poisoning due to neonicotinoid insecticides n.
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  1. POISONING DUE TO NEONICOTINOID INSECTICIDES Allister Vale MD National Poisons Information Service (Birmingham Unit) and West Midlands Poisons Unit, City Hospital, Birmingham, B18 7QH, UK

  2. NICOTINE POISONING • Nicotine was first used as a pesticide in 1690 • Resistance to nicotine developed • Severe and fatal poisoning can occur  Following ingestion (within a few minutes)  Occupational skin exposure • Minor insecticide, now marketed in few counties e.g. China

  3. NICOTINE POISONING • Nicotine poisoning is characterized by:  Nausea, vomiting, abdominal pain and diarrhoea  Sweating and tachycardia Increased salivation  Hyperpnoea and bronchorrhoea  Muscular spasms, tremor  Confusion  Seizures  Circulatory collapse

  4. NEONICOTINOIDS • Seven neonicotinoids are marketed:  Acetamiprid  Clothianidin  Dinotefuran Imidacloprid  Nitempyram  Thiacloprid  Thiamethoxam(metabolized to clothianidin)

  5. N C H 3 N H NICOTINE AND NEONICOTINOIDS Nicotine Imidacloprid

  6. NEONICOTINOIDS: INTRODUCTION AND USES • A major new class of insecticides developed in the past three decades • Neonicotinoids are replacing OP and carbamate insecticides • Neonicotinoids are applied as foliage treatments • They are used as seed applied pesticides

  7. NEONICOTINOIDS: INTRODUCTION AND USES • Neonicotinoids are employed as soil treatments: Taken up by plant roots Diffuse into the plant vascular system Ingested by piercing-sucking insects (e.g. aphids, whiteflies, mealybugs, soft scales, and thrips) • Imidacloprid and nitempyram are also highly effective in controlling fleas in cats and dogs

  8. NEONICOTINOIDS: INTRODUCTION AND USES • Selected on the basis that they are highly specific for sub-types of nicotinic acetylcholine receptors (nAChRs) that occur only in insects • Hence, they should have much lower toxicity than nicotine containing pesticides • Should be more effective than nicotine containing insecticide formulations

  9. NICOTINE VERSUS NEONICOTINOIDS • In arthropods, nicotinic acetylcholine receptors (nAChRs) are confined to the CNS (α4- nicotinic) • In humans nAChRs are found:  at neuromuscular junctions in skeletal muscle (α1- nicotinic)  in autonomic ganglia (α3- nicotinic)  in the CNS (α4- nicotinic)



  12. NICOTINE VERSUS NEONICOTINOIDS • Nicotine acts as an agonist at nAChRs by mimicking the action of ACh • α4β2 nAChR subtype is responsible for the CNS effects of nicotine in both man and insects • Nicotine is more selective for mammalian nAChR than insect nAChR

  13. NICOTINE VERSUS NEONICOTINOIDS • Neonicotinoids prefentially bind to a unique insect α4β2 nAChR subtype • In addition, humans are thought to be partially protected from neonicotinoid toxicity because of the poor permeability of the blood-brain barrier to these compounds • These two differences provide the neonicotinoids with a potentially more favourable toxicological profile


  15. IMIDACLOPRID: TOXICOKINETICS • Imidacloprid is rapidly and very extensively absorbed (>92%) after ingestion • Peak [plasma] are reached within 2-3 hours • Metabolism is rapid • 75% of an administered dose is eliminated in the urine; the remainder is excreted in the faeces • Main urine metabolites are 6-chloronicotinic acid and its glycine conjugate

  16. NEONICOTINOID POISONING: EPIDEMIOLOGY • Despite their widespread use, only 77 cases of human exposure to neonicotinoids (imidacloprid) have been reported:  India (n=2)  Japan (n=1) Portugal (n=2)  Sri Lanka (n=68)*  Taiwan (n=4) • Eight publications and one personal communication*

  17. NEONICOTINOID POISONING: EPIDEMIOLOGY • Six of the 77 (8%) patients died • Two of six had co-ingested an OP insecticide (quinalphos) • Four of six had consumed a formulation containing N-methyl pyrrolidine • Features are not necessarily attributable to imidacloprid alone


  19. IMIDACLOPRID: SOUTH ASIAN CLINICAL TOXICOLOGY RESEARCH COLLABORATION • Mohamed et al collected data prospectively in 68 patients poisoned with imidacloprid • Admitted to three hospitals in Sri Lanka • 61 of 68 cases followed ingestion • 7 of 68 due to occupational exposure • Ingestion confirmed in 38 of 61 patients by HPLC/MSMS (9 of 38 had [insignificant])

  20. IMIDACLOPRID: SOUTH ASIAN CLINICAL TOXICOLOGY RESEARCH COLLABORATION • All occupational exposures were discharged within 24 hours • In 26 of 61 non-occupational cases, the amount ingested was unknown • Median amount ingested in 35 of 61 patients was 15 mL (IQR* 10-50) • Median time of presenting to hospital was 240 minutes (IQR* 135-360) [*interquartile range]

  21. IMIDACLOPRID: SOUTH ASIAN CLINICAL TOXICOLOGY RESEARCH COLLABORATION • The median GCS on presentation was 15 (IQR 10-15) • 56 of 61 patients had only one of the following symptoms: Nausea or vomiting  Abdominal pain  Diarrhoea Headache  Dizziness

  22. IMIDACLOPRID: SOUTH ASIAN CLINICAL TOXICOLOGY RESEARCH COLLABORATION • Five of 61 patients developed cholinergic features • Four patients developed respiratory arrest and were mechanically ventilated, but three of these had co-ingested quinalphos (n=2) or fenthion (n=1) • No patient ingesting imidacloprid alone died • Two patients co-ingesting quinalphos died

  23. IMIDACLORID POISONING: NINE PATIENTS • Features observed included:  miosis  sweating  hypersalivation and bronchorrhoea  breathlessness  hyperactive bowel sounds  bradycardia • Suggestive of the development of the cholinergic syndrome • Mortality four of nine (45%) patients

  24. IMIDACLOPRID POISONINGHUNGet al, 2005; 2006 • A 64-year-old woman presented to the ED 1-2 hours after ingesting 150 mL of imidacloprid 9.6% (containing N-methyl pyrrolidone) • She developed nausea, vomiting, breathlessness, increased salivation, bronchorrhoea, miosis, ataxia, a reduced level of consciousness and hyperactive bowel sounds

  25. IMIDACLOPRID POISONING(HUNGet al, 2005; 2006) • Endotracheal intubation was performed because of reduced level of consciousness • Atropine 2 mg IV for ? bronchorrhoea • AChE activity was normal • CT brain was normal • She developed pneumonia (day 5) and died

  26. IMIDACLOPRID POISONING(HUNGet al, 2006) • A 71-year-old man was admitted to hospital after ingesting 200 mL imidacloprid 9.6% (containing N-methyl pyrrolidone) • He developed nausea, vomiting, miosis, diaphoresis, bradycardia and coma • Atropine 2 mg was administered • AChE activity was normal • Patient was discharged 6 days later

  27. IMIDACLOPRID POISONING(AGARWAL AND SRINIVAS, 2007) • A 24-year-old male farmer presented with agitation, incoherence, sweating and breathlessness after inhaling 17.8% imidacloprid while spraying • Prior to admission he had become unconscious after inhaling the spray • Examination revealed extreme agitation, frothy secretions, cyanosis, diaphoresis and disorientation

  28. IMIDACLOPRID POISONING(AGARWAL AND SRINIVAS, 2007) • He was febrile, his pulse rate was 132 beats/min, his blood pressure was 166/98 and his respiratory rate was 36 breaths/min • Chest auscultation revealed "bilateral conducted sounds" • CXR was normal and arterial blood gases were suggestive of type II respiratory failure

  29. IMIDACLOPRID POISONING(AGARWAL AND SRINIVAS, 2007) • The patient was intubated and ventilated • Extreme agitation persisted despite lorazepam 8 mg/hr and necessitated propofol infusion (5 mg/kg/hr) • Dark urine developed on the third day of admission • Creatine kinase activity was elevated to 1200 U/L (14-148 U/L)

  30. IMIDACLOPRID POISONING(AGARWAL AND SRINIVAS, 2007) • Normal serum potassium and creatinine concentrations • Delirium and weakness persisted until day 6, after which he was extubated successfully • AChE activity was normal

  31. NEONICOTINOID POISONING: MANAGEMENT • Activated charcoal is known to bind imidacloprid in vitro (Daneshvaret al, 2007) • Activated charcoal may be considered if a patient presents ≤ 1 hr after ingesting a significant quantity of pesticide • In patients who are unconscious, an airway should be established • Measure erythrocyte AChE activity to exclude OP and carbamate poisoning

  32. NEONICOTINOID POISONING: MANAGEMENT • Atropine 2 mg IV, repeated as necessary, should be given to control hypersalivation and bronchorrhoea • Hypotension and cardiac dysrhythmias should be managed conventionally • Acid-base and electrolyte imbalance should be corrected

  33. CONCLUSIONS • Neonicotinoids are a major new class of insecticides • Neonicotinoids are replacing OP and carbamate insecticides • They are very effective against sucking and soil insects, as seed dressings, and as foliar treatments • Also highly effective in controlling fleas in cats and dogs

  34. CONCLUSIONS • Deliberate ingestion or accidental inhalation of substantial amounts of imidacloprid has resulted in features similar to those found in nicotine poisoning • Overall, there was an 5% mortality in patients ingesting imidacloprid alone • The neonicotinoids are more toxic than first claimed