Nonoccupational Exposure to Pyrethroids and Risk of Coronary Heart

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Non-occupational exposure to pyrethroids and risk of coronary heart disease in the Chinese population Jiajun Han, Liqin Zhou, Mai Luo, Yiran Liang, Wenting Zhao, Peng Wang, Zhiqiang Zhou, and Donghui Liu Environ. Sci. Technol., Just Accepted Manuscript • DOI: 10.1021/acs.est.6b05639 • Publication Date (Web): 14 Dec 2016 Downloaded from http://pubs.acs.org on December 14, 2016

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Environmental Science & Technology

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Non-occupational exposure to pyrethroids and risk of coronary heart disease in the Chinese

2

population

3

Names of the authors：：

4

Jiajun Han1, Liqin Zhou2, Mai Luo1, Yiran Liang1, Wenting Zhao1, Peng Wang1, Zhiqiang Zhou1,

5

Donghui Liu1*

6

Affiliations of all authors:

7

1

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Applied Chemistry, China Agricultural University, Beijing, 100193, People’s Republic of China

9

2

:Beijing Advanced Innovation Center for Food Nutrition and Human Health, Department of

: Xinzhou City People's Hospital, Xinzhou, Shanxi, 034000, People’s Republic of China

10

Name of and contact information for corresponding author:

11

Corresponding author: Donghui Liu

12

Mailing address: Beijing Advanced Innovation Center for Food Nutrition and Human Health,

13

Department of Applied Chemistry, China Agricultural University, Beijing 100193, People’s Republic

14

of China

15

Email address: [email protected]

16

Phone and fax number: 86 010-62732937

17

Abstract

18

Pyrethroids and the metabolites have been frequently observed in the environment. Animal

19

data suggests that pyrethroids can induce adverse effect on the cardiovascular system but there

20

are no human studies examining pyrethoids exposure as a risk for coronary heart disease (CHD).

21

We analyzed three nonspecific pyrethroids metabolites in urine and studied the association with

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CHD risk. A total of 72 CHD patients and 136 healthy subjects were recruited in Shanxi province

ACS Paragon Plus Environment


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in China from 2013-2014 by matching age and gender. The median concentrations of urinary

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cis-CDDA (cis-3-(2,2-dichlorovinyl)-2,2-dimethyl cyclopropane carboxylic acid), trans-CDDA

25

(trans-3-

26

(3-phenoxybenzoic acid) among healthy subjects were 1.03, 0.42, 0.74 μg/L respectively, while

27

the median concentrations of the three metabolites among CHD patients were 1.93, 1.07, 1.09

28

μg/L respectively, significantly higher than healthy subjects. Upper tertile of urinary pyrethroid

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metabolites were associated with an increased risk of CHD compared with the lowest tertile

30

(cis-CDDA: ORT3vsT1= 6.86, 95% CI: 2.76-17.06, p-trend = 0.000; trans-CDDA: ORT3vsT1= 6.94; 95% CI:

31

2.80-17.19; p-trend = 0.000; 3-PBA: ORT3vsT1= 3.62; 95% CI: 1.48-8.88; p-trend = 0.009; total

32

pyrethroid metabolites: ORT3vsT1= 4.55; 95% CI: 1.80-11.54; p-trend = 0.002). This study provides

33

information on pyrethroids exposure in China and reveals a possible positive association

34

between pyrethroids exposure and the risk of coronary heart disease.

35

TOC

(2,2-dichlorovinyl)-2,2-dimethyl

cyclopropane

carboxylic

acid)

and

3-PBA

36 37

Introduction

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Pyrethroids are synthetic insecticides with chemical structures related to the botanical

39

insecticide pyrethrin which is extracted from Chrysanthemum cinerariaefolium.1 Numerous

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pyrethroid analogs have been developed since the chemical structure of the pyrethrins was

41

elucidated in 1959. More than 20 of these analogs are registered and used commercially


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worldwide. Pyrethroids, in total, are the second-most used insecticides in the world. The annual

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production value exceeds $3 billion dollars.2 Pyrethroids, in small amounts, exhibit fast insect

44

knockdown and kill. For this reason they are extensively used in many areas including agriculture,

45

forestry, horticulture, animal health, termite control, and the protection of textiles.3 Because of

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their instability to heat, light, and oxygen, as well as selective toxicity to insects over mammals,

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pyrethrins are often used to control urban pests in residential areas.4 However, pyrethroids are

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considerably more photostable than pyrethrins and generally have much longer residual activity

49

periods following application.5 Therefore, pyrethroids generally present greater human safety

50

issues.

51

Pyrethroids have relatively low toxicity to humans because the mammalian

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voltage-dependent sodium channel differs from that of insects6 and pyrethroids can be

53

converted to non-toxic metabolites and quickly eliminated from the body.1,7,8 However,

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pyrethroids may not be as safe as previously thought. Guixiang assessed non-occupational

55

exposure to pyrethroids by measuring urinary 3-PBA levels, and observed a significant negative

56

correlation between the urinary 3-PBA level and sperm concentration. A positive correlation

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between urinary 3-PBA level and sperm DNA fragmentation was also found.9 The risk of acute

58

lymphocytic leukemia among children with urinary pyrethroid metabolites in the highest quartile

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was approximately 2 times greater than those in the lowest quartiles.10 Humans may also be

60

affected by pyrethroids before birth. Maternal transfer of the pyrethroids has been found

61

through analysis of breast milk and placenta samples.11

62

Pyrethroids have been detected widely in the environment, including river water, fish,

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sediment, vegetables, tobacco, and fruit crops11. In addition, because pyrethroids are used



64

widely as urban pesticides, residues are frequently detected in residences and human samples12，

65

such as urine and breast milk. In many locations, the concentration of pyrethroids is higher than

66

the maximum residual limit suggested by FAO-WHO. Therefore, the risk of non-occupational

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exposure to pyrethroids is a potential problem. Reviews about pyrethroids exposure and health

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effects have mainly focused on pyrethroids effects on male fertility and prenatal development.

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Information regarding pyrethroids exposure associated with other chronic diseases is limited.13,14

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Coronary heart disease (CHD) is caused by a gradual build-up waxy substance called plaque

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inside the coronary arteries. This leads to narrowed coronary arteries and reduced flow of

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oxygen-rich blood to the heart. CHD is the leading cause of death in the world. Compared with

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western countries, the incidence of CHD is relatively lower in China.15,16 However, the percentage

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of CHD mortality in the Chinese population has increased dramatically since 1980.17 Vadhana

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reported that permethrin can induce oxidative damage to purine bases in rat heart cells.

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Cardiovascular diseases such as coronary heart disease are associated with increased generation

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of reactive oxygen species (ROS).18 These data indicate that it is important to investigate the

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association between pyrethroids exposure and the risk of CHD.

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We evaluated the correlation between non-occupational exposure to pyrethroids with

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CHD through a cross-sectional study. Pyrethroids exposure was determined by analyzing three

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pyrethroid metabolites in urine samples of apparently healthy people and coronary disease

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patients. Among pyrethroid metabolites, cis-DCCA, trans-DCCA and 3-PBA are the most

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frequently detected. 3-PBA is a nonspecific metabolite of a variety of pyrethroids, including

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cycloprothrin, cyfluthrin, cyhalothrin, cypermethrin, deltamethrin, etofenprox, fenvalerate,

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permethrin, and tetramethrin.19 Trans-DCCA and cis-DCCA are geometric isomeric metabolites


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for chlorinated pyrethroids, such as permethrin, cypermethrin, and cyfluthrin.12 Cis-DCCA,

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trans-DCCA and 3-PBA were used as biomarkers of pyrethroids exposure in this study.

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Materials and methods

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Chemicals and reagents

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3-PBA (98%) and internal standard (chlorpyrifos, 98%) were purchased from Sigma−Aldrich Corp.

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(St. Louis, MO). Cis/trans-DCCA (98%) were obtained from Jiangsu Yangnong Chemical Group Co.

92

(Jiangsu,

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N,N-diisopropylcarbodiimide (DIC, 98%) were purchased from Aladdin Industrial Inc. (Shanghai,

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China). Water was purified by a Milli-Q water purification system (Bedford, MA, USA). All

95

solvents were HPLC grade. For each analyte, stock solutions of 10 μg/mL concentrations were

96

prepared in n-hexane and stored at -20°C before use.

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Study Subjects

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The subjects in this study were recruited in Xin Zhou City of Shanxi Province, which is one of the

99

most backward cities located in middle China. From October 2013 to January 2014, we recruited

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72 patients with coronary heart disease, and 136 healthy subjects. All the subjects were

101

informed of the study details and agreed to donate a urine sample. A consent form was signed

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by every subject before collection of personal information and urine samples. In order to

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minimize the influence of confounding factors the case group and control group had similar

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gender ratios and age group parameters. Subjects with a family history of coronary heart disease,

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adverse medical history, and occupational chemical exposures were excluded. This study was

106

approved by the Institutional Review Board of China Agricultural University and the ethics

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committee of the Xinzhou City People's Hospital.

China).

1,1,1,3,3,3-Hexafluoroisopropanol


(HFIP,

99.5%)

and


108

Sample collection

109

All subjects were required to donate fasting urine in the morning, and single spot urine samples

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were collected in 50-ml labeled high-density polypropylene centrifuge tubes (Corning

111

Incorporated, USA). Urine samples were immediately stored at −80°C until shipment to China

112

Agricultural University for pyrethroid metabolites analysis. At the same day, personal information

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of subjects was collected by trained interviewers. Information included age, sex, location of

114

residence, alcohol consumption, smoking, and education level.

115

Analysis of pyrethroids metabolites

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Samples were extracted using liquid/liquid extraction. A 1 mL aliquot of urine was added to a

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15-mL polypropylene centrifuge tube and 5 mL dichloromethane also was added for extraction.

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The suspension was homogenized using vortex mixer for 3 min. The dichloromethane layer was

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transferred to a 10-mL tube after centrifugation for 5 min at 4000 rpm. The extraction was

120

repeated once more and the extraction solvents were combined. Then, the extracts were

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evaporated to dryness with a stream of nitrogen. Derivatization of pyrethroid metabolites was

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based on previous studies. 20,21 Briefly, the residue was suspended in 250 μL of acetonitrile, and

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reprivatized with 30 μL of HFIP and 10 μL of DIC. Then 0.5 mL water and 1 mL n-hexane was

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added followed by vortex mixing and centrifugation. The n-hexane solution was filtered through

125

a 0.2 μm ultracentrifuge filter (Millipore inc.), and subjected to GC/MS analysis.

126

A Quantum GC tandem with Quantum triple quadrupole mass spectrometer (Thermo Fisher

127

Scientific, USA) using electro spray ionization (ESI) in positive ion (NI) mode was used throughout.

128

Analytical separations of the pyrethroid metabolites on the GC system were performed on the

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HP-5 MS (30 m×0.25 mm×0.25μm) analytical column. Good linearity was obtained with


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correlation coefficients ranging from 0.9824 to 0.9993. The recoveries for three pyrethroids

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metabolites ranged from 89.07–104.29% at three metabolites levels (0.5, 5.0, and 50.0 μg/L)

132

with relative standard deviations of 1.94–6.46%. The limit of detection (LOD) for three

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metabolites was all 0.1 μg/L, which based on the signal-to-noise ratio of three.

134

Statistical Analysis

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Statistical analyses were performed using SPSS Statistical Software (version 20.0, SPSS Inc.) All

136

tests were two-tailed and p < 0.05 was regarded as statistical significance. Descriptive statistics

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of the Demographic Characteristics of subjects, and detection rate, median, range, selective

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percentiles of cis-DCCA, trans-DCCA, and 3-PBA were calculated. (Table 1, Table 2) The p-values

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of the continuous variables (age and BMI) were obtained by Mann-Whitney U test. But the other

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variables are categorical variables, so the p-values were obtained by Chi-square test. The

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distributions of the pyrethroid metabolites were tested by Skewness–Kurtosis test and the

142

results showed that all of the distributions were skewed, therefore, the significant discrepancy

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between control group and case group was obtained by the Mann−Whitney test. Every individual

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pyrethroid metabolite and total metabolites were categorized into three equal sized proportions

145

based on the concentration of the control group. A logistic regression model with step wise

146

variable selection was used to calculate the odds ratio (OR) and 95% confidence interval (CI). The

147

following baseline information was collected as potential confounders: sex (male or female),

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smoking status was categorized into 3 groups (never, occasional, often, “occasional” was defined

149

as less than 1 cigarette per day, and “often” was defined as more than 1 cigarette per day),

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alcohol status was categorized into 3 groups (never, occasional, often, “occasional” was defined

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as less than 3 times per week, and “often” was defined as more than 3 times per week), duration



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of educations was categorized into 3 groups (< 9 years, 9 years< n 13 years), place of

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residence was either a rural area or a city. Age and body mass index (BMI) were continuous

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variables. The confounder which is significantly different (p < 0.1) between case and control

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group was included in the logistic regression model to calculate the adjusted OR. The correlation

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between different pyrethroid metabolites was assessed by Spearman Rank Correlation

157

Coefficient Test. In order to visualize inherent clustering between control and case group, PCA

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was applied to the metabolites data using Origin 2015

159

Results

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The data from the study subjects is summarized in Table 1. There was no statistically significant

161

difference between CHD patients and healthy subjects based on the distribution of sex, BMI,

162

smoking status, alcohol status and duration of educations. However, the age and place of

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residence of these two groups were significant different. The CHD patients were older than

164

healthy subjects. In addition, people residing in urban areas were more vulnerable to CHD than

165

rural dwellers. Therefore the age and place of residence were included into the logistic

166

regression model to calculate the adjusted OR.

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The detection rate, range, and percentile of distribution are shown in Table 2. The detection

168

rates of both control and case groups were very high (79.4%-98.6%). For most of the selected

169

percentiles, the CHD patients group had higher concentrations of these three pyrethroid

170

metabolites than the healthy subjects group. The Spearman Rank Correlation Analysis was used

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to analyze the correlation between cis-DCCA, trans-DCCA, and 3-PBA. The result showed that

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they were significantly correlated with each other at 0.01 level. (Control: r = 0.445-0.631, case: r

173

= 0.378-0.573). The two groups were compared using the Mann-Whitney U test and found that


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all the p values of the three pyrethroid metabolites were < 0.05 (Table 2), indicated a significant

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difference between CHD patients and healthy subjects. The figure of PCA showed that there

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were two outliers in control group, and the PCA results indicated that clusters of case group and

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control group are almost distinct from each other. (Figure 1)

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In order to explore the relationship between pyrethroids exposure and the risk of coronary heart

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disease, we categorized every individual pyrethroids metabolite into three equally sized

180

proportions based on the concentration of the control group (Table 3). A logistic regression

181

model involving age and place of residence was constructed to obtain the adjusted OR value (95%

182

CI). The upper tertile of individual pyrethroid metabolites was associated with increased CHD risk

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(Cis-CDDA: ORT3vsT1= 6.86; 95% CI: 2.76-17.06; p-trend = 0.000; trans-CDDA: ORT3vsT1= 6.94; 95%

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CI: 2.80-17.19; p-trend = 0.000; 3-PBA: ORT3vsT1= 3.62; 95% CI: 1.48-8.88; p-trend = 0.009). .

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Similar result was obtained with total pyrethroid metabolites (ORT3vsT1= 4.55; 95% CI: 1.80-11.54;

186

p-trend = 0.002). Odds ratio for CHD associated with urinary pyrethroid metabolite levels among

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urban population and rural population were provided in the SI file separately (Table S1, Table

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S2).

189

Discussion

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Sometimes, it is difficult to obtain the accurate information about pesticide application locations

191

and quantities used. It is therefore challenging to assess the risks from pesticide exposure. This is

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the first report about urinary pyrethroids exposure in the less developed agricultural area of

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central China. Pyrethroids are considered to be relatively safe pesticides due to their selective

194

toxicity. They are toxic to insects but less harmful to humans, partly due to the rapid metabolic

195

detoxification of pyrethroids in mammals. However, the risks of long-term exposure have not



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been rigorously studied. Most of the previous researches focused on the risks associated with

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reproductive health. The epidemiologic studies on pyrethroids are summarized in Table 4.

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Some animal bioassay studies have revealed properties of pyrethroids that may be related to

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cardiovascular disruption. Vadhana group found a significant decrease in heart surface area in

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permethrin treated rats. The increased transcription level of the Nrf2 gene indicated oxidative

201

stress occurred in heart tissue.31 They also reported that permethrin can induce oxidative

202

damage to purine bases in rat heart cells.18 Jaakko demonstrated that deltamethrin appears to

203

be cardiotoxic to the crucian carp by interfering with cardiac Na+ channel function.32 A clinical

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case reported that a 59-year-old female was in complete heart block after accidental exposure to

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a pyrethroid spray.33 There is increasing evidence that pyrethroids exposure can have adverse

206

effects on cardiovascular function.

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Our research is the first epidemiologic study to examine the association between pyrethroids

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and coronary heart disease. Urinary pyrethroid metabolites were used as biomarkers because

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they are easier and less invasive to collect compared with blood or tissue samples and most

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pyrethroid metabolites are excreted in urine. Most of the OR values of higher tertiles exceed 1,

211

indicating the exposure to pyrethroids is associated with an increased risk of coronary heart

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disease. Pyrethroids can induce oxidative stress through generation of reactive oxygen species

213

(ROS). Cardiovascular diseases such as coronary heart disease are associated with increased

214

generation of reactive oxygen species (ROS). 18 This could help explain the association between

215

pyrethroids exposure and coronary heart disease.

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The median concentrations of urinary cis-CDDA, trans-CDDA and 3-PBA among healthy subjects

217

were 1.03, 0.42, and 0.74 μg/L respectively. The detection rate and concentration were much


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lower than those in other studies performed in eastern China (detection rate was 100%, and

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median concentration of urinary 3-PBA was 1.149 μg/L) 22, which indicates that the eastern

220

Chinese people had greater pyrethroids exposure. Most of the differences can be attributed to

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geographic location. There is significantly more agricultural land and pest problems in eastern

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China. However, pyrethroids exposure in our study was much higher compared with the data

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from the USA general population as documented in the Fourth National Report on Human

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Exposure to Environmental Chemicals (NHANES).34 The median values of cis-CDDA and

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trans-CDDA in NHANES were below the limits of detection, and the median value of 3-PBA was

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0.382 μg/L. These results are consistent with pesticide use data. Approximately 4400 tons of

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pyrethroids are used in China annually which is much higher than any other western country.35

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The distribution of pyrethroid metabolites levels in this study could be used as reference data for

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pyrethroids exposure in China. Furthermore, the issues of pyrethroids abuse and overuse in

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China deserve greater attention.

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Most of the pyrethroids have relatively short half-lives and human exposures could arise from a

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variety of treatment sources. As such, urinary pyrethroid metabolites probably exhibit

233

substantial temporal variability, between and within individuals.36 Research indicates that a

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single measurement of urinary pyrethroid metabolites may lead to measurement error or

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misclassification, because the urinary pyrethroid metabolites levels always change over time37.

236

Therefore, the sampling method and collection time frame may significantly affect the results of

237

epidemiologic investigations and risk assessments. Thanks to the large scale of the partner

238

hospital and trained staff in this study, we were able to collect all the urine samples within 3

239

months, while most of the other epidemiologic investigations spent 2-5 years collecting samples.



240

All the urine samples were provided by the fasting subjects at the same time point in the

241

morning, reducing concerns about individual variability compared with previous epidemiology

242

investigations. We excluded subjects using a rigorous set of criteria. The accepted subjects could

243

not have a family history of coronary heart disease, adverse medical history, and occupational

244

chemical exposures. Potential confounding factors, such as age and location of residence were

245

included in the Logistic regression model, increasing the statistical power of the analysis.

246

This research study had certain limitations. The pyrethroid metabolites were general metabolites

247

rather than specific target pesticides. On the other hand, pyrethroids are rapidly metabolized

248

and excreted in mammalian systems, so substantial within-subject variability may result in

249

misclassification. Most epidemiologic studies about contaminant toxins with short half-lives have

250

faced the same problem. More stable models are needed to characterize the effects of long

251

term-exposure to short half-life pesticides. Although we excluded many potential confounding

252

factors, the effect of several factors to the total CVD outcome cannot be ruled out, including

253

genetics, dietary habits, and the other environmental pollutants.

254

Our study indicates that there may be a positive correlation between pyrethroids exposure and

255

increased risk of coronary heart disease. The risks of long-term exposure to pyrethroids should

256

be recognized and mitigated. Besides, additional epidemiological investigations of pyrethroids

257

and coronary heart disease should be conducted to verify this conclusion.

258

Abbreviations

259

CHD, coronary heart disease; Cis-CDDA, cis-3-(2,2-Dichlorovinyl)-2,2-dimethylcyclopropane

260

carboxylic acid; Trans-CDDA, trans-3-(2,2-Dichlorovinyl)-2,2-dimethylcyclopropane carboxylic

261

acid; 3-PBA, 3-Phenoxybenzoic acid; OR, odds ratio; CI, conﬁdence interval; LOD, limit of


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detection; ROS, reactive oxygen species

263

Acknowledgements

264

We would like to thank the Xinzhou City People's Hospital and the subjects participated in this

265

study. It was a significant amount of tedious work to collect and keep the samples properly. We

266

would also like to especially thank LetPub (www.letpub.com) for its linguistic assistance during

267

the preparation of this manuscript. This work was supported by the National Natural Science

268

Foundation of China (Grant numbers 21307155, 21337005).

269

Competing financial interests declaration:

270

The authors declare no competing ﬁnancial interest.

271

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Table1. Demographic profiles of the study population control(n=136) No.(%) mean ± SD sex male female age（years） BMI(kg/m2) smoke never occasional often alcohol never occasional often duration of education（years） N

Nonoccupational Exposure to Pyrethroids and Risk of Coronary Heart

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