Time Patterns in Internal Human Exposure Data to Bisphenols, Phthalates, DINCH, Organophosphate Flame Retardants, Cadmium and Polyaromatic Hydrocarbons in Europe.

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.

Suspect and non-targeted screening-based human biomonitoring identified 74 biomarkers of exposure in urine of Slovenian children.

Human exposure to organic contaminants is widespread. Many of these contaminants show adverse health effects on human population. Human biomonitoring (HBM) follows the levels and the distribution of biomarkers of exposure (BoE), but it is usually done in a targeted manner. Suspect and non-targeted screening (SS/NTS) tend to find BoE in an agnostic way, without preselection of compounds, and include finding evidence of exposure to predicted, unpredicted known and unknown chemicals. This study describes the application of high-resolution mass spectrometry (HRMS)-based SS/NTS workflow for revealing organic contaminants in urine of a cohort of 200 children from Slovenia, aged 6-9 years. The children originated from two regions, urban and rural, and the latter were sampled in two time periods, summer and winter. We tentatively identified 74 BoE at the confidence levels of 2 and 3. These BoE belong to several classes of pharmaceuticals, personal care products, plasticizers and plastic related products, volatile organic compounds, nicotine, caffeine and pesticides. The risk of three pesticides, atrazine, amitraz and diazinon is of particular concern since their use was limited in the EU. Among BoE we tentatively identified compounds that have not yet been monitored in HBM schemes and demonstrate limited exposure data, such as bisphenol G, polyethylene glycols and their ethers. Furthermore, 7 compounds with unknown use and sources of exposure were tentatively identified, either indicating the entry of new chemicals into the market, or their metabolites and transformation products. Interestingly, several BoE showed location and time dependency. Globally, this study presents high-throughput approach to SS/NTS for HBM. The results shed a light on the exposure of Slovenian children and raise questions on potential adverse health effects of such mixtures on this vulnerable population.

Glyphosate and AMPA in Human Urine of HBM4EU Aligned Studies: Part A Children.

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.

Polycyclic aromatic hydrocarbons (PAHs) in men and lactating women in Slovenia: Results of the first national human biomonitoring.

In the first national human biomonitoring study in the Slovenian population of adults (18-49 years), including men (n = 297) and lactating primiparous women (n = 304), exposure to polycyclic aromatic hydrocarbons (PAHs) was evaluated. Nine urinary metabolites of four parent PAHs were determined. These included 1-hydroxypyrene (1-OHPYR), 2-hydroxynaphthalene (2-OHNAP), 2-hydroxyphenanthrene (2-OHPHE), 3-hydroxyphenanthrene (3-OHPHE), 4-hydroxyphenanthrene (4-OHPHE), a combination of 2-hydroxyfluorene and 3-hydroxyfluorene (2/3-OHFLU) and a combination of 1-hydroxyphenanthrene and 9-hydroxyphenanthrene (1/9-OHPHE). For comparison, the analysed phenanthrene metabolites were reported as a sum (ΣOHPHE = 1/9-OHPHE + 2-OHPHE + 3-OHPHE + 4-OHPHE) and all the analysed PAH metabolites were reported as a sum (ΣOHPAH = 1-OHPYR + 2/3-OHFLU + 2-OHNAP + ΣOHPHE). All metabolites or their combinations were determined in more than 91% of the samples, except 4-OHPHE, which was determined in only 5% of the samples. The highest concentration was found for 2-OHNAP. This was followed by 2/3-OHFLU and the phenanthrene metabolites, while the lowest concentration was determined for 1-OHPYR. Among the phenanthrene metabolites, the highest concentration was determined for 2-OHPHE, followed by 1/9-OHPHE and then by 3-OHPHE. Values in units of volume and values adjusted for specific gravity were significantly higher in men than in lactating primiparous women for all metabolites, whereas values in units adjusted for creatinine were generally higher in lactating primiparous women than in men. The difference between the two study groups, men and lactating primiparous women, was no longer significant in statistical models adjusted for specific gravity, suggesting that smoking, wood-burning exposure, and/or education largely explained the difference in PAH exposure in both study groups. For most metabolites, predictors of exposure were less significant in lactating primiparous women than in men. Also, site-specific patterns of exposure were observed, with additional predictors identified in certain areas, namely, proximity to roads and release of particulate matter (PM10) from industry. The time of year in which sampling took place appeared to be an important determinant in urban areas and in the case of participants who used wood for heating. Specific dietary factors could not be identified, as the study questionnaire did not include information on PAH-related diet. Despite the low number of paired partners (women and men living in the same household, n = 84), significant positive correlations for all metabolites were observed. This indicated that 31%-56% of variability in exposure could be explained by shared exposure to sources within the households (such as diet and wood-burning-related determinants).

Arsenic, cadmium, lead and mercury levels in blood of Finnish adults and their relation to diet, lifestyle habits and sociodemographic variables.

The Northern Finland Birth Cohort program (NFBC) is the epidemiological and longitudinal prospective general population research program, which was established to promote health and wellbeing of the population in northern Finland. The aim of present study, as a part of the NFBC program, was to analyze the blood levels of arsenic (B-As), cadmium (B-Cd), lead (B-Pb), total mercury (B-Hg) and selenium (B-Se); to compare these levels with threshold limits; to study sociodemographic factors; and to correlate these levels with calcium and haemoglobin. The study was comprised of 249 NFBC subjects, of which 123 were female and 126 were male (ages 31.1 ± 0.3 and 31.1 ± 0.4, respectively). All participants were asked to complete a questionnaire regarding diet and living habits. The geometric means (± SD) of B-As were 0.49 ± 2.80 µg/l and 0.44 ± 2.72 µg/l; B-Cd were 0.18 ± 4.02 µg/l and 0.12 ± 3.21 µg/l; B-Pb were 17.0 ± 1.8 µg/l and 9.06 ± 2.20 µg/l; B-Hg were 2.18 ± 2.02 µg/l and 1.85 ± 1.78 µg/l; and B-Se were 106.0 ± 1.3 and 94.3 ± 1.3 µg/l in males and females, respectively. Among the subjects in the present analysis, 23 % of males and 17.1 % of females had B-As levels above the ATSDR normal human levels of B-As in unexposed individuals (1.0 µg/l). The B-Pb geometric mean (12.44 µg/l) was approximately one eighth the CDC toxicological cut-off point of 100 µg/l. Twenty-one individuals (8.4 %) exceeded a B-Hg level of 5.8 µg/l. Fifty-eight females (47 %) had a B-Hg higher than 2.0 µg/l, the German Federal Environmental Agency cut-off point for women (18-69 years) who consume fish at least three times/month; therefore, their babies could be at risk of adverse effects during development.

Low cadmium exposure in males and lactating females-estimation of biomarkers.

BACKGROUND: Urine cadmium (Cd) and renal function biomarkers, mostly analysed in urine spot samples, are well established biomarkers of occupational exposure. Their use and associations at low environmental level are common, but have recently been questioned, particularly in terms of physiological variability and normalisation bias in the case of urine spot samples. AIM: To determine the appropriateness of spot urine and/or blood Cd exposure biomarkers and their relationships with renal function biomarkers at low levels of exposure. To this end, we used data from Slovenian human biomonitoring program involving 1081 Slovenians (548 males, mean age 31 years; 533 lactating females, mean age 29 years; 2007-2015) who have not been exposed to Cd occupationally. RESULTS: Geometric means (GMs) of Cd in blood and spot urine samples were 0.27ng/mL (0.28 for males and 0.33 for females) and 0.19ng/mL (0.21 for males and 0.17 for females), respectively. Differing results were obtained when contrasting normalisation by urine creatinine with specific gravity. GMs of urine albumin (Alb), alpha-1-microglobulin (A1M), N-acetyl-beta-glucosaminidase (NAG), and immunoglobulin G (IgG) were far below their upper reference limits. Statistical analysis of unnormalised or normalised urine data often yielded inconsistent and conflicting results (or trends), so association analyses with unnormalised data were taken as more valid. Relatively weak positive associations were observed between urine Cd (ng/mL) and blood Cd (ß=0.11, p=0.002 for males and ß=0.33, p<0.001 for females) and for females between urine NAG and blood Cd (ß=0.14, p=0.04). No associations were found between other renal function biomarkers and blood Cd. Associations between Cd and renal function biomarkers in urine were stronger (p<0.05, ß=0.11-0.63). Mostly, all of the associations stayed significant but weakened after normalisation for diuresis. In the case of A1M, its associations with Cd were influenced by current smoking and blood Pb in males and by pre-pregnancy smoking and blood Se in females (ß up to 0.34, p<0.001). Statistical analysis of unnormalised or normalised urine data often yielded inconsistent and conflicting results (or trends), so association analyses data with unnormalised were taken as more valid. CONCLUSIONS: The observed uncertainties introduced by urine normalisation, particularly by creatinine, confirm blood Cd as a superior low-Cd exposure biomarker versus urine Cd in cases when 24h urine is unattainable. Evidence that A1M can be positively related to Cd, smoking (current or pre-pregnancy), Pb, and Se status, points to the versatile biological functions of A1M.

Exposure determinants of cadmium in European mothers and their children.

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.

Urinary BPA measurements in children and mothers from six European member states: Overall results and determinants of exposure.

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.

Cadmium, mercury and lead in the blood of urban women in Croatia, the Czech Republic, Poland, Slovakia, Slovenia, Sweden, China, Ecuador and Morocco.

OBJECTIVES: The aim of the study was to make an international comparison of blood levels of cadmium (B-Cd), lead (B-Pb) and mercury (B-Hg) of women in seven European, and three non-European cities, and to identify determinants. MATERIALS AND METHODS: About 50 women (age: 46-62) from each city were recruited (totally 480) in 2006-2009. Interview and questionnaire data were obtained. Blood samples were analysed in one laboratory to avoid interlaboratory variation. RESULTS: Between the European cities, the B-Pb and B-Cd results vary little (range of geometric means: 13.5-27.0 µg/l and 0.25-0.65 µg/l, respectively); the variation of B-Hg was larger (0.40-1.38 µg/l). Between the non-European cities the results for B-Pb, B-Cd and B-Hg were 19.2-68.0, 0.39-0.99 and 1.01-2.73 µg/l, respectively. Smoking was a statistically significant determinant for B-Cd, while fish and shellfish intakes contributed to B-Hg and B-Pb, amalgam fillings also contributed to B-Hg. CONCLUSIONS: The present results confirm the previous results from children; the exposure to lead and cadmium varies only little between different European cities suggesting that other factors than the living area are more important. The study also confirms the previous findings of higher cadmium and lead levels in some non-European cities. The geographical variation for mercury is significant.