Manganese Health Research Program: Phase 2, Core 20

Project Objectives:

• To evaluate Mn-exposed welders’ general cognitive, mood, and motor function 3 ½  years later, at a follow-up  in 2008 after baseline testing in January 2005. A brief screening was completed after 15 months in 2006.
• To evaluate blood levels of manganese and lead at follow-up
• To evaluate and compare welders’ olfaction, sleep and sexual function from baseline to follow-up.
• To evaluate welders’ respiratory status at baseline and follow-up

Project Description:

Brief abstract describing scope of project

This study was designed to follow-up a group of 43 confined space welders, first studied in 2005, who had dose-effect relationships for manganese in blood and air in a cumulative exposure index. Their exposure to Mn, unprotected and with poor ventilation lasted an average of 16.5 months. After the MHRP funding became available, they were followed-up after 3 ½ years with neuropsychological, neurological, respiratory and olfactory tests.

Despite extensive efforts to contact the forty-three welders, only 37 were reached for re-testing. Of those who could be reached, 26 welders came to their appointments resulting in a response rate of 26/37 (70%).  Mostly the same health professionals, neuropsychologists, graduate students, phlebotomist, and pulmonary technician retested these welders with a similar test battery. The primary analysis used a general linear model where the dependent variable was the individual-specific difference between 2008 and 2005 and the independent variable was ethnicity. The mean age of the group at follow-up was 47 years with an average of 12.4 years of education. The mean months and total years of welding since baseline was 23 months and 16.9 years, respectively. Only 50% of the group was ‘currently’ welding.

Welders had significantly lower Mn levels at follow-up than baseline (8.6 and 9.6 respectively). Those still welding had significantly higher Mn blood levels (9.876) than those no longer welding (6.842). Significant improvement on cognitive functions was observed with primarily medium to large effect sizes. While fine tactile manipulative ability improved, psychomotor speed was similar to baseline but grip strength scores worsened. In neurological examinations, rigidity was significantly worse and dominant tremor on the CATSYS worsened (approaching significance. Olfactory and respiratory function remained impaired.  Emotional disturbance, although somewhat improved clinically, (but not statistically), remains.  Welders continue to have clinical levels of depression and anxiety and score in the range of psychiatric patients, although they had not had any psychiatric complaints before the confined space bridge welding.

Although some improvement in neuropsychological function was found in the bridge welders, they continue to have tremors, rigidity, loss in grip strength and olfaction. They also continue to have emotional disturbance of anxiety and depression. Good mental health is needed in order to work in the highly demanding job of automatic welding. This suggests permanent impairment with only partial recovery. Welding-fume exposure appears to have a damaging effect on multiple organs. This may be due to both a reduction in uptake of dopamine and the almost entirely respirable fraction of welding fume.

Project Status:

We have developed both an in vivo and an in vitro model to understand the contribution of manganese to Parkinsonian symptoms. The principle goal of the in vivo studies was to determine if the behavioral phenotype of manganese exposure is due to selective loss of dopaminergic cells. To this end, Dr. Michael Aschner's laboratory prepared C57BL/6 mice animals that were given intraperitoneal injections of MnCl2 (5 mg/kg/day) or saline daily for 30 days. These animals were used to determine if manganese induced alterations in protein expression in the basal ganglia circuit, which would be consistent with a specific loss of dopaminergic neurons. The McLaughlin and Aschner labs collaboratively developed immunohistochemical analyses and cell counting techniques in which we determined there was a 17% reduction in neurons expressing tyrosine hydroxylase, an enzyme required for the production of dopamine, in the substantia nigra (SN) of Mn-treated animals. Quantification of Nissl bodies through cresyl-violet staining revealed a widespread reduction total neuronal number throughout the SN. One of the consequences of loss of dopaminergic cells would be a loss of GAD67, the rate-limiting enzyme in GABA production in the striatum, which receives projections from the substantia nigra. We observed decreases in numbers of GAD67 expressing interneurons within the STR and the GP of Mn-treated mice. This decrease was 39.4% in the STR and 14% in the GP. While we did not observe changes in the activated form of the cell death protein caspase 3 in the substantia nigra, striatum or other regions, we hypothesize that this was likely due to the fact that cleavage of this protease is an earlier event in the chronic exposure paradigm. The results of these studies suggest that Mn exposure can produce neurochemical dysfunction in key areas of the basal ganglia, including the striatum and globus pallidus. Ongoing experiments using primary cultures of ventral midbrain neurons are elucidating the cell signaling mechanism responsible for the selective vulnerability observed with Mn exposure.

Publications:

Stankowski J., Leitch D., Aschner M., McLaughlin B. and Stanwood G. D. (2008) Selective vulnerability of dopaminergic systems to Manganese: Relevance to occupational exposure. Neurotoxicology And Teratology 30, 259.

Key research accomplishments:

The study was carried out as planned and data scoring and analyses are now complete.  A presentation of the findings will be presented in a symposium entitled: “Manganese health effects in Welding: Scientific investigation addressing the controversy” at the American Psychological Association convention on August 9, 2009 in Toronto, Canada.  This research has had participation from numerous doctoral and Master’s level students who have learned much about neurotoxicity and its evaluation. Additional analyses on the Latinos in the group are underway and several more manuscripts will be completed.

Publications/Presentations arising from project:

the first article is near completion on this Follow-up study which will be submitted to OEM

Last updated: April 1, 2009