ࡱ> WYVY PbjbjWW p==ZLa]NNNNNNND&Ti(oqqq?p0$[O^TNT NN  NNoNNNNo  z:gNNoz ~ .e OHES Newsletter Special Issue 2/99 EDITORIAL The contents of this special issue of the OHES Newsletter have been prepared by the Scientific Advisory Group to IMnI under the chairmanship of Dr. E.G. Astrup of Elkem ASA, one of the leading experts in Europe on industrial toxicology. The details are, of necessity, in a condensed form and the references are listed in full so that readers can carry out their own study of this important subject matter. IMnI will be co-sponsoring an international conference on the general topic of "Manganese in Human Health" in 2001. More complete details and information will be available by the end of the year. V. Trelut, Chairman, OHES Committee C.D. DesForges, Executive Director April 1999 BACKGROUND In 1992 when IMnI arranged a major symposium on manganese toxicity, most previously published papers in the general medical literature described the cardinal signs of clinical overt manganism including bradykinesia, rigidity, tremor and postural/gait abnormalities. These same signs also characterised idiopathic Parkinson's Disease (PD) Most scientific papers describing human and animal experimental studies held the view that manganism like idiopathic PD was associated with: a progressive degeneration of dopaminergic cells in the central nervous system (CNS); the substantia nigra; clinical presentation in humans occurring only after a substantial reduction (80% and more) in the nigrostriatal dopamine concentration. Up to this point in time, there had been cases where workers exposed to manganese received different diagnoses depending whether the assessment was carried out by a neurologist or a neuropsychologist. This showed that occupational health physicians, basing their judgement on general medical expertise, were unable to differentiate between these two diseases if clinical symptoms alone were taken into account. Manganese exposure levels were rarely measured or considered. In the last decade, scientific conferences and the published literature have disclosed new information on disease mechanisms and that, by using new diagnostic techniques, it is now possible for manganism to be clinically differentiated from idiopathic PD. This information is of great value to occupational health physicians serving IMnI-member companies and this article is designed to give a brief introduction to the extensive body of information contained in the selected papers, leaving the individual physician or medical advisor to make his own judgement and interpretation of the contents of the selected papers. The Scientific Advisory Group (SAG) to the OHES Committee of the IMnI recommends the study of the original documents, as a supplement to current knowledge, enabling personal judgements and interpretations of the papers selected (see reference listing). The main objective of this particular exercise is to provide a documentary source which will enable industry to manage the primary Mn production processes so that manganism does not occur in the workforce. The information may well be of value to the various user industry sectors which handle manganese alloys and compounds in the manufacture of end products. A secondary objective is to provide those charged with the monitoring and the surveillance of the health of the relevant work forces with information on the optimum techniques for diagnosing possible manganism and enabling its differentiation from PD. IMnI is collating a list of physicians skilled in this diagnostic area of neurology and will ensure that it is both kept up to date and expanded as these skills become more widely diffused within medicine. PAPERS J. Rodier (1955) This early seminal paper by Rodier can provide the basis for the commonly-accepted knowledge of this subject and is outstanding for its clarity and the way in which illustrations and examples are provided. Introduction Rodier described the clinical syndrome of 150 cases of manganism in a Moroccan mine employing about 4 000 workers. He stated that "even if manganese since 1837 has been recognised as a poison affecting the CNS, it is less well known than other metallic poisons, and manganism continues to be rare since only a limited number of workers come into contact with manganese in a dangerous form." Rodier considered underground mining where the operations of "crushing/ pulverising ore" and dry boring of charge holes for blasting with a pneumatic drill, and the blasting operation itself, represent the highest health risk. 132 out of his 150 cases were using these drills. Both particle diameter distributions and concentration of manganese (Mn) were monitored, showing airborne Mn dust-concentration in the range of (120-872) mg/m3 at two of the mines. The number of particles in the respirable dimensions was also determined at each site. Rodier also discusses a whole range of other topics thought to be important for the ultimate risk of manganism in these Moroccan mines/sintering plants at that time. The neurological syndrome (CNS effects) Rodier described the disease of manganism as having three phases : The prodromal period with a number of listed subjective symptoms ; An intermediate phase corresponding with the onset of the earliest objective symptoms ; The period of full blown illness characterised by severe disorders leading to permanent disability. The variation in the onset of the disease is presented in a table, ranging from soon after one or two months of work, to one or two years of exposure and only rarely after a decade. However, this may be dose-dependent. The general onset is slow and progressive, but occasionally it will appear suddenly within a week accompanied by severe lumbar pain, where lumbar pain and cramps in the lower limbs are frequent. These three phases of disease are described by Rodier in very instructive detail. Sexually-related symptoms such as impotence were monitored in nearly 80% of his patients in the prodromal period. Commentary It is thus recommended that all plant physicians and medical advisors should read the symptom descriptions and carefully study the many tables showing the frequency of occurrence of the various symptoms during the three different phases, as well as the symptomatology of the disease related to varying degrees of disability. The details contained in pages 22 to 27 provide an essential input to the diagnostic tools of any occupational health physician concerned with exposure to manganese and its compounds and alloys. Rodier was searching for a test for manganese poisoning, but absolutely indisputable ones were not found. In the section "prophylaxis" he describes "Examination on first employment" and "Periodic medical inspection". Examinations were prescribed every two months for those workers he considered at highest risk. How to examine and follow up every worker who had stopped work for any reason and before eventually resuming work, is also described. Pre-manganism According to Rodier "the gravity of manganese poisoning demands in effect detection of a pre-manganism stage so that irreversible neurological manifes- tations [IMnI comment - now classified as overt manganism] may be avoided. The time that elapses between first contact with the metal and the appearance of neural lesions is of varying length. During this latent period it is reasonable to suppose that functional disturbances may precede organic lesions. The demonstration of such functional disorders would constitute an excellent clue to pre-manganism. Unfortunately, despite our research we have not been able to discover an absolute specific test for pre-manganism." However, Rodier claims that periodic examinations will allow the objective and subjective signs of intoxication to be observed. The only possible treatment is immediately to withdraw from the workplace anyone presenting the first symptom of intoxication, and from that moment the aim must be to rid the system (the organism) completely of manganese. COMMENTS ON OTHER LISTED REFERENCES As can be seen from the titles of the papers selected, manganism seems to have occurred in several occupational settings : The dry battery industry Welding of manganese-rich steel In ferro-manganese alloy plants In mining and crushing/milling some manganese ores Careful assessment of the papers discloses that studies and/or case descriptions of the workforce from a ferro-manganese alloy smelter in Taiwan gave rise to several of the papers listed. Wang J-D et al, (1989), Wolters E.C. et al (1991), Huang C-C et al (1993), Calne D.B. et al (1994), Shinotoh H et al (1997), Huang C-C et al (1997), Huang C-C et al (1998). The "Taiwan" cases relate the consequences of an overexposure to very high levels of airborne manganese (above 28.8 mg/m3) due to an accidental closing down of the ventilation system for 8 months in 1985. In order to differentiate between manganism and idiopathic PD, however, the paper by Calne D.B. et al (1994) "Manganism and idiopathic Parkinsonism; Similarities and Differences" needs to be highlighted. There are also other papers addressing this problem : Olanow C.W. (1996) on rhesus monkey, Shinotoh H. et al (1997) as well as several earlier papers where this is being discussed, with the tone of the debate somewhat depending on whether the paper is "manganism-based" or "Parkinsonism-based". At the international conference "Manganese - are there effects from long-term, low-level exposure" held in Little Rock, Arkansas, USA, in October 1997, it was stated that there should now be a consensus in the scientific world that these two disease conditions differ organically and therefore functionally. It should be pointed out that specific papers provided information on new diagnostic tools which might be used to the benefit of patients suspected of having "manganism". These include the use of single photon emission computer tomography (SPECT); positron emission tomography (PET) and magnetic resonance imaging (MRI). All these techniques are used on live patients and provide for examination of the brain in real time. These methods are costly, can only be administered in hospitals, demand skilled and experienced personnel, and above all require the informed consent of the patient since they may be invasive and require immobility for lengthy periods of time. Their future development will be of great value to occupational health surveillance projects. A brief explanation of each technique is provided at this point. Magnetic Resonance Imaging (MRI) is based on signals emitted by paramagnetic substances. It seems that the accumulation in the brain of manganese in paramagnetic form, can, depending on concentration, be revealed as a MRI signal change. Intravenous injection of paramagnetic substances which then enter the brain can also be used in combination with MRI. MRI can measure the diffusion of water in the tissues and during recent years it has also been further developed so as to register variables relating to blood circulation within the brain. PET and SPECT are isotopic methods in which the distribution of radio-labelled tracers in minute amounts is recorded. PET and SPECT have a much higher resolution than MRI and thus studies of receptors in the brain (at picomol concentrations) can be performed. Both are dependent on the injection of radioactive isotopes into the brain. Fluoro - 18 - labelled L-DOPA (L-deoxyphenyl-alanine) is used to mimic a precursor of dopamine in dopaminergic areas of the brain. Reduced fluoro-L-DOPA uptake in putamen can be seen in idiopathic PD, showing that the substantia nigra is the primary site of PD, while the same method applied to patients with manganism shows that dopamine production in substantia nigra pars compacta (basal ganglia) is not impaired. Manganism is therefore dependent on a defect downstream of the dopaminergic production in striatum and palladium (globus pallidus and substantia nigra pars reticularis). Comment : MRI may be used to differentiate between manganism and idiopathic PD. MRI may reveal a signal change attributable to manganism, while any such signal is absent in PD. (These changes are in "high field strength T-weighed MRIs" - consisting primarily of high signal abnormalities in the globus pallidus, striatum and substantia nigra pars reticularis (but not the substantia nigra pars compacta). Manganism, at least in the later stages of disease, never responds to treatment with L-DOPA, while PD does. Liver function should always be assessed in patients undergoing diagnosis for possible manganism as a dysfunctional liver may not allow the normal metabolism of manganese and may of itself lead to Mn accumulation without the individual having been specifically exposed to Mn. Selected List of References The literature references below have been listed chronologically to show how knowledge and understanding of this important medical issue have developed in recent years. Two text books, recently published (1996, 1997), have been included in this list, but it should be noted that they do not describe recent developments, recorded in the current scientific literature, and in particular do not describe the differential diagnoses of manganism and PD. This is a result of the lengthy time lags between text preparation and publication in book form. Rodier J. (1955) Manganese poisoning in Moroccan miners. Brit. J. lnd. Med., 12, p 21  35. Emara A.M. et al (1971) Chronic manganese poisoning in the dry battery industry. Brit. J. Ind. Med, p 78  82. Smyth L.T. et al. (1973) Clinical Manganism and Exposure to Manganese in the Production and Processing of Ferro-manganese Alloy. J. Occup. Med., p 101  109. Calne S., Schoenberg B., Martin W., Uitti R.J., Spencer P., Calne D.B. (1987) Familial Parkinson's Disease: Possible Role of Environmental Factors. Can. J. Neurol. Sci, p 303  305. Wang JD et al. (1989) Manganese-induced parkinsonism: an outbreak due to an unrepaired ventilation control system in a ferromanganese smelter. Brit. J. lnd. Med., 46, p 856  859. Wolters E.Ch. et al. (1989) Positron Emission Tomography in Manganese Intoxication. Ann. Neurol., 26, p. 647  651. Hua M-S. and Huang C-C. (1991) Chronic Occupational Exposure to Manganese and Neurobehavioral Function. J. Clin. Exp. Neuropsychology, 13, p 495 507. Tetrud, J.W., (1991) Preclinical Parkinson's disease: Detection of motor and nonmotor manifestations. Neurology, 41, (suppl 2) p 69  72. Watts R.L. et al. (1991) Electrophysiologic analysis of early Parkinson's disease. Neurology, 41 (suppl 2) p 44  48. International Manganese Institute, Paris (1992). Proceedings (pp 197). Symposium on Manganese Toxicity. K. Oygard et al p. 179 - 184 (See R.G. Feldman p. 143  159, and "Panel discussion", p 185  197). Shuqin K. et al. (1992) A report of two cases of chronic serious manganese poisoning treated with sodium para-aminosalicylic acid. Brit. J. Ind. Med., 49, p 66  69. Huang CC. et al (1993) Progression after chronic manganese exposure. Neurology, 43, p 1479  1483. Nelson K. et al. (1993) Manganese encephalopathy: utility of early magnetic resonance imaging. Brit. J. lnd. Med., 50, p 510  513. Semchuk K.M. et al (1993) Parkinson's disease: A test of the multifactorial etiologic hypothesis. Neurology, 43, p 1173  1180. Beuter A. et al (1994). Diadocho-kinesimetry: A Study of Patients with Parkinson's Disease and Manganese-Exposed Workers. NeuroToxicology, p 655  664. Calne D.B. et al. (1994) Manganism and idiopathic Parkinsonism: Similarities and differences. Neurology, 44, 1583  1586. Lill D.W. et al. (1994) Technetium 99mHMPAO Brain SPECT Evaluation of Neurotoxicity due to Manganese Toxicity. J. Nuclear Med., p 863 865. Chia, SE. et al (1995) Postural Stability Among Manganese-Exposed Workers. NeuroToxicology, p 519 526. Henry L. et al. (1995). Parkinson professionnel d au manganse: un diagnostic difficile. Arch. Mal Prof., 57, p 235  237. (in French). Larsen J.P. (1995) Differensialdiagnostikk ved parkinsonisme. (Differential diagnosis of Parkinsons Disease). Tidskr.Nor.Laegef., 115, p 1236  9. (in Norwegian, Abstract in English). Montgomery E.B. et al (1995) Heavy metals and the aetiology of Parkinson's disease and other movement disorders. Toxicology, p 3  9. Hochberg F. et al. (1996) Late motor deficits of Chilean manganese miners: A blinded control study. Neurology, 47 p. 788  795. Inoue, N et Makita, Y (1996) Neurological Aspects in Human Exposures to Manganese, Chapter 25, p 415  420. In "Toxicology of Metals" Ed Chang. L.W. CRC, Lewis publishers, New York, ISBN 1566708036. Mutti A. et al (1996) Serum Prolactin in Subjects Occupationally Exposed to Manganese. Ann. Clini. and Lab. Science, p 10  17. Olanow C.W. et al (1996) Manganese intoxication in the rhesus monkey: A clinical, imaging, pathologic, and biochemical study. Neurology, 46, p 492  498. Huang CC. et al (1997) Clinical/Scientific Notes, Cock Gait in Manganese Intoxication. Movement Disorders, 12, p 807  817. Manganese, Section 10 (Chapter 29, 30, 31 & 32) (1997) Mineral and metal neurotoxicology Ed: Yasui, M. et al. CRC Press, New York, ISBN 0849376645. Shinotoh H. et al. (1997) Presynaptic and postsynaptic striatal dopaminergic function in patients with manganese intoxication: A positron emission tomography study. Neurology, 48, p. 1053  1055. Barrington W.W. et al. (1998) Autonomic Function in Manganese Alloy Workers. Environmental Research, Section A 78, p 50  58. Huang CC. et al. (1998) Longterm progression in chronic manganism, Ten years of follow-up. Neurology, 50, p 698  700. Suggested supplementary reading of published literature on human studies This article has been written so that the best available current information can be disseminated on the differential diagnosis of manganism and idiopathic PD. In consequence, a number of papers dealing with the response of humans and other primates to manganese exposure have been excluded from this analytical review. IMnI maintains for its members a data-base which includes these papers. Some important categories are listed below. Many recent papers deal with total parental nutrition (TNP); the use of MRI; hepatic encephalopathy in relation to manganese blood levels and possible manganese toxicity, eg, the relationship/link between chronic liver failure and manganese intoxication. Papers covering research on humans involving the development of tests requiring scientific validation as specific for demonstrating "pre-manganism" (Rodier J.); "early changes in motor function" (Chia S.E.); "pre-clinical manganism" (Wennberg et al) and/or "sub-clinical manganism" (Roels H.; Mergler D.; Lucchini R.; Iregren A. etc). Papers specifically covering manganese exposure and its possible effect on the human reproductive function. Numerous papers on humans dealing more specifically with the mechanism of manganese toxicity and its dependence on exposure routes with possible mechanisms within brain tissues and cells. This includes the "historic" papers by Cotzias and more recent research on animal primates as well as in vitro research on different types of CNS cells and mitochondrial transport/function. Copyright April 1999 No part of this publication may be reproduced in any form whatsoever without obtaining IMnI's prior written consent. IMnI - 17 Av. 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