Advertisement

Pathology of the Ear

  • Kenneth A. SchaferEmail author
Chapter

Abstract

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.

Key words

Ototoxicity Pinna Vestibular apparatus Cochlea Tympanic bulla Zymbal’s gland 

References

  1. Anonymous (2015) Guidance for industry and review staff: nonclinical safety evaluation of reformulated drug products and products intended for administration by an alternate route. U.S. Department of Health and Human Services, Food and Drug Administration. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm079245.pdf
  2. Aran JM, Chappert C, Dulon D, Erre JP, Aurousseau C (1995) Uptake of amikacin by hair cells of the guinea pig cochlea and vestibule and ototoxicity: comparison with gentamicin. Hear Res 82(2):179–183CrossRefGoogle Scholar
  3. Campo P, Maguin K (2007) Solvent-induced hearing loss: mechanisms and prevention strategy. Int J Occup Med Environ Health 20(3):265–270.  https://doi.org/10.2478/v10001-007-0031-3CrossRefPubMedGoogle Scholar
  4. Chen GD, Chi LH, Kostyniak PJ, Henderson D (2007) Styrene induced alterations in biomarkers of exposure and effects in the cochlea: mechanisms of hearing loss. Toxicol Sci 98(1):167–177.  https://doi.org/10.1093/toxsci/kfm078CrossRefPubMedGoogle Scholar
  5. Crofton KM, Lassiter TL, Rebert CS (1994) Solvent-induced ototoxicity in rats: an atypical selective mid-frequency hearing deficit. Hear Res 80(1):25–30CrossRefGoogle Scholar
  6. Dallos P, Fakler B (2002) Prestin, a new type of motor protein. Nat Rev Mol Cell Biol 3(2):104–111.  https://doi.org/10.1038/nrm730CrossRefPubMedGoogle Scholar
  7. Davis RR, Murphy WJ, Snawder JE, Striley CA, Henderson D, Khan A, Krieg EF (2002) Susceptibility to the ototoxic properties of toluene is species specific. Hear Res 166(1–2):24–32CrossRefGoogle Scholar
  8. Falk SA (1972) Combined effects of noise and ototoxic drugs. Environ Health Perspect 2:5–22CrossRefGoogle Scholar
  9. Fechter LD, Carlisle L (1990) Auditory dysfunction and cochlear vascular injury following trimethyltin exposure in the guinea pig. Toxicol Appl Pharmacol 105(1):133–143CrossRefGoogle Scholar
  10. Fechter LD, Young JS, Nuttall AL (1986) Trimethyltin ototoxicity: evidence for a cochlear site of injury. Hear Res 23(3):275–282CrossRefGoogle Scholar
  11. Fechter LD, Clerici WJ, Yao L, Hoeffding V (1992) Rapid disruption of cochlear function and structure by trimethyltin in the guinea pig. Hear Res 58(2):166–174CrossRefGoogle Scholar
  12. Forge A, Schacht J (2000) Aminoglycoside antibiotics. Audiol Neurootol 5(1):3–22CrossRefGoogle Scholar
  13. Gagnaire F, Langlais C (2005) Relative ototoxicity of 21 aromatic solvents. Arch Toxicol 79(6):346–354.  https://doi.org/10.1007/s00204-004-0636-2CrossRefPubMedGoogle Scholar
  14. Gauvin D, Yoder J, Tapp R, Cole P (2016) Defining “Best Practices” for critical endpoints in preclinical screening of new chemical entities for ototoxicity liability. Otoloaryngol Open J 2(2):58–69CrossRefGoogle Scholar
  15. Hoeffding V, Fechter LD (1991) Trimethyltin disrupts auditory function and cochlear morphology in pigmented rats. Neurotoxicol Teratol 13(2):135–145CrossRefGoogle Scholar
  16. Ikeda K, Oshima T, Hidaka H, Takasaka T (1997) Molecular and clinical implications of loop diuretic ototoxicity. Hear Res 107(1–2):1–8CrossRefGoogle Scholar
  17. Johnson KR, Zheng QY, Noben-Trauth K (2006) Strain background effects and genetic modifiers of hearing in mice. Brain Res 1091(1):79–88.  https://doi.org/10.1016/j.brainres.2006.02.021CrossRefPubMedPubMedCentralGoogle Scholar
  18. Jones SM, Jones TA, Johnson KR, Yu H, Erway LC, Zheng QY (2006) A comparison of vestibular and auditory phenotypes in inbred mouse strains. Brain Res 1091(1):40–46.  https://doi.org/10.1016/j.brainres.2006.01.066CrossRefPubMedPubMedCentralGoogle Scholar
  19. Karlsson KK, Flock A (1990) Quinine causes isolated outer hair cells to change length. Neurosci Lett 116(1–2):101–105CrossRefGoogle Scholar
  20. Karlsson KK, Flock B, Flock A (1991) Ultrastructural changes in the outer hair cells of the guinea pig cochlea after exposure to quinine. Acta Otolaryngol 111(3):500–505CrossRefGoogle Scholar
  21. Lataye R, Campo P, Pouyatos B, Cossec B, Blachere V, Morel G (2003) Solvent ototoxicity in the rat and guinea pig. Neurotoxicol Teratol 25(1):39–50CrossRefGoogle Scholar
  22. Liberman MC (1990) Quantitative assessment of inner ear pathology following ototoxic drugs or acoustic trauma. Toxicol Pathol 18(1 Pt 2):138–148CrossRefGoogle Scholar
  23. Liu J, Marcus DC, Kobayashi T (1996) Inhibitory effect of erythromycin on ion transport by stria vascularis and vestibular dark cells. Acta Otolaryngol 116(4):572–575CrossRefGoogle Scholar
  24. Loquet G, Campo P, Lataye R (1999) Comparison of toluene-induced and styrene-induced hearing losses. Neurotoxicol Teratol 21(6):689–697CrossRefGoogle Scholar
  25. Maguin K, Lataye R, Campo P, Cossec B, Burgart M, Waniusiow D (2006) Ototoxicity of the three xylene isomers in the rat. Neurotoxicol Teratol 28(6):648–656.  https://doi.org/10.1016/j.ntt.2006.08.007CrossRefPubMedGoogle Scholar
  26. Mattsson JL (2000) Ototoxicity: an argument for evaluation of the cochlea in safety testing in animals. Toxicol Pathol 28(1):137–141CrossRefGoogle Scholar
  27. Raphael Y, Altschuler RA (2003) Structure and innervation of the cochlea. Brain Res Bull 60(5–6):397–422CrossRefGoogle Scholar
  28. Ryals B, Westbrook E, Schacht J (1997) Morphological evidence of ototoxicity of the iron chelator deferoxamine. Hear Res 112(1–2):44–48CrossRefGoogle Scholar
  29. Rybak LP, Whitworth C, Scott V (1991) Comparative acute ototoxicity of loop diuretic compounds. Eur Arch Otorhinolaryngol 248(6):353–357CrossRefGoogle Scholar
  30. Rybak LP, Whitworth CA, Mukherjea D, Ramkumar V (2007) Mechanisms of cisplatin-induced ototoxicity and prevention. Hear Res 226(1–2):157–167.  https://doi.org/10.1016/j.heares.2006.09.015CrossRefPubMedGoogle Scholar
  31. Schacht J (1986) Molecular mechanisms of drug-induced hearing loss. Hear Res 22:297–304CrossRefGoogle Scholar
  32. Schacht J, Weiner N (1986) Aminoglycoside-induced hearing loss: a molecular hypothesis. ORL J Otorhinolaryngol Relat Spec 48(2):116–123CrossRefGoogle Scholar
  33. Schafer KA, Bolon B (2013) Ear. In: Haschek WM, Rousseaux CG, Wallig MA (eds) Haschek and Rousseaux’s handbook of toxicologic pathology, vol 3, 3rd edn. Academic Press, Amsterdam, pp 2187–2218CrossRefGoogle Scholar
  34. Song BB, Schacht J (1996) Variable efficacy of radical scavengers and iron chelators to attenuate gentamicin ototoxicity in guinea pig in vivo. Hear Res 94(1–2):87–93CrossRefGoogle Scholar
  35. Song BB, Anderson DJ, Schacht J (1997) Protection from gentamicin ototoxicity by iron chelators in guinea pig in vivo. J Pharmacol Exp Ther 282(1):369–377PubMedGoogle Scholar
  36. Stone JS, Oesterle EC, Rubel EW (1998) Recent insights into regeneration of auditory and vestibular hair cells. Curr Opin Neurol 11(1):17–24CrossRefGoogle Scholar
  37. Stypulkowski PH (1990) Mechanisms of salicylate ototoxicity. Hear Res 46(1–2):113–145CrossRefGoogle Scholar
  38. Tawackoli W, Chen GD, Fechter LD (2001) Disruption of cochlear potentials by chemical asphyxiants. Cyanide and carbon monoxide. Neurotoxicol Teratol 23(2):157–165CrossRefGoogle Scholar
  39. Tran Ba Huy P, Bernard P, Schacht J (1986) Kinetics of gentamicin uptake and release in the rat. Comparison of inner ear tissues and fluids with other organs. J Clin Invest 77(5):1492–1500.  https://doi.org/10.1172/jci112463CrossRefPubMedPubMedCentralGoogle Scholar
  40. Yoshitomo K, Boorman GA (1990) Eye and associated glands. In: Pathology of the Fischer rat: reference and atlas. Academic Press, Inc, San Diego, pp 239–259Google Scholar
  41. Young JS, Fechter LD (1986) Trimethyltin exposure produces an unusual form of toxic auditory damage in rats. Toxicol Appl Pharmacol 82(1):87–93CrossRefGoogle Scholar
  42. Zheng QY, Johnson KR, Erway LC (1999) Assessment of hearing in 80 inbred strains of mice by ABR threshold analyses. Hear Res 130(1–2):94–107CrossRefGoogle Scholar
  43. Zheng QY, Tong YC, Alagramam KN, Yu H (2007) Tympanometry assessment of 61 inbred strains of mice. Hear Res 231(1–2):23–31.  https://doi.org/10.1016/j.heares.2007.05.011CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Greenfield Pathology Services, Inc.GreenfieldUSA

Personalised recommendations