pesticide illness

Pesticide IllnessPesticide Illness

22

PesticidesPesticidesPesticidesPesticides Farmers, pesticide applicators, Farmers, pesticide applicators,

crop duster pilots, and crop duster pilots, and manufacturers with high manufacturers with high exposures to pesticides, have high exposures to pesticides, have high rates of blood and lymphatic rates of blood and lymphatic system cancers, cancers of the lip, system cancers, cancers of the lip, stomach, lung, brain, and stomach, lung, brain, and prostate, as well as melanoma and prostate, as well as melanoma and other skin cancers.other skin cancers.

Farmers, pesticide applicators, Farmers, pesticide applicators, crop duster pilots, and crop duster pilots, and manufacturers with high manufacturers with high exposures to pesticides, have high exposures to pesticides, have high rates of blood and lymphatic rates of blood and lymphatic system cancers, cancers of the lip, system cancers, cancers of the lip, stomach, lung, brain, and stomach, lung, brain, and prostate, as well as melanoma and prostate, as well as melanoma and other skin cancers.other skin cancers.

33

Toxicology, Diagnosis & Toxicology, Diagnosis & Management of Pesticide Illness by Management of Pesticide Illness by

Functional CategoryFunctional Category

InsecticidesInsecticides Fumigants Fumigants FungicidesFungicides Herbicides Herbicides DisinfectantsDisinfectants MiscellaneousMiscellaneous

44

InsecticidesInsecticides

Cholinesterase Cholinesterase InhibitorsInhibitors– CarbamatesCarbamates

– OrganophosphatesOrganophosphates

Pyrethrins & Pyrethrins & PyrethroidsPyrethroids

Organochlorines Organochlorines

55

InsecticidesInsecticidesCholinesterase InhibitorsCholinesterase Inhibitors

N-methyl CarbamatesN-methyl Carbamates– aldicarb (Temik), carbofuran (Furadan), carbaryl aldicarb (Temik), carbofuran (Furadan), carbaryl

(Sevin)(Sevin)

Organophosphates (OPs)Organophosphates (OPs)– chlorpyrifos (Dursban, Lorsban), diazinon, chlorpyrifos (Dursban, Lorsban), diazinon,

malathionmalathionRO O

P OX

RO

R O

N C

R X

Generic structure for N—methyl carbamates

Generic structure for organophosphates

66

Cholinesterase Normal Function Cholinesterase Normal Function

Acetylcholine (ACh)

3. End organ activates in presence of acetylcholine

Acetylcholinesterase

Choline + Acetyl

5. Choline reuptake

Acetyl CoA + Choline

Cholinergic Nerve Terminal

2. ACh binds to receptor

1. Nerve signal releases ACh

4. Choline regeneration by acetylcholinesterase

77

Inhibition of CholinesteraseInhibition of Cholinesterase

Acetylcholine

R1 R2

O==P

O

Cholinergic Nerve Terminal

3. Activity of end organ does not cease

1. Nerve signal releases ACh

2. ACh binds to receptor

4. OP binds to cholinesterase, preventing regeneration

88

Organophosphates & Carbamates Organophosphates & Carbamates Signs & Symptoms (I)Signs & Symptoms (I)

SystemSystem ReceptorReceptor OrganOrgan Sign/symptomSign/symptomParasympatheticParasympatheticMuscarinicMuscarinic EyeEye Miosis,Miosis,

Blurred visionBlurred vision

Parasympathetic Parasympathetic MuscarinicMuscarinic GlandsGlands Tearing, Tearing, salivation,salivation,

sweating,sweating, & Sympathetic& Sympathetic pulmonarypulmonary

edemaedemaHeartHeart Bradycardia,Bradycardia,

arrhythmiaarrhythmiaMisc. Misc. Broncho-,Broncho-, smoothsmooth constriction,constriction,muscle muscle vomiting, vomiting,

diarrhea, diarrhea, excess excess or or

involuntary involuntary urinationurination

99

SystemSystem ReceptorReceptor Organ Organ Sign/symptomSign/symptom

Neuro-Neuro- NicotinicNicotinic Skeletal Skeletal Fasciculations, muscularFasciculations, muscular muscle muscle cramps, twitching cramps, twitching

(Parasympathetic)(Parasympathetic) muscle weakness,muscle weakness, paralysisparalysis

CNSCNS BrainBrain Headache,Headache, dizziness,dizziness,malaise, confusion,malaise, confusion, bizarre behavior, loss bizarre behavior, loss of consciousnessof consciousness

Organophosphates & Carbamates Organophosphates & Carbamates Signs & Symptoms (II)Signs & Symptoms (II)

1010

Commonly-used Acronyms for Commonly-used Acronyms for Cholinesterase Inhibition SyndromesCholinesterase Inhibition Syndromes

SSalivationalivation LLacrimationacrimation UUrinationrination DDiarrheaiarrhea

DDiarrheaiarrhea UUrinationrination MMiosisiosis BBronchorrhearonchorrhea EEmesismesis LLacrimationacrimation SSalivation alivation

1111

Cholinesterase Inhibitors Cholinesterase Inhibitors Clinical Presentations VaryClinical Presentations Vary

Some signs & symptoms may be Some signs & symptoms may be absentabsent– Bronchorrhea more likely with high-dose Bronchorrhea more likely with high-dose

exposures (ingestion)exposures (ingestion) Common presentations Common presentations

– Nausea, vomitingNausea, vomiting– Miosis Miosis – Sweating, urinary frequency Sweating, urinary frequency

– Non-specific constitutional symptomsNon-specific constitutional symptoms

1212

66 year-old male with eye irritation, 66 year-old male with eye irritation, abdominal pain, nausea, vomiting, abdominal pain, nausea, vomiting, headache, dizziness, frequent urination, headache, dizziness, frequent urination, muscle shaking. Symptoms began after muscle shaking. Symptoms began after weeding a cotton field for 4 hours.weeding a cotton field for 4 hours.

Occasional palpitations but no other Occasional palpitations but no other symptoms over the past 6 monthssymptoms over the past 6 months

33 other crew members complain of 33 other crew members complain of similar symptomssimilar symptoms

Case Case

Farmworker with Multiple Farmworker with Multiple SymptomsSymptoms

1313

Farmworker with Multiple SymptomsFarmworker with Multiple Symptoms

Exposure HistoryExposure History 4:00 am: Aerial application of 4:00 am: Aerial application of

– Carbofuran (N-methyl Carbofuran (N-methyl carbamate)carbamate)

– Abamectin (macrolytic lactone) Abamectin (macrolytic lactone)

– Mepiquat chloride (growth Mepiquat chloride (growth regulator)regulator)

6:00 am: Workers entered 6:00 am: Workers entered field field

10:00 am: Symptoms10:00 am: Symptoms

1414


Physical ExamPhysical Exam

Nausea & abdominal painNausea & abdominal pain

Conjunctival injectionConjunctival injection

Irregularly irregular pulse; Irregularly irregular pulse; rate 106-155, rate 106-155,

Lungs clear, no murmurs; Lungs clear, no murmurs; neurological exam normalneurological exam normal

This warning sign was posted after the workers entered the field and became ill.

1515


Initial Laboratory ResultsInitial Laboratory Results EKGEKG

TFTs, CPKTFTs, CPK

1616

Farmworker with Multiple Symptoms Farmworker with Multiple Symptoms Initial Summary & Differential DiagnosisInitial Summary & Differential Diagnosis

Differential diagnosesDifferential diagnoses– Myocardial infarction (ruled out with CPK)Myocardial infarction (ruled out with CPK)– Thyroid disease (ruled out with TFT)Thyroid disease (ruled out with TFT)– Food-borne illness (ruled out: no Food-borne illness (ruled out: no

common food source)common food source)– Atrial fibrillation unrelated to pesticidesAtrial fibrillation unrelated to pesticides– Pesticide-related illnessPesticide-related illness

1717


Toxicity of Pesticides InvolvedToxicity of Pesticides Involved Carbofuran: Carbofuran:

N-methyl N-methyl carbamatecarbamate

Abamectin: Abamectin: macrolytic lactonemacrolytic lactone

Mepiquat chloride: Mepiquat chloride: growth regulatorgrowth regulator

1818

Cholinesterase-inhibitor Poisoning: Cholinesterase-inhibitor Poisoning: Confirmatory TestsConfirmatory Tests

Cholinesterase blood tests Cholinesterase blood tests

Urine metabolites Urine metabolites

Foliage and clothing pesticide Foliage and clothing pesticide residuesresidues

Diagnosis is Diagnosis is primarily clinicalprimarily clinical

1919

Cholinesterase Blood TestsCholinesterase Blood Tests

Two cholinesterase enzymesTwo cholinesterase enzymes– RBC RBC

““true”/ acetylcholinesterasetrue”/ acetylcholinesterase

– Plasma Plasma ““pseudo”/ butyrylcholinesterasepseudo”/ butyrylcholinesterase

Preferential inhibition possiblePreferential inhibition possible– Dichlorvos: plasma > RBC Dichlorvos: plasma > RBC

cholinesterasecholinesterase

2020

Cholinesterase Blood Tests Cholinesterase Blood Tests InterpretationInterpretation

20% variability in population “baseline”20% variability in population “baseline”

Correlation with symptoms Correlation with symptoms unpredictableunpredictable

Enzyme activity reversibleEnzyme activity reversible– CarbamatesCarbamates– Sample temperatureSample temperature– Storage timeStorage time

2121

Cholinesterase Blood TestsCholinesterase Blood TestsUsesUses

Biologic monitoring of workers Biologic monitoring of workers potentially exposed to potentially exposed to cholinesterase inhibitorscholinesterase inhibitors

0

0.5

1

1.5

2

2.5

0 20 40 60 80

Days

Cho

lines

tera

se a

ctiv

ity (u

nits

)

Retrospective diagnosis of acute poisoning with cholinesterase inhibitors

RBC Plasma

2222

Urine MetabolitesUrine Metabolites

Sensitive indicator of pesticide Sensitive indicator of pesticide exposureexposure

Results do not correlate with health Results do not correlate with health effectseffects

Requires specific pesticide information Requires specific pesticide information

Clinical labs may not perform testsClinical labs may not perform tests

2323

Pesticide Residues on Pesticide Residues on Foliage & ClothingFoliage & Clothing

Provides evidence of pesticide Provides evidence of pesticide exposure in environmentexposure in environment

Does not prove internal exposureDoes not prove internal exposure

Limited clinical availabilityLimited clinical availability

2424


Pesticide Lab Test ResultsPesticide Lab Test Results Cholinesterase Cholinesterase

– Plasma-- 4,142 u/L Plasma-- 4,142 u/L (lab normal range 1,667-5,883)(lab normal range 1,667-5,883)

– RBC-- 4,167 u/L RBC-- 4,167 u/L (lab normal range 8,871-16,993)(lab normal range 8,871-16,993)

Urine metabolites of carbofuran Urine metabolites of carbofuran – Carbofuran 7-phenolCarbofuran 7-phenol– Carbofuran 3-keto-7-phenolCarbofuran 3-keto-7-phenol– Carbofuran 3-hydroxy-7-phenolCarbofuran 3-hydroxy-7-phenol

2525


Pesticide Residue AnalysisPesticide Residue Analysis

FoliageFoliage– Carbofuran up to 0.77 Carbofuran up to 0.77

g/cmg/cm22 – Abamectin up to 0.009 Abamectin up to 0.009

g/cmg/cm22

– Dicofol up to 0.58 Dicofol up to 0.58 g/cmg/cm22

Clothing (per item)Clothing (per item)– Carbofuran up to 91 mg Carbofuran up to 91 mg – Abamectin up to 6000 Abamectin up to 6000 g g

2626


Assessment & Case ClassificationAssessment & Case Classification

DefiniteDefinite Pesticide-Related Illness Pesticide-Related Illness11::

1.1. Evidence of pesticide exposureEvidence of pesticide exposure

2.2. Pesticide-related adverse health effectsPesticide-related adverse health effects

3.3. Exposure—effect relationshipExposure—effect relationship

1NIOSH case definition (CDC 2000) http://www.cdc.gov/niosh/pestsurv/

2727

Specific Management for Specific Management for

Cholinesterase Inhibitor PoisoningCholinesterase Inhibitor Poisoning Collect serum, urine, & clothing Collect serum, urine, & clothing

samplessamples Hospitalize for severe symptomsHospitalize for severe symptoms Specific treatment Specific treatment

– AtropineAtropine– Pralidoxime (2-PAM)--OPs onlyPralidoxime (2-PAM)--OPs only

Workplace restrictionsWorkplace restrictions

2828

Cholinesterase Inhibitors: TreatmentCholinesterase Inhibitors: TreatmentAtropine vs. 2-PAMAtropine vs. 2-PAM

Atropine 2-PAM Drug Class Belladonna

alkaloid Oxime

Indications Hypersecretion, bradycardia; OPs or carbamates

Muscle paralysis, respiratory failure; OPs only

Mode of action

Antagonist: temporarily blocks binding of acetylcholine to receptor

Antidote: permanently reverses OP inhibition of cholinesterase

2929

Treatment: AtropineTreatment: Atropine Reverses SLUD, DUMBELS Reverses SLUD, DUMBELS

syndromesyndrome Intravenous dose:Intravenous dose:

– Diagnostic Diagnostic 1 mg adult 1 mg adult 0.01 mg/kg pediatric0.01 mg/kg pediatric

– Therapeutic Therapeutic 1 mg - 4 mg adult1 mg - 4 mg adult0.05 mg/kg pediatric0.05 mg/kg pediatricRepeat every 10-30 minutesRepeat every 10-30 minutes

3030

Treatment: Pralidoxime (2-PAM)Treatment: Pralidoxime (2-PAM)

AChE--OP

OP 2-PAM

AChE OPAging

Regenerated enzyme

Permanent bondNo treatment

2-PAMAChE +

Enzyme aging Enzyme aging occurs if not occurs if not treatedtreated

Treatment Treatment effective within 48 effective within 48 hourshours

2-PAM reactivates 2-PAM reactivates cholinesterasecholinesterase

Cholinesterase Cholinesterase levels riselevels rise

3131

2-PAM Treatment Regimen2-PAM Treatment Regimen IV infusion over 30 minutes or longerIV infusion over 30 minutes or longer

– > 12 years> 12 years1.0-2.0 g at 1.0-2.0 g at << 0.2 g/min in 100 mL saline 0.2 g/min in 100 mL saline

– << 12 years 12 years20-50 mg/kg body weight in 100 mL saline20-50 mg/kg body weight in 100 mL saline

Repeat doses usually requiredRepeat doses usually required– 1-2 hours, then 10-12 hour intervals1-2 hours, then 10-12 hour intervals

Treatment side effectsTreatment side effects– ArrhythmiaArrhythmia– HypertensionHypertension

3232


Case Management & CourseCase Management & Course

Decontamination Decontamination

Intravenous hydrationIntravenous hydration

Treatment of atrial fibrillation Treatment of atrial fibrillation

Converted to sinus rhythm as Converted to sinus rhythm as outpatientoutpatient

Grower fined Grower fined

3333


Carbamates and Persistent EffectsCarbamates and Persistent Effects

Health effects reported three Health effects reported three months after exposuremonths after exposure

Possible explanations:Possible explanations:

– Persistent effects of acute exposurePersistent effects of acute exposure

– Continued exposureContinued exposure

Anecdotal reports but literature Anecdotal reports but literature lacking lacking

3434

Case Case Grape Harvester with Subacute PoisoningGrape Harvester with Subacute Poisoning

25 year-old grape harvester with 25 year-old grape harvester with dizziness, disorientation, and dizziness, disorientation, and vomiting. vomiting.

Vital signs normal; mild epigastric Vital signs normal; mild epigastric and suprapubic tenderness. CBC and suprapubic tenderness. CBC and chemistry normal. and chemistry normal.

Discharged after treatment with 2.5 Discharged after treatment with 2.5 liters of 5% dextrose/ 0.25 normal liters of 5% dextrose/ 0.25 normal salinesaline

3535

Grape Harvester with Subacute PoisoningGrape Harvester with Subacute Poisoning Persistent SymptomsPersistent Symptoms

24 hours later: persistent weakness, 24 hours later: persistent weakness, dizziness, diarrhea, crampy abdominal dizziness, diarrhea, crampy abdominal pain, lacrimation, and salivation. pain, lacrimation, and salivation.

Examination: weak, pulse rate 48 Examination: weak, pulse rate 48 beats/min; vital signs otherwise normal. beats/min; vital signs otherwise normal. Pupils 3 mm, lungs clear, abdomen Pupils 3 mm, lungs clear, abdomen nontender.nontender.

Labs:Labs:– Normal CBC, chemistry panel, UA. Normal CBC, chemistry panel, UA. – Cholinesterase: Plasma 304 u/L (964 - 2,400) Cholinesterase: Plasma 304 u/L (964 - 2,400)

RBC 4,360 u/L (9,348 - 16,996 u/L)RBC 4,360 u/L (9,348 - 16,996 u/L)

3636

Grape Harvester with Subacute PoisoningGrape Harvester with Subacute Poisoning

Exposure HistoryExposure History Phosalone emulsion applied to Phosalone emulsion applied to

grapesgrapes– half-life up to 30 dayshalf-life up to 30 days

Worker entered field one week Worker entered field one week after restricted entry interval after restricted entry interval

Residues of phosalone on leaf Residues of phosalone on leaf samplessamples

P

SC2H5O

C2H5OS CH2

O

N

O Cl

Phosalone

3737


Hospital CourseHospital Course

Severe bradycardia while in Severe bradycardia while in hospitalhospital

Heart rate responded to atropine Heart rate responded to atropine IVIV

Excess respiratory secretions Excess respiratory secretions absentabsent

3838


Illness Among CoworkersIllness Among Coworkers Health effects Health effects

among crew:among crew:– Asymptomatic Asymptomatic

bradycardiabradycardia

– Asymptomatic Asymptomatic plasma, RBC plasma, RBC cholinesterasecholinesterase depression depression

3939


Incident SummaryIncident Summary

Gradual-onset Gradual-onset poisoningpoisoning

Respiratory Respiratory symptoms absent symptoms absent

Sentinel health event Sentinel health event

Phosalone use Phosalone use restrictedrestricted

4040

Acute Non-Cholinesterase Effects Acute Non-Cholinesterase Effects of Organophosphatesof Organophosphates

Odor health effectsOdor health effects

Irritant effectsIrritant effects

Organophosphate-Organophosphate-induced delayed induced delayed polyneuropathy polyneuropathy (OPIDP)(OPIDP)

4141


Cholinesterase InhibitorsCholinesterase Inhibitors

– CarbamatesCarbamates

– OrganophosphatesOrganophosphates

Pyrethrins & PyrethroidsPyrethrins & Pyrethroids

OrganochlorinesOrganochlorines

4242

InsecticidesInsecticidesPyrethrins & PyrethroidsPyrethrins & Pyrethroids

PyrethrinsPyrethrins

– Natural insecticidal Natural insecticidal extract extract

– UnstableUnstable

Pyrethroids Pyrethroids

– Synthetic derivatives Synthetic derivatives

– Used with piperonyl Used with piperonyl butoxidebutoxide

4343

Pyrethrins: Health EffectsPyrethrins: Health Effects

Low systemic toxicityLow systemic toxicity Respiratory sensitizationRespiratory sensitization

– AsthmaAsthma Skin reactionsSkin reactions

– Paresthesia Paresthesia – Allergic dermatitisAllergic dermatitis

C

O

O

CH3 CH3

CHCCH3

CH3

O

CH3

CH2CH CHCH CH2

Pyrethrin I

4444

Pyrethroid InsecticidesPyrethroid Insecticides

Use increasingUse increasing Examples of useExamples of use

– Structural & agriculturalStructural & agricultural– Pet flea controlPet flea control– PediculicidePediculicide

Vector controlVector control– West Nile virusWest Nile virus– Aircraft “disinsectionAircraft “disinsection””

Source: CDC

4545

Pyrethroids: Health Effects Pyrethroids: Health Effects SkinSkin

Paresthesia, dermatitisParesthesia, dermatitis RespiratoryRespiratory

Rhinitis Rhinitis SystemicSystemic

Dizziness, headacheDizziness, headache Fasciculations, Fasciculations,

seizures,seizures, Hormonal disruption Hormonal disruption in in

vitrovitro

4646

Pyrethrins & PyrethroidsPyrethrins & PyrethroidsMechanism of ToxicityMechanism of Toxicity

Prolong inactivation Prolong inactivation of nerve membrane of nerve membrane sodium channels sodium channels

Pyrethroid structure Pyrethroid structure Type I (non-cyano) Type I (non-cyano)

Shorter inactivationShorter inactivation

Type II (Type II (-cyano)-cyano) Longer inactivationLonger inactivation

Pyrethroid structure

R’RCompound

4747

Pyrethrin & Pyrethroid Illness:Pyrethrin & Pyrethroid Illness: TreatmentTreatment

DecontaminationDecontamination Vitamin E cream Vitamin E cream Symptomatic Symptomatic

therapy therapy Remove from Remove from

further exposure if further exposure if neededneeded

4848

Case Case

Woman Exposed to Flea BombWoman Exposed to Flea Bomb 35 year-old non-pregnant female 35 year-old non-pregnant female

with skin burning, itching and chest with skin burning, itching and chest tightness after putting on clothes tightness after putting on clothes from closet. from closet.

Physical examPhysical exam– Arms and face bright redArms and face bright red– Vital signs normalVital signs normal– Lungs clearLungs clear

4949

Woman Exposed to Flea BombWoman Exposed to Flea Bomb

IngredientsIngredients LabelLabel

– 0.435% permethrin 0.435% permethrin – 0.05% pyrethrins 0.05% pyrethrins – 0.4% piperonyl butoxide0.4% piperonyl butoxide– 99.115% inert ingredients 99.115% inert ingredients

Recommended no entry for 4 hours Recommended no entry for 4 hours after foggingafter fogging

5050


Cholinesterase InhibitorsCholinesterase Inhibitors– CarbamatesCarbamates– OrganophosphatesOrganophosphates

Pyrethrins & PyrethroidsPyrethrins & Pyrethroids OrganochlorinesOrganochlorines

5151

Insecticides: OrganochlorinesInsecticides: Organochlorines

DDT (prototype)DDT (prototype) Chlordane Chlordane Lindane (Kwell, etc.)Lindane (Kwell, etc.) HexachlorobenzeneHexachlorobenzene

– (Fungicide)(Fungicide)

5252

Organochlorine ToxicityOrganochlorine Toxicity

CNS toxicityCNS toxicity– Headache, dizziness, irritability, Headache, dizziness, irritability,

incoordination, tremor, seizures, incoordination, tremor, seizures, paresthesia (DDT), paresthesia (DDT),

CarcinogenicityCarcinogenicity– Hepatic tumors in rodents Hepatic tumors in rodents – Breast cancer (?)Breast cancer (?)

Endocrine disruptionEndocrine disruption

5353

Skin Effects of OrganochlorinesSkin Effects of Organochlorines

DDTDDT– ChloracneChloracne

Lindane Lindane – Irritant reactionsIrritant reactions

– Negative in Negative in patch test seriespatch test series

5454

Skin Effects of OrganochlorinesSkin Effects of Organochlorines DienochlorDienochlor

Patch test develops hyperpigmentation in 15-20% of subjects tested with dienochlor - resembles reaction to Balsam of PeruClCl

Cl Cl

Cl

Cl Cl

Cl

Dienochlor

5555

Case Case

Child With SeizuresChild With Seizures 9 year-old child with myoclonic seizures 9 year-old child with myoclonic seizures

witnessed by parents. No history of witnessed by parents. No history of seizures, head trauma, etc.seizures, head trauma, etc.

In ER, child sleepy, oriented; In ER, child sleepy, oriented; complaining of abdominal cramping, complaining of abdominal cramping, throat burning. Exam normal.throat burning. Exam normal.

Pho

to c

ourt

esy

of C

alifo

rnia

Poi

son

Con

trol

Sys

tem

5656

Insecticide Illness: SummaryInsecticide Illness: Summary

Occupational and environmental Occupational and environmental exposure exposure

Toxicity varies by chemical classToxicity varies by chemical class Specific therapy limitedSpecific therapy limited Prevent illness by reducing usePrevent illness by reducing use

Sou

rce

: U

SD

A

pesticide illness

Documents

high exposures

muscle vomiting

nerve signal releases

nerve signal releases

pesticide applicators

muscle shaking

skin cancers

p ocholinergic nerve