Ototoxicity

Template:Use dmy dates Template:Infobox medical condition (new) Template:Wikiversity Template:Wikimedia Commons Ototoxicity is the property of being toxic to the ear (oto-), specifically the cochlea or auditory nerve and sometimes the vestibular system, for example, as a side effect of a drug. The effects of ototoxicity can be reversible and temporary, or irreversible and permanent. It has been recognized since the 19th century.<ref>Template:Cite journal</ref> There are many well-known ototoxic drugs used in clinical situations, and they are prescribed, despite the risk of hearing disorders, for very serious health conditions.<ref>Template:Cite book</ref> Ototoxic drugs include antibiotics (such as gentamicin, streptomycin, tobramycin), loop diuretics (such as furosemide), and platinum-based chemotherapy agents (such as cisplatin and carboplatin). A number of nonsteroidal anti-inflammatory drugs (NSAIDS) have also been shown to be ototoxic.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> This can result in sensorineural hearing loss, dysequilibrium, or both. Some environmental and occupational chemicals have also been shown to affect the auditory system and interact with noise.<ref name="Johnson_2010">Template:Cite journal</ref>

Signs and symptoms

Ototoxicity results in cochlear and/or vestibular dysfunction which can manifest as sensorineural hearing loss, tinnitus, hyperacusis, dizziness, vertigo, or imbalance.<ref name=":0">Template:Cite journal</ref><ref name=":3">Template:Cite journal</ref> Presentation of symptoms vary in singularity, onset, severity and reversibility.<ref name=":0" />

Auditory symptoms

Hearing loss

Ototoxicity-induced hearing loss typically impacts the high frequency range, affecting above 8000 Hz prior to impacting frequencies below.<ref name=":1">American Academy of Audiology. 2009. “Position Statement and Clinical Practice Guidelines: Ototoxicity Monitoring.” https://audiology-web.s3.amazonaws.com/migrated/OtoMonGuidelines.pdf_539974c40999c1.58842217.pdf</ref> There is not global consensus on measuring severity of ototoxicity-induced hearing loss as there are many criteria available to define and measure ototoxicity-induced hearing loss.<ref name=":02">Template:Cite journal</ref><ref name=":32">Template:Cite journal</ref> Guidelines and criteria differ between children and adults.<ref name=":1" />

Ototoxicity grades (Hearing Loss)

There are at least 13 classifications for ototoxicity.<ref name=":4">Template:Cite journal</ref> Examples of ototoxicity grades for hearing loss are the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE), Brock's Hearing Loss Grades, Tune grading system, and Chang grading system.<ref name=":02" />

National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) (as described in the American Academy of Audiology Ototoxicity Monitoring Guidelines from 2009):<ref name=":1" />

• Grade 1: Threshold shift or loss of 15–25 dB relative to baseline, averaged at two or more contiguous frequencies in at least one ear
• Grade 2: Threshold shift or loss of >25-90 dB, averaged at two contiguous test frequencies in at least one ear
• Grade 3: Hearing loss sufficient to indicate aural rehabilitation such as hearing aids and/or speech-language services
• Grade 4: Indications of cochlear implant candidacy

Brock's Hearing Loss Grades (as described in the American Academy of Audiology Ototoxicity Monitoring Guidelines from 2009):<ref name=":1" />

• Grade 0: Hearing thresholds <40 dB at all frequencies
• Grade 1: Thresholds 40 dB or greater at 8000 Hz
• Grade 2: Thresholds 40 dB or greater at 4000-8000 Hz
• Grade 3: Thresholds 40 dB or greater at 2000-8000 Hz
• Grade 4: Thresholds 40 dB or greater at 1000-8000 Hz

Chang grading system (as reported in Ganesan et al., 2018):<ref name=":02" />

• 0: ≤ 20 dB at 1, 2, and 4 kHz
• 1a: ≥ 40 dB at any frequency 6 to 12 kHz
• 1b: > 20 and < 40 dB at 4 kHz
• 2a: ≥ 40 dB at 4 kHz and above
• 2b: > 20 and < 40 dB at any frequency below 4 kHz
• 3: ≥ 40 dB at 2 or 3 kHz and above
• 4: ≥ 40 dB at 1 kHz and above

Tune grading system (as reported in Ganesan et al., 2018):<ref name=":02" />

• 0: No hearing loss
• 1a: Threshold shift of ≥ 10 dB at 8, 10, and 12.5 kHz
• 1b: Threshold shift of ≥ 10 dB at 1, 2, and 4 kHz
• 2a: Threshold shift of ≥ 20 dB at 8, 10, and 12.5 kHz
• 2b: Threshold shift of ≥ 20 dB at 1, 2, and 4 kHz
• 3: ≥ 35 dB HL at 1, 2, and 4 kHz
• 4: ≥ 70 dB HL at 1, 2, and 4 kHz

Hyperacusis

Hyperacusis is abnormally increased sensitivity to intensity (perceived as loudness) to what is typically deemed as normal/tolerable loudness.

Vestibular symptoms

Vestibular symptoms from ototoxicity, which would specifically be vestibulotoxicity, can include general dizziness, vertigo, imbalance, and oscillopsia.

Ototoxic agents

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Antibiotics

Antibiotics in the aminoglycoside class, such as gentamicin and tobramycin, may produce cochleotoxicity through a poorly understood mechanism.<ref name="pmid16549744">Template:Cite journal</ref> It may result from antibiotic binding to NMDA receptors in the cochlea and damaging neurons through excitotoxicity.<ref name="pmid8946832">Template:Cite journal</ref> Aminoglycoside-induced production of reactive oxygen species may also injure cells of the cochlea.<ref name="pmid12053140">Template:Cite journal</ref> Once-daily dosing<ref name="pmid8722531">Template:Cite journal</ref> and co-administration of N-acetylcysteine<ref name="pmid17653228">Template:Cite journal</ref> may protect against aminoglycoside-induced ototoxicity. The anti-bacterial activity of aminoglycoside compounds is due to inhibition of ribosome function and these compounds similarly inhibit protein synthesis by mitochondrial ribosomes because mitochondria evolved from a bacterial ancestor.<ref name="pmid17116475">Template:Cite book</ref> Consequently, aminoglycoside effects on production of reactive oxygen species as well as dysregulation of cellular calcium ion homeostasis may result from disruption of mitochondrial function.<ref name="pmid23616556">Template:Cite journal</ref> Ototoxicity of gentamicin can be exploited to treat some individuals with Ménière's disease by destroying the inner ear, which stops the vertigo attacks but causes permanent deafness.<ref name="pmid12616197">Template:Cite journal</ref> Due to the effects on mitochondria, certain inherited mitochondrial disorders result in increased sensitivity to the toxic effects of aminoglycosides.

Macrolide antibiotics, including erythromycin, are associated with reversible ototoxic effects.<ref name="ototoxicity"/> The underlying mechanism of ototoxicity may be impairment of ion transport in the stria vascularis.<ref name="ototoxicity"/> Predisposing factors include renal impairment, hepatic impairment, and recent organ transplantation.<ref name="ototoxicity"/>

Loop diuretics

Certain types of diuretics are associated with varying levels of risk for ototoxicity. Loop and thiazide diuretics carry this side effect. The loop diuretic furosemide is associated with ototoxicity, particularly when doses exceed 240 mg per hour.<ref name="pmid3430953">Template:Cite journal</ref> The related compound ethacrynic acid has a higher association with ototoxicity, and is therefore used only in patients with sulfa allergies. Diuretics are thought to alter the ionic gradient within the stria vascularis.<ref>Template:Cite book</ref> Bumetanide confers a decreased risk of ototoxicity compared to furosemide.<ref name="ototoxicity">Template:Cite book</ref>

Chemotherapeutic agents

Platinum-containing chemotherapeutic agents, including cisplatin and carboplatin, are associated with cochleotoxicity characterized by progressive, high-frequency hearing loss with or without tinnitus (ringing in the ears).<ref name="pmid16484702">Template:Cite journal</ref> Ototoxicity is less frequently seen with the related compound oxaliplatin.<ref name="pmid19116379">Template:Cite journal</ref> The severity of cisplatin-induced ototoxicity is dependent upon the cumulative dose administered<ref>Template:Cite journal</ref> and the age of the patient, with young children being most susceptible.<ref>Template:Cite journal</ref> The exact mechanism of cisplatin ototoxicity is not known. The drug is understood to damage multiple regions of the cochlea, causing the death of outer hair cells, as well as damage to the spiral ganglion neurons and cells of the stria vascularis.<ref>Template:Cite journal</ref> Long-term retention of cisplatin in the cochlea may contribute to the drug's cochleotoxic potential.<ref>Template:Cite journal</ref> Once inside the cochlea, cisplatin has been proposed to cause cellular toxicity through a number of different mechanisms, including through the production of reactive oxygen species.<ref name="pmid17113254">Template:Cite journal</ref> The decreased incidence of oxaliplatin ototoxicity has been attributed to decreased uptake of the drug by cells of the cochlea.<ref name="pmid19116379"/> Administration of amifostine has been used in attempts to prevent cisplatin-induced ototoxicity, but the American Society of Clinical Oncology recommends against its routine use.<ref name="pmid19018081">Template:Cite journal</ref>

The vinca alkaloids,<ref>Template:Cite journal</ref><ref>Template:Cite book</ref><ref>Template:Cite book</ref> including vincristine,<ref>Template:Cite journal</ref> are also associated with reversible ototoxicity.<ref name="ototoxicity"/>

Antiseptics and disinfectants

Topical skin preparations such as chlorhexidine and ethyl alcohol have the potential to be ototoxic should they enter the inner ear through the round window membrane.<ref name="ototoxicity"/> This potential was first noted after a small percentage of patients undergoing early myringoplasty operations experienced severe sensorineural hearing loss. It was found that in all operations involving this complication the preoperative sterilization was done with chlorhexidine.<ref>Template:Cite journal</ref> The ototoxicity of chlorhexidine was further confirmed by studies with animal models.<ref name="ototoxicity"/>

Several other skin preparations have been shown to be potentially ototoxic in the animal model. These preparations include acetic acid, propylene glycol, quaternary ammonium compounds, and any alcohol-based preparations. However, it is difficult to extrapolate these results to human ototoxicity because the human round window membrane is much thicker than in any animal model.<ref name="ototoxicity"/>

Other medicinal ototoxic drugs

At high doses, quinine, aspirin and other salicylates may also cause high-pitch tinnitus and hearing loss in both ears, typically reversible upon discontinuation of the drug.<ref name="ototoxicity"/> Erectile dysfunction medications may have the potential to cause hearing loss.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> However the link between erectile dysfunction medications and hearing loss remains uncertain.<ref name="pmid28923561">Template:Cite journal</ref>

Previous noise exposure has not been found to potentiate ototoxic hearing loss.<ref name="Campbell_2007" /><ref>Template:Cite journal</ref> The American Academy of Audiology includes in their position statement that exposure to noise at the same time as aminoglycosides may exacerbate ototoxicity. The American Academy of Audiology recommends people being treated with ototoxic chemotherapeutics avoid excessive noise levels during treatment and for several months following cessation of treatment. Opiates in combination with excessive noise levels may also have an additive effect on ototoxic hearing loss.<ref>Template:Cite book</ref>

Ototoxicants in the environment and workplace

Ototoxic effects are also seen with quinine, pesticides, solvents, asphyxiants, and heavy metals such as mercury and lead.<ref name="Johnson_2010" /><ref name="ototoxicity" /><ref>Template:Cite journal</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> When combining multiple ototoxicants, the risk of hearing loss becomes greater.<ref>Template:Cite book</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> As these exposures are common, this hearing impairment can affect workers in many occupations and industries.<ref>Template:Cite book</ref><ref>Template:Cite journal</ref> This risk probably been overlook because individual hearing tests conducted on workers, pure tone audiometry, does not allow one to determine if a hearing effects are a consequence of noise or chemical exposure.<ref>Template:Cite journal</ref>

Examples of activities that often have exposures to both noise and solvents include:<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

• Printing
• Painting
• Construction
• Fueling vehicles and aircraft
• Firefighting
• Weapons firing
• Pesticide spraying

Ototoxic chemicals in the environment (from contaminated air or water) or in the workplace interact with mechanical stresses on the hair cells of the cochlea caused by noise in different ways. For mixtures containing organic solvents such as toluene, styrene or xylene, the combined exposure with noise increases the risk of occupational hearing loss in a synergistic manner.<ref name="Johnson_2010" /><ref name="Fechter_2004">Template:Cite journal</ref> The risk is greatest when the co-exposure is with impulse noise.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> Carbon monoxide has been shown to increase the severity of the hearing loss from noise.<ref name="Fechter_2004" /> Given the potential for enhanced risk of hearing loss, exposures and contact with products such as fuels, paint thinners, degreasers, white spirits, exhaust, should be kept to a minimum.<ref>Template:Cite report</ref> Noise exposures should be kept below 85 decibels, and the chemical exposures should be below the recommended exposure limits given by regulatory agencies.

Drug exposures mixed with noise potentially lead to increased risk of ototoxic hearing loss. Noise exposure combined with the chemotherapeutic cisplatin puts individuals at increased risk of ototoxic hearing loss.<ref name="Campbell_2007">Template:Cite book</ref> Noise at 85 dB SPL or above added to the amount of hair cell death in the high frequency region of the cochlea in chinchillas.<ref name="pmid2076973">Template:Cite journal</ref>

The hearing loss caused by chemicals can be very similar to a hearing loss caused by excessive noise. A 2018 informational bulletin by the US Occupational Safety and Health Administration (OSHA) and the National Institute for Occupational Safety and Health (NIOSH) introduces the issue, provides examples of ototoxic chemicals, lists the industries and occupations at risk and provides prevention information.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Ototoxicity Monitoring/Management

Several guidelines have been published around the world, though there is not consensus on one universally agreed-upon protocol.<ref name=":32" /><ref name=":4" />

Guidelines released:

• The American Speech-Language-Hearing Association (ASHA) released guidelines in 1994.<ref name=":2">{{#invoke:citation/CS1|citation

|CitationClass=web }}</ref> There are details on the different monitoring procedures on timelines depending on age and responsiveness.<ref name=":2" />

• The American Academy of Audiology (AAA) released guidelines in 2009.<ref name=":12">{{#invoke:citation/CS1|citation

|CitationClass=web }}</ref> There are details on the kinds of tests which can be used.

• The Health Professions Council of South Africa (HPSCA) released guidelines in 2018.<ref>{{#invoke:citation/CS1|citation

|CitationClass=web }}</ref>

Auditory testing

Auditory testing involved in ototoxicity monitoring/management (OtoM) is typically general audiological evaluation, high frequency audiometry (HFA), and otoacoustic emissions (OAEs).<ref name=":12" /><ref name=":2" /> High frequency audiometry evaluates hearing thresholds beyond 8000 Hz, which is the typical cut-off for conventional audiometry.<ref name=":12" /> It is recommended a baseline evaluation be performed prior to treatment beginning.<ref name=":12" /><ref name=":2" />

Significant change criteria

There are several guidelines on what constitutes a significant change in hearing<ref name=":12" /><ref name=":42">Template:Cite journal</ref> which can indicate further action must be taken, whether that be to implement aural rehabilitation or adjust the source of ototoxic exposure (eg. chemotherapy). With pure tone audiometry, ASHA considers a significant change to have occurred if there is a:<ref name=":03">Template:Cite journal</ref><ref name=":2" />

• ≥ 20 dB decrease in pure tone thresholds at any test frequency OR
• ≥ 10 dB decrease at two adjacent frequencies OR
• no response at three consecutive test frequencies where responses were previously obtained

If using distortion product ototoacoustic emissions (DPOAEs), a significant shift is observed if there is a reduction in amplitude by 6 dB or more than the baseline within the sensitive range of ototoxicity.<ref name=":03" />

Vestibular testing

Vestibular tests for vestibulotoxicity specifically can include caloric testing, rotational testing, vestibular evoked myogenic potentials (VEMPs), and computerized dynamic posturography (CDP); however, there are no globally accepted guidelines for monitoring/management of vestibular function during or following ototoxic treatments.<ref name=":12" /><ref>Template:Cite journal</ref>

External links

• OSHA-NIOSH 2018. Preventing Hearing Loss Caused by Chemical (Ototoxicity) and Noise Exposure Safety and Health Information Bulletin (SHIB), Occupational Safety and Health Administration and the National Institute for Occupational Safety and Health. SHIB 03-08-2018. DHHS (NIOSH) Publication No. 2018-124. https://doi.org/10.26616/NIOSHPUB2018124
• The Ear Poisons, The Synergist, American Industrial Hygiene Association, 2018.
• World Report on Hearing, World Health Organization, 2021.
• International Ototoxicity Management Group.
• Wikiversity page for the International Ototoxicity Management Group:https://en.wikiversity.org/wiki/International_Ototoxicity_Management_Group_(IOMG)