POISONING DUE TO NEONICOTINOID INSECTICIDES

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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

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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

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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

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NEONICOTINOIDS

• Seven neonicotinoids are marketed
• ? Acetamiprid
  
• ? Clothianidin
  
• ? Dinotefuran
• ? Imidacloprid
• ? Nitempyram
• ? Thiacloprid
• ? Thiamethoxam (metabolized to clothianidin)

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NICOTINE AND NEONICOTINOIDS
Imidacloprid
Nicotine
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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

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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

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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

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NICOTINE VERSUS NEONICOTINOIDS

• In arthropods, nicotinic acetylcholine receptors
  (nAChRs) are confined to the CNS (a4- nicotinic)
• In humans nAChRs are found
  ? at neuromuscular junctions in skeletal
  muscle (a1- nicotinic)
  ? in
  autonomic ganglia (a3- nicotinic) ? in the
  CNS (a4- nicotinic)

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NEUROMUSCULAR JUNCTION
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AUTONOMIC GANGLIA
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NICOTINE VERSUS NEONICOTINOIDS

• Nicotine acts as an agonist at nAChRs by
  mimicking the action of ACh
• a4ß2 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

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NICOTINE VERSUS NEONICOTINOIDS

• Neonicotinoids prefentially bind to a unique
  insect a4ß2 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

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SPECIFICITY OF NEONICOTINOIDS FOR a4ß2 NICOTINIC
RECEPTORS
Neonicotinoid IC50 nM IC50 nM Selectivity ratio
Neonicotinoid Insect Vertebrate Selectivity ratio
Acetamiprid 8.3 700 84
Clothianidin 2.2 3,500 1,591
Dinotefuran 900 gt100,000 gt111
Imidacloprid 4.6 2,600 565
Nicotine 4000 7 0.002
Concentration of neonicotinoid or nicotine that produces 50 inhibition of the nicotinic receptor (Tomizawa and Casida, 2005) Concentration of neonicotinoid or nicotine that produces 50 inhibition of the nicotinic receptor (Tomizawa and Casida, 2005) Concentration of neonicotinoid or nicotine that produces 50 inhibition of the nicotinic receptor (Tomizawa and Casida, 2005) Concentration of neonicotinoid or nicotine that produces 50 inhibition of the nicotinic receptor (Tomizawa and Casida, 2005)
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IMIDACLOPRID TOXICOKINETICS

• Imidacloprid is rapidly and very extensively
  absorbed (gt92) 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

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NEONICOTINOID POISONING EPIDEMIOLOGY

• Despite their widespread use, only 77 cases of
  human exposure to neonicotinoids (imidacloprid)
  have been reported
  ? India (n2)
  
  ? Japan (n1)
  ? Portugal (n2)
  
  ? Sri Lanka (n68)
  ? Taiwan (n4)
• Eight publications and one personal
  communication

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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

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

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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

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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

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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 (n2) or fenthion
  (n1)
• No patient ingesting imidacloprid alone died
• Two patients co-ingesting quinalphos died

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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

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IMIDACLOPRID POISONING HUNG et 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

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IMIDACLOPRID POISONING (HUNG et 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

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IMIDACLOPRID POISONING (HUNG et 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

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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

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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

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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)

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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

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NEONICOTINOID POISONING MANAGEMENT

• Activated charcoal is known to bind imidacloprid
  in vitro (Daneshvar et 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

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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

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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

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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