The history of the pyrethroid insecticides The synthetic pyrethroid insecticides were defences against insect pests. For thousands Compared to natural pyrethrins, the synthetic Early landmarks in the discovery of the developed at Rothamsted Research, which of years they have been extracted and used The development of the synthetic pyrethroids are more stable in direct sunlight. synthetic pyrethroids receives strategic funding from BBSRC, in the to combat insect pests. However, the natural They are also signifi antly more effective against pyrethroids at Rothamsted was led 1960s and 1970s. Today they account for around pyrethrins are not particularly effective when a wider range of insects, so farmers need to apply • Pyrethrin insecticides from pyrethrum daisies one sixth of global insecticide sales1, and global used on fields of crops as th y are quite unstable, by Michael Elliott. Elliott joined the less insecticide to their crops. This also means (Chrysanthemum cinerariaefolium) have been used in various forms for thousands of years. They were annual sales of pyrethorids exceed US$1.4Bn. breaking down quickly when exposed to sunlight. institute in 1948 to investigate the pyrethroids are less likely to build up to dangerous originally discovered in China and imported into Europe They are also used to impregnate bed nets, which link between molecular structure levels in the environment2. as ‘Persian powder’. help to reduce the spread of malaria as part of To overcome their limitations, scientists developed and biological activity in the the World Health Organisation’s Global Malaria synthetic compounds, called pyrethroid natural pyrethrins. He used this However, pyrethroids can harm some beneficial • Hermann Staudinger and Lavoslav Ružička published a Programme. insecticides, based on the chemistry of the insects such as bees or the parasitic wasps that definiti e study on the structure of natural pyrethrins in knowledge to create the synthetic 4 natural pyrethrins. Both work by targeting prey on pests, and they are also toxic to fish and 1924 . pyrethroids. Elliott won numerous The science of pyrethroids sodium channels in the cell membranes of insect other aquatic organisms. Because humans possess • Pest control research at Rothamsted began before the Natural pyrethrins are derived from nervous systems. By locking these channels open, awards over the course of his enzymes that quickly break down pyrethroid Second World War when other pest control options Chrysanthemums, the same genus as common the pyrethroids block normal nerve impulses, career, and received a CBE in 1982. insecticides, the pyrethroids are only toxic to people often relied on arsenic or cyanide. Work on plant daisies, and are an important component of plant paralysing the insect and ultimately killing it1. in large quantities or over long periods of time3. breeding near Rothamsted in the 1920s supported the establishment of the pyrethrum industry in Kenya. 1940 1960 1970 1980 1990 2000 2010 1949 1962 1972 1980s 2002 2011 The first ynthetic pyrethroids, allethrin and In the UK, Michael Elliott creates resmethrin, Michael Elliott develops permethrin, the Professor Chris Curtis at the London School Deltamethrin is the world’s highest-selling The WHO recommends the use of 12 long- bioallethrin, are developed in America by a ‘first gene ation’ synthetic pyrethroid, by first field- able pyrethroid. It is much more of Hygiene and Tropical Medicine begins pyrethroid with annual sales worth US$208M lasting insecticidal mosquito nets to tackle Milton S. Schechter and colleagues5,6. They altering the molecular structure of naturally- suitable for use in agricultural settings as it to investigate the potential of insecticide- (around £132M)18. malaria. The nets all rely on pyrethroids are around twenty times more effective at occurring pyrethrin. At the time such structure- does not break down so quickly in sunlight2. treated bed nets to control malaria. He developed at Rothamsted22. killing insects than DDT without the serious activity studies were not common practice. The development of permethrin leads to a campaigns for aid agencies to distribute 2004 environmental or health impacts7. second round of licensing deals with the agro- the nets for free to communities in affected BBSRC-funded researchers at Rothamsted, Resmethrin, named in honour of the chemical industry. regions to help reduce mosquito numbers working with Australian colleagues, develop a Rothamsted Experimental Station in and lifespan10. product to overcome resistance to pyrethroid Harpenden, UK, where the discovery was 1972 insecticides that is appearing in several made, is much more effective against DDT is banned in the US following growing 1983 insect crop pests. Their product first release houseflies than natu al pyrethrins. However, it concerns about bioaccumulation and its Pyrethroids make up 25.1% of the global an enzyme inhibitor to disable the insect’s is still unstable in sunlight and unsuitable for persistence in the environment. Because they insecticide market and 33 million hectares resistance mechanism. Several hours later use outdoors8. break down in sunlight, pyrethroids do not of crops are treated with pyrethroids it releases the insecticide, which kills the accumulate in the same way. annually11. Pyrethroids developed by Elliott insect19. 1967 and colleagues at Rothamsted constitute two 1991 11 Elliott produces another first gene ation thirds of the global pyrethroid market . An MRC-funded study shows that using 2007 pyrethroid, bioresmethrin, by isolating one of insecticide-treated mosquito nets (ITNs) in Pyrethroids account for 17% of global 1 the active compounds from resmethrin. 1984 a rural region of the Gambia can reduce the insecticide sales . Total global sales of 11 20 Michael Elliott retires from Rothamsted . number of deaths of children under the age insecticides are around $8Bn . Bioresmethrin is a single isomer of resmethrin, Around one quarter of the profits made by UK of fi e by around two-thirds15. The ITNs used which exists as a mixture of four different firm Mi chell Cotts this year are attributed to in the study were treated with permethrin. 2009 isomers, i.e. compounds with identical the sale of pyrethroid insecticides13. Mitchell A Cochrane Collaboration review of earlier molecular formulas but with different shapes. Cotts were one of the original licencees for Early 1990s trials confirms that ITNs reduce death At the time, other compounds with several pyrethroids. Sales of synthetic pyrethroids reach amongst children under fi e by around isomers were produced as a mixture, but US$1.2Bn per year9. one fifth. Th y also signifi antly reduce the the agro-chemical companies, working Late 1980s incidence of illness caused by malaria21. alongside Rothamsted scientists, were able to The World Health Organisation (WHO) 1998 8 manufacture just the bioresmethrin isomer . recommends using pyrethroids developed New long-lasting insecticidal nets (LLINs), at Rothamsted, including deltamethrin and which use pyrethroids such as cypermethrim, 14 Late 1960s permethrin, for ITNs . Pyrethroids are the form one of four pillars to tackle malaria in The first gene ation synthetic pyrethroids are 1976 only class of insecticides recommended for Japanese chemical company Sumitomo the World Health Organisation’s international supported and commercially exploited by the use in such nets due to their low toxicity to 16, 17 independently discovers fenvalerate. Elliott Roll Back Malaria Programme . National Research Development Corporation humans and other mammals. Their physical becomes aware of the development of the (NRDC), a group established by HM Treasury properties also mean manufacturers can work through his colleague Professor Izuru to commercialise the outputs of UK research, easily incorporate pyrethroids into the fibre Yamamoto in Japan and through the patents and its successor, the British Technology Group. used to make bed nets. filed y the company. He realises he can build An initial licensing deal is agreed by NRDC with on their success in his own work. six companies (Mitchell Cotts, the Wellcome Foundation, Roussel Uclaf, Sumitomo, FMC The results are two new pyrethroids, and Penick) interested in manufacturing and cypermethrin and deltamethrin, the latter in selling pyrethroids9. particular is an extremely potent insecticide8. The history of the pyrethroid insecticides Notes and References Thanks to Professor John Pickett and Professor Bhupinder Khambay for providing much of the historical information about the work of Dr Michael Elliott at Rothamsted Research, and for their comments on a draft of this case study. 1. Davies, T.G., Field, L.M., Usherwood, P.N., & Williamson, M.S. (2007). DDT, pyrethrins, pyrethroids and insect sodium channels. IUBMB Life. 59(3), pp151-162. doi: 10.1080/15216540701352042. Available online: http://www.ncbi.nlm.nih.gov/pubmed/17487686 2 Elliott, M., (1976). Properties and Applications of Pyrethroids. Environmental Health Perspectives. 14, pp 3 – 13. Available online at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1475105/ 3. Mikata, K., Isobe, N., Kaneko, H. (2012) Biotransformation and enzymatic reactions of synthetic pyrethroids in mammals. Topics in Current Chemistry. 314, pp 113 – 135. Available online: http://www.ncbi.nlm.nih.gov/pubmed/21952844 4. Staudinger, H. und Ruzicka, L. (1924). “Über die wirksamen Bestandteile des dalmatinischen Insektenpulvers”. Helv chim acta. 7: 177. doi:10.1002/hlca.19240070124. 5. Obituaries: Milton