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Manganese Exposure, Motor Symptom Progression May Be Dose-Related

Samson, Kurt

doi: 10.1097/01.NT.0000512096.41679.50


Researchers have documented for the first time what they believe is evidence that motor symptoms resembling parkinsonism in welders exposed to manganese fumes appear to follow a dose-dependent track, with higher exposure levels associated with more rapid decline.

In the first longitudinal study examining estimated manganese (Mn) exposure levels and motor symptoms, investigators at Washington University Medical School in Saint Louis followed 886 welders for up to 10 years after their baseline status was determined. The findings were published in the online December 28, 2016 edition of Neurology.

Follow-up analysis showed an annual change of 0.24 in the Unified Parkinson Disease Rating Scale motor subsection part 3 (UPDRS3) scores for each mg Mn/m3-year of exposure. The youngest worker was 18 while the oldest was 86 years of age. The average age was 46 years, lead investigator Brad A. Racette, MD, FAAN, professor and executive vice chairman of the department of neurology, told Neurology Today.

The most common progressive symptoms were upper limb bradykinesia, upper and lower limb rigidity, and impaired speech and facial expression. The association was especially significant among welders who worked in confined spaces and those whose baseline examination was within five years of first exposure.

The annual increase in upper limb bradykinesia was especially notable among such welders. According to the researchers, this suggests a neurodegenerative pathophysiology consistent with prior small case series of patients with such symptoms that have shown continued progression, even after they were removed from Mn exposure.

The investigators were unable to directly measure workers' cumulative Mn exposure because there are no biomarkers of cumulative exposure. Exposure was determined by taking a complete job history in person to estimate welding years and cumulative exposure to welding fumes.

Although there are regulatory levels for Mn exposure, employers are not required by law to monitor actual workplace exposure. Nonetheless, the estimated exposure levels in the study were at or significantly below regulatory limits, said Dr. Racette.

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The team conducted 1,492 movement disorder examinations in the 886 welders, including 398 workers who had 606 follow-up examinations. Ninety percent of workers had at least one follow-up exam.

Data on almost all of 886 workers showed parkinsonism to be the predominant phenotype. A total of 135 workers, or 15.2 percent, had a UPDRS3 score greater than 15. Among the 886 workers, 398 already had at least one follow-up UPDRS3 exam at baseline, with a mean total follow-up of 4.2 years. The average annual change in UPDRS3 score for welders was 0.57.

“The most significant implication of our findings is that these symptoms and their progression occurred in welders exposed to manganese well below current regulatory thresholds,” Dr. Racette said.

“Now that we have this data, we hope the Occupational Safety and Health Administration [OSHA] will consider lowering mandatory exposure levels. We owe this to the volunteers who participated in this study.”

Dr. Racette said the researchers will be working with trade union representatives and health agency officials who are interested in the findings.

OSHA's current exposure standard is a ceiling of 5 mg/m3, while the American Conference of Governmental Industrial Hygienists in 2013 recommended a tenfold reduction in the current threshold measured over an eight-hour shift from 0.2 mg/m3 to 0.02 mg/m3.

Dr. Racette said the researchers are now conducting an ongoing imaging study examining whether the effects are caused by dysfunction in the dopamine system.

They are also in discussions with regulatory officials and trade union representatives.

Although movement disorders in workers exposed to Mn have been well-documented, imaging has shown that parts of the brain affected in Parkinson's disease (PD) and mechanisms of action in so-called manganism appear to be significantly different. Moreover, not all experts believe that such symptoms are related to manganese exposure, noting that other confounders or factors are unknown.

While Mn-induced parkinsonism and PD share some similarities, there are striking differences in the clinical and pathologic manifestations between both disorders, including symptoms and affected parts of the brain, said Dr. Racette.

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The authors of an accompanying editorial highlighted those differences. “Parkinsonian symptoms include rigidity, gait abnormalities, dysarthria, hypomimia, and bradykinesia, however ‘the high-stepping gait’ disturbance associated with Mn poisoning is easily distinguishable from the shuffling gait of PD,” wrote Marcia H. Ratner, PhD, project manager in the department of pharmacology & experimental therapeutics at Boston University School of Medicine, and Edward Fitzgerald, PhD, O'Leary Professor of Environmental Health Science at the University of Albany School of Public Health in New York.

Although symptoms of Mn-parkinsonism are often mistaken for PD, the underlying biology is also different, they noted. In PD, many dopamine-producing cells in the substantia nigra degenerate, resulting in dopamine deficiency. In Mn-parkinsonism however, the problem is not with dopamine production or supply but in the brain's ability to release available dopamine into synapses.



A decrease in dopamine release has been implicated in Mn neurotoxicity; primate and human studies have indicated that Mn-PDism is not associated with a substantial loss of dopaminergic neurons within the substantia nigra.

The authors said that in making a differential diagnosis, a trial of dopaminergic agents is warranted because response to dopaminergic therapeutics in Mn-parkinsonism reflects a neuropathology related, in part, to the tissue distribution of Mn.

The researchers were able to see the accumulation of Mn as symmetric hyperintensities on T1-weighted magnetic resonance imaging (MRI), they noted.

“Because the signal normalizes with cessation of exposure, MRI is most useful for the diagnosis of Mn-PDism if performed before or shortly after cessation of exposure,” according to the authors. “The bilateral tissue distribution of Mn within the brain results in a bilateral onset of parkinsonian symptoms, a clinical finding that is much less common in PD.”

A major strength of the study was the inclusion of MRI studies showing a dose-dependent increase in pallidal index scores in a subgroup of welders, which may also apply to better understanding the progression in individual patients, they added.

As the researchers noted, the study had several limitations, according to the editorial. First, because cumulative Mn exposure was based on work histories, “the specific cumulative ambient air dose-response relationships reported herein should be interpreted with caution,” they wrote.

Second, because welders are often exposed to other neurotoxic chemicals, the role of these agents in symptom progression “cannot be excluded.”

In addition, relying solely on the UPDRS3 does not permit an assessment of the dose-response relationship between “the full spectrum of behavioral and cognitive effects associated with Mn exposure,” according to the editorial.

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James Mortimer, PhD, FAAN, professor emeritus of the University of South Florida College of Public Health in Tampa, said that although the findings are interesting, non-linearity of the UPDRS3 is an important limitation of this study.

“The UPDRS3 is non-linear, and therefore the differences observed may depend on baseline scores on this instrument,” he told Neurology Today. “One possibility is that participants with higher scores at baseline might show greater change at follow-up. Because the outcome was not adjusted for baseline scores it is difficult to interpret the findings.”

“The authors present a figure showing an association between the duration of welding and the score on the UPDRS3. How much of this association is due to the older age of welders who worked longer as welders is not clear.”

Dr. Mortimer was lead author of a 2012 meta-analysis of manganese exposure and PD that found no association between the two. In fact, the researchers found that exposed workers were less likely to develop the disease, according to the study, published in Neurology.

“We looked at data on more than one million person-years of follow-up, and welding and manganese exposure was not associated with increased PD risk. However, this does not preclude the possibility that high manganese exposure may lead to early pre-clinical Parkinson signs in some individuals.”

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•. Racette B, SS Nielsen, Criswell SR, et al. Dose-dependent progression of parkinsonism in manganese-exposed welders Neurology 2016; Epub Dec 28.
    •. Ratner MH, Fitzgerald E. Understanding the role of manganese in parkinsonism and Parkinson disease Neurology 2016; Epub Dec 28.
      •. Mortimer JA, Borenstein AR, Nelson LM. Associations of welding and manganese exposure with Parkinson disease: Review and meta-analysis http:// Neurology 2012; 79:1174–1180.
        •. Harris RC, Lundin JI, Criswell SR, et al. Effects of parkinsonism on health status in welding exposed workers Parkinsonism Relat Disord 2011;17:672–676.
          •. Kwakye GF, Paoliello MB, Mukhopadhya S, et al. Manganese-induced parkinsonism and Parkinson's disease: Shared and distinguishable features http:// Int J Environ Res Public Health 2015; 12:7519–7540.
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