Pesticide IllnessPesticide IllnessPart 3Part 3

Fumigants, Fungicides, Fumigants, Fungicides, Herbicides, Disinfectants, Herbicides, Disinfectants, Miscellaneous PesticidesMiscellaneous Pesticides

Prepared by:

Rupali Das, MD, MPH, California Department of Health Services, Michael O’Malley, MD, MPH, University of California, Davis, Laura Styles, MPH, Public Health Institute

22

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

33

FumigantsFumigants Halogenated hydrocarbonsHalogenated hydrocarbons

– Methyl bromideMethyl bromide– Ethylene dibromide, DBCP Ethylene dibromide, DBCP

Inorganic compoundsInorganic compounds– Sulfuryl fluorideSulfuryl fluoride

Pro-fumigants Pro-fumigants – Metam sodiumMetam sodium

Metal phosphidesMetal phosphides– Aluminum, Zinc, Magnesium Aluminum, Zinc, Magnesium

US

DO

T

44

Fumigants Fumigants Methyl BromideMethyl Bromide

High vapor High vapor pressurepressure

Heavier than airHeavier than air OdorlessOdorless

– Chloropicrin addedChloropicrin added Toxic mechanismToxic mechanism

– Tissue methylationTissue methylation

C

H

H

Br H

55

Methyl Bromide Acute ToxicityMethyl Bromide Acute Toxicity

VesicantVesicant

– Blistering dermatitisBlistering dermatitis

Lower respiratory toxicantLower respiratory toxicant

– Delayed pulmonary edemaDelayed pulmonary edema

Central nervous system Central nervous system depressantdepressant

– Usual cause of deathUsual cause of death

66

Methyl Bromide Acute ToxicityMethyl Bromide Acute ToxicityDifferential DiagnosisDifferential Diagnosis

CNS depressionCNS depression– Other CNS depressantsOther CNS depressants

Pulmonary edemaPulmonary edema– Hepatic & renal diseaseHepatic & renal disease– Acute severe asthmaAcute severe asthma

77

Methyl Bromide Acute Toxicity Methyl Bromide Acute Toxicity ManagementManagement

Serum bromide Serum bromide levelslevels– 3-6 ppm: Possible 3-6 ppm: Possible

exposureexposure– >15 ppm: Acute >15 ppm: Acute

poisoning poisoning – >50 ppm: Severe >50 ppm: Severe

poisoning/ deathpoisoning/ death

Treatment Treatment – Symptomatic Symptomatic

Bromide levels - Reporting Bromide levels - Reporting unitsunits

ppm = mg/literppm = mg/liter mg/L=10 mg /deciliter mg/L=10 mg /deciliter

(USA)(USA) ppm = 80 milli-equivalents ppm = 80 milli-equivalents

(meq)/liter (European)(meq)/liter (European)

88

Methyl Bromide Chronic ToxicityMethyl Bromide Chronic Toxicity

Central nervous systemCentral nervous system– Cognitive, behavioral effects Cognitive, behavioral effects – PolyneuropathyPolyneuropathy

Reproductive systemReproductive system– Teratogen Teratogen

– Genotoxic, mutagenicGenotoxic, mutagenic

99

Methyl Bromide Chronic ToxicityMethyl Bromide Chronic ToxicitySerum Bromide Levels Serum Bromide Levels

Long serum half lifeLong serum half life – 11—15 days11—15 days

Chronic exposureChronic exposure– Asymptomatic high Asymptomatic high

levels possiblelevels possible

1010

Case Case

Illness AfterIllness After House FumigationHouse Fumigation

1111

Illness AfterIllness After House FumigationHouse Fumigation

Pesticide Application HistoryPesticide Application History

Uncovered electrical conduit: one pipe had a 2” diameter and the others a 1” diameter

Methyl bromide fumigation

1212

Illness AfterIllness After House FumigationHouse Fumigation

Health EffectsHealth Effects Tenant found convulsing on floor Tenant found convulsing on floor

the following evening the following evening

Serum bromide level 270 ppmSerum bromide level 270 ppm

Refractory seizures, intermittent Refractory seizures, intermittent fever, multi-organ failurefever, multi-organ failure

1313

Methyl Bromide Phase-outMethyl Bromide Phase-out

Ozone depletion Ozone depletion – ““100% reduction” in 100% reduction” in

2005 2005

ExemptionsExemptions– Critical agricultural uses Critical agricultural uses

– Pre-shipment & Pre-shipment & quarantinequarantine

– Emergency usesEmergency uses

No “ideal” No “ideal” substitutesubstitute

Source: US EPA “Frequently Asked Questions” on methyl bromide phase-out

1414

FumigantsFumigantsSulfuryl FluorideSulfuryl Fluoride

PulmonaryPulmonary– Dyspnea, cough, delayed pulmonary Dyspnea, cough, delayed pulmonary

edema, fatal hypoxiaedema, fatal hypoxia Renal Renal CNS CNS

– Weakness, nausea, vomiting, Weakness, nausea, vomiting, restlessness, muscle twitching, restlessness, muscle twitching, seizuresseizures

1515

FumigantsFumigantsMetam SodiumMetam Sodium

Hydrolyzes to mixture of irritantsHydrolyzes to mixture of irritants

Health effectsHealth effects– Irritant dermatitisIrritant dermatitis– Reactive airways dysfunction Reactive airways dysfunction

syndrome/asthmasyndrome/asthma

CH3NH C

S

S

Na+ . 2 H2O

MITC

CH3N C S

H2SCS2CH3 NH2

MethylamineCarbon disulfide Hydrogen sulfide

MIC - up to 4% of the level of MITC

H2O+

+ ++

CH3N C O

1616

Case Case

Transportation Worker with CoughTransportation Worker with Cough

40 year-old male transportation 40 year-old male transportation worker with metallic taste; worker with metallic taste; burning eyes, chest, nose; burning eyes, chest, nose; nausea; dizziness.nausea; dizziness.

Recurrent cough with wheezing, Recurrent cough with wheezing,

phlegm for 5 days. Chest phlegm for 5 days. Chest tightness, dyspnea on exertion.tightness, dyspnea on exertion.

1717

Transportation Worker with CoughTransportation Worker with Cough

Exposure HistoryExposure History

Tank car derailment Tank car derailment – >19,000 gallons >19,000 gallons

metam sodium metam sodium releasedreleased

Worker involved in Worker involved in response to accidentresponse to accident– Symptoms onset Symptoms onset

within 20 minuteswithin 20 minutes– Worked 6.5 hours Worked 6.5 hours

alongside riveralongside river

1818

Transportation Worker with CoughTransportation Worker with Cough

Physical EvaluationPhysical Evaluation

Exam 6 months laterExam 6 months later– Mild nasal inflammation,Mild nasal inflammation,

– Spirometry Spirometry FEVFEV11: 87%, FVC: 101%, : 87%, FVC: 101%,

FEVFEV11/FVC: 69%, FEF/FVC: 69%, FEF25-7525-75: : 26%26%

– Methacholine challenge Methacholine challenge test test

PCPC100100: 1.2 mg/ml : 1.2 mg/ml (normal >4 mg/ml)(normal >4 mg/ml)

1919

FumigantsFumigantsChronic EffectsChronic Effects

NeurologicNeurologic ReproductiveReproductive OtherOther

Methyl Methyl bromidebromide

Cognitive, Cognitive, behavioralbehavioral

Animal studiesAnimal studies

Sulfuryl Sulfuryl fluoridefluoride

Olfactory, Olfactory, cognitivecognitive

Metam Metam sodiumsodium

Animal studiesAnimal studies RADS, RADS, asthmaasthma

2020

CaseCase

Drift After Metam ApplicationDrift After Metam Application

Metam sodium Metam sodium applied to carrot applied to carrot fieldsfields

Illness reported Illness reported amongamong

– School children School children

– Workers Workers

California Department of Health Services, 2001

2121

Drift After Metam ApplicationDrift After Metam Application

Investigation FindingsInvestigation Findings MITC detected at MITC detected at

school, beyond school, beyond 500 foot buffer 500 foot buffer zonezone

Workers required Workers required to monitor field to monitor field for odorfor odor

Field where metam-sodium applied

School:workers &children ill

500 foot buffer zone

Figure not to scale

~ 1 mile

Other workers exposed

2222

FumigantsFumigantsPhosphide CompoundsPhosphide Compounds

Metal phosphides Metal phosphides hydrolyzehydrolyze– Aluminum, zinc, magnesiumAluminum, zinc, magnesium

PhosphinePhosphine– Colorless, fish/garlic odorColorless, fish/garlic odor– Highly explosive, corrosiveHighly explosive, corrosive– Rapidly oxidizes to Rapidly oxidizes to

phosphoric acidphosphoric acid

2323

Phosphine: Illness SyndromesPhosphine: Illness Syndromes

May resemble viral syndromesMay resemble viral syndromes

Pulmonary toxicityPulmonary toxicity

CNS toxicityCNS toxicityMulti-organ failureMulti-organ failure

2424

CaseCase Fatality After In-Transit FumigationFatality After In-Transit Fumigation

Unemployed male Unemployed male in railcar fumigated in railcar fumigated with aluminum with aluminum phosphide phosphide

Badly decomposed Badly decomposed body found on body found on arrival at arrival at destinationdestination

Sou

rce:

BC

Wor

kers

Com

p

2525

FungicidesFungicides ThiocarbamatesThiocarbamates

– Zineb, maneb, ziram, thiram Zineb, maneb, ziram, thiram Pthalimide derivativesPthalimide derivatives

– Captan, captafol, Captan, captafol, Substituted aromaticsSubstituted aromatics

– Chlorothalonil, hexachlorobenzeneChlorothalonil, hexachlorobenzene Inorganic Inorganic

– SulfurSulfur

2626

Health Effects of FungicidesHealth Effects of Fungicides

AcuteAcute– Irritant & allergic dermatitisIrritant & allergic dermatitis

ChronicChronic– Chronic dermatitisChronic dermatitis– Possible carcinogensPossible carcinogens

2727

Fungicides: ThiocarbamatesFungicides: Thiocarbamates

Resemble rubber Resemble rubber accelerator thiuram accelerator thiuram

Sensitization reported Sensitization reported in exposed workersin exposed workers

S

CH3

N C S

CH3

S C N

CH3

CH3S

Thiram

CH3

CH3

N C S Zn S C NCH3

CH3SS

X>1X

S

NH C S

CH2

CH2

C S MnNH

S

Ziram

Maneb

2828

ThiocarbamatesThiocarbamates

Antabuse-like ReactionsAntabuse-like Reactions

S

CH3

N C S

CH3

S C N

CH3

CH3S

Thiuram

S

CH3

N C S

CH3

S C N

CH3

CH3S

Thiram

2929

CaseCase

Pear Pickers with Skin RashPear Pickers with Skin Rash 26 people picking pears 26 people picking pears

complained of skin rashes complained of skin rashes Physical exam: Physical exam:

– Contact dermatitis Contact dermatitis Applied five days before:Applied five days before:

– NAA 800NAA 800– Ziram GranufloZiram Granuflo USDA Graphics

3030

Pear Pickers with Skin RashPear Pickers with Skin Rash

Pesticide ApplicationPesticide Application Workers followed requirements for Workers followed requirements for

re-entryre-entry Ziram applications Ziram applications

– D'Anjou pears, Golden Delicious applesD'Anjou pears, Golden Delicious apples– Symptoms in Bosc pear pickers only Symptoms in Bosc pear pickers only

Postulated mechanism of dermatitisPostulated mechanism of dermatitis– Sharp latent bud on Bosc pearsSharp latent bud on Bosc pears– Increased susceptibility to dermal Increased susceptibility to dermal

irritationirritation

3131

Pear Pickers with Skin RashPear Pickers with Skin Rash

Regulatory ActionRegulatory Action Re-entry interval of 14 days Re-entry interval of 14 days

established for formulations of ziram established for formulations of ziram on Bosc pearson Bosc pears

S

CH3

N C ZnS

CH3

S C N

CH3

CH3S

Ziram

3232

Fungicides: CaptanFungicides: Captan

Dermatitis Dermatitis 5% of volunteers sensitized 5% of volunteers sensitized

N

O

O

S CCl3

Captan

3333

Case Case

Nursery Worker with UrticariaNursery Worker with Urticaria Itching and hives in Itching and hives in

redwood nursery workerredwood nursery worker Chlorothalonil patch test:Chlorothalonil patch test:

– Local Type I Local Type I hypersensitivity hypersensitivity

1% chlorothalonil open 1% chlorothalonil open testtest– Systemic Type I reaction Systemic Type I reaction

3434

Chlorothalonil: Pigmentary ChangesChlorothalonil: Pigmentary Changes

Blue-gray Blue-gray pigmentation in pigmentation in antecubital areaantecubital area

Positive skin reaction Positive skin reaction to chlorothalonilto chlorothalonil

Diagnosis: Ashy Diagnosis: Ashy dermatitisdermatitis

3535

Ashy Dermatitis: MechanismAshy Dermatitis: Mechanism Disruption of Disruption of

basal membrane basal membrane of epidermisof epidermis

Melanin deposits Melanin deposits in dermisin dermis

ClCl

Cl

Cl

C N

C N

Chlorothalonil

Panagos et al. 1996

3636

Fungicides: Elemental SulfurFungicides: Elemental Sulfur

Potent skin Potent skin irritantirritant– Animal Animal

experiments experiments equivocalequivocal

Airway irritantAirway irritant

3737

CaseCase

Applicator With Skin IrritationApplicator With Skin Irritation Pesticide applicator Pesticide applicator

applied sulfur dust to applied sulfur dust to rosesroses

Contact dermatitisContact dermatitis– Burning painBurning pain

– Maculopapular rashMaculopapular rash

.

3838

Sulfur: Allergic Skin ReactionsSulfur: Allergic Skin Reactions

Positive patch test Positive patch test reactions to sulfur reactions to sulfur in nursery workers in nursery workers applying sulfurapplying sulfur

Case reports Case reports support sulfur-support sulfur-induced allergyinduced allergy

3939

Postulated Mechanism ofPostulated Mechanism ofSulfur Irritation and AllergySulfur Irritation and Allergy

SO3

pHtemperatureionic strength

S2O31/2

HSO3 H2O1/2

Allergic reactionsAllergic reactions– Oxidation/reduction Oxidation/reduction

productsproducts

Type IV delayed Type IV delayed hypersensitivityhypersensitivity

4040

HerbicidesHerbicides

Dipyridyl compoundsDipyridyl compounds– ParaquatParaquat

– DiquatDiquat Glyphosate Glyphosate Phenoxy compoundsPhenoxy compounds

– 2,4,5-trichlorophenoxyacetic acid (2,4,5-T)2,4,5-trichlorophenoxyacetic acid (2,4,5-T)– 2,4 dichlorophenoxyacetic acid (2,4-D)2,4 dichlorophenoxyacetic acid (2,4-D)

4141

Herbicides: Dipyridyl CompoundsHerbicides: Dipyridyl Compounds

ParaquatParaquat

DiquatDiquat

Sou

rce:

Fin

nish

Pla

tfor

m o

f th

e E

U-N

GD

O L

iais

on C

omm

ittee

4242

Dipyridyl Compounds: ParaquatDipyridyl Compounds: Paraquat

Extremely toxic via Extremely toxic via ingestion ingestion – LDLD5050 3-5 mg/kg 3-5 mg/kg

ToxicityToxicity– Skin, pulmonarySkin, pulmonary– Parkinson Disease?Parkinson Disease?

4343

Paraquat Toxicity Paraquat Toxicity

Bot

ella

et a

l, 19

85

Hof

fer

and

Te

itelm

an,

19

89

4444

Paraquat (PQ)

PQ

Alveolar cell membrane

PQ2+

O2 O2-

Lipid peroxidation

Cell death

Paraquat Toxicity: IngestionParaquat Toxicity: Ingestion

1-4 days1-4 days– GI tract edema, ulcersGI tract edema, ulcers

24-72 hours24-72 hours– Hepatocellular injuryHepatocellular injury– Acute tubular Acute tubular

necrosisnecrosis 72-96 hours72-96 hours

– Pulmonary fibrosisPulmonary fibrosis

NADPH NADP+

4545

Outcome Outcome Urine level, Urine level, 24 hours 24 hours (mg/mL)(mg/mL)11

Plasma Plasma level level (mg/kg)(mg/kg)22

Survival Survival likelylikely

<1 <1 < 20< 20

Pulmonary Pulmonary fibrosisfibrosis

1-10001-1000 20-4020-40

Death Death within 24 within 24 hourshours

10-10,000 10-10,000 > 40mg> 40mg

Paraquat Levels Predict Outcome Paraquat Levels Predict Outcome

4646

Paraquat Toxicity: Treatment Paraquat Toxicity: Treatment Skin, Eye DecontaminationSkin, Eye Decontamination GI decontaminationGI decontamination FluidsFluids HemoperfusionHemoperfusion Oxygen contraindicatedOxygen contraindicated Severe casesSevere cases

– High dose steroids and cyclophosphamideHigh dose steroids and cyclophosphamide

4747

Case Case

Farmer Attempts Suicide Farmer Attempts Suicide 46 year-old male farmer intentionally 46 year-old male farmer intentionally

ingested a greenish liquid. ingested a greenish liquid.

Complains of dysphagia, sore throat. Complains of dysphagia, sore throat. Previous history of depression. Previous history of depression.

Profuse, prolonged vomitingProfuse, prolonged vomiting

Plasma paraquat at 4 hoursPlasma paraquat at 4 hours

– 3 mg/mL3 mg/mL

4848

Farmer Attempts SuicideFarmer Attempts Suicide Hospital CourseHospital Course

Day 2: Severe Day 2: Severe dysphagia dysphagia

Day 3: SOB Day 3: SOB

Day 4-9: pODay 4-9: pO22 33. 33.

Day 12: Pt died Day 12: Pt died due to respiratory due to respiratory failure.failure.

4949

Herbicides: GlyphosateHerbicides: Glyphosate

Health effectsHealth effects– Case reports of eye, skin irritationCase reports of eye, skin irritation– Death due to ingestion of large amountsDeath due to ingestion of large amounts– Experimental studies fail to show skin Experimental studies fail to show skin

irritationirritation

Mechanism of human toxicity Mechanism of human toxicity unknownunknown– Surfactant preservative?Surfactant preservative?

5050

Chlorophenoxy HerbicidesChlorophenoxy Herbicides

2,4,5-trichlorophenoxyacetic acid 2,4,5-trichlorophenoxyacetic acid (2,4,5-T)(2,4,5-T)– Derived from tetrachlorobenzeneDerived from tetrachlorobenzene

– Dioxin byproductsDioxin byproducts

2,4-dichlorophenoxyacetic acid 2,4-dichlorophenoxyacetic acid (2,4-D)(2,4-D)– Derived from phenolDerived from phenol

– Dioxin contaminants not present Dioxin contaminants not present

5151

Chlorophenoxy HerbicidesChlorophenoxy Herbicides

AcuteAcute– CNS depressionCNS depression

– Skin, GI, mucous membrane irritationSkin, GI, mucous membrane irritation

– Renal failure, myopathyRenal failure, myopathy

ChronicChronic– Anemia, hepatic, renal effectsAnemia, hepatic, renal effects

– Tumor formation(?)Tumor formation(?)

5252

Antimicrobials & DisinfectantsAntimicrobials & Disinfectants

Sodium hypochlorite Sodium hypochlorite Isopropyl alcoholIsopropyl alcohol Gluteraldehyde, formaldehydeGluteraldehyde, formaldehyde MixturesMixtures

– NaOCl + HNaOCl + H++ => Cl => Cl22

– NaOCl + NHNaOCl + NH33=> NHCl=> NHCl22, NH, NH22ClCl

5353

Chlorine Disinfectant MixturesChlorine Disinfectant Mixtures

ToxicityToxicity AcuteAcute

– Asthma exacerbation, Asthma exacerbation, bronchitis bronchitis

Chronic: Chronic: – RADSRADS

TreatmentTreatment– Oxygen, bronchodilatorsOxygen, bronchodilators

5454

CaseCase

Custodian with Shortness of BreathCustodian with Shortness of Breath

29 year-old custodian with cough, sore 29 year-old custodian with cough, sore throat, shortness of breath after throat, shortness of breath after mixing bleach and ammoniamixing bleach and ammonia

Exam: Exam: – Cough, dyspnea, RR=36; Cough, dyspnea, RR=36; – Lungs: rales & wheezes; Lungs: rales & wheezes;

– OO22 saturation 94% on room air saturation 94% on room air

– PEFR 80% PEFR 80%

5555

Miscellaneous PesticidesMiscellaneous Pesticides

Propargite (Omite)Propargite (Omite)

Diethyltoluamide Diethyltoluamide (DEET)(DEET)

CHCCH2

O

SO(CH3)3 C O

Propargite

CH3

CN

C2H5

C2H5

O

Diethyl toluamide

5656

AcaricideAcaricide

Propargite Contact DermatitisPropargite Contact DermatitisSustained-release Sustained-release

propargitepropargite

Severe dermatitis Severe dermatitis with scarringwith scarring

5757

SkinSkin– IrritationIrritation– Contact urticaria Contact urticaria

CNS CNS – Seizures, Seizures,

encephalopathy encephalopathy Children < 5 yearsChildren < 5 yearsHigh High

dose/concentrationsdose/concentrations

Insect Repellant Insect Repellant

DEET Acute ToxicityDEET Acute Toxicity

5858

Acute Toxicity SummaryAcute Toxicity Summary

Organs most often affectedOrgans most often affected– SkinSkin– LungsLungs– CNSCNS

Severity greatest in developing Severity greatest in developing nationsnations

Exposures occur at work, home, etc.Exposures occur at work, home, etc. Prevention: regulation, substitutionPrevention: regulation, substitution