Manganese toxicity

Exposure to excessive amount of manganese can result in manganese toxicity also known as “manganism” or “manganese-induced neurotoxicity”, a neurological disorder with symptoms similar to those of Parkinson’s disease ¹, ², ³, ⁴, ⁵, ⁶, ⁷, ⁸, ⁹, ¹⁰, ¹¹. Manganese toxicity classically results from elevated exposure levels in drinking water or air. Manganese is widely used in industrial processes and commercial products. Excessive occupational exposure to manganese is most common in mining, welding, ore processing, dry battery manufacture, and organochemical fungicide use ¹², ¹³, ¹⁴, ¹⁵. Manganese toxicity can also arise from an impaired or under-developed excretion system, including in patients receiving total parenteral nutrition (TPN) therapy ¹⁶, ¹⁷, patients with hepatic encephalopathy ¹⁸ and abusers of ephedrone (methcathinone) ¹⁹.

Manganese toxicity is caused by the preferential accumulation of manganese in brain areas rich in dopaminergic neurons such as the caudate nucleus, putamen, globus pallidus, substantia nigra, and subthalamic nuclei (the extrapyramidal system) ⁴, ⁶, ⁷, ⁵, ¹, ², ³. The extrapyramidal system is a part of your brain that controls involuntary movements, maintains posture, and regulates muscle tone. Visual reaction time, hand steadiness, and eye-hand coordination were affected in chronically-exposed workers.

The most common health problems in workers exposed to high levels of manganese involve the central nervous system (brain and spinal cord). The early stages of manganese toxicity include psychiatric symptoms such as emotional liability, mania, compulsive or aggressive behavior, irritability, movements that may become slow and clumsy, hallucinations, feeding and sex dysfunctions, intellectual deficits, humor changes and mild motor impairment. This combination of symptoms when sufficiently severe is referred to as “manganism” or “manganese-induced neurotoxicity”. Other less severe nervous system effects such as slowed hand movements have been observed in some workers exposed to lower concentrations in the work place. In situations of established manganese-induced neurotoxicity, the characteristic extrapyramidal symptoms (motor symptoms), such as a mask-like face, become evident ²⁰.

The inhalation of a large quantity of dust or fumes containing manganese may cause irritation of the lungs which could lead to pneumonia. Loss of sex drive and sperm damage has also been observed in men exposed to high levels of manganese in workplace air.

The manganese concentrations that cause effects such as slowed hand movements in some workers are approximately twenty thousand times higher than the concentrations normally found in the environment. Manganism has been found in some workers exposed to manganese concentrations about a million times higher than normal air concentrations of manganese.

Manganese neurotoxicity can occur following high-dose oral, inhalation, or parenteral exposure to manganese ⁵. The development of manganese neurotoxicity following different routes of exposure indicates that the manganese dose to target tissue is the critical determinant of manganese toxicity, regardless of route ⁵. The association between manganese and neurotoxicity (damage to the brain) was first noted by Couper in 1837 who reported abnormal neurologic effects in workers at an ore-grinding plant where “black oxide of manganese” was processed ²¹. Most epidemiologic research on manganese conducted during the late 20th century focused on occupational inhalation exposure. Manganese toxicity may result in multiple neurologic problems and is a well-recognized health hazard for people who inhale manganese dust. Subsequent epidemiologic studies of welders, manganese miners, battery producers, smelters and other manganese workers have clearly established a causal association between chronic high-dose-manganese exposure via inhalation and neurotoxicity ²², ²³, ²⁴, ²⁵. Unlike ingested manganese, inhaled manganese is transported directly to your brain before it can be brokendown in your liver ²⁶, ²⁷. Hallmarks of manganese neurotoxicity in adults include behavioral changes, cognitive deficits, progressive bradykinesia, dystonia, and other gait abnormalities ²⁸, ²⁹, ³⁰. There has been increasing concern regarding the role of environmental manganese exposure and children’s health ³¹. Manganese has been identified as a risk factor for the development of aggressive behavior, attention deficit, cognitive decline resulting in lowered IQ, and learning deficits in infants and children ³², ³³, ³⁴, ³⁵.

Manganese neurotoxicity can occur following high-dose oral, inhalation, or parenteral exposure to manganese ⁵. The symptoms of manganese neurotoxicity generally appear slowly over a period of months to years. In its worst form, manganese neurotoxicity can result in a permanent neurological disorder with symptoms similar to those of Parkinson’s disease (also known as manganese-induced parkinsonism) with symptoms such as tremors, difficulty walking, and facial muscle spasms. Excessive manganese accumulation in the central nervous system (brain and spinal cord) is an established clinical entity, referred to as manganism. Manganism resembles idiopathic Parkinson’s disease (the term “idiopathic” means that the cause is unknown) in its clinical features, resulting in adverse neurological effects both in laboratory animals and humans ⁴, ²². Manganism is sometimes preceded by psychiatric symptoms, such as irritability, aggressiveness, and even hallucinations ³⁶, ³⁷.

Analysis of brain samples have shown that manganese accumulates within the human striatum, globus pallidus, and substantia nigra ³⁸, ³⁹. Manganese accumulation in these brain regions is associated with the presence of the divalent metal transporter 1 (DMT1) although additional transporters may play a role in brain uptake of manganese ⁴⁰, ⁴¹, ⁴². Brain imaging studies that rely on the paramagnetic properties of manganese that result in increased signal intensity seen with T1-weighted magnetic resonance imaging (MRI), allow for visual inspection of the brain for evidence of manganese accumulation at this site. Brain MRI studies of highly exposed people reveal signal intensity changes in the globus pallidus, striatum, and midbrain consistent with manganese accumulation at these sites ⁴³, ⁴⁴. Studies performed in nonhuman primates have shown that changes in the T1-weighted image correlate with manganese tissue concentration ⁴⁵. The primary neuropathologic target of manganese neurotoxicity is the globus pallidus (particularly the internal segment) with sparing of the substantia nigra pars compacta and an absence of Lewy bodies ⁴⁶. Studies of a manganese-exposed South African mine worker have revealed reduced astrocyte and neuron density in both the caudate and putamen ⁴⁷. Chronic manganese neurotoxicity in people is also associated with decreased gamma-aminobutyric acid (GABA) neurons, reduced myelinated fibers, and moderate astrocytic proliferation in the medial segment of the globus pallidus ⁴⁶.

Figure 1. Manganese exposure (pathways of human manganese exposure)

[Source ⁴⁸ ]

Several studies have examined neurochemical changes following high-dose-manganese exposure. Because manganese neurotoxicity results in dysregulation of motor control, many studies have focused on the striatal and pallidal dopaminergic system. Manganese reacts with dopamine and other biogenic amines resulting in oxidative damage to the neurotransmitters ⁴⁹. One pathway involves manganese catalyzed oxidation of the alpha hydroxyl group of dopamine forming a semi-quinone radical. The semi-quinone radical then reacts with oxygen to generate superoxide anion radical [O2•−] and a quinone. Oxygen can reoxidize the quinone to quinol to generate hydrogen peroxide ⁴⁹. Manganese-catalyzed dopamine auto-oxidation may also involve semiquinone and aminochrome intermediates, l-cysteine or copper, and NADH facilitation ⁵⁰, ⁵¹. Excess manganese may also alter glutamate homeostasis in the basal ganglia ⁵². Changes in glutamate homeostasis have been associated with excitotoxicity in the brain ⁵².

Limited evidence suggests that high manganese intakes from drinking water may be associated with neurological symptoms similar to those of Parkinson’s disease. Severe neurological symptoms were reported in 25 people who drank water contaminated with manganese and probably other contaminants from dry cell batteries for two to three months ⁵³. Water manganese concentrations were found to be 14 mg/L almost two months after symptoms began and may have already been declining ²³. A study of older adults in Greece found a high prevalence of neurological symptoms in those exposed to water manganese levels of 1.8 to 2.3 mg/L ⁵⁴, while a study in Germany found no evidence of increased neurological symptoms in people drinking water with manganese levels ranging from 0.3 to 2.2 mg/L compared to those drinking water containing less than 0.05 mg/L of manganese ⁵⁵. Manganese in drinking water may be more bioavailable than manganese in food. However, none of the studies measured dietary manganese, so total manganese intake in these cases is unknown. In the US, the Environmental Protection Agency (EPA) recommends 0.05 mg/L as the maximum allowable manganese concentration in drinking water ⁵⁶ and the World Health Organization (WHO) health-based guideline value for manganese in drinking water is 0.08 mg/L ⁵⁷, ⁵⁸. Current acceptable levels of manganese in drinking water are 0.04 mg/L and a tolerable intake of manganese from dietary sources should not exceed 0.06 milligrams/kg ⁵⁹

Additionally, several cross-sectional studies have associated high levels of manganese in drinking water with cognitive and behavioral deficits in children ⁶⁰. For example, a cross-sectional study of 362 children (ages 6-13 years) in Canada found children with the highest manganese concentrations in home tap water (median of 216 microgram/L) had a 6.2-point lower Full Scale IQ (lower Performance IQ but not Verbal IQ) than those with lowest manganese levels in home tap water (median of 1 μg/L) ⁶¹. A cohort study that followed 287 of these children for a mean of 4.4 years found that exposure to higher concentrations of manganese in drinking water was linked to a lower Performance IQ among girls but a higher Performance IQ among boys ⁶². Additionally, a prospective cohort study among 1,265 children in Bangladesh did not find manganese concentration in drinking water (medians of 0.20 mg/L during pregnancy and 0.34 mg/L at 10 years) to be associated with any measure of cognitive ability (i.e., IQ, verbal comprehension, perceptual reasoning, working memory, processing speed) when assessed at age 10 ⁶³. Yet, this study associated manganese in drinking water with higher risks of conduct problems among boys and low prosocial scores among girls ⁶³. In a population-based cohort study in Denmark that followed 643,401 children, exposure to higher manganese concentrations in drinking water was linked to a heightened risk of one subtype of attention-deficit hyperactive disorder (ADHD) ⁶⁴. Specifically, exposure to a manganese concentration in drinking water of at least 100 mcg/L was associated with a 51% higher risk of the ADHD-Inattentive subtype in girls and a 20% higher risk in boys, in comparison to exposure of <5 mcg/L — using these exposure comparisons, a 9% increased risk of ADHD-Overall was observed in girls and no difference found in boys ⁶⁴.

Only a few adverse effects of manganese intake from supplements have been documented. A single case of manganese toxicity was reported in a person who took large amounts of mineral supplements for years ⁶⁵, while another case was reported as a result of a person taking a Chinese herbal supplement ³⁶. More recently, Parkinson’s disease was reported in a woman taking 100 mg/day of manganese chloride for at least two years, followed by 30 mg/day for two months ⁶⁶.

Manganese neurotoxicity has been observed in individuals receiving total parenteral nutrition (TPN), both as a result of excessive manganese in the solution and as an incidental contaminant ⁶⁷. Total parenteral nutrition (TPN) is a method of feeding that involves delivering nutrients directly into the bloodstream through a vein (IV). Total parenteral nutrition (TPN) is used when the digestive system isn’t working properly, or when a person can’t or shouldn’t receive oral or tube feedings. Neonates (newborn babies) are especially vulnerable to manganese-related neurotoxicity ⁶⁸. Infants receiving manganese-containing TPN can be exposed to manganese concentrations about 100-fold higher than breast-fed infants ⁶⁹. Because of potential manganese neurotoxicities, some argue against including manganese in parenteral nutrition ⁷⁰.

Individuals with increased susceptibility to manganese neurotoxicity:

Chronic liver disease: Manganese is eliminated from the body mainly in bile. Therefore, impaired liver function may lead to decreased manganese excretion. Manganese accumulation in individuals with cirrhosis or liver failure may contribute to neurological problems and Parkinson’s disease-like symptoms ⁷¹, ²³.
Infants and children: Compared to adults, infants and children have higher intestinal absorption of manganese, as well as lower biliary excretion of manganese ⁷², ⁵⁹. Therefore, infants and children are especially susceptible to any negative, neurotoxic effects of manganese. Several studies in school-aged children have reported deleterious cognitive and behavioral effects following excessive manganese exposure ⁷³, ⁷⁴, ⁷⁵, ⁷⁶, ⁷⁷, ⁷⁸, ⁷⁹, ⁶¹. Additional studies have associated higher manganese exposures during pregnancy with cognitive and motor deficits in children under six years of age ⁶⁰.
Iron-deficient populations: Iron deficiency has been shown to increase the risk of manganese accumulation in the brain ⁸⁰.
Individuals with occupational exposures to airborne manganese, such as welders, miners, and smelters ⁶⁹.
Abusers of the illicit drug, methcathinone (ephedrone): Intravenous use of manganese-contaminated methcathinone (i.e., when the drug is synthesized with potassium permanganate as the oxidant) can cause lasting neurological damage and a parkinsonism disorder ⁸¹, ⁸².

Manganese toxicity resulting from food alone has not been reported in humans, even though certain vegetarian diets could provide up to 20 mg/day of manganese ⁶⁵, ⁸³.

Additionally, environmental or occupational inhalation of manganese can cause an inflammatory response in your lungs ⁸⁴, with clinical symptoms including cough, acute bronchitis, and decreased lung function ⁸⁵.

Due to the severe implications of manganese neurotoxicity, the Food and Nutrition Board of the Institute of Medicine set very conservative tolerable upper intake levels (UL) for manganese; the tolerable upper intake levels (ULs) are listed in Table 1 according to age ⁸³. The Tolerable Upper Intake Level (UL) is the highest level of daily nutrient intake that is likely to pose no risk of adverse health effects in almost all individuals ⁸³. The Tolerable Upper Intake Levels (ULs) for Manganese do not apply to individuals who are taking supplemental manganese under medical supervision.

Older adults (>50 years)

The requirement for manganese is not known to be higher for older adults. However, liver disease is more common in older adults and may increase the risk of manganese toxicity by decreasing the elimination of manganese from the body. Manganese supplementation beyond 100% of the Daily Value (DV) (2 mg/day) is not recommended.

Table 1. Tolerable Upper Intake Levels (ULs) for Manganese

Age Group	UL (mg/day)
Infants 0-12 months	Not possible to establish*
Children 1-3 years	2 mg/day
Children 4-8 years	3 mg/day
Children 9-13 years	6 mg/day
Adolescents 14-18 years	9 mg/day
Adults 19 years and older	11 mg/day

Footnote: *Breast milk, formula, and food should be the only sources of manganese for infants.

[Source ⁸⁶ ]

What is manganese?

Manganese (Mn) is a mineral element that is both nutritionally essential at low levels in your diet and at the same time it can also be potentially neurotoxic and scientists are still working to understand the diverse effects of manganese deficiency and manganese neurotoxicity in living organisms ²³, ⁸⁷, ²⁴. Manganese (Mn) is the 10th most common mineral in the Earth’s crust usually occurring with iron (Fe) in the environment where it can be found in rocks and soil and your body needs trace amounts of manganese to stay healthy. Manganese (Mn) can exist in 11 oxidation states, often as chloride, oxides and sulfates ⁵⁸. The most common oxidation states for manganese in natural water are Mn²⁺ and Mn⁴⁺ ⁸⁸, ⁵⁸. Divalent manganese (Mn²⁺) is absorbed by clay minerals and organic material, and this form is the most significant in plant nutrition ⁸⁹. Manganese is used principally in the manufacture of iron and steel alloys, and manganese compounds such as potassium and sodium permanganate are ingredients in various products used for cleaning, bleaching and disinfection ⁵⁸. Manganese compounds are additionally used in some locations for potable water treatment and can also be an impurity in coagulants used during water treatment ⁵⁸. Manganese occurs naturally in many surface water and groundwater sources; although naturally occurring manganese is usually the most important source for drinking-water, human activities can also contribute to high levels of manganese in water ⁵⁸. Manganese also occurs naturally in many food sources, and the greatest exposure to manganese is usually from food. Manganese is also available as a dietary supplement.

Your body uses manganese to make energy and protect your cells from damage. Your body also needs manganese for strong bones, reproduction, blood clotting, and a healthy immune system ⁹⁰. Manganese is a compound that is essential for the activity for many enzymes serving as an enzyme cofactor and is incorporated into several metalloenzymes, including manganese superoxide dismutase (MnSOD), arginase, glutamine synthetase, phosphoenolpyruvate decarboxylase, and pyruvate carboxylase ⁹¹, ⁹², ⁹³, ⁹⁴. Through the action of these enzymes, manganese is involved in amino acid (a building block of protein), cholesterol, glucose, and carbohydrate metabolism (the process by which the body converts carbohydrate into energy through chemical reactions in cells); reactive oxygen species scavenging; bone formation; reproduction; and immune response ⁸³, ⁹⁵, ⁹⁶, ⁹⁷, ⁶⁹. Manganese also plays a role in blood clotting and stopping bleeding in combination with vitamin K ⁹⁶.

The human body’s nutritional requirements for manganese are normally met through dietary intake via food and drinking water. The Adequate Intake (AI) for manganese in adult men is 2.3 mg/day, women is 1.8 mg/day and 1.5 mg/day for children 4 to 8 years of age ⁸³. A Tolerable Upper Intake Level (maximum daily intake unlikely to cause adverse health effects) for manganese was set for adults at 11 mg/day based on a no-observed-adverse-effect level (NOAEL) for Western diets ⁸³.

Only a small percentage of dietary manganese is absorbed. Manganese is absorbed in the small intestine through an active transport system and, possibly, through diffusion when intakes are high ⁹⁴. After absorption, some manganese remains free, but most is bound to transferrin, albumin, and plasma alpha-2-macroglobulin. Manganese is taken up by your liver and other tissues, but the mechanism of this process is not well understood ⁹⁴, ⁹³. Manganese inhibited iron absorption, both from a solution and from a hamburger meal ⁹⁸.

How much manganese do I need?

The amount of manganese you need depends on your age and sex. Average daily recommended amounts are listed below in milligrams (mg). Intake recommendations for manganese and other nutrients are provided in the Dietary Reference Intakes (DRIs) developed by an expert committee of the Food and Nutrition Board at the National Academies of Sciences, Engineering, and Medicine ⁸³. The Dietary Reference Intake (DRI) is the general term for a set of reference values used for planning and assessing nutrient intakes of healthy people. These values vary by age and sex and they include:

Recommended Dietary Allowance (RDA): Average daily level of intake sufficient to meet the nutrient requirements of nearly all (97%–98%) healthy individuals; often used to plan nutritionally adequate diets for individuals
Adequate Intake (AI): Intake at this level is assumed to ensure nutritional adequacy; established when evidence is insufficient to develop an Recommended Dietary Allowance (RDA).
Estimated Average Requirement (EAR): Average daily level of intake estimated to meet the requirements of 50% of healthy individuals; usually used to assess the nutrient intakes of groups of people and to plan nutritionally adequate diets for them; can also be used to assess the nutrient intakes of individuals
Tolerable Upper Intake Level (UL): Maximum daily intake unlikely to cause adverse health effects

In its 2001 evaluation, the Food and Nutrition Board found the existing data insufficient to derive an Estimated Average Requirement (EAR) for manganese. The Food and Nutrition Board therefore established Adequate Intakes (AIs) for all ages based on usual manganese intakes in healthy populations ⁸³. The Adequate Intake (AI) for manganese in adult men is 2.3 mg/day and women is 1.8 mg/day ⁸³. A Tolerable Upper Intake Level (maximum daily intake unlikely to cause adverse health effects) for manganese was set for adults at 11 mg/day based on a no-observed-adverse-effect level (NOAEL) for Western diets ⁸³. Table 3 lists the current Adequate Intakes (AIs) for manganese.

Table 2. Adequate Intakes (AIs) for Manganese

Age	Male	Female	Pregnancy	Lactation
Birth to 6 months*	0.003 mg	0.003 mg
7–12 months	0.6 mg	0.6 mg
1–3 years	1.2 mg	1.2 mg
4–8 years	1.5 mg	1.5 mg
9–13 years	1.9 mg	1.6 mg
14–18 years	2.2 mg	1.6 mg	2.0 mg	2.6 mg
19–50 years	2.3 mg	1.8 mg	2.0 mg	2.6 mg
51+ years	2.3 mg	1.8 mg

Footnote: *For infants from birth to age 6 months, the Adequate Intake (AI) is based on mean manganese intakes of infants fed primarily human milk.

[Source ⁸⁶ ]

Manganese food sources

Many foods contain manganese. You can get recommended amounts of manganese by eating a variety of foods, including the following ⁹⁰:

Whole grains, such as brown rice, oatmeal, and whole-wheat bread
Clams, oysters, and mussels
Nuts, such as hazelnuts and pecans
Legumes, such as soybeans and lentils
Leafy vegetables, such as spinach and kale
Some fruits, such as pineapple and blueberries
Tea
Many spices, such as black pepper

In the US, estimated average dietary manganese intakes range from 2.1 to 2.3 mg/day for men and 1.6 to 1.8 mg/day for women. People eating vegetarian diets and Western-type diets may have manganese intakes as high as 10.9 mg/day ⁹⁹. Rich sources of manganese include whole grains, nuts, leafy vegetables, and teas. Foods high in phytic acid, such as beans, seeds, nuts, whole grains, and soy products, or foods high in oxalic acid, such as cabbage, spinach, and sweet potatoes, may slightly inhibit manganese absorption. Although teas are rich sources of manganese, the tannins present in tea may moderately reduce the absorption of manganese ¹⁰⁰. Intake of other minerals, including iron, calcium, and phosphorus, have been found to limit retention of manganese ⁹⁹. The manganese content of some manganese-rich foods is listed in milligrams (mg) in Tables 3 and 4. For more information on the nutrient content of foods, search the USDA food composition database ¹⁰¹.

Humans absorb only about 1% to 5% of dietary manganese ⁹⁴, ⁹⁶, ⁶⁹. Infants and children tend to absorb greater amounts of manganese than adults ⁶⁹. In addition, manganese absorption efficiency increases with low manganese intakes and decreases with higher intakes, but little is known about the mechanisms that control absorption ⁹³, ⁹⁴. Systemic manganese regulation is achieved through intestinal control of manganese absorption and hepatic excretion of manganese into bile ⁹⁶.

Dietary iron intakes and iron status (measured by serum ferritin concentration) appear to be inversely associated with manganese absorption ¹⁰², ¹⁰³. The mechanism for this effect is unknown, but the shared transporter of iron and manganese in the intestine might play a role ⁹⁴. In addition, men appear to absorb dietary manganese less efficiently than women, possibly because men usually have higher iron status ⁶⁹, ¹⁰⁴. Infants absorb higher proportions of manganese than adults; limited research shows that formula-fed infants retain about 20% of the manganese they consume ⁹⁶.

Table 3. Manganese content of selected foods

Food	Milligrams (mg) per serving	Percent Daily Value (DV)*
Mussels, blue, cooked, 3 ounces	5.8	252
Hazelnuts, dry roasted, 1 ounce	1.6	70
Pecans, dry roasted, 1 ounce	1.1	48
Brown rice, medium grain, cooked, ½ cup	1.1	48
Oysters, Pacific, cooked, 3 ounces	1	43
Clams, cooked, 3 ounces 0.9	0.9	39
Chickpeas, cooked, ½ cup	0.9	39
Spinach, boiled, ½ cup	0.8	35
Pineapple, raw, chunks, ½ cup	0.8	35
Soybeans, boiled, ½ cup	0.7	30
Bread, whole wheat, 1 slice	0.7	30
Oatmeal, cooked, ½ cup	0.7	30
Peanuts, oil-roasted, 1 ounce	0.5	22
Tea, black, brewed, 1 cup	0.5	22
Lentils, cooked, ½ cup	0.5	22
Potato, flesh and skin, baked, 1 medium	0.3	13
White rice, long grain, cooked, ½ cup	0.3	13
Kidney beans, canned, drained, rinsed, ½ cup	0.3	13
Squash, acorn, cooked, cubed, ½ cup	0.3	13
Blueberries, raw, ½ cup	0.3	13
Sesame seeds, dried, 1 tablespoon	0.2	9
Kale, raw, 1 cup	0.2	9
Black pepper, 1 gram (about ½ tsp)	0.2	9
Asparagus, boiled, ½ cup	0.1	4
Apple, raw, with skin, 1 medium	0.1	4
Lettuce, romaine, raw, shredded, 1 cup	0.1	4
Coffee, brewed, 1 cup	0.1	4
Shrimp, cooked, 3 ounces	0	0
Tuna, white, canned in water, drained, 3 ounces	0	0
Chicken, breast, roasted, 3 ounces	0	0
Ground beef, cooked, 3 ounces	0	0
Egg, whole, hard-boiled, 1 large	0	0
Milk, 1%, 1 cup	0	0
Yogurt, low-fat, plain, 1 cup	0	0

Footnotes: *DV = Daily Value. The U.S. Food and Drug Administration (FDA) developed Daily Values (DVs) to help consumers compare the nutrient contents of foods and dietary supplements within the context of a total diet. The Daily Value (DV) for manganese is 2.3 mg for adults and children age 4 years and older. FDA does not require food labels to list manganese content unless manganese has been added to the food. Foods providing 20% or more of the DV are considered to be high sources of a nutrient, but foods providing lower percentages of the DV also contribute to a healthful diet.

[Sources ¹⁰⁵, ⁸⁶, ⁸³ ]

Table 4. Food sources of Manganese

Food	Serving	Manganese (mg)
Pineapple, raw	½ cup, chunks	0.77
Pineapple juice	½ cup (4 fl. oz.)	0.63
Pecans	1 ounce (19 halves)	1.28
Almonds	1 ounce (23 whole kernels)	0.65
Peanuts	1 ounce	0.55
Instant oatmeal (prepared with water)	1 packet	0.99
Raisin bran cereal	1 cup	0.78-3.02
Brown rice, cooked	½ cup	1.07
Whole wheat bread	1 slice	0.6
Pinto beans, cooked	½ cup	0.39
Lima beans, cooked	½ cup	0.49
Navy beans, cooked	½ cup	0.48
Spinach, cooked	½ cup	0.84
Sweet potato, cooked	½ cup, mashed	0.44
Tea (green)	1 cup (8 ounces)	0.41-1.58
Tea (black)	1 cup (8 ounces)	0.18-0.77

Breast milk and infant formulas

Infants are exposed to varying amounts of manganese depending on their source of nutrition. Manganese concentrations in breast milk, cow’s milk–based infant formulas, and soy-based formula range from 3 to 10 mcg/L, 30 to 50 mcg/L, and 200 to 300 mcg/L, respectively ⁹⁶, ¹⁰⁶. Limited research suggests that the absorption rate of manganese from human milk (8.2%) is much higher than that from soy formula (0.7%) and cow’s milk formula (3.1%) ¹⁰⁷. However, manganese deficiencies in breast-fed infants or toxicities in formula-fed infants have not been reported ¹⁰⁸.

Water

Manganese concentrations in drinking water range from 1 to 100 micrograms/liter (μg/L), but most sources contain less than 10 μg/L ¹⁰⁹. The US Environmental Protection Agency (EPA) recommends 0.05 mg (50 mcg)/L as the maximum allowable manganese concentration in drinking water ¹¹⁰.

Manganese Deficiency

Manganese deficiency is very rare in humans and there is more concern for toxicity related to manganese overexposure. Manganese deficiency has been observed in a number of animal species. Signs of manganese deficiency include impaired growth, impaired reproductive function, skeletal abnormalities, impaired glucose tolerance, and altered carbohydrate and lipid metabolism. In humans, demonstration of a manganese deficiency syndrome has been less clear ¹¹¹, ¹¹². The very limited evidence in humans suggests that manganese deficiency might cause bone demineralization and poor growth in children; skin rashes, hair depigmentation, decreased serum cholesterol, and increased alkaline phosphatase activity in men; and altered mood and increased premenstrual pain in women ⁹⁴, ⁸³. Manganese deficiency might also alter lipid and carbohydrate metabolism and cause abnormal glucose tolerance ⁹⁵.

A child on long-term total parenteral nutrition (TPN) lacking manganese developed bone demineralization and impaired growth that were corrected by manganese supplementation ¹¹³, ¹¹⁴, ¹¹⁵. Young men who were fed a low-manganese diet developed decreased serum cholesterol levels and a transient skin rash ¹¹⁶. Blood calcium, phosphorus, and alkaline phosphatase levels were also elevated, which may indicate increased bone remodeling as a consequence of insufficient dietary manganese ¹¹⁶. Young women fed a manganese-poor diet developed mildly abnormal glucose tolerance in response to an intravenous (IV) infusion of glucose ¹¹⁷. Overall, manganese deficiency is quite rare, and there is more concern for toxicity related to manganese overexposure.

Causes of manganese toxicity

Manganese (Mn) is an essential mineral in human nutrition, playing a crucial role in several physiological processes. Manganese is necessary for the functioning of enzymes involved in metabolism, bone formation, and regulation of blood sugar levels. Manganese also supports the antioxidant defense system by contributing to the activity of superoxide dismutase. While manganese is important for overall health, your body requires only small amounts of manganese, with the recommended intake for adults being around 1.8 to 2.3 mg per day (1.8 mg per day for women, and 2.3 mg for men) ¹¹⁸, ¹¹⁹, ⁸⁶. Manganese neurotoxicity can occur following high-dose oral, inhalation, or parenteral exposure to manganese ⁵. However, the mechanism of action of manganese neurotoxicity remains the subject of ongoing research ¹²⁰. Most clinically recorded instances of manganese poisoning are the result of occupational exposure. The main route of exposure in occupational manganese poisoning is inhalation of airborne manganese. Manganese toxicity causes include occupational manganese exposure from welding or working in a factory where steel is made, battery manufacturing, mining, consumption of contaminated well water, tap water, infant formula, or total parenteral nutrition (TPN) leads to excessive absorption and cellular uptake of manganese ¹²¹, ¹²², ¹²³, ¹¹⁹. Because manganese is a natural component of the environment, you are always exposed to low levels of it in water, air, soil, and food. Manganese is routinely contained in groundwater, drinking water and soil at low levels. Drinking water containing manganese or swimming or bathing in water containing manganese may expose you to low levels of this metal ¹¹⁹.

Air also contains low levels of manganese, and breathing air may expose you to manganese. Releases of manganese into the air occur from:

Industries using or manufacturing products containing manganese.
Mining activities.
Automobile exhaust. Methylcyclopentadienyl manganese tricarbonyl (MMT) is a manganese-containing compound used in gasoline as an anti-knock additive. Although it has been used for this purpose in Canada for more than 20 years, uncertainty about adverse health effects from inhaled exhaust emissions kept the US EPA from approving its use in unleaded gasoline. In 1995, a US court decision made MMT available for widespread use in unleaded gasoline ¹²⁴. A study in Montreal, where MMT had been used for more than 10 years, found airborne manganese levels to be similar to those in areas where MMT was not used ¹²⁵. A more recent Canadian study found higher concentrations of respirable manganese in an urban versus a rural area, but average concentrations in both areas were below the safe level set by the US EPA ¹²⁶. Manganese exposure via the skin is also a concern for those who come into contact with organic forms of manganese, such as the gasoline additive methylcyclopentadienyl manganese tricarbonyl (MMT) ¹¹⁹. The impact of long-term exposure to low levels of MMT combustion products, however, has not been thoroughly evaluated and will require additional study ¹²⁷. A single case of reversible neurotoxicity and seizures following unintentional MMT ingestion has been documented: a 54-year old man accidentally drank an MMT-containing anti-knock agent that he assumed was an energy drink due so similar product labeling ¹²⁸.

Lifestyle traits may also lead to exposure to manganese. People who smoke tobacco or inhale second-hand smoke are typically exposed to manganese at levels higher than those not exposed to tobacco smoke.

Several studies have examined neurochemical changes following high-dose-manganese exposure. Because manganese neurotoxicity results in dysregulation of motor control, many studies have focused on the striatal and pallidal dopaminergic system. Manganese reacts with dopamine (DA) and other biogenic amines resulting in oxidative damage to the neurotransmitters ⁴⁹, ¹²⁹. The primary neuropathologic target of manganese neurotoxicity is the globus pallidus (particularly the internal segment) with sparing of the substantia nigra pars compacta and an absence of Lewy bodies ⁴⁶. Studies of a manganese-exposed South African mine worker have revealed reduced astrocyte and neuron density in both the caudate and putamen ⁴⁷. Chronic manganese neurotoxicity in people is also associated with decreased gamma-aminobutyric acid (GABA) neurons, reduced myelinated fibers, and moderate astrocytic proliferation in the medial segment of the globus pallidus ⁴⁶.

One pathway involves manganese catalyzed oxidation of the alpha hydroxyl group of dopamine forming a semi-quinone radical. The semi-quinone radical then reacts with oxygen to generate superoxide anion radical [O2•−] and a quinone. Oxygen can reoxidize the quinone to quinol to generate hydrogen peroxide ⁴⁹. Manganese-catalyzed dopamine auto-oxidation may also involve semiquinone and aminochrome intermediates, l-cysteine or copper, and NADH facilitation ⁵⁰, ⁵¹. Excess manganese may also alter glutamate homeostasis in the basal ganglia ⁵². Changes in glutamate homeostasis have been associated with excitotoxicity in the brain ⁵².

The biphasic condition seen in patients with manganese toxicity is most likely explained by changes in striatal dopamine (DA) levels. An early phase of elevated dopamine (DA) production has been linked to psychotic episodes in psychiatric patients ¹³⁰. Catecholamine levels fall as manganese poisoning progresses, most likely owing to the death of nigrostriatal dopaminergic neurons, and Parkinson-like symptoms follow ¹²⁹, ¹³¹, ¹³². As a result, in the early phases of manganese toxicity, symptoms may be reversed by discontinuing manganese exposure, but manganese toxicity is permanent in individuals with motor abnormalities ¹³³.

Inhaled manganese

Manganese toxicity may result in multiple neurological problems and is a well-recognized health hazard for people who inhale manganese dust, such as welders and smelters ¹³⁴,⁹⁹. Unlike ingested manganese, inhaled manganese is transported directly to the brain before it can be metabolized in the liver ¹²⁴. The symptoms of manganese toxicity generally appear slowly over a period of months to years. In its worst form, manganese toxicity can result in a permanent neurological disorder with symptoms similar to those of Parkinson’s disease, including tremors, difficulty walking, and facial muscle spasms. This syndrome, often called manganism, is sometimes preceded by psychiatric symptoms, such as irritability, aggressiveness, and even hallucinations ¹³⁵, ¹³⁶. Additionally, environmental or occupational inhalation of manganese can cause an inflammatory response in the lungs ¹³⁷. Clinical symptoms of effects to the lung include cough, acute bronchitis, and decreased lung function ¹³⁸.

Ingested manganese

Diet is the primary source of manganese in the general population ¹³⁹. Manganese is abundant in plant-based foods, including whole grains, rice, nuts, and leafy vegetables. Animal foods, including meat, fish, poultry, eggs, and dairy, lack manganese ¹⁴⁰. Daily intakes of manganese typically range from 2 to 6 mg, of which about 1 to 5% is normally absorbed ¹⁴¹. Due to the dual role of manganese as an essential nutrient and a potent toxin, whole-body manganese levels are tightly controlled by regulating intestinal absorption and excretion of the metal through homeostatic mechanisms ⁹⁶. Thus far, manganese toxicity from high dietary manganese intakes in humans has not been reported ¹⁴².

Limited evidence suggests that high manganese intakes from drinking water may be associated with neurological symptoms similar to those of Parkinson’s disease. Severe neurological symptoms were reported in 25 people who drank water contaminated with manganese, and probably other contaminants, from dry cell batteries for two to three months ¹⁴³. Water manganese levels were found to be 14 mg/liter (mg/L) almost two months after symptoms began and may have already been declining. A study of older adults in Greece found a high prevalence of neurological symptoms in those exposed to water manganese levels of 1.8 to 2.3 mg/L ¹⁴⁴, while a study in Germany found no evidence of increased neurological symptoms in people drinking water with manganese levels ranging from 0.3 to 2.2 mg/L compared to those drinking water containing less than 0.05 mg/L ¹⁴⁵. Manganese in drinking water may be more bioavailable than manganese in food. However, none of the studies measured dietary manganese, so total manganese intake in these cases is unknown. In the US, the EPA recommends 0.05 mg/L as the maximum allowable manganese concentration in drinking water ¹⁴⁶.

Additionally, more recent studies have shown that children exposed to high levels of manganese through drinking water experience cognitive and behavioral deficits ¹⁴⁷. For instance, a cross-sectional study in 142, 10-year old children, who were exposed to a mean manganese water concentration of 0.8 mg/L, found that children exposed to higher manganese levels had significantly lower scores on three tests of intellectual function ¹⁴⁸. Another study associated high levels of manganese in tap water with hyperactive behavioral disorders in children ¹⁴⁹. These and other recent reports have raised concern over the neurobehavioral effects of manganese exposure in children ¹⁴⁷.

A single case of manganese toxicity was reported in a person who took large amounts of mineral supplements for years ¹⁵⁰, while another case was reported as a result of a person taking a Chinese herbal supplement ¹³⁵. Manganese toxicity resulting from foods alone has not been reported in humans, even though certain vegetarian diets could provide up to 20 mg/day of manganese ⁹⁹, ¹⁰⁹.

Intravenous manganese

Intravenous delivery of drugs containing high quantities of manganese is another manganese exposure route that bypasses gastrointestinal tract control, resulting in 100% manganese metal absorption ¹⁵¹, ¹⁵². Manganese neurotoxicity has been observed in individuals receiving total parenteral nutrition (TPN), both as a result of excessive manganese in the solution and as an incidental contaminant ¹⁵³. Neonates are especially vulnerable to manganese-related neurotoxicity ¹⁵⁴. Premature newborns, for example, do not absorb adequate nutrition owing to an underdeveloped gastrointestinal tract or certain disorders. As a result, newborns are often supplemented with total parenteral nutrition (TPN) by intravenous injection, which includes several trace elements necessary for life support. Infants on total parenteral nutrition (TPN) are more vulnerable to manganese toxicity. Infants receiving manganese-containing total parenteral nutrition (TPN) can be exposed to manganese concentrations about 100-fold higher than breast-fed infants ¹⁰⁸. Furthermore, manganism has been described because of intravenous consumption of methcathinone, which contains manganese dioxide as a by-product from production ¹⁵⁵, ¹⁵⁶. The absorbed quantity of manganese may range between 60 and 180 mg per day, greatly above the typical dietary intake ¹⁵⁶, ¹⁵⁷. Because of potential manganese toxicities, some argue against including manganese in parenteral nutrition ¹⁵⁸.

Manganese prenatal exposure

In utero, manganese exposure is often overlooked since the actual relationship between manganese exposure and health consequences is unclear ⁸⁸. However, there has been an increase in the number of studies examining the relationship between in utero manganese exposure and newborn health. The average manganese concentration (78.8 mg/L) in umbilical cord blood is higher than in the mother’s whole blood (55.0 mcg/L), and an inverted U-shaped curve has been observed between manganese levels in mother’s whole blood and birth weights, as well as between manganese levels in umbilical cord blood and birth weights ¹⁵⁹. Other research has shown that both low and high maternal blood manganese levels are related to poor newborn health ¹⁶⁰, ¹⁶¹.

Manganese toxicity symptoms

Early symptoms of manganese toxicity involves changes in the person’s psychiatric and emotional state ⁷¹. A person with manganese toxicity may experience personality changes with periods of rapid emotional fluctuations, which need to be qualitatively differentiated from that person’s baseline personality ¹⁶². Psychiatric symptoms include hallucinations and psychosis ¹⁶³. Other symptoms reported in a case study from China included memory impairment and insomnia ¹⁶⁴. In a group of California welders, manganese exposure during their everyday duties was analyzed over their work period from 2003 to 2004; neuropsychiatric symptoms developed in these welders included a measured decrease in IQ score, decreased sex drive, depression, and anxiety ¹⁶⁵.

Early neurological dysfunction was also a hallmark in manganese toxicity patients, characteristic of the basal ganglia/nigrostriatal system involvement ⁷¹. Symptoms discovered included tremor, gait abnormalities, headaches, dysfunctional speech, hyperreflexia, hypertonicity, and tremors ¹⁶⁴. Other acute neurological signs and symptoms in the study introduced above from California included bradykinesia, postural instability, decreased motor dexterity and speed, and olfactory dysfunction ¹⁶⁵. Severe symptoms include the “cock-walk” described in the earliest manganese studies, which is characterized by patients walking on their toes with a forward tilt as they move ¹⁶⁶. Other severe symptoms are worsening tremor and dystonic movements of arms and legs ⁷¹.

Other systems affected by manganese exposure include the heart, blood vessels and pulmonary systems. A form of obstructive lung disease formed in approximately one-third of the welders involved in the California study by Bower et. al ¹⁶⁵. Animal studies have shown that overexposure to manganese causes hemodynamic changes, including hypotension and bradycardia, concomitant with a prolonged PR and QRS interval. These studies, however, have not been validated in humans, and often the reverse findings are present (tachycardia, hypertension, shortened PR interval) ¹⁶⁷, ¹⁶⁸.

Manganese toxicity diagnosis

Manganese (Mn) is the fifth most abundant metal in the environment and twelfth most abundant element as a whole in the environment where it can be found in rocks and soil and your body needs trace amounts of manganese to stay healthy. Every year, natural earth erosion releases tonnes of manganese into the air, soil, and rivers for microbes, plants, and animals to absorb ¹⁶⁹. Manganese (Mn) can exist in 11 oxidation states, often as chloride, oxides and sulfates ⁵⁸. The most common oxidation states for manganese in natural water are manganese²⁺(Mn²⁺) and manganese⁴⁺ (Mn⁴⁺) ⁸⁸, ⁵⁸. Manganese is used principally in the manufacture of iron and steel alloys, and manganese compounds such as potassium and sodium permanganate are ingredients in various products used for cleaning, bleaching and disinfection ⁵⁸. Manganese compounds are additionally used in some locations for potable water treatment and can also be an impurity in coagulants used during water treatment ⁵⁸. Manganese occurs naturally in many surface water and groundwater sources; although naturally occurring manganese is usually the most important source for drinking-water, human activities can also contribute to high levels of manganese in water ⁵⁸. Manganese also occurs naturally in many food sources, and the greatest exposure to manganese is usually from food. Manganese is also available as a dietary supplement.

When suspecting a person of manganese toxicity, patient’s occupational history can confirm the diagnosis in patients suspected of having manganese toxicity. Patients will have an occupational history consistent with exposure, including welding, metal manufacturing, mining, battery manufacturing, smelting, those intimately exposed to gasoline combustion, and steelworkers ²⁷, ¹⁷⁰. Inquire about personal protective equipment the patients utilize daily, as those without appropriate respiratory protection are more at risk for the development of symptoms ¹⁶⁵. If the patient recently immigrated or is traveling from a country with sub-standard public drinking water conditions, they may have been chronically ingesting high amounts of manganese-toxic water ⁵⁹, ⁷³. Identify patients whose water source is well-water, as their well may be spoiled by leaching from mineral-laden soil ⁷⁸, ¹⁷¹

Query the patient about drug use, as recent studies have shown, bath salts use intravenously puts patients at risk for manganese overload due to poor purification processes ¹⁷². Chronic intravenous TPN also puts patients at risk of manganese toxicity, therefore inquiring about recent hospitalizations may be helpful.

Further discussion of patients’ past medical histories should include known or presumed liver insufficiency, as patients with decreased liver function are at increased risk for developing manganese toxicity ¹⁷³. Male patients who note difficulty conceiving (male infertility) with an unremarkable maternal work-up coincident with a known occupational history may also be a clue, as manganese toxicity results in decreased fertility ¹⁷⁴.

Manganese toxicity tests

Several tests are available to measure manganese in blood, urine, hair, or feces. Because manganese is normally present in your body, some is always found in tissues or fluids.

Normal ranges of manganese levels in the general population is 4–15 mcg/L in blood, 1–8 mcg/L in urine, and 0.4–0.85 mcg/L in serum (the fluid portion of the blood), though the usefulness of urine and serum manganese as biomarkers for exposure is limited ¹⁷⁵, ¹⁷⁶. Blood manganese levels have a half-life of approximately 40 days ¹⁷⁷ and are higher with female sex, younger ages, and Asian origins ¹⁷⁸, ¹⁷⁹.

Because excess manganese is usually removed from the body within a few days, past exposures are difficult to measure with common laboratory tests.

A medical test known as magnetic resonance imaging (MRI), can detect the presence of increased amounts of manganese in the brain. Brain imaging studies that rely on the paramagnetic properties of manganese that result in increased signal intensity seen with T1-weighted magnetic resonance imaging (MRI), allow for visual inspection of the brain for evidence of manganese accumulation at this site. Brain MRI studies of highly exposed people reveal signal intensity changes in the globus pallidus, striatum, and midbrain consistent with manganese accumulation at these sites ⁴³, ⁴⁴. Studies performed in nonhuman primates have shown that changes in the T1-weighted image correlate with manganese tissue concentration ⁴⁵. However, magnetic resonance imaging (MRI) test is qualitative, and has not been shown to reliably reflect or predict toxicologically meaningful exposures.

The latest research presented at the 2016 conference on manganese neurotoxicity described new methodologies of identification of manganism, including the use of fMRI, PET scans, and new methods of using blood manganese and ferritin levels to detect globus pallidus accumulation of toxic metal concentrations ¹⁸⁰, ¹⁸¹, ¹⁸².

In summary, manganese neurotoxicity diagnosis requires a high clinical suspicion alongside recognition of the risk factors placing patients at risk for manganese toxicity ⁷¹. Ideal evaluation for the determination of manganese toxicity includes a team-based approach, based on early recognition and outpatient referral to neurology for definitive care ⁷¹. Early consultation with a clinical toxicologist may aid in the identification of the cause of the patient’s symptoms. Usage of MRI or serum-based studies should be done at the request of specialists familiar with heavy metals toxicity and the latest research.

Manganese toxicity differential diagnosis

The following conditions can be considered in the differential diagnosis of manganese toxicity ⁷¹:

Idiopathic Parkinson disease: Idiopathic Parkinson disease is characterized by bradykinesia, shuffling gait, postural instability, and resting pill-rolling tremor. Parkinson disease is most clinically similar to manganese toxicity. Distinguishing differences between Parkinson disease and manganese neurotoxicity include less prominent tremors in manganese neurotoxicity, the reversal of psychiatric symptom onset (later in Parkinson disease, earlier in manganese neurotoxicity), the age of onset is typically younger in manganese neurotoxicity as compared to Parkinson disease and clear occupational correlation with manganese neurotoxicity ¹⁸³.
Dementia with Lewy bodies: Patients with dementia with Lewy bodies develop a parkinsonian syndrome in combination with many cognitive dysfunctions in the 5th to 6th decade of life. Early cognitive deficits include short term memory difficulties, multi-tasking deficits, and visuospatial deficiencies. These symptoms will develop alongside visual hallucinations and motor difficulties consistent with Parkinson disease. Lewy Body dementias process can be differentiated from both Parkinson’s disease and manganese neurotoxicity by the presence of characteristic hallucinations and concurrent development of neuropsychiatric and motor dysfunction ¹⁸⁴.
Frontotemporal dementia: Frontotemporal dementia is characterized by several different phenotypes, which include a behavioral/executive dysfunction type and two primary language deficiency types. Clinical features of the behavioral frontotemporal dementia subtype include disinhibition, apathy, compulsive behaviors, hyper-orality, and overall diminished executive function skills. Features of the language dysfunction variants include difficulties with daily life due to speech deficits, aphasia, speech apraxia, and other speech and comprehension impairments. Frontotemporal dementia can easily be mistaken for manganese neurotoxicity in its early stages if behavioral symptoms predominate, given manganese neurotoxicity’s early neuropsychiatric manifestations. An adequate history-taking can differentiate these two distinct conditions ¹⁸⁵.
Essential tremor: Essential tremor is a chronic, progressive neurologic disorder characterized by a high-frequency action tremor. Essential tremor can affect the neck, jaw, and other body regions alongside that of the arms and hands. Manganese neurotoxicity will produce tremors early on in the disease process, typically after the development of psychiatric dysfunction. Differentiation of essential tremor from manganese neurotoxicity involves elucidating occupational history, lack of family history, and identification of concomitant neuropsychiatric features in manganese toxicity ¹⁸⁶.
Multiple system atrophy: As its name denotes, multiple system atrophy (MSA) is a complex disorder characterized by autonomic dysfunction, orthostatic hypotension, cerebellar dysfunction, parkinsonian symptoms unresponsive to L-dopa, and earlier age in onset (greater than 30 years old). Multiple system atrophy (MSA) can be distinguished from manganese neurotoxicity due to its multiple accompanying system dysfunction, autonomic dysfunction, and cerebellar findings ¹⁸⁷.
Corticobasal degeneration: As the name denotes, corticobasal degeneration affects predominantly the brain cortices and basal ganglia, resulting in apraxia (a neurological disorder that makes it difficult to perform tasks or movements, even though the person understands the request and is willing to do it), hemineglect symptoms, alterations in behavior and emotion, rigidity, bradykinesia, and myoclonus. Corticobasal degeneration signs and symptoms are very similar to manganese neurotoxicity; however, it can be differentiated based on history and chronicity in relation to exposure risk for manganese ¹⁸⁸.
Progressive supranuclear palsy: Progressive supranuclear palsy (PSP) is an levodopa (L-dopa) responsive parkinsonian syndrome similar to corticobasilar degeneration. Features of progressive supranuclear palsy include vertical supranuclear palsy and parkinsonian symptoms. Progressive supranuclear palsy can be differentiated from manganese neurotoxicity by their responsiveness to L-dopa therapy ¹⁸⁸.
Drug-induced Parkinsonism: Drug-induced Parkinsonism is most common cause of parkinsonian symptoms and is an often under-appreciated disease process. Common precipitants include antipsychotic medications, anti-emetics, anti-motility agents, some rarely prescribed calcium channel blockers, and dopamine depleting medications. A clear and concise medication history can lead to the diagnosis in drug-induced Parkinsonism cases ¹⁸⁹.
Methcathinone (ephedrone). Methcathinone (also called Bathtub speed, Cadillac express, cat, crank, ephedrone, gag- ers, go-fast, goob, qat, slick superspeed, star, the C, tweeker, wild cat and wonder star) is a monoamine alkaloid and psychoactive stimulant, a substituted cathinone ¹⁹⁰. Methcathinone is used as a recreational drug due to its potent stimulant and euphoric effects and is considered to be addictive, with both physical and psychological withdrawal occurring if its use is discontinued after prolonged or high-dosage administration ¹⁹⁰. It is usually snorted, but can be smoked, injected, or taken orally. Case reports have suggested chronic use of methcathinone is linked to the development of manganese toxicity, substantiated by the evidence of parkinsonian features and MRI correlate abnormalities in the basal ganglia. Drug use and medication history may lead to the discovery of this diagnosis ¹⁹¹.
Other neurodegenerative disorders, including Huntington’s disease, repeated and chronic head trauma, several infections such as syphilis, HIV, progressive multifocal leukoencephalopathy, structural brain disorders such as intraparenchymal masses or hydrocephalus, and metabolic disorders such as Wilson disease, hypoparathyroidism, chronic liver failure, and hemochromatosis ¹⁹².

Manganese toxicity treatment

Manganese toxicity treatment involves the treatment of the acute threats from the manganese toxicity and the management of chronic manganese exposure. The most accessible form of treatment for manganese toxicity is the removal of the individual from the source exposure, whether the source is occupational, environmental, or iatrogenic ⁷¹.

Chelation therapy for manganism involves the use of calcium sodium ethylenediaminetetraacetate (CaNa₂EDTA) and para-aminosalicylic acid (PAS) ¹⁹³, ⁷¹. The use of calcium sodium ethylenediaminetetraacetate (CaNa₂EDTA) has been shown to effectively increase urine concentration of manganese and decrease blood levels of manganese ⁷¹. However, these findings did not coincide with the finding of decreased observed clinical neurotoxicity, owing to the chronic nature of manganese toxicity and incomplete reversibility ¹⁶⁴. Furthermore, calcium sodium ethylenediaminetetraacetate (CaNa₂EDTA) prevents further manganese from crossing the blood-brain barrier, deactivating manganese ability to enter into the brain and spinal cord to exert its toxic effects ¹⁹⁴, ¹⁹⁵, ¹⁹⁶. Unfortunately, calcium sodium ethylenediaminetetraacetate (CaNa₂EDTA) has a poor bioavailability for brain tissue and does not appear to be able to completely reverse the neurotoxic effects of manganese ⁷¹. Therefore, in patients with chronic manganese toxicity or advanced manganism, chelation therapy is likely to not reverse the significant clinical deterioration ¹⁹⁷.

Another chelation molecule called para-aminosalicylic acid (PAS) – typically used as an anti-tuberculosis medication – has shown clinical benefit for use in patients with manganese toxicity ⁷¹. Para-aminosalicylic acid (PAS) and its metabolites concentrate within the choroid plexus, brain tissue and cerebrospinal fluid (CSF), making para-aminosalicylic acid (PAS) an ideal chelator for manganese toxicity ¹⁹⁸. Para-aminosalicylic acid (PAS) has the additional benefit of chelating both the manganese²⁺ (Mn²⁺) and manganese³⁺ (Mn³⁺) molecules ¹⁹⁹. The anti-inflammatory properties of the salicylic acid component may also produce a beneficial effect, as studies have illustrated neuroprotective benefits from the use of other nonsteroidal anti-inflammatory drugs (NSAIDs) in Alzheimer disease, Parkinson disease, and amyotrophic lateral sclerosis ²⁰⁰, ²⁰¹.

Previous attempted treatments included levodopa (L-dopa) supplementation ⁷¹. Initial studies supported a benefit with L-dopa administration, but more recent data suggests prolonged L-dopa treatment results in poor clinical response ²⁰². Also, after the cessation of L-dopa use, patients had a progression of manganese toxicity disease despite initial therapy ²⁰³

Several vitamins and supplements appear to improve clinical response and provide a means of prevention for patients. In addition to chelation therapy, iron supplementation was shown to improve neurological symptom improvement compared to a treatment group that received chelation alone ²⁰⁴. Vitamin E was shown to prevent the supposed oxidative stress brought on by manganese-induced toxicity ²⁰⁵. Glutathione and N-acetylcysteine have also shown to be beneficial in test tube study for decreasing the downstream effects of manganese-induced cell toxicity ²⁰⁶. Several plants and plant extracts have also been shown to be beneficial, including Silymarin, Acai, Lycopene, Nicotine, and Lemon balm (Melissa officinalis) ²⁰⁷, ²⁰⁸, ²⁰⁹, ²¹⁰.

Newer therapies are currently being investigated include the use of taurine and Rasagiline (a medication which is used in the treatment of Parkinson’s disease) ⁷¹. Taurine use decreases the toxic effects of manganese in test tube study, mostly through the preservation of mitochondrial functionality in brain tissues ²¹¹, ²¹². Taurine also appears to improve the learning and memory impairments associated with chronic manganese toxicity ²¹³. Rasagiline (a medication which is used in the treatment of Parkinson’s disease) is a monoamine oxidase inhibitor (MAOI) used to block the breakdown of dopamine in patients with Parkinson disease. Rasagiline appeared to offer a benefit through protection from reactive oxygen species (ROS) created by manganese toxicity ²¹⁴.

Manganese toxicity prognosis

There are very small number of studies on the prognosis of patients suffering ongoing manganese exposure and of patients who have successfully removed themselves from manganese exposure after the development of manganese toxicity. What little literature exists suggests that, with removal from manganese source exposure, recovery in some neuropsychiatric symptoms is possible while improbable in others ⁷¹. Bouchard et al. ²¹⁵ followed a group of workers exposed to manganese (Mn) over the course of 15 years and observed signs of recovery approximately 14 years after their documented exposure. Specific neurological deficits that remained included poor performance on simple and alternating movements, drawing ability, and diminished hand stability ²¹⁵. These findings are validated by prior studies by Hochberg et al and Pal et al ²¹⁶, ³⁶. Bouchard et al. ²¹⁵ also found a trend towards more feelings of anger, hostility, confusion, and a sensation of fatigue. This finding was correlated with greater cumulative doses of manganese. Finally, their group identified a relationship between manganese exposure and respiratory tract pathology, possibly secondary to the induced inflammatory state ²¹⁵.

In addition, older patients who are exposed to manganese often develop more significant neurotoxicity than younger patients, owing to possible pre-exposure neurological degenerative changes. This is theorized to lead to the observed age-related cognitive deficits that persist after manganese exposures cease. Research by Bouchard et al in 2005 and 2007 ²¹⁷, ²¹⁸ showed that individuals who were exposed that were at least greater than or equal to 45 years old had persistent cognitive deficits after cessation of toxic exposure to manganese.

In another follow-up study by Roels et al. ²¹⁹, workers from a battery manufacturing plant were followed for 8 years after cessation of manganese exposure. Variables measured included hand steadiness and reaction time. Analysis of their study group (workers from a battery manufacturing plant) yielded no improved steadiness of the hands and no improvement in reaction time ²¹⁹. The study group (workers from a battery manufacturing plant) did, however, observe an improvement in hand-forearm movements beyond that of their baseline, which suggested some partial recovery from their toxicity ²¹⁹. Lucchini et al. ²²⁰ measured improvement in manganse toxic patients 5 years after exposure was decreased and found similar results during and after their exposures. This lack of improvement may be due to the fact that manganese exposure was reduced but not definitively eliminated.

The trend following cessation of manganese exposure appears to be that of mostly recovery, with residual deficits remaining in the behavioral and neurologic symptoms ⁷¹. This lends credence to the mainstay of therapy, which is to abstain from any further activity, which puts individuals at risk for further mangnese toxicity. Overall, the prognosis is more related to the illness than death and is overall favorable once the individual is removed from manganese exposure setting. More research will be needed to further outline the expected clinical course following manganese toxicity, especially with the addition of new treatment modalities such as supplementation and chelators ⁷¹.

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