Bipyridyl Herbicides

The bipyridyl compounds, paraquat and diquat, are nonselective contact

herbicides. Both are still used widely and are responsible for significant
morbidity.44,45

EPIDEMIOLOGY
Paraquat is a fast-acting, nonselective herbicide. It is used for killing grass
and weeds and is manufactured as a liquid, granules, or an aerosol and is
commonly combined with diquat and other herbicides. Most products
contain a blue dye, a stenchant, and an emetic. Ingestion is responsible
for the majority of paraquat deaths.44 Deaths have been reported after
transdermal exposure, ingestion, and inhalation. Inhalation exposures to
sprays are very irritating to conjunctiva and the airway, but are unlikely to
cause systemic toxicity.

PATHOPHYSIOLOGY
Paraquat is a severe local irritant and devastating systemic toxin. The
lethal oral dose of the 20% solution is 10 to 20 mL in an adult and 4 to 5
mL in a child. There is minimal transdermal absorption of paraquat in the
absence of preexisting skin lesions. Ingested paraquat is absorbed rapidly,
particularly if the stomach is empty. Plasma concentration peaks within
minutes to 2 hours after ingestion. Paraquat is then distributed to most
organs, with the highest concentrations found in the kidneys and lungs.
Paraquat actively accumulates in the alveolar cells of the lungs, where it is
transformed into a reactive oxygen species, the superoxide radical. This
anion is responsible for lipid peroxidation that leads to degradation of cell
membranes, cell dysfunction, and death. A redox reaction results in two
phases of lung injury. An initial destructive phase is characterized by loss
of type I and type II alveolar cells, infiltration by inflammatory cells, and
hemorrhage. These changes may be reversible. The later, proliferative
phase is characterized by fibrosis in the interstitium and alveolar spaces.
Paraquat and oxygen enhance each other's toxicity by sustaining the
redox cycle. Myocardial injury and necrosis of the adrenal glands may
occur.
Diquat has a similar structure and mechanism as paraquat but is
considered to be less toxic. Formulations containing diquat do not contain
the dye, stenching agent, or emetic added to paraquat. The lethal dose for
diquat is similar to that of paraquat, but severe poisoning is less common,
likely due to a lower occurrence of pulmonary injury and fibrosis because
of diquat's lower affinity for pulmonary tissue. Diquat is caustic to the skin
and GI tract, and exposure can result in renal and liver necrosis.

CLINICAL FEATURES
Paraquat's severe caustic effects produce local skin irritation and
ulceration of epithelial surfaces. Severe corrosive corneal injury may result
from eye exposure. Upper respiratory tract exposure may result in
mucosal injury and epistaxis. Inhalation may lead to cough, dyspnea,
chest pain, pulmonary edema, epistaxis, and hemoptysis. Respiratory
symptoms may persist for several weeks after inhalation exposure.
Ingestion causes GI mucosal lesions and ulcerations. An acute burning
sensation of the lips or mouth may be followed by ulceration 1 to 2 days
later. Buccopharyngeal, esophageal, and abdominal pain and vomiting
occur. Caustic lesions of lips, oral cavity, and GI tract can occur within a

few minutes to hours. Hypovolemia occurs from GI fluid losses and

decreased oral intake.
Multisystem effects include GI tract corrosion, acute renal failure, cardiac
failure, hepatic failure, and extensive pulmonary injury. The effects can be
evident within a few hours following large ingestions, but, more typically,
manifestations of renal failure and hepatocellular necrosis develop
between the second and fifth days, with progressive pulmonary fibrosis
leading to refractory hypoxemia 5 days to several weeks later. Metabolic
(lactic) acidosis is common as a result of pulmonary effects (hypoxemia)
and multisystem failure.

DIAGNOSIS
Early diagnosis and therapy are important. The history may be indicative
of an accidental or intentional poisoning and of the route of exposure. The
differential diagnosis includes exposure to other corrosive agents and
herbicides. Qualitative and quantitative analyses for paraquat in urine and
blood can assist in the diagnosis.46 Nomograms have been presented for
predicting survival based on plasma paraquat concentration and time of
ingestion.47,48 If the 10-hour level is >0.4 milligram/L, prognosis for
survival is poor. Serial pulmonary function tests, chest radiographs, and
arterial blood gas determinations, including alveolar-arterial gradient, may
be used to monitor toxicity.
Laboratory abnormalities generally reflect multi-organ necrosis. Chest
radiographs may show pneumomediastinum or pneumothorax due to
corrosive rupture of the esophagus. Radiographic abnormalities of diffuse
consolidation indicating parenchymal injury on the chest radiograph may
not parallel the severity of clinical symptoms. Upper GI endoscopy should
be performed to identify the extent and severity of mucosal lesions.

TREATMENT
The goal of early and vigorous decontamination is to prevent
pulmonary toxicity. Any exposure to paraquat is a medical
emergency, with hospitalization indicated even if the patient is
asymptomatic. Early treatment is mainly supportive but is an important
determinant of survival. An attempt should be made to prevent
superoxide radical formation by using low inspired oxygen to produce a
therapeutic hypoxemia with the goal of reducing pulmonary injury. The
use of low oxygen mixtures (fraction of inspired oxygen<21%) with
positive pressure ventilation reduces pulmonary toxicity in experimental
models and may be of therapeutic benefit. Supplemental oxygen should
be avoided except for severe respiratory failure.
Remove clothing and decontaminate skin with mild detergent and water.
Take care to avoid skin abrasions that may increase absorption. If there is
conjunctival irritation, irrigate with copious amounts of water or saline.
Fluid and electrolytic losses can occur from GI tract damage, vomiting,
and cathartics. Maintain intravascular volume and urine output to prevent
prerenal failure. Pain associated with oropharyngeal lesions should be
treated with opioids. Emesis is common, but gastric lavage via orogastric
tube is recommended despite the risk of perforation.
Immediate GI decontamination with absorbents that bind paraquat is
indicated. Activated charcoal (1 to 2 grams/kg), diatomaceous fuller's
earth (1 to 2 grams/kg in 15% aqueous suspension), or bentonite (1 to 2
grams/kg in a 7% aqueous slurry) should be used and repeated every 4

hours. Charcoal hemoperfusion can remove paraquat and should be

instituted as soon as possible and continued for 6 to 8
hours. Methylprednisolone and cyclophosamide may improve outcomes
and therefore are sometimes used.
Supportive care includes airway protection, maintaining intravascular
volume, pain relief, treatment of renal failure and complications, and
treatment of infection. Maintaining renal function will assist in avoiding
toxic accumulation in other tissues.

DISPOSITION AND FOLLOW-UP

An attempt to determine prognosis should be made. The mortality rate
from ingestion is as high as 75%. Outcome is determined by the amount
ingested; therefore, intentional ingestions tend to have a worse prognosis.
Prognosis is worsened by ingesting a highly concentrated formulation on
an empty stomach, when ingestion results in upper GI ulcerations and
renal failure.44,46 Ingestion of a concentrated liquid solution is usually fatal.
Dilute solid formulations rarely cause death.
Three prognostic categories have been described. Ingestion of <20
milligrams/kg of paraquat ion (or 28 milligrams/kg of paraquat dichloride)
produces no or only moderate GI symptoms. Recovery is usually without
sequelae. Ingestion of 20 to 40 milligrams/kg usually results in death 5
days to several weeks after ingestion from pulmonary fibrosis. 49 Early
development of GI corrosion, acute renal failure, and symptoms of
systemic toxicity predominate, with subsequent extensive pulmonary
injury and pulmonary fibrosis causing death in most patients. Patients who
ingest >40 to 50 milligrams/kg of paraquat will die in 1 to 5 days from
multi-organ failure, corrosive GI effects, and cardiogenic shock.
Treatment for diquat poisoning is similar to that for paraquat, and despite
the lower toxicity for diquat, mortality approaches 50% following
intentional diquat ingestion.

BIPYRIDYLCOMPOUNDS
Thebipyridyl(alsocalleddipyridyl)compounds,paraquatanddiquat,wererst
investigatedinthelate1950sandearly1960s.Theyareextremelyeffective
contactherbicidesthatarerapidlyinactivatedbythesurroundingsoilinthe
eventofoverspray.Paraquatisactivatedwhenexposedtosunlight,whichled
toitsuseastheherbicideofchoiceduringaerialsprayingofmarijuanabythe
U.S.andMexicangovernments.Afterspraying,however,growerssimply
wouldharvestthecropsbeforetheplantswereexposedtoenoughsunlightto
damagetheplants,resultinginanapparentlyhealthyharvestbutone
contaminatedwithparaquat.Theburningofmarijuanapyrolyzesparaquat
intoanontoxicform,afactthatwaslostinthewarningmessagesdispensedby
thegovernmentatthattime.58

PrinciplesofDisease
Ofthetwobipyridylcompoundsinuse,paraquatisthemostclinicallysigni
cantintermsofnumberofcasesandtoxiceffects.Paraquatuseistightly

regulatedintheUnitedStatesbutiswidespreadthroughouttheworld.Diquatis
lessregulatedintheUnitedStatesandisincludedinsomeformulationsof
Roundup.Paraquatisabsorbedthroughtheskin,GItract,andrespiratorytract.
Almostallfatalexposureshaveresultedfromtheingestionofparaquat,
althoughafewcasereportshaveinvolvedextensiveskincontamination.59
Toxicityhasoccurred,butnofatalcaseshavebeenreportedfrominhalationof
paraquatvapororaerosols.Diquatispoorly
Chapter161/Pesticides

2058

absorbedthroughintactskin,andmostcasesoftoxicityresultfromingestion.60
AformulationchangeinSriLanka,addinganemeticmagnesiumsulfate
andanalginatebinder,decreasedmortalityby9.5%incasesofintentional
ingestionofparaquat.61
Paraquatstoxiceffectresultsfromtheproductionofsuperoxidescreated
duringcyclicoxidationreductionreactionsofthecompoundintissues.Lipid
peroxidationofcellularmembranesseemstobeonesignicantpathwayof
cellularinjury.62,63
Paraquatselectivelyconcentratesinthelungsbecauseofanamineuptake
mechanisminalveolarcells.Inaddition,highconcentrationsofoxygensigni
cantlyincreasetheextentofparaquatinducedinjurysothatthelungsarethe
majortargetorgan.Thepathophysiologiclesionsincludedirectinjurytothe
alveolarcapillarymembranefollowedbysurfactantloss,adultrespiratory
distresssyndrome,progressivepulmonarybrosis,andrespiratoryfailure.64
Paraquatdamagesothermajororgansystemsbythesamecellularmembrane
effects,includingtheliver,kidneys,heart,andcentralnervoussystem.Diquat
hassimilareffects,withmostofitstoxicityconcentratedinthekidneysand
notpreferentiallyinlungtissue.60

ClinicalFeatures
SignsandSymptoms
Bothagentsareextremelycorrosiveandcausenausea,vomiting,andsevere
chemicalburnsoftheoropharynxsoonafteringestion.Patientswhoingest
concentratedparaquatfrequentlydieasaresultofesophagealperforationand
mediastinitisbeforedevelopmentofthecharacteristicprogressivepulmonary
injury.Patientswithdermalparaquatexposuresshowsignicantskinirritation,

andocularexposuresmayproduceseverecornealinjury.65
Theclassicndingofparaquatinducedprogressivepulmonaryinjuryusually
occursover1to3weeks,althoughtheclinicalcoursevariesconsiderablywith
severityofpoisoning,involvementofotherorgansystems,andunderlying
medicalproblems.64Thisisnotafactorintheemergencydepartment,andthe
delayedpulmonaryinjuryisnotdiscussedhere.Incontrasttoparaquat,diquat
usuallysparesthelungsbutproducessimilartoxicityinallotherorgan
systems.60

DiagnosticStrategies
Paraquatismeasurableintheblood,andthenomogramprovidesafairly
accurateprognosis.TheassayisnotreadilyavailableintheUnitedStates,and
inmostcases,bythetimetheresultsareobtained,nothingmorecanbedoneto
changetheeventualoutcome.Thereisaqualitativebedsidetestthatusesthe
reductionofparaquatordiquatinalkalinizedurinebysodiumdithionite,but
thereagentfrequentlyisnotavailable.57Studiesotherthanevaluationofcaustic
GIinjuryandpulmonaryandrenaldamageshouldbedirectedtoward
secondaryeffectsofthepoisoning.

DifferentialConsiderations
Apersonwithacuteparaquatordiquatingestionislikelytopresentwiththe
initialcomplaintofanacutecorrosiveinjury;thedifferentialdiagnosisshould
encompassallcorrosiveagents.Successfultherapeuticinterventionfor
paraquattoxicityisextremelytimedependent,andpatientoutcomedepends
onthehistory.Anypatientwhohasevidenceofpulmonaryorotherorgan
injurycausedbyparaquatexposureisprobablyalreadybeyondrecovery.

ManagementandDisposition
Therearenostudiescomparingvarioustreatmentstrategies,butthekeyto
successfultreatmentofanacuteparaquatexposurelikelydependsonearly
decontaminationmeasurestolimitabsorption.Thoroughskincleansingis
obviousandstraightforwardindermalexposures.Carefulgastriclavageand
administrationofactivatedcharcoalmaybelifesaving,butthesemeasures
shouldbeundertakeninconsultationwithapoisoncenterandmayevenbe
hazardousinthecontextofacorrosiveingestion.Earlyendoscopyandsurgical
interventionmaybenecessaryifthereisevidenceofesophagealperforation
andmediastinitis.AlthoughFullersearthandbentonitearerecommendedas
adsorbentsinparaquatingestions,activatedcharcoalismuchmorereadily
availableintheUnitedStatesandhasequal,ifnotgreater,efcacy. 66
Althoughcontroversial,manytoxicologistsrecommendrapidinitiationof

charcoalhemoperfusiontorapidlylowerplasmaparaquatlevelsandtolimit
pulmonaryandotherorgansystemuptakeofparaquat.Manyalsorecommend
serialandcombinedhemoperfusionandhemodialysis,particularlyduringthe
rst24hoursafterexposure.67,68Therearemultiplesuggestedtreatment
protocolsforparaquat,suchasNacetylcysteine,lowfractionofinspired
oxygen,andcytoprotectiveagentssuchasamifostine,butnosingletherapyhas
provenconsistentlysuccessful.69,70
Patientswithanysignicantdermalparaquatexposureandallpatientswith
ingestedparaquatrequirehospitalizationandconsiderationofenhanced
eliminationtherapy.Thesepatientsshouldbeobservedandtreatedexpectantly
untilparaquatlevelsarereportedtobenonexistentornontoxic.