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EDITORIAL: OTOTOXICITY Ian J Mackenzie MD MSc ical experimentation and a careful and accurate Liverpool School of Tropical Medicine recording system of any Pembroke Place side effects a drug gener- Liverpool L3 5QA ates. Subtle side effects, UK like tinnitus and deafness, are not identified until Email: [email protected] many people are affected and it is reported in the he majority of illnesses world- medical literature. It is wide are treated with medication. difficult, particularly in TMedicines have been used in the animal experiments, to treatment of illness for hundreds of years. record tinnitus or deafness The medicines of today are sophisticated as a side effect of a drug, and their development is at the forefront even though the hearing of science. Medicines have eradicated and balance systems are some diseases and controlled others. The anatomically very delicate Teaching and learning at a School for the Deaf in Afghanistan successful conquering of some cancers, and sensitive to toxins. previously thought untreatable, show Photo: SHIP/CBM the ingenuity and science that has been Ototoxicity the problem may be whether or not to part of their development. However, the The term ototoxicity covers any damage prescribe certain essential drugs know- development of new drugs takes a long to hearing and balance caused by a toxin, ing that there is a high chance of leav- time and is a very expensive process. as it affects the end organs of the eighth ing the patient with a long term hearing deficit. There is little information on the Side Effects of Medicines cranial nerve. The toxin can enter the body by ingestion, inhalation or with side effects of herbal and homeopathic Drugs of all sorts have known side effects skin contact. When a patient needs life- medication. which can only be discovered by clin- saving medication for severe illness, The long term cost to the community CONTENTS of ototoxicity is not known but hearing impairment, deafness, tinnitus or dizzi- Community Ear and Hearing Health 2006; 3:17-32 Issue No.4 ness can cause difficulties with language EDITORIAL Ian J Mackenzie 17 development and learning in children, LEAD ARTICLES: OTOTOXICITY and with work communication and Deafness Caused by Ototoxicity in Developing Rajan N Patel 18 performance. Countries Solvent Exposure at the Workplace: Adrian Fuente 22 In many instances, these side effects are Workers’ Hearing in Jeopardy not present if drugs are prescribed prop- erly. Some drugs may interact with each Ototoxicity: A Canadian View Peter W Alberti 24 other and lead to increased toxicity, but Molecular Diagnosis of Mitochondrial Genes: Min-Xin Guan 25 these interactions are not well under- Early Detection and Prevention of Aminoglycoside stood. When the cause of deafness is not Ototoxicity identified, it is important to review occu- REPORTS pation and medication to see if there is The Need of a Programme for the Prevention of Diego J Santana-Hernández 28 any toxin responsible for the deafness. Hearing Impairment in Beni State, Bolivia Ototoxicity is more common than often Atfaluna News Update Geraldine Shawa 30 suggested and in most cases is a prevent- ABSTRACTS 31 able cause of deafness.

COMMUNITY EAR AND HEARING HEALTH: 2006; 3: 17-32 Issue No. 4 www.icthesworldcare.com 17 Ototoxicity in Developing Countries DEAFNESS CAUSED BY OTOTOXICITY IN DEVELOPING COUNTRIES Rajan N Patel Table 1: Grades of Hearing Impairment Medical Student Grade of impairment Corresponding audiometric ISO* value Department of Child and Reproductive 0 - None 25 dB or better Health 1 – Slight 26-40 dB Liverpool School of Tropical Medicine Pembroke Place 2 – Moderate 41-60 dB Liverpool L3 5QA 3 - Severe 61-80 dB

UK 4 – Profound 81 dB or greater *International Organization for Standardization Email: [email protected]

his report attempts to review million people in the world had a disa- Grades of Hearing Impairment systematically the current liter- bling hearing impairment and that two- Deafness can be expressed as a complete ature on deafness caused by thirds of these people lived in develop- loss in the ability to hear from one or T ing countries.2 Furthermore, Torrigiani ototoxicity in developing countries and both ears. It can also be described as a make an appraisal of its current status in Geneva outlined that avoidable hearing threshold of 81dB or greater, in different regions of the developing hearing impairment and deafness are averaged at frequencies 0.5, 1, 2, 4 kHz.2 world. This involves critically assessing an important public health problem, Table 1 provides the different grades of research and accessing routine electronic particularly in low-income countries. hearing impairment.2 literature databases. Although infectious conditions, such as otitis media, account for the largest Ototoxicity and its Causes Deafness Worldwide proportion of conductive hearing loss, Ototoxicity refers to the harmful effect Deafness is a worldwide problem. It is damage to sensori-neural hearing caused of a drug, chemical substance or heavy estimated that 1:1000 children are born by ototoxic medication has been increas- metal on the organ of hearing or balance, deaf, while 2:1000 children are born ingly reported from countries in recent which may lead to a hearing impair- 3 hard of hearing.1 In 2002, the World years. ment, and/or balance problems. Table 2 Health Organization estimated that 250 displays some of these substances.3

Table 2: Causes of Hearing Impairment and/or Balance Problems Aminoglycosides Gentamicin, streptomycin, kanamycin, amikacin, tobramycin, neomycin, netilmicin, polymyxin-B Macrolides Erythromycin, azithromycin, clarithromycin Loop diuretics Furosemide, bumetanide, ethacrinic acid Salicylates Antimalarials Quinine, chloroquine (high dosage) Non-steroid anti-inflammatory drugs Naproxen, indomethacin (no definite findings) Anti-neoplastic drugs Cisplatin, bleomycin, carboplatinum Chelating agents Desferoxamine Topical otological preparations Antibiotic solutions: Neomycin Aminoglycosides Polymyxin-B Chloramphenicol Fosfomycin Anti-inflammatory: Propylene-glycol, hydrocortisone Antiseptic: Chlorohexidine, povidone-iodine (?) Acidifying: 2% acetic acid solution (?) Chemical agents Heavy metals: Mercury, lead (Industrial pollution, cosmetics). Solvents: Toluene, styrene Others: Arsenic, cobalt, cyanides, benzene, propylene-glycol, potassium bromide

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Ototoxicity tends to be thought of in caused by the prescription of ototoxic which the main criterion for classify- the context of drug administration lead- drugs, one should assume that preven- ing economies is gross national income ing to damage of the cochlea or vestib- tive measures could be taken effectively. (GNI) per capita. Based on its GNI per ular portion of the inner ear, causing Minja makes reference to the prevent- capita, every economy is classified as transitional or permanent sensorineural ability of deafness due to ototoxicity, low income, middle income (subdivided hearing loss (SNHL) and/or vertigo. despite its variety of causes.1 Suggestions into lower middle and upper middle), Antibiotics, diuretics and anti-malarial will be made regarding methods and or high income. Table 3 identifies some pharmaceuticals have been implicated strategies for the prevention of ototoxic- of the developing countries that will be as potentially toxic to both the auditory ity in developing countries. discussed in this report, and others that and vestibular systems. Kanamycin and are noteworthy.7 neomycin are perhaps the most alarm- Another report refers to the extensive use ing ototoxic drugs at this time.4 This and abuse of aminoglycosides and how To summarise this introduction to report will later discuss and evaluate the they are a major concern.3 It suggests ototoxicity-induced deafness, it is impor- current status of ototoxicity due to these that the most common cause of hearing tant to note that the global magnitude of substances. This will be accomplished by impairment from ototoxic damage by the problem is not accurately known assessing and reviewing different litera- drugs is due to injectable aminoglyco- and that there is a great need for more ture written about the use of these chem- sides. It is also implied that gentamicin detailed research on ototoxicity. icals in various regions of the world, and is cheaper than newly available alterna- in particular, the developing world. tives and, hence, is more widely avail- Discussion and Results able. Additionally, WHO recognises that This report will now analyse and review While aminoglycosides have been largely the global resurgence of tuberculosis is the literature found. It will discuss the replaced over the last decades by modern leading to greater use of streptomycin.3 current status of ototoxicity in develop- antibiotics with fewer side effects, they For example, in South Africa, strepto- ing countries by comparing results from remain a mainstay in medicine. In fact, mycin and kanamycin form part of the clinical studies carried out. It will then they may be the most commonly used drug regimen administered to multi- assess the disagreements, strengths and antibiotics worldwide, chiefly due to drug resistant tuberculosis (MDR-TB) weaknesses of various papers. The prob- their use in developing countries. Their sufferers.6 One of the aims of this report lems facing people in developing coun- high efficacy, coupled with extremely is to ascertain the extent to which these tries will also be considered in depth. low cost, frequently makes aminoglyco- antibiotics are being abused. side antibiotics the only affordable drugs. The fact that aminoglycosides and other Furthermore, since tuberculosis is on This report will also consider the many drugs, such as antimalarials, can produce the rise worldwide, particularly in low agents within the workplace, particularly ototoxicity has been well established in income countries, aminoglycoside use within heavy industry, that can poten- both humans and experimental animals. will not be reduced.5 tially bring about chemical trauma to the The ototoxicity can take the form of ear. Examples include xylene, toluene, damage to the auditory system or the Streptomycin and kanamycin are part of mercury, tin, lead and carbon monox- vestibular system, or both.8 In one study, the recommended regimen of the World ide.4 Tange et al showed that malaria patients Health Organization against tuberculo- experienced adverse effects related to sis, and their widespread use makes these The meaning of a developing country ototoxicity induced by quinine: 9 had antibiotics a major cause of preventable is a final point of importance in this impaired hearing, 11 tinnitus, 8 had hearing loss in the world today.5 Given introduction. It has been defined by feeling of pressure on the ears and 4 that most drug-induced hearing loss is the World Bank Income Groupings, in felt giddiness.9 While malaria may cause deafness, the drugs used in the treatment Table 3: High Income, Upper Middle Income, Lower Middle Income and Low Income are potentially ototoxic. Quinine is the Countries drug of choice in the treatment of chlo- roquine resistant falciparum malaria in High Income Upper Middle Lower Middle Low Income the developing world. Minja observed Income Income ($765 or less) 354 pupils at a School for the Deaf in Dar es Salaam, of which five had become Australia Argentina Brazil Bangladesh totally deaf following intravenous infu- France Barbados China Ghana sion of quinine.1 Table 4 displays the Germany Botswana Colombia India distribution of the 354 children accord- Hong Kong Chile Indonesia Kenya ing to causes of deafness. Ototoxicity can Ireland Costa Rica Iran Malawi be seen as a cause in 20 % of cases.1 Italy Czech Republic Morocco Nepal Japan Latvia Namibia Nigeria Studies on the ototoxicity of quinine in Korea Lebanon Paraguay Pakistan humans are scarce, however, and there Netherlands Malaysia Peru Sudan are still some questions about the revers- ibility of quinine induced hearing loss. Singapore Mauritius Philippines Tanzania Nevertheless, quinine induced ototoxic- Switzerland Mexico South Africa Uganda ity in patients and volunteers appears to UK Oman Sri Lanka Zambia be largely, if not completely, reversible.9 USA Poland Thailand Zimbabwe The salicylates and diuretics produce

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Table 4: Causes of Deafness in Dar-es-Salaam depending on the type ard screening process recruited patients of aminoglycoside.6 As in with normal hearing from a TB-hospital Causes of deafness No. of children most developing countries, in the Western Cape, after consent was Meningitis 76 acquired causes of deaf- received, and treated them with strepto- Ototoxicity 66 ness and hearing impair- mycin and kanamycin.6 ment are also common in Mumps 53 Tanzania. Minja reports In a number of developing countries, Congenital 36 that gentamicin and strep- it is reported that sub-standard drugs Otitis media 28 tomycin, prescribed for are readily available. After collecting 96 Measles 13 treatment of septicaemia samples of chloroquine from Nigeria and tuberculosis respec- and Thailand, the results indicated that Febrile convulsions 5 tively, was a cause of deaf- 36.5% were sub-standard.13 Not only Unknown 77 ness in 18.6% of cases.1 does this imply discrepancies in clinical Other aminoglycosides studies, but this may, in itself, be a cause temporary hearing loss that may be show varying ototoxic of ototoxicity in developing countries. reversible, fully or partially, when the effects. Gatell et al showed that slight patient is taken off the medication.4 or mild auditory toxicity developed in Following the industrial revolution, new 42.1% of patients given tobramycin and health hazards appeared, and indus- 11 Conversely, aminoglycosides, such as 35.2 percent of those given amikacin. trial solvents, chemicals and pollutants streptomycin and kanamycin, cause the became a new category of environmental 5 destruction of outer hair cells and hear- Despite the lack of data on deafness in factors causing hearing loss. For exam- ing changes are most likely irreversi- developing countries, the ototoxic effect ple, in Colombia, environmental causa- ble.6 These antibiotics alerted the medi- of drugs such as aminoglycosides is clear tion was found to be a cause of deafness 14 cal community and the public more than to see. However, there are disagreements in 33.8% of cases. Most notable among any others with regard to the ototoxic side between reported incidences of ototox- these chemicals, and of concern today, effects of medications. This is despite the icity-induced deafness. For example, are solvents such as organotoxins or fact that at the time of its introduction, reports on the toxicity of streptoduocin toluene, but also carbon monoxide and 10 streptomycin was the long-sought cure have been contradictory. a number of lesser-used chemicals which for tuberculosis.5 Sixty cases treated with can adversely affect the hearing and 5 streptoduocin and sixty cases treated The discrepancy between the incidence balance functions of the inner ear. It is with streptomycin were studied clinically rates can be attributed to the criteria now known that certain organic solvents and by various tests in Kanpur, India to used to define ototoxicity by different in industry are ototoxic when inhaled in find their ototoxicity. It was established writers. Most studies consider ototox- excess. They may produce brain damage that 25 % of the patients on streptodu- icity to have occurred if at any time involving the vestibular pathways and ocin (mixture of streptomycin and dihy- after a base-line audiogram has been the inner ear directly. One must keep drostreptomycin) developed ototoxicity obtained, an increase occurs in the audi- in mind agents within the workplace, as 8 compared to 10 percent on streptomy- tory threshold of 15dB or more. Yet, well as medications prescribed by health cin. Table 5 summarises the findings on one study describes criteria for auditory professionals. There is one further area the incidence of ototoxicity as a result of dysfunction as a hearing loss greater than which may be a much greater cause 10 streptoduocin and streptomycin admin- 10dB and others use a ≥20dB change of ototoxic hearing loss than has been 11,12 istration.10 in threshold. It is important to note recognised up to now - the synergistic the different definitions for ototoxicity action of noise exposure and inhaled It can be noted that the toxicity of strep- presented by clinical studies in develop- volatile organic substances. tomycin is almost exclusively directed ing countries. against the vestibular system, whereas, As with occupational noise, many devel- dihydrostreptomycin (a derivative which The disagreements between papers can oping countries have little or no legisla- is chemically different in only one posi- also be accounted for by referring to the tion to prevent critical exposure to toxic tion of the molecule) can cause irrevers- patients used in the studies. Screening substances. Regulations that do exist are ible hearing loss.5,6,10 by questionnaire, otoscopy and tympa- poorly enforced and implemented, and 12 nometry has been used, whereas Minja many workers remain ignorant of such 4 In South Africa, streptomycin and relied on the policy of admission to a deaf problems. 1 kanamycin form part of the drug regi- school in Dar es Salaam. Another study men administered to MDR-TB suffer- carried out a loudness balance test and a A large proportion of hearing impairment ers. In the Western Cape, the incidence difference limen test (a test of loudness related to ototoxic drugs results from 10 of ototoxicity varies between 0-20% perception) before recruiting, which their inappropriate or indiscriminate use may have been insufficient. A gold stand- by health care providers.3 In Cambodia, Table 5 : Ototoxicity after Streptoduocin and Streptomycin Treatment Total number Auditory Vestibular Auditory and Group Total of patients toxicity toxicity vestibular toxicity Streptoduocin 60 10 - 5 15 (25%) Streptomycin 60 - 6 - 6 (10%)

20 www.icthesworldcare.com COMMUNITY EAR AND HEARING HEALTH: 2006; 3: 17-32 Issue No. 4 Ototoxicity in Developing Countries as in other developing countries, there developing countries, the government Thus, we need to explore more efficient is a disturbing tendency for misuse of infrastructure is grossly deficient, unable ways of monitoring, in order to do more antibiotics by certain practitioners - for to provide the high quality, high volume with limited resources. Only then will example, the use of antibiotics to prevent health care services which can cope with ototoxicity be detected early and the nega- infections rather than treat established the many ototoxicity-related health prob- tive side-effects avoided or alleviated.6 disease, treatment of untreatable infec- lems.4 Encouragingly, Schacht and Hawkins tions, treatment of infections of undeter- believe there is real hope that ototoxic- mined origin, without adequate biologi- Hearing loss due to ototoxicity is gener- ity can be conquered. Simple over-the- cal knowledge, and frequently improper ally irreversible but avoidable in most counter supplements and medications dosage. Not only does this malprac- instances, given proper preventive action will become part of an inexpensive phar- tice encourage increased microbial resist- through controlled use of drugs in the macological protection to render drug- ance, but it also raises the potential for health care system and by consum- induced hearing loss a medical concern ototoxic effects from those drugs that ers.3 Minja’s findings indicate that most of the past.5 are dangerous to the ear.3,4 In Tanzania, (75.8%) of the causes of acquired deaf- however, these drugs are controlled and ness are preventable through immuni- The lack of general knowledge, however, strictly available on prescription only, sation, early diagnosis and proper treat- about the risk of ototoxic damage and although one study notes that situations ment of ear infections and avoidance of insufficient public education on ototox- arise when the use of drugs (gentamicin prescribing ototoxic drugs.1 The World icity is a great obstacle to preventive and streptomycin) is required in the Health Organization reports that there action. The aim of public education absence of any substitute.1 are no restrictions in most develop- should be to provide individuals with ing countries limiting the availability of information about the use of medicines Health care professionals are not only to drugs causing ototoxicity.3 in an appropriate way.3 blame. Health authorities, in general, can also be put to shame. To date, out of 122 In one study, deafness due to ototoxicity In reading ototoxicity-related scientific institutions in the Western Cape, South is substantial, yet preventable at primary papers, the existence of limitations and Africa, where aminoglycoside treatment and secondary levels of health care. The controversies has become apparent. For is provided to TB sufferers, ototoxicity alarming rate of deafness due to the example, one study reports that for the monitoring takes place at only one.6 The use of ototoxic drugs calls for a delib- first 10 courses of aminoglycosides, the injudicious use of drugs with ototoxic erate policy to create awareness among therapeutic benefit could be considered side-effects can also be attributed to self- prescribers and the public to avoid these to outweigh the risk of cochleotoxicity.12 diagnosis and self-medication. The easy drugs as much as possible.1 In China, The result of this high-dose therapy is availability of these drugs ‘over the coun- aminoglycosides are available with or contradictory and not in keeping with ter’ and without a physician’s prescrip- without prescription; in India, there are many other studies. tion favours self-medication with poten- strict rules for their delivery, but regu- tially harmful drugs.3 lations are not enforced.3 Legislation One particular drawback is the general should be introduced in countries where lack of concern or ignorance towards The ototoxic potential of drugs should it does not yet exist, and, where legisla- ototoxicity-induced deafness in develop- be stressed during training of staff, tion exists, it should be strictly enforced. ing countries. Small doses of quinine, for with regular refresher courses to update example, can cause tinnitus in suscep- relevant knowledge.3 This approach is Conclusion tible persons. However, because of the already demonstrated in Dar es Salaam The conclusion to this report considers lack of clinical significance, the interest where all health workers are taught about future problems facing people in low- in the ototoxicity of quinine has been the potential hazard of using these drugs income countries and summarises what subdued.9 during pregnancy and in treating trivial needs to be done to resolve them. It refers infections.1 to the limitations and controversies in In summary, it is important to real- some of the studies carried out in devel- ise that this report and the studies cited It is well known that the use of aminogly- oping countries. represent only a fraction of the true coside antibiotics carries a risk of damage extent of deafness caused by ototoxicity to the cochlea. In spite of the intro- The global magnitude of the problem of in developing countries. More research duction of new classes of antibiotics, hearing impairment or deafness due to is needed to find out if there is any the aminoglycosides still remain primary ototoxicity is not accurately known, but substance that could reduce damage agents of choice in treating serious gram- it is probably responsible for 3-4% of all from ototoxic drugs during their admin- negative infections.12 Gatell et al also deafness in children in developing coun- istration. More importantly, national refer to the fact that despite the intro- tries.3 Childhood deafness has two seri- surveillance systems are needed in most duction of new cephalosporins and peni- ous consequences; delayed speech and developing countries to set up a moni- cillins, aminoglycosides still have their language development, leading to the toring system for ototoxic damage.3 place amongst treatment options.11 Their need for special education. These prob- low-cost to developing countries is the lems are worse in low-income countries References reason for this. Along with their effec- where economic difficulty, human and 1. Aetiology of deafness among tiveness against gram-negative bacteria, material resources to enable early diag- children at the Buguruni School this advantage has led to the persist- nosis and appropriate rehabilitation are for the Deaf in Dar es Salaam, 1 ence of aminoglycoside use, especially lacking. Tanzania. Minja BM. Int J Pediatr in countries like South Africa.6 In some Otorhinolaryngol. 1998; 42: 225-231.

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2. World Health Organization. Facts 7. The World Bank Group. Data and 12. Occurrence and risk of cochleotoxicity in about deafness. Prevention of Statistics. Country Groups: By Income, cystic fibrosis patients receiving repeated blindness and deafness, 2005. www. 2005. http://web.worldbank.org/WBSITE/ high-dose aminoglycoside therapy. who.int.pbd/deafness/facts/en/index. EXTERNAL/DATASTATISTICS/ Mulheran M, Degg C, Burr S, Morgan html (accessed 29 January 2006). W, Stableforth DE. Antimicrob Agents 8. Aminoglycoside-induced hearing Chemother. 2001; 45(9): 2502-2509. 3. World Health Organization. Strategies loss in humans. Brummett RE, for prevention of hearing impairment Kaye EF. Antimicrob Agents 13. Assessment of the incidence of from ototoxic drugs. Report of a WHO Chemother. 1989; 33(6): 797-800. substandard drugs in developing informal consultation. WHO/PDH/95.2. countries. Shakoor O, Taylor 9. Ototoxic reactions of quinine in healthy Geneva: World Health Organization, 1994. RB, Behrens RH. Trop Med Int persons and patients with Plasmodium Health. 1997; 2(9); 839-845. 4. Word from Phnom Penh, Cambodia. falciparum infection. Tange RA, Dreschler Vaughan G. Unpublished personal WA, Claessen FAP, Perenboom RM. Auris 14. Study of the aetiology of deafness in an communication, 2006. Nasus Larynx. 1997; 24 (2): 131-136. institutionalized population of Colombia. Tamayo ML, Bernal BE, Tamayo GE, Frias 5. Sketches of otohistory. Part 11: 10. A clinical study of ototoxicity due to JL. Am J Med. 1992: 44(4): 405-408. ototoxicity: drug-induced hearing streptoduocin. Sinha SN. Nigam JP, loss. Schacht J, Hawkins JE. Audiol Narang RK. Ind J Tub. 1971; 18(3): 87-91. 15. Continuing dysfunctional affects of Neuro-otol. 2006; 11(1): 1-6. ototoxicity. Alberti P. Unpublished 11. Comparison of nephrotoxicity and personal communication, 2006. 6. Division of communication sciences auditory toxicity of tobramycin and and disorders, University of Cape Town. amikacin. Gatell JM, San Miguel JG, 16. Roland PS, Rutka JA. In Ototoxicity. Comparison of conventional pure tone Zamora L, Araujo V, Bonet M, Bohe M, Hamilton. Ontario: BC Decker audiometry and 2f1-f2 distortion product Jimenez de Anta MT, Farre M, Elena M, Inc 2004. ISBN: 1550092634. otoacoustic emissions in TB sufferers Ballesta A, Marin JL. Antimicrob Agents receiving aminoglycosides 2004. www. Chemother. 1983; 23(6): 897-901. saslha.co.za (accessed 29 January 2006). Solvent Exposure at the Workplace SOLVENT EXPOSURE AT THE WORKPLACE: WORKERS’ HEARING IN JEOPARDY Adrian Fuente BSc Organic solvents fall within this cate- dyes - in the manufacture of artificial gory. It has been widely demonstrated leather, detergents, medicines, perfumes, Doctoral Student that solvents may adversely affect the fabric and paper coatings, photogravure Division of Speech and Hearing Sciences central and peripheral nervous system inks, spray surface coatings and insect The University of Hong Kong and other body structures. More recently, repellents (Table 1). In many occupa- 5F Prince Philip Dental Hospital the ototoxic properties of solvents have tional settings, workers are often exposed 34 Hospital Road also been uncovered by a number of to a combination of solvents and other Hong Kong different research groups.1,2 Despite this hazardous agents such as noise.3 new scientific knowledge, audiologists, Email: [email protected] industrial hygienists and occupational Focusing on the ototoxic properties of safety and health professionals have been solvents, studies have demonstrated odern industry no doubt brings focused on noise as the main agent capa- that solvents such as toluene, styrene, enormous benefits to our ble of inducing hearing loss in the work- and xylene may induce damage on the Msociety. New industrial tech- place. In developed and some developing peripheral auditory system (the cochlea). niques accelerate and improve produc- countries, workers exposed to solvents This means that these chemicals may tion. New machinery improves the effi- receive epidemiological surveil- ciency of manufacture, often creating lance programmes focused on the better quality products, at a better price effects of these chemicals on the for consumers. In developed countries, central nervous system. Currently, the use of high technology machinery, as in most countries not much atten- well as the introduction of less toxic raw tion is paid to the ototoxic prop- materials, has allowed workers to have erties of solvents. This is surpris- less contact with hazardous chemicals. ing, considering the diverse range However, in developing countries newer of solvents in daily use. technology is not always available and non-toxic chemicals are not always used, Solvents and Their Effects due to economic factors. Solvents are now widely used in industrial processes such as in Since the start of the industrial revolu- automotive and aviation fuels, tion, many raw materials have been iden- plastics industries, as a thinner tified as dangerous for human health. for paints, lacquers, coatings, and A factory in Vietnam Photo: Adrian Fuente

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Table 1: Solvents: Effects on Hearing and Recommendations to Avoid Hearing Loss

Industrial processes where solvents are used Toluene: printing, rubber manufacture, wood stains and varnishes, and footwear manufacture. Styrene: pulp and paper manufacture and in plastics, resins, coatings, and paint manufacture. Xylene: paint manufacture, paint stripping, paper coating, pesticide manufacture, pharmaceuticals manufacture and printing. Effects of solvents on hearing Peripheral auditory system: adverse effects on hearing thresholds in a wider range than 4000-6000 Hz. Central auditory system: difficulties in discriminating speech, especially in the presence of background noise. Synergism between solvents and noise Recommendations to avoid solvent-induced hearing loss  Alert both employers and employees to the hazardous effects of solvents on hearing.  Replacement of solvents with less toxic compounds such as water.  Implementation of hearing conservation programmes for all workers exposed to solvents, independent of the noise level in the workplace. adversely affect hearing thresholds. The agents may have by itself. Unfortunately, cheaper costs of labour. However, from audiometric pattern of solvent-induced this combination of agents frequently the occupational safety and health point hearing loss is not necessarily the same as occurs in factories, especially in develop- of view, the factories are not an improve- that seen in noise-induced hearing loss. ing countries. The high intensity of noise ment. Many of these factories do not The latter typically shows a ‘noise notch’ produced by non-renovated machinery control the levels of solvents that they around 4000-6000 Hz, while in solvent- plus the presence of solvents in the envi- use, and the environmental concentra- induced hearing loss a wider range of ronment, together with the absence of tions of these chemicals at workplaces high frequencies may be affected. Other protective equipment or measures to may be totally unknown. Even worse, studies have demonstrated that solvents diminish solvent and noise exposure, regulations concerning the use of venti- may also induce damage to the central is commonly seen. Workers may not lation systems and the provision of structures of the auditory system. This be exposed necessarily to high intensi- masks, gloves or other personal protec- means that an affected person may not ties of noise, but when solvents are also tive equipment do not exist in many necessarily have poor hearing thresh- present, an adverse effect on hearing of these factories. In addition, highly olds but he or she may encounter diffi- may still be induced. Hearing conserva- hazardous solvents such as benzene are culties in understanding what others say, tion programmes should be conducted still being used in many factories of especially in the presence of background for all workers exposed to solvents and Asian countries. All this makes such noise. The effect of solvents on the noise even when the latter is less than factories potentially hazardous for work- central auditory system may be related 85 dBA TWA. This type of programme ers. Taking into account this scenario, to the ability that solvents have to pene- should include not only the early detec- plus the fact that solvent-induced hear- trate into lipid structures. tion of hearing loss induced by solvents ing loss is a relatively recently discov- but also implement the necessary meas- ered pathology and, therefore, not widely Hearing Health Care and ures to avoid workers being exposed to known among health care profession- Solvents high intensities of noise and to solvents als, even for those who specialise in The multiple effects of solvents on the above the recommended levels. occupational medicine, the idea of regu- auditory system make it difficult to lar hearing conservation programmes assess and identify workers with solvent- The Situation in Asia in workers exposed to solvents is still induced hearing loss, especially when At present, there is little consideration a new one in countries such as China. hearing health care professionals are of the ototoxic properties of solvents. Recently, new guidelines and standards unaware of the problem. This scenario Many countries still use solvents without have emerged in some non-Asian coun- becomes more complex still when work- control. In Asia, for instance, many facto- tries that consider the inclusion of work- ers are also exposed to other oto- or ries use high concentrations of solvents in ers exposed to ototoxic agents in hearing neurotoxic agents such as noise. Noise different industrial processes. The foot- conservation programmes. These regu- has been extensively recognised as an wear industry is a good example. Asia is lations should be considered as a refer- agent that may induce hearing loss when the dominant producing region in the ence by legislators in Asian countries for exposures are above certain limits (85 world. Its contribution to world produc- implementing similar programmes. dBA TWA*). A number of studies have tion of shoes has steadily increased from suggested a synergistic effect on human 51% in 1985 to 63% in 1993, and 77% *TWA means ‘time-weighted average’: - The average exposure to a contaminant or hearing when noise and solvent expo- in 1999, with China by far the first in condition (such as noise) to which workers sure occur together. In other words, the the world. In China alone, millions of may be exposed without adverse effect over a combined effect of solvents and noise footwear industry workers are likely to period such as in an 8-hour day or 40-hour may induce auditory damage more be affected.4 Factories of many famous week. See http://www.answers.com/topic/ severe than the effect that each of these brands have moved to Asia due to the time-weighted-average

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What We Can Do effects of solvents on hearing, especially Kopke R, Salvi R, Hamernik R. Noise It is within the scope of health care when they co-exist with noise. Hearing induced hearing loss: basic mechanisms, prevention and control, pp 293-304. professionals to alert both employers and conservation programmes should be London: Noise Research Network (2001). employees about the hazardous effects implemented for all workers exposed of solvents and so help them to avoid to solvents only, noise only or solvents 2. Auditory and vestibular functions solvent-related diseases (Table1). It is combined with noise. Research so far after single or combined exposure the role of the scientific community to has consistently identified solvents as to toluene: a review. Morata T C, work towards the introduction of new oto- and neurotoxic agents, it is now the Nylen P, Johnson A C, Dunn D E. non-toxic materials which have similar responsibility of all of us - researchers, Arch Toxicol. 1995; 69: 431-443. or better properties than toxic solvents, clinicians, workers, and employers - 3. Organic solvents in hearing loss: and, thus, help employers to adapt their to take the necessary actions to avoid the challenge for audiology. factories to use these new raw materials. solvent-induced hearing loss in workers. Fuente A, McPherson B. Int J One example is the possibility of replacing References Audiol. 2006; 45: 367-381. solvents such as toluene or benzene with 1. Auditory function after single or multiple 4. China’s ‘Market Economics in water in some industrial processes. It is exposure to styrene: a review. Morata T Command’: Footwear Workers’ Health the responsibility of hearing health care C, Campo P. In Henderson D, Prasher D, in Jeopardy. Chen M S, Chan A. Int professionals to be aware of the adverse J Health Serv. 1999; 29: 793-811. Ototoxicity: A Canadian View OTOTOXICITY: A CANADIAN VIEW Peter W Alberti the ototoxic effects of aminoglycosides perforations caused by bullets. Here, MD MB PhD FRCSC FRCS because they will not be excreted, lead- although the risk was known, life saving ing to cumulative high (and toxic) blood therapy took precedence over saving the Professor Emeritus levels. Quite a few elderly patients on sense of balance. Toronto temporary renal dialysis recover from Canada their renal shutdown only to find them- New medications may bring their own totoxicity continues to be a selves ataxic, and even with bobbing problems. This was seen with cisplatin, a significant cause of hearing oscillopsia. (Oscillopsia - the sensation useful but initially unrecognised ototoxic loss and vestibular dysfunction that viewed objects are moving or waver- agent; its very success in treating malig- O nant disease led to the discovery of long throughout the world. Just when one ing back and forth). thinks the problem has been virtually term side effects of the therapy. This still eliminated, another cause appears. Immigrants from China and may not be recognised and the patients Eastern Europe may suffer unnecessarily from a hearing Ototoxicity in Canada Canada is a land of immigrants, no loss which could be rehabilitated with a The present causes of ototoxicity in more so at present than Chinese. It is hearing aid. Canada include some long standing ones, not well recognised that some Chinese Noise and Organic Solvents such as aminoglycosides, although the suffer from an (m)RNA transmitted injudicious and inappropriate systemic hereditary susceptibility to the ototoxic There is one further area which may be use is rare. However, the systemic or affects of aminoglycosides. If it has not a much greater cause of ototoxic hear- local absorption of topically applied already done so, it will inevitably lead to ing loss than has been recognised up aminoglycosides continues to produce more unexpected vestibular disturbance to now - the synergistic action of noise hearing loss and imbalance. They may be and hearing loss. A small but steady exposure and inhaled volatile organic given as topical ointment or ear drops. number of immigrants with ototoxic solvents. It is now known that certain hearing loss were treated with strepto- organic solvents used in industry are Until quite recently, the most commonly mycin or gentamicin in Eastern Europe ototoxic when inhaled to excess. They used ear drop in Canada was a gentamicin for long periods - for infections which may produce brain damage involving steroid mix, usually safe in the pres- in Canada would have been treated by the vestibular pathways and they may ence of a disease thickened middle ear safer (but costlier) antibiotics. Likewise, involve the inner ear directly. The most mucosa, and if given for a short time, but immigrants arrive with hearing loss used chemical is toluene, but workers in potentially toxic with longer use, espe- caused by quinine and other antimalarial the petrochemical industry are also at cially in the presence of a thin middle treatment, either those cured of cerebral risk, as are those using some of the adhe- ear mucosa. This was sufficiently seri- malaria, or long time regular consumers, sives which have replaced riveting in the ous that Health and Welfare Canada often retired regular soldiers. aerospace industry. It has been shown put out a warning notice in 2002 about that toluene, certainly, and other solvents the hazards of prolonged use. They are Medications may act synergistically with noise, so that being replaced by safer ciprofloxacin, Aminoglycosides are still used to treat safe levels of one may still lead to hear- which is, however, up to four times as severe infections such as caused by motor ing loss if the worker is exposed to both expensive. Gentamicin containing oint- vehicle accidents or gunshot wounds. The simultaneously, as often happens. The ments may be used to treat burns or writer has seen a patient with bobbing loss is similar to that produced by exces- infected skin sites around catheters, such oscillopsia which was the result of treat- sive noise exposure, but greater than as are used for intra-peritoneal dialy- ment by gentamicin for multiple bowel would be expected from the noise dose sis. Any renal compromise potentiates alone.

24 www.icthesworldcare.com COMMUNITY EAR AND HEARING HEALTH: 2006; 3: 17-32 Issue No. 4 Ototoxicity: Genetic Aspects MOLECULAR DIAGNOSIS OF MITOCHONDRIAL GENES: EARLY DETECTION AND PREVENTION OF AMINOGLYCOSIDE OTOTOXITY Min-Xin Guan PhD hearing loss.7,8 The problem of ototoxic if the C at position 1494 is mutated to T, side effects is more acute in developing or the A at position 1555 is mutated to Division of Human Genetics and countries, where highly effective and low a G, then a base pair is formed extend- Center for Hearing and Deafness cost drugs such as aminoglycosides are ing the adjacent stem by one nucleotide Research often prescribed without adequate moni- and making the mitochondrial ribosome Cincinnati Children’s Hospital Medical toring. Due to the widespread use of more bacteria-like (Figure 1). This new Center these antibiotics, 20-30% of two cohorts G-C or A-U pair in 12S rRNA creates a Cincinnati, Ohio 45229 of Chinese deaf populations could be binding site for aminoglycosides, which USA due to the administration of various facilitates the binding of these drugs.12,13,16 E-mail: [email protected] aminoglycosides.9,10 The type and doses In fact, the human cell lines carrying the of aminoglycoside medication, the length A1555G or C1494T mutation exhibited Hearing Loss; Gene of treatment, and age at the time of drug the sensitivity to aminoglycosides. 12,17 Aberrations and Ototoxic administration may relate to the Drugs severity of hearing impairments earing loss is one of the most in some subjects. At very high ABSTRACT common human sufferings, dose of these drugs, most indi- Aminoglycosides such as gentamicin, affecting one in 1000 newborns.1 viduals will exhibit toxicity. By H streptomycin, kanamycin and tobramycin Hearing loss can be caused by gene aber- contrast, some patients developed rations or environmental factors, includ- aminoglycoside-induced hearing are clinically important drugs. The use ing ototoxic drugs such as aminoglyco- loss after treatment with conven- of these drugs can frequently lead to side antibiotics.2 These antibiotics, such tional doses, even one dose of a irreversible hearing loss. Aminoglycoside drug, over a short period. as gentamicin, streptomycin, kanamycin ototoxicity accounts for a significant and tobramycin, are clinically impor- Maternal Transmission portion of deafness. In familial cases of tant drugs. They are particularly active and Mutations against aerobic, gram-negative bacteria ototoxic deafness, the aminoglycoside and act synergistically against certain In familial cases of ototoxic deaf- hypersensitivity is often maternally gram-positive organisms. In developed ness, the aminoglycoside hyper- transmitted, suggesting that the mutation(s) countries, these drugs are mainly used sensitivity is often maternally in mitochondrial DNA is the molecular transmitted.9,10 In these families, in the treatment of hospitalised patients basis of this disorder. Mutational analysis with aerobic gram-negative bacterial a woman carrying the trait will has led to the identification of several infections, particularly in patients with have inherited the trait, but only chronic infections such as cystic fibro- a female can pass the trait on to ototoxic mutations in mitochondrial 12S sis or tuberculosis. However, in devel- the subsequent generation. The rRNA. In particular, the A1555G and oping countries, aminoglycosides are maternal transmission of deaf- C1494T mutations account for significant more routinely used, even for relatively ness suggested that mutation(s) cases of aminoglycoside ototoxicity. The (changes in the gene) in mito- minor infections. The use of these drugs A1555G or C1494T mutation creates the can frequently lead to toxicity, which chondrial DNA (mtDNA) could binding sites of the highly conserved A- involves the renal, auditory and vestibu- be the molecular basis for this lar systems.3,4,5 The renal impairment is susceptibility.5,11 Mutational anal- site of 12S rRNA and make the secondary usually reversible, but the auditory and yses of the mitochondrial genome structure of this RNA more closely vestibular ototoxicity is frequently irre- of families with maternally trans- resemble the corresponding region of versible. Although all of the aminoglyco- mitted aminoglycoside ototox- bacterial 16S rRNA. Thus, these mutations icity have led to the identifica- sides are capable of affecting cochlear and facilitate the binding of aminoglycosides, vestibular functions, some (streptomycin tion of several ototoxic mtDNA thereby accounting for the fact that the and gentamicin) produce predominately mutations, especially the A1555G vestibular damage, while others (neomy- and C1494T mutations in the 12S exposure to aminoglycosides can induce or cin and kanamycin) cause mainly coch- ribosomal RNA (rRNA).11,12,13 worsen hearing loss in individuals carrying lear damage. Tobramycin affects both Both A1555G and C1494T muta- these mutations. Therefore, these data equally.4 tions are located at the highly have been providing valuable information conserved aminoacyl-tRNA bind- and technology to predict which individuals Aminoglycosides; Dosage and ing site (A-site) of the small ribos- Age of Patients omal sub-unit, which is an impor- are at risk of ototoxicity, to improve the In the United States, almost 4 million tant locus of action for aminogly- safety of aminoglycoside antibiotic therapy, courses of aminoglycosides are admin- cosides.14,15 In human 12S rRNA, and eventually to decrease the incidence of istrated annually.6 It is estimated that at the 1494C and 1555G bases are deafness. least 2-5% of patients treated with these in apposition to each other but antibiotics develop clinically significant do not form a base pair. However,

COMMUNITY EAR AND HEARING HEALTH: 2006; 3: 17-32 Issue No. 4 www.icthesworldcare.com 25 Ototoxicity: Genetic Aspects

G--C should be screened for 12S rRNA muta- G--C A = Adenine tions. Those, who are positive for 12S C--G C = Cytosine rRNA mutations, should be warned that they are at risk of aminoglycoside upper stem 1405 G--C G = Guanine Escherichia coli U U 1495 ototoxicity and avoid the use of these 16S rRNA C--G U = Uracil drugs. Therefore, genetic and molec- A ular approaches can help us predict internal loop A A 1409 C--G 1491 which individuals are at risk of ototox- A--U icity, improve the safety of aminoglyco- C--G side antibiotic therapy, and eventually lower stem C--G decrease the incidence of deafness. A Acknowledgement C--G C--G C--G These investigations were supported G--C G--C G--C U U U U U U by NIH grants DC04958 and DC05230 C--G C--G C--G from the National Institute on Deafness A A A A A A and Other Communication Disorders to A A A C C C M.X.G. Homo sapiens C C C mitochondrial 12S rRNA 1494 C A 1555 1494 C -- G 1555 1494 U -- A 1555 References C--G C--G C--G U--A U--A U--A 1. Genetic epidemiology of hearing C--G C--G C--G impairment. Morton ME. Ann C--G C--G C--G NY Acad Sci. 1991; 630:16-31. B C D 2. Genetics, genomics and gene discovery Wild Type Mutant in auditory system. Morton CC. Hum Fig. 1: The sites of the A1555G and C1494T mutations in the decoding region of mitochondrial Mol Genet. 2002; 11: 1229-1240. 12S rRNA. 3. Aminoglycosides. Lortholary O, Tod Mutations, Aminoglycosides or C1494T mutation. Aminoglycosides, M, Cohen Y, Petitjean O. Med Clin and Hearing Loss which are concentrated in the peril- North Am. 1995; 79: 761-798. ymph and endolymph of the inner ear,24 The A1555G mutation has been found in 4. Antimicrobial agents. Sande MA, Mandell can worsen mitochondrial dysfunctions GL. In Goodman and Golman’s: The many families and sporadic cases world- in cochlear cells in susceptible subjects wide,12,18,19,20 while the C1494T muta- Pharmacological Basis of Therapeu- carrying the A1555G or C1494T muta- tics, 8th Edition. Gilman A G, Rall T W, tion has been reported in Chinese and tion. As a consequence, exposure to 13,21 Nies A S, Taylor P (Eds): 1098-1116. Spanish families. These mutations aminoglycosides leads to tissue specific Pergamon Press, Elmsford, NY (1990). account for approximately 20% of deaf- defects in those cells, thereby inducing 5. Genetic factors in aminoglycoside ness patients with a history of exposure or worsening hearing loss in individuals to aminoglycosides.11,22,23 In the absence toxicity. Fischel-Ghodsian N. carrying these ototoxic mtDNA muta- Pharmacogenomics. 2005; 6:27-36. of exposure to aminoglycosides, the tions. In particular, those children, under A1555G or C1494T mutation also pro- ten years old, carrying these ototoxic 6. Aminoglycoside research 1975-1985: 13,18 duces a non-syndromic hearing loss. mtDNA mutations will develop severe prospects for development of improved agents. Price K E. Antimicrob Agent Matrilineal relatives among families or or profound hearing loss if given these Chemother. 1986; 29: 543-548. within families carrying these muta- drugs, even at conventional doses. tions exhibited variable penetrance and 7. Risk factors for the development of expressivity, including severity and age Mutations in mitochondrial 12S rRNA auditory toxicity in patients receiving of onset in hearing impairment, ranging are one of the molecular bases for aminoglycosides. Moore R D, Smith CR, from profound congenital deafness, to aminoglycoside ototoxicity. Two ototoxic Lietman P S. J Infect Dis. 1984; 149:23-30. severe and moderate progressive hearing mitochondrial 12S rRNA mutations 8. Drug ototoxicity. Rybak L P. Ann Rev loss of later onset, to completely normal account for approximately 20% of cases Pharmacol Toxicol. 1986; 26:79-99. 12,13,18,19,20 hearing. In some families car- with aminoglycoside ototoxicity.11,21,23 rying these ototoxic mutations, only one 9. Genetic aspects of antibiotic induced These data have significant clinical and deafness: mitochondrial inheritance. or a few matrilineal relatives suffered from social impacts. However, the ototoxicity deafness, while the majority of mem- Hu D N, Qui W Q, Wu B T, Fang L Z, associated with these mutations can be Gu Y P, Zhang Q H, Yan J H, Ding Y Q, bers in these families exhibited normal preventable through a combination of 20 Wong H. J Med Genet. 1991; 28:79-83. hearing. The incomplete penetrance evaluating family history and molecular 10. Mutational analysis of the mitochon- of hearing loss and the mild biochem- analysis of 12S rRNA gene in suscepti- ical defects indicated that the A1555G drial 12S rRNA gene in Chinese pediatric ble individuals. Every individual, prior subjects with aminoglycoside induced or C1494T mutation itself is insufficient to an administration of aminoglycosides, to produce the deafness phenotype.11 and non-syndromic hearing loss. Li Z, Li should be examined for a family history. R, Chen J, Liao Z, Zhu Y, Qian Y, Xiong S, Therefore, other modifier factors, such If a member(s) of a family suffered from as aminoglycosides, are required for the Heman-Ackah S, Wu J, Choo D I, Guan aminoglycoside-induced deafness, others M-X. Hum Genet. 2005; 117: 9-15. phenotypic manifestation of the A1555G

26 www.icthesworldcare.com COMMUNITY EAR AND HEARING HEALTH: 2006; 3: 17-32 Issue No. 4 Ototoxicity: Genetic Aspects

11. Prevalence of mitochondrial 12S rRNA a DNA polymorphism, which causes Q, Qin H, Li R, Zhang X, Kang D, Cao J, mutations associated with amino- aminoglycoside-induced deafness. Young W Y, Guan M X. Biochem Biophys glycoside ototoxicity. Guan MX. The Hamasaki K, Rando R R. Biochem- Res Commun. 2006; 340:194-199. Volta Review. 2005; 105: 211-237. istry. 1997; 36:12323-12328. 21. Molecular and clinical characterisa- 12. Mitochondrial ribosomal RNA mutation 17. A biochemical basis for the inherited tion of three Spanish families with associated with both antibiotic- susceptibility to aminoglycoside maternally inherited non-syndromic induced and non-syndromic deafness. ototoxicity. Guan M X, Fischel- hearing loss caused by the 1494C->T Prezant T R, Agapian J V, Bohlman Ghodsian N, Attardi G. Hum Mol mutation in the mitochondrial 12S M C, Bu X, Oztas S, Qiu W Q, Arnos Genet. 2000; 9:1787-1793. rRNA gene. Rodriguez-Ballesteros M, K S, Cortopassi G A, Jaber L, Rotter Olarte M, Aguirre L A, Galan F, Galan 18. Familial progressive sensorineural J I, Shohat M, Fischel-Ghodsian N. R, Vallejo L A, Navas C, Villamar M, deafness is mainly due to the mtDNA Nature Genet. 1993; 4: 289-294. Moreno-Pelayo M A, Moreno F, del A1555G mutation and is enhanced by Castillo I. J Med Genet. 2006; 43:e54. 13. Maternally inherited aminoglycoside- treatment with aminoglycosides. Esti- induced and non-syndromic deafness is vill X, Govea N, Barcelo A, Perello E, 22. Mitochondrial gene mutation is a signifi- associated with the novel C1494T muta- Badenas C, Romero E, Moral L, Scozzari cant predisposing factor in aminogly- tion in the mitochondrial 12S rRNA R, D’Urbano L, Zeviani M, Torroni coside ototoxicity. Fischel-Ghodsian gene in a large Chinese family. Zhao H, A. Am J Hum Genet. 1998; 62: 27-35. N, Prezant T R, Chaltraw WE, Wendt Li R, Wang Q, Yan Q, Deng J H, Bai Y, K A, Nelson R A, Arnos K S, Falk R E. 19. Non-syndromic deafness associated with Young W Y, Guan M X. Am. J. Hum. Am J Otolaryngol. 1997; 18:173 -178. a mutation and a polymorphism in the Genet. 2004; 74: 139-152. mitochondrial 12S ribosomal RNA gene 23. Prevalence of mitochondrial gene 14. Interactions of a small RNA with in a large Zairean pedigree. Matthijs mutations among hearing impaired antibiotic and RNA ligands of the G, Claes S, Longo-Bbenza B, Cassiman patients. Usami S I, Abe S, Akita J, 30S subunit. Purohit P, Stern S. J-J. Eur J Hum Genet. 1996; 4:46-51. Namba A, Shinkawa H, Ishii M, Iwasaki Nature. 1994; 370: 659–662. S, Hoshino T, Ito J, Doi K, Kubo T, 20. Extremely low penetrance of deafness Nakagawa T, Komiyama S, Tono T, 15. Interaction of antibiotics with functional associated with the mitochondrial 12S Komune S. J Med Genet. 2000; 37:38–40. sites in 16S ribosomal RNA. Moazed D, rRNA mutation in 16 Chinese families: Noller H F. Nature. 1987; 327: 389-394. implication for early detection and 24. Pharmacokinetics of aminoglycoside anti- prevention of deafness. Dai P, Liu X, biotics in blood, inner ear fluids and their 16. Specific binding of aminoglycosides Han D, Qian Y, Huang D, Yuan H, Li W, relationship to ototoxicity. Henley C M, to a human rRNA construct based on Yu F, Zhang R, Lin H, He Y, Yu Y, Sun Schacht J. Audiology. 1988; 27:137-146.

1st INTERNATIONAL CONFERENCE ON PREVENTION For more information please check: AND REHABILITATION OF HEARING IMPAIRMENT • www.chinadeaf.com/prhi/list/list_59_1.html Beijing, 26-28 April, 2007 • www.who.int/pbd/deafness/en/ Hosted by the CHINA REHABILITATION RESEARCH CENTER FOR DEAF CHILDREN Or contact: (CRRCDC), and co-sponsored by the CRRCDC and the WORLD HEALTH ORGANIZATION. China Rehabilitation Research Center The conference will address: for Deaf Children (CRRCDC) A8, Huixin Li, Chaoyang District • Setting up National Programmes for • Early detection of hearing impairment prevention: obligations and functions in neonates, infants and young children Beijing, 100029 CHINA of governments and NGOs • Epidemiology and economic aspects • Prevention of hearing impairment of prevention of hearing impairment Email: [email protected] through the life span • Hearing and speech rehabilitation Conference Organizers • Prevention of particular causes • Technologies of assistive devices Email: [email protected] of hearing impairment • Provision of affordable hearing • Prevention of hearing impairment aids and services World Health Organization in the community and at the Email: [email protected] primary level of health care

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www.icthesworldcare.com • Community Ear and Hearing Health • Developing Mental Health Contact: Dr Murray McGavin ICTHES World Care, PO BOX 4101 • Community Dermatology Glasgow G53 9AF Scotland, UK • Repair and Reconstruction Tel: +44 (0)141 429 3377 E-mail: [email protected] Please state: Name, Full Postal Address, E-mail Address & Occupation

COMMUNITY EAR AND HEARING HEALTH: 2006; 3: 17-32 Issue No. 4 www.icthesworldcare.com 27 Prevention of Hearing Impairment: Bolivia THE NEED OF A PROGRAMME FOR THE PREVENTION OF HEARING IMPAIRMENT IN BENI STATE, BOLIVIA Diego J Santana-Hernández MD Life expectancy is 62.9 years (men: 61.3 years; women: 64.5 years). South America Foundation Totai Bolivia has the lowest number of Casilla 158 deliveries attended by health profes- Trinidad-Beni sionals and the highest maternal Bolivia mortality in South America: 234 for every 100,000 live births. (In E-mail: [email protected] the year 2000, the World Health Organization reported an average Dr Diego Santana-Hernández of 20 per 100,000 live births in the is an ENT Surgeon and General developed countries). Hospital early Practitioner. Since 2000 he has neonatal mortality (during first 7 worked as a missionary doctor in days of life) and infant mortality Bolivia, commended and supported (under 1 year) are 10 and 54 per together with his wife Joanne by 1000 live births, respectively.1 Carrubbers Christian Centre in Edinburgh, Scotland. He presently Justification Organization, based upon investiga- chairs Foundation Totai, a community tions carried out in countries with simi- orientated charity. 1. Absence of programmes for promotion lar characteristics, estimate that 10% of ear and hearing health of the population suffer some type of Introduction In a preliminary population based survey, disability.2 The Japanese International n the Bolivian Amazonian prai- out of a sample group of 658 school chil- Cooperation Agency (JICA), according ries, Beni State has a surface area dren (age 7 to 18), 105 presented with ear to investigations carried out in Bolivia Iof 213,564 km2 (approximately half or hearing problems (16%). Impacted in 1998, established that 9.13% of the the size of Spain). It has a dispersed wax in the ear canal was the main find- people with disability studied suffer a population of 406,982 inhabitants, of ing, followed by chronic otitis media. disabling hearing loss according to the 3 which 89,613 live in Trinidad, capital of 2. Absence of programmes for the preven- WHO definition. 1 Beni. Bolivia is the poorest country in tion of hearing impairment South America (64% of the people live Correlating those figures to the popu- below the poverty line). In 2004, GNP There are no population based studies lation in Beni (0.913%), we estimate a per capita was $US 1051 (871€). Direct to determine either incidence or preva- prevalence of 3,716 persons with a disa- foreign investment exceeds public invest- lence of hearing impairment in Bolivia, biling hearing disability. In 2004, 8,268 ment. $US 6.5 per person per year is nor is there a register of people with births were registered in the State (out of provided for health care. 1 hearing disabilities. The World Health 13,528 expected by the Instituto Nacional

Average Time Elapsed up to Integration Impairment to Suspicion Suspicion to Enrollment Females 1y 5m 2y 10m 1y 3m 7m 1y 6m Total: 7y 7m Enrollment to Consultation Consultation to Diagnosis Diagnosis to Gender Integration

Males 1y 8m 4y 7m 1y 8m 1m 3y 6m Total: 11y 6m

Combined 1y 7m 3y 9m 1y 5m 5m 2y 7m Total: 9y 9m Males/Females

0 1 2 3 4 5 6 7 8 9 10 11 12 Time (Years) from Damage to Integration Fig. 1: Representation of the reality of stage sequence in the process of diagnosis and integration

28 www.icthesworldcare.com COMMUNITY EAR AND HEARING HEALTH: 2006; 3: 17-32 Issue No. 4 Prevention of Hearing Impairment: Bolivia

3. Medical consultation to definitive 4. DDHI-ESS (Diagnosis to school- diagnosis of hearing impairment ing): 1 year 5 months (MCR-DDHI) 5. ESS-IS (School to integration): 4. Definitive diagnosis to enrollment in 2 years 7 months. special school (or special support group) (DDHI-ESS) Interpretation 5. Enrollment in special school to ‘inte- There is a significant and important gration’ into society (ESS-IS) delay for congenital hearing impair- ment in stage 1: an average 2 years 4 Findings months passed before relatives suspect Fig. 2: Community hearing testing in Cobija The generally accepted aetiological it (compared to 2 months, 2 weeks in Photo: Diego Santana proportions for congenital deafness are: acquired cases). However, the most de Estadística1), and, of these, 2473 were 50% hereditary, 25% non-hereditary and significant delay in diagnosis happens in hospital births in Trinidad alone. Our 25% idiopathic. 6,7 These differ from our stage 2, from family suspicion to request- locally determined aetiology for hearing study: the hereditary group is relatively ing specialist consultation: average 5 impairment in Trinidad (under 18 years smaller (31%); non-hereditary (34%) years, 2 months, with a significant differ- old) is: 36% acquired, 50% congeni- and idiopathic (34%) are greater. This ence between genders: males: 6 years 3 tal and 14% perinatal. Due to moderate finding is not unique to our popula- months; females: 4 years 1 month. The hearing loss being largely undiagnosed tion and is to be expected in an environ- negative symbol of stage 3 indicates that in our population of reference, we have ment with a high prevalence of infec- the norm is to enter special schooling been unable to gather enough data to tious diseases and limited methods for before medical or audiological evaluation give a realistic estimated incidence for establishing a diagnosis.5 takes place. For a clearer interpretation moderate hearing loss. of the sequence see Figure 1. 3. Absence of programmes for early detec- The high proportion of prematurity/ low birth weight and foetal complica- Frequently, the request for consultation tion of deafness tions such as severe hypoxia in perinatal takes place at the schools (special or main Early diagnosis of a hearing impair- cases (89% of total), and of meningitis in stream); this fact and eventuality delays ment in Trinidad-Beni (before 2 years) acquired cases (39% of medical causes), definite diagnosis due to lack of referral occurs in 7.8% of cases, and late diagno- is described by other authors, however, routes to health services. As defined by 8 ‘ sis in 92.2%. In developed countries, 50% their relative proportion is elevated in our Flores and Berruecos, It is important to cases of deafness are diagnosed before population. The same is true of acquired distinguish between identification and age 3 years.4 Average age at diagnosis in hearing impairment due to trauma, diagnosis, the latter being the one which Trinidad is 9 years 1 month (Females: 8 where 26% of our series contrast with the leads to the appropriate therapeutic and years; Males: 10 years, 4 months), chil- significantly lower figures of developed rehabilitation programmes.’ dren with a profound hearing loss being countries (not greater than 9%). Thirty- 9 diagnosed earlier than those whose loss six percent (36%) of acquired hearing We agree with other authors that the is severe.5 impairment in a mainly infant popu- best solution to reduce time elapsed from lation, highlights the need to carry out moment of hearing damage to specialist Study programmes to educate and enable the consultation (stages 1 and 2) is to estab- A retrospective closed analytical study population to prevent hearing impair- lish systems of universal screening at the of 64 students attending the only School ment and related systemic illnesses.5 health institutions. This action is limited for the Deaf in Trinidad was performed, in our environment, as the Public Health aiming to study the aetiology of hear- Reality in Beni Insurance, for both the mother through- ing impairment and reasons for the In our study, average total time elapsed out pregnancy until 6 months after deliv- delayed diagnosis of deafness. All the from the moment when hearing damage ery and for the child up to 5 years of students had a chronic hearing impair- occurred until ‘integration into soci- age, is hugely underused and lacks basic ment greater than 60 dB HL average for ety’ (school or work) of the hearing provision. the better ear. Both aetiology and the impaired person took place is: 9 years diagnostic process (timing and investiga- and 9 months. A significant difference tions) were examined. In order to better exists between genders: males: 11 years evaluate such delay in reaching a diagno- 6 months; females: 7 years, 7 months 5 sis, the period from the moment when (Figure1). hearing impairment occurred until final integration into society took place, was The average time elapsed by stage is: divided into 5 stages: 1. HIO-FSHI (Impairment to suspi- 1. Hearing impairment occurred (day cion): 1 year 7 months of delivery in congenital cases) to moment when family suspected 2. FSHI-MCR (Suspicion to consulta- hearing impairment (HIO-FSHI) tion): 5 years 2 months 2. Family suspicion of hearing impair- 3. MCR-DDHI (Consultation to diag- Fig. 3: Donated hearing instrument ment until medical consultation nosis): -1 year 10 months (Guayaramerín) was requested (FSHI-MCR) Photo: Joanne Santana COMMUNITY EAR AND HEARING HEALTH: 2006; 3: 17-32 Issue No. 4 www.icthesworldcare.com 29 Prevention of Hearing Impairment: Bolivia

Present Setting resident health professionals and exter- 7. Sensorineural Hearing Loss in Chil- Currently there are two special Schools nal aid agencies. To integrate it into the dren-Genetic. Paparella MM, of/for the Deaf in Beni: ‘Arca Maranata’ in National Health Service will take some Schachern PA. In Otolaryngology; vol Riberalta and IDEPPSO-Beni, Trinidad. extra help. By their fruit you will recog- II: Otology and Neuro-Otology. Papa- 11 rella et al. Third Edition, W B Saun- In 2005, the first School enrolled 37 nise them. ders Company, Philadelphia (1991). students and the second 50. This high- lights the situation of the estimated 1000 References 8. Identificación y Diagnóstico tempranos children of school age with hearing disa- 1. Population Census 2001/Projections. de los problemas auditivos. Berruecos bility, in the Beni, who are neither identi- Economical data 2002-2004. INE (Insti- P. In El niño sordo de edad preescolar. fied nor registered. tuto Nacional de Estadística de Bolivia) Flores L, Berruecos P, Edito- / WHO. In Indicadores Demográficos rial Trillas, Mexico D F (1991). Seventy-seven percent (77%) of our y Económicos. Web Page: http://www. 9. Detección Precoz de la hipoacusia. study group are under 19 years old, ine.gov.bo and Government links. Martínez R, Benito JI, Condado Ma comparable to 75% of disabled people 2. Estimación de la población con A et al. Acta Otorrinolaringológica attending rehabilitation institutions in Española. 2003; 54: 309-315. Bolivia reported by JICA. According to discapacidad en países subdesar- rollados. OMS / WHO. (1997). M. Guevara,10 in Bolivia, only 1.6% of 10. Población integrada a la educación those with hearing disability are inte- 3. Study of 16,880 persons with disability formal. Guevara M. In Ofertas Educativas para personas con nece- grated into education and the labour attended by rehabilitation programmes sidaes educativas especiales en Bolivia. market, which represents 6% of the total in Bolivia. JICA (Japanese International Cooperation Agency). In Realidad Social Guevara M, Dirección Nacional de disabled population (or with learning Educación Especial, La Paz (1997). difficulties) successfully integrated in the de las Personas con Discapacidad en country. Bolivia. JICA Reports. La Paz. (1999). 11. The New Testament: Matthew. 4. Inner ear, genetic sensorineural hearing In The Holy Bible, New Inter- Programme loss. Strasnick B, Hoffmann K. Eastern national Version, Holman Bible The setting of a programme for the Virginia Med School. 2003 [Medline]. Publishers, Nashville (1998). prevention of hearing impairment, with 5. Ser sordo en el Beni, Bolivia: Manejo activities for primary, secondary and del Déficit Auditivo en países tertiary prevention, seems to be the way deprimidos. Santana-Hernández DJ, forward to alleviate the burden of hear- Santana-Hernández JL, Barboza I. GRAPHIC DESIGN. WEB DEVELOPMENT. ing disability in Beni and Bolivia. ENT News Español. 2004; 1(6): 6-11. Bespoke design: websites, promotional materials, branding, magazines and much more. Hope 6. Epidemiology, etiology and genetic patterns. Cohen MM, Gorlin RJ. Oxford [email protected] For such a programme to see the light, University Press. NY (1995): 9-21. 0 (44) 141 552 9900 (Glasgow, UK) it will be necessary to join the efforts of www.freshfacemedia.com Atfaluna News Update ATFALUNA NEWS UPDATE, JANUARY 2006

A T F A L U N A

Atfaluna Society for Deaf Children people are on the streets. It’s post-elec- all sizes…hands whose eloquent move- PO Box 1296 – 72 Philisteen St tion Palestine and the mood is one of ments so expressive and so meaningful Gaza City uncertainty and apprehension. Years of in context and concept, that stories of The Gaza Strip military occupation and political unrest thousands of words are expressed in only The Palestinian Authority have instilled in most an uncanny sense a few minutes. I watch as two three-year- of when it’s just best to stay indoors and olds hug each other and say how much Email: [email protected] wait it out. they’ve missed each other and it’s clear that they mean it. Very Dear Friends The children are back to school today following their three-week mid-year How good it feels to see the children It’s a warm and sunny morning here break. They are clearly happy to be back hold their heads up high in surroundings in the Gaza Strip, and already there are where their friends, teachers, and staff where disability has always carried with subtle signs of spring in the air. The clear members ‘speak’ their native tongue, it social stigma that cannot be erased blue skies made for a perfect day to be Palestinian Sign Language. This morn- overnight. I feel proud of the children, outdoors, but few cars and even fewer ing the playground was a sea of hands of their parents, their teachers. I feel proud

30 www.icthesworldcare.com COMMUNITY EAR AND HEARING HEALTH: 2006; 3: 17-32 Issue No. 4 Atfaluna News Update of what we have been able to achieve is an excellent role model for other deaf for all your support to the children in our through the help and partnerships with children. A natural comedienne and care…children like Fedwa who would our good friends and supporters the talented actor, Fedwa is active in the never have had a chance in life without world over. Atfaluna Deaf Theatre Group where her your encouragement and support. favourite role is the mean stepmother in One of the exciting new programmes the group’s Cinderella production. One Sincerely being implemented at Atfaluna this year of her favourite pastimes is baking tradi- Geraldine (Gerry) Shawa is a 4-year training course to teach young tional sweets which she learned in an Executive Director deaf women and men to be teaching Atfaluna culinary arts training course. assistants. Both practical and theoreti- Fedwa had thought of starting a home- cal training takes place at Atfaluna where based sweets business with her mother, Editor’s Comment the participants assist experienced teach- but decided that helping other deaf chil- ers of the deaf in the classroom, learn dren was her responsibility. She is excited Although this letter from Geraldine to prepare lesson plans and teaching about becoming an assistant teacher Shawa of the Atfaluna Society resources, and acquire the skills needed one day and hopes to be able to help for Deaf Children was received to assist in classroom management. deaf children to understand more easily many months ago, its warm things that she had difficulty grasping as Fedwa, now 19 years old, was one of a student. and encouraging news of a very the first students to attend the Atfaluna significant programme is considered School when it was established in 1992. On behalf of everyone here at Atfaluna, important to share with our readers. Always an outstanding student, Fedwa I would like to thank you most sincerely

Abstracts Combined effects of noise and mixed solvents exposure on the hearing function among workers in the aviation industry Kim J, Park H, Ha E, Jung T, worked in avionics jobs in Kimhae, risks, adjusted for age, were estimated to Paik N, Yang S Korea, who kept records of work envi- be 4.3 (95% CI 1.7-10.8) for the noise ronment evaluations and medical exami- only group, 8.1 (95% CI 2.0-32.5) for the Department of Preventive Medicine nations. The Cumulative Exposure Index noise and solvents group, and 2.6 (95% College of Medicine (CEI) was constructed to assess the life- CI 0.6-10.3) for the solvents-mixture Ewha Womans University time cumulative exposure of the workers, group. These suggest that chronic expo- 911-1, Mok-6-dong and pure tone audiometry (PTA) data sure to mixed solvents had a toxic effect Yangcheon-ku of the workers from the biannual medi- on the auditory system. This raises the Seoul 158-060 cal surveillance was used to assess hear- issue of whether hearing conversation Korea ing loss. The prevalence of hearing loss regulations should be applied to all work- found in the group exposed to noise and ers exposed to solvents. This study aims to evaluate the effect mixed solvents simultaneously (54.9%) of occupational exposure to noise and was higher than those in the other groups Published Courtesy of: organic solvents on hearing loss in the (6.0% in the unexposed, 17.1% in the Ind Health. 2005; 43 (3): 567-573 aviation industry. The study popula- noise-only, and 27.8% in the exposed tion comprised 542 male workers, who to only solvents mixture). The relative

Toxic solvents in car paints increase the risk of hearing loss associated with occupational exposure to moderate noise intensity El-Shazly A noise-induced hearing loss (NIHL) in was an associated disease in workers with humans. In this study, a 160 pure tone NIHL exposed to car paints and moder- Misr University for Science and audiometric test was performed in work- ate noise simultaneously. These results Technology ers in two independent factories to inves- may indicate that toxic solvents in car College of Medicine tigate whether toxic solvents in car paints paints act in synergism with moder- Department of Otolaryngology can result in noise-induced hearing loss in ate noise exposure, damaging the coch- Cairo workers exposed to moderate noise levels lear hair cells. The results also constitute Egypt of less that 85 decibels (dB). It is shown firm grounds for monitoring the hearing that toxic solvents in car paints increase of these workers and adherence to strict E-mail: [email protected] the risk associated with moderate noise regulations about wearing special gowns exposure of less than 85 dB, with levels and filtered masks during working hours Solvents in car paints are a recognised of NIHL being similar to those in work- to protect against this preventable occu- source of occupational toxicity. In partic- ers exposed only to loud noises between pational disease. ular, they can cause DNA damage and 92.5 dB and 107 dB. Tinnitus and spells occupational rhinobronchitis. However, of dizziness were associated symptoms Published Courtesy of: little is known about their toxic effect in in all workers with NIHL, and asthma B-ENT. 2006; 2 (1): 1-5

COMMUNITY EAR AND HEARING HEALTH: 2006; 3: 17-32 Issue No. 4 www.icthesworldcare.com 31 Community Ear & Hearing Health Abstract

Organic solvents and hearing loss: The challenge for audiology auditory pathways. Studies conducted 2006; 3:17-32 Issue No. 4 Fuente A, McPherson B with both animals and humans demon- Centre for Communication Disorders strate that the hearing frequencies Editor The University of Hong Kong affected by solvent exposure are differ- Hong Kong Dr Ian J Mackenzie ent to those affected by noise, and that China solvents may interact synergistically with E-mail: [email protected] Editorial Board noise. The present article aims to review the contemporary literature of solvent- Prof Jose M Acuin (Philippines) Organic solvents have been reported to induced hearing loss, and consider the Dr Piet van Hasselt adversely affect human health, includ- implications of solvent-induced auditory (CBM: The Netherlands) ing hearing health. Animal models damage for clinical audiologists. Possible Dr D D Murray McGavin have demonstrated that solvents may audiological tests that may be used when (ICTHES: UK) induce auditory damage, especially to auditory damage due to solvent exposure Dr Ian J Mackenzie (UK) the outer hair cells. Research on workers is suspected are discussed. Prof Valerie E Newton (UK) exposed to solvents has suggested that Dr Beatriz C W Raymann these chemicals may also induce auditory Published Courtesy of: (Brazil) damage through effects on the central Int J Audiol. 2006; 45 (7): 367-381 Dr Andrew W Smith (WHO) Editorial Board, Community Ear and Hearing Health Regional Consultants Prof Jose M Acuin (Philippines) Dr Juan Madriz (Costa Rica) Dr Beatriz C W Raymann (Brazil) Beatriz Raymann ICTHES World Care Executive Director / Editor Dr Murray McGavin International Development Officer Mrs Mary Bromilow Murray McGavin, Ian Mackenzie, Andrew Smith, Valerie Newton, Jose Acuin Piet van Hasselt Associate Editor Photo: Ruth McGavin Ms Caroline McGavin Administration / Newsletter COMMUNITY EAR AND HEARING HEALTH Mrs Ruth McGavin Aim Ms Manon ten Cate • To promote ear and hearing health in developing countries Objectives Design/DTP • To facilitate continuing education for all levels of health worker, particularly in Mr Daniel Chadney at developing countries Freshface Media Ltd. • To provide a forum for the exchange of ideas, experience and information in order www.freshfacemedia.com to encourage improvements in the delivery of ear and hearing health care and rehabilitation. Supported by Guidelines for Authors Christian Blind Mission eV Please see Issue No. 1. (CBM) Also online at: www.icthesworldcare.com World Health Organization The Scottish Executive: The Correspondence/Enquiries to: Devolved Government of ICTHES World Care, PO BOX 4101, Glasgow G53 9AF, Scotland, UK Scotland Tel: +44 (0)141 429 3377 E-mail: [email protected] or [email protected] Printed by © Community Ear and Hearing Health The Heyford Press Ltd Articles may be photocopied, reproduced or translated provided these are not used for commercial or personal profit. Acknowledgements should be made ISSN 1743-9914 to the author(s) and to Community Ear and Hearing Health.

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