Manganese Exposure May Boost Parkinsonism Risk Among Welders

By: MICHELE G. SULLIVAN, Internal Medicine News Digital Network

BARCELONA Long-term welding work may be a risk factor for developing parkinsonism perhaps because manganese can travel directly into the midbrain via the olfactory nerve.

Two recent studies suggest a dose-response association, with increased risk as years of exposure accumulate.

Long-term welding work may be a risk factor for developing parkinsonism.

“Manganese, in particular, has been shown to be a neurotoxin,” stated Jessica Lundin, a Ph.D. candidate at the University of Washington, Seattle, who presented early findings from a cross-sectional study during a poster session at the meeting. “There is some evidence that it enters via an olfactory route.”

Recent studies have also indicated that long-term exposure to inhaled manganese is associated with neurologic and neurobehavioral deficits, according to the agency. “These effects include changes in mood and short-term memory, modified reaction time, and reduced hand-eye coordination. Affected workers frequently show abnormal accumulations of manganese in a region of the brain known as the globus pallidus.”

Ms. Lundin and her colleagues recruited 581 welders from three U.S. ship-building sites for a 3-year follow-up study. All welders underwent a baseline neurologic assessment by a movement disorders specialist. Assessments in the National Institute of Environmental Health Sciencessponsored study included the Unified Parkinsons Disease Rating Scale (motor subsection 3), timed motor tasks, and a questionnaire about occupational history (including prior welding jobs), lifestyle, and medical history, including smoking and neurotoxic exposure, especially to pesticides.

At baseline, individuals in the cohort had a mean age of 45 years and had welded for a mean of 23,000 hours. Individuals in the study were considered to be normal if their UPDRS3 scores were 6 or less; to be mildly affected by parkinsonian symptoms with scores of 6-14; and to have parkinsonism with scores of 15 or higher. At baseline, 199 were considered normal, with a score of 3 or lower; 306 had mild parkinsonian symptoms, with a mean UPDRS3 score of 10; and 76 qualified as having diagnosable parkinsonism with a mean UPDRS3 of 19.

Ms. Lundin compared UPDRS3 scores with total hours of welding exposure at baseline. She found a linear association, with risk increasing along with total exposure.

Subjects considered normal had a mean age of 41 years and a total exposure of 18,300 hours. Those with mild parkinsonian symptoms were a mean of 46 years old and had a mean total exposure of 25,100 hours. Those with parkinsonism had a mean age of 48 years, with a mean total exposure of 26,800 hours.

The prevalence ratio also rose with increasing exposure. Those with a total of less than 2,900 hours were considered the reference group, with no increase over expected background rates. The prevalence of parkinsonism increased by 20% for those with a total exposure of 2,900-9,600 hours, by 40% with 9,600-26,400 hours of exposure, and by 60% with more than 26,400 hours.

None of these baseline differences in UPDRS3 scores and prevalence of parkinsonism were statistically significant, but they provided a trend strong enough to justify the 3-year follow-up, Ms. Lundin stated in an interview. “We will follow this group to determine incident cases of Parkinsons symptoms and symptom progression. We also have some industrial hygienists working with us to collect samples of manganese [on surfaces] in the shipyard and in the air.”

Further work will include comparison to a nonwelding reference group, as well as blood samples indicating exposure to manganese, cadmium, lead, aluminum, copper, and other metals. These analyses will be part of a multivariate regression that will control for age, she added.

Primary investigator Dr. Susan Criswell, Washington University, St. Louis, conducted an imaging study of 20 asymptomatic welders, also primarily recruited from shipyards. These were compared to 20 subjects with idiopathic Parkinsons disease and 20 normal controls. Positron emission tomography with 6- Fluoro-L-dopa (FDOPA) measured dopaminergic presynaptic nerve terminal dysfunction in different brain regions in all of the participants.

The mean ages of the groups ranged from 45 to 55 years, but the difference was not statistically significant. The welders had a mean exposure of 30,968 hours. The average level of manganese in their blood was 20 mcg/L twice the upper limit of normal.

At baseline, those with Parkinsons disease had a significantly higher mean UPDRS3 score (19.7) than did either welders (8) or normal controls (1). The welders mean UPDRS3 score was significantly higher than was the normal controls score. But Dr. Criswell noted that welders were not significantly different from controls in terms of clinical parkinsonian symptoms.

Imaging revealed significantly higher pallidal index scores among welders than those of both control subjects and those with Parkinsons disease. This difference was significantly related to increased exposure hours, but not to blood manganese levels.

After the researchers controlled for age, dopaminergic function also differed significantly between the groups. Welders had almost 12% lower dopaminergic uptake in the anterior putamen, compared with the other two groups. The uptake pattern also varied significantly from those with Parkinsons disease, measuring lowest in the caudate, followed by the anterior putamen and then the posterior putamen. “This pattern was reversed from the idiopathic Parkinsons disease subject pattern,” in which dopaminergic uptake was lowest in the posterior putamen, followed by the anterior putamen and finally, the caudate, Dr. Criswell said.

There were no significant interactions between dopaminergic uptake and pallidal index, manganese levels, and UPDRS3 scores. However, Dr. Criswell noted, the decrease in dopaminergic uptake among welders suggests presynaptic nigrostriatal dysfunction.

The findings suggest that manganese preferentially affects dopaminergic neurons in the caudate, rather than the putamen, Dr. W.R. Wayne Martin wrote in an accompanying editorial (Neurology 2011;76:1286-7). “In Parkinsons disease, decreased caudate [dopaminergic uptake] correlates with impaired executive function,” wrote Dr. Martin of the movement disorders clinic at Glenrose Rehabilitation Hospital in Edmonton, Alta. “This is consistent with the possibility that, with manganese toxicity, cognitive and behavioral symptomatology may be more prominent than motor changes, at least in its early stages.”

However, he cautioned, only longitudinal follow-up can determine the true relationship between manganese exposure and any increased risk of Parkinsons disease.

Ms. Lundin reported having no financial disclosures. Dr. Criswell reported receiving research support from numerous pharmaceutical companies; her study was funded by the Michael J. Fox Foundation for Parkinsons Research, the National Institutes of Health, the American Parkinson Disease Association, Advanced Research Center at Washington University, the Greater St. Louis Chapter of the APDA, and the McDonnell Center for Higher Brain Function, and the Barnes-Jewish Hospital Foundation.

Dr. Martin reported receiving speaker honoraria from Allergan Inc.


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Submited at Monday, April 25th, 2011 at 5:00 pm on Neurology by
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