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Anatomy and Physiology
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Normal hearing begins when sound waves are captured by the external auricle, traverse the external auditory canal, and are conducted to the tympanic membrane, the three auditory ossicles of the middle ear, and move through the oval window to the perilymph in the scala vestibuli of the cochlea (Figs. 26–1 and 26–2). The sound wave is then transferred through the Reissner membrane at the roof of the cochlear duct, to the endolymph and the organ of Corti.54,167 The specialized hair cells of the organ of Corti convert mechanical waves into neurologic signals. The hair cells contain cross-linked stereocilia projections that detect transmitted shear forces, which lead to the influx of potassium from the endolymph through opened potassium channels.43,104 Depolarization of the hair cells results in calcium influx and neurotransmitter release to the cochlear nerve. Neurologic signals from the cochlear nerve are conducted to the cochlear nucleus of the pons; bilateral projections are then sent to the superior olivary nucleus of the midbrain, nuclei of lateral lemnisci, inferior colliculus, medial geniculate body of the thalamus, and then to the auditory cortex of the temporal lobe.167 Interruption or damage to any part of the hearing mechanism may lead to auditory impairment.
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The anatomy and physiology of the cochlea and its importance in the biomechanics of hearing are reviewed in order to better understand the potential for xenobiotic injury. The word cochlea is derived from the Greek word kochlias, meaning snail, and describes its general structure—a 2.5-turn, spirally wound tube. The cochlea is further divided into three inner tubular structures: the upper tube or scala vestibuli, the middle tube or cochlear duct, and the lower tube or scala tympani. The scala vestibuli and the scala tympani contain the perilymph fluid. The cochlear duct contains endolymph fluid, the Reissner membrane at the roof, and the organ of Corti.167 The cochlear fluids serve multiple functions: to conduct sound waves to the hair cells; to provide nutrients for and remove waste from the cells lining the cochlear duct; to control pressure distribution in the cochlea; and to maintain an electrochemical gradient for the function of the hair cells. The sodium concentration of the perilymph is similar to that of the extracellular fluid, and the potassium concentration of the endolymph is similar to that of the intracellular fluid.56 Any significant alterations of the sodium or potassium concentrations will depress the cochlear potential and function. The stria vascularis controls the production of the cochlear fluids and the repolarization of the hair cells, and maintains the electrochemical gradient between the endolymph and the perilymph. The stria vascularis contains a high concentration of the oxidative enzymes, Na+-K+-adenosine triphosphatase (ATPase), adenylate cyclase, and carbonic anhydrase, which are all highly susceptible to xenobiotics.20,84,148
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Although human speech is composed of sounds in the frequency of 250 to 3000 Hz, humans can normally detect sounds in the frequency range of 20 to 20,000 Hz.125 The cochlea is a “tuned” structure with varying width and stiffness, such that different regions can receive different sound waves. The stiffer and wider base of the cochlea serves as a receptacle for higher-frequency sounds, whereas the apex is responsible for receiving the lower-frequency sounds.54 Because various regions of the cochlea are susceptible to different forms of injury, appropriate audiologic testing should be tailored specifically to each patient.27
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Xenobiotic-Induced Ototoxicity
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Ototoxicity includes effects on the cochlear and vestibular system. This section focuses on cochlear toxicity. Quinine and salicylates were widely recognized in the 1800s and streptomycin in the 1940s as causes of ototoxicity.85,143 Several hundred xenobiotics are implicated as causes of either reversible or irreversible ototoxicity (Table 26–4).23,89,97,121 Ototoxic xenobiotics primarily affect two different sites in the cochlea: the organ of Corti—specifically the outer hair cells—and the stria vascularis. Because of the limited regenerative capacity of the sensory hair cells and other supporting cells, when significant cellular damage occurs, the loss is often permanent.47,54,85,165 Although cell death of the outer hair cells from inflammation and necrosis is expected when sufficient insults occur, apoptotic cell death is now postulated to be a major mechanism of ototoxicity from certain xenobiotics such as cisplatin and aminoglycosides.20,23,44,85,89,140 Inhibition of caspases and calpain associated with apoptosis of the hair cells is demonstrated to decrease ototoxicity from cisplatin and aminoglycosides in animals.140,164 Heat shock proteins are endogenous molecules that respond to cellular stress and inhibit apoptosis. Xenobiotics that can up-regulate heat shock proteins such as celestrol prevent cisplatin and aminoglycoside toxicity in animal models.40,59 Further studies are required to demonstrate clinical utility. Evidence supports the concept that otic injury can be potentiated by loud noises. Although the actual cellular mechanisms for many forms of ototoxicity remain unclear,185 some of the mechanisms are known.63 Loop diuretics, such as furosemide, bumetanide, and ethacrynic acid, cause physiologic dysfunction and edema at the stria vascularis, resulting in reversible hearing loss.85,109,181 The underlying mechanisms appear to be the inhibition of potassium pumps and G proteins associated with adenylate cyclase.9 Studies of loop diuretics demonstrate decreased potassium activity in the endolymph and a decreased endocochlear potential.145 Permanent hearing loss associated with furosemide and ethacrynic acid is also reported, and may be related to direct interference with oxidative metabolism in the outer hair cells.98,109,145
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Salicylates are a well-known cause of ototoxicity. Aspirin (acetylsalicylic acid)-induced hearing impairment was first reported in 1877.93 Salicylate-induced hearing loss is generally mild to moderate (a loss of 20–40 decibels {dB}) and reversible.17,87 Animal studies demonstrate immediate hearing impairment with the use of high doses of salicylates.16,110,111,132 The mechanism of salicylate-induced ototoxicity is unclear, although multiple factors are postulated. Salicylates and other NSAIDs inhibit cyclooxygenase, which converts arachidonic acid to prostaglandin G2 and prostaglandin H2. These effects may interfere with Na+-K+-ATPase pump function at the stria vascularis, and also decrease cochlear blood flow.29,50,93 A reversible decrease in outer hair cell turgor secondary to membrane permeability changes may impair otoacoustic emissions.131,135 In support of these theories, pretreatment of animals with leukotriene antagonists and α-adrenergic receptor antagonists attenuates or prevents salicylate-induced ototoxicity.93
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NSAIDs and quinine also cause reversible hearing loss, particularly at the higher frequencies.31,85 Occasionally, quinine-induced hearing loss may be permanent.85,149 The primary mechanism is related to prostaglandin inhibition.93 Quinine inhibits the enzyme phospholipase A2, which converts phospholipids to arachidonic acid. Quinine also inhibits calcium channels that interact with prostaglandins.93
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Certain chemotherapeutics, such as cisplatin, vinblastine, and vincristine, can cause permanent ototoxicity.85 Cisplatin is the most toxic of the group, with clinically apparent hearing loss noted in 30% to 70% of the patients receiving doses of 50 to 100 mg/m2. These antineoplastics typically damage the outer hair cells but may also affect the stria vascularis.85 The underlying mechanisms may be related to the inhibition of adenylate cyclase in the stria vascularis, the inhibition of protein synthesis, and the formation of oxygen free radicals.9,85,155 The generation of oxygen free radicals and the depletion of antioxidants result in the irreversible damage to the hair cells.52 Furthermore, cranial radiation will cause synergistic toxicity if radiation precedes cisplatin therapy. Various antioxidants and free radical scavengers prevent cisplatin-induced ototoxicity in animals, perhaps preventing oxidative injury–induced apoptosis to hair cells.102,116,119,137,140,144,169,184 Amifostine, a precursor to a thiol free radical scavenger, prevents cisplatin-induced nephrotoxicity, but does not appear to prevent cisplatin-induced ototoxicity.147
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The aminoglycosides are best known for their association with irreversible ototoxicity,130 but they are not concentrated in the cochlea. The endolymph concentration of gentamicin is approximately 10% of that in the serum. It is postulated that toxicity is related to the metabolites of aminoglycosides and not the parent compounds because toxicity can be reproduced in vivo, but not in vitro.148 Neomycin and kanamycin are the most ototoxic, although all aminoglycosides are potentially toxic.98 With the development of the newer aminoglycosides and therapeutic drug monitoring, the incidence of aminoglycoside-related ototoxicity appears to be decreasing. The reported rates of ototoxicity for the more commonly used aminoglycosides gentamicin and tobramycin are between 5% and 8%.108 In China, where aminoglycosides are readily available as nonprescription medications, as much as 66% of deafness may be directly related to aminoglycoside toxicity.61,105 Several uncommon genetic mutations that predispose to aminoglycoside-induced ototoxicity are identified, including A1555G and C1494T mutations.57,75 The genetic transmission appears to be maternal via mitochondrial DNA and the defects increase aminoglycoside binding to mitochondrial 12S ribosomal RNA.57 These patients may experience rapid and severe hearing loss compared with normal people with a similar aminoglycoside exposure.140
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Several mechanisms of aminoglycoside ototoxicity are postulated, including antagonism of calcium channels of the outer hair cells of the cochlea, blocking transduction of the hair cells and resulting in acute, reversible hearing deficits as well as binding to polyphosphoinositides of cell membranes to alter their functions. Polyphosphoinositides are essential for the generation of the second messengers diacylglycerol and inositol triphosphate and their ultimate cellular function, for the maintenance of lipid membrane structure and permeability, and as a source for arachidonic acid.85,140 However, the most important mechanism is that aminoglycosides interact with iron and copper to generate free radicals, damaging the hair cells. Aminoglycosides also inhibit ornithine decarboxylase which is important for cellular recovery following an injury and makes the cell more susceptible to toxicity.148 The outer hair cells of the cochlea are increasingly susceptible to aminoglycosides and damage progresses from the inner row of the outer hair cells to the basal turn of the cochlea, and, ultimately, to the apex.4,7,98,140
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The risks of ototoxicity are increased with a duration of therapy of more than 10 days, concomitant use of other ototoxic xenobiotics, and the development of elevated serum concentrations.7,55,146 There is no evidence that single daily dosing of aminoglycosides alters the risk of ototoxicity.127,179 Loop diuretics increase aminoglycoside toxicity by increasing aminoglycoside penetration into the endolymph. In animal models, certain free radical scavengers, such as glutathione, amifostine, and deferoxamine, decrease aminoglycoside-induced ototoxicity.64,149,170,177,180 Fosfomycin, a phosphonic antibiotic, has limited efficacy in reducing aminoglycoside-induced ototoxicity.124 Leupeptin and Z-DEVD-FMK, calpain and caspase inhibitors, respectively, that affect the apoptotic pathway, decrease ototoxicity in animal models.32,63,159,164 Further studies are required to determine their applicability to humans. Salicylates, which may act as free radical scavengers in therapeutic concentration, were effective in preventing gentamicin ototoxicity in animals. Two randomized human trials using concomitant salicylate therapy at 1.5 and 3 g/day significantly attenuated gentamicin-induced otoxicity.12,160 Gastric adverse effects, including bleeding, were also more common in the salicylate group. Confirmation of these findings and determining safer alternatives are warranted.
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Erythromycin, vancomycin, and their respective analogs are ototoxic. There are a number of reports of hearing loss following erythromycin therapy in humans and an animal study supporting the ototoxic potential. Most deficits in humans are transient, although several cases of permanent hearing loss are reported.21,22 The mechanisms of toxicity remain unclear, although the proposed effects are on the central auditory pathways. Erythromycin-induced hearing loss occurs at both lower and higher frequencies for speech, allowing for recognition in the early stages of ototoxicity.21 Similarly, both reversible and irreversible ototoxicities from the newer macrolide antibiotics clarithromycin and azithromycin were also reported.
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The evidence for vancomycin-induced ototoxicity is less convincing. Although numerous cases of presumed vancomycin-related ototoxicity are reported, concomitant use of other ototoxic antibiotics was common or audiometric studies were not performed. In limited animal studies, vancomycin alone does not induce ototoxicity, but it increases ototoxicity when administered concomitantly with an aminoglycoside. Vancomycin analogs such as teicoplanin and daptomycin probably have similar ototoxic potentials.
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Bromates are among the most extensively studied ototoxic xenobiotics.31,36,107,133 Bromates are used in hair “neutralizers,” bread preservatives, and as fuses in explosive devices.86,133,173 Following bromate administration the stria vascularis and hair cells of the organ of Corti are irreversibly damaged.133 Substantial exposure to bromates may also cause acute kidney injury, which decreases bromate elimination and, in turn, increases its ototoxic potential.86,133
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It is intriguing that xenobiotics, such as the bromates, loop diuretics, and aminoglycosides, primarily affect both the cochlea and the kidneys. One possible explanation is that the stria vascularis and the renal tubules have similar functions in maintaining electrochemical gradients.124,125 However, renal tubules may regenerate, while damage to the hair cells and the stria vascularis of the cochlea is more likely to be permanent.
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Sudden hearing loss is reported with recreational drug use, particularly with cocaine and opioids. For cocaine, the mechanism of injury may be related to cochlear hemorrhage and hypoxia from vasoconstriction.37,123,171 While other mechanisms such as a direct effect on the potassium channels in the hair cells and sodium channels of the auditory nerve have been postulated, they are not well elucidated in animal models. Concomitant opioid use and adulterants should be considered. Various opioids, including heroin, methadone, and hydrocodone, are associated with hearing loss.34,154,156,162 Neither the route of use nor the presence of adulterants such as quinine can adequately explain the hearing loss. Most cases of opioid associated hearing loss are reversible, but some are permanent. The mechanisms of opioid associated hearing loss are unclear. One potential mechanism is that the stimulation of opioid receptors in the cochlea inhibits adenylate cyclase activity, leading to hearing loss.53 Various opioid receptors have been identified in the cochlea, such as in the inner hair cells, outer hair cells, and the spiral ganglion. Others postulate that opioids have potential roles as neurotransmitters or neuromodulators that affect auditory function.91
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Other xenobiotics implicated as ototoxins are carbon monoxide, lead, arsenic, mercury, toluene, xylene, and styrene.82,166 However, both human and animal data are quite limited. Carbon disulfide, carbon tetrachloride, and trichloroethylene are also suspected of being ototoxic, but toxicity has not been demonstrated in humans.82,156 Because exposures to xenobiotics are frequently occupational, they are of great concern as they may potentiate or be additive to other types of occupational hearing impairments.95,138
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High-frequency hearing is most vulnerable, and early or limited impairment may not be noticeable unless audiometry, especially at 8000 kHz and above, is performed.178 These hearing tests can be performed in infants using the measurement of auditory brainstem response.14
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Noise-Induced Hearing Impairment
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Noise-induced hearing impairment has been recognized for hundreds of years, but became a great concern and increasingly prevalent with the industrial revolution and the discovery of gunpowder.54 Some of the anatomic changes in the organ of Corti and the audiometric features of noise-induced hearing impairment were well described by 1900.2,3,112 Unfortunately, few longitudinal studies on noise-induced hearing impairment have been performed.
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Although noises of sufficient magnitude may cause hearing impairment with limited exposure, most noise-induced hearing losses result from preventable prolonged cumulative occupational exposure. NIOSH has estimated that up to 1.7 million workers in the United States between 50 and 59 years of age have significant occupation-related hearing loss.125 Noise can be defined as any unwanted sound, which can be further characterized by duration, time pattern (continuous, intermittent, or impulsive), frequency, and intensity. Although loud sounds from concerts and personal listening devices may not be classified as noise, they are included as noise for the purpose of the discussion. The intensity is measured in sound pressure levels (SPLs) and expressed in a logarithmic scale in decibels (dB). The intensity of a normal conversation is approximately 65 dB (Table 26–5).125 The risk of noise-induced hearing loss is related to cumulative duration of exposure, intensity, and individual susceptibility.122,128,183 Much of the risk assessment of noise-induced hearing loss is inexact. Most authorities agree that sounds with maximal intensity below 75 to 80 dB will not cause hearing impairment, regardless of the duration of exposure.122 At higher intensity, the risk of hearing impairment increases with increased duration of exposure. Continued occupational exposure at 90 to 94 dB typically causes some high-frequency hearing loss in approximately 10 years.2,128 Further exposure results in hearing loss in the lower-frequency range. The Occupational Safety and Health Administration (OSHA) established guidelines for permissible occupational noise exposure based on an analysis of the average intensity and duration of exposure (Table 26–6).2,183
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The pathophysiology of noise-induced hearing impairment is related to an excessive energy impact on the cochlea, but the exact biochemical changes are unclear. Apoptotic death of the hair cells can be demonstrated and inhibition of apoptosis pathways mitigates noise-induced toxicity in animal models. A limited exposure to excessive noise results in a temporary hearing impairment or temporary threshold shift with a duration of hours to weeks. However, prolonged exposure results in a permanent threshold shift or hearing impairment.3,54,183 Initially, outer hair cells are lost, but more significant exposures result in damage to both inner and outer hair cells and all supporting structures in the organ of Corti. Cochlear nerve fibers degenerate after hair cell damage.54,183 The section of the cochlea most at risk from loud noises is at the region of 9 to 13 mm (total length is 32 mm).112 This region is responsible for hearing at the range of 3000 to 6000 kHz, corresponding to the typical noise-induced hearing loss pattern.
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Much of the clinical assessment and monitoring of noise-induced hearing loss is based on pure tone hearing loss, demonstrating an audiometric deficit at 3000 to 6000 kHz.125,128,183 Although human speech is composed mainly of low frequency sounds, the ability to perceive the higher frequency sounds is extremely important in speech recognition. For this reason, the major impairment in patients with noise-induced hearing loss is an inability to discriminate speech, particularly from background noise.2,42 Currently, the science of the investigation of speech discrimination is limited with extensive areas for research.
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Blast injury to the ear results from exposure of extremely short duration, but very high-intensity sound waves, usually greater than 140 dB. Military personnel are particularly at risk.30,129,175,178 Hearing loss from blast injury may be related to rupture of the tympanic membrane, disruption of the ossicles, temporary cochlear dysfunction, and permanent cochlear dysfunction from labyrinthine fistulae and basilar membrane rupture.28 When a large tympanic membrane rupture or disruption of the ossicles occurs, surgical intervention may be required to treat hearing impairment.28
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Prevention of any type of noise-induced hearing loss remains the best solution. Various hearing-protection devices are available if the noise exposure cannot be reduced. Better monitoring and more longitudinal studies are required on noise-induced hearing loss. Exposures to xenobiotics that can impair hearing may have synergistic effects with noise-induced hearing loss.95,97 These factors should be considered when noise exposure is evaluated. Furthermore, noise exposure is not limited to the workplace. Significant noise exposure may occur at home or from leisure activities, such as the use of power tools, loud music, and ambient exposure.15,38,74,128 The impact of noise exposure outside of the workplace has only recently attracted the attention of investigators.
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Tinnitus is the sensation of sound not resulting from mechanoacoustic or electric signals. Virtually all humans experience tinnitus during their lives. The exact mechanism or mechanisms resulting in tinnitus are largely unknown.152 Tinnitus may or may not be associated with hearing loss. Several theories are proposed, but none is completely satisfactory. Tinnitus may result from spontaneous neurologic discharges when the hair cells or cochlear nerve is injured. Altered sound perception may result from local or central effects when feedback mechanisms are interrupted.45,51,88,111 Severing the cochlear nerve terminates tinnitus in less than half of affected patients, suggesting important central mechanisms.10 Furthermore, certain etiologies of tinnitus, such as migraine headache and temporal lobe seizures, do not affect hearing directly. N-methyl-d-aspartate (NMDA) glutamate receptor activation (and enhanced cochlear signal transmission) is implicated as a mechanism for tinnitus in animal models; NMDA receptor activation may result from cyclooxygenase inhibition or neurologic injuries.76,131 Xenobiotics, including salicylate, may cause hair cell dysfunction and may modify neurotransmission centrally in both the cochlear nucleus and the inferior colliculis.65,182 Although the probable sites involved in tinnitus may be classified as peripheral (external ear, middle ear, or cochlear {CN VIII}), central, or extra-auditory (vascular, nasopharyngeal), some etiologies may affect peripheral and central sites, and many etiologies remain unknown.35,51,111
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Numerous xenobiotics are associated with tinnitus (Table 26–7), but the incidence is probably low and the implied relationships are usually supported only by case reports.33,157,158 Tinnitus may or may not be associated with transient or permanent hearing loss. It is probable that the xenobiotics associated with hearing loss affect cochlear function, while those that produce tinnitus without hearing loss probably act on signal transmission at the cochlea in the CNS. Xenobiotics that frequently produce tinnitus include streptomycin, neomycin, indomethacin, doxycycline, ethacrynic acid, furosemide, heavy metals, and high doses of caffeine.69,157,158 Only a few xenobiotics, such as quinine and salicylates, consistently cause tinnitus at toxic doses.16,51 These two xenobiotics also serve as examples of how the presence of tinnitus may be an indicator of drug toxicity.
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Tinnitus associated with salicylates usually begins when serum concentrations are in the high therapeutic or low toxic range of approximately 20 to 40 mg/dL.117 Membrane permeability changes cause a loss of outer hair cell turgor in the organ of Corti which may impair acoustic emissions, explaining tinnitus to some extent.131,132,135 NMDA-receptor activation from cyclooxygenase inhibition may also cause tinnitus.131 Before the wide availability of serum salicylate measurements, physicians treating gout or rheumatoid arthritis often titrated the salicylate dosage until tinnitus developed.117 Tinnitus and other signs and symptoms of salicylism (Chap. 39) should be sufficient for physicians to diagnose salicylate toxicity before serum salicylate concentrations are available. However, tinnitus may not be evident in patients with hearing impairment despite significantly elevated salicylate concentrations.117 The classic constellation of symptoms of quinine and salicylate toxicity, called cinchonism, includes nausea, vomiting, tinnitus, and visual disturbances.4,26,120 Because serum quinine concentrations are not readily available, symptoms of quinine toxicity define the clinical diagnosis (Chap. 59).168