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,
alpha-methylstyrene, trans-
beta-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-
alpha-methylstyrene<trans-
beta-methylstyrene=
toluene< or =
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 (
alpha-methylstyrene and trans-
beta-methylstyrene) decreased the
ototoxicity of
styrene.