Environment International 153 (2021) 106545

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Environment International
journal homepage: www.elsevier.com/locate/envint

Association between pyrethroid exposure and cardiovascular disease: A

national population-based cross-sectional study in the US
Qingping Xue a, b, An Pan c, Ying Wen d, Yichao Huang e, Da Chen e, Chun-Xia Yang f,
Jason HY Wu g, Jie Yang h, Jay Pan b, j, *, Xiong-Fei Pan c, g, i, *
a
Department of Epidemiology and Biostatistics, School of Public Health, Chengdu Medical College, Chengdu, Sichuan, China
b
HEOA Group, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, Sichuan, China
c
Department of Epidemiology and Biostatistics, Ministry of Education & Ministry of Environmental Protection Key Laboratory of Environment and Health, and State Key
Laboratory of Environmental Health (incubation), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei,
China
d
Shenzhen Center for Disease Control and Prevention, Shenzhen, Guangdong, China
e
School of Environment and Guangdong Key Laboratory of Environmental Pollution and Health, Jinan University, Guangzhou, Guangdong, China
f
Department of Epidemiology and Biostatistics, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, Sichuan, China
g
The George Institute for Global Health, University of New South Wales, Sydney, New South Wales, Australia
h
International Clinical Research Center & Department of Neurology, Clinical Medical College and The First Affiliated Hospital of Chengdu Medical College, Chengdu,
China
i
Division of Epidemiology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
j
Institue for Healthy Cities, West China School of Public Health, Sichuan University, Chengdu, Sichuan, China

A R T I C L E I N F O A B S T R A C T

Handling Editor: Martí Nadal Objective: Pyrethroids-containing products are widely used as commercial and household insecticides. While
animal studies and clinical case reports have shown acute cardiovascular outcomes of pyrethroids exposure, little
Keywords: has been known on the effect of chronic pyrethroid exposure on cardiovascular disease (CVD). We aimed to
Pyrethroids examine the associations between chronic pyrethroid exposure and CVD in the US adults.
3-phenoxybenzoic acid
Methods: Cross-sectional data from the National Health and Nutrition Examination Survey 1999–2002 and
Cardiovascular disease
2007–2012 were analyzed. The exposure to pyrethroids was determined as the urinary level of 3-phenoxybenzoic
Coronary heart disease
Stroke acid (3-PBA), and CVD was ascertained based on self-reported physician diagnoses. Multivariable logistic
regression models were fitted to evaluate associations of pyrethroid exposure with CVD, coronary heart disease
(CHD), and stroke.
Results: Included were 6,471 participants with a mean age of 44.77 years (standard error, 0.39) for final analyses.
The weighted prevalence of CVD, CHD, and stroke was 6.85%, 4.57% and 2.27%, respectively. With adjustments
for major confounders, participants in the highest tertile of urinary 3-PBA had higher odds of CVD (odds ratio,
1.58; 95% confidence interval: 1.12, 2.23) and CHD (OR, 1.75; 95% CI: 1.17, 2.61) compared to those in the
lowest tertile. There were linear associations for CVD (P for trend = 0.04) and CHD (P for trend = 0.02).
However, no significant association was noted for stroke (1.29; 0.78, 2.16) in the main analyses.
Conclusions: 3-PBA was adversely associated with CVD and CHD in the US adults. Our findings highlight potential
cardiovascular risk of chronic exposure to pyrethroids, and should be validated in large prospective studies in
different populations in future.

1. Introduction of naturally occurring pyrethrins from the flowers of Chrysanthemum

cineraraefolum (Matsuo, 2019). Owing to high insecticidal activity,
Pyrethroids are a group of synthetic insecticides that are derivatives insensitivity to air and light, and relatively low mammalian toxicity

* Corresponding authors at: Department of Epidemiology and Biostatistics, West China School of Public Health and West China Fourth Hospital, Sichuan Uni­
versity, 3-17 Renmin Nanlu, Chengdu, Sichuan Province 610041, China (J. Pan). Department of Epidemiology and Biostatistics, School of Public Health, Tongji
Medical College, Huazhong University of Science and Technology, 13 Hangkong Rd, Wuhan 430030, China (X.-F. Pan).
E-mail addresses: panjie.jay@scu.edu.cn (J. Pan), pxiongfei@gmail.com (X.-F. Pan).

https://doi.org/10.1016/j.envint.2021.106545
Received 30 December 2020; Received in revised form 9 March 2021; Accepted 23 March 2021
Available online 9 April 2021
0160-4120/© 2021 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).
Q. Xue et al.
(Kaneko, 2010), pyrethroids are widely used for pest control in agri­
cultural settings, indoor environments, pet shampoos, and scabies
treatments, and in the manufacturing of clothing and fabric (Saillenfait
et al., 2015). Their usage has grown substantially in recent decades due
to restrictions and bans placed on competing insecticides such as or­
ganophosphates (Costa, 2015; Power and Sudakin, 2007).
Adverse health effects of pyrethroids are increasingly recognized in
recent years. Due to the wide use of pyrethroid-containing products,
exposure to pyrethroids can occur through inhalation, dermal absorp­
tion, and food/water ingestion (Chrustek et al., 2018). Pyrethroids affect
the nervous system via disrupting voltage-gated sodium channels, which
increases the impulse of neurons to cause paralysis and death of insects
(Davies et al., 2007). In humans, acute illnesses and injuries (e.g., res­
piratory, neurological, and gastrointestinal symptoms) were reported
following occasional occupational exposure to pyrethroids (Yang et al.,
2002). Cardiomyocytes are known to be rich in sodium channels that are
the targets of pyrethroids (Spencer et al., 2001). Several case studies
reported that adverse cardiovascular outcomes can occur such as com­
plete heart block (Singh et al., 2016), sinus arrest (Bhaskar et al., 2010)
or cerebral infarction derived from cardiac arrhythmia (Bong et al.,
2017) after accidental or intentional exposure to pyrethroids. Such re­
ports raised concerns regarding the relationship between pyrethroid
exposure and cardiovascular disease (CVD). Recently, a prospective
cohort study showed that pyrethroid exposure was associated with
higher all-cause mortality and cardiovascular mortality in the US Na­
tional Health and Nutrition Examination Survey (NHANES) 1999–2002
(Bao et al., 2020). However, the focus of this study was on premature
mortality, and prevalent CVD cases were not assessed. In another small
case-control study (N = 208) in China, pyrethroids exposure was asso­
ciated with higher odds of coronary heart disease (CHD) (Han et al.,
2017). Although there are concerns of cardiovascular risk for chronic
exposure to low-level pyrethroids, epidemiological evidence from the
general population is still scarce.
To address the knowledge gap, we aimed to examine the associations
of urinary 3-phenoxybenzoic acid (3-PBA), a validated biomarker for
pyrethroids exposure, with CVD and its main subtypes (CHD and stroke)
in the US adults using data from a nationally representative population.
2. Material and methods
2.1. Study population and design
Our analyses were based on cross-sectional data from the National
Health and Nutrition Examination Survey (NHANES) 1999–2002 and
2007–2012. The NHANES is a nationally representative health survey
conducted by the National Center for Health Statistics of the Centers for
Disease Control and Prevention (CDC) to assess the health and nutrition
status of noninstitutionalized US civilian population. The study design,
sampling procedures, and survey methods of NHANES were reported in
detail elsewhere (NCHS, 2020). Briefly, using a complex, multistage
probability sampling design, the NHANES enrolled participants from
across the US and collected data through questionnaires, physical ex­
aminations, and biospecimen measurements at enrollment. The
NHANES was approved by the Ethical Review from the NCSH, and
written informed consent was obtained from all study participants.
In our analyses, we used data from 8,141 participants aged 20 years
and older enrolled in five NHANES cycles (NHANES 1999–2000,
2001–2002, 2007–2008, 2009–2010 and 2011–2012). 1,670 partici­
pants were excluded due to lack of information of pyrethroids, CVD,
sociodemographics, and behavior and metabolic factors. A total of 6,471
participants were included in our main analyses (Supplementary Fig. 1).
2.2. Urinary pyrethroid exposure assessment
Spot urine samples collected at enrollment were stored under − 20 ◦ C
and analyzed by the US CDC’s National Center for Environmental Health
2
Environment International 153 (2021) 106545
laboratory. Urinary concentrations of pyrethroid metabolites, including
3-PBA, cis-3-(2,2-dichlorovinyl)-2,2-dimethylcylopropane carboxylic
acid (cis-DCCA), trans-3-(2,2-dichlorovinyl)-2,2-dimethylcylopropane
carboxylic acid (trans-DCCA), 4F-3-PBA, and cis-(2,2-dibromovinyl)-
2,2-dimethylcyclopropane-1-carboxylic acid (cis-DBCA) were measured
using validated laboratory procedures (Baker et al., 2004; Barr et al.,
2010; Olsson et al., 2004). Briefly, 2 mL urine was spiked with an in­
ternal standard mixture (isotopically labeled 3-PBA and trans-DCCA)
and incubated with β-glucuronidase/sulfatase to convert conjugated
metabolites to free metabolites, and the hydrolysates were extracted
using OASIS HLB (Waters Corp., Milford, MA) mixed-mode solid-phase
extraction cartridges (Barr et al., 2010). The cartridges were subse­
quently washed with 5% methanol in a 0.1% acetic acid solution, and
metabolites were further eluted through methanol. The extracts were
concentrated and assayed by high-performance liquid chromatography
coupled with electrospray chemical ionization and tandem mass spec­
trometry. 3-PBA and trans-DCCA were measured using isotope dilution
calibration, while 4F-3-PBA, cis-DCCA, and cis-DBCA were measured
using the labeled 3-PBA, labeled trans-DCCA, and labeled trans-DBCA as
internal standards. The limits of detection (LODs) were 0.10, 0.10, 0.40,
0.20, and 0.10 μg/L for 3-PBA, cis-DCCA, trans-DCCA, 4F-3-PBA, and cis-
DBCA (Barr et al., 2010). Quality assurance and control procedures were
reported in the NHANES Laboratory Procedure Manual (CDC, 2013).
Since pyrethroids are primarily excreted via urine, urinary levels of
pyrethroid metabolites are usually used as the pyrethroid exposure
biomarkers. In the NHANES, 3-PBA could be detected among ~70% of
adults (at a LOD of 0.10 ng/mL for 3-PBA), while other metabolites of
pyrethroids were only measurable in a small proportion of participants
(Barr et al., 2010). Given that data analyses would not be reliable with
large amount of data imputations, we utilized urinary 3-PBA as the
primary exposure. 3-PBA is a common metabolite that represents an
exposure to a wide range of pyrethorids, including permethrin, cyper­
methrin, deltamethrin, allethrin, resmethrin, fenvalerate, cyhalothrin,
fenpropathrin, and tralomethrin. 3-PBA concentrations in spot urine
samples were used to evaluate the exposure of pyrethroid pesticides in
human biomonitoring studies (Wielgomas, 2013), and were regarded as
an acceptable biomarker of pyrethroid exposure in population studies
(Bao et al., 2020; Wagner-Schuman et al., 2015). In the current analyses,
3-PBA concentrations lower than the detection limit were replaced by
0.07 μg/L (i.e., LOD divided by the square root of 2: 0.10/20.5) in line
with previous studies (Bao et al., 2020; Park et al., 2019).
2.3. Ascertainment of CVD
CVD was defined as a composite of self-reported doctor diagnoses of
CHD, myocardial infarction, angina pectoris, congestive heart failure, or
stroke (Sontrop et al., 2013). CHD was defined as a composite of self-
reported doctor diagnosis of CHD, myocardial infarction, and angina
pectoris (Alexander et al., 2003). The five diseases for defining CVD
were inquired in the NHANES surveys. CVD was the primary outcome in
our analyses, while CHD and stroke were secondary outcomes.
2.4. Measurement of covariates
Based on previous work (Bao et al., 2020; Park et al., 2019) and
biological considerations, covariates were determined a priori, including
NHANES cycles, urinary creatinine concentration, sociodemographic
characteristics (age, sex, race/ethnicity, education, marital status, and
family poverty-to-income ratio), lifestyle factors and medical conditions
(diet quality, physical activity, smoking, alcohol intake, body mass
index [BMI], diabetes, hyperlipidemia, and hypertension) were consid­
ered as potential confounding factors. The NHANES cycles were treated
as an ordinal variable in our analyses (1999–2000, 2001–2002,
2007–2008, 2009–2010 and 2011–2012 were coded as 0, 1, 2, 3, and 4).
Age was regarded as a continuous variable. Sex was dichotomized into
two groups (male and female). Education was categorized into three
Q. Xue et al.
groups (less than high school, high school, and college or higher). Self-
identified race/ethnicity was grouped as Hispanic (including Mexican
and non-Mexican Hispanic), non-Hispanic white, non-Hispanic black,
and others). Marital status was categorized into three groups (married,
separated, and never married). Family poverty-to-income was defined as
the total family income divided by the poverty threshold and classified
into three groups (<1.3, 1.3–3.5 and >3.5) (Bao et al., 2020), with a
higher family poverty-to-income indicating a higher family income
status. Diet quality was assessed using the Healthy Eating Index-2015
(HEI-2015) based on food and nutrient intakes which were assessed
from 24-hour dietary recalls administered by trained interviewers. It
scored from 0 to 100, with a higher score indicating a higher diet quality
(Kennedy et al., 1995). Diet quality was categorized into three groups
based on HEI-2015 tertiles: low (less than 46), moderate (46–57), and
high (more than 57). Physical activity was categorized as low (less than
150 min per week), moderate (150–300 min per week), and high (more
than 300 min per week) according to the 2018 Physical Activity
Guidelines for Americans (Bao et al., 2020). Smoking was defined as
never (participants who smoked less than 100 cigarettes in their life­
time), former (participants who smoked more than 100 cigarettes in
their lifetime but did not smoke amid of the survey), and current
smoking (participants who smoked more than 100 cigarettes in their
lifetime and smoked amid of the survey) (Wang et al., 2018). Alcohol
intakes were defined as none (consumed less 12 alcohol drinks in a given
year), moderate (consumed <1 (women) or <2 (men) drinks per day),
and heavy (consumed ≥1 [women] or ≥2 [men] drinks per day) (Zhang
et al., 2013). BMI was modeled continuously as body weight in kilo­
grams divided by height in meters squared. Urinary creatinine concen­
trations were measured by an automated colorimetric method based on
a modified Jaff reaction on a Beckman Synchron AS/ASTRA clinical
analyszer (Barr et al., 2010), and were modeled as a continuous variable.
Diabetes was determined by fasting glucose measures (FBG ≥ 126 mg/dl
or HbA1c ≥ 6.5%) or self-reported antidiabetic medication taken via
questionnaires (Liu et al., 2013). Hypertension was determined by blood
pressure (systolic blood pressure (SBP) ≥ 140 mm Hg or diastolic blood
pressure (DBP) ≥ 90 mm Hg) or self-reported antihypertension medi­
cation taken via questionnaires (Ostchega et al., 2012). Hyperlipidemia
was defined as triglycerides ≥ 200 mg/dL, HDL-cholesterol < 40 mg/dL,
LDL-cholesterol ≥ 130 mg/dL, total cholesterol ≥ 150 mg/dL or total
cholesterol/ HDL-cholesterol ≥ 5 (Tadewos et al., 2012).
2.5. Statistical analysis
The NHANES generated survey-specific sample weights to account
for the complex survey design (including oversampling of certain pop­
ulations), survey non-response, and post-stratification so that calculated
estimates were representative of the US civilian noninstitutionalized
population. Following the NHANES Analytic and Reporting Guidelines,
we incorporated the combined sample weights for 1999–2002 and
2007–2012 in our statistical analyses (CDC, 2020).
Geometric mean and its 95% confidence interval (CI) were reported
for volume-based urinary 3-PBA concentrations and creatinine-
corrected urinary 3-PBA. Urinary 3-PBA concentrations were
compared between groups using the Wald F-test after natural log-
transformation. Given that creatinine concentrations can vary with
age, sex, and race/ethnicity, creatinine-correction for 3-PBA concen­
trations might not be optimal in the diverse population of the NHANES.
We adopted the recommendation by other NHANES studies (Barr et al.,
2005) of using volume-based 3-PBA concentration as the primary
exposure and additional creatinine correction in regression models.
Urinary 3-PBA was modeled both as a continuous variable with log-
transformation, and as tertiles with the lowest tertile regarded as the
reference group. Logistic regression models were conducted to estimate
odds ratios (ORs) and 95% CIs for associations between 3-PBA and
prevalent CVD, CHD, and stroke. To understand the confounding effects
of various covariates, we adjusted for them in three models in a stepwise
3
Environment International 153 (2021) 106545
manner. We adjusted for urinary creatinine and NHANES cycles in
Model 1; additionally sociodemographic factors including age, sex, ed­
ucation, race/ethnicity, marital status, and family poverty-to-income
ratio in Model 2; and additionally lifestyle factors and medical condi­
tions, including diet quality (as represented by the HEI-2015 score),
physical activity, smoking, alcohol intake, BMI, diabetes, hypertension,
and hyperlipidemia in Model 3. Linear trends in the associations (dose-
response relationships) between 3-PBA and CVD (and its subtypes) were
evaluated by assigning the median 3-PBA value for each 3-PBA tertile
and modelling it as a continuous variable. We also applied the logistic
regression based on restricted cubic splines with three knots to explore
nonlinear associations.
Two sensitive analyses were conducted. First, instead of adjusting for
urinary creatinine as a covariate, we used creatinine-corrected 3-PBA as
a secondary exposure variable to test the robustness of identified asso­
ciations. Second, we repeated the main analyses after excluding highly
diluted (creatinine concentration <30 mg/dL) or concentrated (creati­
nine concentration >300 mg/dL) samples according to the World Health
Organization recommendations (WHO, 1996).
We conducted subgroup analyses by age (<60 and ≥ 60), sex (male
and female), BMI (<25, 25–29.9, and ≥ 30 kg/m2), diabetes (yes and
no), hypertension (yes and no), and hyperlipidemia (yes and no). We
further examined potential effect modifications (interactions) by adding
a product term of each individual stratifying variable and 3-PBA in the
main model and assessing it via a likelihood ratio test. Statistical ana­
lyses were performed using the “survey” package in R software 3.6.1. P
values less than 0.05 were considered statistically significant.
3. Results
3.1. Basic characteristics of study participants
A total of 6,471 participants were included in our analysis. 51.87%
were female, 13.62% were Hispanic, 53.81% were never smokers,
66.96% were moderate drinkers, and mean age was 44.77 years (SD,
0.39). 602, 405, and 201 participants (weighted proportions, 6.85%,
4.57%, and 2.27%) had prevalent CVD, CHD, and stroke, respectively.
Weighted geometric mean (95% CI) of volume-based and creatinine-
corrected urinary 3-PBA concentrations were 0.41 μg/L (95% CI: 0.39,
0.44) and 0.42 μg/g (95% CI: 0.40, 0.45), respectively. Both volume-
based and creatinine-corrected urinary 3-PBA concentrations were
significantly higher in participants with diabetes (P = 0.01 and 0.02),
hyperlipidemia (P = 0.01 and <0.001), CVD (P = 0.01 and 0.01), CHD
(P = 0.01 and 0.02), and stroke (P = 0.04 and 0.01; Table 1), compared
to those without corresponding conditions. In addition, the volume-
based 3-PBA concentrations were higher in participants who were
heavy drinkers, had a higher BMI, or had a high urinary creatinine level
compared to their counterparts. The creatinine-corrected 3-PBA con­
centrations were higher in participants who were older, female, had a
higher diet quality, or had a low urinary creatinine level or had
(Table 1).
3.2. Associations between 3-PBA and CVD
Compared with those in the lowest tertile, participants in the highest
tertile of urinary 3-PBA levels had higher odds of CVD (OR, 1.58; 95%
CI: 1.12, 2.23) and CHD (OR, 1.75; 95% CI: 1.17, 2.61), but no signifi­
cant association was noted for stroke (OR, 1.29; 95% CI: 0.78, 2.16) after
adjusting for potential confounding variables. In addition, there were
linear trends in the association with CVD (P for trend = 0.04) and CHD
(P for trend = 0.02; Table 2) across tertiles of 3-PBA. Regressions based
on restricted cubic splines did not find evidence that the relationships
between log-transformed 3-PBA and CVD, CHD and stroke were
nonlinear (P ≥ 0.14 for all; Fig. 1).
Using creatinine-corrected 3-PBA as a secondary exposure, partici­
pants in the highest tertile of creatinine-corrected 3-PBA levels had
Q. Xue et al. Environment International 153 (2021) 106545

Table 1 Table 1 (continued )

Baseline characteristics of study participants in the NHANES (N = 6,471). Characteristics Total, n Urinary volume-based Urinary creatinine-
Characteristics Total, n Urinary volume-based Urinary creatinine- (%)a 3-PBA, μg/L corrected 3-PBA, μg/g
(%)a 3-PBA, μg/L corrected 3-PBA, μg/g
Geometric P Geometric P
Geometric P Geometric P mean valueb mean valueb
mean valueb mean valueb (95% CI) (95% CI)
(95% CI) (95% CI)
1848 0.37 (0.34, 0.42 (0.38,
Total – 0.41 (0.39, – 0.42 (0.40, – (23.36) 0.41) 0.46)
0.44) 0.45) Moderate 4086 0.42 (0.38, 0.42 (0.39,
Age, years 0.08 <0.001 (66.96) 0.45) 0.46)
20–39 2343 0.39 (0.36, 0.35 (0.33, Heavy 537 0.49 (0.42, 0.48 (0.41,
(40.76) 0.43) 0.38) (9.69) 0.56) 0.55)
40–59 2227 0.41 (0.38, 0.46 (0.42, BMI, kg/m2 0.01 0.45
(41.86) 0.45) 0.50) <25 1968 0.38 (0.35, 0.44 (0.40,
≥60 1901 0.46 (0.40, 0.55 (0.49, (32.63) 0.42) 0.48)
(17.38) 0.52) 0.62) 25–29.9 2202 0.40 (0.36, 0.41 (0.37,
Sex 0.36 <0.001 (34.15) 0.44) 0.46)
Male 3086 0.42 (0.39, 0.36 (0.33, ≥30 2301 0.46 (0.42, 0.42 (0.39,
(48.13) 0.46) 0.39) (33.21) 0.50) 0.46)
Female 3385 0.40 (0.37, 0.50 (0.46, Urinary <0.001 <0.001
(51.87) 0.44) 0.54) creatininec
Education 0.05 0.23 Low 2033 0.20 (0.18, 0.50 (0.46,
Less than high 1771 0.47 (0.42, 0.46 (0.41, (32.45) 0.22) 0.54)
school (17.78) 0.52) 0.52) Moderate 2208 0.46 (0.42, 0.43 (0.40,
High school 1436 0.41 (0.36, 0.42 (0.38, (33.37) 0.50) 0.47)
(21.76) 0.45) 0.46) High 2230 0.74 (0.68, 0.36 (0.33,
College or 3264 0.40 (0.37, 0.42 (0.39, (34.18) 0.81) 0.40)
higher (60.45) 0.43) 0.45) Diabetes 0.01 0.02
Race/ethnicity <0.001 <0.001 No 5565 0.40 (0.38, 0.41 (0.39,
Hispanic 1722 0.37 (0.33, 0.34 (0.31, (90.51) 0.43) 0.44)
(13.62) 0.41) 0.38) Yes 906 0.50 (0.44, 0.53 (0.47,
Non-Hispanic 3067 0.40 (0.37, 0.44 (0.40 (9.49) 0.57) 0.61)
white (69.88) 0.43) 0.47) Hypertension 0.85 0.22
Non-Hispanic 1287 0.55 (0.50, 0.40 (0.37, No 4254 0.41 (0.38, 0.42 (0.39,
black (10.68) 0.61) 0.44) (72.89) 0.44) 0.45)
Others 395 0.45 (0.37, 0.56 (0.46, Yes 2217 0.41 (0.38, 0.44 (0.41,
(5.82) 0.56) 0.69) (27.11) 0.44) 0.48)
Marital status 0.01 0.58 Hyperlipidemia 0.01 <0.001
Married 3466 0.38 (0.35, 0.41 (0.38, No 1970 0.47 (0.42, 0.49 (0.44,
(56.94) 0.42) 0.44) (29.60) 0.52) 0.54)
Separated 1809 0.50 (0.46, 0.54 (0.50, Yes 4501 0.39 (0.37, 0.40 (0.38,
(24.02) 0.55) 0.58) (70.40) 0.42) 0.43)
Never married 1196 0.40 (0.36, 0.36 (0.32, Cardiovascular disease 0.01 0.01
(19.03) 0.45) 0.40) No 5869 0.40 (0.38, 0.42 (0.39,
Family poverty-to-income 0.14 0.61 (93.15) 0.43) 0.45)
ratio Yes 602 0.52 (0.45, 0.54 (0.47,
<1.3 1757 0.47 (0.42, 0.45 (0.41, (6.85) 0.61) 0.61)
(19.30) 0.52) 0.51) Coronary heart 0.01 0.02
1.3–3.5 2230 0.40 (0.37, 0.41 (0.37, disease
(31.88) 0.44) 0.44) No 6066 0.41 (0.38, 0.42 (0.40,
>3.5 1924 0.40 (0.35, 0.43 (0.39, (95.43) 0.43) 0.45)
(42.04) 0.45) 0.47) Yes 405 0.51 (0.43, 0.52 (0.44,
Unknown 560 0.41 (0.34, 0.41 (0.34, (4.57) 0.60) 0.61)
(6.78) 0.50) 0.49) Stroke 0.04 0.01
Diet quality 0.73 <0.001 No 6270 0.41 (0.38, 0.42 (0.40,
Low 2000 0.42 (0.38, 0.38 (0.35, (97.73) 0.44) 0.45)
(32.97) 0.45) 0.41) Yes 201 0.57 (0.43, 0.62 (0.48,
Moderate 2092 0.41 (0.38, 0.42 (0.38, (2.27) 0.76) 0.80)
(33.02) 0.45) 0.46)
Abbreviations: 3-PBA, 3-phenoxybenzoic acid; CI: confident interval; NHANES:
High 2379 0.41 (0.37, 0.48 (0.44,
(34.01) 0.45) 0.52) National Health and Nutrition Examination Survey.
a
Physical activity 0.16 0.21 Weighted percentages that were different from crude proportions.
b
Low 2783 0.41 (0.38, 0.42 (0.39, Urinary 3-PBA was nature log-transformed and differences between groups
(37.58) 0.44) 0.45) were assessed by the Wald F tests.
Moderate 751 0.37 (0.32, 0.38 (0.33, c
Urinary creatinine was categorized into three groups based on the tertiles:
(12.25) 0.42) 0.44) low (<78 mg/dL), moderate (78–146 mg/dL), and high (>146 mg/dL).
High 2937 0.43 (0.39, 0.44 (0.40,
(50.17) 0.47) 0.48)
Smoking 0.14 0.45 higher odds of CVD (OR, 1.36; 95% CI: 1.03, 1.80). Despite large point
Never 3470 0.40 (0.37, 0.42 (0.39, effect estimates, no significant association was noted for CHD (OR, 1.37;
(53.81) 0.43) 0.45) 95% CI: 0.97, 1.93) and stroke (OR, 1.29; 95% CI: 0.85, 1.95; Supple­
Former 1607 0.42 (0.37, 0.44 (0.40,
mental Table 1) after adjusting for potential confounders, compared
(23.87) 0.46) 0.49)
Current 1394 0.43 (0.39, 0.43 (0.39, with those in the lowest tertile. Excluding the participants with poten­
(22.32) 0.48) 0.46) tially invalid spot urinary samples did not materially change the effect
Alcohol intake 0.01 0.25 estimates in main analyses: 1.57 and 1.78 for CVD and CHD for extreme-
None
tertile comparisons (Supplemental Table 2).
The association between 3-PBA and CVD was noted in participants

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Q. Xue et al. Environment International 153 (2021) 106545

Table 2 4. Discussion
Associations between volume-based 3-PBA and cardiovascular disease, coronary
heart disease and stroke in the NHANES. In this large population-based study, we found that higher concen­
Diseases Volume-based 3-PBA levels, OR (95% CI) P for trations of urinary 3-PBA were associated with increased odds of both
Log (3- Tertile 1 Tertile 2 Tertile 3
trenda CVD and CHD. Our findings remained robust in sensitivity analyses and
PBA) consistent across most subgroups.
Urinary 3-PBA concentrations could vary in different countries. The
Cardiovascular disease 0.04
Cases/ 602/6,471 176/ 199/2,166 227/2,210 geometric mean of creatinine-corrected 3-PBA concentration was 0.42
participants 2,095 μg/g creatine in our study. It was lower than reported in China (0.93 μg/
Model 1 1.10 1.00 1.52 (1.14, 1.70 (1.21, g) (Han et al., 2008) and South Korea (~1.95 μg/g) (Hwang et al.,
(1.01, (Ref.) 2.02) 2.38) 2019), but was equivalent to that in Japan (0.40 μg/g) (Ueyama et al.,
1.19)
Model 2 1.07 1.00 1.56 (1.15, 1.63 (1.16,
2009). The discrepancies between countries could be due to availability
(0.99, (Ref.) 2.12) 2.27) of different types of pyrethroid-contained products and their pyrethroid
1.17) contents, and use of different amounts of pyrethroid-contained products
Model 3 1.08 1.00 1.48 (1.07, 1.58 (1.12, in daily life. In addition, in two analyses of data from the NHANES
(0.99, (Ref.) 2.05) 2.23)
1999–2002 and 2007–2012, while there was no significant trend of
1.18)
Coronary heart disease 0.02 urinary 3-PBA levels for 1999–2002 (Barr et al., 2010), a rising trend
Cases/ 405/6,471 123/ 132/2,166 150/2,210 was noted in both children and adults in 2007–2012 (Lehmler et al.,
participants 2,095 2020), which indicates that pyrethroid exposure is a potential public
Model 1 1.09 1.00 1.68 (1.18, 1.82 (1.25, health hazard of concern in the US.
(1.00, (Ref.) 2.39) 2.66)
1.19)
In our study, participants with higher 3-PBA were more likely to have
Model 2 1.07 1.00 1.73 (1.19, 1.77 (1.22, CVD. Our findings were in line with clinical case studies that reported
(0.98, (Ref.) 2.53) 2.57) acute cardiovascular outcomes (e.g., transient complete heart block,
1.17) cardiac conduction disturbance, and acute cerebral infarction) after
Model 3 1.08 1.00 1.64 (1.08, 1.75 (1.17,
pyrethroid exposure (Bhaskar et al., 2010; Bong et al., 2017; Singh et al.,
(0.98, (Ref.) 2.49) 2.61)
1.20) 2016). Consistently, a recent study based on the NHANES 1999–2002
Stroke 0.55 data showed an adverse association between urinary 3-PBA concentra­
Cases/ 201/6,471 60/ 65/2,166 76/2,210 tions and total and CVD mortality during a follow-up of 14.4 years
participants 2,095 among 2,116 adults (Bao et al., 2020). The two studies (including ours)
Model 1 1.13 1.00 1.39 (0.87, 1.51 (0.87,
(0.99, (Ref.) 2.22) 2.62)
in the US population collectively supported increased likelihood of CVD
1.30) or mortality associated chronic pyrethroid exposure. Besides CVD out­
Model 2 1.10 1.00 1.38 (0.87, 1.33 (0.77, comes, adverse associations were also noted for CVD risk factors such as
(0.96, (Ref.) 2.21) 2.30) higher BMI (Yoo et al., 2016), and diabetes and glucose disturbance
1.27)
(Hansen et al., 2014; Park et al., 2019; Wang et al., 2011). Data for 3,671
Model 3 1.10 1.00 1.32 (0.84, 1.29 (0.78,
(0.96, (Ref.) 2.07) 2.16) adults from the Korean National Environmental Health Survey
1.26) 2009–2011 showed that 3-PBA correlated with higher BMI (Yoo et al.,
2016). In addition, cross-sectional analyses of data for 2,796 adults from
Abbreviation: 3-PBA, 3-phenoxybenzoic acid; CI: confident interval; NHANES:
National Health and Nutrition Examination Survey; OR: odds ratio.
NHANES 2007–2010 found an harmful association of 3-PBA and dia­
Model 1: Adjusted for urinary creatinine (continuous, mg/dL) and NHANES betes (Park et al., 2019). Similarly, pyrethroid exposure was associated
cycles. with abnormal glucose regulation in Denmark (Hansen et al., 2014) and
Model 2: Adjusted for age (continuous, years), sex (male and female), education China (Wang et al., 2011). These associations with CVD risk factors thus
(less than high school, high school and college or higher) and race/ethnicity consolidate the link between pyrethroid exposure and CVD.
(Hispanic, non-Hispanic white, non-Hispanic black, and others), marital status In our secondary analyses for CHD and stroke, there were adverse
(married, separated, and never married), and family poverty-to-income ratio associations of 3-PBA with CHD but not stroke, suggesting that the 3-
(<1.3, 1.3–3.5, >3.5, and unknown) plus variables in Model 1. PBA/CVD association might be primarily driven by CHD. In a study
Model 3: Adjusted for diet quality (continuous, HEI-2015 score), physical ac­ among 72 patients with CHD and 136 healthy controls (matched on age
tivity (low, moderate, high), smoking (never, former, and current), alcohol
and sex) in China from 2013 to 2014, participants in the highest tertile of
intake (none, moderate, and heavy), body mass index (continuous, kg/m2),
urinary 3-PBA were 3.62 times more likely to have CHD compared to
diabetes (yes and no), hypertension (yes and no), and hyperlipidemia (yes and
no) plus variables in Model 2.
those in the lowest tertile, and a linear association was also observed
a
P values for trend were estimated by by assigning the median 3-PBA value across three tertiles (Han et al., 2017), which agrees well with our data.
for each 3-PBA tertile and modelling it as a continuous variable. It is uncertain whether the adverse cardiovascular effects of 3-PBA are
specific for CHD as there have been no data from other studies on stroke;
with diabetes but not in their counterparts (1.32 vs 0.99; P = 0.01; identified null associations for stroke could also be merely chance
Fig. 2), while no heterogeneities in the effect estimates were observed findings. In this regard, animal studies could help to elucidate the dif­
between other subgroups. In addition, the association between 3-PBA ferential associations. Despite lack of overall association, there was a
and CHD was stronger in participants with higher BMI (1.21 vs 0.94 potential adverse association between 3-PBA and stroke only among
vs 0.94; P = 0.04) and diabetes (1.33 vs 0.96; P = 0.02; Supplementary participants with diabetes, a heterogeneity also indicated for CVD and
Fig. 2) than their other counterparts. Meanwhile, the association be­ CHD in our analyses, which suggests that individuals at risk for CVD
tween 3-PBA and stroke was observed in participants with diabetes but could be more susceptible to the adverse CVD effects of 3-PBA. All
not in those without diabetes (1.49 vs 1.00; P = 0.03; Supplementary population studies but one (Bao et al., 2020) mentioned above were
Fig. 3). There were similar results for heterogeneities between sub­ cross-sectional or case-control studies, so the direction of associations
groups when creatinine-corrected 3-PBA was assessed secondarily as the could not be determined. While our study used the largest sample size so
exposure variable (Supplementary Figs. 4–6). far to examine the topic, more large-scale prospective studies are needed
to confirm our findings.
Although the mechanisms underlying the link between pyrethroids
and CVD remain unclear, evidence from animal or in vitro experiments

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Q. Xue et al. Environment International 153 (2021) 106545

Fig. 1. Non-linear associations between log-transformed volume-based 3-PBA and cardiovascular disease, coronary heart disease, and stroke. The solid lines and
shaded areas represent the central risk estimates and 95% CIs, respectively, relative to the reference level (− 1.4 of log-transformed 3-PBA). The dotted vertical lines
correspond to the 20th, 40th, 60th, and 80th percentiles of log-transformed 3-PBA. There was no evidence of non-linear associations of urinary 3-PBA with car­
diovascular disease, coronary heart disease, or stroke in logistic regression based on restricted cubic splines (P for non-linearity = 0.15, 0.18, and 0.14). Models were
adjusted for urinary creatinine (continuous, mg/dL), NHANES cycles, age (continuous, years), sex (male and female), education (less than high school, high school
and college or higher) and race/ethnicity (Hispanic, non-Hispanic white, non-Hispanic black, and others), marital status (married, separated, and never married), and
family poverty-to-income ratio (<1.3, 1.3–3.5, >3.5, and unknown), diet quality (continuous, HEI-2015 score), physical activity (low, moderate, high), smoking
(never, former, and current), alcohol intake (none, moderate, and heavy), body mass index (continuous, kg/m2), diabetes (yes and no), hypertension (yes and no),
and hyperlipidemia (yes and no). Abbreviations: 3-PBA, 3-phenoxybenzoic acid; CI: confident interval; OR: odds ratio.

can provide some clues. First, one of the primary actions of pyrethroids
is to modify neuronal sodium channels, which are highly present in
cardiac myocytes (Georgiadis et al., 2018). Pyrethroids could prolong
ventricular action potentials, evoke afterdepolarizations, and extend the
duration of sodium currents in rat myocytes, resulting in an increase in
the variability of contractile force and potential arrhythmias (Spencer
et al., 2001), which could contribute to the development of CVD. Sec­
ond, early life low-level permethrin insecticide (one type of pyrethroid
insecticide) exposure in Wistar rats could lead to increased calcium
influx, overexpressed Nrf2 gene, and cardiac hypotrophy in old age
(Vadhana et al., 2013). Third, pyrethroid exposure could induce
oxidative stress (Gupta et al., 1999; Kale et al., 1999). Oxidative stress
was related with excessive production of reactive oxygen species and
pancreatic β-cell dysfunction, which could increase risk of CVD (Ceriello
and Motz 2004; Lakshmi et al., 2009). Besides direct effects on the heart,
it should be noted that the potential cardiovascular effects of pyrethroids
could be attributable to injuries caused to peripheral blood vessels by
pyrethroids as xenobiotic exposures (Forshaw and Bradbury, 1983).
Our study has some major strengths. The population-based design,
multistage sampling, and large sample size strengthen the representa­
tiveness of our findings in the US population. Well-characterized data
including sociodemographics, lifestyle and risk factors for CVD, physical
and lab measurements allow us to control for a variety of potential
confounding factors. However, certain limitations should be acknowl­
edged when interpreting our findings. First, due to the cross-sectional
design, the identified association between pyrethroids and CVD could
hardly be causal. However, coupled with findings from case reports and
population studies, our study indicates that potential cardiovascular
effects of chronic low-level pyrethroid exposure should be evaluated.
Second, we used self-report physician diagnoses to ascertain CVD out­
comes, so misclassifications could be possible due to recall errors.
However, the misclassifications of CVD might not be differential be­
tween participants with different levels of pyrethroids exposure, thus
not affecting the overall associations. Third, the temporal variability of
pyrethroid exposure could not be captured by one single spot urine
samples. In addition, the short half-life (6–24 h) of pyrethroids in
humans also damages the credibility of 3-PBA to reflect the long-term
exposure status. However, previous biomonitoring studies showed that
the frequent exposure to environmental chemicals could balance the
rapid clearance and yield a stable metabolite in urinary concentration
(Bradberry et al., 2005). Future studies with repeated measures of 3-PBA
can improve the accuracy of the estimated associations with CVD.
Fourth, there were slight differences in 3-PBA/CHD associations be­
tween volume-based 3-PBA plus creatinine adjustment versus creatinine
corrected 3-PBA, which poses uncertainties around the evidence. While
we regard the former as a more reliable method for a diverse population

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Q. Xue et al. Environment International 153 (2021) 106545

Fig. 2. Association between log-transformed volume-based 3-PBA and cardiovascular disease in subgroups. Models were adjusted for urinary creatinine (continuous,
mg/dL), NHANES cycles, age (continuous, years), sex (male and female), education (less than high school, high school and college or higher) and race/ethnicity
(Hispanic, non-Hispanic white, non-Hispanic black, and others), marital status (married, separated, and never married), and family poverty-to-income ratio (<1.3,
1.3–3.5, >3.5, and unknown), diet quality (continuous, HEI-2015 score), physical activity (low, moderate, high), smoking (never, former, and current), alcohol
intake (none, moderate, and heavy), body mass index (continuous, kg/m2), diabetes (yes and no), hypertension (yes and no), and hyperlipidemia (yes and no). P
values for interaction were estimated by adding a product term of each individual stratifying variable and 3-PBA in the main model and assessing it via a likelihood
ratio test. Abbreviations: 3-PBA, 3-phenoxybenzoic acid; BMI, body mass index; CI, confidence interval; OR, odds ratio.

in the NHANES, as recommended by other studies (Barr et al., 2005), our
findings should be replicated in future studies in other populations.
5. Conclusions
3-PBA was adversely associated with CVD and CHD in the US adults.
Our findings highlight the adverse cardiovascular effects of chronic
exposure to pyrethroids. Our findings should be validated in large pro­
spective studies in different populations in future, and regular moni­
toring of pyrethroid exposure in the population might be considered if
mature evidence of adverse associations is accumulated.
CRediT authorship contribution statement
Qingping Xue: Conceptualization, Methodology, Software, Writing -
original draft. An Pan: Writing - review & editing. Ying Wen: Meth­
odology, Writing - review & editing. Yichao Huang: Writing - review &
editing. Da Chen: Writing - review & editing. Chun-Xia Yang: Writing -
review & editing. Jason HY Wu: Writing - review & editing. Jie Yang:
Writing - review & editing. Jay Pan: Supervision, Writing - review &
editing. Xiong-Fei Pan: Conceptualization, Supervision, Methodology,
Writing - review & editing.
Acknowledgement
JP and XFP conceived the study. QX conducted the analyses and
drafted the manuscript. QX, AP, YW, YH, DC, CXY, JHYW, JY, JP, and
XFP revised the manuscript for intellectual content. All authors
contributed to and approved the final manuscript.
Funding
Q Xue was supported by Chengdu Medical College (CYZ19-33). A
Pan was supported by the National Key Research and Development
Program of China (2017YFC0907504). Jay Pan was supported by the
National Natural Science Foundation of China (Grant No. 71874116 and
72074163), Ministry of Education of China (Grant No. 18YJA790062),
Chengdu Federation of Social Science Association (Grant No. ZZ05),
Sichuan University (Grant No. 2018hhf-27 and SKSYL201811), and
China Medical Board (Grant No. 17-276). XF Pan was supported by the
International Postdoctoral Exchange Fellowship Program of the China
Postdoctoral Council (No 20180062). The funding agencies had no role
in design, analysis, interpretation, or writing of this study.
Appendix A. Supplementary material

Declaration of Competing Interest
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influence
the work reported in this paper.
Supplementary data to this article can be found online at https://doi.
org/10.1016/j.envint.2021.106545.
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