Histopathology and Cell Replication Responses in the Respiratory Tract of Rats and Mice Exposed by Inhalation to Glutaraldehyde for up to 13 Weeks

In addition to being a respiratory tract irritant and cross-linkingagent, glutaraldehyde has a number of properties in common withthe rodent nasal carcinogen, formaldehyde. The acute and subchronicresponses to glutaraldehyde in the respiratory tract of ratsand mice were characterized using histopathology and epithelialcell labeling index as end points. Male and female F344 ratsand B6C3F1 mice were whole-body exposed for 1 day, 4 days, 6weeks, or 13 weeks to 0, 62.5, 125, 250, 500, or 1000 ppb glutaraldehydeusing a recycling inhalation chamber. The respiratory tract,with special reference to the nose, was examined by light microscopyand histoautoradiography. Unit length labeling index (ULLI)was determined by nuclear thymidine labeling for selected sites,chosen on the basis of histopathology. A small number of animalsexposed to 1000 ppb (rats and mice) or 500 ppb (mice) died beforethe 6-week time point; these deaths were attributed to glutaraldehydeexposure-associated occlusion of the external nares. Treatment-inducedlesions, including epithelial erosions, inflammation, and squamousmetaplasia, were confined to the anterior third of the noseand were present in both sexes and species. No histopathologicalevidence of glutaraldehyde-induced responses was observed inthe trachea, central airways, or lungs, while the larynx showedminimal changes. There were clear increases in ULLI in associationwith acute and subacute cytotoxic responses, with similar concentration-responserelationships. Neutrophilic infiltration of the squamous epitheliumof the nasal vestibule, present in both rats and mice, becameprogressively more severe with increasing exposure time andwas associated with increased ULLI. The latter responses weregenerally most severe at the higher glutaraldehyde exposureconcentrations, while in female mice they were present at allconcentrations of glutaraldehyde studied. Lesions induced byglutaraldehyde were more anterior in the nose than those reportedfor formaldehyde, they differed in character, and no evidenceof "pre-neoplastic" lesions or karyomegaly, reported for formaldehyde,was observed with glutaraldehyde.