The role of toxicokinetics in xylene-induced ototoxicity in the rat and guinea pig.
In the rat, some aromatic solvents cause a high level of ototoxicity that is characterized by damage to outer hair cells in the cochlea, which results in irreversible hearing loss. However, there is a vast difference in their potency. Among the three isomers of xylene, only para-xylene has been shown to be ototoxic in the rat. Moreover, all the species do not show the same susceptibility to ototoxic solvents, the rat being the most susceptible and the guinea pig seeming resistant to this ototoxic effect. The objective of the study was to determine whether toxicokinetic factors could explain the differences in ototoxicity observed among the three isomers of xylene in the rat and the species-dependent ototoxicity in the rat and the guinea pig. Blood and brain concentrations of each isomer were monitored in Sprague-Dawley rats treated orally by gastric intubation with a single dose or a 10 day-repeated treatment of 8.47 mmol/kg (an ototoxic dosage for para-xylene) of each isomer. Moreover, histology of the cochlea was carried out and the toxicokinetics of meta-xylene was monitored in rats treated with a single dose or a 10 day-repeated treatment of 16.94 mmol/kg meta-xylene, a non-ototoxic isomer. Similarly, histology of the cochlea was carried out and the toxicokinetics of para-xylene was followed in guinea pigs treated by gavage with a single dose or a 10 day-repeated treatment of 8.47 mmol/kg para-xylene. Finally, the blood and brain concentrations of para-xylene were measured in both the rats and the guinea pigs after a 4-h exposure to 1800 ppm of para-xylene. Among the three isomers studied, para-xylene yielded the highest blood and brain concentrations in the acutely and repeatedly exposed rats. When given a high dosage of meta-xylene (16.94 mmol/kg), the rats showed blood and brain concentrations of meta-xylene in the same order as those obtained with 8.47 mmol/kg para-xylene, but no outer hair cell loss was observed. No outer hair cell loss was observed in the guinea pigs treated with para-xylene. Whatever the exposure pattern, the blood and brain concentrations of para-xylene in the rats were 3.1-9.5 times higher than those measured in the guinea pigs. These results indicate that toxicokinetic factors cannot explain the differences in ototoxicity observed with the three isomers in the rat. However, they suggest that the differences in susceptibility to para-xylene observed between the rats and the guinea pigs might be due to toxicokinetic factors.
Gagnaire
F
F
Département Polluants et Santé, Institut National de Recherche et de Sécurité, Avenue de Bourgogne, BP 27, 54501 Vandoeuvre Cedex, France. francois.gagnaire@inrs.fr
Marignac
B
B
Blachère
V
V
Grossmann
S
S
Langlais
C
C
D000818:Animals; D003051:Cochlea / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D006199:Hair Cells, Auditory, Inner / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018072:Hair Cells, Auditory, Outer / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D019570:Inhalation Exposure; D007536:Isomerism; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012997:Solvents / Q000737:chemistry / Q000493:pharmacokinetics* / Q000633:toxicity; D013329:Structure-Activity Relationship; D014992:Xylenes / Q000737:chemistry / Q000493:pharmacokinetics* / Q000633:toxicity
D012997:Solvents; D014992:Xylenes