Noise-induced hearing disorders: Clinical and investigational tools^a)

Noise-induced hearing loss (NIHL) and noise-induced tinnitus (NIT) are two of the most common injuries for Service members and disabilities for Veterans (Yankaskas, 2013; Gordon et al., 2017; Swan et al., 2017). NIHL and NIT significantly impact quality of life for affected Service members and Veterans, can impact mission readiness and operational performance, and carry a significant financial cost. The United States (U.S.) Department of Defense (DoD) Hearing Center of Excellence (HCE) was, therefore, legislated by Congress in the 2009 National Defense Authorization Act. The mission of the U.S. DoD HCE is to enhance operational performance, medical readiness, and quality of life through collaborative leadership and advocacy for hearing and balance health. In addition to NIHL and NIT, other noise-induced auditory disorders are also known to emerge as a consequence of exposure to loud sound, including, for example, supra-threshold hearing-in-noise deficits. Hearing-in-noise deficits can significantly impact mission readiness (Grantham, 2012). This article uses the term noise-induced hearing disorders (NIHD) to broadly capture NIHL, NIT, noise-induced hearing-in-noise deficits, and other sound detection or sound processing deficits that can occur independently or in parallel with NIHL.

One of the working groups specifically focused on NIHD and their prevention is the Pharmaceutical Interventions for Hearing Loss (PIHL) group within the U.S. DoD HCE. The PIHL group broadly welcomes members of the scientific community from academia, industry, foundations, and other organizations. Subcommittees within the PIHL group have led the development of a series of special issues published in diverse journals to promote knowledge and research in the overall areas of NIHD and chemical ototoxicity, including novel discovery and topical reviews. Across these journal issues, a common theme is the prevention, diagnosis, mitigation, treatment, and rehabilitation of hearing loss and auditory injury.

Special issues with extensive content on NIHD, organized by the PIHL group, can be found in Otology and Neurotology (see Hammill and Packer, 2016), Hearing Research (see Yankaskas et al., 2017), and The Journal of the Acoustical Society of America (see Le Prell et al., 2019b). Drug-induced hearing loss (DIHL) and chemically induced ototoxic injury overlap with noise in their mechanisms of injury, and chemical exposure in the workplace often occurs in parallel with exposure to loud sound. Special issues dedicated to ototoxicity and associated perceptual deficits, organized by the PIHL group, can be found in Frontiers in Cellular Neuroscience (see Steyger et al., 2018) and the International Journal of Audiology (see Boudin-George et al., 2018). Several special issues developed outside of the PIHL group are also worth noting here given their additional expert commentary on topics in ototoxicity, otoprotection, and the development of investigational medicines for the inner ear. A special issue in Seminars in Hearing is notable for content on ototoxicity, ototoxic monitoring, and prevention of ototoxicity (see DiSogra, 2019). A special issue in the American Journal of Audiology provides a broad discussion of tests and technologies relevant to ototoxicity and ototoxicity monitoring, including patient narratives (see Garinis et al., 2021). A special issue in Hearing Research provided content from the second international symposium on inner ear therapeutics held in Hannover, Germany in 2019 (see Warnecke et al., 2022). A special issue of The Journal of the American Academy of Audiology was dedicated to the topics of hearing restorative and protective therapies (see Gifford, 2021). Last but not least, an organized collection of forum review articles discussing hearing protection strategies was published in the June 2022 issue of Antioxidants and Redox Signaling.

Challenges in the criteria used to diagnose hearing loss (and its prevention) are evident across the PIHL special issues (see, for example, Campbell et al., 2016; Henry, 2016; Brungart et al., 2017; Jiang et al., 2017; Liberman and Kujawa, 2017; King and Brewer, 2018; Kamerer et al., 2019a; Le Prell et al., 2019a) and other noted special issues (see, for example, Lord, 2019; Bramhall et al., 2020; Clark et al., 2021; Hinton et al., 2021; Le Prell, 2021; Konerding et al., 2022; Le Prell, 2022). The present collection within The Journal of the Acoustical Society of America builds not only on the rich foundation of the above special issues but also the wealth of information published more broadly. The current special issue provides new articles that directly and comprehensively address important problems in the clinical investigation of NIHD and their prevention.

Basic understanding of the regulatory pathways for inner ear medicines is essential for the design of clinical investigations into NIHD and their prevention. The regulatory pathway for medicines that prevent NIHL was reviewed by Lynch et al. (2016), with development of a proprietary ebselen formulation used as a case study (see also Foster et al., 2022). The review process through the U.S. Food and Drug Administration (FDA) was additionally described by Hammill (2017), with detailed discussion of the drug development pathway and challenges for the development of inner ear medicines provided by Cousins (2019; 2022). Additional commercial pipeline reviews document the large number of investigational medicines for the inner ear that are in various stages of clinical testing and development (Schilder et al., 2019; Isherwood et al., 2022). The large number of pipeline medicines highlights the urgent need for understanding of the regulatory pathway for inner ear medicines.

In the U.S., the FDA is responsible for regulating the assessment of investigational medicines, and study sponsors are required to submit an investigational new drug (IND) application when they wish to conduct clinical trials evaluating drug safety or efficacy. Clinical trials classified as phase I are largely limited to safety measures, whereas phases Ib, II, and III clinical trials include efficacy measures in addition to ongoing safety assessments, with phase III clinical trials including larger sample sizes than earlier phases. Efficacy measures proposed for use in phases II and III are reviewed by the FDA to assure that they are clinically meaningful (e.g., improvement in symptoms, whether trial participants feel or function better, and whether participants live longer) and the results are used to assess whether the observed clinical benefits outweigh any adverse side effects.

In the context of clinical trials, an “outcome measure” is the measured variable (e.g., threshold sensitivity, signal-to-noise threshold on a hearing-in-noise test, and score on a tinnitus rating scale). In contrast, a “study end point” refers to the specific analyzed parameter used to determine if the drug provided the expected clinical benefit (e.g., change from baseline measured 14 days post-noise using 4 kHz threshold). In addition to the above, clinical trials will sometimes include biomarkers, test measures which provide an objective measurement and indicator of normal biological processes, pathologic processes, or response to an exposure or intervention, including therapeutic intervention. As per FDA guidance on surrogate end points, validated surrogate end points are the subset of biomarkers (laboratory results) that are predictive of clinical outcomes (for additional discussion, see Katz, 2004; Haase and Prasad, 2016). Clinical trials under the oversight of the FDA are required to be listed online,¹ and study outcome measures are included as part of the clinical trial description, including a description of any genetic testing elements involved in the clinical trial.

In 2019, the FDA issued guidance to increase the efficiency of drug development and support precision medicine, including tailoring treatments to those patients who will benefit based on genetic variation even in the absence of a documented mechanism of action. The major challenge of pharmacogenetics for NIHL is reviewed in this collection by Brutnell et al. (2022), including suggestions that drug efficacy and the likelihood of success in clinical trials will be increased when populations are stratified or subtyped based on relevant genetic variation or the trials are designed with multidrug combinations to reach a broader segment of individuals suffering or at risk from NIHL.

The development of medical devices for auditory rehabilitation indications (hearing aids, middle ear implants, cochlear implants, and brainstem implants) is similarly subject to FDA regulation but through device regulations rather than drug regulations. New challenges will almost certainly emerge as efforts to combine investigational inner ear medicines with cochlear implant surgeries progress. Scheper et al. (2020) recently assessed an investigational oral therapeutic for possible protection of residual hearing during cochlear implant surgery. Systemic steroid therapy has also been assessed for preservation of residual hearing using oral and intravenous methods of delivery (O'Leary et al., 2021; Skarzynska et al., 2022), transtympanic treatment prior to surgery (Kuthubutheen et al., 2017), or topical application during surgery (Ramos et al., 2015). The possibility of drug-eluting implants is also advancing and one day may provide novel opportunities for synergistic interactions of drug and device combinations (Tan et al., 2020). Last but not least, the possibility that regenerative therapies might someday be combined with cochlear implants cannot be discounted (Gunewardene et al., 2012). Lessons from the clinical assessment of cochlear implant devices relevant to NIHD are discussed in this collection in Biever et al. (2022).

One of the major themes of the present special issue is outcome measures and study end points that may be appropriate for use in clinical trials evaluating experimental inner ear medicines. Expert review and commentary were solicited to provide insights into the strengths and weaknesses of various potential outcome measures and, where possible, end points that have been used by others. Content included in these articles is intended to facilitate the selection of clinical trial outcomes and end points, although it must be remembered that the FDA, or equivalent national regulatory agency, has the ultimate responsibility for accepting end points that are proposed for use in research conducted under an IND application. Although the audiogram is widely used and generally serves as the primary outcome, its sensitivity to cochlear damage is limited. Current clinical trials on NIHL prevention have also included an array of other auditory measures, such as distortion product otoacoustic emission (DPOAE) tests, extended high frequency (EHF) audiometry, speech-in-noise tests, sound-evoked potentials and electrocochleography, tinnitus surveys, and survey-based patient-reported global measures of change (for recent review, see Le Prell, 2022). As introduced below, the current collection of articles includes detailed discussion of the diverse array of outcome measures that have been used or could be considered for possible use in phase II and III studies on prevention or amelioration of NIHD.

The audiogram is widely used in the assessment of investigational medicines that may ameliorate NIHL as well as DIHL and diverse forms of sensorineural hearing loss (SNHL; Le Prell, 2021). An overview of the use of the audiogram in identifying and monitoring NIHL was previously provided by Campbell et al. (2016). In this collection, Le Prell et al. (2022) provide in-depth discussion of the diverse audiogram-based criteria for significant hearing loss as applied to NIHL and DIHL. In addition, they discuss special considerations in the use of the audiogram in clinical trials evaluating hearing restoration after gene, small molecule, or stem-cell-based regenerative interventions. Le Prell et al. (2022) also discuss how the expected effects of age have the potential to confound the interpretation of NIHL. To complement this broad discussion of the audiogram, Carr et al. (2022) review the changes in the audiogram after sound exposure during magnetic resonance imaging, and Sonstrom Malowski et al. (2022) discuss the impact of firearm noise exposure on the audiogram.

The opportunity for boothless audiometric testing emerged well in advance of the global COVID-19 pandemic (see, for example, Meinke et al., 2017). However, the pandemic resulted in a significant shift to telehealth modalities for many healthcare professions, including audiology. The contribution from Robler et al. (2022) provides detailed discussion of audiometric testing using telehealth methods and introduces the ways in which advances in telehealth could support decentralized clinical trials (DCTs) for evaluation of inner ear medicines as a way to decrease barriers to participation (building on Banks, 2021; Chiamulera et al., 2021; Coert et al., 2021; Van Norman, 2021).

It must be remembered that the audiogram is confounded by the presence of background noise, which can mask quiet tones. Discussion of the potential contamination of the audiogram by background environmental noise in boothless settings is provided by Meinke and Martin (2023). New boothless technologies will need to provide enhanced noise attenuation to ensure audiograms are reliable when measured outside of the booth. In addition, transducers newly developed for the measurement of audiograms in boothless settings must provide reference equivalent threshold sound pressure levels (RETSPLs) to ensure that new devices report thresholds using the normative hearing level (HL) scale. These essential data are reported here by Clavier et al. (2022) for the Wireless Automated Hearing Test System, which is designed to provide high attenuation from ambient noise, building on Smull et al. (2019) data for the Sennheiser HD280 Pro (Old Lyme, CT) and the RadioEar DD450 (Middlefart, Denmark).

Whereas the audiogram is routinely assessed at frequencies through 8 kHz, testing at EHFs from 9 to 20 kHz provides additional insights into the health of the basal regions of the cochlea, which are particularly vulnerable to noise exposure and the effects of ototoxic drugs. Multiple laboratories have detected hearing loss in the EHF range in participants with a history of noise exposure (Liberman et al., 2016; Grose et al., 2017; Prendergast et al., 2017b; Valderrama et al., 2018), even in the absence of hearing loss at 3, 4, and 6 kHz—frequencies that are routinely identified as the most vulnerable to noise injury when testing is limited to the “conventional” range of 125 Hz–8 kHz. The evaluation of EHF hearing in clinical settings and clinical trials is discussed in the contribution from Lough and Plack (2022), which importantly notes geographic differences in the uptake of EHF hearing tests as well as continued uncertainty regarding relationships between EHF hearing and speech perception difficulties. EHF threshold deficits in pediatric populations have also been described, with recent data suggesting that EHF deficits are associated with hearing-in-noise deficits in children with hearing thresholds that are within normal limits within the conventional frequency range (Hunter et al., 2020; Mishra et al., 2022). Lough and Plack (2022) additionally discuss technical issues, such as the need for RETSPLs for the EHF range.

Difficulties understanding speech in noisy backgrounds are a major patient complaint, and these difficulties can occur in the presence of hearing thresholds that are within normal limits. For example, out of 100 000 patient records, 10% were determined to have been seen for hearing-in-noise complaints with no audiometric loss at testing (Parthasarathy et al., 2020). Relationships between the audiogram and hearing-in-noise have been elusive, resulting in suggestions that hearing-in-noise be incorporated into test batteries (Shub et al., 2020) and increasing awareness of issues related to intelligibility and listening effort (Baese-Berk et al., 2023). Given the tremendous unmet clinical need, a variety of earlier review papers solicited under the umbrella of the PIHL working group discussed the importance of hearing-in-noise ability and strategies for its measurement (Le Prell and Brungart, 2016; Bressler et al., 2017; Brungart et al., 2017; Keller et al., 2017; Le Prell and Clavier, 2017; Manning et al., 2017). Nevertheless, hearing-in-noise measures have not been routinely included in clinical trials evaluating inner ear medicines for NIHL, DIHL, or SNHL indications (Le Prell, 2021; 2022).

In the current collection, the role of speech-in-noise testing in clinical trials is addressed in the contribution from Sanchez et al. (2022), who provide detailed commentary on considerations in pediatric testing, testing of underrepresented populations, including racial, ethnic, and linguistic minorities, biological sex and/or gender differences, binaural fitness for duty assessments to determine if individuals can detect, recognize, and localize sounds in the workplace, use of speech-in-noise tests in clinical trials, and opportunities for online and mobile hearing assessment. An example of the role of hearing-in-noise tests within a clinical trial is presented in Foster et al. (2022), and Brungart et al. (2022) reviews how to measure small changes in hearing longitudinally using hearing-in-noise metrics.

In addition to the use of clinical test measures, survey-based tools have also been used to broadly assess hearing difficulty. Systematic exploration of relationships between noise exposure history and performance on standardized surveys has been limited, although some data exist for firefighters who are at risk for NIHL (Jamesdaniel et al., 2019) and recreational firearm users (Stewart et al., 2002). Hearing handicap in firefighters and firearm users was estimated using the hearing inventory for adults (HHIA), which was developed by Newman and colleagues (Newman et al., 1990; 1991). Data collected using the 12-item version of the Speech, Spatial, and Qualities of Hearing Scale (SSQ12, Noble et al., 2013) have emerged as well, with recent data suggesting that a history of impulse noise exposure is associated with lower SSQ12 scores (Kamerer et al., 2022). Other approaches have also appeared. Using four questions from screening versions of the HHIA, Tremblay et al. (2015) found increased odds of self-reported hearing difficulty for those with a history of loud hobbies or firearm noise exposure when analyzing data from the Beaver Dam Offspring Study. Similarly, Spankovich et al. (2018) found increased odds of self-reported hearing difficulty for those with a history of either occupational or nonoccupational noise exposure when analyzing questionnaire data from the National Health and Nutrition Examination Survey (NHANES).

In this collection, a survey-based approach to quantifying the effects of combined noise and jet fuel exposure on hearing ability is provided by Dreisbach et al. (2022), who used the (modified) Amsterdam Inventory for Auditory Disability and Handicap (mAIAD; Meijer et al., 2003). The mAIAD assesses the nature and degree of listening difficulties. A separate but related issue is the quantification of noise exposure using survey tools, a challenge discussed in detail by Guest et al. (2018a). Using the NHANES questionnaire as a metric for noise exposure, Humes and Moore (2022) further explore the NHANES database and report that the odds of hearing loss are increased in NHANES participants with combined recreational and occupational noise exposure. Taken together, despite the use of different self-report surveys and questions to evaluate possible relationships between self-reported noise exposure and self-reported hearing difficulty, the results are broadly consistent across investigations. Standardization of self-report measures would be helpful, although it is not clear at this time what the best self-report tool or questions would be. Additional research validating relationships between clinical test results and various available survey approaches is warranted.

Despite the previous suggestion that DPOAEs, which provide a measurement of outer hair cell function, could be considered for use in clinical trials (Konrad-Martin et al., 2016), there has been little uptake of this metric within clinical trials evaluating NIHL (Le Prell, 2022) or DIHL and SNHL (Le Prell, 2021), even as a secondary outcome. One of the major challenges for the use of DPOAEs in clinical trials is that they do not directly measure patient function but rather provide a possible biomarker through the objective measurement of outer hair cell function. In this series of articles, the influence of noise exposure history on DPOAEs is discussed by Poling et al. (2022), and the possibility that DPOAEs may reflect effects of firearm noise exposure not captured by the audiogram is discussed by Sonstrom Malowski et al. (2022). In addition, Bramhall (2021) considers in detail the challenges in using DPOAEs to adjust for the effects of outer hair cell loss when trying to identify functional deficits that result from cochlear synaptopathy.

The afferent neural pathway begins in the periphery with the synapses connecting the inner hair cells to the auditory nerve dendrites and includes the neurons projecting from their inner hair cells to their central auditory system targets in the auditory brainstem (cochlear nucleus, superior olivary complex), the auditory mid-brain (inferior colliculus, thalamus), and ultimately the auditory cortex located in the temporal lobe of the brain. Loss of the initial peripheral component of the afferent pathway, the synaptic connections between the inner hair cells and the auditory nerve fibers, is termed cochlear synaptopathy.

Cochlear synaptopathy alters the signal that ascends to the brain from the cochlea. In animal models where synapse counts are feasible, synapse loss is associated with decreases in amplitude of wave I of the auditory brainstem response (ABR; Kujawa and Liberman, 2009; Sergeyenko et al., 2013), decreases in the amplitude of the middle ear muscle reflex (MEMR, also termed the acoustic reflex; Valero et al., 2016), and decreases in the envelope following response (EFR; Shaheen et al., 2015). Synapse counts from donated human temporal bones provide evidence that cochlear synaptopathy is not limited to rodents; it clearly occurs in humans with and without accompanying sensory cell loss (Viana et al., 2015; Wu et al., 2019; Wu et al., 2020). These results have driven significant interest in functional deficits that may accompany this pathology, with hearing-in-noise difficulty, tinnitus, and hyperacusis as candidates of interest (for review and discussion, see Kujawa and Liberman, 2015; Liberman and Kujawa, 2017; Bramhall et al., 2019a; Kujawa and Liberman, 2019).

A variety of approaches have been used to investigate associations between auditory evoked potential metrics and specific risk factors in widespread efforts to find indirect (physiological) evidence consistent with cochlear synaptopathy. One common approach is enrollment of participants who have a specific type of noise exposure assumed to put them at risk for cochlear synaptopathy relative to controls who do not have the same risk (Liberman et al., 2016; Bramhall et al., 2017; Grose et al., 2017; Bal and Derinsu, 2021; Megha et al., 2021; Nam et al., 2021; Suresh and Krishnan, 2021; Grinn and Le Prell, 2022). A second common approach is the enrollment of participants with varied exposure histories for whom exposure can be assessed using a continuous risk scale rather than membership in a specific exposure group (Prendergast et al., 2017a; Prendergast et al., 2017b; Valderrama et al., 2018; Marmel et al., 2020). Estimation of lifetime exposure is subject to errors in recall, therefore, a variant of this approach uses noise exposure surveys specific to the previous year with enrollment limited to participants for whom the previous year is representative of longer periods of time (Stamper and Johnson, 2015a,b; Fulbright et al., 2017; Grinn et al., 2017; Spankovich et al., 2017; Ridley et al., 2018). Prospective monitoring of potentially at-risk individuals has been used in a much smaller number of studies (Grinn et al., 2017; Wang et al., 2021).

Studies using the above methodological approaches have provided mixed observations, including various combinations of EHF threshold deficits, DPOAE amplitude deficits, and/or evoked potential amplitude deficits, depending on the study population and design. Reproducibility of test results (test-retest reliability) are increasingly well understood for various clinical measures (Guest et al., 2019; Kamerer et al., 2019b), and multiple reviews are available (Barbee et al., 2018; Bharadwaj et al., 2019; Bramhall et al., 2019a; Le Prell, 2019; Lokwani and Prabhu, 2022). As discussed in those review papers, lack of precision in noise exposure quantification is one source of variability in the results, and effects of biological sex on evoked potential amplitude must be controlled for. In addition, data from mice clearly document that noise exposure is not the only cause of cochlear synaptopathy, with well documented evidence of cochlear synaptopathy as a consequence of aging (Sergeyenko et al., 2013) and the potential for synergistic interactions between noise exposure and aging to result in greater than expected neural loss (Kujawa and Liberman, 2006). Synapse counts from donated human temporal bones provide evidence consistent with age-related cochlear synaptopathy in human temporal bones as well (Viana et al., 2015; Wu et al., 2019).

Because noise is not the only cause of auditory pathology, various recent studies have used an alternative approach and sought evidence of relationships between evoked potential metrics and functional metrics without regard for noise as a specific risk factor (Bharadwaj et al., 2015; Mehraei et al., 2016; Verhulst et al., 2016; Grant et al., 2020; Mepani et al., 2020; Mepani et al., 2021; Grant et al., 2022). In the current series, we include contributions that review recent findings related to the ABR (Bramhall, 2021), MEMR/acoustic reflex (Trevino et al., 2023), and EFR (Van Der Biest et al., 2023), all of which are continuing to be developed as possible biomarkers for cochlear synaptopathy in humans. In addition, Harris and Bao (2022) discuss novel metrics that may be useful in the identification of possible deafferentation in the human cochlea, including, for example, automated quantification, a multi-metric approach that includes a measure of neural synchrony and use of artificial intelligence.

Diagnostic tools that are sensitive to cochlear synaptopathy and identification of functional deficits that are associated with cochlear synaptopathy are needed given that efforts to identify investigational inner ear medicines that support regeneration of cochlear synapses are under way. Neurotrophic factors, such as BDNF, NT-3, or Trk agonists (Szobota et al., 2019; Fernandez et al., 2021), and bisphosphonate agents (Seist et al., 2020) are all of potential interest (for review, see Wei et al., 2020). First and foremost, patients with the pathology of interest must be able to be identified if clinical trials assessing experimental medicines are to be successful. In addition, because clinical trials are expected to measure clinically meaningful outcomes, functional end points that are associated with synaptic integrity will be essential in assessing investigational synaptic repair medicines. Thus, research assessing relationships between synaptic integrity, sensory cell survival, and functional measures is critically important.

The medial olivocochlear (MOC) efferent system provides descending inhibitory input primarily to the ear contralateral to the site of stimulation; broadband sound delivered to the right ear would, for example, decrease the outer hair cell DPOAE and auditory nerve compound action potential (CAP) response for sounds delivered to the left ear while the right ear is being stimulated (Maison et al., 2007). This contralateral inhibition is termed the MOC reflex, and it is reasonably well understood that the integrity of the MOC reflex is associated with vulnerability to noise injury (Rajan, 1995; Reiter and Liberman, 1995). The contribution from Bramhall et al. (2022) builds on this work by investigating the strength of the MOC reflex in a population of Veterans exposed to noise. Their data suggest that the MOC reflex is systematically smaller in groups with a history of noise exposure, a pattern of results that may reflect efferent pathology or perhaps afferent pathology as the descending MOC reflex is driven by the ascending afferent signal. Marrufo-Pérez and Lopez-Poveda (2022) also discuss the contribution of the MOC system to various temporal processing and hearing-in-noise tests, raising significant questions that will need to be addressed in future research.

Some of the earliest discussions regarding the “hidden” effects of afferent damage focused on relationships between afferent input (decreased ABR wave I amplitude) and tinnitus (Schaette and McAlpine, 2011). The relationships between noise exposure and tinnitus in Service members and Veterans are well known (Bramhall et al., 2019b). Given the high prevalence of tinnitus, including but not limited to NIT, it is clear that there is a need for standardized tinnitus surveys within clinical trials (Henry, 2016). Despite the wide availability of standardized tinnitus measures, there has been little use of validated surveys in clinical trials evaluating NIHL prevention (Le Prell, 2021; 2022), a surprising finding given that NIT is a common comorbidity for NIHL. The contribution by Jin and Tyler (2022) provides information and insight about tinnitus metrics that could be used in clinical trials evaluating investigational inner ear medicines that may ameliorate tinnitus, including tinnitus that occurs as a comorbidity of noise exposure or treatment with an ototoxic medication. Their summary of clinically significant change criteria for different tinnitus questionnaires is certain to be useful for clinical trial design, including the selection of clinically significant end point criteria.

Although there are no objective measures of tinnitus, it is interesting that objective deficits may be measured in parallel to subjective tinnitus rating data. For example, a recent systematic review and meta-analysis revealed associations between tinnitus and EHF hearing with poorer EHF thresholds in participants reporting tinnitus (Jafari et al., 2022). In addition, amplitude of the auditory nerve action potential is often found to be reduced in participants reporting tinnitus with effects that are frequency and level dependent (for systematic review and meta-analysis, see Chen et al., 2021; see also Ting et al., 2022). How these measures might be used in combination warrants consideration and discussion.

There is very little agreement on how to document or measure hyperacusis, a decreased tolerance to sound, and it has not been routinely included in clinical trials. The strategies for and challenges inherent in the measurement of hyperacusis are discussed by Jahn (2022). The development of standardized metrics for this sensory issue is critical given that hyperacusis can accompany NIHL.

Self-reports of noise exposure have been the most common instrument used to assess exposure in studies of cochlear synaptopathy and NIHL more broadly (see, for example, Humes and Moore, 2022). These are, however, subject to recall and social desirability bias resulting in over- or underestimates of actual individual exposures (Guest et al., 2018a). When trying to quantify individual exposure to hazardous noise, the gold standard is the noise dosimeter, a device that integrates noise exposure over time. Yet, even with a noise dosimeter, certain noise exposures can be difficult to quantify, including exposures from daily life activities such as listening to music through earphones. The Apple Hearing Study, discussed in Neitzel et al. (2022), aims to use wearables and smartphones to estimate overall noise exposure and assess hearing acuity across a large subject population (>120 000 subjects) and over a relatively long period of time (years). Preliminary findings of this unique study highlight the continued need for increased access to hearing healthcare and hearing loss prevention interventions across a broad swath of the population.

While the measurement of noise exposure over long periods of time can be challenging, the estimate of hearing damage risk criteria for those exposed to high impulse noise can also be problematic, requiring special equipment for accurate results (Lobarinas et al., 2016; Smalt et al., 2017; Davis et al., 2019; Smalt et al., 2022). Smalt and Brungart (2022) address some of the requirements set by military and scientific standards regarding the sampling rate necessary for an accurate measurement that would not “miss” the amplitude of the peak. Ultimately, their analysis shows that the sampling rate should be selected based on the highest frequency likely to contribute to acoustic injury to the ear rather than the need for high resolution measurements. This finding is especially important as clinical trials for prophylactic drugs will need to capture personalized exposures in noise environments that include continuous and impulsive sounds. Furthermore, whereas the relationship between long term noise exposure and permanent threshold shift has been well documented (Clark and Bohne, 1999; Ryan et al., 2016), the relationship between short term noise exposure, temporary threshold shift (TTS), and long term NIHL is not as well understood.

Kulinski et al. (2022) and Brungart et al. (2019) have shown a link between TTS and difficulty hearing speech-in-noise, even without any documented permanent threshold shift. In a study described within this special issue, Servi et al. (2022) compare the difference between pre- and postexposure thresholds and noise dose measured in the ear (under hearing protection) vs on-body (as with a typical noise dosimeter). Their findings suggest that in-ear, personalized, dosimetry may be more relevant to study damage risk criteria than the more commonly used “on-body” free-field dosimetry, especially for populations routinely exposed to high but variable noise environments. Tracking of total acoustic energy exposure will likely play a significant role in evaluating the effectiveness of interventions that aim to prevent noise-induced hearing injury.

Prevention of NIHL (and NIHD more broadly) should always start at the source through engineering controls. When those are not enough, workers and Service members must use hearing protection devices (HPD) to reduce the impact of noise on their hearing. Most individuals exposed to noise are, thus, faced with the decision of choosing a hearing protector that will prevent hazardous exposure to noise but still allow them to perform their job adequately, including communicating with others in their environment. The selection of a “good” earplug, then, becomes an important factor in the prevention of NIHD. In this collection, two articles on the subject are included. Murphy et al. (2022) propose that individual fit testing is a much more accurate way to assess whether a specific earplug is appropriate for a particular individual and situation as opposed to the use of derating practices intended to account for the high variability in proper earplug insertion (Berger and Voix, 2022; OSHA, 2022). Also, affecting comfort and use, the occlusion effect caused by earplugs inserted into the ear canal can be difficult to assess objectively. To that end, Saint-Gaudens et al. (2022) propose an objective method to assess the magnitude of the occlusion effect for a given earplug. This technique could make it easier to develop a simple metric that would allow noise-exposed users to assess some of the comfort-related qualities (Doutres et al., 2019) of individual hearing protectors.

The articles included in the current series of papers expand the emphasis of previous work sponsored by the U.S. DoD HCE PIHL committees with a focus on the advanced diagnostic tests that are of interest for better documenting NIHD in clinical and epidemiological research and measuring potential improvements in NIHD with investigational inner ear medicines. These papers were specifically invited with two goals in mind: (1) establishing a framework that supports advances in the scientific understanding of noise injury by identifying the key elements of diagnostic test batteries available for basic and clinical investigations of NIHD, and (2) informing ongoing conversations about evidence-based standardization of primary and secondary outcomes and end points in clinical trials, which will ultimately facilitate comparisons of drug efficacy. Authors invited to contribute manuscripts were specifically asked to consider the use of advanced diagnostics in patient care, basic scientific inquiry, and clinical trials. The editors are grateful for the authors' outstanding efforts and contributions to this series.

As discussed in multiple special issue contributions, significant questions remain regarding relationships between damage to the afferent neural pathway, outer hair cell pathology, and hearing-in-noise deficits (see also Henry, 2022). Thus, woven throughout the issue, references to one of the major questions in hearing science were found, specifically, can the pathology underlying hearing-in-noise deficits be diagnosed as an outer hair cell or neural injury? Answers to this question are essential not only for diagnostic purposes but also for recruitment into clinical investigations to ensure that pathology in study participants is matched to mechanism of action for drugs of interest. Many questions remain given the mixed evidence currently available. For example, speech-in-noise ability was not associated with lifetime noise exposure or electrophysiological measures, including the ABR and EFR in participants with self-reported speech-in-noise difficulties, despite normal audiometric thresholds (≤20 dB HL from 0.25 to 8 kHz) in a study by Guest et al. (2018b). Similarly, no relationships between speech-in-noise ability and CAP amplitude were detected by Parker (2020), although DPOAE amplitude was statistically significantly related to speech-in-noise ability. However, other recent investigations have reported the opposite pattern with statistically significant relationships between hearing-in-noise ability and various evoked potential measures in the absence of statistically significant relationships with DPOAE amplitude (Grant et al., 2020; Mepani et al., 2020; Mepani et al., 2021; Grant et al., 2022).

Based on systematic review of the literature, Lokwani and Prabhu (2022) recommend that EHF audiometry be included in standard test batteries and speech-in-noise or tone-in-noise tests be considered for inclusion. Articles in this special issue similarly advocate the inclusion of EHF audiometry and strongly recommend hearing-in-noise measures with the use of DPOAE measures to gain insights into outer hair cell health also recommended. Additionally, the articles provide information about tinnitus, hyperacusis, and electrophysiological tests that could be considered within functional test batteries to advance basic scientific understanding and for assessment of possible functional benefits of investigational medicines for the inner ear. Addressing hearing loss prevention more broadly, contributions discussing the documentation of HPD attenuation for individual workers are important, as effective use of HPDs is not routinely documented either within occupational hearing loss prevention programs or for participants enrolled in research investigations unless HPD fit is the specific topic of interest. In clinical trials in which less than the “expected” amount of NIHL has been observed even in the control conditions, more effective use of HPDs during clinical trial enrollment has been presumed to have confounded the study results (Le Prell et al., 2011; Kopke et al., 2015; Campbell, 2016). Thus, issues related to HPD use are a key factor for consideration in clinical trials. Taken together, the collected articles provide important considerations for the design of research into NIHD and its prevention using drugs or devices.

The authors gratefully acknowledge administrative support and helpful conversations with Kathryn Marshall and Suheily Lovelace (HCE), and the editorial support of Liz Bury, Kelly Quigley, and James Lynch (Acoustical Society of America). C.G.L. is currently supported by USAMRAA (U.S. Army Medical Research Acquisition Activity) W81XWH-19-C-0054, JPC-8/SRMRP W81XWH1820014, the American Academy of Audiology Foundation, and the Emilie and Phil Schepps Professorship in Hearing Science. C.G.L. has previously received contract funding and/or clinical trial material from industry partners, including 3M Inc., Sound Pharmaceuticals, Inc., Edison Pharmaceuticals, Inc., and Hearing Health Science, Inc. O.H.C. is a Principal Engineer at and part owner of Creare LLC. She is also a part owner and member of the board of managers of Edare LLC. O.H.C. is currently funded for research related to NIHL in the DOD under Small Business Innovation Research (SBIR) Contract Nos. W81XWH19C0076, W81XWH22C0066, and W81K0422P0015, and a subcontract to W81XWH-HRRP-FRA. J.B. is a cofounder at Gateway Biotechnology Inc., and his work is currently funded for research related to hearing loss and tinnitus under USAMRAA W81XWH-19-C-0054, R44DC018759, and R42AG078721. The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the U.S. DoD, Centers for Disease Control and Prevention, or the National Institute for Occupational Safety and Health.