OBJECTIVE:The association between occupational exposure to chlorinated solvents and lung cancer remains inconclusive. This study investigated this relationship using data from the internationally pooled SYNERGY study. METHODS:Data from 14 case-control studies conducted in 13 European countries and Canada were pooled, including 28 048 participants (12 329 cases and 15 719 controls). Lifetime occupational exposure to chlorinated solvents was assessed using the ALOHA+job-exposure matrix. ORs and 95% CIs were estimated using unconditional logistic regression, adjusted for study centre, age, sex, smoking (pack-years and cessation), cumulative exposure to five occupational lung carcinogens (asbestos, hexavalent chromium, polycyclic aromatic hydrocarbons, respirable crystalline silica and diesel engine exhaust), cumulative benzene exposure and employment in high-risk occupations ('List A' jobs). Associations were estimated across categories of exposure levels, durations and analyses stratified by smoking status and lung cancer subtypes. RESULTS:We found no evidence of an association between ever exposure to chlorinated solvents and lung cancer risk (OR 1.03; 95% CI 0.96 to 1.10). Among exposed individuals, a positive trend with cumulative exposure was observed (p=0.031), but not when non-exposed individuals were included (p=0.173). Positive trends were found with exposure duration (p=0.005 for exposed; p=0.048 overall); risks were modestly elevated (OR 1.11) in those exposed for 20 or more years. No increased risk was observed across smoking strata or lung cancer subtypes. CONCLUSIONS:This pooled analysis provides limited evidence of an association between occupational exposure to chlorinated solvents and lung cancer, though exposure-response trends were noted among exposed individuals.

Public health concerns about organic UV filters are increasing, yet exposure levels among children remain poorly characterized. In particular, the contribution of non-sunscreen sources is still unclear. To address this gap, we recruited 301 children aged 6-11 years with limited sunscreen use from Indonesia, Thailand, and Saudi Arabia during 2017-2018. Human biomonitoring of octocrylene (OC), 2-ethylhexyl salicylate (EHS), and homosalate (HMS) was conducted by analyzing eight novel urinary biomarkers using online-SPE-LC-MS/MS. Daily intakes were estimated by reverse dosimetry. Our results demonstrated widespread exposure to OC and EHS in children, whereas HMS exposure was rare. Significant inter-country differences were observed, with the highest concentrations of CPAA (biomarker for OC) in Thai children (92.3% > LOQ) and of 5cx-EPS (for EHS) in Indonesian children (76.4% >LOQ). Reported sunscreen use was not associated with urinary metabolite concentrations. None of the metabolites exceeded the HBM-I value; however, the maximum 5cx-EPS concentration (6.26 µg/L) approached this threshold. Among the children, OC and EHS exposures were not associated with reported sunscreen use, but were significantly associated with other potential sources, including antimicrobial soap use and fish consumption. Several country-specific sources were also identified: OC exposure was associated with recent wardrobe replacement (Indonesia), and frequent use of toilet detergents (Thailand), while EHS exposure was associated with the use of bath products in Indonesia and paper-based food storage containers (Saudi Arabia). These findings establish baseline exposure levels of major organic UV filters in children and highlight the importance of non-sunscreen sources in shaping exposure pathways.

Objectives Traditional epidemiological approaches usually assume a constant relationship between cumulative exposure and disease, which implies that exposure duration and intensity contribute equally to the studied outcome. But individuals with the same cumulative exposure but different temporal exposure patterns may show different risks. Trajectory classification is a good way to assess exposure–risk associations and leads to a better understanding of lifetime variability in exposure levels. Therefore, this study aimed to estimate lung cancer risk according to the exposure trajectory classes on welding fumes and cigarette smoking.Design Two population-based German case–control studies.Participants 3498 male lung cancer cases and 3539 male control subjects.Methods Separate latent class mixed models (LCMM) were determined to identify profiles of exposure trajectories of cigarette smoking and occupational exposure to welding fumes. To investigate the risk of lung cancer by class membership, ORs with 95% CI were estimated via multiple logistic regression analyses.Results LCMM each identified four latent classes of smoking and welding-fume exposure. Classes of smokers showed much higher risk of lung cancer compared with never smokers or subjects exposed to welding fumes. Smokers in one class characterised with the highest exposure over the past 10 years had the highest adjusted lung cancer risk (OR=39; 95% CI 29 to 53). For welding, the highest lung cancer risks were found for the class in which exposure to welding fumes in the past 10 years prior to the diagnosis of lung cancer was highest and the duration of welding was also quite high (OR=1.71; 95% CI 0.92 to 3.15).Conclusions In summary, LCMM opens a new perspective on dose–effect relationships and could be employed to complement established epidemiological methods.

Abstract Sunscreens are an important protection measure against harmful effects of ultraviolet radiation. However, potential health effects of several commonly used UV filters are currently being discussed. We conducted a human biomonitoring (HBM)-based exposure and risk assessment for octocrylene (OC), 2-ethylhexyl salicylate (EHS), and homosalate (HMS; a mixture of cis- and trans-HMS) in urine samples collected in Queensland and across Australia from 2012 to 2023, pooled by age, sex, and collection period (187 pools representing approximately 18,700 individuals). The pooled urines were analyzed by LC–MS/MS for specific exposure biomarkers of these UV filters. Determinants of exposure were investigated using Tobit regression. Biomarker concentrations increased over time, and clear age trends were observed, with children showing roughly one order of magnitude higher concentrations than adolescents/adults. Concentrations of the EHS biomarker 5cx-EPS exceeded the health-based guidance value (HBM-I) in 23% of children’s pooled urines. For the cis-HMS biomarker HMS-CA5, most pooled urines of children exceeded HBM-I (80%) and 53% even HBM-II. These findings indicate the need to reduce HMS exposure in at least some individuals, confirming the necessity for stricter regulations for homosalate in Australia, as recently enforced in the European Union and recommended by Australian authorities, to ensure sunscreen safety.

BACKGROUND:Microsampling using filter cards for dried blood spots (DBS) and dried plasma spots (DPS) is a well-established technique offering practical advantages for blood collection and subsequent processing. For DBS/DPS, only a small sample volume is required it enables transport and storage at ambient temperature, and it is well suited for decentralized sample collections and resource-limited settings, as well as collection from elderly individuals, when venous blood collection might be problematic. Many protein-based biomarker assays like enzyme-linked immunosorbent assays (ELISA) depend on blood, plasma, or serum as sample matrix. Calretinin is an established biomarker for the early detection of mesothelioma. Herein, we investigated whether DPS are suitable for the determination of calretinin protein by ELISA in comparison to commonly used plasma samples. METHODS:Plasma samples of 47 mesothelioma patients and 47 matched asbestos-exposed controls were spotted onto filter cards. After drying, calretinin was reconstituted and determined using ELISA. RESULTS:It was revealed that the use of filter cards, i.e., DPS as sample matrix, was comparable to and in good agreement with the use of plasma. Calretinin could be determined reliably and comparably even after storage for 5 days at ambient temperature. Additionally, the performance of calretinin as biomarker using DPS is improved in comparison to the use of plasma, resulting in a slightly increased sensitivity at constant specificity. CONCLUSION:The findings of this proof-of-concept study suggest that filter cards represent a valuable alternative sampling method to determine calretinin for the detection or monitoring of mesothelioma.

Polygenic risk scores (PRSs), which quantify inherited susceptibility to complex traits and diseases, have emerged as valuable tools for risk stratification and precision medicine. Despite their promise, PRS developed on European cohorts often demonstrate substantially reduced predictive accuracy in non-European populations, due to differences in genetic architecture. The disproportionate representation of European ancestry cohorts in genome-wide association studies (GWAS) leads to inequitable deployment of PRS technologies across diverse populations. Here, we introduce PRANA (Polygenic Risk Adaptation via Neural-network Architecture), a deep learning framework that adapts an existing PRS developed on one population to other ancestries. Unlike methods that require large-scale GWAS in the target population, PRANA leverages pre-trained PRS models derived from European cohorts and adapts them using modestly sized cohorts from the target population. We evaluated PRANA on seven complex traits in South Asian, East Asian and Ashkenazi Jewish populations, as well as in selected smaller East Asian subpopulations where the scarcity of training data poses a particular challenge. PRANA mostly improved predictive performance of the baseline PRS models by 5%-20% in terms of effect size (β) and Nagelkerke's R2, and, in most cases, outperformed existing cross-ancestry multi-PRS approaches. These results highlight PRANA as a scalable and practical strategy to reduce disparities in genomic risk prediction and advance the equitable application of PRS in diverse populations.

2,4-Di-tert-butylphenol (DTBP) is a degradation product of the antioxidant and plastic additive tris(2,4-di-tert-butylphenyl)phosphite. DTBP can migrate into food or drinking water from high production volume polyolefins containing this additive, leading to potential human exposures, confirmed by findings of DTBP in blood and urine. Natural sources of DTBP have also been described. We have recently developed a sensitive analytical method for the quantification of urinary DTBP and its postulated oxidised metabolite 2-tert-butyl-4-(2-hydroxy-1,1-dimethylethyl)phenol (DTBP-4-OH) after enzymatic cleavage of glucuronides. This method has now been employed in a human metabolism study. Five adult volunteers were orally dosed with 9.715 mg of DTBP and their urine voids were quantitatively and separately collected for 48 h. DTBP and DTBP-4-OH were quantifiable in all post-dose samples and biphasic excretion kinetics were observed. Urinary peak concentrations of the oxidised metabolite DTBP-4-OH were around six times higher than those of DTBP and occurred around the same time (1.5-3.8 h). Overall, we recovered 62.2% of the oral dose as DTBP-4-OH and 9.3% as parent DTBP within 48 h. Over 95% of the excretion occurred within the first 24 h. External contamination with DTBP e.g. from commonly used polypropylene tubes was observed, potentially interfering with the determination of parent DTBP. Hence, we strongly recommend using DTBP-4-OH as the most robust and most sensitive urinary exposure biomarker in human biomonitoring studies. With the toxicokinetic information provided here, reverse dosimetry of DTBP-4-OH enables an informed exposure and risk assessment for DTBP both in environmentally and occupationally exposed populations.

Face masks effectively reduce airborne disease transmission, but data on their physiological impact on children remain limited compared to adults. This study evaluates the physiological and thermal effects of surgical masks (SM) and filtering face piece mask (FFP2) on children during typical classroom sessions. In a randomized crossover study with repeated measures conducted in late summer, 39 children (23 girls and 16 boys; age 8-14 years, mean 11 +/- 1 years) were monitored during 90-minute school lessons under three conditions: no mask (NM), surgical mask (SM), and FFP2 mask. Continuous recordings included core body temperature (T-core), heart rate (HR), breathing rate (BR), and oxygen saturation (sO(2)). Additionally, microclimate parameters under the mask, such as relative humidity (RHmask), temperature (T-mask and T-skin), and inhaled/exhaled carbon dioxide (pCO(2in/ex)), were measured. Subjective exertion was assessed using the BORG scale. No significant changes in HR, BR, sO(2), or T-core were observed. Wearing SM or FFP2 mask led to a minor statistically significant, yet clinically irrelevant, increase in pCO(2in/ex) (< 2 mmHg) compared to NM. While T-mask and RHmask increased significantly (with FFP2 showing higher values than SM), T-skin rose only slightly across all conditions. Subjective exertion (BORG) increased marginally with FFP2 masks but remained in the "very slight" range. Wearing SM or FFP2 masks for up to 90 min does not impair cardiopulmonary function or oxygenation in healthy children. Observed physiological changes were within normal limits, primarily associated with local thermal effects and minimal discomfort. Face masks are therefore considered safe for short-term use in school settings.

The incidence of germ-cell testicular cancer (TC) has increased in recent decades. Current evidence does not indicate a unanimous association between occupational exposure to welding fumes and TC risk. However, most publications do not provide information on exposure levels to welding fumes. We investigated the association between occupational exposure to welding fumes and the risk of TC in a German case-control study (268 cases and 797 control subjects). A measurement-based welding-exposure matrix was used to estimate year-specific exposure values which were linked to job-task descriptions. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated via logistic regression, conditional on study area and 5-year age groups. ORs were adjusted for a history of cryptorchidism, a family history of TC, and ever exposure to metal-working fluids (MWF). Regular welding was associated with an elevated TC risk (OR: 2.26, CI: 0.92-5.53) compared to occasional welding (OR: 1.14, CI: 0.78-1.69). For non-seminoma, there was an indication of a strong association among regular welders (OR: 3.71, CI: 1.08-12.80) and for non-welders using MWFs (OR: 3.39, CI: 1.21-9.53). However, these estimates were based on few exposed cases. We did not observe dose-effect relationships with increasing lifetime exposure to welding fumes, duration, or average intensity. We found an association between regular welding and TC risk based on standardized job-task descriptions, but not when using the year-specific exposure values.

BACKGROUND:Glove occlusion increases skin susceptibility to irritants ('occlusion effect'). Previous experimental data showed that applying protective creams (PCs) before glove occlusion does not prevent this effect and may even aggravate irritant responses. OBJECTIVES:To assess whether the application of PCs after glove occlusion modifies the occlusion effect. METHODS:In a randomized, single-blind (participants were blinded) study, 68 healthy volunteers were examined over 10 days. Two commercially available PCs (A, B) and one standardized model cream (C) were applied after occlusion for over 4 h to defined forearm sites. On day 8, sites were exposed to 0.5% sodium lauryl sulphate (SLS) for 24 h to evaluate skin irritation susceptibility. Additional conditions included (I) daily application of cream C without occlusion until day 7 or (II) until Day 8, with the final application 10 min before SLS exposure. Skin responses were assessed by TEWL, corneometry, colourimetry and clinical scoring. Wilcoxon signed-rank tests were used to compare control areas to sides after PC application. RESULTS:Post-occlusion application of the PCs did not demonstrate a consistent protective effect. Cream A slightly reduced SLS-induced TEWL (10.88 g/m2/h after application following glove use vs. 12.13 g/m2/h without application; adjusted p > 0.05), whereas cream B increased TEWL (13.44 vs. 12.42 g/m2/h; adjusted p > 0.05). Cream C showed no significant effect on TEWL (11.99 vs. 12.38 g/m2/h; p > 0.05). In contrast, application of cream C shortly before SLS exposure in the absence of occlusion (condition II) significantly reduced TEWL (7.09 vs. 12.38 g/m2/h; adjusted p < 0.0001) and erythema. However, earlier application (condition I) did not yield a protective effect (11.92 vs. 12.38 g/m2/h). CONCLUSIONS:In the majority of study scenarios, application of PCs after glove occlusion did not have a clinically relevant positive effect on the skin responses studied. Protective efficacy probably depends on formulation and timing, underscoring the need for evidence-based recommendations.

BACKGROUND:Mortality data, i.e., information on whether individuals are living or dead and the causes of death, provide essential endpoints for the assessment of disease progression in clinical-epidemiological studies. In Germany, mortality data for scientific research are often available only through municipal offices, and rarely from registries. In this study, we collected and compared mortality data from these two sources. METHODS:As part of a study on the early detection of lung cancer and pleural mesothelioma, we collected mortality data on patients recruited in 2014-2015 and on control subjects in the general population. These data were obtained from registration and public health offices and (except for the control subjects) through record linkage with the Cancer Registry North Rhine-Westphalia. RESULTS:448 of the 460 patients consented to follow-up via the cancer registry, and 429 consented to municipal-office-based follow up, as did 197 of the 207 control subjects. Much more effort was needed to collect data from municipal offices than through record linkage with the cancer registry. Over a 5-year period, the percentage of deaths recorded was slightly higher when assessed with data from the cancer registry (51.1% versus 49.7%). Further information on the causes of death was more frequently available through the cancer registry (98% versus 84%). CONCLUSION:Follow-up data from the cancer registry were generally more informative, and required less organizational effort to collect, than data from municipal offices. Obtaining data from cancer registries is, therefore, preferable for future cancer studies, although nationwide registry structures for mortality data are still lacking.

The German Environmental Specimen Bank (ESB) annually archives 24-h urine samples since the early 1980s. In this study, we analyzed 420 of these samples from the years 2014 to 2022 for metabolites of 18 phthalates and two substitutes. We merged the new data with the data from previous measurement campaigns to a combined dataset of 1825 samples covering a 35-year period from 1988 to 2022 to investigate time trends, calculate daily intakes and perform an anti-androgenic mixture risk assessment. With the extended set of 41 biomarkers, we are now able to monitor the exposure to all EU-labelled reprotoxic phthalates. Most phthalate exposures continued to decrease since first measurements in the 80s, with biggest drops for DnBP (96.6 %) and DEHP (90.9 %). DiNP and DiDP, seen on the rise in earlier campaigns, now declined. Exposures to the newly included, reprotoxic phthalates were generally negligible. Regarding mixture risk, 5 % of the highly exposed still exceeded the Hazard Index (HI) of 1 in 2009. In the current measurement campaign only three individuals (0.7 %) exceeded the HI of 1 (with exceedances still driven by DEHP and DnBP).In 2022, 20 % of the individuals still had an HI > 0.2, which we propose as a benchmark for interpreting phthalate mixture risk, considering concurrent exposures to other anti-androgens. Exposure to the substitutes DINCH and DEHTP continues to increase, with daily intakes of DEHTP exceeding those of DEHP since 2018. Compared with the United States (US) National Health and Nutrition Examination Survey (NHANES) phthalate exposures seem to align, except for DEHTP with up to ten times higher levels in the US. Human biomonitoring (HBM) is the ideal tool to capture actual mixture exposures per individual, integrating all external exposure sources and pathways, thus we will continue to use HBM in exposure and risk assessment of phthalates and other (anti-androgenic) chemicals.

This prospective cohort study aimed to monitor the humoral immune response to SARS-CoV-2 proteins over 3 years in relation to repeated vaccination or infection. Quantitative immunoassays traceable to international IgG units were used to measure and compare IgG levels against Wuhan type and Omicron spike-S1 and nucleocapsid proteins over 3 years. In addition, the Euroimmun-N-test was used to determine positive IgG values against the nucleocapsid. A total of 1223 serum samples from 126 participants without evidence of COVID-19 at enrollment were analyzed and used to calculate antibody half-lives following vaccination or infection, as reported by the questionnaire. Antibody levels and half-life against both variants of the spike S1 protein increased significantly with each additional vaccination or after infection. IgG against the Wuhan type was, on average, three times higher than against the Omicron variant. The half-lives of antibodies against the Wuhan type after the second and third vaccinations and after infection were significantly longer than those of IgG against the Omicron variant. Two-thirds of the cohort reported COVID-19 infection, detected with a sensitivity of 70% by the quantitative nucleocapsid IgG assay and 83% by the Euroimmun-N-test. The level of anti-nucleocapsid-IgG after infection in the vaccinated cohort was significantly lower than anti-S1-IgG and also lower than in unvaccinated infected persons. Despite repeated vaccinations and progressively increasing IgG antibody levels targeting the spike protein, most of the cohort reported breakthrough infections, possibly due to the lower concentration and reduced half-life of antibodies against the Omicron variant.

Supplementary Figure from Occupational Exposure to Polycyclic Aromatic Hydrocarbons and Lung Cancer Risk: Results from a Pooled Analysis of Case–Control Studies (SYNERGY)

Metallaktivgas- und Metallinertgas-Schweißen ist mit Gesundheitsrisiken durch einatembare Gefahrstoffe verbunden. Insbesondere bei der Verarbeitung von rostfreien Stahlsorten kann es zu Expositionen gegenüber kanzerogenen Chrom- und Nickelverbindungen kommen. Hier wurden die Expositionen gegenüber alveolengängigen Chrom- und Nickelverbindungen bei 20 Werkstattversuchen (InterWeld-Pilotstudie) mit Expositionen an 28 realen Arbeitsplätzen (WELDOX-Studien) verglichen. An realen Arbeitsplätzen zeigten sich beim Schweißen mit chrom- und nickelhaltigem Schweißdraht deutlich höhere Expositionen gegenüber alveolengängigem Chrom (CrA) und Nickel (NiA) als bei den Werkstattversuchen. Außer der Dicke der zu schweißenden Bleche zeigt der effektive Einsatz einer lokalen Absaugung sowohl im Experiment als auch an realen Arbeitsplätzen einen großen Einfluss auf die Exposition des Schweißers. Der Einsatz einer lokalen Absaugung – ob nachzuführend oder brennerintegriert – führte im Experiment zu einer mittleren Reduktion der CrA-Exposition auf nur 10 % der Exposition bei Schweißversuchen ohne Absaugung. An realen Arbeitsplätzen halbierte sich die Exposition durch eine wirksame Absaugung. Bei NiA reduzierte die Absaugung die Exposition auf 15 %, an realen Arbeitsplätzen auf 30 % gegenüber MiG-Schweißen ohne Absaugung. Prozessfaktoren wie Lichtbogenbrenndauer, Schweißstromstärke und Drahtvorschub beeinflussen gleichsinnig die Schweißrauchemission und damit die Exposition des Schweißers. Um Expositionsmessungen besser bewerten und vergleichen zu können, sollten diese Determinanten bei zukünftigen Arbeitsplatzmessungen systematisch dokumentiert werden.

The breast cancer risk conferred by germline protein truncating variants (PTVs) in known and putative breast cancer genes has been extensively investigated. However, the effect of FANCM PTVs on breast cancer risk remains unclear. Our previous clinical, genetic and functional results on the N-terminal p.Arg658∗ and the two C-terminal p.Gln1701∗ and p.Gly1906Alafs∗12 variants suggested that FANCM PTVs may confer different risks for ER-negative (ER-neg) and triple-negative (TN) breast cancer subtypes. Here, we performed meta-analyses of seven studies totaling 144 681 breast cancer cases and 123 632 controls. FANCM PTVs were tested for association with breast cancer risk overall and the disease clinical subtypes by single variant and burden analyses. Two CRISPR-Cas9-based functional assays were also conducted to test the fitness of cells after knock-in of the p.Arg658∗, p.Gln1701∗ and p.Gly1906Alafs∗12 PTVs and the sensitivity of different FANCM regions to genome editing. Our results suggest that the N-terminal FANCM region upstream of p.Tyr725 harbors essential functions, whereas downstream regions appear dispensable. This is supported by our genetic data which indicate that all FANCM PTVs, excluding the two C-terminal p.Gln1701∗ and p.Gly1906Alafs∗12, are associated with an increased risk of ER-neg (OR = 1.41, P = 0.023) and TN (OR = 1.64, P = 0.0023). Notably, PTVs upstream of AA position 670 are associated with a moderate risk of developing TN breast cancer, and that even when the p.Arg658∗ carriers were excluded from the analysis. Importantly, our results confirm previous data indicating that p.Arg658∗ carriers are at moderate risk of developing ER-neg (OR = 2.08, P = 0.030) and TN (OR = 3.26; P = 0.0034), whereas carriers of p.Gln1701∗ and p.Gly1906Alafs∗12 should not be considered at increased risk. Our data are useful for counseling carriers of FANCM PTVs, but further analyses are warranted to obtain more precise risk estimates.

Bronopol is a preservative mainly used in various industrial applications, but also in cosmetics and pharmaceuticals. The aim of this study was to investigate the human toxicokinetics of Bronopol after oral administration. Five volunteers (two male and three female) were orally dosed with 9.715 mg Bronopol (0.100 to 0.154 mg/kg bw) and their urine was collected for 48 h. The samples were analyzed for the postulated metabolite 2-nitro-1,3-propanediol using an analytical human biomonitoring method. The maximum urinary concentrations of 1830–7666 µg/L (1981–5847 µg/g creatinine) were reached around 2.5 h (1.7–4.7 h) post dose. The excretion profile was monophasic with an average half life of 6.3 h (4.7–8.6 h). In total, 29.2