Metaplastic changes of nasal respiratory epithelium in rats exposed to hexamethylphosphoramide (HMPA) by inhalation.

Rats exposed by inhalation to hexamethylphosphoramide (HMPA) at concentrations of 50, 100, 400, and 4000 parts per billion (ppb) for 6-24 months revealed nasal tumors and squamous metaplasia with inflammation in the nasal epithelium, but no changes were observed at 10 ppb. The ciliated cells were most susceptible to HMPA, showing degenerative changes, with abnormal cilia and extensive deciliation. The desquamated nasal epithelium was repaired initially by undifferentiated mucus or microvillous cuboidal cells, and subsequently the lining cells were replaced with squamous cells migrating upward from the basal layer. In the early stage of squamous metaplasia, thickened nasal epithelium revealed indifferent cells, undifferentiated glandular cells, transitional cells from glandular to squamous cells, poorly differentiated squamous cells, and intermediate cells showing features of glandula and squamous differentiation. Subsequently, the undifferentiated glandular cells were replaced mainly with the squamous or intermediate cells. the undifferentiated glandular cells appeared to be biphasic reserve cells capable of differentiating to glandular or squamous cells. The intermediate cells appeared to be derived from the undifferentiated glandular cells and converted into keratinizing squamous cells. Numerous secretory vesicles and mucus droplets were observed in the squamous cells adjacent to the keratinized area and keratin plates.