Relevant Exposure Research Articles

Rapamycin inhibits tamoxifen-induced endometrial proliferation in vitro as a pilot approach for endometrial protection in breast cancer

Tamoxifen, a common adjuvant therapy for hormone receptor-positive breast cancer, is associated with an increased risk of endometrial pathologies, such as hyperplasia, polyps, and carcinoma. This study investigates rapamycin, an mTOR inhibitor, as a potential novel strategy for preventing tamoxifen-induced endometrial proliferation. This in vitro study utilised endometrial stromal cells isolated from infertile women. The cells were treated with tamoxifen alone or in combination with rapamycin, and proliferation was assessed using the CCK-8 assay. The activation of the mTOR pathway, as well as apoptosis and cell cycle markers, was evaluated by Western blotting to elucidate the molecular mechanisms underlying these effects. The study design emphasised simulating clinically relevant exposure levels. Tamoxifen significantly increased endometrial cell proliferation in a dose-dependent manner. Rapamycin effectively inhibited this proliferation, even at concentrations lower than those typically observed in clinical settings. Quantitative analysis by Western blotting showed activation of the mTOR pathway and cell cycle in the tamoxifen group, and inhibition of these pathways in the tamoxifen plus rapamycin combination group, whereas there was no change in apoptosis. In conclusion, rapamycin shows promise as a prophylactic agent against tamoxifen-induced endometrial pathologies, with potential implications for fertility preservation and endometrial protection in breast cancer patients.

Evaluating the Exposome Score for Schizophrenia in a Transdiagnostic Psychosis Cohort: Associations With Psychosis Risk, Symptom Severity, and Personality Traits.

Investigations of causal pathways for psychosis can be guided by the identification of environmental risk factors. A recently developed composite risk tool, the exposome score for schizophrenia (ES-SCZ), which controls for intercorrelations between risk factors, has shown fair to good performance. We tested the transdiagnostic psychosis classifier performance of the ES-SCZ with the Bipolar-Schizophrenia Network for Intermedial Phenotypes data and examined its relationship with clinical-level outcomes. We computed the case-control classifier performance for the ES-SCZ from cross-sectional data on 1055 volunteers with psychotic diagnoses (schizophrenia, schizoaffective, bipolar psychosis) and 510 controls. Multivariate regression models were used to control for the correlations between outcomes and to correct for the effects of age, sex, and family socioeconomic status across outcomes. We estimated association for the ES-SCZ with psychosis and mood symptom severity, the 5-factor model of personality, and function across biologically defined biotypes, traditional diagnostic categories, and controls. ES-SCZ classifier performance for psychosis was fair to good. ES-SCZ associations with personality factor scores were qualitatively similar between psychosis groups and controls with decreased conscientiousness and agreeableness and increased neuroticism. The patterns of associations between ES-SCZ and symptoms differed across biotypes and diagnoses. Biotype 3 and bipolar disorder had consistent within-group associations where greater exposome score predicted more severe symptoms and worse function. ES-SCZ performance was consistent with previous reports in this transdiagnostic psychosis sample (adjusted odds ratio: 3.331 [2.834, 3.915], P < .001; area under the curve: 0.762 [0.735, 0.789]). Individual differences in ES-SCZ magnitude may be useful for investigating causal pathways between developmentally relevant exposures and symptomatic expression of psychosis.

Life in green: Associations between greenspace availability and mental health over the lifecourse - A 40-year prospective birth cohort study.

The beneficial impacts of greenspace availability on mental health are well-documented. However, longitudinal evidence using a spatial lifecourse perspective is rare, leaving the dynamics of how greenspace influences mental health across the lifecourse unclear. This study first uses prospective birth cohort data to examine the associations between greenspace availability in childhood (0-16years) and mental health in adolescence (16years) and between greenspace availability and mental health across adulthood (18-40years). Data were obtained from the Christchurch Health and Development Study, comprised 1,265 cohort members born in Christchurch, New Zealand, in 1977. Mental health outcomes including depressive symptoms, anxiety disorders and suicidal ideation were assessed in adolescence (16years), and in adulthood (18-40years). Greenspace availability from birth to age 40years was measured as the proportion of vegetated areas within circular buffers (radius from 100m to 3000m) around members' geocoded residential addresses using a time-series impervious surfaces data from 1985 to 2015. Bayesian Relevant Lifecourse exposure models examined the associations between childhood greenspace availability and adolescent mental health and tested for critical/sensitive age periods. Generalised Estimating Equation logistic regression models assessed the associations between greenspace availability and mental health across adulthood. These analyses were adjusted for various important individual, family, and area-level covariates. No associations were found between childhood greenspace availability and any adolescent mental health conditions. However, in adulthood, a one standard deviation increase in greenspace availability within 1500m and 2000m buffers was associated with a 12% and 13% reduced risk of depressive symptoms, respectively, after adjusting for various covariates. This study supports the protective effects of greenspace on adult depressive symptoms, highlighting the significance of employing a spatial lifecourse epidemiology framework to examine the long-term effects of environmental factors on health over the lifecourse.

Exploring seasonal dynamics of sea spray aerosol bioactivity: Insights into molecular effects on human bronchial epithelial cells.

Sea spray aerosol (SSA) is a complex mixture of natural substances that can be inhaled by coastal residents. Previous studies have suggested that SSA may have positive effects on human health, but the molecular mechanisms and the factors influencing these effects are poorly understood. In this study, we exposed human bronchial epithelial cells (BEAS-2B) to natural SSA samples, collected monthly using quartz microfiber filters mounted on tripods within 15m of the waterline, with air drawn through pumps, throughout a one-year period at the Ostend coast, Belgium, and measured cellular gene expression changes using RNA sequencing. To simulate environmentally relevant exposure conditions, SSA extracts were applied at scaled doses equivalent to human alveolar exposure levels (multiplicative factors M = 10, 20, 40, and 80). We found that SSA exposure influenced the expression of genes involved in critical signaling pathways: mTOR, PI3K, Akt, and NF-κB were downregulated, while AMPK was upregulated. Downregulation of mTOR, PI3K, Akt, and NF-κB potentially indicates a protective response against tumor-promoting and inflammatory signals, whereas upregulation of AMPK may confer a beneficial effect on metabolic regulation. The number and direction of differentially expressed genes (DEGs) varied depending on the SSA sampling time and correlated with the phytoplankton density and chemical diversity of the SSA samples. Our results suggest that SSA contains bioactive compounds that may originate from marine algae and modulate cellular processes related to human health. We provide novel insights into the molecular effects of SSA exposure and highlight its potential as a source of natural therapeutics. To our knowledge, this is the first study to expose human lung cells to natural SSA at environmentally relevant levels, presenting a pioneering exploration of seasonal variations in exposure effects.

Endocrine-disrupting chemical, methylparaben, in environmentally relevant exposure promotes hazardous effects on the hypothalamus-pituitary-thyroid axis.

Methylparaben (MP) belongs to the paraben class and is widely used as a preservative in personal care products, medicines, and some foods. MP acts as an endocrine disrupting chemical (EDC) on the hypothalamic-pituitary-thyroid (HPT) axis. However, the effects of MP have not yet been completely elucidated, as published results are scarce and controversial. The objective of this work was to evaluate the effects of subacute exposure to MP on the HPT axis of male rats. To achieve this, in this study the animals were divided into four experimental groups: control, MP3, MP30 and MP300 (3, 30 and 300 μg/kg/day, respectively). The rats were gavage for 14 days and sacrificed at the end of MP treatment. Our findings demonstrated that MP can promote important changes in thyroid morphology, including a decrease in follicular area, colloid area, epithelial area, and epithelial height, affecting the homeostasis of the HPT axis, and affecting the expression of genes related to hormonal biosynthesis. Furthermore, changes in interstitial collagen deposition were also demonstrated. Finally, we conclude that exposure to MP can be harmful to health, as it is involved in the dysregulation of the thyroid gland, affecting its morphophysiology, suggesting that even doses considered safe by current legislation can be dangerous and should be reconsidered.

Drug-Drug Interaction Potential of Mavacamten with Midazolam: Combined Results from Clinical and Model-Based Studies.

Mavacamten is a potential inducer of cytochrome P450 (CYP) 3A4 and could reduce the effectiveness of concomitant drugs that are metabolized by CYP3A4, such as midazolam. This study aimed to determine if repeat doses of mavacamten achieving clinically relevant exposures affected midazolam exposure. This was a single-center, open-label study in healthy participants. Participants received: on day 1, midazolam 5 mg; on days 2-3, mavacamten 25mg; on days 4-16, mavacamten 15 mg; and on day 17, mavacamten 15 mg and midazolam 5 mg. Plasma concentrations of mavacamten, midazolam, and the midazolam metabolite 1'-hydroxymidazolam were measured. A physiologically based pharmacokinetic (PBPK) model was used to simulate the effect of mavacamten-mediated CYP3A4 induction on midazolam exposure by CYP2C19 phenotype. Thirteen adult participants were enrolled (46.2% were female; mean [SD] age: 34.0 [9.0] years). Compared with midazolam alone, midazolam coadministered with mavacamten decreased the maximum observed plasma concentration (Cmax), area under the drug concentration-time curve (AUC) from time zero to infinity (AUC0-inf), and AUC from time zero to last measurable concentration (AUC0-last) for midazolam by 7%, 13%, and 24%, respectively; for 1'-hydroxymidazolam, AUC0-inf and AUC0-last increased by 20% and 11%, respectively. Ten participants experienced adverse events and the majority were mild in severity. The PBPK model predicted the clinical trial data well. The PBPK simulation assessed that the overall impact of mavacamten on midazolam Cmax and AUC was predicted to be weak regardless of CYP2C19 phenotype. At clinically relevant exposures, mavacamten had a negligible effect on midazolam exposure.

Development of a fully integrated hydrological fate and transport model for plant protection products: incorporating groundwater, tile drainage, and runoff

IntroductionPlant protection products (PPPs) such as pesticides and herbicides are experiencing increased use worldwide. In the context of PPP authorization and registration, water exposure assessments (drinking water and aquatic exposure) use numerical modeling to simulate relevant hydrological processes and exposure pathways. A common practice for estimating PPP leaching to groundwater, PPP loading onto surface water via tile drainage, or PPP transport via runoff utilizes multiple one-dimensional models, each representing a separate exposure pathway. Separate analysis of individual exposure pathways can result in disparate assumptions being made that represent relative worst-case scenarios for each pathway, rather than an integrated reasonable worst-case scenario for all pathways.MethodsThe interplay between PPP degradation, leaching to groundwater, transport in tile drainage, and runoff is well-suited for simulation using an integrated surface–subsurface hydrologic and chemical fate and transport model. This study presents functionality added to HydroGeoSphere (HGS), a three-dimensional, fully integrated, surface–subsurface hydrologic model. HGS was verified against other recognized models: PRZM, HYDRUS, PEARL, PELMO, and MACRO. Added features include automatic irrigation, non-linear adsorption, temperature and soil water content-dependent degradation, and solute uptake by plant roots.Results and DiscussionHGS results for leaching of PPP mass to groundwater showed the highest correlation, lowest error, and lowest bias relative to PEARL model results. Simulation of macropore flow to tile drains in HGS produced an intermittent tile drain flow in summer that resulted in generally lower peak effluent concentrations compared to the MACRO model. Simulation of runoff in HGS produced a higher total runoff compared to the PRZM model, attributed to lower evapotranspiration in HGS. Use of the integrated HGS model resulted in a greater agreement in water balance components relative to using multiple models to simulate individual hydrologic pathways.

Semi-mechanistic population pharmacokinetic modeling of DZIF-10c, a neutralizing antibody against SARS-Cov-2: predicting systemic and lung exposure following inhaled and intravenous administration

DZIF-10c (BI 767551) is a recombinant human monoclonal antibody of the IgG1 kappa isotype. It acts as a SARS-CoV-2 neutralizing antibody. DZIF-10c has been developed for both systemic exposure by intravenous infusion as well as for specific exposure to the respiratory tract by application as an inhaled aerosol generated by a nebulizer. An integrated preclinical/clinical semi-mechanistic population pharmacokinetic model was developed to characterize the exposure profile of DZIF-10c in the systemic circulation and lungs. To inform and reduce uncertainty around exposure in the lungs following different methods of dosing, preclinical cynomolgus monkey data was combined with human data using allometric scaling principles. Human serum concentrations of DZIF-10c from two clinical trials were combined with serum/plasma and lung epithelial lining fluid (ELF) concentrations from three preclinical studies to characterize the relationship between dosing, serum/plasma, and lung exposure. The final model was used to predict exposure in the lungs following different routes of administration. Simulations showed that inhalation provides immediate and relevant exposure in the lung ELF at a much lower dose compared with an infusion. Combining inhalation with intravenous therapy results in high and sustained DZIF-10c exposure in the lungs and systemic circulation, thereby combining the benefits of both routes of administration. By combining preclinical data with clinical data (via allometric scaling principles), the developed population pharmacokinetic model reduced uncertainty around exposure in the lungs allowing evaluation of alternative dosing strategies to achieve the desired concentrations of DZIF-10c in human lungs.

Development and confirmation of humanized plasma and epithelial lining fluid exposures of meropenem, cefiderocol and tobramycin in a standardized neutropenic murine pneumonia model.

Murine pneumonia models play a fundamental role in the preclinical development of novel compounds seeking an indication for the treatment of pneumonia. It is vital that plasma exposures in these models are not used as a surrogate for exposure in pulmonary epithelial lining fluid (ELF). Herein, human-simulated regimens (HSRs) in both plasma and ELF of meropenem, cefiderocol and tobramycin are described in the standardized COMBINE murine neutropenic pneumonia model. HSRs were developed in both plasma and ELF for meropenem and cefiderocol as 2 g q8h 3 h infusions, and tobramycin 7 mg/kg 30 min infusion. Pharmacokinetic studies were performed to confirm plasma and ELF exposures in mice that recapitulated %fT > MIC for meropenem and cefiderocol, and fCmax and fAUC0-24 for tobramycin in humans. Concentration-time profiles and relevant pharmacodynamic exposures for all three compounds were well matched in mice relative to humans. None of the plasma HSRs were able to appropriately humanize the ELF. Thus, modifications of the plasma HSRs were necessary to provide unique HSRs specific to ELF exposure for each compound. It should not be assumed that lung penetration in mice relative to humans is equivalent. With HSRs confirmed for these three drugs with established clinical use in the treatment of patients with pneumonia, these humanized exposures within the standardized model will allow for back-translation of anticipated efficacy and provide purposeful quantitative benchmarks for cfu/lung assessments for researchers on an international scale.

6PPD, Not 6PPD-Quinone, Induced Serious Zebrafish Eye Damage by Disrupting the Thyroid Signaling Pathway.

N-(1,3-Dimethylbutyl)-N'-phenyl-1,4-phenylenediamine (6PPD) and its oxidation product 6PPD-quinone (6PPDQ) showed different acute toxicities and bioaccumulation potencies in fish. In this study, we compared the thyroid disrupting effects of 6PPD and 6PPDQ through in vitro, in silico, and in vivo assays. Interestingly, although 6PPD and 6PPDQ showed similar docking affinities with thyroid hormone receptor (TR) isoforms and GH3 cell inhibition effects, the thyroid signaling pathway, eye development, phototactic behaviors, and cell density in the retinal layer in the larval zebrafish were significantly affected only following 6PPD exposure. Further investigation demonstrates that 6PPD can act as a TR antagonist to reduce the opsin protein abundance and inhibit the cone photoreceptor cell proliferation, which finally alters the retinal layer structure and causes microphthalmus in zebrafish. Especially, under environmental relevant concentration exposure, 6PPD induced alterations of trβ, opn1lw1, opn1mw1, rpe65a, nr2e3 gene expressions although no significant eye histopathological change was observed. This study illustrates for the first time the more serious visual system impairment of 6PPD compared to 6PPDQ, with thyroid signaling disruption being a contributing factor, while other important toxic targets still require further research.

Sex Differences in the Anxiolytic Properties of Common Cannabis Terpenes, Linalool and β-Myrcene, in Mice.

Volatile organic compounds, colloquially referred to as "terpenes", have been proposed to impact the therapeutic qualities that are traditionally ascribed to cannabis. However, the contribution of these terpenes in anxiety, at relevant levels and exposure methods common with cannabis use, is lacking empirical assessment. We tested the anxiolytic properties of two prominent cannabis terpenes, linalool and β-myrcene, in male and female mice using short duration vapor pulls to model human inhalation when combusting flower or vaping cannabis oil. We observed sex differences in the locomotor effects in the open field and anxiolytic properties in the elevated plus maze of these terpenes that depended on their exposure characteristics. Both linalool and β-myrcene had anxiolytic effects in female mice when delivered in discrete vapor pulls over the course of 30 min. In male mice, only a single vapor hit containing linalool or β-myrcene had anxiolytic effects. The combination of sub-effective levels of linalool and the phytocannabinoid, cannabidiol (CBD), had synergistic anxiolytic effects in females, but these entourage effects between CBD and terpenes were absent with β-myrcene for females and for either terpene in males. Together, our findings reveal sex differences in the anxiolytic properties of common cannabis terpenes and highlight the potential benefits of unique combinations of CBD and terpenes in expanding the therapeutic dose window.

Sunscreen use associated with elevated prevalence of anti-nuclear antibodies in U.S. adults.

Antinuclear antibody (ANA) prevalence in the U.S. population increased from 1988 to 2012, especially in white and more educated individuals. In adults ages 20-39 years from the National Health and Nutrition Examination Survey (NHANES) 2003-2004 and 2011-2012, ANA prevalence was previously associated with urinary concentrations of a common sunscreen ingredient, benzophenone 3, measured in winter. Spot urines may not capture relevant chronic exposures, thus we examined whether ANA was related to sunscreen use. In a cross-sectional study of adults ages 20-59 (N=416 ANA positive, 2656 ANA negative, by Hep-2 immunofluorescence, 1:80 dilution), we examined associations of ANA with reported sunscreen use when in the sun for 1h or more. Logistic regression was used to calculate covariate-adjusted prevalence odds ratios (POR) and 95% Confidence Intervals (CI), overall and stratified by demographic factors, season, and vitamin D. We explored associations and joint effects with other sun protective behaviors and sunburn in the past 12 months. The association of ANA with sunscreen differed by age (interaction p=0.004): for ages 20-39, we saw an exposure response (POR 2.61, 95% CI 1.50, 4.24 for using sunscreen always or most of the time, and POR 1.85; 1.12, 3.05 for less frequent versus never-use; trend p<0.001). These associations were more apparent in females (interaction p=0.082), non-Hispanic white and black participants (vs. other race/ethnicity, interaction p=0.023), and those with sufficient serum vitamin D (≥50 vs. <50nmol/L, interaction p=0.001). ANA was not associated with other protective behaviors and not confounded or modified by these behaviors or recent sunburn. These cross-sectional findings showed frequent sunscreen was associated with ANA in younger adults, supporting the need for replication, and longitudinal studies with detailed exposure histories.

Exposure to environmentally relevant concentrations of di-(2-ethylhexyl) phthalate (DEHP) induced reproductive toxicity in female koi carp (Cyprinus carpio).

A frequently utilized plasticizer is di-(2-ethylhexyl) phthalate (DEHP), considered a ubiquitous contaminant in the environment and reported to have severe impacts on animals. Although it disrupts the female reproductive system in mammals, little is known about how it effects on fish reproduction. The reproductive parameters of female adult koi carp (Cyprinus carpio) were investigated in this study subjected to environmentally relevant exposure of DEHP (1, 10 and 100 μg/L). After 60 days experiment, significantly lower GSI was recorded in females of 10 and 100 μg/L DEHP-exposed groups. The examination of ovarian histology showed defective histoarchitecture, which included the existence of atretic oocytes, the emergence of intra-oocyte vacuoles as well as necrosis. The groups exposed to DEHP (10 and 100 μg/L) showed significant decreases in fecundity and ova-diameter values. Significant changes in the biochemical (total protein, glucose and cholesterol) and ionic (sodium, potassium, calcium and magnesium) composition were noticed in the ovarian fluid of exposed groups. The groups treated with DEHP showed higher levels of 11-ketotestosterone along with reduced levels of 17β-estradiol. Using real-time PCR, the mRNA expression of several genes linked to reproduction, such as Fshr, Lhr, Ar, Erα and Erβ were assessed and observed that there was a concentration-dependent alternation. The pairing of exposed females with untreated males significantly lowered the rates of fertilization, hatching and larval survival. In summary, the results of this investigation validated that exposure to DEHP in a nominal concentration could potentially reduce the reproductive health of female fish.

Delineating lipidomic landscapes in human and mouse ovaries: Spatial signatures and chemically-induced alterations via MALDI mass spectrometry imaging: Spatial ovarian lipidomics

This study addresses the critical gap in understanding the ovarian lipidome’s abundance, distribution, and vulnerability to environmental disruptors, a largely unexplored field. Leveraging the capabilities of matrix-assisted laser desorption ionization mass spectrometry imaging (MALDI MSI), we embark on a novel exploration of the ovarian lipidome in both mouse and human healthy tissues. Our findings reveal that the obesogenic chemical tributyltin (TBT), at environmentally relevant exposures, exerts a profound and region-specific impact on the mouse ovarian lipidome. TBT exposure predominantly affects lipid species in antral follicles and oocytes, suggesting a targeted disruption of lipid homeostasis in these biologically relevant regions. Our comprehensive approach, integrating advanced lipidomic techniques and bioinformatic analyses, documents the disruptive effects of TBT, an environmental chemical, on the ovarian lipid landscape. Similar to mice, our research also unveils distinct spatial lipidomic signatures corresponding to specific ovarian compartments in a healthy human ovary that may also be vulnerable to disruption by chemical exposures. Findings from this study not only underscore the vulnerability of the ovarian lipidome to environmental factors but also lay the groundwork for unraveling the molecular pathways underlying ovarian toxicity mediated through lipid dysregulation.

Environmental Risk Factors for Parkinson's Disease: A Critical Review and Policy Implications.

The age-standardized prevalence of Parkinson's disease (PD) has increased substantially over the years and is expected to increase further. This emphasizes the need to identify modifiable risk factors of PD, which could form a logical entry point for the prevention of PD. The World Health Organization (WHO) has recommended reducing exposure to specific environmental factors that have been reported to be associated with PD, in particular pesticides, trichloroethylene (TCE), and air pollution. In this review we critically evaluate the epidemiological and biological evidence on the associations of these factors with PD and review evidence on whether these putative associations are causal. We conclude that when considered in isolation, it is difficult to determine whether these associations are causal, in large part because of the decades-long lag between relevant exposures and the incidence of manifest PD. However, when considered in tandem with evidence from complementary research lines (such as animal models), it is increasingly likely that these associations reflect harmful causal effects. Fundamentally, whilst we highlight some evidence gaps that require further attention, we believe the current evidence base is sufficiently strong enough to support our call for stronger policy action. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

(Corrosion Division Morris Cohen Graduate Student Award) Respirometric Monitoring of Corrosion

Accurate measurement of the corrosion rate of metals and alloys under realistic exposure conditions is crucial for the elucidation of corrosion mechanisms, the development of new corrosion protection measures, and for reliable corrosion prediction. A respirometric approach to monitor corrosion rates based on quantifying the rates of the main cathodic reactions during corrosion is presented. With the proposed gravimetric, manometric, or flow cell experimental setups it is possible to follow the rates of the H2 evolution reaction (HER), the O2 reduction reaction (ORR), or both cathodic reactions simultaneously.The respirometric method can universally provide real-time corrosion rate monitoring for atmospheric corrosion conditions under thin electrolyte films, where suitable corrosion monitoring capabilities have been lacking so far. Furthermore, respirometric methods applicable to corrosion under immersion conditions are presented and coupled with electrochemical measurements. It was demonstrated on various relevant engineering metals and alloys that reliable and sensitive real-time monitoring is possible without influencing the corrosion process by the measurement itself. The accuracy and validity of the developed methodology was confirmed by independent parallel measurement methods such as mass loss, solution analysis by ion chromatography, profilometry, and electrochemical measurements. Parallel imaging of the corroding surface was carried out to visually link changes of the respirometric rates and of the exposure conditions to observations of the surface morphology, gas evolution and corrosion propagation.Besides measuring corrosion rates, the respirometric method can be used to elucidate corrosion mechanisms. The effect of changes in different exposure conditions on the corrosion rate and on the rate of the cathodic reactions could be followed in situ. This includes changes in the temperature, the composition of electrolyte, or wet–dry cycling. The role of the ORR for Mg alloy corrosion was investigated and it was found that besides HER, the ORR contributes substantially to the cathodic reactions both for atmospheric corrosion and immersion. A change in the mechanism from ORR to HER was observed with the onset of localized corrosion of Al alloys under atmospheric conditions. In the context of biodegradable metallic implants, the time-dependent corrosion behavior of Zn and Mg alloys was investigated and compared in simulated body fluids of increasing complexity. The contribution of the two-electron ORR pathway was confirmed for Zn under immersion conditions and quantified for the different simulated body fluids.By coupling the respirometric method with electrochemical measurements, it was shown that the contribution of the involved reactions and pathways to the net electric current can be extracted at different applied currents or potentials. As a result, it was possible to deconvolute dynamic polarization curves into the contributing partial reactions. Unexpected cathodic reactions (negative difference effect) during localized corrosion at anodic polarization as well as unexpected anodic dissolution (cathodic corrosion) under cathodic polarization could be revealed and quantified with the respirometric method. Moreover, the fraction of anodic current related to the O2 evolution reaction could be differentiated from the fraction of current that caused transpassive corrosion.A more sensitive respirometric method was developed that is suitable to measure corrosion rates of more corrosion resistant materials or materials in weakly corrosive environments. Corrosion scenarios that were investigated with this high resolution respirometric method include breakdown of passivity of Al and stainless steel, H2 evolution of Zn anodes in Zn ion batteries and corrosion of metals in ionic liquids. While this approach is certainly promising for laboratory applications, also the applicability to respirometric field measurements will be demonstrated. A respirometric probe was developed that can be attached to corroding structures in the field.Overall, the respirometric method provides a monitoring tool to establish the relationship between relevant exposure parameters and accurate corrosion rates. The advantages and possibilities of the developed respirometric methods open up new doors to in situ investigation of corrosion and other electrode processes Figure 1

A common phthalate replacement disrupts ovarian function in young adult mice

Di-2-ethylhexyl terephthalate (DEHTP) is a replacement for its structural isomer di-2-ethylhexyl phthalate (DEHP), a known endocrine disrupting chemical and ovarian toxicant. DEHTP is used as a plasticizer in polyvinyl chloride products and its metabolites are increasingly found in biomonitoring studies at levels similar to phthalates. However, little is known about the effects of DEHTP on the ovary. In this research, we tested the hypothesis that DEHTP is an ovarian toxicant and likely endocrine disrupting chemical like its isomer DEHP. The impact of environmentally relevant exposure to DEHTP and/or its metabolite mono-2-ethylhexyl terephthalate (MEHTP) on the mouse ovary was investigated in vivo and in vitro. For the in vivo studies, young adult CD-1 mice were orally dosed with vehicle, 10 µg/kg, 100 µg/kg, or 100 mg/kg of DEHTP for 10 days. For the in vitro studies, isolated untreated ovarian follicles were exposed to vehicle, 0.1, 1, 10, or 100 µg/mL of DEHTP or MEHTP. Follicle counts, hormone levels, and gene expression of steroidogenic enzymes, cell cycle regulators, and apoptosis factors were analyzed. In vivo, DEHTP exposure altered follicle counts compared to control. DEHTP exposure also decreased expression of cell cycle regulators and apoptotic factors compared to control. In vitro, follicle growth was reduced compared to controls, and expression of the cell cycle regulator Cdkn2b was increased. Overall, these results suggest that DEHTP and MEHTP may be ovarian toxicants at low doses and should be subjected to further scrutiny for reproductive toxicity due to their similar structures to phthalates.

EPID-22. MUTATIONAL SIGNATURE ASSOCIATED WITH HALOALKANE EXPOSURE ENRICHED IN FIREFIGHTERS IN THE ADULT GLIOMA STUDY

Abstract Using data from The Cancer Genome Atlas (TCGA) and Glioma Longitudinal Analysis (GLASS), we identified specific environmentally related mutational signatures in glioma including a signature associated with haloalkane exposure (SBS42) from the Catalogue of Somatic Mutational Signatures (COSMIC). Haloalkanes are widely used commercially including in flame retardants and fire extinguishants and are an intriguing finding given an observed increased glioma risk in firefighters. To validate our findings, we use new study participants with data on occupation (not available in either TCGA/GLASS) from the University of California, San Francisco Adult Glioma Study (AGS) to compare mutational signatures in tumors from 17 persons with glioma and documented occupational exposure to firefighting with those of 18 matched glioma patients without history of firefighting. Using whole exome sequencing, we identified environmental exposure signatures in tumor tissue from firefighters as well as in non-firefighters who had other relevant occupational exposure (e.g. auto/truck mechanic work). In these data, glioma is largely associated with aging and mutational signatures relating to endogenous mutational processes that correlate with age, such as spontaneous or enzymatic deamination of 5-methylcytosine. However, some gliomas have detectable signatures associated with exogenous mutational processes, such as SBS42 haloalkanes. Thus, we confirm detection of haloalkane signatures in persons likely highly exposed, i.e. long-term firefighters. Identifying exogenous mutational processes in cancers are important as they may inform public health intervention strategy to reduce mutagenesis and prevent cancer inception. Identifying occupational correlates with SBS42, associated with occupational exposure to haloalkanes, will pinpoint occupational hazards that may be avoidable. This is especially important for glioma and other cancers where exogenous mutagenesis is not well established.

Safety of non-invasive brain stimulation in patients with implants: a computational risk assessment.

Non-invasive brain stimulation (NIBS) methodologies, such as transcranial electric (tES) are increasingly employed for therapeutic, diagnostic, or research purposes. The concurrent presence of active/passive implants can pose safety risks, affect the NIBS delivery, or generate confounding signals. A systematic investigation is required to understand the interaction mechanisms, quantify exposure, assess risks, and establish guidance for NIBS applications. We used measurements, simplified generic, and detailed anatomical modeling to: (i) systematically analyze exposure conditions with passive and active implants, considering local field enhancement, exposure dosimetry, tissue heating and neuromodulation, capacitive lead current injection, low-impedance pathways between electrode contacts, and insulation damage; (ii) identify risk metrics and efficient prediction strategies; (iii) quantify these metrics in relevant exposure cases and (iv) identify worst case conditions. Various aspects including implant design, positioning, scar tissue formation, anisotropy, and frequency were investigated. At typical tES frequencies, local enhancement of dosimetric exposure quantities can reach up to one order of magnitude for deep brain stimulation (DBS) and stereoelectroencephalography implants (more for elongated passive implants), potentially resulting in unwanted neuromodulation that can confound results but is still 2-3 orders of magnitude lower than active DBS. Under worst-case conditions, capacitive current injection in the active implants' lead can produce local exposures of similar magnitude as the passive field enhancement, while capacitive pathways between contacts are negligible. Above 10 kHz, applied current magnitudes increase, necessitating consideration of tissue heating. Furthermore, capacitive effects become more prominent, leading to current injection that can reach DBS-like levels. Adverse effects from abandoned/damaged leads in direct electrode vicinity cannot be excluded. Safety related concerns of tES application in the presence of implants are systematically identified and explored, resulting in specific and quantitative guidance and establishing basis for safety standards. Furthermore,several methods for reducing risks are suggested while acknowledging the limitations(see Sec. 4.5).

Unveiling mercury exposure sources in e-waste recycling with biomonitoring - A Portuguese case study

Abstract Background Mercury (Hg), a global pollutant, poses risks to both human and environmental health. The management and recycling of electrical and electronic waste (e-waste) is recognized as having the potential to promote workers’ exposure to this pollutant. Human biomonitoring (HBM) is a tool that can be used to evaluate exposure and monitor the health of workers. The objective of this study was to characterize exposure of workers from an e-waste recycling company and to analyze the relevance that HBM holds in the detailed characterization of exposure. Methods A cross-sectional observational study was conducted using data collected within the framework of the European Human Biomonitoring Initiative (HBM4EU). Data from environmental monitoring (settled dust) and biological monitoring (urine and hair) of 30 workers potentially exposed to Hg were analyzed in comparison with 12 unexposed workers from other occupational settings (controls). Results Exposed workers did not exhibit significantly higher concentrations of Hg in urine when compared to control workers. We found a significantly positive correlation between the concentration of Hg in urine (ρ = 0.688; p ≤ 0.001) and hair (ρ = 0.470; p ≤ 0.01) and the consumption of fish and shellfish. Conclusions Diet appears to be the most significant source of Hg in this context. These results suggest the importance of information and dietary habits to prevent mercury exposure. HBM stands out as an essential tool for identifying the most relevant exposure sources and risk management measures for workers and the general population. Key messages • Diet appears to be the most significant Hg source in workers from a Portuguese e-waste company. • HBM stands out as essential for identifying the most relevant exposure sources and risk management.