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POISONING DUE TO NEONICOTINOID INSECTICIDES

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. NICOTINE POISONING. Nicotine was first used as a pesticide in 1690

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POISONING DUE TO NEONICOTINOID INSECTICIDES

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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)

  10. NEUROMUSCULAR JUNCTION

  11. AUTONOMIC GANGLIA

  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

  14. SPECIFICITY OF NEONICOTINOIDS FOR α4β2 NICOTINIC RECEPTORS

  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

  18. PERSISTENCE OF ACUTE NEUROLOGICAL FEATURES (US EPA, 1992) Time after exposure (days) IMIDACLOPRID GAUCHO®

  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

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