Substances Included Synonyms

Therapeutic Toxic Class

A)

Specific Substances

A)

1) BRAUNITE
2) COLLOIDAL MAGANESE
3) COLLOIDAL MANGANESE
4) CUTAVAL
5) MAGNACAT
6) MANGACAT
7) MANGAN (Polish)
8) MANGANESE-55
9) MANGANESE, ELEMENTAL
10) MANGANESE METAL
11) MANGAN NITRIDOVANY (Czech)
12) MANGANOSITE
13) MANGANUM
14) TRONAMANG

1) Black Dioxide (MnO2)
2) Pyrolusite (MnO2)
3) Hausmannite (Mn3O4)
4) Manganite (Mn2O3.H2O)
5) Manganosite (MnO)
6) Braunite (3Mn2O3.MnSiO3)
7) Rhodochrosite (MnCO3)
8) Psilomelane

1.2.1) MOLECULAR FORMULA
1) Mn (metal)

Available Forms Sources

A)

1) Manganese is a gray-white, silvery, hard, brittle, lustrous transition metal. It exists in four allotropic forms (alpha, beta, gamma, and delta), of which alpha is most important. Its physical characteristics vary depending on the allotropic form (Ashford, 1994; Bingham et al, 2001; Budavari, 2001; Lewis, 1998; Lewis, 2001).
2) Manganese is a widely-distributed, abundant element, constituting 0.085% of the earth's crust. As the twelfth most abundant element and the fifth most abundant metal, it can be found in numerous mineral forms. Mineral forms of manganese that are most common are oxides (pyrolusite, manganite, psilomelane, and hausmannite), silicates (braunite and rhodonite), sulfides (manganese blend and hauserite), and carbonates (manganoan calcite and rhodocrosite) (Bingham et al, 2001; Budavari, 2001).
3) There is one stable isotope of manganese, the natural isotope (55) (Budavari, 2001).
4) Available grades of manganese include: technical, pure or electrolytic, and powdered (Lewis, 2001).
5) Manganese can exist in inorganic and organic forms; inorganic forms in the oxidation states Mn(II), Mn(III), or Mn (IV) are most often encountered in the environment and in the workplace. Oxidation states ranging from -3 to +7 result in compound formation, of which the most common are salts, oxides, and organomanganese (Bingham et al, 2001; ATSDR, 2000).
6) Manganese is a trace element, and is considered essential for animal and plant life. However, well-defined deficiencies have not been demonstrated in humans (ACGIH, 1996a; Lewis, 2001; Lewis, 1998).

B)

1) Manganese is found in minute quantities in water, plants and animals. It is normally ingested as a trace element in food (Budavari, 2001; Sittig, 1991).
2) The elemental form of manganese is normally not encountered in the workplace or in nature. It is found in nature in more than 100 various minerals. The most important ore of manganese is black dioxide (MnO2) or pyrolusite. Other important ores are manganite, psilomelane, and rhodochrosite. Open-hearth slags are an important source of manganese. Submarginal concentrations are also usually associated with iron ores (Lewis, 2001; ACGIH, 1996a; Bingham et al, 2001; Harbison, 1998).
3) The U.S. Bureau of Mines classifies manganese ores by their manganese content. Manganese ore contains 35% or more manganese; ferruginous manganese ore is 10% to 35% manganese; and manganiferous ore is 5% to 35% manganese. In 1986, the content of manganese in ore produced worldwide was estimated 8.8 million tons. This level did not change significantly until the 1995 to 1997 time frame, when there was a slight decline down to 7.7 million tons in 1997 (IPCS, 1999; Zenz, 1994).
4) Manganese can be derived from the reduction of the oxide with carbon or aluminum. Pure manganese is procured through the electrolytic processing of a sulfate or chloride solution (Lewis, 2001).
5) PATIENTS UNDERGOING HEMODIALYSIS - Elevated serum manganese, neurologic manifestations consistent with manganese toxicity, and MRI evidence of hyperintense changes in the basal ganglia have been reported in some patients on chronic hemodialysis (da Silva et al, 2007).
6) PATIENTS RECEIVING PARENTERAL NUTRITION - Hyperintense changes in the basal ganglia on MRI have been reported in patients receiving manganese-containing perioperative parenteral nutrition following gastrointestinal surgeries (Iwase et al, 2002).
7) METHCATHINONE (EPHEDRONE) ABUSE - Four cases of manganism, presented as impaired postural control, hypophonic dysarthria, hypokinesia and dystonia have been reported in persons using repeated intravenous injections of methcathinone solution, prepared by combining pseudoephedrine and potassium permanganate. Manganese content of the final mixture was 0.6 g/L with ephedrone yield of approximately 44% (Sikk et al, 2007). One man developed manganese-induced levodopa-resistant parkinsonism with profound hypophonia after intravenously injecting himself once or twice daily for several months with a methcathinone solution, prepared by combining 12 tablets containing 60 mg of pseudoephedrine hydrochloride with 0.3 g of potassium permanganate (deBie et al, 2007).

C)

1) Metallic manganese is primarily used in the manufacture of steel and as an ingredient in the production of ferrous and nonferrous alloys. More than 90% of the world's manganese consumption is associated with iron and steel production. Manganese reagent is used to reduce oxygen and sulfur and thus remove sulfides and oxides during steel, cast iron, and nonferrous metal production. As an alloying agent, it imparts increased strength, hardness and abrasion resistance in finished steel (Bingham et al, 2001; ITI, 1995; Zenz, 1994; Harbison, 1998).
2) Manganese is also combined with aluminum, copper, nickel, silver and titanium. These alloys are mainly used in chemical/electrical resistance applications (Ashford, 1994).
3) Aluminum-manganese alloys provide strength, hardness, and stiffness when used as an ingredient in aluminum beverage container manufacturing (Bingham et al, 2001).
4) This element is also used as a bronze ingredient, in high-purity salts for various chemical processes, and as a scavenging and purifying agent in metal production (Ashford, 1994; Lewis, 2001).
5) Its use in phosphating of mild and galvanized steel and aluminum adds to adhesion and corrosion resistance of paint, wax, and oil finishes (ILO, 1998).
6) Manganese is used for electrode coating in welding rods and fluxes, for rock crushers, and railway points and crossings. Manganese salts are utilized in fertilizers, as driers for linseed oil, for glass and textile bleaching, and for leather tanning. Manganese chloride is used as a catalyst, in dry-cell batteries, and as an animal feed supplement (ILO, 1998; Zenz, 1994; ACGIH, 1996a).
7) Manganese and its compounds are utilized in the manufacture of dry cell batteries, paints, varnishes, inks, dyes, matches, and fireworks, as decolorizers and coloring agents in the glass and ceramics industry, and as a fertilizer, disinfectant, bleaching agent, and laboratory reagent. Manganese is used in the chemical industry as an oxidizing agent and for the production of potassium permanganate and other manganese-related chemicals (ILO, 1998; Baselt, 2000; ACGIH, 1996a).
8) Manganese is also used in the manufacture of rubber and wood preservatives and fungicides (Hathaway et al, 1996).
9) An organic manganese compound (manganese ethylene bisdithiocarbamate) is contained in the fungicide Maneb (Zenz, 1994). Other pesticides are reported to contain manganese and may cause manganism in agricultural workers (Lee, 2000).
10) Cases of manganese poisoning have been reported in patients on chronic total parenteral nutrition, with manganese added as a trace element (Masumoto et al, 2001).

Overview

Life Support

A)

Clinical Effects

0.2.1)

A) USES: Manganese is found in rock, soil, water, and food. Metallic manganese is used to harden and prevent corrosion and rusting of steel. It is also used in black paints and to decolorize glass. Manganese dioxide is used in dry cell batteries as a depolarizer. Potassium permanganate is covered in a separate management.
B) PHARMACOLOGY: Manganese is an essential nutrient and is a cofactor for many biologic enzyme systems.
C) TOXICOLOGY: Manganese deposition throughout the brain may lead to neurotoxicity. Manganese primarily deposits in the basal ganglia. Severe toxicity is characterized by a Parkinson's-like syndrome.
D) EPIDEMIOLOGY: Toxicity from acute ingestion or acute inhalation of manganese is rare. Chronic inhalation over many years, usually from occupational exposure, may lead to manganese toxicity. Chronic manganese toxicity is exceedingly rare in the developed world due to workplace regulations. Manganese toxicity has been rarely reported in individuals injecting methcathinone that has been synthesized by combining pseudoephedrine and potassium permanganate.
E) WITH POISONING/EXPOSURE

1) OVERDOSE: Little data is available regarding clinical effects in overdose. Most toxicity is due to chronic workplace exposure.
2) MILD TO MODERATE TOXICITY: Neurotoxicity is the primary manifestation of manganese toxicity. Patients may develop headaches, dizziness, memory loss, emotional instability, hyperreflexia, and a mild tremor. Chronic excess inhalational exposures may lead to pulmonary inflammation and subsequent reactive airway disease. Metal fume fever has been reported with manganese inhalation. Manganese is poorly absorbed dermally and systemic toxicity from this route is not expected. Dermal exposures may lead to a dermal irritation and contact dermatitis.
3) SEVERE ACUTE TOXICITY (INGESTION): Can cause mental status changes, vomiting, diarrhea, dehydration, hypotension, acute hepatic and renal failure, metabolic acidosis, multiorgan system failure and death.
4) SEVERE CHRONIC TOXICITY: Manganese may lead to neurotoxicity that resembles Parkinson disease. These patients may have bradykinesia, resting tremor, psychiatric disturbances, and shuffling gait. Manganese neurotoxicity has been shown to progress 10 years after cessation of exposure. "Manganese madness" is characterized by compulsiveness, anxiety, and aggressiveness. Pleuritis and/or severe or fatal pneumonia have been reported among manganese workers.

0.2.20)

A) Manganese injection has produced teratogenic effects in experimental animals, although ingestion and inhalation studies showed no effect. Manganese deficiency during gestation has demonstrated adverse effects on the central nervous system of the developing fetus in experimental animals.

0.2.21)

A) Manganese exposure has not been related to cancer occurrence in humans. However, manganese deficiency has been related to cancer in humans.

Laboratory Monitoring

A)

B)

C)

Treatment Overview

0.4.2)

A) MANAGEMENT OF MILD TO MODERATE TOXICITY

1) The primary treatment is to determine and eliminate the source of the exposure.

B) MANAGEMENT OF SEVERE TOXICITY

1) Conflicting reports suggest that levodopa may transiently improve some of the neuromuscular signs of manganism, though the reversal is incomplete, at best.

C) DECONTAMINATION

1) PREHOSPITAL: No gastrointestinal decontamination therapy is likely to alter the absorption of manganese significantly. Removal of the patient from the exposure is the most important action for prehospital providers. Wash dermal exposures with soap and water to remove any residual manganese as soon as possible.
2) HOSPITAL: No gastrointestinal decontamination measures are indicated. Patients with dermal exposure should be decontaminated with soap and water.

D) AIRWAY MANAGEMENT

1) Manganese exposure is not expected to cause airway compromise. Chronic excess inhalational exposure may lead to pulmonary inflammation and fibrosis. Airway management may be indicated for acute hypoxic exacerbations of chronic lung disease.

E) ANTIDOTE

1) 20% Calcium disodium ethylenediaminetetraacetic acid (Ca-EDTA), 1 g daily for 3 days has been used to decrease the body burden of manganese in acute manganese toxicity. However, this treatment has not been shown to improve neurologic symptoms in most patients. Sodium para-aminosalicylic acid has been associated with improvement in neurologic function in a small number of patients with chronic manganese toxicity, but there have been no controlled studies.

F) ENHANCED ELIMINATION PROCEDURE

1) Hemodialysis and hemoperfusion have not been studied, but might be useful if they can be performed soon after a large, acute exposure. Enhanced elimination is not expected to be of benefit for chronic manganese exposures.

G) PATIENT DISPOSITION

1) HOME CRITERIA: The majority of manganese exposures can be managed at home. Dermal exposures may be managed at home with decontamination measures. Single acute inhalational exposures with no pulmonary symptoms can be managed at home.
2) OBSERVATION CRITERIA: Patients with acute ingestions should be observed until gastrointestinal symptoms have passed. Patients with pulmonary symptoms should be observed for 6 hours and evaluated for inhalational pneumonitis.
3) ADMISSION CRITERIA: Very few patients with manganese exposures require admission since progression is almost always subacute due to chronic exposure.
4) CONSULT CRITERIA: A neurologist should be consulted for severe neuromuscular symptoms or associated neuroimaging findings.

H) PITFALLS

1) Reliance on blood testing rather than neuroimaging in symptomatic patients with manganese exposure may lead to failure to diagnose manganism. Failure to consider other causes of extrapyramidal symptoms.

I) TOXICOKINETICS

1) Manganese salts are poorly absorbed from the gastrointestinal tract. Following intravenous administration, serum half-life is less than 2 hours. Whole body elimination of manganese is considerably longer, on the order of weeks to months. More than 95% of manganese elimination is through biliary excretion, thus pre-existing liver disease may yield a longer duration of exposure to the metal.

J) DIFFERENTIAL DIAGNOSIS

1) Antipsychotics may lead to extrapyramidal symptoms that resemble manganese neurotoxicity. Other basal ganglia toxins, such as carbon monoxide and (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) must be considered. Lead-induced neurotoxicity should be considered. Other pulmonary irritants, such as zinc and nickel, should be considered. Medical diagnoses such as Parkinson disease and sarcoidosis may yield the same clinical effects.

0.4.3)

A) Inhalation is the predominant route of exposure. Removing the patient from the exposure/workplace is the most important factor in limiting further sequelae. Bronchodilators and oxygen therapy should be provided to patients with bronchospasm or acute pneumonitis. Anti-inflammatory therapies such as corticosteroids may be given for exacerbation of chronic inflammatory lung disease.

0.4.4)

A) Irrigation with isotonic fluid 1 to 2 L should be performed to remove debris and normalize pH.

0.4.5)

A) OVERVIEW

1) Decontamination with soap and water is the mainstay of treatment of dermal exposures.

0.4.6)

A) Parenteral exposure due to long-term administration of parenteral nutrition with high manganese content has resulted in toxicity. Eliminating manganese from the parenteral nutrition is the most appropriate step. Parkinsonism has been reported in individuals injecting methcathinone contaminated with manganese. Chelation therapy has been attempted with no improvement of neurologic outcome.

Range Of Toxicity

A)

B)

C)

Clinical Effects

Summary Of Exposure

A)

B)

C)

D)

E)

1) OVERDOSE: Little data is available regarding clinical effects in overdose. Most toxicity is due to chronic workplace exposure.
2) MILD TO MODERATE TOXICITY: Neurotoxicity is the primary manifestation of manganese toxicity. Patients may develop headaches, dizziness, memory loss, emotional instability, hyperreflexia, and a mild tremor. Chronic excess inhalational exposures may lead to pulmonary inflammation and subsequent reactive airway disease. Metal fume fever has been reported with manganese inhalation. Manganese is poorly absorbed dermally and systemic toxicity from this route is not expected. Dermal exposures may lead to a dermal irritation and contact dermatitis.
3) SEVERE ACUTE TOXICITY (INGESTION): Can cause mental status changes, vomiting, diarrhea, dehydration, hypotension, acute hepatic and renal failure, metabolic acidosis, multiorgan system failure and death.
4) SEVERE CHRONIC TOXICITY: Manganese may lead to neurotoxicity that resembles Parkinson disease. These patients may have bradykinesia, resting tremor, psychiatric disturbances, and shuffling gait. Manganese neurotoxicity has been shown to progress 10 years after cessation of exposure. "Manganese madness" is characterized by compulsiveness, anxiety, and aggressiveness. Pleuritis and/or severe or fatal pneumonia have been reported among manganese workers.

Heent

3.4.3)

A) WITH POISONING/EXPOSURE

1) As part of the chronic effects on the neurological system, decreased movement of the eyes and eyelids without paresis, nystagmus, oculogyric crisis or loss of Bell's palsy. Normal visual fields and ocular fundi are found (Grant & Schuman, 1993). However, NYSTAGMUS has been seen, and retrobulbar neuritis has also occurred (Grant & Schuman, 1993; Hine & Pasi, 1975).
2) CORNEAL INJURY: Two to three days after exposure of rabbit eyes to 0.1 M manganous chloride solution, corneas lacking their epithelia developed opacification and vascularization (Grant & Schuman, 1993).
3) VISUAL IMPAIRMENT: A 22-year-old woman developed manganese encephalopathy after receiving total parenteral nutrition (TPN). Her neurological symptoms included fluctuating level of consciousness, weak at following commands, impaired vision, diffuse hyperreflexia, ankle clonus and downgoing toes, myoclonic jerks, and diffuse paratonia. Her serum manganese concentration, obtained on day 10, was elevated (11.5 mg/L; normal less than 2). Her condition gradually improved and she was discharged home with only mild bilateral visual impairment (Chalela et al, 2010).

3.4.4)

A) WITH POISONING/EXPOSURE

1) HEARING: Chronic manganese exposure has been associated with hearing loss; the effect seems to be exacerbated by exposure to noise (Rybak, 1992).

Cardiovascular

3.5.2)

A) CARDIOVASCULAR FINDING

1) CHRONIC occupational manganese exposure has resulted in significant decrease in heart rate variability in both time and frequency domains. It was suggested that heart rate variability be used as an index of autonomic dysfunction in occupational manganese workers (Angle & Barrington, 1995).
2) CASE REPORT: A 50-year-old man presented with lethargy, diffuse abdominal pain, vomiting and profuse diarrhea after ingesting Epsom salts (3 tablespoons with 3 glasses of water) containing manganese instead of magnesium sulfate heptahydrate. Despite supportive care, he developed fulminant liver failure with coagulopathy, acute renal failure, acute respiratory distress, myocardial dysfunction, and shock with lactic acidosis. He underwent continuous venovenous hemofiltration, and multiple transfusions; however, his condition deteriorated and he died 72 hours after onset of symptoms. At this time, it was determined that the supplier had inadvertently prepared the Epsom salts with hydrated manganese sulfate instead of magnesium sulfate heptahydrate. Other cases (n=33) were quickly identified and were treated with chelation therapy (EDTA) (Sanchez et al, 2012).

Respiratory

3.6.2)

A) PNEUMONITIS

1) ACUTE: Inhalation has caused mild to moderate inflammation of the respiratory tract and manganese pneumonitis. Pathologic changes include epithelial necrosis and mononuclear proliferation (Casarett & Doull, 1975). No known permanent pulmonary sequelae developed in these cases (Barceloux, 1999).
2) CHRONIC: A high incidence of pneumonia has been reported after exposure to manganese dust or fumes (ACGIH, 1996). "Manganese pneumonia" has been reported in mine workers (Tepper, 1961). The clinical signs of this pneumonia are acute alveolar inflammation, marked dyspnea, cough and bronchitis, shallow respiration and subsequent facial cyanosis (Barceloux, 1999; Rodier, 1955).

B) ACUTE RESPIRATORY DISTRESS

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A 50-year-old man presented with lethargy, diffuse abdominal pain, vomiting and profuse diarrhea after ingesting Epsom salts (3 tablespoons with 3 glasses of water) containing manganese instead of magnesium sulfate heptahydrate. Despite supportive care, he developed fulminant liver failure with coagulopathy, acute renal failure, acute respiratory distress, myocardial dysfunction, and shock with lactic acidosis. He underwent continuous venovenous hemofiltration, and multiple transfusions; however, his condition deteriorated and he died 72 hours after onset of symptoms. At this time, it was determined that the supplier had inadvertently prepared the Epsom salts with hydrated manganese sulfate instead of magnesium sulfate heptahydrate. Other cases (n=33) were quickly identified and were treated with chelation therapy (EDTA) (Sanchez et al, 2012).

C) BRONCHITIS

1) Occupational manganese exposure is associated with an increased incidence of "colds", bronchitis and pneumonia (ACGIH, 1996). An increased prevalence of acute bronchitis and exercise-induced dyspnea has been observed in relationship to inhalation exposure to inorganic manganese (Roels et al, 1987).

D) METAL FEVER

1) "Metal fume fever" can result from inhalation of manganese oxide fumes (Barceloux, 1999) Baselt, 1992).

Neurologic

3.7.2)

A) EXTRAPYRAMIDAL DISEASE

1) WITH POISONING/EXPOSURE

a) Early and established intoxications are manifested by neurologic changes and disorders of the extrapyramidal system resembling a dystonic parkinsonism (Lee, 2000; Clayton & Clayton, 1994; Florence & Stauber, 1988; Wang et al, 1989). Damage to the nervous system may improve after withdrawal from the exposure, however, some effects may be irreversible. Degeneration of the basal ganglia, especially the globus pallidus with sparing of the substantia nigra, characterized by gait alteration, bradykinesia, loss of balance, fine tremor, loss of facial expressions, and speech disturbances develops prior to the onset of parkinsonism, with muscle rigidity, staggering gait, dysphagia, and a course intention tremor appearing. (Barceloux, 1999).
b) ONSET OF SYMPTOMS: Manganese-induced neurological toxicity is insidious and can occur over several months to several years following exposure (Sadek et al, 2003).
c) FREQUENT SYMPTOMS INCLUDE: Apathy, generalized muscle weakness, a low monotonous voice, muscle twitching, and limb stiffness, followed by impairment of speech, insomnia, incoordination, difficulty with fine movements, diminished libido or impotence, back pain, headache, clumsiness, sweating and salivation, personality changes, inappropriate crying and laughing, and restlessness (Harbison, 1998).
d) MINOR INFREQUENT SYMPTOMS INCLUDE: Tremor (Chandra et al, 1981), paresthesias, cramps, loss of short term memory, urinary incontinence, metallic taste, anorexia, nervousness. The prognosis is more favorable for younger patients with shorter duration of exposure.
e) Other symptoms of chronic poisoning include languor, sleepiness, leg weakness, fatigue, irritability, esthesia, psychotic behavior, hallucinations, followed by signs and symptoms of extrapyramidal damage (mask-like face, emotional instability, spastic gait) (ACGIH, 1996; (Clayton & Clayton, 1994; Hathaway et al, 1996).
f) In chronic intoxication, neurologic abnormalities are often permanently established 1 to 2 years after the onset of symptoms (Mena et al, 1967).

1) PATIENTS UNDERGOING HEMODIALYSIS: One study determined that the bilaterally increased T1 MR imaging signal intensity observed in the globus pallidus in patients undergoing hemodialysis could reflect manganese accumulation in the CNS. However, this study had shown only weak evidence of an association.

a) MR imaging examinations were performed in 9 patients with chronic renal failure, 5 of whom were undergoing maintenance hemodialysis. Elevated serum manganese levels and symmetric hyperintensities within the globus pallidus were observed in all patients undergoing hemodialysis. Four of these patients experienced parkinsonian symptoms, myoclonus, and syndromes with vestibular and vestibular-auditory symptoms. In contrast, none of the patients without dialytic treatment had such signal-intensity abnormalities on MR imaging or symptoms of manganism; however, two patients had elevated serum manganese levels (da Silva et al, 2007).

2) Effects include mask-like faces, bradykinesia, gait disorder (wide-based with high stepping), lack of balance, impaired postural stability, speech difficulty, fine or coarse action tremor of hands and tongue, rigidity, memory loss, dystonia, hypophonia, micrographia, emotional lability and compulsive behavior (Cook et al, 1974; Harbison, 1998; Huang et al, 1989; Huang et al, 1993; Reynolds, 1982; Shuqin et al, 1992).
3) The parkinsonian effects may continue to progress after exposure ceases (Huang et al, 1993). In a case-control study of 15 welders exposed to inhalational Mn, it was concluded that welding may act as an accelerant for the development of parkinsonism (Racette & Perlmutter, 2001). It was further suggested that welding-induced Mn toxicity may lead to delayed and progressive typical parkinsonism (Sadak & Schulz, 2001).
4) In a study of 43 welders who were employed in a confined spaces during the reconstruction of the Bay Bridge (San Francisco) for up to 2 years, 11 cases of manganism were observed, presenting with the following symptoms: sleep disturbances, mood changes, bradykinesia, headaches, sexual dysfunction, olfaction loss, muscular rigidity, tremors, hallucinations, slurred speech, postural instability, monotonous voice, and facial masking. Laboratory analysis revealed mean air manganese concentration of 0.22 mg/m(3) and mean blood manganese of 9.93 mcg/L (Bowler et al, 2007).
5) CASE REPORT: A 31-year-old worker with a 12-year dermal and inhalation exposure to powdered manganese developed signs of manganese neurotoxicity after onset of moderate hepatic dysfunction from hepatitis C infection. Neurological examinations revealed a severe action tremor, unsteady gait, 4+ hyperreflexia, and silent plantar responses. Laboratory results showed an increased whole blood level of manganese (30.8 mg/L). Cerebral T1-weighted MRIs showed symmetric hyperintensity in the globus pallidus and ventral midbrain, characteristic of manganese deposition. Following antiviral therapy and removal from manganese exposure, manganese levels decreased and neurotoxicity lessened with hepatic recovery (Schaumburg et al, 2006).
6) CASE REPORT: After 21 years of occupational airborne exposure to manganese, a 50-year-old woman with symptoms of Parkinson disease (palpitation, hand tremor, lower limb myalgia, hypermyotonia, and a distinct fetinating gait) received 15 courses of p-aminosalicylic acid (6 grams/day IV drip infusion for 4 days and rested for 3 days). Her symptoms improved considerably. At age 67 years of age, a follow-up examination revealed a general normal presentation in clinical, neurologic, brain magnetic resonance imaging, and handwriting examinations with minor gait abnormalities (Jiang et al, 2006).

g) PARKINSON DISEASE VS PARKINSONIAN SYNDROME - MANGANISM

1) SIMILARITIES: Tremor, masked facies, generalized bradykinesia (abnormal slowed movement associated with movement initiation difficulties) and cogwheel rigidity (Bowler et al, 2007).
2) DIFFERENCES:

a) MANGANISM: More frequent dystonia; a tendency to fall forward; younger age of onset; little or no response to levodopa. MR imaging may show manganese deposition in the brain, exhibiting a T1-weighted signal hyperintensity, especially in the globus pallidus and striatum (Bowler et al, 2007).
b) PARKINSON DISEASE: Less frequent dystonia; a tendency to fall backward, MR imaging shows lesions in the substania nigra pars compacta (Bowler et al, 2007).

B) CHRONIC HEPATOCEREBRAL DEGENERATION

1) WITH POISONING/EXPOSURE

a) Acquired hepatocerebral degeneration (AHD) is a rare syndrome that may develop in manganese-intoxicated patients with chronic liver disease or portal-systemic shunt. These patients may experience parkinsonism, certain movement disorders, or other neuropsychiatric manifestations (Park et al, 2008).

1) A 38-year-old man with an 11-month history of alcoholic liver cirrhosis presented with severe tremors of the tongue, jaw, and both hands, reduced facial expression, hypophonic voice, mild bradykinesia and cogwheel rigidity in all 4 limbs. His symptoms started one year before presentation. Eight months before presentation, he also developed one episode of hallucination, delirium, and cognitive impairment caused by hepatic encephalopathy. Laboratory results revealed elevated liver enzymes, whole blood manganese of 38 mcg/L (normal less than 8 mcg/L), and a 24-hour urinary copper excretion of 94 mcg (normal, 38 to 70 mcg). He was successfully treated with trientine, levodopa-carbidopa, propranolol, clonazepam, and trihexyphenidyl. After 1 year of treatment, a brain MRI revealed significantly decreased high signal intensities in the bilateral globus pallidus, cerebral peduncle, and dentate nuclei of the cerebellum (Park et al, 2008).

C) IMPAIRED COGNITION

1) Patients with manganese-induced parkinsonism may have impaired intellectual function as assessed by IQ tests and mini mental status exams, as well as defective information processing speed, micrographia (small, cramped handwriting) and hypophonia (soft speech) (Hua & Huang, 1991; Huang et al, 1993).
2) A cross-sectional study of 142 10-year-old children in Bangladesh who consumed tube-well water, tested intellectual function (Wechsler Intelligence Scale for Children) in 4 approximately equal sized groups, based on well water manganese (Mn) levels. The children were divided into the following groups: group 1 (reference), Mn < 200 mcg/L (n=38); group 2, Mn >/= 200 to < 500 mcg/L (n=45); group 3, Mn >/= 500 to < 1000 mcg/L (n=31); group 4, Mn >/= 1000 mcg/L (n=28).

a) After adjustment for sociodemographic covariates, groups 1 and 4 were significantly different for Full-Scale, Performance, and Verbal scores (B-values = -21.28, -18.43, and -3.19). Compared with group 1, children in groups 2 and 3 also had lower, but not significantly lower, Full-Scale (B-values = -8.57 and -7.90, respectively) and Performance scores (B-values = -7.79 and -7.34, respectively). Verbal scores between group 1 and groups 2 and 3 did not approach significance (Wasserman et al, 2006).

3) Some authors believe that manganese deposition in the brain may be involved in chronic hepatic encephalopathy, as indicated by magnetic resonance imaging (Butterworth, 2000; Fredstrom et al, 1995; Ikeda et al, 2000).
4) In a cross-sectional study, the relationship between manganese exposure from drinking water and IQ score of school-age children (n=362; 6 to 13 years of age) was evaluated. Manganese concentrations were obtained in home tap water (MnW) and children's hair (MnH). The median tap MnW was 34 mcg/L (range, 1 to 2700 mcg/L). Manganese from drinking water, but not from the dietary intake, was significantly associated with increased MnH. Children with higher MnW and MnH had significantly lower IQ scores. When adjusting for maternal intelligence, family income, and other confounders, a10-fold increase in MnW was associated with a decrease of 2.4 IQ points (95% CI: -3.9 to -0.9; p less than 0.01). A 6.2 Full Scale IQ point difference was observed between children in the lowest (1 mcg manganese/L) and highest MnW quintiles (216 mcg manganese/L) (Bouchard et al, 2011).

D) DISORDER OF BRAIN

1) WITH POISONING/EXPOSURE

a) TOTAL PARENTERAL NUTRITION-INDUCED ENCEPHALOPATHY

1) CASE REPORT: A 22-year-old woman who was admitted to the ICU for eclampsia, and was intubated for seizures, developed ileus 4 days after receiving IV magnesium and phenytoin. Laboratory results revealed hyperamylasemia and abnormal imaging findings, indicating a diagnosis of necrotizing pancreatitis. Her condition worsened and she developed acute respiratory distress syndrome, acute renal failure, and pulmonary sepsis. At this time, she received TPN after not tolerating enteral nutrition. Two weeks later, neurological consultation was obtained for worsening neurological symptoms (ie, fluctuating level of consciousness, weak at following commands, impaired vision, diffuse hyperreflexia, ankle clonus and downgoing toes, myoclonic jerks, and diffuse paratonia). All diagnostic studies, including electroencephalography, spinal fluid examination, and general blood chemistry studies, were normal. A brain MRI showed bilateral enhancing lesions in the thalamo-capsular region. Her serum manganese concentration, obtained on day 10, was elevated (11.5 mg/L; normal less than 2). A diagnosis of manganese encephalopathy was made. Her condition gradually improved and she was discharged home (Chalela et al, 2010).

E) MUSCLE WEAKNESS

1) GROOTE EYLANDT SYNDROME: A spectrum of neurological disorders has been identified in an Australian aboriginal population exposed to high environmental manganese concentrations.

a) Affected individuals display weakness and wasting, primarily distal and affecting lower limbs, brisk deep tendon reflexes, foot deformity, ataxia, incoordination, intention tremor, and nystagmus (Kilburn, 1987). The role of manganese versus heredity has not been completely resolved.

F) NEUROPATHY

1) SUBCLINICAL NEUROLOGIC IMPAIRMENT: In some studies, manganese-exposed workers without clinical evidence of parkinsonism have had poorer motor speed, visual scanning, visuomotor response speed and coordination and impaired performance of rapid alternating movements (especially at maximum velocity) in comparison with controls (Beuter et al, 1994; Chia et al, 1993; Hochberg et al, 1996; Wennberg et al, 1992; Wennberg et al, 1991).
2) Psychomotor scores were decreased in a study of 35 ferroalloy workers exposed to manganese (Lucchini et al, 1997; Lucchini et al, 1995).
3) The use of neuropsychological tests of motor functions, response speed and memory to assess asymptomatic manganese workers has been proposed (Iregren, 1994).
4) ACUTE: In one case, contamination of a dialysate with 3.2% manganese sulfate resulted in perioral numbness, which was reversible on discontinuation of the dialysate (Taylor & Price, 1982).

G) MYOCLONUS

1) CHRONIC Mn poisoning has been associated with myoclonic involuntary movements, without parkinsonism, due to inhalation of welding fumes. Elevated levels of Mg were reported in blood (4.3 mcg/dL) and hair (1.4 ppm). High-intensity signals were seen in the globus pallidus on T1-weighted MR images. Symptoms improved following 5 days of chelation therapy with calcium-EDTA (Ono et al, 2002).

H) HEADACHE

1) CHRONIC, mild Mn poisoning due to intermittent parenteral nutrition over 4 and 5 year periods has been reported in two teenage boys. Headache, dizziness and weakness were reported. Symptoms disappeared after stopping the IV administration of trace elements containing Mn (Masumoto et al, 2001). Dizziness is an autonomic effect of chronic manganese toxicity (Angle & Barrington, 1995).

I) SEIZURE

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A previously healthy 3-year-old male developed seizure activity that was unresponsive to antiepileptic therapies (e.g., valproic acid, diazepam, phenytoin, phenobarbital, carbamazepine, etc) following inadvertent exposure to manganese (serum Mn levels peaked at 20 mcg/L) from electrode-welding of a bannister in the home. Due to the patient's neurological deterioration, chelation therapy with intravenous CaNa2EDTA (1 g/meter(2) body surface per day) was begun which immediately decreased both the duration and intensity of the seizure activity. A total of three series of 5-day treatment were administered with an absence of any further seizure activity and complete neurological recovery (Hernandez et al, 2003).

J) LACK OF EFFECT

1) PERIPHERAL NERVES seem to be unaffected by manganese (Nabi Abdel & Kayed, 1965).

3.7.3)

A) ANIMAL STUDIES

1) CNS EFFECTS

a) An extensive review of animal models of neurological manganese toxicology has been published (Newland, 1999).

Gastrointestinal

3.8.2)

A) GASTROINTESTINAL IRRITATION

1) WITH POISONING/EXPOSURE

a) Large oral doses cause GI irritation (Casarett & Doull, 1975).
b) CASE REPORT: A 50-year-old man presented with lethargy, diffuse abdominal pain, vomiting and profuse diarrhea after ingesting Epsom salts (3 tablespoons with 3 glasses of water) containing manganese instead of magnesium sulfate heptahydrate. Despite supportive care, he developed fulminant liver failure with coagulopathy, acute renal failure, acute respiratory distress, myocardial dysfunction, and shock with lactic acidosis. He underwent continuous venovenous hemofiltration, and multiple transfusions; however, his condition deteriorated and he died 72 hours after onset of symptoms. At this time, it was determined that the supplier had inadvertently prepared the Epsom salts with hydrated manganese sulfate instead of magnesium sulfate heptahydrate. Other cases (n=33) were quickly identified and were treated with chelation therapy (EDTA) (Sanchez et al, 2012).

B) EXCESSIVE SALIVATION

1) Excessive salivation is reported with chronic toxicity (Nelson et al, 1993; Shuqin et al, 1992). It occurred in about 5% of cases in one series (Rodier, 1955).

C) PANCREATITIS

1) Acute pancreatitis with abdominal pain, hyperamylasemia and pancreatic enlargement developed in a patient who received manganese (3.2% manganese sulfate) in her dialysate solution. The blood concentration 24 hours after exposure was 4.55 mcmol/L (normal, 0.09 to 0.18 mcmol/L) (Taylor & Price, 1982).

Hepatic

3.9.2)

A) LIVER DAMAGE

1) Liver changes, including prominent Golgi apparatus in hepatocytes, dilated biliary canaliculi, and lipid droplets and collagen in the space of Disse, were seen concomitantly with increases in manganese levels due to injection of potassium permanganate (Lustig et al, 1982).
2) Cirrhosis has been reported (Harbison, 1998).
3) CASE REPORT: A 50-year-old man presented with lethargy, diffuse abdominal pain, vomiting and profuse diarrhea after ingesting Epsom salts (3 tablespoons with 3 glasses of water) containing manganese instead of magnesium sulfate heptahydrate. Despite supportive care, he developed fulminant liver failure with coagulopathy, acute renal failure, acute respiratory distress, myocardial dysfunction, and shock with lactic acidosis. He underwent continuous venovenous hemofiltration, and multiple transfusions; however, his condition deteriorated and he died 72 hours after onset of symptoms. At this time, it was determined that the supplier had inadvertently prepared the Epsom salts with hydrated manganese sulfate instead of magnesium sulfate heptahydrate. Other cases (n=33) were quickly identified and were treated with chelation therapy (EDTA) (Sanchez et al, 2012).

3.9.3)

A) ANIMAL STUDIES

1) HEPATIC NECROSIS

a) High doses of inorganic magnesium produced liver damage in experimental animals, including decreased clearance of bilirubin with cholestasis, hepatic necrosis, alterations in enzyme activity and metabolic function (Clayton & Clayton, 1994).

Genitourinary

3.10.2)

A) ACUTE RENAL FAILURE SYNDROME

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A 64-year-old man developed acute renal failure (serum creatinine 3.4 mg/dL [normal range 0.4-1.4]; serum BUN 43 mg/dL [normal range 6-21]), abdominal pain, and mild methemoglobinemia after ingesting 700 mL of a manganese-containing fertilizer (155 mg of manganese). His manganese blood and urine levels were 195 mcg/L (normal, less than 15) and 79.5 mcg/L (normal, 0-7.9), respectively. Following hemodialysis and supportive care, he recovered and was discharged after 1 week (Huang & Lin, 2004).
b) CASE REPORT: A 50-year-old man presented with lethargy, diffuse abdominal pain, vomiting and profuse diarrhea after ingesting Epsom salts (3 tablespoons with 3 glasses of water) containing manganese instead of magnesium sulfate heptahydrate. Despite supportive care, he developed fulminant liver failure with coagulopathy, acute renal failure, acute respiratory distress, myocardial dysfunction, and shock with lactic acidosis. He underwent continuous venovenous hemofiltration, and multiple transfusions; however, his condition deteriorated and he died 72 hours after onset of symptoms. At this time, it was determined that the supplier had inadvertently prepared the Epsom salts with hydrated manganese sulfate instead of magnesium sulfate heptahydrate. Other cases (n=33) were quickly identified and were treated with chelation therapy (EDTA) (Sanchez et al, 2012).

Hematologic

3.13.2)

A) METHEMOGLOBINEMIA

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A 64-year-old man developed acute renal failure, abdominal pain, and mild methemoglobinemia (methemoglobin level 2.4%; normal 1.4%-1.5%) after ingesting 700 mL of a manganese-containing fertilizer (155 mg of manganese). His manganese blood and urine levels were 195 mcg/L (normal, less than 15) and 79.5 mcg/L (normal, 0-7.9), respectively. Following hemodialysis and supportive care, he recovered and was discharged after 1 week. The authors suggested that the mildly elevated methemoglobin level may have been caused by the nitrate or the manganese in the fertilizer (Huang & Lin, 2004).

3.13.3)

A) ANIMAL STUDIES

1) ERYTHROCYTES ABNORMAL

a) HEMATOPOIESIS: Manganese sulfate injections stimulate hematopoiesis in animals; however, high levels of manganese in the diet of lambs caused a reduction in hemoglobin, perhaps due to interference with dietary iron absorption (Clayton & Clayton, 1981).

Dermatologic

3.14.2)

A) DERMATITIS

1) Papular erythematous dermatitis can result from exposure, but manganese is generally nontoxic to intact skin (ITI, 1995).

B) EXCESSIVE SWEATING

1) Excessive sweating is a symptom seen in about 18 percent of cases (Rodier, 1955) and has been reported in chronic occupational exposures (Angle & Barrington, 1995).

Endocrine

3.16.2)

A) HYPOGLYCEMIA

1) Although both oral and IV manganese induced hypoglycemia in one diabetic, this effect has not been substantiated with other cases (Rubenstein et al, 1962).
2) Manganese may increase the hypoglycemic action of insulin (Dukes & Beeley, 1988).

B) HYPERPROLACTINEMIA

1) In one study, serum prolactin levels were higher in manganese-exposed workers than in non-exposed controls. Prolactin levels were negatively related to age and positively related to blood and urine manganese levels but not to cumulative manganese exposure index (Mutti et al, 1995).
2) In one study, prolactin levels in 179 manganese-exposed welders (mean whole blood manganese level, 16.6 mcg/L, range 10 to 36.6) and 95 non-exposed control subjects (mean whole blood manganese level, 5.08 mcg/L, range 4.07 to 9.56 mcg/L) were compared. A significant correlation between serum prolactin and whole blood manganese was observed. Manganese-exposed group had significantly higher levels of serum prolactin (mean prolactin level 19 ng/mL; range 6 to 41 ng/mL) as compared with the control group (p less than 0.001). It was determined that the blood manganese levels above 10 mcg/L combined with increased prolactin levels may be a strong biomarker for toxic manganese exposure (Tutkun et al, 2014).

Reproductive

3.20.1)

A) Manganese injection has produced teratogenic effects in experimental animals, although ingestion and inhalation studies showed no effect. Manganese deficiency during gestation has demonstrated adverse effects on the central nervous system of the developing fetus in experimental animals.

3.20.2)

A) ANIMAL STUDIES

1) EMBRYOTOXICITY

a) Intraperitoneal injection of 12.5 mg/kg to mice produced a 2 percent incidence of exencephaly. Higher doses were embryolethal. Both of these doses produce severe maternal toxicity (Webster & Valois, 1987).
b) MANEB, which contains manganese, has been shown to cause decreased maternal weight, increased fetal loss, and increased numbers of fetal wavy ribs in rats exposed to 55 mg/m(3) (Lu & Kennedy, 1986).
c) Various manganese salts have not been teratogenic in mice, rats, hamsters, or rabbits, but may have been embryotoxic at high doses (Barlow & Sullivan, 1982; Saakadze & Vasilov, 1977).
d) Manganese chloride tetrahydrate did not affect the total number of implants, early resorptions, sex ratio, or fetal death in experimental animals. Late resorptions were increased at doses of 4 to 16 mg/kg/day, and fetotoxicity was increased at a dose of 8 and 16 mg/kg/day when signs of maternal toxicity were present. The NOAEL for embryo- or fetotoxicity was 2 mg/kg/day (Sanchez et al, 1993).

2) CNS CONGENITAL ANOMALY

a) Manganese deficiency during gestation is teratogenic, acting on the nervous system and producing ataxia in rats, guinea pigs, cattle and mice, but not in swine, and limb and vertebral defects in deer (Schardein, 1993).
b) In pigs, manganese deficiency produced death and affected reproduction, without teratogenicity (Schardein, 2000).
c) A crossover study of pregnant mice found that exposure to manganese dust of the dam and litters in utero and/or post partum affected the balance and coordination ability of the offspring (Massaro et al, 1980).
d) Inhalation of manganese dioxide did not produce structural defects in mice, but did produce post-natal defects (Schardein, 2000).
e) Manganese chloride induced skeletal malformations in rats when given in doses of 30 micromol/kg intravenously but not when administered orally (Grant et al, 1997). No effect was noted in rabbits. Manganese chloride also caused skeletal defects in rat fetuses but not in guinea pigs (Schardein, 2000).
f) Mangafodipir trisodium, a manganese chelate under development as a magnetic resonance contrast agent, induced skeletal malformations in rats at an intravenous dose of 20 mcmol/kg given on days 6 to 17 of gestation; the highest incidence occurred when the agent was given on days 15 to 17. Manganese chloride induced similar effects (Treinen et al, 1995).
g) In another study, intravenous injections of mangafodipir (10 to 40 micromol/kg/d) throughout organogenesis produced skeletal abnormalities in the rat (Grant et al, 1997). No effect was seen in rabbits at 20 micromol/kg/d or in either species when mangafodipir was given orally. Treatment of maternal rats (40 micromol/kg/d) resulted in reduced survival and body weight in neonates and impaired functional but not physical development.

3) LACK OF EFFECT

a) Chronic dietary ingestion of manganese in rats (up to 3500 ppm) did not produce teratogenesis (Laskey et al, 1982).
b) Inhalation studies in animals have not demonstrated teratogenicity, although depressed neonatal motor activity was seen (Lown et al, 1984).
c) Manganese at doses up to 1,000 ppm in the diet was not teratogenic in rats (Barlow & Sullivan, 1982).

3.20.3)

A) ANIMAL STUDIES

1) PLACENTAL BARRIER

a) Manganese can cross the placenta in many animal species; the fetus preferentially concentrates manganese in the brain (Barlow & Sullivan, 1982; ILO, 1998; Barceloux, 1999). Manganese levels are similar in the fetus and mother (Friberg et al, 1986; Tsuchiya, 1984).

2) COORDINATION ABNORMAL

a) MICE - A crossover study of pregnant mice found that exposure of the dam and litters to manganese dust in utero and/or post partum affected the balance and coordination ability of the offspring (Massaro et al, 1980).

3) UTERINE DISORDER

a) A manganese chloride tetrahydrate dose of 8,000 mg/L given to female mice decreased the number of implantations and viable fetuses, but did not affect fetal resorption. Ovarian weight and uterine weight were increased, without an accompanying increase in overall body weight, in females exposed to 4,000 or 8,000 mg/L (Elbetieha et al, 2001).

3.20.5)

A) IMPOTENCE

1) Decreased libido and impotence are considered neurological consequences of chronic exposure (Harbison, 1998) Raffle, 1994). There have been reports of impotence in men with severe manganese poisoning and exposure to airborne concentrations as high as 900 mg/m(3) (Barlow & Sullivan, 1982; Bingham et al, 2001).

B) FERTILITY DECREASED MALE

1) Significantly fewer children were born to manganese workers during exposure without other factors to account for this; it was suggested that manganese may interfere with male reproductive capacity (ACGIH, 1996; (Bingham et al, 2001). Men exposed to airborne concentrations of 0.07 to 8.61 mg/m(3) of manganese had fewer than expected children (Lauwerys et al, 1985).

C) LACK OF EFFECT

1) Manganese at doses up to 1,000 ppm in the diet did not affect female fertility (Barlow & Sullivan, 1982).

D) ANIMAL STUDIES

1) Manganese salts have selectively affected male fertility in the mouse, rat, and rabbit (Barlow & Sullivan, 1982; Chandra, 1975; Gray & Laskey, 1980; Laskey et al, 1982; Seth, 1973).
2) This effect was antagonized by zinc. Manganese injected intraperitoneally into rats caused structural damage to the testes, which was inhibited by zinc (Chandra, 1975).
3) When given orally, manganese decreased testosterone levels in rats (Laskey et al, 1985).
4) Oral manganese dosed at 15 and 30 mg/kg/day in mice caused a decrease in sperm motility and sperm counts; there were no alterations in fertility or pathology of the testicular tissue (Ponnapakkam et al, 2003).

Carcinogenicity

3.21.1)

A) IARC Carcinogenicity Ratings for CAS7439-96-5 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):

1) Not Listed

3.21.2)

A) Manganese exposure has not been related to cancer occurrence in humans. However, manganese deficiency has been related to cancer in humans.

3.21.3)

A) CARCINOMA

1) DEFICIENCY - Manganese deficiency has been associated with high cancer rates in Finland (Clayton & Clayton, 1981a).

B) LACK OF EFFECT

1) Manganese exposure has not been related to cancer occurrence in humans (Proctor et al, 1988).
2) The EPA has classified manganese as Group D, not classifiable as to human carcinogenicity (ACGIH, 1996).

3.21.4)

A) CARCINOMA

1) Subcutaneous or intraperitoneal injection of manganese chloride produced increased lymphosarcoma in mice (Hathaway et al, 1996). Tumors developed at the site of intramuscular application in rats (RTECS , 2001).

Genotoxicity

A)

Laboratory Monitoring

Monitoring Parameters Levels

4.1.1)

A) Normal levels of manganese: 4 to 14 mcg/L in whole blood, 0.97 to 1.07 mcg/L in urine, and 0.15 to 2.65 mcg/L in serum. The metal is cleared from the body rapidly, therefore, testing in patients with exposures more than several hours prior to the blood draw is unlikely to reveal abnormal results. Blood and urine testing do not correlate well with toxicity.
B) MRI will reveal manganese deposition in the basal ganglia and globus pallidus in patients with manganism.
C) An abdominal x-ray should be performed to estimate the size of the overdose when acute ingestion of manganese is suspected.

4.1.2)

A) TOXICITY

1) Interpret blood manganese levels with caution: increased blood levels may be found in asymptomatic workers exposed to high concentrations of manganese; conversely, symptomatic patients may have normal tissue concentrations (Cotzias et al, 1968; Mena et al, 1967a).
2) There is no direct correlation between the occurrence and severity of manganese poisoning or the resultant neurological deficit, and the levels of manganese in blood and urine. However, urine levels may reflect recent exposure, and blood levels may be indicative of total body burden and duration of exposure (Clayton & Clayton, 1994; Zenz, 1994).

B) BLOOD/SERUM CHEMISTRY

1) One study found that serum calcium was increased in mild to severe poisonings. Adenosine deaminase levels were also increased in moderate to severe poisonings (Chandra et al, 1974).

4.1.3)

A) URINARY LEVELS

1) Increased urinary concentrations of manganese do not correlate with neurological symptoms in chronic intoxication (Zenz, 1994; Friberg et al, 1979). Urinary manganese determinations may be useful in acute intoxication, reflecting recent exposure. Using EDTA to mobilize manganese is not diagnostic (Clayton & Clayton, 1994; Cook et al, 1974).

4.1.4)

A) OTHER

1) CEREBROSPINAL FLUID

a) Usual CSF reference range: 0.0004 to 0.0012 mg/100 mL (Nilubol et al, 1968).

2) HAIR

a) HAIR ANALYSIS: Interpretation is somewhat unclear, but may be of some diagnostic value. Chest hair concentrations were 3 times the concentration in head hair (Rosenstock et al, 1971).

Radiographic Studies

A)

1) MRI findings include increased signal intensity in the basal ganglia (globus pallidus) on T1-weighted images. Recent manganese exposure and high concentrations of blood manganese are associated with high signal intensity on T1-weighted MRI; these parameters appear to be correlated. When the exposure is ended, the high signal intensity also disappears (Martin et al, 2001; Nelson et al, 1993).
2) MRI results have been inconsistent; MRI scans may be normal in confirmed manganism patients (Wolters et al, 1989).

a) PATIENTS UNDERGOING HEMODIALYSIS - One study suggested that the bilaterally increased T1 MR imaging signal intensity observed in the globus pallidus in patients undergoing hemodialysis could reflect manganese accumulation in the CNS. However, this study had shown only weak evidence of an association.

1) MR imaging examinations were performed in 9 patients with chronic renal failure, 5 of whom were undergoing maintenance hemodialysis. Elevated serum manganese levels and symmetric hyperintensities within the globus pallidus were observed in all patients undergoing hemodialysis. Four of these patients experienced parkinsonian symptoms, myoclonus, and syndromes with vestibular and vestibular-auditory symptoms. In contrast, none of the patients without dialytic treatment had such signal-intensity abnormalities on MR imaging or symptoms of manganism; however, two patients had elevated serum manganese levels (da Silva et al, 2007).

b) PATIENTS RECEIVING PARENTERAL NUTRITION - In one study, hyperintense lesions in the basal ganglia on T1-weighted MRI were observed in 16 of 48 patients receiving manganese containing perioperative parenteral nutrition (PN) following gastrointestinal surgeries and elevated blood manganese concentrations were observed in 10 of the 16 patients with positive MRI abnormalities. None of the patients in the control group (receiving PN that did not contain manganese) had any abnormal findings (Iwase et al, 2002).
c) PARKINSON'S DISEASE VS PARKINSONIAN SYNDROME (MANGANISM): In patients with manganism (Parkinsonian syndrome), an MR imaging may show manganese deposition in the brain, exhibiting a T1-weighted signal hyperintensity, especially in the globus pallidus and striatum. In patients with Parkinson's disease, an MR imaging shows lesions in the substantia nigra pars compacta (Bowler et al, 2007).
d) Based on available evidence, manganese sequestered in the brain may be seen with MRI, but MRI results do not correlate with clinical signs (Newland et al, 1989; Mirowitz et al, 1991) nor does the brain manganese level correlate with blood levels (Mena et al, 1967; Newland et al, 1989).
e) The degree to which MRI changes may be seen depends on length of exposure to manganese and time since last exposure (Newland et al, 1989).
f) The location of abnormal areas does not vary with route of administration; however, inhaled manganese may remain in the body longer because the lungs act as reservoir (Newland et al, 1989).
g) The characteristic manganese toxicity image pattern includes symmetrical hyperintense signals on T1-weighted image seen especially in the basal ganglia (globus pallidus) and tegmentum of midbrain (Ejima et al, 1992; Mirowitz et al, 1991; Angle & Nelson, 1992). T1 relaxation time is shortened, especially in the midbrain (Angle & Nelson, 1992; Newland et al, 1989).
h) Cranial MRI demonstrated a hyperdense signal on T1-weighted images in the right lenticular and caudate nuclei and normal T2-weighted images (Arjona et al, 1997).

B)

1) TRODAT-1 (99m-Tc-TRODAT-1) brain SPECT imaging was used to evaluate five patients with chronic managanese toxicity to assess DAT (dopamine transporter) function to evaluate the integrity of the presynaptic dopaminergic terminals in manganese-induced parkinsonism. The images with 99mTc-TRODAT-1 found a significantly higher uptake in patients with chronic manganism as compared with Parkinson's disease (PD) patients (a control group) indicating that manganism affects the brain differently and may be a useful tool in differentiating between manganism and PD (Huang et al, 2003).
2) HMPAO (Tc-99m-hexamethylpropyleneamine oxime) SPECT detected decreased regional cerebral blood flow to the thalamus and right caudate head nucleus in a 52-year-old female patient with chronic manganese exposure; MRI results were normal for age (Lill et al, 1994).

Methods

A)

1) Many methods are available for blood or water manganese analysis; considerable variation exists between them.
2) A colorimetric method has been used to measure toxic levels of manganese in the urine; however, urine is a relatively unimportant route for elimination (Baselt, 1997; Baselt & Cravey, 1995).
3) Endogenous manganese may be detected by atomic absorption spectrophotometry (Baselt & Cravey, 1995; Chandra et al, 1974).
4) Nilubol et al (1968) used neutron activation analysis to detect low levels of manganese in body fluids of exposed and unexposed people.

B)

1) Heparin may influence serum analysis for manganese because it may contain substantial concentrations of manganese (Friberg et al, 1979).

Treatment

Life Support

A)

Patient Disposition

6.3.1)

6.3.1.1) ADMISSION CRITERIA/ORAL

A) Very few patients with manganese exposures require admission since progression is almost always subacute due to chronic exposure.

6.3.1.2) HOME CRITERIA/ORAL

A) The majority of manganese exposures can be managed at home. Dermal exposures may be managed at home with decontamination measures. Single acute inhalational exposures with no pulmonary symptoms can be managed at home.

6.3.1.3) CONSULT CRITERIA/ORAL

A) A neurologist should be consulted for severe neuromuscular symptoms or associated neuroimaging findings.

6.3.1.5) OBSERVATION CRITERIA/ORAL

A) Patients with acute ingestions should be observed until gastrointestinal symptoms have passed. Patients with pulmonary symptoms should be observed for 6 hours and evaluated for inhalational pneumonitis.

Monitoring

A)

B)

C)

Oral Exposure

6.5.1)

A) PREHOSPITAL: No gastrointestinal decontamination therapy is likely to alter the absorption of manganese significantly. Removal of the patient from the exposure is the most important action for prehospital providers. Wash dermal exposures with soap and water to remove any residual manganese as soon as possible.

6.5.2)

A) HOSPITAL: No gastrointestinal decontamination measures are indicated.

6.5.3)

A) MONITORING OF PATIENT

1) Normal levels of manganese: 4 to 14 mcg/L in whole blood, 0.97 to 1.07 mcg/L in urine, and 0.15 to 2.65 mcg/L in serum. The metal is cleared from the body rapidly, therefore, testing in patients with exposures more than several hours prior to the blood draw is unlikely to reveal abnormal results. Blood and urine testing do not correlate well with toxicity.
2) MRI will reveal manganese deposition in the basal ganglia and globus pallidus in patients with manganism.
3) An abdominal x-ray should be performed to estimate the size of the overdose when acute ingestion of manganese is suspected.

B) CHELATION THERAPY

1) EFFICACY

a) Enhanced urinary excretion and mobilization of manganese from the blood and tissues occurs without restoring normal physiologic function. The efficacy of chelators is uncertain because the manganese body burden does not seem to correlate well to the clinical manifestations of manganese poisoning (Stokinger, 1981).
b) Chelation therapy may be effective early in the psychiatric phase of intoxication, before permanent neurological damage (Rodier, 1955). However, the effectiveness of chelation treatment in improving existing neurological findings or preventing neurologic deterioration has not been clearly demonstrated. A poor response has been seen in patients removed from long-term exposures (Cook et al, 1974).

2) CALCIUM EDTA

a) SUMMARY: 20% Calcium disodium ethylenediaminetetraacetic acid (Ca-EDTA), 1 g daily for 3 days has been used to decrease the body burden of manganese in acute manganese toxicity. However, this treatment has not been shown to improve neurologic symptoms in most patients.
b) One study used EDTA on three patients and two controls, and although it produced temporary improvement, this was not always maintained. The dose given was 1 g in 500 mL D5W or saline, given over 5 hours twice a day for 3 days (Cook et al, 1974).
c) Others have used EDTA with general success, with results being more positive when EDTA was used early in the intoxication (Rodier, 1955; Kosai & Boyle, 1956; Penalver, 1957; Whitlock et al, 1966; Wynter, 1962).
d) No significant improvement was noted in three patients with chronic manganese intoxication after treatment with EDTA (Huang et al, 1989). The dose administered was not specified. It is reported that calcium EDTA is increases urinary manganese excretion, but has minimal effect on clinical symptoms (Angle & McIntire, 1995).
e) CASE REPORT: A previously healthy 3-year-old boy developed seizure activity that was unresponsive to antiepileptic therapies (e.g., valproic acid, diazepam, phenytoin, phenobarbital, carbamazepine, etc) following inadvertent exposure to manganese (serum Mn levels peaked at 20 mcg/L) from electrode-welding of a bannister in the home. Due to the patient's neurological deterioration, chelation therapy with intravenous CaNa2EDTA (1 g/meter(2) body surface per day) was begun which immediately decreased both the duration and intensity of the seizure activity. A total of three series of 5-day treatment were administered with an absence of any further seizure activity and complete neurological recovery. The effect of EDTA on urinary or blood manganese concentration was not determined in this case report (Hernandez et al, 2003).
f) CASE REPORT: A 17-year-old boy with myoclonic involuntary movement associated with chronic manganese poisoning (whole blood Mn level 4.3 mcg/dL; normal 0.8 to 2.5 mcg/dL) was given an intravenous infusion of 2 grams calcium-EDTA daily for 5 days. Significant urinary excretion of manganese was reported (less than 1.0 mcg/dL prior to therapy; 30 to 31 mcg/dL during therapy). Myoclonic activity was markedly reduced at the end of chelation therapy. Follow-up at 3 months after chelation showed the high-intensity signal on T1-weighted MRI had completely disappeared and blood manganese was decreased to 1.6 mcg/dL (Ono et al, 2002).

3) SODIUM PARA-AMINOSALICYLIC ACID

a) SUMMARY: Sodium para-aminosalicylic acid has been associated with improvement in neurologic function in small numbers of patients with chronic manganese toxicity, but there have been no controlled studies.
b) CASE REPORT: After 21 years of occupational airborne exposure to manganese, a 50-year-old woman with symptoms of Parkinson disease (palpitation, hand tremor, lower limb myalgia, hypermyotonia, and a distinct fetinating gait) received 15 courses of p-aminosalicylic acid (6 grams/day IV drip infusion for 4 days and rested for 3 days). Her symptoms improved considerably, and improvement was maintained at 17 year follow up (Jiang et al, 2006).
c) CASE REPORTS: Two patients with chronic manganese poisoning were treated with intravenous sodium para-aminosalicylic acid (PAS), 6 g in 500 mL 10 percent glucose, administered as an infusion over 24 hours. PAS was administered daily for 4 days followed by a 3-day rest period. One patient was treated for 3.5 months; the duration of therapy in the other was not specified. Both patients demonstrated considerable improvement in neurologic function that was maintained on follow-up 6 to 19 months later (Shuqin et al, 1992).

4) DIMERCAPROL/BAL

a) LACK OF EFFICACY: One study used dimercaprol (British anti-Lewisite, or BAL) on patients with chronic neurological deficit without success (Wynter, 1962).

5) SUCCIMER

a) LACK OF EFFICACY: Oral succimer (dimercaptocuccinic acid (DMSA)) therapy was administered to two men with chronic manganese poisoning. Doses of 1 g/m(2)/day for 7 days followed by 0.67 g/m(2)/day for 14 days were given orally. Subjective clinical results were not seen. Whole blood manganese remained unchanged. Urinary manganese increased on day 6 from 0.8 to 26 mcg/day in one subject only. The authors concluded that the negligible effect of succimer on manganese excretion does not support further studies (Angle & McIntire, 1995).

C) LEVODOPA

1) SUMMARY: Conflicting reports suggest that levodopa may transiently improve some of the neuromuscular signs of manganism, though the reversal is incomplete, at best.
2) The response to levodopa (3.5 g daily) is generally positive. Doses up to 12 g a day have been given without major side effects; there is a suggestion that patients with chronic manganism can tolerate higher doses of levodopa than patients with Parkinsonism (Rosenstock et al, 1971).
3) In one study, L-dopa increased the weakness, muscular hypotension, tremor and hypokinesia. This patient was then aided with 5-hydroxy tryptophan (Mena et al, 1970).
4) It is possible that concomitant administration of carbidopa might result in greater benefit. Statistically significant improvement in modified Columbia Rating Scale scores over baseline were noted in six patients treated with 3 to 6 tablets of levodopa 100 mg/carbidopa 25 mg daily for 8 weeks (Huang et al, 1989). This was not a controlled study. Additional studies are needed to demonstrate levodopa/carbidopa efficacy in the treatment of manganese intoxication.
5) In general, the response to levodopa seems to be a function of the neurological pattern of symptoms of the patient, and improvement in symptoms has been reported to continue after stabilization of dose. Cook et al (1974) state that levodopa is less effective or ineffective in the absence of rigidity or dystonia, and was not effective in three of their patients who received up to 8 g/day (Cook et al, 1974).
6) One study used up to 5 g/day on four patients with bradykinesia and gait impairment. No improvement was seen (Greenhouse, 1971).
7) In a double-blind placebo-controlled study of four patients with chronic manganese-induced parkinsonism, levodopa/carbidopa at doses of 100 mg/25 mg, 200 mg/50 mg and 300 mg/75 mg did not produce any clinical improvement. All patients had previously received treatment with levodopa/carbidopa and/or bromocriptine with an apparent early clinical response, which faded after 3 to 6 months (Lu et al, 1994).
8) Based on the theory that the failure of levodopa in some cases related to too rapid metabolism of the l-dopa in peripheral nerves, alpha methyldopa hydrazine (Carbidopa) has been administered with the levodopa. This agent is an l-aromatic amino acid decarboxylase inhibitor and initially seems to stabilize the l-dopa content in peripheral sites and stabilize the diurnal performance of unstable patients (Stokinger, 1981).
9) ANIMAL STUDY: An animal model of manganese neurotoxicity has demonstrated enhanced dopamine depletion with levodopa, at least during the early or acute phase of poisoning (Parenti et al, 1986).

D) ANTICHOLINERGIC

1) Trihexyphenidyl hydrochloride (Artane(R)) has been reported to reduce intention tremor in 2 patients with known manganism. DOSE: 1 to 5 mg daily in divided doses (Park et al, 2008; Hine & Pasi, 1975). Because of limited experience, this agent should be used with caution.

E) EXPERIMENTAL THERAPY

1) HYDROXYTRYPTOPHAN: L-5-hydroxytryptophan is a serotonin precursor. Up to 3 g daily was given with good results to a patient whose symptoms failed to respond to levodopa (Mena et al, 1970a). Because of limited experience, this agent should be used with caution.
2) TRIENTINE: A 38-year-old man with tremors due to manganese poisoning (38 mcg/L; normal less than 8 mcg/L) and acquired hepatocerebral degeneration was successfully treated with trientine (2000 mg/day). Trientine was added to his regimen of levodopa/carbidopa, propranolol, clonazepam, and trihexyphenidyl, which significantly reduced his tremors and other features of parkinsonism. His whole blood manganese concentration decreased to 5.6 mcg/L after 4 months of therapy. After one year of treatment with trientine, a brain MRI revealed significantly decreased high signal intensities in the bilateral globus pallidus, cerebral peduncle, and dentate nuclei of the cerebellum (Park et al, 2008).

Inhalation Exposure

6.7.1)

A) Inhalation is the predominant route of exposure. Removing the patient from the exposure/workplace is the most important factor in limiting further sequelae. Bronchodilators and oxygen therapy should be provided to patients with bronchospasm or acute pneumonitis. Anti-inflammatory therapies such as corticosteroids may be given for exacerbation of chronic inflammatory lung disease.
B) METAL FUME FEVER: can result from inhalation of manganese oxide fumes. Refer to "METAL FUME FEVER" management for further information. Long term follow up may be necessary in patients with chronic Mn inhalation exposure.

6.7.2)

A) SUPPORT

1) In the initial stages, removal from exposure to manganese may result in a remission of symptoms. Refer to ORAL MAIN SECTIONS for information on specific treatment.

B) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Eye Exposure

6.8.1)

A) Irrigation with isotonic fluid 1 to 2 L should be performed to remove debris and normalize pH.

Dermal Exposure

6.9.1)

A) Decontamination with soap and water is the mainstay of treatment of dermal exposures.

Enhanced Elimination

A)

1) Hemodialysis and hemoperfusion have not been studied, but might be useful if they can be performed soon after a large, acute exposure. Enhanced elimination is not expected to be of benefit for chronic manganese exposures.
2) CASE REPORT - A 64-year-old man developed acute renal failure, abdominal pain, and mild methemoglobinemia after ingesting 700 mL of a manganese-containing fertilizer (155 mg of manganese). His manganese blood and urine levels were 195 mcg/L (normal, less than 15) and 79.5 mcg/L (normal, 0-7.9), respectively. Following hemodialysis and supportive care, he recovered and was discharged after 1 week (Huang & Lin, 2004).

Abstracts

Case Reports

A)

1) A 62-year-old man exposed to maneb developed acute renal failure, hoarseness, and ECG abnormalities, which disappeared after hemodialysis. These signs possibly occurred because of toxicity of the components of maneb, i.e., manganese and carbamates (Koizumi et al, 1979).
2) Manganese toxicity has been reported in a patient with cholestatic jaundice who was treated with total parenteral nutrition. The patient developed a Parkinson-like syndrome that resolved only after discontinuation of parenteral manganese. Concurrent dosing with haloperidol contributed to the syndrome (Mehta & Reilly, 1990).

Range Of Toxicity

Summary

A)

B)

C)

Therapeutic Dose

7.2.1)

A) GENERAL

1) There is no evidence that the conventional amounts of manganese in the diet or air can be related to any disease processes.
2) The ambient air concentration averages 0.1 mcg/m(3) air (Fishbein, 1972).
3) The estimated safe and adequate daily dietary intake of manganese in adults is 2 to 5 mg/day (Gilman et al, 1990).

7.2.2)

A) GENERAL

1) An Estimated Safe and Adequate Daily Dietary Intake (ESADDI) for manganese has been estimated as 0.3-0.6 mg/day for infants from birth to 6 months, 0.6-1 mg/day for infants aged 6 months to 1 year, 1-1.5 mg/day for children aged 1-3 years, 1-2 mg/day for children aged 4-10 years of age, and 2-5 mg/day for children aged 10 years to adult (ATSDR, 2000).

Minimum Lethal Exposure

A)

B)

Maximum Tolerated Exposure

A)

1) US Environmental Protection Agency (EPA) recommends not more than 0.05 ppm in drinking water and the US Occupational Safety and Health Administration (OSHA) recommends a 8-hour time weighted average of not more than 0.2 mg/m(3) for particulate matter. For exposure to manganese fumes, the National Institute for Occupational Safety and Health (NIOSH) recommends an 8-hour time weighted average of not more than 1 mg/m(3), a short term exposure limit of 3 mg/m(3) and considers 500 mg/m(3) immediately dangerous to life and health (American Conference of Governmental Industrial Hygienists, 2010; National Institute for Occupational Safety and Health, 2007).
2) Long-term occupational inhalation exposure to dusts containing manganese may cause progressive neurological dysfunction, leading to a disabling syndrome known as manganism. Advanced stages of neurological abnormalities resemble Parkinsonism (IPCS, 1999; Zenz, 1994).
3) CASE REPORT - A 64-year-old man developed acute renal failure, abdominal pain, and mild methemoglobinemia after ingesting 700 mL of a manganese-containing fertilizer (155 mg of manganese). His manganese blood and urine levels were 195 mcg/L (normal, less than 15) and 79.5 mcg/L (normal, 0-7.9), respectively. Following hemodialysis and supportive care, he recovered and was discharged after 1 week (Huang & Lin, 2004).
4) In some studies, blood levels as low as 7.5 mcg/L have been associated with neurological dysfunction. In one study (n=273), patients with Mn levels of 7.5 mcg/L or higher were more often associated with alterations in coordination of upper limb movement, and poorer learning and recall. Other studies have suggested that serum Mn levels poorly correlate with recent exposure or clinical symptoms (Sadek et al, 2003).
5) CASE SERIES/LACK OF EFFECT - In a study of 489 workers (both office workers and miners) employed in two manganese mining towns in South Africa, average exposure for total dust across all jobs was near the ACGIH TLV of 0.2 mg/m(3) with no manganese-related neurological effects reported at this level (Myers et al, 2003).
6) Studies of manganese toxicity generally evaluate effects through dosage of manganese compound formulations (i.e., manganese chloride, manganese dioxide, manganese sulfate, potassium permanganate, etc.). ATSDR (2000) provides lowest observed adverse effect levels (LOAELs) for numerous manganese compounds from animal and human studies. LOAELS are classified as "serious" when effects are those that evoke failure in a biological system and can lead to morbidity or mortality, and "less serious" when effects are not expected to cause significant dysfunction or death or when the effect's significance to the organism is not entirely clear (IPCS, 1999; ATSDR, 2000).
7) Most manganese intake from the environment is as Mn(II) or Mn(IV), and changes in oxidation state occurs within the body according to limited data. Redox reactions may be determinants in retention time in the body (IPCS, 1999).
8) Attempts to induce effects to the brain through oral dosing of manganese compounds showed that inorganic manganese is absorbed slowly and incompletely into the bloodstream when orally administered. Inhaled manganese compounds generally produce more severe toxicity than those that are ingested (ACGIH, 1996a; IPCS, 1999).
9) Manganese is considered a nutritionally essential element, supporting enzymes critical to the central nervous, skeletal, and reproductive systems. Food intake is estimated to be 2 to 9 mg/day for adults, with an absorbed amount of about 100 to 450 mcg/day based on 5% gastrointestinal absorption (Bingham et al, 2001; (IPCS, 1999) Baxter, 2000; (ATSDR, 2000).

B)

1) No cases of manganese poisoning occurred among mill workers exposed to airborne concentrations less than 30 mg/m(3) (ACGIH, 1996a).
2) Manganese exposure at low levels [0.19 to 1.39 mg/m(3)] for 1 to 45 years is reported to have caused pre-clinical signs of manganism, and worker exposure to levels less than 1 mg/m(3) caused an observed effect on performance of psychometric tests and neuropsychiatric symptoms (Hathaway et al, 1996) Baxter, 2000).
3) An estimate of a no observed adverse effect level (NOAEL) for neurological effects of 30 mcg/m(3) was used in the recent development of a 0.15 mcg/m(3) WHO guidance value for manganese in air. The NOAEL was calculated based on a benchmark dose in a study that examined neurobehavioral endpoints in workers exposed to manganese dioxide at an alkaline battery plant and workers without industrial manganese exposure. Manganese exposed workers exhibited significantly poorer hand-eye coordination, hand steadiness, and visual reaction time (IPCS, 1999).
4) The World Health Organization (WHO) concluded that adverse CNS effects associated with manganese exposure may occur at airborne manganese concentrations of 2-5 mg/m(3) (ACGIH, 1996a).

Serum Plasma Blood Concentrations

7.5.1)

A) THERAPEUTIC CONCENTRATION LEVELS

1) Normal levels of manganese: 4 to 14 mcg/L in whole blood, 0.97 to 1.07 mcg/L in urine, and 0.15 to 2.65 mcg/L in serum.

7.5.2)

A) TOXIC CONCENTRATION LEVELS

1) GENERAL

a) CASE REPORT: A 22-year-old woman developed manganese encephalopathy after receiving total parenteral nutrition (TPN). Her serum manganese concentration, obtained on day 10, was elevated (11.5 mg/L; normal less than 2). Her condition gradually improved and she was discharged home with only mild bilateral visual impairment (Chalela et al, 2010).
b) CASE REPORT: A 50-year-old man presented with lethargy, diffuse abdominal pain, vomiting and profuse diarrhea after ingesting Epsom salts (3 tablespoons with 3 glasses of water) containing hydrated manganese sulfate instead of magnesium sulfate heptahydrate. Despite supportive care, he developed fulminant liver failure with coagulopathy, acute renal failure, acute respiratory distress, myocardial dysfunction, and shock with lactic acidosis. He underwent continuous venovenous hemofiltration, and multiple transfusions; however, his condition deteriorated and he died. Elemental manganese concentrations in biological samples were as follows: Blood: 6650 mcg/L, bile: 376,000 mcg/L, lung: 7470 mcg/kg, liver: 63,400 mcg/kg, heart: 89,400 mcg/kg, brain: 3090 mcg/kg, pancreas: 26,200 mcg/kg, spleen: 9600 mcg/kg, fat: 1740 mcg/kg, muscle: 6610 mcg/kg, kidney: 25,500 mcg/kg (Sanchez et al, 2012).
c) CASE REPORT: A man with Parkinsonism-like syndrome and acquired hepatocerebral degeneration had a whole blood manganese of 38 mcg/L (normal, less than 8 mcg/L) (Park et al, 2008).
d) In a study of 43 welders who were employed in a confined spaces during the reconstruction of th Bay Bridge (San Francisco) for up to 2 years, 11 cases of manganism were observed, presenting with the following symptoms: sleep disturbances, mood changes, bradykinesia, headaches, sexual dysfunction, olfaction loss, muscular rigidity, tremors, hallucinations, slurred speech, postural instability, monotonous voice, and facial masking. Laboratory analysis revealed mean air manganese concentration of 0.22 mg/m(3) (range, 0.006 to 0.312) and mean blood manganese of 9.93 mcg/L (range, 5.85 to 14.6) (Bowler et al, 2007).
e) Blood manganese levels of over 600 nmol/L were found in six patients with neurological disease possibly related to manganese exposure (Cawte et al, 1987).
f) Interpretation of elevated levels of manganese in body fluids is difficult; manganese levels do not always correlate with the severity of the clinical signs or the clinical course of manganese toxicity (Barceloux, 1999; Finkel, 1983). Because approximately 85% of manganese is bound to hemoglobin in erythrocytes, serum manganese levels (range, 0.9 to 2.9 mcg Mn/L) are generally much lower than whole blood manganese concentrations (Barceloux, 1999).
g) CASE REPORT: A 64-year-old man developed acute renal failure, abdominal pain, and mild methemoglobinemia after ingesting 700 mL of a manganese-containing fertilizer (155 mg of manganese). His manganese blood and urine levels were 195 mcg/L (normal, less than 15) and 79.5 mcg/L (normal, 0-7.9), respectively. Following hemodialysis and supportive care, he recovered and was discharged after 1 week (Huang & Lin, 2004).

Workplace Standards

A)

1) Editor's Note: The listed values are recommendations or guidelines developed by ACGIH(R) to assist in the control of health hazards. They should only be used, interpreted and applied by individuals trained in industrial hygiene. Before applying these values, it is imperative to read the introduction to each section in the current TLVs(R) and BEI(R) Book and become familiar with the constraints and limitations to their use. Always consult the Documentation of the TLVs(R) and BEIs(R) before applying these recommendations and guidelines.

a) Adopted Value

1) (Manganese and inorganic compounds, as Mn)

a) TLV:

1) TLV-TWA: (0.2 mg/m(3))
2) TLV-STEL:
3) TLV-Ceiling:

b) Notations and Endnotes:

1) Carcinogenicity Category: Not Listed
2) Codes: Not Listed
3) Definitions: Not Listed

c) TLV Basis - Critical Effect(s): (CNS impair)
d) Molecular Weight: 54.94

1) For gases and vapors, to convert the TLV from ppm to mg/m(3):

a) [(TLV in ppm)(gram molecular weight of substance)]/24.45

2) For gases and vapors, to convert the TLV from mg/m(3) to ppm:

a) [(TLV in mg/m(3))(24.45)]/gram molecular weight of substance

e) Additional information:

1) See Notice of Intended Changes; Adopted values enclosed in parentheses are those for which changes are proposed in the Notice of Intended Changes.

b) Adopted Value

1) (Manganese and inorganic compounds, as Mn)

a) TLV:

1) TLV-TWA: (0.2 mg/m(3))
2) TLV-STEL:
3) TLV-Ceiling:

b) Notations and Endnotes:

1) Carcinogenicity Category: Not Listed
2) Codes: Not Listed
3) Definitions: Not Listed

c) TLV Basis - Critical Effect(s): (CNS impair)
d) Molecular Weight: Varies

1) For gases and vapors, to convert the TLV from ppm to mg/m(3):

a) [(TLV in ppm)(gram molecular weight of substance)]/24.45

2) For gases and vapors, to convert the TLV from mg/m(3) to ppm:

a) [(TLV in mg/m(3))(24.45)]/gram molecular weight of substance

e) Additional information:

1) See Notice of Intended Changes; Adopted values enclosed in parentheses are those for which changes are proposed in the Notice of Intended Changes.

c) Notice of Intended Changes

1) Manganese, elemental and inorganic compounds, as Mn

a) TLV:

1) TLV-TWA: 0.02 mg/m(3)
2) TLV-STEL:
3) TLV-Ceiling:

b) Notations and Endnotes:

1) Carcinogenicity Category: A4
2) Codes: R
3) Definitions:

a) A4: Not Classifiable as a Human Carcinogen: Agents which cause concern that they could be carcinogenic for humans but which cannot be assessed conclusively because of a lack of data. In vitro or animal studies do not provide indications of carcinogenicity which are sufficient to classify the agent into one of the other categories.
b) R: Respirable fraction; see Appendix C, paragraph C (of TLV booklet).

c) TLV Basis - Critical Effect(s): CNS impair
d) Molecular Weight: Varies

1) For gases and vapors, to convert the TLV from ppm to mg/m(3):

a) [(TLV in ppm)(gram molecular weight of substance)]/24.45

2) For gases and vapors, to convert the TLV from mg/m(3) to ppm:

a) [(TLV in mg/m(3))(24.45)]/gram molecular weight of substance

e) Additional information:

d) Notice of Intended Changes

1) Manganese, elemental and inorganic compounds, as Mn

a) TLV:

1) TLV-TWA: 0.2 mg/m(3)
2) TLV-STEL:
3) TLV-Ceiling:

b) Notations and Endnotes:

1) Carcinogenicity Category: A4
2) Codes: I
3) Definitions:

a) A4: Not Classifiable as a Human Carcinogen: Agents which cause concern that they could be carcinogenic for humans but which cannot be assessed conclusively because of a lack of data. In vitro or animal studies do not provide indications of carcinogenicity which are sufficient to classify the agent into one of the other categories.
b) I: Inhalable fraction; see Appendix C, paragraph A (of TLV booklet).

c) TLV Basis - Critical Effect(s): CNS impair
d) Molecular Weight: 54.94

1) For gases and vapors, to convert the TLV from ppm to mg/m(3):

a) [(TLV in ppm)(gram molecular weight of substance)]/24.45

2) For gases and vapors, to convert the TLV from mg/m(3) to ppm:

a) [(TLV in mg/m(3))(24.45)]/gram molecular weight of substance

e) Additional information:

B) NIOSH REL and IDLH Values for CAS7439-96-5 (National Institute for Occupational Safety and Health, 2007):

1) Listed as: Manganese compounds and fume (as Mn)
2) REL:

a) TWA: 1 mg/m(3)
b) STEL: 3 mg/m(3)
c) Ceiling:
d) Carcinogen Listing: (Not Listed) Not Listed
e) Skin Designation: Not Listed
f) Note(s): [*Note: Also see specific listings for Manganese cyclopentadienyl tricarbonyl, Methyl cyclopentadienyl manganese tricarbonyl, and Manganese tetroxide.]

3) IDLH:

a) IDLH: 500 mg Mn/m3 (as Mn)
b) Note(s): Not Listed

C) Carcinogenicity Ratings for CAS7439-96-5 :

1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed ; Listed as: (Manganese and inorganic compounds, as Mn)
2) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed ; Listed as: (Manganese and inorganic compounds, as Mn)
3) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): A4 ; Listed as: Manganese, elemental and inorganic compounds, as Mn

a) A4 :Not Classifiable as a Human Carcinogen: Agents which cause concern that they could be carcinogenic for humans but which cannot be assessed conclusively because of a lack of data. In vitro or animal studies do not provide indications of carcinogenicity which are sufficient to classify the agent into one of the other categories.

4) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): A4 ; Listed as: Manganese, elemental and inorganic compounds, as Mn

a) A4 :Not Classifiable as a Human Carcinogen: Agents which cause concern that they could be carcinogenic for humans but which cannot be assessed conclusively because of a lack of data. In vitro or animal studies do not provide indications of carcinogenicity which are sufficient to classify the agent into one of the other categories.

5) EPA (U.S. Environmental Protection Agency, 2011): D ; Listed as: Manganese

a) D : Not classifiable as to human carcinogenicity.

6) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): Not Listed
7) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed ; Listed as: Manganese compounds and fume (as Mn)
8) MAK (DFG, 2002): Not Listed
9) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

D) OSHA PEL Values for CAS7439-96-5 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):

1) Listed as: Manganese compounds (as Mn)
2) Table Z-1 for Manganese compounds (as Mn):

a) 8-hour TWA:

1) ppm:

a) Parts of vapor or gas per million parts of contaminated air by volume at 25 degrees C and 760 torr.

2) mg/m3: 5

a) Milligrams of substances per cubic meter of air. When entry is in this column only, the value is exact; when listed with a ppm entry, it is approximate.

3) Ceiling Value: (C) - An employee's exposure to this substance shall at no time exceed the exposure limit given.
4) Skin Designation: No
5) Notation(s): Not Listed

3) Listed as: Manganese fume (as Mn)
4) Table Z-1 for Manganese fume (as Mn):

a) 8-hour TWA:

1) ppm:

a) Parts of vapor or gas per million parts of contaminated air by volume at 25 degrees C and 760 torr.

2) mg/m3: 5

a) Milligrams of substances per cubic meter of air. When entry is in this column only, the value is exact; when listed with a ppm entry, it is approximate.

3) Ceiling Value: (C) - An employee's exposure to this substance shall at no time exceed the exposure limit given.
4) Skin Designation: No
5) Notation(s): Not Listed

Toxicity Information

7.7.1)

A) References: ITI, 1995 Lewis, 2000 RTECS, 2002

1) LD50- (ORAL)RAT:

a) 9 g/kg

2) TCLo- (INHALATION)HUMAN:

a) 2300 mcg/m(3) -- degenerative changes in brain and coverings; motor activity changes and muscle weakness

3) TCLo- (INHALATION)RAT:

a) 3709 mg/m(3) for 6H/13W-intermittent -- degenerative changes in brain and coverings; motor activity change; changes in lung, thorax, or respiration

Pharmacology Toxicology

Pharmacologic Mechanism

A)

Toxicologic Mechanism

A)

1) Mitochondrial dysfunction is reported in patients exhibiting chronic manganese poisoning. Brown & Taylor (1999) proposed an interaction between inhibition of mitochondrial energy transduction, generation of free radicals and mutations of the mitochondrial genome in the etiology of chronic manganese poisoning resulting in neurotoxic effects.

B)

Physicochemical

Physical Characteristics

A)

1) The four allotropic forms are described as follows (Budavari, 2001):

a) alpha-form: body-centered cubic crystals that are stable below approximately 710 degrees C.
b) beta-form: cubic crystals that are stable in the range of 710-1079 degrees C.
c) gamma-form (electrolytic manganese): can exist in two crystalline structures, as face-centered cubic crystals that are stable in the range of 1079-1143 degrees C or as face-centered tetragonal crystals when stabilized at room temperature.
d) delta-form: body-centered cubic crystals that are stable from 1143 degrees C to its melting point.

B)

Molecular Weight

A)

Other

A)

1) Not Listed (CHRIS , 1999)

Animal Toxicology

Range Of Toxicity

11.3.1)

A) CATTLE

1) One report found that cows fed less than 56 ppm manganese during pregnancy were more likely to deliver calves with deformities including twisted forelimbs and knuckled over pasterns. Cattle forages low in manganese include barley and cottonseed meal (Dyer et al, 1964).

11.3.2)

A) SPECIFIC TOXIN

1) Manganese chloride administered subcutaneously at a dose of 50 milligrams/kilogram was lethal to mice, rabbits, and guinea pigs (ACGIH, 1986).
2) Intravenous doses of 18 milligrams/kilogram manganese chloride were lethal to rabbits (ACGIH, 1986).
3) Intravenous doses of 56 milligrams/kilogram manganese chloride were lethal to dogs (ACGIH, 1986).

References

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MANGANESE

Classification | Detailed evidence-based information

Therapeutic Toxic Class

Specific Substances

Available Forms Sources

Life Support

Clinical Effects

Laboratory Monitoring

Treatment Overview

Range Of Toxicity

Summary Of Exposure

Heent

Cardiovascular

Respiratory

Neurologic

Gastrointestinal

Hepatic

Genitourinary

Hematologic

Dermatologic

Endocrine

Reproductive

Carcinogenicity

Genotoxicity

Monitoring Parameters Levels

Radiographic Studies

Methods

Life Support

Patient Disposition

Monitoring

Oral Exposure

Inhalation Exposure

Eye Exposure

Dermal Exposure

Enhanced Elimination

Case Reports

Summary

Therapeutic Dose

Minimum Lethal Exposure

Maximum Tolerated Exposure

Serum Plasma Blood Concentrations

Workplace Standards

Toxicity Information

Pharmacologic Mechanism

Toxicologic Mechanism

Physical Characteristics

Molecular Weight

Other

Range Of Toxicity

General Bibliography