Induction of systemic inflammation by welding fume exposure in office workers as well as welders in welding factories

Abstract

Welding fumes are metal particles of 1 µm or less generated during welding. Welding fumes generated in welding factories spread throughout the workplace. However, the effects of exposure have been measured primarily in welding workers, and no research has been conducted on the effects of fumes on workplace office workers. In this study, we recruited welding and office workers who worked in the same factories at ten workplaces in Japan, mainly in the Kyushu and Kanto regions, and separated their serum after blood sampling. We also obtained serum from the general subjects of Minami-Kagoshima City, which is located far from the welding factory. Cytokines and chemokines were quantified in the serum samples, and the concentration of interleukin (IL)-1β was significantly increased in office workers and welders compared with general subjects. Importantly, the serum concentrations of IL-12p70, IL-17A, IL-33, tumor necrosis factor α, and C-C motif chemokine ligand 3 in office workers were significantly higher than those in the general subjects, and there was no significant difference in the levels of these inflammatory molecules between welders and general subjects. This study suggests that office workers exposed to high fume concentrations exhibit increased systemic inflammation. Exposure assessments should be conducted not only for welders but also for office workers to reduce exposure risks.

INTRODUCTION

Welding is a procedure used to join metallic components by melting metals under high temperatures or pressures. Welding fumes are complex mixtures of airborne particles generated during the welding processes, and primarily consist of metal oxides, including iron, manganese, chromium, and other trace metals, which can vary depending on the welding materials and methods used (Taylor et al., 2003). Welding fumes can induce various lung disorders, such as asthma, chronic obstructive pulmonary disease, lung cancer, granulomatous disease, giant cell interstitial pneumonitis, chemical pneumonitis, and interstitial fibrosis (Nemery, 1990; Kelleher et al., 2000; Meo and Al-Khlaiwi, 2003; Cha et al., 2022). Specific conditions, such as metal fume fever attributed to exposure to various metals, are also reported (Malaguarnera et al., 2013). Several studies have been conducted on respiratory toxicity in welders in Japan. A relationship between welding fume exposure and lung function has been reported in 143 male welders (Nakadate et al., 1998). Pneumoconiosis induced by exposure to respirable dust was also investigated by examining 1,006 chest X-ray films of workers, including shipyard welders (Takigawa et al., 2002). Manganese exposure from welding fumes, especially long-term inhalation, has also been linked to the progression of adverse psychological effects and several neurodegenerative diseases, specifically Parkinson's diseases (Tsuji et al., 2023b; Rana et al., 2019).

Welding fume exposure is involved in inflammation, which may contribute to the onset and progression of several disorders (Brand et al., 2014). Welding fume exposure is reportedly associated with systemic inflammation, as evidenced by the significant metabolic changes observed in a study of 52 boiler-makers (Shen et al., 2018). Metabolites linked to inflammation, such as glucocorticoids, acylcarnitines, and amino acids, were altered after exposure. We previously reported that the inflammatory cytokine interleukin (IL)-24 was upregulated by welding fume exposure in the dermal microvascular endothelium (Kono et al., 2024). Welding fumes contain heavy metals, such as lead, manganese, iron, chromium, and cadmium, which can induce oxidative stress by increasing the levels of reactive oxygen species (ROS) by direct Fenton/Harber–Weiss reactions and mitochondrial uncoupling, and altering the expression of antioxidant enzymes (Valko et al., 2006). Oxidative damage is recognized by the immune system as a danger signal, leading to activation of inflammatory pathways (Albano et al., 2022). ROS can activate transcription factors such as nuclear factor kappa B and activator protein 1, which regulate the expression of pro-inflammatory genes (Roebuck, 1999). The development of chromium (VI)-reduced flux-cored wires has been suggested as a method to reduce the cytotoxicity and inflammatory potential of welding fumes, highlighting the importance of heavy metals in the induction of inflammation (McCarrick et al., 2021).

The mask fit test is a test to confirm the wearing conditions of the facepiece in welders and has been conducted once a year since 2023 in Japan to avoid increasing health risks to welding workers and to ensure that respirators are properly worn (Tsuji et al., 2023a). Therefore, efforts to manage these risks for welders are progressing. However, in factories in which offices are located on the same premises, employees other than welders may be exposed to welding fumes. However, to the best of our knowledge, no previous study in Japan has investigated the inflammatory status of office workers in a welding factory. In this study, we aimed to estimate the fume exposure risk in welders, office workers, and general subjects from a city located far away from the factory by measuring the levels of cytokines/chemokines in the blood.

MATERIALS AND METHODS

Human serum samples

This study was approved by the Institutional Ethics Committee of the University of Occupational and Environmental Health (R2-011 and UOEHCRB20-197), the Ethics Committee of the Kagoshima University Graduate School of Medical and Dental Sciences (190097(691)Epi-Rev1), and the Ethics Committee of the Hiroshima University (E2020-2181-02 and E2018-1440-05). After blood samples were collected, blood was allowed to clot for approximately 1 hr and centrifuged at 3,000 × g for 15 min to separate the serum in blood. The sera were transferred to clean tubes and stored at −80°C until further use.

Determination of serum cytokine concentrations

The concentrations of cytokines (IL-1β, IL-6, IL-8, IL-10, IL-12p70, IL-17A, IL-18, IL-23, IL-33, and tumor necrosis factor α (TNFα)), interferon γ (IFNγ), and chemokines (C-C motif chemokine ligand 2 (CCL2), CCL3, CCL4, CCL11, CCL17, CCL20, chemokine C-X-C motif ligand 1 (CXCL1), CXCL5, CXCL9, CXCL10, and CXCL11) in the serum were determined with a LEGENDplex™ Human Cytokine Panel and LEGENDplex™ HU Proinflam Chemokine Panel (BioLegend, San Diego, CA, USA) using a CytoFREX S flow cytometer (Beckman-Coulter, Tokyo, Japan), as previously described (Tanaka et al., 2023).

Statistics

All data were analyzed using GraphPad Prism 10 (GraphPad Software, San Diego, CA, USA) and are presented as violin plots. One-way analysis of variance with Dunnett's corrected multiple comparison test was used to compare the general subjects and other groups. Statistical significance was set at p < 0.05, as indicated in each figure.

RESULTS AND DISCUSSION

We recruited 105 welders and 129 office workers (non-welders) from ten welding factories (Table 1 and Fig. S1). Thirty people living in Minami-Kyushu City, far from a welding factory, participated in the study. We determined the serum concentrations of 22 inflammation markers, particularly IL-1β, IL-6, IL-8, IL-10, IL-12p70, IL-17A, IL-18, IL-23, IL-33, TNFα, IFNγ, CCL2, CCL3, CCL4, CCL11, CCL17, CCL20, CXCL1, CXCL5, CXCL9, CXCL10 and CXCL11. The serum concentration of IL-1β was significantly higher in office workers and welders than that in general subjects (Fig. 1). Welding fumes also induce systemic inflammation. Krabbe et al. showed that exposure to zinc- and copper-containing welding fumes increased C-reactive protein levels (Krabbe et al., 2023). Exposure to zinc- and copper-containing welding fumes also reportedly increases the number of neutrophils and expression of myeloperoxidase in the blood (Reisgen et al., 2020). In this study, the levels of the inflammatory cytokine IL-1β were significantly increased in welders, confirming that systemic inflammation was induced during the welding process, probably due to exposure to welding fumes.

Table 1. Number of subjects recruited in welding factories

Office	Location	Welders	Office workers
A	Kyushu region, Japan	3	7
B	Kyushu region, Japan	5	5
C	Kyushu region, Japan	6	6
D	Kyushu region, Japan	15	17
E	Kanto region, Japan	16	16
F	Kanto region, Japan	16	16
G	Kanto region, Japan	16	16
H	Kyushu region, Japan	10	10
I	Chugoku region, Japan	16	16
J	Kyushu region, Japan	2	20
Total		105	129

Fig. 1

Concentration of cytokines and interferon in the serum of general subjects, office workers, and welders. Serum was collected from general subjects (N = 36), office workers (N = 129) and welders (N = 105) and then serum concentrations of interleukin (IL)-1β, IL-6, IL-8, IL-10, IL-12p70, IL-17A, IL-18, IL-23, IL-33, TNFα and IFNγ were measured using the Legend Plex system. Cytokine and interferon concentrations are represented as violin plots. Data were analyzed using one-way analysis of variance (ANOVA), followed by Dunnett’s multiple comparison test.

Importantly, the serum concentrations of IL-12p70, IL-17A, IL-33, TNFα, and CCL3 in office workers were significantly higher than those in general subjects, and there was no significant difference in the levels of these inflammatory molecules between welders and general subjects (Fig. 1 and 2). Therefore, office workers are considered to be at high risk of systemic inflammation, and it has been suggested that office workers in welding factories are exposed to welding fumes. Smoking is also involved in systemic inflammation (Derella et al., 2021). The smoking rate among welding workers was 51%, whereas that among office workers was 47%, with no significant difference in the smoking rate according to the chi-square test. Therefore, the smoking rate cannot explain the high risk of systemic inflammation in office workers. Mask-fit tests are mandatory for welding workers in Japan. If the fit test is not passed, the mask-wearing method must be checked, a retest must be conducted, and legislation must be enacted to protect welding workers from fume exposure. However, there are no obligations for workers other than welding workers in the welding factories. This may explain why office workers are exposed to higher concentrations of welding fumes than welders and therefore exhibit higher levels of systemic inflammation. The PM₅ concentrations were 201 μg/m³ and 79 μg/m³ in the factory and office, respectively, in a welding factory in the Kyushu region, Japan, and PM₅ concentrations were 67 μg/m³ and 75 μg/m³ in the factory and office, respectively, in a welding factory in the Chugoku region, Japan. On the other hand, annual average of PM_2.5 concentrations at Kiire City next to Minami-Kyushu City measured by the Ministry of the Environment, Japan in 2024 was 8.7 μg/m³. In addition, the annual average value of all monitoring stations in Japan set up by the Ministry of the Environment in 2019 was approximately 10 μg/m³. Therefore, we are not exposed by high levels of PM from outside air. These suggest that office workers may be exposed to high concentrations of particulates including welding fumes. As short-term fume exposure has been reported to not cause systemic inflammation (Gube et al., 2014), it is believed that office workers are exposed to fumes for a long period of time.

Fig. 2

Concentration of chemokines in the serum of general subjects, office workers, and welders. Serum was collected from general subjects (N = 36), office workers (N = 129) and welders (N = 105), and the serum concentrations of CCL2, CCL3, CCL4, CCL11, CCL17, CCL20, CXCL1, CXCL5, CXCL9, CXCL10, and CXCL11 were measured using the Legend Plex system. Chemokine concentrations are represented as violin plots. Data were analyzed using one-way ANOVA followed by Dunnett’s multiple comparison test.

Baumann et al. reported that IL-6 is an early biomarker of exposure to zinc-based metal fumes (Baumann et al., 2016). Another report showed an increase in urinary IL-6 levels in welding workers after exposure (Lai et al., 2021). In this study, no significant differences were found in serum IL-6 levels between welding and office workers compared with general subjects. The induction of an inflammatory response by a metal depends on the type and amount of the metal (Xia et al., 2023). Interestingly, the serum levels of the chemokines CXCL10 and CXCL11 in welders were significantly lower than those in general subjects (Fig. 2). The exposure markers for the welding fumes varied depending on the welding conditions. Therefore, a detailed approach that considers both the welding environment and biological system is necessary to identify the markers.

This study had several limitations. We were unable to measure the individual exposure levels and blood metal concentrations of office workers or the working environment, such as the PM concentration in the office. Therefore, it was difficult to assess welding fume exposure of office workers. In addition, there are insufficient data to conduct detailed studies on the mask-wearing status and mask performance of office workers, as well as mask fit tests for welding workers; thus, it is difficult to examine whether the concentration of welding fumes in the work environment and protective equipment contribute to the differences in systemic inflammation between office and welding workers observed in this study. It is necessary to develop and implement a research plan to conduct a risk assessment and investigate the actual state of welding fume exposure in office workers to establish risk management methods for office workers as soon as possible.

In conclusion, this study showed that both welders and office workers working in the same factory may develop systemic inflammation owing to exposure to welding fumes. In the future, it is important to closely examine the exposure status and risk management of office workers and welders.

ACKNOWLEDGMENTS

This study was supported by the MHLW Program (JPMH 200501 to MT), a KAKENHI grant from the Japan Society for the Promotion of Science (grant number 24K03085 to YI), Environment Research and Technology Development Funds of the Environmental Restoration and Conservation Agency of Japan (JPMEERF20215003 and JPMEERF20205007 to YI), and the Smoking Research Foundation (to YI). We would like to thank Editage (www.editage.jp) for English language editing.

Author contributions

Conceptualization: MT and YI; methodology: MT and YI; investigation: MT, CK, TN, US, and MT; visualization: MT and YI; funding acquisition: MT and YI; project administration: MT and YI; writing – original draft: MT and YI; writing – review and editing: all authors. All the authors have read and agreed to the published version of the manuscript.

Conflict of interest

The authors declare that there is no conflict of interest.

REFERENCES

•  Albano,  G.D.,  Gagliardo,  R.P.,  Montalbano,  A.M. and  Profita,  M. (2022): Overview of the Mechanisms of Oxidative Stress: Impact in Inflammation of the Airway Diseases. Antioxidants, 11.
•  Baumann,  R.,  Joraslafsky,  S.,  Markert,  A.,  Rack,  I.,  Davatgarbenam,  S.,  Kossack,  V.,  Gerhards,  B.,  Kraus,  T.,  Brand,  P. and  Gube,  M. (2016): IL-6, a central acute-phase mediator, as an early biomarker for exposure to zinc-based metal fumes. Toxicology, 373, 63-73.
•  Brand,  P.,  Bauer,  M.,  Gube,  M.,  Lenz,  K.,  Reisgen,  U.,  Spiegel-Ciobanu,  V.E. and  Kraus,  T. (2014): Relationship between welding fume concentration and systemic inflammation after controlled exposure of human subjects with welding fumes from metal inert gas brazing of zinc-coated materials. J. Occup. Environ. Med., 56, 1-5.
•  Cha,  E.W.,  Jeon,  D.,  Kang,  D.,  Kim,  Y.K. and  Kim,  S.Y. (2022): Chemical Pneumonitis Caused by the Inhalation of Zinc Oxide Fumes in an Arc Welder. Int. J. Environ. Res. Public Health, 19.
•  Derella,  C.C.,  Tingen,  M.S.,  Blanks,  A.,  Sojourner,  S.J.,  Tucker,  M.A.,  Thomas,  J. and  Harris,  R.A. (2021): Smoking cessation reduces systemic inflammation and circulating endothelin-1. Sci. Rep., 11, 24122.
•  Gube,  M.,  Kraus,  T.,  Lenz,  K.,  Reisgen,  U. and  Brand,  P. (2014): Biological effects of emissions from resistance spot welding of zinc-coated material after controlled exposure of healthy human subjects. J. Occup. Environ. Med., 56, 673-677.
•  Kelleher,  P.,  Pacheco,  K. and  Newman,  L.S. (2000): Inorganic dust pneumonias: the metal-related parenchymal disorders. Environ. Health Perspect., 108 (Suppl 4), 685-696.
•  Kono,  M.,  Ishihara,  N.,  Nakane,  T.,  Nabetani,  Y.,  Kajino,  M.,  Okuda,  T.,  Hayashi,  M.,  Koriyama,  C.,  Vogel,  C.F.,  Tsuji,  M. and  Ishihara,  Y. (2024): Enhancement of keratinocyte survival and migration elicited by interleukin 24 upregulation in dermal microvascular endothelium upon welding-fume exposure. J. Toxicol. Environ. Health A, 87, 792-810.
•  Krabbe,  J.,  Hansen,  C.,  Otte,  N. and  Kraus,  T. (2023): Short-term exposure to zinc- and copper-containing welding fumes: effects on pulmonary function in humans. J. Trace Elem. Med. Biol., 78, 127169.
•  Lai,  C.H.,  Ho,  S.C.,  Pan,  C.H.,  Chen,  W.L.,  Wang,  C.C.,  Liang,  C.W.,  Chien,  C.Y.,  Riediker,  M.,  Chuang,  K.J. and  Chuang,  H.C. (2021): Chronic exposure to metal fume PM_2.5 on inflammation and stress hormone cortisol in shipyard workers: A repeat measurement study. Ecotoxicol. Environ. Saf., 215, 112144.
•  Malaguarnera,  M.,  Drago,  F.,  Malaguarnera,  G.,  Li Volti,  G.,  Salomone,  S.,  Caraci,  F.,  Galvano,  F.,  Vacante,  M.,  Bucolo,  C. and  Malaguarnera,  M. (2013): Metal fume fever. Lancet, 381, 2298.
•  McCarrick,  S.,  Romanovski,  V.,  Wei,  Z.,  Westin,  E.M.,  Persson,  K.A.,  Trydell,  K.,  Wagner,  R.,  Odnevall,  I.,  Hedberg,  Y.S. and  Karlsson,  H.L. (2021): Genotoxicity and inflammatory potential of stainless steel welding fume particles: an in vitro study on standard vs Cr(VI)-reduced flux-cored wires and the role of released metals. Arch. Toxicol., 95, 2961-2975.
•  Meo,  S.A. and  Al-Khlaiwi,  T. (2003): Health hazards of welding fumes. Saudi Med. J., 24, 1176-1182.
•  Nakadate,  T.,  Aizawa,  Y.,  Yagami,  T.,  Zheg,  Y.Q.,  Kotani,  M. and  Ishiwata,  K. (1998): Change in obstructive pulmonary function as a result of cumulative exposure to welding fumes as determined by magnetopneumography in Japanese arc welders. Occup. Environ. Med., 55, 673-677.
•  Nemery,  B. (1990): Metal toxicity and the respiratory tract. Eur. Respir. J., 3, 202-219.
•  Rana,  H.K.,  Akhtar,  M.R.,  Ahmed,  M.B.,  Liò,  P.,  Quinn,  J.M.,  Huq,  F. and  Moni,  M.A. (2019): Genetic effects of welding fumes on the progression of neurodegenerative diseases. Neurotoxicology, 71, 93-101.
•  Reisgen,  M.,  Thomas,  K.,  Beilmann,  V.,  Markert,  A.,  Gerhards,  B.,  Krichel,  T.,  Schmidt,  K.,  Kraus,  T.,  Martin,  C.,  Brand,  P. and  Krabbe,  J. (2020): Increased Neutrophil Granulocyte and Myeloperoxidase Levels Indicate Acute Inflammation Due to the Exposure of Zinc- and Copper-Containing Welding Fumes. J. Occup. Environ. Med., 62, 618-627.
•  Roebuck,  K.A. (1999): Oxidant stress regulation of IL-8 and ICAM-1 gene expression: differential activation and binding of the transcription factors AP-1 and NF-kappaB. Int. J. Mol. Med., 4, 223-230. (Review) (Review)
•  Shen,  S.,  Zhang,  R.,  Zhang,  J.,  Wei,  Y.,  Guo,  Y.,  Su,  L.,  Chen,  F. and  Christiani,  D.C. (2018): Welding fume exposure is associated with inflammation: a global metabolomics profiling study. Environ. Health, 17, 68.
•  Takigawa,  T.,  Kishimoto,  T.,  Nabe,  M.,  Nishide,  T.,  Wang,  D.H.,  Seki,  A.,  Uchida,  G. and  Kira,  S. (2002): The current state of workers’ pneumoconiosis in relationship to dusty working environments in Okayama Prefecture, Japan. Acta Med. Okayama, 56, 303-308.
•  Tanaka,  M.,  Okuda,  T.,  Itoh,  K.,  Ishihara,  N.,  Oguro,  A.,  Fujii-Kuriyama,  Y.,  Nabetani,  Y.,  Yamamoto,  M.,  Vogel,  C.F. and  Ishihara,  Y. (2023): Polycyclic aromatic hydrocarbons in urban particle matter exacerbate movement disorder after ischemic stroke via potentiation of neuroinflammation. Part. Fibre Toxicol., 20, 6.
•  Taylor,  M.D.,  Roberts,  J.R.,  Leonard,  S.S.,  Shi,  X. and  Antonini,  J.M. (2003): Effects of welding fumes of differing composition and solubility on free radical production and acute lung injury and inflammation in rats. Toxicol. Sci., 75, 181-191.
•  Tsuji,  M.,  Hori,  H.,  Koriyama,  C.,  Tanaka,  R.,  Isse,  T.,  Ishihara,  Y.,  Ishizuka,  T.,  Hasegawa,  W.,  Goto,  M.,  Yatera,  K.,  Kunugita,  N.,  Kuwamura,  M.,  Sakuragi,  T.,  Yasumura,  Y.,  Yamamoto,  M. and  Ueno,  S. (2023a): The effect of mask fit test on the association between the concentration of metals in biological samples and the results of time-weighted average personal exposure: A study on Japanese male welders. J. Occup. Health, 65, e12399.
•  Tsuji,  M.,  Koriyama,  C.,  Ishihara,  Y.,  Isse,  T.,  Ishizuka,  T.,  Hasegawa,  W.,  Goto,  M.,  Tanaka,  R.,  Kakiuchi,  N.,  Hori,  H.,  Yatera,  K.,  Kunugita,  N.,  Yamamoto,  M.,  Sakuragi,  T.,  Yasumura,  Y.,  Kono,  M.,  Kuwamura,  M.,  Kitagawa,  K. and  Ueno,  S. (2023b): Associations between welding fume exposure and neurological function in Japanese male welders and non-welders. J. Occup. Health, 65, e12393.
•  Valko,  M.,  Rhodes,  C.J.,  Moncol,  J.,  Izakovic,  M. and  Mazur,  M. (2006): Free radicals, metals and antioxidants in oxidative stress-induced cancer. Chem. Biol. Interact., 160, 1-40.
•  Xia,  L.,  Park,  J.H.,  Biggs,  K.,  Lee,  C.G.,  Liao,  L. and  Shannahan,  J.H. (2023): Compositional variations in metal nanoparticle components of welding fumes impact lung epithelial cell toxicity. J. Toxicol. Environ. Health A, 86, 735-757.