Carcinogenesis Advance Access published online on May 22, 2003
Carcinogenesis, doi:10.1093/carcin/bgg087
© 2003 by Oxford University Press
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CARCINOGENESIS
1 Curriculum in Toxicology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599
* Corresponding author. E-mail: james_swenberg{at}unc.edu.
Received 13 November 2002
; revised 26 March 2003
; accepted 4 May 2003
Propylene oxide [PO] is a high-volume chemical intermediate that causes a low incidence of nasal tumors in rodents exposed to high concentrations (
Molecular dosimetry of N7-(2-hydroxypropyl)guanine in tissues of F344 rats after inhalation exposure to propylene oxide
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
300 p.p.m.). PO reacts with DNA forming mainly N7-(2-hydroxypropyl)guanine [7-HPG]. The exposure-dependent accumulation of 7-HPG in nasal respiratory epithelium [NRE], lung and liver was determined in male F344 rats exposed to PO (0, 5, 25, 50, 300 or 500 p.p.m.) by the inhalation route for 3 or 20 days (6 hr/day; 5 days/week). These exposures ranged from low concentrations, such as those potentially occurring in the workplace, to high concentrations that proved to be carcinogenic in rodents. Analysis of 7-HPG in DNA by gas chromatography-high resolution mass spectrometry [GC-HRMS] showed a linear response in 7-HPG for all three tissues after 3 days of exposure, and for NRE and lung after 20 days of exposure. A slightly sublinear response in 7-HPG was observed in liver after 20 days of exposure. For both exposure periods, the NRE had the highest concentration of 7-HPG, followed by lung and liver. The amount of 7-HPG in NRE was 7-times and 17-times higher than in lung and liver, respectively, for the 3-day exposures. For the 20-day exposures, the concentration of 7-HPG in NRE was 6-times and 13-times higher than that in lung and liver, respectively, over the concentration range studied. These results demonstrate a much higher extent of DNA alkylation in the target tissue for carcinogenesis, than in non-target tissues. Since PO-induced tumor formation was highly sublinear, occurring only at high vapor concentrations, whereas 7-HPG adducts were shown to be linearly dependent on airborne concentration, these results suggest that 7-HPG is not sufficient for PO nasal carcinogenesis and that other factors such as increased cell proliferation may be important in determining the tumor exposure response.
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