Brief Background on the Health Effects of Manganese
Manganese is a mineral that is required in small amounts in the human body to manufacture enzymes necessary for the metabolism of proteins and fats. A partial list of manganese-dependent enzyme families includes oxidoreductases, transferases, hydrolases, lyases, isomerases, and ligases. Manganese is involved in the function of numerous organ systems and is needed for normal immune function, regulation of blood sugars, production of cellular energy, reproduction, digestion, and bone growth. Manganese works with vitamin K to support clotting of the blood. As a vital component of superoxide dismutase (SOD), manganese has important antioxidant properties since manganese-SOD (Mn-SOD) is one of the body's main front-line defense mechanisms against damaging free radicals. The National Research Council has recommended an Estimated Safe and Adequate Daily Dietary Intake (ESADDI) for Mn of 2 to 5 mg per day for adults.
A deficiency in manganese intake can retard growth, cause seizure activity, lead to poor bone formation, impair fertility, and cause birth defects in humans. At the other spectrum, excessive exposure to manganese is associated with an irreversible brain disease with prominent psychological and neurological disturbances known as manganism.
Manganese neurotoxicity has been attributed to symptoms in a few workers that have been chronically exposed to aerosols or dusts that contain high levels (> 5 mg Mn/m3) of manganese (ATSDR, 2000; Mergler et al., 1994; Pal et al., 1999). Manganese-induced neurotoxicity may also occur following ingestion. Kawamura and coworkers (1941) and Kondakis et al., (1989) documented outbreaks of manganese toxicity in Japan and Greece due to the consumption of water from wells contaminated with extremely high levels of manganese (1.8 to 14 mg Mn/L). More recently, Woolf et al. (2002) reported that a 10-year old boy with abnormal verbal and visual memory function had elevated serum (0.90 µg/dL vs. normal value of < 0.265 µg/dL), whole blood, urine, and hair manganese concentrations following chronic ingestion of well water containing moderately elevated levels (~1.2 ppm) of manganese. Typical manganese water levels in the US are <0.05 ppm.
Manganism is associated with elevated brain levels of manganese, primarily in those areas known to contain high concentrations of non-heme iron, especially the caudate-putamen, globus pallidus, substantia nigra, and subthalamic nuclei. Manganism could initially be characterized by a psychiatric disorder (locura manganica) that closely resembles schizophrenia. Symptoms could include compulsive or violent behavior, emotional instability, and hallucinations. Other early manifestations of manganese neurotoxicity include fatigue, headache, muscle cramps, loss of appetite, apathy, insomnia, and diminished libido. As exposure continues and the disease progresses, patients may develop prolonged muscle contractions (dystonia), decreased muscle movement (hypokinesia), rigidity, and muscle tremors (Pal et al., 1999). These signs are associated with damage to dopaminergic neurons within brain structures that control muscle movement.
Individuals with manganism resemble patients with Parkinson’s disease; however, these syndromes can be distinguished clinically (Calne et al., 1994; Pal et al., 1999). Unlike Parkinsonism, manganism also produces dystonia; a neurological sign associated with damage to the globus pallidus (Calne et al., 1994). A comprehensive survey of patients afflicted by Parkinson’s disease or manganism concludes that although similar in many respects, there are distinct differences between the two neurological disorders. Similarities between Parkinson’s disease and manganism include the presence of generalized bradykinesia and widespread rigidity. Dissimilarities between Parkinson’s disease and manganism were also recognized, notably the following in manganism: (a) a less frequent resting tremor, (b) more frequent dystonia, (c) a particular propensity to fall backward, (d) failure to achieve a sustained therapeutic response to levodopa, and (e) failure to detect a reduction in fluorodopa uptake by positron emission tomography (see Calne et al., 1994; Pal et al., 1999). Given these differences, it has been proposed that manganese intoxication is associated with preservation of the nigrostriatal dopaminergic pathway, and that chronic manganese intoxication causes parkinsonism-like effects by damaging output pathways downstream of the nigrostriatal dopaminergic pathway (Calne et al., 1994; Pal et al., 1999). Nevertheless, in a recent small study, Parkinsonism in welders was recently distinguished clinically only by age at onset, suggesting that welding fumes, and potentially manganese, may be a risk factor for Parkinson’s disease (Racette et al., 2001).
These uncertainties, along with a limited understanding of transport mechanisms of manganese into the brain, and lack of standardized exposure assessments and reconstruction methodologies, have led to the development of the MHRP.