Search

Thermal spray coating is an industrial process in which molten metal is sprayed at high velocity onto a surface as a protective coating. An automated electric arc wire thermal spray coating aerosol generator and inhalation exposure system was developed to simulate an occupational exposure and, using this system, male Sprague-Dawley rats were exposed to stainless steel PMET720 aerosols at 25 mg/msup3/sup × 4 h/day × 9 day. Lung injury, inflammation, and cytokine alteration were determined. Resolution was assessed by evaluating these parameters at 1, 7, 14 and 28 d after exposure. The aerosols generated were also collected and characterized. Macrophages were exposed in vitro over a wide dose range (0-200 µg/ml) to determine cytotoxicity and to screen for known mechanisms of toxicity. Welding fumes were used as comparative particulate controls. In vivo lung damage, inflammation and alteration in cytokines were observed 1 day post exposure and this response resolved by day 7. Alveolar macrophages retained the particulates even after 28 day post-exposure. In line with the pulmonary toxicity findings, in vitro cytotoxicity and membrane damage in macrophages were observed only at the higher doses. Electron paramagnetic resonance showed in an acellular environment the particulate generated free radicals and a dose-dependent increase in intracellular oxidative stress and NF-kB/AP-1 activity was observed. PMET720 particles were internalized via clathrin and caveolar mediated endocytosis as well as actin-dependent pinocytosis/phagocytosis. The results suggest that compared to stainless steel welding fumes, the PMET 720 aerosols were not as overtly toxic, and the animals recovered from the acute pulmonary injury by 7 days.

Thermal spray coating (TSC) is a surface treatment process whereby feedstock material is sprayed onto surfaces under pressure where it solidifies and forms a solid coating. In metal TSC processes, large quantities of aerosols, including fine and ultrafine metal particles are generated. However, exposure assessment for TSC is lacking. The goal of this study was to construct a TSC aerosol generation system and to characterize the physicochemical properties of aerosols generated during coating processes. A computer-controlled, automated electric arc wire-TSC aerosol generator system was built in an enclosed room, where a rotary motor rotates a metal feedstock pipe in circular and up-and-down directions to allow even deposition of coating material on the pipe surface. The characteristics of aerosolized particles during spray coating using a stainless-steel wire (PMET 720) showed that: 1) respirable mass concentrations ranged from 142–218 mg/m3 (3 spray shots with each shot of 1-sec during 20-min sampling), 2) diameter of peak particle number concentrations was between 360 nm and 400 nm, 3) mass median aerodynamic diameter determined by an impactor ranged from 290–370 nm, 4) particle morphology was observed to be diverse including chain-like agglomerates and spherical and cylinder-like shapes, and 5) metal composition was 80% iron, 17% chromium, and 3% manganese with trace amounts of nickel and copper. These findings are limited to one wire type and suggests the need for further investigations evaluating various parameters (e.g., wire/powder types, high/low energy, ventilation on/off) to obtain emission rates and recommend control measures.

It is estimated that greater than 1 million workers are exposed to welding fume (WF) by inhalation daily. The potentially toxic metals found in WF are known to cause multiple adverse pulmonary and systemic effects, including cardiovascular disease, and these metals have also been shown to translocate to the liver. This occupational exposure combined with a high fat (HF) Western diet, which has been shown to cause hyperlipidemia and non-alcoholic fatty liver disease (NAFLD), has the potential to cause significant mixed exposure metabolic changes in the liver. The goal of this study was to use matrix assisted laser desorption ionization imaging mass spectrometry (MALDI-IMS) to analyze the spatial distribution and abundance changes of lipid species in Sprague Dawley rat liver maintained on a HF diet combined with WF inhalation. The results of the MALDI-IMS analysis revealed unique hepatic lipid profiles for each treatment group. The HF diet group had significantly increased abundance of triglycerides and phosphatidylinositol lipids, as well as decreased lysophosphatidic lipids and cardiolipin. Ceramide-1-phosphate was found at higher abundance in the regular (REG) diet WF-exposed group which has been shown to regulate the eicosanoid pathway involved in pro-inflammatory response. The results of this study showed that the combined effects of WF inhalation and a HF diet significantly altered the hepatic lipidome. Additionally, pulmonary exposure to WF alone increased lipid markers of inflammation.

Studies suggest that alterations in circulating factors are a driver of pulmonary-induced cardiovascular dysfunction. To evaluate, if circulating factors effect endothelial function after a pulmonary exposure to welding fumes, an exposure known to induce cardiovascular dysfunction, serum collected from Sprague Dawley rats 24 h after an intratracheal instillation exposure to 2 mg/rat of 2 compositionally distinct metal-rich welding fume particulates (manual metal arc welding using stainless steel electrodes [MMA-SS] or gas metal arc welding using mild steel electrodes [GMA-MS]) or saline was used to test molecular and functional effects of in vitro cultures of primary cardiac microvascular endothelial cells (PCMEs) or ex vivo organ cultures. The welding fumes elicited significant pulmonary injury and inflammation with only minor changes in measured serum antioxidant and cytokine levels. PCME cells were challenged for 4 h with serum collected from exposed rats, and 84 genes related to endothelial function were analyzed. Changes in relative mRNA patterns indicated that serum from rats exposed to MMA-SS, and not GMA-MS or PBS, could influence several functional aspects related to endothelial cells, including cell migration, angiogenesis, inflammation, and vascular function. The predictions were confirmed using a functional in vitro assay (scratch assay) as well as an ex vivo multicellular environment (aortic ring angiogenesis assay), validating the concept that endothelial cells can be used as an effective screening tool of exposed workers for determining bioactivity of altered circulatory factors. Overall, the results indicate that pulmonary MMA-SS fume exposure can cause altered endothelial function systemically via altered circulating factors.

Graphical abstract, Highlights • An automated thermal spray coating generator and inhalation exposure system was designed and developed. • The system can generate a consistent concentration of particles during thermal spray coating for an extended period. • The aerosols were complex metal oxides and arranged as chain-like agglomerates. • A short-term exposure study indicated that thermal spray coating stainless-steel aerosols significantly increased lung toxicity. • With the development of this thermal spray coating system, dose-response animal toxicology studies can be performed., Thermal spray coating involves spraying a product (oftentimes metal) that is melted by extremely high temperatures and then applied under pressure onto a surface. Large amounts of a complex metal aerosol (e.g., Fe, Cr, Ni, Zn) are formed during the process, presenting a potentially serious risk to the operator. Information about the health effects associated with exposure to these aerosols is lacking. Even less is known about the chemical and physical properties of these aerosols. The goal was to develop and test an automated thermal spray coating aerosol generator and inhalation exposure system that would simulate workplace exposures. An electric arc wire-thermal spray coating aerosol generator and exposure system was designed and separated into two areas: (1) an enclosed room where the spray coating occurs; (2) an exposure chamber with different measurement devices and controllers. The physicochemical properties of aerosols generated during electric arc wire-thermal spray coating using five different consumable wires were examined. The metal composition of each was determined by inductively coupled plasma-atomic emission spectroscopy (ICP-AES), including two stainless-steel wires [PMET720 (82 % Fe, 13 % Cr); PMET731(66 % Fe, 26 % Cr)], two Ni-based wires [PMET876 (55 % Ni, 17 % Cr); PMET885 (97 % Ni)], and one Zn-based wire [PMET540 (99 % Zn)]. The particles generated regardless of composition were poorly soluble, complex metal oxides and mostly arranged as chain-like agglomerates and similar in size distribution as determined by micro-orifice uniform deposit impactor (MOUDI) and electrical low-pressure impactor (ELPI). To allow for continuous, sequential spray coating during a 4-hr exposure period, a motor rotated the metal pipe to be coated in a circular and up-and-down direction. In a pilot animal study, male Sprague-Dawley rats were exposed to aerosols (25 mg/m3 × 4 h/d × 9 d) generated from electric arc wire- thermal spray coating using the stainless-steel PMET720 consumable wire. The targeted exposure chamber concentration was achieved and maintained during a 4-hr period. At 1 d after exposure, lung injury and inflammation were significantly elevated in the group exposed to the thermal spray coating aerosol compared to the air control group. The system was designed and constructed for future animal exposure studies to generate continuous metal spray coating aerosols at a targeted concentration for extended periods of time without interruption.

Welding fumes were reclassified as a Group 1 carcinogen by the International Agency for Research on Cancer in 2017. Gas metal arc welding (GMAW) is a process widely used in industry. Fume generated from GMAW-mild steel (MS) is abundant in iron with some manganese, while GMAW-stainless steel (SS) fume also contains significant amounts of chromium and nickel, known carcinogenic metals. It has been shown that exposure to GMAW-SS fume in A/J mice promotes lung tumors. The objective was to determine if GMAW-MS fume, which lacks known carcinogenic metals, also promotes lung tumors in mice. Male A/J mice received a single intraperitoneal injection of corn oil or the initiator 3-methylcholanthrene (MCA; 10 μg/g) and, one week later, were exposed by whole-body inhalation to GMAW-MS aerosols for 4 hours/day x 4 days/week x 8 weeks at a mean concentration of 34.5 mg/m3. Lung nodules were enumerated by gross examination at 30 weeks post-initiation. GMAW-MS fume significantly increased lung tumor multiplicity in mice initiated with MCA (21.86 ± 1.50) compared to MCA/air-exposed mice (8.34 ± 0.59). Histopathological analysis confirmed these findings and also revealed an absence of inflammation. Bronchoalveolar lavage analysis also indicated a lack of lung inflammation and toxicity after short-term inhalation exposure to GMAW-MS fume. In conclusion, this study demonstrates that inhalation of GMAW-MS fume promotes lung tumors in vivo and aligns with epidemiologic evidence that shows MS welders, despite less exposure to carcinogenic metals, are at an increased risk for lung cancer.

Thermal spray coating is a process that applies a molten metal product under pressure onto a surface. Although thermal spray processes have been used for decades, exposure to aerosols formed during thermal spray coating is an emerging risk. Reports indicate that high concentrations of aerosols composed of toxic metals (e.g. chromium) are generated in the workplace. A knowledge gap exists related to the physicochemical properties of thermal spray coating aerosols as well as any potential associated health effects. The objective of this manuscript was to review thermal spray coating and previous studies that have examined the aerosols produced from this process. A thermal spray coating generator and exposure system is also described that has recently been developed to further evaluate the physical and chemical properties of aerosols formed during thermal spray coating as well as to assess the possible health effects of this process in an effort to mitigate potential occupational health hazards related to the industry.

Iron oxides are Group 3 (not classifiable as to its carcinogenicity to humans) according to the International Agency for Research on Cancer (IARC). Occupational exposures during iron and steel founding and hematite underground mining as well as other iron predominant exposures such as welding are Group 1 (carcinogenic to humans). The objective of this study was to investigate the potential of iron as iron (III) oxide (Fe(2)O(3)) to initiate lung tumors in A/J mice, a lung tumor susceptible strain. Male A/J mice were exposed by oropharyngeal aspiration to suspensions of Fe(2)O(3) (1 mg) or calcium chromate (CaCrO(4); 100 μg; positive control) for 26 weeks (once per week). Shams were exposed to 50 μL phosphate buffered saline (PBS; vehicle). Mice were euthanized 70 weeks after the first exposure and lung nodules were enumerated. Both CaCrO(4) and Fe(2)O(3) significantly increased gross-observed lung tumor multiplicity in A/J mice (9.63 ± 0.55 and 3.35 ± 0.30, respectively) compared to sham (2.31 ± 0.19). Histopathological analysis showed that bronchiolo-alveolar adenomas (BAA) and carcinomas (BAC) were the primary lung tumor types in all groups and were increased in the exposed groups compared to sham. BAC were significantly increased (146 %) in the CaCrO(4) group and neared significance in the Fe(2)O(3) group (100 % increase; p = 0.085). BAA and other histopathological indices of toxicity followed the same pattern with exposed groups increased compared to sham control. In conclusion, evidence from this study, in combination with our previous studies, demonstrate that exposure to iron alone may be a potential risk factor for lung carcinogenesis.

Background Previous studies have shown that inhalation of welding fumes may induce pulmonary and systemic inflammation and organ accumulation of metal, to which spermatogenesis and endocrine function may be sensitive. Also obesity may induce low-grade systemic inflammation. This study aimed to investigate the effects on sperm production of inhaled metal nanoparticles from stainless steel welding, and the potential exacerbation by intake of a high fat diet. Both the inbred Brown Norway and the outbred Sprague Dawley rat strains were included to study the influence of strain on the detection of toxicity. Rats were fed regular or high fat (HF) diet for 24 weeks and were exposed to 20 mg/m3 of gas metal arc-stainless steel (GMA-SS) welding fumes or filtered air for 3 h/day, 4 days/week for 5 weeks, during weeks 7–12. Outcomes were assessed upon termination of exposure (week 12) and after recovery (week 24). Results At week 12, the GMA-SS exposure induced pulmonary inflammation in both strains, without consistent changes in markers of systemic inflammation (CRP, MCP-1, IL-6 and TNFα). GMA-SS exposure lowered daily sperm production compared to air controls in Sprague Dawley rats, but only in GMA-SS Brown Norway rats also fed the HF diet. Overall, HF diet rats had lower serum testosterone levels compared to rats on regular diet. Metal content in the testes was assessed in a limited number of samples in Brown Norway rats, but no increase was obsedrved. At week 24, bronchoalveolar lavage cell counts had returned to background levels for GMA-SS exposed Sprague Dawley rats but remained elevated in Brown Norway rats. GMA-SS did not affect daily sperm production statistically significantly at this time point, but testicular weights were lowered in GMA-SS Sprague Dawley rats. Serum testosterone remained lowered in Sprague Dawley rats fed the HF diet. Conclusion Exposure to GMA-SS welding fumes lowered sperm production in two strains of rats, whereas high fat diet lowered serum testosterone. The effect on sperm counts was likely not mediated by inflammation or lowered testosterone levels. The studied reproductive outcomes seemed more prone to disruption in the Sprague Dawley compared to the Brown Norway strain.

The goal of this study was to use liquid chromatography mass spectrometry to assess metabolic changes of two different diets in three distinct rat strains. Sprague-Dawley, Fischer 344, and Brown-Norway male rats were maintained on a high-fat, or regular diet for 24 weeks. Liver tissue was collected at 4, 12, and 24 weeks to assess global small molecule metabolite changes using high resolution accurate mass spectrometry coupled to ultra-high-performance liquid chromatography. The results of the global metabolomics analysis revealed significant changes based on both age and diet within all three strains. Principal component analysis revealed that the influence of diet caused a greater variation in significantly changing metabolites than that of age for the Brown Norway and Fisher 344 strains, whereas diet had the greatest influence in the Sprague Dawley strain only at the 4-week time point. As expected, metabolites involved in lipid metabolism were changed in the animals maintained on a high fat diet compared to the regular diet. There were also significant changes observed in the concentration of Tri carboxylic acid cycle intermediates that were extracted from the liver of all three strains based on diet. The results of this study showed that a high fat diet caused significant liver and metabolic changes compared to a regular diet in multiple rat strains. The inbred Fisher 344 and Brown Norway rats were more metabolically sensitive to the diet changes than outbred Sprague Dawley strain. The study also showed that age, as was the case for Sprague Dawley, is an important variable to consider when assessing metabolic changes.

The exposome is the measure of all exposures of an individual in a lifetime and how those exposures relate to health. The goal was to examine an experimental model integrating multiple aspects of the exposome by collecting biological samples during critical life stages of an exposed animal that are applicable to worker populations. Genetic contributions were assessed using strains of male rats with different genetic backgrounds (Fischer-344, Sprague Dawley, and Brown-Norway) maintained on a regular or high-fat diet for 24 weeks. At week 7 during diet maintenance, groups of rats from each strain were exposed to stainless steel welding fume (WF; 20 mg/m3 × 3 h/d × 4 days/week × 5 weeks) or air until week 12, at which time some animals were euthanized. A separate set of rats from each strain were allowed to recover from WF exposure until the end of the 24-week period. Bronchoalveolar lavage fluid and serum were collected at 7, 12, and 24 weeks to assess general health indices. Depending on animal strain, WF exposure and high-fat diet together worsened kidney toxicity as well as altered different serum enzymes and proteins. Diet had minimal interaction with WF exposure for pulmonary toxicity endpoints. Experimental factors of diet, exposure, and strain were all important, depending on the health outcome measured. Exposure had the most significant influence related to pulmonary responses. Strain was the most significant contributor regarding the other health indices examined, indicating that genetic differences possibly drive the exposome effect in each strain.

The ends of chromosomes shorten at each round of cell division, and this process is thought to be affected by occupational exposures. Occupational hazards may alter telomere length homeostasis resulting in DNA damage, chromosome aberration, mutations, epigenetic alterations and inflammation. Therefore, for the protection of genetic material, nature has provided a unique nucleoprotein structure known as a telomere. Telomeres provide protection by averting an inappropriate activation of the DNA damage response (DDR) at chromosomal ends and preventing recognition of single and double strand DNA (ssDNA and dsDNA) breaks or chromosomal end-to-end fusion. Telomeres and their interacting six shelterin complex proteins in coordination act as inhibitors of DNA damage machinery by blocking DDR activation at chromosomes, thereby preventing the occurrence of genome instability, perturbed cell cycle, cellular senescence and apoptosis. However, inappropriate DNA repair may result in the inadequate distribution of genetic material during cell division, resulting in the eventual development of tumorigenesis and other pathologies. This article reviews the current literature on the association of changes in telomere length and its interacting proteins with different occupational exposures and the potential application of telomere length or changes in the regulatory proteins as potential biomarkers for exposure and health response, including recent findings and future perspectives.

Assessing the potential health risks for newly developed nanoparticles poses a significant challenge. Nanometer-sized particles are not generally detectable with the light microscope. Electron microscopy typically requires high-level doses, above the physiologic range, for particle examination in tissues. Enhanced dark-field microscopy (EDM) is an adaption of the light microscope that images scattered light. Nanoparticles scatter light with high efficiency while normal tissues do not. EDM has the potential to identify the critical target sites for nanoparticle deposition and injury in the lungs and other organs. This study describes the methods for EDM imaging of nanoparticles and applications. Examples of EDM application include measurement of deposition and clearance patterns. Imaging of a wide variety of nanoparticles demonstrated frequent situations where nanoparticles detected by EDM were not visible by light microscopy. EDM examination of colloidal gold nanospheres (10–100 nm diameter) demonstrated a detection size limit of approximately 15 nm in tissue sections. EDM determined nanoparticle volume density was directly proportional to total lung burden of exposed animals. The results confirm that EDM can determine nanoparticle distribution, clearance, transport to lymph nodes, and accumulation in extrapulmonary organs. Thus, EDM substantially improves the qualitative and quantitative microscopic evaluation of inhaled nanoparticles.

Exposure to welding fumes may result in disorders of the pulmonary, cardiovascular, and reproductive systems. Welders are also at a greater risk of developing symptoms similar to those seen in individuals with idiopathic Parkinson’s disease. In welders, there are studies that suggest that alterations in circulating prolactin concentrations may be indicative of injury to the dopamine (DA) neurons in the substantia nigra. The goal of these studies was to use an established model of welding particulate exposure to mimic the effects of welding fume inhalation on reproductive functions. Since previous investigators suggested that changes in circulating prolactin may be an early marker of DA neuron injury, movement disorders, and reproductive dysfunction, prolactin, hypothalamic tyrosine hydroxylase (TH) levels (a marker of DA synthesis), and other measures of hypothalamic-pituitary-gonadal (HPG) function were measured after repetitive instillation of welding fume particulates generated by flux core arc-hard surfacing (FCA-HS), manual metal arc-hard surfacing (MMA-HS) or gas metal arc-mild steel (GMA-MS) welding, or manganese chloride (MnCl(2)). Exposure to welding fume particulate resulted in the accumulation of various metals in the pituitary and testes of rats, along with changes in hypothalamic TH and serum prolactin levels. Exposure to particulates with high concentrations of soluble manganese (Mn) appeared to exert the greatest influence on TH activity levels and serum prolactin concentrations. Thus, circulating prolactin levels may serve as a biomarker for welding fume/Mn-induced neurotoxicity. Other reproductive measures were collected, and these data were consistent with epidemiological findings that prolactin and testosterone may serve as biomarkers of welding particulate induced DA neuron and reproductive dysfunction.

Inhalation of welding fume (WF) can result in the deposition of toxic metals, such as manganese (Mn), in the brain and may cause neurological changes in exposed workers. Alterations in telomere length are indicative of cellular aging and, possibly, neurodegeneration. Here, we investigated the effect of WF inhalation on telomere length and markers of neurodegeneration in whole brain tissue in rats. Male Fischer-344 (F-344) rats were exposed by inhalation to stainless steel WF (20 mg/m(3) × 3 h/d × 4 d/wk × 5 wk) or filtered air (control). Telomere length, DNA-methylation, gene expression of Trf1, Trf2, ATM, and APP, protein expression of p-Tau, α-synuclein, and presenilin 1 and 2 were assessed in whole brain tissue at 12 wk after WF exposure ended. Results suggest that WF inhalation increased telomere length without affecting telomerase in whole brain. Moreover, we observed that components of the shelterin complex, Trf1 and Trf2, play an important role in telomere end protection, and their regulation may be responsible for the increase in telomere length. In addition, expression of different neurodegeneration markers, such as p-Tau, presenilin 1–2 and α-synuclein proteins, were increased in brain tissue from the WF-exposed rats as compared to control. These findings suggest a possible correlation between epigenetic modifications, telomere length alteration, and neurodegeneration because of the presence of factors in serum after WF exposure that may cause extra-pulmonary effects as well as the translocation of potentially neurotoxic metals associated with WF to the central nervous system (CNS). Further studies are needed to investigate the brain region specificity and temporal response of these effects.

Millions of workers in the US and worldwide are exposed to complex, metal-rich welding fumes. Although welding is a crucial industrial process, the generated fumes are known to cause acute and chronic health effects when inhaled. The International Agency for Research on Cancer (IARC) classified welding fumes as carcinogenic to humans (Group 1) in 2017, based on sufficient epidemiological evidence and limited evidence in animals, an upgrade from the former Group 2B (possibly carcinogenic to humans) classification. There is human evidence that both iron-abundant mild steel as well as chromium- and nickel-containing stainless steel welding fumes contribute to an increased risk of lung cancer. Recent animal studies show that welding fumes may act as lung tumor promoters, regardless of the presence or absence of potentially carcinogenic metals, such as chromium and nickel. The goal of this manuscript was to examine the pulmonary responses associated with welding fumes by reviewing a series of recent experimental animal studies that assessed the influence of welding fume metal composition (e.g., stainless steel versus mild steel welding fume) on markers of lung toxicity and tumor development. Additional in vivo laboratory studies are needed to further explore the association between welding and lung cancer and to help advance our understanding of a potential mechanistic link.

The objective of the current study was to determine if age, diet, and genetic disposition (animal strain) in an animal model had early effects on specific molecular markers in circulating peripheral blood mononuclear cells (PBMCs). Three strains [Sprague-Dawley (SD), Fischer 344 (F344), and Brown-Norway (BN)] of male rats were maintained on a high-fat (HF) or regular diet. Blood was collected at 4, 12, and 24 wk to assess chemistry and to recover PBMCs. Triglycerides and body weight gain increased at all time points in the HF diet group for each strain. Telomere length in PBMCs decreased in the HF diet group compared to the regular diet group up to 24 wk in all strains. Telomere length decreased in PBMCs at 24 wk compared to baseline in all strains, indicating an age-related effect. These findings highlight that diet and age cause changes in PBMCs recovered from different strains of rats. The next tier of studies will examine the contribution of an occupational exposure (e.g., welding fume inhalation) in combination with diet, age, and strain, to assess changes in the molecular responses of isolated PBMCs. In addition, studies involving lifestyle exposure (e.g., tobacco smoke) are in the planning stages and will assess the long-term effects of exposure in our animal model.

Occupational exposure to silica has been observed to cause pulmonary fibrosis and lung cancer through complex mechanisms. Telomeres, the nucleoprotein structures with repetitive (TTAGGG) sequences at the end of chromosomes, are a molecular “clock of life”, and alterations are associated with chronic disease. The shelterin complex (POT1, TRF1, TRF2, Tin2, Rap1, and POT1 and TPP1) plays an important role in maintaining telomere length and integrity, and any alteration in telomeres may activate DNA damage response (DDR) machinery resulting in telomere attrition. The goal of this study was to assess the effect of silica exposure on the regulation of the shelterin complex in an animal model. Male Fisher 344 rats were exposed by inhalation to Min-U-Sil 5 silica for 3, 6, or 12 wk at a concentration of 15 mg/m3 for 6 hr/d for 5 consecutive d/wk. Expression of shelterin complex genes was assessed in the lungs at 16 hr after the end of each exposure. Also, the relationship between increased DNA damage protein (γH2AX) and expression of silica-induced fibrotic marker, αSMA, was evaluated. Our findings reveal new information about the dysregulation of shelterin complex after silica inhalation in rats, and how this pathway may lead to the initiation of silica-induced pulmonary fibrosis.

The early incorporation of exposure assessment can be invaluable to help design, prioritize, and interpret toxicological studies or outcomes. The sum total of the exposure assessment findings combined with preliminary toxicology results allows for exposure-informed toxicological study design and the findings can then be integrated, together with available epidemiologic data, to provide health effect relevance. With regard to engineered nanomaterial inhalation toxicology in particular, a single type of material (e.g. carbon nanotube, graphene) can have a vast array of physicochemical characteristics resulting in the potential for varying toxicities. To compound the matter, the methodologies necessary to establish a material adequate for in vivo exposure testing raises questions on the applicability of the outcomes. From insights gained from evaluating carbon nanotubes, we recommend the following integrated approach involving exposure-informed hazard assessment and hazard-informed exposure assessment especially for materials as diverse as engineered nanomaterials: 1) market-informed identification of potential hazards and potentially exposed populations, 2) initial toxicity screening to drive prioritized assessments of exposure, 3) development of exposure assessment-informed chronic and sub-chronic in vivo studies, and 4) conduct of exposure- and hazard-informed epidemiological studies.

Pulmonary toxicity studies often use bronchoalveolar lavage (BAL) to investigate potential adverse lung responses to a particulate exposure. The BAL cellular fraction is counted, using automated (i.e. Coulter Counter®), flow cytometry or manual (i.e. hemocytometer) methods, to determine inflammatory cell influx. The goal of the study was to compare the different counting methods to determine which is optimal for examining BAL cell influx after exposure by inhalation or intratracheal instillation (ITI) to different particles with varying inherent pulmonary toxicities in both rat and mouse models. General findings indicate that total BAL cell counts using the automated and manual methods tended to agree after inhalation or ITI exposure to particle samples that are relatively nontoxic or at later time points after exposure to a pneumotoxic particle when the response resolves. However, when the initial lung inflammation and cytotoxicity was high after exposure to a pneumotoxic particle, significant differences were observed when comparing cell counts from the automated, flow cytometry and manual methods. When using total BAL cell count for differential calculations from the automated method, depending on the cell diameter size range cutoff, the data suggest that the number of lung polymorphonuclear leukocytes (PMN) varies. Importantly, the automated counts, regardless of the size cutoff, still indicated a greater number of total lung PMN when compared with the manual method, which agreed more closely with flow cytometry. The results suggest that either the manual method or flow cytometry would be better suited for BAL studies where cytotoxicity is an unknown variable.

In 2017, the International Agency for Research on Cancer classified welding fumes as “carcinogenic to humans” (Group 1). Both mild steel (MS) welding, where fumes lack carcinogenic chromium and nickel, and stainless steel (SS) increase lung cancer risk in welders; therefore, further research to better understand the toxicity of the individual metals is needed. The objectives were to (1) compare the pulmonary toxicity of chromium (as Cr(III) oxide [Cr2O3] and Cr (VI) calcium chromate [CaCrO4]), nickel [II] oxide (NiO), iron [III] oxide (Fe2O3), and gas metal arc welding-SS (GMAW-SS) fume; and (2) determine if these metal oxides can promote lung tumors. Lung tumor susceptible A/J mice (male, 4–5 weeks old) were exposed by oropharyngeal aspiration to vehicle, GMAW-SS fume (1.7 mg), or a low or high dose of surrogate metal oxides based on the respective weight percent of each metal in the fume: Cr2O3 + CaCrO4 (366 + 5 μg and 731 + 11 μg), NiO (141 and 281 μg), or Fe2O3 (1 and 2 mg). Bronchoalveolar lavage, histopathology, and lung/liver qPCR were done at 1, 7, 28, and 84 days post-aspiration. In a two-stage lung carcinogenesis model, mice were initiated with 3-methylcholanthrene (10 μg/g; intraperitoneal; 1x) or corn oil then exposed to metal oxides or vehicle (1 x/week for 5 weeks) by oropharyngeal aspiration. Lung tumors were counted at 30 weeks post-initiation. Results indicate the inflammatory potential of the metal oxides was Fe2O3 > Cr2O3 + CaCrO4 > NiO. Overall, the pneumotoxic effects were negligible for NiO, acute but not persistent for Cr2O3 + CaCrO4, and persistent for the Fe2O3 exposures. Fe2O3, but not Cr2O3 + CaCrO4 or NiO significantly promoted lung tumors. These results provide experimental evidence that Fe2O3 is an important mediator of welding fume toxicity and support epidemiological findings and the IARC classification.

The effects of acute pulmonary coexposures to silica and diesel particulate matter (DPM), which may occur in various mining operations, were investigated in vivo. Rats were exposed by intratracheal instillation (IT) to silica (50 or 233 µg), DPM (7.89 or 50 µg) or silica and DPM combined in phosphate-buffered saline (PBS) or to PBS alone (control). At one day, one week, one month, two months and three months postexposure bronchoalveolar lavage and histopathology were performed to assess lung injury, inflammation and immune response. While higher doses of silica caused inflammation and injury at all time points, DPM exposure alone did not. DPM (50 µg) combined with silica (233 µg) increased inflammation at one week and one-month postexposure and caused an increase in the incidence of fibrosis at one month compared with exposure to silica alone. To assess susceptibility to lung infection following coexposure, rats were exposed by IT to 233 µg silica, 50 µg DPM, a combination of the two or PBS control one week before intratracheal inoculation with 5 × 105 Listeria monocytogenes. At 1, 3, 5, 7 and 14 days following infection, pulmonary immune response and bacterial clearance from the lung were evaluated. Coexposure to DPM and silica did not alter bacterial clearance from the lung compared to control. Although DPM and silica coexposure did not alter pulmonary susceptibility to infection in this model, the study showed that noninflammatory doses of DPM had the capacity to increase silica-induced lung injury, inflammation and onset/incidence of fibrosis.

Exposure to silica can cause lung fibrosis and cancer. Identification of molecular targets is important for the intervention and/or prevention of silica-induced lung diseases. Telomeres consist of tandem repeats of DNA sequences at the end of chromosomes, preventing chromosomal fusion and degradation. Regulator of telomere length-1 (RTEL1) and telomerase reverse transcriptase (TERT), genes involved in telomere regulation and function, play important roles in maintaining telomere integrity and length. The goal of this study was to assess the effect of silica inhalation on telomere length and the regulation of RTEL1 and TERT. Lung tissues and blood samples were collected from rats at 4, 32, and 44 wk after exposure to 15 mg/m3 of silica × 6 h/d × 5 d. Controls were exposed to air. At all-time points, RTEL1 expression was significantly decreased in lung tissue of the silica-exposed animals compared to controls. Also, significant increases in telomere length and TERT were observed in the silica group at 4 and 32 wk. Telomere length, RTEL1 and TERT expression may serve as potential biomarkers related to silica exposure and may offer insight into the molecular mechanism of silica-induced lung disease and tumorigeneses.

Welding fumes (WF) are a complex mixture of toxic metals and gases, inhalation of which can lead to adverse health effects among welders. The presence of manganese (Mn) in welding electrodes is cause for concern about the potential development of Parkinson's disease (PD)-like neurological disorder. Consequently, from an occupational safety perspective, there is a critical need to prevent adverse exposures to WF. As the fume generation rate and physicochemical characteristics of welding aerosols are influenced by welding process parameters like voltage, current or shielding gas, we sought to determine if changing such parameters can alter the fume profile and consequently its neurotoxic potential. Specifically, we evaluated the influence of voltage on fume composition and neurotoxic outcome. Rats were exposed by whole-body inhalation (40 mg/m(3); 3h/day × 5 d/week × 2 weeks) to fumes generated by gas-metal arc welding using stainless steel electrodes (GMA-SS) at standard/regular voltage (25 V; RVSS) or high voltage (30 V; HVSS). Fumes generated under these conditions exhibited similar particulate morphology, appearing as chain-like aggregates; however, HVSS fumes comprised of a larger fraction of ultrafine particulates that are generally considered to be more toxic than their fine counterparts. Paradoxically, exposure to HVSS fumes did not elicit dopaminergic neurotoxicity, as monitored by the expression of dopaminergic and PD-related markers. We show that the lack of neurotoxicity is due to reduced solubility of Mn in HVSS fumes. Our findings show promise for process control procedures in developing prevention strategies for Mn-related neurotoxicity during welding; however, it warrants additional investigations to determine if such modifications can be suitably adapted at the workplace to avert or reduce adverse neurological risks.

Welding generates a complex aerosol of incidental nanoparticles and cytotoxic metals, such as chromium (Cr), manganese (Mn), nickel (Ni), and iron (Fe). The goal was to use both in vivo and in vitro methodologies to determine the mechanisms by which different welding fumes may damage the lungs. Sprague-Dawley rats were treated by intratracheal instillation (ITI) with 2.0 mg of gas metal arc-mild steel (GMA-MS) or manual metal arc-stainless steel (MMA-SS) fumes or saline (vehicle control). At 1, 3, and 10 days, bronchoalveolar lavage (BAL) was performed to measure lung toxicity. To assess molecular mechanisms of cytotoxicity, RAW264.7 cells were exposed to both welding fumes for 24 h (0–100 μg/ml). Fume composition was different: MMA-SS (41% Fe, 29% Cr, 17% Mn, 3% Ni) versus GMA-MS (85% Fe, 14% Mn). BAL indicators of lung injury and inflammation were increased by MMA-SS at all time points and by GMA-MS at 3 and 10 days after exposure. RAW264.7 cells exposed to MMA-SS had elevated generation of reactive oxygen species (ROS), protein-HNE (P-HNE) adduct formation, activation of ERK1/2, and expression of cyclooxygenase-2 (COX-2) compared to GMA-MS and control. Increased generation of ROS due to MMA-SS exposure was confirmed by increased expression of Nrf2 and heme oxygenase-1 (HO-1). Results of in vitro studies provide evidence that stainless steel welding fume mediate inflammatory responses via activation of ROS/P-HNE/ERK1/2/Nrf2 signaling pathways. These findings were corroborated by elevated expression of COX-2, Nrf2, and HO-1 in homogenized lung tissue collected 1 day after in vivo exposure.

Epidemiologic studies suggest an increased risk of lung cancer with exposure to welding fumes, but controlled animal studies are needed to support this association. Oropharyngeal aspiration of collected “aged” gas metal arc–stainless steel (GMA–SS) welding fume has been shown by our laboratory to promote lung tumor formation in vivo using a two-stage initiation–promotion model. Our objective in this study was to determine whether inhalation of freshly generated GMA-SS welding fume also acts as a lung tumor promoter in lung tumor-susceptible mice. Male A/J mice received intraperitoneal (IP) injections of corn oil or the chemical initiator 3-methylcholanthrene (MCA; 10 μg/g) and 1 week later were exposed by whole-body inhalation to air or GMA-SS welding aerosols for 4 h/d × 4 d/w × 9 w at a target concentration of 40 mg/m(3). Lung nodules were enumerated at 30 weeks post-initiation. GMA-SS fume significantly promoted lung tumor multiplicity in A/J mice initiated with MCA (16.11 ± 1.18) compared to MCA/air-exposed mice (7.93 ± 0.82). Histopathological analysis found that the increased number of lung nodules in the MCA/GMA-SS group were hyperplasias and adenomas, which was consistent with developing lung tumorigenesis. Metal deposition analysis in the lung revealed a lower deposited dose, approximately fivefold compared to our previous aspiration study, still elicited a significant lung tumorigenic response. In conclusion, this study demonstrates that inhaling GMA-SS welding fume promotes lung tumorigenesis in vivo which is consistent with the epidemiologic studies that show welders may be at an increased risk for lung cancer.

Limited information exists regarding the health risks associated with inhaling aerosols that are generated during resistance spot welding of metals treated with adhesives. Toxicology studies evaluating spot welding aerosols are non-existent. A resistance spot welding aerosol generator and inhalation exposure system was developed. The system was designed by directing strips of sheet metal that were treated with an adhesive to two electrodes of a spot welder. Spot welds were made at a specified distance from each other by a computer-controlled welding gun in a fume collection chamber. Different target aerosol concentrations were maintained within the exposure chamber during a 4-h exposure period. In addition, the exposure system was run in two modes, spark and no spark, which resulted in different chemical profiles and particle size distributions. Complex aerosols were produced that contained both metal particulates and volatile organic compounds (VOCs). Size distribution of the particles was multi-modal. The majority of particles were chain-like agglomerates of ultrafine primary particles. The submicron mode of agglomerated particles accounted for the largest portion of particles in terms of particle number. Metal expulsion during spot welding caused the formation of larger, more spherical particles (spatter). These spatter particles appeared in the micron size mode and accounted for the greatest amount of particles in terms of mass. With this system, it is possible to examine potential mechanisms by which spot welding aerosols can affect health, as well as assess which component of the aerosol may be responsible for adverse health outcomes.

Spot welding is used in the automotive and aircraft industries, where high-speed, repetitive welding is needed to join thin sections of metal. Epoxy adhesives are applied as sealers to the metal seams. Pulmonary function abnormalities and airway irritation have been reported in spot welders, but no animal toxicology studies exist. Therefore, the goal of this study was to investigate vascular, immune and lung toxicity measures after exposure to these metal fumes in an animal model. Male Sprague-Dawley rats were exposed by inhalation to 25 mg/m³ to either mild-steel spot welding aerosols with sparking (high metal, HM) or without sparking (low metal, LM) for 4 h/d for 3, 8 and 13 d. Shams were exposed to filtered air. Bronchoalveolar lavage (BAL), lung gene expression and ex vivo BAL cell challenge were performed to assess lung toxicity. Lung resistance (R(L)) was evaluated before and after challenge with inhaled methacholine (MCh). Functional assessment of the vascular endothelium in isolated rat tail arteries and leukocyte differentiation in the spleen and lymph nodes via flow cytometry was also done. Immediately after exposure, baseline R(L) was significantly elevated in the LM spot welding aerosols, but returned to control level by 24 h postexposure. Airway reactivity to MCh was unaffected. Lung inflammation and cytotoxicity were mild and transient. Lung epithelial permeability was significantly increased after 3 and 8 d, but not after 13 d of exposure to the HM aerosol. HM aerosols also caused vascular endothelial dysfunction and increased CD4+, CD8+ and B cells in the spleen. Only LM aerosols caused increased IL-6 and MCP-1 levels compared with sham after ex vivo LPS stimulation in BAL macrophages. Acute inhalation of mild-steel spot welding fumes at occupationally relevant concentrations may act as an irritant as evidenced by the increased R(L) and result in endothelial dysfunction, but otherwise had minor effects on the lung.

Graphical abstract, Highlights • An automated welder was designed to expose animals to galvanized spot welding fume. • Generated particles generally were in the submicron and ultrafine size ranges. • The primary metals present in galvanized spot welding fumes were iron and zinc. • Zinc appeared to be the causative agent in the development of acute lung inflammation., Resistance spot welding is a common process to join metals in the automotive industry. Adhesives are often used as sealers to seams of metals that are joined. Anti-spatter compounds sometimes are sprayed onto metals to be welded to improve the weldability. Spot welding produces complex aerosols composed of metal and volatile compounds (VOCs) which can cause lung disease in workers. Male Sprague-Dawley rats (n = 12/treatment group) were exposed by inhalation to 25 mg/m3 of aerosol for 4 h/day × 8 days during spot welding of galvanized zinc (Zn)-coated steel in the presence or absence of a glue or anti-spatter spray. Controls were exposed to filtered air. Particle size distribution and chemical composition of the generated aerosol were determined. At 1 and 7 days after exposure, bronchoalveolar lavage (BAL) was performed to assess lung toxicity. The generated particles mostly were in the submicron size range with a significant number of nanometer-sized particles formed. The primary metals present in the fumes were Fe (72.5%) and Zn (26.3%). The addition of the anti-spatter spray and glue did affect particle size distribution when spot welding galvanized steel, whereas they had no effect on metal composition. Multiple VOCs (e.g., methyl methacrylate, acetaldehyde, ethanol, acetone, benzene, xylene) were identified when spot welding using either the glue or the anti-spatter spray that were not present when welding alone. Markers of lung injury (BAL lactate dehydrogenase) and inflammation (total BAL cells/neutrophils and cytokines/chemokines) were significantly elevated compared to controls 1 day after exposure to the spot welding fumes. The elevated pulmonary response was transient as lung toxicity mostly returned to control values by 7 days. The VOCs or the concentrations that they were generated during the animal exposures had no measurable effect on the pulmonary responses. Inhalation of galvanized spot welding fumes caused acute lung toxicity most likely due to the short-term exposure of particles that contain Zn.

Welding fume inhalation causes pulmonary toxicity, including susceptibility to infection. We hypothesized that airway epithelial ion transport is a target of fume toxicity, and investigated the effects of fume particulates from manual metal arc-stainless steel (MMA-SS) and gas metal arc-mild steel (GMA-MS) on ion transport in normal human bronchial epithelium (NHBE) cultured in air-interface. MMA-SS particles, more soluble than GMA-MS particles, contain Cr, Ni, Fe and Mn; GMA-MS particles contain Fe and Mn. MMA-SS or GMA-MS particles (0.0167–166.7 μg/cm 2 ) were applied apically to NHBEs. After 18 h transepithelial potential difference (V t ), resistance (R t ), and short circuit current ( I sc ) were measured. Particle effects on Na + and Cl¯ channels and the Na + ,K + ,2Cl¯-cotransporter were evaluated using amiloride (apical), 5-nitro-2-[(3-phenylpropyl)amino]benzoic acid (NPPB, apical), and bumetanide (basolateral), respectively. MMA-SS (0.0167–16.7 μg/cm 2 ) increased basal V t . Only 16.7 μg/cm 2 GMA-MS increased basal V t significantly. MMA-SS or GMA-MS exposure potentiated I sc responses (decreases) to amiloride and bumetanide, while not affecting those to NPPB, GMA-MS to a lesser degree than MMA-SS. Variable effects on R t were observed in response to amiloride, and bumetanide. Generally, MMA-SS was more potent in altering responses to amiloride and bumetanide than GMA-MS. Hyperpolarization occurred in the absence of LDH release, but decreases in V t , R t , and I sc at higher fume particulate doses accompanied LDH release, to a greater extent for MMA-SS. Thus, Na + transport and Na + ,K + ,2Cl¯-cotransport are affected by fume exposure; MMA-MS is more potent than GMA-MS. Enhanced Na + absorption and decreased airway surface liquid could compromise defenses against infection.

Arc welding processes generate complex aerosols composed of potentially hazardous metal fumes and gases. Millions of workers worldwide are exposed to welding aerosols daily. A health effect of welding that is of concern to the occupational health community is the development of immune system dysfunction. Increased severity, frequency, and duration of upper and lower respiratory tract infections have been reported among welders. Specifically, multiple studies have observed an excess mortality from pneumonia in welders and workers exposed to metal fumes. Although several welder cohort and experimental animal studies investigating the adverse effects of welding fume exposure on immune function have been performed, the potential mechanisms responsible for these effects are limited. The objective of this report was to review both human and animal studies that have examined the effect of welding fume pulmonary exposure on local and systemic immune responses.

It is observed that 1 → 3-β-glucan, a major cell wall component of fungi, induces pulmonary inflammation. There is inconsistency in determining the correlation between the levels of glucan measured by current extraction methods and the respiratory inflammation observed in individuals or lab animals exposed to environmental dust samples. The glucan-specific limulus amebocyte lysate (G-LAL) method was used after extraction with dimethyl sulfoxide (DMSO) or sodium hydroxide (NaOH) to analyze the glucan content of office dust samples collected from a water-damaged building. C3HeB/FeJ mice, an endotoxin-sensitive strain, were treated with different dust samples (2.5 mg kg−1 body weight) or saline (vehicle control) by pharyngeal aspiration. At 1 day after aspiration, bronchoalveolar lavage (BAL) was performed, and lung inflammation and injury were assessed by measuring: (1) neutrophil (PMN) infiltration, (2) inflammatory cytokine (IL-6, IL-10, MCP-1, IFN-γ, TNF-α, and IL12-p70) levels, and (3) albumin and lacta...

Debate exists as to whether welding fume is carcinogenic, but epidemiological evidence suggests that welders are an at-risk population for development of lung cancer. Our objective was to expose, by inhalation, lung tumor susceptible (A/J) and resistant C57BL/6J (B6) mice to stainless steel (SS) welding fume containing carcinogenic metals and characterize the lung-inflammatory and tumorigenic response. Male mice were exposed to air or gas metal arc (GMA)-SS welding fume at 40 mg/m(3)×3 h/day for 6 and 10 days. At 1, 4, 7, 10, 14, and 28 days after 10 days of exposure, bronchoalveolar lavage (BAL) was done. Lung cytotoxicity, permeability, inflammatory cytokines, and cell differentials were analyzed. For the lung tumor study, gross tumor counts and histopathological changes were assessed in A/J mice at 78 weeks after 6 and 10 days of exposure. Inhalation of GMA-SS fume caused an early, sustained macrophage and lymphocyte response followed by a gradual neutrophil influx and the magnitudes of these differed between the mouse strains. Monocyte chemotactic protein-1 (MCP-1), macrophage inflammatory protein-2 (MIP-2), and tumor necrosis factor-α (TNF-α) were increased in both strains while the B6 also had increased interleukin-6 (IL-6) protein. BAL measures of cytotoxicity and damage were similar between the strains and significantly increased at all time points. Histopathology and tumorigenesis were unremarkable at 78 weeks. In conclusion, GMA-SS welding fume induced a significant and sustained inflammatory response in both mouse strains with no recovery by 28 days. Under our exposure conditions, GMA-SS exposure resulted in no significant tumor development in A/J mice.

Welding generates complex metal aerosols, inhalation of which is linked to adverse health effects among welders. An important health concern of welding fume (WF) exposure is neurological dysfunction akin to Parkinson's disease (PD), thought to be mediated by manganese (Mn) in the fumes. Also, there is a proposition that welding might accelerate the onset of PD. Our recent findings link the presence of Mn in the WF with dopaminergic neurotoxicity seen in rats exposed to manual metal arc-hard surfacing (MMA-HS) or gas metal arc-mild steel (GMA-MS) fumes. To elucidate the molecular mechanisms further, we investigated the association of PD-linked (Park) genes and mitochondrial function in causing dopaminergic abnormality. Repeated instillations of the two fumes at doses that mimic ∼1 to 5 yr of worker exposure resulted in selective brain accumulation of Mn. This accumulation caused impairment of mitochondrial function and loss of tyrosine hydroxylase (TH) protein, indicative of dopaminergic injury. A fascinating finding was the altered expression of Parkin (Park2), Uchl1 (Park5), and Dj1 (Park7) proteins in dopaminergic brain areas. A similar regimen of manganese chloride (MnCl(2)) also caused extensive loss of striatal TH, mitochondrial electron transport components, and Park proteins. As mutations in PARK genes have been linked to early-onset PD in humans, and because welding is implicated as a risk factor for parkinsonism, PARK genes might play a critical role in WF-mediated dopaminergic dysfunction. Whether these molecular alterations culminate in neurobehavioral and neuropathological deficits reminiscent of PD remains to be ascertained.

Welding generates complex metal fumes that vary in composition. The objectives of this study were to compare the persistence of deposited metals and the inflammatory potential of stainless and mild steel welding fumes, the two most common fumes used in US industry. Sprague-Dawley rats were exposed to 40 mg/m(3) of stainless or mild steel welding fumes for 3 h/day for 3 days. Controls were exposed to filtered air. Generated fume was collected, and particle size and elemental composition were determined. Bronchoalveolar lavage was done on days 0, 8, 21, and 42 after the last exposure to assess lung injury/inflammation and to recover lung phagocytes. Non-lavaged lung samples were analyzed for total and specific metal content as a measure of metal persistence. Both welding fumes were similar in particle morphology and size. Following was the chemical composition of the fumes-stainless steel: 57% Fe, 20% Cr, 14% Mn, and 9% Ni; mild steel: 83% Fe and 15% Mn. There was no effect of the mild steel fume on lung injury/inflammation at any time point compared to air control. Lung injury and inflammation were significantly elevated at 8 and 21 days after exposure to the stainless steel fume compared to control. Stainless steel fume exposure was associated with greater recovery of welding fume-laden macrophages from the lungs at all time points compared with the mild steel fume. A higher concentration of total metal was observed in the lungs of the stainless steel welding fume at all time points compared with the mild steel fume. The specific metals present in the two fumes were cleared from the lungs at different rates. The potentially more toxic metals (e.g., Mn, Cr) present in the stainless steel fume were cleared from the lungs more quickly than Fe, likely increasing their translocation from the respiratory system to other organs.

Serious questions have been raised by occupational health investigators regarding a possible causal association between neurological effects in welders and the presence of manganese (Mn) in welding fume. Male Sprague-Dawley rats were exposed by inhalation to 40 mg/m(3) of gas metal arc-mild steel (MS) welding fume for 3 h/day for 10 days. Generated fume was collected in the animal chamber during exposure, and particle size, composition, and morphology were characterized. At 1 day after the last exposure, metal deposition in different organ systems and neurological responses in dopaminergic brain regions were assessed in exposed animals. The welding particles were composed primarily of a complex of iron (Fe) and Mn and were arranged as chain-like aggregates with a significant number of particles in the nanometer size range. Mn was observed to translocate from the lungs to the kidney and specific brain regions (olfactory bulb, cortex, and cerebellum) after MS fume inhalation. In terms of neurological responses, short-term MS fume inhalation induced significant elevations in divalent metal ion transporter 1 (Dmt1) expression in striatum and midbrain and significant increases in expression of proinflammatory chemokines (Ccl2, Cxcl2) and cytokines (IL1beta, TNFalpha) in striatum. In addition, mRNA and protein expression of glial fibrillary acidic protein (GFAP) was significantly increased in striatum after MS fume exposure. However, the 10-day MS welding fume inhalation did not cause any changes in dopamine and its metabolites or GABA in dopaminergic brain regions nor did it produce overt neural cell damage as assessed by histopathology. In summary, short-term MS welding fume exposure led to translocation of Mn to specific brain regions and induced subtle changes in cell markers of neuroinflammatory and astrogliosis. The neurofunctional significance of these findings currently is being investigated in longer, more chronic welding fume exposure studies.

Occupational exposure to welding fumes is a known health hazard. To isolate elements in stainless steel welding fumes with high potential for adverse health outcomes, fumes were generated using a robotic gas metal arc system, using four shield gases of varying oxygen content. The objective was to measure Cr(VI) concentrations in a broad spectrum of gas metal arc welding processes, and identify processes of exceptionally high or low Cr(VI) content. The gases used were 95% Ar/5% O(2), 98% Ar/2% O(2), 95% Ar/5%CO(2), and 75% He/25% Ar. The welder was operated in axial spray mode (Ar/O(2), Ar/CO(2)), short-circuit (SC) mode (Ar/CO(2) low voltage and He/Ar), and pulsed axial-spray mode (98% Ar/2% O(2)). Results indicate large differences in Cr(VI) in the fumes, with Ar/O(2) (Pulsed)Ar/O(2)Ar/CO(2)Ar/CO(2) (SC)He/Ar; values were 3000+/-300, 2800+/-85, 2600+/-120, 1400+/-190, and 320+/-290 ppm respectively (means +/- standard errors for 2 runs and 3 replicates per run). Respective rates of Cr(VI) generation were 1.5, 3.2, 4.4, 1.3, and 0.46 microg/min; generation rates were also calculated in terms of microg Cr(VI) per metre of wire used. The generation rates of Cr(VI) increased with increasing O(3) concentrations. Particle size measurements indicated similar distributions, but somewhat higher0.6 microm fractions for the short-circuit mode samples. Fumes were also sampled into 2 selected size ranges, a microspatter fraction (or=0.6 microm) and a fine (0.6 microm) fraction; analysis indicated that Cr(VI) is primarily associated with particles0.6 microm. The conclusion of the study is that Cr(VI) concentrations vary significantly with welding type and shield gas type, and this presents an opportunity to tailor welding practices to lessen Cr(VI) exposures in workplaces by selecting low Cr(VI)-generating processes. Short-circuit processes generated less Cr(VI) than axial-spray methods, and inert gas shielding gave lower Cr(VI) content than shielding with active gases. A short circuit He/Ar shielded process and a pulsed axial spray Ar/O(2) process were both identified as having substantially lower Cr(VI) generation rates per unit of wire used relative to the other processes studied.

Carbon nanotubes (CNT), with their applications in industry and medicine, may lead to new risks to human health. CNT induce a robust pulmonary inflammation and oxidative stress in rodents. Realistic exposures to CNT may occur in conjunction with other pathogenic impacts (microbial infections) and trigger enhanced responses. We evaluated interactions between pharyngeal aspiration of single-walled CNT (SWCNT) and bacterial pulmonary infection of C57BL/6 mice with Listeria monocytogenes (LM). Mice were given SWCNT (0, 10, and 40 mug/mouse) and 3 days later were exposed to LM (10(3) bacteria/mouse). Sequential exposure to SWCNT/LM amplified lung inflammation and collagen formation. Despite this robust inflammatory response, SWCNT pre-exposure significantly decreased the pulmonary clearance of LM-exposed mice measured 3 to 7 days after microbial infection versus PBS/LM-treated mice. Decreased bacterial clearance in SWCNT-pre-exposed mice was associated with decreased phagocytosis of bacteria by macrophages and a decrease in nitric oxide production by these phagocytes. Pre-incubation of naïve alveolar macrophages with SWCNT in vitro also resulted in decreased nitric oxide generation and suppressed phagocytizing activity toward LM. Failure of SWCNT-exposed mice to clear LM led to a continued elevation in nearly all major chemokines and acute phase cytokines into the later course of infection. In SWCNT/LM-exposed mice, bronchoalveolar lavage neutrophils, alveolar macrophages, and lymphocytes, as well as lactate dehydrogenase level, were increased compared with mice exposed to SWCNT or LM alone. In conclusion, enhanced acute inflammation and pulmonary injury with delayed bacterial clearance after SWCNT exposure may lead to increased susceptibility to lung infection in exposed populations.

The present study examines the effects of pre-exposure to zymosan (a 1 --3-beta-glucan from baker yeast) on lung defense against bacterial infection. Rats received a single dose of zymosan A (0.6, 1.2, or 2.5 mg/kg body weight [bw]) or vehicle control (saline) via intratracheal instillation 3 days prior to intratracheal inoculation with 5 x 10(5) Listeria monocytogenes. Left lungs were homogenized and cultured to assess bacterial clearance, and bronchoalveolar lavage was performed on the right lungs to monitor lung inflammation and injury. Prior to bacterial infection, zymosan exposure resulted in elevated inflammation and oxidant production in the lungs. Zymosan treatment followed by infection led to an accelerated pulmonary clearance of bacteria when compared to the saline control group in a dose-dependent fashion. In addition, lower levels of injury and inflammation were associated with the enhanced bacteria clearance observed in zymosan-infected rats. Our findings suggest that zymosan exposure may enhance the lung immune response by activating alveolar macrophages prior to infection, and stimulating T cells involved in the adaptive immune response early after infection, thus resulting in a heightened pulmonary immune response.