EVALUATION OF NASAL TRACT LESIONS IN DERIVATION OF THE INHALATION REFERENCE CONCENTRATION FOR HEXAMETHYLENE DIISOCYANATE

Derivation of the inhalation reference concentration (RfC) for HDI, a highly reactive and irritant gas, required consideration of several sc ientific issues, including toxicological judgment on severity versus i ncidence of lesions, and occurrence and toxicological significance of adaptive nasal lesions. Analysis of data from a chronic study with hex amethylene diisocyanate (HDI) revealed that the lesion incidence withi n the nasal cavity was not a clear indicator of toxicologic significan ce. Although chronic inflammation exhibited a clear concentration-resp onse relationship for incidence, the corresponding severity scores for this lesion were virtually unchanged. Degeneration of the olfactory e pithelium did follow a concentration-response relationship for both in cidence and severity. Such results indicate that information on both i ncidence and severity may be necessary to make valid toxicological jud gments. A considerable portion of nasal cavity histopathology in the a nimals exposed to HDI may be considered adaptive. Exposure of nasal ti ssues 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 manif estations of these events (mucus hyperplasia, squamous metaplasia, and keratinization of respiratory epithelium) were all observed in this s tudy. The boundary between an adaptive and toxic response is not alway s clearly delineated, and, in this case, many of these alterations may be considered to be adaptive rather than a functional impairment. Thu s, 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 mu g/m(3) based on a chronic inhalation study in rats with a critical effect of olfactory epitheli al degeneration.