Evaluation of Nasal Tract Lesions in Derivation of The Inhalation Reference Concentration for Hexamethylene Diisocyanate

Abstract

Derivation of the inhalation reference concentration (RfC) for HDI, a highly reactive and irritant gas, required consideration of several scientific issues, including toxicological judgment on severity versus incidence of lesions, and occurrence and toxicological significance of adaptive nasal lesions. Analysis of data from a chronic study with hexamethylene diisocyanate (HDI) revealed that the lesion incidence within the nasal cavity was not a clear indicator of toxicologic significance. Although chronic inflammation exhibited a clear concentration-response relationship for incidence, the corresponding severity scores for this lesion were virtually unchanged. Degeneration of the olfactory epithelium did follow a concentration-response relationship for both incidence and severity. Such results indicate that information on both incidence and severity may be necessary to make valid toxicological judgments. A considerable portion of nasal cavity histopathology in the animals exposed to HDI may be considered adaptive. Exposure of nasal tissues to an irritant, such as HDI, may lead to increased production of mucus, morphologic changes in or replacement of sensitive cells, and barriers at the irritant/tissue interface. The histopathological manifestations of these events (mucus hyperplasia, squamous metaplasia, and keratinization of respiratory epithelium) were all observed in this study. The boundary between an adaptive and toxic response is not always clearly delineated, and, in this case, many of these alterations may be considered to be adaptive rather than a functional impairment. Thus, many of these alterations are not clearly adverse toxic responses. On the other hand, degeneration of the olfactory epithelium is clearly adverse. The RfC derived for HDI is 0.01 μg/m³ based on a chronic inhalation study in rats with a critical effect of olfactory epithelial degeneration.