Pone.0005127 1.5

Acute Human Self-Poisoning with ImidaclopridCompound: A Neonicotinoid Insecticide Fahim Mohamed1*, Indika Gawarammana1, Thomas A. Robertson2, Michael S. Roberts2, Chathura Palangasinghe1, Shukry Zawahir1, Shaluka Jayamanne3, Jaganathan Kandasamy4, Michael Eddleston1,5, Nick A. Buckley1,6, Andrew H. Dawson1,7, Darren M. Roberts1,8 1 South Asian Clinical Toxicology Research Collaboration, Department of Clinical Medicine, University of Peradeniya, Peradeniya, Sri Lanka, 2 Therapeutics Research Unit, School of Medicine, University of Queensland, Brisbane, Australia, 3 Polonnaruwa General Hospital, North Central Province, Polonnaruwa, Sri Lanka, 4 Anuradhapura General Hospital, North Central Province, Anuradhapura, Sri Lanka, 5 Scottish Poisons Information Bureau, Royal Infirmary of Edinburgh, and Clinical Pharmacology Unit, University of Edinburgh, Edinburgh, United Kingdom, 6 Medical Professorial Unit, POW Hospital Clinical School, University of New South Wales, Kensington, Australia, 7 School of Medicine and Public Health, University of Newcastle, Callaghan, Australia, 8 Burns, Trauma and Critical Care Research Centre, University of Queensland, Brisbane, Australia Background: Deliberate self-poisoning with older pesticides such as organophosphorus compounds are commonly fataland a serious public health problem in the developing world. The clinical consequences of self-poisoning with newerpesticides are not well described. Such information may help to improve clinical management and inform pesticideregulators of their relative toxicity. This study reports the clinical outcomes and toxicokinetics of the neonicotinoidinsecticide imidacloprid following acute self-poisoning in humans.
Methodology/Principal Findings: Demographic and clinical data were prospectively recorded in patients with imidaclopridexposure in three hospitals in Sri Lanka. Blood samples were collected when possible for quantification of imidaclopridconcentration. There were 68 patients (61 self-ingestions and 7 dermal exposures) with exposure to imidacloprid. Of theself-poisoning patients, the median time to presentation was 4 hours (IQR 2.3–6.0) and median amount ingested was 15 mL(IQR 10–50 mL). Most patients only developed mild symptoms such as nausea, vomiting, headache and diarrhoea. Onepatient developed respiratory failure needing mechanical ventilation while another was admitted to intensive care due toprolonged sedation. There were no deaths. Median admission imidacloprid concentration was 10.58 ng/L; IQR: 3.84–15.58 ng/L, Range: 0.02–51.25 ng/L. Changes in the concentration of imidacloprid in serial blood samples were consistentwith prolonged absorption and/or saturable elimination.
Conclusions: Imidacloprid generally demonstrates low human lethality even in large ingestions. Respiratory failure andreduced level of consciousness were the most serious complications, but these were uncommon. Substitution ofimidacloprid for organophosphorus compounds in areas where the incidence of self-poisoning is high may help reducedeaths from self-poisoning.
Citation: Mohamed F, Gawarammana I, Robertson TA, Roberts MS, Palangasinghe C, et al. (2009) Acute Human Self-Poisoning with Imidacloprid Compound: ANeonicotinoid Insecticide. PLoS ONE 4(4): e5127. doi:10.1371/journal.pone.0005127 Editor: Michael B. Gravenor, University of Swansea, United Kingdom Received January 21, 2009; Accepted March 12, 2009; Published April 8, 2009 Copyright: ß 2009 Mohamed et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permitsunrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: This study is funded by a Wellcome Trust/NHMRC International Collaborative Research Grant GR071669MA through SACTRC (www.sactrc.org). Thefunders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing Interests: The authors have declared that no competing interests exist.
* E-mail: [email protected] in the risk assessment and clinical management of patients withacute exposures and support policy decisions by regulatory Intentional self-poisoning with pesticides is an important public agencies. Previous restrictions in the availability of highly toxic health problem in the Asia- Pacific region with an estimated compounds appeared to substantially reduce deaths from 300,000 deaths occurring each year [1,2]. A large number of these poisoning [3,4,5] without harming agricultural outputs [5].
deaths are due to poisoning with organophosphorus insecticides The neonicotinoids are a new major class of highly potent which are an integral part of agriculture within this region [2].
insecticides that are used for crop protection and flea control [6].
Due to the intrinsic toxicity of these compounds, new pesticides Insecticides within this class include imidacloprid, acetamiprid, continue to be developed and released to the market which almost clothianidine, and thiocloprid. These insecticides are agonists at always occurs in the absence of data on direct human toxicity.
the nicotinic acetylcholine receptors (nAChRs), particularly the Instead, human toxicity is often extrapolated from toxicological a4b2 subtype [7,8], which induces neuromuscular paralysis and studies in animals, the relevance of which is poorly defined.
eventually death. They are highly selective for nAChRs in insects Therefore, data reporting the outcomes from human exposures to compared with mammals, which should reduce morbidity and these newer insecticides are required. This information can assist mortality in cases of human poisoning [7]. If clinical data on PLoS ONE www.plosone.org April 2009 Volume 4 Issue 4 e5127 Imidacloprid Human Case Series human exposures support this, they may potentially replace the Inclusion and exclusion criteria more widely used cholinesterase inhibitors (organophosphorus and All patients presenting to a study hospital with a history of carbamate compounds) in crop protection.
imidacloprid exposure were considered for this study. Patients Imidacloprid (CAS 138261-41-3; figure 1) is the most under 14 years, pregnant women and patients presenting with co- commonly used neonicotinoid insecticide in Sri Lanka. On the ingestions are excluded from the study.
basis of animal studies it is classified as moderately hazardous(Class II WHO; toxicity category II EPA) [9,10]. It has low acute Data collection procedure lethal toxicity to mammals, birds, and fish: the acute oral LD50 Clinical observations of all patients with imidacloprid poisoning (dose that is lethal in 50% of animals) of imidacloprid in rats is were prospectively recorded on a specially designed data base from 475 mg/kg and the acute dermal LD50 exceeds 5000 mg/kg. It March 2002 to March 2007. The poison ingested was identified also does not cause eye irritation (rabbits) or skin sensitization from the patient's or relative's history, examination of the bottle (guinea pigs) [11].
label and/or the doctor's comments on transfer letters. Blood tests Data on human exposure to imidacloprid is limited to such as full blood count, biochemistry or cholinesterase activity occupational exposures [12,13,14,15] and 13 case reports of self- were not performed prospectively as there is limited availability of poisoning [14,16,17,18,19,20,21]. Mild clinical effects such as such services in these predominantly rural hospitals.
tachycardia, hypertension, mydriasis, nausea and vomiting occur, Blood samples were collected from patients for quantification of but more serious sequelae including respiratory failure, seizures the concentration of imidacloprid and other biochemical assays at [15,17,20] and even death [16,18,21] are reported. This raises a later date. Following collection, the plasma was promptly serious doubts about its assumed superior safety profile over older separated and samples were stored at 223uC and transported to insecticides. However, in the majority of cases the concentration of the University of Queensland, Australia on dry ice for analysis.
imidacloprid was not quantified so it was not possible to confirm Samples were analyzed by HPLC (Shimadzu) with MSMS exposure or consider dose in the risk assessment.
detection (Applied Biosystems API2000) of imidacloprid (MRM In this study we sought to further describe the spectrum of 255.9/208.9) and internal standard d4-Imidacloprid (MRM toxicity and clinical outcomes relative to the admission plasma 260.0/213.1) at 3.7 min. Separation of the imidacloprid peak concentration in patients with acute imidacloprid poisoning.
was performed using Strata C18 (5 mm62 mm) online solid phaseextraction and Gemini (50 mm62 mm) analytical columns (Phenomenex) using a standard valve configuration [22], the3 minute equilibration step and 6 minute gradient shown in table 1. Solvent A (Pumps A & B) and Solvent B (Pump C) This observational study was approved by Human Research contained 0.1% formic acid with acetonitrile, water and methanol Ethics committees of the University of Colombo Faculty of in the ratios 5:95:0 and 90:5:5, respectively. Samples were Medicine, The Sri Lankan Medical Association, The Australian prepared by combining plasma (10 mL), d4-imidacloprid (2 mg/ National University and Oxfordshire, UK. Ethics approval mL) in zinc (II) sulfate solution (100 mM, 20 mL) and acetonitrile includes provision of a single blood sample on admission, regular (50 mL). Each sample was prepared by combining the three clinical reviews during hospitalisation and publication of de- components, vortex mixing (5 sec), centrifugation (5 min at indentified clinical data. Multiple blood samples were obtained as 4000 rpm), transfer of supernatant (,70 mL) and LCMS injection part of a smaller sub-study which required additional written of 50 mL (Table 1).
consent. In all cases, informed verbal consent was obtained from Biochemical analyses were conducted by Queensland Health the patient or a relative in their native language.
Forensic and Scientific Services at Princess Alexandra Hospital,Australia. This service is accredited by the National Association of Testing Authorities, Australia and certified to International A prospective observational cohort study of all poisoning Standards (ISO 9001).
presentations was established during 2002 in three hospitals inthe North Central and North Western provinces of Sri Lanka and Table 1. LC Events the cohort was extended to Central province during the year 2005.
Figure 1. Chemical structure of imidacloprid.
doi:10.1371/journal.pone.0005127.g001 PLoS ONE www.plosone.org April 2009 Volume 4 Issue 4 e5127 Imidacloprid Human Case Series Data were entered in to an excel sheet and analyzed using the statistical Program STATA IC 10.
Over the 5 year period, 68 patients presented to study hospitals with a history of imidacloprid exposure. Seven cases wereoccupational dermal exposures, all of whom remained asymptom-atic and were discharged within 24 hours of admission. Fivepatients reported co-ingestion with another pesticide and wereexcluded from further analysis, leaving 56 patients with acuteimidacloprid self-poisoning.
The median time to present to a study hospital since ingestion was 4 hours (IQR 2.3–6.0 hours). The median volume reported asingested in self-poisoning was 15 mL (IQR: 10–50); although in 23the volume ingested was unknown.
The majority of patients (54/56) had only mild symptoms such as nausea, vomiting, headache, dizziness, abdominal pain, and Figure 2. Admission imidacloprid plasma concentrations diarrhoea during the hospital stay which was largely self-resolving.
(n = 33). Compared to other cases of imidacloprid poisoning where The median Glasgow Coma Score (GCS) on presentation was 15 the plasma concentration was quantified (12.5 and 2.05 ng/L post- (IQR: 10–15). There were no deaths giving a case fatality of 0% mortem [16]), our patients survived despite relatively high concentra- (95% CI: 0.0–5.2%). However, two patients developed more severe symptoms requiring management in an intensive care unit and are described in more detail below.
prophylaxis against aspiration pneumonia. His clinical condition improved within 24 hours and he was discharged alive 3 days A 35 year old woman was admitted to a peripheral hospital soon later. Blood samples were not available to confirm exposure in this after ingestion of an unknown amount of imidacloprid. Due to an initial lack of history, she had been managed as a case oforganophosphorus pesticide poisoning. She received forced Toxicokinetics and biochemistry emesis, 1.2 mg of atropine and 1g of pralidoxime before her Of the 56 patients with imidacloprid self-poisoning, 13 patients transfer to the study hospital. At this time, 2 hours post ingestion, provided serial blood samples, 38 patients provided a single blood she was agitated and had a blood pressure of 110/70 mmHg, sample, and 5 patients refused to give any samples. Blood samples regular pulse rate of 120/minute, pupil diameter 3 mm bilaterally from the first 33 cases were analysed as described and the results of and clear lungs. She received a bolus dose of haloperidol (5 mg imidacloprid quantification are shown in figure 2. Exposure was intramuscularly) for agitation. At 16 hours after ingestion she confirmed in 28 patients, with a median admission plasma developed a respiratory arrest requiring endotracheal intubation concentration of 10.58 ng/L; IQR: 3.84–15.58 ng/L and range: using atracurium 25 mg and midazolam 5 mg. She received an 0.02–51.25 ng/L. In 5 patients the concentration was less than the atropine infusion at 1.2 mg/hour and prophylactic cefuroxime level of quantification (0.008 ng/L), consistent with minimal 750 mg 8 hourly and metronidazole 500 mg every 8 hours for exposure to imidacloprid.
suspected pulmonary aspiration. On her second day in ICU, she Imidacloprid was only detected in eight of the patients who became hypotensive which was treated with dopamine infusion.
provided serial blood samples but in one patient the plasma Other treatments included regular pralidoxime (1g every 6 hours) concentrations were all less than 0.3 ng/L. The concentration- and chest physiotherapy. She was extubated on her 4th ICU day time profiles for these seven patients are shown in Figure 3 and after 3 days of mechanical ventilation and discharged home 9 days demonstrate a rapid initial absorption with high concentrations post-ingestion with no apparent residual effects. During her being noted on admission. However, the concentration remained recovery the patient reported a history of imidacloprid only. This elevated for up to 10–15 hours post-ingestion, which might suggest was subsequently confirmed on laboratory testing of a blood that absorption and/or elimination are saturable (zero-order) or sample obtained 5 hours post-ingestion when the plasma concen- prolonged at high doses. In one of the patients there was a rapid tration of imidacloprid was 44.6 ng/L (Figure 2) and the butyryl decrease in concentration soon after the admission sample which cholinesterase activity was normal.
might represent a distribution phase; the reason for this samplediffering from the others is not apparent from this data.
Quantification of metabolite production may further define the A 26 year old man presented to a peripheral hospital following toxicokinetics underpinning these observations, but unfortunately ingestion of an unknown amount of imidacloprid under the these were not able to be conducted at this time.
influence of alcohol. He received forced emesis and atropine (3 mgbolus followed by infusion of 2 mg/hour) and was then transferred to one of the study hospitals. On admission to the study hospital Admission blood samples from the same 33 patients were (4.5 hours post-ingestion) he had vomiting, a regular pulse rate of screened for biochemical abnormalities. No major abnormalities 84/minute, blood pressure 100/80 mmHg, pupil diameter 6 mm were noted in terms of electrolytes, blood glucose, renal function bilaterally, respiratory rate 40/minute, pulse oximetry was 100% and liver function tests. Minor abnormalities included median and GCS 3/15. The patient was transferred to the ICU 9 hours venous bicarbonate of 14 mmol/L (IQR 10–15 mmol/L) and the post-ingestion for closer monitoring. He received nebulised median anion gap was raised at 20 mmol/L (IQR 18–26 mmol/ salbutamol and intravenous cefuroxime and metronidazole for L). We were not able to perform arterial blood gases which might PLoS ONE www.plosone.org April 2009 Volume 4 Issue 4 e5127 Imidacloprid Human Case Series formulation (as observed with some other pesticides) may causeanaerobic metabolism and produce a lactic acidosis which maycause a moderate decrease in bicarbonate.
In animals, imidacloprid penetrates the blood-brain barrier to only a very limited extent [7]. While a decreased level ofconsciousness was uncommon in our study, prolonged sedationand respiratory depression was noted in two patients which mayhave been due to co-ingestion of ethanol. Transient respiratoryimpairment appeared to contribute to deaths reported in patientswith severe poisoning where co-ingestion of ethanol was notreported [20,21].
There are no specific antidotes for neonicotinoid poisoning in mammals [7,25]. On the basis of our experience, symptomatic andsupportive care is all that is required for the management ofpatients with acute imidacloprid poisoning. Treatment withoximes such as pralidoxime is expected to be either ineffectiveor contraindicated. Oximes in the absence of organophosphoruspesticides have a weak inhibitory effect on acetylcholinesterase Figure 3. The toxicokinetics of imidacloprid in patients withself-poisoning (n = 8 patients). The concentration was high on activity and therefore might increase nicotinic effects (tachycardia, admission and remained elevated in the majority of patients suggesting hypertension, muscle weakness). It is notable that our two most either prolonged absorption and/or elimination.
seriously poisoned cases received treatment with pralidoxime.
The concentration-time profile shown in Figure 3 suggests that there is rapid absorption, with high concentrations being noted on have confirmed the presence of high anion gap metabolic acidosis.
admission. In rats, imidacloprid is rapidly and almost completely Median creatine kinase (CK) was measured at 115 IU/L (IQR absorbed (.92%) from the gastrointestinal tract. The peak plasma 75–124), which is within the commonly quoted reference range concentration is observed within approximately 2.5 hours and is and troponin-I was not elevated.
followed by a rapid disposition phase. However, in our patients theconcentrations generally remained elevated for up to 10–15 hours post-ingestion, which might suggest saturation of one or morekinetic (absorption or elimination) pathways in humans at high This is the only prospective human case series reporting doses. A possible factor influencing the observed kinetic profile is outcomes from acute self-poisoning with the neonicotinoid the administration of atropine (commonly given routinely to insecticide imidacloprid. We demonstrated that imidacloprid insecticide poisonings in Sri Lanka) which is known to prolong the self-poisoning resulted in mostly minor toxicity with a case-fatality absorption phase of xenobiotics [26].
of 0%. This is favourable compared to outcomes with other Of the patients who provided serial samples, the final blood insecticides, in particular the widely used organophosphorus sample was generally obtained from patients around the time of compounds which commonly have a case fatality between 5 and discharge, when they appeared to be in good health. It is noted in 30% [23,24]. The most severely poisoned patients were both figure 3 that for many of these patients the imidacloprid administered antidotes used for the treatment of organophospho- concentration remained elevated. Therefore, plasma concentra- rus pesticides (a common cause of poisonings in the region) and tions do not appear to be useful for guiding clinical management, this may have increased the apparent toxicity. Many patients may which may reflect the contribution of metabolites or co- have had a moderate metabolic acidosis on admission; however, formulants. In rats, the metabolism of imidacloprid is rapid and simple supportive care was sufficient to ensure a good outcome for extensive where only 10–16% of a dose is excreted unchanged [6].
all patients in this series.
Metabolites may contribute to human toxicity as they do in insects, Tachycardia and hypertension have usually been reported in in particular the olefin metabolite which retains insecticidal previous cases, and recurrent ventricular fibrillation was the activity and nAChR activity [7]. Potentially, individual variation reported cause of death in a 69 year-old woman with coronary in cytochrome P450 isoenzymes involved in oxidative imidaclo- artery disease [18]. Only 2 patients in our case series developed prid metabolism may contribute to variable toxicity [7,27].
any cardiovascular toxicity which was predominantly hypotension Admire SL 200H (200 g/L), the most popular imidacloprid- and biomarkers of cardiac toxicity were not elevated. While containing product in Sri Lanka, contains dimethylsulfoxide and electrocardiographic monitoring was not conducted in these N-methylpyrolidone as solvents which are irritants and may patients, blood pressure improved with intravenous fluids.
induce gastrointestinal toxicity.
Therefore serious arrhythmias were unlikely to have caused the Four deaths have been reported in the literature, and the post- mortem blood concentrations in two cases were 12.5 and 2.05 ng/ Biochemical abnormalities and rhabdomyolysis have been L [16], which surprisingly is not substantially greater than the reported as potentially serious complications that might lead to median plasma concentration in our study (9.86 ng/L). However, mortality [15,21]. Most of the patients in our series had normal ante-mortem plasma concentrations were not reported in these CK and biochemistry with the exception of low venous two fatalities and a direct comparison of the concentrations may bicarbonate. The cause of this is not clear given the other be misleading. There are no data on the blood/plasma biochemical results, although diarrhoea may be contributory. It concentration ratio or post-mortem redistribution.
may also be due to acidic metabolites of imidacloprid such as 6- This study demonstrates that an acute ingestion of 20% SL chloronicotinic acid and other metabolites [6]; however, metabolic formulations of imidacloprid, even following large ingestions in pathways of imidacloprid have not been extensively studied in patients with self-poisoning, is relatively safe. Therefore, it may be humans. Direct mitochondrial toxicity from a component of the advantageous to promote the use of imidacloprid or similar PLoS ONE www.plosone.org April 2009 Volume 4 Issue 4 e5127 Imidacloprid Human Case Series pesticides in areas where the incidence of self-poisoning is high.
However, before this occur the relative risks and benefits of thisinsecticide (which has been debated)[28,29,30] must be compared We thank SACTRC doctors, directors, medical and nursing staff of thestudy hospitals for their support. We also thank Chigusa Yokobori and to those of existing pesticides. This will require careful consider- Maeno Momoe for translations, and Brian Mullins for coordinating the ation by independent regulatory authorities.
Imidacloprid pesticides appear to be of low toxicity to humans causing only mild symptoms such as vomiting, abdominal pain, Author Contributions headache and diarrhoea in the majority of cases. Large ingestionsmay lead to sedation and respiratory arrest. Patients with a low Conceived and designed the experiments: FM CP SZ ME AD NAB.
GCS should be closely monitored for onset of respiratory Performed the experiments: FM CP SJ JK. Analyzed the data: FM IG SZ compromise but most patients only need symptomatic and ME DR. Contributed reagents/materials/analysis tools: TAR MSR DR.
Wrote the paper: FM IG ME AD NAB DR.
supportive care. More research is required to show if thereplacement in agriculture of older anti-cholinesterase pesticideswith newer pesticides with much lower in-hospital case-fatality willlead to an overall reduction in deaths from self-poisoning.
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