versão publicada jan 2012

7/31/2019 versão publicada jan 2012

http://slidepdf.com/reader/full/versao-publicada-jan-2012 1/844

Poisoning by illegal rodenticides containing acetylcholinesterase

inhibitors (chumbinho): a prospective case seriesFÁBIO BUCARETCHI1 , CAMILA C PRADO1 , MAÍRA M BRANCO1 , PAULA SOUBHIA1 , GISELE M METTA1 ,SUELI MOREIRA MELLO1 , EDUARDO MELLO DE CAPITANI1 , RAFAEL LANARO1 , STEPHEN HYSLOP1 ,JOSE LUIZ COSTA2 , LUCIANE C. R. FERNANDES1 , and RONAN JOSÉ IEIRA1

1 Campinas Poison Control Center, Faculty of Medical Sciences, State University of Campinas, Campinas, Brazil2 Instituto de Criminalística de São Paulo, São Paulo, SP, Brazil

Abstract Objective. To describe a prospective case series o poisonings caused by ingestion o illegal rodenticides containing acetylcholinesteraseinhibitors, mainly “chumbinho,” ollowed-up by the Campinas PCC or a period o 1 year. Case series. Seventy-six cases were included, o which 53.9% were males. Age ranged rom 2 to 74 years (medianϭ36 years). The main circumstances leading to poisoning were intentional(suicide attempts 92.1%; homicide attempts 5.3%), and 65.8% were admitted less than 2 hours ater ingestion. Most o the patients (96.1%)showed cholinergic muscarinic maniestations, particularly salivation (86.8%), myosis (77.6%), sweating (50%), and bronchorrhea (35.5%).Atropine was used in 82.9% o patients (medianϭ2 days), intubation and mechanical ventilation in 46.1% (medianϭ3 days), and themedian length o the hospital stay was 4 days. Plasma samples obtained upon admission in 59 cases revealed (LC-MS/MS): aldicarb (55),carbouran (2), aldicarb and carbouran (1), no active component (1). In most o the plasma and urine samples collected upon admission,the highest concentrations (ng/mL) obtained were or the active metabolite aldicarb sulphoxide (plasma, medianϭ831, IIQϭ99.2–2885;urine, medianϭ9800, IIQϭ2000–15000) than aldicarb (plasma, medianϭ237, IIQϭ35.7–851; urine, medianϭ584, IIQϭ166–1230),indicating rapid metabolism. The excretion o aldicarb and its metabolites was rapid since these compounds were rarely detected inplasma samples 48 hours ater admission. Sequential cholinesterase analysis in 14 patients revealed almost complete reactivation in thefrst 48 hours post-admission, compatible or poisoning by carbamates. Based on the Poisoning Severity Score, the cases were classifedas asymptomatic (5.3%), minor (11.8%), moderate (35.5%), severe (43.4%), and atal (3.9%). Conclusions. Most poisonings involved

aldicarb and resulted rom suicide attempts; the poisonings were generally severe, with a mortality o 3.9%. Aldicarb was rapidly absorbed,metabolized, and excreted.

Keywords Aldicarb; Carbouran; LC-MS/MS; poisoning severity score; “chumbinho”

Introduction

“Chumbinho” is an illegal rodenticide used in Brazil sincethe 1990s.1 The common name in Portuguese “chumbinho”(“small lead pellets”) derives rom the physical appearanceo the product, which generally consists o small, dark grey,regular-shaped granules that resemble small lead pellets

similar to the commercial product Temik®

, which containsonly aldicarb. However, other illegal ormulations containingacetylcholinesterase inhibitors have been identifed, includ-ing solid orms that simulate bait-shaped rodenticide antico-agulants and liquid preparations, with alse labels and othernames (Fig. 1). The labels o these products oten identiy

coumarins as active ingredients. Similar aldicarb-containingproducts are also used as rodenticides in other Latin Ameri-can countries, where they are known as Tres Pasitos , andcases o poisoning by illegally imported products have beenreported in the U.S.2–4 In Brazil, other active ingredientsidentifed in “chumbinho” samples include carbouran andorganophosphates.5–7

Poisoning by “chumbinho” generally reects the easewith which this product can be purchased illegally. Severalretrospective studies have highlighted the high consumptionand severity o poisoning by “chumbinho.”1,5–12 The maincause o poisoning is related primarily to attempted suicideand homicide attempts, with the lethality ranging rom 2 to6%, although non-intentional poisoning has also been docu-mented, especially in children.1,5–11 “Chumbinho” is alsoused or other criminal acts such as the killing o domesticanimals, similar as what has been reported or aldicarb inthe US.13,14

Clinical Toxicology (2012), 50, 44–51Copyright © 2012 Inorma Healthcare USA, Inc.ISSN: 1556-3650 print / 1556-9519 onlineDOI: 10.3109/15563650.2011.639715

CRITICAL CARE

Received 19 September 2011; accepted 8 November 2011.

Address correspondence to Fábio Bucaretchi, Faculty o MedicalSciences, State University o Campinas, Campinas Poison ControlCenter, Centro de Controle de Intoxicacoes de Campinas, Campinas,CEP 13083-887 Brazil. E-mail: [email protected]



Poisoning by illegal rodenticides 45

Copyright © Inorma Healthcare USA, Inc. 2012

Data rom the Campinas Poison Control Center (PCC)in southeastern Brazil indicate an alarming increase in thenumber o poisonings by illegal rodenticides containingacetylcholinesterase inhibitors, mainly “chumbinho,” andnow account or most poisonings by rodenticides, havingsurpassed coumarin-based products. “Chumbinho” was alsothe main cause o death by pesticides in 2008 and 2009 inwhich the cause was confrmed (o 19 deaths attributed topesticides, 10 were caused by “chumbinho”).15

In this report, we describe a prospective case series o poisonings by illegal rodenticides containing acetylcholin-esterase inhibitors, ollowed-up by the Campinas PCC or aperiod o 1 year.

Methods

The case series consisted o individuals diagnosed withpoisoning by illegal rodenticides containing acetylcholin-esterase inhibitors who were ollowed-up at the CampinasPCC rom July 1, 2009 to June 30, 2010. Subjects poisonedby other acetylcholinesterase inhibitors involving commer-cially available products authorized or agricultural use were

excluded rom the study (carbamates, nϭ15; organophos-phates, nϭ50).A standardized orm was used to collect demographic data

or each case, and included sex, age, time o poisoning, placeo initial medical help, and patient’s town/city o origin, aswell as inormation on the poison involved, the nature o theexposure (circumstances, clinical maniestations, treatmentapplied, length o hospital stay and outcome), the analyti-cal fndings, and fnal classifcation o severity based on thePoisoning Severity Score (PSS).16

Based on the PSS, in addition to categories (grade 0) non-toxic or assymptomatic exposure, (grade 1) minor poisoning

(discrete and transient clinical maniestations o rapidresolution) and (grade 4) atal poisoning (atal poisoningas the direct cause or complication o the initial exposure),patients that were treated exclusively with atropine were clas-sifed as moderate poisoning (grade 2) (more pronounced,prolonged, and systemic clinical maniestations that usu-ally require treatment), and those that required atropine andunderwent tracheal intubation and mechanical ventilationwere classifed as severe (grade 3) (intense clinical manies-tations, with risk o death or important sequelae). The PSSwas applied consensually by authors FB and EMDC.

The analytical results were expressed relative to time“zero” which corresponded to the frst sample obtained ateradmission to the emergency unit. Plasmatic and erythrocytecholinesterase analysis was assayed in whole blood, usingmodifed Ellman’s colorimetric method.17,18

Identifcation o the active component(s) in the productand in biological samples (plasma, urine, and gastric lavage)was done by liquid chromatography coupled to mass spec-trometry (LC-MS/MS) in a Prominence chromatographicsystem (Shimadzu, Kyoto, Japan) coupled to a 4000Qtraptriple/quadrupole hybrid mass spectrometer or ion trapping

in linear mode (Applied Biosystems/MDS Analytical Tech-nologies, Toronto, Canada), ftted with a Turbo ioniza-tion source operated in multiple reaction monitoring mode(sMRM) with electrospray ionization (ESI). These analyti-cal procedures were perormed by authors RL and JLC. Asummary o sample preparation and validation proceduresis given below.

Sample preparation

One hundred microliters o sample (plasma, urine, or gastriclavage) was transerred to polypropylene Eppendor tubes

Fig. 1. Some orms o illegal rodenticides containing acetylcholinesterase inhibitors. The samples were obtained rom cases admitted to theCampinas Poison Control Center. (A) Liquid orm (the active ingredient o this ormulation is aldicarb). (B) Pellets similar to coumarin-basedraticide (the active ingredient o this ormulation is aldicarb). (C) Dark grey granules containing aldicarb as the active ingredient; note the

similarity in appearance to the original product, Temik® . (D) Purple granules containing carbouran as the active ingredient. The orms C and Dare popularly known in Brazil as “chumbinho.” (See colour version o this fgure online).



46 F. Bucaretchi et al.

Clinical Toxicology vol. 50 no. 1 2012

ollowed by the addition o 300 μ L o acetonitrile con-taining the internal standard 4-bromo-3,5-dimethylphenylN-methylcarbamate (BDMC, 20 ng/mL). Ater mixing,the tubes were centriuged (12 000 rpm) and 100 μ L o thesupernatant was diluted with 900 μ L o ultrapure water. Tenmicroliters o this mixture was subsequently injected intothe LC-MS/MS system.

Validation

Twenty-seven active ingredients and metabolites o variouspesticides (carbamates, organophosphates, coumarins, andsupercoumarins) were analyzed and validated (analyticaldetails to be published elsewhere). The validation parame-ters studied included linearity, precision, accuracy, recovery,limit o detection, and limit o quantifcation. The qualitycontrols used throughout the study were 5, 50, and 500 ng/ mL. The linearity o the method or all o the analytes wasassessed over a dynamic interval o 5–1000 ng/mL andyielded a coefcient o determination (r2 )Ͼ0.98. Analyterecovery in all biological matrices (plasma, urine, and gas-

tric lavage) was alwaysϾ80%. The limit o detection (LD)was 1 ng/mL and the limit o quantifcation (LQ) was 5 ng/ mL. As an example o these procedures, Table 1 shows theprecision and exactitude or the determination o aldicarb,aldicarb sulphoxide, aldicarb sulphone, and carbouran.

All data previously recorded on the standardized ormswere entered into a digital databank designed specifcallyor this study. Demographic and clinical data are shown asactual numbers or percentages or categorical variables, andas the median and the 25th and 75th percentiles (1st and 3rdquartiles) or continuous variables; the latter were assumedto have a non-Gaussian distribution. Statistical comparisonsamong subgroups o continuous variables were done using theMann–Whitney U-test, with pϽ0.05 indicating signifcance.All data analysis were done using EPI-Ino sotware, version3.5.1. (CDC/WHO, Atlanta, GE, US), SPSS or Windows,version 7.5 (SPSS Inc., Chicago, IL, US) and GraphPad Prism3 (GraphPad Sotware Inc., La Jolla, CA, US). This study wasapproved by the institutional Committee or Ethics in Research(FCM/UNICAMP, protocol no. 0246.0.146.000-09).

Results

Seventy-six cases ulflled the inclusion criteria or acutetoxic exposure to illegal rodenticides containing acetyl-

cholinesterase inhibitors. O these, 10 were treated at ourhospital and 66 were treated at other services; in all cases,ollow up was done until discharge or death. Most o thepatients (53.9%) were men with a median age o 36 years.All exposures resulted or ingestion, and most o themoccurred in urban areas (92.1%) and in a domestic setting(88.2%). In 68 cases (89.5%) it was possible to determinethe time between exposure and admission to the emergency

service; 65.8% o all patients were attended within 2 hourso ingestion. The vast majority o cases (92.1%) were relatedto suicide attempts, and most o the patients (96.1%) showedsome symptoms o poisoning, with the most common beingcholinergic (muscarinic) maniestations, mainly salivation,myosis, sweating, and bronchorrea.

Atropine was used in 82.9% o patients (median dura-tion o treatmentϭ2 days). For those cases treated at ourhospital (nϭ10), the initial median dose o atropine was4 mg, with a total median dose o 36 mg; only one patientdeveloped signs o mild atropine toxicity during the treat-ment. Intubation and mechanical ventilation was used in 35

patients (46.1%). The median duration o hospitalizationwas 4 days. None o the patients received pralidoxime (orany other oxime).

Based on the PSS classifcation, 35.5% were classifedas moderate and 43.4% as severe. O the 72 patients thatwere treated, 68 ully recovered, 1 developed secondary neu-rological sequel that involved hypoxic-ischemic encephal-opathy subsequent to cardiorespiratory arrest, and three died(lethalityϭ3.9%). O the three lethal cases, the pesticidewas identifed in two (aldicarb in one, and an association o aldicarb and carbouran in another). Table 2 summarizes themain demographic and clinical fndings or the patients, andTable 3 shows the main clinical maniestations.

In 68 cases the poison was identifed based on inormationprovided by the patients and relatives that included the men-tion o “chumbinho” or a description o the physical appear-ance o the product; in two cases the product was describedas a liquid. Aldicarb was the sole component in the eightsamples o “chumbinho” brought or identifcation.

Plasma samples were obtained upon admission in 59cases (77.6%). Subsequent analysis by LC-MS/MS identi-fed aldicarb in 55 cases, carbouran in 2 cases, aldicarb andcarbouran in 1 case, and no active component in a urthercase (Table 4). No organophosphates or coumarins weredetected in any o the samples. High concentrations o aldi-

Table 1. alidation parameters (precision and accuracy) or the quantifcation o aldicarb, aldicarb sulphoxide, aldicarb sulphone and carbouranby LC-MS/MS in plasma.

Aldicarb Aldicarb sulphoxide Aldicarb sulphone Carbouran

Precision (C%)5 ng/mL 15.0 4.8 9.5 14.850 ng/mL 5.6 10.2 9.1 7.2500 ng/mL 7.7 9.9 10.3 7.3

Accuracy (%)5 ng/mL 99.9 104.6 90.6 92.250 ng/mL 105.6 93.6 109.0 105.5500 ng/mL 100.4 107.1 100.3 99.7





urine (nϭ29) samples collected upon admission, and theplasma concentrations o these compounds in 35 patientsupon admission and 24 hours post-admission. The aldicarband aldicarb sulphoxide concentrations upon admissionwere signifcantly greater in severe cases (nϭ30) than inmoderate cases (nϭ19) (pϽ0.001, Mann–Whitney U-test;Fig. 3).

Sequential plasmatic and erythrocyte cholinesteraseanalysis in 14 patients revealed almost complete recovery o enzymatic activity 48 hours post-ingestion (Fig. 4).

Discussion

The fndings o this study indicate that poisoning by illegalrodenticides containing acetylcholinesterase inhibitors inmetropolitan area o Campinas (South-Eastern Brazil) isgenerally severe in view o the active compound involved(mainly aldicarb) and the circumstances surroundingmost poisonings (suicide attempts). As with other reportso poisoning by “chumbinho,”1,5–11 aldicarb2–4,19,20 andcarbouran,21–24 most o the patients developed a cholinergicsyndrome, with a predominance o muscarinic maniesta-tions. In several cases, these maniestations required treat-

ment with atropine and mechanical ventilation, high doseso atropine being used in some cases, similar to another caseseries o 35 patients poisoned by the illicit rodenticide Tres

Pasitos (aldicarb).2 The recovery o cholinesterase activitywas generally rapid (as is characteristic o inhibition by car-bamates), with spontaneous decarbamylation o the enzymeactive site. In addition, some o the clinical fndings (e.g.varying degrees o neurological and respiratory depression,mental conusion, and convulsions) may suggest involve-ment o the central nervous system through a direct action o carbamates; these maniestations may have been aggravatedby accompanying hypoxia.

carb were generally detected in the frst gastric lavage sam-ple obtained upon admission. In most o the initial plasmaand urine samples, the predominant aldicarb metabolite wasaldicarb sulphoxide, indicating rapid biotransormation o aldicarb. The excretion o aldicarb and its metabolites wasalso rapid since these compounds were rarely detectedin samples obtained 48 hours ater admission, the excep-tion being the patient exposed to aldicarb and carbouran.The plasma concentrations or carbouran suggested thatthis compound was excreted more slowly than aldicarb.Fig. 2 shows the distribution o the aldicarb and aldicarbsulphoxide concentrations in gastric lavage (nϭ16) and

Table 2. Baseline demographic and clinical characteristics o 76patients who ingested illegal rodenticides containing acetylcholinest-erase inhibitors.

Baseline characteristics

Age (years): median (IIQ; limits) 36 (27–49; 2–74)Men: n (%) 41 (53.9)Circumstances o exposure: n (%)

Suicide attempt 70 (92.1)Homicide attempt 4 (5.3)Non-intentional 2 (2.6)

Time between ingestion and admission toemergency service: median in hour (IIQ)

1 (0.3–2.0)

Time between ingestion and admission basedon categorical variables derived rom timesprovided: n (%)

Ͻ1 hour 31 (40.8)1–2 hours 19 (25.0)

Ͼ2 hours 19 (25.0)Unknown 8 (10.5)

Time between ingestion and start o gastriclavage based on categorical variablesderived rom times provided: n (%)

Ͻ1 hour 24 (31.6) Ͼ1 hour 24 (31.6)

Undetermined 14 (18.4)Not assessed 14 (18.4)

Time between ingestion and start o treatment with activated charcoal, basedon categorical variables derived romtimes provided: n (%)

Ͻ1 hour 13 (17.1) Ͼ1 hour 15 (19.7)

Undetermined 9 (11.8)Not assessed 39 (51.3)

Atropine upon admission: n (%) 63 (82.9)Duration o atropine use: median in days (IIQ) 2 (1–3)Intubation and mechanical ventilation, n (%) 35 (46.1)Duration o mechanical ventilation: median in

days (IIQ)3 (2–8)

Length o hospitalization stay: median indays (IIQ) 4 (2–7)

Classifcation o severity (PSS), n (%)(median, days o hospitalization)

Assymptomatic (grade 0) 4 (5.3) (0) Minor (grade 1) 9 (11.8) (1)

Moderate (grade 2) 27 (35.5) (3)Severe (grade 3) 33 (43.4) (7)Fatal (grade 4) 3 (3.9) (4)

Classifcation o case, based on PSS (grades0–4): median (IIQ)

2 (2–3)

Interquartile interval (IIQ)ϭ1st and 3rd quartile values; PSSϭpoisoningseverity score.

Table 3. Frequency o clinical maniestations at admission in 76patients who ingested illegal rodenticides containing acetylcholinest-erase inhibitors.

Clinical maniestations n (%)

Salivation 66 (86.8)Myosis 59 (77.6)Sweating 38 (50.0)Bronchorrhea 27 (35.5)arying degrees o neurological depression

(sleepiness to coma)27 (35.5)

omiting 23 (30.3)Bradycardia 22 (28.9)Tachycardia 18 (23.7)Localized muscle asiculation 15 (19.7)Diarrhea 12 (15.8)Arterial hypertension 12 (15.8)Mental conusion 11 (14.5)Urinary incontinence 11 (14.5)Arterial hypotension 10 (13.2)Convulsions 8 (10.5)Agitation 7 (9.2)Tremors 5 (6.6)Hyperthermia 4 (5.3)Generalized muscle asciculations 3 (3.9)

Shock 1 (1.3)





is rapidly absorbed by the gastrointestinal tract and, to a

lesser extent, by skin. Aldicarb is rapidly metabolized byhydrolysis and oxidation, with oxidation generating twoactive metabolites that inhibit cholinesterase, namely, aldi-carb sulphone and aldicarb sulphoxide, the latter being themost important and ound in the highest concentrations.26 Aldicarb and its active and inactive metabolites are excretedin the urine within 24 hours o ingestion. Entero-hepaticcirculation o aldicarb and its metabolites has also beendescribed in rats.26

In rats, carbouran is well absorbed by the gastrointestinaltract and, to a lesser extent, by the respiratory system and

gastric lavage urine

plasma

0 240

1000

2000

3000

4000

5000

6000

7000

8000

9000

Time after admission (h)

A l d i c a r b ( n g / m L )

Aldicarb Aldicab sulphoxide0

10000

20000

30000

40000

50000

60000

C o n c e n t r a t i o n ( n g / m L )

Aldicarb Aldicarb sulphoxide0

10000

20000

30000

40000

50000

60000

70000

C o n c e n t r a t i o n ( n g / m L )

0 240

1000

2000

3000

4000

5000

6000

7000

8000

9000


A l d i c a r b s u l p h o x i d e ( n g / m L )

plasma

Fig. 2. Aldicarb and aldicarb sulphoxide concentrations in gastric lavage (nϭ16) and urine (nϭ29) samples collected upon admission; and inplasma samples (nϭ35) collected upon admission and 24 hours post-admission.

Table 4. Analytical results or aldicarb and its active metabolites (aldicarb sulphoxide and aldicarb sulphone) and carbouran in relation to thebiological matrix and sampling time ater admission.

Aldicarb andmetabolites (ng/mL)

Plasma 1st sampleon admission

nϭ59

Plasma 24 hourpost-admission

nϭ36

Plasma 48 hourpost-admission

nϭ24

Gastric lavage 1staspirate on admission

nϭ16

Urine 1st sampleon admission

nϭ29

AldicarbMedian 237 0 0 9830 584IIQ 35.7–851 0–18 0–0 1344–33075 166–1230Not detected (n) (3) (21) (23) (0) (0)

Aldicarb sulphoxideMedian 831 12.6 0.2 159.3 9800IIQ 99.2–2885 0.2–111.5 0–10.2 62.9–434.5 2000–15000Not detected (n) (3) (10) (12) (0) (1)

Aldicarb sulphoneMedian 10.1 0 0 0 57.2IIQ 1.4–30.8 0–0.9 0–0 0–0 0–234Not detected (n) (9) (26) (23) (14) (2)

Carbouran (ng/mL) 277, 370, 2170(nϭ3)

203, 75.5, 1510(nϭ3)

98.5, NA, 1410(nϭ2)

Interquartile interval (IIQ)ϭ1st and 3rd quartile values; NAϭnot assayed.

Aldicarb [2-methyl-2 (methylthio)-propionaldehyde O-

(methylcarbamoyl) oxime], which was implicated in mosto the poisonings in this study, was frst synthesized in the1960s and introduced or agricultural use in the 1970s.Aldicarb is classifed as extremely dangerous by the WorldHealth Organization (WHO Class Ia; LD50 in rats V 0.93mg/kg).25 Carbouran (2,3-dihydro-2,2-dimethyl-7-benzo-uranyl-N-methyl carbamate) was introduced commerciallyin 1965, and is classifed as highly dangerous by the WHO(Class Ib; LD50 in ratsϭ8 mg/kg).25

In mammals, aldicarb is a potent reversible inhibitoro cerebral, erythrocyte and plasma cholinesterase that





skin.27,28 Carbouran is rapidly metabolized by the liver toyield 3-hydroxycarbouran, which also inhibits cholinest-

erase and can undergo entero-hepatic circulation; this com-pound is subsequently metabolized to 3-ketouran.Despite the limitations o extrapolating results rom

animal models to humans, and the act that there may bemarked discrepancies in the toxicity o some pesticidesbetween humans and rats,29 some o the fndings in the pres-ent study are nevertheless similar to those reported romanimal studies,26 e.g. the rapid absorption, metabolism, andexcretion o aldicarb in our patients. This fnding agreeswith the rapid onset o clinical maniestations, the rapidinhibition o cholinesterases, and the high initial concentra-tions o aldicarb and its active metabolite aldicarb sulphox-ide in plasma and urine. We also observed that individuals

with severe poisoning generally had higher concentrationso aldicarb and aldicarb sulphoxide at admission than thosewith moderate poisoning.

Although CG-MS and LC-MS/MS methods or the iden-tifcation and quantifcation o carbouran and aldicarb inhuman serum and ood samples have been described,30–33 to date no study has reported the quantifcation o carbam-

ates, especially o aldicarb and its metabolites, by LC-MS/ MS in such a large series as that described here in dier-

ent biological samples and time intervals. Although poi-soning by carbouran is not uncommon, there have beenew detailed case or case series reports (including atalcases) involving the quantifcation o this compound (byCG-MS).23

Data regarding the ormulation o the illicit rodenticides,including the percentage by weight o the active ingredients,could be relevant, mainly to compare the outcome amongthe dierent case series. Unortunately, neither this studynor that previously reported have determined the concentra-tion o aldicarb or other active ingredients in the analyzedsamples o “chumbinho.” In Brazil, the available commer-cial products (granular ormulations) containing aldicarb

and carbouran are Temik®

(15% by weight) and Furadan®

(5% and 10% by weight), respectively. Despite the lack o inormation on ormulation, the mortality herein describedwas similar as observed in other case series o poisoningcaused by “chumbinho” in Brazil.5–10 Two case series o aldi-carb poisoning reported a mortality o 5% (nϭ2/39)19 and10% (nϭ2/20),20 respectively; however, no concentration

A B

0 24 480

1

2

3

4

5


E r y t h r o c y t e c h o

l i n e s t e r a s e

a c t i v i t y ( I U / m L )

0 24 480

1

2

3

4


P l a s m a c h o l i n e s t e r a s e

a c t i v i t y ( I U / m L )

Fig. 4. Box plots showing the sequential evolution o plasmatic (A) and erythrocyte (B) cholinesterase activity assayed by a modifed Ellmanmethod in samples rom 14 patients exposed to illegal rodenticides containing acetylcholinesterase inhibitors. The samples were obtained atadmission (0 hour), and 24 hours and 48 hours post-admission. In all panels, the interval between the horizontal dashed lines represents the rangeo normal reerence values.

Fig. 3. Box plots o the plasma concentrations o aldicarb (A) and aldicarb sulphoxide (B) upon admission in moderate (nϭ9) and severe (nϭ30)cases o poisoning. The Poisoning Severity Score (PSS) was used to classiy the severity o poisoning. *pϽ0.001 (Mann-Whitney U-test).





o aldicarb in the original product samples was describedin both studies. In a study o poisoning caused by the illicitrodenticide Tres Pasitos , the authors report the identifca-tion o 12% aldicarb by weight, using HPLC, in samplespurchased rom several groceries in areas o New York Cityknown to serve populations o Dominican descent.2

In comparison to organophosphates, complications suchas delayed neuropathy are very rare ater poisoning by

carbamates, although some cases have been reported orcarbouran.22 O the three cases o poisoning involving car-bouran in this study, one was moderate, one was severe andthe third was atal, and involved association with aldicarb.In this atal case, the plasma concentrations o aldicarb andaldicarb sulphoxide decreased more slowly than in patientspoisoned only with aldicarb; this discrepancy may indicatesaturation o the enzymatic pathways involved in metaboliz-ing these compounds, resulting in more prolonged poisoningand a greater risk o complications. A retrospective study o acute poisonings by pesticides in the Brazilian state o MatoGrosso do Sul ound a lethality rate o 4.1% in 96 cases o poisoning by carbouran.34 In contrast, in a large, prospec-

tive cohort study o intentional poisoning by agriculturalpesticides in Sri Lanka, the lethality in 479 cases o poison-ing by carbouran was 1%.29

Despite the widespread use o gastric lavage to treat acutepoisoning by pesticides in Brazil the true beneft o this pro-cedure has yet to be established in randomized controlledclinical trials. The use o gastric lavage and the administra-tion o activated charcoal may be considered (with severalrestrictions) as possibly useul in patients who have ingestedpotentially lethal doses o acetylcholinesterase-inhibitingpesticides when implemented within 1 hour o poisoning.These procedures should be undertaken in adequate acili-ties, or patients who have given explicit consent to the pro-cedure, or to unconscious patients with adequate protectiono the respiratory airways.35–38 Although high concentrationso aldicarb were detected in the gastric lavage samples, theinvestigational approach used here and the limited numbero patients studied precluded a rigorous comparative analy-sis o the benefts o gastrointestinal decontamination in thepopulation studied.

The use o oximes in carbamate poisoning is still quitecontroversial and not without risks, particularly in view o the reversible inhibition o cholinesterases and the relativelyrapid recovery o enzymatic activity.24,38,39 Moreover, arecent randomized controlled clinical trial suggested that

pralidoxime increased the lethality in patients with organo-phosphate poisoning.40 It is not clear how aldicard is commercialized as a

rodenticide in Brazil, although it is most likely through theclandestine sale o legally and illegally imported material.In view o the currently easy access to these products, thehigh toxicity o aldicarb and carbouran, the high requencyo intentional poisonings, and their severity, perhaps thebest approach to reducing the availability o these com-pounds would be or the Brazilian sanitary authorities torestrict their importation, in a manner similar to proceduresalready implemented by other countries based on WHO

guidelines.41,42 In this regard, a recent study rom Sri Lankahas shown that replacing extremely and highly toxic pesti-cides (WHO Classes Ia and Ib pesticides) by less toxic onesdid not adversely aect the agricultural productivity o thecountry.43

This study has several limitations. Since most o thesamples analyzed were rom patients admitted to emer-gency services other than our hospital, it is possible that

some important inormation may not have been adequatelyrecorded during flling in o the questionnaire by telephone.The Glasgow Coma Scale was not recorded in all cases; theavailability o this inormation would have allowed a moreuniorm analysis and comparison o those patients whodeveloped signs o neurological depression. We were notable to ollow up patients ater hospital discharge, and thusit is impossible to ascertain i any patient developed delayedneuropathy.

Conclusions

The results described here indicate that most poisoningscaused by illegal rodenticides containing acetylcholinest-erase inhibitors in metropolitan area o Campinas involvethe use o aldicarb in suicide attempts, and result in serioussystemic eects with a mortality o 3.9%. Aldicarb was rap-idly absorbed, metabolized, and excreted.

Acknowledgments

GMM was supported by an undergraduate studentship orscientifc research (PIBIC/UNICAMP/CNPq). SH is sup-ported by a research ellowship rom Conselho Nacional deDesenvolvimento Cientí fco e Tecnológico (CNPq).

Declaration of interest

The authors report no conicts o interest. The authors aloneare responsible or the content and writing o this paper.

References

Lima JS, Reis CAG. Poisoning due to illegal use o carbamates1.as a rodenticide in Rio de Janeiro. J Toxicol Clin Toxicol 1995;33(6):687–690.Nelson LS, Perrone J, DeRoos F, Stork C, Homan RS. Aldicarb2.

poisoning by an illicit rodenticide imported into the United States:Tres Pasitos. J Toxicol Clin Toxicol 2001; 39(5):447–452.Waseem M, Perry C, Bomann S, Pai M, Gernsheimer J. Cholinergic3.crisis ater rodenticide poisoning. Western J Emerg Med 2010;11(5):524–527.Jang DH, Nelson LS. Images in emergency medicine. Woman with4.unresponsiveness. Ann Emerg Med 2010; 56(2):201–207.Lanzarin LD, Bresciani AP, Schuh DC, alois CM, Barotto A,5.Resener MC, et al. Análise das intoxicações por “chumbinho”registrados no CIT/SC em 2006. Resumos do II Congresso Brasileirode Toxicologia Clí nica. Rev Bras Toxicol 2007; 20(Supl 1):1.Lanzarin LD, Bresciani AP, alois CM, Barotto A, Resener6.MC, Grando M, Zannin M. Análise dos casos de intoxicação por“chumbinho” registrados no CIT/SC entre 1984 e 2006. Resumos

versão publicada jan 2012

Documents