The Association between Blood Concentrations of PCDD/DFs, DL-PCBs and Risk of Type 2 Diabetes Mellitus and Thyroid Cancer

The Association between Blood Concentrations of PCDD/DFs, DL-PCBs and Risk of Type 2 Diabetes Mellitus and Thyroid Cancer | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research The Association between Blood Concentrations of PCDD/DFs, DL-PCBs and Risk of Type 2 Diabetes Mellitus and Thyroid Cancer Su Hyun Lee, Joyce Mary Kim, Young Wook Lim, Youn Seok Kang, Keum Ji Jung, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-674870/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background and Objectives : Dioxin, classified as a human carcinogen by International Cancer Research Institute, shows inconsistent results on type 2 diabetes mellitus (T2DM) and cancer in epidemiological studies. International Cancer Research Institute classifies dioxin as a human carcinogen, but epidemiological studies of its effects on type 2 diabetes mellitus (T2DM) and cancer show inconsistent results. Therefore, we conducted a Korean population study to ascertain if the blood concentration of dioxin-like polychlorinated biphenyls (DL-PCBs) and polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/DFs) is associated with T2DM and thyroid cancer. Methods : Within a nested case-control study, we identified 15 people diagnosed with thyroid cancer, 30 people diagnosed with T2DM, and 55 for control. Due to the 4ml human blood requirement for PCDD/DF and DL-PCB concentrations tests, a total of 500 samples were used in 100 pooling samples. The continuous variable of a pooled sample was calculated as an average value taking into account the blood weight of each sample. The odds ratios (ORs) and 95% confidence interval (95% CI) for determining the association between total dioxins and risk of T2DM and thyroid cancer were estimated using the multivariable logistic regression. Results : The study population included 100 participants from the KCPS-II (median [IQR] baseline age, 54.06 [21.04] years; 48 women). The toxic equivalents of PCDD/DFs showed a significant positive association with T2DM and thyroid cancer, after adjustments for potential confounders (T2DM ORs = 1.23; 95% CI = 1.05-1.43; Thyroid cancer ORs = 1.34; 95% CI = 1.12-1.61). These results showed a stronger association in women than in men. Conclusion : In this study, both T2DM and thyroid cancer appear to be associated with the levels of PCDD/DFs serum. The association between T2DM and levels of PCDD/DFs serum is found in women and not in men. Our findings suggest that further biochemical in vivo research and epidemiologic studies are needed to clarify the nature of the association between dioxins concentrations and diseases. Environmental Policy Health Policy PCDD PCDFs Dioxin-like PCBs type 2 diabetes mellitus thyroid cancer epidemiology Figures Figure 1 Figure 2 Figure 3 Introduction Dioxins are a chemical compound consisting of 75 polychlorinated dibenzo-p-dioxin (PCDD) and 135 polychlorinated dibenzofurans (PCDFs) that occur most frequently during waste incineration processes and automobile emissions and cigarette smoke [ 1 – 4 ]. Polychlorinated dibenzo-p-dioxins, dibenzofurans (PCDD/DFs), and dioxin-like polychlorinated biphenyls (DL-PCBs) are persistent environmental pollutants (POPs), which are the compounds that accumulate in the environment and human body [ 5 , 6 ]. Dioxins are a new candidate for the risk factors of type 2 diabetes mellitus (T2DM). An epidemiological investigation of a group exposed to a relatively high concentration of dioxins due to an accident or occupation shows a significant relationship between the blood dioxins concentration and the onset of T2DM or death from T2DM [ 7 – 14 ]. However, the relationship between dioxins concentration in blood and T2DM identified in groups exposed to relatively high concentrations of dioxins due to accidents or occupations is not completely consistent [ 10 , 13 ]. In addition, studies on the association between dioxins and diabetes use estimate made using half-life in the dioxins body, so there is a problem with the accuracy of the exposure assessment, calling for caution when interpreting the results. Thus, in recent years, there have been studies on the association between low dioxins concentration, PCBs exposure, and T2DM in general environments, but due to the ethic of the Asian group, this is very rare [ 15 , 16 ]. In 1997, the International Agency for Research on Cancer classified TCDD as a human carcinogen (IARC, 1997). Among PCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is the most toxic to Ah-R, and molecular studies have shown that TCDD is a strong carcinogen that can disrupt various endocrine pathways in animals and humans [ 6 , 17 ]. However, the relationship between TCDD and cancer incidence or mortality tested by epidemiology studies was inconsistent [ 8 – 10 , 12 , 18 – 30 ]. Evidence of how it affects humans have long been controversial [ 31 ]. A meta-analysis of epidemiological studies on carcinogenicity was published in 2016, and both external exposure and blood level of TCDD were significantly associated with all cancer mortality, but no studies confirming the relationship with thyroid cancer were included in this study [ 32 ]. Most of the dioxins studies are animal-based experiments. The reason epidemiological studies that confirm the occurrence of human diseases are rare that about 4ml of whole blood is needed to measure dioxins in human blood [ 33 ]. In addition, it takes a long time to study cohort considering the context of dioxins exposure and disease development. Therefore, we pooled the amount of blood needed for dioxin analysis using the pooling method in large-scale cohort data and investigated whether the blood concentration of DL-PCB and PCDD/DF is associated with T2DM and thyroid cancer in the Korean population. Methods Study population This study was designed as a nested case-control study of 500 Koreans (men: 263, women: 237) selected from the Korean cancer prevention study-II (KCPS-II) (Supplementary Fig. 1). KCPS-II included 156,704 adults aged 20 to 84 who visited 18 health promotion centers nationwide from April 2004 to December 2013. A detailed description of the KCPS-II study design was published elsewhere [ 34 ]. In this study, the baseline period for the collected blood samples of participants was determined from January 2004 to December 2004. Due to the 4ml human blood requirement for dioxins tests [ 35 ], a blood sample was produced by combining 0.3 ml to 1.0 ml of the individual serum sample of five to nine participants. The subjects with disease samples were pooled with considerations for sex and age, and the control group sample was pooled with consideration of the sex, age and body mass index (BMI) of the disease group. A total of 500 samples were used in 100 pooling samples consisting of 30 cases of T2DM, 15 cases of thyroid cancer, and 55 for the control group. Measurements Sample Collection After 12 hours of fasting, serum and whole blood were collected from each participant and put into storage at -70ºC for future study. These samples were used for PCDD/DFs, DL-DCBs measurements, as well as other clinical chemistry parameters, such as fasting blood glucose, total cholesterol, triglyceride, HDL-C, and LDL-C. In compliance with the protocols of the Korean Organization of Laboratory Quality Management, the quality control of the clinical chemistry laboratory was maintained. Analysis of dioxins The analysis and quality control of 2,3,7,8-substituted PCDD/DFs and DL-PCBs in the pooled serum samples were performed with a slight modification of the Center for Disease Control and Prevention [ 36 ]. Before solid phase extraction, pooled serum samples were spiked 13C-labeled 2,3,7,8-substituted PCDD/DFs and DL-PCBs and were made to homogenization. Series of 20 samples were processed on manifolds. Formic acid and pure water were added to samples prior to extraction. SPE-C18 cartridges (octadecyl, 2g) were pre-conditioned using methanol and water. Each cartridge was dried and eluted with 15 mL of hexane, followed by the eluate was concentrated to 1mL. The eluate was applied to a multilayer silica gel column (44% sulfuric acid and 10% AgNo 3 silica gel) then eluted with 20mL of hexane. The final evaporation using a nitrogen concentrator (Eyela MGS 3100) was performed after addition of nonane as keeper. Quantification and identification of 2,3,7,8-substituted PCDD/DFs congeners and DL-PCBs were performed by high resolution gas chromatography (HRGC) (Thermo scientific Trace 1310)/high resolution mass spectrometry (HRMS) (Thermo Scientific DFS). The HRMS was operated in the electron impact mode and in the selected ion monitoring mode at a resolution R > 10,000 (10% valley). Separation was achieved using a HRGC instrument equipped with a DB-5MS (Agilent Technologies; 60 m length, 0.32 mm i.d., 0.25 µm film thickness) capillary column with a splitless and solvent-cut mode. The column ovens for DB5-MS was programmed from an initial temperature of 160℃ to a final temperature of 310℃ (total running time 60 min). Before quantitative analysis, 13C-labeled 1,2,3,4-TeCDD, 1,2,3,7,8,9-HxCDD, 3,3’,4,5’-TetraCB, 2,3,3’,5,5’-pentaCB and 2,3,3’,4,5,5’-hexaCB as internal standards were added for the estimation of recovery. Mean recovery of the spiked 13C-labeled 2,3,7,8-substituted PCDD/DFs and DL-PCBs in the entire analytical procedures were 75 ± 11% and 80 ± 25%, respectively. The levels were expressed in 2,3,7,8-TeCDD toxic equivalents using calculations of World Health Organization Toxic Equivalent Factors (WHO-TEFs) for PCDD/DFs and DL-PCBs. The definition of outcome (Diagnosis of thyroid cancer and T2DM) The incidence of thyroid cancer was collected from the registry of the National Cancer Center (NCC). And thyroid cancer code C73 of the 10th Amendment to the International Classification of Diseases (ICD-10) (WHO 2010) was used. The incidence of T2DM was identified from the National Health Insurance System (NHIS). Statistical analysis As POPs are mainly carried in the lipid portion of the blood, epidemiological studies have used lipid-adjusted concentrations (ng/g lipid) [ 37 ]. Concentrations adjusted for lipids (ng/g lipids) were determined using the formula proposed by Bernert et al (2007) [ 38 ]. The continuous variable of a pooled sample of 500 samples was calculated as an average value taking into account the blood weight of the configured sample. The average value considering the blood mass of the sample calculated by the PROC SURVEYSMEANS statement in SAS 9.4 was measured using the equation below: $$\text{A}\text{v}\text{e}\text{r}\text{a}\text{g}\text{e} \text{v}\text{a}\text{l}\text{u}\text{e} \text{c}\text{o}\text{n}\text{s}\text{i}\text{d}\text{e}\text{r}\text{i}\text{n}\text{g} \text{t}\text{h}\text{e} \text{w}\text{e}\text{i}\text{g}\text{h}\text{t} \text{o}\text{f} \text{b}\text{l}\text{o}\text{o}\text{d} \text{v}\text{o}\text{l}\text{u}\text{m}\text{e}= \sum \left(blood volume \times value\right)/\sum \left(blood volume\right)$$ We reported continuous variables as medians (± interquartile range; IQR) and categorical variables as proportions. We conducted the Kruskal-Wallis test to analyze between-group differences, as appropriate. Multiple logistic regression analyses were conducted to display the association between PCDD/DFs, DL-PCBs concentrations and thyroid cancer and T2DM. Additional sensitivity analyses were performed with the use of multivariable logistic regression adjusted for predefined baseline covariates. P values < 0.05 in the two-tailed test were considered significant. Statistical analyses were performed with the use of SAS software, version 9.4 (SAS Institute) and R software, version 4.1.2 (R Foundation for Statistical Computing). Results Study population and PCDD/DFs, DL-PCBs, and total dioxins in blood The characteristics of the study population are shown in Table 1 . Regarding the number of subjects according to disease group, the numbers for the non-disease group, T2DM, and thyroid cancer were 55, 30, and 15, respectively. Due to the study design, the participants were distributed almost equally according to sex, age, and BMI. The proportion of men and women were 48% and 52%, respectively, and the median value of age was 54.06 years (IQR = 21.04), and a median value of BMI was 24.28 kg/m 2 (IQR = 2.15). Table 1 Baseline characteristics of 500 who constructed 100 blood samples in the KCPS-II Characteristic Overall Control (n = 55) Type 2 Diabetes (n = 30) Thyroid Cancer (n = 15) P-value Sex N (%) 0.795 Male 48 (48.00) 27 (49.09) 15 (50.00) 6 (40.00) Female 52 (52.00) 28 (50.91) 15 (50.00) 9 (60.00) Median (IQR) Age, years 54.06 (21.04) 54.25 (20.57) 54.04 (22.14) 52.60 (19.20) 0.813 BMI, kg/m 2 24.28 (2.15) 24.31 (1.94) 24.36 (2.21) 24.20 (1.83) 0.619 FBS, mg/dl 92.88 (14.23) 89.42 ( 6.73) 135.73 (40.13) 92.88 ( 7.59) < 0.001 HDL-C, mg/dl 52.89 (9.57) 55.20 (12.23) 51.56 ( 6.70) 50.00 ( 5.23) 0.004 LDL-C, mg/dl 117.32 (26.32) 112.35 (27.29) 121.61 (22.17) 115.51 (18.99) 0.046 SBP, mmHg 123.71 (14.35) 121.81 (10.95) 129.50 (12.44) 116.25 (16.32) 0.005 TG, mg/dl 135.95 (66.38) 131.56 (61.10) 163.28 (67.74) 125.05 (45.32) 0.009 TSH, uIU/mL 1.66 (0.83) 1.66 (0.82) 1.64 (0.79) 1.69 (0.92) 0.659 IQR, interquartile range; BMI, body mass index; SBP, systolic blood pressure; FBS, fasting blood sugar; HDL-C, high-density lipoprotein-cholesterol; LDL-C, low-density lipoprotein-cholesterol; TG, triglyceride; TSH, thyroid stimulation hormone *p values from Kruskal-Wallis test and all variables are calculated by weighted blood volume Figure 1 presents the blood TEQ concentration of PCDD/DFs, DL-PCBs, and total dioxins. For the TEQ of DL_PCBs, the difference in exposure levels between groups was not statistically significant (P-value < 0.34). The median of the PCDD/DFs and total dioxins material was highest in the thyroid cancer group, and the difference in exposure levels between groups is statistically significant (both P-value < 0.01). Association between dioxins in blood and T2DM The multiple-adjusted associations between blood levels of dioxins and T2DM are presented in Fig. 2 . The PCDD/DFs TEQ and total dioxins, but not of DL-PCBs, showed significant associations with T2DM. The age and sex-adjusted ORs of T2DM and total dioxins were 1.14 (95% CI = 1.03–1.25). Stratifying analyses by sex showed positive orientation but were not statistically significant in men (men ORs = 1.20; 95% CI = 0.99–1.45, women ORs = 1.15; 95% CI = 1.01–1.31) However, since the results are not considered significant at the boundary of the 95% confidence interval, increasing the sample size can be statistically significant. To assess the possibility of confounding by BMI or systolic blood pressure or high-density lipoprotein, an analysis for T2DM was performed by additionally adjusting for the effects of these variables. In the adjusted models that include these variables (Model 2), the odds ratio for total dioxins was 1.20 (95% CI = 1.06–1.36). The results of Model 2 also showed statistically significant results only in the women group (men ORs = 1.16; 95% CI = 0.93–1.43, women ORs = 1.21; 95% CI = 1.02–1.45). Specifically, a 1-SD increase in 2378-TCDF level, is associated with a 71% increased risk of T2DM (ORs = 1.71; 95% CI = 1.0-2.91) (Supplementary Table 2). Association between dioxins in blood and thyroid cancer The multiple-adjusted associations between blood levels of dioxins and thyroid cancer are presented in Fig. 3 . TEQ of PCDD/DFs and total dioxins, but not of DL-PCBs, showed significant associations with thyroid cancer. The age, sex-adjusted ORs of thyroid cancer of total dioxins were 1.25 (95% CI = 1.10–1.42). Both men and women subgroup analyses showed positive orientation (men ORs = 1.31; 95% CI = 1.02–1.67), women ORs = 1.24; 95% CI = 1.04–1.48). To assess the possibility of confounding by TSH serum levels or body mass index, an analysis for thyroid cancer was performed by additionally adjusting for the effects of these variables. In the adjusted models, which include body mass index (Model 2) or TSH serum levels (Model 3), the odds ratio for total dioxins was 1.28 for both models (both models 95% CI = 1.10–1.48). The DL-PCB TEQ did not show a significant association with thyroid cancer. However, the 1-SD increase at 4CB-77 levels was associated with an increase in risk of thyroid cancer (OR = 1.92; 95% CI = 1.02–3.64) (Supplement Table 3). Discussion This study measured DL_PCB and PCDD/DF using pooled serum from general population. PCDD/DFs in blood showed a significant positive association with T2DM and thyroid cancer development, but no significant association with DL_PCB was observed. In 2016, International Agency for Research on Cancer (IARC) upgraded the classification of the PCBs to Category 1 carcinogenic to humans from the previous Category 2A classification on the basis of sufficient evidence of carcinogenicity in humans and animals [ 39 , 40 ]. However, no evidence of a relationship between PCB exposure and the risk of malignant melanoma has been identified in the latest meta-analysis [ 41 ], and reviews of epidemiological studies on PCB exposure and cancer risk were inconsistent for other cancers [ 42 ]. Our result that DL_PCBs are not associated with cancer is similar to that of recently reported studies [ 41 , 42 ]. Although previous studies have found an association between PCB levels and T2DM in women, our results are inconsistent with reports from other studies suggesting that PCBs are positively associated with T2DM in women. [ 43 , 44 ]. However, the PCBs used in previously reported studies are a combination of DL-PCBs and non-dioxin-PCBs. In this study, however, there was included only DL-PCBs. To the best of our knowledge, no case-control studies have yet been conducted to establish an association between dioxins and thyroid cancer. However, recent in vitro studies using immortal mouse cells have shown that TCDD exposure regulates the script of an endothelial carcinogen network thought to affect thyroid carcinoma [ 45 ]. TCDD can interfere with the activity and metabolism of thyroid hormones through various processes, including binding to protein transport of thyroid hormone [ 46 ], direct damage to the thyroid gland, and activation of thyroid metabolizing enzymes [ 47 ]. Previous reported epidemiological studies have found significantly increasing trends in mean TSH with TCDD category [ 48 ]. Having a high TSH level within the normal range is an independent risk factor for DTC, and may contribute to the initiation of thyroid carcinogenesis [ 49 , 50 ]. These mechanisms can support the association between blood PCDD/DFs and thyroid cancer risks identified in our study. Dioxins have been identified as endocrine disruptors of the environment, but epidemiology studies of their effect on diabetes found inconsistent results [ 7 , 11 , 18 , 51 ]. In particular, this association is found in women and not in men [ 12 , 44 ], which is similar to the results confirmed in our study. Several assumptions can explain this gender difference. First, men have lower levels of exposure and a higher prevalence of smoking, which stimulates the aryl hydrocarbon receptor related to the increased excretion of PCBs [ 52 ]. Second, women have a higher proportion of fat, resulting in these lipophilic compounds being stored longer. Third, women have higher estrogen levels and PCDFs. Certain PCBs can cause gene expression of CYP1A1 and CYP1B1 [ 53 , 54 ], which catalyze estradiol A-ring hydroxylation to from 4-hydroxyl estradiol of catechol estrogen that can produce free radicals. It is understood that free radicals induce elevated oxidative stress related to diabetes [ 54 ]. Despite the fact that the results are similar to those of previous studies, there are some limitations in our study. First, we were unable to control the confounding variables such as exercise habits, food consumption, alcohol status, smoking status, and socioeconomic status. In this study, several blood samples were used to make pooled samples. In the case of a continuous variable, the mean value of the characters constituting the sample was used. And categorical variables were not included in this study. However, we used BMI, which is strongly associated with physical activity patterns, waist circumference, and dietary consumption, and may thus be considered a proxy indicator for such variables. Second, as an exposure measure, we used a 1-time dioxins level measurement in the blood and did not have accumulated exposure dose information. However, we had the strength of measuring PCDD/DFs and DL-PCB concentrations directly within the Korean population to collect exposure data. Also, since the half-life of PCDD/Fs in the serum can last for seven years or longer [ 51 , 55 ] and over that duration, the causes of environmental exposure remained constant, we could conclude that the dioxins level in a given participant has remained similar over the years. This study also has strengths. This analysis is the first study between blood concentration of dioxin and health outcomes in general populations with low dose exposure. Thus, it has been evaluated for the health impact of dioxin on the general population. And the analysis showed the possibility of studying dioxins that needs a large amount of blood for detection using a pooled sample. Furthermore, this research will serve as a base for future studies, which identifies dioxin's health impact mechanism. Conclusion To our knowledge, this is the first study that shows the association between PCDD/DFs, DL-PCBs serum levels, and T2DM and thyroid cancer risk in the Korean population. In this study, both T2DM and thyroid cancer appear to have an association with PCDD/DFs serum levels. Our findings suggest that further biochemical in vivo research and epidemiologic studies are needed to clarify the nature of the association between dioxins concentration and diseases. Declarations Funding : This research was supported by a grant (19162MFDS094) from the Ministry of Food and Drug Safety in 2020. Conflicts of interest/Competing interests : The authors have no conflicts of interest to declare that are relevant to the content of this article. Availability of data and material : Due to the nature of this research, participants of this study did not agree for their data to be shared publicly, so supporting data is not available. Code availability : Statistical analyses were performed with the use of SAS software, version 9.4 (SAS Institute) and R software, version 4.1.2 (R Foundation for Statistical Computing). Authors' contributions : All authors contributed to the study’s conception and design. Material preparation, data collection, and analysis were performed by Su Hyun Lee, Joyce Mary Kim, Young Wook Lim, Youn Seok Kang, and Sun Ha Jee. 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Wang, S.L., et al., Increased Risk of Diabetes and Polychlorinated Biphenyls and Dioxins: A 24-year follow-up study of the Yucheng cohort. Diabetes Care, 2008. 31 (8): p. 1574-1579. Reale, C., et al., A Toxicogenomic Approach Reveals a Novel Gene Regulatory Network Active in In Vitro and In Vivo Models of Thyroid Carcinogenesis. International Journal of Environmental Research and Public Health, 2019. 16 (1): p. 122. Lans, M.C., et al., Different competition of thyroxine binding to transthyretin and thyroxine-binding globulin by hydroxy-PCBs, PCDDs and PCDFs. 1994. 270 (2-3): p. 129-136. Brouwer, A., et al., Interactions of Persistent Environmental Organohalogens With the Thyroid Hormone System: Mechanisms and Possible Consequences for Animal and Human Health. Toxicology and Industrial Health, 1998. 14 (1-2): p. 59-84. Pavuk, M., et al., Serum 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) Levels and Thyroid Function in Air Force Veterans of the Vietnam War. Annals of Epidemiology, 2003. 13 (5): p. 335-343. Kim, H.K., et al., Higher TSH level is a risk factor for differentiated thyroid cancer. 2013. 78 (3): p. 472-477. Haymart, M.R., et al., Higher Serum Thyroid Stimulating Hormone Level in Thyroid Nodule Patients Is Associated with Greater Risks of Differentiated Thyroid Cancer and Advanced Tumor Stage. 2008. 93 (3): p. 809-814. Kerger, B.D., et al., Re-analysis of Ranch Hand study supports reverse causation hypothesis between dioxin and diabetes. 2012. 42 (8): p. 669-687. Safe, S.H., Development validation and problems with the toxic equivalency factor approach for risk assessment of dioxins and related compounds. Journal of Animal Science, 1998. 76 (1): p. 134. Wang, S.-L., et al., Body Burdens of Polychlorinated Dibenzo-p-dioxins, Dibenzofurans, and Biphenyls and Their Relations to Estrogen Metabolism in Pregnant Women. 2006. 114 (5): p. 740-745. Ceriello, A., Possible Role of Oxidative Stress in the Pathogenesis of Hypertension. Diabetes Care, 2008. 31 (Supplement 2): p. S181-S184. Michalek, J.E. and M. Pavuk, Diabetes and Cancer in Veterans of Operation Ranch Hand After Adjustment for Calendar Period, Days of Spraying, and Time Spent in Southeast Asia. 2008. 50 (3): p. 330-340. Supplementary Files 4SupplementaryMaterialDioxinandT2DMThyroidcancer.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-674870","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research","associatedPublications":[],"authors":[{"id":53753883,"identity":"75eb2632-9eb6-4260-9726-a4343f2239c5","order_by":0,"name":"Su Hyun Lee","email":"","orcid":"","institution":"Yonsei University Graduate School of Public Health","correspondingAuthor":false,"prefix":"","firstName":"Su","middleName":"Hyun","lastName":"Lee","suffix":""},{"id":53753884,"identity":"6d0d45eb-42e7-4301-8423-8dc17f2a0900","order_by":1,"name":"Joyce Mary Kim","email":"","orcid":"","institution":"Yonsei University Graduate School of Public Health","correspondingAuthor":false,"prefix":"","firstName":"Joyce","middleName":"Mary","lastName":"Kim","suffix":""},{"id":53753885,"identity":"4d77c545-dd2d-4288-9a07-acb4ffa244fb","order_by":2,"name":"Young Wook Lim","email":"","orcid":"","institution":"Yonsei University College of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Young","middleName":"Wook","lastName":"Lim","suffix":""},{"id":53753886,"identity":"61991e7d-eeff-4e64-b7b0-fad89cfe7f8c","order_by":3,"name":"Youn Seok Kang","email":"","orcid":"","institution":"Eurofins Korea Ltd","correspondingAuthor":false,"prefix":"","firstName":"Youn","middleName":"Seok","lastName":"Kang","suffix":""},{"id":53753887,"identity":"ffdb9baf-9943-4580-bf7a-7b95f5378a1b","order_by":4,"name":"Keum Ji Jung","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAt0lEQVRIiWNgGAWjYBACCYYDCUDKBsQiTUsaSVrA4DAJWiQbDzyTLvh1PnHD7fYHDD9qiNAizXAgTXpm3+3EDXfOGDD2HCNCixxIC28PUMuNHAYG3gbitZwDakl/wPiXGC1gh/H8OADUkmDATJQtkg0Hkq15G5KNZ97IMTgsQ4xfJG6cSbzN88dOtu9G+sOHb4gJMQaJMwkMjG0MjiAnHSBGAwMDfztQ4R8Ge+JUj4JRMApGwYgEAO0GPnh7aF1zAAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0003-4993-0666","institution":"Yonsei University Graduate School of Public Health","correspondingAuthor":true,"prefix":"","firstName":"Keum","middleName":"Ji","lastName":"Jung","suffix":""},{"id":53753888,"identity":"88f18147-cef5-4d47-8305-b5b1a47b1881","order_by":5,"name":"Sun Ha Jee","email":"","orcid":"","institution":"Yonsei University Graduate School of Public Health","correspondingAuthor":false,"prefix":"","firstName":"Sun","middleName":"Ha","lastName":"Jee","suffix":""}],"badges":[],"createdAt":"2021-07-01 01:55:23","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-674870/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-674870/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":14065722,"identity":"81c7dce2-6fba-462c-8061-31ec138c6e52","added_by":"auto","created_at":"2021-09-28 15:31:23","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":60434,"visible":true,"origin":"","legend":"Serum concentrations for PCDD/DFs, DL-PCBs of the study group\nViolin plots show differences in blood of concentrations for DL_PCBs (A), PCDD/DFs (B), Total Dioxins (C) at the controls group (n=55), type 2 diabetes (n=30), or thyroid cancer (n=15). The line in the white box represents the median. The width of the shape represents blood concentration density, and the length illustrates the range of the blood concentration.","description":"","filename":"Onlinefloatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-674870/v1/aa24b88fb03a65c1d0acf93a.png"},{"id":14065922,"identity":"5070bb82-b2f2-4737-ac2d-f294f7c9839b","added_by":"auto","created_at":"2021-09-28 15:34:23","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":36818,"visible":true,"origin":"","legend":"Odds Ratios of blood concentrations of PCDD/DFs, DL-PCBs (pgTEQ/g_lipid) and Type 2 Diabetes mellitus\nOR, Odds ratio; CI, confidence interval\n*Model 1: Adjusted for age and sex \n*Model 2: Adjusted for the model 1 variables, body mass index, systolic blood pressure and high-density lipoprotein","description":"","filename":"Onlinefloatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-674870/v1/8c63b166a422c066793ae57d.png"},{"id":14065723,"identity":"c9c47fab-843c-48ee-a2d0-0cf80369c14b","added_by":"auto","created_at":"2021-09-28 15:31:23","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":38473,"visible":true,"origin":"","legend":"Odds Ratios of blood concentrations of PCDD/DFs, DL-PCBs (pgTEQ/g_lipid) and Thyroid Cancer\nOR, Odds ratio; CI, confidence interval\n*Model 1: Adjusted for age and sex \n*Model 2: Adjusted for the model 1 variables and body mass index\n*Model 3: Adjusted for the model 2 variables and thyroid stimulating hormone","description":"","filename":"Onlinefloatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-674870/v1/303ec6059696965a73594d9d.png"},{"id":14065923,"identity":"9b4d5ccd-8131-49d7-9a68-c3de4d8abb22","added_by":"auto","created_at":"2021-09-28 15:34:27","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":784488,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-674870/v1/26db3c88-1a21-4e85-887d-abcd3650c4bc.pdf"},{"id":14065725,"identity":"630cd007-574c-4861-9c13-1b4af995a1b4","added_by":"auto","created_at":"2021-09-28 15:31:24","extension":"docx","order_by":6,"title":"","display":"","copyAsset":false,"role":"supplement","size":130576,"visible":true,"origin":"","legend":"","description":"","filename":"4SupplementaryMaterialDioxinandT2DMThyroidcancer.docx","url":"https://assets-eu.researchsquare.com/files/rs-674870/v1/68c93b3e3e01d96bfea5a468.docx"}],"financialInterests":"","formattedTitle":"\u003cp\u003eThe Association between Blood Concentrations of PCDD/DFs, DL-PCBs and Risk of Type 2 Diabetes Mellitus and Thyroid Cancer\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eDioxins are a chemical compound consisting of 75 polychlorinated dibenzo-p-dioxin (PCDD) and 135 polychlorinated dibenzofurans (PCDFs) that occur most frequently during waste incineration processes and automobile emissions and cigarette smoke [\u003cspan additionalcitationids=\"CR2 CR3\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Polychlorinated dibenzo-p-dioxins, dibenzofurans (PCDD/DFs), and dioxin-like polychlorinated biphenyls (DL-PCBs) are persistent environmental pollutants (POPs), which are the compounds that accumulate in the environment and human body [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eDioxins are a new candidate for the risk factors of type 2 diabetes mellitus (T2DM). An epidemiological investigation of a group exposed to a relatively high concentration of dioxins due to an accident or occupation shows a significant relationship between the blood dioxins concentration and the onset of T2DM or death from T2DM [\u003cspan additionalcitationids=\"CR8 CR9 CR10 CR11 CR12 CR13\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. However, the relationship between dioxins concentration in blood and T2DM identified in groups exposed to relatively high concentrations of dioxins due to accidents or occupations is not completely consistent [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. In addition, studies on the association between dioxins and diabetes use estimate made using half-life in the dioxins body, so there is a problem with the accuracy of the exposure assessment, calling for caution when interpreting the results. Thus, in recent years, there have been studies on the association between low dioxins concentration, PCBs exposure, and T2DM in general environments, but due to the ethic of the Asian group, this is very rare [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn 1997, the International Agency for Research on Cancer classified TCDD as a human carcinogen (IARC, 1997). Among PCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is the most toxic to Ah-R, and molecular studies have shown that TCDD is a strong carcinogen that can disrupt various endocrine pathways in animals and humans [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. However, the relationship between TCDD and cancer incidence or mortality tested by epidemiology studies was inconsistent [\u003cspan additionalcitationids=\"CR9\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan additionalcitationids=\"CR19 CR20 CR21 CR22 CR23 CR24 CR25 CR26 CR27 CR28 CR29\" citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. Evidence of how it affects humans have long been controversial [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. A meta-analysis of epidemiological studies on carcinogenicity was published in 2016, and both external exposure and blood level of TCDD were significantly associated with all cancer mortality, but no studies confirming the relationship with thyroid cancer were included in this study [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. Most of the dioxins studies are animal-based experiments. The reason epidemiological studies that confirm the occurrence of human diseases are rare that about 4ml of whole blood is needed to measure dioxins in human blood [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. In addition, it takes a long time to study cohort considering the context of dioxins exposure and disease development. Therefore, we pooled the amount of blood needed for dioxin analysis using the pooling method in large-scale cohort data and investigated whether the blood concentration of DL-PCB and PCDD/DF is associated with T2DM and thyroid cancer in the Korean population.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy population\u003c/h2\u003e \u003cp\u003eThis study was designed as a nested case-control study of 500 Koreans (men: 263, women: 237) selected from the Korean cancer prevention study-II (KCPS-II) (Supplementary Fig.\u0026nbsp;1). KCPS-II included 156,704 adults aged 20 to 84 who visited 18 health promotion centers nationwide from April 2004 to December 2013. A detailed description of the KCPS-II study design was published elsewhere [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e].\u003c/p\u003e \u003cp\u003e In this study, the baseline period for the collected blood samples of participants was determined from January 2004 to December 2004. Due to the 4ml human blood requirement for dioxins tests [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e], a blood sample was produced by combining 0.3 ml to 1.0 ml of the individual serum sample of five to nine participants. The subjects with disease samples were pooled with considerations for sex and age, and the control group sample was pooled with consideration of the sex, age and body mass index (BMI) of the disease group. A total of 500 samples were used in 100 pooling samples consisting of 30 cases of T2DM, 15 cases of thyroid cancer, and 55 for the control group.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eMeasurements\u003c/h2\u003e \u003cdiv id=\"Sec5\" class=\"Section3\"\u003e \u003ch2\u003eSample Collection\u003c/h2\u003e \u003cp\u003eAfter 12 hours of fasting, serum and whole blood were collected from each participant and put into storage at -70\u0026ordm;C for future study. These samples were used for PCDD/DFs, DL-DCBs measurements, as well as other clinical chemistry parameters, such as fasting blood glucose, total cholesterol, triglyceride, HDL-C, and LDL-C.\u003c/p\u003e \u003cp\u003eIn compliance with the protocols of the Korean Organization of Laboratory Quality Management, the quality control of the clinical chemistry laboratory was maintained.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eAnalysis of dioxins\u003c/h2\u003e \u003cp\u003eThe analysis and quality control of 2,3,7,8-substituted PCDD/DFs and DL-PCBs in the pooled serum samples were performed with a slight modification of the Center for Disease Control and Prevention [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]. Before solid phase extraction, pooled serum samples were spiked 13C-labeled 2,3,7,8-substituted PCDD/DFs and DL-PCBs and were made to homogenization. Series of 20 samples were processed on manifolds. Formic acid and pure water were added to samples prior to extraction. SPE-C18 cartridges (octadecyl, 2g) were pre-conditioned using methanol and water. Each cartridge was dried and eluted with 15 mL of hexane, followed by the eluate was concentrated to 1mL. The eluate was applied to a multilayer silica gel column (44% sulfuric acid and 10% AgNo\u003csub\u003e3\u003c/sub\u003e silica gel) then eluted with 20mL of hexane. The final evaporation using a nitrogen concentrator (Eyela MGS 3100) was performed after addition of nonane as keeper. Quantification and identification of 2,3,7,8-substituted PCDD/DFs congeners and DL-PCBs were performed by high resolution gas chromatography (HRGC) (Thermo scientific Trace 1310)/high resolution mass spectrometry (HRMS) (Thermo Scientific DFS). The HRMS was operated in the electron impact mode and in the selected ion monitoring mode at a resolution R\u0026thinsp;\u0026gt;\u0026thinsp;10,000 (10% valley). Separation was achieved using a HRGC instrument equipped with a DB-5MS (Agilent Technologies; 60 m length, 0.32 mm i.d., 0.25 \u0026micro;m film thickness) capillary column with a splitless and solvent-cut mode. The column ovens for DB5-MS was programmed from an initial temperature of 160℃ to a final temperature of 310℃ (total running time 60 min). Before quantitative analysis, 13C-labeled 1,2,3,4-TeCDD, 1,2,3,7,8,9-HxCDD, 3,3\u0026rsquo;,4,5\u0026rsquo;-TetraCB, 2,3,3\u0026rsquo;,5,5\u0026rsquo;-pentaCB and 2,3,3\u0026rsquo;,4,5,5\u0026rsquo;-hexaCB as internal standards were added for the estimation of recovery. Mean recovery of the spiked 13C-labeled 2,3,7,8-substituted PCDD/DFs and DL-PCBs in the entire analytical procedures were 75\u0026thinsp;\u0026plusmn;\u0026thinsp;11% and 80\u0026thinsp;\u0026plusmn;\u0026thinsp;25%, respectively. The levels were expressed in 2,3,7,8-TeCDD toxic equivalents using calculations of World Health Organization Toxic Equivalent Factors (WHO-TEFs) for PCDD/DFs and DL-PCBs.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eThe definition of outcome (Diagnosis of thyroid cancer and T2DM)\u003c/h2\u003e \u003cp\u003eThe incidence of thyroid cancer was collected from the registry of the National Cancer Center (NCC). And thyroid cancer code C73 of the 10th Amendment to the International Classification of Diseases (ICD-10) (WHO 2010) was used. The incidence of T2DM was identified from the National Health Insurance System (NHIS).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eAs POPs are mainly carried in the lipid portion of the blood, epidemiological studies have used lipid-adjusted concentrations (ng/g lipid) [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. Concentrations adjusted for lipids (ng/g lipids) were determined using the formula proposed by Bernert et al (2007) [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe continuous variable of a pooled sample of 500 samples was calculated as an average value taking into account the blood weight of the configured sample. The average value considering the blood mass of the sample calculated by the PROC SURVEYSMEANS statement in SAS 9.4 was measured using the equation below:\u003cdiv id=\"Equa\" class=\"Equation\"\u003e\u003cdiv format=\"TEX\" class=\"mathdisplay\" id=\"FileID_Equa\" name=\"EquationSource\"\u003e\n\n$$\\text{A}\\text{v}\\text{e}\\text{r}\\text{a}\\text{g}\\text{e} \\text{v}\\text{a}\\text{l}\\text{u}\\text{e} \\text{c}\\text{o}\\text{n}\\text{s}\\text{i}\\text{d}\\text{e}\\text{r}\\text{i}\\text{n}\\text{g} \\text{t}\\text{h}\\text{e} \\text{w}\\text{e}\\text{i}\\text{g}\\text{h}\\text{t} \\text{o}\\text{f} \\text{b}\\text{l}\\text{o}\\text{o}\\text{d} \\text{v}\\text{o}\\text{l}\\text{u}\\text{m}\\text{e}= \\sum \\left(blood volume \\times value\\right)/\\sum \\left(blood volume\\right)$$\u003c/div\u003e\u003c/div\u003e\u003c/p\u003e \u003cp\u003eWe reported continuous variables as medians (\u0026plusmn;\u0026thinsp;interquartile range; IQR) and categorical variables as proportions. We conducted the Kruskal-Wallis test to analyze between-group differences, as appropriate. Multiple logistic regression analyses were conducted to display the association between PCDD/DFs, DL-PCBs concentrations and thyroid cancer and T2DM. Additional sensitivity analyses were performed with the use of multivariable logistic regression adjusted for predefined baseline covariates. P values\u0026thinsp;\u0026lt;\u0026thinsp;0.05 in the two-tailed test were considered significant. Statistical analyses were performed with the use of SAS software, version 9.4 (SAS Institute) and R software, version 4.1.2 (R Foundation for Statistical Computing).\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e\n\u003ch2\u003eStudy population and PCDD/DFs, DL-PCBs, and total dioxins in blood\u003c/h2\u003e\n\u003cp\u003eThe characteristics of the study population are shown in Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e. Regarding the number of subjects according to disease group, the numbers for the non-disease group, T2DM, and thyroid cancer were 55, 30, and 15, respectively. Due to the study design, the participants were distributed almost equally according to sex, age, and BMI. The proportion of men and women were 48% and 52%, respectively, and the median value of age was 54.06 years (IQR\u0026thinsp;=\u0026thinsp;21.04), and a median value of BMI was 24.28 kg/m\u003csup\u003e2\u003c/sup\u003e (IQR\u0026thinsp;=\u0026thinsp;2.15).\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab1\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eBaseline characteristics of 500 who constructed 100 blood samples in the KCPS-II\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eCharacteristic\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eOverall\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eControl\u003c/p\u003e\n\u003cp\u003e(n\u0026thinsp;=\u0026thinsp;55)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eType 2 Diabetes\u003c/p\u003e\n\u003cp\u003e(n\u0026thinsp;=\u0026thinsp;30)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eThyroid Cancer\u003c/p\u003e\n\u003cp\u003e(n\u0026thinsp;=\u0026thinsp;15)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eP-value\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSex\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"4\" align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eN (%)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.795\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMale\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e48 (48.00)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e27 (49.09)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e15 (50.00)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6 (40.00)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eFemale\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e52 (52.00)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e28 (50.91)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e15 (50.00)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e9 (60.00)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd colspan=\"4\" align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eMedian (IQR)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAge, years\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e54.06 (21.04)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e54.25 (20.57)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e54.04 (22.14)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e52.60 (19.20)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.813\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBMI, kg/m\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e24.28 (2.15)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e24.31 (1.94)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e24.36 (2.21)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e24.20 (1.83)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.619\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eFBS, mg/dl\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e92.88 (14.23)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e89.42 ( 6.73)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e135.73 (40.13)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e92.88 ( 7.59)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHDL-C, mg/dl\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e52.89 (9.57)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e55.20 (12.23)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e51.56 ( 6.70)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e50.00 ( 5.23)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.004\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eLDL-C, mg/dl\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e117.32 (26.32)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e112.35 (27.29)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e121.61 (22.17)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e115.51 (18.99)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.046\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSBP, mmHg\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e123.71 (14.35)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e121.81 (10.95)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e129.50 (12.44)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e116.25 (16.32)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.005\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eTG, mg/dl\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e135.95 (66.38)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e131.56 (61.10)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e163.28 (67.74)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e125.05 (45.32)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.009\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eTSH, uIU/mL\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.66 (0.83)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.66 (0.82)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.64 (0.79)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.69 (0.92)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.659\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003ctfoot\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"6\"\u003eIQR, interquartile range; BMI, body mass index; SBP, systolic blood pressure; FBS, fasting blood sugar; HDL-C, high-density lipoprotein-cholesterol; LDL-C, low-density lipoprotein-cholesterol; TG, triglyceride; TSH, thyroid stimulation hormone\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"6\"\u003e*p values from Kruskal-Wallis test and all variables are calculated by weighted blood volume\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tfoot\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eFigure \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e presents the blood TEQ concentration of PCDD/DFs, DL-PCBs, and total dioxins. For the TEQ of DL_PCBs, the difference in exposure levels between groups was not statistically significant (P-value\u0026thinsp;\u0026lt;\u0026thinsp;0.34). The median of the PCDD/DFs and total dioxins material was highest in the thyroid cancer group, and the difference in exposure levels between groups is statistically significant (both P-value\u0026thinsp;\u0026lt;\u0026thinsp;0.01).\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\n\u003ch2\u003eAssociation between dioxins in blood and T2DM\u003c/h2\u003e\n\u003cp\u003eThe multiple-adjusted associations between blood levels of dioxins and T2DM are presented in Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e. The PCDD/DFs TEQ and total dioxins, but not of DL-PCBs, showed significant associations with T2DM. The age and sex-adjusted ORs of T2DM and total dioxins were 1.14 (95% CI\u0026thinsp;=\u0026thinsp;1.03\u0026ndash;1.25). Stratifying analyses by sex showed positive orientation but were not statistically significant in men (men ORs\u0026thinsp;=\u0026thinsp;1.20; 95% CI\u0026thinsp;=\u0026thinsp;0.99\u0026ndash;1.45, women ORs\u0026thinsp;=\u0026thinsp;1.15; 95% CI\u0026thinsp;=\u0026thinsp;1.01\u0026ndash;1.31) However, since the results are not considered significant at the boundary of the 95% confidence interval, increasing the sample size can be statistically significant.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTo assess the possibility of confounding by BMI or systolic blood pressure or high-density lipoprotein, an analysis for T2DM was performed by additionally adjusting for the effects of these variables. In the adjusted models that include these variables (Model 2), the odds ratio for total dioxins was 1.20 (95% CI\u0026thinsp;=\u0026thinsp;1.06\u0026ndash;1.36). The results of Model 2 also showed statistically significant results only in the women group (men ORs\u0026thinsp;=\u0026thinsp;1.16; 95% CI\u0026thinsp;=\u0026thinsp;0.93\u0026ndash;1.43, women ORs\u0026thinsp;=\u0026thinsp;1.21; 95% CI\u0026thinsp;=\u0026thinsp;1.02\u0026ndash;1.45). Specifically, a 1-SD increase in 2378-TCDF level, is associated with a 71% increased risk of T2DM (ORs\u0026thinsp;=\u0026thinsp;1.71; 95% CI\u0026thinsp;=\u0026thinsp;1.0-2.91) (Supplementary Table\u0026nbsp;2).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\n\u003ch2\u003eAssociation between dioxins in blood and thyroid cancer\u003c/h2\u003e\n\u003cp\u003eThe multiple-adjusted associations between blood levels of dioxins and thyroid cancer are presented in Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e. TEQ of PCDD/DFs and total dioxins, but not of DL-PCBs, showed significant associations with thyroid cancer. The age, sex-adjusted ORs of thyroid cancer of total dioxins were 1.25 (95% CI\u0026thinsp;=\u0026thinsp;1.10\u0026ndash;1.42). Both men and women subgroup analyses showed positive orientation (men ORs\u0026thinsp;=\u0026thinsp;1.31; 95% CI\u0026thinsp;=\u0026thinsp;1.02\u0026ndash;1.67), women ORs\u0026thinsp;=\u0026thinsp;1.24; 95% CI\u0026thinsp;=\u0026thinsp;1.04\u0026ndash;1.48). To assess the possibility of confounding by TSH serum levels or body mass index, an analysis for thyroid cancer was performed by additionally adjusting for the effects of these variables. In the adjusted models, which include body mass index (Model 2) or TSH serum levels (Model 3), the odds ratio for total dioxins was 1.28 for both models (both models 95% CI\u0026thinsp;=\u0026thinsp;1.10\u0026ndash;1.48). The DL-PCB TEQ did not show a significant association with thyroid cancer. However, the 1-SD increase at 4CB-77 levels was associated with an increase in risk of thyroid cancer (OR\u0026thinsp;=\u0026thinsp;1.92; 95% CI\u0026thinsp;=\u0026thinsp;1.02\u0026ndash;3.64) (Supplement Table\u0026nbsp;3).\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study measured DL_PCB and PCDD/DF using pooled serum from general population. PCDD/DFs in blood showed a significant positive association with T2DM and thyroid cancer development, but no significant association with DL_PCB was observed.\u003c/p\u003e \u003cp\u003eIn 2016, International Agency for Research on Cancer (IARC) upgraded the classification of the PCBs to Category 1 carcinogenic to humans from the previous Category 2A classification on the basis of sufficient evidence of carcinogenicity in humans and animals [\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e, \u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e]. However, no evidence of a relationship between PCB exposure and the risk of malignant melanoma has been identified in the latest meta-analysis [\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e], and reviews of epidemiological studies on PCB exposure and cancer risk were inconsistent for other cancers [\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e]. Our result that DL_PCBs are not associated with cancer is similar to that of recently reported studies [\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e, \u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAlthough previous studies have found an association between PCB levels and T2DM in women, our results are inconsistent with reports from other studies suggesting that PCBs are positively associated with T2DM in women. [\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e, \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e]. However, the PCBs used in previously reported studies are a combination of DL-PCBs and non-dioxin-PCBs. In this study, however, there was included only DL-PCBs.\u003c/p\u003e \u003cp\u003eTo the best of our knowledge, no case-control studies have yet been conducted to establish an association between dioxins and thyroid cancer. However, recent in vitro studies using immortal mouse cells have shown that TCDD exposure regulates the script of an endothelial carcinogen network thought to affect thyroid carcinoma [\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e]. TCDD can interfere with the activity and metabolism of thyroid hormones through various processes, including binding to protein transport of thyroid hormone [\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e], direct damage to the thyroid gland, and activation of thyroid metabolizing enzymes [\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e]. Previous reported epidemiological studies have found significantly increasing trends in mean TSH with TCDD category [\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e]. Having a high TSH level within the normal range is an independent risk factor for DTC, and may contribute to the initiation of thyroid carcinogenesis [\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e, \u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e]. These mechanisms can support the association between blood PCDD/DFs and thyroid cancer risks identified in our study.\u003c/p\u003e \u003cp\u003eDioxins have been identified as endocrine disruptors of the environment, but epidemiology studies of their effect on diabetes found inconsistent results [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e]. In particular, this association is found in women and not in men [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e], which is similar to the results confirmed in our study. Several assumptions can explain this gender difference. First, men have lower levels of exposure and a higher prevalence of smoking, which stimulates the aryl hydrocarbon receptor related to the increased excretion of PCBs [\u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e]. Second, women have a higher proportion of fat, resulting in these lipophilic compounds being stored longer. Third, women have higher estrogen levels and PCDFs. Certain PCBs can cause gene expression of CYP1A1 and CYP1B1 [\u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e, \u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e], which catalyze estradiol A-ring hydroxylation to from 4-hydroxyl estradiol of catechol estrogen that can produce free radicals. It is understood that free radicals induce elevated oxidative stress related to diabetes [\u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eDespite the fact that the results are similar to those of previous studies, there are some limitations in our study. First, we were unable to control the confounding variables such as exercise habits, food consumption, alcohol status, smoking status, and socioeconomic status. In this study, several blood samples were used to make pooled samples. In the case of a continuous variable, the mean value of the characters constituting the sample was used. And categorical variables were not included in this study. However, we used BMI, which is strongly associated with physical activity patterns, waist circumference, and dietary consumption, and may thus be considered a proxy indicator for such variables. Second, as an exposure measure, we used a 1-time dioxins level measurement in the blood and did not have accumulated exposure dose information. However, we had the strength of measuring PCDD/DFs and DL-PCB concentrations directly within the Korean population to collect exposure data. Also, since the half-life of PCDD/Fs in the serum can last for seven years or longer [\u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e, \u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e] and over that duration, the causes of environmental exposure remained constant, we could conclude that the dioxins level in a given participant has remained similar over the years. This study also has strengths. This analysis is the first study between blood concentration of dioxin and health outcomes in general populations with low dose exposure. Thus, it has been evaluated for the health impact of dioxin on the general population. And the analysis showed the possibility of studying dioxins that needs a large amount of blood for detection using a pooled sample. Furthermore, this research will serve as a base for future studies, which identifies dioxin's health impact mechanism.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eTo our knowledge, this is the first study that shows the association between PCDD/DFs, DL-PCBs serum levels, and T2DM and thyroid cancer risk in the Korean population. In this study, both T2DM and thyroid cancer appear to have an association with PCDD/DFs serum levels. Our findings suggest that further biochemical in vivo research and epidemiologic studies are needed to clarify the nature of the association between dioxins concentration and diseases.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e: This research was supported by a grant (19162MFDS094) from the Ministry of Food and Drug Safety in 2020.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of interest/Competing interests\u003c/strong\u003e: The authors have no conflicts of interest to declare that are relevant to the content of this article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and material\u003c/strong\u003e: Due to the nature of this research, participants of this study did not agree for their data to be shared publicly, so supporting data is not available.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCode availability\u003c/strong\u003e: Statistical analyses were performed with the use of SAS software, version 9.4 (SAS Institute) and R software, version 4.1.2 (R Foundation for Statistical Computing).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors' contributions\u003c/strong\u003e: All authors contributed to the study\u0026rsquo;s conception and design. Material preparation, data collection, and analysis were performed by Su Hyun Lee, Joyce Mary Kim, Young Wook Lim, Youn Seok Kang, and Sun Ha Jee. The first draft of the manuscript was written by Keum Ji Jung and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval: \u003c/strong\u003eThe study was approved by the Severance Medical Ethics Committee of A (No. 4-2019-0351).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to participate\u003c/strong\u003e: Informed consent was obtained from all individual participants included in the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e: The participant has consented to the submission of the case report to the journal.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eAndersson, P., et al., \u003cem\u003eA constitutively active dioxin/aryl hydrocarbon receptor induces stomach tumors.\u003c/em\u003e Proceedings of the National Academy of Sciences, 2002. \u003cstrong\u003e99\u003c/strong\u003e(15): p. 9990-9995.\u003c/li\u003e\n\u003cli\u003eBirnbaum, L.S. and L.A. 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S181-S184.\u003c/li\u003e\n\u003cli\u003eMichalek, J.E. and M. Pavuk, \u003cem\u003eDiabetes and Cancer in Veterans of Operation Ranch Hand After Adjustment for Calendar Period, Days of Spraying, and Time Spent in Southeast Asia.\u003c/em\u003e 2008. \u003cstrong\u003e50\u003c/strong\u003e(3): p. 330-340.\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"PCDD, PCDFs, Dioxin-like PCBs, type 2 diabetes mellitus, thyroid cancer, epidemiology","lastPublishedDoi":"10.21203/rs.3.rs-674870/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-674870/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003e\u003cem\u003eBackground and Objectives\u003c/em\u003e:\u003c/strong\u003e Dioxin, classified as a human carcinogen by International Cancer Research Institute, shows inconsistent results on type 2 diabetes mellitus (T2DM) and cancer in epidemiological studies. International Cancer Research Institute classifies dioxin as a human carcinogen, but epidemiological studies of its effects on type 2 diabetes mellitus (T2DM) and cancer show inconsistent results. Therefore, we conducted a Korean population study to ascertain if the blood concentration of dioxin-like polychlorinated biphenyls (DL-PCBs) and polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/DFs) is associated with T2DM and thyroid cancer.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003e\u003cem\u003eMethods\u003c/em\u003e:\u003c/strong\u003e Within a nested case-control study, we identified 15 people diagnosed with thyroid cancer, 30 people diagnosed with T2DM, and 55 for control. Due to the 4ml human blood requirement for PCDD/DF and DL-PCB concentrations tests, a total of 500 samples were used in 100 pooling samples. The continuous variable of a pooled sample was calculated as an average value taking into account the blood weight of each sample. The odds ratios (ORs) and 95% confidence interval (95% CI) for determining the association between total dioxins and risk of T2DM and thyroid cancer were estimated using the multivariable logistic regression.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003e\u003cem\u003eResults\u003c/em\u003e:\u003c/strong\u003e The study population included 100 participants from the KCPS-II (median [IQR] baseline age, 54.06 [21.04] years; 48 women). The toxic equivalents of PCDD/DFs showed a significant positive association with T2DM and thyroid cancer, after adjustments for potential confounders (T2DM ORs = 1.23; 95% CI = 1.05-1.43; Thyroid cancer ORs = 1.34; 95% CI = 1.12-1.61). These results showed a stronger association in women than in men.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003e\u003cem\u003eConclusion\u003c/em\u003e:\u003c/strong\u003e In this study, both T2DM and thyroid cancer appear to be associated with the levels of PCDD/DFs serum. The association between T2DM and levels of PCDD/DFs serum is found in women and not in men. Our findings suggest that further biochemical in vivo research and epidemiologic studies are needed to clarify the nature of the association between dioxins concentrations and diseases.\u003c/p\u003e","manuscriptTitle":"The Association between Blood Concentrations of PCDD/DFs, DL-PCBs and Risk of Type 2 Diabetes Mellitus and Thyroid Cancer","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2021-09-28 15:31:22","doi":"10.21203/rs.3.rs-674870/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"0d05df47-1244-4333-9c41-fe7c58b56d4d","owner":[],"postedDate":"September 28th, 2021","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":7501184,"name":"Environmental Policy"},{"id":7501185,"name":"Health Policy"}],"tags":[],"updatedAt":"2021-09-28T15:31:23+00:00","versionOfRecord":[],"versionCreatedAt":"2021-09-28 15:31:22","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-674870","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-674870","identity":"rs-674870","version":["v1"]},"buildId":"_2-kVJe1T_tPrBINL-cwx","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}