Pathology of the Ear

Pathology of the ear, especially the middle and inner ear, can present unique challenges in preclinical safety assessment. Obtaining histopathology samples of the middle and inner ear requires the use of non-routine processing techniques and generally requires the pathologist to have experience and/or special training in ototoxicity assessment. Several laboratory animals serve as animal models for assessment of ototoxicity and selection of a particular species is dependent on a number of variables. Ototoxicants generally fall into only a few categories and those reviewed include: aminoglycoside antibiotics, solvents, loop diuretics, nonsteroidal anti-inflammatory drugs (NSAIDs), cis-platinum compounds, organometals, cellular asphyxiants, and high levels of ambient noise. Common background lesions of the external ear and pinna are often similar to other areas of the skin and in rodents include tumors of the Zymbal’s gland. In the middle and inner ear background lesions are less common but include bacterial otitis and cholesteatomas. Test article-related changes to the outer ear are generally confined to contact irritants. Changes to the middle and inner ear generally depend on the route of administration, duration, and the mechanism of action. Assessing ototoxicity, although not typically done in preclinical studies, may be required for compounds applied directly to the ear or when clinical signs are reported in human trials.