Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Morgantown, West Virginia 26505
Received April 22, 2003; accepted June 10, 2003
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ABSTRACT |
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Key Words: welding fumes; free radicals; lung inflammation; lung injury; electron spin resonance.
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INTRODUCTION |
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There are an estimated 800,000 full-time welders employed worldwide (Sundin, 1988) and approximately 410,040 workers employed as welders, cutters, solderers, and brazers in the United States (Bureau of Labor, 1999
). Many more are estimated to perform intermittent welding as part of their employment. Epidemiological studies have indicated that large numbers of welders experience some type of respiratory illness. Respiratory effects observed include acute and chronic bronchitis, airway irritation, chemical pneumonitis, occupational asthma, and a possible increase in lung cancer (Sferlazza and Beckett, 1991
).
Some studies have been undertaken to evaluate the toxicity of welding fumes using both in vitro and in vivo models. Stern and Pigott (1983) and Pasanen et al. (1986)
demonstrated that SS fumes from manual metal arc welding were much more cytotoxic to rat macrophages than fumes from a variety of other welding processes. Antonini et al. (1996
, 1997
) demonstrated that welding fumes generated from SS materials were more cytotoxic to rat macrophages while inducing a greater release of reactive oxygen species (ROS) from them. The SS fumes were also more pneumotoxic in vivo and were cleared from the lungs at a slower rate than fumes collected from MS welding. In addition, the SS fume treatment caused increased levels of tumor necrosis factor-(TNF)-
and interleukin-(IL)-1ß in the lungs of exposed rats. The authors noted in these studies that the lung response to MS fumes was transient and reversible, similar to the pulmonary response to iron oxide, a mineral particle characterized as a nuisance dust with little pneumotoxic potential. The effects that they observed may have been due to differences in the metal composition and solubility of the SS and MS welding fumes, the persistence of the SS fumes, and presence of inflammatory cytokines following SS fume treatment.
Indirect evidence of a possible role of free radical production by the SS fumes in lung toxicity was found by Antonini et al. (1998). They demonstrated that freshly generated SS fumes induced greater lung injury and inflammation than aged fumes, indicating a possible presence of reactive components on the fume surface. In addition, an in vitro study by Antonini et al. (1999)
found differences in the metal compositions and solubilities of fumes collected during gas metal arc (GMA) welding or flux-covered manual metal arc (MMA) welding with both MS and SS electrodes. The MMA-SS fume was found to be much more water-soluble than either the GMA-SS or GMA-MS fumes, and the soluble fraction of the MMA-SS fumes was comprised mainly of Cr. The small soluble fraction of the GMA-MS sample contained Mn with little Fe, whereas a more complex mixture of Mn, Ni, Fe, Cr, and Cu was found in the GMA-SS fume. When rat alveolar macrophages were treated in vitro with the soluble fractions of the fumes, the MMA-SS sample was shown to be most cytotoxic and have the greatest impact on their function, reducing their ability to produce ROS when stimulated.
The goals of the present study were to examine the acute effects of three different welding fumes (GMA-MS, GMA-SS, and MMA-SS) of differing compositions and solubilities on lung inflammation and injury in rats. Furthermore, the effects of the water-soluble and insoluble components of the MMA-SS fume were also examined in an attempt to identify the constituents of the fume responsible for the toxicity. These effects were correlated with the free radical production potential of each fume.
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MATERIALS AND METHODS |
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Preparation of welding fume samples.
The three-fume particle samples (GMA-MS, GMA-SS, MMA-SS) were suspended in sterile phosphate-buffered saline (PBS), pH 7.4, and sonicated for 1 min. The MMA-SS fume was further divided into soluble and insoluble components. The MMA-SS suspension (MMA-SS-Tot; 6.67 mg/ml) was incubated overnight at 37°C with shaking and then centrifuged at 12,000 x g for 30 min. The supernatant (MMA-SS-Sol) was recovered and filtered with 0.22-µm filters (Millipore Corp., Bedford, MA). The pellet (MMA-SS-Insol) was resuspended with the original volume of PBS. Because GMA-MS and GMA-SS were found to be mostly water-insoluble in a previous study (Antonini et al., 1999), they were not further divided into soluble and insoluble components for animal treatment in this current study.
Sample characterization.
The characterization of the fumes used in this study was previously reported by Antonini et al. (1999). Briefly, the amounts of seven different metals commonly found in welding fumes (Cr, Cu, Fe, Mn, Ni, Ti, and V) were measured using inductively coupled argon plasma atomic emission spectroscopy (NIOSH, 1994
). The particle sizes of all three fumes were found to be of respirable size, ranging from 0.92- to 1.38-µm count mean diameters, as reported in Antonini et al. (1999)
.
Laboratory animals.
All studies were performed on adult male pathogen-free Sprague-Dawley rats (Hla: [SD] CVF; 200300g; Hilltop Laboratory Animals, Scottdale, PA). They were given a conventional laboratory diet and water ad libitum and housed in an AAALAC-approved animal facility with restricted access and HEPA-filtered air, monitored free of pathogens, and allowed to acclimate for at least one week before treatment.
Intratracheal treatment.
The rats were intratracheally (i.t) instilled with 2 mg of welding fume in 0.3-ml PBS, or the equivalent volume of the soluble fraction of MMA-SS, or the saline vehicle. This dose of fume was selected based on a doseresponse study reported by Antonini et al. (1996). A lower dose of fume (0.2 mg/100 g body weight) did not produce inflammatory responses, while a higher dose (5.0 mg/100 g body weight) produced drastic pulmonary inflammation and injury 1 day post-treatment. Also in that study, the responses to a positive control, silica, and a negative control, iron oxide, were reported to help gauge the responses observed after welding fume treatment. Prior to instillation, the animals were anesthetized with Brevital (sodium methohexital, 3 mg/kg), and the instillations were preformed as described in Taylor et al. (2000)
.
Bronchoalveolar lavage (BAL).
To harvest the pulmonary cells for morphologic and functional analysis and to obtain acellular fluid for damage indicator analysis, the rats were euthanized at the respective time points with an overdose of sodium pentobarbital and then exsanguinated by severing the left renal artery. BAL was performed at 3 h and 1, 3, and 6 days after i.t. welding fume or vehicle treatment by washing out the lungs with aliquots of calcium- and magnesium-free PBS. The left lung was clamped off and removed prior to BAL. The first BAL volume was administered as 1 ml per 100 g body weight, and this volume was instilled into the lungs for 30 s with light massaging, withdrawn, and again instilled into the lungs for another 30 s. Once withdrawn, this aliquot (designated the first BAL fraction) was kept separate from the rest of the BAL fluid. BAL was continued with similar aliquots and pooled until 40 ml of BAL fluid, containing BAL cells, were recovered. The recovered fluid was then centrifuged (500 x g, 10 min, 4° C), the supernatant decanted, and the cells resuspended. The first BAL fraction was centrifuged separately, and the supernatant was assayed for lactate dehydrogenase activity and albumin content as described below. The cells from the first BAL fraction were then pooled with the rest of the cells recovered from that animal, and the total BAL cells were counted using a Coulter Counter equipped with a Channelizer (model Zb, Coulter Electronics, Hialeah, FL). Cell differentials were performed visually following cytospin preparations of microscope slides (Shandon Cytospin II, Shandon Inc., Pittsburgh, PA) and Wright-Geimsa staining (Hema-Tec 2000, Bayer Corp., Elkhart, IN).
Analysis of albumin.
The integrity of the alveolarcapillary barrier was evaluated by measuring the amount of albumin, a protein from the blood, in the first BAL fraction. BAL fluid albumin was determined according to a Sigma Diagnostics method utilizing the reaction of albumin with bromcresol green. The reaction product was then measured with a spectrophotometer at 628 nm and quantified against known concentrations of bovine serum albumin.
Analysis of lactate dehydrogenase (LDH) activity.
LDH activity in the first BAL fraction was used as an indicator of cellular integrity. LDH leaks from cells as a result of damage or when membrane integrity is lost at cell death. LDH activity was determined by the oxidation of lactate coupled to the reduction of NAD+ at 340 nm over time. Measurements were performed with a Cobas Mira analyzer (Roche Diagnostics Systems, Montclair, NJ).
Free radical measurements.
Electron spin resonance (ESR) with spin trapping was used to examine free radical generation. Spin trapping involves the addition reaction of a short-lived radical with a paramagnetic compound (i.e., spin trap) to form a relatively long-lived free radical product, termed the spin adduct, which can be studied with conventional ESR. The intensity of the spin adduct signal corresponds to the amount of short-lived radical trapped, and the pattern of hyperfine splittings of the spin adduct is generally characteristic of the original, short-lived, trapped radical. To determine the presence of hydroxyl radicals, 5, 5-dimethyl-1-pyrroline N-oxide (DMPO) was used as a spin trap in these studies. Measurements were made with a Bruker ESP 300E spectrometer and a flat cell assembly (Bruker Instruments Inc., Billeria, MA). Spex 300 software (Clarksville, MD) was used for data collection and analysis. The Fenton reaction (Fe2SO4 + H2O2) was used to generate hydroxyl radicals as a positive control for one system, while Cr(VI), NADPH, and glutathione reductase (GSSG-R) were used in another one. Final concentrations for the reactants are listed in the figure legends.
Measurement of lipid peroxidation (LPO) markers.
The lipid peroxidation products malondialdehyde (MDA) and 4-hydroxyalkenals (4-HNE) were measured using the BIOXYTECH® LPO-586TM Colorimetric Assay for Lipid Peroxidation Markers (Oxis International, Inc., Portland, OR). Briefly, the left lungs from treated or control animals were removed, weighed, and homogenized with a PowerGen 700 (Fisher Scientific, Pittsburgh, PA) for 30 s. The homogenate was centrifuged at 1,500 x g for 10 min, and the supernatant was decanted and frozen at -80°C for subsequent analysis. The LPO-586 assay is based on the reaction of a chromogenic reagent, N-methyl-2-phenylindole with MDA and 4-hydroxyalkenals at 45°C. One molecule of either MDA or 4-HNE reacts with two molecules of the chromogenic reagent to yield a stable chromophore with maximal absorbance at 586 nm.
Cytokine analyses.
Levels of the cytokines TNF-, IL-1ß, IL-6, and IL-10 were assayed in the first fraction of BAL fluid 3 h and 1, 3, and 6 days after i.t. welding fume or saline treatment. Cytokine protein concentrations were determined with enzyme-linked immunosorbent assay (ELISA) kits from Biosource International (Camarillo, CA). The results of this colorimetric assay were obtained with a Spectramax 250 plate spectrophotometer using Softmax Pro 2.6 software (Molecular Devices Corp., Sunnyvale, CA).
Statistics.
All data are presented as means ± standard error of measurement (SEM). Comparisons between means were made using a two-way ANOVA followed by Tukeys protected t post-hoc test (GB-STAT, Dynamic Microsystems Inc, Silver Spring, MD). Statistical significance was established when p < 0.05.
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RESULTS |
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DISCUSSION |
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Particle size can play a role in determining the toxicity of welding fumes. Individual fume particles are first formed near the arc in the submicron ultrafine size range (0.010.10 µm) (Voitkevich, 1995). Due to the turbulent conditions resulting from the extreme heat generation at the arc, the particles quickly aggregate together in the air to form longer chains of primary particles (Clapp and Owen, 1977
; Zimmer and Biswas, 2001
). In the atmosphere of the welders breathing zone, welding fume particles have been observed to be 0.502.0 µm in aerodynamic diameter (Villaume et al., 1979
; Voitkevich, 1995
). This is very similar to the size of the particles used in this study, which, after collection, resuspention, and sonication, were GMA-MS, 0.83 ± 0.15; GMA-SS, 0.77 ± 0.48; and MMA-SS, 0.92 ± 0.11 (Antonini et al., 1997
, 1998
). Therefore, it was concluded that the collection by filtration and subsequent resuspension used in this study did not significantly alter the particle size as compared to what is observed in the welders breathing zone.
In this study, the pulmonary responses to different welding fumes were compared following intratracheal instillation. Thus a bolus of particles in liquid was given at one time, as opposed to a more gradual accumulation of particles that occurs during inhalation (Driscoll et al, 2000). To minimize the effects of this route of administration, a dose of fume was chosen that produced measurable effects without causing massive toxicity based on a doseresponse curve constructed during a previous study (Antonini et al., 1997
). Henderson et al. (1995)
compared the inflammatory response of the lungs to particulates of high and low toxicity by intratracheal instillation and inhalation. Their results indicated that the degree of pulmonary inflammation caused by various doses of different particulates could be evaluated appropriately using either exposure method. A recent study by Reasor and Antonini (2001)
found similar results when intratracheally administering the same total dose of silica at one time or spread across five daily separate instillations. Thus the effect of the large bolus of particles seems to be minimal as long as the dose is not overly large.
While the intratracheal route of administration is less physiological, there are advantages to its use in this study as well. The actual dose of fume to each animal is very uniform and can be delivered accurately, without concern for any particles being removed nasally. Additionally, aspects of this study examining the results of the soluble and insoluble fractions of the MMA-SS fume would be impossible to ascertain via inhalation. Furthermore, by comparing these fumes by intratracheal instillation, experiments using inhalational exposure of particular fumes of interest can be planned, and possible mechanisms underlying the toxicity can be explored.
It is well documented that free radical generation is a significant contributor to the pathogenesis of lung disease caused by particulate inhalation (Vallyathan and Shi, 1997). Several metals present in the welding fumes have been shown to produce free radicals under various conditions, including Cr (Leonard et al., 2000
; Ye et al., 1999
) and Ni (Huang et al., 2001
). Antonini et al. (1998)
also reported indirect evidence of reactive species involvement in welding fume-induced pneumotoxicity when they found fresh fume to be more pneumotoxic to rats than aged fume of the same composition. Thus, the ability of these fumes to produce free radicals was examined by ESR in the current study. The MMA-SS fume was the only fume to produce hydroxyl radicals when reacted with H2O2. When analyzed separately, the Insol fraction produced a greater signal than the Sol fraction, and both were less than Tot. Thus the lung damage from each fraction could be attributed to possible free radical production. Furthermore, the MMA-SS was the only fume to contain reactive Cr(VI), evident from the characteristic Cr(V) signal. In this instance, the Sol fraction produced a significantly stronger signal intensity as compared to Insol. Thus the ESR experiments demonstrated that the MMA-SS was the most reactive fume, with each fraction able to produce free radicals in various conditions. The implied reactivity of Cr(VI) in the Sol fraction correlates with the amount of soluble Cr present in that fume as compared to the other fumes. This result corroborates a previous study (White et al., 1982
) in which animals were administered a single i.t. instillation of soluble and insoluble fractions of a stainless-steel welding fume or potassium dichromate containing the same Cr(VI) concentrations found in the fumes. They observed that most of the toxicity observed 7 days following i.t. treatment was attributable to the soluble Cr(VI) in the fume. The inflammation subsided over time, leading them to conclude that this was due to the removal of the soluble Cr(VI) from the lungs.
To study the ability of the fumes to produce lung inflammation and damage, the same amount of each fume, including the Sol and Insol fractions of the MMA-SS, was intratracheally administered to the rats. Parameters of damage and inflammation were then assessed at 3 h and 1, 3, and 6 days following treatment. The administration of the various fumes produced differing inflammatory profiles. All of the fumes eventually led to an increase in macrophages in all of the treatment groups, with the MMA-SStreated group tending to be higher. Both the Sol and Insol fractions of the MMA-SS were required for the maximal response. Treatment with the relatively insoluble GMA-SS fume produced an early neutrophil influx while only the MMA-SS fume treatment led to eosinophil recruitment. Further experiments with MMA-SS demonstrated that the Sol fraction was responsible for the eosinophil recruitment, whereas the Insol fraction led to the recruitment of neutrophils. This indicates a differential inflammatory response, with neutrophils responding to the insoluble particulates of the MMA-SS fume and eosinophils being recruited following treatment with the soluble constituents. While soluble metals are most likely the cause, additional experiments are required to determine the exact metal or metals responsible and the recruitment pathways involved.
The increased number of eosinophils in the BAL fluid following the MMA-SS treatment indicates a possible immune reaction following fume treatment. It has been reported that respiratory infections are increased in severity, duration, and frequency among welders (Howden et al., 1988). Chemical irritation of the airways caused by metal fumes is a suspected cause of increased incidence of lung infection (Coggen et al., 1994). Wergeland and Iverson (2001)
have discussed the potentially lethal risk association of pneumonia with the inhalation of metal fumes, such as those generated in welding. Thus the recruitment of eosinophils after MMA-SS treatment in rats may also be a marker for the occurrence of an immune dysfunction. Chromium has been implicated in the development of respiratory sensitization leading to asthma (Park et al., 1994
), indicating that it is capable of causing abnormal immune reactions. Thus chromium may be responsible for the abnormal recruitment of eosinophils to the lungs following MMA-SS-Sol treatment.
Differential responses in lung damage parameters were observed after treatment with the various welding fumes, with the MMA-SS fume being the most toxic. The left lung weight of animals treated with GMA-SS peaked at day 1, while following MMA-SS treatment the weight continued to increase until day 6. This indicates a continuing increase in edema and/or damage, which corresponds to the increase in cellularity of the BAL fluid. The MMA-SS-Sol and Insol fractions produced additive effects at this time point, indicating that both are necessary for the total response.
Albumin, a protein normally found in the blood, is used as an indicator of alveolarcapillary barrier damage when increased amounts are found in the airspace. The MMA-SS fume treatment caused maximal albumin leakage at day 3 with the MMA-SS-Sol and Insol fraction responses being equal and additive. LDH activity in the BAL fluid, an indicator of cellular damage and death, was increased following all three fume treatments, but it was highest and more sustained following MMA-SS treatment. Analysis following treatment with the MMA-SS fractions again revealed an equal and additive response following MMA-SS-Sol and Insol treatment. MMA-SS fume treatment caused the only significant increase in LPO at day 3, indicating oxidative damage to lung tissue. The increase in LPO was caused mainly by the Insol fraction of the MMA-SS fume. Several mechanisms may be involved in this response. The oxidative damage could be caused by direct free radical production, as the insoluble fume particles were shown to generate OH and would tend to remain in the lungs longer than soluble metals. Also, the recruitment and activation of phagocytes capable of producing reactive oxygen and nitrogen species, as indicated by increased neutrophil and macrophage numbers and the presence of pro-inflammatory cytokines, discussed below, could be responsible. Finally, a combination of both factors could have been involved in the oxidative tissue damage observed after MMA-SS treatment.
The toxicity profile of these fumes correlates with a previous study (Antonini et al., 1996) that examined later time points. They reported that fumes from the welding of SS materials produced more lung injury and inflammation than fumes produced from MS welding at 14 and 35 days posti.t., with the toxicity decreasing at the latest time point.
Both the GMA-SS and MMA-SS fumes caused an increase in the amount of TNF- in the acellular first BAL fluid fraction at day 1. TNF-
is a major pro-inflammatory cytokine produced in response to a variety of exposures (Luster et al., 1999
). Interestingly, the MMA-SS-Sol fraction was responsible for most of the TNF-
increase at this time point, although the responses to both fractions were additive in relation to the response from treatment with the MMA-SS-Tot fume. IL-6 in the first BAL fraction was increased only by the MMA-SS treatment, with the MMA-SS-Insol fraction being responsible for most of the response. IL-6 activates specific immune responses, indicating that differential inflammatory pathways are activated following MMA-SS treatment. This is further indicated by the presence of eosinophils in the BAL fluid, which were recruited mainly by the MMA-SS Sol fraction. Overall, the MMA-SS caused a greater inflammatory response, indicated by the eventual increase in total cells recovered by BAL. This reaction, however, may not indicate a stimulated immune response in the lungs. In a separate study (Antonini et al., 2001
), it was found that MMA-SS fume pre-treatment slowed the clearance of a bacterial pathogen from the lungs whereas the GMA-MS and GMA-SS fumes had no effects. Taken together, these data suggest that MMA-SS fumes are capable of causing immune dysfunction and possible abnormal immune responses.
The effects of MMA-SS proved in most cases to be dependent on both the soluble and insoluble fractions of the fume. This is unique in that studies of urban air particulates and residual oil fly ash (ROFA) particles have attributed many of their pneumotoxic effects to the soluble metals associated with the particulates (Dreher et al., 1997; Gavett et al., 1997
; Kodavanti et al, 1998
; Pritchard et al., 1996
). Dreher et al. (1997)
demonstrated that transition metals are the causative agents of ROFA-induced acute lung injury. A leachate prepared from the ROFA, as well as a surrogate transition metal sulfate solution, largely reproduced the lung injury caused by the entire ROFA sample. Another study (Gavett et al., 1997
) reinforced these results by comparing two different ROFA samples with differing soluble metals. Kodavanti et al. (1998)
analyzed ten ROFA samples from different parts of a power plant and with differing leachable metal compositions. They were able to attribute different aspects of the toxicity to different transitional metals, namely Ni and V, by different pathways. The mechanisms of acute lung damage by welding fumes are less understood, but it was hypothesized that the soluble metals of the relatively soluble welding fume MMA-SS would largely be responsible for the toxicity of the fumes based on the above ROFA studies. This was not the case, as both fume fractions were often required to produce the maximal response. Further studies will be necessary to identify the components responsible for the damage from each fraction.
The results of the current study indicate that welding fumes of differing metal composition produce differential acute lung toxicities. Furthermore, the fume that produced the most free radicals in two acellular systems proved to be the most toxic, indicating free radical production as a possible mechanism for the toxicity. The effects of the MMA-SS proved in most cases to be dependent on both the soluble and insoluble fractions of the fume, which is different from ROFA particles, in which the soluble metals are associated with their pneumotoxic effects. The mechanisms of lung toxicity from welding fumes are less well characterized, but the evidence provided in this study suggests that both the soluble and insoluble fractions are involved with various aspects of the acute lung damage and inflammation following MMA-SS welding fume treatment.
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ACKNOWLEDGMENTS |
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NOTES |
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