Manganism – Misdiagnosed as Parkinson’s – Linked to Toxic Exposures

Have you or someone you know been diagnosed with Parkinson’s even though drugs used to treat Parkinson’s don’t help?

In this situation, the condition may well not be Parkinson’s after all. It is increasingly becoming apparent that another condition may well be responsible for many Parkinson’s-like conditions.

The condition is called Manganism – named after the common mineral manganese. Symptoms of manganism are very similar to Parkinson’s – shaking of the hands, arms and other appendages, loss of motor control, fixed facial expressions or facial muscle spasms, difficulty swallowing and others.

Initially, symptoms may only be irritability, a lack of coordination and mood changes. But compulsive behavior and violence hhavealso been linked to immediate manganese toxicity.

This was underscored by decades-old research on the initial effects of manganism. In 1991, research by Dr. Louis Gottschault as reviewed by Health Canada studied manganese toxicity among violent prisoners and found that many prisoners had excess levels of manganese oxides in their hair analyses.

Years later – even multiple decades later – long after the compulsive behavior ends, Parkinson’s-like symptoms begin to appear. And just as Parkinson’s does – those symptoms get worse as time goes on.

Most of these cases are unfortunately diagnosed as Parkinson’s, but also sometimes Lou Gehrig’s disease or multiple sclerosis. And often the drugs often used to treat Parkinson’s, namely levodopa-type drugs, don’t seem to work. This should be a tell-tale sign for the suspicion of manganism. Often and unfortunately, the doctor ends up telling the patient that perhaps they have something else – perhaps a different sort of Parkinson’s.

The cause of manganism is associated with manganese overexposure. Manganese is a necessary nutritional mineral, and it is used for many metabolic processes in the body. Healthy manganese content is found in the liver, brain, bone, blood, kidneys, pancreas and elsewhere.

Manganese can be part of a healthy diet at between 2 and 9 milligrams per day. Manganese is also often found in drinking water to varying degrees. The World Health Organization has set a standard for manganese in drinking water at 400 micrograms per liter. The U.S. EPA’s maximum standard for manganese in drinking water is 500 micrograms per liter.

Sources of manganese oxide poisoning

Healthy consumption aside, our industrial modern world has stirred up manganese poisoning. This comes typically in the form of oxidized manganese – a manganese oxide of one form or another.

As the research indicates, manganese toxicity can come from numerous sources. The most widely held is the toxicity from welding, as many welders over the decades have been found with manganism. This gave birth to the first name of manganism – ‘welder’s disease.’ In these cases, manganese oxide gases were found to have wafted through welding shops from metal composites used to manufacture steel parts.

Besides this, we have several other sources of manganese toxicity, as summarized in a 1999 paper:

“Chronic manganese intoxication leads to adverse neurologic and psychological disorders (Barbeau et al., 1976; Chandra et al., 1979; Gorell et al., 1997; Mena et al., 1967). Health risks of exposure to manganese have been associated with organic manganese-containing pesticides, such as manganese ethylene-bis-dithiocarbamate (MANEB) (Ferraz et al., 1988), inorganic manganese dust or vapor among steel manufacturing workers or welders (Roels et al., 1987, Wang et al., 1989), or a cocaine-based drug called Bazooka, which is contaminated with manganese carbonate (Ensing, 1985). Recently, several countries, including the United States, have replaced lead (Pb) in gasoline with the manganese-containing antiknock compound methylcyclopentadienyl manganese tricarbonyl (MMT). In the United States, MMT is produced by the Ethyl Corporation and marketed as HITEC 3000 or AK-33X. MMT contains 24.4–25.2% manganese (Frumken and Solomon, 1997; Zayed et al., 1994). The combustion of MMT in the automobile with the expected increase in ambient manganese level has raised concerns about the health risks associated with environmental exposure to manganese.”

Unleaded gas toxin – MMT

To elaborate on this latter point, one of the prime, yet not widely recognized, is exposure to the unleaded fuel additive, MMT – or methylcyclopentadienyl manganese tricarbonyl. This fuel additive boosts the octane of gasoline, and has been long considered and argued as a primary source of manganism.

Numerous studies have been done on MMT exposure in gasoline, and the U.S. Environmental Protection agency along with Health Canada have reviewed research along with petitions from MMT manufacturer Ethyl Corporation. I have sifted through a lot of this research and documentation, and here is my understanding of it:

MMT use in gasoline began in 1974. Then in 1977, the EPA halted its use until it was proven safe, and later because some thought it was harmful to catalytic converters and increased hydrocarbons.

Ethyl Corp fought the EPA on this for several years, and eventually achieved a waiver after it won a 1995 court battle with the EPA in the U.S. Court of Appeals.

Since then, MMT has been used in our unleaded gas. And MMT is still being used in unleaded gasoline, with a supposed maximum level of 8.3 milligrams of manganese per liter. The EPA also established a maximum ambient – air pollution – safe limit of .05 micrograms per meter squared (microg/m3).

Today, MMT is manufactured by the Afton Chemical Corporation and by Cestoil Chemical Inc. – a Canadian company.

While U.S. exposure took full force in the mid-1990s, Canada has continually used MMT in their gasoline since 1976. Early levels approached 18 milligrams per liter and average levels from a 2000 study found MMT in Canadian unleaded gas at 11.9 milligrams per liter – almost 25 percent higher than the EPA limit. This means that Canadians have been exposed to MMT at much greater levels than their Southern neighbors.

The research studies over these years are complex and arduous. But it basically confirmed that MMT was hazardous when either absorbed through the skin or its exhaust is breathed. There is no argument here. The argument has regarded the extent of exposure – and whether a consumer who handles gas and spills it on his hands now and again will end up with manganese poisoning – or that the manganese levels in the air could be poisoning everyone in smoggy areas.

Much of this research has concluded that MMT in unleaded gas is not that toxic. For example, a 1999 Canadian study concluded:

“Exposures to manganese among the general population in Toronto are well within safe limits determined by the U.S. EPA and other standard setting bodies around the world.”

This debate has continued, with research on either side. But neither side is arguing that MMT is not toxic in an occupational setting. Both the EPA and Health Canada reviews of research have confirmed that handling MMT or breathing in MMT fumes or exhaust in an occupational setting runs the risk of manganese poisoning, and manganism.

In fact, several studies have linked manganese exposure in smog with increased Parkinson’s-type diagnoses. Research from McMaster University and the University of Toronto found that smog from the city of Hamiton at air pollution levels of 150 nanograms per square meter of manganese was linked to significantly increased Parkinson’s-type diagnoses. The researchers stated:

“Examination of prevalence curves suggested that exposure to ambient manganese advances the age of diagnosis of Parkinson’s disease, consistent with the theory that exposure to manganese adds to the natural loss of neurons attributable to the aging process.”

This is also the findings of multiple studies on rats, where MMT exposure was found to accumulate manganese within the tissues over time:

“Thus, MMT-derived manganese appeared likely to accumulate in the body following repeated exposure.”

One of the suspicions is that manganese toxicity may be greater for those who are susceptible to neurotoxicity – given their diet or other lifestyle factors. A 2004 study from Wake Forest University stated:

“It has been proposed that populations already at heightened risk for neurodegeneration may also be more susceptible to manganese neurotoxicity, which highlights the importance of investigating the human health effects of using the controversial compound, methylcyclopentadienyl manganese tricarbonyl (MMT), in gasoline to increase octane.”

Those who handle gasoline throughout the day and work amongst gasoline-powered equipment in close proximity would have a much greater exposure to manganese given their occupations. This might be applicable to those who work in occupations that run boats, cars or motorcycles on unleaded gas. Or other equipment, for example, chainsaws and other logging equipment. Or those who work in mines or subways.

Water with industrial manganese contamination

Some water supplies have become contaminated with manganese from nearby mining or steel-working operations. A study from Bangladesh found manganese content in drinking water in some areas to be about 2,000 micrograms per liter – four times the WHO’s limit.

Bangladesh children exposed to this toxicity were found in research to be associated with poor test scores in mathematics.

Canada has long been a location for mining and steel working. A 2007 study from the University of Quebec tested 46 children between 6 and 15 years old who drink from varying wells. They found that kids whose water had higher levels of manganese had significantly higher levels of hyperactivity. A 2011 study from the same university studied high manganese levels in drinking water and compared the IQ of 362 children. They found that children whose groundwater contained higher levels of manganese had lower IQ levels – by as much as 6.2 points.

In this latter study, some Canadian groundwater had as much as 2,700 micrograms per liter of manganese.

The source of the high manganese levels can vary. One culprit appears to be regions where mining takes place. For example, a 2012 study from Italy’s University of Brescia found an increased incidence of Parkinson-like symptoms of people living in the Valcamonica region of Italy. This area maintained a ferroalloy plant that processed a number of minerals and emitted high airborne and soil levels of manganese – which also found its way to drinking water.

In this study, houses and areas that had the highest manganese content also had the highest prevalence of impaired motor coordination, hand dexterity and other symptoms.

In a 2012 study from Columbia University, researchers analyzed test scores and manganese levels in the water among 840 children from different areas of Bangladesh. They found that areas where manganese levels were above the World Health Organization’s standard limit of 400 micrograms per liter had significantly lower test scores. Those children – aged between 8 and 11 years old – had an average of 6.4% lower test scores if they lived in an area with higher manganese levels.

Occupational Exposures

Whether mining, welding or handling or breathing MMT, occupational exposure to manganese oxides is a significant risk for manganism. Researchers from Purdue University reviewed the research on manganese toxicity over the past decade. They wrote in a recent paper:

“Emerging data suggest that beyond traditionally recognized occupational manganism, manganese exposures and the ensuing toxicities occur in a variety of environmental settings, nutritional sources, contaminated foods, infant formulas, and water, soil, and air with natural or man-made contaminations. Upon fast absorption into the body via oral and inhalation exposures, manganese has a relatively short half-life in blood, yet fairly long half-lives in tissues. Recent data suggest manganese accumulates substantially in bone, with a half-life of about 8-9 years expected in human bones. Manganese toxicity has been associated with dopaminergic dysfunction by recent neurochemical analyses and synchrotron X-ray fluorescent imaging studies. Evidence from humans indicates that individual factors such as age, gender, ethnicity, genetics, and pre-existing medical conditions can have profound impacts on manganese toxicities.”

Their point regarding occupational exposures is critical, especially since manganism was initially called “welder’s disease.”

This occupational exposure is underscored by researchers noted above:

“While manganese deficiency rarely occurs in humans, manganese toxicity is known to occur in certain occupational settings through inhalation of manganese-containing dust.”

What about manganese from food?

There may be concern for supplements that unnaturally add to one’s manganese content. But a healthy diet that contains manganese from plant-foods has not been shown to be unhealthy.

The issue here is the absorption of manganese oxides. Absorption levels from airborne oxidized manganese from welding or steel operations have been solidly linked to Parkinson’s-type symptoms, or manganism. And manganese oxides from mining operations have been linked to drinking water as discussed above.

But natural manganese levels in water or food have not been found to be a cause of concern by researchers. Manganese deficiency has, however. Consuming less than 2.2 milligrams per day for adult and teenage men and 1.6 milligrams for adult and teenage women can result in deficiency. Manganese deficiency has been linked to osteoporosis, diabetes and epilepsy.

Eating natural foods that contain combinations of minerals that promote health are important. Our body utilizes a wide mix of minerals from nature – which provide for a full slate of metabolism within the body.

Testing for Manganese poisoning

One of the ways to test whether a person has higher manganese tissue levels is hair analysis. This is because hair analysis typically uncovers latent tissue exposure that blood analysis may not reveal.

We mentioned the prison study above: This was done using hair analysis.

A study of 46 children from Quebec compared hair analysis data with their drinking water exposure. The children drank from one of two wells – one of which averaged 610 micrograms per liter and the other that averaged 160 micrograms per liter.

Those children who drank from the higher-manganese well had nearly twice the levels of manganese in their hair analysis studies (6.2 micrograms per gram versus 3.3 micrograms per gram).

Is there a solution or treatment for manganism?

The most obvious strategies for prevention are to avoid smoggy areas, areas with mining operations, jobs where steel is welded and jobs where unleaded gasoline is handled daily.

But this offers little help for those with previous long-term exposure who may be suffering from manganism with Parkinson’s-type symptoms – possibly misdiagnosed as Parkinson’s. For those, many Parkinson’s drugs do not reduce symptoms – because the problem isn’t the production of dopamine.

Within the medical research, we find three potential treatments. The first is chelation therapy with EDTA (Ethylenediaminetetraacetic acid). This chelation approach has been used in cases of heavy metal toxicity of different types.

A paper from the University of Barcelona and the Mother Teresa Hospital described a situation where manganese exposure of a number of people that was successfully treated with EDTA chelation.

Another case study, from the University of Turin, found that seven workers who were diagnosed with severe Parkinson’s-type manganism after occupational exposure also had success with CaNa2EDTA (calcium disodium versenate) chelation therapy.

However, other research has shown that long-term exposure is difficult to treat with chelation. In the paper discussed below, we find the following statement regarding several human cases of manganism:

“Poor results with CaNa2EDTA in several cases in the advanced phase but encouraging results only in one patient with early signs and symptoms was also reported.”

This and the other evidence indicates that treatment for recent exposure with EDTA or CaNa2EDTA may be successful. But longer-term success with CaNa2EDTA is questionable.

Another potential treatment that has been uncovered by research is sodium para-aminosalicylic acid. This chemical relative of aspirin – which was derived by duplicating the plant-based chemical, salicylic acid – has been shown in both animal and a few human case studies to treat manganism.

In one study, doctors from Guangxi Medical College treated two patients with sodium para-aminosalicylic acid. One patient was treated with CaNa2EDTA for six months first, and the symptoms were reduced, but then the symptoms increased an intensified a year later. Another six months of CaNa2EDTA reduced symptoms again – only to re-emerge a couple of years later.

Then the doctors began treatment with sodium para-aminosalicylic acid – first in tablet form for two weeks and then for three months in the form of a 500 ml IV drip with six grams of sodium para-aminosalicylic acid with a 10 percent glucose solution.

After this treatment for 3-1/2 months, the patient’s symptoms gradually disappeared. A 19-month follow-up showed complete remission of manganism symptoms.

After 25 years, the patient continued to show no symptoms.

Since that initial case in 1984, there have been several animal studies, and another case-study that have confirmed the therapeutic ability of sodium para-aminosalicylic acid for manganism. One study found it was able to transport across the blood-brain barrier.

Certainly this is not a resounding confirmation of success as would be indicated by a large clinical study. But it is something for doctors to consider.

Another potential treatment has been explored. This is a Chinese herbal medicine nicknamed by researchers as the “B401 formula.”

The formula is based upon an ancient Chinese mix of six herbs – notably:

Panax ginseng
Astragalus membranaceus
Angelica sinensis
Rehmannia glutinosa
Ligustri Fructus
Eclipta prostrata

This complex of herbs has been used to treat anxiety and nerve disorders, and has been tested on Huntington’s disease.

While a mouse study will never confirm an ability to treat humans, a mice study did show the effectiveness of the herbal mix to reduce levels of manganese toxicity.

The herbal formula is produced by Taiwan’s Brion Research Institute.

Don’t self-medicate: Talk to your doctor.

REFERENCES:

Kwakye GF, Paoliello MM, Mukhopadhyay S, Bowman AB, Aschner M. Manganese-Induced Parkinsonism and Parkinson’s Disease: Shared and Distinguishable Features. Int J Environ Res Public Health. 2015 Jul 6;12(7):7519-40. doi: 10.3390/ijerph120707519.

Dobson AW, Erikson KM, Aschner M. Manganese neurotoxicity. Ann N Y Acad Sci. 2004 Mar;1012:115-28.

O’Neal SL, Zheng W. Manganese Toxicity Upon Overexposure: a Decade in Review. Curr Environ Health Rep. 2015 Sep;2(3):315-28. doi: 10.1007/s40572-015-0056-x.

Bouchard M, Laforest F, Vandelac L, Bellinger D, Mergler D. Hair manganese and hyperactive behaviors: pilot study of school-age children exposed through tap water. Environ Health Perspect. 2007 Jan;115(1):122-7.

Khan K, Wasserman GA, Liu X, Ahmed E, Parvez F, Slavkovich V, Levy D, Mey J, van Geen A, Graziano JH, Factor-Litvak P. Manganese exposure from drinking water and children’s academic achievement. Neurotoxicology. 2012 Jan;33(1):91-7. doi: 10.1016/j.neuro.2011.12.002.

Bouchard MF, Sauvé S, Barbeau B, Legrand M, Brodeur MÈ, Bouffard T, Limoges E, Bellinger DC, Mergler D. Intellectual impairment in school-age children exposed to manganese from drinking water. Environ Health Perspect. 2011 Jan;119(1):138-43. doi: 10.1289/ehp.1002321.

Abbott PJ. Methylcyclopentadienyl manganese tricarbonyl (MMT) in petrol: the toxicological issues. Sci Total Environ. 1987 Dec;67(2-3):247-55.

Walsh MP. The global experience with lead in gasoline and the lessons we should apply to the use of MMT. Am J Ind Med. 2007 Nov;50(11):853-60.

Finkelstein MM, Jerrett M. A study of the relationships between Parkinson’s disease and markers of traffic-derived and environmental manganese air pollution in two Canadian cities. Environ Res. 2007 Jul;104(3):420-32.

Crump KS. Manganese exposures in Toronto during use of the gasoline additive, methylcyclopentadienyl manganese tricarbonyl. J Expo Anal Environ Epidemiol. 2000 May-Jun;10(3):227-39.

Health Canada. Fuel additive MMT. 2001

Boudia N, Halley R, Kennedy G, Lambert J, Gareau L, Zayed J. Manganese concentrations in the air of the Montreal (Canada) subway in relation to surface automobile traffic density. Sci Total Environ. 2006 Jul 31;366(1):143-7.

Cooper WC. The health implications of increased manganese in the environment resulting from the combustion of fuel additives: a review of the literature. J Toxicol Environ Health. 1984;14(1):23-46.

Lynam DR, Roos JW, Pfeifer GD, Fort BF, Pullin TG. Environmental effects and exposures to manganese from use of methylcyclopentadienyl manganese tricarbonyl (MMT) in gasoline. Neurotoxicology. 1999 Apr-Jun;20(2-3):145-50.

Herrero Hernandez E, Discalzi G, Valentini C, Venturi F, Chiò A, Carmellino C, Rossi L, Sacchetti A, Pira E. Follow-up of patients affected by manganese-induced Parkinsonism after treatment with CaNa2EDTA. Neurotoxicology. 2006 May;27(3):333-9.

Sánchez B, Casalots-Casado J, Quintana S, Arroyo A, Martín-Fumadó C, Galtés I. Fatal manganese intoxication due to an error in the elaboration of Epsom salts for a liver cleansing diet. Forensic Sci Int. 2012 Nov 30;223(1-3):e1-4. doi: 10.1016/j.forsciint.2012.07.010.

Li SJ, Li Y, Chen JW, Yuan ZX, Mo YH, Lu GD, Jiang YM, Ou CY, Wang F, Huang XW, Luo YN, Ou SY, Huang YN. Sodium Para-aminosalicylic Acid Protected Primary Cultured Basal Ganglia Neurons of Rat from Manganese-Induced Oxidative Impairment and Changes of Amino Acid Neurotransmitters. Biol Trace Elem Res. 2015 Aug 19.

Qin WP, Liang TJ, Jiang YM. [A chronic moderate manganism poisoning treated with sodium p-aminosalicylic acid]. Zhonghua Lao Dong Wei Sheng Zhi Ye Bing Za Zhi. 2011 Aug;29(8):619-20.

Jiang YM, Mo XA, Du FQ, Fu X, Zhu XY, Gao HY, Xie JL, Liao FL, Pira E, Zheng W. Effective treatment of manganese-induced occupational Parkinsonism with p-aminosalicylic acid: a case of 17-year follow-up study. J Occup Environ Med. 2006 Jun;48(6):644-9.

Ky SQ, Deng HS, Xie PY, Hu W. A report of two cases of chronic serious manganese poisoning treated with sodium para-aminosalicylic acid. Br J Ind Med. 1992 Jan;49(1):66-9.

Hong L, Xu C, O’Neal S, Bi HC, Huang M, Zheng W, Zeng S. Roles of P-glycoprotein and multidrug resistance protein in transporting para-aminosalicylic acid and its N-acetylated metabolite in mice brain. Acta Pharmacol Sin. 2014 Dec;35(12):1577-85. doi: 10.1038/aps.2014.103.

Hsu CH, Lin CL, Wang SE, Sheu SJ, Chien CT, Wu CH. Oral treatment with herbal formula B401 alleviates penile toxicity in aging mice with manganism. Clin Interv Aging. 2015 May 28;10:907-18. doi: 10.2147/CIA.S82026.