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Background: Perfluoroalkyl substances (PFAS) and phthalates are synthetic chemicals widely used in various types of consumer products. There is epidemiological and experimental evidence that PFAS and phthalates may alter thyroid hormone levels; however, studies in children and adolescents are limited., Aim: To investigate the association of exposure to PFAS and phthalate with serum levels of thyroid hormones in European adolescents., Methods: A cross-sectional study was conducted in 406 female and 327 male adolescents (14-17 years) from Belgium, Slovakia, and Spain participating in the Aligned Studies of the HBM4EU Project (FLEHS IV, PCB cohort, and BEA, respectively). Concentrations of perfluorooctanoic acid (PFOA), perfluorooctane sulfonate (PFOS), perfluorononanoic acid (PFNA), free thyroxine (FT4), free triiodothyronine (FT3), and thyroid-stimulating hormone (TSH) were measured in sera from study participants, and urinary metabolites of six phthalates (DEP, DiBP, DnBP, BBzP, DEHP, and DiNP) and the non-phthalate plasticizer DINCH® were quantified in spot urine samples. Associations were assessed with linear regression and g-computational models for mixtures. Effect modification by sex was examined., Results: In females, serum PFOA and the PFAS mixture concentrations were associated with lower FT4 and higher FT3 levels; MEP and the sums of DEHP, DiNP, and DINCH® metabolites (∑DEHP, ∑DiNP, and ∑DINCH) were associated with higher FT4; ∑DEHP with lower FT3; and the phthalate/DINCH® metabolite mixture with higher FT4 and lower FT3. In males, PFOA was associated with lower FT4 and the PFAS mixture with higher TSH levels and lower FT4/TSH ratio; MEP and ∑DiNP were associated with higher FT4; and MBzP, ∑DEHP, and the phthalate/DINCH® metabolite mixture with lower TSH and higher FT4/TSH. PFOA, mono-(2-ethyl-5-hydroxyhexyl) phthalate (OH-MEHP), mono-(2-ethyl-5-oxohexyl) phthalate (oxo-MEHP), and monocarboxyoctyl phthalate (MCOP) made the greatest contribution to the mixture effect., Conclusions: Results suggest that exposure to PFAS and phthalates is associated with sex-specific differences in thyroid hormone levels in adolescents., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Exposure to Perfluoroalkyl acids (PFAS) can impair human reproductive function, e.g., by delaying or advancing puberty, although their mechanisms of action are not fully understood. We therefore set out to evaluate the relationship between serum PFAS levels, both individually and as a mixture, on the Hypothalamic-Pituitary-Gonadal (HPG) axis by analyzing serum levels of reproductive hormones and also kisspeptin in European teenagers participating in three of the HBM4EU Aligned Studies. For this purpose, PFAS compounds were measured in 733 teenagers from Belgium (FLEHS IV study), Slovakia (PCB cohort follow-up), and Spain (BEA study) by high performance liquid chromatography-tandem mass spectrometry (HPLC/MS) in laboratories under the HBM4EU quality assurance quality control (QA/QC) program. In the same serum samples, kisspeptin 54 (kiss-54) protein, follicle-stimulating hormone (FSH), total testosterone (TT), estradiol (E2), and sex hormone-binding globulin (SHBG) levels were also measured using immunosorbent assays. Sex-stratified single pollutant linear regression models for separate studies, mixed single pollutant models accounting for random effects for pooled studies, and g-computation and Bayesian kernel machine regression (BKMR) models for the mixture of the three most available (PFNA, PFOA, and PFOS) were fit. PFAS associations with reproductive markers differed according to sex. Each natural log-unit increase of PFOA, PFNA, and PFOS were associated with higher TT [18.41 (6.18; 32.31), 15.60 (7.25; 24.61), 14.68 (6.18; 24.61), respectively] in girls, in the pooled analysis (all studies together). In males, G-computation showed that PFAS mixture was associated with lower FSH levels [-10.51 (-18.81;-1.36)]. The BKMR showed the same patterns observed in G-computation, including a significant increase on male Kiss-54 and SHBG levels. Overall, effect biomarkers may enhance the current epidemiological knowledge regarding the adverse effect of PFAS in human HPG axis, although further research is warranted., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Ltd.)

Early puberty has been found to be associated with adverse health outcomes such as metabolic and cardiovascular diseases and hormone-dependent cancers. The decrease in age at menarche observed during the past decades has been linked to an increased exposure to endocrine-disrupting compounds (EDCs). Evidence for the association between PFAS and phthalate exposure and menarche onset, however, is inconsistent. We studied the association between PFAS and phthalate/DINCH exposure and age at menarche using data of 514 teenagers (12 to 18 years) from four aligned studies of the Human Biomonitoring for Europe initiative (HBM4EU): Riksmaten Adolescents 2016-2017 (Sweden), PCB cohort (follow-up; Slovakia), GerES V-sub (Germany), and FLEHS IV (Belgium). PFAS concentrations were measured in blood, and phthalate/DINCH concentrations in urine. We assessed the role of each individual pollutant within the context of the others, by using different multi-pollutant approaches, adjusting for age, age- and sex-standardized body mass index z-score and household educational level. Exposure to di(2-ethylhexyl) phthalate (DEHP), especially mono(2-ethyl-5-hydroxyhexyl) phthalate (5OH-MEHP), was associated with an earlier age at menarche, with estimates per interquartile fold change in 5OH-MEHP ranging from -0.34 to -0.12 years in the different models. Findings from this study indicated associations between age at menarche and some specific EDCs at concentrations detected in the general European population, but due to the study design (menarche onset preceded the chemical measurements), caution is needed in the interpretation of causality.

As one of the core elements of the European Human Biomonitoring Initiative (HBM4EU) a human biomonitoring (HBM) survey was conducted in 23 countries to generate EU-wide comparable HBM data. This survey has built on existing HBM capacity in Europe by aligning national or regional HBM studies, referred to as the HBM4EU Aligned Studies. The HBM4EU Aligned Studies included a total of 10,795 participants of three age groups: (i) 3,576 children aged 6-12 years, (ii) 3,117 teenagers aged 12-18 years and (iii) 4,102 young adults aged 20-39 years. The participants were recruited between 2014 and 2021 in 11-12 countries per age group, geographically distributed across Europe. Depending on the age group, internal exposure to phthalates and the substitute DINCH, halogenated and organophosphorus flame retardants, per- and polyfluoroalkyl substances (PFASs), cadmium, bisphenols, polycyclic aromatic hydrocarbons (PAHs), arsenic species, acrylamide, mycotoxins (deoxynivalenol (total DON)), benzophenones and selected pesticides was assessed by measuring substance specific biomarkers subjected to stringent quality control programs for chemical analysis. For substance groups analyzed in different age groups higher average exposure levels were observed in the youngest age group, i.e., phthalates/DINCH in children versus teenagers, acrylamide and pesticides in children versus adults, benzophenones in teenagers versus adults. Many biomarkers in teenagers and adults varied significantly according to educational attainment, with higher exposure levels of bisphenols, phthalates, benzophenones, PAHs and acrylamide in participants (from households) with lower educational attainment, while teenagers from households with higher educational attainment have higher exposure levels for PFASs and arsenic. In children, a social gradient was only observed for the non-specific pyrethroid metabolite 3-PBA and di-isodecyl phthalate (DiDP), with higher levels in children from households with higher educational attainment. Geographical variations were seen for all exposure biomarkers. For 15 biomarkers, the available health-based HBM guidance values were exceeded with highest exceedance rates for toxicologically relevant arsenic in teenagers (40%), 3-PBA in children (36%), and between 11 and 14% for total DON, Σ (PFOA + PFNA + PFHxS + PFOS), bisphenol S and cadmium. The infrastructure and harmonized approach succeeded in obtaining comparable European wide internal exposure data for a prioritized set of 11 chemical groups. These data serve as a reference for comparison at the global level, provide a baseline to compare the efficacy of the European Commission's chemical strategy for sustainability and will give leverage to national policy makers for the implementation of targeted measures., Competing Interests: Declarations of competing interest The authors declare no conflict of interest. José V. Tarazona is employed by the European Food Safety Authority (EFSA). The views expressed in this publication are those of the authors and should not be interpreted as representing the official position of EFSA., (Copyright © 2023 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Phthalates are mainly used as plasticizers and are associated inter alia with adverse effects on reproductive functions. While more and more national programs in Europe have started monitoring internal exposure to phthalates and its substitute 1,2-Cyclohexanedicarboxylic acid (DINCH), the comparability of results from such existing human biomonitoring (HBM) studies across Europe is challenging. They differ widely in time periods, study samples, degree of geographical coverage, design, analytical methodology, biomarker selection, and analytical quality assurance level. The HBM4EU initiative has gathered existing HBM data of 29 studies from participating countries, covering all European regions and Israel. The data were prepared and aggregated by a harmonized procedure with the aim to describe-as comparably as possible-the EU-wide general population's internal exposure to phthalates from the years 2005 to 2019. Most data were available from Northern (up to 6 studies and up to 13 time points), Western (11; 19), and Eastern Europe (9; 12), e.g., allowing for the investigation of time patterns. While the bandwidth of exposure was generally similar, we still observed regional differences for Butyl benzyl phthalate (BBzP), Di(2-ethylhexyl) phthalate (DEHP), Di-isononyl phthalate (DiNP), and Di-isobutyl phthalate (DiBP) with pronounced decreases over time in Northern and Western Europe, and to a lesser degree in Eastern Europe. Differences between age groups were visible for Di-n-butyl phthalate (DnBP), where children (3 to 5-year olds and 6 to 11-year olds) had lower urinary concentrations than adolescents (12 to 19-year-olds), who in turn had lower urinary concentrations than adults (20 to 39-year-olds). This study is a step towards making internal exposures to phthalates comparable across countries, although standardized data were not available, targeting European data sets harmonized with respect to data formatting and calculation of aggregated data (such as developed within HBM4EU), and highlights further suggestions for improved harmonization in future studies.

The European Joint Programme HBM4EU coordinated and advanced human biomonitoring (HBM) in Europe in order to provide science-based evidence for chemical policy development and improve chemical management. Arsenic (As) was selected as a priority substance under the HBM4EU initiative for which open, policy relevant questions like the status of exposure had to be answered. Internal exposure to inorganic arsenic (iAs), measured as Toxic Relevant Arsenic (TRA) (the sum of As(III), As(V), MMA, DMA) in urine samples of teenagers differed among the sampling sites (BEA (Spain) > Riksmaten adolescents (Sweden), ESTEBAN (France) > FLEHS IV (Belgium), SLO CRP (Slovenia)) with geometric means between 3.84 and 8.47 μg/L. The ratio TRA to TRA + arsenobetaine or the ratio TRA to total arsenic varied between 0.22 and 0.49. Main exposure determinants for TRA were the consumption of rice and seafood. When all studies were combined, Pearson correlation analysis showed significant associations between all considered As species. Higher concentrations of DMA, quantitatively a major constituent of TRA, were found with increasing arsenobetaine concentrations, a marker for organic As intake, e.g. through seafood, indicating that other sources of DMA than metabolism of inorganic As exist, e.g. direct intake of DMA or via the intake of arsenosugars or -lipids. Given the lower toxicity of DMA(V) versus iAs, estimating the amount of DMA not originating from iAs, or normalizing TRA for arsenobetaine intake could be useful for estimating iAs exposure and risk. Comparing urinary TRA concentrations with formerly derived biomonitoring equivalent (BE) for non-carcinogenic effects (6.4 μg/L) clearly shows that all 95th percentile exposure values in the different studies exceeded this BE. This together with the fact that cancer risk may not be excluded even at lower iAs levels, suggests a possible health concern for the general population of Europe., (Copyright © 2023 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Within the European Human Biomonitoring (HBM) Initiative HBM4EU we derived HBM indicators that were designed to help answering key policy questions and support chemical policies. The result indicators convey information on chemicals exposure of different age groups, sexes, geographical regions and time points by comparing median exposure values. If differences are observed for one group or the other, policy measures or risk management options can be implemented. Impact indicators support health risk assessment by comparing exposure values with health-based guidance values, such as human biomonitoring guidance values (HBM-GVs). In general, the indicators should be designed to translate complex scientific information into short and clear messages and make it accessible to policy makers but also to a broader audience such as stakeholders (e.g. NGO's), other scientists and the general public. Based on harmonized data from the HBM4EU Aligned Studies (2014-2021), the usefulness of our indicators was demonstrated for the age group children (6-11 years), using two case examples: one phthalate (Diisobutyl phthalate: DiBP) and one non-phthalate substitute (Di-isononyl cyclohexane-1,2- dicarboxylate: DINCH). For the comparison of age groups, these were compared to data for teenagers (12-18 years), and time periods were compared using data from the DEMOCOPHES project (2011-2012). Our result indicators proved to be suitable for demonstrating the effectiveness of policy measures for DiBP and the need of continuous monitoring for DINCH. They showed similar exposure for boys and girls, indicating that there is no need for gender focused interventions and/or no indication of sex-specific exposure patterns. They created a basis for a targeted approach by highlighting relevant geographical differences in internal exposure. An adequate data basis is essential for revealing differences for all indicators. This was particularly evident in our studies on the indicators on age differences. The impact indicator revealed that health risks based on exposure to DiBP cannot be excluded. This is an indication or flag for risk managers and policy makers that exposure to DiBP still is a relevant health issue. HBM indicators derived within HBM4EU are a valuable and important complement to existing indicator lists in the context of environment and health. Their applicability, current shortcomings and solution strategies are outlined., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2022 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Background: Parents of children who have a congenital anomaly can experience significant worry about their child's health. Access to clear, helpful, and trustworthy information can provide a valuable source of support. In this study the aim was to explore the information needs of parents/carers of children with congenital anomalies across Europe., Method: A cross-sectional online survey was developed in nine languages to measure parents' information needs, including: (1) the 'helpfulness'/'trustworthiness' of information received from eight relevant sources, and (2) overall satisfaction with information received. Parents/carers of children (0-10 years) with cleft lip, spina bifida, congenital heart defect [CHD] requiring surgery, and/or Down syndrome were recruited online via relevant organisations in 10 European countries from March-July 2021. Quantitative analyses using multivariable logistic regressions were performed., Results: One thousand seventy parents/carers of children with a cleft lip (n = 247), spina bifida (n = 118), CHD (n = 366), Down syndrome (n = 281), and Down syndrome with CHD (n = 58) were recruited in Poland (n = 476), the UK (n = 120), Germany (n = 97), the Netherlands/Belgium (n = 74), Croatia (n = 68), Italy (n = 59), other European countries (n = 92), and not specified/non-European countries (n = 84). Most participants were mothers (92%) and aged 31-40 years (71%). Participants were most likely to rate support groups (63%), patient organisations (60%), specialist doctors/nurses (58%), and social media (57%) as 'very helpful' information sources. 'Very trustworthy' ratings remained high for specialist doctors/nurses (61%), however, they declined for support groups (47%), patient organisations (48%), and social media (35%). Germany had the highest proportion of participants who were 'very satisfied' (44%, 95% CI = 34%-54%) with information, whereas this percentage was lowest in Croatia (11%, 95% CI = 3%-19%) and Poland (15%, 95% CI = 11%-18%). Parents of children with Down syndrome had significantly lower satisfaction ratings than parents of children with CHD; 13% (95% CI = 8%-18%) reported being 'very satisfied' compared to 28% (95% CI = 23%-33%) in the CHD group., Conclusions: Findings suggest that informal sources of information (e.g. support groups) are of value to parents, however, they are not deemed as trustworthy as specialist medical sources. Satisfaction ratings differed across countries and by anomaly, and were particularly low in Croatia and Poland, as well as for parents of children with Down syndrome, which warrants further investigation., (© 2022. The Author(s).)

Background: Congenital anomalies are a major cause of perinatal, neonatal and infant mortality., Objectives: The aim was to investigate temporal changes and geographical variation in survival of children with major congenital anomalies (CA) in different European areas., Methods: In this population-based linkage cohort study, 17 CA registries members of EUROCAT, the European network for the surveillance of CAs, successfully linked data on 115,219 live births with CAs to mortality records. Registries estimated Kaplan-Meier survival at 28 days and 5 years of age and fitted Cox's proportional hazards models comparing mortality at 1 year and 1-9 years of age for children born during 2005-2014 with those born during 1995-2004. The hazard ratios (HR) from each registry were combined centrally using a random-effects model. The 5-year survival conditional on having survived to 28 days of age was calculated., Results: The overall risk of death by 1 year of age for children born with any major CA in 2005-2014 decreased compared to 1995-2004 (HR 0.68, 95% confidence interval [CI] 0.53, 0.89). Survival at 5 years of age ranged between registries from 97.6% to 87.0%. The lowest survival was observed for the registry of OMNI-Net (Ukraine) (87.0%, 95% CI 86.1, 87.9)., Conclusions: Survival of children with CAs improved for births in 2005-2014 compared with 1995-2004. The use of CA registry data linked to mortality data enables investigation of survival of children with CAs. Factors such as defining major CAs, proportion of terminations of pregnancy for foetal anomaly, source of mortality data and linkage methods are important to consider in the design of future studies and in the interpretation of the results on survival of children with CAs., (© 2022 The Authors. Paediatric and Perinatal Epidemiology published by John Wiley & Sons Ltd.)

Human biomonitoring has become a pivotal tool for supporting chemicals' policies. It provides information on real-life human exposures and is increasingly used to prioritize chemicals of health concern and to evaluate the success of chemical policies. Europe has launched the ambitious REACH program in 2007 to improve the protection of human health and the environment. In October 2020 the EU commission published its new chemicals strategy for sustainability towards a toxic-free environment. The European Parliament called upon the commission to collect human biomonitoring data to support chemical's risk assessment and risk management. This manuscript describes the organization of the first HBM4EU-aligned studies that obtain comparable human biomonitoring (HBM) data of European citizens to monitor their internal exposure to environmental chemicals. The HBM4EU-aligned studies build on existing HBM capacity in Europe by aligning national or regional HBM studies. The HBM4EU-aligned studies focus on three age groups: children, teenagers, and adults. The participants are recruited between 2014 and 2021 in 11 to 12 primary sampling units that are geographically distributed across Europe. Urine samples are collected in all age groups, and blood samples are collected in children and teenagers. Auxiliary information on socio-demographics, lifestyle, health status, environment, and diet is collected using questionnaires. In total, biological samples from 3137 children aged 6-12 years are collected for the analysis of biomarkers for phthalates, HEXAMOLL ® DINCH, and flame retardants. Samples from 2950 teenagers aged 12-18 years are collected for the analysis of biomarkers for phthalates, Hexamoll ® DINCH, and per- and polyfluoroalkyl substances (PFASs), and samples from 3522 adults aged 20-39 years are collected for the analysis of cadmium, bisphenols, and metabolites of polyaromatic hydrocarbons (PAHs). The children's group consists of 50.4% boys and 49.5% girls, of which 44.1% live in cities, 29.0% live in towns/suburbs, and 26.8% live in rural areas. The teenagers' group includes 50.6% girls and 49.4% boys, with 37.7% of residents in cities, 31.2% in towns/suburbs, and 30.2% in rural areas. The adult group consists of 52.6% women and 47.4% men, 71.9% live in cities, 14.2% in towns/suburbs, and only 13.4% live in rural areas. The study population approaches the characteristics of the general European population based on age-matched EUROSTAT EU-28, 2017 data; however, individuals who obtained no to lower educational level (ISCED 0-2) are underrepresented. The data on internal human exposure to priority chemicals from this unique cohort will provide a baseline for Europe's strategy towards a non-toxic environment and challenges and recommendations to improve the sampling frame for future EU-wide HBM surveys are discussed.

Chronic biological stress may adversely affect adolescents' physical and mental health, but insight in the personal and environmental factors that determine chronic stress is limited. We measured 3-month cumulative hair cortisol concentration (HCC) in 419 adolescents, participating in the Flemish Environment and Health Study. Adolescents' health and lifestyle characteristics, household and neighborhood socio-economic status as well as neighborhood urbanicity were assessed as potential determinants of HCC, using multiple linear regression models. We additionally explored heterogeneity of our results by sex. HCC were significantly higher in boys from densely populated neighborhoods, the association was not significant in girls. Accordingly, boys living outside cities had significantly lower HCC than boys, living in cities. HCC was significantly lower in adolescents with an optimal vitality, a measure of a positive mental health status. In adolescent girls, menarcheal status (pre-/postmenarche) was a significant determinant of HCC. Our findings are the first to suggest that residential urbanicity may have an impact on chronic biological stress in a general population of adolescent boys., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Verheyen, Remy, Govarts, Colles, Koppen, Martin, Nielsen, Bruckers, Bijnens, Vos, Morrens, Coertjens, Loots, De Decker, Franken, Den Hond, Nelen, De Henauw, Covaci, Van Larebeke, Teughels, Nawrot and Schoeters.)

Polycyclic aromatic hydrocarbons (PAHs) are environmental pollutants of public health concern. Multiple biological mechanisms have been hypothesized to contribute to PAHs-associated adverse health effects. Little is known about the impact of PAHs on endocrine stress and inflammation in adolescence. We examined 393 Flemish adolescents (14-15 years) cross-sectionally, measured urinary concentrations of hydroxylated naphthalene, fluorene, phenanthrene and pyrene metabolites, and calculated the sum of all measured metabolites. We determined hair cortisol concentration (HCC) as endocrine stress biomarker, leucocyte counts and neutrophil-lymphocyte ratio (NLR) in peripheral blood as inflammatory biomarkers, and urinary 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) concentration as oxidative stress biomarker. Exposure-response associations were analyzed by multiple regression, adjusted for a priori selected covariates. A doubling of 1-hydroxypyrene concentration was associated with a factor of 1.13 (95% CI: 1.03, 1.24) increase in HCC and a factor of 1.07 (95% CI: 1.02, 1.13) increase in 8-oxodG. Doublings of 2- and 3-hydroxyphenanthrene concentrations were associated with a factor of 1.08 (95% CI: 1.02, 1.14) and 1.06 (95% CI: 1.00, 1.12) increase in 8-oxodG, respectively. Doubling of 2-hydroxyphenanthrene and of the sum of 2- and 3-hydroxyfluorene was associated with, respectively, a factor of 1.08 (95% CI: 1.02, 1.14) and 1.06 (95% CI: 1.01, 1.13) increase in NLR. Our results indicate the glucocorticoid pathway as a potential target for PAH exposure in adolescents and suggest oxidative stress, endocrine stress, and inflammation in adolescence as underlying mechanisms and early markers for PAH-related adverse health effects.

Objective: Thirty years ago it was demonstrated that folic acid taken before pregnancy and in early pregnancy reduced the risk of a neural tube defect (NTD). Despite Public Health Initiatives across Europe recommending that women take 0.4 mg folic acid before becoming pregnant and during the first trimester, the prevalence of NTD pregnancies has not materially decreased in the EU since 1998, in contrast to the dramatic fall observed in the USA. This study aimed to estimate the number of NTD pregnancies that would have been prevented if flour had been fortified with folic acid in Europe from 1998 as it had been in the USA. Design and Setting: The number of NTD pregnancies from 1998 to 2017 that would have been prevented if folic acid fortification had been implemented in the 28 countries who were members of the European Union in 2019 was predicted was predicted using data on NTD prevalence from 35 EUROCAT congenital anomaly registries and literature searches for population serum folate levels and folic acid supplementation. Results: From 1998 to 2017 an estimated 95,213 NTD pregnancies occurred amongst 104 million births in the 28 countries in the EU, a prevalence of 0.92 per 1,000 births. The median serum folate level in Europe over this time period was estimated to be 14.1 μg/L. There is a lack of information about women taking folic acid supplements before becoming pregnant and during the first trimester of pregnancy, with one meta-analysis indicating that around 25% of women did so. An estimated 14,600 NTD pregnancies may have been prevented if the European countries had implemented fortification at the level adopted by the USA in 1998 and 25% of women took folic acid supplements. An estimated 19,500 NTD pregnancies would have been prevented if no women took folic acid supplements. Conclusions: This study suggests that failure to implement mandatory folic acid fortification in the 28 European countries has caused, and continues to cause, neural tube defects to occur in almost 1,000 pregnancies every year., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Morris, Addor, Ballardini, Barisic, Barrachina-Bonet, Braz, Cavero-Carbonell, Den Hond, Garne, Gatt, Haeusler, Khoshnood, Lelong, Kinsner-Ovaskainen, Kiuru-Kuhlefelt, Klungsoyr, Latos-Bielenska, Limb, O'Mahony, Perthus, Pierini, Rankin, Rissmann, Rouget, Sayers, Sipek, Stevens, Tucker, Verellen-Dumoulin, de Walle, Wellesley, Wertelecki and Bermejo-Sanchez.)

Human biomonitoring (HBM) monitors levels of environmental pollutants in human samples, which often is a topic of concern for residents near industrially contaminated sites (ICSs). Around an ICS area in Menen (Belgium), including a (former) municipal waste incinerator and a metal recovery plant, increasing environmental concentrations of dioxins and polychlorinated biphenyls (PCBs) were observed, causing growing concern among residents and authorities. The local community succeeded in convincing the responsible authorities to investigate the problem and offer research funding. Persistent organic pollutants (POPs) were measured in two consecutive HBM studies (2002-2006 and 2010-2011), in the context of the Flemish Environment and Health Study (FLEHS), as well as in soil and locally produced food. Meanwhile, local authorities discouraged consumption of locally produced food in a delineated area of higher exposure risk. Ultimately, HBM and environmental data enabled tailored dietary recommendations. This article demonstrates the usefulness of HBM in documenting the body burdens of residents near the ICS, identifying exposure routes, evaluating remediating actions and providing information for tailored policy strategies aiding to further exposure reduction. It also highlights the role of the local stakeholders as an example of community-based participatory research and how such an approach can create societal support for research and policy.

Restrictions on the use of legacy phthalate esters (PEs) as plasticizer chemicals in several consumer products has led to the increased use of alternative plasticizers (APs), such as di-(iso-nonyl)-cyclohexane-1,2-dicarboxylate (DINCH) and di-(2-ethylhexyl) terephthalate (DEHTP). In the fourth cycle of the Flemish Environment and Health Study (FLEHS IV, 2016-2020), we monitored exposure to seven PEs (diethyl phthalate (DEP), di-(2-ethylhexyl) phthalate (DEHP), di-isobutyl phthalate (DiBP), di-n-butyl phthalate (DnBP), butylbenzyl phthalate (BBzP, di-isononyl phthalate (DINP), and di-isodecyl phthalate (DIDP))and three APs (DINCH, DEHTP, and di-(2-ethylhexyl) adipate (DEHA)) by measuring multiple biomarkers in urine of 416 adolescents from Flanders, Belgium (14-15 years old). The reference values show that exposure to PEs is still widespread, although levels of several PE metabolites (e.g., sum of DEHP metabolites, mono-normal-butyl phthalate (MnBP) and mono-benzyl phthalate (MBzP)) have decreased significantly compared to previous human biomonitoring cycles (2003-2018). On the other hand, metabolites of DINCH and DEHTP were detected in practically every participant. Concentrations of AP exposure biomarkers in urine were generally lower than PE metabolites, but calculations of estimated daily intakes (EDIs) showed that exposure to DINCH and DEHTP can be considerable. However, preliminary risk assessment showed that none of the EDI or urinary exposure levels of APs exceeded the available health-based guidance values, while a very low number of participants had levels of MiBP and MnBP exceeding the HBM value. Several significant determinants of exposure could be identified from multiple regression models: the presence of building materials containing PVC, ventilation habits, socio-economic status and season were all associated with PE and AP biomarker levels. Cumulatively, the results of FLEHS IV show that adolescents in Flanders, Belgium, are exposed to a wide range of plasticizer chemicals. Close monitoring over the last decade showed that the exposure levels of restricted PEs have decreased, while newer APs are now frequently detected in humans., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Communicating individual human biomonitoring results to study participants has been the subject of debate for some time. This debate is dominated by ethical considerations from a researchers' perspective on whether or not to communicate, thereby overlooking more practice-based questions from a participants' perspective on what and how to communicate. We conducted a small scale follow-up study based on eleven face-to-face interviews with mothers participating in the third cycle of the Flemish Environment and Health Study (FLEHS III 2012-2015) to investigate how they experienced and interpreted individual biomonitoring results. Key findings indicate that respondents were generally satisfied with participating in the biomonitoring study, but the report-back process especially lacked contextualized information and interactive communication options to better comprehend and cope with personal results. These findings also argue in favor of a more tailored approach in which report-back methods, formats and content are diversified according to the type of results and the preferences of participants. A reflexive research practice with active engagement in follow-up research is crucial to improve participants' understanding and use of personal biomonitoring results.

Because of their dirt-, water- and oil-repelling properties, per- and polyfluoroalkyl substances (PFASs) are frequently used in a broad variety of consumer products. They have been detected in human samples worldwide. In Flanders, Belgium, the Flemish Environment and Health Studies (FLEHS) measured the levels of five PFAS biomarkers in four different age groups of the Flemish population and identified determinants of variability in exposure. Cord plasma or peripheric serum samples and questionnaire data were available for 220 mother-newborn pairs (2008-2009), 269 mother-newborn pairs (2013-2014), 199 adolescents (14-15 years old, 2010), 201 adults (20-40 years old, 2008-2009) and 205 adults (50-65 years old, 2014). Measured levels of perfluorooctane sulfonate (PFOS), perfluorooctanoic acid (PFOA), perfluorohexane sulfonic acid (PFHxS) and perfluorononanoic acid (PFNA) in Flanders are in the middle or low range compared to concentrations reported in other Western countries. Levels of perfluorobutanesulfonic acid (PFBS) were below the quantification limit in 98%-100% of the samples. Despite decreasing levels in time for PFOS and PFOA, 77% of the adults (2014) had serum levels exceeding HBM-I values of 5 μg/L for PFOS and 2 μg/L for PFOA. Beside age, sex, fish consumption, parity and breastfeeding, the multiple regression models identified additionally consumption of offal and locally grown food, and use of cosmetics as possible exposures and menstruation as a possible route of elimination. Better knowledge on determinants of exposure is essential to lower PFASs exposure., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

During the last 15 years, VITO has established an infrastructure for biobanking a collection of biological samples from the general population in Flanders (Belgium). This biobank was set up to contribute to future, yet unspecified, research questions in the field of environment and health. Biobank@VITO is a population biobank in which bio-specimen including human peripheral blood, cord blood, and blood derivatives (e.g., serum, plasma, cells, RNA, DNA), urine, hair, nails, exhaled breath condensate, saliva DNA, and human breast milk collected from non-diseased populations are preserved. Currently, the biobank stores about 70,000 samples from 7,700 individuals. These biospecimen were collected since 2002 in different human biomonitoring studies comprising European (e.g., DEMOCOPHES, HBM4EU), national (e.g., WHO human breastmilk studies), Flemish (Flemish Environment and Health Study (FLEHS) campaigns), and local (e.g., hotspots, 3xG project) well-defined and ethically approved research projects. Participants to the surveys included different age groups (newborns, children, adolescents, and adults) and were representatively selected with regard to gender, age class, residence, and/or socioeconomic status (SES). In each campaign, samples were stored in the Biobank@VITO. The registration, preservation, and management of the samples in the biobank were done in a qualitative and uniform manner which guarantees the traceability of all samples. The samples in the biobank have an extended information backbone on the lifestyle, environment, and health status of the donor. The biological samples in the biobank are an invaluable archive that can be used to address specific policy and research questions in the future, to test old samples with new technology and according to the latest methods and insights or to measure newly identified pollutants in old samples looking for long-term trends., (Copyright © 2020 Van Den Heuvel, Den Hond, Colles, Nelen, Van Campenhout and Schoeters.)

Nutrition during early childhood is linked to metabolic programming. We hypothesized that breastfeeding has long-term consequences on the energy metabolism exemplified by mitochondrial DNA (mtDNA). As part of the third cycle of the Flemish Environment and Health Study (FLEHSIII) cohort, 303 adolescents aged 14-15 years were included. We associated breastfeeding and blood mtDNA content 14-15 years later while adjusting for confounding variables. Compared with non-breastfed adolescents, mtDNA content was 23.1% (95%CI: 4.4-45.2; p = 0.013) higher in breastfed adolescents. Being breastfed for 1-10 weeks, 11-20 weeks, and >20 weeks, was associated with a higher mtDNA content of respectively 16.0% (95%CI: -7.1-44.9; p = 0.191), 23.5% (95%CI: 0.8-51.3; p = 0.042), and 31.5% (95%CI: 4.3-65.7; p = 0.021). Our study showed a positive association between breastfeeding and mtDNA content in adolescents which gradually increased with longer periods of breastfeeding. Higher mtDNA content may be an underlying mechanism of the beneficial effects of breastfeeding on children's metabolism.

Background: We investigated whether human environmental exposure to chemicals that are labeled as (potential) carcinogens leads to increased (oxidative) damage to DNA in adolescents., Material and Methods: Six hundred 14-15-year-old youngsters were recruited all over Flanders (Belgium) and in two areas with important industrial activities. DNA damage was assessed by alkaline and formamidopyrimidine DNA glycosylase (Fpg) modified comet assays in peripheral blood cells and analysis of urinary 8-hydroxydeoxyguanosine (8-OHdG) levels. Personal exposure to potentially carcinogenic compounds was measured in urine, namely: chromium, cadmium, nickel, 1-hydroxypyrene as a proxy for exposure to other carcinogenic polycyclic aromatic hydrocarbons (PAHs), t,t-muconic acid as a metabolite of benzene, 2,5-dichlorophenol (2,5-DCP), organophosphate pesticide metabolites, and di(2-ethylhexyl) phthalate (DEHP) metabolites. In blood, arsenic, polychlorinated biphenyl (PCB) congeners 118 and 156, hexachlorobenzene (HCB), dichlorodiphenyltrichloroethane (DDT) and perfluorooctanoic acid (PFOA) were analyzed. Levels of methylmercury (MeHg) were measured in hair. Multiple linear regression models were used to establish exposure-response relationships., Results: Biomarkers of exposure to PAHs and urinary chromium were associated with higher levels of both 8-OHdG in urine and DNA damage detected by the alkaline comet assay. Concentrations of 8-OHdG in urine increased in relation with increasing concentrations of urinary t,t-muconic acid, cadmium, nickel, 2,5-DCP, and DEHP metabolites. Increased concentrations of PFOA in blood were associated with higher levels of DNA damage measured by the alkaline comet assay, whereas DDT was associated in the same direction with the Fpg-modified comet assay. Inverse associations were observed between blood arsenic, hair MeHg, PCB 156 and HCB, and urinary 8-OHdG. The latter exposure biomarkers were also associated with higher fish intake. Urinary nickel and t,t-muconic acid were inversely associated with the alkaline comet assay., Conclusion: This cross-sectional study found associations between current environmental exposure to (potential) human carcinogens in 14-15-year-old Flemish adolescents and short-term (oxidative) damage to DNA. Prospective follow-up will be required to investigate whether long-term effects may occur due to complex environmental exposures., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Early life exposure to endocrine disrupting chemicals (EDCs) has been frequently associated with impaired perinatal growth, an important risk factor for later onset of metabolic disorders. We analyzed whether the cord blood transcriptome showed early indications of alterations in metabolic processes in 195 human samples in relation to cord blood levels of dichlorodiphenyldichloroethylene (p,p'-DDE), polychlorinated biphenyl-153 (PCB-153), perfluorooctanoic acid (PFOA), and perfluorooctane sulfonate (PFOS). Overall, 39 metabolically relevant transcription factors were significantly enriched (31 by p,p'-DDE, 10 by PCB-153, 8 by PFOA, and 2 by PFOS). These included the glucocorticoid receptor (p,p'-DDE and PCB-153) and the progesterone receptor (PFOA and PFOS). The 'insulin receptor signaling', 'acute phase response signaling', 'Interleukin(IL)-6 signaling', and 'prolactin signaling' pathways were significantly enriched in relation to p,p'-DDE. Transcriptional changes at birth suggest a role for specific metabolic targets as a link between prenatal EDC exposure and metabolic disorders later in life., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objective: Phthalates and their metabolites are classified as endocrine modulators. They affect the hormonal balance in both children and adults. The aim of this publication was to compare the urinary levels of phthalate metabolites in selected populations of the Czech Republic (CZ), Slovakia (SK), and Hungary (HU) in relation to the sources of phthalate exposure identified by means of questionnaire (personal care products, floor and wall coverings, plastic toys, and some kinds of foods)., Methods: Data were obtained through the twin projects COPHES (COnsortium to Perform Human biomonitoring on a European Scale) and DEMOCOPHES (DEMOnstration of a study to COordinate and Perform Human biomonitoring on a European Scale) from 2009 to 2012. The target groups were children aged 6-11 years old and their mothers up to 45 years of age. The metabolites of phthalates (monomethyl phthalate (MMP), monoethyl phthalate (MEP), monobenzyl phthalate (MBzP), mono-cyclohexyl phthalate (MCHP), mono-(2-ethylhexyl) phthalate (MEHP), mono-(2-ethyl-5-hydroxyhexyl) phthalate (5OH-MEHP), and mono-(2-ethyl-5-oxohexyl) phthalate (5OXO-MEHP)) were analysed in first morning urine samples. After enzymatic glucuronide cleavage, the urine sample analyses were performed using ultra-high-performance liquid chromatography-electrospray ionization tandem mass spectrometry (UHPLC-ESI-MS/MS) in one laboratory that qualified in the External Quality Assessment exercises organised by COPHES., Results: Significant differences in phthalate exposure between countries were revealed for children only but not for mothers. The concentrations of 5-OH-MEHP (P<0.001), 5OXO-MEHP (P<0.001), and their sum (P<0.001) were the highest in SK compared to CZ and HU. The health based guidance values for the sum of DEHP metabolites 5-OH MEHP and 5OXO-MEHP established by the German Commission for biomonitoring of 300 µg/L and 500 µg/L for women adults and children, respectively, were only exceeded in one mother and three boys. A significant difference was also found for MEP (P=0.0149), with the highest concentrations detected in HU. In all countries, the increasing frequency of using personal care products significantly elevated the concentrations of MEP., Conclusion: Some differences were observed between countries in the concentrations of individual urinary phthalate metabolites in children. However, the questionnaire results give no direct explanation for the differences between the countries except the variation in using personal care products., (Copyright © 2014 Elsevier Inc. All rights reserved.)

The potential of Human Biomonitoring (HBM) in exposure characterisation and risk assessment is well established in the scientific HBM community and regulatory arena by many publications. The European Environment and Health Strategy as well as the Environment and Health Action Plan 2004-2010 of the European Commission recognised the value of HBM and the relevance and importance of coordination of HBM programmes in Europe. Based on existing and planned HBM projects and programmes of work and capabilities in Europe the Seventh Framework Programme (FP 7) funded COPHES (COnsortium to Perform Human Biomonitoring on a European Scale) to advance and improve comparability of HBM data across Europe. The pilot study protocol was tested in 17 European countries in the DEMOCOPHES feasibility study (DEMOnstration of a study to COordinate and Perform Human biomonitoring on a European Scale) cofunded (50%) under the LIFE+ programme of the European Commission. The potential of HBM in supporting and evaluating policy making (including e.g. REACH) and in awareness raising on environmental health, should significantly advance the process towards a fully operational, continuous, sustainable and scientifically based EU HBM programme. From a number of stakeholder activities during the past 10 years and the national engagement, a framework for sustainable HBM structure in Europe is recommended involving national institutions within environment, health and food as well as European institutions such as ECHA, EEA, and EFSA. An economic frame with shared cost implications for national and European institutions is suggested benefitting from the capacity building set up by COPHES/DEMOCOPHES., (Copyright © 2014 Elsevier Inc. All rights reserved.)

For the first time in Europe, both European-wide and country-specific levels of urinary Bisphenol A (BPA) were obtained through a harmonized protocol for participant recruitment, sampling and quality controlled biomarker analysis in the frame of the twin projects COPHES and DEMOCOPHES. 674 child-mother pairs were recruited through schools or population registers from six European member states (Belgium, Denmark, Luxembourg, Slovenia, Spain and Sweden). Children (5-12 y) and mothers donated a urine sample. Information on socio-demographic characteristics, life style, dietary habits, and educational level of the parents was provided by mothers. After exclusion of urine samples with creatinine values below 300 mg/L or above 3000 mg/L, 653 children and 639 mothers remained for which BPA was measured. The geometric mean (with 95% confidence intervals) and 90th percentile were calculated for BPA separately in children and in mothers and were named "European reference values". After adjustment for confounders (age and creatinine), average exposure values in each country were compared with the mean of the "European reference values" by means of a weighted analysis of variance. Overall geometric means of all countries (95% CI) adjusted for urinary creatinine, age and gender were 2.04 (1.87-2.24) µg/L and 1.88 (1.71-2.07) µg/L for children (n=653) and mothers (n=639), respectively. Multiple regression analysis was used to identify significant environmental, geographical, personal or life style related determinants. Consumption of canned food and social class (represented by the highest educational level of the family) were the most important predictors for the urinary levels of BPA in mothers and children. The individual BPA levels in children were significantly correlated with the levels in their mothers (r=0.265, p<0.001), which may suggest a possible common environmental/dietary factor that influences the biomarker level in each pair. Exposure of the general European population was well below the current health-based guidance values and no participant had BPA values higher than the health-based guidance values., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Within the European Environment and Health Action Plan an initiative to establish a coherent human biomonitoring approach in Europe was started. The project COPHES (COnsortium to Perform Human biomonitoring on a European Scale ) developed recommendations for a harmonized conduct of a human biomonitoring (HBM) survey which came into action as the pilot study DEMOCOPHES (DEMOnstration of a study to COordinate and Perform Human biomonitoring on a European Scale). Seventeen European countries conducted a survey with harmonized instruments for, inter alia, recruitment, fieldwork and sampling, in autumn/winter 2011/2012. Based on the countries' experiences of conducting the pilot study, following lessons learnt were compiled: the harmonized fieldwork instruments (basic questionnaire, urine and hair sampling) turned out to be very valuable for future HBM surveys on the European scale. A school approach was favoured by most of the countries to recruit school-aged children according to the established guidelines and country specific experiences. To avoid a low participation rate, intensive communication with the involved institutions and possible participants proved to be necessary. The communication material should also include information on exclusion criteria and offered incentives. Telephone contact to the participants the day before fieldwork during the survey can prevent the forgetting of appointments and first morning urine samples. To achieve comparable results on the European scale, training of interviewers in all issues of recruitment, fieldwork and sampling through information material and training sessions is crucial. A survey involving many European countries needs time for preparation and conduct. Materials for quality control prepared for all steps of recruitment, fieldwork and sampling proved to be important to warrant reliable results., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Human biomonitoring (HBM) is an effective tool for assessing actual exposure to chemicals that takes into account all routes of intake. Although hair analysis is considered to be an optimal biomarker for assessing mercury exposure, the lack of harmonization as regards sampling and analytical procedures has often limited the comparison of data at national and international level. The European-funded projects COPHES and DEMOCOPHES developed and tested a harmonized European approach to Human Biomonitoring in response to the European Environment and Health Action Plan. Herein we describe the quality assurance program (QAP) for assessing mercury levels in hair samples from more than 1800 mother-child pairs recruited in 17 European countries. To ensure the comparability of the results, standard operating procedures (SOPs) for sampling and for mercury analysis were drafted and distributed to participating laboratories. Training sessions were organized for field workers and four external quality-assessment exercises (ICI/EQUAS), followed by the corresponding web conferences, were organized between March 2011 and February 2012. ICI/EQUAS used native hair samples at two mercury concentration ranges (0.20-0.71 and 0.80-1.63) per exercise. The results revealed relative standard deviations of 7.87-13.55% and 4.04-11.31% for the low and high mercury concentration ranges, respectively. A total of 16 out of 18 participating laboratories the QAP requirements and were allowed to analyze samples from the DEMOCOPHES pilot study. Web conferences after each ICI/EQUAS revealed this to be a new and effective tool for improving analytical performance and increasing capacity building. The procedure developed and tested in COPHES/DEMOCOPHES would be optimal for application on a global scale as regards implementation of the Minamata Convention on Mercury., (Copyright © 2014 Elsevier Inc. All rights reserved.)

The aim of this study was to explore data from the DEMOCOPHES study population for Romania, Portugal and Poland, in order to assess smoking patterns and the extent of ETS exposure and compare the national study samples with reference to the respective anti-smoking laws. The subset of the DEMOCOPHES study sample consisted of 360 children and their mothers (120 in each of the three countries - Romania (RO), Portugal (PT) and Poland (PL). Smoking was assessed using a detailed questionnaire for the participants, which addresses both active and passive smoking. This assessment uses exposure-relevant questionnaire data, in particular on the home environment and residence, socio-demographic characteristics, lifestyle such as nutrition, smoking behavior, other exposure-relevant behavior and occupational history, as well as urinary cotinine and creatinine measurements. We performed general statistical analysis and innovative receiver operating characteristic (ROC) curve analyses. Smoking prevalence as evaluated by the questionnaire was generally high, and higher than official statistics, which suggests some under-reporting in the countries, particularly in Romania. Urinary cotinine levels provided biochemical confirmation of the high and similar smoking prevalence for the three countries. Concerning ETS exposure, Romania presented significantly higher levels, for children as well as for non-smoking mothers, with Portugal showing significantly lower levels. Compared to non-smoking mothers, the children showed relatively higher ETS exposure levels in all three countries. The established country-specific optimal cut-off values in urinary cotinine to distinguish smokers from non-smokers vary more than those to discriminate ETS exposure extent in non-smoking mothers and children. Although different between countries, these values are a valuable output to monitor effectiveness of both national antismoking laws and educational programs in the three countries. The findings of this study point to the urgent need for stronger, more effective and well enforced smoke-free legislation in the three countries., (Copyright © 2015 Elsevier Inc. All rights reserved.)

The toxicity of methylmercury (MeHg) in humans is well established and the main source of exposure is via the consumption of large marine fish and mammals. Of particular concern are the potential neurodevelopmental effects of early life exposure to low-levels of MeHg. Therefore, it is important that pregnant women, children and women of childbearing age are, as far as possible, protected from MeHg exposure. Within the European project DEMOCOPHES, we have analyzed mercury (Hg) in hair in 1799 mother-child pairs from 17 European countries using a strictly harmonized protocol for mercury analysis. Parallel, harmonized questionnaires on dietary habits provided information on consumption patterns of fish and marine products. After hierarchical cluster analysis of consumption habits of the mother-child pairs, the DEMOCOPHES cohort can be classified into two branches of approximately similar size: one with high fish consumption (H) and another with low consumption (L). All countries have representatives in both branches, but Belgium, Denmark, Spain, Portugal and Sweden have twice as many or more mother-child pairs in H than in L. For Switzerland, Czech Republic, Hungary, Poland, Romania, Slovenia and Slovakia the situation is the opposite, with more representatives in L than H. There is a strong correlation (r=0.72) in hair mercury concentration between the mother and child in the same family, which indicates that they have a similar exposure situation. The clustering of mother-child pairs on basis of their fish consumption revealed some interesting patterns. One is that for the same sea fish consumption, other food items of marine origin, like seafood products or shellfish, contribute significantly to the mercury levels in hair. We conclude that additional studies are needed to assess and quantify exposure to mercury from seafood products, in particular. The cluster analysis also showed that 95% of mothers who consume once per week fish only, and no other marine products, have mercury levels 0.55 μg/g. Thus, the 95th percentile of the distribution in this group is only around half the US-EPA recommended threshold of 1 μg/g mercury in hair. Consumption of freshwater fish played a minor role in contributing to mercury exposure in the studied cohort. The DEMOCOPHES data shows that there are significant differences in MeHg exposure across the EU and that exposure is highly correlated with consumption of fish and marine products. Fish and marine products are key components of a healthy human diet and are important both traditionally and culturally in many parts of Europe. Therefore, the communication of the potential risks of mercury exposure needs to be carefully balanced to take into account traditional and cultural values as well as the potential health benefits from fish consumption. European harmonized human biomonitoring programs provide an additional dimension to national HMB programs and can assist national authorities to tailor mitigation and adaptation strategies (dietary advice, risk communication, etc.) to their country's specific requirements., (Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.)

A communication strategy was developed by The Consortium to Perform Human Biomonitoring on a European Scale (COPHES), as part of its objectives to develop a framework and protocols to enable the collection of comparable human biomonitoring data throughout Europe. The framework and protocols were tested in the pilot study DEMOCOPHES (Demonstration of a study to Coordinate and Perform Human biomonitoring on a European Scale). The aims of the communication strategy were to raise awareness of human biomonitoring, encourage participation in the study and to communicate the study results and their public health significance. It identified the audiences and key messages, documented the procedure for dissemination of results and was updated as the project progressed. A communication plan listed the tools and materials such as press releases, flyers, recruitment letters and information leaflets required for each audience with a time frame for releasing them. Public insight research was used to evaluate the recruitment material, and the feedback was used to improve the documents. Dissemination of results was coordinated in a step by step approach by the participating countries within DEMOCOPHES, taking into account specific national messages according to the needs of each country. Participants received individual results, unless they refused to be informed, along with guidance on what the results meant. The aggregate results and policy recommendations were then communicated to the general public and stakeholders, followed by dissemination at European level. Several lessons were learnt that may assist other future human biomonitoring studies. Recruitment took longer than anticipated and so social scientists, to help with community engagement, should be part of the research team from the start. As a European study, involving multiple countries, additional considerations were needed for the numerous organisations, different languages, cultures, policies and priorities. Therefore, communication documents should be seen as templates with essential information clearly indicated and the option for each country to tailor the material to reflect these differences. Future studies should consider setting up multidisciplinary networks of medical professionals and communication experts, and holding training workshops to discuss the interpretation of results and risk communication. Publicity and wide dissemination of the results helped to raise awareness of human biomonitoring to the general public, policy makers and other key stakeholders. Effective and timely communication, at all stages of a study, is essential if the potential of human biomonitoring research to improve public health is to be realised., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

The metal cadmium (Cd) is a widespread environmental pollutant with documented adverse effects on the kidneys and bones from long-term environmental exposure, but with insufficiently elucidated public health consequences such as risk of cardiovascular disease, hormone-related cancer in adults and developmental effects in children. This study is the first pan-European human biomonitoring project that succeeded in performing harmonized measurements of Cd in urine in a comparable way in mother-child couples from 16 European countries. The aim of the study was to evaluate the overall Cd exposure and significant determinants of Cd exposure. A study population of 1632 women (24-52 years of age), and 1689 children (5-12 years of age), from 32 rural and urban areas, was examined within a core period of 6 months in 2011-2012. Women were stratified as smokers and non-smokers. As expected, smoking mothers had higher geometric mean (gm) urinary cadmium (UCd; 0.24 µg/g crea; n=360) than non-smoking mothers (gm 0.18 µg/g crea; n=1272; p<0.0001), and children had lower UCd (gm 0.065 µg/g crea; n=1689) than their mothers at the country level. Non-smoking women exposed to environmental tobacco smoke (ETS) at home had 14% (95% CI 1-28%) higher UCd than those who were not exposed to ETS at home (p=0.04). No influence of ETS at home or other places on UCd levels was detected in children. Smoking women with primary education as the highest educational level of the household had 48% (95% CI 18-86%) higher UCd than those with tertiary education (p=0.0008). The same observation was seen in non-smoking women and in children; however they were not statistically significant. In children, living in a rural area was associated with 7% (95% CI 1-13%) higher UCd (p=0.03) compared to living in an urban area. Children, 9-12 years had 7% (95% CI 1-13%) higher UCd (p=0.04) than children 5-8 years. About 1% of the mothers, and 0.06% of the children, exceeded the tolerable weekly intake (TWI) appointed by EFSA, corresponding to 1.0 µg Cd/g crea in urine. Poland had the highest UCd in comparison between the 16 countries, while Denmark had the lowest. Whether the differences between countries are related to differences in the degree of environmental Cd contamination or to differences in lifestyle, socioeconomic status or dietary patterns is not clear., (Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.)

Human biomonitoring (HBM) is a scientific technique that allows us to assess whether and to what extent environmental pollutants enter humans. We review here the current HBM efforts for organophosphate esters, emerging flame retardants, perfluoroalkyl substances, and phthalate esters. Use of some of these chemicals has already been banned or restricted; they are regularly detected in the environment, wildlife, and human matrices. Traditionally, blood and urine collection have been widely used as sampling methods. New non-invasive approaches (e.g., saliva, hair, nails) are emerging as valid alternatives since they offer advantages with respect to sampling, handling, and ethical aspects, while ensuring similar reliability and sensitivity. Nevertheless, the identification of biomarkers of exposure is often difficult because chemicals may be metabolized in the human body. For many of the above-mentioned compounds, the mechanisms of the favorable metabolization pathways have not been unraveled, but research on important metabolites that could be used as biomarkers of exposure is growing. This review summarizes the state of the art regarding human exposure to, (non-invasive) HBM of, and metabolism of major organophosphate esters, emerging flame retardants, perfluoroalkyl substances, and phthalate esters currently detected in the environment.

The study aim was to investigate the association between prenatal exposure to endocrine disrupting chemicals (EDCs) and the body composition of 7 to 9 year old Flemish children. The subjects were 114 Flemish children (50% boys) that took part in the first Flemish Environment and Health Study (2002-2006). Cadmium, PCBs, dioxins, p,p'-DDE and HCB were analysed in cord blood/plasma. When the child reached 7-9 years, height, weight, waist circumference and skinfolds were measured. Significant associations between prenatal exposure to EDCs and indicators of body composition were only found in girls. After adjustment for confounders and covariates, a significant negative association was found in girls between prenatal cadmium exposure and weight, BMI and waist circumference (indicator of abdominal fat) and the sum of four skinfolds (indicator of subcutaneous fat). In contrast, a significant positive association (after adjustment for confounders/covariates) was found between prenatal p,p'-DDE exposure and waist circumference as well as waist/height ratio in girls (indicators of abdominal fat). No significant associations were found for prenatal PCBs, dioxins and HCB exposure after adjustment for confounders/covariates. This study suggests a positive association between prenatal p,p'-DDE exposure and indicators of abdominal fat and a negative association between prenatal cadmium exposure and indicators of both abdominal as well as subcutaneous fat in girls between 7 and 9 years old., (Copyright © 2014 Elsevier Inc. All rights reserved.)

The objective of COPHES (Consortium to Perform Human biomonitoring on a European Scale) was to develop a harmonised approach to conduct human biomonitoring on a European scale. COPHES developed a systematic approach for designing and conducting a pilot study for an EU-wide cross-sectional human biomonitoring (HBM) study and for the implementation of the fieldwork procedures. The approach gave the basis for discussion of the main aspects of study design and conduct, and provided a decision making tool which can be applied to many other studies. Each decision that had to be taken was listed in a table of options with their advantages and disadvantages. Based on this the rationale of the decisions could be explained and be transparent. This was important because an EU-wide HBM study demands openness of all decisions taken to encourage as many countries as possible to participate and accept the initiative undertaken. Based on this approach the following study design was suggested: a cross-sectional study including 120 children aged 6-11 years and their mothers aged up to 45 years from each participating country. For the pilot study the children should be sampled in equal shares in an urban and a rural location. Only healthy children and mothers (no metabolic disturbances) should be included, who have a sufficient knowledge of the local language and have been living at least for 5 years at the sampling location. Occupational exposure should not be an exclusion criterion. Recruitment should be performed via inhabitant registries or schools as an alternative option. Measures suitable to increase the response rate should be applied. Preferably, the families should be visited at home and interviewed face-to-face. Various quality control measures to guarantee a good fieldwork performance were recommended. This comprehensive overview aims to provide scientists, EU officials, partners and stakeholders involved in the EU implementation process full transparency of the work carried out in COPHES. Thus this report presents the discussion and consensus in COPHES on the main aspects of designing and conducting fieldwork of a human biomonitoring study. Furthermore, it provides an example for a systematic approach that may be useful to other research groups or pan-European research initiatives. In the study protocol that will be published elsewhere these aspects are elaborated and additional aspects are covered (Casteleyn et al., 2012). Meanwhile the respective pilot study DEMOCOPHES had been conducted and assessed. The results and lessons learned will be published elsewhere., (Copyright © 2013 Elsevier GmbH. All rights reserved.)

Due to possible health risks, quantification of mercury accumulation in humans was included in the Flemish biomonitoring programmes FLEHS I (2002-2006) and FLEHS II (2007-2011). The general objective of FLEHS I was to assess regional exposure levels in order to link possible differences in these internal exposure levels to different types of local environmental pressure. Therefore, Hg and MMHg (methylmercury) were only measured in pooled blood samples per region and per age class. In FLEHS II, mercury concentrations were measured in hair of each participant. About 200 adolescents and 250 mothers (reference group) and two times 200 adolescents (2 hotspots) were screened. The main objectives of the FLEHS II study were: (1) to determine reference levels of mercury in hair for Flanders; (2) to assess relations between mercury exposure and possible sources like fish consumption; (3) to assess dose-effect relations between mercury exposure and health effect markers. The results showed that mercury concentrations in the Flemish population were rather low compared to other studies. Mercury levels in the Flemish populations were strongly related to the age of the participants and consumption of fish. Significant negative associations were observed between mercury in hair and asthma, having received breast feeding as a newborn, age at menarche in girls, allergy for animals and free testosterone levels. Significant correlations were also observed between mercury in hair and genes JAK2, ARID4A, Hist1HA4L (boys) and HLAdrb5, PIAS2, MANN1B1, GIT and ABCA1 (girls)., (Copyright © 2013 Elsevier GmbH. All rights reserved.)

Animal studies showed that the developing brain is particularly sensitive to chemical exposure. Human studies carried out in areas with high exposures have proven neurodevelopmental disorders in relation to e.g. lead and PCBs. Whether these chemicals are associated with behavioural problems in childhood at current environmental levels is not well known. Therefore, we assessed the association between prenatal exposure to lead, cadmium, PCBs, dioxin-like compounds, HCB and p,p'-DDE and behavioural problems in 7-8year old children. Prenatal exposure data were obtained from the Flemish mother-new-born cohort. Lead, cadmium, PCBs, dioxin-like compounds, HCB and p,p'-DDE were analysed in cord blood. When the child reached 7-8years, 270 mothers completed the Strengths and Difficulties Questionnaire assessing their children's behavioural health. We found that doubling the prenatal lead exposure (cord blood lead levels) was associated with a 3.43 times higher risk for hyperactivity in both boys and girls. In addition, total difficulties were 5.08 times more likely in the highest tertile for prenatal lead exposure compared to the lowest tertile. In girls, total difficulties were 4.92 more likely when doubling cord blood p,p'-DDE, whereas no significant association was found in boys. Further, we noted in boys a 1.53 times higher risk for emotional problems when doubling cord blood cadmium, whereas no significant association was found in girls. These results indicate that the presence of environmental contaminants influences the mental health of the next generation., (© 2013.)

Flanders, Belgium, is one of the most densely populated areas in Europe. The Flemish Environment and Health Survey (2002-2006) aimed at determining exposure to pollutants of neonates, adolescents, and older adults and to assess associated biological and health effects. This study investigated genome wide gene expression changes associated with a range of environmental pollutants, including cadmium, lead, PCBs, dioxin, hexachlorobenzene, p,p'-DDE, benzene, and PAHs. Gene expression levels were measured in peripheral blood cells of 20 adults with relatively high and 20 adults with relatively low combined internal exposure levels, all non-smokers aged 50-65. Pearson correlation was used to analyze associations between pollutants and gene expression levels, separately for both genders. Pollutant- and gender-specific correlation analysis results were obtained. For organochlorine pollutants, analysis within genders revealed that genes were predominantly regulated in opposite directions in males and females. Significantly modulated pathways were found to be associated with each of the exposure biomarkers measured. Pathways and/or genes related to estrogen and STAT5 signaling were correlated to organochlorine exposures in both genders. Our work demonstrates that gene expression in peripheral blood is influenced by environmental pollutants. In particular, gender-specific changes are associated with organochlorine pollutants, including gender-specific modulation of endocrine related pathways and genes. These pathways and genes have previously been linked to endocrine disruption related disorders, which in turn have been associated with organochlorine exposure. Based on our results, we recommend that males and females be considered separately when analyzing gene expression changes associated with exposures that may include chemicals with endocrine disrupting properties., (Copyright © 2013 Wiley Periodicals, Inc.)

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 programme emphasizing 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., (Copyright © 2011 Elsevier GmbH. All rights reserved.)

An increasing number of studies have addressed the concern that environmental pollutants may contribute to the early origin of diseases. Epidemiologic studies suggest that prenatal exposure to air pollutants, several food contaminants, and chemicals present in consumer products are associated with nongenetically transmitted adverse health effects, which manifest after birth. Changes in neurobehavior, sexual development, the prevalence of asthma and allergy, and growth curves have been shown to be associated with pollutant exposure at early life stages. This review focuses on human molecular epidemiologic studies that contribute knowledge by introducing biomarker measurements to obtain a mechanistic understanding of the relation between early life exposures and health outcome. It has been hypothesized that subtle effects induced by pollutant exposure during development can lead to functional deficits and altered programming, which leads to increased disease or dysfunction risk later in life. Biomarker analysis may provide sensitive tools to trace these subtle changes and obtain mechanistic insight about the causal pathway between external exposure and health effects in human population studies. Biomarkers of exposure can be measured in mothers before conception, during pregnancy, or after birth. Different biological tissues-such as peripheral or cord blood samples, hair samples, meconium, and urine-provide specific information that reflects the actual dose during pregnancy or at birth. Biomarkers of effect may include changes in hormone concentrations, oxidative stress variables, changes in gene expression levels, and epigenetic changes.

This retrospective incidence-based cost-of-illness analysis aims to quantify the costs associated with female breast cancer in Flanders for the year prior to diagnosis and for each of the 5 years following diagnosis. A bottom-up analysis from the societal perspective included direct health care costs and indirect costs of productivity loss due to morbidity and premature mortality. A case-control study design compared total costs of breast cancer patients with costs of an equivalent standardised population with a view to calculating the additional costs that can be attributed to breast cancer. Total average costs of breast cancer amounted to 107,456 per patient over 6 years. Total costs consisted of productivity loss costs (89% of costs) and health care costs (11% of costs). Health care costs did not vary with age at diagnosis. Health care costs of breast cancer patients converged with those of the general population at 5 years following diagnosis. Patients with advanced breast cancer stadia had higher health care costs. Cost estimates provided by this analysis can be used to determine priorities for, and inform, future research on breast cancer. In particular, attention needs to be focussed on decreasing productivity loss from breast cancer.

Flanders is densely populated with much industry and intensive farming. Sexual maturation of adolescents (aged 14-15 years) was studied in relation to internal exposure to pollutants. Serum levels of pollutants and sex hormones were measured in 1679 participants selected as a random sample of the adolescents residing in the study areas. Data on sexual development were obtained from the medical school examination files. Self-assessment questionnaires provided information on health, use of medication and lifestyle factors. In boys, serum levels of hexachlorobenzene (HCB), p,p'-DDE and polychlorinated biphenyls (sum of marker PCB138, 153 and 180) were significantly and positively associated with pubertal staging (pubic hair and genital development). Higher levels of serum HCB and blood lead were associated with, respectively, a lower and a higher risk of gynecomastia. In girls, significant and negative associations were detected between blood lead and pubic hair development; higher exposure to PCBs was significantly associated with a delay in timing of menarche. Environmental exposures to pollutants at levels actually present in the Flemish population are associated with measurable effects on pubertal development. However, further understanding of toxic mode of action and sensitive windows of exposure is needed to explain the current findings.

Flanders is densely populated with much industry and intensive farming. Hormonal status of 14- to 15-year-old male adolescents was studied in relation to internal exposure to pollutants. A total of 887 participants were selected as a random sample of the adolescents residing in the study areas. Confounding factors and significant covariates were taken into account. Serum levels of testosterone, free testosterone and estradiol, and the aromatase index showed significant positive associations with serum levels of marker polychlorobiphenyls (sum of PCBs 138, 153, and 180) and of hexachlorobenzene (HCB) and a negative association with urinary cadmium concentration. Serum levels of estradiol also showed a positive association with serum levels of dichlorodiphenyldichloroethylene (DDE). A doubling of serum concentrations of marker PCBs and HCB and of urinary concentration of cadmium were, respectively, associated with an increase of 16.4% (P<0.00001) and 16.6% (P<0.001) and a decrease of 9.6% (P<0.001) in serum testosterone concentration. Similar findings were made after additional adjustment for concurrent exposures. Associations between biological effects and internal exposures were, in terms of the regression coefficient, often stronger at exposures below the median. Environmental exposures to pollutants resulting in "normal" levels of internal exposure were associated with quite substantial differences in hormone concentrations.

Onset and development of puberty is regulated by the neuroendocrine system. Population-based studies worldwide have observed secular trends towards earlier puberty development. These changes are apparently caused by environmental factors such as improved socio-economic status, improved health care and nutrition. However, they may also partly result from endocrine-disrupting chemicals in the environment. Epidemiological studies have investigated the relationship between pubertal development and exposure to endocrine-disrupting chemicals (polychlorinated biphenyls, polybrominated biphenyls, 1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane, phthalate esters, furans and the pesticide endosulfan). Associations with both perinatal and postnatal exposure have been reported. Studies in experimental animals support some of these findings and point to differential endocrine regulatory mechanisms linked to pubertal development acting in the perinatal and the pre-pubertal period. Pubertal development is naturally associated with growth and body composition. There is increasing evidence for a link between prenatal development and pubertal onset. In girls born small for gestational age (SGA), pubertal onset and age at menarche often are advanced, especially if there has been an extensive catch-up growth during the first months of life. In utero growth retardation may have multiple causes including exposure to xenobiotic substances as was suggested for some endocrine-disrupting chemicals. An abnormal perinatal environment of children born SGA may alter the endocrine status and the sensitivity of the receptors for endocrine and metabolic signalling that may have effects on maturation of brain and gonads. However, the causal pathways and the molecular mechanisms that may link the pubertal growth pattern of children born SGA, pubertal development and endocrine-disrupting chemicals need further study.

Lipophilic contaminants are present in the environment and bioaccumulate in the food chain. Therefore, their intake via animal fat of various sources was assessed for three age groups of the Flemish population, participating in a large biomonitoring program of the Flemish government. In total, 1636 adolescents (14-15 years), 1186 mothers (18-44 years), and 1586 adults (50-65 years) participated in the study and completed a semi quantitative food frequency questionnaire. Individual consumption data were combined, via a so-called simple distribution approach, with recent data on polychlorinated dibenzo-p-dioxins/furans and dioxin-like polychlorinated biphenyls, measured via the chemical-activated luciferase gene expression (CALUX) bio-assay in food items available on the Flemish market. The median (95th percentile) estimated intakes of dioxin-like contaminants were 2.24 (4.61), 2.09 (4.26), and 1.74 (3.53) pg CALUX-TEQ kg(-1) bw d(-1) for, respectively adolescents, mothers and adults. These data are in the same range as those found in other European studies. The CALUX-TEQ results of respectively 59.8%, 53.7% and 36.2% of the adolescent, mother and adult population exceed the tolerable weekly intake (TWI) of 14 pg WHO-TEQ kg(-1) bw w(-1), as derived by the Scientific Committee on Food [Scientific Committee on Food, 2001. Opinion of the Scientific Committee on Food on the Risk Assessment of Dioxins and Dioxin-like PCBs in Food, CS/CNTM/DIOXIN/20 final Brussels, Belgium]. The main contributors of dioxin-like substances are fish and seafood (25-43% of the total intake), added fats (22-25% of the total intake) and dairy products (17-20% of the total intake).

The purpose of this study was to determine if ambulatory blood pressure measurement predicted total and cardiovascular mortality over and beyond clinic blood pressure measurement and other cardiovascular risk factors; 5292 untreated hypertensive patients referred to a single blood pressure clinic who had clinic and ambulatory blood pressure measurement at baseline were followed up in a prospective study of mortality outcome. Multiple Cox regression was used to model time to total and cause-specific mortality for ambulatory blood pressure measurement while adjusting for clinic blood pressure measurement and other risk factors at baseline. There were 646 deaths (of which 389 were cardiovascular) during a median follow-up period of 8.4 years. With adjustment for gender, age, risk indices, and clinic blood pressure, higher mean values of ambulatory blood pressure were independent predictors for cardiovascular mortality. The relative hazard ratio for each 10-mm Hg increase in systolic blood pressure was 1.12 (1.06 to 1.18; P<0.001) for daytime and 1.21 (1.15 to 1.27; P<0.001) for nighttime systolic blood pressure. The hazard ratios for each 5-mm Hg increase in diastolic blood pressure were 1.02 (0.99 to 1.07; P=NS) for daytime and 1.09 (1.04 to 1.13; P<0.01) for nighttime diastolic pressures. The hazard ratios for nighttime ambulatory blood pressure remained significant after adjustment for daytime ambulatory blood pressure. These results have 2 important clinical messages: ambulatory measurement of blood pressure is superior to clinic measurement in predicting cardiovascular mortality, and nighttime blood pressure is the most potent predictor of outcome.

To be suitable for the management of hypertension, self-measurement of blood pressure (BP) at home should follow international recommendations. The use of accurate and validated measuring devices is an important prerequisite. Upper arm BP monitors are the first choice, while wrist and finger devices cannot be recommended. Measurements should, preferentially, be downloaded from the memory of a device or printed. Reference values have been proposed, but were mostly based on cross-sectional observations and have not yet been widely validated by prospective outcome studies. Currently, levels of home BP of <135 mm Hg systolic and 85 mm Hg diastolic are usually considered normal. Home BP measurement is sometimes recommended as an alternative to ambulatory BP monitoring to diagnose white-coat hypertension.However, home BP measurement cannot replace ambulatory BP monitoring in the diagnosis of hypertension (white-coat), but both techniques have complementary roles. The appropriateness of home BP measurement to guide antihypertensive treatment has only been tested in one large-scale randomized trial: the THOP (Treatment of Hypertension Based on Home or Office Blood Pressure) trial. The THOP trial showed that antihypertensive treatment based on home instead of office BP led to less intensive drug treatment, but also to less BP control with no differences in general wellbeing and left ventricular mass. Home BP monitoring also contributed to the identification of patients with white-coat hypertension. On balance, most evidence supports the view that office BP measurement remains the key in the diagnosis and treatment of hypertension. Treatment can be started without confirmation of elevated office BP in patients with high office BP and target organ damage, or a high cardiovascular risk profile. In patients with raised office BP but without target organ damage (white-coat hypertension), or with normal office BP but unexplained target organ damage (masked hypertension), ambulatory or home BP monitoring or both must be used to confirm the diagnosis. Few longitudinal studies have addressed the long-term prognostic meaning of home BP measurement. Until more prospective data become available, management of hypertension exclusively based on self-measurement of BP at home cannot be recommended.

Objective and Methods: In this randomized clinical trial, conducted in 400 hypertensive patients [sitting diastolic blood pressure (DBP) >95 mmHg], blood pressure-lowering therapy was adjusted in a stepwise manner, either on the basis of the self-measured DBP at home or on the basis of conventional DBP measured at the doctor's office., Results: Therapy guided by home blood pressure instead of office blood pressure led to less intensive drug treatment and marginally lower costs, but also to less blood pressure control with no differences in left ventricular mass. Self-measurement helped to identify patients with white-coat hypertension., Conclusions: The present findings support a stepwise strategy for the evaluation of blood pressure, in which self-measurement and ambulatory monitoring are complementary to conventional office blood pressure measurement.

Background: Many studies have analysed the relation between cardiovascular risk factors and oral contraceptive use in adult women, whereas information on the possible health effects of oral contraceptive use during adolescence is lacking., Design: The effect of current contraceptive pill use on blood pressure and serum total cholesterol concentration was studied in a cross-sectional sample of 120 adolescent girls with a mean age of 17.4 years., Methods: After the girls had rested for 5 minutes in the sitting position, trained study nurses measured blood pressure three times consecutively using a mercury sphygmomanometer. The nurses also administered a questionnaire gathering information on the use of oral contraceptives, smoking and parental social class. In the morning blood samples were taken for the measurement of serum total cholesterol., Results: Mean age (+/-SD) was 17.4+/-0.8 years. Blood pressure averaged (+/-SD) 108.7+/-9.9 systolic and 68.0+/-8.2 mmHg diastolic. Serum total cholesterol was 4.5+/-0.7 mmol/l. Forty-nine girls (41%) were taking the contraceptive pill. Of these, 44 (90%) were on a combination of ethinyloestradiol (20-35 microg) and a progestogen, four (8%) on anti-androgens (35 microg) and one (2%) only on a progestogen. After adjustment for age, body mass index, smoking and alcohol status systolic blood pressure was 4.6 mmHg higher (95% CI 1.2-8.1; P<0.001) in current pill users than in girls not currently on the pill (111.4 versus 106.8 mmHg). Adjusted for the aforementioned covariates, diastolic blood pressure was not related to pill use (68.2 versus 67.8 mmHg; P=0.7). Serum total cholesterol was 0.43 mmol/l (95% CI 0.18-0.60; P=0.001) higher among girls using oral contraceptives (4.7 versus 4.3 mmol/l), irrespective of whether or not the model was adjusted for age, body mass index, smoking and alcohol status., Conclusions: In 17-year-old girls, the use of oral contraceptives was associated with a nearly 5 mmHg higher systolic blood pressure and a 0.4 mmol/l higher level of serum total cholesterol. The long-term prognostic implications of our findings remain to be elucidated.

Hypertension is present in 60% to 70% of the population over 60 years of age and may result in cardiovascular complications such as stroke, coronary heart disease, and heart failure. In this review, the role of arterial stiffness, endothelial function, atherosclerosis, and oxidative stress in the pathogenesis of hypertension is discussed extensively. Antihypertensive drug treatment may control high blood pressure and prevent complications. This review summarizes the results of several placebo-controlled and comparative clinical trials that have studied the efficacy of different classes of antihypertensive drugs.

Background: The relationship between LV mass and systolic blood pressure at baseline was studied in the pooled database of the APTH (n = 408) and THOP (n = 376) trials., Methods: Partial correlation coefficients were calculated between electrocardiographic and echocardiographic LV mass at baseline and different types of blood pressure, that is, office blood pressure (OBP), 24-h ambulatory blood pressure (ABP), daytime ABP and night-time ABP., Results: Electrocardiographic LV mass correlated equally well (P < or = 0.001) with all types of systolic blood pressure (partial r = 0.19 to 0.22 for the Sokolow-Lyon index, 0.20 to 0.22 for the sum of the Sokolow-Lyon index plus the R-wave in aVl, and 0.12 to 0.19 for the Cornell voltage). The findings were similar for echocardiographic LV mass index (partial r = 0.15 to 0.22). However, for echocardiographic mean wall thickness, there was a stronger association with ABP than with OBP (partial r = 0.30 for 24-h ABP, 0.29 for daytime ABP, 0.26 for night-time ABP versus 0.15 for OBP (P < or = 0.05)). CONCLUSIONS In the combined dataset of the APTH and THOP trials, electrocardiographic and echocardiographic LV mass at baseline correlated significantly with all types of systolic blood pressure. For mean wall thickness, the relationship was stronger for ABP than OBP.

Polychlorinated aromatic hydrocarbons (PCAHs) have been described as endocrine disruptors in animals and in accidentally or occupationally exposed humans. In the present study we examined the effect of moderate exposure to PCAHs on sexual maturation. Two hundred adolescents (mean age, 17.4 years) who resided in two polluted suburbs and a rural control area in Flanders (Belgium) participated. We measured the serum concentration of polychlorinated biphenyl (PCB) congeners 138, 153, and 180 and dioxin-like compounds [chemically activated luciferase expression (CALUX) assay] as biomarkers of exposure. School physicians assessed the pubertal development of boys and girls and measured testicular volume. In one suburb near two waste incinerators, compared with the other suburb and the control area, fewer boys (p < 0.001) had reached the adult stages of genital development (62% vs. 92% and 100%, respectively) and pubic hair growth (48% vs. 77% and 100%). Also, in the same suburb, fewer girls (p = 0.04) had reached the adult stage of breast development (67% vs. 90% and 79%). In individual boys, a doubling of the serum concentration of PCB congener 138 increased the odds of not having matured into the adult stage of genital development by 3.5 (p = 0.04); similarly for PCB congener 153 in relation to male pubic hair growth, the odds ratio was 3.5 (p = 0.04). In girls, a doubling of the serum dioxin concentration increased the odds of not having reached the adult stage of breast development by 2.3 (p = 0.02). Left plus right testicular volume was lower in both polluted areas than in the control area (42.4 mL vs. 47.3 mL, p = 0.005) but was not related to the current exposure of the adolescents to PCAHs. Through endocrine disruption, environmental exposure to PCAHs may interfere with sexual maturation and in the long-run adversely affect human reproduction.