Manganism

Manganism
SpecialtyOccupational medicine 
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Manganism or manganese poisoning is a toxic condition resulting from chronic exposure to manganese.[1] It was first identified in 1837 by James Couper.[2]

Signs and symptoms

Chronic exposure to excessive manganese levels can lead to a variety of psychiatric and motor disturbances, termed manganism. Generally, exposure to ambient manganese air concentrations in excess of 5 micrograms Mn/m3 can lead to Mn-induced symptoms.[3]

In initial stages of manganism, neurological symptoms consist of reduced response speed, irritability, mood changes, and compulsive behaviors.[4] Upon protracted exposure symptoms are more prominent and resemble those of idiopathic Parkinson's disease, as which it is often misdiagnosed, although there are particular differences in both the symptoms; for example, the nature of the tremors, 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).[5][6][7]

Manganism is also documented in reports of illicit methcathinone manufacturing.[8] This is due to manganese being a byproduct of methcathinone synthesis if potassium permanganate is used as an oxidiser.[9] 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.[10]

Reports also mention such sources as contaminated drinking water,[11] and fuel additive methylcyclopentadienyl manganese tricarbonyl (MMT),[12] which on combustion becomes partially converted into manganese phosphates and sulfate that go airborne with the exhaust,[13][14][15] and manganese ethylene-bis-dithiocarbamate (Maneb), a pesticide.[16]

Pathophysiology

Manganese may affect liver function, but the threshold of acute toxicity is very high. On the other hand, more than 95 percent of manganese is eliminated by biliary excretion. Any existing liver damage may slow this process, increasing its concentration in blood plasma.[17] The exact neurotoxic mechanism of manganese is uncertain but there are clues pointing at the interaction of manganese with iron,[18][19][20][21] zinc,[22] aluminum,[18][22] and copper.[22] Based on a number of studies, disturbed iron metabolism could underlie the neurotoxic action of manganese.[23]

It participates in Fenton reactions and could thus induce oxidative damage, a hypothesis corroborated by the evidence from studies of affected welders.[24] A study of the exposed workers showed that they have significantly fewer children.[25] 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.[26] It is found in large quantities in paint and steelmaking.

Diagnosis

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,[27][28][29] but the response to treatment goes down after 2 or 3 years,[30] with worsening condition of the same patients noted even after 10 years since last exposure to manganese.[31] 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.[32][33]

Increased ferroportin protein expression in human embryonic kidney (HEK293) cells is associated with decreased intracellular manganese concentration and attenuated cytotoxicity, characterized by the reversal of Mn-reduced glutamate uptake and diminished lactate dehydrogenase (LDH) leakage.[3]

Epidemiology

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.[34]

References

  1. ↑ Silva Avila, Daiana; Luiz Puntel, Robson; Aschner, Michael (2013). "Chapter 7. Manganese in Health and Disease". In Astrid Sigel, Helmut Sigel and Roland K. O. Sigel (ed.). Interrelations between Essential Metal Ions and Human Diseases. Metal Ions in Life Sciences. Vol. 13. Springer. pp. 199–227. doi:10.1007/978-94-007-7500-8_7. PMC 6589086. PMID 24470093.
  2. ↑ Couper, J. (1837). "Sur les effets du peroxide de manganèse". Journal de chimie médicale, de pharmacie et de toxicologie. 3: 223–5.
  3. 1 2 Yin, Zhaobao; Jiang, Haiyan; Lee, Eun-Sook Y.; Ni, Mingwei; Erikson, Keith M.; Milatovic, Dejan; Bowman, Aaron B.; Aschner, Michael (2010). "Ferroportin is a manganese-responsive protein that decreases manganese cytotoxicity and accumulation" (PDF). Journal of Neurochemistry. 112 (5): 1190–8. doi:10.1111/j.1471-4159.2009.06534.x. PMC 2819584. PMID 20002294.
  4. ↑ Roth JA (2006). "Homeostatic and toxic mechanisms regulating manganese uptake, retention, and elimination". Biol. Res. 39 (1): 45–57. doi:10.4067/S0716-97602006000100006. PMID 16629164.
  5. ↑ Fryzek JP, Hansen J, Cohen S, Bonde JP, Llambias MT, Kolstad HA, Skytthe A, Lipworth L, Blot WJ, Olsen JH (May 2005). "A cohort study of Parkinson's disease and other neurodegenerative disorders in Danish welders" (PDF). Journal of Occupational and Environmental Medicine. 47 (5): 466–72. doi:10.1097/01.jom.0000161730.25913.bf. PMID 15891525. S2CID 29870690.
  6. ↑ Fored, C M; Fryzek, JP; Brandt, L; Nise, G; Sjögren, B; McLaughlin, JK; Blot, WJ; Ekbom, A (2006). "Parkinson's disease and other basal ganglia or movement disorders in a large nationwide cohort of Swedish welders". Occupational and Environmental Medicine. 63 (2): 135–40. doi:10.1136/oem.2005.022921. PMC 2078076. PMID 16421393.
  7. ↑ Marsh GM, Gula MJ (October 2006). "Employment as a welder and Parkinson disease among heavy equipment manufacturing workers". Journal of Occupational and Environmental Medicine. 48 (10): 1031–46. doi:10.1097/01.jom.0000232547.74802.d8. PMID 17033503. S2CID 1355456.
  8. ↑ 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.
  9. ↑ 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. S2CID 11564105.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  10. ↑ Ensing, J. G. (1985). "Bazooka: Cocaine-Base and Manganese Carbonate". Journal of Analytical Toxicology. 9 (1): 45–46. doi:10.1093/jat/9.1.45. PMID 3981975.
  11. ↑ Kondakis, Xenophon G.; Makris, Nicolas; Leotsinidis, Michael; Prinou, Mary; Papapetropoulos, Theodore (1989). "Possible Health Effects of High Manganese Concentration in Drinking Water". Archives of Environmental Health. 44 (3): 175–178. doi:10.1080/00039896.1989.9935883. PMID 2751354.
  12. ↑ Hudnell, HK (1999). "Effects from environmental manganese exposures: A review of the evidence from non-occupational exposure studies". Neurotoxicology. 20 (2–3): 379–397. PMID 10385898.
  13. ↑ Lynam, DR; Roos, JW; Pfeifer, GD; Fort, BF; Pullin, TG (1999). "Environmental effects and exposures to manganese from use of methylcyclopentadienyl manganese tricarbonyl (MMT) in gasoline". Neurotoxicology. 20 (2–3): 145–150. PMID 10385878.
  14. ↑ Reynolds JG, Roos JW, Wong J, Deutsch SE. Manganese particulates from vehicles using MMT fuel. In 15th International Neurotoxicology Conference, Little Rock, AR, 1997.
  15. ↑ Lynam, D.R.; Pfeifer, G.D.; Fort, B.F.; Gelbcke, A.A. (1990). "Environmental assessment of MMT™ fuel additive". Science of the Total Environment. 93: 107–114. Bibcode:1990ScTEn..93..107L. doi:10.1016/0048-9697(90)90098-F. PMID 2113712.
  16. ↑ Ferraz, H. B.; f. Bertolucci, P. H.; Pereira, J. S.; Lima, J.G.C.; f. Andrade, L. A. (1988). "Chronic exposure to the fungicide maneb may produce symptoms and signs of CNS manganese intoxication". Neurology. 38 (4): 550–553. doi:10.1212/WNL.38.4.550. PMID 3352909. S2CID 20400188.
  17. ↑ Ballatori, N. (2000). "12. Molecular mechanisms of hepatic metal transport". In Zalups, R.K.; Koropatnick, J. (eds.). Molecular Biology and Toxicology of Metals. Taylor & Francis. pp. 346–381. ISBN 0748407987.
  18. 1 2 Verity, MA (1999). "Manganese neurotoxicity: A mechanistic hypothesis". Neurotoxicology. 20 (2–3): 489–497. PMID 10385907.
  19. ↑ Zheng, Wei; Zhao, Qiuqu (2001). "Iron overload following manganese exposure in cultured neuronal, but not neuroglial cells". Brain Research. 897 (1–2): 175–9. doi:10.1016/S0006-8993(01)02049-2. PMC 3980869. PMID 11282372.
  20. ↑ Zheng, Wei; Zhao, Qiuqu; Slavkovich, Vesna; Aschner, Michael; Graziano, Joseph H (1999). "Alteration of iron homeostasis following chronic exposure to manganese in rats". Brain Research. 833 (1): 125–132. doi:10.1016/S0006-8993(99)01558-9. PMC 4126166. PMID 10375687.
  21. ↑ Zheng, Wei (2001). "Neurotoxicology of the Brain Barrier System: New Implications" (PDF). Clinical Toxicology. 39 (7): 711–719. doi:10.1081/CLT-100108512. PMC 4111935. PMID 11778669.
  22. 1 2 3 Lai, JC; Minski, MJ; Chan, AW; Leung, TK; Lim, L (1999). "Manganese mineral interactions in brain". Neurotoxicology. 20 (2–3): 433–444. PMID 10385902.
  23. ↑ Zheng, Wei; Ren, Sean; Graziano, Joseph H. (1998). "Manganese inhibits mitochondrial aconitase: A mechanism of manganese neurotoxicity". Brain Research. 799 (2): 334–342. doi:10.1016/S0006-8993(98)00481-8. PMC 4126159. PMID 9675333.
  24. ↑ Li G, Zhang L, Lu L, Wu P, Zheng W (2004). "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. 46 (3): 241–8. doi:10.1097/01.jom.0000116900.49159.03. PMC 4126160. PMID 15091287.
  25. ↑ Lauwerys, Robert (1985). "Fertility of male workers exposed to mercury vapor or to manganese dust: A questionnaire study". American Journal of Industrial Medicine. 7 (2): 171–176. doi:10.1002/ajim.4700070208. PMID 3976664.
  26. ↑ Treinen, Kimberley A.; Gray, Tim J. B.; Blazak, William F. (1995). "Developmental toxicity of mangafodipir trisodium and manganese chloride in Sprague-Dawley rats". Teratology. 52 (2): 109–115. doi:10.1002/tera.1420520207. PMID 8588182.
  27. ↑ Lee, J.-W. (2000). "Manganese Intoxication". Archives of Neurology. 57 (4): 597–599. doi:10.1001/archneur.57.4.597. PMID 10768639.
  28. ↑ Mena I, Court J, Fuenzalida S, Papavasiliou PS, Cotzias GC (1970). "Modification of chronic manganese poisoning. Treatment with L-dopa or 5-OH tryptophane". N Engl J Med. 282 (1): 5–10. doi:10.1056/NEJM197001012820102. PMID 5307796.
  29. ↑ Rosenstock HA, Simons DG, Meyer JS (1971). "Chronic manganism. Neurologic and laboratory studies during treatment with levodopa". JAMA. 217 (10): 1354–8. doi:10.1001/jama.217.10.1354. PMID 4998860.
  30. ↑ Huang, C.-C.; Lu, C.-S.; Chu, N.-S.; Hochberg, F.; Lilienfeld, D.; Olanow, W.; Calne, D. B. (1993). "Progression after chronic manganese exposure". Neurology. 43 (8): 1479–83. doi:10.1212/WNL.43.8.1479. PMID 8351000. S2CID 12621501.
  31. ↑ Huang, C.-C.; Chu, N.-S.; Lu, C.-S.; Chen, R.-S.; Calne, D. B. (1998). "Long-term progression in chronic manganism: Ten years of follow-up". Neurology. 50 (3): 698–700. doi:10.1212/WNL.50.3.698. PMID 9521259. S2CID 34347615.
  32. ↑ Ono, Kenjiro; Komai, Kiyonobu; Yamada, Masahito (2002). "Myoclonic involuntary movement associated with chronic manganese poisoning". Journal of the Neurological Sciences. 199 (1–2): 93–96. doi:10.1016/S0022-510X(02)00111-9. PMID 12084450. S2CID 40327454.
  33. ↑ Calne, DB; Chu, NS; Huang, CC; Lu, CS; Olanow, W (1994). "Manganism and idiopathic parkinsonism: Similarities and differences". Neurology. 44 (9): 1583–1586. doi:10.1212/WNL.44.9.1583. PMID 7936278. S2CID 28563940.
  34. ↑ "Groundwater Pollution Red River Delta/Vietnam". Eawag — Swiss Federal Institute of Aquatic Science and Technology. 2011.
    Winkel LH, Pham TK, Vi ML, Stengel C, Amini M, Nguyen TH, Pham HV, Berg M (2011). "Arsenic pollution of groundwater in Vietnam exacerbated by deep aquifer exploitation for more than a century". Proc Natl Acad Sci U S A. 108 (4): 1246–51. doi:10.1073/pnas.1011915108. PMC 3029707. PMID 21245347.

Further reading

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