Down for the count: The critical endpoint in ototoxicity remains the cytocochleogram.

There are three major assays that must be conducted in standard investigational new drug (IND) -enabling ototoxicity study designs: 1) functional acoustic threshold measurements (Auditory Brainstem Respsonse, ABR); 2) otohistopathology and 3) cytocochleograms. We provide evidence to demonstrate the unreliability of auditory threshold shifts (ABRs) to predict cochlear cell death and build a case for conducting full cochlea processing and cell count measurements from the complete cochlea from apex to base.

Small Compartment Toxicity: CN VIII and Quality of Life: Hearing Loss, Tinnitus, and Balance Disorders.

Life experiences, industrial/environmental exposures, and administration of Food and Drug Administration (FDA)-approved drugs may have unintended but detrimental effects on peripheral and central auditory pathways. Most relevant to the readership of this journal is the role that drug treatments approved by the FDA as safe and effective appear to interact with 3 independent modes of toxicity within the small compartment of the ear. What may seem to be trivial drug-induced toxicity has the potential to change important measures of quality of life and functional capacity of mid- to late-life patients. Drugs meant to treat can become the source of interference in the activities of daily living, and as a result, treatment compliance may be jeopardized. Ototoxicity has been defined as the tendency of certain therapeutic agents and other chemical substances to cause functional impairments and cellular degeneration of the tissues of the inner ear resulting in hearing loss. However, one of the largest contributors to hospitalizations is fall-related injuries in the elderly patients associated with disorders of vestibular function linked to progressive and drug-induced toxicities. Tinnitus affects 35 to 50 million adults representing approximately 25% of the US population, with 12 million seeking medical care and 2 to 3 million reporting symptoms that were severely debilitating. This review is intended to highlight these targets of neurotoxicity that threaten the usefulness of drug treatments deemed safe and effective prior to access by the general public.

The failure to detect drug-induced sensory loss in standard preclinical studies.

Over the years a number of drugs have been approved for human use with limited signs of toxicity noted during preclinical risk assessment study designs but then show adverse events in compliant patients taking the drugs as prescribed within the first few years on the market. Loss or impairments in sensory systems, such as hearing, vision, taste, and smell have been reported to the FDA or have been described in the literature appearing in peer-reviewed scientific journals within the first five years of widespread use. This review highlights the interactive cross-modal compensation within sensory systems that can occur that reduces the likelihood of identifying these losses in less sentient animals used in standard preclinical toxicology and safety protocols. We provide some historical and experimental evidence to substantiate these sensory effects in and highlight the critical importance of detailed training of technicians on basic ethological, species-specific behaviors of all purpose-bred laboratory animals used in these study designs. We propose that the time, effort and cost of training technicians to be better able to identify and document very subtle changes in behavior will serve to increase the likelihood of early detection of biomarkers predictive of drug-induced sensory loss within current standard regulatory preclinical research protocols.

Utility of the auditory brainstem response evaluation in non-clinical drug safety evaluations.

INTRODUCTION: The Food and Drug Administration (FDA) requires thorough evaluation of the potential safety hazards of all new drugs, food additives, and therapeutic devices that are intended for human use. Drugs that are otically administered (i.e., ear drops), or are known to systemically distribute to the inner ear, require additional specialized safety testing to ensure that the drug does not permanently impair auditory function. METHODS: To properly determine a drug's impact on auditory function, the FDA's Center for Drug Evaluation and Research requires the use of the Auditory Brainstem Response (ABR) evaluation. The ABR evaluation uses auditory stimuli evoked potentials to assess function by establishing minimum intensity thresholds. These thresholds can be monitored following drug treatment to determine an impact on hearing loss. This review discusses methodical considerations for conducting ABR evaluations as they apply to specialized drug safety studies. Alternative assays are discussed and compared to the utility of the ABR evaluation. CONCLUSIONS: The ABR evaluation provides reliable and sensitive measures of hearing function that are suitable for definitive drug safety evaluations or hazardous risk assessments.