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
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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