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 responses of nasal tissues in vitro, using loss of intracellular ATP and potassium as indices of toxicity, with the pathological changes occurring following in vivo exposure to four test compounds. Turbinates were incubated in vitro with the test compounds for 4 h, for 24 h or for 4 h followed by 20 h in 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-methylindole markedly decreased ATP in both tissues. Intracellular potassium concentrations were generally affected to a lesser degree. In vivo, no morphological changes were observed in the nasal cavity following inhalation exposure to either titanium dioxide or sodium carbonate. Inhalation of acetic acid resulted in a very focal lesion in the RE of the dorsal meatus of level 1, while administration of 3-methylindole by intraperitoneal injection caused severe degeneration of OE. In further experiments olfactory turbinates were exposed to a range of concentrations (0-100 mM) of sodium carbonate, acetic acid and 3-methylindole for 4 h and ATP concentrations determined. Concentration-dependent decreases in ATP were observed for sodium carbonate and 3-methylindole, with EC(50) values estimated as 2.57 and 0.91 mM, respectively. Acetic acid only decreased ATP significantly at the 100-mM concentration. In summary, this in vitro model has predicted the nasal toxicity of several compounds, including both direct-acting agents (sodium carbonate, acetic acid) and one requiring metabolic activation (3-methylindole). However, the lack of airflow-dependent dosimetry, results in some lack of discrimination between the different regions of the nasal cavity and may make this model overly sensitive.
Kilgour
J D
JD
School of Biomolecular Sciences, Liverpool John Moores University, Byrom Street, Liverpool, UK.
Simpson
S A
SA
Alexander
D J
DJ
Reed
C J
CJ
D019342:Acetic Acid / Q000633:toxicity; D000255:Adenosine Triphosphate / Q000032:analysis; D000818:Animals; D002254:Carbonates / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D008297:Male; D009297:Nasal Mucosa / Q000737:chemistry / Q000187:drug effects* / Q000473:pathology; D011188:Potassium / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D012862:Skatole / Q000633:toxicity; D014025:Titanium / Q000633:toxicity
D002254:Carbonates; C009495:titanium dioxide; C005686:sodium carbonate; D000255:Adenosine Triphosphate; D012862:Skatole; D014025:Titanium; D019342:Acetic Acid; D011188:Potassium