Core 7 - James Antonini

Dey/Antonini, Manganese Health Research Program Phase 2, Core 7

Research Core Project:
Neurotoxicity after Pulmonary Exposure to Welding Fumes Containing Manganese

Core Principal Investigator (CPI): 

Richard Dey, Ph.D.,
Neurobiology and Anatomy
West Virginia University
Health Sciences Center North 4013a
Morgantown, WV 2506

Dr. Dey is officially the CPI on the contract between Vanderbilt and West Virginia University.



Key Collaborators: 
James M. Antonini, Ph.D., James P. O’Callaghan, Ph.D., Diane B. Miller, Ph.D., Krishnan Sriram, Ph.D., Stanley Benkovic, Ph.D.,
Health Effects Laboratory Division,
National Institute for Occupational Safety and Health,
1095 Willowdale Road,
Morgantown, WV 26505

Project Objectives:

  1. To determine the pulmonary and neurotoxic effects of animals exposed by inhalation or intratracheal instillation to welding fumes that are comprised of varying concentrations of manganese
  2. To determine the manganese content in the blood, lungs, liver, kidneys, heart, and specific brain regions from animals exposed by inhalation or intratracheal instillation to welding fumes that are comprised of varying concentrations of manganese
  3. To compare the neurotoxic effects and brain concentrations of manganese after exposure to welding fumes with the same effects after intratracheal instillation of insoluble or soluble manganese

Project Description:
Serious questions have been raised regarding a possible causal association between neurological effects in welders and the presence of manganese in welding consumables. The goal of the study is to examine the potential neurotoxic effect of manganese in rats after inhalation exposure to welding fumes that contain differing levels of manganese. Neurotoxicity will be detected and quantified by measuring for increased expression of glial fibrillary acidic protein (GFAP) and using silver degeneration staining technology. Because dopaminergic systems have been implicated as targets of manganese exposure, levels of dopamine and tyrosine hydroxylase, biomarkers of dopaminergic neuronal damage, will be measured. In addition, the fate of manganese after deposition in the lungs also will be assessed following exposure to welding fumes. Manganese concentrations will be determined in other organ systems and discrete brain regions after exposure. Results from this study will significantly advance the understanding of the potential neurotoxic effects of manganese associated with welding fume exposure from a mechanistic and dosimetric perspective. Such information may assist NIOSH, OSHA, and National Toxicology Program in risk assessment and the development of prevention strategies for workers exposed to manganese-containing welding fumes.

Project Status:

Project started: February 28, 2006
Schedule completion date: February 28, 2008
Anticipated completion date: February 28, 2008

Key Research Accomplishments:

Advancements made to date:
Our research group at NIOSH has developed an automated robotic welder to expose laboratory animals. Short-term inhalation exposures to gas metal arc-mild steel welding fume, the most common in U.S. industries, were performed. Important findings from the short-term exposures indicate that manganese can translocate from the respiratory tract to other organ systems. Manganese was observed to deposit in the olfactory bulb. Due to the significant number of nanometer-sized particles (<0.1 mm), it is possible that intact particles are being transported along olfactory nerve processes to the brain regions, bypassing the blood brain barrier. There was no evidence of observable changes in neuronal cell injury as assessed by histopathology. However, subtle changes in cell markers of neuroinflammatory and gliosis were observed. Similar observations were made after exposing animals by the intratracheal instillation method (an exposure method that bypasses olfactory uptake processes) with fumes containing differing levels of manganese. Manganese was found to translocate from the lungs via the circulation to other organs, in particular, dopaminergic brain areas. Consistent with the observed accumulation of manganese in specific brain regions, intratracheal instillation of welding fumes with varying levels of manganese were observed to induce subtle increases in metal transporter expression and neuroinflammatory responses in the olfactory bulb, striatum, and midbrain. These observations suggest that exposure to manganese-containing welding fumes could potentially cause dopaminergic neurotoxicity. Whether such exposures can lead to neurofunctional changes, progressive dopaminergic cell loss, or induce Parkinson-like pathology remains to be elucidated.

Publications

  1. Antonini JM, Afshari AA, Stone S, Chen B, Schwegler-Berry D, Fletcher WG, Goldsmith WT, Vandestouwe KH, McKinney W, Castranova V, and Frazer DG.  Design, Construction, and Characterization of a Novel Robotic Welding Fume Generation and Inhalation Exposure System for Laboratory Animals. J Occup Environ Hyg 3:194-203, 2006.

  2. Antonini JM, Santamaria A, Jenkins NT, Albini E, and Lucchini R. Fate of manganese associated with the inhalation of welding fumes: Potential neurological effects. Neurotoxicol 27:304-310, 2006.

  3. Antonini JM, O’Callaghan JP, Miller DB. Development of an animal model to study the potential neurotoxic effects associated with welding fume inhalation. Neurotoxicol 27:745-751, 2006.

  4. Antonini JM, Stone S, Roberts JR, Chen B, Schwegler-Berry D, Afshari AA, and Frazer DG. Effect of short-term stainless steel welding fume inhalation exposure on lung inflammation, injury, and defense responses in rats. Toxicol Appl Pharmacol 223:234-245, 2007.

  5. Antonini JM, Roberts JR, Stone S, Chen BT, Schwegler-Berry D, and Frazer DG. Short-term inhalation exposure to mild steel welding fume had no effect on lung inflammation and injury but did alter defense responses to bacteria in rats. Inhal Toxicol 21:182-192, 2009.

Presentations

  1. Antonini JM, Miller DB, and O’Callaghan JP. Characterization of welding fumes and their neurotoxic effects. 22nd International Neurotoxicology Conference: Manganese Symposium, Research Triangle Park, NC, September 2005.

  2. Antonini JM, O’Callaghan JP, and Miller DB. Characterization of welding fumes and their potential neurotoxic effects. International Workshop: Neurotoxic Metals- Lead, Mercury, and Manganese, From Research to Prevention. Brescia, Italy, June 2006.

  3. Antonini JM, Roberts JR, Benkovic SA, Sriram K, O’Callaghan JP, and Miller DB. Potential neurotoxic responses in rats after pulmonary administration of welding fume with varying concentrations of manganese. 23rd International Neurotoxicology Conference: Health Effects of Manganese Exposure- Human and Animals Models, Little Rock, AR, September 2006.

  4. Antonini JM, Roberts JR, Sriram K, Benkovic SA, O’Callaghan JP, and Miller DB. Extrapulmonary tissue distribution of metals following repeated lung exposures to welding fumes with different elemental profiles. Society of Toxicology Annual Meeting, Seattle, WA, March 2008.

  5. Antonini JM, Stone S, Roberts JR, Schwegler-Berry D, Moseley A, Donlin M, Cumpston J, Afshari A, and Frazer DG. Pulmonary effects and tissue distribution of metals after inhalation of mild steel welding fume. American Thoracic Society International Conference, Toronto, Ontario, May 2008.

  6.  Antonini JM, Schwegler-Berry D, Stone S, Chen TB, Zeidler-Erdely PC, Frazer DG, and Roberts JR. Comparison of the persistence of deposited particles and the inflammatory potential of stainless steel versus mild steel welding fume in rat lungs after inhalation. Society of Toxicology Annual Meeting, Baltimore, MD, March 2009.

Last updated: July 27, 2007

MHRP
Web: http://www.manganese-health.org