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Few data are available on the exposure of children to glyphosate (Gly) in Europe. Within HBM4EU, new HBM exposure data were collected from aligned studies at five sampling sites distributed over Europe (studies: SLO CRP (SI); ORGANIKO (CY); GerES V-sub (DE); 3XG (BE); ESTEBAN (FR)). Median Gly concentrations in urine were below or around the detection limit (0.1 µg/L). The 95th percentiles ranged between 0.18 and 1.03 µg Gly/L. The ratio of AMPA (aminomethylphosphonic acid; main metabolite of Gly) to Gly at molar basis was on average 2.2 and the ratio decreased with higher Gly concentrations, suggesting that other sources of AMPA, independent of metabolism of Gly to AMPA in the monitored participants, may concurrently operate. Using reverse dosimetry and HBM exposure data from five European countries (east, west and south Europe) combined with the proposed ADI (acceptable daily intake) of EFSA for Gly of 0.1 mg/kg bw/day (based on histopathological findings in the salivary gland of rats) indicated no human health risks for Gly in the studied populations at the moment. However, the absence of a group ADI for Gly+AMPA and ongoing discussions on e.g., endocrine disrupting effects cast some uncertainty in relation to the current single substance ADI for Gly. The carcinogenic effects of Gly are still debated in the scientific community. These outcomes would influence the risk conclusions presented here. Finally, regression analyses did not find clear associations between urinary exposure biomarkers and analyzed potential exposure determinants. More information from questionnaires targeting exposure-related behavior just before the sampling is needed. HBM4EU is co-financed under Horizon 2020 (grant agreement No733032) and by national HBM programs. Sí

The risk assessment of pesticide residues in food is a key priority in the area of food safety. Most jurisdictions have implemented pre-marketing authorization processes, which are supported by prospective risk assessments. These prospective assessments estimate the expected residue levels in food combining results from residue trials, resembling the pesticide use patterns, with food consumption patterns, according to internationally agreed procedures. In addition, jurisdictions such as the European Union (EU) have implemented large monitoring programs, measuring actual pesticide residue levels in food, and are supporting large-scale human biomonitoring programs for confirming the actual exposure levels and potential risk for consumers. The organophosphate insecticide chlorpyrifos offers an interesting case study, as in the last decade, its acceptable daily intake (ADI) has been reduced several times following risk assessments by the European Food Safety Authority (EFSA). This process has been linked to significant reductions in the use authorized in the EU, reducing consumers' exposure progressively, until the final ban in 2020, accompanied by setting all EU maximum residue levels (MRL) in food at the default value of 0.01 mg/kg. We present a comparison of estimates of the consumer's internal exposure to chlorpyrifos based on the urinary marker 3,5,6-trichloro-2-pyridinol (TCPy), using two sources of monitoring data: monitoring of the food chain from the EU program and biomonitoring of European citizens from the HB4EU project, supported by a literature search. Both methods confirmed a drastic reduction in exposure levels from 2016 onwards. The margin of exposure approach is then used for conducting retrospective risk assessments at different time points, considering the evolution of our understanding of chlorpyrifos toxicity, as well as of exposure levels in EU consumers following the regulatory decisions. Concerns are presented using a color code, and have been identified for almost all studies, particularly for the highest exposed group, but at different levels, reaching the maximum level, red code, for children in Cyprus and Israel. The assessment uncertainties are highlighted and integrated in the identification of levels of concern. This study was part of the HBM4EU project receiving funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No. 733032. Sí

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 sociodemographics, 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 under represented. 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. The HBM4EU initiative is co-financed under Horizon 2020 (grant agreement No 733032). Additional financial support for the conduct of the studies is provided by each participating country. More information on co-funding of the individual studies is provided in Supplementary Materials, Table S14. info:eu-repo/semantics/publishedVersion

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. Funding: The HBM studies were conducted within the framework of the Flemish Center of Expertise on Environment and Health (FLEHS 2002–2006 and 2007–2011), funded by the Flemish Government, Department of Environment & Spatial Development, Flemish Planning Bureau for the Environment and Spatial Development (formally: Department of Environment, Nature & Energy); Department of Economics, Science and Innovation and the Flemish Agency for Care and Health. The scienceto-policy process of the HBM results was funded by the Department of Environment & Spatial Development, Flemish Planning Bureau for the Environment and Spatial Development (formally: Department of Environment, Nature & Energy) and the Flemish Agency for Care and Health. The egg study was funded by the Government of Flanders, Department of Environment & Spatial Development, Flemish Planning Bureau for the Environment and Spatial Development (formally: Department of Environment, Nature & Energy); the Flemish Agency for Care and Health and the Flanders Environment Agency. The views expressed herein are those of the author(s) and are not necessarily endorsed by the Flemish Government. Acknowledgments: The authors wish to express their gratitude to the participants of the studies for their cooperation and to the study nurses and study fieldworkers for their contribution to the study. We also thank the SGS laboratory for collection and analysis of the egg samples and Josworld for designing the leaflet on dietary recommendations for consumption of home-produced eggs.

The ubiquitous use of organophosphate flame retardants and plasticizers (PFRs) in a variety of consumer products has led to widespread human exposure. Since certain PFRs are developmental and carcinogenic toxicants, detailed exposure assessments are essential to investigate the risk associated with environmental exposure levels. However, such data are still lacking for European countries. In this study, concentrations of thirteen PFR metabolites were measured in urine samples from 600 adolescents from Flanders, Belgium. 1-Hydroxy-2-propyl bis(1-chloro-2-propyl) phosphate (BCIPHIPP), diphenyl phosphate (DPHP), bis(1,3-dichloro-isopropyl) phosphate (BDCIPP), 2-hydroxyethyl bis(2-butoxyethyl) phosphate (BBOEHEP), 2-ethylhexyl phenyl phosphate (EHPHP) and 2-ethyl-5-hydroxyhexyl diphenyl phosphate (5-HO-EHDPHP) were frequently detected (>83%) in all participants. Comparisons with study populations from outside the EU showed that urinary levels of DPHP, BDCIPP and BCIPHIPP were generally within the same range. Only exposure to 2-ethylhexyl diphenyl phosphate (EHDPHP) was presumably higher in Flemish adolescents. However, determinants analysis through multivariate regression analyses did not reveal significant predictors that may explain this finding. Significantly higher levels of BDCIPP were observed in participants with new decorations at home, while adolescents with highly educated parents had higher levels of BBOEHEP and BDCIPP. Furthermore, multiple PFR metabolite concentrations followed a seasonal pattern. Estimated daily intakes (EDIs) were calculated from the internal dose by including fractions of urinary excretion (FUE) estimated in in vitro metabolism studies. EDIs ranged from 6.3 ng/kg bw/day for TBOEP to 567.7 ng/kg bw/day for EHDPHP, which were well below the available oral reference doses for all investigated PFRs. This suggests that the associated risk is low at present. This is the first report on internal exposure to seven commonly used PFRs in a European population. We thank the participating adolescents and their families. Without their effort this study would not have been possible. We also thank J. Bombeke for his assistance during the sample preparation. This paper is based on research conducted within the framework of the Flemish Center of Expertise on Environment and Health (FLEHS 2016-2020), funded by the Government of Flanders, Department of Environment & Spatial Development. The views expressed herein are those of the author (s) and are not necessarily endorsed by the government of Flanders. The Flemish Environment and Health Study was commissioned, financed and steered by the Ministry of the Flemish Community (Department of Environment) (grant ID: Steunpunt Milieu & Gezondheid), including the partial funding of the Ph.D. of Michiel Bastiaensen. Celine Gys acknowledges the funding of a PhD fellowship from Research Foundation Flanders (project G0E5216N).

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. Government of Flanders, Department of Environment & Spatial Development; Flemish Center of Expertise on Environment and Health

Background: Exposure to air pollution and traffic noise are associated with adverse health outcomes in adolescents. Chronic endocrine stress and systemic inflammation have been hypothesized to underlie the adverse health effects. Simultaneous assessment of inflammation and chronic endocrine stress in epidemiological studies is lacking. The aim of the study was to investigate biomarkers of chronic endocrine stress and inflammation in relation to long-term residential exposure to air pollution and traffic noise in adolescents. Methods: In Flemish adolescents (14-15 years), we determined hair cortisol concentration (HCC) as a chronic stress biomarker in 3-cm scalp-near hair sections (n = 395), and leucocyte and leucocyte subtype counts (neutrophils, monocytes, lymphocytes) as inflammatory biomarkers in peripheral blood (n = 385). Daily particulate matter (PM2.5, PM10), nitrogen dioxide (NO2) and black carbon (BC) concentrations were modelled at the residential address and averaged over 3-month and 1-year periods prior to sampling. Residential traffic noise level was estimated and classified in 5 dB intervals. Sex-specific associations between residential exposures and effect biomarkers were studied using linear regression models, adjusted for a priori selected covariates. Results: In boys, HCC increased with a factor 1.30 (95% CI: 1.10, 1.54) for an increase in 1-year mean NO2 from the 25th to 75th percentile (p75/p25), after adjustment for age, BMI, personal and neighborhood socioeconomic status. The corresponding estimate for PM10 was 1.24 (95% CI: 1.02, 1.51). Total leucocyte count in boys, adjusted for the aforementioned covariates and recent health complaints, was positively associated with PM2.5, PM10, NO2 and BC. In particular, the neutrophil count increased with a factor 1.11 (95% CI: 1.03, 1.19) for a (p75/p25)-factor increase in 1-year mean BC, corresponding estimates for PM2.5, PM10 and NO2 were 1.10 (95% CI: 1.01, 1.19), 1.10 (95% CI: 1.01, 1.20) and 1.08 (95% CI: 1.00, 1.16). Lymphocyte count increased with a factor 1.05 (95% CI: 1.01, 1.10) for a (p75/p25)-factor increase in 1-year mean NO2. Similar results were observed for 3-month mean exposures. Results were robust to adjustment for recent air pollution exposure. In girls, air pollutants were not associated with HCC or differential leucocyte count. Residential traffic noise level was not associated with HCC or leucocyte counts in boys nor girls. Conclusions: Long-term residential exposure to air pollutants was positively associated with chronic endocrine stress and inflammation in adolescent boys, not in girls. This study may contribute to a better understanding of the early pathophysiological changes that may underlie adverse health effects of air pollution exposure in adolescents. Government of Flanders, Department of Environment & Spatial Development; PhD fellowship at the University of Antwerp; VITO - Flemish Center of Expertise on Environment and Health

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.

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 mu/L for PFOS and 2 mu g/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. This paper is based on research conducted within the framework of the Flemish Centre of Expertise on Environment and Health, funded by the Environment, Nature and Energy Department of the Flemish government, the Department of Public Health and the Department of Science of the Flemish government. The views expressed herein are those of the authors and are not necessarily endorsed by the Flemish government. Colles, A (reprint author), VITO Hlth, Boeretang 200, B-2400 Mol, Belgium. ann.colles@vito.be

Background: Environmental justice research shows how socially disadvantaged groups are more exposed and more vulnerable to environmental pollution. At the same time, these groups are less represented and, thus, less visible in biomedical studies. This socioeconomic participation bias is a form of environmental injustice within research practice itself. Methods: We designed, implemented and evaluated a targeted recruitment strategy to enhance the participation of socially disadvantaged pregnant women in a human biomonitoring study in Belgium. We focused on women of Turkish and Moroccan descent and developed a setup using personal buddies that enabled information transfer about study conditions in the pre-parturition period as well as support and follow-up with questionnaires in the post-parturition period. Results: We identified four barriers to the participation of women with a vulnerable social and ethnic background which were related to psychosocial and situational factors. Lack of trust in researchers and no perceived study benefits were important personal barriers; the complex study design and difficult self-administered questionnaires were equally significant barriers. Conclusion: By investing in direct, person-to-person contact with trusted buddies and supported by practical advice about cultural and linguistic sensitivity, it was possible to increase study participation of socially disadvantaged people. Above all, this required openness and flexibility in the mind-set of researchers so that study design and procedures could be better grounded in the experiences and circumstances of underprivileged groups. The Flemish Environmental and Health Studies (FLEHS) are commissioned, financed and steered by the Ministry of the Flemish Community (Department of Economics, Science and Innovation; Flemish Agency for Care and Health; and the Department of Environment, Nature and Energy). We acknowledge additional financial support from the Flemish government to invest in a targeted recruitment strategy for socially vulnerable people.

To follow time trends in exposure to environmental chemicals, three successive campaigns of the Flemish Environment and Health Study (FLEHS) have recruited and sampled in total 5825 participants between 2002 and 2014. Cord samples from newborns, urine and blood samples from 14 to 15 years old adolescents and from adults between 50 and 65 years old were analysed in geographical representative samples of the Flemish population. The data of the different campaigns were considered per age group and per biomarker after adjustment for predefined covariates to take into account differences in characteristics of the study populations over time. Geometric means were calculated. Multiple linear regression was used to evaluate time trends. The concentration of serum biomarkers for persistent organic pollutants (POPs), such as marker polychlorinated biphenyls (PCBs), dichlorodiphenyldichloroethylene (p,p'-DDE), the major metabolite of dichlorodiphenyltrichloroethane (DDT), and hexachlorobenzene (HCB) expressed per g lipid, decreased significantly with time. The levels of DDE in all age groups and those of PCBs in cord and adolescent serum samples were almost halved in a time period of ten years. HCB levels were reduced by a factor of 4 in adolescents and in adults. Mean serum concentrations of the more recently regulated perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) were significantly lower in cord samples of 2013 compared to samples of 2007. The decline was more pronounced for PFOS than for PFOA. In the same period, mean metabolite levels of di-2-ethylhexyl phthalate (DEHP) and of di-n-butyl phthalate (DBP) decreased significantly in urine samples of adolescents with sharper declines for DEHP than for DBP. Cadmium and lead levels in cord and adolescent blood samples were significantly lower in the recent campaigns than 10 years before. Also the mean urinary cadmium level in adults was 35% lower compared to adult samples of 2002. Such favourable trends were not observed for arsenic and thallium measured in cord blood. Similar, the concentrations of 1-hydroxypyrene, a marker for exposure to poly cyclic aromatic hydrocarbons (PAHs), was not lower in urine from adolescents sampled in 2013 compared to 2003. In contrast, concentrations of t,t'-muconic acid, a marker of benzene exposure, showed clearly reduced levels. The FLEHS program shows that concentrations of well-regulated chemicals especially traditional POPs and cadmium and lead are decreasing in the population of Flanders. Response to regulatory measures seems to happen rapid, since concentrations in humans of specific regulated perfluorinated compounds and phthalates were significantly reduced in five years time. Biomarker concentrations for arsenic, thallium, and polyaromatic hydrocarbons are not decreasing in this time span and further follow up is warranted. (C) 2016 Published by Elsevier GmbH.

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. Morrens, B (corresponding author), Univ Antwerp, Fac Social Sci, B-2000 Antwerp, Belgium. bert.morrens@uantwerpen.be; hans.jonker@uantwerpen.be; elly.denhond@provincieantwerpen.be; dries.coertjens@uantwerpen.be; ann.colles@vito.be; greet.schoeters@vito.be; nicolas.vanlarebeke@ugent.be; tim.nawrot@uhasselt.be; adrian.covaci@uantwerpen.be; vera.nelen@provincieantwerpen.be; frederic.vandermoere@uantwerpen.be; ilse.loots@uantwerpen.be

The broadly used industrial chemical bisphenol A (BPA), applied in numerous consumer products, has been under scrutiny in the past 20 years due to its widespread detection in humans and the environment and potential detrimental effects on human health. Following implemented restrictions and phase-out initiatives, BPA is replaced by alternative bisphenols, which have not received the same amount of research attention. As a part of the fourth cycle of the Flemish Environment and Health Study (FLEHS IV, 2016–2020), we monitored the internal exposure to six bisphenols in urine samples of 423 adolescents (14–15 years old) from Flanders, Belgium. All measured bisphenols were detected in the study population, with BPA and its alternatives bisphenol F (BPF) and bisphenol S (BPS) showing detection frequencies > 50%. The reference values show that exposure to these compounds is extensive. However, the urinary BPA level decreased significantly in Flemish adolescents compared to a previous cycle of the FLEHS (2008–2009). This suggests that the replacement of BPA with its analogues is ongoing. Concentrations of bisphenols measured in the Flemish adolescents were generally in the same order of magnitude compared to recent studies worldwide. Multiple regression models were used to identify determinants of exposure based on information on demographic and lifestyle characteristics of participants, acquired through questionnaires. Some significant determinants could be identified: sex, season, smoking behavior, educational level of the parents, recent consumption of certain foods and use of certain products were found to be significantly associated with levels of bisphenols. Preliminary risk assessment showed that none of the estimated daily intakes (EDIs) of BPA exceeded the tolerable daily intake, even in a high exposure scenario. For alternative bisphenols, no health-based guidance values are available, but in line with the measured urinary levels, their EDIs were lower than that of BPA. This study is, to the best of our knowledge, the first to determine internal exposure levels of other bisphenols than BPA in a European adolescent population.

Background: In 2007, the second cycle of the Flemish human biomonitoring survey started, with a main focus on 14–15 year-old adolescents. Objectives: The main objectives were generating reference values for exposure markers, determining the pollution pressure in industrial hotspots and establishing dose–effect relationships between exposure to pollutants and hormone levels, sexual development, asthma and allergy, genotoxic and hematological markers. Methods: Geometric means with 95% confidence intervals (CI) were calculated for a reference population of 200 14–15 year-old adolescents. Stepwise multiple regression analyses with correction for confounders and covariates were performed to establish dose–effect relationships. Results: Geometric mean concentrations (with 95% CI) of 49.6 (45.7, 53.8), 70.8 (63.6, 78.8) and 8.34 (7.76, 8.97) ng g−1 lipid for the sum of PCB 138, 153 and 180, p,p′-DDE and HCB were respectively 23%, 26% and 60% lower than those obtained five years earlier. Geometric mean concentrations of 108 (101, 114) and 32.1 (30.1, 34.2) pg CALUX-BEQ g−1 lipid were observed for the PCDD/Fs and dioxin-like PCBs, respectively. Multiple dose–effect relationships were observed between POPs and several effect markers, including positive (boys) and negative (girls) associations with data on sexual development and positive associations with asthma, animal allergy and free thyroxine (boys and girls). Conclusions: Our findings suggest that chlorinated POP concentrations are decreasing over time and that even relatively low concentrations are associated with biological effects. Keywords: Chlorinated POPs, FLEHS II, Dose–effect, Hormones, Human biomonitoring, Sexual development

Research on the environment, health, and well-being nexus (EHWB) is shifting from a silo toward a systemic approach that includes the socio-economic context. To disentangle further the complex interplay between the socio-exposome and internal chemical exposure, we performed a meta-analysis of human biomonitoring (HBM) studies with internal exposure data on per-and polyfluoroalkyl substances (PFASs) and detailed information on risk factors, including descriptors of socio-economic status (SES) of the study population. PFASs are persistent in nature, and some have endocrine-disrupting properties. Individual studies have shown that HBM biomarker concentrations of PFASs generally increase with SES indicators, e.g., for income. Based on a meta-analysis (five studies) of the associations between PFASs and SES indicators, the magnitude of the association could be estimated. For the SES indicator income, changes in income were expressed by a factor change, which was corrected by the Gini coefficient to take into account the differences in income categories between studies, and the income range between countries. For the SES indicator education, we had to conclude that descriptors (&lt, college, x years of study, etc.) differed too widely between studies to perform a meta-analysis. Therefore, the use of the uniform ISCED (International Standard Classification of Education) is recommended in future studies. The meta-analysis showed that a higher income is associated with a higher internal exposure to PFASs (PFOS or perfluorooctanesulfonic acid, PFOA or perfluorooctanoic acid, PFNA or perfluorononanoic acid, PFHxS or perfluorohexane sulfonate). This is opposite to the environmental justice hypothesis, referring to an inequitable distribution of detrimental environmental effects toward poor and minority communities by a practice or policy. With a doubling of the income, internal exposure increased on average by 10%&ndash, 14%. Possible explanations for this difference are given, e.g., underlying differences in diet. However, other sources can also contribute, and the exact causes of SES-related differences in PFAS concentrations remain unclear. Studies are needed that include social descriptors together with lifestyle and dietary information as explanatory variables for internal chemical exposure levels. This will help clarify the underlying factors that link SES with inequity to environmental exposures, and will raise awareness and knowledge to strengthen the capacities of people and communities to advocate chemical exposure reduction in order to reduce this health inequity.

Within the Flemish Environment and Health stud- ies (FLEHS I, 2002-2006, and FLEHS II, 2007-2012), pes- ticide exposure, hormone levels and degree of sexual matura- tion were measured in 14-15-year-old adolescents residing in Flanders (Belgium). In FLEHS II, geometric mean concentra- tions (with 95 % confidence interval (CI)) of 307 (277-341) and 36.5 ng L �1 (34.0-39.2) were found for p,p'- dichlorophenyldichloroethylene (p,p'-DDE) and hexachlorobenzene (HCB). These values were respectively 26 and 60 % lower than levels in FLEHS I, 5 years earlier. Metabolites of organophosphorus pesticides (OPPs) and of para-dichlorobenzene were measured for the first time in FLEHS II, yielding concentrations of 11.4, 3.27 and 1.57 μ gL �1 for the sum of dimethyl- and diethyl phosphate metabolites and 2,5-dichlorophenol (2,5-DCP), respectively. Data on internal exposure of HCB showed a positive correla- tion with sexual maturation, testosterone and the aromatase index for boys and with free thyroxine (fT4) and thyroid stimulating hormone (TSH) (both boys and girls). For both p,p'-DDE and HCB, a negative association with sexual devel- opment in girls was found. The OPP metabolites were nega- tively associated with sex hormone levels in the blood of boys and with sexual maturation (both boys and girls). The pesti- cide metabolite 2,5-DCP was negatively correlated with free T4, while a positive association with TSH was reported (boys and girls). These results show that even exposure to relatively low concentrations of pesticides can have significant influ- ences on hormone levels and the degree of sexual maturation in 14-15-year-old adolescents.

As part of the second Flemish Environment and Health Study (FLEHS II), bisphenol-A (BPA) and different phthalate metabolites were analyzed, for the first time, in the urine of 210 adolescents in Flanders, Belgium. All chemicals had a detection frequency above 90%. For all compounds, except the sum of DEHP, highest levels were detected during spring. Average values for the Flemish adolescents were in an agreement with concentrations found in different international studies, all confirming the ubiquity of BPA and phthalate exposure. There was a significant correlation between BPA and the different phthalate metabolites (r between 0.26 and 039; p < 0.01). Shared sources of exposure to BPA and phthalates, such as food packaging, were suggested to be responsible for this positive correlation. Different determinants of exposure were evaluated in relation to the urinary concentrations of these chemicals. For BPA, a significant association was observed with household income class, smoking and exposure to environmental tobacco smoke. For phthalates, the following significant associations were observed: age (MBzP), educational level of the adolescent (MBzP), equivalent household income (MnBP), use of personal care products (MnBP and MBzP), wall paper in house (MnBP and MBzP) and use of local vegetables (MnBP and MBzP). (C) 2014 Elsevier Inc. All rights reserved.

Due to possible health risks, quantification of mercury accumulation in humans was included in the Flem-ish biomonitoring programmes FLEHS I (20022006) and FLEHS II (20072011). The general objectiveof FLEHS I was to assess regional exposure levels in order to link possible differences in these internalexposure levels to different types of local environmental pressure. Therefore, Hg and MMHg (methylmer-cury) were only measured in pooled blood samples per region and per age class. In FLEHS II, mercuryconcentrations were measured in hair of each participant. About 200 adolescents and 250 mothers (ref-erence group) and two times 200 adolescents (2 hotspots) were screened. The main objectives of theFLEHS II study were: (1) to determine reference levels of mercury in hair for Flanders; (2) to assess rela-tions between mercury exposure and possible sources like fish consumption; (3) to assess doseeffectrelations between mercury exposure and health effect markers. The results showed that mercury con-centrations in the Flemish population were rather low compared to other studies. Mercury levels in theFlemish populations were strongly related to the age of the participants and consumption of fish. Signif-icant negative associations were observed between mercury in hair and asthma, having received breastfeeding as a newborn, age at menarche in girls, allergy for animals and free testosterone levels. Significantcorrelations were also observed between mercury in hair and genes JAK2, ARID4A, Hist1HA4L (boys) andHLAdrb5, PIAS2, MANN1B1, GIT and ABCA1 (girls).

Personal care products (PCPs), such as soaps, perfumes, cosmetics, lotions, etc., contain a variety of chemicals that have been described as potentially hormone disrupting chemicals. Therefore, it is important to assess the internal exposure of these chemicals in humans. Within the 2nd Flemish Environment and Health Study (FLEHS II, 2007–2011), the human exposure to three classes of pollutants that are present in a wide variety of PCPs – i.e. polycyclic musks (galaxolide, HHCB and tonalide, AHTN in blood), parabens (urinary para -hydroxybenzoic acid, HBA) and triclosan (urinary TCS) – was assessed in 210 Flemish adolescents (14–15 years) and in 204 adults (20–40 years) randomly selected from the general population according to a stratified two stage clustered study design. The aim of this study was to define average levels of exposure in the general Flemish population and to identify determinants of exposure. Average levels (GM (95% CI)) in the Flemish adolescents were 0.717 (0.682–0.753) μg/L for blood HHCB; 0.118 (0.108–0.128) μg/L for blood AHTN; 1022 (723–1436) μg/L for urinary HBA and 2.19 (1.64–2.92) μg/L for urinary TCS. In the adults, levels of HBA were on average 634 (471–970) μg/L. Inter-individual variability was small for HHCB and AHTN, intermediate for HBA, and large for TCS. All biomarkers were positively associated with the use of PCPs. Additionally, levels of HHCB and AHTN increased with higher educational level of the adolescents. Both in adults and adolescents, urinary HBA levels were negatively correlated with BMI. We define here Flemish exposure values for biomarkers of PCPs, which can serve as baseline exposure levels to identify exposure trends in future biomonitoring campaigns.

The second Flemish human biomonitoring survey (2007–2011) generated information on the distribution of biomarker values for a large number of environmental pollutants in a representative sample of the Flemish population. The study was implemented by the Flemish Centre of Expertise for Environment and Health, which was funded and steered by the Flemish government. From May 2008 to July 2009, 255 newborns and their mothers, 210 adolescents (14–15 years old) and 204 adults (20–40 years old) were recruited as a representative sample of the Flemish population. In all age groups, invitation letters, information brochures, letter of informed consent and self-administered questionnaires were distributed. The collected samples consisted of cord blood from the newborns, blood from the mothers, the adolescents and the adults, urine from the adolescents and the adults, and hair from the mothers. In addition to historical compounds (i.e. heavy metals, persistent chlorinated compounds, 1-hydroxy pyrene and t,t-muconic acid), new emerging pollutants were analyzed for the first time in individual samples from the Flemish population. Perfluorinated compounds and polycyclic musk compounds could be detected in all analyzed blood samples. Levels of brominated flame retardants were under the limit of quantification in most individual blood samples. Bisphenol A, metabolites of phthalates and para-hydroxybenzoic acid, a metabolite of parabens, could be detected in 90% or more of the urine samples. For metabolites of organophosphate pesticides, the highest detection frequency was observed for DMTP, detected in 90–95% of the individual urine samples. In addition, 2,5-DCP, a metabolite of para-dichlorobenzene, could be detected in over 80% of the individual urine samples. Margins of safety (MOS) were calculated by dividing the P90 obtained in FLEHSII by the available health based biomonitoring equivalants (BEs). MOS below 10 were found for toxicologically relevant arsenic, cadmium, lead, MeHg, HCB and phthalates.