Search

Abstract Background Zinc fever is well described in medical literature, particularly in workers after handling zinc-containing materials at high temperatures e.g., in the welding of hot-dip galvanized steel sheets. It is not known whether zinc fever also occurs at low temperatures. Case presentation We present the case of a 33-year-old Caucasian atopic painter and varnisher with work-related dyspnea, sweating, as well as multiple occurrences of fever. He was sent to Institute for Prevention and Occupational medicine of the German Social Accident Insurance, Institute of the Ruhr-Universität Bochum (IPA) for the evaluation of isocyanate asthma, but an inhalative challenge with hexamethylene diisocyanate was negative. Since symptoms were closely related to the use of zinc coatings at room temperature without adequate protective measures, the diagnosis of zinc fever was made. After exposure cessation the worker immediately became symptom-free. The work as painter and varnisher may be associated with various exposures to hazardous substances. Besides solvents, epoxy compounds and isocyanates, which can cause obstructive respiratory diseases; additionally, zinc-containing agents should be considered as health hazards. Conclusions This case demonstrates that zinc fever may occur also after application of zinc coatings by spray painting at low temperatures.

Abstract Background Inhalation of biopersistent fibers like asbestos can cause strong chronic inflammatory effects, often resulting in fibrosis or even cancer. The interplay between fiber shape, fiber size and the resulting biological effects is still poorly understood due to the lack of reference materials. Results We investigated how length, diameter, aspect ratio, and shape of synthetic silica fibers influence inflammatory effects at doses up to 250 µg cm-2. Silica nanofibers were prepared with different diameter and shape. Straight (length ca. 6 to 8 µm, thickness ca. 0.25 to 0.35 µm, aspect ratio ca. 17:1 to 32:1) and curly fibers (length ca. 9 µm, thickness ca. 0.13 µm, radius of curvature ca. 0.5 µm, aspect ratio ca. 70:1) were dispersed in water with no apparent change in the fiber shape during up to 28 days. Upon immersion in aqueous saline (DPBS), the fibers released about 5 wt% silica after 7 days irrespectively of their shape. The uptake of the fibers by macrophages (human THP-1 and rat NR8383) was studied by scanning electron microscopy and confocal laser scanning microscopy. Some fibers were completely taken up whereas others were only partially internalized, leading to visual damage of the cell wall. The biological effects were assessed by determining cell toxicity, particle-induced chemotaxis, and the induction of gene expression of inflammatory mediators. Conclusions Straight fibers were only slightly cytotoxic and caused weak cell migration, regardless of their thickness, while the curly fibers were more toxic and caused significantly stronger chemotaxis. Curly fibers also had the strongest effect on the expression of cytokines and chemokines. This may be due to the different aspect ratio or its twisted shape.

OBJECTIVES: The quantitative job-exposure matrix SYN-JEM consists of various dimensions: job-specific estimates, region-specific estimates, and prior expert ratings of jobs by the semi-quantitative DOM-JEM. We analyzed the effect of different JEM dimensions on the exposure–response relationships between occupational silica exposure and lung cancer risk to investigate how these variations influence estimates of exposure by a quantitative JEM and associated health endpoints. METHODS: Using SYN-JEM, and alternative SYN-JEM specifications with varying dimensions included, cumulative silica exposure estimates were assigned to 16 901 lung cancer cases and 20 965 controls pooled from 14 international community-based case-control studies. Exposure–response relationships based on SYN-JEM and alternative SYN-JEM specifications were analyzed using regression analyses (by quartiles and log-transformed continuous silica exposure) and generalized additive models (GAM), adjusted for age, sex, study, cigarette pack-years, time since quitting smoking, and ever employment in occupations with established lung cancer risk. RESULTS: SYN-JEM and alternative specifications generated overall elevated and similar lung cancer odds ratios ranging from 1.13 (1st quartile) to 1.50 (4th quartile). In the categorical and log-linear analyses SYN-JEM with all dimensions included yielded the best model fit, and exclusion of job-specific estimates from SYN-JEM yielded the poorest model fit. Additionally, GAM showed the poorest model fit when excluding job-specific estimates. CONCLUSION: The established exposure–response relationship between occupational silica exposure and lung cancer was marginally influenced by varying the dimensions of SYN-JEM. Optimized modelling of exposure–response relationships will be obtained when incorporating all relevant dimensions, namely prior rating, job, time, and region. Quantitative job-specific estimates appeared to be the most prominent dimension for this general population JEM.

Abstract Objective Lung cancer is the second most frequent cancer type and the most common cause of cancer-related deaths worldwide. Alteration of gene copy numbers are associated with lung cancer and the determination of copy number variations (CNV) is appropriate for the discrimination between tumor and non-tumor tissue in lung cancer. As telomerase reverse transcriptase (TERT) and v-myc avian myelocytomatosis viral oncogene homolog (MYC) play a role in lung cancer the aims of this study were the verification of our recent results analyzing MYC CNV in tumor and non-tumor tissue of lung cancer patients using an independent study group and the assessment of TERT CNV as an additional marker. Results TERT and MYC status was analyzed using digital PCR (dPCR) in tumor and adjacent non-tumor tissue samples of 114 lung cancer patients. The difference between tumor and non-tumor samples were statistically significant (p

ObjectivesThe COVID-19 pandemic changed the future of work sustainably and led to a general increase in mental stress. A study conducted during the second and third pandemic wave with a retrospective survey of the first wave among 1,545 non-healthcare workers confirmed an increase in anxiety and depression symptoms and showed a correlation with the occupational SARS-CoV-2 infection risk. This online follow-up survey aims to examine changes in mental distress as the pandemic progressed in Germany and to identify factors influencing potential changes.MethodsLongitudinal data from 260 subjects were available for this analysis. Mental distress related to anxiety and depression symptoms, assessed by the Patient Health Questionnaire-4 (PHQ-4), and occupational risk factors were solicited at the end of 2022 and retrospectively at the fifth wave. Categorized PHQ-4 scores were modelled with mixed ordinal regression models and presented with odds ratios (OR) and 95% confidence intervals (95% CI).ResultsA previous diagnosis of a depressive or anxiety disorder was a strong risk factor for severe symptoms (OR 3.49, 95% CI 1.71-7.11). The impact of occupational SARS-CoV-2 infection risk on mental distress was increased, albeit failing to reach the formal level of statistical significance (high risk OR 1.83, 95% CI 0.59-5.63; probable risk OR 1.72, 95% CI 0.93-3.15). Mental distress was more pronounced in those with a previous diagnosis of anxiety and depression. Confirmed occupational risk factors were protective measures against occupational SARS-CoV-2 infection perceived as inadequate, chronic work-related stress, overcommitment, reduced interactions with fellow-workers, and work-privacy conflicts.ConclusionsThe pandemic had a negative impact on anxiety and depression symptoms among the studied non-healthcare workers, particularly early in the pandemic, although this effect does not appear to be permanent. There are modifiable risk factors that can protect workers' mental health, including strengthening social interactions among employees and reducing work-privacy conflicts.

Acetamiprid (ACE) and imidacloprid (IMI) are insecticides of global importance and are used as spray and watering agents for ornamental plants to control biting and sucking insects or as topical medications on pets to remove and control fleas. Human biomonitoring data on ACE and IMI exposures when applying these products are limited. We investigated exposures to ACE and IMI in male volunteers after the domestic application of either an ACE-containing agent or an IMI-containing spot-on medication. Complete and consecutive urine samples were collected for up to 56 h after application. Urine samples were analyzed for ACE, IMI, and their respective metabolites (N-desmethyl-ACE, IMI-olefin, and sum of 4−/5-hydroxy-IMI) by liquid chromatography–tandem mass spectrometry. Fairly uniform concentrations of N-desmethyl-ACE could be observed before and after orchid treatment, so that an ACE exposure associated with orchid treatment can most likely be excluded. In contrast, after the application of the IMI-containing medication, elevated concentrations of IMI, 4−/5-hydroxy-IMI, and IMI-olefin were quantified in urine samples post-20 h with maximum concentrations of 3.1, 14.9, and 8.0 μg/g creatinine, respectively, well above general background levels. Nevertheless, the IMI intake (10.6 μg/kg bw), calculated from the excreted amounts, was around five times below the current European acceptable daily intake. Based on the case results here, household exposures to ACE and IMI after spray treatment of ornamental plants and anti-flea treatment of dogs can be regarded as low and safe. However, people regularly applying neonicotinoid-containing formulations, such as professional gardeners and employees in animal shelters, should be studied in more detail.

IntroductionPolycyclic aromatic hydrocarbons (PAHs) are carcinogenic to humans and are formed by incomplete combustion. PAHs are always present during firefighting operations, and fire department members can be exposed to them in the workplace.MethodsIn this study, we analyzed 1-hydroxypyrene (1-OHP) in 36 urine samples from nine firefighters, collected before and after fire training sessions, and 32 urine samples from eight employees at respiratory protection and hose workshops. To assess breakthrough PAH exposure through personal protective equipment and potential dermal uptake, some of the workshop employees wore cotton garments under their regular workwear. Cotton samples were then examined for the presence of 17 semi-volatile and low-volatility PAHs.ResultsAfter firefighting exercises, we observed approximately a fivefold increase in mean 1-OHP concentrations in samples from firefighters, from 0.24 μg/L to 1.17 μg/L (maximum: 5.31 μg/L). In contrast, 1-OHP levels in workshop employees were found to be low, with the majority of urine samples yielding concentrations below the limit of quantification (LOQ: 0.05 μg/L, maximum: 0.11 μg/L). Similarly, low PAH levels were found on the workshop employees' cotton undergarments, with maximum concentrations of 250 and 205 ng/g for pyrene and benzo[a]pyrene, respectively.DiscussionIn conclusion, significant increases in 1-OHP in urine were observed in firefighters after training sessions, whereas work-related exposure remained low among workshop employees.

The UV filters octocrylene (OC) and 2-ethylhexyl salicylate (EHS) are commonly used in sunscreens and frequently detected in environmental media. However, knowledge on human exposures is scarce.In this human biomonitoring (HBM) study, we analyzed concentrations of exposure biomarkers specific to OC (CPAA, DOCCA, 5OH-OC) and EHS (5OH-EHS, 5oxo-EHS, 5cx-EPS) in 24-h urine samples (n = 420) from the German Environmental Specimen Bank (ESB). These samples were collected from German students (20–29 years; 30 males/30 females per year) between 1996 and 2020 (4-year intervals; collection in winter).We found continuously increasing OC and EHS exposures (Jonckheere-Terpstra; p LOQ) and 0.060 µg/L 5cx-EPS (88 %>LOQ). This general trend was confirmed by the other biomarkers, however at lower detection rates. Based on metabolite excretion in the 24-h urine samples and human toxicokinetic data, we calculated maximum daily intakes (DI) of 17 µg/(kg bw * d) OC and 59 µg/(kg bw * d) EHS. Based on a derived no-effect level (DNEL) of 0.8 mg/(kg bw * d), the OC exposures of individuals in our study did not indicate any health risk. Similarly, for EHS all biomarker concentrations were well below the HBM-I values of 12 µg/L 5OH-EHS and 11 µg/L 5cx-EPS.Our data proves the general applicability of specific OC and EHS metabolites for HBM in the general population and shows clearly increasing exposures. Higher (co-)exposures must be expected in populations with increased sunscreen use such as (summer) vacationers, children and outdoor workers.

Abstract To quantify the subjective and cognitive impairment caused by wearing face masks at work, 20 men and 20 women (median age 47 years, range 19–65) were tested under different ergometer workloads while wearing surgical mask, community mask, FFP2 respirator or no mask in a randomized and partially double-blinded design. Masks were worn also at the workplace for four hours. Subjective impairment was recorded by questionnaires. Cognitive performance was tested before and after the workplace examination. Subjective feeling of heat, humidity, and difficult breathing increased with rising physical exertion and wearing time for all three mask types, most notably for FFP2. Even when blinded, participants with FFP2 reported difficult breathing already at rest. During physical exertion, individuals with low tolerance to discomfort reported significantly stronger impairment (OR 1.14, 95% CI 1.02–1.27). Regarding light work, older subjects (OR 0.95, 95% CI 0.92–0.98) and women (OR 0.84, 95% CI 0.72–0.99) showed significantly lower and atopic subjects stronger impairment (OR 1.16, 95% CI 1.06–1.27). No significant influence of mask wearing was detected on cognitive performance. Wearing a mask had no effect on cognitive performance, but led to discomfort which increased with physical exertion and wearing time. Individuals who tolerate discomfort poorly felt more impaired by wearing a mask during physical exertion.

Abstract The use of face masks became mandatory during SARS-CoV-2 pandemic. Wearing masks may lead to complaints about laboured breathing and stress. The influence of different masks on cardiopulmonary performance was investigated in a partially double-blinded randomized cross-over design. Forty subjects (19–65 years) underwent body plethysmography, ergometry, cardiopulmonary exercise test and a 4-h wearing period without a mask, with a surgical mask (SM), a community mask (CM), and an FFP2 respirator (FFP2). Cardiopulmonary, physical, capnometric, and blood gas related parameters were recorded. Breathing resistance and work of breathing were significantly increased while wearing a mask. During exercise the increase in minute ventilation tended to be lower and breathing time was significantly longer with mask than without mask. Wearing a mask caused significant minimal decreases in blood oxygen pressure, oxygen saturation, an initial increase in blood and inspiratory carbon dioxide pressure, and a higher perceived physical exertion and temperature and humidity behind the mask under very heavy exercise. All effects were stronger when wearing an FFP2. Wearing face masks at rest and under exercise, changed breathing patterns in the sense of physiological compensation without representing a health risk. Wearing a mask for 4-h during light work had no effect on blood gases.

Abstract Background Most threshold limit values are based on animal experiments. Often, the question remains whether these data reflect the situation in humans. As part of a series of investigations in our exposure lab, this study investigates whether the results on the inflammatory effects of particles that have been demonstrated in animal models can be confirmed in acute inhalation studies in humans. Such studies have not been conducted so far for barium sulfate particles (BaSO4), a substance with very low solubility and without known substance-specific toxicity. Previous inhalation studies with zinc oxide (ZnO), which has a substance-specific toxicity, have shown local and systemic inflammatory respones. The design of these human ZnO inhalation studies was adopted for BaSO4 to compare the effects of particles with known inflammatory activity and supposedly inert particles. For further comparison, in vitro investigations on inflammatory processes were carried out. Methods Sixteen healthy volunteers were exposed to filtered air and BaSO4 particles (4.0 mg/m3) for two hours including one hour of ergometric cycling at moderate workload. Effect parameters were clinical signs, body temperature, and inflammatory markers in blood and induced sputum. In addition, particle-induced in vitro-chemotaxis of BaSO4 was investigated with regard to mode of action and differences between in vivo and in vitro effects. Results No local or systemic clinical signs were observed after acute BaSO4 inhalation and, in contrast to our previous human exposure studies with ZnO, no elevated values of biomarkers of inflammation were measured after the challenge. The in vitro chemotaxis induced by BaSO4 particles was minimal and 15-fold lower compared to ZnO. Conclusion The results of this study indicate that BaSO4 as a representative of granular biopersistent particles without specific toxicity does not induce inflammatory effects in humans after acute inhalation. Moreover, the in vitro data fit in with these in vivo results. Despite the careful and complex investigations, limitations must be admitted because the number of local effect parameters were limited and chronic toxicity could not be studied.

Abstract Use of menopausal hormone therapy (MHT) is associated with increased risk for breast cancer. However, the relevant mechanisms and its interaction with genetic variants are not fully understood. We conducted a genome-wide interaction analysis between MHT use and genetic variants for breast cancer risk in 27,585 cases and 34,785 controls from 26 observational studies. All women were post-menopausal and of European ancestry. Multivariable logistic regression models were used to test for multiplicative interactions between genetic variants and current MHT use. We considered interaction p-values

Abstract To examine the effect of night shift on salivary cortisol at awakening (C1), 30 min later (C2), and on the cortisol awakening response (CAR, the difference between C2 and C1). We compared shift and non-shift workers with a focus on the impact of worker chronotype. Our study included 66 shift-working females (mean age = 37.3 years, SD = 10.2) and 21 non-shift working females (mean age = 47.0 years, SD = 8.9). The shift workers collected their saliva samples at C1 and C2 on each two consecutive day shifts and night shifts. Non-shift workers collected their samples on two consecutive day shifts. We applied linear mixed-effects models (LMM) to determine the effect of night shift on CAR and log-transformed C1 and C2 levels. LMMs were stratified by chronotype group. Compared to non-shift workers, shift workers before day shifts (i.e. after night sleep) showed lower cortisol at C1 (exp $$(\widehat{\beta })$$ ( β ^ ) =0.58, 95% CI 0.42, 0.81) but not at C2. In shift workers, the CARs after night shifts (i.e. after day sleep) were lower compared to CARs before day shifts ( $$\widehat{\beta }$$ β ^ = − 11.07, 95% CI − 15.64, − 6.50). This effect was most pronounced in early chronotypes (early: $$\widehat{\beta }$$ β ^ = − 16.61, 95% CI − 27.87, − 5.35; intermediate: $$\widehat{\beta }$$ β ^ = − 11.82, 95% CI − 18.35, − 5.29; late: $$\widehat{\beta }$$ β ^ = − 6.27, 95% CI − 14.28, 1.74). Chronotype did not modify the association between night shift and CAR. In our population of shift workers, there was a mismatch between time of waking up and their natural cortisol peak at waking up (CAR) both during day and night shift duties.

Abstract Background Smoking intensity, which is generally based on self-reported average cigarettes per day (CPD), is a major behavioural risk factor and strongly related to socioeconomic status (SES). To assess the validity of the CPD measure, correlations with objective markers of tobacco smoke exposure – such as urinary nicotine metabolites – were examined. Yet, it remains unclear, whether this correlation is affected by SES, which may indicate imprecise or biased self-reports of smoking intensity. Methods We investigated the role of SES in the association between CPD and nicotine metabolites in current smokers among the participants of the population-based, prospective Heinz Nixdorf Recall Study. We determined urinary cotinine and additionally trans-3′-hydroxy-cotinine. SES was assessed by the International Socio-Economic Index of occupational status, and education. We calculated correlations (Pearson’s r) between logarithmised CPD and cotinine in subgroups of SES and analysed SES and further predictors of cotinine in multiple linear regression models separately by gender. Results Median reported smoking intensity was 20 CPD in male and 19 CPD in female smokers. Men showed higher cotinine concentrations (median 3652 μg/L, interquartile range (IQR) 2279–5422 μg/L) than women (3127 μg/L, IQR 1692–4920 μg/L). Logarithmised CPD correlated moderately with cotinine in both, men and women (Pearson’s r 0.4), but correlations were weaker in smokers with lower SES: Pearson’s r for low, intermediate, and high occupational SES was 0.35, 0.39, and 0.48 in men, and 0.28, 0.43, and 0.47 in women, respectively. Logarithmised CPD and urinary creatinine were main predictors of cotinine in multiple regression models, whereas SES showed a weak negative association in women. Results were similar for trans-3′-hydroxy-cotinine. Conclusions Decreasing precision of self-reported CPD was indicated for low SES in men and women. We found no strong evidence for biased self-reports of smoking intensity by SES.

Abstract Background Genome-wide association studies (GWAS) have identified multiple common breast cancer susceptibility variants. Many of these variants have differential associations by estrogen receptor (ER) status, but how these variants relate with other tumor features and intrinsic molecular subtypes is unclear. Methods Among 106,571 invasive breast cancer cases and 95,762 controls of European ancestry with data on 173 breast cancer variants identified in previous GWAS, we used novel two-stage polytomous logistic regression models to evaluate variants in relation to multiple tumor features (ER, progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and grade) adjusting for each other, and to intrinsic-like subtypes. Results Eighty-five of 173 variants were associated with at least one tumor feature (false discovery rate

Homosalate (HMS) is a salicylate UV filter broadly used in sunscreens and personal care products. The aim of this study was the collection of human toxicokinetic data on HMS as a tool for risk assessment. For this purpose, metabolism and urinary excretion after a single oral HMS dose (98.2–149.1 µg (kg body weight)−1) were investigated in four volunteers (two male, two female). As commercial products generally contain a mixture of cis- and trans-HMS, both cis-rich and trans-rich isomer mixtures were studied to investigate possible differences in metabolism. Initial metabolite screening tentatively identified six oxidative metabolite subgroups, of which hydroxylated and carboxylic acid metabolites were studied in more detail. Unchanged parent HMS and the previously identified HMS metabolites 5-((2-hydroxybenzoyl)oxy)-3,3-dimethylcyclohexane-1-carboxylic acid (HMS-CA) and 3-hydroxy-3,5,5-trimethylcyclohexyl 2-hydroxybenzoate (3OH-HMS), respectively, were quantified separately as cis- and trans-isomers via authentic standards by isotope dilution analysis. In addition, further alkyl-hydroxylated and carboxylic acid metabolites were investigated semi-quantitatively. Peak concentrations in urine were reached 1.5–6.3 h post-dose and more than 80 % of each of the quantitatively investigated metabolites (and at least 70 % of the semi-quantitatively investigated metabolites) was excreted within the first 24 h. Plasma and urine data indicated that oral bioavailability of cis-HMS was one order of magnitude below that of trans-HMS. Furthermore, the mean total urinary excretion fraction (Fue) for the metabolites derived from trans-HMS (6.4 %) was two orders of magnitude higher than for the metabolites derived from cis-HMS (0.045 %). Our data proves diastereoselectivity in toxicokinetics of cis- and trans-HMS, emphasizing the necessity to address isomer ratios in future studies including HMS exposure and risk assessments.

Lung cancer is the most often diagnosed cancer and the main cause of cancer deaths in the world compared with other tumor entities. To date, the only screening method for high‐risk lung cancer patients is low‐dosed computed tomography which still suffers from high false‐positive rates and overdiagnosis. Therefore, there is an obvious need to identify biomarkers for the detection of lung cancer that could be used to guide the use of low‐dosed computed tomography or other imaging procedures. We aimed to assess the performance of the protein cysteine‐rich angiogenic inducer 61 (CYR61) as a circulating biomarker for the detection of lung cancer. CYR61 concentrations in plasma were significantly elevated in 87 lung cancer patients (13.7 ± 18.6 ng·mL−1) compared with 150 healthy controls (0.29 ± 0.22 ng·mL−1). Subset analysis stratified by sex revealed increased CYR61 concentrations for adenocarcinoma and squamous cell carcinoma in men compared with women. For male lung cancer patients versus male healthy controls, the sensitivity was 84% at a specificity of 100%, whereas for females, the sensitivity was 27% at a specificity of 99%. The determination of circulating CYR61 protein in plasma might improve the detection of lung cancer in men. The findings of this pilot study support further verification of CYR61 as a biomarker for lung cancer detection in men. Additionally, CYR61 is significantly elevated in women but sensitivity and specificity for CYR61 are too low for the improvement of the detection of lung cancer in women.

OBJECTIVES: We investigated general job demands as a risk factor for lung cancer as well as their role in the association between occupational prestige and lung cancer. METHODS: In 13 case–control studies on lung cancer, as part of the international SYNERGY project, we applied indices for physical (PHI) and psychosocial (PSI) job demands – each with four categories (high to low). We estimated odds ratios (OR) and 95% confidence intervals (CI) for lung cancer by unconditional logistic regression, separately for men and women and adjusted for study centre, age, smoking behavior, and former employment in occupations with potential exposure to carcinogens. Further, we investigated, whether higher risks among men with low occupational prestige (Treiman’s Standard International Occupational Prestige Scale) were affected by adjustment for the job indices. RESULTS: In 30 355 men and 7371 women, we found increased risks (OR) for lung cancer with high relative to low job demands in both men [PHI 1.74 (95% CI 1.56–1.93), PSI 1.33 (95% CI 1.17–1.51)] and women [PHI 1.62 (95% CI 1.24–2.11), PSI 1.31 (95% CI 1.09–1.56)]. OR for lung cancer among men with low occupational prestige were slightly reduced when adjusting for PHI [low versus high prestige OR from 1.44 (95% CI 1.32–1.58) to 1.30 (95% CI 1.17–1.45)], but not PSI. CONCLUSIONS: Higher physical job demands were associated with increased risks of lung cancer, while associations for higher psychosocial demands were less strong. In contrast to physical demands, psychosocial demands did not contribute to clarify the association of occupational prestige and lung cancer.

Alzheimer’s disease (AD), the leading cause of dementia, is a growing health issue with very limited treatment options. To meet the need for novel therapeutics, existing drugs with additional preferred pharmacological profiles could be recruited. This strategy is known as ‘drug repurposing’. Here, we describe dimethyl fumarate (DMF), a drug approved to treat multiple sclerosis (MS), to be tested as a candidate for other brain diseases. We used an APP-transgenic model (APPtg) of senile β-amyloidosis mice to further investigate the potential of DMF as a novel AD therapeutic. We treated male and female APPtg mice through drinking water at late stages of β-amyloid (Aβ) deposition. We found that DMF treatment did not result in modulating effects on Aβ deposition at this stage. Interestingly, we found that glutathione-modified DMF interacts with the ATP-binding cassette transporter ABCC1, an important gatekeeper at the blood–brain and blood–plexus barriers and a key player for Aβ export from the brain. Our findings suggest that ABCC1 prevents the effects of DMF, which makes DMF unsuitable as a novel therapeutic drug against AD. The discovered effects of ABCC1 also have implications for DMF treatment of multiple sclerosis.

Abstract Background Given the high heterogeneity among breast tumors, associations between common germline genetic variants and survival that may exist within specific subgroups could go undetected in an unstratified set of breast cancer patients. Methods We performed genome-wide association analyses within 15 subgroups of breast cancer patients based on prognostic factors, including hormone receptors, tumor grade, age, and type of systemic treatment. Analyses were based on 91,686 female patients of European ancestry from the Breast Cancer Association Consortium, including 7531 breast cancer-specific deaths over a median follow-up of 8.1 years. Cox regression was used to assess associations of common germline variants with 15-year and 5-year breast cancer-specific survival. We assessed the probability of these associations being true positives via the Bayesian false discovery probability (BFDP

There exist relatively sparse and conflicting data on high-level microsatellite instability (MSI-H) and deficient mismatch repair (dMMR) in cutaneous malignancies. We aimed to determine the expression profiles of MMR proteins (MSH2, MSH6, MLH1, and PMS2) in different progression stages of cutaneous squamous cell carcinoma (cSCC, 102 patients in total) by immunohistochemistry, and search for MSI-H in patients with low-level MMR or dMMR using multiplex-PCR. Low-level MMR protein expression was observed in five patients: One patient with primary cSCC < 2 mm thickness and low-level MLH1, three patients with primary cSCC > 6 mm (including one with low-level MSH2, as well as MSH6 expression, and two with low-level PMS2), and one patient with a cSCC metastasis showing low-level MSH2 as well as MSH6. Intergroup protein expression analysis revealed that MLH1 and MSH2 expression in actinic keratosis was significantly decreased when compared to Bowen’s disease, cSCC < 2 mm, cSCC > 6 mm, and cSCC metastasis. In cases with low-level MMR, we performed MSI-H tests revealing three cases with MSI-H and one with low-level MSI-L. We found low-level MMR expression in a small subset of patients with invasive or metastatic cSCC. Hence, loss of MMR expression may be associated with tumour progression in a small subgroup of patients with non-melanoma skin cancer.

Nonylphenol (NP) has been under scrutiny for decades due to its endocrine-disrupting properties and its ubiquity in the environment. Despite its widespread occurrence, robust and reliable exposure data are rare. In this study, we used human biomonitoring (HBM) measuring the novel urinary alkyl-chain-oxidized biomarkers OH-NP and oxo-NP to determine NP exposure in 7-year-old Japanese children. The new biomarkers are advantageous over measuring unchanged NP because they are not prone to external contamination. We analyzed 180 first morning void urine samples collected between 2012 and 2017. OH-NP and oxo-NP were detected in 100% and 66% of samples at median concentrations of 2.69 and 0.36 µg/L, respectively. 10-fold concentration differences between OH-NP and oxo-NP are in line with recent findings on human NP metabolism. Based on OH-NP we back-calculated median and maximum NP daily intakes (DI) of 0.14 and 0.95 µg/(kg bw*d). These DIs are rather close to but still below the current provisional tolerable daily intake of 5 µg/(kg bw*d) by the Danish Environmental Protection Agency. Between 2012 and 2017 the DIs decreased by an average of 4.7% per year. We observed no seasonal changes or gender differences and questionnaire data on food consumption, housing characteristics or pesticide use showed no clear associations with NP exposure. Urinary OH-NP was weakly associated with the oxidative stress (lipid peroxidation) biomarkers N-ε-hexanoyl-lysine (HEL) and trans-4-hydroxy-2-nonenal (HNE) (Spearman ρ = 0.30 and 0.22, respectively), but not with 8-hydroxy-2′-deoxyguanosine (8-OHdG). Further research is needed to identify and understand the major sources of NP exposure and to investigate a potential role in oxidative stress. This study is the first to investigate NP exposure in Japanese children based on robust and sensitive HBM data. It is a first step to fill the long-standing gap in quantitative human NP exposure monitoring and risk assessment.

Street cleaning is an integral part of the solid waste management system. There are different ways to achieve clean streets depending on the availability of equipment, the type and magnitude of dirt, the surface conditions encountered or traffic conditions. In general, hand sweeping by an individual worker or a group, hose flushing, or machine sweeping or flushing are applied. In order to obtain information about the occurrence and relevance of occupational health hazards of street cleaners, the current international literature, as well as corresponding German regulations, were reviewed and evaluated. Street cleaning includes a variety of health hazards for employees. These can be subdivided into effects of occupational tasks and effects of working conditions such as weather or road traffic. The hazards result from physical, chemical and biological exposures, but may also be due to physiological and psychological burden or inadequate safety aspects. The most commonly reported work-related complaints are musculoskeletal and respiratory disorders, cuts, slips, and road traffic accidents. In developing countries, street cleaners seem to be still heavily exposed to dust and, in most cases, no suitable protective measures are available. Especially in industrialized countries there exist a number of standards and recommendations for waste workers that aim to reduce their occupational health impacts. Int J Occup Med Environ Health. 2020;33(6):701–32

Abstract Objective Calretinin is a well-known immunohistochemical tissue marker in the diagnosis of malignant mesothelioma. Promising results also indicate the use in early detection. In the present cross-sectional survey, correlations of calretinin plasma levels with clinical features were investigated. Plasma samples of 60 patients with malignant pleural mesothelioma (MPM) and 111 cancer-free controls formerly exposed to asbestos were compared. Calretinin concentrations were determined in plasma using an enzyme-linked immunosorbent assay (ELISA). Results The median concentration was higher in MPM patients than in controls (0.79 vs. 0.23 ng/ml; p

Abstract Background For the detection of malignant mesothelioma additional markers are needed besides the established panel consisting of calretinin and mesothelin. The aim of this study was the identification and verification of long non-coding RNAs (lncRNAs) as complementing circulating markers. Methods Candidate lncRNAs were identified in silico using previously published RNA expression profiles and verified using quantitative PCR (qPCR) in mesothelioma cell lines as well as human plasma samples from mesothelioma patients and asbestos-exposed controls. Results GAS5 (growth arrest-specific transcript 5) as a single marker is marked by a low sensitivity of 14%, but the combination of GAS5 with calretinin and mesothelin increased the panel’s sensitivity from 64 to 73% at a predefined specificity of 97%. Circulating GAS5 is not affected by pleurectomy before blood collection, age, or smoking status. Conclusions GAS5 is verified as an appropriate circulating marker for the supplement of calretinin and mesothelin to detect malignant mesothelioma. Although the sensitivity of GAS5 is too low for the use as a single marker, the addition of GAS5 as a third marker improves the performance of the established marker panel. The benefit of GAS5 for the detection of malignant mesothelioma at early stages needs to be validated in a prospective study.

Abstract Background Exposure to airborne zinc oxide (ZnO) particles occurs in many industrial processes, especially in galvanizing and welding. Systemic inflammation after experimental inhalation of ZnO particles has been demonstrated previously, but little is known about the impact on the cardiovascular system, particularly on the autonomic cardiac system and the risk of arrhythmias. In this study we investigated the short-term effects of ZnO nanoparticles on heart rate variability (HRV) and repolarization in healthy adults in a concentration-dependent manner at rest and during exercise in a controlled experimental set-up. Methods Sixteen healthy subjects were exposed to filtered air and ZnO particles (0.5, 1.0 and 2.0 mg/m3) for 4 h, including 2 h of cycling at low workloads. Parameters were assessed before, during, immediately after, and about 24 h after each exposure. For each subject, a total number of 46 10-min-sections from electrocardiographic records were analyzed. Various parameters of HRV and QT interval were measured. Results Overall, no statistically significant effects of controlled ZnO inhalation on HRV parameters and QT interval were observed. Additionally, a concentration-response was absent. Conclusion Inhalation of ZnO nanoparticles up to 2.0 mg/m3 for 4 h does not affect HRV and cardiac repolarization in healthy adults at the chosen time points. This study supports the view that cardiac endpoints are insensitive for the assessment of adverse effects after short-term inhalation of ZnO nanoparticles.

Urine-based biomarkers are a rational and promising approach for the detection of bladder cancer due to the proximity of urine to the location of the tumor site and the non-invasive nature of its sampling. A well-known and highly investigated biomarker for bladder cancer is survivin. For detection of very small amounts of urinary survivin protein a highly sensitive assay was developed. The assay is based on the immuno-PCR technology, more precisely a solid-phase proximity ligation assay (spPLA). The limit of detection for the survivin spPLA was 1.45 pg/mL, resulting in an improvement of the limit of detection by a factor of approximately 23 compared to the previously in-house developed survivin ELISA. A key step in development was the initial isolation of survivin by a molecular fishing rod based on magnetic beads. Interfering matrix compounds pose a special challenge for further analytical application, but can be overcome by this isolation step. The assay is designed to work with only 500 μL of voided urine. The survivin spPLA showed a sensitivity of 30% and specificity of 89% for bladder cancer detection in this study of 110 bladder cancer cases and 133 clinical controls. Moreover, the results demonstrated again that survivin is a useful complementary marker in combination with UBC® Rapid by increasing the overall sensitivity to 70% with a specificity of 86%. Although the performance for detection of bladder cancer was rather low, the herein developed assay might serve as a new tool for survivin biomarker research in diverse human fluids, even if the biological matrix is complex or survivin is only present in small amounts.

Malignant pleural mesothelioma (MPM) is a cancer associated with asbestos exposure and its diagnosis is challenging due to the moderate sensitivities of the available methods. In this regard, miR-103a-3p was considered to increase the sensitivity of established biomarkers to detect MPM. Its behavior and diagnostic value in the Mexican population has not been previously evaluated. In 108 confirmed MPM cases and 218 controls, almost all formerly exposed to asbestos, we quantified miR-103-3a-3p levels in leukocytes using quantitative Real-Time PCR, together with mesothelin and calretinin measured in plasma by ELISA. Sensitivity and specificity of miR-103-3a-3p alone and in combination with mesothelin and calretinin were determined. Bivariate analysis was performed using Mann-Whitney U test and Spearman correlation. Non-conditional logistic regression models were used to calculate the area under curve (AUC), sensitivity, and specificity for the combination of biomarkers. Mesothelin and calretinin levels were higher among cases, remaining as well among males and participants ≤60 years old (only mesothelin). Significant differences for miR-103a-3p were observed between male cases and controls, whereas significant differences between cases and controls for mesothelin and calretinin were observed in men and women. At 95.5% specificity the individual sensitivity of miR-103a-3p was 4.4% in men, whereas the sensitivity of mesothelin and calretinin was 72.2% and 80.9%, respectively. Positive correlations for miR-103a-3p were observed with age, environmental asbestos exposure, years with diabetes mellitus, and glucose levels, while negative correlations were observed with years of occupational asbestos exposure, creatinine, erythrocytes, direct bilirubin, and leukocytes. The addition of miR-103a-3p to mesothelin and calretinin did not increase the diagnostic performance for MPM diagnosis. However, miR-103a-3p levels were correlated with several characteristics in the Mexican population.

Abstract Objective Standardised quantitative analysis of the humoral immune response to SARS‐CoV‐2 antigens may be useful for estimating the extent and duration of immunity. The aim was to develop enzyme‐linked immunosorbent assays (ELISAs) for the quantification of human IgG antibodies against SARS‐CoV‐2 antigens. Methods Enzyme‐linked immunosorbent assays were developed based on monoclonal antibodies against human IgG and recombinant SARS‐CoV‐2 antigens (Spike‐S1 and Nucleocapsid). The WHO 67/086 immunoglobulin and WHO 20/136 SARS‐CoV‐2 references were used for standardisation. Sera of a study group of COVID‐19‐positive subjects (n = 144), pre‐pandemic controls (n = 135) and individuals vaccinated with BioNTech–Pfizer BNT162b2 vaccine (n = 48) were analysed. The study group sera were also tested using EuroImmun SARS‐CoV‐2‐ELISAs and a quantitative S1‐specific fluorescence enzyme immunoassay (FEIA) from Thermo Fisher. Results The ELISA results were repeatable and traceable to international units because of their parallelism to both WHO references. In the study group, median anti‐S1‐IgG concentrations were 102 BAU mL−1, compared to 100 and 1457 BAU mL−1 in the vaccination group after first and second vaccination, respectively. The ELISAs achieved an area under the curve (AUC) of 0.965 (S1) and 0.955 (Nucleocapsid) in receiver operating characteristic (ROC) analysis, and a specificity of 1 (S1) and 0.963 (Nucleocapsid) and sensitivity of 0.903 (S1) and 0.833 (Nucleocapsid) at the maximum Youden index. In comparison, the commercial assays (S1‐FEIA, S1 and Nucleocapsid ELISA EuroImmun) achieved sensitivities of 0.764, 0.875 and 0.882 in the study group, respectively. Conclusions The quantitative ELISAs to measure IgG binding to SARS‐CoV‐2 antigens have good analytical and clinical performance characteristics and units traceable to international standards.

BackgroundNight and shift work are suspected to cause various adverse effects on health and sleep. Sleep deprivation through shift work is assumed to be compensated on free days. So far it is not clear how different shift systems and shift lengths affect sleep structure on work and free days. Especially working night shifts disrupts the circadian rhythm but also extended working hours (12h) might affect sleep characteristics. Hitherto, the magnitude of sleep debt, social jetlag, and Locomotor Inactivity During Sleep (LIDS) in different shift systems is unknown.MethodsHere, we investigated the impact of five different shift rosters on sleep in 129 industrial workers from Germany. Permanent night work with multiple shift systems with and without night shifts and with different shift lengths were compared. Wrist-activity was monitored over 28 days revealing sleep on- and offsets as well as LIDS as proxy for sleep quality. Overall, 3,865 sleep bouts comprising 22,310 hours of sleep were examined.ResultsThe mean daily age-adjusted sleep duration (including naps) was 6:43h and did not differ between shift workers of different rosters. However, sleep duration on workdays was particularly low in rotational shift systems with 12h-shifts (5:00h), while overall sleep debt was highest. Shift workers showed a median absolute social jetlag of 3:03h, which differed considerably between shift types and rosters (pConclusionsShift work leads to partial sleep deprivation, which particularly affects workers in 12h-shifts and permanent night shifts. Working these shifts resulted in higher sleep debts and larger absolute social jetlag whereas sleep quality was especially reduced in permanent night shift workers compared with shift workers of other rosters.

Alzheimer’s disease (AD) is the most common cause of dementia. Fingolimod has previously shown beneficial effects in different animal models of AD. However, it has shown contradictory effects when it has been applied at early disease stages. Our objective was to evaluate fingolimod in two different treatment paradigms. To address this aim, we treated male and female APP-transgenic mice for 50 days, starting either before plaque deposition at 50 days of age (early) or at 125 days of age (late). To evaluate the effects, we investigated the neuroinflammatory and glial markers, the Aβ load, and the concentration of the brain-derived neurotrophic factor (BDNF). We found a reduced Aβ load only in male animals in the late treatment paradigm. These animals also showed reduced microglia activation and reduced IL-1β. No other treatment group showed any difference in comparison to the controls. On the other hand, we detected a linear correlation between BDNF and the brain Aβ concentrations. The fingolimod treatment has shown beneficial effects in AD models, but the outcome depends on the neuroinflammatory state at the start of the treatment. Thus, according to our data, a fingolimod treatment would be effective after the onset of the first AD symptoms, mainly affecting the neuroinflammatory reaction to the ongoing Aβ deposition.

Abstract Background Workers in the zinc production and processing of galvanized sheet steel are exposed to a complex mixture of particles and gases, including zinc oxide (ZnO) that can affect human health. We aimed to study the effects of short-term controlled exposure to nano-sized ZnO on airway inflammatory markers in healthy volunteers. Methods Sixteen subjects (8 females, 8 men; age 19–42, non-smokers) were exposed to filtered air and ZnO nanoparticles (0.5, 1.0 and 2.0 mg/m3) for 4 h, including 2 h of cycling with a low workload. Induced sputum samples were collected during a medical baseline and a final examination and also about 24 h after each exposure. A number of inflammatory cellular and soluble markers were analyzed. Results Frequency and intensity of symptoms of airway irritation (throat irritation and cough) were increased in some subjects 24 h after ZnO exposures when compared to filtered air. The group comparison between filtered air and ZnO exposures showed statistically significant increases of neutrophils and interleukin-8 (IL-8), interleukin-6 (IL-6), matrix metalloproteinase (MMP-9) and tissue inhibitors of metalloproteinases (TIMP-1) in sputum starting at the lowest ZnO concentration of 0.5 mg/m3. However, a concentration-response relationship was absent. Effects were reversible. Strong correlations were found between neutrophil numbers and concentrations of total protein, IL-8, MMP-9, and TIMP-1. Conclusions Controlled exposures of healthy subjects to ZnO nanoparticles induce reversible airway inflammation which was observed at a concentration of 0.5 mg/m3 and higher. The lack of a concentration-response relationship warrants further studies.

Malignant mesothelioma (MM) is a severe disease mostly caused by asbestos exposure. Today, one of the best available biomarkers is the soluble mesothelin-related protein (SMRP), also known as mesothelin. Recent studies have shown that mesothelin levels are influenced by individual genetic variability. This study aimed to investigate the influence of three mesothelin (MSLN) gene variants (SNPs) in the 5′-untranslated promoter region (5′-UTR), MSLN rs2235503 C > A, rs3764246 A > G, rs3764247 A > C, and one (rs1057147 G > A) in the 3′-untranslated region (3′-UTR) of the MSLN gene on plasma concentrations of mesothelin in 410 asbestos-exposed males without cancer and 43 males with prediagnostic MM (i.e., with MM diagnosed later on) from the prospective MoMar study, as well as 59 males with manifest MM from Germany. The mesothelin concentration differed significantly between the different groups (p < 0.0001), but not between the prediagnostic and manifest MM groups (p = 0.502). Five to eight mutations of the four SNP variants studied were associated with increased mesothelin concentrations (p = 0.001). The highest mesothelin concentrations were observed for homozygous variants of the three promotor SNPs in the 5′-UTR (p < 0.001), and the highest odds ratio for an elevated mesothelin concentration was observed for MSLN rs2235503 C > A. The four studied SNPs had a clear influence on the mesothelin concentration in plasma. Hence, the analysis of these SNPs may help to elucidate the diagnostic background of patients displaying increased mesothelin levels and might help to reduce false-positive results when using mesothelin for MM screening in high-risk groups.

Glyphosate-based pesticides are the highest-volume used herbicides worldwide. International concerns regarding the potential human adverse effects of glyphosate exposures have heightened since IARC classified glyphosate as probably carcinogenic to humans. Human biomonitoring (HBM) studies have identified ubiquitous exposure to glyphosate and its main breakdown product, aminomethylphosphonic acid (AMPA), from environmental exposures. The IMAGE research project aimed to investigate farm and non-farm families’ exposure to glyphosate while aligning with the Human Biomonitoring for Europe (HBM4EU) initiative. The study recruited non-farm and farm families (who use glyphosate on their farms). Each family member provided a urine sample that was analysed using gas chromatography coupled with tandem mass spectrometry, with a limit of quantification of 0.05 µg/L for glyphosate and AMPA. In addition to general information on background exposures in farm and non-farm families, we investigated relationships in exposure between families and family members. We recruited 68 families, including 54 non-farm and 14 farm families (180 vs. 45 individuals). Some pesticide users (n = 14, all male farmers) had slightly elevated AMPA levels compared to other adult participants but, overall, we observed no significant differences between farm and non-farm families. The main metabolite, AMPA, was quantifiable in twice as many samples as glyphosate (61% vs. 32%), with a maximum concentration of 7.24 µg/L vs. 3.21 µg/L. Compared to previous studies, exposure levels were relatively low and far below current health-based guidance values (3% or less for glyphosate and AMPA). Study results suggest potential exposures from residential co-exposures or living with a pesticide user. This is the first study internationally to investigate glyphosate and AMPA across family members (farm and non-farm). We found comparably low glyphosate and AMPA exposures among these families. These results enhance our understanding of glyphosate exposures for different demographic groups and contribute to the scientific knowledge on exposures required for regulatory risk assessments and the re-evaluation of glyphosate in 2022 by the European Commission.

Abstract Objective Malignant mesothelioma is an aggressive cancer of the serous membranes. For the detection of the tumor at early stages non- or minimally-invasive biomarkers are needed. The circulating biomarkers miR-132-3p, miR-126-3p, and miR-103a-3p were analyzed in a nested case–control study using plasma samples from 17 prediagnostic mesothelioma cases and 34 matched asbestos-exposed controls without a malignant disease. Results Using prediagnostic plasma samples collected in median 8.9 months prior the clinical diagnosis miR-132-3p, miR-126-3p, and miR-103a-3p revealed 0% sensitivity on a defined specificity of 98%. Thus, the analyzed miRNAs failed to detect the cancer in prediagnostic samples, showing that they are not feasible for the early detection of malignant mesothelioma. However, the miRNAs might still serve as possible markers for prognosis and response to therapy, but this needs to be analyzed in appropriate studies.

Objectives Calretinin and mesothelin are molecular markers for the detection of malignant mesothelioma at early stages. Our objective was the re-evaluation of factors influencing calretinin and mesothelin concentrations in plasma of cancer-free men in order to minimise false-positive tests when using commercial assays approved for clinical diagnostics.Setting This re-evaluation used data and archived blood samples of the population-based Heinz Nixdorf Recall Study (HNRS) collected from 2011 to 2014.Participants The present analysis comprised of 569 cancer-free men at the time of blood sampling (median age 70 years) from HNRS.Primary and secondary outcomes Mesothelin plasma concentration was determined using ELISA and CLEIA (chemiluminescent enzyme immunoassay). Calretinin plasma concentration was assessed using ELISA.Results Compared with the previous determination of concentrations, we detected less false-positive tests using the commercial assays. In this analysis, we found nine false-positive calretinin tests using the ELISA (specificity 98.4%, 95% CI 97.0% to 99.2%) and 24 false-positive mesothelin tests using both ELISA and CLEIA (specificity 95.8%, 95% CI 93.8% to 97.2%). We confirmed renal dysfunction as major predictor of elevated marker concentrations. Mesothelin was additionally affected by bronchitis. Furthermore, elevated inflammation values and hypertension only affected the mesothelin concentration determined by ELISA.Conclusions The newly available assays of calretinin and mesothelin approved for clinical diagnostics showed high specificities in the population-based cohort of elderly men without a malignant disease. The current evaluation provides a basis to consider influencing factors in order to further improve the diagnostic procedure.

N-methyl-2-pyrrolidone (NMP) and its substitute N-ethyl-2-pyrrolidone (NEP) are aprotic solvents used in many technical applications, but also in carpets, and consumer products such as cleaning agents, and cosmetics. NMP and NEP are classified as reproductive toxicants. As a substance of very high concern (SVHC), NMP is included in the European REACH (Registration, Evaluation, Authorisation of Chemicals) candidate list for authorisation. NMP and NEP metabolites were measured in more than 2100 urine samples of 3- to 17-year-old children and adolescents, participating in the population-representative German Environmental Survey for Children and Adolescents 2014–2017 (GerES V). The two NMP metabolites 5-hydroxy-N-methyl-2-pyrrolidone (5-HNMP) and 2-hydroxy-N-methylsuccinimide (2-HMSI) could be detected and quantified in all urine samples, and the two NEP metabolites 5-hydroxy-N-ethylpyrrolidone (5-HNEP) and 2-hydroxy-N-ethylsuccinimide (2-HESI) in 32% and 87% of the urine samples. Geometric mean concentrations were 103.1 µg/L (88.21 µg/gcreatinine) for the sum of NMP metabolites and 11.86 µg/L (10.15 µg/gcreatinine) for the sum of NEP metabolites, thus remaining below the current health-based human biomonitoring values.For NMP, highest exposure was found in young children, but exposure pathways could not be revealed. Exposure to NEP was highest in adolescents and participants with low socio-economic status or migration background. Associations to usage of personal care products suggested the choice of products to have a distinct impact on NEP exposure.The presented data can be used by the German Human Biomonitoring Commission to derive new reference values (RV95) for NMP and NEP for children and adolescents in Germany. This will facilitate to recognise changing exposure levels in this population group in Germany.

In several human biomonitoring surveys, changes in the usage patterns of phthalates have come to light, but their influence on the risks associated with combined exposures is insufficiently understood. Based on the largest study to date, the 27-year survey of urinary phthalate metabolite levels in 24-hour urine samples from the German Environmental Specimen Bank, we present a deep analysis of changing phthalate exposures on mixture risks. This analysis adopts the Hazard Index (HI) approach based on the five phthalates DBP, DIBP, BBP, DEHP and DINP. Calculations of the hazard index for each study participant included updated phthalate reference doses for anti-androgenicity (RfDAAs) that take account of new evidence of phthalates’ developmental toxicity.The Maximum Cumulative Ratio (MCR) approach was used to establish whether a subject’s combined exposure was dominated by one phthalate or was influenced by several phthalates simultaneously. Generally, over the years there was a shift towards lower HIs and higher MCRs, reflecting an increased complexity of the combined exposures. The decade from 1988 to about 1999 was characterised by rather high HIs of between 3 and 7 (95th percentile) which were driven by exposure to DBP and DEHP, often exceeding their single acceptable exposures. Traditional single phthalate risk assessments would have underestimated these risks by up to 50%. From 2006 onwards, no study participant experienced exposures above acceptable levels for a single phthalate, but combined exposures were still in excess of HI = 1. From 2011 onwards most individuals stayed below HI = 1. In interpreting these results, we caution against the use of HI = 1 as an acceptable limit and develop proposals for improved and more realistic mixture risk assessments that take account of co-exposures to other anti-androgenic substances also capable of disrupting the male reproductive system. From this perspective, we regard HIs between 0.1 and 0.2 as more appropriate for evaluating combined phthalate exposures. Assessed against lowered HIs of 0.1 – 0.2, the combined phthalate exposures of most study participants exceeded acceptable levels in all study years, including 2015. Continued monitoring efforts for phthalate combinations are required to provide the basis for appropriate risk management measures. Keywords: Phthalates, Urinary metabolites, Human biomonitoring, Daily intake, Cumulative risk assessment, Hazard Index

Most of the occupational exposure limits (OELs) are based on local irritants. However, exposure to much lower concentrations of irritant substances can also lead to health complaints from workers. Exposure to irritants is often accompanied by strong unpleasant odors, and strong odors might have distracting effects and hence pose a safety risk. The findings obtained in human exposure studies with chemically sensitive, stressed, or anxious persons suggest that their ability to direct attention away from the odorous exposure and to focus on a cognitive task is reduced. In addition, after repeated odor exposure, these persons show signs of sensitization, i.e., difficulties in ignoring or getting used to the exposure. The question arises as to whether certain health conditions are accompanied by a change in sensitivity to odors and irritants, so that these persons are potentially more distracted by odors and irritants and therefore more challenged in working memory tasks than nonsusceptible persons. In our study, susceptible persons with sensory airway hyperreactivity (“capsaicin-sensitive”) respond more strongly to mechanical skin stimuli than controls and show altered network connectivity. Capsaicin-sensitive subjects have a lower pain threshold and thus are more sensitive to mechanical skin stimuli. The intrinsic functional connectivity of their saliency network is higher, and the lower the GABAergic tone of the thalamus, the higher their pain sensitivity to mechanical stimuli. It seems that the increased communication between resting-state networks promotes a stronger perception of the sensory input signal. The results can be used to inform about actual risks (i.e., attention diversion and increased risk of accidents) and “pseudo” risks such as odor perception without a negative impact on one’s well-being. This way, uncertainties that still prevail in the health assessment of odorous and sensory irritating chemicals could be reduced.

The WHO classified air pollution as a human lung carcinogen and polycyclic aromatic hydrocarbons (PAHs) are components of both indoor (e.g., tobacco smoke and cookstoves) and outdoor (e.g., wildfires and industrial and vehicle emissions) air pollution, thus a human health concern. However, few studies have evaluated the adverse effects of low molecular weight (LMW) PAHs, the most abundant PAHs in the environment. We hypothesized that LMW PAHs combined with the carcinogenic PAH benzo[a]pyrene (B[a]P) act as co-carcinogens in human lung epithelial cell lines (BEAS-2B and A549). Therefore, in this paper, we evaluate several endpoints, such as micronuclei, gap junctional intercellular communication (GJIC) activity, cell cycle analysis, anti-BPDE-DNA adduct formation, and cytotoxicity after mixed exposures of LMW PAHs with B[a]P. The individual PAH doses used for each endpoint did not elicit cytotoxicity nor cell death and were relevant to human exposures. The addition of a binary mixture of LMW PAHs (fluoranthene and 1-methylanthracene) to B[a]P treated cells resulted in significant increases in micronuclei formation, dysregulation of GJIC, and changes in cell cycle as compared to cells treated with either B[a]P or the binary mixture alone. In addition, anti-BPDE-DNA adducts were significantly increased in human lung cells treated with B[a]P combined with the binary mixture of LMW PAHs as compared to cells treated with B[a]P alone, further supporting the increased co-carcinogenic potential by LMW PAHs. Collectively, these novel studies using LMW PAHs provide evidence of adverse pulmonary effects that should warrant further investigation.

Abstract Background Inhalation of high concentrations of zinc oxide particles (ZnO) may cause metal fume fever. In an earlier human inhalation study, no effects were observed after exposure to ZnO concentrations of 0.5 mg/m3. Further data from experimental studies with pure ZnO in the concentration range between 0.5 and 2.5 mg/m3 are not available. It was the aim of this experimental study to establish the concentration-response relationship of pure nano-sized ZnO particles. Methods Sixteen healthy subjects were exposed to filtered air and ZnO particles (0.5, 1.0 and 2.0 mg/m3) for 4 h on 4 different days, including 2 h of cycling with a low workload. The effects were assessed before, immediately after, and about 24 h after each exposure. Effect parameters were symptoms, body temperature, inflammatory markers and clotting factors in blood, and lung function. Results Concentration-dependent increases in symptoms, body temperature, acute phase proteins and neutrophils in blood were detected after ZnO inhalation. Significant effects were detected with ZnO concentrations of 1.0 mg/m3 or higher, with the most sensitive parameters being inflammatory markers in blood. Conclusion A concentration-response relationship with nano-sized ZnO particles in a low concentration range was demonstrated. Systemic inflammatory effects of inhaled nano-sized ZnO particles were observed at concentrations well below the occpational exposure limit for ZnO in many countries. It is recommended to reassess the exposure limit for ZnO at workplaces.

Abstract For years occupational allergies have been among the most frequently recorded occupational diseases, and both the skin as well as the respiratory tract may be affected. An estimated 9 to 15% of adult asthma is (partially) caused by work-related exposure. Gender-specific differences in exposure cause different risks in the workplace which affect the health of employees. This also applies to exposure and working conditions when handling sensitizing working substances. The presented gender-specific analysis of the German documentation of confirmed occupational respiratory allergic diseases and occupational skin diseases reveals clear differences between men and women in the number of diseases and also in exposure conditions and working areas.

OBJECTIVES: We investigated the association of shift and night work with the incidence of prostate cancer using data of the population-based prospective Heinz Nixdorf Recall Study from the highly industrialized Ruhr area in Germany. METHODS: Participants of the baseline survey were recruited between 2000–2003. A follow-up survey including, a detailed interview on shift and night work, was conducted from 2011–2014. We included 1757 men who did not report a history of prostate cancer at baseline. We assessed shift- and night-work exposure up to time of the baseline interview. Incident prostate cancers were recorded from baseline through September 2014. We calculated hazard ratios (HR) of shift- and night-work exposure using Cox proportional hazards regression with age at event as timescale, adjusting for smoking status, family history of prostate cancer, education (≤13, 14–17, ≥18 years), and equivalent income (low, medium, high). RESULTS: We observed a twofold increased HR for prostate cancer among shift and night workers. Ever employment in shift work was associated with HR 2.29, 95% confidence interval (CI) 1.43–3.67 and night work with HR 2.27, 95% CI 1.42–3.64. HR increased steadily with duration of employment in shift or night work. Stratifying analyses by preferred midpoint of sleep, yielded strongly elevated HR among subjects with early sleep preference, although these analyses were limited by small number of cases. CONCLUSIONS: We identified increased risks for prostate cancer among men with employment in shift or night work. HR were strongly elevated among long-term employed shift workers and men with early preferred midpoint of sleep.

Abstract Amyloid-β (Aβ) deposition is one of the hallmarks of the amyloid hypothesis in Alzheimer’s disease (AD). Mouse models using APP-transgene overexpression to generate amyloid plaques have shown to model only certain parts of the disease. The extent to which the data from mice can be transferred to man remains controversial. Several studies have shown convincing treatment results in reducing Aβ and enhancing cognition in mice but failed totally in human. One model-dependent factor has so far been almost completely neglected: the endogenous expression of mouse APP and its effects on the transgenic models and the readout for therapeutic approaches. Here, we report that hAPP-transgenic models of amyloidosis devoid of endogenous mouse APP expression (mAPP-knockout / mAPPko) show increased amounts and higher speed of Aβ deposition than controls with mAPP. The number of senile plaques and the level of aggregated hAβ were elevated in mAPPko mice, while the deposition in cortical blood vessels was delayed, indicating an alteration in the general aggregation propensity of hAβ together with endogenous mAβ. Furthermore, the cellular response to Aβ deposition was modulated: mAPPko mice developed a pronounced and age-dependent astrogliosis, while microglial association to amyloid plaques was diminished. The expression of human and murine aggregation-prone proteins with differing amino acid sequences within the same mouse model might not only alter the extent of deposition but also modulate the route of pathogenesis, and thus, decisively influence the study outcome, especially in translational research.

Abstract Background Malignant mesothelioma (MM) is a deadly cancer mainly caused by previous exposure to asbestos. With a latency period up to 50 years the incidence of MM is still increasing, even in countries that banned asbestos. Secondary prevention has been established to provide persons at risk regular health examinations. An earlier detection with tumor markers might improve therapeutic options. Previously, we have developed a new blood-based assay for the protein marker calretinin. Aim of this study was the verification of the assay in an independent study population and comparison with the established marker mesothelin. Methods For a case-control study in men, a total of 163 cases of pleural MM and 163 controls were available from Australia, another 36 cases and 72 controls were recruited in Germany. All controls had asbestosis and/or plaques. Calretinin and mesothelin were determined by ELISA (enzyme-linked immunosorbent assay) in serum or plasma collected prior to therapy. We estimated the performance of both markers and tested factors potentially influencing marker concentrations like age, sample storage time, and MM subtype. Results Calretinin was able to detect all major subtypes except for sarcomatoid MM. Calretinin showed a similar performance in Australian and German men. At a pre-defined specificity of 95% the sensitivity of calretinin reached 71% and that of mesothelin 69%, when excluding sarcomatoid MM. At 97% specificity, the combination with calretinin increased the sensitivity of mesothelin from 66% to 75%. Sample storage time did not influence the results. In controls the concentrations of calretinin increased 1.87-fold (95% CI 1.10–3.20) per 10 years of age and slightly more for mesothelin (2.28, 95% CI 1.30–4.00). Conclusions Calretinin could be verified as a blood-based marker for MM. The assay is robust and shows a performance that is comparable to that of mesothelin. Retrospective analyses would not be limited by storage time. The high specificity supports a combination of calretinin with other markers. Calretinin is specific for epithelioid and biphasic MM but not the rarer sarcomatoid form. Molecular markers like calretinin and mesothelin are promising tools to improve and supplement the diagnosis of MM and warrant further validation in a prospective study.

BackgroundWe compared psychomotor vigilance in female shift workers of the Bergmannsheil University Hospital in Bochum, Germany (N = 74, 94% nurses) after day and night shifts.MethodsParticipants performed a 3-minute Psychomotor Vigilance Task (PVT) test bout at the end of two consecutive day and three consecutive night shifts, respectively. Psychomotor vigilance was analyzed with respect to mean reaction time, percentage of lapses and false starts, and throughput as an overall performance score, combining reaction time and error frequencies. We also determined the reaction time coefficient of variation (RTCV) to assess relative reaction time variability after day and night shifts. Further, we examined the influence of shift type (night vs. day) by mixed linear models with associated 95% confidence intervals (CI), adjusted for age, chronotype, study day, season, and the presence of obstructive sleep apnea (OSA).ResultsAt the end of a night shift, reaction times were increased (β = 7.64; 95% CI 0.94; 14.35) and the number of lapses higher compared to day shifts (exp(β) = 1.55; 95% CI 1.16-2.08). By contrast, we did not observe differences in the number of false starts between day and night shifts. Throughput was reduced after night shifts (β = -15.52; 95% CI -27.49; -3.46). Reaction times improved across consecutive day and night shifts, whereas the frequency of lapses decreased after the third night. RTCV remained unaffected by both, night shifts and consecutive shift blocks.DiscussionOur results add to the growing body of literature demonstrating that night-shift work is associated with decreased psychomotor vigilance. As the analysis of RTCV suggests, performance deficits may selectively be driven by few slow reactions at the lower end of the reaction time distribution function. Comparing intra-individual PVT-performances over three consecutive night and two consecutive day shifts, we observed performance improvements after the third night shift. Although a training effect cannot be ruled out, this finding may suggest better adaptation to the night schedule if avoiding fast-changing shift schedules.

We identified DNA methylation targets specific for urothelial cancer (UC) by genome-wide methylation difference analysis of human urothelial (RT4, J82, 5637), prostate (LNCAP, DU-145, PC3) and renal (RCC-KP, CAKI-2, CAL-54) cancer cell lines with their respective primary epithelial cells. A large overlap of differentially methylated targets between all organs was observed and 40 Cytosine-phosphate-Guanine motifs (CpGs) were only specific for UC cells. Of those sites, two also showed high methylation differences (≥47%) in vivo when we further compared our data to those previously obtained in our array-based analyses of urine samples in 12 UC patients and 12 controls. Using mass spectrometry, we finally assessed seven CpG sites in this “bladder-specific” region of interest in urine samples of patients with urothelial (n = 293), prostate (n = 75) and renal (n = 23) cancer, and 143 controls. DNA methylation was significantly increased in UC compared to non-UC individuals. The differences were more pronounced for males rather than females. Male UC cases could be distinguished from non-UC individuals with >30% sensitivity at 95% specificity (Area under the curve (AUC) 0.85). In summary, methylation sites highly specific in UC cell lines were also specific in urine samples of UC patients showing that in-vitro data can be successfully used to identify biomarker candidates of in-vivo relevance.

An association between low socioeconomic status (SES) and lung cancer has been observed in several studies, but often without adequate control for smoking behavior. We studied the association between lung cancer and occupationally derived SES, using data from the international pooled SYNERGY study.Twelve case-control studies from Europe and Canada were included in the analysis. Based on occupational histories of study participants we measured SES using the International Socio-Economic Index of Occupational Status (ISEI) and the European Socio-economic Classification (ESeC). We divided the ISEI range into categories, using various criteria. Stratifying by gender, we calculated odds ratios (OR) and 95% confidence intervals (CI) by unconditional logistic regression, adjusting for age, study, and smoking behavior. We conducted analyses by histological subtypes of lung cancer and subgroup analyses by study region, birth cohort, education and occupational exposure to known lung carcinogens.The analysis dataset included 17,021 cases and 20,885 controls. There was a strong elevated OR between lung cancer and low SES, which was attenuated substantially after adjustment for smoking, however a social gradient persisted. SES differences in lung cancer risk were higher among men (lowest vs. highest SES category: ISEI OR 1.84 (95% CI 1.61-2.09); ESeC OR 1.53 (95% CI 1.44-1.63)), than among women (lowest vs. highest SES category: ISEI OR 1.54 (95% CI 1.20-1.98); ESeC OR 1.34 (95% CI 1.19-1.52)).SES remained a risk factor for lung cancer after adjustment for smoking behavior.