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Original Investigation
December 30, 2019

Association Between Exposure to Pyrethroid Insecticides and Risk of All-Cause and Cause-Specific Mortality in the General US Adult Population

Author Affiliations
  • 1Department of Epidemiology, College of Public Health, University of Iowa, Iowa City
  • 2Department of Occupational and Environmental Health, College of Public Health, University of Iowa, Iowa City
JAMA Intern Med. 2020;180(3):367-374. doi:10.1001/jamainternmed.2019.6019
Key Points

Question  Is pyrethroid exposure associated with long-term mortality in the general US adult population?

Findings  In this cohort study of a nationally representative sample of 2116 adults in the United States, higher exposure to pyrethroid insecticides, indicated by higher levels of general pyrethroid metabolite 3-phenoxybenzoic acid in urine samples, was associated with a higher risk of death from all causes or cardiovascular disease over 14 years of observation.

Meaning  Environmental exposure to pyrethroid insecticides appears to be associated with an increased risk of long-term all-cause mortality and cardiovascular mortality in the US general adult population.


Importance  Widespread exposure to pyrethroid insecticides has been reported among the general population in the United States and worldwide. However, little is known about the association of pyrethroid exposure with long-term health outcomes in adults.

Objective  To examine the association of pyrethroid exposure with all-cause and cause-specific mortality among adults in the United States.

Design, Setting, and Participants  The nationally representative cohort included 2116 adults aged 20 years and older who participated in the US National Health and Nutrition Examination Survey conducted from 1999 to 2002 and provided urine samples for pyrethroid metabolite measurements. Participants were linked to mortality data from the survey date through December 31, 2015. Data were analyzed from May to August 2019.

Exposures  Urinary levels of 3-phenoxybenzoic acid, a general pyrethroid metabolite and commonly used biomarker for pyrethroid exposure, were determined by using high-performance liquid chromatography coupled with electrospray chemical ionization and tandem mass spectrometry.

Main Outcomes and Measures  Mortality from all causes, cardiovascular disease, and cancer.

Results  This cohort study of 2116 adults comprised 1145 women (weighted proportion, 51.6%) and 971 men (weighted, 48.4%), with a weighted mean (SE) age of 42.6 (0.5) years; 958 participants (weighted, 68.4%) were of non-Hispanic white ancestry, 646 (weighted, 14.7%) of Hispanic ancestry, 419 (weighted, 11.3%) of non-Hispanic black ancestry, and 93 (weighted, 5.6%) of other ancestry. During a median of 14.4 years (range, 0.1-16.8 years) of observation, 246 deaths occurred, including 41 associated with cardiovascular disease and 52 associated with cancer. Participants with higher urinary 3-phenoxybenzoic acid levels were at a higher risk of death during the follow-up period, with death occurring in 8.5% (unweighted, 75 of 709), 10.2% (unweighted, 81 of 701), and 11.9% (unweighted, 90 of 706) of participants across increasing tertiles of urinary 3-phenoxybenzoic acid levels. After adjustment for age, sex, race/ethnicity, socioeconomic status, dietary and lifestyle factors, body mass index, and urinary creatinine levels, the hazard ratios for all-cause mortality, cardiovascular disease mortality, and cancer mortality among participants with the highest tertile compared with those with the lowest tertile of urinary 3-phenoxybenzoic acid levels were 1.56 (95% CI, 1.08-2.26), 3.00 (95% CI, 1.02-8.80), and 0.91 (95% CI, 0.31-2.72), respectively.

Conclusions and Relevance  In this nationally representative sample of US adults, environmental exposure to pyrethroid insecticides was associated with an increased risk of all-cause and cardiovascular disease mortality. Further studies are needed to replicate the findings and determine the underlying mechanisms.

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    3 Comments for this article
    Biologic plausibility of Wei Bao Pyrethroid findings
    George Anstadt, MD | U of Rochester
    Bao and colleagues reported a large and unexpected 50% increase in cardiovascular deaths based on a single determination of urinary pyrethrin levels in a HNIS cohort taken over 10 years ago. A single determination of these rapidly metabolized agents is not likely to reflect a real chronic difference in levels between the low and high tertiles, or indeed any real difference integrated over observation period because these are commonly and episodically applied to human skin as insect repellents. Further, there is little corroborating data suggesting cardiovascular toxicity for these compounds. This low biologic probability of real difference suggests methodological problems, such as a flawed risk adjustment process.  
    Flawed adjustment would have produced cancer correlation
    George Henderson | Auckland University of Technology
    Anstadt suggests that the adjustment process may have been flawed, but residual confounding from the baseline characteristics recorded would have produced a similar association with cancer had that been the case. The specificity of the CVD association, especially considering popular assumptions about pesticides and cancer, is impressive.
    We have been told to avoid red meat because of a completely non-specific association with CVD of HR 1.2 at best. We have been told to limit saturated fat as much as possible because of an association with CVD of HR 0.97. In this context, perhaps an HR of 3.00 warrants further
    Biological Effects of Higher Pyrethroid Exposures for other Populations than those in NHANES 99-00
    Konstantinos Makris, PhD | Cyprus International Institute for Environmental and Public Health, Cyprus University of Technology
    Bao and Colleagues studied the effects of pyrethroid exposures on the cardiac mortality risk in the general adult population of U.S. The median 3-PBA levels back in 1999-2000 from NHANES was 0.25 ug/g. Since then, pyrethroid use globally has increased, with concomitant increase in NHANES 2009-2010 median 3-PBA levels (about 0.38 ug/g). In other parts of the globe such as in South Europe, our group noted a 3-PBA increase of about an order of magnitude higher for children (median of 2.0 ug/g); an increase that the age groups difference can not explain alone (https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0219420)
    It would be interesting to evaluate
    the shape and behavior of the respective dose response function for such populations exposed at higher pyrethroid levels than those mentioned in the study.