Differences in Ototoxicity across Species.
OBJECTIVE
To illustrate some differences between humans and rodents in the dose-effect relationships for two ototoxic drugs.


METHODS
Controlled animal study using typical research regimens for gentamicin and cisplatin compared with human data from the clinical literature.


METHODS
Auditory brainstem response testing was carried out over months in two groups of animals exposed to typical dose regimens for ototoxic drugs. In the first group, 30 guinea pigs received either 3 or 6 mg/kg of cisplatin on alternate days for 5 days (total dose 15 or 30 mg/kg). In the second group, 24 C57 mice received saline or 19 daily doses of gentamicin 120 mg/kg. The findings in rodents were contrasted with human toxicity in the literature.


RESULTS
Cisplatin increased click thresholds (32 +/- 27 dB) in guinea pigs. Doses of 15 mg/kg caused less hearing loss than 30 mg/kg, but the higher dose was associated with greater mortality owing to renal insufficiency. These findings are comparable with expectations of similar doses of cisplatin in humans. In contrast, gentamicin produced less hearing loss in mice, although the dose employed was well above the lethal dose for humans.


CONCLUSIONS
Ototoxic doses of cisplatin in guinea pigs are similar to those of humans, but C57 mice appear to be highly resistant to gentamicin-induced hearing loss compared to humans. Animal models of ototoxicity need to be considered carefully in translational research.
Blakley
Brian W
BW
Department of Otolaryngology, University of Manitoba, Winnipeg, Manitoba.
Hochman
Jordan
J
Wellman
Mark
M
Gooi
Adrian
A
Hussain
Abdulmohsen E
AE
D000818:Animals; D001309:Auditory Threshold / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology / Q000633:toxicity*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005839:Gentamicins / Q000494:pharmacology / Q000633:toxicity*; D006168:Guinea Pigs; D006198:Hair Cells, Auditory / Q000187:drug effects; D006319:Hearing Loss, Sensorineural / Q000139:chemically induced* / Q000401:mortality / Q000503:physiopathology; D006801:Humans; D007274:Injections, Intraperitoneal; D016014:Linear Models; D051379:Mice; D008810:Mice, Inbred C57BL; D011336:Probability; D011897:Random Allocation; D012016:Reference Values; D018570:Risk Assessment; D013045:Species Specificity; D015996:Survival Rate
D005839:Gentamicins; D002945:Cisplatin