Associations between polychlorinated dibenzo-dioxins and polychlorinated dibenzo-furans exposure and oxidatively generated damage to DNA and lipid

Chemosphere 227 (2019) 237e246

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Associations between polychlorinated dibenzo-dioxins and polychlorinated dibenzo-furans exposure and oxidatively generated damage to DNA and lipid Zhuang Zhang a, b, Jintong He a, c, Tingming Shi d, Naijun Tang e, Sukun Zhang f, Sheng Wen d, Xiao Liu d, Ming Zhao a, Dongming Wang a, b, Weihong Chen a, b, * a

Department of Occupational and Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, and State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China c Zhuhai Center for Chronic Disease Control, Zhuhai, Guangdong, 519060, China d Hubei Provincial Key Laboratory for Applied Toxicology, Hubei Provincial Center for Disease Control and Prevention, Wuhan, Hubei, 430079, China e Department of Occupational and Environmental Health, School of Public Health, Tianjin Medical University, Tianjin, 300070, China f South China Institute of Environmental Sciences (SCIES), Ministry of Environmental Protection (MEP), Guangzhou, 510655, China b

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


PCDD/Fs levels were measured in both air and food samples.
Individual PCDD/Fs exposure of workers and residents was estimated.
Dose-response relationships between PCDD/Fs exposure and urinary 8oxodG and 8-iso-PGF2a levels were explored in foundry and incineration workers respectively.
PCDD/Fs exposure associated with oxidative stress levels in both smokers and nonsmokers.

a r t i c l e i n f o

a b s t r a c t

Article history: Received 2 January 2019 Received in revised form 8 April 2019 Accepted 8 April 2019 Available online 9 April 2019

Polychlorinated dibenzo-dioxins and polychlorinated dibenzo-furans (PCDD/Fs) have been reported to induce reactive oxygen species and oxidative stress, but the dose-response relationships have not been explored in molecular epidemiological studies. In this study, a total of 602 participants were recruited, comprising of 215 foundry workers, 171 incineration workers and 216 residents living more than 5 km away from the plants as the reference group. Individual PCDD/Fs exposures were estimated according to PCDD/Fs levels of working and living ambient air and daily foods. Urinary 8-oxo-7,8-dihydro-20 -deoxyguanosine (8-oxodG) and 8-iso-prostaglandin-F2a (8-isoPGF2a) were determined to reflect oxidatively generated damage to DNA and lipid. Generalized linear models were used to access the associations between PCDD/Fs exposure and oxidative stress biomarkers. We found that PCDD/Fs exposure and urinary oxidative stress biomarkers of workers were all higher than those of the reference group. Significantly positive exposure-response relationships between individual PCDD/Fs exposures and urinary 8-oxodG and 8-iso-PGF2a were found. Each 1-unit increase in ln-transformed levels of PCDD/Fs exposure generated a 0.78 nmol/mmol creatinine increase in ln-transformed 8-oxodG and a 0.50 ng/

Handling Editor: A. Gies

Keywords: Polychlorinated dibenzo-dioxins and polychlorinated dibenzo-furans Dioxins Foundry plant

* Corresponding author. Department of Occupational and Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China. E-mail address: [email protected] (W. Chen). https://doi.org/10.1016/j.chemosphere.2019.04.057 0045-6535/© 2019 Elsevier Ltd. All rights reserved.

238 Waste incineration Oxidative stress

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mmol creatinine increase in ln-transformed 8-isoPGF2a in foundry workers, a 0.49 nmol/mmol creatinine increase in ln-transformed 8-oxodG and a 0.26 ng/mmol creatinine increase in ln-transformed 8isoPGF2a in incineration workers, compared with the reference group. And such associations were not modified by tobacco use. Our findings could help to understand the dose-response relationships between PCDD/Fs and oxidatively generated damage to DNA and lipid, and provide an epidemiologic basis for conducting research on the carcinogenesis and other toxicity mechanisms of PCDD/Fs. © 2019 Elsevier Ltd. All rights reserved.

1. Introduction Polychlorinated dibenzo-dioxins and polychlorinated dibenzofurans (PCDD/Fs) are a group of chlorinated organic chemicals formed of two benzene rings bonded by oxygen atoms. The main sources of environmental PCDD/Fs are anthropogenic activities, especially industrial processes. Waste incineration, metal smelting and sintering plants in the steel industry, and chlorinated chemical manufacturing are thought to be the main industrial sources of PCDD/Fs all over the world (Anderson and Fisher, 2002; McKay, 2002; Quass et al., 2004; Aries et al., 2006; Kulkarni et al., 2008). In China, waste incineration and metal smelting account for over 60% of total PCDD/Fs emission (Lv et al., 2008). As well-known persistent organic pollutants (POPs), PCDD/Fs could exist in ambient air, water or soil for a long time, and will bioaccumulate in the human body through environmental exposure and food ingestion (Marinkovic et al., 2010). Food ingestion is reported to be the dominant way for PCDD/Fs to enter human body in general public (Kogevinas, 2001). In addition, for workers, exposure thorough inhalation of the relatively high levels PCDD/Fs in the workplaces (Li et al., 2015; Miniero et al., 2017; Sun et al., 2017) is also an important source that could not be ignored. The adverse health effects of PCDD/Fs exposure, including carcinogenicity, cardiovascular, endocrine, reproductive, nervous and immune system disruption (Pohjanvirta and Tuomisto, 1994; Kogevinas, 2001), make it an important public health problem worldwide. International Agency for Research on Cancer (IARC) has classified 2,3,7,8-Tetrachlorodibenzo-para-dioxin (TCDD), the most potent PCDD/Fs congener as a human carcinogen. The possible mechanisms by which PCDD/Fs induce health hazards may include excessive oxidative stress and oxidatively generated damage (Knerr and Schrenk, 2006; Lin et al., 2007; Pereira et al., 2013; Wan et al., 2014). The published literature reports that TCDD could induce oxidative stress in animal tissues such as rat liver and brain tissues (Hassoun et al., 2000) or mice testis (Jin et al., 2008) in vivo tests, as well as in cells such as rat hepatocytes (Aly and Domenech, 2009) and neuroblastoma cell line (Sul et al., 2009) in vitro experiments. Studies of TCDD induced oxidative stress on human cells are relatively fewer (Lin et al., 2007; Wan et al., 2014). A possible reason for this may be attributable to the low affinity of human aryl hydrocarbon receptor (AhR) (Ema et al., 1994), which make human tissues tend to be less sensitive to TCDD than their mice counterparts (Gassmann et al., 2010; Kovalova et al., 2017; Organtini et al., 2017). Moreover, PCDD/Fs often arise as a series of compounds in reality, rather than TCDD only. Therefore, the associations and exposureresponse relationships between PCDD/Fs and oxidative stress levels need to be better defined in epidemiologic studies. Urinary 8-oxo-7,8-dihydro-20 -deoxyguanosine (8-oxodG) is an abundant pre-mutagenic DNA lesion. Measurement of urinary 8oxodG can serve as a non-invasive, stable and quantitative assessment of oxidative stress (European Standards Committee on Urinary Lesion et al., 2010). As a series of prostaglandin F2a-like compounds produced by the free radicalecatalyzed peroxidation of

arachidonic acid independent of the cyclooxygenase, 8-iso-prostaglandin-F2a (8-isoPGF2a) is one of the most reliable marker of in vivo oxidative stress (Kadiiska et al., 2005; Milne et al., 2007). Considering that PCDD/Fs are mainly the byproducts of industrial process, workers in waste incineration and foundry industries are thought to be long-term exposed to high levels of PCDD/Fs. In the present study, a total of 386 workers of one municipal solid waste incinerator (MSWI) and one foundry plant and 216 reference controls without occupational exposure to PCDD/Fs in central China were recruited. Individual PCDD/Fs exposures were estimated through summing inhalation and daily diet intake of PCDD/Fs. Urinary 8-oxodG and 8-iso-PGF2a were measured to reflect the level of oxidative stress. The objectives of this study were to compare PCDD/Fs exposure from the ambient air and daily diet in workers and reference controls; and to evaluate the relationships between PCDD/Fs exposure and oxidatively generated damage to DNA and lipid. 2. Methods 2.1. Study population All staff in one MSWI and one foundry plant located in the Hubei province of central China were recruited for this study. Healthy residents who have never been occupationally exposed to PCDD/Fs and lived more than 5 km away from above plants were invited to participate as the reference controls. Participants who did not finish the questionnaire or had serious diseases in cardiovascular, respiratory or urinary system or tumor were excluded. Finally, 215 workers from the MSWI, 171 workers from the foundry plant, and 216 healthy residents as reference controls were included. Detailed information about demographic characteristics, history of diseases, occupational history, living habits and customs including tobacco use and alcohol drinking status of each participant were obtained from structured questionnaires through a face to face interview. With their written informed consent, all participants finished the physical examination and provided 20 mL fasting morning urine samples at the same day. Urine samples were stored at 20  C until laboratory examination. The research protocol was approved by the Ethics and Human Subject Committee of Tongji Medical College, Huazhong University of Science and Technology. 2.2. Sample collection According to the production process of the two plants, air sampling sites were set at the main worksites and residential areas. In the foundry plant, the sampling sites included the casting area, shakeout area, surface treatment area and administrative office. In MSWI, the sampling sites included the incineration boiler, outlet of the baghouse, central control room and administrative office. Four sampling sites were set in the residential areas of the two plants, three in the foundry plant, one in the MSWI, to reflect the PCDD/Fs level after work. A total of five sampling sites were set in the

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residential community of the participants in the reference group. Air sampling process was conducted according to the method reported by Wang et al. (2013). Briefly, samples were collected via high volume air samplers, with sampling flow rate as 0.238 m3,min1 for 24e72 h. The Glass fiber filters (GFF, 10.16 cm diameter) were used to collect particle-bound PCDD/Fs, and polyurethane foam (PUF, 6.3 cm diameter, 7.6 cm length) materials were used to absorb vapor-phase PCDD/Fs. Five types of foods including meat, eggs, milk, fish and vegetables were randomly purchased at various local markets near the plants or community of the reference group for PCDD/Fs determination. Each individual sample was sealed into a polyethylene bag after wrapped by aluminum foil and kept at 20  C, except that egg samples were kept at 4  C. 2.3. PCDD/Fs determination Samples were cleaned up according to the method adapted from US EPA Method 1613B (Agency, 1994), as Wang et al. reported (Wang et al., 2013). After being extracted with an n-hexanedichloromethane mixture (1:1) in a Soxhlet extractor for 24 h, a cocktail of 13C12-labeled extraction standards for PCDD/Fs was spiked in the samples before extraction. A multi-step clean-up process with multilayer silica columns, an alumina column and a florisil column was performed to remove the matrix and potential interfering components. The PCDD/Fs fraction was collected and concentrated with nitrogen flow. Then the samples were injected with 13C-labeled injection standards before mass analysis. The final volume was adjusted to 10 mL. Quantification of PCDD/Fs in the samples was performed by isotope dilution, high resolution capillary column gas chromatography (HRGC)/high resolution mass spectrometry (HRMS), referring to US EPA Method 1613B and the method Wen et al. reported (Wen et al., 2008). Exactly 1 mL of sample solution was injected in splitless mode. 2.4. Individual PCDD/Fs exposures estimation Individual PCDD/Fs exposures were estimated as the summation of inhalation and dietary intake. Inhalation exposure was estimated by the following equation derived from the research of Nouwen et al. (2001). PCDD/Fs inhalation in worksites and/or residential area were considered separately.

P2 Inh ¼

i¼1 ðfr

 Ci  Ti  Vri Þ W

(1)

In the above equation, Inh represents inhalation exposure of PCDD/Fs in pg TEQ/kg/day. The alveolar fraction retained in the lungs (f r) is 0.75. C1 and C2 are PCDD/Fs concentrations in the air of worksites and residential areas respectively, expressed in pg TEQ/ Nm3. TEQs are calculated by WHO-TEQ 2005 (Van den Berg et al., 2006). T1 and T2 represent time fraction during working and non-working hours respectively. For workers, T1 is collected by questionnaires, and T2 is (24- T1) h. For the reference controls, T1 is 0 h and T2 is 24 h Vr1 is ventilation rate at work in Nm3/h, derived from the research of Liu et al. (1990). Vr2 is ventilation rate after work in Nm3/h, derived from the research of Liu et al. (2016). W is body weight in kg. Dietary PCDD/Fs intake was estimated by multiplying PCDD/Fs levels in each kind of food and corresponding amount of food consumption by the following equation.

Pn Diet ¼

i¼1 ðCi

W

 Qi Þ

(2)

239

In the above equation, diet is the amount of dietary PCDD/Fs intake in pg TEQ/kg/day. Ci are PCDD/Fs concentrations in edible part of various food i expressed in pg TEQ/g wet weight. TEQs are calculated by WHO-TEQ 2005 (Van den Berg et al., 2006). Qi is daily consumption of food i expressed in g/day as Liu has reported before (Liu, 2012). W is body weight in kg. 2.5. Urinary oxidative stress biomarkers determination Determination of 8-oxodG was performed by HPLC following the method reported by Yuan et al. (Yuan et al., 2008). Briefly, after being centrifuged to remove precipitates, 1.5 mL urine was absorbed on preconditioned cartridges (Bond Elut LRC C18eOH, Angilent, USA) and successively eluted by 3 mL KH2PO4 (0.1 mol,L1, pH ¼ 6.0) and 3 mL 5% methanol, then pumped for 5 min, and finally eluted by pure methanol. Subsequently, the eluate was evaporated to remove methanol to be analyzed by a HPLC system with an electrochemical detector (Waters, USA). Determination of 8-iso-PGF2a was conducted by using commercial EIA kit (Cayman, USA), following the manufacturer's instructions. Urinary creatinine was measured by an automated chemistry analyzer using sarcosine oxidase method. Concentrations of 8-oxodG and 8-iso-PGF2a in urine determined by above methods were adjusted by urinary creatinine. 2.6. Quality control In the process of sample cleaning up, all vessels and instruments were rinsed by dichloromethane and hexane respectively prior to use. Field and laboratory blank samples covering whole analytical procedure were set in every batch of samples (7 or 11 samples one batch). Recovery of all 13C- labeled surrogates was within the range of 45%e110%, fulfilling the requirement in USEPA 1613B. PCDD/Fs in samples below limit of detection (LOD) were considered as half of LOD in subsequent calculation. Meanwhile, the laboratory is certified by China National Accreditation Service for Conformity Assessment (CNAS). 2.7. Statistical analysis Normally distributed variables were presented as mean and standard deviation and were compared using Student's t-test. Skewed distributed variables were presented as median and interquartile range and were compared by Wilcoxon rank sum test. Categorical variables were compared using Chi-square test. Associations between PCDD/Fs exposure and oxidative stress biomarkers were assessed by generalized linear models, considering PCDD/Fs exposure level as categorical variable or continuous variable, respectively. Urinary 8-oxodG, 8-iso-PGF2a concentrations and PCDD/Fs exposure levels were ln-transformed in the model due to their skewed distributions. Potential confounders including age, sex, body mass index (BMI), tobacco use and alcohol drinking status were adjusted in the models. Participants smoking at least one cigarette per day for more than half a year were defined as current smokers, and those who drink at least once per week for more than half a year were defined as current drinkers. Since tobacco use is reported to induce oxidative stress (Wooten et al., 2006), we further conducted stratified analyses to investigate whether tobacco use could modify the associations between PCDD/Fs exposure and oxidative stress. A two-sided p < 0.05 was defined as statistically significant for all analyses. All statistical analyses were conducted using SAS version 9.4 (SAS Institute, Cary, South Carolina).

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reference group contained 1,2,3,4,7,8-HxCDF and 2,3,4,7,8-PeCDF as the predominant congeners.

3. Results 3.1. General characteristics General characteristics, urinary 8-oxodG and 8-iso-PGF2a levels of the participants are listed in Table 1. The mean age of all 602 participants (433 men, 70.29%) was 38.41 years old. Urinary 8oxodG and 8-iso-PGF2a levels in the two exposed groups were significantly higher than those of the reference group.

3.2. PCDD/Fs levels and profiles of air and food samples PCDD/Fs levels in the air and food samples are shown in Fig. 1A and Fig. 1B, respectively. In general, PCDD/Fs levels in the MSWI were the highest. PCDD/Fs TEQ concentrations in the workplace air of MSWI ranged from 0.05 to 3.02 pg TEQ/Nm3. And the highest PCDD/Fs level was observed in the outlet of the baghouse (I5 in Fig. 1A), which was also the highest level among all sampling sites. PCDD/Fs concentrations in the workplace air of foundry plant ranged from 0.05 to 0.43 pg TEQ/Nm3, and the highest concentration was observed in surface treatment area (F7 in Fig. 1A). Average air PCDD/Fs concentrations in the residential areas of the MSWI, foundry plant and reference group were 1.70 pg TEQ/Nm3, 0.09 pg TEQ/Nm3 and 0.08 pg TEQ/Nm3 respectively. Residential area of the MSWI was very close (less than 50 m) to the workshops. As is shown in Fig. 1B, foods from the MSWI contained the highest PCDD/Fs TEQ levels on the whole. Average PCDD/Fs TEQ levels of five types of foods in the MSWI, the foundry plant and the reference group were 0.020 pg TEQ/g wet weight, 0.012 pg TEQ/g wet weight and 0.013 pg TEQ/g wet weight respectively. Among all kinds of food samples, the highest PCDD/Fs TEQ levels were observed in the poultry or fish samples and the lowest were observed in the vegetable samples. Fig. 2 demonstrates PCDD/Fs congener profiles in air samples. In the MSWI, OCDD and 1,2,3,4,6,7,8-HpCDD dominated PCDD/Fs concentration profiles, which contributed the most to total mass concentrations. In the foundry plant, 1,2,3,4,6,7,8-HpCDF, OCDF and OCDD were the predominant congeners. As for the reference group, no significantly predominant congeners were found in the air samples. PCDD/Fs TEQ congener profiles of the food samples are presented in Fig. 3. In general, OCDD dominated PCDD/Fs concentration profiles among the most food samples. In the two plants, meat and vegetable samples all contained OCDD as the most abundant congener. In the milk samples from the MSWI, OCDF was the greatest contributor to total concentrations. In the foundry plant, milk samples contained 1,2,3,4,7,8-HxCDF and 2,3,4,7,8-PeCDF as the predominant congeners, and egg samples contained 2,3,7,8TCDF and 1,2,3,6,7,8-HxCDD as the predominant ones. As for the reference group, OCDD was the main congener in fish, poultry, pork, egg and vegetable samples. Beef and milk samples from the

3.3. Individual PCDD/Fs exposures in different groups Estimated individual PCDD/Fs exposures by inhalation and dietary intake are shown in Table 2. PCDD/Fs exposure of incineration workers was the highest, followed by the foundry workers. PCDD/ Fs exposure of residents in the reference group was the lowest. Median of total PCDD/Fs exposure of the incineration workers was 515.15 fg TEQ/kg/day, over four times higher than foundry workers, six times higher than the reference group. Inhalation was the main source of PCDD/Fs for workers, and it contributed about 82% of the total exposure of incineration workers and about 59% of total exposure in foundry workers. PCDD/Fs exposure through diet accounted for over 76% among the total exposure of the reference group. 3.4. Associations between PCDD/Fs exposure and urinary 8-oxodG or 8-iso-PGF2a levels Table 3 presents the results that indicate associations between urinary 8-oxodG or 8-iso-PGF2a levels and PCDDD/Fs exposure which was analyzed as both continuous and categorical variables. In continuous analyses, each 1-unit increase in ln-transformed levels of PCDD/Fs exposure generated a 0.78 nmol/mmol creatinine increase in ln-transformed urinary 8-oxodG and a 0.50 ng/ mmol creatinine increase in ln-transformed urinary 8-iso-PGF2a (both p < 0.001) in foundry workers and the reference controls. Each 1-unit increase in ln-transformed levels of PCDD/Fs exposure generated a 0.49 nmol/mmol creatinine increase in ln-transformed urinary 8-oxodG and a 0.26 ng/mmol creatinine increase in lntransformed urinary 8-iso-PGF2a (both p < 0.001) in incineration workers and the reference controls. In categorical analyses, urinary concentrations of two oxidative stress biomarkers both monotonically increased with PCDD/Fs exposure tertiles in both the foundry workers and the incineration workers after adjusting for potential confounders. Compared with the reference controls, estimated changes of both two biomarkers in increasing tertiles of PCDD/Fs exposure also presented significantly increasing trends (p < 0.001) in both the foundry workers and the incineration workers. Since tobacco use has been reported to induce oxidative stress (Wooten et al., 2006), stratified analysis were further conducted by tobacco use (Fig. 4). In general, tobacco use did not modify the associations between PCDD/Fs exposure and the two urinary oxidative stress biomarker levels. Compared with the reference controls, both in the foundry workers and the incineration workers, a significantly increasing trend of estimated changes of both two biomarkers presented as PCDD/Fs exposure tertiles increased, in both smokers and nonsmokers (P < 0.01).

Table 1 General characteristics of participants in different groups. Variables

Reference group

Foundry plant

MSWI

No. of subjects Age (years, mean ± SD) Male sex, n (%) BMI (kg/m2, mean ± SD) Current smokers, n (%) Current drinkers, n (%) 8-oxodG (nmol/mmol creatinine, median (25%e75%)) 8-iso-PGF2a, (ng/mmol creatinine, median (25%e75%))

216 39.28 ± 7.80 136 (62.96) 24.43 ± 3.83 84 (38.89) 72 (33.33) 11.02 (5.00e21.12) 10.38 (6.84e17.68)

215 43.10 ± 6.07 a 158 (73.49) a 23.51 ± 2.94 a 101 (46.98) 99 (46.05) a 21.77 (14.01e45.03) 19.88 (12.88e36.39)

171 31.09 ± 8.80 a 133 (77.78) a 22.69 ± 3.28 a 61 (35.67) 58 (33.92) 25.04 (16.36e43.52) 16.59 (11.75e23.07)

a

Significant difference was found compared with the reference group.

a a

a a

Z. Zhang et al. / Chemosphere 227 (2019) 237e246

241

Fig. 1. PCDD/Fs concentrations of the air and food samples. (A) PCDD/Fs TEQ levels in the air samples. Air sampling sites description: The reference group: R1- R5 were the five sampling sites set in the residential community of the reference group. The foundry plant: F1-F3 were the three different sampling sites in the residential areas. F4 was in the administrative office, F5-F7 were in the casting area, shakeout area, and surface treatment area respectively. The MSWI: I1 were in the staff dormitory. I2 were in the administrative office. I3-I5 were in the central control room, beside the boiler and near the outlet of the baghouse respectively. (B) PCDD/Fs TEQ levels in food samples from the sampling sites.

Fig. 2. PCDD/Fs congener profiles in the air samples. (A) PCDD/Fs congener profiles in air samples from the residential community of reference group. (B) PCDD/Fs congener profiles in air samples from the foundry plant. (C) PCDD/Fs congener profiles in air samples from the MSWI. Descriptions of air sampling sites were the same as Fig. 1A.

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Fig. 3. PCDD/Fs congener profiles in the foods samples. (A) PCDD/Fs congener profiles in different types of foods bought from the residential community of the reference group. (B) PCDD/Fs congener profiles in different types of foods bought from the local markets near the foundry plant. (C) PCDD/Fs congener profiles in different types of foods bought from the local markets near the MSWI.

Table 2 Individual PCDD/Fs exposure levels (fg TEQ/kg/day) in the participants of different groups a. Exposure routes

Reference group

Foundry plant

MSWI

Inhalation of air Ingestion of food Total exposure

17.79 (13.39e21.52) 58.92 (30.38e71.70) 77.07 (44.23e93.08)

81.45 (56.9e140.72) 45.32 (39.44e52.78) 134.15 (102.46e189.98)

420.01 (234.03e571.80) 91.75 (66.92e113.97) 515.15 (306.95e668.71)

a

All values were median (25%e75%).

Table 3 Association between PCDD/Fs exposure and the oxidative stress biomarker levels in workers compared with the reference controls. Urinary oxidative stress biomarkers

Foundry workers 8-oxodG (nmol/mmol creatinine) 8-iso-PGF2a (ng/mmol creatinine) Incineration workers 8-oxodG (nmol/mmol creatinine) 8-iso-PGF2a (ng/mmol creatinine)

Estimated changes of urinary oxidative stress biomarkers (95% CI) by continuous PCDD/Fs exposure b

Concentration

b Concentration

a

a

b Concentration

b Concentration

b

a

a

\ 0.78 (0.61e0.94) \ 0.50 (0.35e0.64) \ 0.49 (0.38e0.60) \ 0.26 (0.18e0.35)

b

b

b

b

Estimated changes of urinary oxidative stress biomarkers by tertiles of PCDD/Fs exposure b (fg TEQ/kg/day) Reference group

T1

T2

T3

11.02 (5.00e21.12) 0 (reference) 10.38 (6.84e17.68) 0 (reference)

18.13 (11.86e30.71) 0.67 (0.41e0.92) 16.30 (12.16e31.99) 0.52 (0.30e0.74)

22.57 (13.98e37.82) 0.85 (0.60e1.10) 19.98 (13.11e33.61) 0.65 (0.43e0.87)

26.53 (16.21e53.09) 1.10 (0.84e1.37) 23.18 (14.24e41.99) 0.75 (0.53e0.98)

11.02 (5.00e21.12) 0 (reference) 10.38 (6.84e17.68) 0 (reference)

22.03 (16.15e44.18) 0.85 (0.56e1.14) 15.87 (12.12e22.53) 0.44 (0.20e0.68)

24.62 (16.77e40.13) 0.87 (0.56e1.18) 16.97 (11.89e21.89) 0.48 (0.23e0.73)

28.84 (16.80e46.80) 1.09 (0.78e1.40) 17.48 (11.60e25.02) 0.53 (0.28e0.79)

P value for trend

<0.001 <0.001

<0.001 <0.001

a

Values of urinary oxidative stress biomarkers were presented as median (25%e75%). b 95% CI of estimated changes by generalized linear regression, after adjustment for age, sex, bmi, smoking and alcohol drinking status. PCDD/Fs exposure and urinary oxidative stress biomarkers levels were ln-transformed.

4. Discussion In this study, we observed that PCDD/Fs levels in workplace air of the MSWI and the foundry plant were much higher than those of general residential community. PCDD/Fs levels in foods from markets near the MSWI were also higher than those from general residential community. After adjustment for potential confounders,

our findings provided strong evidence that individual PCDD/Fs exposure was significantly associated with increased urinary 8oxodG and 8-iso-PGF2a levels. Such associations were not modified by tobacco use. Accompanying the rapid industrial developments in recent decades, increasing attention has been paid to PCDD/Fs contamination. As commonly encountered persistent organic pollutants, even

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243

Fig. 4. Associations between PCDD/Fs exposure and urinary 8-oxodG and 8-iso-PGF2a concentrations in smokers and nonsmokers. The values of the y-axis represent the estimated regression coefficients and 95% confidence intervals, adjusting for age, sex, bmi, tobacco use and alcohol drinking status. Figure legends: Round spots represent standardized regression coefficients by tertiles of PCDD/Fs exposure in the foundry workers. Triangles represent standardized regression coefficients by tertiles of PCDD/Fs exposure in the incineration workers.

low dose of PCDD/Fs exposure can biomagnify and bioaccumulate in human bodies through long-term exposure, thus cause significantly negative effects that cannot be neglected. The underlying mechanisms for toxicity of PCDD/Fs remain unclear. Currently available laboratory data indicated that oxidative stress plays an important role in the carcinogenic potential and other adverse health effects of TCDD (Knerr and Schrenk, 2006; Pereira et al., 2013; Wan et al., 2014). However, epidemiologic studies on PCDD/Fs induced oxidative stress are relatively limited. And the exposure-response relationships need to be better defined. Associations between individual PCDD/Fs exposure and oxidatively generated damage to DNA and lipid found in the present study provided more epidemiological evidences to understand possible mechanisms or pathways for PCDD/Fs caused health effects. In the present study, PCDD/Fs levels of air samples from the MSWI workshop were the highest, except for the central control room. TEQ levels beside the boiler and near the outlet of the baghouse were slightly lower than that discharged from the incinerator of one MSWI in Korea (Oh et al., 2006), and much lower than TEQ levels in stack gas from MSWIs in Northern China (Zhu et al., 2018). Compared with PCDD/Fs concentration data in the ambient air near the MSWIs in the world, the atmospheric PCDD/Fs TEQ levels of the MSWI in the present study (represented by TEQ concentrations in the administrative office of 0.37 pg TEQ Nm3) were several times higher than that around MSWIs in Taiwan (Lee et al., 2004) and East China (Li et al., 2018), much higher than that in a MSWI in Spain (Rovira et al., 2018), but similar to those near the largest MSWI in China (Zhou et al., 2016), one MSWI in Shenzhen (Ben et al., 2017), and one MSWI in Korea (Oh et al., 2006). TEQ levels in the workshops of the foundry plant in the present study were similar to that in the steel plants in north (Li et al., 2015) and northeast China (Li et al., 2010). Atmospheric PCDD/Fs TEQ levels in the residential area of the foundry plant and the reference group were comparable to those of Taiwan (Lee et al., 2004), northeast

China (Li et al., 2010) and Italy (Colombo et al., 2013), and lower than that of Shanghai (Li et al., 2008), which is the most developed city in China. Food PCDD/Fs TEQ levels in the MSWI were also the highest. Pork, poultry and vegetable samples from the MSWI contained comparable or slightly lower PCDD/Fs TEQ levels than those of other provinces in China (Li et al., 2007; Zhang et al., 2015; Wang et al., 2017). PCDD/Fs TEQ levels of food samples from the foundry plant and the reference group were similar in general, and were lower than those of other provinces like Zhejiang and Guangdong (Shen et al., 2017; Wu et al., 2018). Relatively lower PCDD/Fs TEQ levels of the foods from Hubei in the present study can be explained by lower industrialization level of Hubei province than aforementioned province (Li et al., 2009). PCDD/Fs are lipophilic and will bioaccumulate in the food chains (Startin, 1994; Huwe, 2002). It has been reported that the general population are exposed to dioxins mostly through the foods they consume (Kiviranta et al., 2002, 2004; Bocio et al., 2007), which is consistent with our findings in the reference group. While for incineration and foundry workers, our data indicated that air inhalation at work was the main contributor for workers’ PCDD/Fs exposure. This was due to relatively higher PCDD/Fs concentrations in air of plants in the present study. Total exposure of workers was higher than general residents in the present study, which is consistent with previous studies (Li et al., 2010; Shen et al., 2017). To investigate PCDD/Fs induced oxidative stress on humans, a number of epidemiologic studies conducted among high PCDD/Fs exposed populations have observed elevated oxidative stress levels by determing some general markers, such as malondialdehyde in urine or plasma (Leem et al., 2003; Yoshida et al., 2003; Chen et al., 2006; Chia et al., 2008; Liu et al., 2008), DNA strand breakage (comet assay) (Kim et al., 2004b; Chia et al., 2008), erythrocyte malondialdehyde and glutathione (Chen et al., 2006), blood lipid peroxide and total urinary biopyrrins (Yoshida et al., 2003). But the

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exposure-response relationship has not been established. Urinary 8-oxodG, derived from oxidatively generated damage to 20 -deoxyguanosine, is the most widely measured biomarker for noninvasive assessment of DNA oxidation (Evans et al., 2010, 2016). Measurement of urinary 8- oxodG can offer a quantitative and specific biomarker reflecting systemic excretion of repaired oxidatively generated DNA damage (Kim et al., 2004a). Determination of 8-iso-PGF2a levels serves as a biomarker for lipid peroxidation, which has been shown to induce disturbance of membrane organization and functional loss and modification of proteins and nucleobases (Kadiiska et al., 2005; Milne et al., 2007; Niki, 2009). These two products can serve as reliable and specific biomarkers for oxidative stress to DNA and lipid. Several researches have reported that urinary 8-oxodG associates with PCDD/Fs exposure in electrical and electronic equipment dismantling workers (Wen et al., 2008) and MSWI workers (Yoshida et al., 2003). However, one study conducted among 73 workers from two secondary metal recovery plants in Taiwan did not find a significant difference of urinary 8-oxodG between workers ever joined the smelting work and workers never joined the smelting work (Chia et al., 2008). And serum dioxins levels are not associated with urinary 8-oxodG concentrations in 57 MSWI workers in Japan (Yoshida et al., 2006). The population sample size of above researches were all less than one hundred. Limited sample size and narrow exposure range may lead to the inconsistency. Nearly no published paper evaluated the effects of PCDD/Fs exposure on urinary 8-iso-PGF2a, expect one research found elevated urinary 8iso-PGF2a level in 11 TCDD-exposed patients compared with controls (Pelclova et al., 2011), whose findings were in agreement with ours. Our study estimated individual PCDD/Fs exposure from both air and diet in a relatively large population, found positive exposure-response associations between PCDD/Fs exposure and urinary 8-oxodG and 8-iso-PGF2a in both incineration and foundry workers, after adjusting for potential confounders. Once PCDD/Fs entered the body, AhR mediates their toxicity. AhR activation will induce gene expression related to cytochrome P450 1A1 and cytochrome P450 1A2 enzymes (Huff et al., 1994; Matsumura, 2003). During the monooxygenation reactions, oxygen activated by the input of electrons to P450 can be released from the enzyme and lead to ROS production (Zangar et al., 2004; Kopf and Walker, 2010). Besides, PCDD/Fs can disrupt mitochondrial transmembrane potential, alter calcium homeostasis, inhibit respiratory chain complexes II and IV activities, and decrease mitochondrial glutathione reductase activity, ultimately lead to mitochondrial dysfunction and ROS production (Senft et al., 2002; Aly and Domenech, 2009; Kennedy et al., 2013; Pereira et al., 2013). Elevated ROS will attack 20 -deoxyguanosine or lipids, generating oxidative stress biomarkers like 8-oxodG and 8-iso-PGF2a. There are some strengths and limitations in the present study. To the best of our knowledge, this study was conducted with a large sample size to evaluate the associations between PCDD/Fs exposure and oxidative stress level. Secondly, individual PCDD/Fs exposures were evaluated through air inhalation and daily diet by sampling and determination of PCDD/Fs in workplaces, living environments and five types of common foods. One limitation of this study was that we didn't calculate cumulative PCDD/Fs exposure for lack of previous sampling. In addition, other pollutants such as polycyclic aromatic hydrocarbons and metals may also induce oxidative stress. Therefore, future studies are needed to evaluate these other toxicants induced oxidative stress. In summary, we provided evidence that positive exposureresponse relationships exist between PCDD/Fs exposure and oxidatively generated damage to DNA and lipid in populationbased study, and tobacco use did not modify such association. Our findings would help explain the possible mechanisms or

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