Olfactory toxicity of beta,beta'-iminodipropionitrile in the rat.

Abstract

Following a pilot study which revealed olfactory epithelial degeneration induced by beta,beta'-iminodipropionitrile (IDPN), dose-response and time-course analyses were undertaken to further characterize the effects of IDPN on the olfactory system. Male rats were sacrificed at multiple time points ranging from 24 hr after a single dose to 56 days after three consecutive daily doses of IDPN (0-400 mg/kg i.p.). Nasal cavities were fixed, decalcified and embedded in paraffin; 5 microns sections were stained with hematoxylin and eosin, middle neurofilament protein antibody or olfactory marker protein antiserum. Olfactory bulbs were removed for slot blot analyses of glial fibrillary acidic protein, synapsin I and p38. Another group of rats was treated with saline or IDPN and perfused 6 hr or 1, 2, 3, 7, 14 or 28 days after the last dose. Olfactory bulb axonal degeneration was visualized using a modified Gallyas technique. Twenty-four hours after treatment with 200 or 400 mg/kg IDPN, there was severe, highly site-specific mucosal degeneration in the dorsal-medial nasal cavity; regeneration was incomplete 8 weeks later. IDPN increased olfactory bulb glial fibrillary acidic protein, peaking 7 days after three daily 400 mg/kg doses, and remaining significantly elevated 8 weeks after treatment. Olfactory bulbs contained substantial silver deposition in afferent axon bundles in the glomerular layer, beginning 24 hr after the first dose and persisting for 14 days after dosing. Although only a portion of the olfactory epithelium was damaged by IDPN, all axon bundles entering the olfactory bulb were involved, suggesting the lack of a clear topographic arrangement of sensory endings in the olfactory bulb.