Pyrethroid Insecticides

Derived from natural product -- –Pyrethrum –Found in Chrysanthemum cinerarifolium Synthetic pyrethroids –Variable in structure, toxicity –Generally benign environmentally most are highly toxic to fish Major uses in –Home and garden –Agriculture –Medical entomology

Natural Pyrethrum Mixture of esters: –Chrysanthemic acid or pyrethric acid –+ pyrethrolone, cinerolone, and/or jasmololone Structural features essential for insecticidal activity: –3-C ring Variables: –Enantiomers around asymmetric carbon atoms

General structure of pyrethroid insecticides Mix-and-match substituents acid ester Pyrethrin I: A+C = 10% Pyrethrin II: B+C = 9% Cinererin I: A+D = 2% Cinererin II B+D = 3% Jasmolin I: A+E = 1% Jasmolin II: B+E = 1%

Structural considerations Contact with receptor must occur at 3 points Isobutenyl moiety of acid Dimethylcyclopentane ting Unsaturated side chain of keto-alcohol

Pyrethroids have several asymmetric carbon atoms. Stereochemistry of these cabin atoms matters –Toxicity to insects varies with enantiomers Steroisomers

Synthetic pyrethroids Objectives –Increase persistence by decreasing insect inactivation By decreasing photodegradation By using synergists –Maintain –Level of insecticidal activity –Range of insects killed Stages –1st generation Varied R, R ’ with alkyl and aryl substituents –2nd generation Used Cl, Br, F Last 4-7 days on foliage in sunlight –3rd generation Cyano group Last up to 10 days Applied at 0.01 to 0.05 lb/A

1st generation 2nd generation 3rd generation

Toxicity of various pyrethroids *Registration cancelled 2004 **Registration cancelled 1992 * **

Systemic toxicity: Type I Pyrethroids without cyano group Target –CNS, primarily brain stem Cerebellum and cerebrum not primary targets –Progressive development of fine whole body tremor –Exaggerated startle reflex Large increase in metabolic rate Uncoordinated twitching Hyperexcitability Hyperthermia Death results from metabolic exhaustion and hyperthermia

Systemic toxicity: Type II Pyrethroids with cyano group Target: –CNS –All regions affected Symptoms complex –Salivation –Rolling gait - increased extensor tone in hind limbs –Spasms due to sensory stimuli –Tonic seizures –Apnea –death

Allergic Reactions Of topical exposure –Contact dermatitis Either natural or synthetic pyrethroids –Irritant effect Not inflammatory response Lasts up to 24 hours May include numbness or parasthesias –“ Annoying but not disabling ” –Apparently completely reversible Systemic allergic responses –Pyrethroids derive from chrysanthemum components –Allergies are well known to occur Respiratory May be serious Rarely, fatal Occupational exposure ---> emphysema (rare?)

Cellular Toxicity Insecticidal activity: –Prolong opening of voltage-gated sodium channels Mammalian toxicity –Sodium channels Variable, depending on isoform –Some voltage-gated calcium channels –Some voltage-gated chloride channels –Peripheral-type benzodiazepene receptors Contributing to convulsive effects Variations of effects on ion channels: –Pyrethroids have high affinity for active membrane Na + channels Only affect open channels, blocking them –“ Open channel blockers ” –Pyrethroids without alpha-cyano group Cause nerve channels to close very slowly –Pyrethroids with alpha-cyano group (4th generation) Cause delayed closure of Na channels

Transmembrane channels Formed by proteins Hydrophilic channels through the lipid membrane May be permanently open May be gated: normally closed, open for cause Gates respond to Ligands Electrical charge Gates may close rapidly after opening, even if signal is still being given Example: neuromuscular junction –Electric nerve impulse reaches nerve terminal

Neuromuscular junction Signal: electrical –Depolarization of nerve impulse –Decrease in membrane polarization opens voltage-gated Ca + channels in presynaptic membrane – Ca + ions stream into cell, triggering release of ACh ACh receptors are ligand-gated –Transiently permeable to Na + and K + in presence of ACh

Gated transmembrane channels: presynaptic terminal –At terminal of axon: Depolarization opens voltage-gated Ca +2 channel Responds to nerve impulse Releases Ca +2 into axon terminal Causes ACh release into synaptic cleft

Degradation of pyrethroids Photolytic –Very rapid for pyrethrum, early pyrethroids Metabolic –Extremely rapid for pyrethrum, early pyrethroids –Less rapid for later generations of synthetics –Mediated by P450s –Inhibited by synergists Piperonyl butoxide

LD 50 = > 7500 mg/kg, rats, po Inhibits cytochromes P450 Synergizes –Pyrethroids –Some OPs, carbamates

Ecotoxicology of Pyrethroids Extremely toxic to fish Mammalian toxicity –Minimal for most pyrethroids –Exceptions Deltamethrin, mg/kg Flucythrinate, mg/kg Natural pyrethroids –Benign except for toxicity to fish Synthetic pyrethroids –Increased persistence not of an order to raise concern about bioaccumulation –Movement into water from terrestrial applications is a danger with more persistent pyrethroids Low application rates minimize this