Metabolic activation of WHO-congeners PCB28, 52, and 101 by human CYP2A6: evidence from in vitro and in vivo experiments.

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

Iron-sulfur cluster loss in mitochondrial CISD1 mediates PINK1 loss-of-function phenotypes.

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

Parkinson's disease affects millions of people worldwide, causing progressively worse symptoms like stiffness, tremors and difficulty moving. These issues result from the death of neurons in the brain that produce the neurotransmitter dopamine. While most cases have no known cause, 10 to 15 per cent are due to inherited gene mutations. This includes mutations in the genes that code for the proteins PINK1 and Parkin which are essential for maintaining healthy mitochondria, the powerhouse of the cell. Mutations in this quality control system affect a protein called CISD1, which sits within the outer surface of the mitochondria. CISD1 contains a cluster of iron and sulfur ions, and is involved in regulating iron levels and mitochondrial energy production. However, its role in inherited cases of Parkinson's disease, particularly those related to mutations in PINK1 and Parkin, is poorly understood. To understand the impact of CISD1, Bitar et al. studied genetically modified fruit flies and dopamine-producing neurons from Parkinson's patients with PINK1 mutations. This revealed that losing PINK1 activity led to higher levels of CISD1 proteins which lacked the iron-sulfur cluster due to a bond forming between two CISD1 molecules. Reducing levels of the CISD1-equivalent protein in the flies helped to alleviate most of the symptoms caused by PINK1 and Parkin gene mutations, such as difficulties climbing and impaired wing posture. These findings suggest that iron-depleted CISD1 contributes to the symptoms associated with Parkinson's disease, underscoring its potential as a drug target. Drugs that target CISD1 already exist, which could ease the way for further research. Recent studies have shown that cases of Parkinson's related to mutations in PINK-1 share features with some non-inherited instances of the disease, suggesting that this approach could potentially benefit many patients.

Occupational exposure to polychlorinated biphenyls: Development of neuropsychological functions over time.

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

Trends of Exposure to Acrylamide as Measured by Urinary Biomarkers Levels within the HBM4EU Biomonitoring Aligned Studies (2000-2021).

Acrylamide, a substance potentially carcinogenic in humans, represents a very prevalent contaminant in food and is also contained in tobacco smoke. Occupational exposure to higher concentrations of acrylamide was shown to induce neurotoxicity in humans. To minimize related risks for public health, it is vital to obtain data on the actual level of exposure in differently affected segments of the population. To achieve this aim, acrylamide has been added to the list of substances of concern to be investigated in the HBM4EU project, a European initiative to obtain biomonitoring data for a number of pollutants highly relevant for public health. This report summarizes the results obtained for acrylamide, with a focus on time-trends and recent exposure levels, obtained by HBM4EU as well as by associated studies in a total of seven European countries. Mean biomarker levels were compared by sampling year and time-trends were analyzed using linear regression models and an adequate statistical test. An increasing trend of acrylamide biomarker concentrations was found in children for the years 2014-2017, while in adults an overall increase in exposure was found to be not significant for the time period of observation (2000-2021). For smokers, represented by two studies and sampling for, over a total three years, no clear tendency was observed. In conclusion, samples from European countries indicate that average acrylamide exposure still exceeds suggested benchmark levels and may be of specific concern in children. More research is required to confirm trends of declining values observed in most recent years.

Time Trends of Acrylamide Exposure in Europe: Combined Analysis of Published Reports and Current HBM4EU Studies.

More than 20 years ago, acrylamide was added to the list of potential carcinogens found in many common dietary products and tobacco smoke. Consequently, human biomonitoring studies investigating exposure to acrylamide in the form of adducts in blood and metabolites in urine have been performed to obtain data on the actual burden in different populations of the world and in Europe. Recognizing the related health risk, the European Commission responded with measures to curb the acrylamide content in food products. In 2017, a trans-European human biomonitoring project (HBM4EU) was started with the aim to investigate exposure to several chemicals, including acrylamide. Here we set out to provide a combined analysis of previous and current European acrylamide biomonitoring study results by harmonizing and integrating different data sources, including HBM4EU aligned studies, with the aim to resolve overall and current time trends of acrylamide exposure in Europe. Data from 10 European countries were included in the analysis, comprising more than 5500 individual samples (3214 children and teenagers, 2293 adults). We utilized linear models as well as a non-linear fit and breakpoint analysis to investigate trends in temporal acrylamide exposure as well as descriptive statistics and statistical tests to validate findings. Our results indicate an overall increase in acrylamide exposure between the years 2001 and 2017. Studies with samples collected after 2018 focusing on adults do not indicate increasing exposure but show declining values. Regional differences appear to affect absolute values, but not the overall time-trend of exposure. As benchmark levels for acrylamide content in food have been adopted in Europe in 2018, our results may imply the effects of these measures, but only indicated for adults, as corresponding data are still missing for children.

Concept for the Evaluation of Carcinogenic Substances in Population-Based Human Biomonitoring.

The Human Biomonitoring (HBM) Commission at the German Environment Agency holds the opinion that for environmental carcinogens for which no exposure levels can be assumed and are harmless to health, health-based guidance values corresponding to the classical definition of the HBM-I or HBM-II value cannot be established. Therefore, only reference values have been derived so far for genotoxic carcinogens from exposure data of the general population or subpopulations. The concept presented here opens up the possibility of performing health risk assessments of carcinogenic substances in human biomonitoring, and thus goes decisively beyond the purely descriptive statistical reference value concept. Using the presented method, quantitative dose descriptors of internal exposure can be derived from those of external exposure, provided that sufficient toxicokinetic information is available. Dose descriptors of internal exposure then allow the simple estimate of additional lifetime cancer risks for measured biomarker concentrations or, conversely, of equivalent concentrations for selected risks, such as those considered as tolerable for the general population. HBM data of chronic exposures to genotoxic carcinogens can thus be used to assess the additional lifetime cancer risk referring to the general population and to justify and prioritize risk management measures.

Decomposition Products of the Initiator Bis(2,4-dichlorobenzoyl)peroxide in the Silicone Industry: Human Biomonitoring in Plasma and Urine of Workers.

Bis(2,4-dichlorobenzoyl)peroxide (2,4-DCBP) is used as an initiator for silicone rubber production. During hot curing, 2,4-DCBP decomposes into 2,4-dichlorobenzoic acid, 1,3-dichlorobenzene, and the polychlorinated biphenyl (PCB) congeners PCB-47, PCB-51, and PCB-68. The extent of occupational exposure to these decomposition products has not been investigated yet. We determined for the first time the corresponding internal exposure of employees (n = 104) of a German silicone rubber facility by human biomonitoring in plasma and urine. Collected samples were investigated by gas chromatography/mass spectrometry for levels of PCBs in plasma and by liquid chromatography/tandem mass spectrometry for urinary post-shift levels of 2,4-dichlorobenzoic acid (2,4-DCBA) and the metabolites 3,5-dichlorocatechol (3,5-DCK), 2,4-dichlorophenol (2,4-DCP), and 3,5-dichlorophenol (3,5-DCP). PCB-47 and PCB-68 levels correlated significantly and were found in >97% of all samples with maximum values of 4.43 and 0.77 µg/L, respectively. 2,4-DCBA, 3,5-DCK, 2,4-DCP, and 3,5-DCP were quantified in >80% of all urine samples with maximum levels of 1.46; 26.92; 7.68; and 0.39 mg/L, respectively. There is a considerable uptake of decomposition products of 2,4-DCBP in workers of a silicone rubber facility, affecting employees in all work areas. Individual levels depended on the work task. Considering the carcinogenic potential of PCBs, the workers' additional exposure to PCB-47 and PCB-68 might be of concern.

Blood Lead Monitoring in a Former Mining Area in Euskirchen, Germany-Volunteers across the Entire Population.

After centuries of mining in the district of Euskirchen, that is, in the communities of Mechernich and Kall, the lead concentration in the soil remains high, often exceeding regulatory guidelines. To clarify the lead body burden among residents in the region, a human biomonitoring study on a voluntary basis was initiated in which the blood lead level (BLL) was assessed. A questionnaire was distributed to evaluate lead exposure routes and confounders. Overall, 506 volunteers participated in the study, of whom 7.5% were children and adolescents, 71.9% were adults from 18 to 69 years, and 19.4% were residents 70 years or older. While the BLLs in the adult population were inconspicuous, among the children and adolescents investigated, 16.7% of the children between 3 and 17 years had BLLs above the recently revised German reference values for BLL in children. These results point towards a higher lead exposure in children living in the region. The hierarchical regression analysis based on the BLL and the questionnaire revealed the significant influence of the factors age, sex, smoking, construction age of the real estate, occupancy, and intensive contact with soil on the BLL. Measures to reduce lead exposure include a focus on improved personal and domestic hygiene to minimize lead intake.

Plasma levels of unintentionally produced non-Aroclor polychlorinated biphenyl (PCB) congeners in workers from the silicone rubber industry.

The unintentional release of non-Aroclor-PCBs 47, PCB 68 and PCB 51 by a silicone manufacturing company in North Rhine-Westphalia, Germany, due to the use of bis-(2,4-dichlorobenzoyl)peroxide (2,4-DCBP) as an initiator has raised serious concerns about the possible uptake of these congeners by workers in silicone rubber production. We have conducted a pilot study in Germany to quantify these congeners in plasma samples of employees working in and handling silicone rubber during production and electrical cable manufacturing. A total of 117 plasma samples were collected from workers in 7 companies and 84 plasma samples from control subjects not working in silicone industry. PCB 47 and PCB 68 were detected in plasma above the limit of quantification (0.01 µg/L) in 84% and 66% of the silicone industry workers, respectively, whereas both congeners were undetectable in plasma of the control group. The maximum levels for PCB 47 were 2.56 µg/L and for PCB 68 were 0.42 µg/L. PCB 51 could not be determined in any plasma sample. Plasma samples of workers making electric cables had in general lower levels than those from workers making silicone rubber. Due to the high persistence of PCBs and the poorly defined toxicological properties of PCB 47 and PCB 68, a replacement of 2,4-DCBP as initiator in silicone rubber production should be considered. Given the large market for silicone products, our results might have a global impact on silicone industry.

Upregulation of CCL7, CCL20, CXCL2, IL-1ß, IL-6 and MMP-9 in Skin Samples of PCB Exposed Individuals-A Preliminary Study.

Polychlorinated biphenyls (PCBs) are well known immunotoxic and carcinogenic compounds. Although cutaneous symptoms are the hallmark of exposure to these compounds, exact pathophysiologic mechanisms are not well understood. We took skin biopsies from moderately high PCB exposed workers (n = 25) after an informed consent and investigated the expression of immunological markers such as CCL-7, CCL-20, CXCL2, IL-1ß and IL-6, as well as the matrix metalloproteinase MMP-9, EPGN and NRF2 by RT-qPCR, and compared expression levels with plasma PCB levels. Statistical analyses showed a significant correlation between CCL-20, CXCL2, IL-6, IL-1ß, CCL-7 and MMP-9 and PCB serum levels. EPGN and NRF2 were not correlated to PCB levels in the blood. We found a significant correlation of genes involved in autoimmune, auto-inflammatory and carcinogenesis in skin samples of PCB exposed individuals with elevated plasma PCB levels. Confirmation of these findings needs to be performed in bigger study groups and larger gen-sets, including multiple housekeeping genes. Further study needs to be performed to see whether a chronical exposure to these and similar compounds can cause higher incidence of malignancies and inflammatory disease.

New data on the metabolism of chloromethylisothiazolinone and methylisothiazolinone in human volunteers after oral dosage: excretion kinetics of a urinary mercapturic acid metabolite ("M-12").

Methylisothiazolinone (MI) as well as the mixture of chloromethylisothiazolinone/methylisothiazolinone [MCI/MI (3:1)] are biocides that are used in a variety of products of every-day life. Due to the skin sensitizing properties of these biocides, their use has come under scrutiny. We have previously examined the human metabolism of MI and MCI after oral dosage of isotope-labelled analogues in human volunteers and confirmed N-methylmalonamic acid to be a major, but presumably unspecific human urinary metabolite. In the present study, we have investigated the urinary kinetics of a mercapturic acid metabolite of MI and MCI using the same set of samples. Four human volunteers received 2 mg of isotopically labelled MI and MCI separately and at least 2 weeks apart. Consecutive urine samples were collected over 48 h and were examined for the content of the (labelled) 3-mercapturic acid conjugate of 3-thiomethyl-N-methyl-propionamide ("M-12"), a known metabolite in rats. On a molar basis, M-12 represented 7.1% (3.0-10.1%) of the dose excreted in urine after dosage of MI. Excretion of this mercapturate was fast with a mean half-life of 3.6 h. Surprisingly, for MCI the mercapturate M-12 represented only 0.13% of the dose excreted in urine. Thus, this biomarker is highly specific for exposures to MI and might be used to distinguish between different exposure patterns of these biocides [use of MI or MCI/MI (3:1)] in the general population.

Estimating plasma half-lives of dioxin like and non-dioxin like polychlorinated biphenyls after occupational exposure in the German HELPcB cohort.

Polychlorinated biphenyls (PCBs) are carcinogenic persistent organic pollutants that have been used as mixtures in transformers, electrical capacitors or hydraulic oils in underground mining until their ban in the late 1980s in Germany. The widespread use of PCBs has led to an age-dependent body burden in the general population. In order to determine the human half-lives of different PCB-congeners, we have used data collected between 2010 and 2017 from the prospective investigation of the German HELPcB-cohort with high initial occupational exposure to PCBs from a transformer recycling company. PCBs were quantified in plasma of the study participants in six cross-sectional investigations using gas-chromatography coupled to mass-spectrometry. Applying logistic regression on the individual plasma levels after statistical elimination of outliers, the elimination half-lives of 18 PCB-congeners were determined. Further stratifications were performed using adjustment for blood lipids, calculation of the total amount of PCB in the body and by using a statistical model taking into account the individual age-dependent background burden. The calculated plasma half-lives ranged from 0.8 years for PCB 52 until a maximum of 28.9 years for PCB 189, depending on the model applied. E.g. the total body amount related half-live for PCB 28 is 2.41 years, for PCB 74 it is 12.81 years, for PCB 118 it is 6.65 years and for PCB 153 = 10.75 years. The model with adjustment for age dependent background burden led to shorter half-lives. The analysis revealed structure-related differences in the kinetics for the PCB-congeners examined. Congeners with a chlorine substitution in 2,4,(5)- and 4'-position showed longer half-lives than other isomers with one (or two) free 4-positions. Due to the high number of included cases and repeated measurements, our results provide valid half-live data for a large number of PCB congeners. Using these data, a rough estimation of former occupational exposures from current PCB-levels seems feasible.

Arsenic burden in e-waste recycling workers - A cross-sectional study at the Agbogbloshie e-waste recycling site, Ghana.

The export of e-waste from industrialized to developing countries has led to the formation of a large-scale informal e-waste recycling sector in Accra, Ghana. During recycling processes, workers are exposed to several hazardous substances, such as heavy metals. As a common component of e-waste, inorganic arsenic can be released during e-waste recycling processes. The aim of this study was to assess the exposure to inorganic arsenic species in e-waste workers compared to a control group. N = 84 e-waste workers and n = 94 control subjects were included in this analysis. Inorganic arsenic species were determined in urine samples using HPLC-ICP-MS. E-waste workers showed higher median concentrations of As(III), As(V), MMA, DMA and the sum of inorganic arsenic in comparison to the control group. More than 80% of the e-waste workers exceeded the acceptable concentration (14 µg/L), which was significantly higher in comparison to the control group (70%). The tolerable concentration (40 µg/L) was exceeded in 17.2% of the participants, meaning a statistically relevant risk of developing cancer due to arsenic exposure throughout their (working) life. In conclusion, the exposure to inorganic arsenic is not only a problem of informal e-waste recycling, but a major public health concern that needs further investigation.

First-trimester maternal concentrations of polyfluoroalkyl substances and fetal growth throughout pregnancy.

BACKGROUND: Several studies have investigated the possible association between prenatal exposure to perfluoroalkyl substances (PFASs) and birth anthropometry. However, none has assessed fetal size longitudinally. We studied the possible association between PFASs and fetal biometry. METHODS: In 1230 mother-child pairs of three cohorts from the Spanish INMA-Project, we analyzed perfluorohexanesulfonic acid (PFHxS), perfluorooctanesulfonic acid (PFOS), perfluorooctanoic acid (PFOA), and perfluorononanoic acid (PFNA) in first-trimester maternal plasma (collection: 2003-2008). We measured abdominal circumference (AC), femur length (FL), biparietal diameter (BPD), and estimated fetal weight (EFW) by ultrasounds at 12, 20, and 34 gestational weeks. We conducted multivariable linear regression analyses between log2-transformed (PFASs) and SD-scores of fetal parameters in each cohort and subsequent meta-analysis. We also assessed effect modification by sex and maternal smoking. RESULTS: PFHxS, PFOA, PFOS, and PFNA medians were: 0.58, 2.35, 6.05, and 0.65 ng/mL, respectively. There were no associations for the whole population in any trimester of pregnancy. However, we found an indication that maternal smoking modified the effect in different directions depending on the PFAS. Among smokers (31%), we found negative associations between both PFOA and PFNA and FL or EFW at week 20 (% change ranging between -6.8% and -5.7% per twofold PFAS increase) and positive associations between PFHxS or PFOS and BPD at week 34 (6.8% and 6.3%, respectively). CONCLUSIONS: Results did not suggest an overall association between prenatal PFASs and fetal growth. The results among smokers should be taken with caution and further studies are warranted to elucidate the possible role of smoking in this association.

Altered Gene Expression in Dioxin-Like and Non-Dioxin-Like PCB Exposed Peripheral Blood Mononuclear Cells.

Polychlorinated biphenyls (PCBs) are well known carcinogenic persistent environmental pollutants and endocrine disruptors. Our aim was to identify the possible dysregulation of genes in PCB exposed peripheral blood mononuclear cells (PBMCs) in order to give more insight into the differential pathophysiological effects of PCB congeners and mixtures, with an emphasis on immunological effects and oxidative stress. The PBMCs of a healthy volunteer (male, 56 years old) were exposed to a mixture of dioxin-like (DL)-PCBs (PCB 77, 81, 105, 114, 118, 123, 126, 156, 157, 167, 169, and 189, 250 µg/L resp.) or non-dioxin-like (NDL)-PCBs (PCB 28, 52, 101, 138, 153, 180, 250 µg/L resp.) or single PCB congener (no.28, 138, 153, 180, 250 µg/L resp.). After an incubation period of 24 h, a microarray gene expression screening was performed, and the results were compared to gene expression in control samples (PBMCs treated with the vehicle iso-octane). Treatment of PBMCs with the DL-PCB mixture resulted in the largest number of differentially regulated genes (181 upregulated genes >2-fold, 173 downregulated >2-fold). Treatment with the NDL-PCB mix resulted in 32 upregulated genes >2-fold and 12 downregulated genes >2-fold. A gene set enrichment analysis (GSEA) on DL-PCB treated PBMCs resulted in an upregulation of 125 gene sets and a downregulation of 76 gene sets. Predominantly downregulated gene sets were involved in immunological pathways (such as response to virus, innate immune response, defense response). An upregulation of pathways related to oxidative stress could be observed for all PCB congeners except PCB-28; the latter congener dysregulated the least number of genes. Our experiment augments the information known about immunological and cellular stress responses following DL- as well as NDL-PCB exposure and provides new information on PCB 28. Further studies should be performed to evaluate how disruption of these pathways contributes to the development of autoimmune diseases and cancer.

Functional and structural liver abnormalities in former PCB exposed workers - analyses from the HELPcB cohort.

The effects of polychlorinated biphenyls (PCB) on liver function and structure are still under debate. Although higher transaminase activity and tumor promoting potential of PCB reported for animal and human studies was suggested, these studies were not able to provide definitive evidence on the ability of these chemicals to affect liver function and contribution to tumor development. The aim of this study was to determine the influence of PCB on liver function and morphology in a cohort of former PCB exposed workers. Over 5 years, a longitudinal analysis of the association between PCB concentration and hepatic transaminases such as alanine transaminase (ALT) aspartate amino transaminase (AST) and gamma glutamyltransferase (γGT), as well as liver size and structure was undertaken. Data demonstrated a significant inverse association between PCB concentration and γGT activity levels but there was no marked relationship with AST and ALT activities. Regarding sonographic examination, a significant association was found between liver size and PCB concentration. This association remained, even after adjusting for alcohol consumption, liver affecting drugs, timespan of internal exposure, or age. No marked correlation was noted between PCB concentration and liver structure changes. In summary, an association was observed between PCB concentration and γGT activity levels as well as liver size in humans. The long-term health consequences attributed to PCB on liver and in particular in tumorigenesis are not foreseeable in our cohort thus far, but remain a focus in further ongoing surveillance.

Expression of CYP1A1, CYP1B1 and IL-1ß in PBMCs and skin samples of PCB exposed individuals.

Polychlorinated biphenyls (PCBs) are well- known man-made persistent environmental pollutants and endocrine disruptors. As a result of mass production in the past, background levels of these compounds can be measured in human blood worldwide. In 2010 high internal levels of PCBs were discovered in workers of a transformer-recycling company in Germany. Our aim was to measure, whether the expression of CYP1A1, CYP1B1, and IL-1ß is dysregulated in peripheral blood mononuclear cells (PBMCs) of the exposed individuals (n = max 308). Further, we measured the regulation of CYP1A1, CYP1B1, AHRR (aromatic hydrocarbon receptor repressor) and IL-1ß in skin samples of 25 workers with elevated plasma PCB levels using quantitative PCR (q-RT-PCR). We found a significant correlation between the regulation of IL-1ß in skin samples and lipid adjusted PCB levels. In the PBMCs, the expression levels of CYP1A1, CYP1B1 and IL-1ß decreased over time with decreasing PCB plasma levels. The upregulation of the cytokine IL-1ß in exposed individuals with higher PCB plasma levels warrants further investigation in order to examine its role in the pathophysiology of autoimmune disorders and tumor promotion.

Hyperpigmentation and higher incidence of cutaneous malignancies in moderate-high PCB- and dioxin exposed individuals.

Polychlorinated biphenyls (PCB) are well known persistent and toxic environmental pollutants. Our aim was to identify effects of moderate-high exposure to dioxin-like (dl) and non-dioxin-like (ndl)-PCBs on the skin in order to provide more insight in the pathophysiological effects of these compounds. We performed a dermatological examination on 92 former workers from a transformer recycling company with known elevated serum PCB and/or dioxin (polychlorinated dibenzo-p-dioxin/polychlorinated dibenzo-p-furan (PCDD/F)) levels. In addition, we performed a skin cancer screening over a period of seven years (2010-2016) on resp. 268, 271, 210, 149, 92, 129 and 79 participants. We found a higher incidence of acne and malignancies of the skin (malignant melanoma, basal cell carcinoma and mycosis fungoides) in the workers compared to normal population. The probability of having hyperpigmentation on the skin was statistically significantly higher in workers with higher sumPCBs- (OR:1.09(1.12-2.17)), dioxin-like (dl)-PCBs- (OR:1.56(1.12-2.17)) and dioxin (PCDD/Fs) (OR:1.09(1.02-1.16)) levels. Age was a confounding factor in this model. Formation of hyperpigmentation could be an indicator for (moderate-high) exposure to toxic compounds like PCBs. The higher incidence of cutaneous malignancies found in the workers might be associated with PCB- and dioxin exposure, warranting further investigation on larger cohorts.

Nicotine delivery efficiency of first- and second-generation e-cigarettes and its impact on relief of craving during the acute phase of use.

Knowledge about the change in blood nicotine concentrations during the first five minutes (acute phase) of e-cigarette vaping is important to determine whether the used product has a dependence potential or may be an efficient nicotine replacement product. To address this issue, we monitored blood nicotine levels during the acute phase in volunteers using disposable cigalikes (CLs) and a tank model (TM) and compared them with blood nicotine levels in subjects using a tobacco cigarette (TC). In parallel, heart rate changes were continually measured and withdrawal symptoms and craving were assessed with the Questionnaire on Smoking Urges before and immediately after the vaping/smoking sessions. Additionally, at the end of each session negative health effects were rated on a visual analog scale. After five minutes of e-cigarette or TC use, the mean nicotine plasma concentrations were as follows: CLs, 5.5ng/ml; TM, 9.3ng/ml; TC, 17.1ng/ml. Nicotine levels increased significantly faster in the first 4min of consuming a TC than with the CLs and the TM. The highest rate of increase in nicotine concentration was found with the TC (6.8ng/ml) and TM (2.3ng/ml) between the 1st and 2nd minute, whereas the CLs showed comparatively small changes in the amount delivered over the five minutes. Withdrawal and craving for smoking decreased with the TM by the same amount as with the TC, even though less nicotine was delivered to the blood and considerably fewer side effects occurred. The heart rate of TM users was also markedly lower than that of the TC users. Unlike CLs, TM e-cigarettes represent an effective source of nicotine and might be used as an alternative nicotine replacement product to aid smoking cessation. However, nicotine plasma levels observed in TM users after short-time vaping have also the potential to produce and sustain nicotine addiction.

[Electronic Shiazo waterpipes: a new source of indoor air pollutants]. / Elektrische Shiazo-Wasserpfeifen: eine neue Quelle für Innenraumluftschadstoffe.

BACKGROUND: For some time, a new form of waterpipe smoking has been advertised, where steam stones moistened with aroma fluids (Shiazo) are heated electronically. Since there is no combustion of tobacco, it is often assumed that the produced vapor is not harmful to health. To clarify this issue, we performed a comprehensive inner and outer exposure assessment during the use of an electronic Shiazo waterpipe. METHODS: Three volunteers smoked an electronic waterpipe operated with nicotine-free Shiazo stones in a thoroughly ventilated room for 2 h. In three smoking sessions, three fluids with different flavorings were vaporized. In parallel, emissions of particles, volatile organic compounds, polycyclic aromatic hydrocarbons (PAH), and metals were measured in indoor air. Within a biomonitoring study, urinary metabolite profiles of air pollutants were checked. For comparison, the components of the Shiazo fluids were also analyzed. RESULTS: During the smoking sessions, concentrations of formaldehyde, acetaldehyde, glycerine, and propylene glycol rose significantly in the indoor environment. The content of putative carcinogenic PAH in indoor air increased by 42% to 174 ng/m3. Particle number concentrations ranged from 39,968 to 65,610 particles/cm3 (median), with peaks at diameters from 25 to 31 nm. 3­HPMA, the mercapturic acid metabolite of the pyrolysis product acrolein, was strongly elevated in urine samples of the smokers. All fluids contained high amounts of contact allergens. CONCLUSIONS: Electronic Shiazo waterpipes release various harmful substances that considerably impact indoor air quality. Compared to conventional waterpipes, the release of pollutants is lower. Nevertheless, smoking with Shiazo waterpipes is a source of health risks for both users and bystanders.