The audiogram: Detection of pure-tone stimuli in ototoxicity monitoring and assessments of investigational medicines for the inner ear

Abstract

Pure-tone thresholds have long served as a gold standard for evaluating hearing sensitivity and documenting hearing changes related to medical treatments, toxic or otherwise hazardous exposures, ear disease, genetic disorders involving the ear, and deficits that develop during aging. Although the use of pure-tone audiometry is basic and standard, interpretation of thresholds obtained at multiple frequencies in both ears over multiple visits can be complex. Significant additional complexity is introduced when audiometric tests are performed within ototoxicity monitoring programs to determine if hearing loss occurs as an adverse reaction to an investigational medication and during the design and conduct of clinical trials for new otoprotective agents for noise and drug-induced hearing loss. Clinical trials using gene therapy or stem cell therapy approaches are emerging as well with audiometric outcome selection further complicated by safety issues associated with biological therapies. This review addresses factors that must be considered, including test-retest variability, significant threshold change definitions, use of ototoxicity grading scales, interpretation of early warning signals, measurement of notching in noise-induced hearing loss, and application of age-based normative data to interpretation of pure-tone thresholds. Specific guidance for clinical trial protocols that will assure rigorous methodological approaches and interpretable audiometric data are provided.

FIG. 1.

Audiometric data tables from Occupational Safety and Health Administration (1981) are plotted to illustrate the increasingly notched shape of the audiogram as workplace exposure levels (85, 90, 95, and 100 dBA) and years of employment (10, 20, 30, or 40 yr) increase. The range in degree of noise-induced hearing loss is reflected through illustration of the 10th percentile, median, and 90th percentile. In the OSHA data tables, the expected contributions of aging to hearing loss have been subtracted from each individual participant's thresholds based on the individual participant's age as cumulative effects of aging confound NIHL that increases over time simultaneous with but not parallel to changes in hearing expected with aging.