Noise-induced hearing loss and its prevention: Integration of data from animal models and human clinical trials.

Animal models have been used to gain insight into the risk of noise-induced hearing loss (NIHL) and its potential prevention using investigational new drug agents. A number of compounds have yielded benefit in pre-clinical (animal) models. However, the acute traumatic injury models commonly used in pre-clinical testing are fundamentally different from the chronic and repeated exposures experienced by many human populations. Diverse populations that are potentially at risk and could be considered for enrollment in clinical studies include service members, workers exposed to occupational noise, musicians and other performing artists, and children and young adults exposed to non-occupational (including recreational) noise. Both animal models and clinical populations were discussed in this special issue, followed by discussion of individual variation in vulnerability to NIHL. In this final contribution, study design considerations for NIHL otoprotection in pre-clinical and clinical testing are integrated and broadly discussed with evidence-based guidance offered where possible, drawing on the contributions to this special issue as well as other existing literature. The overarching goals of this final paper are to (1) review and summarize key information across contributions and (2) synthesize information to facilitate successful translation of otoprotective drugs from animal models into human application.

Noise-induced hearing loss: Translating risk from animal models to real-world environments.

Noise-induced hearing loss (NIHL) is a common injury for service members and civilians. Effective prevention of NIHL with drug agents would reduce the prevalence of NIHL. There are a host of challenges in translation of investigational new drug agents from animals into human clinical testing, however. Initial articles in this special issue describe common pre-clinical (animal) testing paradigms used to assess potential otoprotective drug agents and design-related factors that impact translation of promising agents into human clinical trials. Additional articles describe populations in which NIHL has a high incidence and factors that affect individual vulnerability. While otoprotective drugs will ultimately be developed for use by specific noise-exposed populations, there has been little effort to develop pre-clinical (animal) models that accurately model exposure hazards across diverse human populations. To facilitate advances in the translational framework for NIHL otoprotection in pre-clinical and clinical testing, the overarching goals of the current series are to (1) review the animal models that have been used, highlighting the relevance to the human populations of interest, (2) provide insight into the populations for whom pharmaceutical interventions might, or might not, be appropriate, and (3) highlight the factors that drive the significant individual variability observed in humans.

Octave band noise exposure: Laboratory models and otoprotection efforts.

With advances in the understanding of mechanisms of noise injury, the past 30 years have brought numerous efforts to identify drugs that prevent noise-induced hearing loss (NIHL). The diverse protocols used across investigations have made comparisons across drugs difficult. A systematic review of the literature by Hammill [(2017). Doctoral thesis, The University of Texas at Austin] identified original reports of chemical interventions to prevent or treat hearing loss caused by noise exposure. An initial search returned 3492 articles. After excluding duplicate articles and articles that did not meet the systematic review inclusion criteria, a total of 213 studies published between 1977 and 2016 remained. Reference information, noise exposure parameters, species, sex, method of NIHL assessment, and pharmaceutical intervention details for these 213 studies were entered into a database. Frequency-specific threshold shifts in control animals (i.e., in the absence of pharmaceutical intervention) are reported here. Specific patterns of hearing loss as a function of species and noise exposure parameters are provided to facilitate the selection of appropriate pre-clinical models. The emphasis of this report is octave band noise exposure, as this is one of the most common exposure protocols across pharmacological otoprotection studies.

Characterization of acute hearing changes in United States military populations.

Until recently, most hearing conservation programs, including those in the military, have used permanent shifts in the pure-tone audiometric threshold as the gold standard for measuring hearing impairment in noise-exposed populations. However, recent results from animal studies suggest that high-level noise exposures can cause the permanent destruction of synapses between the inner hair cells and auditory nerve fibers, even in cases where pure-tone audiometric thresholds eventually return to their normal pre-exposure baselines. This has created a dilemma for researchers, who are now increasingly interested in studying the long-term effects that temporary hearing shifts might have on hearing function, but are also concerned about the ethical considerations of exposing human listeners to high levels of noise for research purposes. One method that remains viable to study the effects of high noise exposures on human listeners, or to evaluate the efficacy of interventions designed to prevent noise-related inner ear damage, is to identify individuals in occupations with unavoidable noise exposures and measure hearing before and as soon as possible after exposure. This paper discusses some of the important factors to be considered in studies that attempt to measure acute hearing changes in noise-exposed military populations.

Decreased sound tolerance associated with blast exposure.

Current research on blast and other injuries sustained by United States Service members and Veterans of the Iraq and Afghanistan Wars reveals a multitude of auditory complaints linked to exposures experienced during these conflicts. Among these complaints is decreased sound tolerance, which refers to a class of auditory-related problems including physical and/or psychological reactions to aspects of everyday sounds. Limited attention has been given to the possible relationship between blast exposure and decreased sound tolerance in Service members and Veterans, which is the purpose of this report. Baseline data were gathered and analyzed from 426 Service members (n = 181) and Veterans (n = 245) who participated in the Noise Outcomes in Servicemembers Epidemiology (NOISE) Study. Logistic regression analyses were performed to generate odds ratios (ORs) with 95% confidence intervals (CIs) for each group, adjusted for age and sex. Of those who reported blast exposure, 33% of Service members (adjusted OR = 1.4; CI = 0.7-2.8) and 48% of Veterans (adjusted OR = 1.9; CI = 1.1-3.3) reported decreased sound tolerance. Among Service members and Veterans who did not report blast exposure, 28% and 34% respectively, also reported decreased sound tolerance. Overall, blast exposure increased the likelihood of participants reporting decreased sound tolerance. The strength of this association was significant in Veterans.

I'm Wearing My Hearing Protection - Am I Still At Risk for Hearing Loss? Lurking Ototoxins in the Military Environment.

OBJECTIVE: Information is summarized from the overall body of published literature regarding ototoxic chemicals encountered outside of clinical exposures, largely in occupational settings. While summarizing the most common non-pharmaceutical ototoxins, this review provides clinically relevant information and recommendations such that hearing health professionals may adopt a more comprehensive and appropriate diagnostic case history, test battery, documentation scheme, and education delivery. METHODS: Solvents, metals, and asphyxiants literature was reviewed using PubMed, national and international agency websites, and communications with known ototoxicity experts. RESULTS: Initial intentions to summarize the existing programs for occupational ototoxicity monitoring fell short when it was discovered that such programs have not yet formalized across the major oversight agencies in the United States. Instead, recommended guidance documents and fact sheets, which highlight existing occupational exposure limits and suggest monitoring and education are discussed. CONCLUSIONS: While evidence in humans is limited, potentially ototoxic substances are worthy of improved surveillance and further research to understand their ototoxic mechanisms, effects, and possible mitigation strategies. A triad approach of monitoring, protecting, and educating is recommended for effective prevention of hearing loss: the Department of Defense Hearing Center of Excellence's Comprehensive Hearing Health Program model employs such an approach.

Protection for medication-induced hearing loss: the state of the science.

OBJECTIVE: This review will summarise the current state of development of pharmaceutical interventions (prevention or treatment) for medication-induced ototoxicity. DESIGN: Currently published literature was reviewed using PubMed and ClinicalTrials.gov to summarise the current state of the science. Details on the stage of development in the market pipeline are provided, along with evidence for clinical safety and efficacy reported. STUDY SAMPLE: This review includes reports from 44 articles and clinical trial reports regarding agents in clinical or preclinical trials, having reached approved Investigational New Drug status with the Federal Drug Administration. RESULTS: Vitamins and antioxidants are the most common agents currently evaluated for drug-induced ototoxicity intervention by targeting the oxidative stress pathway that leads to cochlear cell death and hearing loss. However, other strategies, including steroid treatment and reduction of ototoxic properties of the primary drugs, are discussed. CONCLUSIONS: Retention of hearing during and after a life threatening illness is a major quality-of-life issue for patients receiving ototoxic drugs and their families. The agents discussed herein, while not mature enough at this point, offer great promise towards that goal. This review will provide a knowledge base for hearing providers to inquiries about such options from patients and interdisciplinary care teams alike.

Research 101: An Initiative to Encourage and Facilitate Quality Resident Research in a Military Setting.

Objective Describe and evaluate a structured research program initiated at a tertiary Department of Defense (DOD) Medical Training Facility (MTF) to encourage and facilitate the conduct of research investigations, specifically among residents and junior or inexperienced investigators, but applicable for all DOD otolaryngology (ENT) and audiology providers. Methods A new comprehensive program was deployed in the ENT clinic at Madigan Army Medical Center (MAMC) to help improve the research program. Identified gaps in research methods and regulatory training were incorporated into the existing graduate medical education program along with structured mentorship between residents and senior staff. Academic achievements (eg, research protocols, publications, presentations at national/international meetings, and funding) for the ENT clinic were examined from 1992 to 2016, and changes in academic achievements were analyzed for success. Results The implementation of a structured research curriculum improved the number of protocols submitted and the quality of research being accepted for publication (ie, journal impact factor). Funding for research increased significantly to represent a third of the total research portfolio for the entire hospital. Discussion The benefit of employing a research specialist to oversee the resident research experience can greatly influence the quantity and quality of a resident program's research portfolio. Implications for Practice Improving resident research activity can potentially advance the quality of the resident program, help with evidence-based medical approaches, and increase residents' chances of matching for fellowship.

A review of the progress and pitfalls of FDA policy process: Planning a pathway for pharmaceutical interventions for hearing loss development.

The Federal Food and Drug Administration, or FDA is generally considered a powerful gatekeeper, able to deliver or withhold life-saving cures and create or destroy economic windfalls. As the decades go by, and technologies, diseases, public health demands, and politics evolve, we can identify patterns of change, action and inter-action among some of these traditional stakeholders in the FDA's policy sphere. A careful examination of this agency's colorful history can shed light on central features of the agency's policy process, which has been quite receptive to its stakeholders and adaptive to change over the decades and, in turn, show the way for development in lanes which do not fit neatly into the current paradigms offered by the agency. This paper will explore the history of FDA policy process, through examination of seminal moments in FDA history, the prominent actors and focusing events within them, and the outcomes of those events, in an attempt to illuminate a pattern of behavior or processes by which a struggling field of pharmaceutical development such as interventions for hearing loss can advance.

Economic Burden of Hearing Loss for the U.S. Military: A Proposed Framework for Estimation.

The goal of this multiphased research is to develop methods to comprehensively determine the economic impact of hearing impairment and noise-induced hearing injury among active duty U.S. Service Members. Several steps were undertaken to develop a framework and model for economic burden analysis: (1) a literature review identifying studies reporting the cost of health conditions and injuries in the Department of Defense, (2) consultation with a panel of subject matter experts who reviewed these cost items, and (3) discussions with DoD data stewards and review of relevant data dictionaries and databases. A Markov model was developed to represent the cumulative economic effect of events along the career span, such as retraining after hearing impairment and injury, by synthesizing inputs from various sources. The model, as developed and proposed in this study, will be a valuable decision-making tool for the DoD to identify high-risk groups, take proactive measures, and develop focused education, customized equipping, and return-to-duty and reintegration programs, thereby maximizing the retention of skilled, experienced, and mission-ready Service Members.

The impact of hearing impairment and noise-induced hearing injury on quality of life in the active-duty military population: challenges to the study of this issue.

The objectives of this research were to 1) summarize the available evidence on the impact of hearing loss on quality of life (QOL) among U.S. active-duty service members, 2) describe the QOL instruments that have been used to quantify the impact of hearing loss on quality of life, 3) examine national population-level secondary databases and report on their utility for studying the impact of hearing loss on QOL among active-duty service members, and 4) provide recommendations for future studies that seek to quantify the impact of hearing loss in this population. There is a lack of literature that addresses the intersection of hearing impairment, the military population, and quality of life measures. For audiological research, U.S. military personnel offer a unique research population, as they are exposed to noise levels and blast environments that are highly unusual in civilian work settings and can serve as a model population for studying the impact on QOL associated with these conditions. Our team recommends conducting a study on the active-duty service member population using a measurement instrument suitable for determining decreases in QOL specifically due to hearing loss.

The Department of Defense Epidemiologic and Economic Burden of Hearing Loss study.

Although studies have examined the relation between military-related noise and hearing, comprehensive data to calculate rates of hearing loss across all Services and to determine economic impact are lacking. The goal of the multiphase Department of Defense (DoD) Epidemiologic and Economic Burden of Hearing Loss (DEEBoHL) project is to examine rates of hearing impairment and noise-induced hearing injury, relevant noise exposures, and to determine the economic burden of these outcomes to the DoD and Service Members. The DoD Hearing Center of Excellence is supporting the following Phase I specific aims, among active duty Service Members to (1) calculate rates of hearing impairment and noise-induced hearing injury, and (2) develop a framework for the DoD to conduct comprehensive economic burden studies for hearing impairment and noise-induced hearing injury. The study is led by a multidisciplinary team from The University of Texas School of Public Health, The University of Texas Health Science Center at San Antonio, and The Geneva Foundation, with guidance from experts who make up the study advisory board. In this article, we focus on an overview of the DEEBoHL study, the methods for the first aim of this effort, and describe future plans for the study.