Olfactory Mucosal Toxicity. Integration of Morphological and Biochemical Data in Mechanistic Studies: Dibasic Esters as an Example

Abstract

The olfactory mucosa of the common laboratory rat is a complicated organ comprised of a variety of cell types. Each cell type has specific biochemical and physiologic functions critical to the normal function of the tissue as the organ of olfaction. Damage to the olfactory epithelium leading to a dysfunctional state can result in anosmia, and since olfaction is an important defense mechanism against noxious chemicals, loss of olfaction could compromise the ability to avoid chemical exposure. The olfactory mucosa is organized into epithelial and lamina propria components, each separated by a continuous basement membrane. The epithelium is comprised of sensory cells, sustentacular cells, ducts of Bowman’s glands, and basal cells, while the lamina propria contains acini of Bowman’s glands, connective tissue, capillary endothelium, and nerve bundles. Histochemical techniques can be used to identify specific cell types within the mucosa, and these are often useful as early markers of cellular differentiation following atrophy and regenerative hyperplastic responses to chemical insult. Localization of biotransformation enzymes using histochemical techniques is a valuable contribution to mechanistic studies of olfactory toxicity. A variety of histochemical markers are reviewed. A range of nonneoplastic lesions of the olfactory epithelium is also reviewed, with emphasis on the importance of histopathology to the elucidation of mechanisms of olfactory toxicity, Finally, the mechanism of action of dibasic esters solvents is reviewed as an example of the role of histochemical and biochemical studies in olfactory toxicity research. Research on dibasic esters reveals a common mechanism of action for organic esters on olfactory epithelium. Organic esters absorbed by the olfactory mucosa are hydrolyzed via carboxylesterases in sustentacular cells and Bowman’s glands to their corresponding acids, which are the ultimate toxicant. Organic acids ultimately induce toxicity through a mechanism that probably includes a decrease in intracellular pH. Studies with human nasal tissue demonstrate that carboxylesterase-mediated hydrolysis of dibasic esters is less pronounced than in rat tissue. Thus, humans are at greatly reduced risk of dibasic ester toxicity of the olfactory epithelium.