Human biomonitoring (HBM) data in Europe are often fragmented and collected in different EU countries and sampling periods. Exposure levels for children and adult women in Europe were evaluated over time. For the period 2000-2010, literature and aggregated data were collected in a harmonized way across studies. Between 2011-2012, biobanked samples from the DEMOCOPHES project were used. For 2014-2021, HBM data were generated within the HBM4EU Aligned Studies. Time patterns on internal exposure were evaluated visually and statistically using the 50th and 90th percentiles (P50/P90) for phthalates/DINCH and organophosphorus flame retardants (OPFRs) in children (5-12 years), and cadmium, bisphenols and polycyclic aromatic hydrocarbons (PAHs) in women (24-52 years). Restricted phthalate metabolites show decreasing patterns for children. Phthalate substitute, DINCH, shows a non-significant increasing pattern. For OPFRs, no trends were statistically significant. For women, BPA shows a clear decreasing pattern, while substitutes BPF and BPS show an increasing pattern coinciding with the BPA restrictions introduced. No clear patterns are observed for PAHs or cadmium. Although the causal relations were not studied as such, exposure levels to chemicals restricted at EU level visually decreased, while the levels for some of their substitutes increased. The results support policy efficacy monitoring and the policy-supportive role played by HBM.

• Klíčová slova
• DINCH, OPFRs, PAHs, bisphenols, cadmium, hazardous chemical, human biomonitoring, phthalates,
• Publikační typ
• časopisecké články MeSH

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.

• Klíčová slova
• HBM4EU, exposure, human biomonitoring, phthalates, pollutants,
• Publikační typ
• časopisecké články MeSH

BACKGROUND: Many phthalates are environmental pollutants and toxic to humans. Following phthalate regulations, human exposure to phthalates has globally decreased with time in European countries, the US and Korea. Conversely, exposure to their substitutes DEHT and/or DINCH has increased. In other countries, including China, little is known on the time-trends in human exposure to these plasticizers. OBJECTIVE: We aimed to estimate time-trends in the urinary concentrations of phthalates, DEHT, and DINCH metabolites, in general population from non-European countries, in the last decade. METHODS: We compiled human biomonitoring (HBM) data from 123 studies worldwide in a database termed "PhthaLit". We analyzed time-trends in the urinary concentrations of the excreted metabolites of various phthalates as well as DEHT and DINCH per metabolite, age group, and country/region, in 2009-2019. Additionally, we compared urinary metabolites levels between continents. RESULTS: We found solid time-trends in adults and/or children from the US, Canada, China and Taiwan. DEHP metabolites decreased in the US and Canada. Conversely in Asia, 5oxo- and 5OH-MEHP (DEHP metabolites) increased in Chinese children. For low-weight phthalates, the trends showed a mixed picture between metabolites and countries. Notably, MnBP (a DnBP metabolite) increased in China. The phthalate substitutes DEHT and DINCH markedly increased in the US. SIGNIFICANCE: We addressed the major question of time-trends in human exposure to phthalates and their substitutes and compared the results in different countries worldwide. IMPACT: Phthalates account for more than 50% of the plasticizer world market. Because of their toxicity, some phthalates have been regulated. In turn, the consumption of non-phthalate substitutes, such as DEHT and DINCH, is growing. Currently, phthalates and their substitutes show high detection percentages in human urine. Concerning time-trends, several studies, mainly in Europe, show a global decrease in phthalate exposure, and an increase in the exposure to phthalate substitutes in the last decade. In this study, we address the important question of time-trends in human exposure to phthalates and their substitutes and compare the results in different countries worldwide.

• Klíčová slova
• Asia, Human biomonitoring, North America., Phthalate plasticizers, Phthalate substitutes, Time-trends,
• MeSH
• diethylhexylftalát * MeSH
• dítě MeSH
• dospělí MeSH
• kyseliny ftalové * moč   MeSH
• látky znečišťující životní prostředí * moč   MeSH
• lidé MeSH
• vystavení vlivu životního prostředí analýza   MeSH
• zvláčňovadla analýza   metabolismus   MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Severní Amerika MeSH
• Názvy látek
• diethylhexylftalát * MeSH
• kyseliny ftalové * MeSH
• látky znečišťující životní prostředí * MeSH
• phthalic acid MeSH Prohlížeč
• zvláčňovadla MeSH

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.

• Klíčová slova
• DINCH, HBM4EU, Human biomonitoring (HBM), Phthalates, Science-policy uptake, indicator,
• MeSH
• biologický monitoring MeSH
• dítě MeSH
• kyseliny ftalové * MeSH
• kyseliny karboxylové MeSH
• lidé MeSH
• mladiství MeSH
• postup MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• kyseliny ftalové * MeSH
• kyseliny karboxylové MeSH
• phthalic acid MeSH Prohlížeč

A quality assurance/quality control program was implemented in the framework of the EU project HBM4EU to assess and improve the comparability of biomarker analysis and to build a network of competent laboratories. Four rounds of proficiency tests were organized for 15 phthalate and two DINCH urinary biomarkers (0.2-138 ng/mL) over a period of 18 months, with the involvement of 28 laboratories. A substantial improvement in performance was observed after the first round in particular, and by the end of the program, an average satisfactory performance rate of 90% was achieved. The interlaboratory reproducibility as derived from the participants' results varied for the various biomarkers and rounds, with an average of 24% for the biomarkers of eight single-isomer phthalates (e.g., DnBP and DEHP) and 43% for the more challenging biomarkers of the mixed-isomer phthalates (DiNP, DiDP) and DINCH. When the reproducibility was based only on the laboratories that consistently achieved a satisfactory performance, this improved to 17% and 26%, respectively, clearly demonstrating the success of the QA/QC efforts. The program thus aided in building capacity and the establishment of a network of competent laboratories able to generate comparable and accurate HBM data for phthalate and DINCH biomarkers in 14 EU countries. In addition, global comparability was ensured by including external expert laboratories.

• Klíčová slova
• HBM4EU, QA/QC, external quality assurance scheme (EQUAS), human biomonitoring (HBM), interlaboratory comparison investigation (ICI), proficiency testing,
• Publikační typ
• časopisecké články MeSH