DNA methylation in the adipose tissue and whole blood of Agent Orange-exposed Operation Ranch Hand veterans: a pilot study.

BACKGROUND: Between 1962 and 1971, the US Air Force sprayed Agent Orange across Vietnam, exposing many soldiers to this dioxin-containing herbicide. Several negative health outcomes have been linked to Agent Orange exposure, but data is lacking on the effects this chemical has on the genome. Therefore, we sought to characterize the impact of Agent Orange exposure on DNA methylation in the whole blood and adipose tissue of veterans enrolled in the Air Force Health Study (AFHS). METHODS: We received adipose tissue (n = 37) and whole blood (n = 42) from veterans in the AFHS. Study participants were grouped as having low, moderate, or high TCDD body burden based on their previously measured serum levels of dioxin. DNA methylation was assessed using the Illumina 450 K platform. RESULTS: Epigenome-wide analysis indicated that there were no FDR-significantly methylated CpGs in either tissue with TCDD burden. However, 3 CpGs in the adipose tissue (contained within SLC9A3, LYNX1, and TNRC18) were marginally significantly (q < 0.1) hypomethylated, and 1 CpG in whole blood (contained within PTPRN2) was marginally significantly (q < 0.1) hypermethylated with high TCDD burden. Analysis for differentially methylated DNA regions yielded SLC9A3, among other regions in adipose tissue, to be significantly differentially methylated with higher TCDD burden. Comparing whole blood data to a study of dioxin exposed adults from Alabama identified a CpG within the gene SMO that was hypomethylated with dioxin exposure in both studies. CONCLUSION: We found limited evidence of dioxin associated DNA methylation in adipose tissue and whole blood in this pilot study of Vietnam War veterans. Nevertheless, loci in the genes of SLC9A3 in adipose tissue, and PTPRN2 and SMO in whole blood, should be included in future exposure analyses.

[Serum polychlorinated biphenyls in workers of a second-smelting steel mill]. / Policlorobifenili sierici nei lavoratori di una acciaieria di seconda fusione.

SUMMARY: In the steel industry polychlorodibenzodioxins (PCDD), polychlorinated dibenzofurans (PCDF) and polychlorinated biphenyls (PCBs) may be present deriving from the fusion of ferrous and non-ferrous scrap, as well as for the thermal decomposition of the plastic materials (thermoplastic and thermosetting resins) contained therein and not removed before melting at high temperatures. The aim of the study was to assess in 52 workers of a secondmelting steel plant the PCBs exposure deriving from the manual handling of ferrous scrap waste eventually contaminated. The population was divided by production department (scrap, casting and office). Static air sampling of PCDD, PCDF, PCBs and biological monitoring of serum dioxin-like PCBs (DL-PCBs) were performed. The comparison of serum DL-PCB values between workers from the scrap department and those from the casting did not find any statistically significant differences (Mann- Whitney U test). The range of serum DL-PCBs was 7.74-78.55 ng/g lipids with an average of 24.21 ng/g lipids, much lower than the reference values measured in the Italian general population in 2011. Mean and median TEQ WHO 1998 of DL-PCBs were 0.22 pg/g lipids and 0.15 pg/g lipids respectively. The low concentrations of serum DL-PCBS in the studied population can be explained by the progressive reduction of environmental PCBs contamination.

Estimated PCDD/F TEQ and total TEQ concentrations in the serum of 7-10 year old Finnish children.

Polychlorinated dibenzo-p-dioxins and furans (PCDD/Fs) and polychlorinated biphenyls (PCBs) are persistent organic pollutants that have detrimental health effects. As people are exposed to them mainly through the diet, EU has set maximum food dioxin and PCBs levels. EFSA CONTAM Panel made new risk assessment in 2018 that lowered the tolerable weekly intake (TWI) from 14 pg-TEQ/kg bw/week to 2 pg-TEQ/kg bw/week. Critical effect was decreased semen count at the age of 18-19 years if serum total TEQ at the age of 9 years exceeded the No Observed Adverse Effect Level (NOAEL) of 7 pg/g lipid. However, it is largely unknown to what extent NOAEL is exceed in European boys currently. We thus measured PCBs from small volume of serum in 184 Finnish children 7-10 years of age. To estimate the TEQ levels of children from measured PCB levels, we used our existing human milk PCDD/F and PCB concentrations to create a hierarchical Bayesian regression model that was used to estimate TEQs from measured PCBs. For quality control (QC), three pooled blood samples from 18 to 20 year old males were measured for PCDD/Fs and PCBs, and estimated for TEQs. In QC samples measured and estimated TEQs agreed within 84%-106%. In our estimate for 7-10 year old children, PCDD/F TEQ exceeded NOAEL only in 0.5% and total TEQ in 2.7% of subjects. Risk management following the decreased TWI proposed by the CONTAM Panel should be carefully considered if total TEQ in children is already largely below the NOAEL.

Associations of peri-pubertal serum dioxins and polychlorinated biphenyls with growth and body composition among Russian boys in a longitudinal cohort.

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.

Associations of Benzo(ghi)perylene and Heptachlorodibenzo-p-dioxin in Serum of Service Personnel Deployed to Balad, Iraq, and Bagram, Afghanistan Correlates With Perturbed Amino Acid Metabolism in Human Lung Fibroblasts.

OBJECTIVE: A study was conducted to identify metabolic-related effects of benzo(ghi)perylene (BghiP) and 1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin (HpCDD), on primary human fibroblasts to verify biological associations previously found in occupational health research. METHODS: Human lung fibroblasts were exposed to BghiP or HpCDD and extracts were analyzed with a metabolome-wide association study to test for pathways and metabolites altered relative to controls. Gene expression was measured by quantitative-real time polymerase chain reaction. RESULTS: Metabolic perturbations in amino-acid, oxidative stress, and fatty-acid pathways were observed for BghiP and HpCDD. HpCDD but not BghiP exposure increased gene expression of the amino acid transporters SLC7A5 and SLC7A11. CONCLUSIONS: Exposure to polycyclic aromatic hydrocarbons (PAH) or dioxins perturbs amino acid pathways at physiologically relevant concentrations with different mechanisms. These findings imply an effect on central homeostatic systems by environmental exposures which could have implications on disease susceptibility.

Concentrations of PCDD/Fs in Human Blood: A Review of Data from the Current Decade.

Polychlorinated dibenzo-p-dioxins and polychlorinated dibenzo-p-furans (PCDD/Fs) are environmental pollutants with great persistence, the capacity of bioaccumulation, and well known important toxic effects in humans and animals. Incinerators of hazardous, municipal and medical waste, chlorine bleaching of paper pulp, cement plants, and the traffic of motor vehicles are the most frequent emission sources of these compounds. The diet, followed at a great distance by inhalation, is generally the main way of human exposure to PCDD/Fs. Human biomonitoring is of great importance to prevent potential adverse effects derived from exposure to chemicals such as PCDD/Fs. In relation to this, blood is among the most used biological monitors. In the current review, we have summarized the recent information (2000-2009) published in the scientific literature (databases: Scopus and PubMed) on the concentrations of PCDD/Fs in blood samples of non-occupationally exposed populations, as well as in some groups of occupationally exposed individuals. We have revised a number of studies conducted in various African, American, Asian and European countries, and Australia. Unfortunately, the information is quite limited. No data are available for most countries over the world. Based on the results here reviewed, where available, the current health risks for the general populations do not seem to be of concern. Moreover, taking into account the important reductions observed in the levels of PCDD/Fs in foodstuffs, new decreases in the concentrations of PCDD/Fs in blood-and other biological tissues-are very probable in the immediate years.

Exploring the associations of serum concentrations of PCBs, PCDDs, and PCDFs with walking speed in the U.S. general population: Beyond standard linear models.

Studies have shown that persistent organic pollutants (POPs) can have various health effects. However, little is known about the effects of multiple chemicals with possible common sources of exposure on walking speed, a proxy index reflecting lower limb neuromuscular function and physical function. We simultaneously applied multiple linear and nonlinear statistical models to explore the complex exposure-response relationship between a mixture of 22 selected POPs and walking speed. A total of 14 polychlorinated biphenyls (PCBs), 3 polychlorinated dibenzo-p-dioxins (PCDDs), and 5 polychlorinated dibenzofurans (PCDFs) were measured in the serum of participants in the National Health and Nutrition Examination Survey (NHANES) from 1999 to 2002. Walking speed was measured during a physical examination. Linear regression (LR), least absolute shrinkage and selection operator (LASSO), and group LASSO were used to evaluate the linearity of mixtures, while restricted cubic spline (RCS) regression, random forest (RF), and Bayesian kernel machine regression (BKMR) models were used to evaluate the nonlinearity of mixtures. Potential confounders were adjusted in the above models. A total of 436 subjects were included in our final analysis. The results of the LR model did not identify any POP exposure that was significantly associated with walking speed. The LASSO results revealed an inverse association of one PCDD congener and two PCDF congeners with walking speed, while the group LASSO analysis identified PCDFs at the exposure level and at the group level. In the RCS analysis, two PCB congeners presented significant overall associations with walking speed. The PCB congener PCB194 showed statistically significant effects on the outcome (P = 0.01) when a permutation-based RF was used. The BKMR analysis suggested that PCBs and PCDFs (probabilities = 0.887 and 0.909, respectively) are potentially associated with walking speed. Complex statistical models, such as RCS regression, RF and BKMR models, can detect the nonlinear and nonadditive relationships between PCBs and walking speed, while LASSO and group LASSO can identify only the linear relationships between PCDFs and walking speed. Fully considering the influence of collinearity in each method during modelling can increase the comprehensiveness and reliability of conclusions in studies of multiple chemicals.

Spirometric Pulmonary Restriction in Herbicide-Exposed U.S. Vietnam War Veterans.

Spirometric restriction in herbicide-exposed U.S. Army Chemical Corps Vietnam War veterans was examined because no published research on this topic in Vietnam War veterans exists. Spirometry was conducted on 468 veterans who served in chemical operations in a 2013 study assessing the association between chronic obstructive pulmonary disease (COPD) and herbicide exposure. Exposure was verified based on blood serum values of 2,3,7,8-tetrachlorodibenzo-p-dioxin. Further, the association between herbicide exposure and spirometry restriction (forced expiratory volume in one second (FEV1)/forced vital capacity (FVC) ≥ lower limit of normal (LLN) and FVC < LLN) was tested after adjustment for military characteristics, selected anthropometrics, and other predictors using multivariable regression. Spirometric restriction in herbicide sprayers (15.7%, 95% CI: 10.6, 20.9) was almost twice that of nonsprayers (9.91%, 95% CI: 5.9, 13.9) (p = 0.081). While spirometric restriction was not significantly associated with herbicide exposure (adjusted odds ratio (aOR) = 1.64, 95% CI: 0.82, 3.29) despite the greater prevalence of restriction in sprayers versus nonsprayers, spirometric restriction was significantly associated with race/ethnicity (aOR = 3.04, 95% CI: 1.36, 6.79) and waist circumference (aOR = 2.46, 95% CI: 1.25, 4.85). Because restrictive pulmonary disease may result from chemically-induced inflammation or sensitivity, research on chemical exposures and restriction in veterans should continue. Future study should include full pulmonary function testing, targeted research designs, and a wider set of explanatory variables in analysis, such as other determinants of health.

Health risk of childhood exposure to PCDD/Fs emitted from a municipal waste incinerator in Zhejiang, China.

This study aimed to evaluate the body burdens of polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) and their associated health impacts toward school-age children living near a municipal waste incinerator (MWI). A total of 82 children from the exposure area and 49 from the control area were recruited. We measured blood PCDD/F levels, conducted comet assays, calculated the percentage of 5-methylcytosine (%5-mC) and 5-hydroxymethylcytosine (%5-hmC), performed flow cytometry, measured hormonal levels, and analyzed hematological parameters. We also examined 17 congeners of PCDD/Fs in environmental samples, namely, eggs, rice, water, soil, and PM2.5. The mean blood levels of ΣPCDD/Fs and TEQ-ΣPCDD/Fs were statistically higher in the exposure group than in the control group (3.40 vs. 2.77 pg/g wet weight and 0.40 vs. 0.28 pg WHO-TEQ/g wet weight, respectively; p < 0.05). By contrast, the %5-mC and %5-hmC levels were statistically lower in the exposure group than in the control group (1.15% vs. 4.66% and 0.22% vs. 0.30%, respectively; p < 0.01), whereas the mean % tail DNA was statistically higher in the exposure group than in the control group (10.10% vs. 8.28%, p < 0.01). The mean blood levels of ΣPCDD/Fs and TEQ-ΣPCDD/Fs were both negatively correlated with %5-mC (r = -0.245 and r = -0.217, respectively; p < 0.01) but not with %5-hmC and % tail DNA (p > 0.05). Furthermore, the mean ΣPCDD/F levels in eggs and soil obtained from the exposure area were statistically higher than those of the samples obtained from the control area (31.08 vs. 4.32 pg/g dry weight and 1026.04 vs. 674.97 pg/g dry weight, respectively). In conclusion, children living near the MWI may suffer genetic and epigenetic modifications, such as DNA damage or global DNA hypomethylation due to the MWI-emitted PCDD/Fs and other contaminants.

Polychlorinated Dibenzo-p-Dioxins, Polychlorinated Dibenzofurans, and Dioxin-Like Polychlorinated Biphenyls in Umbilical Cord Serum from Pregnant Women Living Near a Chemical Plant in Tianjin, China.

Polychlorinated dibenzo-p-dioxins, polychlorinated dibenzofurans (PCDD/Fs), and dioxin-like polychlorinated biphenyls (dl-PCBs) are bioaccumulative compounds that may affect fetal growth and infant development. The aim of this study was to determine whether the pregnant women living near a chemical plant in Tianjin had a risk of exposure to dioxins. Concentrations of PCDD/Fs and dl-PCBs in 24 umbilical cord serum samples collected from pregnant women were measured using a high-resolution gas chromatograph with a high-resolution mass spectrometer (HRGC-HRMS) and an isotopic dilution method. The levels of ∑(PCDD/Fs + dl-PCBs) were in the range 476-8307 pg·g-1 lipid, with a mean of 3037 pg·g-1. The mean World Health Organization toxicity equivalent (WHO-TEQ) for PCDD/Fs and dl-PCBs was 14.0 and 2.14 pg·g-1 lipid, respectively. The PCDD/Fs and dl-PCBs contributed 86.7% and 13.3%, respectively, to the total TEQ. The octa-CDFs and penta-CBs were predominant for the PCDD/Fs and dl-PCBs, accounting for 57.6% and 74.3%, respectively. Several PCDD/F and dl-PCB congeners were highly correlated, such as PCB 105 and PCB 118 (r = 0.982, p < 0.001). Although the results hint at decreasing trends for PCDD/F and dl-PCBs by comparison with a similar study in Tianjin, a total TEQ of 41.7% of study participants had a body burden that exceeded the biomonitoring equivalents for dioxins. It was shown that pregnant women and infants had a health risk of exposure to dioxins.

[The study of exposure levels of dioxin-like compounds in cord blood of newborns in an e-waste dismantling area in Guangdong Province].

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.

Background levels of dioxin-like polychlorinated biphenyls (dlPCBs), polychlorinated, polybrominated and mixed halogenated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs, PBDD/Fs & PXDD/Fs) in sera of pregnant women in Accra, Ghana.

Human exposure data on dioxins and dioxin-like compounds (DLCs) in Ghana are limited. Based on health risks associated with dioxins and DLCs, the impact of maternal body burdens on foetal exposure is significant. This is the first study that assesses polychlorinated, polybrominated and mixed halogenated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs, PBDD/Fs and PXDD/Fs), and dioxin-like polychlorinated biphenyls (dlPCBs) in sera of primiparous Ghanaians. Our sample selection includes 34 participants from two municipalities (Accra and Tema), and explores contributions from environmental and dietary exposures using questionnaire data. Sample preparation involved C18 solid phase extraction, purification with acidified silica and lipid removal cartridges, and detection with gas chromatography-atmospheric pressure chemical ionization-tandem mass spectrometry. The calculated average toxic equivalent concentration was 5.3 pg TEQ/g lw, with contributions from dlPCBs (1.25 pg TEQ/g lw), PCDD/Fs (3.10 pg TEQ/g lw), PBDD/Fs (0.49 pg TEQ/g lw) and PXDD/Fs (0.50 pg TEQ/g lw). The calculated total TEQ concentration was lower than background TEQ concentrations reported in sera of pregnant women globally. Positive correlations were obtained for total dioxins and DLC concentrations with age and Body Mass Index (BMI). Dietary intake of seafood and dairy products had a strong influence on PCDD/F and dlPCB concentrations. Statistically significant differences were observed for dioxins and DLCs in participants from Accra (in close proximity to Agbogbloshie e-waste site) and Tema. Given the significant TEQ contribution of PBDD/Fs and PXDD/Fs (~20%), it is essential to explore these classes of dioxins and DLCs in future biomonitoring studies as they may pose health risks, and add extra diagnostic information in source exposure investigations.

The 2nd to 4th digit length ratio (2D:4D) among children of Seveso women exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin.

BACKGROUND: Exposure to endocrine-disrupting chemicals (EDCs) during sensitive developmental windows, such as in utero, may influence disease later in life but direct measurement of fetal hormones is not feasible. The ratio of the length of the second finger digit to the fourth digit (2D:4D), a sexually dimorphic trait, is a biomarker of androgen levels and the androgen/estrogen balance in utero. However, it is unclear whether in utero EDC exposure might alter 2D:4D ratio. AIMS: We examined 2D:4D ratio in Seveso children in relation to in utero exposure to a potent EDC, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) using linear regression. STUDY DESIGN: The Seveso Women's Health Study (SWHS) is a historical cohort study, following the health of women exposed to TCDD during a 1976 explosion in Seveso, Italy. Individual-level TCDD was measured for SWHS in serum collected soon after the accident. In 2014, the SWHS children born after the explosion were enrolled in the Seveso Second Generation Study. SUBJECTS: 594 SWHS children born post-explosion to 397 mothers. OUTCOME MEASURES: Right hand 2D:4D ratio. RESULTS: On average, 2D:4D ratio for males was significantly lower than for females (p < 0.05). Overall, in utero TCDD exposure, either as maternal initial serum TCDD concentration or as TCDD extrapolated to pregnancy was not significantly associated with 2D:4D ratio in Seveso children. Results from all adjusted sensitivity analyses remained non-significant. CONCLUSIONS: Our results suggest in utero exposure to TCDD is not associated with alteration in 2D:4D ratio.

Prenatal dioxin exposure and neuropsychological functioning in the Seveso Second Generation Health Study.

BACKGROUND: Prenatal 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure has been shown to alter sexual differentiation of the brain in animal models, impacting pubertal development, behavior, cortical dominance, and cognition. The effects of early life exposure to dioxin-like compounds on human neurodevelopment, however, are less clear and warrant further investigation. METHODS: The Seveso Women's Health Study (SWHS), initiated in 1996, is a well-characterized cohort of 981 Italian women who lived in proximity to an industrial accident in July 1976 that resulted in one of the highest residential TCDD exposures on record. In 2014-2016, we enrolled offspring born after the accident into the Seveso Second Generation Health Study. Children aged 7-17 years old (n = 161) completed a neuropsychological assessment spanning executive function and reverse learning (Wisconsin Card Sort), non-verbal intelligence (Raven's Progressive Matrices), attention and hyperactivity (Connor's Continuous Performance (CPT), and memory (Rey's Auditory Verbal Learning). We used multivariate regression with robust standard error estimates accounting for clustering of siblings to model the associations between these outcomes and prenatal exposure defined as TCDD measured in maternal serum collected soon after the explosion and estimated to pregnancy. RESULTS: The children (82 male, 79 female) averaged 13.1 (±2.9) years of age. Adjusting for covariates, a 10-fold increase in maternal serum TCDD was not adversely associated with reverse learning/set-shifting, memory, attention/impulsivity, or non-verbal intelligence. In sex-stratified models, prenatal TCDD was associated with more non-perseverative errors in boys but not in girls (pint = 0.04). TCDD was also associated with attention deficits on the CPT but only among children with the shortest breastfeeding histories. CONCLUSIONS: While overall, there were no significant associations, the observed differential neurotoxic sensitivities to TCDD by sex and lactation history may warrant confirmation in future studies.

Cohort study of workers at a New Zealand agrochemical plant to assess the effect of dioxin exposure on mortality.

OBJECTIVES: To describe how the exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) influenced mortality in a cohort of workers who were exposed more recently, and at lower levels, than other cohorts of trichlorophenol process workers. DESIGN: A cohort study. SETTING: An agrochemical plant in New Zealand PARTICIPANTS: 1,599 men and women working between 1 January 1969 and 1 November 1988 at a plant producing the herbicide 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) with TCDD as a contaminant. Cumulative TCDD exposure was estimated for each individual in the study by a toxicokinetic model. PRIMARY OUTCOME MEASURES: Calculation of cause-specific standardised mortality ratios (SMRs) and 95% confidence intervals (95% CI's) compared those never and ever exposed to TCDD. Dose-response trends were assessed firstly through SMRs stratified in quartiles of cumulative TCCD exposure, and secondly with a proportional hazards model. RESULTS: The model intercept of 5.1 ppt of TCDD was consistent with background TCDD concentrations in New Zealand among older members of the population. Exposed workers had non-significant increases in all-cancer deaths (SMR=1.08, 95% CI 0.86 to 1.34), non-Hodgkin lymphoma (SMR=1.57, 95% CI: 0.32 to 4.59), soft tissue sarcoma (one death) (SMR=2.38, 95% CI: 0.06 to 13.26), diabetes (SMR=1.27, 95% CI: 0.55 to 2.50) and ischaemic heart disease (SMR=1.21, 95% CI: 0.96 to 1.50). Lung cancer deaths (SMR=0.95, 95% CI: 0.56 to 1.53) were fewer than expected. Neither the stratified SMR nor the proportional hazard analysis showed a dose-response relationship. CONCLUSION: There was no evidence of an increase in risk for 'all cancers', any specific cancer and no systematic trend in cancer risk with TCDD exposure. This argues against the carcinogenicity of TCDD at lower levels of exposure.

Recent decreasing trends of exposure to PCDDs/PCDFs/dioxin-like PCBs in general populations, and associations with diabetes, metabolic syndrome, and gout/hyperuricemia.

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.

Exposure to Environmental Contaminants and Lung Function in Adolescents-Is There a Link?

Dioxins (polychlorinated dibenzo-p-dioxins (PCDDs) and polychlorinated dibenzofurans (PCDF)), polychlorinated biphenyls (PCBs), and brominated flame retardants (BDEs) are well known toxic environmental contaminants. Their possible role in the incidence of respiratory disease is not yet well understood. Previous studies showed a negative effect on lung function in relation to prenatal and lactational dioxin exposure in pre-pubertal children. Effects of BDE exposure on the lung function have not previously been evaluated. As part of a longitudinal cohort study, the effects of perinatal dioxin (PCDD/F) exposure and serum PCDD/F, dl-PCB, and BDE levels on lung function in adolescents were assessed using spirometry, a body box, and diffusion measurements. Thirty-three children (born between 1986 and 1991) consented to the current follow-up study. Prenatal, lactational, and current dioxin, PCB, and BDE concentrations were determined using GC-MS. No relationship was seen between prenatal and lactational dioxin exposure, nor with current PCB body burden, and lung function. Indications of increasing airway obstruction were seen in relation to increasing current BDE exposure. This is a novel finding and certainly warrants further research.

Peripubertal serum dioxin concentrations and subsequent sperm methylome profiles of young Russian adults.

BACKGROUND: The association of exposure to endocrine disrupting chemicals in the peripubertal period with subsequent sperm DNA methylation is unknown. OBJECTIVE: We examined the association of peripubertal serum 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) concentrations with whole-genome bisulfite sequencing (WGBS) of sperm collected in young adulthood. METHODS: The Russian Children's Study is a prospective cohort of 516 boys who were enrolled at 8-9 years of age and provided semen samples at 18-19 years of age. WGBS of sperm was conducted to identify differentially methylated regions (DMR) between highest (n = 4) and lowest (n = 4) peripubertal TCDD groups. RESULTS: We found 52 DMRs that distinguished lowest and highest peripubertal serum TCDD concentrations. One of the top scoring networks, "Cellular Assembly and Organization, Cellular Function and Maintenance, Carbohydrate Metabolism", identified estrogen receptor alpha as its central regulator. CONCLUSION: Findings from our limited sample size suggest that peripubertal environmental exposures are associated with sperm DNA methylation in young adults.

Diabetes, Cardiovascular Disorders and 2,3,7,8-Tetrachlorodibenzo-p-Dioxin Body Burden in Czech Patients 50 Years After the Intoxication.

The correlation between 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) intoxication and the parameters of metabolic impairment was examined in the last eight male survivors of 80 workers exposed to TCDD during the production of herbicides in a chemical factory in 1965-1967. Their median TCDD blood level was 112 (46-390) pg/g lipids, and the median TCDD body deposit was 3.9 (0.8-11.7) µg. This puts these patients into the most severely intoxicated group of subjects, according to back-calculated levels of TCDD. The median TCDD blood level in eight controls was 12 pg/g (<0.10 to 22.2 pg/g). Markers of metabolic impairment - diabetes, dyslipidaemia, arterial hypertension, carotid artery plaque, skin microvascular reactivity, eye fundus hypertensive angiopathy and history of coronary heart disease - were assessed and compared to a general male population of comparable age. Measured parameters compared with a population of comparable age were as follows: prevalence of diabetes (62.5% versus 17.6%), arterial hypertension (87.5% versus 71.8%), dyslipidaemia (87.5% versus 88.8%), history of coronary heart disease (62.5% versus 26.0%) and eye fundus hypertension angiopathy (50% versus 14%). All eight patients (100% versus 43%) developed plaques in carotid arteries, six had stenosis >50% and two had a carotid intervention (stenting or endarterectomy). Total cholesterol levels decreased compared to the earlier study this patient group in 2008, most likely due to a more intensive use of lipid-lowering drugs. Several metabolic parameters were higher (diabetes as much as 3.5-fold) in the group of severely TCDD-intoxicated subjects than in a general population of comparable age. This suggests that TCDD plays a role in the development of metabolic impairment and vascular changes.

The Influence of Obesity on the Pharmacokinetics of Dioxin in Mice: An Assessment Using Classical and PBPK Modeling.

The effects of body fat mass on the elimination of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) was examined in mice. When male C57BL/6J mice are fed a high-fat, simple carbohydrate diet (HFD) for 13 weeks, they develop an obese phenotype. In contrast, A/J mice fed an HFD do not become obese. After 13 weeks on a normal diet (ND) or HFD, male C57BL/6J and A/J mice received a single dose by gavage of 0.1 or 5.0 µg of 2,3,7,8-tetrachloro[1,6-3H] dibenzo-p-dioxin per kg body weight. Using classical pharmacokinetics, the blood elimination half-life of TCDD was approximately 10 and 2 times longer in the C57BL/6J on the HFD compared with the mice on the ND at 0.1 and 5.0 µg/kg doses, respectively. The diet did not increase the blood half-life of TCDD in the A/J mice, which did not get obese. Using a physiologically based pharmacokinetic model for TCDD that incorporated experimentally derived percent body fat mass and tissue partition coefficients, as well as data on hepatic sequestration, did not provide accurate predictions to the data and could not explain the increase in half-life of TCDD in the HFD groups. This work demonstrates that obesity influences the half-life of TCDD, but other undetermined factors are involved in its elimination because the increase in body fat mass, decreases in cytochrome P4501A2, and altered partition coefficients could not completely explain the prolonged half-life.