By Philip R. Fischer, MD, DTM&H

Professor of Pediatrics, Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN

Dr. Fischer reports no financial relationships relevant to this field of study.

SYNOPSIS: There is a statistical association between a urine test suggestive of exposure to pyrethroid insecticides and increased mortality over the subsequent 14 years.

SOURCE: Bao W, Liu B, Simonsen DW, Lehmler HJ. Association between exposure to pyrethroid insecticides and risk of all-cause and cause-specific mortality in the general US adult population. JAMA Intern Med 2019; Dec 30. doi: 10.1001/jamainternmed.2019.6019. [Epub ahead of print].

Pyrethroid insecticides are synthetic analogues of permethrin, a naturally occurring insecticide found in chrysanthemum flowers. The synthetic insecticides are more stable with sun exposure than permethrin. Pyrethroids are used widely for pest control, agricultural spraying, prevention of insect infestations on pets, mosquito-bite prevention in humans, and lice treatment. Pyrethroid use is widespread in the United States and, in the era when organophosphates have been deemed dangerous, increasingly common.

Once inhaled or ingested (or absorbed through the skin, although not much gets into the body this way), pyrethroids are metabolized and excreted in the urine. Although pyrethroids generally are considered to be nontoxic in mammals, chronic pyrethroid exposure has been postulated to relate to chronic diseases, including heart disease and diabetes. To better determine the actual relationship between pyrethroid exposure and mortality, Bao et al used data from the National Health and Nutrition Examination Survey (NHANES) to evaluate links between urinary levels of a pyrethroid metabolite, 3-phenoxybenzoic acid (3-PBA) and subsequent death rates. The subject sample used in the study is representative of the adult U.S. population. A total of 2,116 individuals ≥ age 20 years (mean age 43 years) were tested for urine 3-PBA during the years 1999 to 2002. Researchers reviewed mortality data at the end of 2015, giving about 14 years of follow-up.

There were 246 deaths in the study cohort: 41 associated with cardiovascular disease and 52 with cancer. Higher levels of 3-PBA were associated with higher rates of death (8.5%, 10.2%, and 11.9% in the lowest, middle, and highest tertiles of 3-PBA levels, respectively). Controlling for all relevant factors, 3-PBA levels were associated with all-cause mortality and coronary vascular disease mortality, but not with cancer mortality. The authors noted some limitations. First, single urine tests of pyrethroid metabolites might not be indicative of total chronic exposures over time. Second, 3-PBA can be ingested from the environment, without indicating actual exposure to or contact with the original pre-metabolism pyrethroid compounds. Third, only one metabolite was measured, and this might not be relevant to exposure to different pyrethroids used in different regions of the world. Finally, the pyrethroid exposure measured by 3-PBA might merely have been a marker of concurrent exposure to other toxic insecticides and pesticides without the pyrethroid compound being responsible for the identified risk.

COMMENTARY

Pyrethroid insecticides are used widely and can be considered to be ubiquitous in the United States. Exposure is not easily avoided.1 In fact, pyrethroids can be credited with a low risk of West Nile virus and other arthropod-transmitted infections in many urban areas. Before dropping pyrethroids from our armamentarium against West Nile, Zika, dengue, chikungunya, and malaria, we should realize these data are preliminary and, as the authors suggested, in need of replication.

As detailed by Timothy Winegard in the 2019 book The Mosquito, mosquitoes have been responsible for the outcomes of many key battles in human history, for the rise and fall of empires and civilizations, and for the shortened lives of leaders, including Alexander the Great.2 Even around the time of the founding of the United States, mosquito-borne illnesses caused lethal outbreaks in North America. Still, despite medical and public health advances, malaria kills nearly half a million children each year, mostly in sub-Saharan Africa. Controlling mosquitoes and mosquito-transmitted illnesses is important.

From 2000 to 2016, the authors of 61 different epidemiologic studies evaluated health outcomes as compared to pyrethroid exposures.3 Unfortunately, none of those studies were uniformly strong, and clear cause-effect relationships between pyrethroid exposure and adverse human health outcomes have not been proven.3 Helpful lay literature is available to counsel people concerned about pyrethroid safety.4

Pyrethroids continue to be a key weapon if an imperfect one against mosquitoes. However, the battle rages. Mosquitoes are becoming increasingly resistant to pyrethroids. At least in parts of West Africa, Anopheles mosquitoes increasingly express a sensory appendage protein (SAP2) that makes them resistant to the effects of pyrethroids.5 The expression of this protein increases with exposure to pyrethroids.5 With concerns spreading for pyrethroid resistance among malaria-transmitting mosquitoes, bednets impregnated with pyrethroids have become less effective since 2015.6 Host-seeking mosquitoes tend to fly and swoop from above the torso of the potential host.6 Using added barriers (even including organophosphates) above bednets would provide additional insecticidal activity while keeping the more toxic barrier chemicals beyond the reach of the people (especially children) under the nets.6 These combined “barrier bednets” have been shown to be effective in Burkina Faso.6

Another option is to add a pyrethroid synergist to bednets to make them more effective when mosquitoes develop resistance to pyrethroids. One such agent is piperonyl butoxide, which inhibits the metabolic enzymes in the cytochrome P450 pathway that detoxify pyrethroids. In Cote d’Ivoire, bednets impregnated with both piperonyl butoxide and a pyrethroid were approximately twice as effective in killing Anopheles mosquitoes as a standard pyrethroid-impregnated net.7 Malaria and other mosquito-transmitted infections continue to plague humans in many parts of the world. Pyrethroid insecticides have been helpful in reducing morbidity and mortality from mosquito-borne illnesses, but pyrethroid resistance among mosquitoes is increasing, and legitimate though unproven concerns exist that pyrethroid exposure might increase the risk of human heart disease. Barriers added to conventional pyrethroid-impregnated bednets and combinations of pyrethroids and synergistic agents on bednets might help extend the ability of bednets to protect against malaria.

REFERENCES

  1. Stellman SD, Stellman JM. Pyrethroid insecticides — time for a closer look. JAMA Intern Med 2019; Dec 30. doi: 10.1001/jamainternmed.2019.6093. [Epub ahead of print].
  2. Winegard TC. The Mosquito: A Human History of Our Deadliest Predator. New York: Penguin Random House; 2019.
  3. Burns CJ, Pastoor TP. Pyrethroid epidemiology: A quality-based review. Crit Rev Toxicol 2018;48:297-311.
  4. National Pesticide Information Center. Permethrin general fact sheet. Available at: http://bit.ly/2uidhNA.
  5. Ingham VA, Anthousi A, Douris V, et al. A sensory appendage protein protects malaria vectors from pyrethroids. Nature 2020;577:376-380.
  6. Murray GPD, Lissenden N, Jones J, et al. Barrier bednets target malaria vectors and expand the range of usable insecticides. Nat Microbiol 2020;5:40-47.
  7. Oumbouke WA, Rowland M, Koffi AA, et al. Evaluation of an alpha-cypermethrin + PBO mixture long-lasting insecticidal net VEERALIN LN against pyrethroid resistant Anopheles gambiae ss: An experimental hut trial in M’be, central Côte d’Ivoire. Parasit Vectors 2019;12:544.