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Background and aims: Prenatal chemical exposure has frequently been associated with reduced fetal growth although results have been inconsistent. Most studies associate single pollutant exposure to this health outcome, even though this does not reflect real life situations as humans are exposed to many pollutants during their life time. The objective of this study is to investigate the association between prenatal exposure to a mixture of persistent environmental chemicals and birth weight using multipollutant models. Methods: We combined exposure biomarker data measured in cord blood samples of 1579 women from four Flemish birth cohorts collected over a 10 years' time period. The common set of available and detectable exposure measures in these cohorts are three polychlorinated biphenyls (PCB) congeners (138, 153 and 180), hexachlorobenzene (HCB), dichlorodiphenyldichloroethylene (p,p'-DDE) and the metals cadmium and lead. Multiple linear regression (MLR), Bayesian Information Criterion (BIC), penalized regression using minimax concave penalty (MCP) and Bayesian Adaptive Sampling (BAS) were applied to assess the influence of multiple pollutants in a single analysis on birth weight, adjusted for a priori selected covariates. Results: In the pooled dataset, a median (P25-P75) birth weight and gestational age of 3420 (3140-3700) grams and 39 (39-40) weeks was observed respectively. The median contaminant levels in cord blood were: 15.8, 26.5, 18.0, 16.9 and 91.5 ng/g lipid for PCB 138, PCB 153, PCB 180, HCB and p,p'-DDE, respectively, 0.075 mu g/L for cadmium and 9.7 mu g/L for lead. According to the applied statistical methods for multipollutant assessment, p,p'-DDE and PCB 180 were most consistently associated with birth weight. In addition, PCB 153 was selected when applying MCP and BAS. An inverse association with birth weight was found for the PCB congeners, while an increased birth weight was observed for elevated levels of p,p'-DDE. Conclusions: Assessing the health risk of combinations of exposure biomarkers reflects better real-world situations and thereby allows more effective risk assessment. Our results add to the existing evidence based on detrimental effects of PCBs on birth weight and indicate a possible increase in birth weight due to p,p'-DDE (while correcting for PCBs). The FLEHS studies were carried out by the Flemish Center of Expertise on Environment and Health. The studies of the Center were commissioned, financed and steered by the Ministry of the Flemish Community. NIRAS/ONDRAF (Belgian National Agency for Radioactive Waste and enriched Fissile Material), STORA (Study and Consultation Radioactive Waste Dessel) and MONA (Mols Overleg Nucleair Afval) financed the 3xG study. Govarts, E (corresponding author), Flemish Inst Technol Res VITO, Hlth, Boeretang 200, B-2400 Mol, Belgium. eva.govarts@vito.be

Aims: Decisive evidence on the optimal diuretic agent, dosing schedule, and administration route is lacking in acute heart failure (AHF) with congestion. The Acetazolamide in Decompensated heart failure with Volume OveRload (ADVOR) trial is designed to test the hypothesis that the carbonic anhydrase inhibitor acetazolamide, a potent inhibitor of proximal tubular sodium reabsorption, improves decongestion when combined with loop diuretic therapy in AHF, potentially leading to better clinical outcomes. Methods: The ADVOR trial is set up as a multicentre, randomized, double-blind, placebo-controlled study, aiming to recruit 519 patients with AHF and clinically evident volume overload. All study participants receive high-dose intravenous loop diuretics as background therapy and are randomized towards intravenous acetazolamide at a dose of 500 mg once daily vs. placebo, stratified according to including study centre and ejection fraction (< 40% vs. ≥ 40%). The primary endpoint is successful decongestion with no more than trace oedema assessed on the third morning after hospital admission, with good diuretic efficacy defined as a urine output > 3.5 L during the first 30–48 h of decongestive treatment. Secondary endpoints include all-cause mortality or heart failure readmission after 3 months, length of hospital stay for the index admission, and longitudinal changes in the EuroQol-5 dimensions questionnaire. Conclusion: ADVOR will investigate if acetazolamide combined with loop diuretic therapy improves decongestion in AHF with volume overload. © 2018 The Authors. European Journal of Heart Failure © 2018 European Society of Cardiology

epub ahead of print ispartof: Wiley Interdisciplinary Reviews: Nanomedicine and Nanobiotechnology pages:1-14 status: Published online

In this paper, we propose a method to cluster multivariate functional data with missing observations. Analysis of functional data often encompasses dimension reduction techniques such as principal component analysis (PCA). These techniques require complete data matrices. In this paper, the data are completed by means of multiple imputation, and subsequently each imputed data set is submitted to a cluster procedure. The final partition of the data, summarizing the partitions obtained for the imputed data sets, is obtained by means of ensemble clustering. The uncertainty in cluster membership, due to missing data, is characterized by means of the agreement between the members of the ensemble and fuzziness of the consensus clustering. The potential of the method was brought out on the heart failure (HF) data. Daily measurement for four biomarkers (heart rate, diastolic, and systolic blood pressure, weight) were used to cluster the patients. To normalize the distributions of the longitudinal outcomes, the data were transformed with a natural logarithm function. A cubic spline base with 69 basis functions was employed to smooth the profiles. The proposed algorithm indicates the existence of a latent structure and divides the HF patients into two clusters, showing a different evolution in blood pressure values and weight. In general, cluster results are sensitive to choices made. Likewise for the proposed approach, alternative choices for the distance measure, procedure to optimize the objective function, choice of the scree-test threshold, or the number of principal components, to be used in the approximation of the surrogate density, could all influence the final partition. For the HF data set, the final partition depends on the number of principal components used in the procedure. The authors gratefully acknowledge support from IAP research Network P7/06 of the Belgian government (Belgian Science Policy).

Background and aims: One of the goals of human biomonitoring by the Flemish Centre of Environment and Health was to investigate exposure-response associations for various biomarkers of exposure and effect. The aim of this study is to describe the results of the exposure-effect associations involving exposure to metals and metalloids. Methods: Participants donated blood and/or urine for determination of concentrations of metals and metalloids (by ICP-MS) and biomarkers of effect (by various analytical methods). All subjects filled in a questionnaire to provide information on health, life-style and personal factors. The age groups sampled were mother-newborn pairs (maternal and cord blood), 14-15 year old adolescents (blood and urine) and 20-40 year old adults (urine). Regression models were fitted to determine associations between effect- and exposure markers, adjusted for relevant confounders and covariates (e.g. smoking, age, gender). Results: Many significant associations were in line with previously reported findings, while some were not published before. The size of newborns was negatively correlated with cord blood As, and positively with Cu. For adolescent girls, blood and urinary Tl were negatively correlated with development of pubic hair and breasts. In boys negative correlations were found between urinary Tl and pubic hair development, and between both urinary Tl and blood Pb and genital development. In adolescents, urinary Cd showed a negative correlation with the T4 thyroid hormone and a positive correlation with an indicator of DNA damage, while urinary Cd and urinary Cr showed positive correlation with indicators of kidney damage. Various correlations were found between metals and sex hormones (aromatase, SHBG, testosterone, estradiol) in boys. In adults, there was only a significant negative association between urinary As and blood platelet aggregation. Conclusions: Many exposure-effect associations were supported by the literature, some were reported earlier in a previous cycle of the Flemish human biomonitoring.

In 2002, the Centre for Environment and Health in Flanders, Belgium started a human biomonitoring program (FLEHS I). For 1679 adolescents, residing in nine study areas with differing pollution pressure, exposure to the pesticides p,p'-DDE and HCB, hormone levels and the degree of sexual maturation were measured. Possible confounding effects of lifestyle and personal characteristics were taken into account. In 2007, a second cycle of the Flemish human biomonitoring program (FLEHS II) started. The main purpose was generating reference values for several biomarkers, both of exposure and of effect, and establishing dose-effect relationships. In this survey, not only the pesticides p,p'-DDE and HCB were measured, but also metabolites from organophosphate pesticides and para-dichlorophenol (2,5-DCP), a metabolite of para-dichlorobenzene. Data on internal exposure of the pesticides p,p'-DDE and HCB showed a positive correlation with sexual maturation and the aromatase index for boys and with free T4 (both boys andgirls), while a negative association with sexual development in girls was found. For HCB also a positive correlation was found with testosterone (boys) and TSH levels in the blood (boys and girls). The organophosphate pesticide metabolites were negatively associated with sex hormone levels in the blood of the boys and with sexual maturation (both boys and girls). The pesticide metabolite 2,5-DCP was negatively correlated with free T4, while a positive association with TSH was reported (boys and girls). These results show that even relatively low concentrations of pesticides can have significant influences on hormone levels and the degree of sexual maturation in 14-15 year-old adolescents.

Environmental justice research suggests that inequalities in the distribution of environmental quality systematically disadvantage the lower social strata of society. The effects of these inequalities on the human exposure to specific chemical pollution remain, however, to a large extend unknown, especially in hotspot areas where surrounding neighbourhoods are exposed to a mixture of diverse pollution. In Flanders, the northern part of Belgium, a community-based participatory approach was set up between 2009-2010 to collect blood, urine and hair samples of 197 socially and ethnically diverse adolescents (14-15 years of age) living in the close proximity of a non-ferro industrial area. We conduct a socio- stratification of human biomonitoring results by associating the internal body concentration of three types of chemical pollution (heavy metals, POPs and volatile compounds) with individual socioeconomic status (SES) and ethnic background. Social gradients in exposure to these chemicals are assessed with geometric means, using multiple regression models, controlling for covariates and confounders. Our results show that, depending on the (type of) pollutant, adolescents with a lower SES can either have higher or lower internal concentrations. Socially constructed factors, such as dietary and lifestyle habits, play an important role in these relations. We conclude that when assessing the human exposure concentrations of pollutants, more complex patterns of social stratification emerge than can be assumed on the basis of the environmental justice hypothesis. It therefore remains important to consider the chemical environment in relation to the social environment when monitoring environmental health risks. By emphasising on transparent communication and relevant interaction between residents, local stakeholders and scientists, monitoring environmental health could enhance the empowerment of socioeconomically disadvantaged communities.

To collect information on the concentration levels of Persistent Organic Pollutants (POPs) in the rural areas in Flanders (Belgium), 84 breastfeeding mothers were recruited in rural communities in East and West Flanders and Flemish Brabant in 2009-2010. Polychlorinated biphenyl (PCB) congeners, organochlorine pesticides, brominated flame retardants, perfluorinated compounds, polychlorinated dibenzodioxines and dibenzofurans, and dioxin-like PCBs were measured in individual milk samples and in a pooled milk sample, while some additional pollutants were only measured in the pooled sample. For most pollutants, the concentration levels in this study were lower or comparable to the levels measured in the pooled Belgian sample of the WHO human milk study of 2006, except for the pesticides dichlorodiphenyltrichloroethane DDT (+25% for ?DDT and metabolites) and trans-nonachlor (+94%), and for the brominated flame retardant hexachlorocyclododecane HBCD (+153%). Perfluorinated compounds were for the first time determined in human milk samples from Belgium and the levels were comparable to those from other European countries. Also, interesting associations were found between the levels of POPs measured in human milk and personal characteristics as well as dietary habits of the study population. PFOS en PFOA concentrations were significantly higher in milk of primiparous participants compared to mothers who gave birth to their second child. Lower brominated PBDE congeners increased with increasing BMI of the mothers (p=0.01 for BDE 47, p=0.02 for BDE 99 and p=0.02 for BDE 100). Participants consuming milk or dairy products daily had significant higher levels of sumDDTs (p=0.03) and oxychlordane (p=0.047) in their human milk samples.

Since 2002 a human biomonitoring network has been established in Flanders (Belgium) as part of a programme on environmental health surveillance. The human biomonitoring network should support environmental health policy by identifying priorities for further action. The first cycle of the programme (2002-2006) confirmed the hypotheses that living in areas with different environmental pressure is reflected in different loads of environmental chemicals in the residents. In the second cycle of the programme(2007-2011) the number of environmental chemicals for which human biomonitoring data were obtained was expanded substantially. The goal of the Flemish programme is to use and translate the scientific results into policy actions. Its further orientation in the second cycle to human biomonitoring in hot spots and sensitive age groups or susceptible persons with underlying complications (e.g.persons with diabetes) are linked to these goals. Interaction with stakeholders is embedded in the programmeemphasizing transparency of the choices that are made and direct communication. The Flemish human biomonitoring programme is organized centrally with major involvement of research partners from different disciplines which allows engrafting environmental health research on the programme. One of the major focuses is the question whether combinations of pollutants in the general population are associated with biological effects. The objective of this paper is to review and discuss the options that were taken in the human biomonitoring programme in order to achieve its goals.

Although emissions of PCDD/Fs and PCBs have decreased during recent years, these compounds are still environmental pollutants of concern: 1) since PCDD/Fs and dioxin-like PCBs (dl-PCBs) are persistent in the environment, accumulate in fat tissue and have hormone disrupting properties and 2) because emissions in certain locations in Flanders are still high. Therefore, it is important to include these compounds as biomarkers of exposure in human biomonitoring programs. In 2007, a second cycle of the Flemish Human Biomonitoring program (FLEHS II) started. More than 40 biomarkers of exposure and 10 effect markers were measured in 650 samples, recruited from 14-15 year-old adolescents (n=200), 20-40 year old-adults (n=200) and mother-newborn pairs (n=250). Since only a small amount of serum was available for the PCDD/F and dl-PCB determination, GC-HRMS analysis was not possible. The CALUX bioassay provided a good alternative, since it requires only 5 mL of serum. This publication presents an optimized method for the separate analysis of PCDD/Fs and dl-PCBs in human serum with the newly developed and more sensitive third generation CALUX (H1L7.5c1) cell line.

In juli 2002 werden de resultaten van de "Women's Health Initiative"(WHI)-studie bekendgemaakt, waaruit bleek dat gecombineerde hormonale substitutietherapie (HST) positief geassocieerd was met het ontstaan van borstkanker. Deze informatie sijpelde langzaam door naar het Belgische publiek, met een daling van het HST-gebruik vanaf het 4e trimester van 2002 en een verdere scherpe daling in de volgende 3 jaar tot gevolg. Vanaf 2006 stabiliseerde het gebruik op ongeveer de helft van dit in 2001. Uit de registratie van borstkanker in de provincie Limburg (LIKAR) tussen 1996 en 2005 blijkt dat de borstkankerincidentie bij vrouwen tussen 50 en 69 jaar stijgt tot en met 2002, en dan scherp daalt in 2003 en 2004. In 2005 is er een niet te verklaren stijging van het aantal borstkankers. De incidentie blijft evenwel significant lager dan in 2002. Deze trend wordt alleen vastgesteld bij de vrouwen die veruit het vaakst HST gebruiken, nl. vrouwen tussen 50 en 69 jaar, maar niet in andere leeftijdscategorieën. De WHI-studie heeft dus een aardverschuiving teweeggebracht in het HST-gebruik. De daling van HST-gebruik wordt, zoals in alle landen waar er een hoog gebruik van HST bestond, vrij snel gevolgd door een daling van het aantal borstkankers.

In juli 2002 werden de resultaten van de „Women’s Health Initiative”(WHI)-studie bekendgemaakt, waaruit bleek dat gecombineerde hormonale substitutietherapie (HST) positief geassocieerd was met het ontstaan van borstkanker. Deze informatie sijpelde langzaam door naar het Belgische publiek, met een daling van het HST-gebruik vanaf het 4e trimester van 2002 en een verdere scherpe daling in de volgende 3 jaar tot gevolg. Vanaf 2006 stabiliseerde het gebruik op ongeveer de helft van dit in 2001. Uit de registratie van borstkanker in de provincie Limburg (LIKAR) tussen 1996 en 2005 blijkt dat de borstkankerincidentie bij vrouwen tussen 50 en 69 jaar stijgt tot en met 2002, en dan scherp daalt in 2003 en 2004. In 2005 is er een niet te verklaren stijging van het aantal borstkankers. De incidentie blijft evenwel significant lager dan in 2002. Deze trend wordt alleen vastgesteld bij de vrouwen die veruit het vaakst HST gebruiken, nl. vrouwen tussen 50 en 69 jaar, maar niet in andere leeftijdscategorieën. De WHI-studie heeft dus een aardverschuiving teweeggebracht in het HST-gebruik. De daling van HSTgebruik wordt, zoals in alle landen waar er een hoog gebruik van HST bestond, vrij snel gevolgd door een daling van het aantal borstkankers. ispartof: Tijdschrift voor Geneeskunde vol:66 issue:1 pages:25-30 status: published