Brain, Vol. 123, No. 12, 2571-2573,
December 2000
© 2000 Oxford University Press
Book reviews |
EXPERIMENTAL AND CLINICAL NEUROTOXICOLOGY. Second edition.
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Department of Neurology, Institute of Psychiatry, London, UK
This new edition of Spencer and Schaumburg's Neurotoxicology is greatly welcomed, since the original edition is now long out of date and a large number of compounds, and industrial, pharmaceutical and environmental agents have been identified as likely or proven agents capable of causing some kind of damage to the nervous system. This is a large encyclopaedic volume with 162 contributors and 1253 pages of text, and it must be said at the outset that is it well worth the price. It has several very practical indexes enabling the reader readily to get the information needed by various routes. Thus, in addition to the conventional index and a list of contents with responsible authors, there are two appendices, the first a catalogue of agents with their putative toxic effects listed and in the second the various toxic effects are listed with agents that might be held responsible. Furthermore, a practical addition to these catalogues is a three step classification of each potentially toxic agent on an experimental or clinical level, as to the degree of probability or certainty, in the authors' view, of the agent being responsible for the toxic syndrome. This A/B/C grading of probable responsibility is attached to the agent in the text and in the two appendices making it simplicity itself to find the agent and to assess the likelihood of its toxicity being significant.
Another feature of this edition is the division of the volume into two sections. The first 105 pages deal, in three chapters, with the biological principles of neurotoxicity (Spencer), human neurotoxic disease (Schaumburg) and aspects of veterinary neurotoxicology (three authors). The advantage of the introductory chapters is that repetition of mechanisms is avoided when the individual agents are described. In the first two introductory chapters, however, there is only a limited bibliography made up of textbooks and specialist reference books, and the opinions expressed in the text are those of the authors, who, it must be admitted, have had unique experiences built up over many years of devotion to this field. Unfortunately, the absence of critical references in these sections means that the evidence for many of the statements cannot be readily challenged and only too often the text becomes just a series of unsupported assertions sometimes of rather vague and doubtful veracity. It is intended that the relevant parts of these sections should be read in conjunction with the details of the agents under consideration given elsewhere in the second, larger part of the volume, putting each into some sort of perspective. This may be a very valuable approach for someone coming new to the field with what for them might be a novel problem. The clinical chapter will be particularly appreciated for there will always be great uncertainty in the minds of those suspected of suffering from intoxication from one source or another, for the symptoms will often be vague and only too often hard physical signs of toxic damage may be difficult to elicit, especially in the encephalopathies that may have many possible origins which are rarely easy to prove responsible. Herb Schaumburg lays down some very basic principles to guide the clinician along this tortuous path, and these will no doubt also be closely studied by the coming generation of lawyers seeking to find arguments for or against their clients' suspected poisoning. There is a great deal of wisdom in this chapter.
The remainder of this large volume is given over to an alphabetical catalogue of potentially neurotoxic substances which are given large or small treatment according to the information available and the general importance of the toxic syndrome. Each is classified A, B or C according to whether there is a strong association, a plausible but unproven association or a suggested but unlikely causal relationship. References to published work on each agent are usually full, though occasionally a list may be 10 or 15 years short (e.g. organotin). The list is wide-ranging and global covering industrial and domestic substances, pharmaceuticals as well as plant and animal toxins. The world is small. These days the patient may just as well be living in the unhygienic tropics as to have just returned from a holiday therein with a spider's bite, or the sting of a mollusc or a sea snake during SCUBA diving. Dinoflagellates exist in all parts of the world and so do blue-green algae, both producing potent toxins that accumulate in shellfish and cause paralysis by blocking ion channels in various ways. These accounts are valuable since they are difficult to find in other sources and the authors have combed the world literature to provide a useful reservoir of information on these rare but important and often life-threatening poisons. Browsing through the catalogue is a journey through the realms of biology and pharmacology where untold dangers await the unwary from potentially toxic plants, some of which may also be therapeutically valuable, or from a host of small animals that use potentially toxic agents to protect themselves from predators or to catch and kill the fish or other animals they prey upon. It is instructive to learn that there are more than 500 species of marine cone shells that contain toxins, some of which can be lethal to man. Many agents from such lowly species, valuable for the analysis of ion channels, have been responsible for human fatalities. Albert Ludolph seems to have handled most of these rare and interesting agents and his particular tour de force among these is the various tremogens produced by fungi with their complex multi-ring (`chicken wire') chemical formulae. Toxins from plants are not always directly synthesized by the plant, but sometimes by fungi that invade the plant, and there are a number of such fungal toxins responsible for inducing tremor in animals and on occasions in man. Domestic animals, mainly sheep and cattle, are especially at risk from such agents, with consequent loss of stock.
The last three decades have seen the steady accumulation of detailed data about the clinical effects, and the selective vulnerability of different neurone and glial populations, and the underlying pharmacological and biochemical mechanisms have been largely unravelled, but despite these efforts most of the major chemical intoxications have yet to be fully explained. As an example the section by Marcello Lotti on the, now very complex, problem of organophosphorus intoxications is a tour de force justified by the worldwide use of these compounds, especially in the agrochemical industries. Despite this wealth of information the final mechanism of the `dying back' delayed neuropathy affecting long axons in PNS and CNS is still unknown. The biological question is often the hardest to answer. Another example, acrylamide peripheral neuropathy, once such a valuable experimental tool in the hands of clinical neurologists for developing methods for analysing peripheral neuropathy in man, is still a mechanistic puzzle. Throughout this catalogue of potentially neurotoxic agents most of the descriptive details are accurate and informative, but as with all such encyclopaedic volumes there are minor defects and omissions. Some agents may be mentioned in the clinical section (e.g. stilbamidine) or referred to in the biological section (e.g. chlorohydrin) but have not found their way into the catalogue. Organic (pentavalent) arsenicals, while no longer used to treat syphilis, are still valuable against tropical conditions such as trypanosomiasis and produce severe toxic brain damage (`brain purpura'). The section on arsenic does not make it clear that this unique effect is nothing to do with the toxicity of trivalent arsenic, but is a hypersensitivity response, the management and treatment of which is quite a different matter from trivalent arsenic poisoning. The clinical condition of chronic arsenical neuropathy is often indistinguishable from the neuropathy of beri-beri, as was clearly understood from the Salford epidemic of 1900 where arsenic found its way into the sugar used for brewing beer, so the author of that section need not have been so coy about firmly implicating binding of arsenic to lipoate as the basic mechanism of the neuropathy. Then there is the curious story of the cranial neuropathy induced by the anaesthetic trilene (trichloroethylene), which is not clarified at all here. Only cranial nerves are affected and the disturbance usually begins in the Vth nerves, and in severe cases appears to spread down the brainstem. This has never been reproduced in animals and although efforts have been made to find evidence for a direct toxic action on these centres, the results have been unconvincing and an entirely different process may well be responsible. Neurotoxic mechanisms are a source of endless interest and their diversity is an essential feature of the whole subject. It is rare for two chemically different compounds to produce the same neurotoxic actions, although as an exception one can quote carbon disulphide and 2,5-hexanedione, both substances which, while chemically so different, have the capacity to cross-link axonal neurofilaments and produce identical peripheral nerve lesions. Then there are triethyltin and hexachlorophene (hexachlorophane in UK), two structurally quite different chemicals producing exactly similar vacuolation of the myelin sheath by presumably having the same capacity to shuttle water molecules across myelin membranes by an energy independent mechanism, points not mentioned here
Neurotoxicity is a fascinating subject for any who think of neurological diseases in terms of causal, particularly cellular, mechanisms, for it is here that biochemistry, physiology and morphology come together to bring us to an understanding of the cellular biology of the nervous system. While the modern vogue in clinical research is towards unravelling the genetic basis of neurological disease, cellular neuropathology still presents an endless series of unanswered questions, and it is on the basis of our understanding of what goes wrong in those cells in disease states that therapeutic strategies have to be worked out. Without understanding this intimate biology of the nervous system much of our attempt to mitigate the effects of many severe disease states will be largely blind and ineffectual. We have still a lot to learn and students of neurotoxicology have a lot to offer. This book will be a sound source of information for a wide circle of practitioners in the wards and scientists in the laboratory for a long time to come.
Notes
Edited by P. S. Spencer and H. H. Schaumburg. 2000. New York: Oxford University Press. Price £145. Pp. 1350. ISBN 0-19-508477-2.
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