Characterizing the Exposome of Food Contamination and China Total Diet Study: Project for Improving Food Safety Risk Assessment in China

Exposure to Acrylamide in the Sixth Total Diet Study — China, 2016–2019 161 Exposure to Polybrominated Diphenyl Ethers in the Sixth Total Diet Study — China, 2016–2019 165 Exposure to Emerging and Legacy Polyfluoroalkyl Substances in the Sixth Total Diet Study — China, 2016–2019 168 Exposure to Chlorinated Paraffins in the Sixth Total Diet Study — China, 2016‒2019 172 Exposure to Lead and Cadmium in the Sixth Total Diet Study — China, 2016‒2019 176 Exposure to Bisphenolic Analogues in the Sixth Total Diet Study — China, 2016–2019 180 Exposure to Fipronil Insecticide in the Sixth Total Diet Study — China, 2016–2019 185 SIXTH TOTAL DIET STUDY ISSUE


Summary
What is already known about this topic? Acrylamide (AA) is toxic and potentially carcinogenic and could be formed during the cooking process. It is understood that almost all foods cooked at high temperature contain AA, especially fried foods. The exposure of AA in food threatens human health.

What is added by this report?
In the Sixth China Total Diet Study (TDS), AA was detected in 73.3% samples of the 12 food categories with the concentrations ranging from undetected to 176.90 μg/kg. The average dietary intake of AA was 0.175 μg/kg body weight per day and a significant decrease (45.1%) was observed compared with the Fifth China TDS. Among the 12 food categories, vegetables (59.0%), cereals (18.9%), and potatoes (10.1%) were the main contributors to AA exposure at 88.0%. What are the implications for public health practice? This study highlighted the need to continuously monitor dietary acrylamide exposure in China, including changing food processing methods and making reasonable selection of foodstuffs in the daily diet.
Acrylamide (AA) is widely used in dam and tunnel construction, paper manufacturing, the oil industry, cosmetics, and pharmaceuticals. It has been reported to be a rodent carcinogen (Group 2A) and a probable carcinogen to humans, possibly having toxic effects on the nervous system along with adverse reproductive and developmental effects. Although there is no limit standard for AA in food, relevant control measures have been implemented by several countries. In 2012, the China National Center for Food Safety Risk Assessment released the "Risk Assessment Report of Acrylamide in Food," which evaluated its toxicity, formation, and possible human exposure, and proposed suggestions for its control and prevention (1). Figure 1 showed the contributions of 12 food categories to the overall dietary exposure as analyzed in the Sixth Total Diet Study (TDS), the methodology of which was presented in the Foreword of this issue (2). Vegetables (59.0%) and cereals (18.9%) were the predominant contributors of AA intake, accounting for approximately 80% of the overall estimated dietary intake (EDI). In addition, potatoes were also an important source of AA exposure (10.1%).
Using mean EDI value (0.175 μg/kg body weight per day) with the no observed adverse effect level (NOAEL) value (0.2 mg/kg body weight per day), calculated margin of exposure (MOE) value was 1,142. This result indicates the MOE was well below 10,000. Following the conclusions of European Food Safety Authority (EFSA) committee, a potential human health risk should be concerned.

DISCUSSION
In this study, an up-to-date AA database of the Sixth TDS was established to estimate AA exposure for Chinese adults. We found that cereals and vegetables were 100% contaminated with AA, while water and beverages and alcohol beverages had the lowest contamination rates ( Table 1). The highest contamination level of AA was found in potatoes from Jiangxi (176.90 μg/kg), followed by the vegetables from Guizhou (154.85 μg/kg) and sugar from Hebei (129.31 μg/kg). Foods cooked at high temperatures (above 120 ℃) upon frying, roasting, and baking were found to produce large amounts of acrylamide, especially starchy foods such as potatoes. The mean concentration of potatoes was 17.74 μg/kg, which was only half of our last TDS (3). It was lower than the mean level of non-fried products of potatoes (108 μg/kg) in the report of EFSA (4), and also much lower than the mean level of potato snacks (554.5 μg/kg) in a survey conducted in the Republic of Korea (5). According to the commission regulation European Union (EU) 2017/2158, the AA benchmark levels of potato products (750 μg/kg), barley and ricebased products (150 μg/kg), roast coffee (400 μg/kg), and baby foods (40 μg/kg) were reported, which were above levels found in the Sixth TDS. Due to the differences in eating habits, cooking methods, heating temperature, and amount of amino acids and carbohydrates, the levels of AA in the same food category varied between different provincial-level administrative divisions (PLADs).
The main contributing food group based on the Sixth TDS results was vegetables, followed by cereals, potatoes, legumes and nuts, water and beverages and meat, which was consistent with the Fifth TDS results but different with other international studies. For instance, Japan's main contributor of AA exposure was beverages, followed by confectioneries, vegetables, potatoes and starches, and cereals (6). While for EU countries, the main contributors were potato fries, followed by bread, other potato products, biscuits, crackers and crispbreads, coffee, and other cereal products (7).
The dietary exposure to AA in the Third, Fourth, Fifth, and Sixth TDSs was 0.188, 0.286, 0.319, and 0.175 μg/kg body weight per day, respectively (2). The mean EDIs of AA for the previous 3 studies times showed a significant increasing trend, while a significant decrease of 45.1% (compared with the Fifth TDS) was observed in this study, and the values were the lowest since 2000. According to the 4 TDS results, vegetables were consistently the main contributor of AA intake, and the results were all relatively stable with more than 0.1 μg/kg body weight per day, followed by cereals, potatoes, and legumes ( Table 2). The EDI of cereals decreased significantly compared with the previous three times, resulting in the lowest mean dietary exposure to AA in the Sixth TDS. Furthermore, the EDIs of individual PLADs were compared between the Fourth, Fifth, and Sixth Chinese TDS (Figure 2). The EDIs varied in different PLADs, but fortunately, half of the PLADs' EDI values decreased to the lowest level from 2005 to 2019. For some areas, such as Heilongjiang, Hebei, and Hubei, the main contributors (cereals) decreased compared with the previous study, resulting in a dramatic drop of TDS in these PLADs. The value obtained in the current study was much lower than most international studies (3,6,8), which indicated that the national dietary exposure risk to AA is at a low level compared to the world.
The MOE approach was employed to estimate the risk of AA exposure by Joint Expert Committee for Food Additives (JECFA) in 2021. Based on the NOAEL value for morphological nerve changes (0.2 mg/kg body weight per day), the overall Chinese MOE of the Sixth TDS was 1,142. According to the conclusions of EFSA committee, an MOE value of 10,000 or higher would be of low public health concern. Hence, the current value (1,142) is far below 10,000, indicating a potential human health risk should be of concern for Chinese population. Notably, the MOE value for Guizhou was very low (191), which was lower than the value (310) reported by JECFA. Therefore, efforts should be made to reduce dietary exposure to AA, both by changing food processing methods and promoting healthy eating habits. However, there are several limitations of this study, 59 18. 9 10   Water and beverages 0.08 2.66 0.08 0.08 0.08 0.08 0.08 0.08 0.08 0.08 0.08 0.08 1.65 6.09 0.08 0.08 0.08 0.08 0.08 0.08 0.08 0.08 0.08 0.08 0.50 Alcohol beverages 0.08 0.08 0.08 1.13 1.73 0.08 6.29 8.10 0.08 0.08 0.08 1.36 0.08 4.88 0.08 0.08 5.88 0.08 0.08 0.08 6.29 0.08 0.08  such as food coverage, food processing method (temperature, time, etc.), uncertainties of consumption data, accuracy of detection method, and no assessment for different ages.
In the Sixth TDS, the mean EDI of AA for the Chinese population was 0.175 μg/kg body weight per day, which was lower than the values of the three previous TDSs and other international studies, indicating that measures implemented to reduce AA were effective from 2016 to 2019. However, the calculated MOE value was relatively low, still implying potential human health concerns. Vegetables, cereals, and potatoes were the 3 top predominant sources and accounted for 88% dietary exposure to AA. It is necessary to monitor continuously the AA exposure risk in the Chinese population. In the future, food processing methods and daily diet should be altered to reduce dietary exposure to acrylamide. H e i l o n g j i a n g L i a o n i n g H e b e i S h a n x i H u n a n N i n g x i a S h a n g h a i F u j i a n J i a n g x i H u b e i S i c h u a n G u a n g x i Polybrominated diphenyl ethers (PBDEs) are widely used in many industrial and commercial materials as a class of brominated flame retardants (BFRs), and its related exposure threatens human health (1). Certain PBDEs have been banned worldwide, and the congeners in commercial penta-BDE mixtures, octa-BDE mixtures, and deca-BDE mixtures -including BDE-47, -99, -153, -154, -175, -183, and -209were listed as persistent organic pollutants (POPs) by the Stockholm Convention (2)(3).
The details of the TDS are described in the Foreword of this issue (4), and the measurement of PBDEs was detailed elsewhere (5)(6). PBDEs were detectable in all samples. The concentrations of PBDEs varied greatly among various food groups as depicted in Table 1. The levels of ∑ 7 PBDEs, the summation of 7 PBDE congeners, were dominated by aquatic products with 39.85±33.46 pg/g fresh weight (mean±standard deviation), followed by meats and eggs with concentrations of 29.75±32.73 pg/g fresh weight and 22.19±31.96 pg/g fresh weight, respectively. Lower concentrations were observed in dairy products and other plant origin food samples (P<0.05), which was consistent with other studies (7). Dietary intake of ∑ 7 PBDEs for Chinese adults was 0.24±0.38 ng/kg body weight per day (mean±standard deviation) with a range of 0.02-1.96 ng/kg body weight per day, and the geometric mean was 0.13 ng/kg body weight per day. The dietary exposure varied greatly across all regions, as listed in Table 2. Adults from Zhejiang ingested the highest level of ∑ 7 PBDEs at 1.96 ng/kg body weight per day, followed by those in Inner Mongolia, Guangxi, and Fujian with a dietary intake of 0.39, 0.38, and 0.36 ng/kg body weight per day, respectively. Generally, the dietary exposure levels in southeastern and southern coastal regions with more industrialization were relatively high, while the levels in central and western regions with typical agriculture and animal husbandry such as Ningxia, Qinghai, Shaanxi, and Shanxi were relatively low. Risk assessment was conducted using the margin of exposure (MOE) approach, and in this study, a conservative estimate was applied, calculated through dividing the levels of Σ 7 PBDEs by bench marker dose lower confidence limit 10% (BMDL10) of BDE-47, -99, and -153, respectively, applied by the European Food Safety Authority (EFSA). The large MOEs ranging 1.0×10 3 -1.7×10 7 indicated a low health risk in China.

DISCUSSION
The dietary exposure levels of PBDEs varied widely among countries and regions, ranging from 0.93 ng/kg body weight per day in Latvia to 2.9 ng/kg body weight per day in the United Kingdom (Supplementary Table S1, available in http:// weekly.chinacdc.cn/). The dietary intake level in China was low in comparison to other countries in recent studies, which can be caused by differences in dietary study methods, the origin of samples, or dietary preference. For most regions, meat was the main source of dietary exposure to PBDEs, especially seafood (7). However, in China, the main food sources for PBDEs were meats, cereals, and vegetables contributing 24.4%, 23.4%, and 23.2%, followed by aquatic products contributing 12.7%. Plant foods including cereals, vegetables, potatoes, and legumes contributed 55.6%, as depicted in Supplementary Figure S1 (available in http://weekly.chinacdc.cn/). The range of MOEs was notably higher than the threshold reference recommended by the EFSA, indicating very low health risk concern in China. import, export, production, and use of pentaand octa-BDE (9). In addition, there were only two areas, Zhejiang and Inner Mongolia Autonomous Region, where the dietary intakes were increased, especially in Zhejiang where it increased by 243.2%. In view of the large increase, it is necessary to follow-up with increased monitoring in Zhejiang. And, a limitation of this study is not paying attention to the potential health risk of dietary PBDEs of special populations. Moreover, considering the diverse possibilities of exposure for PBDEs -ranging from dust ingestion to dermal absorption to dietary intake -further studies should be conducted to investigate the current burden of PBDE exposure in populations.
Based on the existing toxicological data, the current health risk caused by dietary exposure was still low. The dietary intake level decreased sharply compared with the Fourth and Fifth TDS, thus, continuous national monitoring is necessary to evaluate the time trends and support the legislation of POPs for China and from international conventions.
Acknowledgements: The 24 provincial-level CDCs.   H e b e i B e i j i n g J i l i n S h a n x i S h a a n x i H e n a n N i n g x i a I n n e r M o n g o l i a Q i n g h a i G a n s u S h a n g h a i F u j i a n J i a n g x i J i a n g s u Z h e j i a n g S h a n d o n g H u b e i S i c h u a n G u a n g x i H u n a n G u a n g d o n g G u i z h o u M e a n H e i l o n g j i a n g L i a o n i n g H e b e i B e i j i n g J i l i n S h a n x i S h a a n x i H e n a n N i n g x i a I n n e r M o n g o l i a Q i n g h a i G a n s u S h a n g h a i F u j i a n J i a n g x i J i a n g s u Z h e j i a n g S h a n d o n g H u b e i S i c h u a n G u a n g x i H u n a n G u a n g d o n g G u i z h o u M e a n

Summary
What is already known about this topic? Perfluoroalkyl substances (PFASs) are persistent organic pollutants, which have multi-organ toxicity and potential health risk to humans.
The PFASs levels in some food category and dietary exposure still need to be continuously monitored, especially for 6:2 Cl-PFESA.
Perfluoroalkyl substances (PFASs) are persistent organic pollutants, which are widely used in consumer and industrial products and can cause direct or indirect toxic effects on multiple organs (1-2). Due to the increasingly stringent controls on the production and use of perfluorooctanoic acid (PFOA) and perfluorooctanesulfonate (PFOS), plenty of alternatives are used. However, recent studies indicated that some alternatives may be more bio-accumulative or toxic than those legacy PFASs (3)(4). In order to investigate the latest dietary exposure of legacy and emerging contaminants for Chinese adults, composite food samples were collected from 24 provincial-level administrative divisions ( The sample preparation and instrumental analysis was described in detail in our previous studies (6-7). The concentrations below the limits of detection (LOD) were set to be LOD/2.
In the present study, PFHxA, PFHpS, PFNS, PFDS, PFDoS, 8:2 Cl-PFESA, and ADONA were not found in all food samples (n=216). The summary of detection frequency (DF) and concentration of detectable PFASs and alternatives in all food samples are shown in Supplementary Table S1 (available in https://weekly.chinacdc.cn/). The most commonly detected PFASs in all samples were PFOS, PFOA, PFUdA, PFDA, PFNA and 6:2 Cl-PFESA, the last of which was one of the contaminants of high concern in recent years. Generally, the DFs of perfluoroalkyl carboxylates (PFCAs) were higher than that of the PFSAs. Except for milk samples, the DF of PFASs in animal-origin food samples was much higher than that in vegetal-origin foods samples. None of PFASs and their alternatives were detected in the milk samples. Most of the PFASs were detected in aquatic food, especially for long chain PFCAs, PFOS, and its predominant alternative (6:2 Cl-PFESA) with 100% DF. Similar to the DF, the levels of PFASs in foods of animal-origin were much higher than those vegetalorigin foods samples. The estimated weekly intakes (EWIs) of PFOS, PFOA, and 6:2 Cl-PFESA in 24 PLADs were shown in Table 1 and Figure 1. The mean EWIs of PFOS and PFOA in the Sixth TDS accounted for 20.9% and 36.2% of the tolerable weekly intake (TWI) set by EFSA in 2018 (13 ng/kg body weight per week for PFOS and 6 ng/kg body weight per week for PFOA) (8). The average TWI of 6:2 Cl-PFESA was very close to PFOS.

DISCUSSION
In the present study, contamination of PFCAs was found commonly in aquatic food. Most of long chain PFCAs (C9-C14) were detected with higher DF and occurrence levels than those of PFOA in aquatic food samples. However, PFOA was still the predominant PFACs in other food groups both for DF and levels. By median, the highest PFOA level was found in the meats group, followed by aquatic food and eggs group. In the meats group, the PFOA level from Shandong was the highest, followed by Zhejiang. Moreover, for the levels of PFOA in aquatic food and eggs group, the highest two values were both from Beijing Municipality and Shandong Province, indicating more PFOA contamination in Shandong than in other PLADs involved in the Sixth China TDS. In vegetalorigin foods, PFOA was only detected in scattered samples with very low levels. Except for PFTeDA, other long chain PFCAs (PFNA, PFDA, PFUdA, PFDoA, and PFTrDA) were found in the meats group, eggs group, and aquatic food, but the DFs and levels of these PFCAs were significantly lower than those in aquatic food. In addition, main isomers of PFOA were analyzed in all food samples. However, br-PFOA was only found in the egg sample from Beijing Municipality with a contribution of 5.6% to total PFOA levels in that sample.
For PFSAs, unlike the case of PFCAs, only PFOS were commonly found in animal-original food. In general, the DF and level of PFOS was more than that of PFOA in aquatic food and egg groups, with the highest median concentration of 0.29 ng/g wet weight in aquatic food. The highest PFOS levels in aquatic food were found in Heilongjiang, which has been higher than the highest PFOS levels in aquatic food in the fourth and fifth TDS (3.47 ng/g wet weight and 1.65 ng/g wet weight, respectively) (9). Some coastal PLADs also showed higher pollution levels of PFOS, such as Shandong, Shanghai, and Jiangsu. In the eggs group, the highest PFOS was also detected in Heilongjiang, followed by Shaanxi and Sichuan. By median, PFOS level in meats group was lower than that in eggs group. In contrast to PFOA, br-PFOS were commonly detected in aquatic food, which accounted for 3.3%-21.2% of total PFOS. The proportions of br-PFOS to total PFOS were all much lower than that in the industrial products. These results may be related to the different bioaccumulation behavior of PFOS isomers in different animal species. Although PFBS, PFPeS, and PFHxS were rarely detected in the present study, PFPeS was found in some vegetable samples with a DF of 37.5%, which was similar to another study, in which short-chain compounds had been found to accumulate at high levels in leafy vegetables (10). This was the first time to determine the contamination of main alternatives of PFOA and PFOS in China TDS. 6:2 CL-PFESA, one of the important alternatives of PFOS in China, was detected in all aquatic food samples with the highest median level among all food groups. The highest 6:2 CL-PFESA in aquatic food samples was observed in Shanghai, which was close to the level of PFOS in that sample. Moreover, the level of 6:2 CL-PFESA in meats from Zhejiang was the highest value (3.74 ng/g wet weight) in all samples, which was also much higher than the level of PFOS (0.53 ng/g wet weight) in the same sample. The results indicated more attention should be paid to this emerging contaminant in food.
Unlike previous studies, the contribution of vegetalorigin food consumption to PFASs exposure was also considered in the Sixth Chinese Total Diet Study. Although the levels of PFOA in vegetal-origin food were much lower than those in animal-origin food, the high consumptions of vegetal-origin food led to their significant contribution to dietary exposure in some PLADs. As shown in Table 1, the highest EWI of PFOA was found in Beijing, followed by Shaanxi and Shandong. The EWIs of PFOA in Beijing and Shaanxi have exceeded the recommended value established by the EFSA in 2018. By average, eggs and meat group were the primary source of PFOA in China, which was different with the survey results in EU by EFSA, in which fish and other seafood were the most important contributors to PFOA. The highest EWI of PFOS was found in Heilongjiang, followed by Zhejiang and Hunan. Only the EWI of PFOS in Heilongjiang exceeded the recommended value established by EFSA in 2018. On average, aquatic food and meats group were the primary source of PFOS, which was similar to the fourth and fifth China TDS, as well as the survey results of EFSA.
The highest EWI of 6:2 Cl-PFESA was observed in Zhejiang, followed by Shanghai and Hunan. On average, the meats group was the main source of 6:2 Cl-PFESA. It should be noted that, although there is no health-based guide value for 6:2 Cl-PFESA, the EWI of 6:2 Cl-PFESA in Zhejiang has been almost 4 times higher than TWI of PFOS established by EFSA. Therefore, the potential health risk of 6:2 Cl-PFESA should not be ignored considering it might be the most bio-persistent PFAS (4).
In general, the present study indicated low health risks via dietary exposure of some PFASs for most of the population in China. However, the levels in food and dietary exposure of high concern PFASs still need to be continuously monitored, which was also an urgent step to address the gap for the corresponding food safety policy in China   Short-chain chlorinated paraffins (SCCPs) are persistent organic pollutants listed in the Stockholm Convention. Medium-chain chlorinated paraffins (MCCPs) structurally similar to SCCPs have similar toxicity. China is the largest producer and consumer of chlorinated paraffins (CPs) in the world. Dietary intake is considered the main route of human exposure to CPs (1).
The China National Center for Food Safety Risk Assessment launched the Sixth China Total Diet Study (TDS). The dietary survey methods, sample collection, and processing methods are referenced in the Foreword in this special issue (2). The concentrations of SCCP and MCCP in each food sample in the Sixth China TDS were 5-265 ng/g wet weight and 4-306 ng/g wet weight, respectively (Table 1). Among the 8 food categories, the highest average concentrations of SCCP and MCCP were found in meats at 63 ng/g wet weight and 70 ng/g wet weight, respectively. The average SCCP and MCCP concentrations in animal-origin foods were generally higher than those in plant-origin foods. A possible reason could be that SCCPs and MCCPs are compounds with high octanol-water partition coefficients and tend to accumulate in the fatty tissues of animals. The highest total concentrations of SCCP in eight food categories were detected in the provincial-level administrative divisions (PLADs) of Hebei, Henan, and Shanxi, while those of MCCP were found in Henan, Hebei, and Ningxia. Overall, the total concentrations of SCCP and MCCP from the eight food samples in the northern PLADs were higher than those in the southern PLADs in this study. The total estimated dietary intake (EDI) for SCCP and MCCP in eight food categories were listed in Table 2, which ranged from 270 to 2,844 ng/kg body weight per day (average: 1,041 ng/kg body weight per day) and 192 to 2,927 ng/kg body weight per day (average: 918 ng/kg body weight per day), respectively.

DISCUSSION
In this study, the average concentrations of SCCP in the eight food categories ranged from 27 ng/g in potatoes to 63 ng/g in meats. The average MCCP concentrations in the present study ranged from 18 ng/g in potatoes to 70 ng/g in meats. The average levels of SCCP from dairy products, meats, eggs, and cereals in this study were much lower than those found in the Republic of Korea, whereas the average levels of SCCP from vegetables in this study were higher than those found from vegetables in the Republic of Korea (15.1 ng/g wet weight) (3). However, the average CP levels in the eight food categories in China were considerably higher than those in southern Germany (4), Sweden (5), and Japan (6), which may be attributed to the higher production and use of CP in China. In general, dietary exposure to CPs in China was equal or higher than that of other studies in the world. A decrease in the production and use of CPs may be helpful to reduce human dietary exposure to CPs.

Chlorinated paraffins PLADs Cereals Vegetables Potatoes Legumes Eggs Dairy products Meats Aquatic foods Total
The highest EDI values of SCCP and MCCP in the present study were much lower than the tolerable daily intake proposed by the International Programme on Chemical Safety (100 μg/kg body weight per day) (10). The European Food Safety Authority margins of exposure for total SCCP and total MCCP in eight food categories were 2×10 3 and 4×10 4 (11), respectively, which were much higher than 1,000, indicating that SCCPs and MCCPs ingested from food may not pose a significant risk to human health in China. The EDI of SCCP and MCCP in cereals was the highest among eight food categories, but cereals did not have the highest concentration of SCCP and MCCP. This could be due to the dietary habits in China, where there was higher daily consumption of cereals than meats.
Some limitations of this study include how apparatus for the food sample collection and storage could had been contaminated by chlorinated paraffins and how the complexity of CP mixtures posed a challenge for analysts. Complete separation or purification of individual isomers or congeners was also difficult. Also, there was a lack of standard methods for analysis of chlorinated paraffins.
The dietary exposure and health risk assessment of CP in 8 food categories of 24 PLADs were investigated in this study. Levels of SCCP and MCCP in legumes, cereals, meats, and aquatic foods exhibited a decrease from the Fifth to the Sixth China TDS, except the increased concentrations of MCCP in meats. The ratio of MCCP to SCCP in the foods investigated in this study tended to increase. The estimated dietary exposure to CPs was lower than the threshold set in the current guidelines. Further studies need to be performed to evaluate the health risks through dietary exposure to CPs and the results would be helpful for the development of chlorinated paraffin regulations.

Summary
What is already known about this topic Lead (Pb) and cadmium (Cd) are widespread toxic heavy metal pollutants in the environment. Dietary intakes of Pb and Cd have been a major concern in the world.

What is added by this report?
The Lead (Pb) and cadmium (Cd) are heavy metal pollutants that are widespread in the environment. Pb mainly damages nervous systems and particularly impacts children's cognitive ability and intelligence. Cd causes damage to multiple body systems and was identified as a human carcinogen by the International Agency for Research on Cancer (1). The dietary intakes of Pb and Cd have always been a major concern in the world.
Since 1990, China has conducted six Total Diet Studies (TDSs) to evaluate the dietary intake of various chemical substances and to assess the related health risks among Chinese population. The samples of this study were collected from the Sixth China TDS during 2016−2019. The dietary survey methods, sample collection, and processing methods are referenced in the Foreword of this special issue (2). The health risks of Pb intake were assessed using the margin of exposure (MOE) approach and that of Cd intake was assessed based on the provisional tolerable monthly intake (PTMI).
The levels of Pb and Cd in the food samples were determined by inductively coupled plasma mass spectrometry (ICP-MS). The limit of detection (LOD) of Pb and Cd determination were 0.08 μg/kg and 0.05 μg/kg, respectively. Data below the LOD was processed using the methods recommended by the World Health Organization (WHO) (3).
The point estimate method was used to calculate the dietary intake of Pb and Cd and the contribution rate of various diets. In 2010, the provisional tolerable weekly intake (PTWI) value for Pb was withdrawn in the 73rd meeting of the Joint Food and Agriculture Organization of the United Nations (FAO)/WHO Expert Committee on Food Additives (JECFA). According to the evaluation results from JECFA, there is currently no health guidance threshold that can be established for Pb. A margin of exposure (MOE) approach was initially recommended by the European Food Safety Authority (EFSA) to assess the risk caused by substances that were both genotoxic and carcinogenic. For adults, Pb exposure of 1.2 μg/kg body weight per day will lead to an increase of 1 mmHg in systolic blood pressure (4). In this study, the benchmark dose level (BMDL 0.1 ) of 1.2 μg/kg body weight per day was used for calculation. When the MOE value was greater than one, it indicated that the health risk of the current intake level was acceptable. In terms of Cd, the PTWI value was replaced by PTMI value at the 73rd JECFA meeting because long-term Cd exposure poses a great threat to health and deserves more attention (5). Therefore, the health risk of dietary exposure to Cd was assessed based on the PTMI of 25 μg/kg body weight per month.
The mean dietary Pb intake for Chinese adult male was 0.318 μg/kg body weight per day, ranging from 0.103 μg/kg body weight per day to 0.746 μg/kg body weight per day in 24 PLADs. The mean Pb intake in northern regions and southern regions were 0.326 μg/kg body weight per day and 0.310 μg/kg body weight per day, respectively. Dietary intake of Pb from 12 food categories for adult males in 24 PLADs from the Sixth China TDS was shown in Figure 1. The top 3 dietary sources of Pb were cereals (43.5%), vegetables (29.0%), and beverages and water (9.8%). The MOE value for the dietary exposure to Pb among H e i l o n g j i a n g L i a o n i n g H e b e i B e i j i n g J i l i n S h a a n x i S h a n x i H e n a n N i n g x i a I n n e r M o n g o l i a Q i n g h a i G a n s u S h a n g h a i F u j i a n J i a n g s u J i a n g x i Z h e j i a n g S h a n d o n g H u b e i S i c h u a n G u a n g x i H u n a n G u a n g d o n g  adult male in 24 PLADs ranged from 1.6 to 11.7. The mean Cd intake for Chinese adult males was 8.26 μg/kg body weight per month (2.60-30.02 μg/kg body weight per month). The mean dietary Cd intakes in southern regions and northern regions were 11.96 μg/kg body weight per month and 4.55 μg/kg body weight per month, respectively. Figure 2 showed the dietary intake of Cd from 12 food categories in 24 PLADs from the Sixth China TDS. The main contributors to Cd intake were cereals and vegetables (56.3% and 26.6%, respectively). The national mean intake of Cd was 33.0% of the PTMI, and the dietary intake of Cd in 24 PLADs ranged between 10.4% and 120% of the PTMI. Only the Cd intake of adult males in Hunan Province (120% PTMI) exceeded the PTMI.

DISCUSSION
The levels of Pb and Cd in all the dietary samples in Sixth China TDS were lower than the China General Standard for Contaminants in Foods (GB 2762-2017). The dietary Pb intake levels were similar in northern and southern regions, but the sources of dietary Pb intake were different. The contribution of cereals to lead intake in the southern region were similar to that of vegetables (31% and 37.1%, respectively). While in the northern region, the contribution of cereals (50.6%) was higher than that of vegetables (19.7%). Although Pb level in beverages and water were low, but the consumption of beverages and water was large. As a result, the national mean contribution rate of beverages and water reached 9.8%. The estimated MOE values were all above 1 for adult males of 24 PLADs, indicating that the risk of dietary exposure to Pb among Chinese adult male was at a safe level.
The dietary Cd intake was significantly higher in the southern region (11.96 μg/kg body weight per month) than in the northern region (4.55 μg/kg body weight per month). There were three possible reasons: 1) the mean Cd levels in many foods were higher in the south than that in the north; 2) the consumption of vegetables was significantly higher in the southern region than that in the northern region (397.8 g/d vs. 297.3 g/d) and vegetables were one of the main sources of Cd intake; or 3) southern and northern regions had different dietary habits. Rice is the main staple food in the south while wheat flour is the main staple food in the north, and rice had higher levels of Cd than flour. PTMI H e i l o n g j i a n g L i a o n i n g H e b e i B e i j i n g J i l i n S h a a n x i S h a n x i H e n a n N i n g x i a I n n e r M o n g o l i a Q i n g h a i G a n s u S h a n g h a i F u j i a n J i a n g s u J i a n g x i Z h e j i a n g S h a n d o n g H u b e i S i c h u a n G u a n g x i H u n a n G u a n g  Figure S1 (available in https://weekly.chinacdc.cn/) shows that dietary Pb intake remained relatively stable during the first three TDSs, and gradually decreased during the latter three TDSs. The dietary Cd intake presented a slight increasing trend from the First TDS to the Fifth TDS, while a significant decrease of 47% (compared with the Fifth TDS) was observed in Sixth TDS. This was likely due to China's efforts in controlling environmental pollution during recent years. However, compared to other countries (Supplementary Table S1, available in https://weekly.chinacdc.cn/), Pb and Cd intakes remained at relatively high levels, which was concerning.
There were some limitations in this study. The current exposure assessment was conducted based on the consumption pattern of Chinese adults and did not involve that of infants and young children.
The present study revealed that the risks of dietary exposure to Pb and Cd among Chinese adult male were generally low, except for the risk of Cd exposure in Hunan Province. Since it is difficult to establish a safety threshold for Pb, JECFA recommended that countries should try to reduce Pb intake to as little as possible. It is necessary to continuously monitor the levels of Pb and Cd in foods to ensure the food safety and health of Chinese population. Bisphenol A (BPA) is used in the synthesis of commercial plastics, including polycarbonates and epoxy resins, which are incorporated into a wide variety of consumer goods. Exposure to BPA was suspected to result in a variety of toxicities in the neurological, reproductive, metabolic, and immune system (1). Considering these potential undesirable effects, European Food Safety Authority (EFSA) established a temporary tolerable daily intake (t-TDI) of 4 μg/kg body weight per day (2).

SUPPLEMENTARY
Abiding by the regulations on the production and restricted use of BPA in European Union, United States, China, and other countries, BPA in commercial products was gradually replaced by its analogues, such as bisphenol S (BPS), bisphenol F (BPF), bisphenol B (BPB), and bisphenol AF (BPAF). After being put into use, these bisphenolic compounds (BPs) were released into the environment and entered the food chain. A variety of foods (cereals, fruits, meats etc.) were found to contain BPS and other analogues. Studies have shown that the genotoxicity and estrogenic activity of these alternatives are like that of BPA (3)(4).
The primary source of exposure to BPA for most people is through the diet from contaminated foodstuffs (5). Dietary exposure of BPA from the Canadian Total Diet Study (TDS) was evaluated in view of BPs in composite food samples (6). In China, BPA from the Fourth China TDS (2007) samples as well as BPA and several analogues from the Fifth China TDS (2010-2012) were analyzed and the estimated daily intakes (EDI) of these BPs was safe for general people (7)(8). However, in past decades, China's sustained development and progress have affected the lives of every resident. Under this circumstance, food consumption and contamination levels might have changed remarkably since China's restriction of BPA in baby products and food contact materials implemented since 2011. The purpose of this study was to evaluate the Chinese daily exposure to BPs from the Sixth TDS (2016-2019) (9).
Levels of BPs in the Sixth China TDS were provided in Supplementary Tables S1-S4 (available in https:// weekly.chinacdc.cn/) and summarized in Table 1, where BPA was detected in 216 out of total 288 samples, with a concentration range of non-detected value (ND) to 20.0 μg/kg, among which the highest level occurred in cereals from Jiangsu Province. The mean concentrations of BPA from food categories ranged from 0.129 μg/kg (milk)-1.02 μg/kg (meat). BPS presented a rate of detection of 78.5%, accounting for 226 samples. The maximum level 67.1 μg/kg was attributed to a sample of meats from Fujian Province. While the second largest value is 16.6 μg/kg from a meat sample in Henan Province. BPF and BPAF were found in 8.33% and 27.1% of samples, with the maximum concentrations of 1.06 μg/kg and 1.75 μg/kg, respectively.
The EDIs of BPA, BPS, BPF, and BPAF for an average male adult are given in Figure 1. For BPA, the highest exposure was found in Henan (56.9 ng/kg body weight per day), while the lowest was found in Jilin (5.74 ng/kg body weight per day). Mean exposure to BPA was estimated to be 18.1 ng/kg body weight per day, significantly below the t-TDI (4 μg/kg body weight per day) recommended by the EFSA (2). The EDI of BPS in the Sixth TDS for an average Chinese male adult was 22.2 ng/kg body weight per day. Jiangsu (120 ng/kg body weight per day) and Fujian (114 ng/kg body weight per day) posed the two highest exposures in this TDS; while the exposure in Jilin residents (0.559 ng/kg body weight per day) was the lowest. BPF and BPAF presented dietary exposures of 0.485 ng/kg body weight per day and 0.384 ng/kg body weight per day, respectively. The contribution of different food categories to total EDI of BPs are shown in Figure 2. The main dietary contributors for BPA were cereals (40.3%), water and beverage (17.4%) as well as vegetables (13.7%). As for BPS, the dominant contribution food groups were cereals (31.4%), followed by meats (25.4%), legumes (11.7%), vegetables (11.7%) and water and beverages (8.76%). Legumes (41.2%), meats (20.7%), and fruits (11.7%) were the top three contributors of BPF. Exposure to BPAF was mainly from cereals (22.6%), aquatic foods (21.5%) and vegetables (21.2%).

DISCUSSION
In the Sixth China TDS, BPS posed a comparable rate of detection as BPA, demonstrating the wide use of BPS. Compared to BPA and BPS, BPF and BPAF appeared to possess evidently lower rates of detection and detection levels. Similar trends were found in the Fifth China TDS (8) and several other reports (10)(11).
Considering the similar endocrine disrupting properties and other toxicological effects of BPs, the exposure levels of BPA, BPS, BPF, and BPAF were summed up to assess the risks through dietary intake. The combined exposure levels (6.45-139 ng/kg body weight per day, Figure 1) were far below the t-TDI of BPA set by EFSA, which implied that the exposure to BPs for Chinese adults was safe.
BPs were concerning in past three China TDSs (Supplementary Table S5, available in https://weekly. chinacdc.cn/). The BPA exposure in the Fourth and Fifth TDS were 43.0 ng/kg body weight per day (7 and 217 ng/kg body weight per day (8), respectively. The increase of BPA exposure might be attributed to the feverish growth of China's BPA consumption from 2000 to 2014. The exposure to BPA in this study was significantly less than that in the Fifth TDS, which may be related to the measures and restrictions of BPA use in China. The exposures to BPS, BPF, and BPAF in the Sixth TDS were also lower than that in the Fifth one.
The most remarkable change was that the exposure to BPS exceeded BPA and became the most dominant BP in the Sixth TDS. In Fujian and Jiangsu, the only two provincial-level administrative divisions (PLADs) where BPs intakes were higher than 100 ng/kg body weight per day, BPS contributed more than 80% of the total BP exposure due to the high levels of BPS in meat from Fujian and cereals from Jiangsu.
It is noteworthy that Jilin implemented the "Restriction on Plastic Bags" from January 1, 2015, stipulating that the production and sale of nondegradable plastic shopping bags and plastic tableware were prohibited throughout the province. It has become China's first PLAD to fully ban "plastics". The EDIs of BPA and BPS in Jilin in this study were 5.74 ng/kg body weight per day and 0.559 ng/kg body weight per day, respectively, ranking lowest among the 24 PLADs. These values were lower by more than an order of magnitude than the results in the Fifth TDS (300 ng/kg body weight per day for BPA and 11.7 ng/kg body weight per day for BPS, respectively), indicating that the implementation of the restrictions affected the reduction of BPs contaminants.
The total dietary exposure to BPA in the Sixth China TDS (18.13 ng/kg body weight per day) was lower than that in France (42.4 ng/kg body weight per day) (12), Canada (52-81 ng/kg body weight per day) (6), the United States (44.6 ng/kg body weight per day) (11), and the EFSA (116-159 ng/kg body weight per day) (2). However, it was higher than that of a  recent survey in United States (6.0 ng/kg body weight per day) (13). The diversity in food consumption habits may be a potential reason for the relatively high BPA exposure to these Western countries. This study has several limitations. Only composite samples were analyzed for the dietary intake assessment of population in a given region, which could reveal realistic information by virtue of appropriate selection of the composite sample size and retesting of select individual samples. As for the samples with extremely high levels of contamination, the original individual samples can be assessed instead. The estimated BPs intake were based on a standard Chinese male adult (18-45 years). There was lack of the dietary exposure data of 0-18 years-old people in this study. Furthermore, young-aged people and pregnant women are prone to be vulnerable to the endocrine disrupting compounds. The chlorinated derivatives of BPA and BPS reported higher estrogenic activity and other potential toxicities. It is necessary to continuously monitor the dietary exposure of the various BPs, including the chlorinated derivatives.
This study investigated the contamination of BPs in composite food samples from the Sixth China TDS during 2016-2019. BPA and BPS were detected in more than 75% of the food samples. Dietary intakes of BPs for Chinese adults were below the t-TDI, and the major contribution was from cereals, water and beverages, meat, and vegetables. The exposure of BPS in the Sixth TDS exceeded that of BPA. This implies the need to strengthen the monitoring of BPs in foodstuffs.
Conflicts   The study results will help health managers understand the health risk of fipronil, and help to better formulate monitoring plans in foods. It is still necessary to strengthen the monitoring of fipronil in foods, especially animal-derived foods.
Fipronil was widely used as an insecticide to kill crop pests. However, the use of fipronil has been restricted in China since 2009 due to its high toxicity to bees and a variety of aquatic organisms (1-3). During 2016-2019, the Sixth China Total Diet Study (TDS) was conducted to study the contamination status and health risk of total fipronils (FIPs) among 24 provincial-level administrative divisions (PLADs) in China. Based on residual data in dietary samples and national consumption data, the average estimated daily intake (EDI) of total FIPs in Chinese adult populations was assessed and compared with acceptable daily intake (ADI) of fipronil as a health-based guide value. In this study, total FIPs were detected in varying degrees in the 12 dietary categories with a mean of 1.96 μg/kg. The average EDI of total FIPs in Chinese adult populations was 15.6 ng/kg body weight per day, accounting for 7.80% of the ADI (200 ng/kg body weight per day). The Sixth China TDS showed that the dietary intake of total FIPs in China was within acceptable level with low health risks. Monitoring of fipronil in food and taking corresponding measures can effectively reduce the health risk of low-level fipronil exposure.
In China, GB 2763-2021 stipulated that fipronil residue should be calculated as the sum of fipronil, fipronil desulfinyl, fipronil sulfone, and fipronil sulfide. Currently, fipronil is only used as an insecticide on a few crop seed coatings, household hygiene products, etc. However, improper or excessive use of fipronil still occurs, leading to its residue in the environment and food.
The details of the Sixth China TDS (2016-2019) are referenced from the Foreword of this issue (4). An ultra-sensitive analytical method to cover a majority of dietary sample matrices was used based on our previous study (5). The instrument parameters were described in Supplementary Table S1 (available in https:// weekly.chinacdc.cn/). In this study, the limits of detection (LOD) of fipronil and its metabolites in 12 dietary samples were all 0.001 μg/kg. Data and statistical analyses for residue levels and dietary exposure to total FIPs were performed using the GraphPad Prism (version 8.01, GraphPad Software, San Diego, CA) and SPSS (version 25.0, SPSS Inc, Chicago, IL, USA).
Residue data and detection frequencies for fipronil and its metabolites from the Sixth China TDS were shown in Table 1 and Supplementary Figure S1 (available in https://weekly.chinacdc.cn/). Among 288 dietary samples, the residue levels of total FIPs ranged from <LOD to 383 μg/kg with a mean of 1.96 μg/kg. The most frequently detected FIPs was fipronil sulfone with a detection frequency of 75.7%, followed by fipronil (60.1%), fipronil desulfinyl (47.2%), and fipronil sulfide (24.0%). According to the sample categories, egg samples from animal-derived foods showed the highest concentration of total FIPs with a    Figure 1A showed that eggs were the main dietary intake contributor of total FIPs for Chinese adult populations (55.3%), followed by vegetables (30.7%), meats (5.90%), cereals (5.30%), and other food categories contributed less than 2%.

DISCUSSION
This study reported the contamination levels of total FIPs in 24 PLADs in the Sixth China TDS, and analyzed the distribution characteristics of fipronil and its metabolites. As shown in Figure 1B, fipronil was found to be a major residue in plant-derived samples, followed by fipronil sulfone. However, fipronil sulfone became the major residue in animal-derived samples, and the parent compound fipronil was less distributed. Besides, fipronil desulfinyl demonstrated another major distribution contribution in dairy and aquatic products. In total, for products of plant origins, fipronil and fipronil sulfone were the main characteristic contaminants, while for products of animal origins, fipronil sulfone and fipronil desulfinyl were found at higher quantifiable levels of residues due to inconsistent metabolic modes of the parent compound in the body and the photolysis mode in the environment.
Due to an outbreak of fipronil egg contamination in Europe, egg samples were one of the key concerns of this study. Among the 12 dietary categories, no matter from the detection frequency and detection concentration in this study, the egg samples were the worst. The maximum residue limit (MRL) of total FIPs in eggs was set at 20 μg/kg in China. In this study, the average concentration level of eggs in 24 PLADs was 21.4 μg/kg, which exceeded the MRL in China. Details were shown in Supplementary Figure  S2 (available in https://weekly.chinacdc.cn/). In addition, considering that the egg samples in this study belonged to composite dietary samples, it means that some individual egg samples were likely to exceed the current MRL value. Compared with the results of the Fifth China TDS (6), as shown in Supplementary Figure S3 (available in https://weekly.chinacdc.cn/), an upward trend for residue levels of total FIPs was observed in Sixth China TDS. Especially for egg samples, a significant increasing trend was observed for residue levels in Gansu, Inner Mongolia, and Liaoning PLADs from the Fifth to Sixth TDS, which exceeded the MRL with concentration levels of 383 μg/kg, 52.9 μg/kg, and 42.8 μg/kg, respectively.
The Sixth TDS results demonstrated that the EDIs of total FIPs in China were within acceptable levels with low health risk. However, the EDIs of total FIPs in Gansu accounted for 68.0% of the ADI, which was worthy of more attention. Compared with the results from the Fifth TDS (6), the EDI of total FIPs in Chinese adult populations increased slightly in the Sixth TDS. Among them, the contribution rate of animal-derived dietary intake to total EDI was greatly increased. The contribution of eggs was significant, which was mainly related to the high detection levels in Gansu, Inner Mongolia, and Liaoning. In the Fifth TDS, total FIPs were basically detected at <1 μg/kg, and the highest detectable concentration level was less than 9 μg/kg, mainly from vegetables (6). However, in the Sixth TDS, the number of dietary samples for concentration level of >1 μg/kg samples increased, and most of them appeared in animal-derived food. Therefore, to prevent improper or excessive use of fipronil, it is necessary to strengthen the monitoring and traceability for different kinds of animal-derived food, especially eggs.
This study was subject to some limitations. First, the current exposure assessment was based on the consumption patterns of Chinese adults, but it was not involved in that for infants and young children, which required follow-up breast milk monitoring or more detailed dietary exposure assessment at different ages. Second, the current exposure assessment only reflected the average exposure level of adults, but did not cover some highly exposed population with high consumption.
In conclusion, some suggestions are put forward to reduce the health risks of low-level fipronil exposure: 1) strengthen the monitoring of total FIPs in food, especially for animal-derived foods, such as eggs; and 2) seek the source of fipronil exposure in diet and provide some reliable suggestions for policymakers. Notably, fipronil, as the main active ingredient of hygienic insecticide, is still widely used in indoor hygiene and seed protection according to the Chinese pesticide information website (7). Several studies reported that fipronil exposure to indoor dust and environmental water reached noticeable levels (8)(9)(10). Therefore, in addition to dietary exposure, other exposure pathways should be close monitored.