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ToxSci Advance Access published online on July 11, 2003
Toxicological Sciences, doi:10.1093/toxsci/kfg187
Toxicological Sciences © Society of Toxicology 2003; all rights reserved
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Received April 9, 2003; accepted June 25, 2003
© 2003 Society of Toxicology

Carcinogenicity

Effects of Propylene Oxide Exposure on Rat Nasal Respiratory Cell Proliferation

Melva N. Ríos-Blanco 1, Shuji Yamaguchi 2, Mukta Dhawan-Robl 3, Winfried Kessler 3, Robert Schoonhoven 2, Johannes G. Filser 3, and James A. Swenberg 4*

1 Curriculum in Toxicology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599
2 Department of Environmental Sciences and Engineering, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599
3 Institute of Toxicology, GSF National Research Center for Environment and Health, D-85764 Neuherberg, Germany
4 Curriculum in Toxicology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599; Department of Environmental Sciences and Engineering, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599

* To whom correspondence should be addressed. E-mail: james_swenberg{at}unc.edu.


  Abstract

Long-term exposure of rodents to propylene oxide (PO) induced inflammation, respiratory cell hyperplasia and nasal tumors at concentrations >= 300 ppm, suggesting a possible role for cytotoxicity and compensatory cell proliferation in PO carcinogenesis. In this study, the effects of PO exposure on histopathology and cell proliferation in nasal and hepatic tissues were studied in male F344 rats exposed by inhalation for 3 or 20 days (0, 5, 25, 50, 300 and 500 ppm). Histopathology revealed an increase in mucous cell hyperplasia in the anterior nasal passages after 20 days of exposure (>= 300 ppm). This was associated with the formation of goblet cell nests. Cell proliferation was measured in the respiratory epithelium (NRE) (mucociliary and transitional) lining the anterior nasal passages, the nasopharyngeal meatus (NPM) and the liver using BrdU administered with 3-day osmotic pumps. Significant increases in cell proliferation occurred (> 3.6 fold) in the mucociliary epithelium lining the anterior nasal cavity at and above 300 ppm for both exposure periods. In the mucocilliary epithelium, the 20-day labeling was commonly associated with nests of goblet cells. Significant increases in cell proliferation (>2.3 fold) were observed in the transitional epithelium at 500 ppm after 3 days of exposure and at 300 and 500 ppm after 20 days of exposure. Significant increases in cell proliferation in the NPM (> 2.8 fold) were evident at 500 ppm PO after 3 days and at 300 and 500 ppm PO after 20 days of exposure. No exposure-related changes in cell proliferation were observed in the liver. These studies demonstrate a clear concordance between the site and exposure concentration for tumor induction and those causing significant increases in cell proliferation in the rat nose.

Key Words: propylene oxide, nose, rat, cytotoxicity, cell proliferation, inhalation .


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