Pyrethroids

1. Pyrethroids + Piperonyl butoxide = Laurel Fink Biol 564 April 29, 2008

2. Pyrethroids and Usage History • Diverse group of insecticides (1,000+) • Many developed in 1970’s and 80’s by Bayer AG Co. • Derived from pyrethrins; natural compounds produced by chrysanthemum flowers (C. cinerariaefolium and C. cineum • Pyrethrins will paralyze insect; animal will recover (enzyme detoxification) • Pyrethroids are synthetic esters derived from pyrethrins; engineered for insect death, “knockdown” effect • Synthetic modifications (addition of synergists) make these compounds more toxic to organisms, less degradable in environment

3. Pyrethroid Structures Permethrin • Pyrethrins are esters of chrysanthemic (I) or pyrethric (II) acid; have been synthetically modified into complex mixture of isomers • Type 1 and 2 pyrethroids • Very lipophillic, low water solubility • Structure of compound (I or II) has different effects and associated poisoning symptoms • Isomerism around the cyclopropane ring greatly influences toxicity All pyrethroids have an acid moiety, a central ester bond, and an alcohol moiety

4. Mode of entry into aquatic environment • Spray drift; pyrethroids often applied aerially and can contaminate nearby waters • Runoff from fields, wastewater from manufacturing facilities

5. Reactivity/Speciation in Water • Rapidly absorbed to particulate matter in water due to high lipophillicity/low solubility--> absorbed state less bioavailable to organisms • Half life for pyrethroids in aquatic medium has been reported between 19 hours (permethrin in pond water,Rawn et al., 1982) to 13.5 weeks (fenpropathrin in distilled water,Takahashi et al., 1985) • Most pyrethroid half lives in water range from 1-2 days • Its speciation varies greatly with compound’s structure, exposure to sunlight, and pH, temperature, and salinity of water medium

6. Mode of Entry into Organisms • Since pyrethroids are highly lipophillic, will readily be absorbed through the gills of aquatic animals • In mammals, toxicity occurs when ingested, not readily absorbed through skin

7. Mode of Toxic Interaction: Neurotoxicity • Acute neurotoxicity is caused by binding to sodium channels--> slows down its activation and inactivation properties which leads to a hyperexcitable state • A normal action potential is converted into double or continuous discharges in nerve and muscle • Current duration dependant on pyrethroid structure; action stereospecific • Insect sodium channels 100x more susceptible than mammals

8. Other Toxic Interactions • Most pyrethroids stimulate protein kinase C-dependant protein phosphorylation (channel activity modulated by phosphorylation state) • Antagonism of GABA-mediated inhibition (seizures) • Enhancement of noradrenalin release • Direct actions on calcium or chloride ion channels (type II only) • Type II pyrethroids produce a more complex poisoning syndrome and act on wider range of tissues

9. Toxicity to Aquatic Life-- Fish • Pyrethrins and pyrethroids are extremely toxic to fish, numerous aquatic invertebrates, can also be accumulated in aquatic plants • Will bioconcentrate on and strongly absorbed to gill tissue; fish seem to be deficient in enzyme that hydrolyses pyrethroids • Deltamethrin is most toxic pyrethroid for fishes, 96LC50 for rainbow trout is 1 ug/L, for bluegill and lake trout, less than 1 ppb • Sub lethal effects include damage to the gills and behavioral changes (including accelerated respiration, loss of movement coordination, convulsions, etc)

10. Toxicity to Aquatic Life-Inverts • Most LC50 values for aquatic invertebrates less than 1 ppb (similar to LC50’s for target species such as mosquito larvae) • These include surface-dwelling insects and crustaceans, such as mayfly nymphs (most sensitive), zooplankton, lobster, and shrimp • At non-lethal concentrations, most have significant behavioral changes, such as ability to respond to tactile stimuli

11. Metabolism and Breakdown • Biological activity destroyed by ester hydrolysis, major route, creates oxidative metabolites • Oxidative reactions catalyzed by cytochrome P450 (CYP) enzymes in all animals (CYP6 family important for insects) • Is thought that insecticidal properties of pyrethroids terminated by oxidative metabolism

12. Defense Strategies/ Detox • Resistance to pyrethroids due to detoxification by CYP monooxygenases • Resistance associated with elevated CYP activity • Pyrethroid resistance in mosquito larvae recorded worldwide; permethrin-resistant strain recently isolated (2007) with 1300-fold resistance • This ISOP450 enzyme mechanism only present in larval stage, adults not resistant

13. Bibliography • Akerblom, N. et al. 2007. Deltamethrin toxicity to the midge Chironomus riparius-- Effects of exposure scenario and sediment quality. Ecotoxicology and Environ. Safety. 70: 53-60. • Go, V. et al. 1999. Estrogenic potential of certain compunds in the MCF-7 human breast carcinoma cell line. Environ. Health Perspectives. 107:3. • Hardstone, M.C., et al., 2007. Cytochrome P450 monooxygenase-mediated permethrin resistance confers limited and larval specific cross-resistance in the southern house mosquito, Culex pipiens quinquefasciatus. Pesticide Biochem and Physio. 89:175-184. • Ray, David E. and Fry, Jeffery R. 2006. A reassessment of the neurotoxicity of pyrethroid insecticides. Pharmacology and Therapeutics. 111:174-193. • Ross, M. K. et al., 2006. Hydrolytic metabolism of pyrethroids by human and other mammalian carboxylesterases. Biochem. Pharmacology. 71:657-669. • Sanchez-Fortun, S., et al. 2004. Comparative study on the environmental risk induced by several pyrethroids in estuarine and freshwater invertebrate organisms. Chemosphere. 59:553-559 • U.S. Department of Health and Human Services. 2003. Toxicological Profile for Pyrethrins and Pyrethroids. Updated 9/2003. http://www.atsdr.cdc.gov/toxprofiles/tp155.pdf • Velisek, J. et al. 2006. Effects of deltamethrin on rainbow trout (Oncorhynchus mykiss). Environ. Tox. and Pharmacology