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publicado em: Environ Health Perspect. 2021;1. https://ehp.niehs.nih.gov/doi/abs/10.1289/isee.2021.P-481 BACKGROUND AND AIM:The development of Human Biomonitoring (HBM) surveys is highly dependent on the cooperation and engagement of the individuals being sampled. As such, in the context of the European Human Biomonitoring Initiative (HBM4EU) an online citizen survey was conducted in Europe to gain insights into the perceptions of the population about HBM and exposure to chemicals. METHODS:The survey was undertaken between September 2020 and February 2021 and was available in the languages of all 30 HBM4EU-participating countries (EU, associated countries, Israel) through the HBM4EU website. Dissemination was done by the HBM4EU country representatives (National Hub Contact Points). RESULTS:Responses were received from 5391 participants. Around half were 35-54 years old and the majority were female, with higher education and employed. Concerning the perception of the respondents on HBM, the majority considers it should be done (81.7%), even if the chemicals are considered well managed. Most participants consider it a reliable method (84.0%) that should be performed more often (87.3%) and be more coordinated either at a European (86.2%) or at a national level (83.7%). The large majority of the respondents thinks that HBM results are important to evaluate the chemical exposure of the population (96.2%), to study the health impact of chemical exposure (96.3%) and to support the development of health policies (94.9%). The respondents also consider HBM results highly relevant to raise awareness and promote understanding of the impact of chemical exposure amongst the general population (94.3%), health professionals and policy makers. CONCLUSIONS:The use of HBM as a tool to assess human exposure to chemicals, allowing its management and health protection, was well perceived by respondents across Europe. Furthermore, the need for more studies conducted in a coordinated way was indicated. Future work should comprise population groups less represented here and should also attempt to understand how perceptions change over time. HBM4EU is funded by the European Union’s Horizon 2020 research and innovation programme under grant agreement Nº 733032 info:eu-repo/semantics/publishedVersion

The aim of this additional deliverable is to analyse the result of the interaction and surveys with the Environment Protection Agency network and the National Reference Centre on Environment & Health. The consultation to both the EPA network and the NRCs was done through a similar targeted survey, with the aim of understanding their perception of the current HBM4EU and their ideas for a future Human Biomonitoring initiative. The online survey also explored if and how their institution would use HBM4EU results in their work and it also explored the focus that their institution considered a future initiative might take. This could be in terms of exploring exposure to new emerging risks or understanding exposure to known chemical risks, such as heavy metals. In addition, it explored interest in participating in a new initiative and openness towards sharing of best practice. This included questions regarding the possible role that the EPAs and NRCs might play in such an initiative. The invitation was sent out to 29 EPA countries and 15 NRCs, from which 19 answers were obtained in total with 4 EPAs answered and 13 NRCs. One of the EPAs is also a HBM4EU partner, whereas from the 15 NRCs, 13 of those provided their countries/institution from which 7 are HBM4EU partners. The survey produced quite interesting results, where it was pointed out that HBM is the only instrument that can assess human exposure in an integrated and reliable way. From the institutions that are not part of HBM4EU, most of them were aware of the project. The ones that were already part of it would like to carry on as such if a future initiative is to take place. Despite the fact that a slightly higher percentage of institutions do not use HBM at the moment in their work (53 % vs 47 %), all of the institutions recognised the value of HBM and plan on using it in the future. All the NRCs and 75 % of the EPAs are interested in being part of a future initiative with a possible role in: positioning Human Biomonitoring in the strategic agenda of implementation of environmental policy and state of the environment in Europe, supporting the activities of the HBM initiative through an existing interest group under the NRC Network, creating joint working initiatives with other relevant networks. It was clear from the answers given that HBM has triggered an interest and there is a willingness to be part of the future initiative. HORIZON2020 Programme - Contract No. 733032 HBM4EU info:eu-repo/semantics/publishedVersion

Since 2002, the Flemish Government decided to carry out the Flemish Environment and Health Survey (FLEHS), an extended human biomonitoring (HBM) program, which is integrated in the environmental health policy. Through the FLEHS studies, a vast amount of data such as biomarkers of exposure and effect, exposure effect associations, time trends and geographical differences, became available to the Flemish policy makers. In order to facilitate the policy interpretation, a phased action-plan was developed collaboratively by FLEHS researchers and policy makers. In this article we look back on more than 15 years of investments of the Flemish government in HBM and reflect on how this large scaled and challenging HBM-initiative contributed to shaping the environmental health policy in Flanders. We used the FLEHS I (2002-2006) and II (2007-2011) results on persistent organic pollutants (POPs) and the resulting policy actions as an example to illustrate the added value of HBM for policy making. Policy measures for POPs, including source-related regulation (e.g. further optimization and tightening of existing Flemish legislation on open fires), investment in monitoring networks and communication and awareness campaigns, are presented and the added value for environmental health policy is discussed. We also reflect on how HBM can support science and innovation in the environmental monitoring context. Finally, we describe what society can gain from HBM in terms of opportunities for (1) feeding the political and societal debate, (2) stimulating community involvement and (3) empowering participants and citizens. All together, the gained insights and phased action plan showed that next to compliance with high scientific standards, results of the Flemish human biomonitoring campaign could be translated in targeted policy actions even for chemicals that have since long been regulated. (C) 2016 Elsevier GmbH. All rights reserved.

Background: Due to their lack of repair capacity mitochondria are critical targets for environmental toxicants. We studied genes and pathways reflecting mitochondrial responses to short-and medium-term PM10 exposure. Methods: Whole genome gene expression was measured in peripheral blood of 98 adults (49% women). We performed linear regression analyses stratified by sex and adjusted for individual and temporal characteristics to investigate alterations in gene expression induced by short-term (week before blood sampling) and medium-term (month before blood sampling) PM10 exposure. Overrepresentation analyses (ConsensusPathDB) were performed to identify enriched mitochondrial associated pathways and gene ontology sets. Thirteen Human MitoCarta genes were measured by means of quantitative real-time polymerase chain reaction (qPCR) along with mitochondrial DNA (mtDNA) content in an independent validation cohort (n = 169, 55.6% women). Results: Overrepresentation analyses revealed significant pathways (p-value

Background: Particulate matter (PM) exposure leads to premature death, mainly due to respiratory and cardiovascular diseases. Objectives: Identification of transcriptomic biomarkers of air pollution exposure and effect in a healthy adult population. Methods: Microarray analyses were performed in 98 healthy volunteers (48 men, 50 women). The expression of eight sex-specific candidate biomarker genes (significantly associated with PM10 in the discovery cohort and with a reported link to air pollution-related disease) was measured with qPCR in an independent validation cohort (75 men, 94 women). Pathway analysis was performed using Gene Set Enrichment Analysis. Average daily PM2.5 and PM10 exposures over 2-years were estimated for each participant’s residential address using spatiotemporal interpolation in combination with a dispersion model. Results: Average long-term PM10 was 25.9 (± 5.4) and 23.7 (± 2.3) μg/m3 in the discovery and validation cohorts, respectively. In discovery analysis, associations between PM10 and the expression of individual genes differed by sex. In the validation cohort, long-term PM10 was associated with the expression of DNAJB5 and EAPP in men and ARHGAP4 (p = 0.053) in women. AKAP6 and LIMK1 were significantly associated with PM10 in women, although associations differed in direction between the discovery and validation cohorts. Expression of the eight candidate genes in the discovery cohort differentiated between validation cohort participants with high versus low PM10 exposure (area under the receiver operating curve = 0.92; 95% CI: 0.85, 1.00; p = 0.0002 in men, 0.86; 95% CI: 0.76, 0.96; p = 0.004 in women). Conclusions: Expression of the sex-specific candidate genes identified in the discovery population predicted PM10 exposure in an independent cohort of adults from the same area. Confirmation in other populations may further support this as a new approach for exposure assessment, and may contribute to the discovery of molecular mechanisms for PM-induced health effects. Citation: Vrijens K, Winckelmans E, Tsamou M, Baeyens W, De Boever P, Jennen D, de Kok TM, Den Hond E, Lefebvre W, Plusquin M, Reynders H, Schoeters G, Van Larebeke N, Vanpoucke C, Kleinjans J, Nawrot TS. 2017. Sex-specific associations between particulate matter exposure and gene expression in independent discovery and validation cohorts of middle-aged men and women. Environ Health Perspect 125:660–669; http://dx.doi.org/10.1289/EHP370

A repeated measures microarray design with 22 healthy, non-smoking volunteers (aging 32+5years) was set up to study transcriptome profiles in Whole blood samples. The result indicate that repeatable data can be obtained with high within-subject correlation. Probes that could discriminate between individuals are Associated with immune and inflammatory funktions. When investigating possible time trends in the microarray data, we have found no differential expression within a sampling period (within-season effect). Differential expression was observed between sampling seasons and the data suggest a weak response of genes related to immune system functioning. Finally, a high number of probes showed significant season-specific expression variability within subjects. Expression variability increased in springtime and there was association of the probe list with immune system functioning. Our study suggests that the blood transcriptome of healthy individuals is reproducible over a time period of several months. A repeated measures microarray design with 22 healthy, non-smoking volunteers (aging 32±5years) was set up to study transcriptome profiles in whole blood samples. The results indicate that repeatable data can be obtained with high within-subject correlation. Probes that could discriminate between individuals are associated with immune and inflammatory functions. When investigating possible time trends in the microarray data, we have found no differential expression within a sampling period (within-season effect). Differential expression was observed between sampling seasons and the data suggest a weak response of genes related to immune system functioning. Finally, a high number of probes showed significant season-specific expression variability within subjects. Expression variability increased in springtime and there was an association of the probe list with immune system functioning. Our study suggests that the blood transcriptome of healthy individuals is reproducible over a time period of several months.

We assessed the exposure of the Flemish population to brominated flame retardants (BFRs) and perfluorinated compounds (PFCs) by analysis of pooled cord blood, adolescent and adult serum, and human milk. Levels of polybrominated diphenyl ethers (PBDEs) in blood (range 1.66.5 ng/g lipid weight, lw) and milk (range 2.06.4 ng/g lw) agreed with European data. Hexabromocyclododecane ranged between

Human exposure to brominated flame retardants (BFRs) varies widely throughout the world as it depends on country-related usage, production and legislation of these chemicals. US and UK exposure assessments show very diverse levels and patterns which in turn, are likely to differ from those in background exposed countries such as Belgium, where levels tend to be about an order of magnitude lower. The current study assessed human exposure to BFRs through the indoor and outdoor environment (e.g. dust, soil, and air) and food for all age groups in Flanders, Belgium. Most relevant food groups were identified based on a national food consumption survey and food items with Flemish origin were collected. Dust samples were collected using a standardized protocol in 43 homes and 10 offices throughout Flanders. Food, human milk and dust samples were analysed for their polybrominated diphenylethers (PBDE) and hexabromocyclodecane (HBCD) content using GC/MS and LC/MS-MS. An exposure model was developed including all analysed data, complemented with literature data. The model covered human exposure of infants, children and adults through human milk, food, dust/soil ingestion and air inhalation. Total human exposure was compared to the existing toxicological criteria and previous exposure estimates. In general, the exposure levels through human milk are consistent with those of a background exposed European population, whereas dust and food intake are at the low end of what has been reported in previous European intake assessments. Total average intake of ΣHBCD and ΣBDE5 at 50th percentile (P50) levels by newborns equals 3.1 and 12.0 ng/kg body weight (bw) day, respectively. This intake increases to 15.2 and 20.9 ng/kg bw day for ΣHBCD and ΣBDE5, for higher exposed newborns (95th percentile=P95 levels). Due to the limited database on health-based limit values for PBDEs and HBCD, it is difficult to assess the immediate health concern for any of the age groups, although the higher intake of newborns indicates the need for ongoing monitoring. For median exposed individuals, the average ΣHBCD intake peaked at the age 3 to 6 years with an intake of 6.59 ng/kg bw day and declines to ∼1 ng/kg bw day at later age. ΣBDE5 intake exhibited a different profile compared to ΣHBCD with maximal levels for newborns and a decline to ∼0.7 ng/kg bw day at adulthood. Keywords: Flanders, PBDEs, HBCD, Human intake, Food, Dust, Risk assessment

With the objective to evaluate exposure of the population in Flanders (Belgium) to perfluorinated compounds (PFCs), we measured perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) in settled dust in homes and offices, in a selection of food items from local origin, in drinking-water and in human serum. We complemented the data with results from a literature survey. Based on this dataset we calculated intake by children and adults from food, drinking-water, settled dust and soil, and air. Dietary exposure dominated overall intake. For adults, average dietary intake equalled 24.2 (P95 40.9) ng PFOS kg−1 d−1 and 6.1 (P95 9.6) ng PFOA kg−1 d−1, whereas for children the dietary intake was about 3 times higher. Predicted intake is high when compared to assessments in other countries, and to serum levels from Flanders, but comparable to the intakes published by The European Food Safety Authority (EFSA) in 2008. Intake of PFOS and PFOA remained below the Tolerable Daily Intake.

The increasing time spent indoors combined with the abundant usage of diverse indoor chemicals led to concerns involving the impact of these compounds on human health. The current study focused on two groups of important indoor contaminants i.e. Brominated flame retardants (BFRs) and Perfluorinated compounds (PFCs). Concentrations of both compound classes have been measured in Flemish indoor dust samples from homes and offices. Sigma Polybrominated diphenyl ethers (PBDEs) (BDE 47, 99, 100, 154, 153, 197, 196 and 203) and BDE 209 in homes ranged between 4-1214 ng g(-1) dw (median 35) and

At four different aquatic sites in Flanders (Belgium) with different types and degrees of contamination, juvenile carp (Cyprinus carpio) were exposed in cages for 4 weeks. After exposure, metals, polychlorinated biphenyls (PCBs), and selected organochlorine pesticides (OCPs) were analyzed in the tissues of the carp. Besides pollutant accumulation, several effects were measured as well. Condition measures such as changes in weight, condition factor (CF), and hepatosomatic index (HSI) were assessed. In addition, activity of acetylcholinesterase (AChE) and a set of blood biochemical parameters were measured. At all sites, accumulation of metals in the fish tissues was observed. Levels of cadmium and lead at some of the exposure sites were higher than the levels at the start and comparable to levels in fish from moderately metal-contaminated sites. For most organic pollutants, however, levels were not significantly higher than at the start. Only for two PCB congeners, levels had slightly increased but were still lower than levels in carp captured at noncontaminated sites. Although food limitation probably caused some of the observed effects, significant relationships were found between metal load in tissues and CF, AChE, plasma osmolality and HSI. This study shows that caged carp might be useful for the assessment of bioaccumulation and some effects of micropollutants in aquatic ecosystems.

Metal accumulation and effects on plasma Ca(2+), alanine transaminase (ALT) and fish condition factor were examined in caged carp (Cyprinus carpio) and resident roach (Rutilus rutilus) at four locations along the Grote Nete River system (Belgium). Cadmium and zinc accumulation were found in carp and roach, with highest concentrations at the most contaminated site (dissolved Cd: 1.82 microg/l, Zn: 967 microg/l). On the tissue level, highest cadmium concentrations were measured in kidneys of carp and roach, followed by gills, intestine and liver, while low concentrations were observed in carcass and muscle. For zinc, a similar pattern was observed (intestine>kidney>gills>liver>carcass>muscle). Comparison between species showed higher cadmium concentrations in feral roach, while zinc levels were lower, owing to the high zinc concentrations in control carp. Furthermore, comparison of metal concentrations between two sampling periods (2005 and 2000-2001) revealed a drastic decrease in cadmium concentration in gills, liver and muscle of roach, similar to the reduction in waterborne cadmium concentrations, while differences for zinc were much less pronounced. In addition to metal accumulation, increased metallothionein concentrations (approximately 2x) were found in carp and roach, while no metal-related effects were found on ALT, Ca(2+)or condition factor. However, negative effects on fish community structure, as assessed by the index of biotic integrity (IBI), were found along the pollution gradient and indicated long-term adverse effects of metal pollution.

Gudgeons (Gobio gobio) from historically Cd and Zn contaminated sites in Flanders (Belgium) were found to be resistant to elevated Cd levels. In previous work, this increased resistance was largely explained by increased metallothionein (MT) expression. Recently, environmental cleanup efforts resulted in a significant decrease in Cd concentrations in the surface water. In this study, we evaluated the use of hepatic metal and metallothionein (MT) concentrations as biomarkers of metal exposure before and after the cleanup. Hepatic MT mRNA levels were determined after the environmental metal levels decreased in order to assess the applicability of MT gene expression as an environmental biomarker in natural fish populations. Our data show that both metallothionein protein and gene expression have the potential to be sensitive biomarkers for metal exposure. Significant correlations were found (a) among accumulated metal concentrations and both MT protein and mRNA levels, and (b) between MT protein and mRNA levels. However, our data illustrated that while MT protein and gene expression give a quantitative picture of metal load at a single time point, quantitative information in natural populations cannot always be obtained when different time points (including different years) are compared, since MT gene and protein expression are affected by many other factors in addition to the metal load. Furthermore, the result of the environmental cleanup was reflected in a decrease of hepatic Cd concentrations. Zn remained the most important factor determining MT concentrations. Finally, two differently sized MT mRNAs were amplified to test the hypothesis that 3'-UTR length can offer a protective advantage in conditions of environmental stress. Our data provided no evidence to support this hypothesis. In contrast, the ratio of the long mRNA variant relative to total MT mRNA was surprisingly constant, and independent of exposure history.

Gene expression changes in carp liver tissue were studied after acute (3 and 24h) and subchronic (7 and 28 days) exposure to a mixture of waterborne (9, 105 and 480 microg/l) and dietary (9.5, 122 and 144 microg/g) cadmium, using a custom-made microarray. Suppression subtractive hybridization-PCR (SSH-PCR) was applied to isolate a set of 643 liver genes, involved in multiple biological pathways, such as energy metabolism (e.g. glucokinase), immune response (e.g. complement C3) and stress and detoxification (e.g. cytochrome P450 2F2, glutathione-S-transferase pi). These genes were subsequently spotted on glass-slides for the construction of a custom-made microarray. Resulting microarray hybridizations indicated a highly dynamic response to cadmium exposure. At low exposure concentrations (9 microg/l through water and 9.5 microg/g dry weight through food) mostly energy-related genes (e.g. glucokinase, elastase) were influenced, while a general stress response was obvious through induction of several stress-related genes, including hemopexin and cytochrome P450 2F2, at high cadmium concentrations. In addition, fish exposed to the highest cadmium concentrations showed liver damage after 7 days of exposure, as measured by elevated alanine transaminase activity in plasma and increased liver water content (wet-to-dry weight ratio). Moreover, decreased hematocrit and growth were found at the end of the experiment. Altogether this study clearly demonstrated the importance of varying exposure conditions for the characterization of the molecular impact of cadmium and showed that microarray results can provide important information, required to unravel the molecular events and responses related to cadmium exposure.

In this study, the influence of exposure time and concentration on the accumulation of cadmium and the occurrence of adverse effects was investigated when carp were simultaneously exposed through contaminated water and food. As exposure concentrations increased (9, 105, and 480 microg/L through water and 9.5, 122, and 141 microg/g dry weight through food) the accumulation pattern of cadmium changed, with progressively more cadmium being accumulated in the liver and especially the kidney and less in the gills and the intestine. A strong concentration- and time-dependent effect of cadmium exposure on plasma calcium concentrations was observed, leading to a decrease, with approximately 16% in the mid group and up to 50% in the group exposed to the highest cadmium concentration. Also at the highest exposure concentrations, sodium and chloride levels as well as plasma osmolality were significantly reduced, indicating a disturbed ion homeostasis. Furthermore, an increase in plasma alanine transaminase activity indicated liver damage caused by the cadmium accumulation in this organ. At the end of the experiment, general stress responses such as decreased hematocrit, growth, and mortality (17%) also were observed. All together, these results suggest that plasma hypocalcemia as an ion-disruptive phenomenon is the most sensitive effect during cadmium exposure, although the occurrence and magnitude both depend on exposure time and concentration.