аЯрЁБс>ўџ CEўџџџBџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџьЅСY ПX9bjbjѓWѓW ŸN‘=‘=є4aџџџџџџ]ШШШ в оооD""""€ЂЖ4"yFіі(    ?Р Р€ Р@$ПєГbdоd6ооі666ъоо ""оооо 6D6z : oоо ъ €CSвб~П"".u OHES Newsletter 1/2000 EDITORIAL The OHES committee which is now chaired by Leif Andreassen (Tinfos, Norway) has met on 3 occasions since the Annual General Assembly held in Biarritz last June. Its principal concern has been to ensure that the overall objectives of the committee’s activities, which were established in 1997, satisfy the current and long-term needs for information, advice and knowledge on OHES affairs. A number of priorities have been established and these will be submitted to the IMnI Board for consideration at the next meeting. The committee has noted with pleasure the excellent response to its newsletter, and has identified the subjects of the various editions to be issued in 2000. The first of these is published below and has been co-written by Professor Michael Aschner (Wake Forest University, NC, USA) and IMnI’s executive director. It provides a general overview of the functioning of the human brain and what happens when it fails to operate normally. This is of interest to the Mn industry since one of the questions of concern is that of “are there long-term effects of low-level exposure to Mn on human health ?” Such effects, if any, are likely to manifest themselves at the level of the brain and in particular in certain specific areas of the brain. It is curious to note that our knowledge of brain function has been materially improved through studies of the effects of exposure to toxic substances. Professor Aschner, who is a leading expert on toxicological effects, is carrying out research on human cells in order to determine what is the role of manganese in cell activity, and from the information and understanding thereby gained, to assess possible beneficial anti-oxidant effects of manganese at the cellular level. His results will be reported at the next major conference on “manganese and human health”, which is being co-sponsored by IMnI and TFA, and will be held in Quebec City, Canada, in June 2001. A formal announcement of the conference and an initial call for papers are attached to this newsletter. It will provide the opportunity for the many interested parties to review the progress made since the “Little Rock” conference held in October 1997. Readers may wish to note that the proceedings of this conference have been peer-reviewed and published in a special issue of “Neurotoxicology” April/June 1999. The chairman and members of the OHES committee join me in wishing all our readers a happy and peaceful New Year and a good start to the twenty-first century. C.D. DesForges, Executive Director January 2000 BRAIN FUNCTION: WHAT CAN GO WRONG AND WHY? ( Introduction The study of poisons to nervous substance, known as neurotoxicology, is an exciting area of science, not only because of the importance of toxic damage to the nervous system in human disease, but also because specific toxins have been invaluable tools in improving our understanding of neurobiology. In fact, much of our knowledge of the organisation and function of the nervous system is based on observations made on the actions of toxins. The binding of drugs or poisons to cell membranes has provided the basis for the definition of specific receptors for signalling chemical substances (neuro-transmitters) within the brain. An understanding of the roles of different cell types in the function of the nervous system is based on the selectivity of certain toxicants in injuring only certain specific brain cell types. Finally, important differences in basic metabolic requirements of different groups of nerve cells have been defined from the effects of these toxins. Background To understand brain diseases, one must appreciate something of the anatomy, physiology, development, and healing capacity of the human nervous system. The complexity of the nervous system, however, can be reduced to a number of generalities that allow a basic understanding of the effects of toxicants. Some of these general principles are: 1. A privileged status of the nervous system that maintains a barrier between itself and the blood circulating within the body. 2. The importance of the energy requirements of the brain. 3. The extensions of the nervous system over space and the requirements of cells with such a complex geometry. 4. The maintenance of an environment rich in fatty materials (lipids). 5. The transmission of information across the space between cells; a fluid surrounding the brain cells (known as cerebrospinal fluid) occupies this space. 6. The brain is situated inside the skull and is surrounded by various membranes (meninges) that ensheath the brain. 7. Silent damage. Each of these features accounts in some fashion for the unique sensitivity of the nervous system to damage by toxic compounds. A discussion of each of the above principles now follows: 1. A privileged status of the nervous system that maintains a barrier between itself and the blood. Given the extraordinary complexity of the blood-brain barrier (BBB), it will be only briefly reviewed. The nervous system is a privileged system in the sense that it is almost completely protected by a barrier function provided by the cells of brain capillaries (known as endothelial cells). To gain entry to the nervous system, chemical molecules (including manganese) must pass through the cell membranes of these cells. As long as this barrier functions properly it protects the central nervous system (CNS), preventing the access of potential toxic substances. However, because of its unique properties it is also a potential target. Thus, when BBB function is compromised the brain can be injured by compounds that are normally excluded from the CNS. The supply of essential compounds to the brain across the BBB can also occur at excessive rates. 2. The importance of the energy requirements of the brain. Neurons (nerve cells; the functional unit of the nervous system) are highly sensitive to being deprived of oxygen. This vulnerability is a reflection of the high dependence of these cells on metabolism using oxygen. These cells share the property of conducting electrical impulses, and their dependence on oxygen emphasizes the high metabolic demand associated with the maintenance and reinstitution of ion gradients across their membranes. These processes occur with a frequency such that the cell must be able to produce large quantities of energy even in a resting state. This dependence on a continual source of energy (in the absence of energy reserves) places the neuron in a vulnerable position. To meet these high-energy requirements, the brain depends on the breakdown of sugars (glycolysis), and therefore, it is extremely sensitive to even brief interruptions of the supply of oxygen or glucose. For these reasons, prolonged lack of oxygen (hypoxia) regardless of its cause, often results in injury to the CNS, eg, drowning deprives an individual of oxygen. Deprivation of oxygen for more than a few minutes leads to a lethal injury of neurons. If the patient can be revived, the period of hypoxia and body temperature (during the hypoxia) will determine the severity of the injury or damage. As temperature is lowered, the need for oxygen is lessened and the cells are unable to conduct electrical impulses, and the brain fails to function. Within a few minutes, the damage is irreversible; neurons have died and, if the individual survives, the neurons will have been lost especially in those areas that are highly dependent on a continuous supply of oxygen. Toxicants that stop respiration have a similar effect. Cyanide and hydrogen sulphide, for example, prevent the cell engine (the mitochondria) from utilising oxygen. Similarly, when carbon monoxide combines with haemoglobin in the blood, the oxygen-carrying capacity of haemoglobin is reduced and high concentrations of carbon monoxide in the blood can completely deprive the organism of oxygen. 3. The extension of the nervous system over space and the requirements of cells with such a complex geometry. Electrical impulses are conducted over great distances at rapid speed and provide information about the environment to the organism in a coordinated manner that allows an organised response to be carried out at a specific site. The intricate organisation of such a communication network places an unusual and unparalleled demand on the cells of the nervous system. Single cells, rather than being spherical and a few micrometers in diameter, are cylindrical in shape and may be more than a metre long. The anatomy of such a complex intracellular network causes changes in both metabolism and cellular geometry that are peculiar to the nervous system. The immediate demands placed on the neuron are the maintenance of a much larger cellular volume and the transport of intracellular materials over great distances. Although the length of neurons may exceed 200,000 times the dimensions of most other cells, the cellular volume has not undergone a similar increase due to the unique ability of very fine cylindrical extensions of the cell to cover these long distances. This in turn leads to a volume that may be hundreds of times greater than that of the cell body itself. This places a great burden on the neuron, and makes it quite susceptible to injury. 4. The maintenance of an environment rich in lipids. The formation and maintenance of a lipid, known as myelin, that insulates the nerve processes, requires metabolic machinery and structural proteins that are unique to the nervous system. There are a variety of hereditary diseases in which myelin is either poorly formed or maintained. A number of genetic defects have provided some insight into the special processes required for maintaining the lipid-rich environment of myelin. Interference with production of myelin leads to abnormal conduction of impulses in neurons and it is easy to imagine how some toxic compounds interfere with this complex process of the maintenance of myelin and result in toxicity. 5. The transmission of information across extracellular space. Communication between nerve cells is established through the space between them, known as the synapse. Chemical messengers or neurotransmitters released from one nerve bind to an adjacent neuronal membrane and produce a response so that a message is sent on. The process of neurotransmission is a target of a variety of therapeutic drugs and there are a variety of toxic compounds that interact directly with the process of neuro-transmission, and hence form the basis of neurotransmitter-associated toxicity. (This is the basis for biological weapons such as nerve gas.) The same process that is the target of drug research programmes, is also the target of certain neurotoxic compounds. 6. The brain is situated within the skull and meninges The term edema is derived from the Greek Oidema, which means swelling. If such a swelling occurs within the closed confines of the skull and meninges, it can lead to life-threatening cessation of blood supply due to the raised intracranial pressure and displacement and damage of the brain tissue. Two types of brain swellings are recognised. One in which there is injury to the vessel wall leading to escape of water and plasma constituents into the surrounding brain tissue. The other type of swelling is characterised by a noxious factor that directly affects the elements of the brain, producing brain swelling, with the vascular permeability remaining relatively undisturbed. 7. Silent damage The endpoint of neurotoxicity may be either reversible or irreversible, depending on the specific effect, the duration and frequency of exposure, and the toxicity of the substance. The age at which neurotoxic effects are evaluated can strongly influence the outcome of exposure. With age, the functional capacity of the brain declines significantly, and chronic exposure to some neurotoxic substances is thought to accelerate this process. A small acceleration in the loss of functional capacity may, with time, have very significant effects. For example, the presumed functional capacity of a brain that has not been chronically (long-term) exposed to neurotoxic substances is more than 80 percent at age 65. However, even a modest acceleration in the rate of neuron death of 0.5% per year results in a functional capacity of 65%, a 15% reduction in this theoretical sample. A 1% acceleration in cell death could result in a large reduction of functional capacity at the same age (65). Hence the importance of avoiding long-term exposure to neurotoxic materials. Michael Aschner Charles DesForges Prof. Aschner is a member of staff at Wake Forest University School of Medicine, Winston-Salem, NC, USA. He can be contacted by e-mail: maschner @ wfubmc.edu The Welding Institute (TWI) based near Cambridge in England, has produced an excellent teaching aid in CD format dealing with welding fume, a potential source of occupational health problems if inadequate precautions are taken. Details by e-mail from: twisoft @ twi.co.uk. TWI is a member of the Joint European Manganese Industry Group (JEMIG) created by IMnI to discuss OHES matters of interest to producers and users of manganese-containing materials. Copyright Љ January 2000 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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