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

3. NICOTINE POISONING l 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 l Seven neonicotinoids are marketed:  Acetamiprid  Clothianidin  Dinotefuran  Imidacloprid  Nitempyram  Thiacloprid  Thiamethoxam (metabolized to clothianidin)

5. NICOTINE AND NEONICOTINOIDS N N CH 3 H ImidaclopridNicotine

6. NEONICOTINOIDS: INTRODUCTION AND USES l A major new class of insecticides developed in the past three decades l Neonicotinoids are replacing OP and carbamate insecticides l Neonicotinoids are applied as foliage treatments l 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) l Imidacloprid and nitempyram are also highly effective in controlling fleas in cats and dogs

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

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

13. NICOTINE VERSUS NEONICOTINOIDS l Neonicotinoids prefentially bind to a unique insect α4β2 nAChR subtype l 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 l These two differences provide the neonicotinoids with a potentially more favourable toxicological profile

14. SPECIFICITY OF NEONICOTINOIDS FOR α4β2 NICOTINIC RECEPTORS Neonicotinoid IC* 50 nMSelectivity ratio InsectVertebrate Acetamiprid8.370084 Clothianidin2.23,5001,591 Dinotefuran900>100,000>111 Imidacloprid4.62,600565 Nicotine400070.002 *Concentration of neonicotinoid or nicotine that produces 50% inhibition of the nicotinic receptor (Tomizawa and Casida, 2005)

15. IMIDACLOPRID: TOXICOKINETICS l Imidacloprid is rapidly and very extensively absorbed (>92%) after ingestion l Peak [plasma] are reached within 2-3 hours l Metabolism is rapid l 75% of an administered dose is eliminated in the urine; the remainder is excreted in the faeces l 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) l Eight publications and one personal communication*

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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