The Eye and Ear

  • Chirukandath Gopinath
  • Vasanthi Mowat


The eye is a complex organ with unique anatomical, functional, and physiological features that render it susceptible to a range of highly specific pathologic changes. In addition, increased longevity in recent decades, particularly in developed countries, has raised the prevalence of age-related diseases such as macular degeneration and glaucoma, increasing the demand for effective treatments for these conditions. Because visual impairment has serious implications for quality of life and independent function, as well as high-cost implications for governments in countries with centrally funded health-care services, specially targeted new drugs and therapies have been developed.


Lacrimal Gland Cynomolgus Monkey Ciliary Body Retinal Degeneration Outer Nuclear Layer 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Short BG. Safety evaluation of ocular drug delivery formulations: techniques and practical considerations. Toxicol Pathol. 2008;36:49–62.PubMedCrossRefGoogle Scholar
  2. 2.
    Teixeira L, Dubielzig RR. Eye. In: Haschek WM, Rousseaux CG, Wallig MA, editors. Haschek and Rousseaux’s handbook of toxicologic pathology. 3rd ed. Boston: Academic; 2013. p. 2095–185.CrossRefGoogle Scholar
  3. 3.
    Galin MA, Nano HD, Hall T. Ocular zinc concentration. Invest Ophthalmol. 1962;1:142–8.PubMedGoogle Scholar
  4. 4.
    Vézina M. Comparative ocular anatomy in commonly used laboratory animals. In: Weir AB, Collins M, editors. Assessing ocular toxicology in laboratory animals. New York: Humana Press; 2013. p. 1–21.Google Scholar
  5. 5.
    Schafer KA, Render JA. Toxicologic pathology of the eye: histologic preparation and alterations of the anterior segment. In: Weir AB, Collins M, editors. Assessing ocular toxicology in laboratory animals. New York: Humana Press; 2013. p. 159–217.Google Scholar
  6. 6.
    Munger RJ, Collins M. Assessment of ocular toxicity potential: basic theory and techniques. In: Weir AB, Collins M, editors. Assessing ocular toxicology in laboratory animals. New York: Humana Press; 2013. p. 23–52.Google Scholar
  7. 7.
    Ver Hoeve JN, Munger RJ, Murphy CJ, Nork TM. Emerging electrophysiological technologies for assessing ocular toxicity in laboratory animals. In: Weir AB, Collins M, editors. Assessing ocular toxicology in laboratory animals. New York: Humana Press; 2013. p. 123–57.Google Scholar
  8. 8.
    Nork TM, Rasmussen CA, Christian BJ, Croft MA, Murphy CJ. Emerging imaging technologies for assessing ocular toxicity in laboratory animals. In: Weir AB, Collins M, editors. Assessing ocular toxicology in laboratory animals. New York: Humana Press; 2013. p. 53–121.Google Scholar
  9. 9.
    Latendresse JR, Warbrittion AR, Jonassen H, Creasy DM. Fixation of testes and eyes using a modified Davidson’s fluid: comparison with Bouin’s fluid and conventional Davidson’s fluid. Toxicol Pathol. 2002;30:524–33.PubMedCrossRefGoogle Scholar
  10. 10.
    Schafer KA, Render JA. Toxicologic pathology of the eye: alterations of the lens and posterior segment. In: Weir AB, Collins M, editors. Assessing ocular toxicology in laboratory animals. New York: Humana Press; 2013. p. 219–57.Google Scholar
  11. 11.
    Bartlett C. Ocular toxicity regulatory considerations for nondrug Food and Drug Administration (FDA) products and the Environmental Protection Agency (EPA). In: Weir AB, Collins M, editors. Assessing ocular toxicology in laboratory animals. New York: Humana Press; 2013. p. 295–305.Google Scholar
  12. 12.
    Greaves P. Histopathology of preclinical toxicity studies. Eye, in 4th ed. London: Elsevier; 2012, p 822–845.Google Scholar
  13. 13.
    Weir AB, Wilson SD. Nonclinical regulatory aspects for ophthalmic drugs. In: Weir AB, Collins M, editors. Assessing ocular toxicology in laboratory animals. New York: Humana Press; 2013. p. 259–94.CrossRefGoogle Scholar
  14. 14.
    Gopinath C, Prentice DE, Lewis DJ. The eye and ear. In: Gopinath C, Prentice D, Lewis DJ, editors. Atlas of experimental toxicologic pathology. Lancaster: MTP Press; 1987. p. 145–55.CrossRefGoogle Scholar
  15. 15.
    Garibaldi BA, Goad ME. Lipid keratopathy in the Watanabe (WHHL) rabbit. Vet Pathol. 1988;25:173–4.PubMedCrossRefGoogle Scholar
  16. 16.
    National Toxicology Program. Toxicology and carcinogenesis studies of malonaldehyde, sodium salt (3-hydroxy-2-propenal, sodium salt) (CAS No. 24382-04-5) in F344/N rats and B6C3F1 mice (gavage studies). Natl Toxicol Program Tech Rep Ser. 1988;331:1–182.Google Scholar
  17. 17.
    Aguirre SA, Huang W, Prasanna G, Jessen B. Corneal neovascularization and ocular irritancy responses in dogs following topical ocular administration of an EP4-prostaglandin E2 agonist. Toxicol Pathol. 2009;37:911–20.PubMedCrossRefGoogle Scholar
  18. 18.
    Newkirk KM, Chandler HL, Parent AE, Young DC, Colitz CM, Wilkie DA, Kusewitt DF. Ultraviolet radiation-induced corneal degeneration in 129 mice. Toxicol Pathol. 2007;35:819–26.PubMedCrossRefGoogle Scholar
  19. 19.
    Leure-Dupree AE. Vascularization of the rat cornea after prolonged zinc deficiency. Anat Rec. 1986;216:27–32.PubMedCrossRefGoogle Scholar
  20. 20.
    Yoshizuka M, McCarthy KJ, Kaye GI, Fujimoto S. Cadmium toxicity to the cornea of pregnant rats: electron microscopy and x-ray microanalysis. Anat Rec. 1990;227:138–43.PubMedCrossRefGoogle Scholar
  21. 21.
    Reindel JF, Gough AW, Pilcher GD, Bobrowski WF, Sobocinski GP, de la Iglesia FA. Systemic proliferative changes and clinical signs in cynomolgus monkeys administered a recombinant derivative of human epidermal growth factor. Toxicol Pathol. 2001;29:159–73.PubMedCrossRefGoogle Scholar
  22. 22.
    Pyrah IT, Kalinowski A, Jackson D, Davies W, Davis S, Aldridge A, Greaves P. Toxicologic lesions associated with two related inhibitors of oxidosqualene cyclase in the dog and mouse. Toxicol Pathol. 2001;29:174–9.PubMedCrossRefGoogle Scholar
  23. 23.
    Kirby TJ. Cataracts produced by triparanol. (MER-29). Trans Am Ophthalmol Soc. 1967;65:494–543.PubMedPubMedCentralGoogle Scholar
  24. 24.
    United States Environmental Protection Agency. Pesticide fact sheet: topramezone. 2005. Office of prevention, pesticides and toxic substances (7501C).
  25. 25.
    Taradach C, Greaves P. Spontaneous eye lesions in laboratory animals: incidence in relation to age. Crit Rev Toxicol. 1984;12:121–47.PubMedCrossRefGoogle Scholar
  26. 26.
    Heywood R, Gopinath C. Morphological assessment of visual dysfunction. Toxicol Pathol. 1990;18:204–17.PubMedGoogle Scholar
  27. 27.
    Heng JE, Vorwerk CK, Lessell E, Zurakowski D, Levin LA, Dreyer EB. Ethambutol is toxic to retinal ganglion cells via an excitotoxic pathway. Invest Ophthalmol Vis Sci. 1999;40:190–6.PubMedGoogle Scholar
  28. 28.
    Chung H, Yoon YH, Hwang JJ, Cho KS, Koh JY, Kim JG. Ethambutol-induced toxicity is mediated by zinc and lysosomal membrane permeabilization in cultured retinal cells. Toxicol Appl Pharmacol. 2009;235:163–70.PubMedCrossRefGoogle Scholar
  29. 29.
    Lucas DR, Newhouse JP. The toxic effect of sodium L-glutamate on the inner layers of the retina. Arch Ophthalmol. 1957;58:193–201.CrossRefGoogle Scholar
  30. 30.
    Butler WH, Ford GP, Newberne JW. A study of the effects of vigabatrin on the central nervous system and retina of Sprague Dawley and Lister-Hooded rats. Toxicol Pathol. 1987;15:143–8.PubMedCrossRefGoogle Scholar
  31. 31.
    Duboc A, Hanoteau N, Simonutti M, Rudolf G, Nehlig A, Sahel JA, Picaud S. Vigabatrin, the GABA-transaminase inhibitor, damages cone photoreceptors in rats. Ann Neurol. 2004;55:695–705.PubMedCrossRefGoogle Scholar
  32. 32.
    Ford MM, Dubielzig RR, Giuliano EA, Moore CP, Narfstrom KL. Ocular and systemic manifestations after oral administration of a high dose of enrofloxacin in cats. Am J Vet Res. 2007;68:190–202.PubMedCrossRefGoogle Scholar
  33. 33.
    Wiebe V, Hamilton P. Fluoroquinolone-induced retinal degeneration in cats. J Am Vet Med Assoc. 2002;221:1568–71.PubMedCrossRefGoogle Scholar
  34. 34.
    Yoshizawa K, Kuro-Kuwata M, Sasaki T, Lai YC, Kanematsu S, Miki H, et al. Retinal degeneration induced in adult mice by a single intraperitoneal injection of N-ethyl-N-nitrosourea. Toxicol Pathol. 2011;39:606–13.PubMedCrossRefGoogle Scholar
  35. 35.
    Mecklenburg L, Schraermeyer U. An overview on the toxic morphological changes in the retinal pigment epithelium after systemic compound administration. Toxicol Pathol. 2007;35:252–67.PubMedCrossRefGoogle Scholar
  36. 36.
    Render JA, Carlton WW. Ocular lesions of 6-aminonicotinamide toxicosis in rabbits. Vet Pathol. 1985;22:72–7.PubMedGoogle Scholar
  37. 37.
    Illanes O, Anderson S, Niesman M, Zwick L, Jessen BA. Retinal and peripheral nerve toxicity induced by the administration of a pan-cyclin dependent kinase (cdk) inhibitor in mice. Toxicol Pathol. 2006;34:243–8.PubMedCrossRefGoogle Scholar
  38. 38.
    Saturno G, Pesenti M, Cavazzoli C, Rossi A, Giusti AM, Gierke B, et al. Expression of serine/threonine protein-kinases and related factors in normal monkey and human retinas: the mechanistic understanding of a CDK2 inhibitor induced retinal toxicity. Toxicol Pathol. 2007;35:972–83.PubMedCrossRefGoogle Scholar
  39. 39.
    Brown WR, Rubin L, Hite M, Zwickey RE. Experimental papilledema in the dog induced by a salicylanilide. Toxicol Appl Pharmacol. 1972;21:532–41.PubMedCrossRefGoogle Scholar
  40. 40.
    Parhad IM, Griffin JW, Price DL, Clark AW, Cork LC, Miller NR, Hoffman PN. Intoxication with beta, beta’ -iminodipropionitrile: a model of optic disc swelling. Lab Invest. 1982;46:186–95.PubMedGoogle Scholar
  41. 41.
    Smith-Thomas L, Moustafa M, Spada CS, Shi L, Dawson RA, Wagner M, et al. Latanoprost-induced pigmentation in human iridial melanocytes is fibroblast dependent. Exp Eye Res. 2004;78:973–85.PubMedCrossRefGoogle Scholar
  42. 42.
    Stjernschantz J, Ocklind A, Wentzel P, Lake S, Hu DN. Latanoprost-induced increase of tyrosinase transcription in iridial melanocytes. Acta Ophthalmol Scand. 2000;78:618–22.PubMedCrossRefGoogle Scholar
  43. 43.
    Yildirim N, Sahin A, Kara S, Baycu C. Latanoprost-induced changes in the iris and trabeculum: an electron-microscopic morphological study. Int Ophthalmol. 2010;30:93–7.PubMedCrossRefGoogle Scholar
  44. 44.
    Matuk Y, Ghosh M, McCulloch C. Distribution of silver in the eyes and plasma proteins of the albino rat. Can J Ophthalmol. 1981;16:145–50.PubMedGoogle Scholar
  45. 45.
    Bencz Z, Ivan E, Cholnoky E. Analysis of cataract and keratotic damage induced by 4-diethylaminoethoxy-alpha-ethyl-benzhydrol (RGH-6201) in rats. Arch Toxicol Suppl. 1985;8:476–9.PubMedCrossRefGoogle Scholar
  46. 46.
    Xu GT, Zigler Jr JS, Lou MF. The possible mechanism of naphthalene cataract in rat and its prevention by an aldose reductase inhibitor (ALO1576). Exp Eye Res. 1992;54:63–72.PubMedCrossRefGoogle Scholar
  47. 47.
    Lou MF, Xu GT, Zigler Jr S, York Jr B. Inhibition of naphthalene cataract in rats by aldose reductase inhibitors. Curr Eye Res. 1996;15:423–32.PubMedCrossRefGoogle Scholar
  48. 48.
    Yoshizawa K, Oishi Y, Nambu H, Yamamoto D, Yang J, Senzaki H, et al. Cataractogenesis in neonatal Sprague–Dawley rats by N-methyl-N-nitrosourea. Toxicol Pathol. 2000;28:555–64.PubMedCrossRefGoogle Scholar
  49. 49.
    Miyazono Y, Harada K, Sugiyama K, Ueno M, Torii M, Kato I, et al. Toxicological characterization of N-methyl-N-nitrosourea-induced cataract in rats by LC/MS-based metabonomic analysis. J Appl Toxicol. 2011;31:655–62.PubMedCrossRefGoogle Scholar
  50. 50.
    Shui YB, Kojima M, Sasaki K. A new steroid-induced cataract model in the rat: long-term prednisolone applications with a minimum of X-irradiation. Ophthalmic Res. 1996;28 Suppl 2:92–101.PubMedCrossRefGoogle Scholar
  51. 51.
    Shui YB, Vrensen GF, Kojima M. Experimentally induced steroid cataract in the rat: a scanning electron microscopic study. Surv Ophthalmol. 1997;42 Suppl 1:S127–32.PubMedCrossRefGoogle Scholar
  52. 52.
    Cenedella RJ, Jacob R, Borchman D, Tang D, Neely AR, Samadi A, et al. Direct perturbation of lens membrane structure may contribute to cataracts caused by U18666A, an oxidosqualene cyclase inhibitor. J Lipid Res. 2004;45:1232–41.PubMedCrossRefGoogle Scholar
  53. 53.
    Gerson RJ, MacDonald JS, Alberts AW, Chen J, Yudkovitz JB, Greenspan MD, et al. On the etiology of subcapsular lenticular opacities produced in dogs receiving HMG-CoA reductase inhibitors. Exp Eye Res. 1990;50:65–78.PubMedCrossRefGoogle Scholar
  54. 54.
    MacDonald JS, Gerson RJ, Kornbrust DJ, Kloss MW, Prahalada S, Berry PH, et al. Preclinical evaluation of lovastatin. Am J Cardiol. 1988;62:16J–27.PubMedCrossRefGoogle Scholar
  55. 55.
    von Sallmann L, Grimes P, Collins E. Triparanol-induced cataract in rats. Trans Am Ophthalmol Soc. 1963;61:49–60.Google Scholar
  56. 56.
    Funk J, Landes C. Histopathologic findings after treatment with different oxidosqualene cyclase (OSC) inhibitors in hamsters and dogs. Exp Toxicol Pathol. 2005;57:29–38.PubMedCrossRefGoogle Scholar
  57. 57.
    Iwai H, Tagawa Y, Hayasaka I, Yanai T, Masegi T. Effects of atropine sulfate on rat harderian glands: correlation between morphological changes and porphyrin levels. J Toxicol Sci. 2000;25:151–9.PubMedCrossRefGoogle Scholar
  58. 58.
    Westwood FR, Iswaran TJ, Greaves P. Long-term effects of an inotropic phosphodiesterase inhibitor (ICI 153,110) on the rat salivary gland, harderian gland, and intestinal mucosa. Toxicol Pathol. 1991;19:214–23.PubMedCrossRefGoogle Scholar
  59. 59.
    Breider MA, Bleavins MR, Reindel JF, Gough AW, de la Iglesia FA. Cellular hyperplasia in rats following continuous intravenous infusion of recombinant human epidermal growth factor. Vet Pathol. 1996;33:184–94.PubMedCrossRefGoogle Scholar
  60. 60.
    Hong HH, Houle CD, Ton TV, Sills RC. K-ras mutations in lung tumors and tumors from other organs are consistent with a common mechanism of ethylene oxide tumorigenesis in the B6C3F1 mouse. Toxicol Pathol. 2007;35:81–5.PubMedCrossRefPubMedCentralGoogle Scholar
  61. 61.
    Kajimura T, Kashimoto Y, Satoh H, Furuhama K. Rapid induction of tumors in the harderian gland of mice receiving urethane after initiation with N-ethyl-N-nitrosourea. J Toxicol Pathol. 2003;16:85–91.CrossRefGoogle Scholar
  62. 62.
    Goodrow TL, Nichols WW, Storer RD, Anderson MW, Maronpot RR. Activation of H-ras is prevalent in 1,3-butadiene-induced and spontaneously occurring murine Harderian gland tumors. Carcinogenesis. 1994;15:2665–7.PubMedCrossRefGoogle Scholar
  63. 63.
    Azzarolo AM, Bjerrum K, Maves CA, Becker L, Wood RL, Mircheff AK, Warren DW. Hypophysectomy-induced regression of female rat lacrimal glands: partial restoration and maintenance by dihydrotestosterone and prolactin. Invest Ophthalmol Vis Sci. 1995;36:216–26.PubMedGoogle Scholar
  64. 64.
    Slatter DH, Davis WC. Toxicity of phenazopyridine: electron microscopical studies of canine lacrimal and nictitans glands. Arch Ophthalmol. 1974;91:484–6.PubMedCrossRefGoogle Scholar
  65. 65.
    Mattsson JL. Ototoxicity: an argument for evaluation of the cochlea in safety testing in animals. Toxicol Pathol. 2000;28:137–41.PubMedCrossRefGoogle Scholar
  66. 66.
    Lataye R, Campo P, Pouyatos B, Cossec B, Blachere V, Morel G. Solvent ototoxicity in the rat and guinea pig. Neurotoxicol Teratol. 2003;25:39–50.PubMedCrossRefGoogle Scholar
  67. 67.
    Campo P, Pouyatos B, Lataye R, Morel G. Is the aged rat ear more susceptible to noise or styrene damage than the young ear? Noise Health. 2003;5:1–18.PubMedGoogle Scholar
  68. 68.
    Johnson AC, Canlon B. Toluene exposure affects the functional activity of the outer hair cells. Hear Res. 1994;72:189–96.PubMedCrossRefGoogle Scholar
  69. 69.
    Johnson AC, Canlon B. Progressive hair cell loss induced by toluene exposure. Hear Res. 1994;75:201–8.PubMedCrossRefGoogle Scholar
  70. 70.
    Prepageran N, Scott AR, Rutka JA. Ototoxicity of loop diuretics. In: Roland PS, Rutka JA, editors. Ototoxicity. Hamilton: BC Decker; 2004. p. 42–8.Google Scholar
  71. 71.
    Prepageran N, Rutka JA. Salicylates, nonsteroidal anti-inflammatory drugs, quinine, and heavy metals. In: Roland PS, Rutka JA, editors. Ototoxicity. Hamilton: BC Decker; 2004. p. 28–42.Google Scholar
  72. 72.
    De Freitas MR, Figueiredo AA, Brito GA, Leitao RF, Carvalho Jr JV, Gomes Jr RM, Ribeiro RA. The role of apoptosis in cisplatin-induced ototoxicity in rats. Braz J Otorhinolaryngol. 2009;75:745–52.PubMedCrossRefGoogle Scholar
  73. 73.
    Garcia-Berrocal JR, Nevado J, Ramirez-Camacho R, Sanz R, Gonzalez-Garcia JA, Sanchez-Rodriguez C, et al. The anticancer drug cisplatin induces an intrinsic apoptotic pathway inside the inner ear. Br J Pharmacol. 2007;152:1012–20.PubMedCrossRefPubMedCentralGoogle Scholar
  74. 74.
    Crofton KM, Kodavanti PR, Derr-Yellin EC, Casey AC, Kehn LS. PCBs, thyroid hormones, and ototoxicity in rats: cross-fostering experiments demonstrate the impact of postnatal lactation exposure. Toxicol Sci. 2000;57:131–40.PubMedCrossRefGoogle Scholar
  75. 75.
    Gold LS, Manley NB, Slone TH, Ward JM. Compendium of chemical carcinogens by target organ: results of chronic bioassays in rats, mice, hamsters, dogs, and monkeys. Toxicol Pathol. 2001;29:639–52.PubMedCrossRefGoogle Scholar
  76. 76.
    Gold LS, Manley NB, Slone TH, Rohrbach L, Garfinkel GB. Supplement to the Carcinogenic Potency Database (CPDB): results of animal bioassays published in the general literature through 1997 and by the National Toxicology Program in 1997–1998. Toxicol Sci. 2005;85:747–808.PubMedCrossRefGoogle Scholar
  77. 77.
    Kato T, Migita H, Ohgaki H, Sato S, Takayama S, Sugimura T. Induction of tumors in the Zymbal gland, oral cavity, colon, skin and mammary gland of F344 rats by a mutagenic compound, 2-amino-3, 4-dimethylimidazo[4, 5-f]quinoline. Carcinogenesis. 1989;10:601–3.PubMedCrossRefGoogle Scholar
  78. 78.
    Kudo M, Ogura T, Esumi H, Sugimura T. Mutational activation of c-Ha-ras gene in squamous cell carcinomas of rat Zymbal gland induced by carcinogenic heterocyclic amines. Mol Carcinog. 1991;4:36–42.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Chirukandath Gopinath
    • 1
  • Vasanthi Mowat
    • 2
  1. 1.Consultant in Toxicology and PathologyCambridgeshireUK
  2. 2.Huntingdon Life SciencesCambridgeshireUK

Personalised recommendations