Journal of Hazardous Materials 449 (2023) 131002

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Journal of Hazardous Materials

journal homepage: www.elsevier.com/locate/jhazmat

Screening of pesticides in serum, urine and cerebrospinal fluid collected

from an urban population in China
Ke-Xin Zhao a, 1, Ming-Yan Zhang b, 1, Dan Yang b, Rong-Shu Zhu c, Zi-Feng Zhang a, *,
Ying-Hua Hu d, *, Kurunthachalam Kannan e
a
International Joint Research Center for Persistent Toxic Substances (IJRC-PTS), State Key Laboratory of Urban Water Resource and Environment/School of
Environment, Harbin Institute of Technology (HIT), Harbin 150090, China
b
Department of Clinical Laboratory, Harbin Medical University Cancer Hospital, Harbin 150081, China
c
Shenzhen Key Laboratory of Organic Pollution Prevention and Control, School of Civil and Environmental Engineering, Harbin Institute of Technology Shenzhen,
Shenzhen 518055, China
d
International Joint Research Center for Persistent Toxic Substances (IJRC-PTS), Heilongjiang Institute of Labor Hygiene and Occupational Diseases/The Second Hospital
of Heilongjiang Province, Harbin 150028, China
e
Department of Pediatrics and Department of Environmental Medicine, New York University Grossman School of Medicine, New York, NY 10016, USA

H I G H L I G H T S G R A P H I C A L A B S T R A C T

• Pesticide exposure levels in the cere­

brospinal fluid of urban populations
were tested.
• Triazole fungicides were found in cere­
brospinal fluid for the first time.
• Pesticides in human are mainly from
environmental exposure and food chain
enrichment.
• The pesticides with the highest risk are
hexachlorobenzene, biphenyls and p,p′ -
DDE.

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

Editor: Amina Salamova Human exposure to pesticides is a topic of public health concern for decades. Pesticide exposures have been
assessed through the analysis of urine or blood matrices, but little is known on the accumulation of these
chemicals in cerebrospinal fluid (CSF). CSF plays an important role in maintaining physical and chemical balance
of the brain and central nervous system and any perturbation can have adverse effects on health. In this study, we
Keywords:
investigated the occurrence of 222 pesticides in CSF from 91 individuals using gas chromatography-tandem mass
OCPs
Triazole fungicides
spectrometry (GC-MS/MS). Measured pesticide concentrations in CSF were compared with those in 100 serum
Risk assessment and urine specimens from individuals living in the same urban location. Twenty pesticides were found in CSF,

* Correspondence to: International Joint Research Center for Persistent Toxic Substances (IJRC-PTS), State Key Laboratory of Urban Water Resource and Envi­
ronment, Harbin Institute of Technology, 73 Huanghe Road, Harbin 150090, China.
E-mail address: zifeng_zhang@aliyun.com (Z.-F. Zhang).
1
These two authors contributed to this manuscript equally.

https://doi.org/10.1016/j.jhazmat.2023.131002
Received 5 December 2022; Received in revised form 3 February 2023; Accepted 11 February 2023
Available online 13 February 2023
0304-3894/© 2023 Elsevier B.V. All rights reserved.
K.-X. Zhao et al. Journal of Hazardous Materials 449 (2023) 131002

Estimated daily intake serum and urine, at levels above the limit of detection. Three most frequently detected pesticides in CSF were
Exposure source analysis biphenyl (100%), diphenylamine (75%), and hexachlorobenzene (63%). Median concentrations of biphenyl in
CSF, serum and urine were 1.11, 10.6, and 1.10 ng/mL, respectively. Six triazole fungicides were found only in
CSF, but not in other matrices. To our knowledge, this is the first study to report pesticide concentrations in CSF
in a general urban population.

1. Introduction collected after fasting overnight. Blood was centrifuged at 3000 rpm to
collect serum, which were stored at − 80 ℃. The sample collection was
Pesticides including insecticides, fungicides, and herbicides are used accomplished by a same group of doctors and nurses to ensure consis­
to improve the crop yield. However, effect from residual exposure of tency. CSF samples were collected from different set of individuals (i.e.,
pesticides on non-target organisms and humans is a topic of concern for not paired with serum and urine samples), by trained clinicians through
several decades. Several studies have reported adverse effects of pesti­ lumbar puncture and stored in sterile glass tubes at − 80 ℃ [16].
cides. Pesticides have been shown to cause neurological damage, gen­
otoxicity and metabolic disorders [15,25,12,7]. Exposure of pesticides 2.2. Chemicals and reagents
in humans were assessed through the measurement of concentrations in
serum and urine [11,27,34]. These studies have showed that exposure to Two hundred and twenty-two pesticides were divided into two
organochlorines, organophosphates, synthetic pyrethroids, and neon­ groups for analysis, with Group A (1ST27671–10E) including 109 pes­
icotinoids were prevalent among general populations in many countries. ticides and Group B (1ST27672–10E) including 113 pesticides, for
A number of cohort studies have linked pesticide exposure to a wide which analytical standards were purchased from First Standard (Alta
range of diseases, from breast cancer to adverse birth outcomes [13,26, Scientific Co., Ltd., Tianjin, China) (details in the supporting informa­
35]. tion). The residue grade organic solvents, dichloromethane, hexane,
In urban settings, human exposure to pesticides can arise from toluene, ethyl acetate and methanol were purchased from Fisher Sci­
contaminated food, water and air [21,42], although little is known on entific (Pittsburgh, PA, USA). The purified water was prepared from a
the exposure levels in China. Furthermore, very few studies have focused Milli-Q system (Millipore, Bedford, MA, USA). Ammonium sulfate was
on the occurrence of pesticides in CSF. CSF plays an important role in purchased from Shanghai Chemical Reagent Co. Ltd. (Shanghai, China).
maintaining physical and chemical balance of the brain and central
nervous system and is protected by the blood-brain barrier, which in­
2.3. Sample preparation
sulates from damage produced by harmful substances to the brain and
nervous system. Occurrence of pesticides in CSF may imply potential
Liquid-liquid extraction was used to extract pesticides from CSF. One
neurological effects [30]. Few studies have explored the link between
milliliter of CSF sample was diluted with 1 mL of purified water. To the
the occurrence of pesticides in CSF and disease outcomes. Vinceti et al.
mixture, 3 mL of ethyl acetate was added and the sample was horizon­
[46] determined 7 organochlorine pesticides (OCPs) and found 5 of
tally shaken for 30 min, centrifuged for 10 min at 4000 rpm, and the
them in CSF of patients with amyotrophic lateral sclerosis. Jorens et al.
supernatant was transferred to a disposable polypropylene tube. The
[19] reported the occurrence of pentachlorophenol in CSF. However, the
extraction process was repeated for 3 times, and the extracts were
few available studies on the occurrence of pesticides in CSF were based
combined and concentrated to 1 mL by a gentle nitrogen stream. The
on a small number of samples, which could be explained by the difficulty
solvent was exchanged to toluene and concentrated to 1 mL, and
in obtaining such matrices for human biomonitoring.
transferred to a glass vial for GC-MS/MS analysis. For each batch of 15
In the present study, a high throughput analysis of pesticides in 91
samples, 3 procedural blanks and 3 spiked samples were analyzed.
CSF samples and 100 paired serum and urine samples from an urban
The serum samples were extracted by solid phase extraction, as
population in Harbin, Northeast of China, was performed. A health risk
described earlier [5]. Briefly, 1 mL of serum was mixed with 2 mL of
assessment that considered multiple exposure indicators was applied,
saturated ammonium sulfate solution, vortexed and centrifuged for 5
and the detected pesticides were ranked in the order of risk indices. To
min at 4000 rpm to remove protein. The supernatant was passed
our knowledge, this is the first study to report pesticide concentrations
through activated ProElut PLS cartridges (200 mg, 3 mL, DiKMA, Bei­
in CSF in a non-occupationally exposed urban population.
jing, China) and 6 mL of purified water was added to remove the inor­
ganic salts. After the cartridge was dried using a vacuum pump, 4 mL
2. Materials and methods
mixture of n-hexane and dichloromethane (v:v=1:1) and 4 mL methanol
were used for elution. The eluent was concentrated to 1 mL under a
2.1. Study population and sampling
gentle nitrogen stream, solvent changed to toluene, concentrated to 0.5
mL, and transferred to a glass vial for instrumental analysis. The urine
Serum, urine and CSF samples analyzed in this study were collected
samples were processed similar to that of serum, except for that there
from the Second Hospital of Heilongjiang Province and the Fourth
was no protein removal step. Two milliliters of urine samples were
Affiliated Hospital of Harbin Medical University (China) in 2019. CSF
extracted and concentrated to 0.5 mL in toluene.
samples were collected from individuals for clinical diagnosis. All par­
ticipants reported no occupational pesticide exposure. The study par­
2.4. GC-MS/MS analysis
ticipants consisted of 52 males and 39 females, with age ranging from 5
to 83 years (Table S1). All participants were informed of the purpose of
Identification and quantification of target analytes were accom­
the study and signed the consent form. The study was reviewed and
plished by Agilent 7890B gas chromatograph (GC) interfaced with
approved by the ethics committee of Second Hospital of Heilongjiang
Agilent 7010B triple quadruple mass spectrometer (MS/MS). Dynamic
Province.
multiple reaction monitoring mode (D-MRM) was used for the detection
All paired serum and urine samples were collected from 100 in­
of analytes. The sample injection volume was 1 μL. Carrier gas was
dividuals undergoing routine physical examination in the same hospital
helium held at a flow rate of 1.1 mL/min. The injection temperature was
mentioned above in 2020. The participants were 50 males and 50 fe­
280 ℃ and the oven temperature program was as follows: 60 ℃ for 1
males, with age ranging from 20 to 60 years (Table S1). Serum was
min, ramped at 40 ℃/min to 120 ℃, and then at 5 ℃/min to 310 ℃
collected from venous blood and urine was the first morning void
which was held for 3 min. The mass spectrometry parameters used in the

2
K.-X. Zhao et al. Journal of Hazardous Materials 449 (2023) 131002

detection pesticides are shown in Table S2.

LOD：limit of detection. DF: detection frequency. HCB: hexachlorobenzene. PCNB: pentachloronitrobenzene. “—”, not available. We provide the urine concentrations adjusted by urinary creatinine in Table S3. The unit
Mean

1.50
0.07

0.03

1.18
0.09
0.07
0.06
0.12
0.18
0.08
0.11
0.09
8.7
—
—

—
—
—
—
2.5. Quality assurance and quality control

Disposable and solvent-rinsed glassware and materials were used to

90th

4.20
0.12

21.4

0.09

1.40
0.20
0.33
0.19
0.41
0.70
0.21
0.35
0.34
—
—

—
—
—
—
reduce background contamination. Matrix effects were assessed by
spiking known amounts of native standards into blank matrices and

＜LOD

＜LOD

＜LOD
＜LOD
＜LOD
＜LOD

＜LOD
＜LOD
comparing the signals to those in methanol-dissolved standards. The

50th

1.00
0.10

1.11
0.08

0.03
baseline concentration of analytes in the blank matrix was subtracted

—
—

—
—
—
—
from sample values. The calibration curves ranging in concentrations
from 0.01 ng/mL to 5 ng/mL (CSF) and 0.01 ng/mL to 10 ng/mL (serum

＜LOD
＜LOD

＜LOD

＜LOD

＜LOD
＜LOD
＜LOD
＜LOD
＜LOD
＜LOD
＜LOD
＜LOD
and urine) were used for quantification and r2 for all pesticides was

10th

0.84
—
—

—
—
—
—
above 0.95. The limit of detection (LOD) of standard sample were 1–90
pg/mL of CSF, 5–920 pg/mL of serum, and 1.7–590 pg/mL of urine

DF (%)
(Table 1). The recoveries of all pesticides in the three matrixes were >

100
52.5% and the variance was < 6.55%. A mid-point calibration standard,

57
63

20

27

75
16
34
27
23
57
47
23
—
—

—
—
—
—
2.5 ng/mL, and a toluene solvent were injected after every 10 samples as
a test for drift in instrumental sensitivity and carryover of target analytes

1.00
0.01
0.03
0.01
1.70
0.01
0.01
5.00
0.03
0.01
0.02
0.01
0.01
0.09
0.04
0.07
0.06
0.01
0.03
0.09
LOD
CSF
between samples.

2.6. Estimated daily intake (EDI)

Mean

95.2
0.03
0.03
0.04

0.12
0.04
17.6
0.40
0.02
0.01
1.65
0.68
—

—
—
—
—
—
—
—
The Joint Food and Agriculture Organization/World Health Orga­
nization (FAO/WHO) Meeting on Pesticide Residues (JMPR) establishes

110.8
90th

0.08
0.04
0.09

0.16
0.05
59.6
0.58
0.03
0.03
4.47
1.38
Acceptable Daily Intake (ADI) in the units of μg/kg bw/day. We esti­

—
—
—
—
—
—
—

for pesticides except dichlorobenzonitrile, p,p′ -DDE, δ-HCH was ng/mL. The unit for dichlorobenzonitrile, p,p′ -DDE, δ-HCH was pg/mL.
mated daily intake of pesticides from measured urinary concentrations
using a toxicokinetic model (Eq. (1)) [20].

＜LOD

＜LOD
50th

93.9
0.03
0.03
0.03

0.12
0.03

0.39
0.02

1.10
0.54
⎛ ⎞

—
—
—
—
—
—
—
μg ( μmol) ( g)
⎜kgbw⎟ Cum L × VU (L) × MW P mol
EDI⎝ ⎠ = (1)
d FUE × BW(kg)
＜LOD

＜LOD

＜LOD

＜LOD
＜LOD
10th

0.02

0.10
0.03

0.24
0.02

0.19
80

—
—
—
—
—
—
—
EDI, Estimated Daily Intake; CUM, molar concentration of pesticides;
VU, total urinary volume excreted within 24 h; MWP, molecular weight
DF (%)

of the parent compound; FUE, urinary excretion fraction of the parent

100

100

100
100
compound, BW, body weight.
69

70

30
99
98
31
72
97
—

—
—
—
—
—
—
—
Eq. (1) could be simplified to Eq. (2) as none of the compounds
detected in the present study were pesticide metabolites.
Pesticides concentrations in serum, urine and cerebrospinal fluid collected from Harbin, China.

5.00
0.01
0.01
0.03
1.70
0.01
0.05

0.16
0.01
0.03
0.02
0.32
0.07
0.02
0.01
0.07
0.03
0.01
0.59
Urine

19.8
LOD

⎛ ⎞
μg ( μg)
⎜kgbw⎟ Cu L × VU (L)
EDI⎝ ⎠ = (2)
d FUE × BW(kg)
152.1

10.49
Mean

45.8
0.10
0.38
0.21

0.05
0.05

1.04
0.05
0.19

2.09
8.6

—
—
—
—
—
—
—
CU, pesticide concentration in urine.
FUE values were mainly based on laboratory animal experiments.
343.0

12.92
90th

51.1
0.27
0.43
0.35

0.06
0.06

1.58
0.06
0.25

4.03

Urine excretion volume was set at 1.5 L [9] and body weight at 70 kg
17

—
—
—
—
—
—
(WHO, 2006). —

Hazard quotient (HQ), which was the ratio of EDI to ADI, was used to
＜LOD

112.1

10.60

compare potential hazards of different pesticides. If HQ was less than 1,

50th

44.9
0.09
0.37
0.21

0.05
0.05

1.01
0.05
0.18

2.08
—
—
—
—
—
—
—

the exposure level was considered harmless.

2.7. Pesticide risk ranking

＜LOD

＜LOD
10th

37.9

0.34
0.08

0.04
0.04
30.2
0.52
0.04
0.14
8.16
0.48
—
—
—
—
—
—
—

Pesticides were ranked based on risks, and all relevant indicators

were normalized by dividing individual indicator by the sum. The
DF (%)

detailed method of normalization of concentrations is given in SI. Five

100

100

100
100

100
100
100
100
75

98
46

97

96
—
—
—
—
—
—
—

different indicators were selected to assess pesticide risk, namely con­

centration in CSF (FCS), ability to cross the blood-brain barrier (FC/S),
Serum

potential for excretion in urine (FU/S), daily intake level (FHQ), and
5.00
0.02
0.01
0.02
5.00
0.01
0.01
5.00
0.92
0.02
0.05
0.03
0.18
0.04
0.02
0.09
0.05
0.02
0.03
0.16
LOD

toxicity level (FTOX). A negative FU/S is indicative of reduced harm with

the increase in excretion through urine.
dichlorobenzonitrile

2.8. Statistical analysis

diphenylamine

cyproconazole
propiconazole
paclobutrazol

tetraconazole
myclobutanil

diniconazole
fludioxonil
acetochlor
dichlorvos
chloroneb
Pesticides

propoxur

biphenyl
p,p′ -DDE

All pesticide concentrations below the limit of detection (LOD) were

Table 1

α-HCH

δ-HCH
β-HCH
PCNB

imputed with a value of zero. Normality of data distribution was

HCB

checked by Kolmogorov-Smirnov test. Differences in the concentrations

3
K.-X. Zhao et al.
of pesticides in males and females were tested by independent T test. The
concentrations of pesticides in different age groups were tested by one-
way analysis of variance (ANOVA). Correlations of pesticides in paired
serum and urine samples were analyzed by Pearson correlation analysis.
Systematic clustering (Pearson correlation method) was used to analyze
pesticides in CSF, serum and urine. The significance level was set as
0.05. SPSS 26.0 software was used for statistical analysis.
3. Results and discussion
3.1. Pesticide concentrations in serum, urine and CSF
The measured concentrations of pesticides in serum, urine, and CSF
are shown in Table 1. In total, 8 organochlorines and 12 non-
organochlorine pesticides were found in all matrices. In serum, 8
OCPs and 5 non-OCPs were detected in nearly all samples. In urine, all
pesticides that were found in serum, except for p,p′ -DDE, were detected
(Fig S1-S3). The distribution of each detected pesticide in serum, urine
and CSF is shown in Fig. 1. Biphenyl was found at the highest concen­
tration (10.5 ng/mL, 70.6% in serum; 1.65 ng/mL, 52.7% in urine),
followed by diphenylamine (2.09 ng/mL, 14.1% in serum; 0.68 ng/mL,
21.6% in urine). Total concentration of HCH and its isomers (α-HCH,
β-HCH, γ-HCH, δ-HCH) was 0.25 ng/mL in serum. Similarly, median
serum HCH concentration in the general population in Wuhan, China
was 1.97 ng/mL [34]. Our results suggest that exposure levels of HCHs
in Harbin were relatively low. However, the presence of HCH in all
samples suggests that urban populations still are exposed to OCPs.
In CSF, only 4 OCPs (dichlorobenzonitrile, HCB, p,p′ -DDE, β-HCH)
and 2 non-OCPs (biphenyl, diphenylamine) were detected. However, it
is worth noting that 7 pesticides that were not found in serum were
detected in CSF, and 6 of them belong to triazole fungicides (Fig. 2). To
our knowledge, this is the first report to document the detection of tri­
azole fungicides in human CSF. Nearly 25% of the samples contained
these triazole fungicides and the detection rates for myclobutanil and
tetraconazole were even higher, at 57% and 47%, respectively. Triazole
fungicides are widely used to control fungal diseases, and some of these
are used to regulate crop growth [17]. Recent studies showed that tri­
azole fungicides can cause neurological disorders [39]. Zhou et al. [56]
pointed out that triazole fungicides can affect embryonic development.
Presence of these triazole fungicides in CSF suggests potential health
risks to urban populations.
Although all the detected OCPs have been banned from production in
China (from Ministry of Industry and Information Technology, China,
Table S4), OCPs are found in air, soil and water due to their persistence
[43,52], and they can also accumulate in humans through the food
chain.
For all non-OCPs except biphenyl and diphenylamine, they are
widely used in agricultural production and pest management, and traces
of these pesticides can be found in foods [28,31]. For biphenyl and
diphenylamine, because both substances have been used as pesticides
and have been shown to affect humans, no pesticide license has been
issued for these two substances (Table S4) [10,29]. However, biphenyl
and diphenylamine are important industrial raw materials and
by-products of industrial processes. Biphenyls exist naturally as com­
ponents of crude oil and coal tar [29], and diphenylamine is an impor­
tant raw material for the synthesis of dyes and antioxidants [10], and is
widely used in rubber products [50]. Given the widespread use of pet­
rochemicals and rubber products, high concentrations of biphenyls and
diphenylamine found in human populations are likely from industrial
products.
3.2. Exposure characteristics
3.2.1. Rurine/serum, RCSF/serum and gender differences
The ratio of pesticide concentrations between urine and serum
(Rurine/serum, Table 2) and correlation between serum and urine
4
Journal of Hazardous Materials 449 (2023) 131002
concentrations were examined (Table S5). Except for p,p′ -DDE, the ratio
was higher suggesting higher excretion rates. Excretion of pesticides
through urine is mainly related to log Kow [6]. The highest Rurine/serum
value was found for α-HCH (Rurine/serum: 240%, log Kow: 3.72, Pearson
correlation: 0.091), followed by dichlorobenzonitrile (200%, 2.74,
0.742), and the lowest Rurine/serum value was for p,p′ -DDE (0%, 6.51, —),
and acetochlor (5%, 4.14, − 0.05). Currently, α-HCH in the environment
is widely distributed in the gas phase and is more likely to be deposited
at high latitudes [47]. The population studied in this research were
located in Harbin, China, at about 45 latitudes. This means that urban
populations in Harbin were more likely to be exposed to α-HCH than
β-HCH and δ-HCH, as indicated by the relatively high concentrations of
α-HCH detected in urine. As α-HCH in serum is more likely to be
adsorbed by adipose tissue and so on, the detected α-HCH in serum is
low, which leads to a high Rurine/serum value.
The ratio of pesticide concentrations between CSF and serum (RCSF/
serum, Table 2) was also analyzed to study the ability of different pesti­
cides to reach CSF. Since the human brain has the highest lipid content
of any organ other than fat tissue [1], pesticides with higher log Kow
were more likely reach the CSF. The highest RCSF/serum value was found
for p,p′ -DDE (RCSF/serum: 100%, log Kow: 6.51), followed by HCB (70%,
5.73) and β-HCH (60%, 3.72). Although the concentration of biphenyls
was the highest in CSF (1.18 ng/mL, 56.8% of the total concentration),
its RCSF/serum was only 11%, so the high concentration was mainly due to
the high level of biphenyls in the serum.
RCSF/serum for 6 triazole fungicides were not available because no
triazole fungicides were detected in serum. It is not known why triazole
fungicides appear only in CSF, but we found that some of the drugs used
to treat neurological diseases and fungal infections are based on the
triazole structure [37,38,45], which may be evidence that the triazole
structure can help chemicals cross the blood-brain barrier. Unfortu­
nately, these studies are usually based on computer simulations or ani­
mal experiments. In fact, studies on the toxicity of triazole fungicides
have generally remained at the animal level [3,32,56], and in these
studies, triazole fungicides have shown neurotoxicity, which may be
side evidence of the tendency of triazole fungicides to invade the central
nervous system.
Serum concentrations of all detected pesticides were slightly higher
∑ ∑
in males (arithmetic mean concentrations of 8 OCPs: 1.12 ng/mL, 5
∑ ∑
non-OCPs: 13.9 ng/mL) than in females ( 8 OCPs: 1.02 ng/mL, 5
non-OCPs: 13.8 ng/mL) (Table 2), and these differences were statisti­
cally significant only for dichlorobenzonitrile, PCNB and propoxur (p＜
0.05). It is worth noting that the concentrations of 5 triazole fungicides
(propiconazole, paclobutrazol, myclobutanil, tetraconazole, dinicona­
zole) in CSF were about twice as high in males than in females. The
reasons for these differences were unknown. Some studies showed that
triazole fungicides could induce Parkinson-related effects in human
nerve cells in vitro [40], and recent studies showed that males were
about twice more likely to develop Parkinson’s disease than females [4].
Further studies are needed to assess sources of triazole fungicides in
humans.
3.2.2. Age difference in pesticide exposure
The participants were categorized into four age groups (＜30,
30 − 39, 40 − 49 and ≥50 years) to evaluate the relationship between
pesticides exposure levels and age. Except for PCNB and δ-HCH, most
pesticides level in serum, urine and CSF were not significantly correlated
with age (Table 3). This lack of age difference may be due to rapid
metabolism of these compounds [41]. For example, half-life is 31 d for
biphenyl, 2.24 d for diphenylamine, 10 min for dichlorvos in human
body (National Center for Biotechnology Information, National Library
of Medicine), and these three pesticides account for 91.7% of total
pesticides exposure. Concentrations of PCNB and δ-HCH differed
significantly among the age groups (p＜0.05). Age dependent accumu­
lation was mainly reported for lipophilic chemicals (PCNB log Kow: 4.64,
δ-HCH log Kow: 3.72). The urinary concentration of PCNB decreased
K.-X. Zhao et al. Journal of Hazardous Materials 449 (2023) 131002

Fig. 1. Distribution of various pesticides detected in serum, urine and cerebrospinal fluid from an urban population in China.

5
K.-X. Zhao et al. Journal of Hazardous Materials 449 (2023) 131002

Fig. 2. Six triazole fungicides found in cerebrospinal fluid.

Table 2
Ratios of pesticides among cerebrospinal fluid, serum and urine: RCSF/serum and Rserum/urine of pesticides and gender differences.
Pesticides RCSF/serum Rurine/serum Serum Urine CSF

male female male female male female

dichlorobenzonitrile 0% 200% 0.05 * 0.04 0.10 * 0.09 — —

HCB 70% 30% 0.11 0.10 0.04 0.03 0.07 0.08
chloroneb 0% 8% 0.36 0.39 0.03 0.03 — —
PCNB 0% 19% 0.25 * 0.18 0.04 0.04 — —
p,p′ -DDE 100% 0% 0.08 0.09 — — 0.01 0.01
α-HCH 0% 240% 0.05 0.05 0.13 0.12 — —
β-HCH 60% 80% 0.05 0.05 0.04 0.03 0.02 0.03
δ-HCH 0% 13% 0.17 0.14 0.01 0.02 — —
dichlorvos 0% 38% 0.92 1.17 * 0.43 0.38 — —
propoxur 0% 40% 0.05 * 0.05 0.02 * 0.02 — —
acetochlor 0% 5% 0.20 0.18 0.01 0.01 — —
biphenyl 11% 16% 10.62 10.35 1.83 1.46 1.24 1.10
diphenylamine 4% 33% 2.12 2.07 0.60 0.75 0.10 0.07
fludioxonil — — — — — — 0.09 * 0.04
propiconazole — — — — — — 0.08 * 0.02
paclobutrazol — — — — — — 0.15 * 0.07
cyproconazole — — — — — — 0.22 0.13
myclobutanil — — — — — — 0.10 * 0.04
tetraconazole — — — — — — 0.15 * 0.06
diniconazole — — — — — — 0.11 * 0.06

The significant level was 0.05, all date with significant difference were marked in bold font.

with age, with arithmetic means of 0.05, 0.03, 0.04, 0.02 ng/mL for age
groups of ＜30, 30 − 39, 40 − 49 and ≥ 50 years, respectively. This
suggested ongoing exposure to PCNB in recent years.
To assess the cumulative risk of pesticide exposure in different age
groups, the trends of total pesticides concentration in serum and urine
were compared. Total pesticide concentrations in serum increased
significantly (p＜0.05) with age, with arithmetic means of 14.1, 14.4,
15.3, 16.1 ng/mL for age groups of ＜30, 30 − 39, 40 − 49 and ≥ 50
years, respectively. Contrary to the trend shown in the serum, total
pesticide levels in urine decreased significantly (p＜0.05) with age, with
arithmetic means of 3.65, 3.38, 2.8, 2.64 ng/mL for age groups of ＜30,
30 − 39, 40 − 49 and ≥ 50 years, respectively. This suggests that the
increase in pesticide concentrations with age may be due to a decrease in
the body’s ability to metabolize these substances.
3.2.3. Cluster analysis
We performed cluster analysis (based on Pearson correlation
method) on pesticides detected in CSF and serum, which can separate

6
K.-X. Zhao et al. Journal of Hazardous Materials 449 (2023) 131002

Table 3
Pesticides concentrations (ng/mL) in human cerebrospinal fluid, serum and urine collected from an urban population by age.
Pesticides CSF Serum Urine

＜30 30–39 40–49 ≥ 50 ＜30 30–39 40–49 ≥ 50 ＜30 30–39 40–49 ≥ 50

dichlorobenzonitrile 0.00 0.00 0.00 0.00 0.04 0.05 0.05 0.05 0.09 0.09 0.09 0.10
HCB 0.08 0.10 0.07 0.07 0.08 0.09 0.12 0.12 0.05 0.03 0.04 0.03
chloroneb — — — — 0.38 0.38 0.38 0.36 0.03 0.03 0.03 0.03
PCNB — — — — 0.16 0.19 0.23 0.30 0.05 0.03 0.04 0.02
p,p′ -DDE 0.00 0.00 0.00 0.01 0.01 0.01 0.01 0.01 — — — —
α-HCH — — — — 0.05 0.05 0.05 0.05 0.12 0.12 0.12 0.13
β-HCH 0.00 0.00 0.01 0.04 0.05 0.05 0.05 0.05 0.04 0.04 0.04 0.03
δ-HCH — — — — 0.11 0.12 0.17 0.23 0.02 0.02 0.01 0.02
dichlorvos — — — — 1.02 1.02 1.14 0.94 0.44 0.40 0.40 0.37
propoxur — — — — 0.05 0.05 0.05 0.05 0.02 0.02 0.02 0.02
acetochlor — — — — 0.18 0.19 0.20 0.19 0.00 0.01 0.01 0.02
biphenyl 1.09 1.12 1.14 1.22 10.02 10.22 10.72 11.10 2.03 1.86 1.36 1.34
diphenylamine 0.10 0.12 0.10 0.08 1.92 1.93 2.12 2.61 0.76 0.73 0.64 0.53
propiconazole 0.08 0.07 0.06 0.05 — — — — — — — —
paclobutrazol 0.14 0.20 0.05 0.13 — — — — — — — —
fludioxonil 0.17 0.06 0.02 0.06 — — — — — — — —
cyproconazole 0.31 0.36 0.07 0.18 — — — — — — — —
myclobutanil 0.09 0.11 0.05 0.08 — — — — — — — —
tetraconazole 0.13 0.16 0.07 0.12 — — — — — — — —
diniconazole 0.12 0.13 0.03 0.10 — — — — — — — —
total 2.31 2.43 1.67 2.14 14.07 14.35 15.29 16.06 3.65 3.38 2.8 2.64

The significant level was 0.05, all date with significant difference were marked in bold font. ＜30, 30 − 39, 40 − 49 and ≥ 50 means people younger than 30 years old,
people between 30 and 39 years old, people between 40 and 49 years old, people over 50 years old, respectively.

pesticides with different exposure sources. As shown in Fig. 3, pesticides
in CSF and serum were divided into 4 clusters. HCH, HCB, PCNB, pro­
poxur and acetochlor were grouped into one category in serum (food
chain sources). These pesticides except for acetochlor and propoxur
were all OCPs with high bioaccumulation factor (2.399 for HCH, 3.448
for HCB, 2.728 for PCNB, EPISuite™). Moreover, the production and use
of these OCPs were banned in China for a long time. We did not detect
γ-HCH in our samples. The absence of γ-HCH suggests that HCH
measured in samples were derived from the past use [47].
Dichlorobenzonitrile, biphenyl, diphenylamine and dichlorvos in
serum were grouped into another category (environmental exposure).
Dichlorobenzonitrile and dichlorvos are both commonly used herbicides
and insecticides in urban areas due to their effective herbicidal and
insecticidal properties, mainly used to maintain urban landscapes and
eliminate pests [14,54]. Biphenyl was an important industrial raw ma­
terial, and a byproduct of the combustion of many fossil fuels [22,23].
Diphenylamine was widely used in the synthesis of antioxidants,
commonly found in plastics and rubber [10,55]. All the triazole fungi­
cides in CSF were clustered as a group, indicating that these substances
have a common source. Triazole fungicides were widely used in fruits
and wheat production in China. Studies have shown that residues of
triazole fungicides can be detected in more than 50% of fruit samples in
China [8]. These results suggest that triazole fungicides in CSF may arise
from food residues.
3.3. Estimated daily intake (EDI) and risk assessment
Results of the EDI calculation were presented in Table 4. It is
important to note that our EDI results are estimates as several assump­
tions were included in the calculation.
The EDI of HCB (0.032 mg/kg bw) and HCH (total: 0.051 mg/kg bw)
were higher than ADI due to its low FUE (2% for HCB, 2.7% for α-HCH,
12.3% for β-HCH). The EDI of dichlorvos (0.031 mg/kg bw for males,
0.024 mg/kg bw for females) was also higher than ADI, which was
mainly due to the relatively higher concentrations in urine (0.40 ng/
mL). The HQ for HCB, α-HCH, β-HCH and dichlorvos were 53.3, 8.80,
1.40, 7.75, respectively. The results showed that the risk from HCB was
greater than the other pesticides analyzed.
The results of ranking of pesticides according risk were listed in
Table 5. The pesticide with the highest score was HCB, followed by

Fig. 3. Correlation and cluster analysis of pesticides detected in serum and cerebrospinal fluid. The clustering method is Pearson correlation.

7
K.-X. Zhao et al. Journal of Hazardous Materials 449 (2023) 131002

Table 4
Estimated Daily Intakes of pesticides based on measured urinary concentrations in an urban population.
Pesticides FUE（%） Reference EDI ADI HQ Reference
(FUE) mg/kg bw mg/kg bw (ADI)
dichlorobenzonitrile 50.76 Wit, Van Genderen ($year$) [49] 0.004 0.01 0.40 JMPR2014
HCB 2 Yang et al., ($year$) [51] 0.032 * 0.0006 53.33 * JMPR1974
chloroneb — — — 0.02 — JMPR2009
PCNB 8.6（62） Tofigueras et al., ($year$) [44] 0.01（0.001） 0.01 1（0.10） JMPR1970
p,p′ -DDE — — — — — —
α-HCH 2.7 Noack et al., ($year$) [36] 0.044 * 0.005 8.80 * JMPR2002
β-HCH 12.32 Lay et al., ($year$) [24] 0.007 0.005 1.40 * JMPR2002
δ-HCH — — — 0.005 — JMPR2002
dichlorvos 27.4 (35) Hutson, Hoadley ($year$) [18] 0.031（0.024）* 0.004 7.75（6）* JMPR2011
propoxur ＜16 Brouwer et al., ($year$) [2] 0.003 0.02 0.15 JMPR1996
acetochlor 16.6 Wester et al., ($year$) [48] 0.001 0.01 0.10 JMPR2015
biphenyl 75.8 Meyer et al., ($year$) [33] 0.047 0.125 0.38 JMPR1972
diphenylamine ＞90 JMPR2001 0.016 0.08 0.20 JMPR2001

The FUE values of some pesticides differed by sex. The data in parenthesis represents the female data. EDI data exceeding the ADI limit has been marked with * . FUE of
propoxur and diphenylamine were 16% and 90%, respectively. “—” means data were not available or not detected in urine.

Environmental implication
Table 5
Ranking of pesticides measured in CSF, urine and serum according to potential
As one of the guarantees of modern agriculture, pesticide’s harm to
for risk.
human has always been the focus of environmental research. Pesticide
Pesticides FCS FC/S FU/S FHQ FTOX F exposure has been shown to be associated with a variety of cancers.
dichlorobenzonitrile 0 0 -0.28 0.01 0.08 -0.19 However, there is a lack of research on the effects of pesticides on the
α-HCH 0 0 -0.33 0.12 0.06 -0.15 human central nervous system. Our study provides the exposure level of
propoxur 0 0 -0.06 0 0.06 0.01
pesticides in the nervous system of urban population for the first time,
PCNB 0 0 -0.03 0.01 0.04 0.02
δ-HCH 0 0 -0.02 0 0.06 0.04 which provides a solid foundation for subsequent relevant studies.
chloroneb 0 0 -0.01 0 0.10 0.09
acetochlor 0 0 -0.01 0 0.10 0.10 CRediT authorship contribution statement
dichlorvos 0 0 -0.05 0.10 0.06 0.11
diphenylamine 0.05 0.02 -0.05 0 0.08 0.11
β-HCH 0.01 0.24 -0.11 0.02 0.06 0.23
Ke-Xin Zhao: Writing – original draft, Data curation, Investigation.
p,p′ -DDE 0.01 0.41 0 0 0.06 0.48 Ming-Yan Zhang: Conceptualization, Methodology. Dan Yang:
biphenyl 0.88 0.04 -0.02 0.01 0.10 1.01 Conceptualization, Methodology. Rong-Shu Zhu: Investigation, Visu­
HCB 0.05 0.29 -0.04 0.74 0.10 1.14 alization. Zi-Feng Zhang: Resources, Supervision. Ying-Hua Hu:
Investigation, Resources. Kurunthachalam Kannan: Writing – review
biphenyl and p,p′ -DDE. The three pesticides had the highest risk mainly & editing.
because they were all found in CSF and had a low capacity for excretion
through urine. HCB was ranked highest because of its high HQ value. Declaration of Competing Interest
Biphenyl was ranked second due to its contribution to nearly half of total
exposure level in serum, urine and CSF. p,p′ -DDE appears to accumulate The authors declare that they have no known competing financial
in CSF. Although our study shows that the residual hazards of OCPs are interests or personal relationships that could have appeared to influence
still the highest, this does not mean that the other pesticides are safe for the work reported in this paper.
humans. In this study, we were unable to assess the risk of many pesti­
cides due to the absence of urine metabolism data. But as we found with Data availability
triazole fungicides, there are several large-scale used pesticides with
potential central nervous system hazards. For example, neonicotinoids, Data will be made available on request.
as a widely used pesticide, are widely found in the environment and
human body ([17,53]; Zhang et al.), but there is a lack of corresponding Acknowledgement
detection for the central nervous system. Although these pesticides were
detected in our study, due to the limitation of the study population, the This study was supported by open project of State Key Laboratory of
results of this study cannot be widely applied to other populations, Urban Water Resource and Environment, Harbin Institute of Technology
which should be the focus of further pesticide research. (No. ESK201702), the Fundamental Research Funds for the Central
Universities (No. 2022FRFK060013) and Fundamental Scientific
4. Conclusions Research funds for Heilongjiang Provincial Institutes, China (No.
CZKYF2021C006). This study was also partially supported by Hei­
Our results showed that 20 pesticides, including 8 OCPs, were longjiang Touyan Team and the Special Project for Sustainable Devel­
detected in serum, urine and CSF of an urban population in China. opment Science Technology in Shenzhen (No.
Biphenyl was dominant in serum, urine and CSF. OCPs detected in KCXFZ20201221173000001).
humans were mainly from the food chain accumulation, whereas
exposure to other pesticides was mainly from the environment. We Appendix A. Supporting information
found 6 triazole fungicides in CSF, none of which were found in the
serum of all participants, suggesting that these substances have special Supplementary data associated with this article can be found in the
properties that enable them to be enriched in CSF. Triazole fungicides online version at doi:10.1016/j.jhazmat.2023.131002.
are widely used in agriculture because of their low toxicity, but our
results raise a cause for concern.

8
K.-X. Zhao et al. Journal of Hazardous Materials 449 (2023) 131002

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