Absence of genotoxicity following pulmonary exposure to metal oxides of copper, tin, aluminum, zinc, and titanium in mice.

Inhalation of nanosized metal oxides may occur at the workplace. Thus, information on potential hazardous effects is needed for risk assessment. We report an investigation of the genotoxic potential of different metal oxide nanomaterials. Acellular and intracellular reactive oxygen species (ROS) production were determined for all the studied nanomaterials. Moreover, mice were exposed by intratracheal instillation to copper oxide (CuO) at 2, 6, and 12 µg/mouse, tin oxide (SnO2) at 54 and 162 µg/mouse, aluminum oxide (Al2O3) at 18 and 54 µg/mouse, zinc oxide (ZnO) at 0.7 and 2 µg/mouse, titanium dioxide (TiO2) and the benchmark carbon black at 162 µg/mouse. The doses were selected based on pilot studies. Post-exposure time points were 1 or 28 days. Genotoxicity, assessed as DNA strand breaks by the comet assay, was measured in lung and liver tissue. The acellular and intracellular ROS measurements were fairly consistent. The CuO and the carbon black bench mark particle were potent ROS generators in both assays, followed by TiO2. Al2O3, ZnO, and SnO2 generated low levels of ROS. We detected no increased genotoxicity in this study using occupationally relevant dose levels of metal oxide nanomaterials after pulmonary exposure in mice, except for a slight increase in DNA damage in liver tissue at the highest dose of CuO. The present data add to the body of evidence for risk assessment of these metal oxides.

Inflammation related to inhalation of nano and micron sized iron oxides: a systematic review.

Inhalation exposure to iron oxide occurs in many workplaces and respirable aerosols occur during thermal processes (e.g. welding, casting) or during abrasion of iron and steel products (e.g. cutting, grinding, machining, polishing, sanding) or during handling of iron oxide pigments. There is limited evidence of adverse effects in humans specifically linked to inhalation of iron oxides. This contrasts to oxides of other metals used to alloy or for coating of steel and iron of which several have been classified as being hazardous by international and national agencies. Such metal oxides are often present in the air at workplaces. In general, iron oxides might therefore be regarded as low-toxicity, low-solubility (LTLS) particles, and are often considered to be nontoxic even if very high and prolonged inhalation exposures might result in diseases. In animal studies, such exposures lead to cancer, fibrosis and other diseases. Our hypothesis was that pulmonary-workplace exposure during manufacture and handling of SPION preparations might be harmful. We therefore conducted a systematic review of the relevant literature to understand how iron oxides deposited in the lung are related to acute and subchronic pulmonary inflammation. We included one human and several in vivo animal studies published up to February 2023. We found 25 relevant studies that were useful for deriving occupational exposure limits (OEL) for iron oxides based on an inflammatory reaction. Our review of the scientific literature indicates that lowering of health-based occupational exposure limits might be considered.

The SAM-Krom biomonitoring study shows occupational exposure to hexavalent chromium and increased genotoxicity in Denmark.

BACKGROUND: Hexavalent chromium (Cr(VI)) is a carcinogen. Exposure to Cr(VI) may occur in different industrial processes such as chrome plating and stainless steel welding. The aim of this study was to assess occupational exposure to Cr(VI) in Denmark. METHODS: This cross-sectional study included 28 workers and 8 apprentices with potential Cr(VI) exposure and 24 within company controls, all recruited from six companies and one vocational school. Use of occupational safety and health (OSH) risk prevention measures were assessed through triangulation of interviews, a questionnaire and systematic observations. Inhalable Cr(VI) and Cr-total were assessed by personal air exposure measurements on Cr(VI) exposed participants and stationary measurements. Cr concentrations were measured in urine and in red blood cells (RBC) (the latter reflecting Cr(VI)). Genotoxicity was assessed by measurement of micronuclei in peripheral blood reticulocytes (MNRET). RESULTS: At announced visits, a consistent high degree of compliance to OSH risk prevention measures were seen in 'chromium bath plating' for both technical devices (e.g. ventilation, plastic balls, sheet coverings) and in the use of personal protective equipment (e.g. gloves, respirators), yet a lesser degree of compliance was observed in 'stainless steel welding'. The geometric mean of the air concentration of Cr(VI) was 0.26 µg/m3 (95% confidence interval (CI): 0.12-0.57) for the Cr(VI)-exposed workers and 3.69 µg/m3 (95% CI: 1.47-9.25) for the Cr(VI)-exposed apprentices. Subdivided by company type, the exposure levels were 0.13 µg/m3 (95% CI: 0.04-0.41) for companies manufacturing and processing metal products, and 0.81 µg/m3 (95% CI: 0.46-1.40) for bath plating companies. Workers with occupational exposure to Cr(VI) had significantly higher median levels of urinary Cr (2.42 µg/L, 5th-95th percentile 0.28-58.39), Cr in RBC (0.89 µg/L, 0.54-4.92) and MNRET (1.59 ‰, 0.78-10.92) compared to the within company controls (urinary: 0.40 µg/L, 0.16-21.3, RBC: 0.60 µg/L, 0.50-0.93,MNRET: 1.06 ‰, 0.71-2.06). When sub-dividing by company type, urinary Cr (4.61 µg/L, 1.72-69.5), Cr in RBC (1.33 µg/L, 0.95-4.98) and MNRET (1.89 µg/L, 0.78-12.92) levels were increased for workers with potential Cr(VI) exposure in bath-plating companies, and when subdividing by work task, workers engaged in process operation had increased levels of urinary Cr (8.51 µg/L, 1.71-69.5), Cr in RBC (1.33 µg/L, 0.95-4.98) and MNRET (1.89 µg/L, 0.82-12.92) levels. CONCLUSION: This biomonitoring study shows that bath platers were highly exposed to Cr(VI), as suggested by relatively high levels of urinary Cr, Cr in RBC and increased levels of micronuclei. The urinary Cr concentrations were high when compared to the French biological limit value of 2.5 µg Cr/L, corresponding to the Danish occupational exposure limit of 1 µg/m3. This, in turn, indirectly suggests that additional exposure routes than via air may contribute to the exposure. For welders, no statistically significant increases compared to within company controls were observed, however, the observed urinary Cr levels were similar to the levels observed in a European study (HBM4EU), and were higher than the levels observed for welders in Sweden (SafeChrom). In spite of a high degree of self-reported and observed compliance to OSH risk prevention measures during announced visits, the biomarkers of exposure reflecting recent exposure (urinary Cr) or exposure during the last four months (Cr in RBC) may point to variation in compliance to OSH risk prevention measures in general. Reduced occupational exposure to Cr(VI) may be achieved by applying the hierarchy of controls in eliminating or substituting Cr(VI), and the use of more effective technical solutions (e.g. automation).

Toxicity and biokinetics following pulmonary exposure to aluminium (aluminum): A review.

During the manufacture and use of aluminium (aluminum), inhalation exposure may occur. We reviewed the pulmonary toxicity of this metal including its toxicokinetics. The normal serum/plasma level based on 17 studies was 5.7 ± 7.7 µg Al/L (mean ± SD). The normal urine level based on 15 studies was 7.7 ± 5.3 µg/L. Bodily fluid and tissue levels during occupational exposure are also provided, and the urine level was increased in aluminium welders (43 ± 33 µg/L) based on 7 studies. Some studies demonstrated that aluminium from occupational exposure can remain in the body for years. Excretion pathways include urine and faeces. Toxicity studies were mostly on aluminium flakes, aluminium oxide and aluminium chlorohydrate as well as on mixed exposure, e.g. in aluminium smelters. Endpoints affected by pulmonary aluminium exposure include body weight, lung function, lung fibrosis, pulmonary inflammation and neurotoxicity. In men exposed to aluminium oxide particles (3.2 µm) for two hours, lowest observed adverse effect concentration (LOAEC) was 4 mg Al2O3/m3 (= 2.1 mg Al/m3), based on increased neutrophils in sputum. With the note that a similar but not statistically significant increase was seen during control exposure. In animal studies LOAECs start at 0.3 mg Al/m3. In intratracheal instillation studies, all done with aluminium oxide and mainly nanomaterials, lowest observed adverse effect levels (LOAELs) started at 1.3 mg Al/kg body weight (bw) (except one study with a LOAEL of ∼0.1 mg Al/kg bw). The collected data provide information regarding hazard identification and characterisation of pulmonary exposure to aluminium.

Cancer incidence in a cohort of Danish firefighters: An extended long-term follow-up 1968-2021.

OBJECTIVES: To update and extend the examination of cancer incidence in a cohort of Danish firefighters, now adding 7 years of follow-up and 2766 additional firefighters. The primary focus was directed toward cancer sites that recently contributed to the hazard evaluation conducted by the International Agency for Research on Cancer (IARC). METHODS: The updated cohort consisted of 11,827 male Danish firefighters who were followed up for cancer from 1968 to 2021. Cohort cancer morbidity was compared with a working population reference group, and standardized incidence ratios (SIR) were used for estimation of relative risks, along with 95% confidence intervals (95% CI). RESULTS: Among full-time firefighters, SIR of skin melanoma was 1.30 (95% CI: 1.02-1.66), and SIR = 1.37 (95% CI: 1.02-1.85) for over 5 years of employment. Slightly positive associations were also observed for cancer of the urinary bladder (SIR = 1.16; 95% CI: 0.93-1.45), prostate (SIR = 1.11; 95% CI: 0.97-1.28), and testis (SIR = 1.11; 95% CI: 0.75-1.63). CONCLUSIONS: This updated study provides evidence indicating an elevated risk of skin melanoma in firefighters. Consistent with IARC's evaluation, we also identified positive associations for urinary bladder, prostate, and testis cancer. In contrast, our findings did not suggest an increased risk of colon cancer, non-Hodgkin lymphoma, and mesothelioma. The latter may be due to small numbers in our still relatively young cohort. Continuous follow-up for cancer in firefighters is warranted, including assessment of influence from surveillance bias.

Pro-inflammatory and genotoxic responses by metal oxide nanomaterials in alveolar epithelial cells and macrophages in submerged condition and air-liquid interface: An in vitro-in vivo correlation study.

Studies on in vitro-in vivo correlations of inflammatory and genotoxic responses are needed to advance new approach methodologies. Here, we assessed pro-inflammatory and genotoxic responses by 13 nanosized metal oxides (nMeOx) and quartz (DQ12) in alveolar epithelial cells (A549) and macrophages (THP-1a) exposed in submerged conditions, and in A549:THP-1a co-cultures in air-liquid interface (ALI) system. Soluble nMeOx produced the highest IL-8 expression in A549 and THP-1a cells in submerged conditions (≥2-fold, p < 0.05), whereas only CuO caused a strong response in co-cultures exposed in the ALI system (13-fold, p < 0.05). IL-8 expression in A549 cells with concentrations as nMeOx specific surface area (SSA) correlated with neutrophil influx in mice (r = 0.89-0.98, p < 0.05). Similarly, IL-8 expression in THP-1a cell with concentrations as mass and SSA (when excluding soluble nMeOx) correlated with neutrophil influx in mice (r = 0.81-0.84, p < 0.05). DNA strand breaks (SB) was measured by the comet assay. We used a scoring system that categorizes effects in standard deviation units for comparison of genotoxicity in different models. Concordant genotoxicity was observed between SB levels in vitro (A549 and co-culture) and in vivo (broncho-alveolar lavage fluid cells and lung tissue). In conclusion, this study shows in vitro-in vivo correlations of nMeOx-induced inflammatory and genotoxic responses.

Circulating lung-cancer-related non-coding RNAs are associated with occupational exposure to hexavalent chromium - A cross-sectional study within the SafeChrom project.

BACKGROUND: Hexavalent chromium (Cr(Ⅵ)) is classified as a group 1 human carcinogen and increases the risk of lung cancer. Non-coding RNAs (ncRNAs) have key regulatory roles in lung cancer, but less is known about their relation to Cr(Ⅵ) exposure. OBJECTIVES: We aimed to 1) measure the expression of lung cancer-related circulating ncRNAs in exposed workers and controls; 2) assess associations between ncRNAs expression and Cr concentrations in red blood cells (RBC) and urine; and 3) evaluate correlations between the ncRNAs. METHODS: The study included 111 Cr(VI) exposed workers and 72 controls recruited from the SafeChrom project. Cr concentrations were measured in RBC (biomarker of long-term exposure) and urine (biomarker of short-term exposure) samples. Long ncRNA (lncRNA) and microRNA (miRNA) were extracted from plasma followed by deoxyribonuclease treatment, complementary DNA synthesis, and quantitative real-time polymerase chain reaction using target-specific assays for three lncRNAs (H19, MALAT1, NORAD), and four miRNAs (miR-142-3p, miR-15b-5p, miR-3940-5p, miR-451a). RESULTS: Expression levels of lncRNAs MALAT1 and NORAD, and all four miRNAs, were significantly lower in Cr(VI) exposed workers compared with controls, and correlated significantly with RBC-Cr concentrations (rS = -0.16 to -0.38). H19 was non-significantly increased in exposed workers but significantly correlated with miR-142-3p (rS = -0.33) and miR-15b-5p (rS = -0.30), and NORAD was significantly positively correlated with all four miRNAs (rS = 0.17 to 0.46). In multivariate regression models adjusting for confounders, expressions of lncRNAs MALAT1 and NORAD and all miRNAs were still significantly lower in the exposed group compared with controls, and the expression decreased with increasing RBC-Cr concentrations. CONCLUSIONS: Cr(VI) exposure was inversely and in a dose-response manner associated with the expression of circulating non-coding RNA, which suggests ncRNAs as potential biomarkers for Cr(VI)-induced toxicity. Correlations between miRNAs and lncRNAs suggest that they participate in the same lncRNA-miRNA-messenger RNA regulatory axes, which may play important roles in Cr(VI) carcinogenesis.

Pulmonary maternal immune activation does not cross the placenta but leads to fetal metabolic adaptation.

The fetal development of organs and functions is vulnerable to perturbation by maternal inflammation which may increase susceptibility to disorders after birth. Because it is not well understood how the placenta and fetus respond to acute lung- inflammation, we characterize the response to maternal pulmonary lipopolysaccharide exposure across 24 h in maternal and fetal organs using multi-omics, imaging and integrative analyses. Unlike maternal organs, which mount strong inflammatory immune responses, the placenta upregulates immuno-modulatory genes, in particular the IL-6 signaling suppressor Socs3. Similarly, we observe no immune response in the fetal liver, which instead displays metabolic changes, including increases in lipids containing docosahexaenoic acid, crucial for fetal brain development. The maternal liver and plasma display similar metabolic alterations, potentially increasing bioavailability of docosahexaenoic acid for the mother and fetus. Thus, our integrated temporal analysis shows that systemic inflammation in the mother leads to a metabolic perturbation in the fetus.

Effects of ethanol or ethylene glycol exposure on PPARγ and aromatase expression in adipose tissue.

The estrogen-synthesizing enzyme aromatase is expressed in adipose tissue where it controls the local concentration of estrogen. It has been suggested that the organic solvents ethanol and ethylene glycol can induce estrogen synthesis by inhibiting PPARγ activity. Since elevated estrogen synthesis in adipose tissue is a risk factor for breast cancer development, it is of interest to further characterize the mechanisms regulating aromatase expression. Here, we explored the mechanisms by which ethanol and ethylene glycol modulate aromatase mRNA expression and the ultimate conversion of androgens into estrogens. NMR spectroscopy revealed that ethanol and ethylene glycol influence the active state of PPARγ. An inhibitory effect on PPARγ was confirmed by adipogenesis assays and PPARγ target gene expression analysis in adipocytes. However, only ethanol increased aromatase mRNA in differentiated human adipocytes. In contrast, ethylene glycol downregulated aromatase in a PPARγ-independent manner. An animal study using female Wistar rats was conducted to assess the acute effects of ethanol and ethylene glycol on aromatase expression in adipose tissue within a physiological context. No changes in aromatase or PPARγ target gene (Adipoq and Fabp4) levels were observed in adipose tissue or ovary in response to the chemical exposures, suggesting an absence of acute PPARγ-mediated effects in these organs. The results suggest that ethanol and ethylene glycol are weak PPARγ antagonists in mouse and human adipocytes as well as in cell-free NMR spectroscopy. Both compounds seem to affect adipocyte aromatase expression in vitro, where ethanol increased aromatase expression PPARγ-dependently and ethylene glycol decreased aromatase expression independently of PPARγ. No acute effects on aromatase expression or PPARγ activity were observed in adipose tissue or ovary in rats in this study design.

Particulate matter constituents trigger the formation of extracellular amyloid ß and Tau -containing plaques and neurite shortening in vitro.

Air pollution is an environmental factor associated with an increased risk of neurodegenerative diseases, such as Alzheimer's and Parkinson's, characterized by decreased cognitive abilities and memory. The limited models of sporadic Alzheimer's disease fail to replicate all pathological hallmarks of the disease, making it challenging to uncover potential environmental causes. Environmentally driven models of Alzheimer's disease are thus timely and necessary. We used live-cell confocal fluorescent imaging combined with high-resolution stimulated emission depletion (STED) microscopy to follow the response of retinoic acid-differentiated human neuroblastoma SH-SY5Y cells to nanomaterial exposure. Here, we report that exposure of the cells to some particulate matter constituents reproduces a neurodegenerative phenotype, including extracellular amyloid beta-containing plaques and decreased neurite length. Consistent with the existing in vivo research, we observed detrimental effects, specifically a substantial reduction in neurite length and formation of amyloid beta plaques, after exposure to iron oxide and diesel exhaust particles. Conversely, after exposure to engineered cerium oxide nanoparticles, the lengths of neurites were maintained, and almost no extracellular amyloid beta plaques were formed. Although the exact mechanism behind this effect remains to be explained, the retinoic acid differentiated SH-SY5Y cell in vitro model could serve as an alternative, environmentally driven model of neurodegenerative diseases, including Alzheimer's disease.

PPARγ antagonists induce aromatase transcription in adipose tissue cultures.

Aromatase is the rate-limiting enzyme in the biosynthesis of estrogens and a key risk factor for hormone receptor-positive breast cancer. In postmenopausal women, estrogens synthesized in adipose tissue promotes the growth of estrogen receptor positive breast cancers. Activation of peroxisome proliferator-activated receptor gamma (PPARγ) in adipose stromal cells (ASCs) leads to decreased expression of aromatase and differentiation of ASCs into adipocytes. Environmental chemicals can act as antagonists of PPARγ and disrupt its function. This study aimed to test the hypothesis that PPARγ antagonists can promote breast cancer by stimulating aromatase expression in human adipose tissue. Primary cells and explants from human adipose tissue as well as A41hWAT, C3H10T1/2, and H295R cell lines were used to investigate PPARγ antagonist-stimulated effects on adipogenesis, aromatase expression, and estrogen biosynthesis. Selected antagonists inhibited adipocyte differentiation, preventing the adipogenesis-associated downregulation of aromatase. NMR spectroscopy confirmed direct interaction between the potent antagonist DEHPA and PPARγ, inhibiting agonist binding. Short-term exposure of ASCs to PPARγ antagonists upregulated aromatase only in differentiated cells, and a similar effect could be observed in human breast adipose tissue explants. Overexpression of PPARG with or without agonist treatment reduced aromatase expression in ASCs. The data suggest that environmental PPARγ antagonists regulate aromatase expression in adipose tissue through two mechanisms. The first is indirect and involves inhibition of adipogenesis, while the second occurs more acutely.

Hexavalent chromium still a concern in Sweden - Evidence from a cross-sectional study within the SafeChrom project.

OBJECTIVES: Hexavalent chromium (Cr(VI)) is classified as a human carcinogen. Occupational Cr(VI) exposure can occur during different work processes, but the current exposure to Cr(VI) at Swedish workplaces is unknown. METHODS: This cross-sectional study (SafeChrom) recruited non-smoking men and women from 14 companies with potential Cr(VI) exposure (n = 113) and controls from 6 companies without Cr(VI) exposure (n = 72). Inhalable Cr(VI) was measured by personal air sampling (outside of respiratory protection) in exposed workers. Total Cr was measured in urine (pre- and post-shift, density-adjusted) and red blood cells (RBC) (reflecting Cr(VI)) in exposed workers and controls. The Bayesian tool Expostats was used to assess risk and evaluate occupational exposure limit (OEL) compliance. RESULTS: The exposed workers performed processing of metal products, steel production, welding, plating, and various chemical processes. The geometric mean concentration of inhalable Cr(VI) in exposed workers was 0.15 µg/m3 (95% confidence interval: 0.11-0.21). Eight of the 113 exposed workers (7%) exceeded the Swedish OEL of 5 µg/m3, and the Bayesian analysis estimated the share of OEL exceedances up to 19.6% for stainless steel welders. Median post-shift urinary (0.60 µg/L, 5th-95th percentile 0.10-3.20) and RBC concentrations (0.73 µg/L, 0.51-2.33) of Cr were significantly higher in the exposed group compared with the controls (urinary 0.10 µg/L, 0.06-0.56 and RBC 0.53 µg/L, 0.42-0.72). Inhalable Cr(VI) correlated with urinary Cr (rS = 0.64) and RBC-Cr (rS = 0.53). Workers within steel production showed the highest concentrations of inhalable, urinary and RBC Cr. Workers with inferred non-acceptable local exhaustion ventilation showed significantly higher inhalable Cr(VI), urinary and RBC Cr concentrations compared with those with inferred acceptable ventilation. Furthermore, workers with inferred correct use of respiratory protection were exposed to significantly higher concentrations of Cr(VI) in air and had higher levels of Cr in urine and RBC than those assessed with incorrect or no use. Based on the Swedish job-exposure-matrix, approximately 17 900 workers were estimated to be occupationally exposed to Cr(VI) today. CONCLUSIONS: Our study demonstrates that some workers in Sweden are exposed to high levels of the non-threshold carcinogen Cr(VI). Employers and workers seem aware of Cr(VI) exposure, but more efficient exposure control strategies are required. National strategies aligned with the European strategies are needed in order to eliminate this cause of occupational cancer.

Orthogonal assay and QSAR modelling of Tox21 PPARγ antagonist in vitro high-throughput screening assay.

Disruption of signalling mediated by the nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) is associated with risk of cancer, metabolic diseases, and endocrine disruption. The purpose of this study was to identify environmental chemicals acting as PPARγ antagonists. Data from the Tox21 PPARγ antagonism assay were replicated using a reporter system in HEK293 cells. Two quantitative structure-activity relationship (QSAR) models were developed, and five REACH-registered substances predicted positive were tested in vitro. Reporter assay results were consistent with Tox21 data since all conflicting results could be explained by assay interference. QSAR models showed good predictive performance, and follow-up experiments revealed two PPARγ antagonists out of three non-interfering chemicals. In conclusion, the developed QSAR models and follow-up experiments are important steps in the discovery of potential endocrine- and metabolism-disrupting chemicals.

Pulmonary toxicity and translocation of gallium phosphide nanowires to secondary organs following pulmonary exposure in mice.

BACKGROUND: III-V semiconductor nanowires are envisioned as being integrated in optoelectronic devices in the near future. However, the perspective of mass production of these nanowires raises concern for human safety due to their asbestos- and carbon nanotube-like properties, including their high aspect ratio shape. Indeed, III-V nanowires have similar dimensions as Mitsui-7 multi-walled carbon nanotubes, which induce lung cancer by inhalation in rats. It is therefore urgent to investigate the toxicological effects following lung exposure to III-V nanowires prior to their use in industrial production, which entails risk of human exposure. Here, female C57BL/6J mice were exposed to 2, 6, and 18 µg (0.12, 0.35 and 1.1 mg/kg bw) of gallium phosphide (III-V) nanowires (99 nm diameter, 3.7 µm length) by intratracheal instillation and the toxicity was investigated 1, 3, 28 days and 3 months after exposure. Mitsui-7 multi-walled carbon nanotubes and carbon black Printex 90 nanoparticles were used as benchmark nanomaterials. RESULTS: Gallium phosphide nanowires induced genotoxicity in bronchoalveolar lavage cells and acute inflammation with eosinophilia observable both in bronchoalveolar lavage and lung tissue (1 and 3 days post-exposure). The inflammatory response was comparable to the response following exposure to Mitsui-7 multi-walled carbon nanotubes at similar dose levels. The nanowires underwent partial dissolution in the lung resulting in thinner nanowires, with an estimated in vivo half-life of 3 months. Despite the partial dissolution, nanowires were detected in lung, liver, spleen, kidney, uterus and brain 3 months after exposure. CONCLUSION: Pulmonary exposure to gallium phosphide nanowires caused similar toxicological effects as the multi-walled carbon nanotube Mitsui-7.

Toxicity dose descriptors from animal inhalation studies of 13 nanomaterials and their bulk and ionic counterparts and variation with primary particle characteristics.

This study collects toxicity data from animal inhalation studies of some nanomaterials and their bulk and ionic counterparts. To allow potential grouping and interpretations, we retrieved the primary physicochemical and exposure data to the extent possible for each of the materials. Reviewed materials are compounds (mainly elements, oxides and salts) of carbon (carbon black, carbon nanotubes, and graphene), silver, cerium, cobalt, copper, iron, nickel, silicium (amorphous silica and quartz), titanium (titanium dioxide), and zinc (chemical symbols: Ag, C, Ce, Co, Cu, Fe, Ni, Si, Ti, TiO2, and Zn). Collected endpoints are: a) pulmonary inflammation, measured as neutrophils in bronchoalveolar lavage (BAL) fluid at 0-24 hours after last exposure; and b) genotoxicity/carcinogenicity. We present the dose descriptors no-observed-adverse-effect concentrations (NOAECs) and lowest-observed-adverse-effect concentrations (LOAECs) for 88 nanomaterial investigations in data-library and graph formats. We also calculate 'the value where 25% of exposed animals develop tumors' (T25) for carcinogenicity studies. We describe how the data may be used for hazard assessment of the materials using carbon black as an example. The collected data also enable hazard comparison between different materials. An important observation for poorly soluble particles is that the NOAEC for neutrophil numbers in general lies around 1 to 2 mg/m3. We further discuss why some materials' dose descriptors deviate from this level, likely reflecting the effects of the ionic form and effects of the fiber-shape. Finally, we discuss that long-term studies, in general, provide the lowest dose descriptors, and dose descriptors are positively correlated with particle size for near-spherical materials.

Polymorphisms within Autophagy-Related Genes as Susceptibility Biomarkers for Multiple Myeloma: A Meta-Analysis of Three Large Cohorts and Functional Characterization.

Multiple myeloma (MM) arises following malignant proliferation of plasma cells in the bone marrow, that secrete high amounts of specific monoclonal immunoglobulins or light chains, resulting in the massive production of unfolded or misfolded proteins. Autophagy can have a dual role in tumorigenesis, by eliminating these abnormal proteins to avoid cancer development, but also ensuring MM cell survival and promoting resistance to treatments. To date no studies have determined the impact of genetic variation in autophagy-related genes on MM risk. We performed meta-analysis of germline genetic data on 234 autophagy-related genes from three independent study populations including 13,387 subjects of European ancestry (6863 MM patients and 6524 controls) and examined correlations of statistically significant single nucleotide polymorphisms (SNPs; p < 1 × 10-9) with immune responses in whole blood, peripheral blood mononuclear cells (PBMCs), and monocyte-derived macrophages (MDM) from a large population of healthy donors from the Human Functional Genomic Project (HFGP). We identified SNPs in six loci, CD46, IKBKE, PARK2, ULK4, ATG5, and CDKN2A associated with MM risk (p = 4.47 × 10-4-5.79 × 10-14). Mechanistically, we found that the ULK4rs6599175 SNP correlated with circulating concentrations of vitamin D3 (p = 4.0 × 10-4), whereas the IKBKErs17433804 SNP correlated with the number of transitional CD24+CD38+ B cells (p = 4.8 × 10-4) and circulating serum concentrations of Monocyte Chemoattractant Protein (MCP)-2 (p = 3.6 × 10-4). We also found that the CD46rs1142469 SNP correlated with numbers of CD19+ B cells, CD19+CD3- B cells, CD5+IgD- cells, IgM- cells, IgD-IgM- cells, and CD4-CD8- PBMCs (p = 4.9 × 10-4-8.6 × 10-4) and circulating concentrations of interleukin (IL)-20 (p = 0.00082). Finally, we observed that the CDKN2Ars2811710 SNP correlated with levels of CD4+EMCD45RO+CD27- cells (p = 9.3 × 10-4). These results suggest that genetic variants within these six loci influence MM risk through the modulation of specific subsets of immune cells, as well as vitamin D3-, MCP-2-, and IL20-dependent pathways.

Common variants of pro-inflammatory gene IL1B and interactions with PPP1R13L and POLR1G in relation to lung cancer among Northeast Chinese.

Lung cancer is a complex disease influenced by a variety of genetic and environmental factors. The cytokine interleukin 1 encoded by IL1B is an important mediator of the inflammatory response, and is involved in a variety of cellular activities. The effect of single nucleotide polymorphisms (SNP) at IL1B has been investigated in relation to cancer with inconsistent results. This Northeastern-Chinese case-control study involving 627 cases and 633 controls evaluated the role of three haplotype-tagging single nucleotide polymorphisms (htSNP) (rs1143633, rs3136558 and rs1143630) representing 95% of the common haplotype diversity across the IL1B gene and assessed interactions with IL1B, PPP1R13L, POLR1G and smoking duration in relation to lung cancer risk. The analyses of five genetic models showed associations with lung cancer risk for rs1143633 in the dominant model [adjusted-OR (95% CI) = 0.67 (0.52-0.85), P = 0.0012] and rs3136558 in the recessive model [adjusted-OR (95% CI) = 1.44 (1.05-1.98), P = 0.025]. Haplotype4 was associated with increased lung cancer risk [adjusted-OR (95% CI) = 1.55 (1.07-2.24), P = 0.021]. The variant G-allele of rs1143633 was protective in smoking sub-group of > 20 years. Using multifactor dimensionality reduction (MDR) analyses, we identified the three best candidate models of interactions and smoking-duration or IL1B rs1143633 as main effect. In conclusion, our findings suggest that IL1B SNP rs1143633 may associate with lower risk of lung cancer, confirming previously identified marker; IL1B SNP rs3136558 and haplotype4 consisting of IL1B htSNPs may associate with increasing risk of lung cancer; interactions of IL1B with POLR1G or PPP1R13L or smoking-duration, which is independent or combined, may involve in risk of lung cancer and lung squamous cell carcinoma.

Pulmonary toxicity of molybdenum disulphide after inhalation in mice.

Molybdenum disulphide (MoS2) is a constituent of many products. To protect humans, it is important to know at what air concentrations it becomes toxic. For this, we tested MoS2 particles by nose-only inhalation in mice. Exposures were set to 13, 50 and 150 mg MoS2/m3 (=8, 30 and 90 mg Mo/m3), corresponding to Low, Mid and High exposure. The duration was 30 min/day, 5 days/week for 3 weeks. Molybdenum lung-deposition levels were estimated based on aerosol particle size distribution measurements, and empirically determined with inductively coupled plasma-mass spectrometry (ICP-MS). Toxicological endpoints were body weight gain, respiratory function, pulmonary inflammation, histopathology, and genotoxicity (comet assay). Acellular reactive oxygen species (ROS) production was also determined. The aerosolised MoS2 powder had a mean aerodynamic diameter of 800 nm, and a specific surface area of 8.96 m2/g. Alveolar deposition of MoS2 in lung was estimated at 7, 27 and 79 µg/mouse and measured as 35, 101 and 171 µg/mouse for Low, Mid and High exposure, respectively. Body weight gain was lower than in controls at Mid and High exposure. The tidal volume was decreased with Low and Mid exposure on day 15. Increased genotoxicity was seen in bronchoalveolar lavage (BAL) fluid cells at Mid and High exposures. ROS production was substantially lower than for carbon black nanoparticles used as bench-mark, when normalised by mass. Yet if ROS of MoS2 was normalised by surface area, it was similar to that of carbon black, suggesting that a ROS contribution to the observed genotoxicity cannot be ruled out. In conclusion, effects on body weight gain and genotoxicity indicated that Low exposure (13 mg MoS2/m3, corresponding to 0.8 mg/m3 for an 8-hour working day) was a No Observed Adverse Effect Concentration (NOAEC,) while effects on respiratory function suggested this level as a Lowest Observed Adverse Effect Concentration (LOAEC).