Degeneration and regeneration of the olfactory epithelium following inhalation exposure to methyl bromide: pathology, cell kinetics, and olfactory function.
The effects of acute inhalation exposure to methyl bromide (MeBr) on the olfactory epithelium of male F-344 rats was investigated by morphologic examination of animals killed at varying timepoints during and following exposure to 200 ppm MeBr 6 hr/day for 5 days. Cell replication rate and histopathology were used to assess the kinetics of repair. In addition, olfactory function, using the buried food pellet test, was assessed and the result compared with morphological recovery. Extensive destruction of the olfactory epithelium was evident in animals killed directly after a single 6-hr exposure to MeBr. Histologic features of these lesions indicate that the primary, or most severe, effect of MeBr exposure was on the sustentacular cells and mature sensory cells; basal cells were generally unaffected. By Day 3, despite continued exposure, there was replacement of the olfactory epithelium by a squamous cell layer that increased in thickness and basophilic cytoplasmic staining over the next 2 days of exposure. One week postexposure, the epithelial region was covered by a layer of polyhedral, basophilic cells, and from 2 to 10 weeks postexposure, the epithelium exhibited progressive reorganization to reform the original olfactory epithelium pattern. By Week 10, 75-80% of the olfactory epithelium appeared morphologically normal. Cell replication showed a single peak of olfactory epithelial cell proliferation at Day 3 of exposure, with a labeling index of 14.5% compared to 0.7% in controls. Cell replication rates returned gradually to control levels by Week 10 postexposure. Behavioral tests of olfactory function in animals after a single 6-hr exposure to 200 ppm MeBr demonstrated a loss of the sense of smell, with recovery of this function by Day 6. Exposure to 90 ppm caused no observable effect on olfactory function or morphology. These findings demonstrate that the olfactory mucosa is highly sensitive to the toxic effects of MeBr and that olfactory epithelial cell proliferation, and possible regeneration, begins and occurs rapidly even in the face of continued exposure. Cell replication was most prominent in the layer of basal cells adjacent to the basal lamina, supporting proposals by other workers that the progenitors of both sustentacular cells and neurons reside in this location. Of interest is the fact that functional recovery occurs prior to complete morphological reorganization, indicating the shortcoming of utilizing olfactory morphology as an index of functional integrity.
Hurtt
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Department of Genetic Toxicology, Chemical Industry Institute of Toxicology, Research Triangle Park, North Carolina 27709.
Thomas
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DA
Working
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Monticello
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TM
Morgan
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KT
D000280:Administration, Inhalation; D000818:Animals; D001345:Autoradiography; D002455:Cell Division / Q000187:drug effects; D002490:Central Nervous System / Q000187:drug effects*; D004848:Epithelium / Q000187:drug effects; D005005:Ethmoid Sinus; D006842:Hydrocarbons, Brominated / Q000008:administration & dosage / Q000633:toxicity*; D008297:Male; D009297:Nasal Mucosa / Q000187:drug effects* / Q000294:innervation / Q000473:pathology; D009300:Nasal Septum; D009833:Olfactory Pathways / Q000187:drug effects* / Q000473:pathology; D051381:Rats; D011916:Rats, Inbred F344; D012903:Smell / Q000187:drug effects* / Q000502:physiology; D013194:Staining and Labeling
D006842:Hydrocarbons, Brominated; C005218:methyl bromide