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Historical estimation of exposure to 1,3-butadiene, styrene, and dimethyldithiocarbamate among synthetic rubber workers.

Quantitative estimates of exposure to 1,3-butadiene (BD), styrene (STY), and dimethyldithiocarbamate (DMDTC) were developed for a follow-up study of workers at six North American synthetic rubber plants. Procedures entailed identifying tasks and jobs involving exposure, identifying factors influencing historical changes in exposure potential, and using mathematical models to calculate job- and time-period-specific exposures. Exposure metrics included 8-hour time-weighted average (TWA) intensity, the annual number of peak exposures (BD: >100 ppm, STY: >50 ppm) and TWA intensity below and above the peak threshold. The 5th and 95th percentiles of the approximate probability distribution of each exposure estimate served as its 90% uncertainty interval. Job- and year-specific estimates were linked with subjects' work histories to obtain cumulative exposure indices. Exposure estimates varied among tasks, jobs, plants, and time periods. BD TWAs were approximately 10 ppm during the 1940s-1960s and declined during the 1970s and 1980s. STY TWAs were always <2 ppm. DMDTC exposure began in the 1950s, was high through the 1960s, and later declined. BD peak exposure accounted for a large proportion of cumulative BD exposure, whereas almost none of the STY exposure was experienced at levels >50 ppm. Exposure indices were correlated. Exposures were higher than previously estimated. Multiple correlations among DMDTC, BD, and STY exposure estimates make it difficult to estimate agent-specific effects. Limitations of the methodology include the potential inaccuracy of the estimates, the lack of adequate industrial hygiene data to validate the estimates, the additional inaccuracy of linkage with poorly specified job groups, and the potential for differential exposure misclassification because the jobs and work areas where excess leukemia mortality occurred were well-known at the time of this study. Nevertheless, the new exposure estimates were highly correlated with the old, yielding equivalent exposure ranking of workers and were comparable to limited industrial hygiene data published by NIOSH.

Butadienes↗

Integrative genomic and transcriptomic analysis of hypertension in a Taiwanese population.

OBJECTIVES: Hypertension is highly prevalent in Asian populations and represents a major cardiovascular risk factor. However, most genome-wide association studies (GWASs) and transcriptome-wide association studies (TWASs) have focused primarily on Caucasian cohorts. This study aimed to identify genetic loci and gene expression signatures associated with hypertension in an Asian population. METHODS: We analyzed 10 739 hypertensive patients and 49 668 controls from the Taiwan Biobank, testing 4 512 191 genome-wide single nucleotide polymorphisms (SNPs). Integrated GWAS, TWAS, and expression quantitative trait locus (eQTL) analyses were conducted to characterize genetic risk. Additionally, a polygenic risk score (PRS) was constructed using a split-sample design to evaluate genetic risk stratification. RESULTS: We identified 14 loci significantly associated with hypertension, including a novel locus at 5p13.1. eQTL analysis linked this locus to DAB2 expression in whole blood. TWAS detected 55 hypertension-associated genes, with 20 (36%) overlapping GWAS loci. Several novel genes outside GWAS loci, including FBXL15, KCNIP2, and CRIP3, were highly significant and implicated in vascular biology and hypertension mechanisms. PRS analysis effectively differentiated hypertension risk, with individuals in the top 10% showing a > 3.5-fold increased risk compared to the bottom 10%. CONCLUSIONS: Our findings provide new insights into the genetic and transcriptomic landscape of hypertension in Asians. The identification of novel loci and genes advances understanding of disease biology and may guide precision medicine approaches for risk prediction and therapeutic development.

Female↗

Integrative Multi-Omics Analysis Identifies Thrombosis-Associated Molecular Features Linked to Germline Susceptibility and Immune Cell Communication in Gastric Cancer.

Emerging evidence indicates that coagulation-related molecular programs are associated with thrombosis, tumor progression, and molecular dysregulation in gastric cancer (GC). However, thrombosis-associated molecular features in GC and their potential links to inherited susceptibility remain insufficiently understood. Integrated analyses of transcriptomic data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets were performed to identify thrombosis-associated genes and establish a machine learning-based prognostic signature. Genome-wide association study (GWAS), expression quantitative trait loci (eQTL), transcriptome-wide association study (TWAS), and Mendelian randomization (MR) analyses were conducted to investigate susceptibility-associated transcriptional programs in GC. Functional assays were used to evaluate candidate genes associated with malignant phenotypes. Single-cell RNA sequencing (scRNA-seq) and cell-cell communication analyses were further performed to characterize cell-type-specific expression patterns and potential intercellular interactions. A total of 22 differentially expressed thrombosis-associated genes were identified, and a prognostic signature comprising 14 genes was established. The signature stratified patients into high- and low-risk groups and showed prognostic performance in both the training and validation cohorts. Integrative GWAS, eQTL, and TWAS analyses identified susceptibility-associated transcriptional programs that were positively correlated with the thrombosis-associated risk score. Silencing ACTN2 and CRYAB significantly reduced GC cell migration and invasion. scRNA-seq analysis revealed relatively high CRYAB expression in neutrophils, and CellChat analysis suggested potential neutrophil-B cell interactions involving COLLAGEN-related signaling. This integrative multi-omics study identified a thrombosis-associated molecular signature linked to prognosis and germline susceptibility-associated transcriptional programs in GC. ACTN2 and CRYAB may represent candidate genes associated with GC cell migration and invasion, while single-cell analysis suggested potential immune-related communication features.

Humans↗

Multi-omics causal inference of childhood asthma triggered by ambient particulate matter.

BACKGROUND: The causal impact of fine particulate matter (PM2.5), an established environmental risk factor, on childhood asthma and its biological mechanisms remain to be elucidated. The objective of the present study was to evaluate the causal association between PM2.5 and childhood asthma and to dissect the mediating role of plasma proteins through a multi-omics integrated Mendelian randomisation (MR) framework. METHODS: Two-sample MR was performed on large-scale genome-wide association data to estimate the causal effect of PM2.5 on childhood asthma. Genes commonly associated with PM2.5 and childhood asthma were screened by transcriptome-wide association study (TWAS) and subjected to enrichment analyses and MR. Mediator proteins were identified by two-step MR. Potential adverse effects were scanned by phenome-wide MR (Phe-MR). RESULTS: MR revealed a significant positive causal effect of PM2.5 on childhood asthma (OR=1.897, 95% CI: 1.063-3.388, p=0.030). TWAS highlighted 70 genes co-expressed in PM2.5 and childhood asthma that were enriched in inflammatory pathways such as lysosome- and leukocyte-mediated immunity. MEAF6 was validated as a protective gene and RNF40 as a risk gene for childhood asthma. Two-step MR identified FUT10 as a positive mediator mediating 19.3% of the causal effect, and CD200 and MANBA as negative mediator proteins. Phe-MR indicated the association of these genes and proteins with multiple other diseases, implying possible adverse effects from therapeutic intervention. CONCLUSION: Long-term PM2.5 exposure is causally linked to childhood asthma with MEAF6, RNF40, CD200, MANBA and FUT10 identified as key molecules. The study provides new evidence for the biological mechanisms linking PM2.5 to childhood asthma.

Journal Article↗

Post-genome-wide association study dissects genetic vulnerability and risk gene expression of Sj&#xf6;gren's disease for cardiovascular disease.

OBJECTIVES: This study aims to clarify the genetic associations between Sj&#xf6;gren's Disease (SD) and cardiovascular disease (CVD) outcomes, and to conduct an in-depth exploration of specific pleiotropic susceptibility genes. METHODS: We performed two-sample and multivariable Mendelian randomization (MR) analysis to investigate the association between SD and the risk of ischemic heart disease (IHD) and stroke. Linkage disequilibrium score regression (LDSC) and Bayesian co-localization analyses were employed to assess the genetic associations between traits. Cross-phenotype analyses were employed to identify shared variants and genes, followed by a Transcriptome-Wide Association Study (TWAS) and Multi-marker Analysis of Genomic Annotation (MAGMA) based on Multi-Trait Analysis of GWAS (MTAG) results. To validate the pleiotropic genes, we further analyzed tissue-specific differentially expressed genes (DEGs) related to SD using RNA sequencing data. RESULTS: The two-sample and multivariable MR analyses revealed that SD confers a genetic vulnerability to IHD and stroke. LDSC and co-localization analyses indicated a strong genetic linkage between SD and CVDs. Cross-phenotype analyses identified 38 and 37 pleiotropic single nucleotide polymorphisms (SNPs) for SD-Stroke and SD-IHD, respectively, primarily located within the MHC class region on 6p21.32:33 loci. Additionally, TWAS and MAGMA analyses identified pleiotropic genes located outside the MHC regions-seven associated with stroke (UHRF1BP1, SNRPC, BLK, FAM167A, ARHGAP27, C8orf12, and PLEKHM1) and two associated with IHD (UHRF1BP1 and SNRPC). Proxy variants within these genes in SD suggested an increased causal risk for stroke or IHD. Co-localization analysis further reinforced that SD and stroke share significant SNPs within the loci of FAM167A, BLK, C8orf12, SNRPC, and UHRF1BP1. DEG analysis revealed a significant up-regulation of the identified genes in SD-specific tissues. CONCLUSIONS: SD appears genetically predisposed to an increased risk of CVDs. Moreover, this research not only identified pleiotropic genes shared between SD and CVDs, but also, for the first time, detected key gene expressions that elevate CVD risk in SD patients-findings that may offer promising therapeutic targets for patient management.

Humans↗

Genetics-Informed Mapping Identifies a CRIM1-Associated Endocardial Inflammatory Remodeling State in Acute Myocardial Infarction.

BACKGROUND Acute myocardial infarction (AMI) reflects inherited susceptibility and inflammatory remodeling, but the cellular contexts linking genetic risk to disease remain unclear. MATERIAL AND METHODS We integrated a meta-transcriptome-wide association study (TWAS) with a human cardiac single-nucleus RNA-sequencing atlas contained 11 individuals (5 AMI and 6 donor) to identify genetics-informed cellular programs. Composite program states were defined by global score quartiles. A fixed 5-gene panel was evaluated for nucleus-level endocardial low-transcriptional-state (Endo_LTS) vs endocardial high-transcriptional-state (Endo_HTS) discrimination within the AMI endocardium using 5-fold leave-1-patient-out cross-validation. Functional follow-up used CRIM1 silencing in hypoxia-treated human induced pluripotent stem cell (hiPSC)-derived endocardial endothelial-like cells and complementary peripheral blood analyses. RESULTS The endocardium exhibited the most prominent infarction-associated increase in TWAS-anchored program activity, with expansion of program-high states and higher CytoTRACE scores. A consensus 5-gene panel (RPS8, PLEC, CFDP1, CRIM1, TNS2) was identified. Among 2163 AMI endocardial nuclei from 5 patients, the state classifier included 364 Endo_LTS and 751 Endo_HTS nuclei; 1048 Endo_MTS nuclei were excluded. Pooled out-of-fold ROC-AUCs ranged from 0.665 to 0.831. The panel also showed discriminatory value in an independent peripheral-blood AMI-vs-control cohort. CRIM1 was prioritized as a candidate linked to the remodeling program. CRIM1 silencing attenuated ACTA2/alpha-SMA, vimentin, LDHA, CCL2, and VEGFA and partially restored CD31, whereas TGF-&#xdf; remained elevated. CONCLUSIONS These findings identify a genetics-informed endocardial inflammatory remodeling state in AMI and define a 5-gene surrogate of its activated state. CRIM1 is prioritized as a candidate linked to selected inflammatory, metabolic, and structural outputs. Persistent TGF-b elevation after CRIM1 silencing argues against a simple linear regulatory model and indicates that further mechanistic validation is required.

Humans↗

[A proposed method for evaluating short-term exposure condition].

High short-term exposure to toxic chemicals can occur during a workday, even if the daily average exposure is lower than the permissible exposure limit, because the exposure concentration varies from minute to minute. To protect workers from acute health effects due to high short-term exposure, the Japan Society for Occupational Health recommends that the maximum value for 15-min time-weighted average (15-min TWA) exposure during a workday should not exceed 1.5 times the occupational exposure limit for 8-hr TWA, and the American Conference of Governmental Industrial Hygienists issues the threshold limit value-short-term exposure limit (TLV-STEL), that is a 15-min TWA exposure which should not be exceeded at any time during a workday. A workday (8 hr) consists of thirty two 15-min periods. If the thirty-two 15-min TWAs are measured, the short-term exposure situation can be appropriately evaluated by comparing the highest measured value with the standard value (e.g. TLV-STEL), but such continuous monitoring consumes a lot of cost and time. In this paper, we propose a method for evaluating short-term exposure by using three or more measured values. This evaluation method corresponds to two different types of selection of sampling periods. One is a random selection of three or more 15-min periods among the 32 periods. If this selection is adopted, a comparison between the 98.44 percentile of the within-day distribution of 15-min TWAs and the standard value can be made by using one-sided tolerance factors, KI, KII and KIII, and the exposure situation is classified into four exposure classes at 95% and 50% confidence levels. Another is a random selection among high exposure periods. If this selection is adopted, a comparison between the specific percentile of the distribution and the standard value can be made with modified one-sided tolerance factors, and the exposure class is determined similarly. This method can provide a precise evaluation of exposure, so that it is useful in the industrial hygiene field.

Chemical Industry↗

Steam-explosion pretreatment for enhancing anaerobic digestion of municipal wastewater sludge.

This study evaluated the use of steam explosion as a pretreatment for municipal wastewater treatment sludges and biosolids as a technique for enhancing biogas generation during anaerobic digestion. Samples of dewatered anaerobic digester effluent (biosolids) and a mixture of thickened waste activated sludge (TWAS) and biosolids were steam-exploded under differing levels of intensity in this study. The results indicate that steam explosion can solublize components of these sludge streams. Increasing the intensity of the steam-explosion pressure and temperature resulted in increased solublization. The steam-explosion pretreatment also increased the bioavailability of sludge components under anaerobic digestion conditions. Increasing the steam-explosion intensity increased the ultimate yield of methane during anaerobic digestion. Batch anaerobic digestion tests suggested that pretreatment at 300 psi was the most optimal condition for enhanced biogas generation while minimizing energy input. Semicontinuous anaerobic digestion revealed that the results that were observed in the batch tests were sustainable in prolonged operation. Semicontinuous digestion of the TWAS/biosolids mixture that was pretreated at 300 psi generated approximately 50% more biogas than the controls. Semicontinuous digestion of the pretreated biosolids resulted in a 3-fold increase in biogas compared with the controls. Based on capillary suction test results, steam-explosion pretreatment at 300 psi improved the dewaterability of the final digested sludge by 32 and 45% for the TWAS/ biosolids mixture and biosolids, respectively, compared with controls. The energy requirements of the nonoptimized steam-explosion process were substantially higher than the additional energy produced from enhanced digestion of the pretreated sludge. Substantial improvements in energy efficiency will be required to make the process viable from an energy perspective.

Bacteria, Anaerobic↗

Exposure of anesthesiologists to nitrous oxide during pediatric anesthesia.

Nitrous oxide (N2O) is one of the most common inhalation anesthetics in current anesthesiological practice. Even though artificial ventilation and active scavenging in operating theaters are employed in most of the modern hospitals, potential N2O contamination persists in regular anesthesia, particularly pediatric operation. In order to understand personal exposure during pediatric anesthesia, ambient monitoring for N2O exposure around the breathing zone of the anesthesiologist was conducted by a portable infra-red Miran 1B2 spectrophotometer. The results demonstrated that general mask anesthesia generated greatest N2O contamination, with the mean time-weighted-average (TWA) concentrations of 85 +/- 48.4 (mean +/- S.D.) ppm in 12 cases. Initial mask induction followed by cuffed endotracheal incubation (6 cases) or intravenous induction followed by uncuffed endotracheal intubation (6 cases) also produced significant pollution to the workers, with the mean TWAs of 33.2 +/- 24.0 ppm and 31.9 +/- 18.0 ppm respectively. These procedures provided exposure levels above the 25 ppm Recommended Exposure Limit (REL) of the National Institute of Occupational Safety and Health (NIOSH), U.S.A. Modification with intravenous induction followed with cuffed endotracheal intubation or mask general anesthesia provided with a ventilation hood diminished the contamination apparently, with the resulting mean TWAs of 11.0 +/- 4.7 ppm and 17.9 +/- 9.8 ppm in 7 and 5 cases respectively. The results indicated that excessive N2O exposure to anesthesiologists was not negligible during routine pediatric anesthesia. Significant reduction could be achieved via appropriate industrial modification.

Air Pollutants, Occupational↗

Ultrasonic sludge treatment for enhanced anaerobic digestion.

Ultrasound is the term used to describe sound energy at frequencies above 20 kHz. High-powered ultrasound can be applied to a waste stream via purpose-designed tools in order to induce cavitation. This effect results in the rupture of cellular material and reduction of particle size in the waste stream, making the cells more amenable to downstream processing. sonix is a new technology utilising high-powered, concentrated ultrasound for conditioning sludges prior to further treatment. This paper presents recent results from a number of demonstration and full-scale plants treating thickened waste activated sludge (TWAS) prior to anaerobic digestion, therefore enhancing the process. The present studies have proved that the use of ultrasound to enhance anaerobic digestion can be achieved at full scale and effectively result in the TWAS (typically difficult to digest) behaving, after sonication, as if it were a "primary" sludge. The technology presents benefits in terms of increased biogas production, better solids reduction, improved dewatering characteristics of the digested sludge mixture and relatively short payback periods of two years or less subject to the site conditions and practices applicable at that time.

Australia↗

NTP Toxicity Study Report on the atmospheric characterization, particle size, chemical composition, and workplace exposure assessment of cellulose insulation (CELLULOSEINS).

Cellulose insulation (CI) is a type of thermal insulation produced primarily from recycled newspapers. The newspapers are shredded, milled, and treated with fire-retardant chemicals. The blowing process for installing CI generates a significant quantity of airborne material that presents a potential inhalation hazard to workers. CI was selected for study based upon the high production volume, the potential for widespread human exposure, and a lack of toxicity data; insufficient information was available to determine whether inhalation studies in laboratory animals were technically feasible or necessary. Studies were conducted to characterize the chemical and physical properties of CI aerosols, to evaluate the potential acute pulmonary toxicity of CI, and to assess occupational exposure of CI installers. Workplace exposure assessments were conducted in collaboration with the National Institute for Occupational Safety and Health (NIOSH, 2001). EVALUATION OF THE CHEMICAL COMPOSITION, PARTICLE SIZE, AND PULMONARY TOXICITY OF CELLULOSE INSULATION: Chemical analyses were performed on samples of bulk CI from four major United States manufacturers. All samples of the bulk CI were found to contain primarily amorphous cellulose (60% to 65%) with a smaller crystalline component (35% to 40%). The crystalline phase was primarily native cellulose (75% to 85%) with a minor amount of cellulose nitrate (15% to 25%). Elemental analyses of acid digests of CI materials indicated that the major components (>0.1% by weight) included aluminum, boron, calcium, sodium, and sulfur. An acid-insoluble residue present in all four materials (3% to 5% of original sample weight) was found to consist primarily of aluminum silicate hydroxide (kaolinite; approximately 85%) with minor amounts (<5% each) of magnesium silicate hydroxide (talc), potassium aluminum silicate hydroxide (muscovite), and titanium oxide (rutile). Solvent extracts of the bulk materials were analyzed for organic components by gas chromatography with flame ionization detection. Analyses revealed a mass of poorly resolved peaks. Because of the very low concentrations, further quantitative and qualitative analyses were not performed. An aerosol generation system was designed to separate CI particles based upon aerodynamic size and to simulate the process used during CI installation at work sites. Less than 0.1% of each of the CI samples was collected as the small respirable particle fraction. The mean equivalent diameter of respirable particles ranged from 0.6 to 0.7 mum. The numbers of fibers in the respirable fractions ranged from 9.7 x 103 to 1.4 x 106 fibers/g of CI. The respirable particle fractions did not contain cellulose material and consisted mainly of fire retardants and small quantities of clays. The respirable fraction from one CI sample was administered by intratracheal instillation to male Fischer 344 rats at doses of 0, 0.625, 1.25, 2.5, 5, or 10 mg/kg body weight; the bronchoalveolar lavage (BAL) fluid cellularity was evaluated 3 days later. Based upon the relatively mild severity of the inflammatory response, a dose of 5 mg/kg body weight was selected for use in a subsequent 28-day study. Rats received CI, titanium dioxide (particle controls), or sterile saline (controls). BAL fluid was evaluated 1, 3, 7, 14, and 28 days after instillation, and lung histopathology was evaluated 14 and 28 days after treatment. CI caused a greater influx of inflammatory cells than titanium dioxide and caused significant increases in BAL fluid protein and lactate dehydrogenase. These CI-induced changes in BAL fluid parameters were transient and by day 14 were not significantly different than those observed in rats treated with titanium dioxide or phosphate-buffered saline. Unlike titanium dioxide, CI treatment caused a minimal to mild nonprogressive, minimally fibrosing granulomatous pneumonitis characterized by nodular foci of macrophages and giant cells. These results indicated that few respirable particles or fibers are likely generated during the CI application and that the acute pulmonary toxicity is minimal. EXPOSURE ASSESSMENT OF CELLULOSE INSULATION APPLICATORS: The CI exposure assessment was conducted with 10 contractors located across the United States. Air samples of total dust and respirable dust were collected for scanning electron microscopy (SEM) to characterize any fibers in the dust. Two SEM air samples for each day of CI activities were collected from the installer and hopper operator. Bulk CI samples were collected and analyzed for metal, boron, and sulfate content. Real-time and video exposure monitoring was conducted to further characterize the CI dust and workers' exposures. The exposure assessment also included a medical component. Investigators collected 175 personal breathing zone (PBZ) total dust, 106 area total dust, and 90 area respirable dust air samples during CI-related activities at the 10 contractor sites. Twenty-six employees' total dust 8-hour time-weighted averages (TWAs) exceeded the Occupational Safety and Health Administration (OSHA) permissible exposure limit (PEL) of 15 mg/m3, and 42 exceeded the American Conference of Governmental Industrial Hygienists (ACGIH) threshold-limit value (TLV) of 10 mg/m3. Respirable dust air sampling and real-time monitoring with particle size discrimination indicated low levels of respirable dust generation. The SEM analyses revealed that fibers were an average 28 mum in length and ranged from 5 mum to 150 mum. CI installers' PBZ total dust, area total dust, and area respirable dust air samples were all significantly higher during dry attic applications than wet attic applications (P<0.01). Conversely, the hopper operators' total dust exposures were significantly higher during wet wall and ceiling applications than dry wall and ceiling applications (P=0.02). Analyses of variance tests revealed that exposure concentrations in total dust air samples collected in the PBZ of all CI workers, including installers working in attics, installers during wall applications, hopper operators during attic applications, and hopper operators during wall and ceiling applications, varied significantly during dry applications (P<0.01). The respirable dust air samples collected in attic areas, hopper areas during attic applications, and hopper areas during wall and ceiling applications also differed significantly during dry applications (P=0.03). Twenty-three workers participated in the medical phase of the investigation. The workers completed medical and work history questionnaires, performed serial peak flow tests, and completed multiple acute symptom surveys. The medical questionnaires indicated respiratory, nasal, and skin symptoms that employees attributed to CI exposure. The most common symptoms reported while working with CI included nasal symptoms (35%), eye symptoms (35%), and morning phlegm production (25%). There was a temporal association between CI exposure and eye symptoms, but there was little evidence of lower respiratory system health conditions associated with CI exposure. CONCLUSIONS: Chemical analyses of the four bulk CI samples revealed only minor differences in additives. The major elemental components detected were aluminum, boron, calcium, sodium, and sulfur, but they were attributed to the fire retardants aluminum sulfate, boric acid, and sodium sulfate. For all four CI samples, less than 0.1% by weight was collected as the small respirable particle fraction. The fractions consisted mainly of fire retardants and smaller quantities of clays and did not contain cellulose material. Intratracheal instillation of the respirable fraction in rats produced minimal to mild inflammatory responses in the lungs with no increase in severity by 28 days after dosage. Although a significant increase in lung collagen was detected at day 28 in treated rats, microscopic evaluation revealed only a minimal to mild increase in collagen fibrils associated with granulomatous nodules. The results of these studies indicated that few respirable particles or fibers are generated during the aerosolization of CI, and that even at very high doses of respirable CI particles, acute pulmonary toxicity is minimal. These results are supported by the NIOSH workplace exposure assessment conducted on CI workers. Based on the air sample data collected from the 10 contractor site visits, there is a potential for overexposure to CI; however, respirable dust concentrations were typically low. There was increased potential for 8-hour TWAs exceeding the OSHA PEL for total and respirable dust when employees were involved in CI application activities for longer periods of time. There was evidence of work-related eye and mucous membrane irritation among some workers, which were possibly caused by the additives present in CI, such as boric acid. There was little evidence of lower respiratory system health conditions associated with CI exposure. Based upon the results of the CI chemical characterization studies, the pulmonary toxicity study, and the worksite exposure assessment, the NTP concluded that additional studies of CI in laboratory animals are not warranted at this time. However, the animal pulmonary toxicity studies and worker health surveys focused on acute CI exposures and do not preclude the possibility of toxicity resulting from chronic exposure. Although exposure concentrations of respirable CI particulate matter were low, additional information is needed on the biodurability and reactivity of CI particles and fibers in the respiratory tract. CI should continue to be regarded as a nuisance dust, and workers should continue to wear protective masks to prevent inhalation exposure to CI dusts.

Aerosols↗

Retinal Transcriptome-Wide Association Study Identifies Novel Alzheimer's Disease Risk Genes.

INTRODUCTION: Alzheimer's disease (AD) is the leading cause of dementia worldwide. The retina shares molecular pathways with the brain, yet no study has systematically linked retinal gene expression to AD risk. METHODS: We performed transcriptome-wide association studies (TWAS) using two independent retinal eQTL panels (Strunz et al., n = 311; EyeGEx, n = 406) and a large meta-analyzed AD genome-wide association study (GWAS) (Bellenguez et al., 111,326 cases, 677,663 controls). Genes were further validated with GWAS in the independent Alzheimer's Disease Sequencing Project (ADSP) using a matched eQTL-panel strategy. RESULTS: We identified 62 AD-associated genes across the two eQTL panels using Bellenguez et al. as the discovery cohort. Of these, 31 were replicated in the ADSP cohort. The findings highlight shared complement-mediated immune dysregulation (CD55, CD46, TREM2) and provide functional transcriptomic evidence to prioritize novel causal drivers of AD pathogenesis, including STYX and the LRRC37 gene family. DISCUSSION: Retinal data capture core AD genetic architecture and reveal novel risk genes, highlighting the retina as a molecularly informative tissue for dementia research.

Alzheimer&#x2019;s disease↗

Derivation of temporary emergency exposure limits (TEELs).

Short-term chemical concentration limits are used in a variety of applications, including emergency planning and response, hazard assessment and safety analysis. Development of emergency response planning guidelines (ERPGs) and acute exposure guidance levels (AEGLs) are predicated on this need. Unfortunately, the development of peer-reviewed community exposure limits for emergency planning cannot be done rapidly (relatively few ERPGs or AEGLs are published each year). To be protective of Department of Energy (DOE) workers, on-site personnel and the adjacent general public, the DOE Subcommittee on Consequence Assessment and Protective Actions (SCAPA) has developed a methodology for deriving temporary emergency exposure limits (TEELs) to serve as temporary guidance until ERPGs or AEGLs can be developed. These TEELs are approximations to ERPGs to be used until peer-reviewed toxicology-based ERPGs, AEGL or equivalents can be developed. Originally, the TEEL method used only hierarchies of published concentration limits (e.g. PEL- or TLV-TWAs, -STELs or -Cs, and IDLHs) to provide estimated values approximating ERPGs. Published toxicity data (e.g. lc(50), lc(LO), ld(50) and ld(LO) for TEEL-3, and tc(LO) and td(LO) for TEEL-2) are included in the expanded method for deriving TEELs presented in this paper. The addition here of published toxicity data (in addition to the exposure limit hierarchy) enables TEELs to be developed for a much wider range of chemicals than before. Hierarchy-based values take precedence over toxicity-based values, and human toxicity data are used in preference to animal toxicity data. Subsequently, default assumptions based on statistical correlations of ERPGs at different levels (e.g. ratios of ERPG-3s to ERPG-2s) are used to calculate TEELs where there are gaps in the data. Most required input data are available in the literature and on CD ROMs, so the required TEELs for a new chemical can be developed quickly. The new TEEL hierarchy/toxicity methodology has been used to develop community exposure limits for over 1200 chemicals to date. The new TEEL methodology enables emergency planners to develop useful approximations to peer-reviewed community exposure limits (such as the ERPGs) with a high degree of confidence. For definitions and acronyms, see Appendix.

Animals↗

[Nitrous oxide exposure to personnel in a recovery room with modern climate control].

Epidemiologic studies have shown that trace concentrations of inhalation anaesthetics polluting the air of operating theatres could have deleterious effects on the personnel's health. Nitrous oxide (N2O) oxidises vitamin B12 and thus decreases DNA production by inactivation of methionine synthase. Therefore, the United States and most European health authorities recommend threshold values to protect against potential health risks. These values range from 25 to 100 ppm, expressed as time-weighted averages (TWA). There is a lack of data concerning measurements of trace concentrations under defined conditions. The aim of this study was to quantify levels of N2O in a recovery room (RR) with an air conditioning system. METHODS. Trace concentrations of N2O were determined in the main RR of the University Hospital of Regensburg (Germany). Measurements were taken for 5 days from 8:00 a.m. to 8:00 p.m. Trace concentrations of N2O were measured directly by means of a highly sensitive photoacoustic infrared spectrometry analyser. The lower detection limit was 0.03 ppm. Samples of room air were taken continuously from six different places in the recovery room, five of which had a distance of 50 cm to the patients' heads. One point represented the nurses' desk 5 m away from the patients. TWAs were calculated for each day and location. RESULTS. All values were below 5 ppm TWA at each location. Typical TWA (range) values recorded at day 2 were for point 1:3.5 ppm (0.4-8.9), point 2:3.2 (0.5-7.3), point 3:3.0 (0.5-5.4), point 4:3.7 (0.5-21.2), point 5:3.2 (0.6-6.6), and at the nurses' desk 3.3 (0.5-6.3). Peak concentrations of nearly 25 ppm were reached for at least 10 min. Significant differences between the days and locations could not be found (P < 0.05, Wilcoxon test). CONCLUSION. Exposure to N2O in a climatised RR is determined by several factors: (1) efficacy of air conditioning, with 10.7 changes per hour without recirculation; (2) recovery room size; (3) transport of the patients takes about 15 min, during which some quantities of N2O leave the patient; and (4) high numbers of patients staying 2 and more hours in the recovery room and exhaling smaller concentrations of N2O into the room air. Because of these factors, all measured values are significantly below the standard international threshold values. Under other conditions of room design, such as ventilation and size, measured values may be higher.

Air Conditioning↗

Biaxial total wrist arthroplasty in rheumatoid arthritis. Satisfactory functional results.

We reviewed 16 uncemented biaxial total wrist arthroplasties (TWA) in 14 patients with rheumatoid or juvenile arthritis. The mean follow-up was 25 months (range 5-60). According to the Hospital for Special Surgery scoring system (HSS), good-to-excellent results were accomplished in 69%, moderate in 19%, and poor in 12%. The mean pain score was 0.4 on a visual analog scale from 0-10 (0=no pain). The Wrightington activities of daily life assessment chart showed a 63% improvement, and we found a threefold increase in range of motion at follow-up. Four TWAs showed early dislocation, one of which was revised. Biaxial TWA yields good short-term results in rheumatoid patients, although instability is a frequent complication.

Adult↗

Self-reported stressors, symptom complaints and psychobiological functioning I: Cardiovascular stress reactivity.

Taking into account neuroticism and lifestyle variables (smoking and alcohol consumption), cardiovascular and psychological reactions to stressful films were studied in four groups of subjects selected on self-reported levels of recent stressor load and symptom complaints (low-load/low-symptoms: low-load/high-symptoms; high-load/low-symptoms; high-load/high-symptoms). The films were known either to stimulate or to depress cardiovascular activity. The results showed that psychological reactions (distress; deactivation; openness/involvement) were associated with group membership and condition. In addition, high-symptom subjects were characterized by faster resting heart rates and smaller ECG T-wave amplitudes (TWAs), reflective of greater sympathetic tone on the myocard. Further, low-symptom subjects, in particular those labeled as stress-resistant (high-load/low-symptoms), exhibited larger myocardial responses to the cardiovascular-stimulating films than did high-symptom subjects. Low-symptom subjects showed predicted variations in physiological responses to the different films, whereas the responses by the high-symptom subjects showed lesser variation across films. It is concluded that the cardiovascular responses of low-symptom subjects more accurately followed the energetic demands of the body, whereas the high-symptom subjects were in a comparatively enduring state of arousal.

Adaptation, Psychological↗

Pulmonary and sensory irritation of diphenylmethane-4,4'- and dicyclohexylmethane-4,4'-diisocyanate.

The use of isocyanates in industry has been increasing and, therefore, the potential for human exposure has also increased. Two such isocyanates are diphenylmethane-4,4'-diisocyanate (MDI) and dicyclohexylmethane-4,4'-diisocyanate (SMDI). Furthermore, there are only a few reports describing the toxicity of these diisocyanates. The pulmonary irritation of the aromatic isocyanate MDI and the sensory and pulmonary irritation of the cycloaliphatic isocyanate SMDI were studied in an animal bioassay. Groups of male, Swiss-Webster mice were exposed to aerosol concentrations of MDI varying from 17 to 67 mg/m3. The total exposure time for both isocyanates was 240 min, and the respiratory patterns and frequency of four mice were recorded during each exposure. Concentrations of MDI and SMDI in the exposure chamber were determined gravimetrically. The mass median aerodynamic diameter (MMAD) and geometric standard deviation for the MDI aerosol were 0.7 micron and 1.6 and for the SMDI aerosol were 0.9 micron and 1.5, respectively. The inhalation responses during the 4-hr exposures to aerosols of MDI and SMDI were investigated, and the animal model was used to determine time-response and concentration-response relationships for all exposures. From these results it was determined that the level of effect was dependent on both the duration of exposure and the exposure concentration. Unlike many other isocyanates tested with this animal model, MDI and SMDI acted primarily as pulmonary irritants, evoking little or no sensory irritation. The concentrations required to reduce the respiratory rate 50% (RD50) due to pulmonary irritation was 32 mg/m3 for MDI and 40 mg/m3 for SMDI. Increases in lung weight were found in groups of animals killed 24 hr following all exposures to MDI and SMDI. Using the animal model, which has been calibrated to human responses with nitrogen dioxide and other pulmonary irritants, the recommended TLV-TWAs for MDI and SMDI in industry should be no higher than 0.3 and 0.4 mg/m3, respectively.

Air Pollutants, Occupational↗

Genetics of constant and severe pain in the NAPS2 cohort of recurrent acute and chronic pancreatitis patients.

Recurrent acute and chronic pancreatitis (RAP, CP) are complex, progressive inflammatory diseases with variable pain experiences impacting patient function and quality of life. The genetic variants and pain pathways in patients contributing to most severe pain experiences are unknown. We used previously genotyped individuals with RAP/CP from the North American Pancreatitis Study II (NAPS2) of European Ancestry for nested genome-wide associated study (GWAS) for pain-severity, chronicity, or both. Lead variants from GWAS were determined using FUMA. Loci with p<1e-5 were identified for post-hoc candidate identification. Transcriptome-wide association studies (TWAS) identified loci in cis and trans to the lead variants. Serum from phenotyped individuals with CP from the PROspective Evaluation of Chronic Pancreatitis for EpidEmiologic and Translational StuDies (PROCEED) was assessed for BDNF levels using Meso Scale Discovery Immunoassay. We identified four pain systems defined by candidate genes: 1) Pancreas-associated injury/stress mitigation genes include: REG gene cluster, CTRC, NEURL3 and HSF22. 2) Neural development and axon guidance tracing genes include: SNPO, RGMA, MAML1 and DOK6 (part of the RET complex). 3) Genes linked to psychiatric stress disorders include TMEM65, RBFOX1, and ZNF385D. 4) Genes in the dorsal horn pain-modulating BDNF/neuropathic pathway included SYNPR, NTF3 and RBFOX1. In an independent cohort BDNF was significantly elevated in patients with constant-severe pain. Extension and expansion of this exploratory study may identify pathway- and mechanism-dependent targets for individualized pain treatments in CP patients. PERSPECTIVE: Pain is the most distressing and debilitating feature of chronic pancreatitis. Yet many patients with chronic pancreatitis have little or no pain. The North American Pancreatitis Study II (NAPS2) includes over 1250 pancreatitis patients of all progressive stages with all clinical and phenotypic characteristics carefully recorded. Pain did not correlate well with disease stage, inflammation, fibrosis or other features. Here we spit the patients into groups with the most severe pain and/or chronic pain syndromes and compared them genetically with patients reporting mild or minimal pain. Although some genetic variants associated with pain were expressed in cells (1) of the pancreas, most genetic variants were linked to genes expressed in the nervous system cells associated with (2) neural development and axon guidance (as needed for the descending inhibition pathway), (3) psychiatric stress disorders, and (4) cells regulating sensory nerves associated with BDNF and neuropathic pain. Similar and overlapping genetic variants in systems 2 -4 are also seen in pain syndromes form other organs. The implications for treating pancreatic pain are great in that we can no longer focus on just the pancreas. Furthermore, new treatments designed for pain disorders in other tissues may be effective in some patient with pain syndromes from the pancreas. Further research is needed to replicate and extend these observations so that new, genetics-guided rational treatments can be developed and delivered.

Humans↗