid,hydrochloridesaltofanamineTobewatersolubleTobeoflowlipophilicityIncreasingparticlesizeIncreasingmolecularweight3.2.1.3

Designingsaferchemicalsfromanunderstandingoftoxicmechanism

1:ToxicMechanismsInvolvingElectrophiles

(亲电性物质)ChemicalsubstancesthatareelectrophilicoraremetabolizedtoelectrophilicspeciesarecapableofreactingcovalentlywithnucleophilicsubstituentsofcellularmacromoleculessuchasDNA,RNA,enzymes,proteins,andothers.

1:ToxicMechanismsInvolvingElectrophiles

(亲电性物质)Examplesofnucleophilicsubstituents:thiolgroups(巯基)ofcysteinyl(半酰氨酸)residuesinprotein,sulfuratomsofmethionyl(甲硫氨酸)residuesinprotein,primaryaminogroupsofarginine(精氨酸)andlysine(赖氨酸)residues,secondaryaminogroups(e.g.,histidine,组氨酸)inprotein,aminogroupsofpurine(嘌呤)basesinRNAandDNA,oxygenatomsofpurinesandpyrimidines(嘧啶),andphosphateoxygens(P=O)ofRNAandDNA1:ToxicMechanismsInvolvingElectrophiles

(亲电性物质)Theseirreversiblecovalentinteractionscanleadtoavarietyoftoxiceffectsincludingcancer,hepatotoxicity(肝中毒),hematotoxicity(血液中毒),nephrotoxicity(肾中毒),reproductivetoxicity,anddevelopmentaltoxicity.

Fortunately,themammalian(哺乳动物)bodyhasseveraldefensesystemsthatoffer“sacrificial”nucleophilesthatcanreactwithforeignelectrophiles.Suchastheglutathione(谷胱甘肽)transferase(转移酶)systemandtheepoxidehydratase(环氧化物水解酶)system

Electrophilicchemicalsubstances

Non-electrophilicChemicalsubstancesElectrophilicchemicalsubstancesReactionwithnucleophileswithinNaturaldefensesystems

MetabolismNon-toxic,Watersolubleadducts

Reactionwithnucleophilesofnon-defenseCellularmacromoleculesExcretionToxicity

Figure3-3Detoxificationofelectrophilicsubstancesorelectrophilicmetapolites1:ToxicMechanismsInvolvingElectrophiles

Table3-4.Examplesofelectrophilicsubstituentscommonlyencounteredincommercialsubstances,thereactiontheyundergowithbiologicalnucleophiles,andtheresultingtoxicity.ElectrophileCharacteristicStructureNeucliophilicreactionToxicEffectAlkylhalidesR-XX=Cl、Br、I、FSubstitutionVarious,e.g.Cancer,granulocytopenia(粒性白细胞减少症)γ-diketonesR1COCH2CH2COR2SchiffbaseformationNeurotoxicityα-βunsaturatedcarbonylandrelatedgroupsC=C—C=OC≡C－C＝0C＝C－C≡NC=C-S-MichaeladditionVarious,e.g.Cancer,mutations,Hepatotoxicities,nephrotoxicity),hematotoxicity),neurotoxicityEpoxides(Terminal)AdditionMutagenicity，TesticularleisionsIsocyanates(异氰酸酯)—N=C=O—N=C=SAdditionCancer,Mutagen