phenylpyrazole insecticide poisoning michael eddleston clinical pharmacology unit, university of...
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Phenylpyrazoleinsecticide poisoning
Michael Eddleston
Clinical Pharmacology Unit, University of Edinburgh
South Asian Clinical Toxicology Research Collaboration,
Scottish Poisons Information BureauRoyal Infirmary of Edinburgh
Funded by the
Insecticides
Cholinergic system• organophosphorus pesticides• carbamates• pyrethroids• neonicotinoids
GABAergic system • organochlorines• N-phenylpyrazoles• avermectins
Miscellaneous: eg chitin synthesis inhibitors
GABAA receptor
Organochlorine insecticides
• Widely used since the 1950s. More recently their use has fallen worldwide after recognition of their environmental persistence. Still cases in India, Iran & Turkey
• Two main groups – cyclodienes (eg. endosulfan) and cycloalkanes (eg lindane).
• 1980s found to bind to and block the GABAA chloride channel in the CNS, resulting in hyperexcitability.
• Severe poisoning causes status epilepticus that is often resistant to therapy. CFR >25%
• Treatment = early benzodiazepines, rapidly followed by phenobarbital, and then general anaesthesia with thiopental
N phenylpyrazole insecticides
EPA CPH 03 Toxline INTOX
• acetoprole (CAS: 209861-58-5) x x 0 x
ethiprole (CAS: 181587-01-9) x √ 2 x
fipronil (CAS: 120068-37-3) 1994 √ 961 x
pyraclofos (CAS: 77458-01-6) (Jap) √ 17,078 OP
pyrafluprole (CAS: 315208-17-4) x x 0 x
pyriprole (CAS: 394730-71-3) x x 0 x
vaniliprole (CAS: 145767-97-1) x x 0 x
• Recent development - fipronil first used in agriculture in the mid-1990s to kill pests of corn, rice and cotton
• Also against animal ticks (fipronil, pyriprole) and ants (fipronil).
fipronil
pyraclofos vaniliprole
Structure
phenyl group + pyrazole carbonitrile
Acute toxicity and fat solubility
rat oral LD50 (mg/kg) logK[ow]
acetoprole NK NK
ethiprole 7080 2.0
fipronil 92 4.0
pyraclofos 237 3.8
pyrafluprole NK NK
pyriprole NK NK
vaniliprole NK NK
chlorpyrifos 135 5.1
dimethoate 150 0.8
endosulfan 80 3.1
Clinical experience of phenylpyrazole poisoning - 1
• 3 papers reporting fipronil poisoning.
No reports for any of the other pesticides.
• Fung 2003 - 77yr old woman unintentionally ate ~0.1mg of fipronil in an ant bait. No clinical features occurred.
• Chodorowski 2004 - 50yr old man occupationally exposed to a 20% formulation during preparation and 0.005% during spraying. Only clinical features: headache, nausea, vertigo, and weakness.
• Mohamed 2004 - 6 men and 1 woman who had intentionally ingested a 5% agricultural formulation of fipronil. Two developed seizures (1x 1 seizure, 1x 2 seizures). The most ill patient was drowsy on admission, sweating profusely, and vomiting. N&V was the commonest feature.
Clinical experience of phenylpyrazole poisoning - 2
• Mohamed 2004 - fipronil was detected in blood for all 6 patients in whom a blood sample was obtained in this prospective study.
• This paper also reported a retrospective case of a 23 yr old male who was reported to have ingested 100 ml of 5% fipronil. He developed status epilepticus and died with bronchopneumonia after 17 days. Ingestion of fipronil was not proven in this case, but the bottle label was present in the notes.
• CURRENT CLINICAL EXPERIENCE
Nausea and vomiting, profuse sweating, self-terminating seizures.
(SACTRC case series 23 patients, CFR: 0 [95%CI 0.0-14.8%])
Retrospective case suggests possibility of severe status epilepticus
Fipronil pharmacokinetics 1
0 10 20 30 40 50 60 700
50
100
1000
2000
3000
4000
#2
#3
#4
#5
#6
#7
3744 ug/L
1600 ug/L
*
*
Hours post-ingestion
Pla
sm
a f
ipro
nil
co
nc
en
tra
tio
n (
g/L
)
Metabolism of fipronil
Fipronil pharmacokinetics - 2
0 10 20 30 400
10
20
30
40
50
60
70
80
90 fipronil sulfone
fipronil
Hours post-ingestion
Pla
sm
a c
on
cen
trat
ion
(
g/L
)
Total
Patient 7
Q - why are phenylpyrazoles relatively less toxic?
• Examined the specificity of binding of fipronil to human and insect GABA receptors via expression of subunits in Sf9 cells
• Endosulfan, lindane and fipronil compete for the same [3H]EBOB binding site on the GABAA with affinities of 0.3–7 nM.
• Resistance to cyclodienes in drosophila (alanine302serine mutation) also confers low sensitivity to fipronil
• Specific combinations of , and subunits confer differential insecticide binding sensitivity
John E Casida, University of Berkeley
Insecticides bind to all 5 subunits from within the pore to prevent
flow of chloride ions
Chen 2006 PNAS
Binding of insecticides to human GABA receptors
Ratra 2001 TAP 172:233
Human 3 monomeric GABAA receptor
Insecticide Hum b3 Native insect Selectivity
GABA R IC50 (nM)alpha-endosulfan 0.34 6.4 0.05lindane 0.66 7.1 0.09fipronil 1.8 4 0.45
Ratra 2001 ToxL 122:215
Has sequence homology toinsect GABA receptor
Binding of insecticides to 3receptor correlates well withbinding to insect receptor
Phenylpyrazole insecticide selectivity
Potency
Insecticide Mammal Insect Selectivity
GABA R IC50 (nM)alpha-endosulfan 28 10 2.8lindane 833 11 76fipronil 4300 2.3 1870
LD50 (mg/kg)alpha-endosulfan 10 5.5 1.8lindane 40 5.5 7.3fipronil 32 0.25 128
Ratra 2001 TAP 172:233
Ikeda et al 2004 - patch clamped dorsal root ganglion cells
Showed that fipronil reduced both frequency of Cl- channels opening and length of time open
Fipronil blocks insectglutamate-activated chloride channels
• Glutamate gated chloride channels exist at central synapses in insects, but not mammals
Narahisha 2007 HET
• Potency compares favourably with GABA chloride channel inhibition: IC50 10.0 nM vs 2.3 nM
Phenylpyrazole insecticides - conclusions
• Recently introduced into agricultural practice
• Only one commonly used - fipronil
• Inhibit the the GABAA chloride channel in the CNS at the same site as organochlorines. May also block glutamate chloride channels. Result in neuronal hyperexcitability.
• Relatively less toxic to mammals due to selective binding to insect vs mammalian GABA receptors.
• Low toxicity in poisoning due to high potency of fipronil. Allows use of small quantities and low concentrations.
• Treatment = benzodiazepines. No evidence currently that other Rx is required. Low case fatality.