Manganism

Manganism
Classification and external resources
Manganese
ICD-10	T57.2
ICD-9	985.2
MeSH	D020149

Manganism or manganese poisoning is a toxic condition resulting from chronic exposure to manganese and first identified in 1837 by James Couper.^[1]

Presentation

Chronic exposure to excessive Mn levels can lead to a variety of psychiatric and motor disturbances, termed manganism. Generally, exposure to ambient Mn air concentrations in excess of 5 μg Mn/m3 can lead to Mn-induced symptoms.^[2]

In initial stages of manganism, neurological symptoms consist of reduced response speed, irritability, mood changes, and compulsive behaviors.^[3] Upon protracted exposure symptoms are more prominent and resemble those of idiopathic Parkinson's disease, which it is often misdiagnosed as, although there are particular differences in both the symptoms (nature of tremors, for example), response to drugs such as levodopa, and affected portion of the basal ganglia. Symptoms are also similar to Lou Gehrig's disease and multiple sclerosis.

Causes

Manganism has become an active issue in workplace safety as it has been the subject of numerous product liability lawsuits against manufacturers of arc welding supplies. In these lawsuits, welders have accused the manufacturers of failing to provide adequate warning that their products could cause welding fumes to contain dangerously high manganese concentrations that could lead welders to develop manganism. Companies employing welders are also being sued, for what colloquially is known as "welders' disease." However, studies fail to show any link between employment as a welder and manganism (or other neurological problems).^[4][5][6]

Manganism is also documented in reports of illicit methcathinone manufacturing.^[7] This is due to manganese being a byproduct of methcathinone synthesis if potassium permanganate is used as an oxidiser.^[8] Symptoms include apathy, bradykinesia, gait disorder with postural instability, and spastic-hypokinetic dysarthria. Another street drug sometimes contaminated with manganese is the so-called "Bazooka", prepared by free-base methods from cocaine using manganese carbonate.^{[9][citation needed]}

Reports also mention such sources as contaminated drinking water,^[10] and fuel additive methylcyclopentadienyl manganese tricarbonyl (MMT),^[11] which on combustion becomes partially converted into manganese phosphates and sulfate that go airborne with the exhaust,^[12][13][14] and manganese ethylene-bis-dithiocarbamate (MANEB), a pesticide.^[15]

Pathological mechanisms

Manganese may affect liver function, but the threshold of acute toxicity is very high. On the other hand, more than 95% of manganese is eliminated by biliary excretion. Any existing liver damage may slow this process, increasing its concentration in blood plasma.^[16] The exact neurotoxic mechanism of manganese is uncertain but there are clues pointing at the interaction of manganese with iron,^{[17][18][19][20]} zinc,^[21] aluminum,^[17][21] and copper.^[21] Based on a number of studies, disturbed iron metabolism could underlie the neurotoxic action of manganese.^[22]

It participates in Fenton reactions and could thus induce oxidative damage, a hypothesis corroborated by the evidence from studies of affected welders.^[23] A study of the exposed workers showed that they have significantly fewer children.^[24] This may indicate that long-term accumulation of manganese affects fertility. Pregnant animals repeatedly receiving high doses of manganese bore malformed offspring significantly more often compared to controls.^[25] Manganism mimics Schizophrenia. It is found in large quantities in paint and steelmaking.

Treatment

The current mainstay of manganism treatment is levodopa and chelation with EDTA. Both have limited and at best transient efficacy. Replenishing the deficit of dopamine with levodopa has been shown to initially improve extrapyramidal symptoms,^[26][27][28] but the response to treatment goes down after 2 or 3 years,^[29] with worsening condition of the same patients noted even after 10 years since last exposure to manganese.^[30] Enhanced excretion of manganese prompted by chelation therapy brings its blood levels down but the symptoms remain largely unchanged, raising questions about efficacy of this form of treatment.^[31][32]

Increased ferroportin protein expression in human embryonic kidney (HEK293) cells is associated with decreased intracellular Mn concentration and attenuated cytotoxicity, characterized by the reversal of Mn-reduced glutamate uptake and diminished lactate dehydrogenase (LDH) leakage.^[2]

Locations

The Red River Delta near Hanoi has high levels of manganese or arsenic in the water, approximately 65 percent of the region’s wells contain high levels of arsenic, manganese, selenium and barium^[33] and published in the Proceedings of the National Academy of Sciences.

References

1. ^ Couper J. Sur les effets du peroxide de manganèse. Journal de chimie médicale, de pharmacie et de toxicologie, 1837; 3:223-225 free access fulltext at googlebooks
2. ^ ^{a b} [1], and also: Cotzias et al. 1968; Olanow 2004; Aschner et al. 2007; Ellingsen et al. 2008
3. ^ Roth JA (2006). "Homeostatic and toxic mechanisms regulating manganese uptake, retention, and elimination". Biol. Res. 39 (1): 45–57. PMID 16629164. 
4. ^ Fryzek JP, Hansen J, Cohen S, Bonde JP, Llambias MT, Kolstad HA, Skytthe A, Lipworth L, Blot WJ, Olsen JH. A cohort study of Parkinson's disease and other neurodegenerative disorders in Danish welders. Journal of occupational and environmental medicine / American College of Occupational and Environmental Medicine 2005 May;47(5):466-72.
5. ^ Fored CM, Fryzek JP, Brandt L, Nise G, Sjögren B, McLaughlin JK, Blot WJ, Ekbom A. Parkinson's disease and other basal ganglia or movement disorders in a large nationwide cohort of Swedish welders. Occupational and environmental medicine 2006 Feb;63(2):135-40.
6. ^ Marsh GM, Gula MJ. Employment as a welder and Parkinson disease among heavy equipment manufacturing workers. Journal of occupational and environmental medicine / American College of Occupational and Environmental Medicine 2006 Oct;48(10):1031-46.
7. ^ de Bie RM, Gladstone RM, Strafella AP, Ko JH, Lang AE (June 2007). "Manganese-induced Parkinsonism associated with methcathinone (Ephedrone) abuse". Arch. Neurol. 64 (6): 886–9. doi:10.1001/archneur.64.6.886. PMID 17562938. http://archneur.ama-assn.org/cgi/pmidlookup?view=long&pmid=17562938. 
8. ^ Sanotsky, Y., Lesyk, R., Fedoryshyn, L., Komnatska, I., Matviyenko, Y. and Fahn, S. (June 2007). "Manganic encephalopathy due to "ephedrone" abuse". Movement Disorders 22 (9): 1337–1343. doi:10.1002/mds.21378. PMID 17566121. 
9. ^ Ensing JG. Bazooka: cocaine-base and manganese carbonate. J. Anal. Toxicol. 1985; 9(1): 45-46.
10. ^ Kondakis XG, Makris N, Leotsinidis M, Prinou M, Papapetropoulos T. Possible health effects of high manganese concentration in drinking water. Arch. Environ. Health 1989; 44(3): 175-178.
11. ^ Hudnell HK. Effects from environmental Mn exposures: a review of the evidence from non-occupational exposure studies. NeuroToxicology 1999; 20(2-3): 379-397.
12. ^ Lynam DR, Roos JW, Pfeifer GD, Fort BF, Pullin TG. Environmental effects and exposures to manganese from use of methylcyclopentadienyl manganese tricarbonyl (MMT) in gasoline. NeuroToxicology 1999; 20(2-3): 145-150.
13. ^ Reynolds JG, Roos JW, Wong J, Deutsch SE. Manganese particulates from vehicles using MMT fuel. In 15th International Neurotoxicology Conference, Little Rock, AK, 1997.
14. ^ Lynam DR, Pfeifer GD, Fort BF, Gelbcke AA. Environmental assessment of MMT fuel additive. Sci. Total Environ. 1990; 93: 107-114.
15. ^ Ferraz HB, Bertolucci PH, Pereira JS, Lima JG, Andrade LA. Chronic exposure to the fungicide maneb may produce symptoms and signs of CNS manganese intoxication. Neurology 1988; 38(4): 550-553.
16. ^ Ballatori N. Molecular mechanisms of hepatic metal transport. In Molecular Biology and Toxicology of Metals, Zalups RK, Koropatnick J (eds). Taylor & Francis: New York, 2000; 346-381.
17. ^ ^{a b} Verity MA. Manganese neurotoxicity: a mechanistic hypothesis. NeuroToxicology 1999; 20(2-3): 489-497.
18. ^ Zheng W, Zhao Q. Iron overload following manganese exposure in cultured neuronal, but not neuroglial cells. Brain Res. 2001; 897(1-2): 175-179
19. ^ Zheng W, Zhao Q, Slavkovich V, Aschner M, Graziano JH. Alteration of iron homeostasis following chronic exposure to manganese in rats. Brain Res. 1999; 833(1): 125-132.
20. ^ Zheng W. Neurotoxicology of the brain barrier system: new implications. J. Toxicol. Clin. Toxicol. 2001; 39(7): 711-719.
21. ^ ^{a b c} Lai JC, Minski MJ, Chan AW, Leung TK, Lim L. Manganese mineral interactions in brain. NeuroToxicology 1999; 20(2-3): 433-444.
22. ^ Zheng W, Ren S, Graziano JH. Manganese inhibits mitochondrial aconitase: a mechanism of manganese neurotoxicity. Brain Res. 1998; 799(2): 334-342.
23. ^ Li G, Zhang L, Lu L, Wu P, Zheng W. Occupational exposure to welding fume among welders: alterations of manganese, iron, zinc, copper, and lead in body fluids and the oxidative stress status. J. Occup. Environ. Med. 2004; 46(3): 241-248.
24. ^ Lauwerys R, Roels H, Genet P, Toussaint G, Bouckaert A, De Cooman S. Fertility of male workers exposed to mercury vapor or to manganese dust: a questionnaire study. Am. J. Ind. Med. 1985; 7(2): 171-176.
25. ^ Treinen KA, Gray TJ, Blazak WF. Developmental toxicity of mangafodipir trisodium and manganese chloride in Sprague-Dawley rats. Teratology 1995; 52(2): 109-115.
26. ^ Lee J-W. Manganese Intoxication. Arch. Neurol. 2000; 57(4):597-599.
27. ^ Mena I, Court J, Fuenzalida S, Papavasiliou PS, Cotzias GC. Modification of chronic manganese poisoning. Treatment with Ldopa or 5-OH tryptophane. New Engl. J. Med. 1970; 282(1): 5-10.
28. ^ Rosenstock HA, Simons DG, Meyer JS. Chronic manganism. Neurologic and laboratory studies during treatment with levodopa. JAMA 1971; 217(10): 1354-1358.
29. ^ Huang CC, Lu CS, Chu NS, Hochberg F, Lilienfeld D, Olanow W, Calne DB. Progression after chronic manganese exposure. Neurology 1993; 43(8): 1479-1483.
30. ^ Huang CC, Chu NS, Lu CS, Chen RS, Calne DB. Long-term progression in chronic manganism: ten years of follow-up. Neurology 1998; 50(3): 698-700.
31. ^ Ono K, Komai K, Yamada M. Myoclonic involuntary movement associated with chronic manganese poisoning. J. Neurol. Sci. 2002; 199(1-2): 93-96.
32. ^ Calne DB, Chu NS, Huang CC, Lu CS, Olanow W. Manganism and idiopathic parkinsonism: similarities and differences. Neurology 1994;44:1583-1586.
33. ^ http://www.watertechonline.com/news.asp?N_ID=75635

External references

• Lucchini et al., "Metals and Neurodegeneration" - Research paper on heavy metals poisoning
• Antonini., "Health Effects of Welding" - Critical review including manganese discussion from National Institute of Occupational Safety and Health (NIOSH)
• Welding and Manganese Poisoning - Safety Corner column in IBEW Journal regarding manganese and welding.
• AWS Study on Welding and Exposure to Manganese - Report of an independent study commissioned by the American Welding Society
• Welding Fume Product Liability - Viewpoint of plaintiffs on welding rod litigation
• Welding Rod Litigation Information Network - Viewpoint of defense on welding rod litigation