pesticide illness pesticide illness. 2 pesticidespesticides farmers, pesticide applicators, crop...
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Pesticide IllnessPesticide Illness
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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.
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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
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InsecticidesInsecticides
Cholinesterase Cholinesterase InhibitorsInhibitors– CarbamatesCarbamates
– OrganophosphatesOrganophosphates
Pyrethrins & Pyrethrins & PyrethroidsPyrethroids
Organochlorines Organochlorines
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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
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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
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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
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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
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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)
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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
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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
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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
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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
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Farmworker with Multiple SymptomsFarmworker with Multiple Symptoms
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.
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Farmworker with Multiple SymptomsFarmworker with Multiple Symptoms
Initial Laboratory ResultsInitial Laboratory Results EKGEKG
TFTs, CPKTFTs, CPK
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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
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Farmworker with Multiple SymptomsFarmworker with Multiple Symptoms
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
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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
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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
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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
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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
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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
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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
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Farmworker with Multiple SymptomsFarmworker with Multiple Symptoms
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
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Farmworker with Multiple SymptomsFarmworker with Multiple Symptoms
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
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Farmworker with Multiple SymptomsFarmworker with Multiple Symptoms
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/
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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
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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
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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
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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
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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
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Farmworker with Multiple SymptomsFarmworker with Multiple Symptoms
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
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Farmworker with Multiple SymptomsFarmworker with Multiple Symptoms
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
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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
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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
Grape Harvester with Subacute PoisoningGrape Harvester with Subacute Poisoning
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
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Grape Harvester with Subacute PoisoningGrape Harvester with Subacute Poisoning
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
Grape Harvester with Subacute PoisoningGrape Harvester with Subacute Poisoning
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
InsecticidesInsecticides
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
InsecticidesInsecticides
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)
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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