Assessment of Tetrabromobisphenol and Hexabromocyclododecanes exposure and risk characterization using occurrence data in foods

Journal Pre-proof Assessment of Tetrabromobisphenol and Hexabromocyclododecanes exposure and risk characterization using occurrence data in foods Joon-Goo Lee, Youngjin Jeong, Dongsul Kim, Gil-Jin Kang, Youngwon Kang PII:

S0278-6915(20)30008-9

DOI:

https://doi.org/10.1016/j.fct.2020.111121

Reference:

FCT 111121

To appear in:

Food and Chemical Toxicology

Received Date: 20 October 2019 Revised Date:

26 December 2019

Accepted Date: 6 January 2020

Please cite this article as: Lee, J.-G., Jeong, Y., Kim, D., Kang, G.-J., Kang, Y., Assessment of Tetrabromobisphenol and Hexabromocyclododecanes exposure and risk characterization using occurrence data in foods, Food and Chemical Toxicology (2020), doi: https://doi.org/10.1016/ j.fct.2020.111121. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Published by Elsevier Ltd.

Author contributions Joon-Goo Lee: Conceptualization, Data Curation Writing-Original Draft, Writingreview & Editing. Youngjin Jeong: Validation, Investigation. Dongsul Kim: Supervision. Gil-Jin Kang: Visualization, Formal analysis. Youngwon Kang: Methodology, Project administration.

Assessment of TBBPA and HBCDs exposure and risk characterization using occurrence data in foods. Joon-Goo Lee, Youngjin Jeong, Dongsul Kim, Gil-Jin Kang and Youngwon Kang*

Food Contaminants Division, Department of Food Safety Evaluation, National Institute of Food and Drug Safety Evaluation, Ministry of Food and Drug Safety, Osong-eup, Cheongwon-gun, Chungcheongbuk-do 363-700, South Korea

*Corresponding author Name: Youngwon Kang Phone: +82-43-719-4360 Fax: +82-43-719-4250 E-mail: [email protected]

Acknowledgement This research was supported by a grant (16161MFDS004) from Ministry of Food and Drug Safety in 2016.

Abbreviations 1

1

BFR, brominated flame retardant; BMDL, benchmark dose of lower confidence limit; DCM, dichloromethane; HBCD, hexabromocyclododecane; KNHANES, Korean National Health and Nutrition Examination Survey; LC-MS/MS, liquid chromatography tandem mass spectrometry; LB, lower-bounder; LOD, limit of detection; MOE, margin of exposure; POP, persistent organic pollutant; RSD, relative standard deviation; RSDr, repeatability; RSDR, reproducibility; TPPBA, tetrabromobisphenol A; UB, upper-bounder; WW, wet weight

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Abstract Tetrabromobisphenol A (TBBPA) and Hexabromocyclododecanes (HBCDs) are two of the most used BFRs and they have cumulated in the environment. TBBPA and HBCDs in food were determined and their risks were assessed. The analytical method used was validated in different food categories, and the performance parameters were acceptable based on the criteria of AOAC. Fish and cephalopods were contaminated with TBBPA higher than other foods, and fish contained higher levels of HBCDs than other foods. α-HBCD was the predominant diastereomer in fish and meat and had strong correlations with HBCDs in fish and cephalopods. HBCDs accumulated easier than TBBPA in food. People were exposed to TBBPA from 0.125 ng kg-1 b.w. day-1 to 0.284 ng kg-1 b.w. day-1 and HBCDs from 0.353 ng kg-1 b.w. day-1 to 1.006 ng kg-1 b.w. day-1 via food and air. Food mainly contributed to exposure to TBBPA and HBCDs

and vegetables were the main contributors for exposure to TBBPA

and HBCDs in food. MOEs for the whole population were over 100, and the risks of exposure to TBBPA and HBCDs from food and the environment were of low concern to public health.

Keywords: Tetrabromobisphenol A, Hexabromocyclododecane, Brominated flame retardants, Determination, Risk characterization, Persistent organic pollutants.

Assessment

of

Tetrabromobisphenol

Hexabromocyclododecanes

exposure

characterization using occurrence data in foods.

1

A and

and risk

1. Introduction Brominated flame retardants (BFRs) are chemicals that are synthetized to reduce the flammability of consumer products, and have been used significantly in the past few decades (de Wit, 2002). They decrease fire-related accidents but contaminate the environment (Barghi et al., 2017). BFRs have become widespread, and some were previously found in biotic samples in the Arctic(de Wit et al., 2010). Tetrabromobisphenol A (TPPBA) and hexabromocyclododecane (HBCD) are two of the most widely used BFRs (Darnerud, 2008). TBBPA is a brominated lipophilic chemical that binds to epoxy, vinyl esters, and polycarbonated resins (Ho et al, 2017). HBCDs are brominated lipophilic organic compounds consisting of α-HBCD (13%), β-HBCD (16%), and γ-HBCD (70%), among others (Goscinny et al., 2011). Law (2006) reported that 119,700 tons of TBBPA and 16,700 tons of HBCDs were produced and used globally in 2001 (Law et al., 2006). TBBPA has been used in electronics including computers and plastics and textiles in vehicles and aircrafts (Strack et al., 2007). HBCDs have also been used in electronics, textiles, and building materials and have been used in extruded and expanded polystyrene foams (Koch et al., 2015). TBBPA is carcinogenic to rodents, affecting cellular signalling pathways and levels of thyroid hormones (Strack et al., 2007; Lai et al., 2015). TBBPA is also regarded as an immunotoxin in mice and a nephrotoxin in new-born rats (Fukuda et al., 2004; Watabane et al., 2010). HBCDs are carcinogens in mice and cytotoxins that form reactive oxygen species (Haseman et al., 1984; Zhang et al., 2008). They are also toxins that affect reproductivity (Ema et al., 2008) and levels of thyroid hormone (Saegusa et al., 2009) in rats. TPPBA is lipophilic and highly persistent in the environment as it bio-accumulates easily (de Boer et al., 1998). HBCDs are highly lipophilic, bioaccumulating in fatty tissues. HBCDs are one class of persistent organic pollutant (POP) selected in the 6th meeting of the Stockholm Convention on POPs, because they are toxic and stable and can travel long distances (UNEP, 2013). TBBPA and HBCDs diffuse into the environment and are taken up by plants through water and air, among other sources, and they are transferred to animals through the food

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chain (Driffeild et al., 2008). Humans are finally exposed to these chemicals through consumption of contaminated plants and animals (Shi et al., 2009). POPs including BFRs are stable in the environment and not broken down; therefore, their contamination levels can be easilymonitored. Many studies have determined TBBPA and HBCD concentrations in the environment such as sea, sediment, and sea animal samples. Places near industrialised areas were found to be more contaminated by TBBPA and HBCDs (de Wit, 2002; Johnson-Restrepo et al., 2008; Harrad et al., 2009; Ramu et al., 2010; Gorga et al., 2013; Yang et al., 2014). Sea animals were also determined to be contaminated by TBBPA and HBCDs (Frederiksen et al., 2007; ten Dam et al., 2012). In 2008, humans were already exposed to TBBPA and HBCDs at similar concentrations to those in sea animals such as dolphins and sharks (Johnson-Restrepo et al., 2008). Further, TBBPA and HBCDs have been found in indoor dust for more than 10 years and were shown to have adverse effects on public health (Zhu et al., 2007; Abdallah et al., 2008; Takigami et al., 2009; den Eede et al., 2011; Barghi et al., 2017). Therefore, the presence of these molecules in the environment has been monitored worldwide, with the Global Monitoring Plan for POPs being one such global effort to monitor POPs in the environment under the Stockholm Convention (Magulova and Priceputu, 2016). However, there are not many studies that have determined TBBPA and HBCD concentrations in foods. Some have determined the content of HBCDs in fish and shellfish (Barghi et al., 2016;; EFSA 2011a; Goscinny et al., 2011; Hu et al., 2011; Schecter et al., 2010; Schecter et al., 2012; Shi et al., 2009), whereas a few have determined TBBPA concentrations in fish and human milks (EFSA 2011b; Shi et al., 2009; ten Dam et al., 2012). Therefore, monitoring of TBBPA and HBCDs in a variety of foods and examining their contamination trends should be perfomed to manage their risks. In this study, we determined the concentrations of TBBPA and HBCDs in different foods and the relationships between them were compared. The risks of exposure to TBBPA and HBCDs through dietary intake were also characterised.

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2. Materials and methods 2.1. Chemicals and materials Standard solutions of TBBPA, α-HBCD, β-HBCD, and γ-HBCD at 50 µg mL−1 in toluene and internal standard solutions of 13C12-labelled TBBPA, α-HBCD, β-HBCD, and γ-HBCD at 50 µg mL−1 in toluene were obtained from Wellington Laboratories (Guelph, ON, Canada). Standard solutions and internal standard solutions were diluted with methanol to obtain working standards at concentrations ranging from 0.5 to 250 ng g−1 wet weight (WW). and 50 ng g−1 WW, respectively. Dichloromethane (DCM), acetone, n-hexane, and methanol of dioxin, of analysis grade, were obtained from Wako Pure Chemical Industries Ltd. (Osaka, Japan). Sulfuric acid obtained from Wako Pure Chemical Industries Ltd. was PCB analysis grade. Sodium sulphate anhydrous and silica gel were purchased from Merk (MA, USA) and Supelco (PA, USA) and activated at 400 °C and 180 °C followed by desiccation. Deionised water was filtered using a Milli-Q System (Bedford, MA, USA).

2.2 Samples For this study, 115 samples from nine food categories were selected for analysis based on consumption amounts from the Korean National Health and Nutrition Examination Survey (KNHANES) (CDC, 2010) and these were purchased from Korean markets in 2016. The food categories and types analysed were as follows: vegetables (rice, Kimchi and brown rice); fish (pollack, anchovy, croaker, tuna, flounder, eel, hairtail, skate, Spanish mackerel, turbot, and cod); fish products (fish cakes and canned tunas); shellfish (manila clams, oysters, turban snails, scallops, and ark clams); meat (duck); meat products (sausages and hams); cephalopods (squid, small octopus, octopus, and short arm octopus); crustaceans (crab and shrimp). Ten samples of each food were purchased, except for oysters, which comprised 11 samples. All samples were grinded and divided into aliquots of 100 g, which was followed by sealing in plastic bags and storage in a freezer at −`20 °C.

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2.3 Sample preparation Samples of 10 g were weighed and extracted by accelerated solvent extraction (ASE-200, Dionex, USA) with a cell pressure of 1,500 psi, static time of 5 min, total flush volume of 60% and nitrogen purge time of 90–180 s at 90 °C. Hexane-acetone (1:1, v/v) was used for extraction. The extracts were dried with nitrogen until the weight is constant with only fat. Fat was loaded on a separate funnel packed with sodium sulphate anhydrous (5 g) and acid silica (30 g, 44%) and eluted with hexane-DCM(45:55, v/v) for 20 min. The eluate was dried with nitrogen to 100 µL for liquid chromatography tandem mass spectrometry (LC-MS/MS) analysis.

2.4 Determination of TBBPA and HBCDs by LC-MS/MS TBBPA and HBCDs were measured as described by ten Dam et al. with some modifications (ten Dam et al., 2012). TBBPA and HBCDs were determined using an LC (Thermo Finnigan Surveyor, Thermo, Waltham, MA, USA) with a tandem mass detector (Thermo TSQ Quantum Ultra, Thermo, Waltham, MA, USA) with an LC column, Symmetry® C18 column (150 mm × 2.1 mm, 3.5µm; Waters, Milford, MA, USA) and electrospray ionisation. Mobile phase A was water and mobile phase B was acetonitrile-methanol (3:7, v/v), both containing acetic acid at 0.01%. Mobile phase B at 50% in mobile phase A was used for 0.2 min, and this was increased to 85% for 1.0 min followed by an increased to 95% for 8.0 min. This was decreased to 50% for 8.1 min and held for 10 min. The flow rate was 300 µL min−1 and analytes of 10 µL were injected. Column temperature, MS source, vaporizer and capillary temperature were 25 °C, 250 °C, 300 °C and 320 °C, respectively. Collision-induced dissociation was conducted with 99.99999% argon gas and energies of 41 eV, 45 eV and 37 eV for TBBPA and 48 eV and 52 eV for HBCDs. Sheath gas and aux gas were used at 60 psi and 55 psi, respectively. MS were obtained with multi reaction monitoring mode a spray voltage of 4000 V. The channels for determining TBBPA were 542.6 → 290.9 (quantification), 542.6 → 80.7, and 542.6 → 79.0 and the channels for HBCDs were 640.7 → 80.7 (quantification) and 640.7→79.1. The internal standards for 13C12-labelled TBBPA and 13C12-labelled HBCDs were 554.7→296.8 (quantitative

5

ion), 554.7→80.7, and 554.7→79.0 and 652.6→81.2 (quantitative ion) and 652.6→79.0, respectively.

2.5 Method validation The analytical method was verified to assure the quality of data. Performance parameters such as specificity, detection limits, linearity, precision, and recovery were obtained. Rice, Spanish mackerel, oysters, duck, squid and shrimp were selected as representative samples for vegetables, fish, shellfish, meats, cephalopods and crustaceans, respectively. Some samples were analysed to find the procedural blank samples with no HBCDs or TBBPA to validate

the method. Specificity was obtained by isolating the standards from noise in a chromatograph of the samples fortified with standards and internal standards. Limits of detection (LODs) were statistically calculated from relative standard deviations of seven independent samples fortified with TBBPA and HBCDs at 0.25 ng g−1 by multiplying by 3.14. Calibration curves for TBBPA and HBCDs were obtained by regression equations of plots of eight standards in a range from 0.5 to 250 ng g−1WW. Their linearities were evaluated by calculating correlation coefficients (R2). Relative recoveries were obtained by fortifying the representative samples with TBBPA and HBCDs at 0.25, 1.25, and 5 ng g−1 WW and comparing their amounts to their measured amounts. Repeatability (RSDr) and reproducibility (RSDR) were calculated by the relative standard deviations (RSDs) acquired by analysing recovery test samples three times per day and over three consecutive days.

2.6 Exposure estimation and risk characterisation The TBBPA and HBCD concentrations in food and food consumption amounts were used to estimate exposure to TBBPA and HBCDs. The food consumption data were obtained from KNHANES. The concentrations of not detected (ND) samples were statistically replaced with the values recommended by the Global Environment Monitoring System-Food Contamination Monitoring and Assessment Programme (GEMS/Food-Euro, 1995). When the proportion of ND

6

samples was less than 60%, half of the LOD was used instead. When the proportion of ND samples was from 60% to 80% and the number of detected samples was > 25 or when the proportion was higher than 80%, the values were replaced with zero for the lower-bounder (LB) and with the LOD for the upper-bounder (UB). Total HBCD contents were estimated by summing α-HBCD, β-HBCD, and γ-HBCD concentrations. The daily dietary exposures to TBBPA and HBCDs were estimated by multiplying the concentration of TBBPA and HBCDs by the daily food consumption amount and dividing by the average body weight (Equation (1)). Daily dietary exposure (ng kg body weight (b.w.) −1 day-1) ng g Concentration of TBBPA and HBCDs g WW × daily consumption( ) day = average body weight (kg) (1) The benchmark dose of the lower confidence limit (BMDL) was used as a health-based guidance value for TBBPA and HBCDs. The BMDL10 was obtained by calculating the 95 % lower confidence limit of a dose showing a 10 % incidence response (Benford et al., 2010). There are no studies on the health effects associated with human exposure to TBBPA, and a BMDL10 of 16 mg kg b.w. −1 day−1 with respect to circulating thyroid hormone (T4) in rats was used as health based guidance value for TBBPA. A margin of exposure (MOE) approach was used because of the limitations and uncertainties associated with the toxicological data for the risk characterisation of TBBPA (EFSA, 2011b). European Food Safety Authority (EFSA) also set a BMDL10 of 0.003 mg kg b.w. −1 day−1 for effects on behaviour in mice as a health based guidance value for HBCDs. MOE was used for the risk characterisation of HBCDs (EFSA, 2011a). The MOE was calculated by dividing the BMDL10 by the estimated daily dietary exposure (Equation (2)). Margin Of Exposure =

ng BMDL+, ( ) kg b. w. day

ng The estimated daily dietary exposure ( ) kg b. w. day (2)

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When the MOE is greater than 100, the risks of exposure to TBBPA and HBCDs are of low concern. The value of 100 is a factor that covers the difference between animals and humans and between humans (EFSA, 2011a; EFSA, 2011b).

3. Results and discussion 3.1 Method validation The analytical method was evaluated by estimating the LOD, the linearity of the calibration curves, relative recovery, and precision (Table 1). The calibration curves of TBBPA and HBCDs showed good linear relationships between concentration and analysed results with correlation coefficients higher than 0.999 according to linear regression analysis. LODs for TBBPA and HBCDs were 0.004–0.021 ng g−1 WW and 0.002-0.048 ng g−1 WW, respectively. Rice had the highest LOD values for TBBPA and HBCDs. The relative recoveries of TBBPA and HBCDs in different foods at a spiking concentration of 0.25 ng g−1 WW were 98.03% – 116.38% and a range of 96.93 to 101.59%, respectively. Repeatability ranged from 0.05 to 9.09 % and reproducibility was from 0.48 to 5.99. All performance values were acceptable by the criteria of the Association of Official Analytical Chemists (Taverniers et al., 2004).

3.2. Occurrence of TBBPA and HBCDs in food 3.2.1. TBBPA in food The concentrations of TBBPA in selected foods were determined with the verified analytical method (Table 2). This compound was detected in all food samples except brown rice. TBBPA was present at lower concentrations than HBCDs even though it is the most used BFR (Law et al., 2006). Similarly, concentrations of TBBPA were lower than those of HBCDs in aquatic biota in another study (ten Dam et al., 2012). This could be because TBBPA has lower bioaccumulation potential and a higher rate of metabolism and elimination potential from organisms than HBCDs. Anchovy samples were contaminated with the highest average concentration of TBBPA among analysed foods, which was followed by sausages, octopus, and

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manila clams. Meat products were more contaminated with TBBPA than other foods with an average concentration of 0.049 ng g–1 WW, and fish and cephalopods contained TBBPA of 0.021 ng g–1 WW and 0.023 ng g–1 WW, respectively. BFRs including TBBPA eventually accumulate in the ocean (Covaci et al, 2006; Sun et al., 2014). Therefore, fish and cephalopods contain higher concentrations of TBBPA. Sausages also contained higher concentrations of TBBPA than other foods because sausage contains a high level of fat and TBBPA is strongly lipophilic and easily accumulates in fat. There are a few studies that have determined TBBPA concentrations in foods. EFSA (2011b) determined TBBPA concentrations in food and showed that fish and meat products also contained higher concentrations of TBBPA than other foods. The concentrations of TBBPA found by EFSA (2011b) in fish including other seafood and meat were 1.00 ng g–1 WW and 0.14 ng g–1 WW, respectively. These are higher than the concentrations in this study. 3.2.2. HBCDs in food Table 2 shows the concentrations of HBCDs in selected foods. HBCDs were detected in all food samples except canned tuna. β-HBCD of the three HBCD diastereomers was detected at the lowest concentrations in all foods. All foods except vegetables contained higher concentrations of α-HBCD than γ-HBCD. This is because α-HBCD is the predominant diastereomer in animal-based food categories and γ-HBCD is the main diastereomer in plantbased foods (Barghi et al., 2016). Fish contained HBCDs at 0.618 ng g−1 WW, which was higher than that in other foods, and shellfish and meat were contaminated with HBCDs at average concentrations of 0.174 ng g−1 WW and 0.120 ng g−1 WW, respectively. Spanish mackerel samples were contaminated with the highest average concentration of HBCDs at 2.705 ng g−1 WW among analysed foods, which was followed by flounders, anchovies, and eels. HBCDs also eventually accumulate in the ocean (Covaci, et al, 2006; Sun, et al., 2014). Therefore, fish and shellfish contain higher concentrations of HBCDs than other foods. Sausages and hams contain high levels of fat, and HBCDs are strongly lipophilic and easily accumulate in fat. The concentrations of HBCDs in foods in this study were lower than those in

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2012 to 2014 (Barghi et al., 2016) (Figure 1). Figure 2 shows the correlation between α-HBCD and total HBCDs and between γ-HBCD and total HBCDs in fish, shellfish, meat products and cephalopods. α-HBCD exhibited strong correlations with HBCDs in fish and cephalopods and weak correlations in shellfish and meat products. γ-HBCD did not show good correlations with HBCDs. Correlations in vegetables and crustaceans were not calculated because most of these samples did not contain HBCDs. Therefore, α-HBCD would be a good indicator of HBCDs in fish and cephalopods. HBCD contamination levels in food were higher than those of TBBPA, except for in octopus, shrimp, and crabs, even though TBBPA has been used more than HBCDs and the concentrations of TBBPA were previously reported to be higher than the concentrations of HBCDs in the environment (Harrad et al., 2009; Gorga et al., 2013). In some other studies, the concentrations of HBCDs were also higher than the concentrations of TBBPA in food (Driffield et al., 2008; Lopez et al., 2018). HBCDs, rather than TBBPA, easilyaccumulate in animals and plants.

3.3 Consumption of foods Food consumption data on the whole population were obtained from the second and third programs of KNHANES IV (2008~2009) with 9,308 sample populations and the first program of KNHANES V (2010) with 10,078 sample populations (Table 3). Koreans

consumed

significant amounts of rice, Kimchi, and fish products such as fish cake and squid, among others. Most food consumption amounts at the 95th percentile were zero, other than rick, Kimchi, fish cake, and brown rice, among others. This is because Koreans consume fish and other foods sometimes, but not frequently, whereas they consume rice, Kimchi and fish cakes frequently.

3.4 Exposure estimation The exposures to TBBPA and HBCDs by food intake were estimated by combining the concentrations of TBBPA and HBCDs and the food consumption data (Table 4). The whole population was exposed to TBBPA on average from 0.071 (LB) to 0.157 (UB) ng kg b.w.

−1

day−1 and to HBCDs from 0.268 (LB) to 0.812 (UB) ng kg b.w. −1 day-1. In terms of individuals,

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vegetables highly contributed to TBBPA exposure (81.7–88.5%), whereas fish and fish products (25%) at the LB and vegetables (76.0%) at the UB contributed to exposure to HBCDs. Vegetables are the main food group contributing to exposure to TBBPA and HBCDs even though vegetables are not contaminated by these compounds. This is because people consume significant amounts of rice and Kimchi. Fish and meat are normally considered to monitor TBBPA and HBCDs since these products contain high levels of fats. However, it is also very important to monitor TBBPA and HBCDs in vegetables due to their high contribution to the exposure to TBBPA and HBCDs. High (95th percentile) dietary exposure to TBBPA for the whole population was from 0.180 (LB) to 0.412 (UB) ng kg b.w. −1 day-1 and to HBCDs from 0.651 (LB) to 1.966 (UB) ng kg b.w. −1 day−1. The two most important pathways of exposure to TBBPA and HBCDs are food consumption and air inhalation (Abdallah et al., 2008). To estimate exposure to TBBPA and HBCDs via the air, we combined the concentration of contaminants in air and the inhalation rate (eq. 3) (EPA, 2015). ADD = Cair × InhR × ET × EF × ED/BW × AT (3) Where ADD = average daily dose (mg kg−1 day−1), Cair = concentration of contaminant in air (mg m−3), InhR = inhalation rate (m3 h−1), ET = exposure time (h day−1), EF = exposure frequency (days year−1), ED = exposure duration (years), BW = b ody weight (kg), AT = a verage time (days). Air in south-east Korea was found to be contaminated by HBCDs at 40.03 pg m−3 (Jo et al., 2017). There are no studies to determine TBBPA in air in Korea and the contents of TBBPA in the air in Japan were used. Air in Hokkaido was found to be contaminated by TBBPA at 7.1 to 9.5 pg m−3 (Takigami et al., 2009). The Japanese inhalation (breathing) rate of 17.3 m3 day−1 was also used (AIST, 2006). Based on these values, Koreans were exposed to HBCDs at 0.012 ng kg b.w. −1 day−1 and TBBPA at 0.002 to 0.003 ng kg b.w. −1 day−1 via air. In total, Koreans are exposed to TBBPA at a range from 0.073 ng kg b.w. −1 day−1 (LB) to 0.160 ng kg b.w. −1

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day−1 (UB), and to HBCDs from 0.280 ng kg b.w. -1 day-1 (LB) to 0.824 ng kg b.w. -1 day-1 (UB) via food and air. Food consumption is the key contributor to exposure to TBBPA and HBCDs.

3.5 Risk characterisation and uncertainty Table 5 shows the MOEs of TBBPA and HBCDs via food intake. All MOEs for the whole population were > 100, and the risks of TBBPA and HBCDs in consumed food are of low concern from a public health point of view. Furthermore, exposure to TBBPA and HBCDs by other routes including air were also > 100 and also of low concern from a public health point of view. Factors influencing the risk characterisation could be uncertainties of contents of TBBPA and HBCD contents in air and statistical bias caused by the left censored data. The food consumption data obtained from the 24-hour recall survey could also contribute to uncertainty in exposure estimation. The health guidance values characterised by oral ingestion could also cause an over-estimate of TBBPA and HBCD inhalation.

4. Conclusion TBBPA and HBCDs have been found ubiquitously in the last few decades since they were invented to reduce flammability and have been released into the environment. People have been exposed to TBBPA and HBCDs from the environment as well as through food intake. Therefore, it is necessary to characterise TBBPA and HBCD exposure from food and to assess their risk to human. In this study, an analytical method to simultaneously analyse TBBPA and HBCDs in different food categories was validated with acceptable linearity of calibration curves, LODs, LOQs, repeatability, reproducibility, and recovery. Fish and cephalopods contained higher concentrations of TBBPA, and fish was also highly contaminated with HBCDs. α-HBCD was the predominant diastereomer in fish and meat and had strong correlations with HBCDs in fish and cephalopods. According to the MOEs of TBBPA and HBCDs, the risks of TBBPA and HBCDs toxicity via food intake and environment uptake are of low concern. The MOE of HBCDs was found to be much lower than that of TBBPA, and risk managers should focus on

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controlling the risk of HBCDs rather than that of TBBPA in food. Future studies could focus on determining the concentrations of TBBPA and HBCDs in air.

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19

Table 1. Linear equations, limits of detections, recoveries and precisions obtained for TBBPA and HBCDs

BFRs

Linear equation

LOD Matrix

(ng/g wet weight)

0.25

RSD r a) (%) 1.25

5

0.25

RSD R b) (%) 1.25

(ng/g wet weight )

(ng/g wet weight )

(ng/g wet weight )

(ng/g wet weight )

(ng/g wet weight )

(ng/g wet weight )

(ng/g wet weight )

99.85

2.63

0.47

1.07

8.10

1.13

1.15

100.27 98.94 98.90 96.92 99.49

7.94 1.60 4.47 7.57 0.13

6.16 0.53 0.95 3.08 0.05

3.33 0.26 0.60 1.48 0.78

5.04 2.99 6.72 5.89 3.22

5.32 0.59 1.12 1.00 0.48

4.18 0.64 1.64 0.52 1.44

100.16

9.09

2.71

1.33

7.23

7.75

0.88

100.53 101.23 98.99 100.36 101.11

0.99 4.75 1.45 3.08 1.26

6.16 0.45 0.83 0.83 0.74

3.33 0.10 0.54 1.71 0.57

2.72 0.59 4.57 2.43 5.99

1.68 3.54 2.68 1.12 2.15

1.49 1.57 0.86 1.68 0.57

99.97

1.54

0.35

0.29

1.82

0.48

0.45

100.91 101.29 100.31 98.50 100.59

2.33 6.46 0.79 0.70 4.14

2.79 1.37 0.55 2.75 1.53

0.52 0.59 0.57 0.56 1.10

3.37 8.13 2.61 1.28 4.53

2.67 1.85 0.85 1.84 1.20

2.65 0.58 1.10 2.28 1.07

99.61

1.55

0.97

1.57

3.67

2.20

1.83

99.62 99.17 101.07 96.95 100.92

2.97 6.79 1.98 6.61 1.45

1.03 0.80 0.24 0.82 1.25

1.29 0.35 0.21 1.54 1.29

2.34 7.24 3.89 5.46 5.96

0.80 5.96 0.40 1.02 1.15

1.28 0.43 1.10 1.61 0.80

Relative recovery (%) 0.25 1.25 5 (ng/g wet weight)

(ng/g wet weight )

Spanish 0.010 101.18 100.70 mackerel Shrimp 0.004 100.57 98.84 = 0.00902331 Squid 0.017 99.60 98.09 TBBPA + 0.0832055 Oyster 0.004 98.03 98.25 (R2=0.9999) Duck 0.006 99.07 98.01 Rice 0.021 111.24 97.02 Spanish 0.014 107.01 100.65 mackerel Shrimp 0.007 100.84 100.06 = 0.0157639 αSquid 0.016 106.77 103.23 HBCD + 0.157319 Oyster 0.007 103.50 99.42 (R2=0.9997 Duck 0.018 107.07 99.55 Rice 0.043 111.47 100.24 Spanish 0.014 101.72 100.11 mackerel Shrimp 0.004 104.55 100.80 = 0.0152003 βSquid 0.014 104.00 99.09 HBCD + 0.0559638 Oyster 0.002 100.39 100.14 2 (R =0.9999) Duck 0.013 101.50 99.67 Rice 0.048 116.38 101.59 Spanish 0.017 103.85 101.19 mackerel Shrimp 0.008 107.27 98.88 = 0.0159373 γSquid 0.019 110.80 109.67 HBCD + 0.0620876 Oyster 0.005 102.67 100.32 (R2=0.9998 Duck 0.018 108.33 99.73 Rice 0.019 116.01 100.09 a) RSDr: Relative standard deviation of repeatability in single-lab. b) RSDR: Relative standard deviation of reproducibility in multi-lab.

5

Table 2. Concentrations of TBBPA and HBCDs in various foods

Food

n

TBBPA (ng g wet weight) -1

Mean Vegetables Rice Kimchi

a)

Range

10 10

0.015±0.025 0.006±0.019

N.D.∼0.069

Brown rice Fish Pollack Anchovy

10

N.D.

N.D.∼0.061 N.D.

10 10

0.015±0.023

N.D.∼0.068

0.078±0.368

Croaker Tuna Flounder Eel Hairtail Skate Spanish mackerel Turbot Cod Fish products Fish cake Canned tuna Shellfish Manila clam Oyster Turban snail Scallop Ark clam Meat

10 10 10 10 10 10

α-HBCD

β-HBCD

γ-HBCD

(ng g-1 wet weight) Mean Range

(ng g-1 wet weight) Mean Range

(ng g-1 wet weight) Mean Range

N.D. b) 0.025±0.079 N.D.

N.D. N.D.∼0.250 N.D.

N.D. N.D.

0.006±0.020 N.D.

N.D.∼0.062 N.D.

N.D.

N.D.

0.004±0.011

N.D.∼0.035

N.D.∼0.023

0.025±0.027 0.133±0.128

N.D.∼0.078

0.056±0.054 0.012±0.021 0.043±0.051 0.105±0.106 0.072±0.112 0.013±0.031

N.D.∼0.175 N.D.∼0.054 N.D.∼0.161 N.D.∼0.372 N.D.∼0.343 N.D.∼0.098

0.101∼0.933

0.015±0.035 0.809±0.836

0.275∼2.908

0.002±0.007 0.007±0.022

0.005±0.008 0.003±0.006 0.016±0.012 0.025±0.048 0.010±0.027 0.017±0.033 0.012±0.029

N.D.∼0.017 N.D.∼0.014 N.D.∼0.030 N.D.∼0.159 N.D.∼0.086 N.D.∼0.098

0.335±0.189 0.226±0.385 0.929±0.666 0.694±0.590 0.377±0.692 0.015±0.033

0.047∼0.749 N.D.∼0.917 N.D.∼2.297 0.037∼1.700 N.D.∼2.191 N.D.∼0.104

N.D. N.D. 0.006±0.014 0.017±0.032 0.004±0.008 0.002±0.006

N.D.∼0.068 N.D. N.D. N.D.∼0.040 N.D.∼0.098 N.D.∼0.019 N.D.∼0.018

N.D.∼0.092

2.417±2.678

0.079∼8.992

0.037±0037

N.D.∼0.105

0.251±0.171

0.021∼0.520

10 10

0.018±0.020 0.027±0.028

N.D.∼0.061 N.D.∼0.081

0.121±0.212 0.035±0.054

N.D.∼0.569 N.D.∼0.137

0.006±0.019 0.002±0.005

N.D.∼0.060 N.D.∼0.016

0.025±0.063 0.015±0.028

N.D.∼0.200 N.D.∼0.081

10 10

0.021±0.060 0.009±0.027

N.D.∼0.191 N.D.∼0.086

0.004±0.011 N.D.

N.D.∼0.036 N.D.

N.D. N.D.

N.D. N.D.

0.002±0.006 N.D.

N.D.∼0.019 N.D.

10 11 10 10 10

0.042±0.079

N.D.∼0.240

0.037∼0.174

0.008±0.012 0.011±0.012

N.D.∼0.032 N.D.∼0.031

0.066±0.071 0.099±0.045 0.005±0.007 0.043±0.025 0.058±0.100

0.009∼0.233

N.D.∼0.033 N.D.∼0.034

0.013±0.009 0.021±0.013 0.001±0.002 0.008±0.009 0.013±0.017

0.003∼0.034

0.017±0.011 0.005±0011

0.099±0.043 0.168±0.112 0.014±0.017 0.096±0.075 0.169±0.112

10

N.D.∼0.109

N.D. N.D.

0.030∼0.362 N.D.∼0.051 0.020∼0.214 0.073∼0.455

0.008∼0.051 N.D.∼0.005 N.D.∼0.031 0.004∼0.062

N.D.∼0.388

0.045∼0.190 N.D.∼0.022 0.011∼0.100 0.012∼0.341

Duck

10

Meat products Sausage 10 0.049±0.076 Ham 10 N.D. Cephalopod Squid 10 0.023±0.047 Small octopus 10 0.010±0.020 Octopus 10 0.044±0.098 Short arm 10 0.014±0.025 octopus Crustacea Shrimp 10 0.002±0.006 Crab 10 0.028±0.018 a) Mean : averages ± standard deviations b) Not Detected (N.D.) : Under LOD values.

N.D.∼0.026

0.052±0.082

N.D.∼0.252

N.D.

N.D.

0.055±0.155

N.D.∼0.493

N.D.∼0.238 N.D.

0.077±0.090 0.106±0.165

N.D.∼0.303 N.D.∼0.546

N.D. N.D.

N.D. N.D.

0.026±0.046 0.031±0.051

N.D.∼0.142 N.D.∼0.167

N.D.∼0.138 N.D.∼0.061 N.D.∼0.315

0.111±0.094 0.015±0.041 0.002±0.008

N.D.∼0.296 N.D.∼0.129 N.D.∼0.024

0.024±0.040 0.002±0.007 N.D.

N.D.∼0.111 N.D.∼0.021 N.D.

0.121±0.179 N.D. N.D.

N.D.∼0.567 N.D. N.D.

N.D.∼0.073

0.010±0.014

N.D.∼0.031

0.002±0.005

N.D.∼0.017

0.020±0.036

N.D.∼0.098

N.D.∼0.017 N.D.∼0.045

0.001±0.003 0.008±0.027

N.D.∼0.008 N.D.∼0.090

N.D. N.D.

N.D. N.D.

N.D. N.D.

N.D. N.D.

Table 3. Daily consumptions of food by whole population

Daily consumption(g day -1) Type

Food mean

P95 a)

Rice

179.784

364.715

Kimchi

114.124

372.029

Brown rice

3.952

22.967

Pollack

3.467

-

Anchovy

2.476

12.540

Croaker

2.354

-

Tuna

1.046

-

Flounder

1.361

-

Eel

1.090

-

Hairtail

1.270

-

Skate

0.792

-

Spanish mackerel

0.557

-

Turbot

1.270

-

Cod

0.522

-

Fish cake

6.829

35.910

Canned tuna

3.123

7.177

Manila clam

1.261

6.890

Oyster

1.348

-

Turban snail

0.267

-

Scallop

0.210

-

Ark Clam

0.242

-

Meat

Duck

2.516

-

Meat products

Sausage

3.159

-

Ham

4.596

33.572

Squid

6.044

33.557

Small octopus

1.239

-

Octopus

0.305

-

Short arm octopus

0.222

-

Shrimp

0.767

-

1.177

-

Vegetables

Fish

Fish products Shellfish

Cephalopod

Crustacea

Crab a) Daily intake of food at the 95th percentile

Table 4. Estimation of dietary exposure to TBBPA and HBCDs

Estimated Exposure (ng kg -1 b.w. day -1) Type

TBBPA

Food

HBCDs P95 a)

Mean

Vegetables

Fish

Shellfish

Rice Kimchi Brown rice Pollack Anchovy Croaker Tuna Flounder Eel Hairtail Skate Spanish mackerel Turbot Cod Fish cake Canned tuna Manila clam Oyster Turban snail Scallop Ark Clam

Mean

P95

LB b)

UB c)

LB

UB

LB

UB

LB

UB

0.046 0.012 0.000 0.001 0.003 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.002 0.000 0.001 0.000 0.000 0.000 0.000

0.090 0.048 0.001 0.001 0.003 0.000 0.000 0.000 0.001 0.000 0.000 0.000 0.000 0.000 0.003 0.001 0.001 0.000 0.000 0.000 0.000

0.092 0.039 0.000 0.017 0.013 0.001 0.005 -

0.182 0.156 0.008 0.017 0.017 0.002 0.006 -

0.018 0.049 0.000 0.002 0.040 0.016 0.004 0.023 0.015 0.010 0.000 0.026 0.003 0.000 0.001 0.000 0.004 0.007 0.000 0.001 0.001

0.353 0.256 0.008 0.004 0.013 0.016 0.005 0.023 0.015 0.010 0.001 0.026 0.004 0.001 0.006 0.002 0.004 0.007 0.000 0.001 0.001

0.037 0.159 0.002 0.203 0.003 0.000 0.021 -

0.716 0.835 0.044 0.065 0.029 0.006 0.021 -

Meat

Duck 0.000 Sausage 0.003 Ham 0.000 Cephalopod Squid 0.002 Small octopus 0.000 Octopus 0.000 Short arm octopus 0.000 Crustacea Shrimp 0.000 Crab 0.001 Food 0.071 Air (Takigami, Suzuki, Hirai & Sakai, 2009; 0.002 AIST, 2006; Jo, Son, Seo & chang, 2017) Total 0.073 th a) Daily intake of food at the 95 percentile

0.000 0.003 0.000 0.004 0.000 0.000 0.000 0.000 0.001 0.157

0.000 0.000 0.000 0.013 0.000 0.000 0.000 0.000 0.000 0.180

0.004 0.020 0.412

0.005 0.006 0.011 0.026 0.000 0.000 0.000 0.000 0.000 0.268

0.006 0.007 0.013 0.028 0.001 0.000 0.000 0.000 0.001 0.812

0.079 0.147 0.651

0.095 0.155 1.966

0.003

0.002

0.003

0.012

0.012

0.012

0.012

0.160

0.182

0.415

0.280

0.824

0.663

1.978

b) Lower bound : the left censored data are regarded as zero c) Upper bound : the left censored data are regarded as LOD

Table 5. Margin of Exposures (MOE) of TBBPA and HBCDs Margin of Exposure (MOE) HBCDs

TBBPA

Type

P95 a)

mean

mean

P95

LB

UB

LB

UB

LB

UB

LB

UB

Vegetable

2.8ｘ108

1.2ｘ108

1.2ｘ108

4.6ｘ107

4.5ｘ104

4.9ｘ103

1.5ｘ104

1.9ｘ103

Fish

2.7ｘ109

1.8ｘ109

5.2ｘ108

4.4ｘ108

2.1ｘ104

2.4ｘ104

1.5ｘ104

3.0ｘ104

Shellfish

1.6ｘ1010

1.6ｘ1010

3.2ｘ109

2.7ｘ109

2.3ｘ105

2.3ｘ105

1.4ｘ105

1.4ｘ105

Meat

5.3ｘ109

5.3ｘ109

-

4.0ｘ109

1.4ｘ105

1.2ｘ105

3.8ｘ104

3.2ｘ104

Cephalopod

8.0ｘ109

4.0ｘ109

1.2ｘ109

8.0ｘ108

1.2ｘ105

1.0ｘ105

2.0ｘ104

1.9ｘ104

Crustacea

3.2ｘ109

1.8ｘ109

6.2ｘ108

4.0ｘ108

5.8ｘ104

5.1ｘ104

1.0ｘ104

9.7ｘ103

Air

1.5ｘ106

1.0ｘ106

1.5ｘ106

1.0ｘ106

2.5ｘ105

2.5ｘ105

2.5ｘ105

2.5ｘ105

2.2ｘ108 1.0ｘ108 a) Daily intake of food at the 95th percentile

8.8ｘ107

3.9ｘ107

1.1ｘ104

3.6ｘ104

4.5ｘ103

1.5ｘ103

Total

(ng/g wet weight)

2012 to 2014

2.00

2016 1.60 1.20 0.80 0.40 0.00

1 2

Fig. 1. Comparison of levels of HBCDs in some foods between 2012 to 2014 and 2016.

3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 1

24 25

Fig. 2. Correlations between HBCDs and α-HBCD, γ-HBCD in foods; (a)fish, (b)shellfish, (c)meat

26

products, (d)cephalopod.

27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43

2

Highlights

A method to simultaneously analyse TBBPA and HBCDs in different foods was validated Fish and cephalopods were highly contaminated by TBBPA and HBCDs. HBCDs easily accumulate in food rather than TBBPA . Vegetables were the main contributors for exposure to TBBPA and HBCDs in food TBBPA and HBCDs in food and the environment are of low concern to public health.

Declaration of interests ☒ The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. ☐The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:

There are no conflict of interests