26: Otolaryngologic Principles

Many xenobiotics adversely affect the senses of olfaction, gustation, and cochlear-vestibular functions. These toxic effects are not life-threatening but may pose significant distress to patients. Health care providers are often not familiar with the pathophysiology of these special senses. ­Furthermore, because of the lack of standardized diagnostic techniques and normal parameters, such adverse effects may be overlooked and dismissed by health care providers, despite significant patient distress and dysfunction. This is particularly true for disorders of olfaction and gustation. This chapter reviews the anatomy and physiology of these senses, describes the effects of xenobiotics on these senses, and examines the significant diagnostic information these senses contribute to identifying the presence of xenobiotics. Understanding the effects of xenobiotics on these senses may allow for early detection, removal, appropriate referral, treatment, and prevention of future events. In occupational settings, understanding these principles may prevent permanent and life-threatening injuries.

Anatomy and Physiology

Olfactory receptors are bipolar neurons located in the superior nasal turbinates and the adjacent septum. There are 10 to 20 million receptor cells per nasal chamber, and the receptor portion of the cell undergoes continuous renewal from the olfactory epithelium.^114,118 Renewed olfactory receptors regenerate neural connections to the olfactory bulb. These olfactory receptor neurons are distinctive in their ability to regenerate.²⁴ The axons of these cells form small bundles that traverse the fenestrations of the cribriform plate of the ethmoid bone to the dura. Within the dura, these bundles form connections with the olfactory bulb from which neural projections then connect to the olfactory cortex. There are extensive interconnections to other parts of the brain, such as the hippocampus, thalamus, hypothalamus, and frontal lobe, suggesting effects on other biologic functions.¹¹⁴ Although primary odor detection is a function of the olfactory nerve (CN I), some irritant odors, such as ammonia and acetone, are transmitted through the trigeminal nerve (CN V) and its receptors.^45,153

The actual olfactory receptor sites are structurally similar to the taste receptors of the mouth and the photoreceptors of the retina. The receptor is a single polypeptide chain consisting of approximately 350 amino acids, which folds back and forth onto itself to traverse the cellular membrane seven times. The outer end of the polypeptide contains an amine group (N-terminal) and the cytosolic end contains a carboxyl group (C-terminal). The transmembranous portions determine the receptor shape and characteristics of the binding site. When a molecule binds to a specific receptor site, the resultant conformational change leads to the activation of the G protein system and calcium and/or sodium channel activation and neurotransmission.⁷⁹

Smelling is an extremely sensitive mechanism of detecting xenobiotics. Olfactory receptors can detect the presence of a few molecules of certain xenobiotics with a sensitivity that is superior to some of the most sophisticated laboratory detection instruments.⁷²

Clinical Use of Odor Recognition

The sense of smell can be extremely useful as a toxicologic warning system. Human olfaction is a variable trait.^5,126,187 For example, 40% to 45% of people have specific anosmia (inability or loss of smell) for the bitter almond odor of cyanide.^46,94,126 There are limited data on the inheritance characteristics or genetic basis of these specific forms of anosmia. While some studies suggest that the ability to detect the odor of cyanide is a sex-linked recessive trait,⁶² other studies yield conflicting results.^5,19,96 Women have a greater ability to detect androsterone, which is prominent in human underarm secretion.⁷² Human olfaction usually can distinguish a mixture of no more than four xenobiotics¹⁰⁰; therefore, specific odors may be masked by other stimuli.

Olfactory fatigue is the process of olfactory adaptation following exposure to a stimulus for a variable period of time. This leads to a temporal diminution of the smell. Unfortunately, this adaptation may provide a false sense of security during continued exposure to a xenobiotic. For example, hydrogen sulfide, which inhibits cytochrome oxidase, is readily detectable as distinct and offensive at the very low concentration of 0.025 ppm. At the higher and potentially toxic concentration of 50 ppm, the odor is less offensive, and recognition may disappear after 2 to 15 minutes of exposure.^8,160 At even higher concentrations when toxicity is likely, the onset of olfactory fatigue is even more rapid. The combination of the rapid onset of olfactory fatigue and systemic toxicity at high concentrations of hydrogen sulfide exposure has contributed to numerous fatalities (Chap. 126).^1,25,174

In industrial settings, it is important to be aware of impaired olfactory function in any worker who may be exposed to chemical vapors or gases.^77,166 Such workers are at increased risk for toxic injury. The National Institute for Occupational Safety and Health (NIOSH) requires that an individual using an air-purifying respirator be capable of detecting the odor of a xenobiotic at concentrations below those producing toxicity.^6,166 Sensory perception at this concentration ensures that the individual can detect filter cartridge “breakthrough” or failure at a safe concentration.¹⁶⁶ The odor safety factor refers to the ratio of the time-weighted average (TWA) threshold limit value (TLV) to the odor threshold for a given xenobiotic. A xenobiotic with a high odor safety factor can be detected despite prolonged exposure.⁶ Nontoxic xenobiotics with a very high odor safety factor, such as ethyl mercaptan, can be added to xenobiotics that are odorless with lower safety factors so that olfactory detection is predictable. This enhanced sensory awareness is the basis for the addition of mercaptans to the odorless natural gases used in the home so as to limit the potential for unrecognized hazardous exposure.

The recognition of odors has traditionally been considered an important diagnostic skill in clinical medicine. Some diseases can be diagnosed accurately by recognizable associated odors of various affected parts of the body such as the breath, sweat, urine, and wounds: diabetic ketoacidosis as a characteristically fruity odor; diphtheria as sweet; scurvy as putrid; typhoid fever as fresh-baked brown bread; and scrofula as stale beer.³⁹ Odors are also described for disorders of amino acid and fatty acid metabolism, such as phenylketonuria, maple syrup urine disease, hypermethioninemia, and isovaleric acidemia.³⁹

The recognition of odors continues to be an important diagnostic skill for the rapid detection of some xenobiotics (Table 26–1). To increase awareness of odors of toxic xenobiotics, a “sniffing bar” of commonly available odors may be prepared.⁶⁷ Nontoxic xenobiotics that simulate the odors of toxic xenobiotics are placed in test tubes, numbered, and inserted in a test tube rack for circulation among staff. The sniffing bar, brief descriptions of clinical presentations, and a table of diagnostic odors (Table 26–1) may be used to teach the recognition of odors in medical toxicology.⁶⁷

Classification of Olfactory Impairment

There are different types of olfactory dysfunction. Anosmia, the inability to detect odors, and hyposmia, a decrease in the perception of certain odors, are the most common forms of olfactory impairment. The etiology of olfactory impairment may be classified as conductive, from anatomic obstruction of inspired air, or perceptive, from dysfunction of the olfactory receptors or signal transmission. Most conductive olfactory dysfunction results in hyposmia, because the obstruction is usually incomplete.^114,150

The most common causes of anosmia and hyposmia are viral infections, trauma, xenobiotics, tumors, and congenital and psychiatric disorders (Table 26–2).^{45,136,142,150} Viral infections may result in olfactory impairment either by obstructing nasal airflow or by causing damage to the olfactory epithelium.⁸⁰ Trauma to the head or nose can shear fragile olfactory nerves crossing the cribriform plate.^153,176

Chronic exposures to numerous xenobiotics are associated with olfactory dysfunction (Table 26–2). The most common toxic mechanism related is perceptive olfactory dysfunction. This may be a result of a direct injury, or of a structural alteration of the receptor or its components such as G proteins, adenylate cyclase, or receptor kinase.^78,79 Anosmia or hyposmia from hydrocarbons, formaldehyde, cadmium, and chemotherapeutics such as cytarabine results from direct effects on the receptor sites.^49,79,84 Local effects on the epithelium and the receptors from antibiotic nose drops may lead to temporary anosmia and hyposmia.^90,186 Inhaled corticosteroids may have local effects on the epithelium, as well as direct effects on both G proteins and adenylate cyclase.⁸¹ Cocaine insufflation causes direct local effects as well as effects on receptor functions.^68,70 Because of the limited local effects of most xenobiotics and the regenerative ability of the olfactory receptor neurons, most xenobiotic-induced olfactory dysfunction is reversible.

Many individuals determined to have anosmia actually have congenital anosmia for select molecules, such as hydrogen cyanide, n-butyl mercaptan, trimethylamine, and isovaleric acid.^7,45 Some extreme forms of congenital anosmia are associated with other abnormalities, such as Kallmann syndrome, a hereditary form of anosmia associated with hypogonadotropic hypogonadism where agenesis of the olfactory bulbs and incomplete development of the hypothalamus are responsible for the anosmia.^45,153

Dysosmia or parosmia is the distorted perception of smell (Table 26–2). Subclassifications of dysosmia include the perception of foul smell or cacosmia, the sensation of smell without a stimulus, or phantosmia, and the sensation of the smell of a burnt or metallic material, torqosmia.¹⁵⁰ The etiologies are classified as peripheral or central. Peripheral etiologies include abnormalities of the nose, sinuses, and upper respiratory tract. Central etiologies may be related to disorders such as Addison disease, hypothyroidism, temporal lobe epilepsy, psychosis, or pregnancy.^45,114,151 How these conditions actually alter the perception of smell is unclear. A number of xenobiotics with similar effects are listed in Table 26–2. Bromocriptine alters dopaminergic transmission and inhibits adenylate cyclase. Levodopa affects the dopaminergic transmission and also chelates zinc, which is important in the maintenance of normal receptor functions.^79,81

Evaluation of Olfactory Impairment

General evaluation of olfactory function should include a detailed history, focusing on types, duration, and progression of symptoms, recent illnesses, head and nose trauma, sinus problems, family history, occupational history, hobbies, and xenobiotic history.^41,71 A physical examination with a detailed examination of the nasopharynx and sinuses should be performed to assess the potential for inflammation or structural abnormality. A simple set of olfactory stimulants, such as ground coffee, almond extract, peppermint extract, and musk, should be used to test each nostril individually with the patient’s eyes closed.^71,153 Standardized smell tests such as the UPSIT (University of Pennsylvania Smell Identification Test) and the CCCRC (Connecticut Chemosensory Clinical Research Center) tests are commercially available, and a composite score based on a panel of tests can determine the degree of olfactory dysfunction.¹⁰⁶ Pungent odors or stimulation associated with ammonia, capsaicin, acetone, and menthol are dependent on the trigeminal nerve (CN V) olfactory function, which is mainly responsible for tactile pressure, pain, and temperature sensation in the mouth and nasal cavity. A patient who has olfactory nerve damage should be able to detect these substances; conversely, a person with hysteria may deny detection of these substances that should physiologically be recognized.^71,153,186 If a xenobiotic-mediated mechanism is suspected, the offending xenobiotic should be discontinued. Coronal computed tomography of the sinuses and nose or magnetic resonance imaging of the brain should be obtained if structural abnormalities are suspected.^153,186 Gas chromatographic analysis of the urine may be useful in patients with fish odor syndrome associated with trimethylaminuria.^101,163 Complicated cases and patients with significant impairment should be referred to an otolaryngologist or neurologist.

Anatomy and Physiology

Taste, the sensory interpretation of oral materials, is determined by taste buds on the tongue, palate, throat, and upper third of the esophagus. The cells in the taste buds have a life span of 10 days and are constantly renewed.^11,153 The taste buds on the anterior two-thirds of the tongue and the palate are innervated by the facial (CN VII) nerve, those on the posterior one-third of the tongue by the glossopharyngeal (CN IX) nerve, and those on the laryngeal and epiglottal regions by the vagus (CN X) nerve. The signals are sent to the solitary nucleus in the brainstem, where they are processed and distributed to various regions of the brain. There are at least 13 known chemical taste receptors responsible for the five primary taste sensations—sweet, sour, bitter, umami (savory) and salty: two sodium receptor types; two potassium receptor types; one chloride receptor; one adenosine receptor; two inosine receptor; two sweet receptor types; two bitter receptor types; one glutamate receptor; and one hydrogen ion receptor.⁷³ One substrate will typically activate multiple taste receptors; the combined effects of these stimulated receptors determine the taste of the substance.⁶⁰

The structure of the taste receptors is similar to that of the olfactory receptors, in that they are coupled to G proteins and sodium and calcium channels permitting neural stimulation. Each receptor is capable of interacting with various classes of xenobiotics, of varying sizes. The pH of the xenobiotic determines sour (acid taste), whereas sodium or potassium concentrations determine salty taste. Many xenobiotics such as sugars, glycols, aldehydes, ketones, amides, amino acids, inorganic salts of lead, and bretylium activate the sweet receptors. Bitter taste may result from long-chain organic substances containing nitrogen, or alkaloids, including quinine, strychnine, caffeine, and nicotine.^13,73 The threshold for bitter receptor stimulation is several orders of magnitudes lower than other taste receptors.¹³ Umami taste is a more recently accepted primary taste, best defined as a pleasant savory taste. The primary xenobiotic that stimulates umami receptor is glutamate, such as monosodium-l-glutamate. Umami receptor stimulation can be enhanced by 5′-ribonucleotide monophosphates such as inosine and guanosine.¹⁹⁰ Salivary proteins, such as zinc-containing gustin and ebnerin, are important in the regulation of taste sensation.^{79,83,103,161} These molecules may serve as binding proteins and growth factors for the regeneration of taste receptors. Taste is also affected significantly by the appreciation of ­aromas or odors and, to a lesser extent, by visual perception.¹⁵¹

Classification of Gustatory Dysfunction

Types of gustatory dysfunction include ageusia, the inability to perceive taste; hypogeusia, the diminished sensitivity of taste; and dysgeusia, the distortion of normal taste. There are several variations of dysgeusia, such as cacogeusia, which is a perceived foul, perverted, or metallic taste.^71,111 Taste impairment is commonly related to direct damage to the taste receptors, adverse effects on their regeneration, or effects on receptor mechanisms.⁸⁰ These effects can result from a xenobiotic, disease, aging, and nutritional disorder (Table 26–3).^{66,73,141,172} Any abnormality that interferes with either the direct contact of a xenobiotic with the gustatory cells of the tongue or cranial nerves VII, IX, or X dramatically affects taste.¹⁵⁰ Most common forms of xenobiotic-induced dysgeusia are related to direct effects on the taste receptor site or effects related to receptor mechanisms such as G proteins, adenylate cyclase, and calcium channels.⁹⁹ Other forms of dysgeusia may result from direct stimulation of chemical receptors by xenobiotics.^73,79

Angiotensin-converting enzyme (ACE) inhibitors commonly cause gustatory impairment, usually hypogeusia and dysgeusia.^{18,68,113,188} ACE inhibitors work by inhibiting zinc-dependent ACE, and chelating zinc from taste receptors and salivary proteins results in gustatory dysfunction. Calcium channel blockers act by inhibiting calcium channels of the taste receptor mechanisms.⁷³ Many diuretics cause zinc depletion by enhancing zinc elimination in the urine,⁷⁹ whereas furosemide and spironolactone may also chelate zinc. Numerous xenobiotics also cause gustatory dysfunction through variable degrees of zinc chelation: amrinone, ethambutol, hydralazine, methyldopa, the nonsteroidal antiinflammatory drugs (NSAIDs), antithyroid agents, penicillamine, and phenytoin.^73,79,189 Arsenic, mercury, chromium, and lead may either chelate zinc or replace zinc in salivary proteins because of a higher level of affinity. Chemotherapeutics and colchicine inhibit cellular division and taste-receptor regeneration. The oral antiseptic chlorhexidine directly alters taste-receptor function.⁵⁸ Acetazolamide causes cacogeusia when carbonated beverages are consumed. The exact mechanism is unclear, but is postulated to be a result of the inhibition of carbonic anhydrase causing carbon dioxide accumulation and an increased tissue bicarbonate.^79,92,115

Anatomy and Physiology

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.

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

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

Xenobiotic-Induced Ototoxicity

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

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

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

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

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

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

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.

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.

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.

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

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.

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

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

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

Noise-Induced Hearing Impairment

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.

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

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.

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.

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

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.

Tinnitus

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

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.

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

• Numerous xenobiotics commonly affect the sense of smell, taste, and hearing, thus causing significant morbidity.

• Some of the events may be predictable, whereas others will require monitoring and appropriate testing.

• Current knowledge about the pathophysiology of xenobiotics and these special organs at the molecular level is rapidly expanding.

• Although no definitive antidote is available for the prevention or treatment of xenobiotic-induced ototoxicity in humans, substantial progress has been achieved in both in vitro and in vivo animal models.

References