title: The ototoxicity of trichloroethylene: extrapolation and relevance of high-concentration, short-duration animal exposure data.
abstract: Inhalation exposure to high concentrations of 1,1, 2-trichloroethylene (TCE) has been shown to damage hearing in the mid-frequency range in the rat. The present study directly evaluated the adequacy of high-concentration, short-term exposures to TCE for predicting the neurotoxicity produced by longer duration exposures. Adult male Long-Evans rats (n = 10-12 per group) were exposed to TCE via inhalation (whole body) in 1-m3 stainless steel flow-through chambers for 6 hr/day, 5 days/week. The following exposures were used: 1 day (4000-8000 ppm), 1 week (1000-4000 ppm), 4 weeks (800-3200 ppm), and 13 weeks (800-3200 ppm). Air-only exposed animals served as controls. Auditory thresholds were determined for a 16-kHz tone 3-5 weeks after exposure using reflex modification audiometry. Results replicated previous findings of a hearing loss at 16 kHz for all exposure durations. The dB15 concentrations (concentration that increases thresholds by 15 dB) for 16-kHz thresholds were 6218, 2992, 2592, and 2160 ppm for the 1-day, 1-week, 4-week and 13-week exposures, respectively. These data demonstrate that the ototoxicity of TCE was less than that predicted by a strict concentration x time relationship. These data also demonstrate that simple models of extrapolation (i.e., C x t = k, Haber's Law) overestimate the potency of TCE when extrapolating from short-duration to longer-duration exposures. Furthermore, these data suggest that, relative to ambient or occupational exposures, the ototoxicity of TCE in the rat is a high-concentration effect.
authors.affiliation: National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina, 27711, USA. crofton.kevin@epamail.epa.gov
authors.forename: K M
authors.initials: KM
authors.lastname: Crofton
authors.forename: X
authors.initials: X
authors.lastname: Zhao
mesh_terms: D000280:Administration, Inhalation; D000704:Analysis of Variance; D000818:Animals; D001299:Audiometry; D001309:Auditory Threshold / Q000187:drug effects*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006319:Hearing Loss, Sensorineural / Q000139:chemically induced*; D008297:Male; D019055:No-Observed-Adverse-Effect Level; D016273:Occupational Exposure; D051381:Rats; D012997:Solvents / Q000008:administration & dosage / Q000633:toxicity*; D013055:Spectrophotometry, Infrared; D014241:Trichloroethylene / Q000008:administration & dosage / Q000633:toxicity*
chemical_list: D012997:Solvents; D014241:Trichloroethylene