So far there is no reference value for lead (Pb) established for the not occupationally exposed Ghanaian population. This is of special interest and will enable interpretation of data from high-risk areas like the Agbogbloshie e-waste dumpsite. The study suggests preliminary reference values for populations in Southern and Western Ghana. Blood specimens from non-exposed population were obtained in three key regions (Ashanti-Offinso, Western-Eikwe and Greater Accra-Accra). Three age groups were evaluated (15–24, 25–34, > 34 years). Individual habits (nutrition, occupation etc.) were documented using a standardized questionnaire. Graphite furnace atomic absorption spectrometry was used for Pb analysis. There was a total of 292 participants (Offinso = 124, Eikwe = 130, Accra = 38). The total mean Pb blood concentration of the Southern Ghanaian population was 43.3 µg/l ± 17.7, with a mean of 48.3 µg/l ± 17.2 for men and a mean of 38.1 µg/l ± 16.8 for women (P = .2.93–10). This value is twice as high as the mean Pb level among Germans, and higher than in most European countries. The 95th percentile for the total collective in Ghana was 81 µg/l and 76 µg/l for men and women, respectively. Based on the 95th percentile of the non-exposed population > 25 years data suggest a preliminary reference value for Pb in Ghana of 81 µg/l for men and of 76 µg/l for women. Since environmental load decreases with increasing distance when unleaded fuel became standard this should be re-evaluated in about 10 years. Future studies should include the eastern and northern regions of Ghana and the analysis of soil for its Pb content as environmental factor.

Puberty relies on a hormone-regulated cascade of events initiated in fetal life and might be disrupted by prenatal exposure to endocrine-disrupting chemicals (EDCs), with alterations manifesting during pubertal development. However, studies addressing prenatal exposure to multiple EDCs remain scarce. This study explores the associations between prenatal exposure to 33 EDCs and early sex maturation in 386 Spanish mother-child pairs (girls: 49%; recruitment: 2003-2005). We measured seven organochlorine compounds (OCs) and four perfluoroalkyl substances (PFAS) in maternal blood, and seven phenols and 15 phthalates in maternal urine. Pubertal development was assessed at age 9 using Tanner staging for genital development (GD), breast development (BD), and pubic hair development (PH) alongside salivary sex hormones. Sex-specific analyses included single-chemical (robust Poisson/linear regression) and mixture (principal components/Bayesian kernel machine regression) analyses. In single-chemical models, higher prenatal p,p'-DDE and p,p'-DDT concentrations were associated with delayed BD and GD, respectively, while PCB-180 and parabens (ETPA, BUPA) were associated with earlier BD, and phthalates were associated with earlier PH (girls: MEHP, MEHHP, MEOHP, and MECPP; boys: MEP and MnBP). For sex hormones, β-HCH (both sexes), p,p'-DDE, PCB-180, PFOS (boys), and p,p'-DDT, OH-MPHP (girls) were positively associated with testosterone, and HCB was positively associated with estradiol (boys). Conversely, BUPA, OH-MPHP (boys), and BPA (girls) were inversely associated with testosterone. In chemical mixture models, the first component of OCs was positively associated with male testosterone, but the results of other mixture analyses were unclear. Overall, prenatal exposure to some EDCs may impair fetal programming of puberty, yet the impact of chemical mixtures remains uncertain.

Polychlorinated Biphenyls (PCBs) are known for several adverse health consequences and their neurotoxicity. As part of the HELPcB cohort, in this study neuropsychological outcomes of five consecutive measurements in occupationally exposed individuals were examined. The longitudinal effects of plasma PCB levels on neuropsychological functions were investigated, specifically differentiating chronic from acute effects. Neuropsychological outcomes included performance in verbal fluency, sensorimotor processing and alertness. PCB levels of low-chlorinated, high-chlorinated and dioxin-like congeners were analysed. Linear Mixed Models were applied, differentiating between accumulated PCB body burden and short-term fluctuations. Results suggest negative effects of plasma PCB levels on all three cognitive domains when examining chronic effects, whereas acute fluctuations of PCB values did not affect performance in neuropsychological tests. This finding points towards the effects of PCBs to be driven by a persistent neurobiological damage that affects cognitive functioning even years after cessation of occupational exposure, while short-term fluctuations in PCB levels are considered to be of lesser importance. An alteration of fronto-striatal dopamine circuits is discussed as a possible mechanism underlying the neurotoxic properties of PCBs.

BACKGROUND:Per- and polyfluoroalkyl substances (PFAS) are highly persistent and bioaccumulative chemicals used in numerous industrial applications, including aqueous film-forming foams (AFFF). Human PFAS exposure has been linked to dyslipidemia, reduced vaccine antibody responses, developmental effects and potential carcinogenicity. OBJECTIVE:To determine whether firefighters with frequent occupational AFFF contact exhibit higher internal PFAS concentrations than firefighters with little or no foam exposure. METHODS:In this observational study, 140 professional and avocational firefighters from five fire departments in the German Rhineland region were enrolled. Plasma concentrations of 27 PFAS were quantified using online SPE-LC/MS/MS. Participants completed a structured questionnaire capturing demographic characteristics, occupational history, AFFF contact frequency and potential confounders. Statistical analyses were performed using Generalized Linear Models (GLM) adjusted for relevant covariates. RESULTS:Six PFAS (PFHxS, PFHpS, PFOA, PFOS, PFNA and PFDA) were detected in all participants. Firefighters reporting more than 10 lifetime AFFF contacts had higher European Food Safety Authority (EFSA) sum (PFHxS + PFOA + PFOS + PFNA) concentrations (mean 5.69 ± 4.19 μg/L) than those with ≤10 contacts (mean 3.79 ± 1.73 μg/L). Age was positively associated with PFAS levels, whereas regular blood donation was associated with lower concentrations. BMI and ski-wax exposure showed no significant associations. CONCLUSIONS:Frequent occupational AFFF contact is associated with elevated internal PFAS concentrations in firefighters suggesting an exposure-biomarker relationship. While measured levels generally remain below international firefighter reference values, several surpassed the HBM-I health based guidance values of the German Human Biomonitoring commission. These findings highlight the need for further investigations into long-term health risks in occupationally exposed populations.

Exposure to endocrine-disrupting chemicals (EDCs), including per- and polyfluoroalkyl substances (PFAS), has been linked to altered pubertal timing, though epidemiological findings remain inconsistent. This study examined associations between prenatal PFAS exposure and pubertal development in children. Concentrations of perfluorohexane sulfonic acid (PFHxS), perfluorooctanoic acid (PFOA), perfluorooctane sulfonic acid (PFOS) and perfluorononanoic acid (PFNA) were quantified in maternal plasma collected during the first trimester of pregnancy in the Spanish INMA (Infancia y Medio Ambiente) cohort. Children's pubertal development was assessed longitudinally between ages 7 and 13 using the parent-reported Pubertal Development Scale (PDS), with specific scales for gonadal and adrenal development. Data were available for 492 mother-girls pairs at the 7-9-year follow up and 475 mother-boys pairs at the 11-13-year follow up based on the typical sex-specific timing of puberty. Poisson regression and Bayesian Kernel Machine Regression (BKMR) were used to estimate associations between PFAS (individually and as mixtures, respectively) and the risk of earlier puberty development (PDS stage 1 vs. 2+), adjusting for confounders. Among girls, PFHxS was associated with an increased risk of early adrenarche (Relative Risk [RR] = 1.85; 95% confidence interval [CI]: 1.05-3.25), while PFOS was inversely associated with early gonadarche RR = 0.61; 95% CI: 0.37-1.00). In boys, PFOS showed a marginal trend toward an increased risk of early overall pubertal onset (RR = 1.47; 95% CI: 0.99-2.19). Stratified analyses mainly revealed stronger associations among overweight/obese children. The mixture analysis suggested a positive trend for early adrenal development in both sexes, with significant associations in boys. Although our findings do not provide definitive evidence of a relationship between prenatal PFAS exposure and pubertal timing, they are compatible with the endocrine-disrupting potential of PFAS. The observed patterns, including possible modification by weight status and mixture signals, warrant further research.

Polychlorinated biphenyls (PCBs) are widespread environmental contaminants that interfere with xenobiotic metabolism, primarily by modulating cytochrome P450 (CYP) enzymes. However, their pharmacokinetic consequences in exposed individuals remain poorly defined. Here, we investigated the impact of PCB exposure on CYP enzyme activity using a combined clinical pharmacokinetic and in vitro mechanistic approach. Ten occupationally PCB-exposed individuals from the German HELPcB cohort and ten controls received a CYP phenotyping cocktail to assess enzyme function (Clinical Trial Registry: DRKS00028922). Plasma drug and metabolite concentrations were quantified to evaluate CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A activity, considering genetically defined metabolizer status. PCB118 exposure was significantly associated with reduced CYP1A2 activity (R2 = 0.155, t = − 2.115, p = 0.049, β = − 0.446), indicating a decrease in CYP1A2 activity with higher PCB118 levels. This was further supported by in vitro assays demonstrating dose-dependent inhibition. In addition, PCB74 exposure showed a trend toward increased CYP2C9 activity, suggesting a potential inductive effect. Mechanistic studies revealed that PCB118 acts as both an inhibitor and a substrate of CYP1A2, generating reactive arene oxide intermediates that may contribute to mechanism-based inhibition. These findings challenge the traditional view of PCBs as merely chronic toxicants, showing that they can acutely alter drug metabolism and potentially impact drug efficacy and safety. Given the widespread presence of PCBs and other persistent organic pollutants, these results highlight the need to integrate environmental toxicant exposure into pharmacokinetic models to optimize drug therapy and minimize adverse effects.

Prenatal chemical exposure has frequently been associated with fetal growth, although the underlying molecular mechanisms remain unclear. This study aims to explore the potential mediating role of hormones in the association between prenatal chemical mixture exposure and birth weight.We used data of 432 newborns from two Flemish birth cohorts. The common set of available and detectable exposure biomarkers and hormones analyzed in cord plasma are: 6 metals/trace elements, 3 polychlorinated biphenyl (PCB) congeners, hexachlorobenzene, dichlorodiphenyldichloroethylene and 2 perfluoroalkyl substances; and 3 thyroid, 3 reproductive and 2 metabolic hormones. Mixtures analyses were performed to assess each of the bilateral associations in the path exposures-hormones-birth weight, including mediation analysis.Combining all exposures, we found an inverse association between PCB 180 and birth weight. PCB 180 was positively associated with sex hormone-binding globulin (SHBG) and negatively associated with leptin and insulin. Similarly, thallium was positively associated with testosterone, estradiol, and SHBG, and negatively with insulin. Lead was positively associated with insulin. Higher free thyroxine (FT4), insulin, and leptin were associated with higher birth weight, whereas higher SHBG was associated with lower birth weight. Mediation analysis for PCB 180 indicated that 94% of the effect of this exposure on birth weight is mediated by FT4, SHBG, leptin, and insulin.Assessing the health risk of chemical mixture exposure reflects better real-world situations, thereby allowing more effective risk assessment. Our results suggest that hormonal markers are on the causal path in the association between environmental exposure and birth weight, adding interesting insights for mechanistic research.

BACKGROUND:Agbogbloshie in Ghana is the world's biggest dumpsite for the informal recycling of electronic waste (e-waste). E-waste is dismantled by rudimentary methods without personal or environmental protection. Workers and occupants are exposed to lead. There are no data so far about the extent and the consequences. We therefore analyzed blood lead levels (BLL) and creatinine levels (CL). METHODS:Full blood samples and basic data (i.e. age, job, length of stay) were collected from dumpsite volunteers. BLL were measured by atomic absorption spectrometry; CL were assessed using the standard clinical laboratory procedures of Aachen Technical University. European BLL reference values were used as Ghana lacks its own. Statistical analysis was by non-parametric tests (Mann-Whitney U test), with p < 0.05. RESULTS:Participants of both sexes (n = 327; 12-68 years; median age 23 years) were assessed. Most workers were aged <30 years. The collective's BLL was in pathological range for 77.7%; 14% had a BLL >10.0 μg/dl with symptoms consistent with high lead exposure including severe (6.5%) and intermediate (39%) renal disorder. BLL above 15.0 μg/dl were found in 5.9% of all workers which is the German threshold for those working with lead. Elevated CL in a pathological range were found in 254 participants. This is problematic as 75% of the lead entering the body is excreted via urine. CONCLUSION:Most of our volunteers had pathological BLL and CL. Preventive strategies are necessary to reduce health risks, particularly for vulnerable populations (i.e. children, pregnant women).

Occupational exposure to polychlorinated biphenyls (PCBs) continues to affect the health of exposed individuals until today. This study aims to expand previous findings by examining the development of neuropsychological functions of occupationally exposed participants over time. Especially verbal fluency and sensorimotor processing, found to be impaired in a previous study, were thus of particular interest. A total of 116 participants, who were part of the HELPcB cohort, underwent a neuropsychological test battery covering a multitude of cognitive functions. Plasma PCB levels were determined for each participant and classified as elevated or normal based on comparative values drawn from the German general population. Two structural equation models were then used to examine the effects of elevated PCB levels on neuropsychological functions. Results suggest that participants who displayed increased PCB plasma levels continued to show impairments in verbal fluency but not in sensorimotor processing after a second examination one year after the first measurement. Specifically, low chlorinated PCBs are associated with impaired verbal fluency, as compared to high-chlorinated and dioxin-like congeners. Alteration of dopamine concentration in response to PCB exposure might be a potential explanation of this result.

Calibrations in LA-ICP-MS are typically very time-consuming and complex, as they need to be matched to the samples being measured and sectioned on a microtome. Alternatively, gelatin can be in droplet form or as a section, which is a more recent development. In this study, we report on investigations where hot multi-element gelatin solutions are placed in a linear fashion on microscopic slides to conduct comparative statistical observations between doped tissue homogenates from the liver and lung. The tissue homogenates served as both samples (complete ablation) and calibration standards (partial ablation) for verification purposes. We explored the effects of different laser fluences (0.50–1.50 J/cm2), gelatin contents (0.3–20.0

Little is known about exposure determinants of acrylamide (AA), a genotoxic food-processing contaminant, in Europe. We assessed determinants of AA exposure, measured by urinary mercapturic acids of AA (AAMA) and glycidamide (GAMA), its main metabolite, in 3157 children/adolescents and 1297 adults in the European Human Biomonitoring Initiative. Harmonized individual-level questionnaires data and quality assured measurements of AAMA and GAMA (urine collection: 2014–2021), the short-term validated biomarkers of AA exposure, were obtained from four studies (Italy, France, Germany, and Norway) in children/adolescents (age range: 3–18 years) and six studies (Portugal, Spain, France, Germany, Luxembourg, and Iceland) in adults (age range: 20–45 years). Multivariable-adjusted pooled quantile regressions were employed to assess median differences (β coefficients) with 95% confidence intervals (95% CI) in AAMA and GAMA (µg/g creatinine) in relation to exposure determinants. Southern European studies had higher AAMA than Northern studies. In children/adolescents, we observed significant lower AA associated with high socioeconomic status (AAMA:β = − 9.1 µg/g creatinine, 95% CI − 15.8, − 2.4; GAMA: β = − 3.4 µg/g creatinine, 95% CI − 4.7, − 2.2), living in rural areas (AAMA:β = − 4.7 µg/g creatinine, 95% CI − 8.6, − 0.8; GAMA:β = − 1.1 µg/g creatinine, 95% CI − 1.9, − 0.4) and increasing age (AAMA:β = − 1.9 µg/g creatinine, 95% CI − 2.4, − 1.4; GAMA:β = − 0.7 µg/g creatinine, 95% CI − 0.8, − 0.6). In adults, higher AAMA was also associated with high consumption of fried potatoes whereas lower AAMA was associated with higher body-mass-index. Based on this large-scale study, several potential determinants of AA exposure were identified in children/adolescents and adults in European countries.

Despite extensive research on the metabolism of polychlorinated biphenyls (PCBs), knowledge gaps persist regarding their isoform-specific biotransformation pathways. This study aimed to elucidate the role of different cytochrome P450 enzymes in PCB metabolism, focusing on WHO-congeners 2,4,4′-trichlorobiphenyl (PCB28), 2,2′,5,5′-tetrachlorobiphenyl (PCB52), and 2,2′,4,5,5′-pentachlorobiphenyl (PCB101). Utilizing engineered HEK293 cell lines, we investigated the in vitro metabolism of these PCBs by CYP1A2, CYP2C8, CYP2C9, CYP3A4, CYP2A6, and CYP2E1, revealing robust production of hydroxylated metabolites. Our results show that CYP2A6 plays a major role in the metabolism of these congeners responsible for predominant formation of para-position hydroxylated metabolites, with concentrations reaching up to 1.61 µg/L (5,89 nM) for PCB28, 316.98 µg/L (1,03 µM) for PCB52, and 151.1 µg/L (441 nM) for PCB101 from a 20 µM parent PCB concentration. Moreover, concentration-dependent cytotoxic and cytostatic effects induced by reactive intermediates of the PCB hydroxylation pathway were observed in HEK293CYP2A6 cells, for all three congeners tested. CYP2A6 was specifically capable of activating PCBs 28 and 101 to genotoxic metabolites which produced genetic defects which were propagated to subsequent generations, potentially contributing to carcinogenesis. In a clinical study examining CYP2A6 enzyme activity in formerly exposed individuals with elevated internal PCB levels, a participant with increased enzyme activity showed a direct association between the phenotypic activity of CYP2A6 and the metabolism of PCB28, confirming the role of CYP2A6 in the in vivo metabolism of PCB28 also in humans. These results altogether reinforce the concept that CYP2A6 plays a pivotal role in PCB congener metabolism and suggest its significance in human health, particularly in the metabolism of lower chlorinated, volatile PCB congeners.

Parkinson's disease (PD) is characterized by the progressive loss of dopaminergic neurons in the substantia nigra of the midbrain. Familial cases of PD are often caused by mutations of PTEN-induced kinase 1 (PINK1) and the ubiquitin ligase Parkin, both pivotal in maintaining mitochondrial quality control. CISD1, a homodimeric mitochondrial iron-sulfur-binding protein, is a major target of Parkin-mediated ubiquitination. We here discovered a heightened propensity of CISD1 to form dimers in Pink1 mutant flies and in dopaminergic neurons from PINK1 mutation patients. The dimer consists of two monomers that are covalently linked by a disulfide bridge. In this conformation CISD1 cannot coordinate the iron-sulfur cofactor. Overexpressing Cisd, the Drosophila ortholog of CISD1, and a mutant Cisd incapable of binding the iron-sulfur cluster in Drosophila reduced climbing ability and lifespan. This was more pronounced with mutant Cisd and aggravated in Pink1 mutant flies. Complete loss of Cisd, in contrast, rescued all detrimental effects of Pink1 mutation on climbing ability, wing posture, dopamine levels, lifespan, and mitochondrial ultrastructure. Our results suggest that Cisd, probably iron-depleted Cisd, operates downstream of Pink1 shedding light on PD pathophysiology and implicating CISD1 as a potential therapeutic target.

1,3-dichlorobenzene (1,3-DCB) is an aromatic solvent that might be formed during thermal decomposition of bis(2,4-dichlorobenzoyl)peroxide used as initiator in silicone rubber production with many workers exposed worldwide. During metabolism of 1,3-DCB, two isomeric mercapturic acids can be formed from ring oxidation of 1,3-DCB in the liver, namely 2,4-dichlorophenylmercapturic acid (24CPhMA) and 3,5-dichlorophenylmercapturic acid (35CPhMA). These urinary mercapturic acids might serve as biomarkers of the toxicologically relevant absorbed dose of 1,3-DCB and have not been determined so far. Thus, we were aimed to develop an analytical method for quantification of these biomarkers. Authentic standards of both mercapturic acids as well as deuterium-labelled analogues were self-synthesized. A method for the quantification of both CPhMAs in human urine using online-SPE LC/MS/MS was developed and validated with an LOQ of 0.1 ng mL(-1) for both CPhMAs. The analytes were extracted from urine by online-SPE on a restricted access material phase, transferred to the analytical column and quantified by tandem mass spectrometry. Interday (n = 6) and Intraday (n = 10) precision for both CPhMAs ranged from 1.7 to 4.3 % with accuracies between 99.4 and 109.9 % at concentrations of 0.6 and 3 ng mL(-1). We applied the method on post-shift urine samples of 16 workers of the silicone rubber industry with occupational exposure to 1,3-DCB. Both CPhMAs were above LOQ in 15 of 16 urine samples with median levels (range) for 24CPhMA and 35CPhMA of 1.64 ng mL(-1) (<0.1 - 8.2 ng mL(-1)) and 3.98 ng mL(-1) (0.36 - 24.1 ng mL(-1)), respectively. This is the first report on specific urinary mercapturic acids of 1,3-DCB in humans. Our results show that ring oxidation of 1,3-DCB is considered to be a toxicologically relevant metabolic pathway in humans. This might improve risk assessment of 1,3-DCB-emissions in silicone rubber industry.