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Polychlorinated dibenzo-p-dioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs) have attracted considerable attention owing to their environmental persistence, bioaccumulation, and high toxicity. This study aimed to investigate changes in serum metabolites following exposure to PCDD/Fs and to reveal a novel pathogenesis of PCDD/Fs. Serum samples were collected from 75 residents living near a municipal solid waste incinerator in China to analyse the relationship between PCDD/Fs and serum metabolic components. The serum level in the low-exposure group [19.07 (13.44-23.89) pg-TEQ/L] was significantly lower than that in the high-exposure group [115.60 (52.28-592.65) pg-TEQ/L]. Non-targeted metabolomic studies based on liquid chromatography-high resolution mass spectrometry have been applied to the metabolomic analysis of serum. Thirty-seven metabolites with significant differences among the different groups were identified as biomarkers. Pathway analysis revealed that high dioxin exposure perturbed various biological processes, including glycerol phospholipid metabolism and the interconversion of pentose and glucuronate. The results of a population health survey showed that the serum dioxin concentration in patients with diabetes was significantly higher than that in the control population. These findings suggest that dioxin exposure is associated with several potential adverse health risks, including inflammation, diabetes, and cardiovascular disease, through metabolic changes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Exposure to dioxin, a known endocrine disruptor and carcinogen, is associated with poor reproductive outcomes. Yet, few studies have explored the role of DNA methylation in these relationships. Utilizing a publicly available dataset from 37 male Air Force Health Study participants exposed to dioxin-contaminated Agent Orange during the Vietnam war, we cross-sectionally examined the relationship of serum dioxin levels with a novel DNA methylation-based measure of sperm age (DNAm-agesperm). DNAm-agesperm was calculated using CpG sites on the Illumina HumanMethylation450 BeadChip. We estimated associations of dioxin levels with DNAm-agesperm using linear regression models adjusted for chronological age, body mass index, and smoking status. Chronological age was highly correlated with DNAmagesperm (r = 0.80). In fully-adjusted linear models, a one percent increase in serum dioxin levels was significantly associated with a 0.0126-year (i.e. 4.6-day) increase in DNAm-agesperm (95%CI: 0.003, 0.022, p = 0.01). Further analyses demonstrated significant negative associations of dioxin levels (β = -0.0005, 95%CI: -0.0010, 0.00004, P = 0.03) and DNAm-agesperm (β = -0.02, 95%CI: -0.04, -0.001, P = 0.03) with methylation levels of FOXK2 - a gene previously reported to be hypomethylated in infertile men. In sum, we demonstrate associations of dioxin with increased methylation aging of sperm. DNAm-agesperm may provide utility for understanding how dioxin levels impact sperm health and potentially male reproductive capacity in human population studies. Moreover, our pilot study contributes further evidence that some environmental toxicants are associated with methylation aging. Additional studies are necessary to confirm these findings, and better characterize dioxin and sperm methylation relationships with male reproductive health., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Serum and breast milk are both important biological samples to evaluate body burden of dioxin-like compounds which include polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans (PCDD/Fs) and dioxin-like polychlorinated biphenyls (dl-PCBs). We collected maternal serum at early pregnancy, and breast milk at 3-8 weeks after delivery from 55 mothers living in Beijing, China, and measured 29 dioxin-like compounds in these samples. The sampling intervals in this study were extended up to 10 months to analyze differences of contents between serum and breast milk under long sampling intervals. The results showed that mean TEq level of PCDD/Fs in serum (9.8 pg TEq g -1 lipid) was 1.7 times higher than that in milk (4.5 pg TEq g -1 lipid), while the TEq concentrations of dl-PCBs in serum (1.2 pg TEq g -1 lipid) was significantly lower than that in milk (2.0 pg TEq g -1 lipid). There were only two congeners, OCDD (r = 0.32) and PCB105 (r = 0.33), the correlations of which between serum and milk were significant. The differences in distributions of congeners in serum and milk might be influenced by number of chlorine substituents and structures of congeners. In addition, maternal age and BMI were positively and negatively correlated with mass concentrations of dioxin-like compounds in milk and serum respectively. These results suggest that, compared with serum, it is limited to use breast milk to assess long-term exposure for the wider population., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Food safety crises involving persistent organic pollutants [POPs, e.g. dioxins, polychlorinated biphenyls (PCBs), organochlorine pesticides] lead to systematic slaughter of livestock to prevent their entry into the food chain. Therefore, there is a need to develop strategies to depurate livestock moderately contaminated with POPs in order to reduce such economic and social damages. This study aimed to test a POPs depuration strategy based on undernutrition (37% of energy requirements) combined with mineral oil (10% in total dry matter intake) in nine non-lactating ewes contaminated with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and PCBs 126 and 153. In order to better understand the underlying mechanisms of the depuration process, POPs kinetics and body lipids dynamics were followed concomitantly over 57-day of depuration in POPs storage (adipose tissue, AT), central distribution (blood) and excretion (faeces) compartments. Faecal POPs concentrations in underfed and mineral oil supplemented ewes increased by 2.0 to 2.6-fold, but not proportionally to lipids concentration which increased by 6-fold, compared to the control ewes. Nonetheless, after 57 days of depuration in undernutrition and mineral oil supplementation, AT POPs concentrations were 1.5 to 1.6-fold higher while serum concentrations remained unchanged compared to the control ewes. This was concomitant with a decrease by 2.7-fold of the AT estimated lipids weight along the depuration period. This reduction of the volume of the storage compartment combined with the increase of POPs faecal excretion in underfed and mineral oil supplemented ewes led to a reduction by 1.5-fold of the PCB 126 AT burden, while no changes were observed for TCDD and PCB 153 burdens (vs. no change for PCB 126 and increases for TCDD and PCB 153 AT burdens in control ewes). The original approach of this study combining the fine description at once of POPs kinetic and of body lipids dynamic improved our understanding of POPs fate in the ruminant., Competing Interests: The authors have declared that no competing interests exist.

Background: Childhood exposure to organochlorines has been associated with alterations in somatic growth. We evaluated the associations of peri-pubertal serum levels of dioxin-like compounds (DLCs) and nondioxin-like polychlorinated biphenyls (NDL-PCBs), with adolescent growth, body composition, and near adult height (NAH) in a longitudinal cohort study of Russian boys., Methods: 473 8-9 year-old boys had serum DLCs and associated toxic equivalents (TEQs) and NDL-PCBs concentrations measured. Physical examinations were performed at enrollment between 2003 and 2005, and annually over 11 years to 2016; annual bio-electric impedance analysis (BIA) of body composition began in 2006. We used mixed effects models to evaluate associations of quartiles of serum chemical concentrations with longitudinal measurements through age 19 of body mass index (BMI-Z) and height (HT-Z) z-scores, annual height velocity (HV), and BIA-derived height-adjusted fat (FMi) and fat-free mass (FFMi) indexes. Potential modification by age of the associations of chemical exposures with growth was evaluated. NAH (defined as HV < 1 cm/year) and age at NAH attainment were estimated using parametric survival models accounting for right censoring., Results: The medians of serum ∑TEQs, ∑DLCs, and ∑NDL-PCBs were 21.1 pg TEQ/g lipid, 362 pg/g lipid, and 250 ng/g lipid, respectively. In multivariable models, higher serum concentrations of peri-pubertal ∑TEQs, ∑DLCs, and ∑NDL-PCBs were associated with significantly lower BMI-Z, FMi, and FFMi over 11 years of follow-up. The differences in FFMi for boys with higher versus lower ΣTEQs and ΣNDL-PCBs increased with age. In multivariable models, higher ∑NDL-PCBs were associated with lower HT-Z, with attenuation of the association with age (interaction p < 0.001). The highest versus the lowest quartiles of ∑NDL-PCBs were not associated with differences in NAH, but were associated with an average of 6 months later attainment of NAH., Conclusions: Our findings suggest that dioxin and NDL-PCB exposures during childhood are associated with alterations in body composition and subsequent somatic growth., (Copyright © 2019 Elsevier GmbH. All rights reserved.)

Objective: The potential health risks of deployment to sites with open burn pits remain poorly understood, in part, because personal exposure monitoring was not performed. Here, we investigated whether postdeployment serum samples contain biomarkers associated with exposure to burn pits., Methods: A total of 237 biomarkers were measured in 800 serum samples from deployed and never-deployed subjects. We used a regression model and a supervised vector machine to identify serum biomarkers with significant associations with exposures and deployment., Results: We identified 101 serum biomarkers associated with polycyclic aromatic hydrocarbons, dioxins or furans, and 54 biomarkers associated with deployment. Twenty-six of these biomarkers were shared in common by the exposure and deployment groups., Conclusions: We identify a potential signature of exposure to open burn pits, and provide a framework for using postexposure sera to identify exposures when contemporaneous monitoring was inadequate.

Background: Exposure to the herbicide Agent Orange during the Vietnam War was widespread and is associated with numerous adverse health outcomes. A continuing concern of veterans is the possibility that exposure to the dioxin-containing herbicide might induce adverse reproductive outcomes. We sought to assess whether exposure to Agent Orange in Vietnam was associated with changes in DNA methylation in sperm in a subset of Vietnam veterans who participated in the Air Force Health Study (AFHS)., Methods: We studied 37 members of the AFHS chosen to have no, low, medium or high exposure to Agent Orange, based upon serum dioxin levels obtained during a series of examinations. DNA from stored semen was extracted and DNA methylation assessed on the Illumina 450 K platform., Results: Initial epigenome-wide analysis returned no loci that survived control for false discovery. However, the TEAD3 gene had four different CpG sites that showed loss of DNA methylation associated with dioxin exposure. Analysis assessing regional DNA methylation changes revealed 36 gene regions, including the region of the imprinted gene H19 to have altered DNA methylation associated with high exposure compared to the low exposure group. Additional comparison of our data with sperm DNA methylation data from Russian boys exposed to dioxin found an additional 5 loci that were altered in both studies and exhibited a consistent direction of association., Conclusions: Studying a small number of sperm samples from veterans enrolled in the AFHS, we did not find evidence of significant epigenome-wide alterations associated with exposure to Agent Orange. However, additional analysis showed that the H19 gene region is altered in the sperm of Agent Orange-exposed Ranch Hand veterans. Our study also replicated several findings of a prior study of dioxin-exposed Russian boys. These results provide additional candidate loci for further investigation and may have implications for the reproductive health of dioxin-exposed individuals.

The 32-mile Detroit River and surrounding tributaries have been designated as a Great Lakes Area of Concern due to pollution from decades of municipal and industrial discharges, sewer overflows and urban development. Key pollutants in fish samples from the Detroit River include mercury, polychlorinated biphenyls (PCBs), dichlorodiphenyldichloroethylene (DDE), dioxins and furans. A biomonitoring study was conducted to assess exposures to these persistent toxic substances in Detroit urban shoreline anglers who may be at high exposure risk due to consumption of locally caught fish. Using a modified venue-based sampling approach, 287 adult shoreline anglers along the Detroit River were recruited and participated in the program. Study participants provided blood and urine specimens and completed a questionnaire following informed consent. We examined percentile estimates for total blood mercury, PCBs, DDE, and dioxin-like total toxic equivalency (TEQ) concentrations among study participants. Multiple linear regression was used to identify important predictors of contaminant concentrations. Participants consumed a median of 64 Detroit River caught fish meals in the past year. The Detroit urban anglers' median total blood mercury concentrations was 3.2 times higher than that for the general adult U.S. population. PCB concentrations among the Detroit anglers aged 18-39 years were higher than the U.S. population of the same race/ethnicity. Elevated levels of DDE and total TEQ concentrations were not observed in the cohort. Eating more locally caught fish was associated with higher total blood mercury and serum PCB concentrations. The biomonitoring data served to inform public health officials and help guide environmental public health actions to reduce harmful exposures., (Published by Elsevier GmbH.)

The concentrations of polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) were analyzed in 40 plasma samples of individuals living in zones under potential influence of the emissions of a hazardous waste incinerator (HWI) (Tarragona County, Catalonia, Spain). Samples corresponded to subjects of different gender, age and specific areas of residence. The levels of PCDD/Fs were compared to those obtained in a baseline study (1998), as well as in previous surveys (2002, 2007 and 2012). The current mean concentration of PCDD/Fs in plasma was 6.79 pg I-TEQ/g lipid, which was significantly lower than the baseline concentration (27.0 pg I-TEQ/g lipid). A significant decrease was also observed in comparison to the results obtained in 2002 and 2007 (15.7 and 9.4 pg I-TEQ/g, respectively), while the current PCDD/F levels were similar to those obtained in 2012 (6.18 pg I-TEQ/g lipid). This important reduction in plasma PCDD/F levels is in accordance with the decreasing trend in the daily dietary intake of PCDD/Fs, which diminished from 210.1 pg I-TEQ (baseline) to 8.54 pg WHO-TEQ (current). OCDD was the predominant congener in plasma, while 2,3,7,8-TeCDD and 1,2,3,4,7,8,9-HpCDF showed the lowest levels. Based on the above results, as well as other recent data on the levels of PCDD/Fs in human milk, we conclude that the presence of the HWI does not mean additional and significant risks -as regards to PCDD/F exposure-for the population living in the neighborhood of the facility., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The notion of 'civilization diseases' is used to describe certain ailments whose aetiology is difficult to explain based on the knowledge about the functioning of the body and its metabolism. Only studies at the cellular level, on biochemical changes shed light on the causes of some diseases described as civilization diseases (cancers, cardiovascular and respiratory diseases, obesity, psychomotor disorders in children and an increase in the frequency of malformations). The factors whose incontestable influence on the increase in the frequency of occurrence of various 'civilization diseases' has been proved are persistent organic pollutants, among others belonging to the group of organohalogen compounds. Among organohalogen pollutants one needs to distinguish organochlorine compounds, which have been used as pesticides, and pollution emitted by various industries such as dioxins and furans, polychlorinated biphenyls, and polybrominated organic compounds used as flame retardants and perfluoroalkylated substances, which are characterized by high chemical and thermal stability as well as high surface activity due to which they may be widely used as oleophobic and hydrophobic factors.

Constant elimination half-life is usually used in first-order one-compartment pharmacokinetic models to assess human exposure to dioxin-like polychlorinated biphenyls (PCBs). However, hepatic clearance rates are usually lower for elders than for young people. In this study, levels of 12 dioxin-like PCBs were determined in blood samples collected in 2012 from 305 individuals from the general population. We estimated the historical daily intake of dioxin-like PCBs for individuals with a validated annual exponential decay function. Based on the blood levels and historical daily intake levels, and using the maximum likelihood estimation by running the first-order one-compartment pharmacokinetic model, elimination rates were optimized as exponential functions of age for PCB118, PCB157, PCB189 and PCB126; linear functions of age for PCB114, PCB123, PCB167 and PCB169; and constant functions of age for PCB105 and PCB156. With the exception of PCB105 and PCB156, half-lives generally increased with age for individuals from 24 to 50 years old: from 0.805 to 1.95 years for PCB189, 2.08-4.54 years for PCB157, 3.32-5.58 years for PCB126, 3.52-6.81 years for PCB123, 5.24-12.29 years for PCB169, 6.60-14.40 years for PCB114, 7.50-14.01 years for PCB118, and 9.97-21.97 years for PCB167. The half-lives of PCB105 (5.79 years) and PCB156 (15.1 years) were independent of age. Our research for the first time clarified the effects of age on the elimination rate of dioxin-like PCBs in individuals from the general population, thus reducing uncertainty in future health risk assessments., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Objective: To study the pollution status of polybrominated diphenyl ethers (PBDEs), polychlorinated biphenyls (PCB), polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) in cord blood of newborns in an e-waste dismantling area of Guangdong Province. Methods: We recruited 20 eligible mothers and newborns who could meet the inclusion criteria in local hospitals of Guiyu in 2007. The inclusion criteria included directly engaged in dismantling e-waste during pregnancy and within 1 year before pregnancy; living in the e-waste dismantling workshops or the distance between living place and the e-waste dismantling areas was ≤200 m; the father of newborn was directly engaged in electronic waste dismantling for more than 1 year; the frequency of visiting the e-waste dismantling workshop during pregnancy was ≥3 times in a week. Questionnaires and physical examinations were performed on maternal and neonatal, and cord blood was collected from newborns to detect PCDD/Fs, PCB and PBDE. The concentration level of organic pollutants was corrected by the blood lipid content, and the total toxicity equivalent was calculated. The correlation between three compounds was analyzed by Spearman correlation. Results: The mothers of the 20 newborns were (23.45±3.27) years old and lived for more than 5 years. The number of one parent engaged in e-waste dismantling, the mother or father smoking, and parent engaged in e-waste dismantling work were 3, 13, 15 and 19, respectively. The weight of newborns ranged from 2.5 to 3.6 kilogram and the Apgar score was 10 points. No adverse birth outcomes such as preterm birth, malformation or stillbirth were found. The median (maximum, minimum) concentration of PCBs, PCDD/Fs and PBDEs in cord blood were 263.22 (328.29, 244.19), 38.42 (147.49, 12.68), 39.33 (265.11, 14.81) pg/g lipid, respectively. The median (maximum, minimum) of toxic equivalence concentrations of PCDD/Fs and PCB were 3.94 (9.24, 2.69) and 15.95 (26.64, 9.28) pg TEQ/g lipid. PBDE, the proportion of PBDE, PCB and PCDD/Fs in cord blood was 50.41%, 49.25% and 0.34%, respectively. PCBs and PBDEs were positively correlated ( r= 0.733, P= 0.039). Conclusion: The high concentrations of PCDD/Fs, PCB, and PBDE were detected in the e-waste dismantling area. It is recommended that the risk of such substances on the health of local people should be assessed in a timely manner.

There is mounting concern about the effects of early-life exposure to chemical substances on children's health and development. We summarize the past and ongoing birth cohort studies carried out worldwide on the association between environmental exposure and children's health. Our PubMed search with the keywords 'birth cohort' revealed that the number of articles jumped from 200-300 in the 1980s to over 1,000 in the 1990s. Many of these articles reported elevated risks to children's health posed by chemical exposure owing their vulnerability. At the same time, policies implemented to reduce exposure to lead and dioxins were successful in the past few decades. Research also demonstrated that intervention to reduce exposure to certain chemicals whose exposure routes were well documented was also successful. We summarize the effects of early-life exposure to chemical substances on children's health and development. Our findings will hopefully help safeguard the environment in which future generations grow and live.

Purpose: Patients with Yusho, a condition caused by exposure to dioxins and dioxin-like compounds, have diverse mental and physical complaints. However, the relationship between dioxins and sleep disorders has not yet been examined. This cross-sectional study was designed to investigate problems associated with sleep among patients with Yusho., Methods: A total of 140 participants (52.9% men, average age: 67.1 ± 12.2 years) were examined using questionnaires and medical interviews by an expert on sleep medicine. Demographic and clinical characteristics, including blood concentrations of 2,3,4,7,8-pentachlorodibenzofuran (PeCDF), which is the major cause of Yusho, were obtained from the results of recent surveys conducted by the Yusho Study Group., Results: Moderate to severe symptoms of insomnia were present in 51.8% of the patients. The median Pittsburgh Sleep Quality Index global score (PSQI GS) was 8 (interquartile range: 5-11). The prevalence of restless legs syndrome/Willis-Ekbom disease (RLS/WED) was 30.7%; 24.3% of patients had severe RLS/WED (distressing symptoms with a frequency ≥ 1day per week). A higher blood concentration of 2,3,4,7,8-PeCDF (≥72.27 pg/g lipid) and severe RLS/WED were associated with higher odds of a PSQI GS ≥8, after adjusting for covariates (odds ratio [95% confidence interval]: 4.84 [1.10-21.25] and 4.15 [1.53-11.28], respectively)., Conclusions: Symptoms of insomnia were frequent, and the prevalence of RLS/WED was high in patients with Yusho. In addition to the presence of RLS/WED, a higher blood concentration of 2,3,4,7,8-PeCDF was associated with lower subjective sleep quality., (Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.)

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) or dioxin, is commonly considered the most toxic man-made substance. Dioxin exposure impacts human health and diseases, birth defects and teratogenesis were frequently observed in children of persons who have been exposed to dioxin. However, the impact of dioxin on human mutation rate in trios has not yet been elucidated at the whole genome level. To identify and characterize the genetic alterations in the individuals exposed to dioxin, we performed whole genome sequencing (WGS) of nine Vietnamese trios whose fathers were exposed to dioxin. In total, 846 de novo point mutations, 26 de novo insertions and deletions, 4 de novo structural variations, and 1 de novo copy number variation were identified. The number of point mutations and dioxin concentrations were positively correlated (P-value < 0.05). Considering the substitution pattern, the number of A > T/T > A mutation and the dioxin concentration was positively correlated (P-value < 0.05). Our analysis also identified one possible disease-related mutation in LAMA5 in one trio. These findings suggested that dioxin exposure might affect father genomes of trios leading to de novo mutations in their children. Further analysis with larger sample sizes would be required to better clarify mutation rates and substitution patterns in trios caused by dioxin., (© 2018 Wiley Periodicals, Inc.)

Background: Prenatal exposure to dioxin-like compounds (DLCs) irreversibly affects fetal reproductive and steroid hormone synthesis., Objective: This study aimed to assess the relationships between maternal DLCs and cord blood reproductive and steroid hormones., Methods: Participants in this study were pregnant women who enrolled in the Sapporo Cohort of the Hokkaido Study between 2002 and 2005. We quantified 29 DLCs during the 2nd and 3rd trimesters in maternal blood. Additionally, we measured the concentrations of progesterone, estradiol (E2), testosterone (T), androstenedione, dehydroepiandrosterone (DHEA), cortisol, cortisone, sex hormone-binding globulin (SHBG), luteinizing hormone (LH), follicle-stimulating hormone (FSH), prolactin, inhibin B, and insulin-like factor-3 (INSL3) in cord blood samples., Results: Data from 183 mother-child pairs were analyzed. We observed sex-dependent associations of DLCs on T/E2 ratios, DHEA, cortisol, cortisone, adrenal androgen/glucocorticoid (AA/GC: sum of DHEA and androstenedione)/(sum of cortisol and cortisone) ratios and SHBG. An increase in maternal DLCs related to decreased T/E2 ratios and SHBG and inhibin B levels, and increased AA/GC ratios and FSH and DHEA levels in male cord blood samples. However, an increase in maternal mono-ortho polychlorinated biphenyls related to increased cortisol, cortisone, and SHBG levels, and decreased DHEA levels and AA/GC ratios in female cord blood samples., Conclusions: Prenatal exposure to DLCs alters steroidogenesis and suppresses the secretion of inhibin B in male cord blood. Relationships between maternal DLCs and cord blood hormones differ between boys and girls. Further studies are required to clarify whether the effects of in utero exposure to DLCs on adrenal hormones extend into infancy and puberty., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Prospective cohort studies evaluating the temporal trends of background-level persistent organic pollutants (POPs) and their potential negative health effects in humans are needed., Objective: The objectives of this study are to examine the five year longitudinal trend in chlorinated and brominated (Cl/Br) POP concentrations in a sample of elderly individuals and to investigate the relationship between gender, changes in body weight, plasma lipid levels and POP concentrations., Methods: In the population-based Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study, plasma samples were collected from the same individuals over a 5 year period. Originally 992 subjects (all aged 70) were sampled between 2001 and 2004 and 814 returning subjects (all aged 75) were sampled again from 2006 to 2009. Plasma concentrations of 16 polychlorinated biphenyls (PCBs), 5 organochlorine pesticides (OCPs), octachlorinated dibenzo-p-dioxin (OCDD), and one polybrominated diphenylether (BDE 47) were determined using high-throughput 96-well plate solid phase extraction and gas chromatography-high resolution mass spectrometry (GC-HRMS)., Results: During the 5-year follow-up, plasma concentrations of all POPs significantly decreased (p < 0.00001). Median reductions ranged from 4% (PCB105) to 45% (PCB 99), with most reductions being in the 30-40% range. For most POPs, a larger decline was seen in men than in women. The relationship between the weight change and change in POP concentrations was generally negative, but a positive relationship between lipid levels and POP concentrations when expressed as wet-weight was observed. In general, similar changes in POP concentrations and their relationships to body weight were observed regardless of using either wet-weight (pg/mL) or lipid-normalized (ng/g lipid) concentrations., Conclusion: In this longitudinal cohort study, gender and minor, but varying changes in body weight and lipid levels greatly influenced the individual-based changes in POP concentrations. In general, our findings suggest that men and women with larger decreases in body weight and greater increases in lipid levels have the slowest decline in body burden of POPs. Based on the results from this study, either wet-weight or lipid normalized concentrations can be used to determine the percent change in POP concentrations and their relationships to physiological changes and differences., (Copyright © 2018. Published by Elsevier Inc.)

The author reviewed recent reports about the blood levels and dietary intake of polychlorinated dibenzo-p-dioxins (PCDDs)/furans (PCDFs)/dioxin-like polychlorinated biphenyls (DL-PCBs) to investigate the trends of dioxin exposure, and epidemiologic studies on the associations of blood levels of dioxins with metabolic diseases. In recent years, dietary intake of dioxins has been decreasing, and the means are equal to or less than 1.0 pg Toxic Equivalents (TEQ)/kg/day in the general populations of several countries. The blood levels of dioxins are also decreasing, probably because of reduced dietary intake. Many cross-sectional studies reported positive associations between blood levels of some isomers or TEQ-based concentrations of PCDDs/PCDFs/DL-PCBs and diabetes in general populations. Three cohort studies on populations with heavy exposure and two nested case-control studies on general populations have also been published, but the results are inconsistent. Three large-scale cross-sectional studies and two cohort studies reported an association between blood levels of some isomers or TEQ-based concentrations of PCDDs/PCDFs/DL-PCBs and metabolic syndrome. In addition, three cross-sectional studies reported significant positive associations with gout/hyperuricemia. Further prospective studies and experimental studies are needed to establish cause-effect relationships, and to clarify the biological mechanisms for the association between background exposure to dioxins and potential health effects. J. Med. Invest. 65:151-161, August, 2018.

Environmental exposure to organic endocrine disrupting chemicals, including dioxins, dibenzofurans, bisphenol A (BPA), and phthalates has been associated with neurodevelopmental disorders, including autism spectrum disorder (ASD). We conducted a pilot monitoring study of 30 ASD cases and 10 typically developing (TD) controls ages 2-8 years from communities along the Gulf of Mexico near Alabama, which houses 14 Superfund sites, to assess the concentrations of dioxins and dibenzofurans in serum, and BPA and phthalate ester metabolites in urine. Based on General Linear Models, the lipid- or creatinine-adjusted geometric mean concentrations of the aforementioned chemicals did not differ between the ASD case and TD control groups (all p ≥ 0.27). We compared our findings to the adjusted means as reported by the National Health and Nutrition Examination Survey, survey years 2011-2012, and found that TD controls in our study had lower BPA (59%) and MEHHP (26%) concentrations, higher MBP (50%) concentration, and comparable (<20% difference) MEP, MBZP, MEOHP, and MCPP concentrations. We also conducted a preliminary investigation of dietary exposures and found that the consumption of certain types of fish may be associated with higher OCDD concentrations, and the consumption of soft drinks and juices may be associated with lower BPA and MEOHP concentrations, respectively., Competing Interests: The authors declare no conflict of interest.

Background: Consistent reports are not available on the effects of dioxin-like polychlorinated biphenyls (PCBs) and polychlorinated dibenzo-p-dioxins (PCDD)/ polychlorinated dibenzofurans (PCDF) (dioxin-like compounds [DLCs]) on child neurodevelopment. Further, the effect of background-level exposure to individual DLC isomers is not known., Objectives: We carried out the Sapporo cohort study to evaluate the effect of prenatal exposure to each DLC isomer on child neurodevelopment at 6 and 18 months of age, and assessed sex-specific differences in these effects., Methods: The levels of all and each individual DLC isomers were estimated in maternal peripheral blood. Neurodevelopment was evaluated using the Bayley Scales of Infant Development-2nd Edition for 6-month-old infants (n = 190) and 18-month-old children (n = 121)., Results: In male children, levels of 10 DLC isomers were significantly negatively associated with the Psychomotor Developmental Index (PDI) at 6 months of age after adjustment for potential confounding variables. However, at 18 months of age, these associations were absent. In female children, the level of only one DLC isomer was significantly negatively associated with PDI at 6 months of age. However, in contrast to the male children, the levels of six DLC isomers in 18-month-old female children were significantly positively associated with the Mental Developmental Index., Conclusions: These findings indicate that adverse neurodevelopmental effects of prenatal background-level exposure to DLCs may be stronger in male children., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objectives: Dioxins and PCBs are highly toxic and persistent environmental pollutants that are measurable in humans worldwide. These persistent organic pollutants are associated with a higher incidence of diabetes mellitus. We hypothesise that perinatal (background) exposure to industrial pollutants like dioxins also influences body mass development and energy metabolism in later life., Study Design: In The Netherlands, the perinatal exposure (prenatal exposure and postnatal lactational intake) to dioxins has been studied prospectively since 1987. Fasting glucose, insulin, HbA1c and leptin were analysed in 33 children of the original cohort of 60. BMI, glucose:insulin and BMI:leptin ratios were calculated. Prenatal exposure, lactational intake and current serum levels of dioxins (PCDD/F), dl-PCBs and PBDE concentrations were determined using (HR)GC-MS., Results: Prenatal dioxin (PCDD/F) exposure was positively correlated to the glucose:insulin ratio (p = 0.024) and negatively correlated to the fasting insulin concentration (p = 0.017) in adolescence. Postnatal lactational PCDD/F intake was also negatively correlated to fasting insulin concentration (p = 0.028). Current serum levels of PCDD/Fs and total TEQ (dl-PCBs+PCDD/Fs) were positively correlated to the fasting serum glucose concentration (p = 0.015 and p = 0.037, respectively).No metabolic effects were seen in association with current serum levels of PBDEs. A positive correlation between the insulin and leptin concentrations (p = 0.034) was observed. No effects were found on leptin levels, BMI:leptin ratio, HbA1c levels or BMI., Discussion/conclusion: This study indicates that prenatal and lactational exposure influences glucose metabolism in adolescents, presumably through a negative effect on insulin secretion by pancreatic beta cells. Additionally, the very low recent background exposure to dioxins in puberty possibly has an effect on the glucose level.

Dioxin-like compounds (DLCs) are monitored in the U.S. population using data collected with the National Health and Nutrition Examination Survey (NHANES). Until recently, participants' serum samples have been analyzed individually, and summary statistics defining reference ranges by age, gender, and race/ethnicity have served as the background by which other biomonitoring data can be evaluated. In the most recent NHANES DLC data, 2005-2006 and 2007-2008, participants' sera have been physically pooled prior to laboratory analysis, introducing major challenges to their utility as a reference population: variability among individuals and relations with covariates are lost, and individual design effects cannot be applied. Further, the substantial drop in limits of detection (LODs) in pooled sample biennials prevents reliable comparisons to individual data, and has complicated estimates of change over time. In this study, we address the drawbacks introduced by pooled samples by generating U.S. population reference ranges based on individual-level data adjusted to 2005-2006 and 2007-2008 levels. Using publicly available data, multiple imputation (MI) generated four NHANES biennials (2001-2008) of individual DLC data; we then trended the change over time in each DLC by demographic stratum. NHANES 2003-2004 individuals were adjusted by the trended change over time. Population estimates of toxic equivalency (TEQ) concentrations were calculated using traditional MI survey analysis methods and reference tables provided for 2005-2006 and 2007-2008 by age, race, and gender. Demographic differences in TEQ concentrations and trended change are reported, e.g. TEQ continues to drop in young adults aged 20-39, but distributions appear stable in older adults 60+; Mexican Americans have consistently lowest dioxins, furans, and PCBs, with non-Hispanic Blacks dropping to the same levels as non-Hispanic Whites in dioxins and PCBs and significantly below non-Hispanic Whites in furans by 2007-2008. Additionally, the ratio of 95th percentile to mean in DLC distributions was found to vary by age, between dioxins, furans, and PCBs, and across mean, making a simple ratio approach impractical for describing population concentrations using pooled samples. We discuss the practical implications of the pooled sample method, the performance of this trending solution in the context of other methods, and expected effects of distribution assumptions on variability and TEQ estimates, particularly in largely undetected congeners. These updated reference populations of individuals, along with information on trending, provide a common and valid basis for interpreting other individually sampled biomonitoring data., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Objectives: We investigated the effects of maternal polymorphisms in 3 genes encoding dioxin-metabolizing enzymes in relation to prenatal dioxin levels on infant birth size in Japan., Methods: We examined the relationship between dioxin exposure and birth size in relation to the polymorphisms in the genes encoding aromatic hydrocarbon receptor (AHR [G>A, Arg554Lys]), cytochrome P450 (CYP) 1A1 (T6235C), and glutathione S-transferase mu 1 (GSTM1; Non-null/null) in 421 participants using multiple linear regression models., Results: In mothers carrying the GSTM1 null genotype, a ten-fold increase in total dioxin toxic equivalency was correlated with a decrease in birth weight of -345g (95% confidence interval: -584, -105)., Conclusions: We observed adverse effects of maternal GSTM1 null genotype on birth weight in the presence of dioxins exposure during pregnancy., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objectives: Exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) has inconsistently been associated with a decreased sex ratio of the offspring (number of male births divided by total births). We conducted a study among men and women who were employed in a New Zealand phenoxy herbicide production plant between 1969 and 1984, to study their offspring sex ratio in relation to their back-calculated TCDD serum concentrations determined in 2007/2008., Methods: A total of 127 men and 21 women reported that 355 children were conceived after starting employment at the plant. The association between their lipid-standardised TCDD serum concentrations back-calculated to the time of their offspring's birth and the probability of a male birth was estimated through logistic regression, adjusting for the age of the exposed parent at birth, current body mass index and smoking., Results: The overall sex ratio was 0.55 (197 boys, 158 girls). For fathers with serum TCDD concentrations ≥20 pg/g lipid at time of birth, the sex ratio was 0.47 (OR 0.49; 95% CI 0.30 to 0.79). The probability of a male birth decreased with higher paternal serum TCDD at time of birth (<4; 4-20; 20-100; ≥100 pg/g lipid), with ORs of 1.00 (reference); 1.00 (95% CI 0.50 to 2.02); 0.52 (95% CI 0.29 to 0.92); 0.45 (95% CI 0.23 to 0.89), p trend 0.007. For exposed mothers, the sex ratio was not reduced., Conclusions: This study indicates that paternal serum TCDD concentrations in excess of an estimated 20 pg/g lipid at time of conception are associated with a reduced sex ratio., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Globally, many river sediments are seriously contaminated with persistent organic pollutants (POPs) known to accumulate in aquatic food. In the Netherlands, toxicological risks of human exposure to dioxins and dioxin-like compounds led to a ban on eel fishing in the Rhine-Meuse delta. The aim of this study is to investigate differences in serum POP levels in consumers of eel from high-polluted areas and consumers of eel from low-polluted areas or aquaculture. In total 80 Dutch men were included, aged 40-70 years, with a habitual eel consumption of at least one portion (150 g) per month. Total levels of dioxins and dioxin-like compounds were measured in serum of all participants with the DR CALUX bioassay, validated with GC-MS. For a subgroup of 38 participants extensive POP measurements were performed. We revealed that consumption of eel from polluted rivers resulted in 2.5 and up to 10 times increased levels of dioxins and polychlorinated biphenyls (PCBs) respectively compared to controls. The highest PCB levels were detected for PCB 153, with a median level of 896 ng/g lipid and a maximum level of 5000 ng/g lipid in the high-exposed group. Furthermore, hydroxylated PCB metabolites (OH-PCBs: sum of 4-OH-CB107, 4-OH-CB146, 4'-OH-CB172, and 4-OH-CB187) were 8 times higher in men who consumed eel from polluted areas, and detected at levels (median 4.5 ng/g ww) reported to cause adverse health effects. Also, the majority of the perfluoroalkyl substances (PFASs) were significantly higher in consumers of eel from pullulated areas. In conclusion, this study is the first to reveal that (past) consumption of eel from polluted rivers resulted in high body burdens of dioxins, PCBs, OH-PCBs and PFASs. We confirmed the predictions made in a former risk assessment, and the high levels of dioxins and dioxin-like compounds as well as the OH-PCBs are of health concern., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Dioxins, furans, and polychlorinated biphenyls (PCBs), dioxin-like and non-dioxin-like, have been linked to alterations in puberty., Objectives: We examined the association of peripubertal serum levels of these compounds [and their toxic equivalents (TEQs)] with pubertal onset and maturity among Russian boys enrolled at ages 8-9 years and followed prospectively through ages 17-18 years., Methods: At enrollment, 473 boys had serum dioxin-like compounds and PCBs measured. At the baseline visit and annually until age 17-18 years, a physician performed pubertal staging [genitalia (G), pubarche (P), and testicular volume (TV)]. Three hundred fifteen subjects completed the follow-up visit at 17-18 years of age. Pubertal onset was defined as TV > 3 mL, G2, or P2. Sexual maturity was defined as TV ≥ 20 mL, G5, or P5. Multivariable interval-censored models were used to evaluate associations of lipid-standardized concentrations with pubertal timing., Results: Medians (interquartile ranges) of the sum of dioxin-like compounds, TEQs, and non-dioxin-like PCBs were 362 pg/g lipid (279-495), 21.1 pg TEQ/g lipid (14.4-33.2), and 250 ng/g lipid (164-395), respectively. In adjusted models, the highest compared to lowest TEQ quartile was associated with later pubertal onset [TV = 11.6 months (95% CI: 3.8, 19.4); G2 = 10.1 months (95% CI: 1.4, 18.8)] and sexual maturity [TV = 11.6 months (95% CI: 5.7, 17.6); G5 = 9.7 months (95% CI: 3.1, 16.2)]. However, the highest compared to the lowest quartile of non-dioxin-like PCBs, when co-adjusted by TEQs, was associated with earlier pubertal onset [TV = -8.3 months (95% CI:-16.2, -0.3)] and sexual maturity [TV = -6.3 months (95% CI:-12.2, -0.3); G5 = -7.2 months (95% CI:-13.8, -0.6)]; the non-dioxin-like PCB associations were only significant when adjusted for TEQs. TEQs and PCBs were not significantly associated with pubic hair development., Conclusions: Our results suggest that TEQs may delay, while non-dioxin-like PCBs advance, the timing of male puberty. Citation: Burns JS, Lee MM, Williams PL, Korrick SA, Sergeyev O, Lam T, Revich B, Hauser R. 2016. Associations of peripubertal serum dioxin and polychlorinated biphenyl concentrations with pubertal timing among Russian boys. Environ Health Perspect 124:1801-1807; http://dx.doi.org/10.1289/EHP154., Competing Interests: The opinions in this article are those of the authors and do not necessarily reflect the official opinion of the U.S. EPA or the NIEHS. T.L. is employed by Gradient (Cambridge, MA). The other authors declare they have no actual or potential competing financial interests.

Background: In the risk assessment of PCDDs, PCDFs, and dioxin-like (DL) PCBs, regulatory authorities support the use of the toxic equivalency factor (TEF)-scheme derived from a heterogeneous data set of the relative effect potency (REPs) estimates., Objectives: We sought to determine REPs for dioxin-like compounds (DLCs) using expression of cytochrome P450 (CYP) 1A1 and 1B1 mRNA in human peripheral blood mononuclear cells representing two different pathways., Methods: We used a sex and age adjusted regression-based approach comparing the strength of association between each DLC and the cytochrome P450 (CYP) 1A1 and 1B1 mRNA expression in 320 adults residing in an organochlorine-polluted area of eastern Slovakia., Results: We calculated REPs based on CYP1A1 expression for 4 PCDDs, 8 PCDFs, and 1 PCB congener, and based on CYP1B1 expression for 5 PCDFs and 11 PCB congeners. REPs from CYP1A1 correlated with REPs previously derived from thyroid volume (ρ=0.85; p<0.001) and serum FT4 (ρ=0.77; p=0.009). The 13 log REPs from CYP1A1 correlated with log WHO-TEFs (r=0.63; p=0.015) and 11 log PCB REPs with PCB consensus toxicity factors (CTFs) for compounds with WHO-TEFs (r=0.80; p=0.003). The complete set of derived 56 log REPs correlated with the log CTFs (r=0.77; p=0.001) and log WHO-TEFs (r=0.81; p<0.001)., Conclusions: REPs calculated from thyroid and cytochrome P450 endpoints realistically reflect human exposure scenarios because they are based on human chronic and low-dose exposures. While the CYP 1A1 seems more suitable for toxicity evaluation of PCDD/Fs, the CYP 1B1 is more apt for PCDFs and PCBs and reflects different pathways., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Objective: The New Zealand Ministry of Health responded to community concern about dioxin exposure during on-site remediation of a pesticide-contaminated rural area by commissioning this exposed-referent study of serum dioxins and health in local residents., Methods: All 200 residents were eligible, with age and sex matching to demographically comparable referents. Face-to-face interviews included questions on health status, health-related quality of life (HRQOL) and perceptions about community consultation. Thirty serum samples were obtained, eligibility being based on likelihood of exposure and age. Both HRQOL and serum outcomes were analysed by the appropriate regression methods., Results: Of 200 eligible residents, 139 (69.5%) participated, with 139 matched referents. Mapua residents had lower physical and psychological HRQOL scores, but no difference in health status. 2,3,7,8 TCDD was below the limit of detection in the majority of all serum samples, with some congeners being higher in referents. Perceptions of the communication process were equivocal., Conclusions: Both dioxin levels and measures of health did not differ significantly between the exposed community and controls. Implications for public health: The results suggest neither significant dioxin exposure nor community health effects. Oversight by expert panel with health expertise, allied to sound communication, may have helped the community understand the risks., (© 2016 Public Health Association of Australia.)

Background: Once ingested, dioxins and dioxin-like compounds are excreted extremely slowly. Excretion can be evaluated by its half-life. Half-lives estimated from observed concentrations are affected by excretion and ongoing exposure. We investigated the change in apparent half-life using a theoretical model based on exposure to dioxin and dioxin-like compounds., Methods: We carried out longitudinal measurements of the blood concentration of dioxins and dioxin-like compounds in a Yusho cohort during 2002 to 2010. We estimated the change in decay rates of 2,3,4,7,8-PeCDF and octachlorodibenzodioxin (OCDD) using a second-order equation., Results: We found that the decay rate of OCDD increased, whereas the decay rate of 2,3,4,7,8-PeCDF of patients with a relatively high concentration of 2,3,4,7,8-PeCDF decreased. OCDD results were in accordance with decreasing levels of dioxin and dioxin-like compounds in the environment. The decay rate of OCDD in the body was affected by the decay rate of OCDD in the environment by ingestion because it was near the steady-state. In contrast, the decay rate of 2,3,4,7,8-PeCDF in the body was affected less by ingestion from the environment because it was far higher than in the steady-state., Conclusion: We demonstrated that the level of 2,3,4,7,8-PeCDF in the environment is decreasing. The excretion half-life is longer than the environmental half-life, thus the excretion half-life in a Yusho patient is increased.

Humans are exposed to a large number of environmental chemicals in their daily life, many of which are readily detectable in blood or urine. It remains uncertain if these chemicals can cause adverse health effects when present together at low doses. In this study we have tested whether a mixture of 27 chemicals administered orally to juvenile male rats for three months could leave a pathophysiological footprint. The mixture contained metals, perfluorinated compounds, PCB, dioxins, pesticides, heterocyclic amines, phthalate, PAHs and others, with a combined dose of 0.16 (Low dose), 0.47 (Mid dose) or 1.6 (High dose) mg/kg bw/day. The lowest dose was designed with the aim of obtaining plasma or urine concentrations in rats at levels approaching those observed in humans. Some single congeners were administered at doses representative of combined doses for chemical groups. With this baseline, we found effects on weight, histology and gene expression in the liver, as well as changes to the blood plasma metabolome in all exposure groups, including low-dose. Additional adverse effects were observed in the higher dosed groups, including enlarged kidneys and alterations to the metabolome. No significant effects on reproductive parameters were observed., Competing Interests: The authors have declared that no competing interests exist.

Background: Elevated blood or urinary concentrations of endocrine-disrupting chemicals (EDCs) may be related to increased risk of type 2 diabetes (T2D). The aim of the present study was to assess the role of EDCs in affecting risk of T2D and related metabolic traits., Methods: MEDLINE was searched for cross-sectional and prospective studies published before 8 March 2014 into the association between EDCs (dioxin, polychlorinated biphenyl [PCB], chlorinated pesticide, bisphenol A [BPA], phthalate) and T2D and related metabolic traits. Three investigators independently extracted information on study design, participant characteristics, EDC types and concentrations, and association measures., Results: Forty-one cross-sectional and eight prospective studies from ethnically diverse populations were included in the analysis. Serum concentrations of dioxins, PCBs, and chlorinated pesticides were significantly associated with T2D risk; comparing the highest to lowest concentration category, the pooled relative risks (RR) were 1.91 (95% confidence interval [CI] 1.44-2.54) for dioxins, 2.39 (95% CI 1.86-3.08) for total PCBs, and 2.30 (95% CI 1.81-2.93) for chlorinated pesticides. Urinary concentrations of BPA and phthalates were also associated with T2D risk; comparing the highest to lowest concentration categories, the pooled RR were 1.45 (95% CI 1.13-1.87) for BPA and 1.48 (95% CI 0.98-2.25) for phthalates. Further, EDC concentrations were associated with indicators of impaired fasting glucose and insulin resistance., Conclusions: Persistent and non-persistent EDCs may affect the risk of T2D. There is an urgent need for further investigation of EDCs, especially non-persistent ones, and T2D risk in large prospective studies., (© 2015 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.)

Persistent organic pollutants are widespread in the environment, and are associated with a particular health and ecological concern. The human body burden of polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDDs/Fs), polybrominated dibenzo-p-dioxins and dibenzofurans (PBDDs/Fs), polychlorinated biphenyls (PCBs), polybrominated diphenylether (PBDEs), and hexabromocyclododecanes (HBCDs) was determined. Blood samples were collected in Germany, originating from 42 randomly selected subjects between 20 and 68 years old. The median (95th percentile) concentrations, expressed as WHO2005-TEQ for PCDD/PCDFs and dioxin-like PCBs, were 6.2 (19.1) pg/g l.w. and 4.1 (8.8) pg/g l.w., respectively. PBDDs/Fs were found with a median of 2.8 pgTEQ/g l.w. and a 95th percentile of 8.7 pgTEQ/g l.w. (using similar interim TEF values as for PCDDs/Fs) On a median basis, the contribution of PCDD/Fs, dioxin-like PCBs, and PBDDs/Fs to total TEQ were 47%, 31%, and 21%, respectively. The sum of the 6 non-dioxin-like PCBs exhibited a median of 267ng/g l.w. and a 95th percentile of 834ng/g l.w. The median value for the sum of six tetra- to hepta-PBDE congeners was 1.7ng/g l.w. (95th percentile: 4.9ng/g l.w.). BDE 209 was the most abundant congener with a median of 1.8ng/g l.w. HBCDs were only found in some samples, and concentrations ranged between the limit of detection (5ng/g l.w.) and the limit of quantification (16ng/g l.w.). Results for PBDEs and HBCDs are comparable to other European studies. Our study demonstrated that the body burden of PCDD/Fs and PCBs declined continously since the last three decades, but exposure may exceed precautionary guideline levels., (Copyright © 2016 Elsevier GmbH. All rights reserved.)

We assessed the association of three chlorinated dibenzo-p-dioxins, a chlorinated dibenzofuran, and four dioxin-like polychlorinated biphenyls (PCBs) in human blood with nephropathy (microalbuminuria or macroalbuminuria) among teens and young adults (12-30 years old) having normal glycohemoglobin (A1c <5.7%). The data were derived from the 1999-2004 National Health and Nutrition Examination Survey (unweighted n=1504, population estimate=38,806,338). In this paper, nephropathy refers to normal A1c with nephropathy. In an all-adult sample (Everett CJ, Thompson OM. Dioxins, furans and dioxin-like PCBs in human blood: causes or consequences of diabetic nephropathy? Environ Res 2014;132:126-31), the cut-offs for these chemicals being considered elevated, were defined as the 75th percentile. Using these same cut-offs again, the proportion of those with one or more of the eight dioxin-like compounds elevated was 9.9%. The four chemicals associated with nephropathy were 1,2,3,6,7,8-hexachlorodibenzo-p-dioxin, PCB 126, PCB 169, and PCB 156. The proportion with one or more of these four dioxin-like chemicals elevated was 3.9% (unweighted n=46) and the odds ratio (OR) for nephropathy was 7.1 [95% confidence interval (CI) 1.8-28.1]. The association was strong among females (OR 17.4, 95% CI 3.4-88.6), but among males there were no cases of nephropathy when one or more of the four dioxin-like chemicals were elevated, and therefore no association. In a separate analysis, elevated toxic equivalency, defined using the eight dioxin-like chemicals (TEQ8), was associated with nephropathy. TEQ8 ≥50.12 fg/g included 2.6% of the sample (unweighted n=28) and had an OR of 5.8 (95% 1.3-25.9) for nephropathy. As found in the analysis of one or more of four dioxin-like chemicals elevated, TEQ8 ≥50.12 fg/g was associated with nephropathy among females (OR 11.9, 95% CI 1.6-87.2), but not males. Trends for least-squares means also differed by gender, but there were no significant differences in mean TEQ8 between normal subjects and those having nephropathy in either males or females. We also evaluated pre-diabetes (A1c 5.7-6.4%) without nephropathy and found no associations when one or more of four dioxin-like compounds were elevated, or when TEQ8 was ≥50.12 fg/g. In this study, associations of dioxin-like chemicals with nephropathy were found among females at an early age. Prospective studies are needed to determine if dioxin-like compounds cause nephropathy, or if these relationships are cases of reverse causation.

Background and Aims: The aim of this study was to explore the effect of a vegetarian versus conventional diet on the serum levels of persistent organic pollutants (POPs) in patients with T2D after 12 weeks of dietary intervention and to assess their relationships with metabolic parameters., Methods and Results: Men and women with T2D were randomly assigned to follow either a vegetarian diet without fish or meat (n = 37) or an isocaloric conventional antidiabetic diet (n = 37). Both diets were energy restricted (minus 500 kcal/day). All foods were provided to the participants. At randomization (week 0) and 12 weeks, the meal test was performed to assess the β-cell function and serum levels of 24 POPs. Dioxins and dioxin-like POPs were analyzed by isotope dilution high-resolution gas chromatography (HRGC) and mass spectrometry after cleanup of the silica and carbon columns. Non-dioxin-like POPs were analyzed by gas chromatography with an electron capture detector (GC-ECD). Statistical analyses used were repeated-measures analysis of variance (ANOVA), a multivariate regression model, and Pearson's correlations. We observed a statistically nonsignificant trend toward increases in the serum levels of most POPs in response to both hypocaloric diets with no differences between groups. In the groups combined, the change in serum concentrations of total POPs was correlated to changes in HbA1c (r = +0.34; p < 0.01), fasting plasma glucose (r = +0.41; p < 0.01) levels, and β-cell function measured as insulin secretion at a reference glucose level (r = -0.37; p < 0.01), independent of the changes in body weight and volume of visceral fat., Conclusion: Short-term hypocaloric vegetarian and conventional diets did not reduce the POP levels, possibly due to mobilization of fat stores. Our findings support the relationship between POPs and diabetes, especially β-cell function., Trial Registration: ClinicalTrials.gov number, NCT00883038, completed., (Copyright © 2016 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Background: Dioxin is an industrial pollutant related to various diseases, but epidemiological data on its effects on the kidney are limited. Therefore, we conducted a study to evaluate the association between dioxin exposure and chronic kidney disease (CKD) and identify the related factors., Methods: We conducted a community-based cross-sectional study and recruited participants from an area where the residents were exposed to dioxin released from a factory. We defined a "high dioxin level" as polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) ≥ 20 pg WHO98-TEQDF/g lipid in the serum and defined CKD as having an estimated glomerular filtration rate (e-GFR) ≤ 60 mL/min/1.73m2 or a diagnosis of CKD by a physician. The renal function was assessed between 2005 and 2010, and we excluded those who had had kidney diseases before the study started. Comparisons between patients of CKD and those who did not have CKD were made to identify the risk factors for CKD., Results: Of the 2898 participants, 1427 had high dioxin levels, and 156 had CKD. In the univariate analyses, CKD was associated with high dioxin levels, age, gender, metabolic syndrome, diabetes mellitus, hypertension, and high insulin and uric acid levels. After adjusting for other factors, we found high dioxin levels (adjusted odds ratio [AOR] = 1.76, 95% confidence interval [CI]: 1.04-2.99), female gender (AOR = 1.74, 95%CI: 1.20-2.53), hypertension (AOR = 1.68, 95%CI: 1.17-2.42), high insulin levels (AOR = 2.14, 95% CI: 1.26-3.61), high uric acid levels (AOR = 4.25, 95% CI: 2.92-6.20), and older age (AOR = 4.66, 95% CI: 1.87-11.62 for 40-64 year and AOR = 26.66, 95% CI: 10.51-67.62 for age ≥ 65 year) were independent predictors of CKD., Conclusion: A high dioxin level was associated with an increased prevalence of CKD. Therefore, the kidney function of populations with exposure to dioxin should be monitored.

The relationship between polychlorinated biphenyl (PCB) burden and several indicators of immune function was investigated as part of the HELPcB (Health Effects in High-Level Exposure to PCB) program, offering bio-monitoring to workers, relatives, and neighbors exposed to PCBs by a German transformers and capacitors recycling company. The present retrospective observational study evaluates the correlation of plasma levels of total PCBs, five indicator congeners (28, 101, 138, 153, 180), and seven dioxin-like congeners (105, 114, 118, 156, 157, 167, 189) with several parameters of immune function. The cross-sectional study was performed immediately after the end of exposure (258 subjects), and one (218 subjects), and two (177 subjects) years later. At the first time point, measurements showed significant positive correlation between congeners with low to medium chlorination and the relative proportion of CD19 positive B-cells among lymphocytes, as well as a negative correlation of PCB114 with serum IgM, and of PCB 28 with suppressor T-cell and NK-cell numbers. Congeners with a high degree of chlorination, in particular PCB157 and 189, were positively associated with expression of the activation marker CD25 on T-cells in the cohort of the second time point. No associations between PCB levels and IFN-y production by T-cells and killing by NK-cells were found. In conclusion, there were several effects on the cellular composition of adaptive immunity, affecting both T- and B-cells. However, the values were not generally outside the reference ranges for healthy adult individuals and did not indicate overt functional immunodeficiency, even in subjects with the uppermost PCB burden.

Exposure to dioxin-related compounds results in many adverse health effects. Several studies have examined the effects of dioxin-related compounds on human bone metabolism with inconsistent results. In Japan in 1968, accidental human exposure to rice oil contaminated with dioxin-related compounds led to the development of Yusho oil disease. The aim of this study was to determine whether exposure to dioxin-related compounds was associated with bone mineral density in Yusho patients. In 2010, 262 women and 227 men underwent dual-energy X-ray absorptiometry bone scans as part of the nationwide Yusho health examination. Serum levels of polychlorinated dibenzo-p-dioxin, polychlorinated dibenzofurans, and non-ortho polychlorinated biphenyls were measured using high-resolution gas chromatography and high-resolution mass spectrometry. When adjusted for prefecture, 1,2,3,4,7,8-HxCDD and 2,3,7,8-TCDF were significantly positively associated with Z-scores in men. No congeners were positively associated with Z-scores in women. After adjustment for prefecture and body mass index, one congener, 1,2,3,4,6,7,8-HpCDD, was negatively associated with Z-scores in women. In contrast, no congeners remained significant in men after adjusting for body mass index. This may suggest that 1,2,3,4,6,7,8-HpCDD has a negative effect on bone mineral density in women; however, the findings should be interpreted carefully, because no increase in the serum level of this congener was observed in patients with Yusho disease., (Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Polychlorinated dibenzo-p-dioxins/furans (PCDD/Fs), polychlorinated biphenyls (PCBs) and polybrominated diphenyl ethers (PBDEs) are important contaminants in the environment. In recent years also polybrominated dibenzo-p-dioxins/dibenzofurans (PBDD/Fs) have been reported as emerging environmental stressors. It has been suggested that hydroxylated polybrominated biphenyl ethers (OH-BDEs) are important - may be even the most important - precursors of brominated dioxins/furans. The aim of this study was to develop a robust, time-saving analytical procedure to collectively separate in animal tissues such compounds prior to determination of individual substances with a gas/liquid chromatograph coupled to an ion trap/time-of-flight mass spectrometer (GC/IT-MS or UPLC/TOF-MS). Two OH-CB/BDE separation methods including alkaline extraction and molecularly imprinted polymers (MIP) were compared. Performance of both methods was validated: absolute recovery values were in the 47-90% range depending on the compound, while recovery relative standard deviation was below 20% in most cases. Levels of the studied compounds have been assessed in some real life samples., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Background: Dioxins, PCBs, chlorinated pesticides, brominated flame retardants, bisphenol A, triclosan, perfluorinated compounds and phthalates are known as endocrine disrupting chemicals (EDCs)., Objectives: The aim of our study was to investigate whether higher exposure to EDCs is associated with increased subfertility in men., Methods: We measured biomarkers of exposure in 163 men, recruited through four fertility clinics. According to WHO guidelines, we used a total motility count (TMC) of 20 million as cut-off value. We assigned patients to the case group when two semen samples - collected at least one week apart - had a TMC<20 and to the control group when both samples had a TMC≥20. To estimate the risk of subfertility and alteration in sex hormone concentrations we used multivariable-adjusted analysis, using logistic and linear regressions, respectively., Results: For an IQR increase in serum oxychlordane, the odds ratio for subfertility was 1.98 (95% CI: 1.07; 3.69). Furthermore, men with serum levels of BDE209 above the quantification limit had an odds of 7.22 (1.03; 50.6) for subfertility compared with those having values below the LOQ. Urinary levels of phthalates and triclosan were negatively associated with inhibin B and positively with LH. Urinary bisphenol A correlated negatively with testosterone levels., Conclusions: Our study in men showed that internal body concentrations of endocrine disrupting chemicals are associated with an increased risk of subfertility together with alterations in hormone levels. The results emphasize the importance to reduce chemicals in the environment in order to safeguard male fertility., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

The formation and environmental release of highly toxic organohalogen compounds associated with informal recycling of waste electric and electronic equipment (e-waste) is a growing problem at e-waste dumps/recycling sites (EWRSs) in many developing countries worldwide. We chose a cross-sectional study design to measure the internal exposure to polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) as well as polychlorinated biphenyls (PCBs) of individuals working on one of the largest EWRSs of Africa, located at Agbogbloshie, Accra, Ghana, and in controls from a suburb of Accra without direct exposure to EWRS activities. In whole blood samples of 21 age matched male exposed individuals (mean age: 24.7 years, SD 6.0) and 21 male controls (mean age: 24.4 years, SD 5.7) 17 PCDD/F congeners were determined. Moreover three indicator PCB congeners (#138, #153 and #180) were measured in blood of 39 exposed (mean age: 27.5 years, SD 11.7) and 19 non-exposed (mean age: 26.8 years, SD 9.7) patients. Besides a health examination, biometric and demographic data, residential and occupational history, occupational exposures and working conditions were recorded using a standardized questionnaire. In the exposed group, median PCDD/F-concentrations were 6.18 pg/g lipid base WHO2005-TEq (range: 2.1-42.7) and significantly higher compared to the control group with 4.60 pg/g lipid base WHO2005-TEq (range: 1.6-11.6). Concentrations were different for 2,3,7,8-TetraCDD, three HexaCDD and all 10 PCDF congeners, indicating a combustion pattern. Using a multivariate regression analysis exposure to EWRS activities was the most important determinant for PCDD/F exposure. Median PCB levels for the indicator congeners #138, #153 and #180 were 0.011, 0.019 and 0.008 μg/l whole blood (ranges: 0.002-0.18, 0.003-0.16, 0.002-0.078) in the exposed group and, surprisingly, significantly higher in the controls (0.037, 0.062 and 0.022; ranges: 0.005-0.46, 0.010-0.46, 0.004-0.21). In a multivariate regression approach e-waste related activities had no positive influence on internal PCB exposure, but rather the time living in Accra. The internal PCB exposure is in particular notable for a country where PCBs have historically never been produced or used. The impact of EWRS activities on organohalogen compound exposure of individuals working at and living in the surroundings of the Agbogbloshie EWRS, and the surprisingly high PCB exposure of people living in Accra not involved in e-waste activities require further investigation., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Aims: Dioxin or dioxin-like compounds are ligands of the aryl hydrocarbon receptor (AhR), which is a ligand-activated nuclear transcription factor. There are limited studies about the association of serum AhR ligand activities and T2DM. Our objective was to investigate the association of serum AhR ligand activities with T2DM and its related metabolic parameters., Methods: This case-control study involved 83 subjects with T2DM as well as age-, sex-, and body mass index (BMI)-matched subjects with impaired glucose tolerance (IGT, n = 130) and normal glucose tolerance (NGT, n = 83). Serum AhR ligand activities were measured using a cell-based AhR ligand assay and standardized as 2,3,7,8-tetrachlorodibenzo-p-dioxin equivalents (TCDDeq, pmol/l)., Results: The T2DM group had the highest AhR ligand activities compared to the IGT and NGT groups [median (interquartile range), 68.1 (53.1, 81.5), 60.2 (45.8, 75.1), and 53.3 (46.1, 63.7) pmol/l, respectively; P = 0.003]. In the multivariate analysis, the log2-transformed TCDDeq levels were significantly associated with the risk of T2DM after adjusting for age, sex, and BMI (odds ratio 2.26, 95 % confidence interval 1.34-3.82; P = 0.002). In nondiabetic subjects, serum AhR ligand activities showed a positive correlation with fasting glucose and insulin concentrations and the homeostasis model assessment of insulin resistance, but showed a negative correlation with adiponectin concentrations., Conclusions: Serum AhR ligand activities were higher in the T2DM group and were correlated with the parameters of insulin resistance. Further investigation is required to elucidate the causal relationship between AhR ligand activity and T2DM.

In 1968, the contamination of cooking oil by heat-degraded polychlorinated biphenyls (PCBs) caused a case of mass poisoning, the so-called Yusho incident. The cause of Yusho disease is thought to be ingested toxic substances, including not only PCBs but also polychlorinated dibenzofuran (PCDFs) in Kanemi rice oil. We previously measured dioxins concentrations in the blood of 854 Yusho patients by annual medical examination from 2001 to 2013. We determined the concentrations of 2,3,4,7,8-PeCDF, 1,2,3,4,7,8-HxCDF, 1,2,3,6,7,8-HxCDF and 3,3',4,4',5,5'-HxCB (#169) in the blood of Yusho patients were more than double those of normal controls. In 2012, a new Yusho criteria was established. Family members living with a Yusho patient were also certified as Yusho patients and called Yusho family cohabitant patients. In this study, we compared the distribution of 2,3,4,7,8-PeCDF concentration in the blood of Yusho patients and Yusho family cohabitant patients. It was suspected that the distribution of 2,3,4,7,8-PeCDF concentration in Yusho family cohabitant patients would be lower than that of Yusho patients.

In this paper, based on the Flemish biomonitoring programs, we describe the associations between internal exposure to organochlorine pollutants and to cadmium (measured in 2004-2005 for adults aged 50-65 years) and self-reported health status obtained through a questionnaire in November 2011. Dioxin-like activity in serum showed a significant positive association with risk of cancer for women. After adjustment for confounders and covariates, the odds ratio for an exposure equal to the 90th percentile was 2.4 times higher than for an exposure equal to the 10th percentile. For both men and women dioxin-like activity and serum hexachlorobenzene (HCB) showed a significant positive association with risk of diabetes and of hypertension. Detailed analysis suggested that an increase in BMI might be part of the mechanism through which HCB contributes to diabetes and hypertension. Serum dichlorodiphenyldichloroethylene (p,p'-DDE) concentration showed a significant positive association with diabetes and hypertension in men, but not in women. Serum polychlorinated biphenyl (PCB) 118 showed a significant positive association with diabetes in both men and women, and after adjustment for correlated exposures, also with hypertension in men. Urinary cadmium concentrations showed a significant positive association with hypertension. Urinary cadmium concentrations were (in 2004-2005) significantly higher in persons who felt in less than good health (in 2011) than in persons who felt in very good health. After adjustment for correlated exposures (to HCB, p,p'-DDE and PCB118) marker PCBs showed a significant negative association with diabetes and hypertension. Serum p,p'-DDE showed in men a significant negative association with risk of diseases based on atheromata. Our findings suggest that exposure to pollutants can lead to an important increase in the risk of diseases such as cancer, diabetes and hypertension. Some pollutants may possibly also decrease the risk of some health problems, although this requires confirmation by other approaches., (Copyright © 2014 Elsevier GmbH. All rights reserved.)

Several studies have suggested that maternal exposure to Polychlorinated dibenzo-p-dioxins (PCDDs), poly-chlorinated dibenzofurans (PCDFs) and dioxin-like polychlorinated biphenyls (PCBs) may affect foetal growth and infant development. The aim of our study was to determine whether the childbearing-aged residents living near a chemical plant have a greater exposure risk. Concentrations of 17 PCDD/Fs congeners and 12 non-ortho and mono-ortho dioxin-like PCBs were measured using HRGC-HRMS in the blood of 30 non-occupational childbearing-aged women living near a chemical plant (Dagu) that had been producing chlorinated pesticides from 1958 to 2004. The factors that influenced the body burden were investigated based on responses to a questionnaire. Levels of PCDD/Fs+PCBs were in the range of 16.43-155.29pg WHO 2005-TEQg(-1) lipid. PCDDs and PCDFs contributed 56.72% and 34.44%, respectively, to the total TEQ value. Total WHO-TEQ was approximately tenfold higher in the participants living in the vicinity of the plant (distance: 1.52±0.148km) than in the groups living farther away (distance: 4.93±1.124km). A negative correlation between total WHO-TEQ and distance to Dagu was observed by multiple linear regression models. The data provide basic information for monitoring dioxin-like chemicals in the district and for the future study of the relationship between POPs and pregnancy outcomes., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

In 2002, a cross-sectional study designed to compare the serum dioxin toxic equivalent concentrations (TEQ) of a population-based sample of Calcasieu Parish, Louisiana residents, to Lafayette Parish was conducted. The mono-ortho polychlorinated biphenyls (PCBs) were measured in order to calculate the TEQ. We compared the sum of lipid adjusted serum concentrations of 27 PCB congeners (total PCBs) in residents of these two parishes and also by their demographic characteristics. The geometric means (GM) [standard errors (SE)] of the concentrations (ngg(-1) lipids) of total PCBs in participants from Calcasieu Parish and Lafayette Parish were 154 (11.8) and 168.6 (20.8) (T-test p=0.54), respectively. Various percentiles of the distribution of serum total PCB concentrations were similar in the two parishes. After adjusting by age and race in the ANCOVA regression model, the adjusted GM for the lipid adjusted total PCBs was statistically higher in the residents in Lafayette than in Calcasieu Parish regardless of age or race (P=0.007). The adjusted GM of lipid adjusted total PCBs for African Americans was significantly higher than for Whites (p<0.001). Serum total PCB levels in residents of both parishes increased linearly with age (P<0.001). The congener profiles were similar in residents of both parishes. We also compared the GMs of a sum of 8 PCBs in Calcasieu and Lafayette Parish residents to those from a representative sample of the U.S. general population in 2001-2002 and they were not significantly different between parishes or between the parish data and the U.S. general population., (Published by Elsevier Ltd.)

Increased electronic waste (e-waste) has raised public concerns regarding exposure to numerous toxic contaminants, particularly polychlorinated biphenyls (PCBs), polybrominated diphenyl ethers (PBDEs) and polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs). In China, the body burdens of PCBs, PBDEs and PCDD/Fs are associated with thyroid hormones in populations from e-waste dismantling sites; however, it is unclear whether this association occurs in children. In this study, we determined the serum levels of PCBs, PBDEs and PCDD/Fs and the endocrine hormones including free triiodothyronine (FT3), total triiodothyronine (TT3), free thyroxine (FT4), total thyroxine (TT4), thyroid-stimulating hormone (TSH), adrenocorticotropic hormone (ACTH), cortisol and growth hormone (GH) in 21 children from an e-waste dismantling area and 24 children from a control area. The results showed that the mean levels of ∑PCBs and ∑PBDEs in the exposure group were significantly higher than in the control group (40.56 and 32.09 ng g(-1) lipid vs. 20.69 and 8.43 ng g(-1) lipid, respectively, p<0.01 for each), and the mean level of ∑PCDD/Fs in the exposure group was higher than in the control group, but the difference was not significant (206.17 vs. 160.27 pg g(-1) lipid, p>0.05). For the endocrine hormones, we did not find significant differences between the exposed and control groups, although the mean levels of FT3, TT3, TT4, ACTH, cortisol and GH were higher, whereas the mean levels of FT4 and TSH were lower in the exposed group. The mean level of ∑PBDEs was positively correlated with the mean levels of ∑PCBs (r=0.60, p<0.05) and ∑PCDD/Fs (r=0.61, p<0.05). Furthermore, the mean level of ∑PBDEs was positively correlated with ACTH (r=0.61, p<0.05). In conclusion, our data suggested that exposure to e-waste dismantling environment increased the body burdens of PCBs and PBDEs in local children and that these contaminants released from the e-waste might contribute to abnormal changes in hormone levels., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Persistent organic pollutants (POPs) are a large group of chemicals widely used and produced in various industrial applications. Many cell culture/animal studies have shown that POPs can induce oxidative stress. Since such data is lacking in humans, we conducted a large population-based study to analyze associations between POPs and oxidative stress markers. We measured following POPs; 16 polychlorinated biphenyls (PCBs), 5 organochlorine (OC) pesticides, octachlorinated dibenzo-p-dioxin, and polybrominated diphenyl ether 47, and oxidative stress markers; homocysteine, reduced [GSH] and oxidized glutathione [GSSG], glutathione ratio [GSSG/GSH], total glutathione, oxidized low-density lipoprotein [ox-LDL], ox-LDL antibodies, conjugated dienes, baseline conjugated dienes of LDL, and total anti-oxidative capacity in plasma samples collected from 992 70-year old individuals (50% women) from the population-based Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) cohort. Linear regression analyses were performed to study the associations between oxidative stress markers and summary measures of POPs including the total toxic equivalence (TEQ), sums of PCBs and OC pesticides (main exposures) while adjusting for potential confounders. In multivariable-adjusted analyses, sum of PCBs showed strong associations with ox-LDL (β=0.94; P=2.9*10(-6)). Further, sum of PCBs showed association with glutathione-related markers (GSSG: β=-0.01; P=6.0*10(-7); GSSG/GSH: β=-0.002; P=9.7*10(-10)), although in reverse direction. Other summary measures did not show any significant association with these markers. In our study of elderly individuals from the general population, we show that plasma levels of POPs are associated with markers of increased oxidative stress thereby suggesting that even low dose background exposure to POPs may be involved in oxidative stress., (Copyright © 2014 Elsevier Ltd. All rights reserved.)