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A 1976 chemical factory explosion near Seveso, Italy exposed residents to high levels of 2,3,7,8-tetracholorodibenzo-p-dioxin (TCDD or dioxin). Dioxin is a known human carcinogen and potent endocrine disruptor. It is highly lipophilic and has a long half-life in humans. Much of what we know and can learn about the risks of dioxin exposure on human health arose from the tragic circumstances of Seveso. This review aims to describe the Seveso accident, summarize the results of 40 years of research on the health of the Seveso population since the accident, and discuss next-stage research on the health of Seveso residents, their children, and grandchildren.

Tumor cell migration is affected by the aryl hydrocarbon receptor (AhR). However, the systematic molecular mechanisms underlying AhR-mediated migration of human neuroblastoma cells are not fully understood. To address this issue, we performed an integrative analysis of mRNA and microRNA (miR) expression profiles in human neuroblastoma SK-N-SH cells treated with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a potent agonist of AhR. The cell migration was increased in a time- and concentration- dependent manner, and was blocked by AhR antagonist (CH223191). A total of 4,377 genes were differentially expressed after 24-hour-treatment with 10-10 M TCDD, of which the upregulated genes were significantly enriched in cell migration-related biological pathways. Thirty-four upregulated genes, of which 25 were targeted by 78 differentially expressed miRs, in the axon guidance pathway were experimentally confirmed, and the putative dioxin-responsive elements were present in the promoter regions of most genes (79 %) and miRs (82 %) in this pathway. Furthermore, two promigratory genes (CFL2 and NRP1) induced by TCDD was reversed by blockade of AhR. In conclusion, AhR-mediated mRNA-miR networks in the axon guidance pathway may represent a potential molecular mechanism of dioxin-induced directional migration of human neuroblastoma cells.

Abstract Background Persistent organic pollutants (POPs) are known to accumulate in adipose tissues (AT). This storage may be beneficial by diverting POPs from other sensitive tissues or detrimental because of chronic release of pollutants as indirectly suggested during weight loss. The aim is to study the biological and/or toxic effects that chronic POP release from previously contaminated grafted AT could exert in a naïve mouse. Methods C57BL/6J male mice were exposed intraperitoneally to 2,3,7,8-tetrachlorodibenzo- p -doxin (TCDD); their epididymal fat pads were collected and grafted on the back skin of uncontaminated recipient mice whose brain, liver, and epididymal ATs were analyzed (TCDD concentration, relevant gene expression). Kinetics of release and redistribution were modeled using Physiologically Based PharmacoKinetics (PBPK). Results The grafts released TCDD over a period of 10 weeks with different kinetics of distribution in the three organs studied. A PBPK model was used to simulate the AT releasing process and the incorporation of TCDD into the major organs. At three weeks post-graft, we observed significant changes in gene expression in the liver and the host AT with signatures reminiscent of inflammation, gluconeogenesis and fibrosis as compared to the control. Conclusions This study confirms that AT-stored TCDD can be released and distributed to the organs of the recipient hence leading to distinct changes in gene expression. This original model provides direct evidence of the potential toxic-relevant effects when endogenous sources of contamination are present. Highlights • A new model to study the release and distribution of POPs • Introduction of a new PBPK model to study the effects of POPs • Internal release of TCDD activates signatures of inflammation & fibrosis. • Internal stores of POPs could play a significant role in long term toxicity. [ABSTRACT FROM AUTHOR]

Objectives To conduct a cross-sectional morbidity survey among 245 former employees of a pesticide production plant exposed to 2,3,7,8-tetrachlorodibenzo- p -dioxin (TCDD) in New Zealand. Methods Demographic factors and health information were collected in face-to-face interviews. TCDD, lipids, thyroid hormones, glucose and immunoglobulin G (IgG) were determined in non-fasting blood. For 111 participants, a neurological examination was conducted. Associations between health outcomes and working in a TCDD exposed job (prevalence 49%) and serum TCDD concentration ≥ 10 pg/g lipid (18%) were assessed using logistic regression whilst controlling for age, gender, smoking, body mass index and ethnicity. Results Diabetes was more common in those who had worked in TCDD exposed jobs (OR 4.0, 95%CI 1.0–15.4) and in those with serum TCDD ≥ 10 pg/g (OR 3.1, 95%CI 0.9–10.7). Non-fasting glucose levels > 6.6 mmol/l were more common in those with TCDD exposed jobs (OR 3.6, 95%CI 1.0–12.9), as were serum free thyroxine 4 < 12.8 pmol/l (OR 4.5, 95%CI 1.4–14.4), triglycerides > 1.7 mmol/l (OR 2.5, 95%CI 1.1–5.7) and high density lipoprotein cholesterol (HDL) < 1 mmol/l (OR 4.0, 95%CI 1.2–13.2). IgG was negatively associated with TCDD (linear regression p = 0.05). The neurological examination revealed a higher frequency of abnormal reflexes in those with serum TCDD ≥ 10 pg/g (OR 4.8, 95%CI 1.1–21.0). Conclusions In this occupationally exposed population, TCDD was associated with an increased risk of diabetes and a range of subclinical responses in multiple systems (peripheral nervous system, immune system, thyroid hormones and lipid metabolism), several decades after last exposure. These results need to be interpreted with caution due to the small study size and the cross-sectional nature of the study. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Several studies have assessed the potential role of environmental chemicals in the onset, growth, and/or physiopathology of endometriosis. However, their contour in terms of considered exposure markers remains limited. The present study aimed to characterize the internal exposure levels of 78 persistent organic pollutants (POPs, including dioxins, polychlorobiphenyls, brominated flame retardants and organochlorine pesticides) in a set of 113 adult French women (45 controls, 68 cases), and to characterize the distribution of these POPs within three biological compartments (omental adipose tissue, parietal adipose tissue, and serum). For all targeted substances, the correlation between the concentrations measured in omental versus parietal adipose tissue was found strongly significant (p < 0.0001). An equivalence of the measures performed in parietal and omental adipose tissue was moreover observed with median levels of 6.4 vs. 7.4 pg/g l.w. for WHO-TEQ 2005 PCDD/F, 4.5 vs. 4.7 pg/g l.w. for WHO-TEQ 2005 dl-PCB, 137.1 vs. 147.9 ng/g l.w. for sum of 6 ndl-PCB, and 2.1 vs. 2.0 ng/g l.w. for sum of 7 i-PBDE, respectively. The same observation was made for individual targeted OCs compounds. Significant correlations were also observed between these concentrations determined in adipose tissue and those measured in serum for dioxins (WHO-TEQ 2005 PCDD/F = 6.1 pg/g l.w), PCBs (WHO-TEQ 2005 dl-PCB = 3.6 pg/g l.w., sum of 6 ndl-PCB = 81.1 ng/g l.w.), and brominated flame-retardants (sum of 7 i-PBDE = 0.9 ng/g l.w.). The circulating versus stored ratio of some exposure markers (Sum PCDDs, 1,2,3,6,7,8-HxCDF, slightly versus highly chlorinated PCBs ratio, PBDE 99 and PBB 153) was found statistically different for control and case individuals. These extended exposure data from deep infiltrating endometriosis patients are the first ones available for France and give a new insight about the equilibrium of chemicals between storage and circulating compartments that should be further considered as new marker of exposure in the context of exposure-health relationship studies. [ABSTRACT FROM AUTHOR]

Background Polychlorinated dibenzo-p-dioxins/dibenzofurans (dioxins) and polychlorinated biphenyls (PCBs) are persistent organic pollutants (POPs) with potentially adverse impact on child neurodevelopment. Whether the potential detrimental effects of dioxins and PCBs on neurodevelopment are of specific or unspecific character is not clear. Objectives The purpose of the current study was to examine the influence of maternal dietary exposure to dioxins and PCBs on ADHD symptoms and cognitive functioning in preschoolers. We aimed to investigate a range of functions, in particular IQ, expressive language, and executive functions. Material and methods This study includes n = 1024 children enrolled in a longitudinal prospective study of ADHD (the ADHD Study), with participants recruited from The Norwegian Mother and Child Cohort Study (MoBa). Boys and girls aged 3.5 years participated in extensive clinical assessments using well-validated tools; The Preschool Age Psychiatric Assessment interview (PAPA), Stanford-Binet 5th revision (SB-5), Child Development Inventory (CDI), and Behavior Rating Inventory of Executive Function, Preschool version (BRIEF-P). Maternal dietary exposure to dioxins and PCBs was estimated based on a validated food frequency questionnaire (FFQ) answered mid-pregnancy and a database of dioxin and PCB concentrations in Norwegian foods. Exposure to dioxins and dioxin-like PCBs (dl-compounds) was expressed in total toxic equivalents (TEQ), and PCB-153 was used as marker for non-dioxin-like PCBs (ndl-PCBs). Generalized linear and additive models adjusted for confounders were used to examine exposure-outcome associations. Results Exposure to PCB-153 or dl-compound was not significantly associated with any of the outcome measures when analyses were performed for boys and girls together. After stratifying by sex, adjusted analyses indicated a small inverse association with language in girls. An increase in the exposure variables of 1 SD was associated with a reduction in language score of − 0.2 [CI − 0.4, − 0.1] for PCB-153 and − 0.2 [CI − 0.5, − 0.1] for dl-compounds in girls. For boys, exposure to PCB-153 or dl-compounds was not associated with language skills. The difference between sex-specific associations was not statistically significant (p-value = 0.13). No sex-specific effects were observed for ADHD-symptoms, IQ scores, or executive functions. Conclusions We found no indications that variation in current low-level exposure to PCB-153 or dl-compounds in Norway is associated with variation ADHD-symptoms, verbal/non-verbal IQ, or executive functions including working memory in preschoolers. However, our findings indicated that maternal dietary exposure to PCB-153 or dl-compounds during pregnancy was significantly associated with poorer expressive language skills in preschool girls, although the sex-specific associations were not significantly different. [ABSTRACT FROM AUTHOR]

On July 10, 1976, an explosion at a chemical plant in Seveso, Italy, released up to 30 kg of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)—the most potent dioxin congener. Twenty years later, the Seveso Women's Health Study (SWHS) initiated a follow-up assessment of a cohort of female Seveso residents. Researchers collected serial blood, measured for TCDD levels, and recorded information about the women's medical history after the explosion. The study's aims were to: 1) modify the human PBPK model for TCDD (Emond et al. 2004; Emond et al. 2005; NCEA-USEPA, 2010) to include repetitive gestation and lactation; 2) simulate TCDD blood concentrations during different life stages including pregnancy and lactation, under different exposure scenarios; and 3) use this PBPK model to compare the influence of gestation and lactation on elimination of TCDD. After optimization of the model, it was assessed using data from the SWHS cohort. The 23 women in Subcohort A, were 4–39 years old and in Subcohort B, the 18 women were 3–17 years old when the explosion occurred. The model accurately predicted the blood concentrations during the 20 years post-exposure, including periods of pregnancy and lactation. The model was also used to analyze the contribution of gestation and lactation to the mother's elimination of TCDD. The results suggest that gestation and lactation do not significantly impact TCDD blood elimination. Future efforts will focus on using additional data to evaluate the PBPK model and improving the mathematical descriptions of lactation and multiple gestations. [ABSTRACT FROM AUTHOR]

Background Prenatal exposure to dioxins and PCBs is potentially harmful to the developing fetus and may increase the risk of delayed or impaired neurodevelopment. Several studies have reported negative associations between prenatal exposure to these compounds and aspects of cognition related to language in early childhood. Objectives The aim was to examine the association between maternal low level dietary exposure to dioxins and PCB during pregnancy and language development in 3 year old children in a large group of mother-child pairs participating in the Norwegian Mother and Child Cohort Study (MoBa). Methods This study includes 44,092 children of women who were recruited to the Norwegian Mother and Child Cohort Study (MoBa) during the years 2002–2009. Maternal dietary exposure to dioxins and PCBs was estimated based on a validated food frequency questionnaire (FFQ) answered mid-pregnancy and a database of dioxin and PCB concentrations in Norwegian foods. Exposure to dioxins and dioxin-like PCBs (dl-compounds) was expressed in total toxic equivalents (TEQ), and PCB-153 was used as marker for non-dioxin-like PCBs (ndl PCBs). Children's language skills at age 3 were assessed by parental report including a Dale and Bishop grammar rating and questions about communication skills from the Ages and Stages Questionnaire (ASQ). Logistic regression models adjusted for confounders were used to examine the association between maternal dietary exposure to dl-compounds or PCB-153 and language development in children. Results The maternal dietary exposure to dl-compounds and PCB-153 was generally low, and 98% of women had intakes of dl-compounds ≤ 14 pg TEQ/kg bw/week, which is the tolerable weekly intake set by EU's Scientific Committee for Food (SCF). High maternal exposure (> 14 pg TEQ/kg bw/week of dl-compounds (median 2.6 pg/kg bw/day, range 2–16) or > 97.5-percentile intake of PCB-153 (median 11 ng/kg bw/day, range 5–28) was associated with higher odds of incomplete grammar (in boys and girls, adjusted ORs 1.1 to 1.3) and severe language delay in girls, adjusted ORs 2.8 [95% CI 1.1, 7.1] for PCB-153 and 2.9 [95% CI 1.4, 5.9] for dl-compounds. Furthermore, high exposure to dl-compounds was associated with moderate language delay 1.4 [95% CI 1.0, 2.0] and lower communication score (ASQ), adjusted OR 1.4 [95% CI 1.1, 1.9] in girls. Conclusions The main findings of this study were: 1) Girls born to mothers who exceeded the tolerable weekly intake for dl-compounds or had a PCB-153 intake above the 97.5 percentile in early pregnancy may have increased risk of language delay at age 3 years. 2) Negative associations with maternal exposure to dl-compounds or PCB-153 were observed for both boys and girls having incomplete grammar, which is a subtle reduction in language skills. This interesting finding should not be considered as deviant at this age. [ABSTRACT FROM AUTHOR]

While the U.S. EPA has issued a draft report with a 1% TCDD effective dose (ED 01 ) of 87.9 pg/kg/day based on continuous integration of key scientific evidence, a detailed and comprehensive uncertainty analysis has not been well documented. In this study, a new estimate for ED 01 was derived based on uncertainty analysis by quantitatively assessing the potential bias arising from the selection of kinetic models, dose–response models and cohorts. The cumulative serum lipid concentration (CSLC) and cumulative body burden (CBB) were reconstructed as dose metrics using a concentration- and age-dependent pharmacokinetic model (CADM), physiologically based pharmacokinetic model (PBPK), and age-dependent half-life model (FV), and the reconstructed dose metrics based on CADM and PBPK were generally higher than those based on the FV model. Three dose–response curves (linear, multiplicative and power) were used to link dose metrics and cancer risk to estimate ED 01 , and the linear model resulted in the lowest ED 01 , followed by the power model and multiplicative model, for the same cohort. Meanwhile, ED 01 based on the CADM model was the highest, followed by those based on the PBPK model and first-order model. Finally, the ED 01 was estimated to be 17.03 ± 7.83 pg/kg/day by statistically analyzing the distribution of ED 01 values based on various kinetic models, cohorts and dose–response models. The study presented here strengthens the scientific basis for understanding the potential health implications of TCDD exposure. [ABSTRACT FROM AUTHOR]

[Display omitted] • Low concentrations of 2,3,7,8-tetrachlorodibenzo-p-dioxin could induce the directional migration of human neuroblastoma cells. • The upregulated genes were significantly enriched in the cell migration-related biological pathways. • The AhR-mediated mRNA and miR expressions involved in the axon guidance pathway played an important role. • The putative dioxin-responsive elements were present in the promoter regions of most genes and miRs in the axon guidance pathway. Tumor cell migration is affected by the aryl hydrocarbon receptor (AhR). However, the systematic molecular mechanisms underlying AhR-mediated migration of human neuroblastoma cells are not fully understood. To address this issue, we performed an integrative analysis of mRNA and microRNA (miR) expression profiles in human neuroblastoma SK- N -SH cells treated with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a potent agonist of AhR. The cell migration was increased in a time- and concentration- dependent manner, and was blocked by AhR antagonist (CH223191). A total of 4,377 genes were differentially expressed after 24-hour-treatment with 10-10 M TCDD, of which the upregulated genes were significantly enriched in cell migration-related biological pathways. Thirty-four upregulated genes, of which 25 were targeted by 78 differentially expressed miRs, in the axon guidance pathway were experimentally confirmed, and the putative dioxin-responsive elements were present in the promoter regions of most genes (79 %) and miRs (82 %) in this pathway. Furthermore, two promigratory genes (CFL2 and NRP1) induced by TCDD was reversed by blockade of AhR. In conclusion, AhR-mediated mRNA-miR networks in the axon guidance pathway may represent a potential molecular mechanism of dioxin-induced directional migration of human neuroblastoma cells. [ABSTRACT FROM AUTHOR]

The Aryl hydrocarbon receptor (AhR) binds a variety of chlorinated and brominated dioxins, furans and biphenyls. Mixed halogenated variants have been recently identified in food at significant levels but full characterisation requires potency data in order to gauge their impact on risk assessment. Rat H4IIE and human MCF-7 cells were treated with various mixed halogenated ligands. Antagonist properties were measured by treating cells with various concentrations of TCDD in the presence of EC 25 of the putative antagonist. Measurement of CYP1A1 RNA was used to quantify the potency of agonism and antagonism. The PXDDs were found to be slightly less potent than the corresponding fully chlorinated congeners with the exception of 2-B,3,7,8-TriCDD which was 2-fold more potent than TCDD. PXDFs and non-ortho-PXBs were found to be more potent than their chlorinated congeners whilst several mono- ortho -substituted PXBs were shown to have partial agonistic properties. REPs were produced for a range of mixed halogenated AhR-activating ligands providing a more accurate estimation of potency for risk assessment. Several environmentally abundant biphenyls were shown to be antagonists and reduce the ability of TCDD to induce CYP1A1. The demonstration of antagonism for AhR ligands represents a challenge for existing REP risk assessment schemes for AhR ligands. [ABSTRACT FROM AUTHOR]

Abstract: Animal evidence suggests an association between exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and adverse pregnancy outcomes. Epidemiologic studies report inconsistent results, but are limited by narrow range of exposure, small sample size, and lack of a biologic measure of highest lifetime exposure. On July 10, 1976, a chemical explosion in Seveso, Italy resulted in the highest known residential exposure to TCDD. In 1996, we initiated the Seveso Women's Health Study (SWHS), a retrospective cohort of TCDD exposure and reproductive health. Individual-level TCDD was measured in serum collected soon after the explosion. After 20years of follow-up, we found no association between maternal TCDD in 1976 serum or estimated at pregnancy and spontaneous abortion (SAB), fetal growth, or gestational length. Here, we present an updated analysis of TCDD exposure and adverse pregnancy outcomes from a subsequent follow-up of the SWHS cohort in 2008–2009. SWHS women had 1211 post-explosion pregnancies through the 2008–2009 follow-up. We found no association between TCDD estimated at pregnancy and SAB, fetal growth, or gestational length. However, we found a non-significant inverse association between maternal 1976 serum TCDD and birthweight (adjusted β =−22.8, 95% CI: −80.1, 34.6). The association was stronger among first post-explosion births, but remained non-significant (adjusted β =−47.7, 95% CI: −107.3, 11.9). SWHS is the first study to be able to consider two potentially relevant measures of TCDD exposure: highest lifetime dose and in utero. Our results, although non-significant, suggest that highest dose may be more relevant in epidemiologic studies of TCDD and pregnancy outcomes. [Copyright &y& Elsevier]

Abstract: Temporal trends of polychlorinated dibenzo-p-dioxins (PCDDs), dibenzofurans (PCDFs) and dioxin-like polychlorinated biphenyls (DL-PCBs) in mothers' milk are still quite rare. Data are particularly scarce when it comes to concentrations from the last decade, 2000 and onwards. The aims of the present study were to assess temporal trends of PCDD, PCDF and DL-PCB in mothers' milk from Stockholm, 1972–2011 and to compare the results with previous analysis of some of the older samples. The samples were analyzed by high resolution GC/MS and results were statistically evaluated for the periods, 1972–2011 and 2002–2011. The rate of which ∑PCDDs, ∑DL-PCBs and the ∑TEQ are decreasing (on pg/g fat WHO-TEQ2005) is higher in the last decade compared to the 40year period, 1972–2011. A similar trend is indicated, but not confirmed, for ∑TEQ of PCDFs, probably due to too many PCDF congeners below LOQ in the period 2002–2011. Concentrations of ∑PCDDs, ∑PCDFs, ∑DLPCBs and ∑TEQ, all expressed as pg/g fat on TEQ-WHO2005-basis, show a statistically significant decline over time, 5.8–6.8% per year, 1972–2011. The last ten years the annual declines for ∑PCDDs, ∑DL-PCBs and ∑TEQ are 9.2–11% and for ∑PCDF, 5.4%. Congener specific trend analysis, 2002–2001, of PCDDs and DL-PCBs showed the same pattern, while the PCDF congeners showed no such general trend. The results from the re-analysis showed good agreement with slightly lower ∑TEQ1998 pg/g fat concentrations in six out of seven samples and mean difference of 13% in ∑TEQ1998. The study shows that time series can be elongated from previous studies, as long as the sample population remains the same. [Copyright &y& Elsevier]

Abstract: Background: Dioxins and PCBs accumulate in the food chain and might exert toxic effects in animals and humans. In large epidemiologic studies, exposure estimates of these compounds based on analyses of biological material might not be available or affordable. Objectives: To develop and then validate models for predicting concentrations of dioxins and PCBs in blood using a comprehensive food frequency questionnaire and blood concentrations. Methods: Prediction models were built on data from one study (n=195), and validated in an independent study group (n=66). We used linear regression to develop predictive models for dioxins and PCBs, both sums of congeners and 33 single congeners (7 and 10 polychlorinated dibenzo-p-dioxins and furans (PCDDs/PCDFs), 12 dioxin-like polychlorinated biphenyls (PCBs: 4 non-ortho and 8 mono-ortho), sum of all the 29 dioxin-like compounds (total TEQ) and sum of 4 non dioxin-like PCBs (∑ CB-101, 138, 153, 183=PCB4). We used the blood concentration and dietary intake of each of the above as dependent and independent variables, while sex, parity, age, place of living, smoking status, energy intake and education were covariates. We validated the models in a new study population comparing the predicted blood concentrations with the measured blood concentrations using correlation coefficients and Weighted Kappa (КW) as measures of agreement, considering КW >0.40 as successful prediction. Results: The models explained 78% (sum dioxin-like compounds), 76% (PCDDs), 76% (PCDFs), 74% (no-PCBs), 69% (mo-PCBs), 68% (PCB4) and 63% (CB-153) of the variance. In addition to dietary intake, age and sex were the most important covariates. The predicted blood concentrations were highly correlated with the measured values, with r=0.75 for dl-compounds 0.70 for PCB4, (p<0.001) and 0.66 (p<0.001) for CB-153. КW was 0.68 for sum dl-compounds 0.65 for both PCB4 and CB-153. Out of 33 congeners 16 (13dl-compounds and 3 ndl PCBs) had КW >0.40. Conclusions: The models developed had high power to predict blood levels of dioxins and PCBs and to correctly rank subjects according to high or low exposure based on dietary intake and demographic information. These models underline the value of dietary intake data for use in investigations of associations between dioxin and PCB exposure and health outcomes in large epidemiological studies with limited biomaterial for chemical analysis. [Copyright &y& Elsevier]

Abstract: Background exposure to persistent organic pollutants (POPs), lipophilic xenobiotics that accumulate mainly in adipose tissue, has recently emerged as a new risk factor for cardiovascular diseases. This prospective study was performed to evaluate if plasma concentrations of selected POPs predict incident stroke among the elderly. Twenty‐one POPs (including 16 polychlorinated biphenyl (PCB) congeners, 3 organochlorine (OC) pesticides, 1 brominated diphenyl ether (BDE), and 1 dioxin) were measured in plasma collected at baseline in 898 participants aged 70years of the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS). Stroke diagnosis was validated by hospital records. During the five year follow-up, 35 subjects developed hospital-treated stroke. After adjusting for known stroke risk factors, most PCBs with 4, 5, or 6 chlorine atoms, p,p′-DDE, trans-nonachlor, and octachlorodibenzo-p-dioxin significantly predicted the risk of stroke. Across quartiles of summary measures of PCBs and OC pesticides, the adjusted ORs were 1.0, 0.8 (95% confidence interval: 0.2–2.5), 1.2 (0.4–3.4), and 2.1 (0.7–6.2) for PCBs and 1.0, 1.2 (0.3–4.2), 2.3 (0.7–6.9), and 3.0 (1.0–9.4) for OC pesticides (P for trend=0.11 and 0.03, respectively). The adjusted ORs among participants ≥90th percentile of the summary measures were 5.5 (1.7–18.1) for PCBs and 4.0 (1.1–14.6) for OC pesticides; corresponding ORs for those ≥95th percentile were 7.8 (2.1–29.6) and 9.5 (2.3–38.9). Background exposure to POPs may play an important role in development or progression of stroke in the elderly. [Copyright &y& Elsevier]

Abstract: Persistent Organic Pollutants (POPs) are a huge group of chemicals that have been linked to various adverse health effects in humans. Large epidemiological studies investigating gender differences in levels of POPs in the elderly are limited and the results from these are not always consistent. The present study was undertaken to examine the background levels of a broad range of POPs in human plasma samples among elderly men and women from Sweden and to assess the influence of gender. Levels of 23 POPs were determined in plasma samples collected during 2001–2004 from 1016 (50.2% women) 70year-old participants from the population-based Prospective Study of the Vasculature in Uppsala Seniors (PIVUS). Measurements were performed using high resolution gas chromatography with high resolution mass spectrometry (HRGC-HRMS) and the POPs studied were 16 polychlorinated biphenyls (PCBs), five organochlorine (OC) pesticides, one dioxin, and one brominated flame retardant. The concentrations of the selected POPs were found similar, or comparable, to other studies of non-occupationally exposed populations from Sweden and Europe. Differences in levels of POPs between men and women were assessed by using Wilcoxon rank-sum (Mann–Whitney) test. Significant (p <0.0001) gender differences in levels of specific POPs were observed and a number of POP concentrations were found to differ between men and women. More specifically, levels of HCB, OCDD, and PCB congeners #74, #105, and #118 were found to be higher in women, while the rest of the majority of POPs were higher in men. [Copyright &y& Elsevier]

Abstract: Objectives: In animal experiments, persistent organic pollutants (POPs) have induced visceral obesity. To address this possibility in humans, we evaluated associations between POPs and abdominal obesity both cross-sectionally and prospectively. Methods: Twenty-one plasma POPs (16 polychlorinated biphenyl (PCB) congeners, 3 organochlorine (OC) pesticides, 1 brominated diphenyl ether (BDE), and 1 dioxin) were measured at baseline in 970 participants aged 70years of the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS), with prospective analyses in 511 participants re-examined after 5years. Abdominal obesity was defined by an increased waist circumference. Results: In the cross-sectional analyses, concentrations of the less chlorinated PCBs, OC pesticides such as p,p′-DDE and dioxin had adjusted odds ratios of 2 to 3 for abdominal obesity. Many relations had inverted U-shapes rather than being linear, particularly in women. In contrast, concentrations of highly chlorinated PCBs were strongly inversely associated with abdominal obesity. In a single model including summary measures of the less chlorinated PCBs, highly chlorinated PCBs, and OC pesticides, both the positive associations and inverse associations strengthened. Similar but somewhat weaker associations were seen between POPs and risk of development of abdominal obesity in the prospective analyses. Conclusion: Using both a cross-sectional and a prospective design, low-dose exposure to less chlorinated PCBs, p,p′-DDE, and dioxin, were associated with existence or development of abdominal obesity, while highly chlorinated PCBs had an opposite association in an elderly population, despite the previous observation of higher incident diabetes associated with these same PCBs. [Copyright &y& Elsevier]

Abstract: Background: Studies on the association of maternal exposure to polychlorinated dibenzo-p-dioxin (PCDDs), polychlorinated dibenzofurans (PCDFs), and polychlorinated biphenyls (PCBs) with decreased birth weight in humans have produced conflicting results. In Japan in 1968, an accidental human exposure to rice oil contaminated with PCDDs, PCDFs, and PCBs, led to the development of Yusho disease. Objective: The Yusho cohort was used to evaluate the effect of maternal exposure to PCDDs, PCDFs, and PCBs on birth weight. Methods: Blood samples, obtained from 101 Yusho women (190 births) who gave birth after exposure, were analyzed for congeners of seven PCDDs, ten PCDFs, and four non-ortho PCBs. Results: Total PCDD TEQ (adjusted beta=−161.9g; 95% CI, −265.3 to −58.6), total PCDF TEQ (adjusted beta=−105.9g; 95% CI, −179.5 to −32.2), and total non-ortho PCBs (adjusted beta=−178.4g; 95% CI, −318.3 to −38.5) levels were inversely associated with birth weight. Significant inverse associations with birth weight were also found for total PCDD TEQ, total PCDF TEQ, and total non-ortho PCB TEQ levels among male, but not female, infants. Significant inverse associations with birth weight were also found for nine congeners among all infants; the adjusted beta coefficients were largest for 1,2,3,6,7,8-HxCDD and smallest for 2,3,4,7,8-PeCDF. Conclusion: In the setting of exposure to high levels of dioxins, maternal blood levels of PCDDs, PCDFs and PCBs are associated with lower birth weight in Yusho patients. The association exhibited gender-specific differences, as male infants are more susceptible than females to growth restriction induced by in utero dioxin exposures. [Copyright &y& Elsevier]

Abstract: Organochlorine chemicals may contribute to an increased risk of non-Hodgkin lymphoma (NHL) within non-occupationally exposed populations. Among these chemicals, dioxins and furans were mainly released by municipal solid waste incinerators (MSWIs) until a recent past in France, a source of exposure that is of public concern. We investigated organochlorines and the risk of NHL among neighbors of a French MSWI with high levels of dioxin emissions (Besançon, France), using serum concentrations to assess exposure. The study area consisted of three electoral wards, containing or surrounding the MSWI. Pesticides, dioxins, furans, and polychlorinated biphenyls (PCBs) were measured in the serum of 34 newly diagnosed NHL cases (2003–2005) and 34 controls. Risks of NHL associated with each lipid-corrected serum concentration were estimated using exact logistic regression. The pesticides β-hexachlorocyclohexane (odds ratio [OR]=1.05, 95% confidence interval [CI]=1.00–1.12, per 10ng/g lipid) and p,p'' dichloro-diphenyl-trichloroethane (DDT) (OR=1.20, 95% CI=1.01-1.45, per 10ng/g lipid) were associated with NHL risk. Evidence indicated an increased NHL risk associated with cumulative WHO1998-toxic equivalency factor (TEQ) concentrations (dioxins, OR=1.12, 95% CI=1.03–1.26; furans, OR=1.16, 95% CI=1.03–1.35; dioxin-like PCBs, OR=1.04, 95% CI=1.00–1.07; and total TEQ, OR=1.04, 95% CI=1.01–1.05), as well as with non dioxin-like PCBs (OR=1.02, 95% CI=1.01–1.05, per 10ng/g lipid). Most congener-specific associations were statistically significant. This study provides strong and consistent support for an association between serum cumulative WHO1998-TEQ concentrations, at levels experienced by people residing in the vicinity of a polluting MSWI, and risk of NHL. [Copyright &y& Elsevier]

Abstract: Trace elements and polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) were analyzed in soils from rural and light-industrialized sites (n =168) of Province of Pavia (Northern Italy). Most of the trace element values fit in typical ranges of concentrations in soils and are similar to the ones reported for rural sites in Italy or sites with no direct anthropogenic impact. Total concentrations of 2,3,7,8 chlorine substituted PCDD/Fs in superficial soils ranged between 24.4 and 1287 pg g−1 dw (0.5–28.9 pg WHO98-TEQ g−1 dw). The North Eastern part of the Province presented significantly higher levels (p <0.001) than the rest of the Province for As, Cd, Hg, Pb, Zn and PCDD/Fs. While the existence of a defined heavy metal polluting source for this specific site has been suggested, in the case of PCDD/Fs, profiles were not linked to any specific emission source fingerprint. In the whole extension of Pavia Province, OCDD/F dominated the 2,3,7,8 chlorine substituted congener soil pattern, followed by the 1,2,3,4,6,7,8 hepta-CDD/F congener. Principal Component Analysis (PCA) showed that this profile could not be associated to any described PCDD/F emission source fingerprint and was relatively similar to the baseline deposition of sites with no direct impact of PCDD/F emission sources independently of land use. [Copyright &y& Elsevier]

Abstract: A novel bioassay with the human adrenocortical carcinoma cell line H295R can be used to screen for endocrine disrupting chemicals that affect the expression of genes important in steroidogenesis. This assay was employed to study the effects of organic contaminants associated with the freshwater pond sediments collected in the Ostrava-Karvina region, Czech Republic. The modulation of ten major genes involved in the synthesis of steroid hormones (CYP11A, CYP11B2, CYP17, CYP19, 17βHSD1, 17βHSD4, CYP21, 3βHSD2, HMGR, StAR) after exposure of H295R cells to sediment extracts was investigated using quantitative real-time polymerase chain reaction (PCR). Crude sediment extracts, containing high concentrations of polycyclic aromatic hydrocarbons (PAHs) and moderate amounts of polychlorinated biphenyls (PCBs) and organochlorine pesticides (OCPs) significantly stimulated expression of the CYP11B2 gene (up to 10-fold induction), and suppressed expression of 3βHSD2 and CYP21 genes. A similar pattern was observed with the extracts after treatment with concentrated sulfuric acid to remove labile chemicals (including PAHs) leaving only persistent PCBs, OCPs and potentially PCDD/Fs. Comparison of the results with other mechanistically based bioassays (arylhydrocarbon receptor, AhR, mediated responses in H4IIE-luc cells, and estrogen receptor mediated effects in MVLN cells) revealed significant endocrine disrupting potencies of organic contaminants present in the sediments (most likely antiestrogenicity). Pronounced effects were observed particularly in sediment extracts from the Pilnok Pond which harbors an unusual intersexual population of the narrow-cawed crayfish Pontastacus leptodactylus (Decapoda, Crustacea). This pilot study provided the first experimental evidence of the wider application of the H295R bioassay for screening complex environmental samples, and the results support the hypothesis of chemical-induced endocrine disruption in intersexual crayfish. [Copyright &y& Elsevier]

Abstract: The Angers municipal solid waste incineration plant, in operation since 1974, was upgraded in 2000 to comply with new European standards. This article discusses the risks associated with past and present emissions from the incinerator and its nearby furnace. Emissions of SO2, HCl, particulate matter, lead, mercury, cadmium and dioxins were studied. We characterised the risks associated with exposure via inhalation and ingestion of locally grown products, before and after the upgrade. Emissions were estimated from regulatory measurements, and ambient air concentrations estimated with a Gaussian dispersion model. The CalTox multimedia model was used to calculate concentrations in the food chain. Food intake rates came from a nationwide survey. Inhalation exposure to respiratory irritants produced a hazard ratio less than 1 in all scenarios, except for SO2 in the immediate neighbourhood of the incinerator, before the change in furnace fuel and in case of high-pressure weather conditions. The individual excess risk of cancer was less than 10−6 and the hazard ratios for metals were less than 1. Before compliance, the average dioxin exposure attributable to the incinerator accounted for roughly one quarter of the average total exposure from traffic and other combustion activities. Although the corresponding hazard ratio was less than 1, the individual lifetime excess risk, assuming no change in emissions, was 2·10−4. After compliance, all hazard ratios and future individual lifetime excess risks appear minimal. These results are consistent with environmental data and other studies, but many uncertainties remain, such as intermedia transfer coefficients for dioxins. Nevertheless compliance has vastly reduced the probability of health effects. [Copyright &y& Elsevier]

Potential synergistic interactions between polycyclic aromatic hydrocarbons in a household sewage sludge compost extract were investigated using the Dioxin-Responsive Chemical-Activated Luciferase gene eXpression (DR-CALUX) assay and reverse-phase high-performance liquid chromatography (RP-HPLC) fractionation. The biological activity of the crude extract was measured in vitro using the CALUX assay. The CALUX activity of the extract was as potent as 360-pg CALUX-TEQ (2,3,7,8-TCDD equivalent value) per g sample, this was 70 times above the WHO-TEQ value which was derived from chemical analyses of dioxins/furans and dioxin-like PCBs of the mixture. The CALUX activity pattern of the crude extract and the retention times of 26 polycyclic aromatic compounds (PACs), as determined by RP-HPLC on an octadecylsilica column, suggested that the dioxin-like compounds with the log KOW (n-octanol/water partition coefficient) values corresponding to 6.0–7.0 contributed highly to the whole activity. The CALUX activity of the crude extract was three times the sum of the CALUX activities of the RP-HPLC separated fractions. Mixture effects were assessed by co-exposure of each HPLC fraction and 2,3,7,8-TCDD to the cells. The four concentration levels of added 2,3,7,8-TCDD corresponded to the TEQ value in the original compost sample. The experimental CALUX activity was higher than the predicted CALUX activity for some fractions. It was demonstrated that some compounds in the compost sample interacted synergistically with 2,3,7,8-TCDD in terms of dioxin-like activity. This finding points out the necessity for detailed investigation of synergistic effects in environmental samples. [Copyright &y& Elsevier]

We have measured the concentrations of polychlorinated dibenzo-p-dioxins (PCDD/F), polychlorinated biphenyls (PCBs), and polybrominated diphenyl ethers (PBDE) in 10 market baskets consisting of almost 4000 individual food samples representing 228 different food items, and also in the total diet basket. Lower bound concentrations of PCDD/Fs ranged between 0.0057 and 5.6 pg/g fresh weight in the market baskets and the corresponding values for PCBs from 39 to 25,000 pg/g. The fish basket contributed most to the concentrations of dioxins and PCBs, and also to concentrations of PBDEs in which the lower bound range was from 0.82 to 850 pg/g. We also assessed the average daily intakes of these substances by the Finnish adult population. The average daily intake of sum of PCDD/Fs and PCBs as WHO toxic equivalents was assessed to be 115 pg, which was 1.5 pg WHO-TEq/kg body weight using an average mean weight of 76 kg for the general population in Finland. The contribution of fish to the intake of PCDD/Fs was between 94% and 72%, depending on whether lower or upper bound concentrations were used. With respect to PCBs, the contribution of fish was 80%. The calculated intake of PBDEs of 44 ng/day was comparable to intake assessments from other countries. Fish also contributed most to the PBDE intake, but there was some other source of PBDEs that distinguishes the exposure to PBDEs from exposure to PCDD/Fs and PCBs. This additional source seemed to be found in the market basket that included beverages, spices, and sweets. [Copyright &y& Elsevier]

• The Seveso Second Generation study is a cohort of children born to TCDD-exposed women. • We examined associations of in utero TCDD exposure with glucose homeostasis. • In utero TCDD exposure was associated with lower insulin resistance in females only. • Observed associations in daughters showed evidence of mediation by body mass index. Exposure to endocrine disrupting compounds such as 2,3,7,8-tetrachlorodibenzo- p -dioxin (TCDD) during susceptible developmental windows may alter risk of metabolic disease later in life. Animal studies of in utero and lactational TCDD exposure report associations with alterations in insulin sensitivity and energy homeostasis, but epidemiologic evidence is limited. We examined the relationship of prenatal TCDD exposure with markers of glucose homeostasis in the Seveso Second Generation study, a unique cohort of children born to TCDD-exposed women resulting from a 1976 explosion in Seveso, Italy. We included 426 children who were 18 years or older with complete follow-up data including a fasting blood draw. Insulin and glucose were measured and the updated homoeostatic model assessment was used to estimate insulin resistance (HOMA2-IR) and beta-cell function (HOMA2-B). Prenatal TCDD exposure was defined in two ways, as initial maternal serum TCDD concentration and TCDD estimated at pregnancy. The children (222 female, 204 male) averaged 28.6 (±6.0) years. We found a 10-fold increase in TCDD estimated at pregnancy was inversely associated with insulin (adj-β = −1.24 μIU/mL, 95% confidence interval (CI): −2.38, −0.09) and HOMA2-B (adj-β = −10.2% decrease, 95% CI: −17.8, −1.9) among daughters, but not sons (insulin: adj-β = 0.57 μIU/mL, 95% CI: −0.84, 1.98, P for interaction = 0.04; and HOMA2-B: adj-β = 0.8% increase, 95% CI −10.7, 13.9, P for interaction = 0.11). Similar effect modification was observed for TCDD estimated at pregnancy and HOMA2-IR (P for interaction = 0.13). The models for initial maternal serum TCDD showed similar effect modification by child sex. The observed associations in daughters showed evidence of mediation by body mass index, which we have previously found to be associated with prenatal TCDD exposure in female offspring. These results suggest prenatal exposure to TCDD is associated with lower insulin resistance and beta compensation in female offspring, and show evidence of mediation by body mass index. [ABSTRACT FROM AUTHOR]