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OrganophosphateToxicity

OrganophosphateToxicity
Author:KennethDKatz,MD,FAAEM,ABMTChiefEditor:AsimTarabar,MDmore...
Updated:Jan27,2015

Background
Organophosphate(OP)compoundsareadiversegroupofchemicalsusedinbothdomesticandindustrialsettings.
Examplesoforganophosphatesincludeinsecticides(malathion,parathion,diazinon,fenthion,dichlorvos,
chlorpyrifos,ethion),nervegases(soman,sarin,tabun,VX),ophthalmicagents(echothiophate,isoflurophate),and
antihelmintics(trichlorfon).Herbicides(tribufos[DEF],merphos)aretricresylphosphatecontainingindustrial
chemicals.
Organophosphatecompoundswerefirstsynthesizedintheearly1800swhenLassaignereactedalcoholwith
phosphoricacid.Shortlythereafterin1854,PhilipdeClermountdescribedthesynthesisoftetraethylpyrophosphate
atameetingoftheFrenchAcademyofSciences.Eightyyearslater,Lange,inBerlin,and,Schrader,achemistat
BayerAG,Germany,investigatedtheuseoforganophosphatesasinsecticides.However,theGermanmilitary
preventedtheuseoforganophosphatesasinsecticidesandinsteaddevelopedanarsenalofchemicalwarfare
agents(ie,tabun,sarin,soman).Afourthagent,VX,wassynthesizedinEnglandadecadelater.DuringWorldWar
II,in1941,organophosphateswerereintroducedworldwideforpesticideuse,asoriginallyintended.
Massiveorganophosphateintoxicationfromsuicidalandaccidentalevents,suchastheJamaicangingerpalsy
incidentin1930,ledtothediscoveryofthemechanismofactionoforganophosphates.In1995,areligioussect,
AumShinrikyo,usedsarintopoisonpeopleonaTokyosubway.Masspoisoningsstilloccurtodayin2005,15
victimswerepoisonedafteraccidentallyingestingethioncontaminatedfoodinasocialceremonyinMagrawa,India.
Nerveagentshavealsobeenusedinbattle,notablyinIraqinthe1980s.Sarin,deliveredbyrockets,wasusedin
thechemicalwarfareattackinDamascus,Syriain2013. [1]Additionally,chemicalweaponsstillposeaveryreal
concerninthisageofterroristactivity.
Exposuretoorganophosphatesisalsopossibleviaintentionalorunintentionalcontaminationoffoodsources.
Althoughnoclinicaleffectsofchronic,lowlevelorganophosphateexposurefromafoodsourcehavebeenshown,
advancementsinriskassessmentandpreparednessareongoing. [2,3]

Pathophysiology
Theprimarymechanismofactionoforganophosphatepesticidesisinhibitionofcarboxylesterhydrolases,
particularlyacetylcholinesterase(AChE).AChEisanenzymethatdegradestheneurotransmitteracetylcholine
(ACh)intocholineandaceticacid.AChisfoundinthecentralandperipheralnervoussystem,neuromuscular
junctions,andredbloodcells(RBCs).
OrganophosphatesinactivateAChEbyphosphorylatingtheserinehydroxylgrouplocatedattheactivesiteofAChE.
Thephosphorylationoccursbylossofanorganophosphateleavinggroupandestablishmentofacovalentbondwith
AChE.
OnceAChEhasbeeninactivated,AChaccumulatesthroughoutthenervoussystem,resultinginoverstimulationof
muscarinicandnicotinicreceptors.Clinicaleffectsaremanifestedviaactivationoftheautonomicandcentral
nervoussystemsandatnicotinicreceptorsonskeletalmuscle.
OnceanorganophosphatebindstoAChE,theenzymecanundergooneofthefollowing:
Endogenoushydrolysisofthephosphorylatedenzymebyesterasesorparaoxonases
Reactivationbyastrongnucleophilesuchaspralidoxime(2PAM)
Irreversiblebindingandpermanentenzymeinactivation(aging)
Organophosphatescanbeabsorbedcutaneously,ingested,inhaled,orinjected.Althoughmostpatientsrapidly
becomesymptomatic,theonsetandseverityofsymptomsdependonthespecificcompound,amount,routeof
exposure,andrateofmetabolicdegradation. [4]

Epidemiology
Frequency
UnitedStates
In2013,theAmericanAssociationofPoisonControlCentersreported2354singleexposurestoorganophosphate
insecticides,alongwith5778singleexposurestoorganophosphateinsecticidesincombinationwithcarbamateor
noncarbarbamateinsecticidestherapywith2PAMwasusedin51cases. [5]Poisoncenterrecordedexposuresto
organophosphateshavedeclinedinrecentdecadesbecauseoftheUnitedStatesEnvironmentalProtectionAgency
phasingoutcommonlyusedhouseholdandagriculturalorganophosphateagents. [6]
International
Pesticidepoisoningsareamongthemostcommonmodesofpoisoningfatalities.IncountriessuchasIndiaand
Nicaragua,organophosphatesareeasilyaccessibleand,therefore,asourceofbothintentionalandunintentional
poisonings.Theincidenceofinternationalorganophosphaterelatedhumanexposuresappearstobe
underestimated. [7]

Mortality/Morbidity
Worldwidemortalitystudiesreportmortalityratesfrom325%.Thecompoundsmostfrequentlyinvolvedinclude
malathion,dichlorvos,trichlorfon,andfenitrothion/malathion.
Mortalityratesdependonthetypeofcompoundused,amountingested,generalhealthofthepatient,delayin
discoveryandtransport,insufficientrespiratorymanagement,delayinintubation,andfailureinweaningoff
ventilatorysupport.

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Complicationsincludeseverebronchorrhea,seizures,weakness,andneuropathy.Respiratoryfailureisthemost
commoncauseofdeath.

Age
Organophosphates(OPs)mayaffectchildrenorotheratriskpopulationsdifferently.Theincreasedsusceptibilityhas
notbeenelucidatedbutmayinvolvedelayedorpersistenteffects.Moreworkinthisareaisunderwayandshould
helpidentifythetrueriskpotential. [8]

ContributorInformationandDisclosures
Author
KennethDKatz,MD,FAAEM,ABMTAssistantProfessor,DivisionofMedicalToxicology,Departmentof
EmergencyMedicine,UniversityofPittsburghMedicalCenterMedicalDirector,PittsburghPoisonCenter
KennethDKatz,MD,FAAEM,ABMTisamemberofthefollowingmedicalsocieties:AmericanAcademyof
EmergencyMedicineandAmericanCollegeofMedicalToxicology
Disclosure:Nothingtodisclose.
Coauthor(s)
DanielEBrooks,MDCoMedicalDirector,BannerGoodSamaritanPoisonandDrugInformationCenter,
DepartmentofMedicalToxicology,BannerGoodSamaritanMedicalCenter
DanielEBrooks,MDisamemberofthefollowingmedicalsocieties:AmericanAcademyofClinicalToxicology,
AmericanCollegeofEmergencyPhysicians,andAmericanCollegeofMedicalToxicology
Disclosure:Nothingtodisclose.
SpecialtyEditorBoard
LisaKirkland,MD,FACP,CNSP,MSHAAssistantProfessor,DepartmentofInternalMedicine,Divisionof
HospitalMedicine,MayoClinicANWIntensivists,AbbottNorthwesternHospital
LisaKirkland,MD,FACP,CNSP,MSHAisamemberofthefollowingmedicalsocieties:AmericanCollegeof
Physicians,SocietyofCriticalCareMedicine,andSocietyofHospitalMedicine
Disclosure:Nothingtodisclose.
FranciscoTalavera,PharmD,PhDAdjunctAssistantProfessor,UniversityofNebraskaMedicalCenter
CollegeofPharmacyEditorinChief,MedscapeDrugReference
Disclosure:MedscapeSalaryEmployment
TimothyDRice,MDAssociateProfessor,DepartmentsofInternalMedicineandPediatricsandAdolescent
Medicine,StLouisUniversitySchoolofMedicine
TimothyDRice,MDisamemberofthefollowingmedicalsocieties:ChristianMedical&DentalSociety
Disclosure:Nothingtodisclose.
ChiefEditor
AsimTarabar,MDAssistantProfessor,Director,MedicalToxicology,DepartmentofEmergencyMedicine,Yale
UniversitySchoolofMedicineConsultingStaff,DepartmentofEmergencyMedicine,YaleNewHavenHospital
Disclosure:Nothingtodisclose.
AdditionalContributors
TheauthorsandeditorsofMedscapeReferencegratefullyacknowledgethecontributionsofpreviousauthors
MarinaCFurtado,MD,andLisaChan,MD,FACEP,tothedevelopmentandwritingofthisarticle.

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