25 Noise-Induced Hearing Loss: Detection, Prevention, and Management

In the early 1700s and 1800s, it was established that noise can induce hearing loss (HL).1,2 Today, HL induced by occupational noise exposure remains a problem with workers in multiple industries exposed to potentially hazardous sound.³ Noise-induced hearing loss (NIHL) is one of the most common occupational diseases, and the second most self-reported occupational injury or illness.⁴ Thus, occupational NIHL is a major problem worldwide. Occupational noise regulations set by the U.S. Occupational Safety and Health Administration specify a personal exposure limit (PEL) of 90 dBA for 8 hours. The U.S. National Institute for Occupational Safety and Health estimates approximately 23% of individuals exposed to the 90 dBA PEL will develop HL over a 40-year work career (HL defined as > 25-dB HL pure-tone-average [PTA] at 0.5, 1, and 2 kHz). Those numbers increase to approximately 32% if higher frequencies are considered (> 25-dB HL PTA at 1, 2, and 3 kHz.⁵ Individuals exposed to occupational noise are an important clinical population.

A second important noise-exposed clinical population is military personnel. Recently, the U.S. Department of Veterans Affairs listed tinnitus and HL as the two most prevalent service-connected disabilities for veterans receiving compensation (2009 fiscal year [FY] report).⁶ Tinnitus affected 639,029 veterans (5.7% of all veterans) and HL affected 570,966 veterans (5.1% of all veterans). These numbers have been growing (number of veterans receiving new compensation for HL or tinnitus in FY2005: 88,366; FY2006: 92,407; FY2007: 112,421; FY2008: 118,935; and FY2009: 135,701). The financial impact of rehabilitation and compensation is tremendous; single-year disability costs related to HL exceeded U.S. $900M for 2006.⁷

A third population worth special note is adolescents and young adults. Some 12.5% of 12 to 19 year old children in United States were reported to have NIHL based on notched configurations in their audiograms (National Health and Nutrition Examination Survey [NHANES] III data).⁸ Comparison of NHANES III with more recent NHANES 2005 to 2006 data resulted in the conclusion that HL was increasing in one analysis,⁹ while a second more recent analysis of these datasets revealed no reliable change.¹⁰ Although older adolescents may be attending loud music performances^11,12 or loud sporting events,^13–15 or they may begin to engage in target shooting or hunting,^16,17 most discussion of NIHL in children has focused on digital audio players (DAP). Clearly, these portable music players can produce harmful sound levels, but the extent to which listeners use these devices at levels and durations that can induce HL remains under debate.^18–20 Safe listening levels (defined as L_Eq for 8 hours < 85 dBA) have been reported by several groups^21,22 although > 50% of participants exceeded the L_Eq (8) 85-dBA limit in a sample of college students coming from the New York City subway.²³ Anecdotal reports of significantly “notched” configuration of the audiogram in a small number of individuals reporting “atypical” music player use suggest potential NIHL,²⁴ and modified screening strategies increase the rate at which notched audiograms are detected in school children.²⁵ Listening levels may be higher for male listeners than female listeners,^26–30 and it is possible that effects of DAP use will be more evident in males than in females,³¹ although females may be “catching up.”¹⁰

Noise exposure can affect virtually all of the cellular subsystems of the inner ear (sensory, neural, and vascular supply). Noise-induced damage to the auditory system is cumulative through one’s lifetime and is usually permanent. The risk for NIHL is based on intensity-duration ratios derived from industrial noise exposure for an 8-hour daily exposure over a working lifetime of 40 years. The consequences of even mild HL due to noise exposure include reduced speech understanding, tinnitus, distortion of loudness tolerance, and pitch perception problems.²³ This chapter will systematically review detection and management of NIHL, as well as prevention efforts.

Detection

HL is typically attributed to noise exposure if the configuration of the patient’s audiogram is “notched” in the high frequencies and the patient reports a history of exposure to loud sound. The high-frequency notch has been attributed to the external and middle-ear transfer functions,³² the half-octave shift,³³ vascular deficiency,³⁴ and reduced glutathione levels in the basal compared with apical cochlea.³⁵ There are multiple definitions of what constitutes a noise notch. Niskar et al⁸ defined a noise notch based on a criteria requiring thresholds ≤ 15 dB HL at 0.5 and 1.0 kHz, with the threshold at 3, 4, or 6 kHz threshold being at least 15 dB worse than the thresholds at both 0.5 and 1.0 kHz. Thresholds were also required to be at least 10 dB worse at 3, 4, or 6 kHz than at 8 kHz. Coles and colleagues³⁶ defined a noise notch as a hearing threshold at 3, 4, or 6 kHz that is at least 10 dB greater than 1 or 2 and 8 kHz. There are a variety of notch definitions in the literature,^37–40 and the definition affects the reported prevalence of notched audiograms.⁴¹ Importantly, not all individuals identified as having a notched audiogram report a history of noise exposure, and not all individuals reporting a history of noise have a notched audiogram.41–43 Other reported causes of high frequency “notched” audiograms include perilymph fistula, ototoxic drugs, head trauma, genetic hearing impairment, and idiopathic HL.⁴² It is also possible to measure an artifactual audiometric notch as a function of the type of earphone used for testing. TDH-39 earphones frequently produce notches between 5 and 10 dB at 6 kHz in otologically normal individuals; 6 dB should be subtracted from the measured threshold at 6 kHz when using TDH-39 earphones.³⁶ Though there is not a precise relationship between a “notched” audiogram and history of noise exposure, the “notched” audiogram in combination with the noise history is a useful clinical metric for identifying noise as a contributing factor to the diagnosis of sensorineural HL.

Otoacoustic emission (OAE) amplitude and extended high frequency (EHF) audiometry have been suggested as potential diagnostic tools in evaluating cases of developing NIHL (for reviews, see works of Sisto et al and Le Prell and Bao).^44,45 OAEs provide a sensitive and objective measure of cochlear micromechanical function, and more specifically, outer hair cell function.^46–48 OAEs are acoustic signals generated in the inner ear, which are measured in the ear canal with a sensitive microphone. They may be either spontaneous otoacoustic emissions (SOAEs) or sound-evoked otoacoustic emissions (EOAEs). EOAEs are typically classified by the recording technique: transient-evoked otoacoustic emissions (TEOAEs) are evoked by a click or tone burst; stimulus frequency otoacoustic emissions (SFOAEs) are evoked at the same frequency as a single-tonal input stimulus; distortion product otoacoustic emissions (DPOAEs) are evoked by two simultaneous tones (f1 and f2).⁴⁴ DPOAEs are measured at expected frequencies mathematically related to the primary tone frequencies. The most commonly reported DPOAEs are 2f₁–f₂ (the “cubic” distortion tone) and f₂–f₁ (the “quadratic” distortion tone or simple difference tone).

The precise sources of OAEs are still under debate^49,50; however, the dominant theory is based on reverse traveling waves, called the two-source theory.^51,52 The two sources include a linear reflection (place-fixed) source and a nonlinear distortion (wave-fixed) source referred to as the reflection and generator source, respectively. The reflection source represents energy reflectance of preexisting perturbations (i.e., cell-to-cell force interactions in normal cochlea) fixed in place along the length of the basilar membrane, while the generator source represents energy induced by the overlap of two traveling waves. SFOAE and TEOAE amplitudes are dominated by the reflection source and DPOAE amplitudes by the generator source. As the two sources exit the cochlea, pass through the middle ear, and are recorded in the ear canal, they can add in a constructive or destructive manner; when measured in small frequency steps this gives rise to OAE fine structure (currently measured with DPOAEs). Excellent reviews of OAE sources are available.^50,53,54

OAE source theory was introduced here given that the two sources (reflection and generator) may have differential susceptibility to pathology. The linear reflection source (associated with amplification) tends to be affected by noise before the generator source (associated with nonlinearity), as indicated by studies demonstrating loss of TEOAEs before the loss of DPOAEs.^44,55,56 Decreases in OAE amplitude that occur in the absence of conventional pure-tone-threshold deficits have been taken to suggest that OAEs can be used to predict an increased vulnerability for later elevations in thresholds.^{44,55,57–63} Although OAEs have been proposed for hearing surveillance in industry,^60,64,65 it has been difficult to implement standardized protocols for use of OAEs in clinical decision-making. Specific challenges include the lack of national and international standards for calibrating OAE test equipment, the lack of national and international test standards, and the lack of normative data for large populations.

EHF audiometry includes threshold tests conducted at frequencies from 9 to 20 kHz. Over the last four decades, ototoxic drugs have induced changes measured during EHF testing before the conventional frequency range has been affected.^66–69 Changes in hearing at EHF frequencies have been reported in populations exposed to occupational noise^70–73 as well as DAP users⁷⁴ and musicians.⁷⁵ Despite these observations, current clinical and industrial practice does not include routine monitoring for NIHL at frequencies beyond 8 kHz.

When NIHL is defined for medicolegal reasons, that is, workers’ compensation, the diagnosis is strictly based on conventional audiometric outcomes. Workers’ compensation, Veterans Administration, and Department of Labor rules regarding the definition of and compensation for NIHL vary from state to state, but all rules have one thing in common—deficits are measured using conventional pure-tone audiometry at some subset of the frequencies including 0.5, 1, 2, and 3 kHz, with some regulatory groups also considering thresholds at 4 and/or 6 kHz.⁷⁶ Once NIHL has been diagnosed, key challenges for the practitioner are management of existing HL and prevention of additional HL.

Management

The management of NIHL depends on when the auditory pathology is identified. Three strategies of intervention and management are suggested based on the above. Primary intervention occurs before exposure or before onset of NIHL. Education about the hazard of noise exposure is an example of a primary intervention. Use of hearing protection devices (HPDs) to prevent NIHL is another form of primary intervention. Primary interventions may require either active or passive involvement of the individual employee. An intervention that requires some sort of behavior change by the individual is an active intervention. A passive intervention (with respect to the individual) does not require a change in the individual’s behavior. For example, consistent use of HPDs would require an active behavioral change, while an environmental change to reduce noise produced by equipment would be passive with respect to the employee. Secondary intervention occurs when the intent is to diminish the progression of HL during its pathogenesis. Hearing screening programs that serve to identify early hearing changes (i.e., standard threshold shift) in occupational settings are examples of secondary intervention. Boundaries are not always clear; however, as hearing screenings can also be considered part of a primary intervention if the baseline hearing screenings before noise exposure are used as an educational tool about risk. Tertiary interventions occur after NIHL has developed, and are designed to reduce the limitations that result from disability as a consequence of acquired NIHL. Thus, NIHL has occurred, interventions intended to slow the progression of HL have been initiated, and rehabilitation is now needed to optimize/enhance hearing ability. Examples of tertiary prevention include use of assistive listening devices (e.g., hearing aids) or tinnitus counseling.

Hearing conservation measures to prevent, minimize progression, and treat/rehabilitate NIHL can be applied at the level of the community organization and individual. At the community-organizational level, efforts can be implemented in noise control of equipment, adoption of conservative noise exposure policies (e.g., use of HPDs at 85 dB regardless of exposure time), and programs to improve early identification.77,78 Despite adaptation of conservative hearing conservation principles, individual compliance is a major concern. At the individual level, health education on the risks of noise exposure, fitting of comfortable HPDs, and training in correct use of HPDs can be critical to achieving appropriate attenuation and consistent use of HPDs. Inconsistent use of HPDs significantly reduces protection provided. Removing HPDs for even brief intervals reduces noise reduction rating (NRR = dB attenuation provided by HPD); greater reductions in protection are observed for HPDs with higher NRRs.⁷⁹

If an HL is identified, referral to an audiologist for a full diagnostic assessment is advised. It is possible a pathology separate from the noise exposure is contributing to the HL and medical referral (e.g., otolaryngologist) may also be necessary. Pending a full audiometric assessment, the audiologist can make recommendations on treatment strategies, including amplification. In the case of tinnitus, many audiologists can offer counseling and treatments (usually a sound-based therapy) to reduce annoyance and effects of tinnitus on quality of life.

Prevention

HPDs include ear plugs and ear muffs, and there are a variety of choices ranging from traditional foam plugs to newer devices with nonlinear filter capabilities.^80–83 Training in appropriate use and verification of correct fit is critical, and several recent improvements are now available to those that actively fit and train workers to use HPDs.^84–87 In addition to ever-improving conventional HPDs, there has been increasing interest in and support for biological protection strategies based on upregulation of the endogenous defense system, and/or directly scavenging noise-induced free radical formation.

Over the past 20 years, the state of scientific understanding has advanced significantly with respect to the metabolic pathways activated by noise.^45,88–90 Critical to development of biological protection strategies, we now know free radical production is increased during noise,^91,92 that free radical production is long lasting and the timing of sensory-cell death is related to the time at which peak free radical production is measured,⁹³ and that prevention of free radical accumulation using free radical scavengers directly mediates both hair cell death and HL.⁹⁴ Endogenous protection against free radical insult is mediated via superoxide dismutase (SOD),^95,96 catalase,⁹⁷ and glutathione,^98,99 as well as enzymes that speed glutathione reactions.¹⁰⁰ The precursors needed for endogenous SOD, catalase, and glutathione production are obtained from dietary sources, suggesting the potential for dietary nutrient intake to importantly influence vulnerability to NIHL.¹⁰¹ In addition, many nutrients are free radical scavengers and can supplement endogenous antioxidant defense. Many studies, primarily in animal models, describe benefits of antioxidant nutrients, polyphenols (flavonoids), and other compounds (e.g., amino acids and endogenous vitamin-like substances). The remainder of this chapter focuses on the role of dietary nutrients—vitamins, minerals, and macronutrients (carbohydrates, fat, and protein)—and their potential role in maintenance of normal hearing and/or prevention of acquired HL.

Vitamin A

There are multiple forms of vitamin A. Retinol, an animal-derived form of vitamin A, is the nonoxidized form of vitamin A that has limited antioxidant properties.^102,103 Retinoic acid is the oxidized form of vitamin A. Both prenoise¹⁰⁴ and postnoise¹⁰⁵ treatments with retinoic acid reduced NIHL in mice, with pretreatment providing better protection than posttreatment. Beta-carotene is the main source of provitamin A in the diet; it is metabolized to retinol and retinyl esters and stored in the liver. With sufficient vitamin A stores, metabolism of β-carotene to vitamin A ceases and β-carotene circulates in plasma. Beta-carotene efficiently scavenges singlet oxygen, quenches peroxyl radicals, and prevents lipid peroxidation.^106–110 Beta-carotene in combination with other nutrients has reduced NIHL,^111–114 and there are preliminary reports stating that drug-induced HL is reduced by nutrient combinations as well.¹¹⁵ Selective vitamin A deficiency increases NIHL,¹¹⁶ suggesting an important role for vitamin A in endogenous defense of the inner ear against NIHL. Recent analysis of the NHANES data as part of a student thesis revealed that β-carotene (alone or in combination with vitamin C) reduced the risk of NIHL.¹⁰¹ A study evaluating hearing levels in older adult populations reported increased serum levels of retinol and provitamin A carotenoids were associated with decreased prevalence of hearing impairment in a community-based epidemiological study in Japan,117 but opposite effects were observed in a population of Australian subjects.¹¹⁸

From a safety perspective, carotenoids are clearly distinguished from preformed vitamin A. High levels of preformed vitamin A (> 10,000 IU/d) increase the risk of birth defects,¹¹⁹ and pregnant women should not consume more than 5000 IU/d from vitamin A supplements.¹²⁰ Some evidence suggests elevated levels can increase the risk of osteoporosis,^121,122 although several large clinical studies found no evidence of increased risk.^123,124 In contrast to preformed vitamin A, β-carotene has not been implicated in teratogenesis at any dose,¹²⁵ and there is no upper daily limit for β-carotene. It should be noted, however, that high-level β-carotene supplements (20 to 30 mg/d) are contraindicated for those with a significant history of tobacco use.¹²⁶ An increase in the risk of lung cancer was reported for smokers who took high-level β-carotene supplements in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) trial in Finland^127,128 as well as smokers and asbestos workers in the β-Carotene and Retinol Efficacy Trial (CARET) in the United States.^128–130

Other Carotenoids

Lycopene is a lipid-soluble antioxidant, involved in gene-function regulation, gap-junction communication, and hormone modulation.¹³¹ In a nutritional epidemiological study of adult’s auditory function and dietary intake, lycopene intake was highly correlated with better auditory function.¹¹⁸

B Vitamins

The B vitamins serve as coenzymes that facilitate metabolism and energy production. The B vitamins include thiamine (B₁), riboflavin (B₂), niacin (B₃), pantothenic acid (B₅), pyridoxine (B₆), biotin (B₇), folic acid/folate (B₉), and cobalamin (B₁₂). Folic acid/folate (B₉) and cobalamin (B₁₂) have been evaluated for effects on auditory function. Folate is the natural form of vitamin B₉, and folic acid is a stable synthetic form of vitamin B₉, often used in supplements and fortified foods.¹³² Folic acid became popular as a supplement after studies demonstrating that maternal folic acid intake reduces fetal neural tube defects.¹³³ Additional enthusiasm arose when folic acid reduced homocysteine levels^134,135 as increased homocysteine is a risk factor for cardiovascular disease.^136,137 However, clinical data have not shown improved cardiovascular outcomes in high-risk patients treated with folic acid supplements.^138,139 As reviewed by Saposnik,¹³⁹ vitamin B supplements have not shown success in large stroke trials (VITAmins TO Prevent Stroke; VITATOPS). There are, however, some positive outcomes with respect to folic acid and hearing.

A 3-year study of folic acid supplementation in older adults revealed slower progression of age-related HL at low frequencies.¹⁴⁰ After 3 years, low frequency PTA (0.5, 1, and 2 kHz) increased by 1.0 dB in the folic acid group and by 1.7 dB in the placebo group (p = 0.020), with no group difference in the high frequency PTA (4, 6, and 8 kHz). Although the changes in hearing were quite small, Dobie¹⁴¹ noted that

If this benefit applies to the entire population (a big “if”) and continues to accrue each year (another big “if”), one might expect a 5-dB reduction in age-related hearing level threshold elevation for PTA512 over a 20-year period. A benefit of this size could reduce the proportion of men who are hearing aid candidates at age 75 years from 33% to 22% (assuming a 5-dB shift across the entire distribution of hearing level thresholds of 75-year-old men). Since more than $4 billion is spent on hearing aids each year in the United States, the potential cost savings could be considerable.

These results contrast with an earlier study in which no relationship between HL in an older population (age range 67 to 78 years) and B vitamin levels in plasma was detected.¹⁴² As folic acid food supplements were prohibited in The Netherlands at the time Durga et al¹⁴⁰ conducted their study, and baseline folate levels in participants were about half the level reported for people living in the United States, where folic acid is a normal food additive, benefit may be limited to those with low folic acid intake at study onset.

Folic acid is not the only form of vitamin B with the potential for beneficial effects on the inner ear. Vitamin B₁₂ reduced temporary threshold shift (TTS) in humans.¹⁴³ The experimental (B₁₂ treated) subjects received 1 mg cyanocobalamin per day for 7 days, followed by a 5-mg dose on the 8th day; placebo-treated controls received placebo injections. Serum B₁₂ was significantly increased, and noise-induced TTS was decreased at 3 kHz when treated subjects were compared with controls. These doses are supraphysiologic, meaning they are greater than can be achieved via diet alone. It is not known whether normal dietary intake of vitamin B₁₂ influences vulnerability to NIHL.

Vitamin C

Virtually all mammals, with the exception of fruit bats, guinea pigs, monkeys, and man, synthesize vitamin C endogenously, that is, they do not require dietary vitamin C.^144–146 Humans do require dietary vitamin C, and it is one of the most commonly taken dietary supplements.¹⁴⁷ When vitamin C donates electrons to quench harmful free radicals, the oxidized vitamin C by-products (ascorbyl radical and dehydroascorbic acid) are relatively unreactive free radicals that can be reduced back to ascorbic acid.¹⁴⁸ Although vitamin C is water-soluble (and thus does not travel into the lipid membranes), vitamin C enhances recycling of α-tocopherol, which does pass into the lipid membranes and prevent lipid peroxidation.^{149,150–152}

Vitamin C reduced NIHL in a study using guinea pigs as subjects¹⁵³ and vitamin C in combination with other nutrients has reduced NIHL,^111–114 age-related HL,^154,155 and there are preliminary reports that drug-induced HL is reduced,¹¹⁵ with all data collected in rodent models including mice, guinea pigs, and rats. In human populations, increased intake of vitamin C has been linked to improved hearing outcomes.118 A dietary supplement that included vitamin C in addition to rebamipide and α-lipoic acid also provided benefit in the form of improved hearing thresholds in elderly subjects¹⁵⁶; however, that study did not include a placebo control and additional verification of benefit is critical. Finally, reductions in HL in cancer patients receiving cisplatin therapy have been reported in patients given a combination of vitamins C and E and selenium (Se).¹⁵⁷ However, there was no overall significant difference between placebo and control with respect to HL; differences in high-frequency HL were found only when comparisons were limited to the patients who had the highest plasma concentrations of the three nutrients.

With the power to manipulate genes in mouse models, there has been a recent effort to identify a role for vitamin C in progression of age-related hearing changes in hearing. Senescence marker protein 30 (SMP30)/gluconolactonase knockout mice cannot synthesize vitamin C, and Kashio et al therefore used this mouse model to examine whether vitamin C mediates age-related HL.¹⁵⁸ Both knockout mice that cannot synthesize vitamin C and wild-type mice that do synthesize vitamin C were maintained on low (1.5 g/L) or high (37.5 mg/L) vitamin-C supplemented water. The knockout mice maintained on low vitamin C water had higher (worse) thresholds and reduced spiral ganglion cell density compared with all other groups. There were no other group differences, thus, the authors concluded that while vitamin C depletion accelerates age-related HL, high-level vitamin C supplements do not reduce normal age-related HL.¹⁵⁸

Vitamin D

Vitamin D is a fat-soluble vitamin that is vital for normal functioning of the nervous system, as well as for bone growth and maintenance of bone density. In the late 1970s, several studies reported compromised auditory function in patients with diets that were deficient in vitamin D.^159,160 Recent efforts to identify a role for vitamin D in the development and maintenance of normal auditory function have drawn on the power to manipulate genes in mouse models. For example, the vitamin D receptor (VDR) knockout mouse lacks functional VDRs. Threshold sensitivity in young (< 6 month) and adult (7- to 14-month old) mice was equivalent, but when aged mice (> 15-month old) were assessed, the VDR mice had worse hearing than their age-matched wild-type counterparts.¹⁶¹ Vitamin D deficiency has been linked with prolonged N1 latencies in rats¹⁶² as well as pure-tone HL in human patients,^159,160 with vitamin D treatment resulting in improved hearing thresholds in some but not all cases.^160,163 Vitamin D intoxication also appears to have a negative effect on the auditory system during aging. The klotho mouse does not regulate vitamin D levels, resulting in high serum levels for vitamin D₃. In one recent study, klotho mice developed HL at an earlier age than wild-type controls, but maintenance on a vitamin D–deficient diet rescued their hearing.¹⁶⁴ In contrast, a case of a human patient with vitamin D intoxication and existing HL revealed no recovery of hearing even with long-term (20 months) treatment.¹⁶⁵ There are no data on the potential for reductions in NIHL using vitamin D supplements.

Vitamin E

Vitamin E is a generic term used to capture all members of the tocopherol family; α-tocopherol is the most biologically active and is the only form actively taken up by the brain.^166,167 Vitamin E is lipophilic (found in cell membranes) and it prevents lipid peroxidation.^106,168 Vitamin E (delivered as synthetic vitamin E, the water-soluble analogue Trolox, or α-tocopherol) reduces NIHL,^94,169,170 as well as cisplatinototoxicity.^171–173 Protection is dose-dependent with higher doses providing the best protection.⁴⁵ A combination that includes Trolox and other nutrients has been used to reduce NIHL in guinea pigs,^111,113 and mice fed a supplemented chow containing increased levels of α-tocopherol and other nutrients have also had reduced NIHL.¹¹² Increased intake of vitamin E has also been linked to improved hearing outcomes in humans.¹⁷⁴

Minerals

There has not been any systematic effort to identify potential roles for common dietary minerals, such as zinc (Zn), copper (Cu), Se, iron (Fe), magnesium (Mg), and/or calcium (Ca), on either protection of the inner ear or maintenance of normal auditory function, although Choi¹⁰¹ has recently explored the NHANES data for evidence of better auditory function in groups with higher Mg or Ca intake. The minerals that have been investigated in some detail are discussed below.

Magnesium

Mg is required for active transport of ions (potassium [K], Ca) across cell membranes, and Mg affects neural conduction (e.g., glutamate).¹⁷⁵ It directly mediates both free radical– induced oxidative stress and DNA repair.^176–179 It is a fairly potent vasodilator,¹⁸⁰ and specifically prevents noise-induced decreases in cochlear blood flow.¹⁸¹ Cellular metabolism depends on adequate oxygen (O₂) and nutrients and the efficient elimination of waste products; thus, a reduction in cochlear blood flow during and/or after noise insult has the potential to disrupt metabolic homeostasis in the cochlea.¹⁸² Mg deficiency increases Ca channel permeability in the inner hair cells, which results in over influx of Ca into the inner hair cells and increased glutamate release from the inner hair cells, ultimately overstimulating glutamate receptors (including NMDA receptors) on the auditory nerve.^183,184 Increased activity at glutamate receptors, either during noise or during infusion of glutamate receptor agonists, is linked to HL.^89,185,186 Mg supplements not only have the potential to modulate glutamate release from the inner hair cells, but they also have the potential to block glutamate receptors on the auditory nerve dendrites. Mg is an NMDA-receptor antagonist,187 which has been considered as a potential therapeutic in multiple disease conditions.^188–192 Observations that MK-801, which is another NMDA-receptor antagonist, reduce the effects of noise,^193,194 ischemia,¹⁹⁵ and excitotoxic¹⁹⁶ or ototoxic drugs^194,197 are consistent with the potential for direct neural protection of the auditory pathway via Mg. Each of these actions may contribute to protection from NIHL seen in several studies using Mg supplements. Two double-blind placebo-controlled studies report that Mg reduces human NIHL.^198–200 However, it does not appear that individual variation in dietary Mg, in the absence of high-level supplements, is adequate to confer protection against NIHL. Walden et al²⁰¹ reported that plasma Mg was not reliably correlated with NIHL measured in male U.S. Army soldiers with long-term (8 to 18 years) exposure to high-level noise of weapons in a single combat unit. Although normal dietary levels of Mg did not meaningfully influence NIHL in that population, this does not preclude a reliable relationship when Mg consumption is supplemented.

Selenium

Se exerts several biological effects including antioxidant defense associated with glutathione peroxidase (GPx), which is an endogenous antioxidant enzyme that speeds glutathione reactions.^202–204 Se has been suggested to protect the inner ear, given reduced HL in workers with the highest Se levels in plasma.²⁰⁵ There is also evidence that Se, delivered in combination with vitamins C and E, reduces ototoxic HL in cancer patients¹⁵⁷; however, as noted above, protection was evident only when comparisons were limited to patients with the highest plasma concentrations. One of the forms of Se that has received significant attention with respect to protection of the inner ear is a synthetic organoselenium compound: ebselen. There is an increasing body of evidence suggesting that ebselen reduces NIHL.^206–209 A phase-I safety study using doses that might be appropriate for protection of the inner ear (200 to 1600 mg) was completed, with 38% of subjects in the placebo group and 38% of the subjects in the treatment group reporting adverse events that were categorized as possibly related to the treatment.²¹⁰ The most commonly reported adverse event in both groups was headache, and ebselen is advancing into phase-II efficacy trials.²¹⁰ Ebselen catalyzes glutathione reactions even more efficiently than GPx, and other synthetic variants can further speed reactions.^211,212

Copper, Zinc, Iron, and Manganese

SODs are enzymes that speed the destruction of the highly toxic superoxide radical into the less toxic-free radicals: O₂ and hydrogen peroxide (H₂O₂). Each SOD has a different metal cofactor. Cu-Zn-SOD binds both copper and zinc, Fe-SOD binds iron, Mn-SOD binds manganese (Mn), and Ni-SOD binds nickel. There are three human SODs identified to date. One is found in cytoplasm [SOD1 (Cu-Zn-SOD)], one in mitochondria [SOD2 (Mn-SOD)], and the other is found extracellularly [SOD3 (Cu-Zn-SOD)]. From knockout mouse models,^95,213 as well as guinea pig studies,⁹⁶ it is clear that SOD1 mediates vulnerability to NIHL. Genetic variation in human SOD1²¹⁴ and SOD2^215,216 is now linked to vulnerability to NIHL in humans as well. There has been little effort to identify potential protective benefits outside the work with SODs, with one exception; Zn has been evaluated as a therapeutic. Zn supplements were recently reported to reduce sudden sensorineural HL in a randomized, placebo-controlled clinical trial.²¹⁷ One of the comorbidities often experienced with NIHL is tinnitus: perceived sound in the absence of an external sound source. Zn has also been evaluated in tinnitus patients. Studies have either reported small benefits that were not statistically reliable,²¹⁸ or no differences.^219,220

Calcium, Potassium, and Sodium

Ca, K, and sodium (Na) have critical roles in function of the auditory system. These include, but are not limited to, maintenance of the endocochlear potential, ion-channel regulation, second-messenger function, mechanoelectrical transduction, synaptic transmission, and efferent regulation.^221–224 There has been no systematic research on the potential for dietary Ca, K, and/or Na to influence hearing or susceptibility to HL. Low-sodium diets have been advocated as early as the 1930s for the treatment of Ménière disease,^225,226 and remain a standard care convention,^227–229

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