Ototoxicity results in cochlear and/or vestibular dysfunction which can manifest assensorineural hearing loss,tinnitus,hyperacusis, dizziness,vertigo, or imbalance.[6][7] Presentation of symptoms vary in singularity, onset, severity and reversibility.[6]
Ototoxicity-induced hearing loss typically impacts the high frequency range, affecting above 8000 Hz prior to impacting frequencies below.[8] 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.[9][10] Guidelines and criteria differ between children and adults.[8]
National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) (as described in the American Academy of Audiology Ototoxicity Monitoring Guidelines from 2009):[8]
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):[8]
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):[9]
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):[9]
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
Antibiotics in theaminoglycoside class, such asgentamicin andtobramycin, may produce cochleotoxicity through a poorly understood mechanism.[12] It may result from antibiotic binding toNMDA receptors in thecochlea and damagingneurons throughexcitotoxicity.[13] Aminoglycoside-induced production ofreactive oxygen species may also injure cells of thecochlea.[14] Once-daily dosing[15] and co-administration ofN-acetylcysteine[16] 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.[17] 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.[18] Ototoxicity of gentamicin can be exploited to treat some individuals withMénière's disease by destroying the inner ear, which stops the vertigo attacks but causes permanent deafness.[19]Due to the effects on mitochondria, certain inherited mitochondrial disorders result in increased sensitivity to the toxic effects of aminoglycosides.
Certain types of diuretics are associated with varying levels of risk for ototoxicity. Loop and thiazide diuretics carry this side effect. Theloop diureticfurosemide is associated with ototoxicity, particularly when doses exceed 240 mg per hour.[21] The related compoundethacrynic 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 thestria vascularis.[22]Bumetanide confers a decreased risk of ototoxicity compared to furosemide.[20]
Platinum-containing chemotherapeutic agents, includingcisplatin andcarboplatin, are associated with cochleotoxicity characterized by progressive, high-frequency hearing loss with or withouttinnitus (ringing in the ears).[23] Ototoxicity is less frequently seen with the related compoundoxaliplatin.[24] The severity of cisplatin-induced ototoxicity is dependent upon the cumulative dose administered[25] and the age of the patient, with young children being most susceptible.[26] The exact mechanism of cisplatin ototoxicity is not known. The drug is understood to damage multiple regions of the cochlea, causing the death of outerhair cells, as well as damage to thespiral ganglion neurons and cells of thestria vascularis.[27] Long-term retention of cisplatin in the cochlea may contribute to the drug's cochleotoxic potential.[28] Once inside the cochlea, cisplatin has been proposed to cause cellular toxicity through a number of different mechanisms, including through the production ofreactive oxygen species.[29] The decreased incidence of oxaliplatin ototoxicity has been attributed to decreased uptake of the drug by cells of the cochlea.[24] Administration ofamifostine has been used in attempts to prevent cisplatin-induced ototoxicity, but theAmerican Society of Clinical Oncology recommends against its routine use.[30]
Topical skin preparations such aschlorhexidine andethyl alcohol have the potential to be ototoxic should they enter the inner ear through theround window membrane.[20] This potential was first noted after a small percentage of patients undergoing earlymyringoplasty operations experienced severe sensorineural hearing loss. It was found that in all operations involving this complication the preoperative sterilization was done with chlorhexidine.[35] The ototoxicity of chlorhexidine was further confirmed by studies with animal models.[20]
Several other skin preparations have been shown to be potentially ototoxic in the animal model. These preparations includeacetic 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.[20]
At high doses, quinine,aspirin and othersalicylates may also cause high-pitchtinnitus and hearing loss in both ears, typically reversible upon discontinuation of the drug.[20] Erectile dysfunction medications may have the potential to cause hearing loss.[36] However the link between erectile dysfunction medications and hearing loss remains uncertain.[37]
Previous noise exposure has not been found to potentiate ototoxic hearing loss.[38][39] The American Academy of Audiology includes in their position statement that exposure to noise at the same time asaminoglycosides 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.[40]
Ototoxic effects are also seen withquinine,pesticides,solvents,asphyxiants, andheavy metals such asmercury andlead.[5][20][41][42] When combining multiple ototoxicants, the risk of hearing loss becomes greater.[43][44][45] As these exposures are common, this hearing impairment can affect workers in many occupations and industries.[46][47] 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.[48]
Examples of activities that often have exposures to both noise and solvents include:[49]
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 astoluene,styrene orxylene, the combined exposure with noise increases the risk ofoccupational hearing loss in asynergistic manner.[5][50] The risk is greatest when the co-exposure is with impulse noise.[51][52]Carbon monoxide has been shown to increase the severity of the hearing loss from noise.[50] 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.[53] 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 chemotherapeuticcisplatin puts individuals at increased risk of ototoxic hearing loss.[38] 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.[54]
The hearing loss caused by chemicals can be very similar to a hearing loss caused by excessive noise. A 2018 informational bulletin by the USOccupational Safety and Health Administration (OSHA) and theNational 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.[55]
Auditory testing involved in ototoxicity monitoring/management (OtoM) is typically general audiological evaluation, high frequency audiometry (HFA), andotoacoustic emissions (OAEs).[57][56] High frequency audiometry evaluates hearing thresholds beyond 8000 Hz, which is the typical cut-off for conventionalaudiometry.[57] It is recommended a baseline evaluation be performed prior to treatment beginning.[57][56]
There are several guidelines on what constitutes a significant change in hearing[57][59] 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:[60][56]
≥ 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.[60]
Vestibular tests for vestibulotoxicity specifically can includecaloric 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.[57][61]
^Schacht J, Hawkins JE (1 January 2006). "Sketches of otohistory. Part 11: Ototoxicity: drug-induced hearing loss".Audiology and Neuro-Otology.11 (1):1–6.doi:10.1159/000088850.PMID16219991.S2CID37321714.
^Jung, T. T.; Rhee, C. K.; Lee, C. S.; Park, Y. S.; Choi, D. C. (October 1993). "Ototoxicity of salicylate, nonsteroidal antiinflammatory drugs, and quinine".Otolaryngologic Clinics of North America.26 (5):791–810.doi:10.1016/S0030-6665(20)30767-2.ISSN0030-6665.PMID8233489.
^abcdAmerican Academy of Audiology. 2009. “Position Statement and Clinical Practice Guidelines: Ototoxicity Monitoring.” https://audiology-web.s3.amazonaws.com/migrated/OtoMonGuidelines.pdf_539974c40999c1.58842217.pdf
^Dobie RA, Black FO, Pezsnecker SC, Stallings VL (March 2006). "Hearing loss in patients with vestibulotoxic reactions to gentamicin therapy".Archives of Otolaryngology–Head & Neck Surgery.132 (3):253–7.doi:10.1001/archotol.132.3.253.PMID16549744.
^Wu WJ, Sha SH, Schacht J (2002). "Recent advances in understanding aminoglycoside ototoxicity and its prevention".Audiology and Neuro-Otology.7 (3):171–4.doi:10.1159/000058305.PMID12053140.S2CID32139933.
^Munckhof WJ, Grayson ML, Turnidge JD (April 1996). "A meta-analysis of studies on the safety and efficacy of aminoglycosides given either once daily or as divided doses".The Journal of Antimicrobial Chemotherapy.37 (4):645–63.doi:10.1093/jac/37.4.645.PMID8722531.
^Li Y, Womer RB, Silber JH (November 2004). "Predicting cisplatin ototoxicity in children: the influence of age and the cumulative dose".European Journal of Cancer.40 (16):2445–51.doi:10.1016/j.ejca.2003.08.009.PMID15519518.
^Yafi FA, Sharlip ID, Becher EF (2017). "Update on the Safety of Phosphodiesterase Type 5 Inhibitors for the Treatment of Erectile Dysfunction".Sexual Medicine Reviews.6 (2):242–252.doi:10.1016/j.sxmr.2017.08.001.PMID28923561.
^abCampbell K (2007).Pharmacology and Ototoxicity for Audiologists. Clifton Park, NY: Delmar Centrage Learning. p. 145.ISBN978-1-4180-1130-7.
^Laurell G, Borg E (1 January 1986). "Cis-platin ototoxicity in previously noise-exposed guinea pigs".Acta Oto-Laryngologica.101 (1–2):66–74.doi:10.3109/00016488609108609.PMID3962651.
^Rawool VW (2012).Hearing Conservation in Occupational, Recreational, Educational, and Home Settings. New York: Thieme. p. 13.ISBN978-1-60406-256-4.
^Rawool V (2012).Hearing Conservation: In Occupational, Recreational, Educational, and Home settings. New York, NY: Thieme. p. 10.ISBN978-1-60406-256-4.
^Venet, Thomas; Carreres-Pons, Maria; Chalansonnet, Monique; Thomas, Aurélie; Merlen, Lise; Nunge, Hervé; Bonfanti, Elodie; Cosnier, Frédéric; Llorens, Jordi (1 September 2017). "Continuous exposure to low-frequency noise and carbon disulfide: Combined effects on hearing".NeuroToxicology.62:151–161.Bibcode:2017NeuTx..62..151V.doi:10.1016/j.neuro.2017.06.013.ISSN0161-813X.PMID28655499.S2CID10324339.
^Johnson, Ann-Christin; Morata, Thais C. (2009).The Nordic Expert Group for criteria documentation of health risks from chemicals. 142, Occupational exposure to chemicals and hearing impairment. Göteborg: University of Gothenburg.ISBN9789185971213.OCLC939229378.
^Lewkowski, Kate; Heyworth, Jane S.; Li, Ian W.; Williams, Warwick; McCausland, Kahlia; Gray, Corie; Ytterstad, Elinor; Glass, Deborah C.; Fuente, Adrian; Si, Si; Florath, Ines (2019). "Exposure to noise and ototoxic chemicals in the Australian workforce".Occupational and Environmental Medicine.76 (5):341–348.doi:10.1136/oemed-2018-105471.hdl:20.500.11937/74587.ISSN1470-7926.PMID30683670.S2CID59275676.
^Venet, Thomas; Campo, Pierre; Thomas, Aurélie; Cour, Chantal; Rieger, Benoît; Cosnier, Frédéric (2015). "The tonotopicity of styrene-induced hearing loss depends on the associated noise spectrum".Neurotoxicology and Teratology.48:56–63.Bibcode:2015NTxT...48...56V.doi:10.1016/j.ntt.2015.02.003.PMID25689156.
