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fbtwitterlinkedinvimeoflicker grey 14rssslideshare1
Chen-Hussey, Vanessa; Behrens, Ron; Logan, James (2014)
Publisher: BioMed Central
Journal: Parasites & Vectors
Languages: English
Types: Article
Subjects: Toxicity, N,N-diethyl-m-toluamide, Insect repellents, Safety, Review
N,N-diethyl-m-toluamide (DEET) has been registered for commercial use as an insect repellent for over five decades,\ud and is used widely across the world. Concerns over the safety of DEET first emerged during the 1980s after reports\ud of encephalopathy following DEET exposure, particularly in children. However, the role of DEET in either the illness\ud or deaths was and remains purely speculative. In response to these cases a number of reviews and investigations of\ud DEET safety were carried out. Here we examine the methods used and information available to determine the\ud safety of DEET in humans. Animal testing, observational studies and intervention trials have found no evidence of\ud severe adverse events associated with recommended DEET use. Minor adverse effects noted in animal trials were\ud associated with very large doses and were not replicated between different test species. The safety surveillance\ud from extensive humans use reveals no association with severe adverse events. This review compares the toxicity\ud assessment using three different models to define the risk assessment and safety threshold for DEET use in humans\ud and discusses the clinical consequences of the thresholds derived from the models.\ud The theoretical risks associated with wearing an insect repellent should be weighed against the reduction or\ud prevention of the risk of fatal or debilitating diseases including malaria, dengue, yellow fever and filariasis. With over\ud 48 million European residents travelling to regions where vector borne diseases are a threat in 2009, restricting the\ud concentration of DEET containing repellents to 15% or less, as modelled in the 2010 EU directive, is likely to result\ud in extensive sub-therapeutic activity where repellents are infrequently applied. Future European travellers, as a\ud consequence of inadequate personal protection, could potentially be at increased risk of vector borne diseases. Risk\ud assessments of repellents should take these factors into account when setting safe limits.
  • The results below are discovered through our pilot algorithms. Let us know how we are doing!

    • 1. Nentwig G: Use of repellents as prophylactic agents. Parasitol Res 2003, 90(Suppl 1):S40-S48.
    • 2. Barnard DR: Repellents and Toxicants for Personal Protection. Position Paper. Global Collaboration for Development of Pesticides for Public Health. Geneva, Switzerland: World Health Organization; 2000 [Global Collaboration for Development of Pesticides for Public Health (Series editor)].
    • 3. U.S. Environmental Protection Agency: Insect Repellent Product Labeling Consumer Survey Report. Washington DC, USA: US Environmental Protection Agency Office of Pesticide Programs; 2012.
    • 4. Kline & Company: Consumer Markets for Pesticides and Fertilizers USA. Parsippany, USA: Kline & Company, Incorporated; 2004.
    • 5. Goodyer LI, Croft AM, Frances SP, Hill N, Moore SJ, Onyango SP, Debboun M: Expert review of the evidence base for arthropod bite avoidance. J Travel Med 2010, 17:182-192.
    • 6. WHO: Guidelines for Efficacy Testing of Mosquito Repellents for Human Skin. Geneva, Switzerland: Control of Neglected Tropical Diseases and WHO Pesticide Evaluation Scheme; 2009.
    • 7. Tawatsin A, Thavara U, Chansang U, Chavalittumrong P, Boonruad T, Wongsinkongman P, Bansidhi J, Mulla MS: Field evaluation of deet, Repel Care, and three plant based essential oil repellents against mosquitoes, black flies (Diptera: Simuliidae) and land leeches (Arhynchobdellida: Haemadipsidae) in Thailand. J Am Mosq Control Assoc 2006, 22:306-313.
    • 8. Robbins PJ, Cherniak MG: Review of the biodistribution and toxicity of the insect repellent N, N-diethyl-m-toluamide (DEET). J Toxicol Environ Health 1986, 18:503-525.
    • 9. Osimitz TG, Murphy JV, Fell LA, Page B: Adverse events associated with the use of insect repellents containing N, N-diethyl-m-toluamide (DEET). Regul Toxicol Pharmacol 2010, 56:93-99.
    • 10. World Health Organization International Programme on Chemical Safety: Principles for the Assessment of Risks to Human Health from Exposure to Chemicals. Geneva: World Health Organization; 1999.
    • 11. U.S. Environmental Protection Agency: Reregistration Eligibility Decision DEET. Washington DC, USA: United States Environmental Protection Agency Office of Pesticide Programs Special Review and Reregistration Division; 1998.
    • 12. McGready R, Hamilton KA, Simpson JA, Cho T, Luxemburger C, Edwards R, Looareesuwan S, White NJ, Nosten F, Lindsay SW: Safety of the insect repellent N, N-diethyl-m-toluamide (DEET) in pregnancy. Am J Trop Med Hyg 2001, 65:285-289.
    • 13. Barr DB, Ananth CV, Yan X, Lashley S, Smulian JC, Ledoux TA, Hore P, Robson MG: Pesticide concentrations in maternal and umbilical cord sera and their relation to birth outcomes in a population of pregnant women and newborns in New Jersey. Sci Total Environ 2010, 408:790-795.
    • 14. Gryboski J, Weinstein D, Ordway N: Toxic Encephalopathy Apparently Related to the Use of an Insect Repellent. N Engl J Med 1961, 264:289-291.
    • 15. Heick H, Shipman R, Nonnan M, James W: Reye-like syndrome associated with use of insect repellent in a presumed heterozygote for ornithine carbamoyl transferase deficiency. J Pediatr 1980, 97:471-473.
    • 16. Roland E, Jan J, Rigg J: Toxic encephalopathy in a child after brief exposure to insect repellents. Can Med Asoc J 1985, 132:155-156.
    • 17. Osimitz TG, Grothaus RH: The present safety assessment of deet. J Am Mosq Control Assoc 1995, 11:274-278.
    • 18. Koren G, Matsui D, Bailey B: DEET-based insect repellents: safety implications for children and pregnant and lactating women. CMAJ 2003, 169:209-212.
    • 19. Briassoulis G: Toxic encephalopathy associated with use of DEET insect repellents: a case analysis of its toxicity in children. Hum Exp Toxicol 2001, 20:8-14.
    • 20. Veltri JC, Osimitz TG, Bradford DC, Page BC: Retrospective analysis of calls to poison control centers resulting from exposure to the insect repellent N, N-diethyl-m-toluamide (DEET) from 1985-1989. J Toxicol Clin Toxicol 1994, 32:1-16.
    • 21. Bell J, Veltri J, Page B: Human exposures to N, N-diethyl-m-toluamide insect repellents reported to the American Association of Poison Control Centers 1993-1997. Int J Toxicol 2002, 21:341-352.
    • 22. Bronstein A, Spyker D, Cantilena L, Green J, Rumack B, Giffin S: Annual report of the American association of poison control Centers' national poison data system (NPDS): 27th annual report. Clin Toxicol 2009, 2010(48):979-1178.
    • 23. Kotsopoulos I, van Merode T, Kessels F, de Krom M, Knottnerus JA: Systematic review and meta-analysis of incidence studies of epilepsy and unprovoked seizures. Epilepsia 2002, 43:1402-1409.
    • 24. Miller JD: Anaphylaxis associated with insect repellent. N Engl J Med 1982, 307:1341-1342.
    • 25. Whitford F, Kronenburg J, Lunchick C, Driver J, Tomerlin R, Wolt J, Spencer H, Winter C, Whitmyre G: Pesticide and Human Health Risk Assessment: Policies, Processes, and Procedures. West Lafayette, USA: Purdue University Cooperative Extension Service; 1999.
    • 26. Antwi FB, Shama LM, Peterson RK: Risk assessments for the insect repellents DEET and picaridin. Regul Toxicol Pharmacol 2008, 51:31-36.
    • 27. Schoenig GP, Osimitz TG, Gabriel KL, Hartnagel R, Gill MW, Goldenthal EI: Evaluation of the chronic toxicity and oncogenicity of N, N-diethylm-toluamide (DEET). Toxicol Sci 1999, 47:99-109.
    • 28. Health Canada: Re-evaluation decision document: personal insect repellents containing DEET (N,N-diethyl-m-toluamide and related compounds). 2002.
    • 29. European Commission: Biocidal Products Directive (Directive 98/8/EC) Assessment Report: N,N-Diethyl-meta-Toluamide (DEET) Product-Type 19 (Repellents and Attractants). European Commission; 2010, http://esis.jrc.ec.europa.eu/doc/ biocides/annex_I/assessment_reports/AnnexI_AR_134-62-3_PT19_en.pdf.
    • 30. Abou-Donia MB, Dechkovskaia AM, Goldstein LB, Abdel-Raham A, Bullman S, Khan W: Co-exposures to pyridostigmine bromide, DEET, and/or permethrin causes sensorimotor deficit and alterations in brain acetylcholinesterase activity. Pharmacol Biochem Behav 2004, 77:253-262.
    • 31. Corbel V, Stankiewicz M, Pennetier C, Fournier D, Stojan J, Girard E, Dimitrov M, Molg√≥ J, Hougard J-M, Lapied B: Evidence for inhibition of cholinesterases in insect and mammalian nervous systems by the insect repellent deet. BMC Biol 2009, 7:47.
    • 32. Abu-Qare AW, Abou-Donia MB: Combined exposure to DEET (N,N-diethylm-toluamide) and permethrin: pharmacokinetics and toxicological effects. J Toxicol Environ Health B Crit Rev 2001, 6:41-53.
    • 33. Hill N, Lenglet A, Arnez AM, Carneiro I: Plant based insect repellent and insecticide treated bed nets to protect against malaria in areas of early evening biting vectors: double blind randomised placebo controlled clinical trial in the Bolivian Amazon. Br Med J 2007, 335:1023.
    • 34. Rowland M, Downey G, Rab A, Freeman T, Mohammad N, Rehman H, Durrani N, Reyburn H, Curtis C, Lines J, Fayaz M: DEET mosquito repellent provides personal protection against malaria: a household randomized trial in an Afghan refugee camp in Pakistan. Trop Med Int Heal 2004, 9:335-342.
    • 35. Debboun M, Strickman D: Insect repellents and associated personal protection for a reduction in human disease. Med Vet Entomol 2012, 27:1-9.
    • 36. Frances SP, Klein TA, Hildebrandt DW, Burge R, Noigamol C, Eikarat N, Sripongsai B, Wirtz RA: Laboratory and field evaluation of deet, CIC-4, and AI3-37220 against Anopheles dirus (Diptera: Culicidae) in Thailand. J Med Entomol 1996, 33:511-515.
    • 37. Kroeger A, Gerhardus A, Kruger G, Mancheno M, Pesse K: The contribution of repellent soap to malaria control. Am J Trop Med Hyg 1997, 56:580-584.
    • 38. Lindsay SW, Ewald JA, Samung Y, Apiwathnasorn C, Nosten F: Thanaka (Limonia acidissima) and deet (di-methyl benzamide) mixture as a mosquito repellent for use by Karen women. Med Vet Entomol 1998, 12:295-301.
    • 39. Frances SP, Mackenzie DO, Rowcliffe KL, Corcoran SK: Comparative field evaluation of repellent formulations containing DEET and IR3535 against mosquitoes in Queensland, Australia. J Am Mosq Control Assoc 2009, 25:511-513.
    • 40. Thavara U, Tawatsin A, Chompoosri J, Suwonkerd W, Chansang UR, Asavadachanukorn P: Laboratory and field evaluations of the insect repellent 3535 (ethyl butylacetylaminopropionate) and deet against mosquito vectors in Thailand. J Am Mosq Control Assoc 2001, 17:190-195.
    • 41. World Tourism Organisation UNWTO: Yearbook of Tourism Statistics: Data 2005-2009. Madrid: United Nations World Tourism Organization; 2011.
    • 42. Fradin M, Day JF: Comparative efficacy of insect repellents against mosquito bites. N Engl J Med 2002, 347:13-18.
    • 43. Frances SP, Eikarat N, Sripongsai B, Eamsila C: Response of Anopheles dirus and Aedes albopictus to repellents in the laboratory. J Am Mosq Control Assoc 1993, 9:474-476.
    • 1. Nentwig G: Use of repellents as prophylactic agents. Parasitol Res 2003, 90(Suppl 1):S40-S48.
    • 2. Barnard DR: Repellents and Toxicants for Personal Protection. Position Paper. Global Collaboration for Development of Pesticides for Public Health. Geneva, Switzerland: World Health Organization; 2000 [Global Collaboration for Development of Pesticides for Public Health (Series editor)].
    • 3. U.S. Environmental Protection Agency: Insect Repellent Product Labeling Consumer Survey Report. Washington DC, USA: US Environmental Protection Agency Office of Pesticide Programs; 2012.
    • 4. Kline & Company: Consumer Markets for Pesticides and Fertilizers USA. Parsippany, USA: Kline & Company, Incorporated; 2004.
    • 5. Goodyer LI, Croft AM, Frances SP, Hill N, Moore SJ, Onyango SP, Debboun M: Expert review of the evidence base for arthropod bite avoidance. J Travel Med 2010, 17:182-192.
    • 6. WHO: Guidelines for Efficacy Testing of Mosquito Repellents for Human Skin. Geneva, Switzerland: Control of Neglected Tropical Diseases and WHO Pesticide Evaluation Scheme; 2009.
    • 7. Tawatsin A, Thavara U, Chansang U, Chavalittumrong P, Boonruad T, Wongsinkongman P, Bansidhi J, Mulla MS: Field evaluation of deet, Repel Care, and three plant based essential oil repellents against mosquitoes, black flies (Diptera: Simuliidae) and land leeches (Arhynchobdellida: Haemadipsidae) in Thailand. J Am Mosq Control Assoc 2006, 22:306-313.
    • 8. Robbins PJ, Cherniak MG: Review of the biodistribution and toxicity of the insect repellent N, N-diethyl-m-toluamide (DEET). J Toxicol Environ Health 1986, 18:503-525.
    • 9. Osimitz TG, Murphy JV, Fell LA, Page B: Adverse events associated with the use of insect repellents containing N, N-diethyl-m-toluamide (DEET). Regul Toxicol Pharmacol 2010, 56:93-99.
    • 10. World Health Organization International Programme on Chemical Safety: Principles for the Assessment of Risks to Human Health from Exposure to Chemicals. Geneva: World Health Organization; 1999.
    • 11. U.S. Environmental Protection Agency: Reregistration Eligibility Decision DEET. Washington DC, USA: United States Environmental Protection Agency Office of Pesticide Programs Special Review and Reregistration Division; 1998.
    • 12. McGready R, Hamilton KA, Simpson JA, Cho T, Luxemburger C, Edwards R, Looareesuwan S, White NJ, Nosten F, Lindsay SW: Safety of the insect repellent N, N-diethyl-m-toluamide (DEET) in pregnancy. Am J Trop Med Hyg 2001, 65:285-289.
    • 13. Barr DB, Ananth CV, Yan X, Lashley S, Smulian JC, Ledoux TA, Hore P, Robson MG: Pesticide concentrations in maternal and umbilical cord sera and their relation to birth outcomes in a population of pregnant women and newborns in New Jersey. Sci Total Environ 2010, 408:790-795.
    • 14. Gryboski J, Weinstein D, Ordway N: Toxic Encephalopathy Apparently Related to the Use of an Insect Repellent. N Engl J Med 1961, 264:289-291.
    • 15. Heick H, Shipman R, Nonnan M, James W: Reye-like syndrome associated with use of insect repellent in a presumed heterozygote for ornithine carbamoyl transferase deficiency. J Pediatr 1980, 97:471-473.
    • 16. Roland E, Jan J, Rigg J: Toxic encephalopathy in a child after brief exposure to insect repellents. Can Med Asoc J 1985, 132:155-156.
    • 17. Osimitz TG, Grothaus RH: The present safety assessment of deet. J Am Mosq Control Assoc 1995, 11:274-278.
    • 18. Koren G, Matsui D, Bailey B: DEET-based insect repellents: safety implications for children and pregnant and lactating women. CMAJ 2003, 169:209-212.
    • 19. Briassoulis G: Toxic encephalopathy associated with use of DEET insect repellents: a case analysis of its toxicity in children. Hum Exp Toxicol 2001, 20:8-14.
    • 20. Veltri JC, Osimitz TG, Bradford DC, Page BC: Retrospective analysis of calls to poison control centers resulting from exposure to the insect repellent N, N-diethyl-m-toluamide (DEET) from 1985-1989. J Toxicol Clin Toxicol 1994, 32:1-16.
    • 21. Bell J, Veltri J, Page B: Human exposures to N, N-diethyl-m-toluamide insect repellents reported to the American Association of Poison Control Centers 1993-1997. Int J Toxicol 2002, 21:341-352.
    • 22. Bronstein A, Spyker D, Cantilena L, Green J, Rumack B, Giffin S: Annual report of the American association of poison control Centers' national poison data system (NPDS): 27th annual report. Clin Toxicol 2009, 2010(48):979-1178.
    • 23. Kotsopoulos I, van Merode T, Kessels F, de Krom M, Knottnerus JA: Systematic review and meta-analysis of incidence studies of epilepsy and unprovoked seizures. Epilepsia 2002, 43:1402-1409.
    • 24. Miller JD: Anaphylaxis associated with insect repellent. N Engl J Med 1982, 307:1341-1342.
    • 25. Whitford F, Kronenburg J, Lunchick C, Driver J, Tomerlin R, Wolt J, Spencer H, Winter C, Whitmyre G: Pesticide and Human Health Risk Assessment: Policies, Processes, and Procedures. West Lafayette, USA: Purdue University Cooperative Extension Service; 1999.
    • 26. Antwi FB, Shama LM, Peterson RK: Risk assessments for the insect repellents DEET and picaridin. Regul Toxicol Pharmacol 2008, 51:31-36.
    • 27. Schoenig GP, Osimitz TG, Gabriel KL, Hartnagel R, Gill MW, Goldenthal EI: Evaluation of the chronic toxicity and oncogenicity of N, N-diethylm-toluamide (DEET). Toxicol Sci 1999, 47:99-109.
    • 28. Health Canada: Re-evaluation decision document: personal insect repellents containing DEET (N,N-diethyl-m-toluamide and related compounds). 2002.
    • 29. European Commission: Biocidal Products Directive (Directive 98/8/EC) Assessment Report: N,N-Diethyl-meta-Toluamide (DEET) Product-Type 19 (Repellents and Attractants). European Commission; 2010, http://esis.jrc.ec.europa.eu/doc/ biocides/annex_I/assessment_reports/AnnexI_AR_134-62-3_PT19_en.pdf.
    • 30. Abou-Donia MB, Dechkovskaia AM, Goldstein LB, Abdel-Raham A, Bullman S, Khan W: Co-exposures to pyridostigmine bromide, DEET, and/or permethrin causes sensorimotor deficit and alterations in brain acetylcholinesterase activity. Pharmacol Biochem Behav 2004, 77:253-262.
    • 31. Corbel V, Stankiewicz M, Pennetier C, Fournier D, Stojan J, Girard E, Dimitrov M, Molg√≥ J, Hougard J-M, Lapied B: Evidence for inhibition of cholinesterases in insect and mammalian nervous systems by the insect repellent deet. BMC Biol 2009, 7:47.
    • 32. Abu-Qare AW, Abou-Donia MB: Combined exposure to DEET (N,N-diethylm-toluamide) and permethrin: pharmacokinetics and toxicological effects. J Toxicol Environ Health B Crit Rev 2001, 6:41-53.
    • 33. Hill N, Lenglet A, Arnez AM, Carneiro I: Plant based insect repellent and insecticide treated bed nets to protect against malaria in areas of early evening biting vectors: double blind randomised placebo controlled clinical trial in the Bolivian Amazon. Br Med J 2007, 335:1023.
    • 34. Rowland M, Downey G, Rab A, Freeman T, Mohammad N, Rehman H, Durrani N, Reyburn H, Curtis C, Lines J, Fayaz M: DEET mosquito repellent provides personal protection against malaria: a household randomized trial in an Afghan refugee camp in Pakistan. Trop Med Int Heal 2004, 9:335-342.
    • 35. Debboun M, Strickman D: Insect repellents and associated personal protection for a reduction in human disease. Med Vet Entomol 2012, 27:1-9.
    • 36. Frances SP, Klein TA, Hildebrandt DW, Burge R, Noigamol C, Eikarat N, Sripongsai B, Wirtz RA: Laboratory and field evaluation of deet, CIC-4, and AI3-37220 against Anopheles dirus (Diptera: Culicidae) in Thailand. J Med Entomol 1996, 33:511-515.
    • 37. Kroeger A, Gerhardus A, Kruger G, Mancheno M, Pesse K: The contribution of repellent soap to malaria control. Am J Trop Med Hyg 1997, 56:580-584.
    • 38. Lindsay SW, Ewald JA, Samung Y, Apiwathnasorn C, Nosten F: Thanaka (Limonia acidissima) and deet (di-methyl benzamide) mixture as a mosquito repellent for use by Karen women. Med Vet Entomol 1998, 12:295-301.
    • 39. Frances SP, Mackenzie DO, Rowcliffe KL, Corcoran SK: Comparative field evaluation of repellent formulations containing DEET and IR3535 against mosquitoes in Queensland, Australia. J Am Mosq Control Assoc 2009, 25:511-513.
    • 40. Thavara U, Tawatsin A, Chompoosri J, Suwonkerd W, Chansang UR, Asavadachanukorn P: Laboratory and field evaluations of the insect repellent 3535 (ethyl butylacetylaminopropionate) and deet against mosquito vectors in Thailand. J Am Mosq Control Assoc 2001, 17:190-195.
    • 41. World Tourism Organisation UNWTO: Yearbook of Tourism Statistics: Data 2005-2009. Madrid: United Nations World Tourism Organization; 2011.
    • 42. Fradin M, Day JF: Comparative efficacy of insect repellents against mosquito bites. N Engl J Med 2002, 347:13-18.
    • 43. Frances SP, Eikarat N, Sripongsai B, Eamsila C: Response of Anopheles dirus and Aedes albopictus to repellents in the laboratory. J Am Mosq Control Assoc 1993, 9:474-476.
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