Skip to main content
SpringerLink
Log in

Relative ototoxicity of 21 aromatic solvents

Archives of Toxicology Aims and scope Submit manuscript

Cite this article

Abstract

Some aromatic solvents (e.g. toluene, p-xylene, styrene, and ethylbenzene) show, in the rat, striking ototoxicity characterized by an irreversible hearing loss, as measured by behavioural or electrophysiological methods, associated with damage to outer hair cells in the cochlea of the exposed animals. To broaden the range of aromatic solvents studied concerning their potential ototoxicity and to compare their ototoxicity quantitatively, 21 aromatic solvents were administered orally by gastric intubation to Sprague–Dawley rats for 5 days/week for a 2-week period. The dose used was 8.47 mmol kg−1 body weight day−1. The possible ototoxicity of the aromatic solvents was evaluated by morphological investigation of the cochlea. Whole-mount surface preparations of the organ of Corti were made to quantify the number of missing hair cells (cytocochleogram). Among the 21 solvents studied, eight (toluene, p-xylene, ethylbenzene, n-propylbenzene, styrene, α-methylstyrene, trans-β-methylstyrene, and allylbenzene) caused histological lesions of the organ of Corti. They differed widely in their potency. The least ototoxic solvents caused outer hair cell (OHC) loss in the middle turn of the organ of Corti. The OHC loss was slight in the first row, and greater in the second and third rows. The most ototoxic solvents caused high losses in the three rows of the outer hair cells along the entire length of the basilar membrane. There were also occasional inner hair cell (ICH) losses in the most affected animals. Although no measurements were made of the chemical concentrations reached in the blood or the brain, tentative ranking of an increasing ototoxicity of the eight aromatic solvents could be proposed on the basis of the histological losses observed—α-methylstyrene<trans-β-methylstyrene=toluene≤p-xylene<n-propylbenzene<styrene=ethylbenzene<allylbenzene. There was no relationship between the degree of ototoxicity and the lipophilic properties of the ototoxic agents as expressed by the octanol/water partition coefficients. However, it seemed that some structural constraint was essential to induce ototoxicity. It seems there must be a single side-chain on the aromatic ring for ototoxicity, except with p-xylene. The other aromatic solvents with two side-chains were not ototoxic. When the saturated side-chain was branched (isopropylbenzene, isobutylbenzene, sec-butylbenzene, tert-butylbenzene), no ototoxicity was observed. The ototoxic potency increased when the length of the saturated side-chain extended from one carbon atom to two carbon atoms. Beyond that point, the ototoxic effect decreased with n-propylbenzene and disappeared with n-butylbenzene. Moreover, unsaturation of the side-chain of allylbenzene increased the ototoxicity of n-propylbenzene substantially. Branching of the unsaturated chain (α-methylstyrene and trans-β-methylstyrene) decreased the ototoxicity of styrene.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

References

  • Campo P, Lataye R, Cossec B, Placidi V (1997) Toluene-induced hearing loss: a mid-frequency location of the cochlear lesions. Neurotoxicol Teratol 19:129–140

    Google Scholar 

  • Campo P, Loquet G, Blachère V, Roure M (1999) Toluene and styrene intoxication route in the rat cochlea. Neurotoxicol Teratol 21:427–434

    Google Scholar 

  • Cappaert NLM, Klis SF, Muijser H, de Groot JCJ, Kulig BM, Smoorenburg GF (1999) The ototoxic effects of ethyl benzene in rats. Hear Res 137:91–102

    Google Scholar 

  • Cappaert NL, Klis SF, Baretta AB, Muijser H, Smoorenburg GF (2000) Ethyl benzene-induced ototoxicity in rats: a dose-dependent mid-frequency hearing loss. J Assoc Res Otolaryngol 1:292–299

    Google Scholar 

  • Cappaert NL, Klis SFL, Muijser H, Kulig BM, Smoorenburg GF (2001) Simultaneous exposure to ethyl benzene and noise: synergistic effects on outer cells. Hear Res 162:67–79

    Google Scholar 

  • Crofton KM, Zhao X (1993) Mid-frequency hearing loss in rats following inhalation exposure to trichloroethylene: evidence from reflex modification audiometry. Neurotoxicol Teratol 15:413–423

    Google Scholar 

  • Crofton KM, Zhao X (1997) The ototoxicity of trichloroethylene: extrapolation and relevance of high-concentration, short-duration animal exposure data. Fundam Appl Toxicol 38:101–106

    Google Scholar 

  • Crofton KM, Lassiter TL, Rebert CS (1994) Solvent-induced ototoxicity in rats: an atypical selective mid-frequency hearing deficit. Hear Res 80:25–30

    Google Scholar 

  • Dehne N, Lautermann J, ten Cate W-JF, Rauen U de Groot H (2000) In vitro effects hydrogen peroxide on the cochlear neurosensory epithelium of the guinea pig. Hear Res 143:162–170

    Google Scholar 

  • El Barbary A, Altschuler RA, Schacht J (1993) Glutathione S-transferase in the organ of Corti of the rat: enzymatic activity, subunit composition and immunohistochemical localization. Hear Res 71:80–90

    Google Scholar 

  • Fechter LD, Liu Y, Herr DW, Crofton KM (1998) Trichloroethylene ototoxicity: evidence for a cochlear origin. Toxicol Sci 42:28–35

    Google Scholar 

  • Gagnaire F, Marignac B, Langlais C, Bonnet P (2001) Ototoxicity in rats exposed to ortho-, meta- and para-xylene vapours for 13 weeks. Pharmacol Toxicol 89:6–14

    Google Scholar 

  • Hansch C, Leo A (1979) Appendix II partition coefficients In: Hansch C, Leo A (eds) Substituent constants for correlation analysis in chemistry and biology. Wiley, New York Chichester Brisbane Toronto

    Google Scholar 

  • Jaspers RM, Muijser H, Lammers JH, Kulig BM (1993) Mid frequency hearing loss and reduction of acoustic startle responding in rats following trichloroethylene exposure. Neurotoxicol Teratol 15:407–412

    Google Scholar 

  • Johnson A-C, Canlon B (1994) Progressive hair cell loss induced by toluene exposure. Hear Res 75:201–208

    Article  CAS  PubMed  Google Scholar 

  • Lataye R, Campo P (1997) Combined effects of a simultaneous exposure to noise and toluene on hearing function. Neurotoxicol Teratol 19:373–382

    Google Scholar 

  • Lataye R, Campo P, Loquet G (1999) Toluene ototoxicity in rats: assessment of the frequency of hearing deficit by electrocochleography. Neurotoxicol Teratol 21:267–276

    Google Scholar 

  • Lataye R, Campo P, Loquet G (2000) Combined effects of noise and styrene exposure on hearing function in the rat. Hear Res 139:86–96

    Google Scholar 

  • Lataye R, Campo P, Barthelemy C, Loquet G, Bonnet P (2001) Cochlear pathology induced by styrene. Neurotoxicol Teratol 23:71–79

    Google Scholar 

  • Loquet G, Campo P, Lataye R (1999) Comparison of toluene-induced and styrene-induced hearing losses. Neurotoxicol Teratol 21:689–697

    Google Scholar 

  • Loquet G, Campo P, Lataye R, Cossec B, Bonnet P (2000) Combined effects of exposure to styrene and ethanol on the auditory function in the rat. Hear Res 148:173–180

    Google Scholar 

  • Makitie A, Pirvola U, Pyykkö I, Sakakibara H, Riihimäki V, Ylikoski J (2002) Functional and morphological effects of styrene on the auditory system of the rat. Arch Toxicol 76:40–47

    Google Scholar 

  • Müller M (1991) Frequency representation in the rat cochlea. Hear Res 51:247–254

    Google Scholar 

  • Pouyatos B, Campo P, Lataye R (2002) Use of DPOAEs for assessing hearing loss caused by styrene in the rat. Hear Res 165:156–164

    Google Scholar 

  • Pryor GT (1994) Assessment of auditory dysfunction. In: Chang LW (ed) Principles of neurotoxicology. Marcel Dekker, New York, pp 345–371

    Google Scholar 

  • Pryor GT, Dickinson J, Howd RA, Rebert CS (1983) Neurobehavioral effects of subchronic exposure of weanling rats to toluene or hexane. Neurobehav Toxicol Teratol 5:47–52

    Google Scholar 

  • Pryor GT, Dickinson J, Feeney E, Rebert CS (1984) Hearing loss in rats exposed to toluene as weanlings or as young adults. Neurobehav Toxicol Teratol 6:111–119

    Google Scholar 

  • Pryor GT, Rebert CS, Howd RA (1987) Hearing loss in rats caused by inhalation of mixed xylenes and styrene. J Appl Toxicol 7:55–61

    Google Scholar 

  • Rebert CS, Sorenson SS, Howd RA, Pryor GT (1983) Toluene induced hearing loss in rats evidenced by the brainstem auditory-evoked response. Neurobehav Toxicol Teratol 5:59–62

    Google Scholar 

  • Rebert CS, Day VL, Matteucci MJ, Pryor GT (1991) Sensory evoked potentials in rats chronically exposed to trichloroethylene: predominant auditory dysfunction. Neurotoxicol Teratol 13:83–90

    Google Scholar 

  • Sha S-H, Taylor R, Forge A, Schacht J (2001) Differential vulnerability of basal and apical hair cells is based on intrinsic susceptibility to free radicals. Hear Res 155:1–8

    Google Scholar 

  • Subramaniam M, Henderson D, Spongr V (1994) The relationship among distortion-product otoacoustic emissions, evoked potential thresholds, and outer hair cell loss following interrupted noise exposures. Ear Hear 15:299–309

    Google Scholar 

  • Subramaniam M, Henselman LW, Spongr V, Henderson D, Powers NL (1995) Effects of high-frequency interrupted noise exposures on evoked-potential thresholds, distortion-product otoacoustic emissions, and outer hair cell loss. Ear Hear 16:372–381

    Google Scholar 

  • Sullivan MJ, Conolly RB (1988) Comparison of blood toluene levels after inhalation and oral administration. Environ Res 45:64–70

    Google Scholar 

  • Sullivan MJ, Rarey KE, Conolly RB (1988) Ototoxicity of toluene in rats. Neurotoxicol Teratol 10:525–530

    Google Scholar 

  • Tan CT, Lee SY, Yao CJ, Liu SH, Lin-Shiau SY (2001) Effects of gentamicin and pH on [Ca2+]I in apical and basal outer hair cells from guinea pigs. Hear Res 154:81–87

    Google Scholar 

  • Usami S, Hjelle OP, Ottersen OP (1996) Differential cellular distribution of glutathione—an endogenous antioxidant—in the guinea pig inner ear. Brain Res 743:337–340

    Google Scholar 

  • Whitlon DS, Wright LS, Nelson SA, Szakaly R, Siegel FL (1999) Maturation of cochlear glutathion-S-transferase correlates with the end of the sensitive period for ototoxicity. Hear Res 137:43–50

    Google Scholar 

  • Yano BL, Dittenber DA, Albee RR, Mattson JL (1992) Abnormal auditory brainstem responses and cochlear pathology in rats induced by an exaggerated styrene exposure regimen. Toxicol Pathol 20:1–6

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Département Polluants et Santé, Institut National de Recherche et de Sécurité, Avenue de Bourgogne, BP 27, +54501, Vandœuvre Cedex, France

    François Gagnaire & Cristina Langlais

Authors
  1. François Gagnaire
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Cristina Langlais
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to François Gagnaire.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Gagnaire, F., Langlais, C. Relative ototoxicity of 21 aromatic solvents. Arch Toxicol 79, 346–354 (2005). https://doi.org/10.1007/s00204-004-0636-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00204-004-0636-2

Keywords

search

Navigation