Date of Graduation

2018

Document Type

Dissertation

Degree Type

PhD

College

School of Medicine

Department

Physiology, Pharmacology & Neuroscience

Committee Chair

Patti C Zeidler-Erdely

Committee Co-Chair

David P Siderovski

Committee Member

Kristin Cummings

Committee Member

Stanley Hileman

Committee Member

Salik Hussain

Committee Member

Timothy Nurkiewicz

Committee Member

Chengfeng Yang

Abstract

Welding fumes were recently reclassified as carcinogenic to humans (Group 1) by the International Agency for Research on Cancer (IARC) based on sufficient epidemiological evidence and limited evidence in animals. It is estimated that 11 million workers worldwide weld full-time, and an additional 110 million have had some type of welding-related exposure. Welding exposures are complex because of the diversity of welding modalities used in the workplace; these modalities include exposures to non-carcinogenic and/or carcinogenic metal containing fumes.;The objective of this dissertation was to determine which welding fumes and their component metals are the most toxic and have the greatest tumorigenic potential. Male A/J mice received intraperitoneal injections of corn oil or the initiator 3-methylcholanthrene (MCA;10 microg/g) and one week later were exposed by whole body inhalation to air or gas metal arc-stainless steel (GMA-SS), GMA-mild steel (MS), or Copper-Nickel welding aerosols for 4 hours/day x 4 days/week x 8-9 weeks at a target concentration of 40 mg/m3. Lung nodules were enumerated at 30 weeks post-initiation. GMA-SS and GMA-MS fumes significantly promoted lung tumor multiplicity in A/J mice initiated with MCA (16.11 +/- 1.18; 21.86 +/- 1.50, respectively) compared to MCA/air-exposed mice (7.93 +/- 0.82; 8.34 +/- 0.59, respectively). Cu-Ni welding aerosols significantly decreased lung tumor multiplicity compared to MCA/air controls (7.11 +/- 0.93 tumors vs. 15.57 +/- 0.75 tumors, respectively). A separate group of mice also received intraperitoneal injections of MCA or corn oil and beginning one week later were exposed to NiO, Fe2O3, Cr2O3 + CaCrO4 or sham once per week for 5 weeks via oropharyngeal aspiration. Component Fe2O3 was the only metal to promote lung tumors in A/J mice. To study lung pneumotoxicity of the welding fumes and their component metals, mice were given a single bolus low or high dose of NiO, Fe2O3, Cr2O3 + CaCrO 4, total GMAW-SS fume or sham at sacrificed at 1 day, 7 days, 28 days, and 84 days post-exposure. An additional group of mice were exposed to GMAW-MS via inhalation for 4 hours/day for 10 days at a target concentration of 40 mg/m3 and sacrificed at the same time points. Bronchoalveolar lavage fluid was collected and analyzed for markers of inflammation and cytotoxicity. GMA-SS fume was more pneumotoxic than the individual components. Component Fe2O3 was the most toxic of the metal oxides. Inhalation of GMAW-MS did not induce inflammation or cytotoxicity in A/J mice.;In conclusion, these studies demonstrates that inhalation of GMA-SS and GMA-MS welding fume as well as Fe2O3 promote lung tumor formation in vivo and provides support for the epidemiology that shows welders, using mild and/or stainless steel, are at an increased risk for lung cancer. It is unclear why Cu-Ni welding aerosols decreased tumor size and number. However, the findings in this dissertation provide a framework for future epidemiological, in vivo, and in vitro studies of welding fumes to further understand the association between lung cancer and welding. A better understanding of which welding fumes and metal oxides are most toxic or tumorigenic could lead to more appropriate worksite regulations and even the development of safer welding consumables which lack the more dangerous components.

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