Toxicology of Sensory Systems: A Perspective
Identifieur interne : 000E43 ( Istex/Corpus ); précédent : 000E42; suivant : 000E44Toxicology of Sensory Systems: A Perspective
Auteurs : E. A. Lock ; E. S. HarpurSource :
- Human & Experimental Toxicology [ 0960-3271 ] ; 1992-11.
English descriptors
- Teeft :
- Acta otolaryngologica, Airflow, Alderley park, Aminoglycoside, Aminoglycoside antibiotics, Animal models, Aran, Carbon monoxide, Cochlea, Cochlear, Critical reviews, Cutaneous sensation, Cytochrome, Drug metabolism, Drug metabolizing enzymes, Environmental health perspectives, Epithelium, Ethacrynic acid, Exhaustive list, Experimental animals, Functional deficit, Gentamicin, Guinea, Guinea pigs, Hair cells, Hearing function, Hearing research, High dosage, High doses, Lesion, Many years, Metabolism, Model system, Nasal, Nasal cavity, Nasal cytochrome, Nasal cytochromes, Nasal epithelium, Nasal lesions, Nasal passages, Nasal tissue, Neurosensory epithelium, Ocular toxicity, Ohcs, Olfactory, Olfactory epithelium, Olfactory toxicity, Ototoxic, Ototoxic aminoglycoside antibiotic, Ototoxic chemicals, Ototoxic drugs, Ototoxic effects, Ototoxicity, Peripheral sensation, Permanent loss, Professor aran, Professor blain, Respiratory epithelium, Retina, Rhesus monkeys, Selective toxicity, Single dose, Species differences, Sterling winthrop research centre, Stria vascularis, Term ototoxicity, Toxicity, Toxicology, Vestibular, Vestibular function, Vestibular system, Wide range.
Abstract
This brief review is the result of a recent meeting of the British Toxicology Society (Toxicology of Sensory Systems, University of York, April 2-3, 1992). The meeting provided the opportunity to discuss the anatomy, physiology and function of the eye, ear, nasal epithelium and peripheral sensation and the methods that are available to detect injury or dysfunction both in the preclinical and clinical situation. In addition, the mechanism whereby certain chemicals can perturb some of these organs was discussed. The aim of this short article is to highlight some of the recent advances in understanding in these areas with regard to their relevance or impact on toxicology. For convenience the areas will be discussed under separate headings.
Url:
DOI: 10.1177/096032719201100602
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ISTEX:C86C7FF70A8A6819ED1CD9ED0A0EBC965B61F05CLe document en format XML
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Harpur</name><affiliation><mods:affiliation>Department of Toxicology, Sterling Winthrop Research Centre, Alnwick, Northumberland, UK</mods:affiliation></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">ISTEX</idno><idno type="RBID">ISTEX:C86C7FF70A8A6819ED1CD9ED0A0EBC965B61F05C</idno><date when="1992" year="1992">1992</date><idno type="doi">10.1177/096032719201100602</idno><idno type="url">https://api.istex.fr/ark:/67375/M70-5JS9RDJ9-R/fulltext.pdf</idno><idno type="wicri:Area/Istex/Corpus">000E43</idno><idno type="wicri:explorRef" wicri:stream="Istex" wicri:step="Corpus" wicri:corpus="ISTEX">000E43</idno></publicationStmt><sourceDesc><biblStruct><analytic><title level="a" type="main" xml:lang="en">Toxicology of Sensory Systems: A Perspective</title><author wicri:is="90%"><name sortKey="Lock, E A" sort="Lock, E A" uniqKey="Lock E" first="E. A." last="Lock">E. A. 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Harpur</name><affiliation><mods:affiliation>Department of Toxicology, Sterling Winthrop Research Centre, Alnwick, Northumberland, UK</mods:affiliation></affiliation></author></analytic><monogr></monogr><series><title level="j">Human & Experimental Toxicology</title><idno type="ISSN">0960-3271</idno><idno type="eISSN">1477-0903</idno><imprint><publisher>Sage Publications</publisher><pubPlace>Sage CA: Thousand Oaks, CA</pubPlace><date type="published" when="1992-11">1992-11</date><biblScope unit="volume">11</biblScope><biblScope unit="issue">6</biblScope><biblScope unit="page" from="442">442</biblScope><biblScope unit="page" to="448">448</biblScope></imprint><idno type="ISSN">0960-3271</idno></series></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0960-3271</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="Teeft" xml:lang="en"><term>Acta otolaryngologica</term><term>Airflow</term><term>Alderley park</term><term>Aminoglycoside</term><term>Aminoglycoside antibiotics</term><term>Animal models</term><term>Aran</term><term>Carbon monoxide</term><term>Cochlea</term><term>Cochlear</term><term>Critical reviews</term><term>Cutaneous sensation</term><term>Cytochrome</term><term>Drug metabolism</term><term>Drug metabolizing enzymes</term><term>Environmental health perspectives</term><term>Epithelium</term><term>Ethacrynic acid</term><term>Exhaustive list</term><term>Experimental animals</term><term>Functional deficit</term><term>Gentamicin</term><term>Guinea</term><term>Guinea pigs</term><term>Hair cells</term><term>Hearing function</term><term>Hearing research</term><term>High dosage</term><term>High doses</term><term>Lesion</term><term>Many years</term><term>Metabolism</term><term>Model system</term><term>Nasal</term><term>Nasal cavity</term><term>Nasal cytochrome</term><term>Nasal cytochromes</term><term>Nasal epithelium</term><term>Nasal lesions</term><term>Nasal passages</term><term>Nasal tissue</term><term>Neurosensory epithelium</term><term>Ocular toxicity</term><term>Ohcs</term><term>Olfactory</term><term>Olfactory epithelium</term><term>Olfactory toxicity</term><term>Ototoxic</term><term>Ototoxic aminoglycoside antibiotic</term><term>Ototoxic chemicals</term><term>Ototoxic drugs</term><term>Ototoxic effects</term><term>Ototoxicity</term><term>Peripheral sensation</term><term>Permanent loss</term><term>Professor aran</term><term>Professor blain</term><term>Respiratory epithelium</term><term>Retina</term><term>Rhesus monkeys</term><term>Selective toxicity</term><term>Single dose</term><term>Species differences</term><term>Sterling winthrop research centre</term><term>Stria vascularis</term><term>Term ototoxicity</term><term>Toxicity</term><term>Toxicology</term><term>Vestibular</term><term>Vestibular function</term><term>Vestibular system</term><term>Wide range</term></keywords></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">This brief review is the result of a recent meeting of the British Toxicology Society (Toxicology of Sensory Systems, University of York, April 2-3, 1992). The meeting provided the opportunity to discuss the anatomy, physiology and function of the eye, ear, nasal epithelium and peripheral sensation and the methods that are available to detect injury or dysfunction both in the preclinical and clinical situation. In addition, the mechanism whereby certain chemicals can perturb some of these organs was discussed. The aim of this short article is to highlight some of the recent advances in understanding in these areas with regard to their relevance or impact on toxicology. 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The meeting provided the opportunity to discuss the anatomy, physiology and function of the eye, ear, nasal epithelium and peripheral sensation and the methods that are available to detect injury or dysfunction both in the preclinical and clinical situation. In addition, the mechanism whereby certain chemicals can perturb some of these organs was discussed. The aim of this short article is to highlight some of the recent advances in understanding in these areas with regard to their relevance or impact on toxicology. 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<contrib-group><contrib contrib-type="author" xlink:type="simple"><name name-style="western"><surname>Lock</surname><given-names>E.A.</given-names></name><aff>ICI Central Toxicology Laboratory, ICI plc, Alderley Park, Macclesfield, Cheshire, UK</aff></contrib></contrib-group>
<contrib-group><contrib contrib-type="author" xlink:type="simple"><name name-style="western"><surname>Harpur</surname><given-names>E.S.</given-names></name><aff>Department of Toxicology, Sterling Winthrop Research Centre, Alnwick, Northumberland, UK</aff></contrib></contrib-group>
<pub-date pub-type="ppub"><month>11</month><year>1992</year></pub-date><volume>11</volume><issue>6</issue><fpage>442</fpage><lpage>448</lpage><abstract><p>This brief review is the result of a recent meeting of the British Toxicology Society (Toxicology of Sensory Systems, University of York, April 2-3, 1992). The meeting provided the opportunity to discuss the anatomy, physiology and function of the eye, ear, nasal epithelium and peripheral sensation and the methods that are available to detect injury or dysfunction both in the preclinical and clinical situation. In addition, the mechanism whereby certain chemicals can perturb some of these organs was discussed. The aim of this short article is to highlight some of the recent advances in understanding in these areas with regard to their relevance or impact on toxicology. For convenience the areas will be discussed under separate headings.</p></abstract><custom-meta-wrap><custom-meta xlink:type="simple"><meta-name>sagemeta-type</meta-name><meta-value>Editorial</meta-value></custom-meta><custom-meta xlink:type="simple"><meta-name>search-text</meta-name><meta-value>442 EditorialToxicology of Sensory Systems: A Perspective SAGE Publications, Inc.1992DOI: 10.1177/096032719201100602 E.A. Lock ICI Central Toxicology Laboratory, ICI plc, Alderley Park, Macclesfield, Cheshire, UK E.S. Harpur Department of Toxicology, Sterling Winthrop Research Centre, Alnwick, Northumberland, UK This brief review is the result of a recent meeting of the British Toxicology Society (Toxicology of Sensory Systems, University of York, April 2-3, 1992). The meeting provided the opportunity to discuss the anatomy, physiology and function of the eye, ear, nasal epithelium and peripheral sensation and the methods that are available to detect injury or dysfunction both in the preclinical and clinical situation. In addition, the mechanism whereby certain chemicals can perturb some of these organs was discussed. The aim of this short article is to highlight some of the recent advances in understanding in these areas with regard to their relevance or impact on toxicology. For convenience the areas will be discussed under separate headings. . The eye and ocular toxicity , . The eye is structurally and functionally a complex organ, whose sole function is photosensory reception. The retina is concerned with the conversion of light energy to neural impulses which are then transmitted to the brain via the optic nerve. The eye also contains two large avascular areas, the lens and cornea, which depend on active transport systems in the eye for maintaining a steady-state of hydration and hence transparency. The organ also possesses a blood-retinal barrier, analogous to the blood-brain barrier, for the supply of nutrients and oxygen. The detailed anatomy and function of the eye was described by Dr Robinson (ICI plc Central Toxicology Laboratory, Alderley Park) and for more detailed information see texts by Martin and Anderson' and Davson .2 A number of techniques of varying degrees of sophistication are available for evaluating the potential effect of chemicals to the eye and they are essentially similar in experimental animals and clinically studies in man. These primarily involve examination of the eye lids, conjunctiva, cornea, lens, vitreous humour and retina using a number of biomicroscopy techniques, such as an ophthalmoscope, or fundus camera. The application of these methods were descriped for laboratory animals (Mr Buist, Huntingdon Research Centre, Huntingdon) and for man (Professor . Arden, Institute of Ophthalmology, Moorfields Eye Hospital, London). These techniques can detect age-related changes in the eye, such as the onset of cataracts and those induced by chemicals such as steroids3 They are also applicable to the detection of compound deposition or accumulation into specific structures which may be damaged as a consequence. For example, gold coloured crystalline deposits in the retina have been described in man after the oral use of drugs containing the carotenoid, canthaxanthin.4 Patients with hypersensitivity of the skin to sunlight have for many years been treated orally with pharmacological doses of carotenoids which accumulate in the skin and act as a protective filter against sunburn. Crystalline retinopathy has been found in patients after long-term drug usage, although none of these patients had visual complaints. Recently, gold dust crystals, very similar to those seen with canthaxanthin intake have been reported in patients who claim not to have used drugs or tanning agents containing this chemical.s Other sources of canthaxanthin are the diet where as E161G it is used as a yellow- orange colourant for soft drinks, sweets and yoghurt and as an additive to chicken and trout- feed to improve the colour of egg yolk and fish meat. Whether this is the source of the canthaxanthin that accumulates in the eye awaits further study. Other techniques which can be used to detect changes in the eye are examination of the retina by fluorescence angiography which can detect vascular abnormalities or pathologically-induced increases in permeability of the blood-retinal 443 barrier. Abnormalities in the formation or drainage of aqueous humour can be determined by monitoring intra-ocular pressure. The eye is specifically adapted to allow electromagnetic radiation in the optical part of the spectrum to penetrate deep within it. Age-related retinal degeneration is the single largest cause of registerable blindness in the western world and light is thought to play a role in the rate at which the retina degenerates. This was the theme developed by Professor Marshall, (Department Ophthalmology, St Thomas' Hospital, London), where he discussed the large metabolic demand and hence blood supply required by the outer retina to meet the rapidly turnover of rods in the eye. The potential for synergistic interactions between drugs or foreign chemicals and light in the retina is obviously unique to this part of the eye, thus photochemically-induced reactions are particularly important with regard to retinal toxicity. The drug chloroquine at high dosage for a long time has been reported to cause retinopathy in man. The clinical findings accompanying chloroquine retinopathy are frequently described in terms of early and late phenomena. Among the early findings are a 'bull's-eye retina', seen as a dark, central pigmented area involving the macula surrounded by a pale ring of depigmentation and then another ring of pigmentation. An electro-oculogram shows a diminished response and some blurred vision and difficulty in reading occurs, these early effects are followed by a number of later events which are irreversible, e.g. narrowing of the retinal artery, colour and night blindness.6 Other drugs that have been shown to cause ocular effects are the phenothiazine tranquilizers, which at high dosage can cause effects involving the cornea, lens and retinae The iron-chelating agent, desferrioxamine, that is used clinically to reduce iron overload in thalassemia major, has been reported to cause ocular toxicity.~~9 Interestingly, desferrioxamine has also been reported to cause acute sensorineural deafness in a patient, with B-thalassemia major anaemia, receiving high doses for treatment of transfu- sional iron overload'O and subacutely in a patient with chronic renal failure receiving low doses." I I The ear and ototoxicity The term ototoxicity is sometimes used to refer to the process by which chemicals, the vast majority of which are drugs, deleteriously affect the sense of hearing or the sense of balance. Although when drug-induced loss of hearing or dysequilibrium was first observed it was believed to result from injury to central pathways, it is now well established that in all known cases of ototoxic injury the lesions in the peripheral end-organs.'z Thus the use of the term ototoxicity is now usually restricted to damage caused to the inner ear. The inner ear can be regarded, in functional terms, as if it were divided into two structures; the cochlea, subserving the sense of hearing, and the vestibular organs, subserving the sense of balance. In fact each of these structures comprises a number of morphologically and physiologically distinct tissues. The complex cellular organization and its relationship to function was the subject of an introductory teaching seminar by Dr Harpur (Sterling Winthrop Research Centre, Alnwick). Each neurosensory epithelium comprises several distinct cell populations including the sensory cells, or hair cells (HCs), the innervating nerve fibres and various supporting cells. Even the HCs are divided into two distinct populations in both the cochlea, where they are organized into what are known as inner hair cells (IHCs) and outer hair cells (OHCs), and the vestibular structures, where the hair cells are designated type I and type II. Ototoxicity is an example of a highly selective organ-directed toxicity. It is apparent that permanent loss of hearing is always associated with death of HCs. HCs appear to die in a very stereotypic fashion, even from a variety of chemically and pharmacologically disparate insults and indeed from the effects of mechanical injury (noise). Typically, in the vestibular system the type I HCs in the centre of the neurosensory epithelia are first affected and at particular doses may be selectively affected. In the organ of Corti (the neurosensory epithelium in the cochlea) the OHCs are often much more affected than the IHCs and HC death almost always first affects the lower end of the cochlea, resulting in a high frequency hearing loss, but can progress to affect HCs nearer the apex of the cochlea and to involve lower frequencies. In contrast to the essentially predictable manner in which HC death results from diverse causes, some compounds which bear a close structural relationship (e.g. the aminoglycoside antibiotics) differ in the extent to which they affect the HCs of the cochlea or the vestibular system. Thus, although gentamicin and tobramycin are both vestibulotoxic and cochleotoxic, dibekacin is predominantly vestibulotoxic" unlike amikacin, which shows a remarkable selectivity for the cochlea." There is much interest in animal models of ototoxicity and in appropriate methods of assessment of morphological damage and derangement of function. There have been very 444 considerable advances in this field in recent years. Indeed, ototoxic drugs have proved invaluable tools to improve our understanding of basic mechanisms of hearing. Professor Aran (Experimental Audiology Laboratory, University of Bordeaux) made the point that there is very good agreement between the functional and morphological changes induced by the administration of ototoxic drugs to guinea pigs; the animal most often used in this field of research. Although ototoxic effects on vestibular function have been successfully monitored in guinea pigs by an objective method - nystagmic (involuntary eye movement) responses to rotational stimulation'3 - most studies have been confined to the effects of drugs on hearing. This is in part because measurement of the electrophysiological responses associated with hearing are more easily recorded than those associated with vestibular function and in part because the drive to study drug-induced loss of hearing is greater, since this is a more serious disability. In most circumstances the human subject can use other sensory input to compensate for permanent loss of sensory function of the vestibular end-organs, whereas sensorineural hearing loss is disabling. In addition to behavioural end-points, serial measurement of hearing function in small animals can be measured by electrodes implanted in the cochlea. This permits, for example, measurement of the development and progression of the deficit ensuing from chronic administration of an aminoglycoside antibiotic.'5 Application of such technology can contribute greatly to our understanding of ototoxic processes and would also be potentially very useful for assessment of the ototoxic potential of a novel chemical. However, the methods are very specialized and do not readily lend themselves to routine application. Recently, it has been discovered that the ear has the ability not only to receive and transduce sound but also to generate and emit sound (otoacoustic emission, OAE), through an active mechanical process. This property is now known to be a function of the OHCs which have been shown to be capable of contraction, when studied in short- term culture. Since the OHCs are the primary target of most ototoxic chemicals, OAEs provide a sensitive and objective means to assess cochlear function, which can be applied non- invasively.16 The procedure can be used repeatedly and reproducibly in individual subjects and is finding increasing application, especially for testing cochlear function in newborn babies. Measurement of OAEs has been shown to be a sensitive, reproducible method for assessment of ototoxic effects in the cochlea of animals.17 Referring to the predictive value of animal studies for ototoxic potential in man, Professor Aran pointed out that most laboratory studies use guinea pigs and very high doses of the test chemicals. Nevertheless, he felt that the animal findings are relevant to man. At clinical doses the response of patients is very variable; some patients appear, for reasons which are only partially understood,12 to be very sensitive and develop ototoxicity. The animal models are predictive not only of the response of the 'average' patient but also of the sensitive patient. Although there is reasonable ground for believing that the guinea pig can provide a valuable predictive model of human ototoxicity, observed species differences in the response of animals to administration of ototoxic chemicals should introduce a note of caution. For example, dihyrostreptomycin, which is potently cochleotoxic in humans and in the patas monkey, is comparatively inoccuous in other species including the macaque monkey.'8.'9 However, there are few other well documented examples of species differences in the response of animals to ototoxic chemicals. Professor Wright (Institute of Laryngology and Otology, London) highlighted the difficulties of monitoring for ototoxicity in patients. Historically, the difficulties have included the complex clinical milieu and the possibility that the disease itself may cause the symptoms of ototoxicity, but particularly the inadequacy of the available methods. To some extent these difficulties persist today, e.g. the problem of assessing hearing function in sick patients on a noisy ward'O or distinguishing an ototoxic effect from the very similar consequences of advancing age (presbycusis) - loss of hearing function at high frequencies. Further problems in studying ototoxicity in patients include the difficulty of obtaining tissue to correlate the presence of a functional deficit with a morphological lesion. However, such data as are becoming available suggest that, on the whole, the correlation between functional deficit and structural injury seen in animals is also observed in humans who have suffered an ototoxic insUlt.21 Attention was focused not only on the predic- tivity of animal models for the risk of ototoxicity occurring in humans but also on some interesting mechanistic investigations. It is apparent that, despite many years of intensive endeavour by a large number of scientists the reason for the selective vulnerability of the inner ear to even a single chemical is not understood. Professor Aran presented data which demonstrated that the explanation does not lie in selective accumulation of chemicals in the perilymphatic fluids which surround the HCs in 445 the cochlea and the vestibular system.22 Evidence against a pharmacokinetic explanation of ototoxicity has also come from other laboratories.23.24 Nevertheless, it has been shown recently25 both that the ototoxic aminoglycoside antibiotic, gentamicin, is present in HCs before the occurrence of functional changes and that the clearance of the drug from the HCs is very slow. Using immunohistochemical techniques, gentamicin has been detected in cochlear HCs of guinea pigs 24 h after daily administration of the drug for 6 d. However, there were no function changes at this stage; indeed, gentamicin was found to persist in the HCs for 41 d post-treatment with only minimal effect on function. Using the synergistic ototoxic interaction of ethacrynic acid with gentamicin as a model system, Professor Aran presented evidence for the presence of aminoglycoside antibiotics inside HCs in the guinea pig cochela, hours after administration of a single dose, prior to the occurrence of any functional changes. Furthermore, the development of permanent injury could be prevented by housing the animals in a soundproof room.26 Thus it was concluded that sound potentiates both the cellular uptake of an ototoxic aminoglycoside antibiotic and its intracellular toxicity. Although the majority of known ototoxic chemicals, and by far the most extensively studied, are drugs, Fechter and his colleaguesz'-3o have studied the effects of environmental chemicals including carbon monoxide and trialkyltins. Dr Fechter (Division of Toxicological Sciences, Johns Hopkins University, Baltimore) reported that, although the potential targets of ototoxic agents in the cochlea are the stria vascularis, an ion-secreting structure, the IHCs and the OHCs and the type I ganglion cells in the primary afferent pathway, there are no environmental agents known to effect the stria vascularis. As an example of an environmental chemical with ototoxic potential, Dr Fechter cited carbon monoxide. It has been demonstrated that carbon monoxide can potentiate noise-induced hearing loss. Exposure to noise and carbon monoxide produces extensive loss of OHCs in t.he organ of Corti.28 The neurotoxicological properties of the trialkyltins have been studied extensively for many years. More recently, trimethyltin has been shown to be ototoxic in both the rat and the guinea pig at the level of the cochlea.27. 29 The effects of a single dose of trimethyltin on auditory function are rapid in onset and only slowly reversible. When measured some weeks after exposure, injury is apparent in both OHCs and the stria vascularis.29 This is associated with loss of the cochlear microphonic (CM) potential, a measure of OHC function, and elevation of the threshold of the compound action potential (CAP) of the cochlear nerve. However, it has recently been shown,30 that the acute changes produced in the cochlea by exposure to either trimethyltin and triethyltin are different to those seen days or weeks after exposure. At early times after exposure CAP is affected selectively; CM is unaffected. This suggests a primary effect on IHC or spiral ganglion cell function, although the exact site and mechanism remains to be resolved. Nasal epithelium and olfactory toxicity The sense of smell, olfaction, is one of the main functions associated with the nose, and is used for: the recognition of surroundings and territory ; recognition of members of the same species for both sexual and asexual purposes; warning of changes in the environment (smoke from a fire or poisonous airborne materials); and in the acquisition of food. Furthermore taste is largely an olfactory function. The extent and distribution of olfactory epithelium, the tissue in the airways that performs olfaction, varies with the degree to which a species makes use of olfaction. In man the olfactory epithelium comprises of an area about 10-12.5 cm2, whereas in a species that relies on olfaction, e.g. the cat, it is about 21 cm2. Olfactory acuity decreases with the decrease in area of olfactory structures, although discriminating abilities appear to be relatively unaffected and seem to be partly learned, e.g. wine conois- seur or perfumer. The conveyance of odorant . particles to the olfactory epithelium appears to be accomplished in a number of ways. Particles may be carried on mucus by ciliary action to the more anterior olfactory epithelium, or may reach the more posterior regions by diffusion. The most important route is by passage in the respiratory air currents, where inhalation or sniffing . can carry materials to the more posterior epithelium. Recently, improved methods for histopatho- . logical examination of the nasal passages, and a greater attention to this organ following exposure to chemicals (particularly following inhalational exposure), have led to the discovery that many chemicals cause injury to the nasal passages.31 Increasingly chemicals are being shown to cause lesions in the olfactory epithelium of experimental animals following different routes of administration such as inhalation or nasal instillation but also following systemic routes (Table 1). In many cases the lesions are restricted to small but distinct areas of the nasal cavity. For example, a wide range of highly water soluble, gaseous 446 Table 1 Chemicals that induce olfactory lesions in experimental animals by either inhalation and or non-inhalation routes. This is not an exhaustive list, but illustrates some of the chemicals that cause selective toxicity to the olfactory epithelium, adapted from Gaskell.43 irritants (e.g. chlorine, hydrogen chloride, dimethylamine and acrolein) induce lesions in the olfactory epithelium of the dorsal meatus and also the respiratory epithelium adjacent to the nasal vestibule and lining the naso- and maxillo- turbinates, whereas the lesions produced by methyl bromide, 3-methylfuran and 3-trifluoromethylpyridine are confined to regions of olfactory epithelium. Such site-selectively may be attributed to two key factors; first, regional deposition of the chemicals within the nasal cavity resulting from respiratory airflow patterns and second, tissue susceptibility, an important component of which is biotransformation. Dr Morgan (Chemical Industry Institute of Toxicology, Research Triangle Park, North Carolina) introduced the area of nasal toxicology, the structure and function of the nasal epithelium and then discussed his current research on airflow patterns in the nasal cavity of experimental animals and its relevance to the distribution of nasal lesions. Regional uptake of gases in the nose is a complex process which may be influenced by many factors, including nasal airflow characteristics and the chemical and physical properties of the gas, such as water solubility, air-water partition, diffusion rate and reactivity.32 An experimental system using clear acrylic moulds of the nasal airways of rats and rhesus monkeys has been developed to monitor the complex inspirational airflows and mixing within the nasal passages using a dynamic water-dye siphon system.33.34 Studies in this model system have shown there is a good correlation between routes of flow, regional and secondary air flows, turbulence and impaction of airstreams on the airway wall, with the reported distribution of formaldehyde-induced nasal lesions in rats and rhesus monkeys The other component which can contribute to the regional selectivity is regional metabolism of chemicals. It is now established that nasal tissue has considerable capacity to metabolize a wide range of chemicals3s-3' and thereby produce potentially toxic and carcinogenic metabolites. Dr Reed (Liverpool John Moores University, Liverpool), discussed the presence of these enzymes in nasal tissue and their relevance to mechanisms of toxicity. Metabolism by nasal cytochromes P450 has been demonstrated for a wide range of substrates and several important points have emerged from these and other studies. First, despite its relatively low tissue concentration, nasal cytochrome P450 is more active than the hepatic enzyme in the metabolism of many of the chemicals investigated. Second, there are multiple forms of nasal cytochrome P450, some of which are novel, hitherto undescribed isoenzymes, e.g. cytochrome P450 IIG. Third, nasal cytochromes P450 show little or no response to the in-vivo administration of classical, hepatic-inducing agents. Fourth, the concentration of cytochromes P450 is higher in the olfactory than in the respiratory epithelium. The precise physiological role of nasal drug metabolic enzymes is not known, but two current hypotheses are that they play a role as a first line of defence for the lungs and/or maintain acuity of olfaction by metabolizing the odorant molecules. However, the toxicological significance of nasal cytochromes P450 in experimental animals is undisputed. Table 2 lists some chemicals that require activation by cytochrome P450 and which induce a toxic or carcinogenic response. Cytochromes P450 are not the only drug metabolizing enzymes present in nasal tissue; other enzymes such as glutathione S- transferase, carboxylesterases, aldehyde and formaldehyde dehydrogenase and flavin monoxygenases are present and play a role in the metabolism of foreign compounds. Dr Reed cited two examples of chemicals that require metabolism to produce olfactory toxicity; one was 3-trifluoromethylpyridine that undergoes oxidation to form an N-oxide which is thought to be responsible for the nasal damage. Inhibition of nasal cytochrome P450 with metyrapone, prevents the formation of the N-oxide and thereby the toxicity.38 The second example was that of certain dibasic esters (e.g. mixtures of dimethyladipate, dimethylsuccinate and dimethylglutarate) that are substrates for carboxylesterases present in the olfactory epithelium where they undergo metabolism and produce selective toxicity to this tissue.39 447 Table 2 Chemicals that cause toxicity or carcinogenicity in the nasal cavity which probably involves in-situ activation by nasal cytochrome P450. This is not an exhaustive list, but illustrates the diversity of chemicals that can undergo metabolism in the olfactory epithelium, adapted from Reed.36 Thus, it is becoming apparent that toxicity of chemicals to the nasal passages is associated with the properties of the chemical, its delivery to and distribution in the airways and its in-situ activation by drug metabolizing enzymes. In order to improve risk extrapolations from data in experimental animals to man, studies of nasal airflow and nasal drug metabolism in man are required. Cutaneous sensation As outlined by Dr Jamal (Institute of Neurological Sciences, University of Glasgow), peripheral sensation is subserved by a wide variety of specialized sensory structures, located for the most part close to the dermo-epithelium junction or in the hair follicles. These receptors are capable of transducing a variety of stimuli, including mechanical, chemical, thermal or painful. Evidence to date suggests that each individual receptor is responsive only to a particular form of energy (e.g. mechanical, thermal), giving rise to a distinctive sensation. However, it is not possible to associate a particular structure with a particular sensation. Furthermore there is evidence that some nociceptive (pain) receptors are polymodal, i.e. they transduce noxious stimuli of different modalities. These appear to be complex structures with numerous transduction sites, which can be sensitized by endogenous chemicals and released at peripheral sites of tissue injury. Thus, given our current incomplete understanding of the complexity of structure and function of cutaneous sensory receptors, it is apparent that study of the adverse effects of chemicals on peripheral sensations is a challenging field. Fortunately there are comparatively few classes of chemical which appear to exert selec- tive adverse effects on peripheral sensation. The synthetic pyrethroid insecticides are a notable exception. The effect of the pyrethroids on cutaneous sensation was discussed by Professor Blain (Department of Environmental and Occupational Medicine, University of Newcastle-upon-Tyne). These chemicals cause repetitive firing of peripheral sensory nerve fibres, mediated by effects on sodium channels.40 This cutaneous sensation, variously described as burning, itching, tingling or prickling4' is probably produced by all pyrethroids and a slow but complete recovery occurs, usually within 24 h. An experimental model has been developed42 in which guinea pigs are shaved on both flanks and treated on one side with the pyrethroid and on the other side with vehicle. The animal responds by licking, rubbing or scratching the site of application of the active chemical and these responses, relative to the vehicle-treated site are quantified over a 5-min period. There seems to be a reasonable correspondence between the guinea pig test system and the human.4' An alternative approach is to apply the chemical to the skin of human volunteers and monitor the cutaneous sensation. Herein lies a difficulty. Most clinicians are trained to look for, and most tests are designed to detect, sensory deficits rather then sensory excitation However, a number of methods of assessment of chemical-induced sensation, including threshold discrimination methods, are available. All of these methods suffer from the disadvantage of being subjective and, at best, only semi-quantitative. Nevertheless, Professor Blain expressed the view that a subjective visual analogue scale could be used to compare the potential of different compounds to produce cutaneous sensory excitation. 448 References Martin CL & Anderson BG Ocular anatomy. In: Veterinary Ophthalmoscopy, Gelatt KN ed, pp. 12-121. London: Bailliere Tyndal, 1981. Davson H. Physiology of the Eye, 3rd ed. New York: Academic Press, 1972. Labkin VL Steroid cataract - a review and conclusions. Journal of Asthma Research 1977; 14: 55-9. Ros AM, Leon H. and Wennersten G. Crystalline retinopathy in patients taking an oral drug containing canthaxanthin . Photodermatology 1985; 2: 183-5. Oosterhius JA , Nijam NM, De Wolf FA & Remky H. Canthaxanthin retinopathy with and without intake of canthaxanthin as a drug. Human and Experimental Toxicology 1988; 7: 45-7. Nylander V. Ocular damage in chloroquine therapy. Acta Ophthalmolgica 1967; 92 (Suppl): 1-71. Boet DJ Toxic effects of phenothiazines on the eye. Documenta Ophthalmologica 1970; 28: 1-69. Davies SC, Hungerford JL, Arden GB et al. Ocular toxicity of high-dose intravenous desferrioxamine. Lancet 1983; ii: 181-4. Rubinstein M. , Dupont P., Doppee JP et al. Ocular toxicity of desferrioxamine . Lancet 1985; i: 817-18. Olivieri NF, Buncic JR, Chew E. et al. 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Acta Otolaryngological 1975; 79: 24-32 Kemp DT, Bray P., Alexander L. & Brown AM Acoustic emission cochleography - practical aspects. Scandanavian Audiology 1986; 25 (Suppl): 71-95. Brown AM, McDowell B. & Forge A. Acoustic distortion products can be used to monitor the effets of chronic gentamicin treatment. Hearing Research 1989 ; 42: 143-56. Hawkins JE, Jr. Drug ototoxicity. In: Handbook of Sensory Physiology Vol 5, Auditory System Part 3, Clinical and Special Topics, Keidel WD & Neff WD eds, pp. 707-48. Berlin: Springer Verlag, 1976. Stebbins WC, McGinn CS, Feitosa Mag et al. Animal models in the study of ototoxic hearing loss. In: Aminoglycoside Ototoxicity, Lerner SA, Matz GJ & Hawkins JE, Jr, eds, pp. 5-25. Boston: Little, Brown and Co., 1981. Davey PG, Jabeen FJ, Harpur ES, Shenoi PM & Geddes AM A controlled study of the reliability of pure tone audiometry for the detection of gentamicin auditory toxicity. Journal of Laryngology and Otology 1983; 97: 27-36. Harpur ES 1987 Ototoxicity: Morphological and functional correlations between experimental and clinical studies. In: Perspectives in basic & applied toxicology, Ballantyne B ed, pp. 42-69. London: Wright, 1987. Dulon D., Aran J-M., Zajic G. & Schacht J. Comparative uptake of gentamicin, netilmicin and amikacin in the guinea pig cochlea and vestibule. Antimicrobial Agents and Chemotherapy 1986; 30: 96-100. Harpur ES The inner ear. In: Target Organ Toxicity, Cohen GM ed, pp. 125-42. Boca Raton: CRC Press, 1986. Henley CM & Schacht J. Pharmacokinetics of aminoglycoside antibiotics in blood, inner-ear fluids and tissues and their relationship to ototoxicity. Audiology 1988; 27: 137-46. Hiel H., Bennani H., Erre J-P., Aurousseau, C & Aran J-M. Kinetics of gentamicin in cochlear hair-cells after chronic treatment. Acta Otolaryngologica 1992; 112: 272-7. Hayashida T. , Hiel H., Dulon D. et al. Dynamic changes following combined treatment with gentamicin and ethacrynic acid with and without acoustic stimulation . Acta Otolaryngologica 1989; 108: 404-13. Fechter LD, Young JS & Nuttall AL Trimethyltin ototoxicity: evidence for a cochlear site of injury. Hearing Research 1986; 23: 275-82. Fechter LD, Young JS & Carlisle L. Potentiation of noise induced threshold shifts and hair cell carbon monoxide . Hearing Research 1988; 34: 463-73. Fechter LD & Carlisle L. Auditory dysfunction and cochlear vascular injury following trimethyltin exposure in the guinea pig. Toxicology and Applied Pharmacology 1990; 104: 133-43. Clerici WJ, Blango Ross Jr & Flechter LD Acute ototoxicity of trialkyltins in the guinea pig. Toxicology and Applied Pharmacology 1991; 109: 547-56. Barrow CS (ed). Toxicology of the Nasal Passages. London: Hemisphere, 1986. Dahl AR, Schlesinger RB, Heck HD'A, Medinsky MA & Lucier GW Comparative dosimetry of inhaled materials: differences among animal species and extrapolation to man. Fundamental and Applied Toxicology 1991; 16: 1-13. Morgan KT & Monticello TM Airflow, gas depostiion and lesion description in the nasal passages. Environmental Health Perspectives 1990; 85: 209-18. Morgan KT, Kimball JS, Monticell TM, Patra AL & Fleishman A. Studies of inspiratory airflow patterns in the nasal passages of the F344 rat and rhesus monkey using nasal molds: relevance to formaldehyde toxicity . Toxicology and Applied Pharmacology 1991 ; 110: 223-40. Bogdanffy MS Biotransformation enzymes in the rodent nasal mucosa: the value of a histochemical approach. Environmental Health Perspectives 1990; 85: 177-86. Dahl AR & Hadley WH Nasal cavity enzymes involved in xenobiotic metabolism: effects on the toxicity of inhalants. Critical Reviews in Toxicology 1991; 21: 345-72. 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</ref-list></back></article></istex:document></istex:metadataXml><mods version="3.6"><titleInfo lang="en"><title>Toxicology of Sensory Systems: A Perspective</title></titleInfo><titleInfo type="alternative" lang="en" contentType="CDATA"><title>Toxicology of Sensory Systems: A Perspective</title></titleInfo><name type="personal"><namePart type="given">E.A.</namePart><namePart type="family">Lock</namePart><affiliation>ICI Central Toxicology Laboratory, ICI plc, Alderley Park, Macclesfield, Cheshire, UK</affiliation></name><name type="personal"><namePart type="given">E.S.</namePart><namePart type="family">Harpur</namePart><affiliation>Department of Toxicology, Sterling Winthrop Research Centre, Alnwick, Northumberland, UK</affiliation></name><typeOfResource>text</typeOfResource><genre type="editorial" displayLabel="editorial" authority="ISTEX" authorityURI="https://content-type.data.istex.fr" valueURI="https://content-type.data.istex.fr/ark:/67375/XTP-STW636XV-K">editorial</genre><originInfo><publisher>Sage Publications</publisher><place><placeTerm type="text">Sage CA: Thousand Oaks, CA</placeTerm></place><dateIssued encoding="w3cdtf">1992-11</dateIssued><copyrightDate encoding="w3cdtf">1992</copyrightDate></originInfo><language><languageTerm type="code" authority="iso639-2b">eng</languageTerm><languageTerm type="code" authority="rfc3066">en</languageTerm></language><abstract lang="en">This brief review is the result of a recent meeting of the British Toxicology Society (Toxicology of Sensory Systems, University of York, April 2-3, 1992). The meeting provided the opportunity to discuss the anatomy, physiology and function of the eye, ear, nasal epithelium and peripheral sensation and the methods that are available to detect injury or dysfunction both in the preclinical and clinical situation. In addition, the mechanism whereby certain chemicals can perturb some of these organs was discussed. The aim of this short article is to highlight some of the recent advances in understanding in these areas with regard to their relevance or impact on toxicology. For convenience the areas will be discussed under separate headings.</abstract><relatedItem type="host"><titleInfo><title>Human & Experimental Toxicology</title></titleInfo><genre type="journal" authority="ISTEX" authorityURI="https://publication-type.data.istex.fr" valueURI="https://publication-type.data.istex.fr/ark:/67375/JMC-0GLKJH51-B">journal</genre><identifier type="ISSN">0960-3271</identifier><identifier type="eISSN">1477-0903</identifier><identifier type="PublisherID">HET</identifier><identifier type="PublisherID-hwp">sphet</identifier><part><date>1992</date><detail type="volume"><caption>vol.</caption><number>11</number></detail><detail type="issue"><caption>no.</caption><number>6</number></detail><extent unit="pages"><start>442</start><end>448</end></extent></part></relatedItem><identifier type="istex">C86C7FF70A8A6819ED1CD9ED0A0EBC965B61F05C</identifier><identifier type="ark">ark:/67375/M70-5JS9RDJ9-R</identifier><identifier type="DOI">10.1177/096032719201100602</identifier><identifier type="ArticleID">10.1177_096032719201100602</identifier><recordInfo><recordContentSource authority="ISTEX" authorityURI="https://loaded-corpus.data.istex.fr" valueURI="https://loaded-corpus.data.istex.fr/ark:/67375/XBH-0J1N7DQT-B">sage</recordContentSource></recordInfo></mods><json:item><extension>json</extension><original>false</original><mimetype>application/json</mimetype><uri>https://api.istex.fr/ark:/67375/M70-5JS9RDJ9-R/record.json</uri></json:item></metadata><serie></serie></istex></record>Pour manipuler ce document sous Unix (Dilib)
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