Pulmonary toxicity and lung tumorigenic potential of surrogate metal oxides in gas metal arc welding–stainless steel fume: Iron as a primary mediator versus chromium and nickel

In 2017, the International Agency for Research on Cancer classified welding fumes as “car- cinogenic to humans” (Group 1). Both mild steel (MS) welding, where fumes lack carcino- genic 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 initi- ated 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 \u3e Cr2O3 + CaCrO4 \u3e 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

Correlation between activities of ALT and arginase in plasma of apoE^−/− mice on different diets.

<p>Regression analysis of ALT and arginase activities for the different diets (n = 5 in each group) is indicated by the solid line. Key to symbols: solid circles, standard diet; solid diamonds, HF diet; open circles, HC diet.</p

Effect of HF and HC diets on plasma levels of ALT.

<p>Values are means ± SE for n = 5 mice in each group. Symbols are defined in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0015253#pone-0015253-g002" target="_blank">Figure 2</a> legend.</p

Induction of arginase mRNA and protein in apoE^−/− mice on HC diet.

<p>(A) Effect of HC diet on arginase I and II mRNAs in heart, lung, spleen and kidney. mRNA levels are expressed relative to the levels in apoE^−/− mice on standard diet (arbitrarily set to 1.0 for each tissue and indicated by dotted line). Values are means ± SE for n = 5–7 in each group. *p<0.05 vs standard diet. (B) Effect of HC diet on arginase II protein abundance in lung, spleen and kidney. For each tissue, the upper panel represents arginase II and the lower panel GAPDH. Western blots of extracts from tissues of 5 representative animals on each diet are shown. Amounts of protein loaded in each lane were 10 µg (lung and kidney) or 25 µg (spleen). An extract of C57BL/6J whole kidney (20 µg for lung and kidney blots, 3 µg for spleen blot) was used in the first lane of each blot as positive control (+CT) for arginase II. Twenty µg protein from kidney of the arginase II knockout mouse <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0015253#pone.0015253-Shi1" target="_blank">[47]</a> was included in the second lane of the kidney blot in order to establish identity of the lowest band as arginase II. (C) Effect of HC diet on arginase I protein abundance in spleen. The upper panel represents arginase I and the lower panel GAPDH. The Western blot represents extracts from spleen (50 µg each lane) of 5 representative animals on each diet and 100 ng of C57BL/6J liver extract (+CT) as positive control. (D) Densitometry of Western blots, represented in arbitrary units (Arginase/GAPDH), was analyzed by Image Quant 5.2 Software. *p<0.01 vs standard diet. Molecular weights are indicated by the following symbols: solid triangles, 39 kDa; solid diamonds, 37 kDa; open triangles, 37 kDa.</p

Effect of HF and HC diets on plasma arginase activity (nmol/ml/min).

<p>Values are means ± SE for n = 10-15 for standard and HC diet and n = 6 for HF diet. Key to symbols: apoE^−/− (open bars); C57BL/6J (black bars); *p<0.05 vs standard diet; ^$p<0.05 vs strain-specific HF diet.</p

Induction of tissue arginase activities in apoE^−/− mice on HC diet.

<p>Values are means ± SE for n = 6 in each group. *p<0.05 vs standard diet.</p

HF and HC diets reduce global arginine bioavailability.

<p>Values are means ± SE for n = 3–4 in each group. Abbreviations: ARG, arginine; ORN, ornithine; CIT, citrulline. Symbols are defined in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0015253#pone-0015253-g002" target="_blank">Figure 2</a> legend.</p

Additional file 1: of Association of pulmonary, cardiovascular, and hematologic metrics with carbon nanotube and nanofiber exposure among U.S. workers: a cross-sectional study

Table S1. Participation rates by facility. Table S2. Current and past self-reported exposure frequency among cross-sectional study participants. Table S3. Scoring method for risk factors used in cardiovascular health metrics score. Table S4. Distribution of cardiovascular health metric (CHM) score values, where a higher score implies better cardiovascular health. Table S5. Frequency of chest symptoms or respiratory illnesses among 108 study participants. Table S6. Results of univariable logistic regression modeling of personal characteristics and occupational exposures for development of chest symptoms or respiratory allergy after the start of CNT/F work. Table S7. Results of univariable linear regression modeling of pulmonary function metrics (highlight indicates selected in “best model” by Schwarz Bayesian Criterion and considered as potential confounder in multiple linear regression model with main exposure variables). Table S8. Results of univariable linear regression modeling of cardiovascular metrics (highlight indicates selected in “best model” by Schwarz Bayesian Criterion and considered as potential confounder in multiple linear regression model with main exposure variables). Table S9. Results of univariable linear regression modeling of natural log (ln)-transformed WBC and differential metrics (highlight indicates selected in “best model” by Schwarz Bayesian Criterion and considered as potential confounder in multiple linear regression model with main exposure variables). Table S10. Results of univariable linear regression modeling of other transformed CBC metrics (highlight indicates selected in “best model” by Schwarz Bayesian Criterion and considered as potential confounder in multiple linear regression model with main exposure variables). (DOCX 41 kb

Additional file 3: of Association of pulmonary, cardiovascular, and hematologic metrics with carbon nanotube and nanofiber exposure among U.S. workers: a cross-sectional study

Supplementary information. (DOCX 24 kb

Additional file 1: Figure S1. of Evaluation of pulmonary and systemic toxicity following lung exposure to graphite nanoplates: a member of the graphene-based nanomaterial family

Images of cells recovered by BAL from animals exposed to DM or 40 μg of Gr20, Gr5, Gr1, or CB, at 4 h, 7 days, and 2 months post-exposure illustrating particle burden in macrophages from the alveolar region. (PDF 1663 kb