Pesticide Toxicology
Week 2:
Organophosphate Insecticides
a. Acute toxicity
History
• World War II nerve gases
– Britain
– Germany
• Gerhard Schrader
• TEPP as first commercial OP insecticide
• Post-WWII transfer of IG Farben chemicals
to US
– Parathion
Basics
• Esters of phosphoric acid
• Inhibit acetylcholinesterase (AChE)
– Prevent dissociation of acetyl choline (ACh) into
acetate and choline
– Consequences: facilitation of transmission of nerve
impulses across cholinergic synapses
– All insecticidal action of OPs is due to inhibition of
AChE
• Estimated 250,000 insecticidal structures
A brief pause to discuss
transmission of neural signals
across synapses
plasma membrane of axon
ending of presynaptic cell
plasma membrane of receiving cell
synaptic
vesicle
membrane receptor for neurotransmitter
Structure of Acetylcholine
AChE dimer
Michaelis Complex Between
AChE and ACh
Interaction of OP and AChE
General Structure of
AChE-inhibiting OPs
• X - leaving group
– X may be F
– X may also be alkyl,
aryl, O-alkyl, O-aryl,
S-alkyl, or S-aryl
• R1 and R2
• R1 and R2 may be
alkyl, aryl, O-alkyl, Oaryl, N-alkyl, N-aryl
250,000 active OPs possible
TEPP:
Tetraethyl pyrophosphate
Parathion-ethyl
Role of =S vs =O
• =S does not interact
with AChE
• Conversion of =S to
=O is quite rapid in
mammals and insects,
but not instantaneous
• =S provides a safety
factor, especially in
field exposures
Other Structural Variables
Affecting Toxicity
• Electronegativity of leaving group
– All else being equal, the more the leaving group
pulls electrons from P, the more toxic the OP
will be to mammals
• Length of alkyl chain for R1 and R2
– All else being equal, methyl (OCH3 ) is less
toxic to mammals than ethyl (OC2CH5)
– Isopropyl is even less toxic than methyl, but
insecticidal activity begins to suffer
Other Structural Variables
Affecting Toxicity
Clinical Toxicity of OPs
• Acute toxicity depends on % AChE inhibited
• Symptoms
– Inhibition > 50%
•
•
•
•
Bronchoconstriction
Tremors increasing to convulsions
Light sensitivity
Salivation, nausea, vomiting, diarrhea
– Inhibition > 70-80% is lethal
• Suffocation due to mucus production
• Exhaustion
• CNS effects?
Determinants of Inhibition
• Species
– Fit of OP on AChE
• Insect and mammalian AChE differ in dimensions of active site
• Distance between esteratic, anionic sites
• Age and sex may influence toxicity
• Within species:
– Dose
– Route of administration
• Slower absorption through skin may reduce peak inhibition
– Relative affinity of OP for AChE vs other ChEs
• chlorpyrifos
AChE Inhibition
• Depends on specific OP
• Results from interaction between
– Affinity for AChE, ChE
– Regeneration
• O-methyl >O-ethyl > O-isopropyl
• Regeneration may occur either in plasma and brain
– Dichlorvos
• Degradation vs activation
– Malathion is rapidly degraded in mammals, but not in
insects
– Aging
• isopropyl > O-methyl >/= O-methyl
Antidotes
• Atropine
– Competes for binding sites on postsynaptic receptor
• Toxic in its own right
• Paralyzes muscles
– Acts at any time
– Large doses necessary
• 2-PAM
– Regenerates free enzyme from OP-AChE complex
Acts only before complex ages