A rat nasal epithelial model for predicting upper respiratory tract toxicity: in vivo-in vitro correlations

An in vitro model of the rat nasal cavity has been used to compare the resp onses of nasal tissues in vitro, using loss of intracellular ATP and potass ium as indices of toxicity, with the pathological changes occurring followi ng in vivo exposure to four test compounds. Turbinates were incubated in vi tro with the test compounds for 4 h, for 24 h or for 4 h followed by 20 h i n fresh medium. Titanium dioxide caused little or no loss of ATP in either olfactory epithelium (OE) or respiratory epithelium (RE). Sodium carbonate decreased olfactory, but not respiratory ATP, while acetic acid and 3-methy lindole markedly decreased ATP in both tissues. Intracellular potassium con centrations were generally affected to a lesser degree. In vivo, no morphol ogical changes were observed in the nasal cavity following inhalation expos ure to either titanium dioxide or sodium carbonate. Inhalation of acetic ac id resulted in a very focal lesion in the RE of the dorsal meatus of level 1; while administration of 3-methylindole by intraperitoneal injection caus ed severe degeneration of OE. In further experiments olfactory turbinates w ere exposed to a range of concentrations (0-100 mM) of sodium carbonate, ac etic acid and 3-methylindole for 4 h and ATP concentrations determined. Con centration-dependent decreases in ATP were observed for sodium carbonate an d 3-methylindole, with EC50 values estimated as 2.57 and 0.91 mM, respectiv ely. Acetic acid only decreased ATP significantly at the 100-mM concentrati on. In summary, this in vitro model has predicted the nasal toxicity of sev eral compounds, including both direct-acting agents (sodium carbonate, acet ic acid) and one requiring metabolic activation (3-methylindole). However, the lack of airflow-dependent dosimetry, results in some lack of discrimina tion between the different regions of the nasal cavity and may make this mo del overly sensitive. (C) 2000 Published by Elsevier Science Ireland Ltd. A ll rights reserved.