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ToxSci Advance Access published online on March 6, 2007
Toxicological Sciences, doi:10.1093/toxsci/kfm038
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© The Author 2007. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Evaluation of Effects from Repeated Inhalation Exposure of F344 Rats to High Concentrations of Propylene

LH Pottenger*,a, LA Malley{dagger}, MS Bogdanffy{dagger}, EM Donner{dagger}, PB Upton{ddagger}, Y Li{ddagger}, VE Walker§, JR Harkema, MI Banton|| and JA Swenberg{ddagger}

* Toxicology & Environmental Research and Consulting, The Dow Chemical Company, Midland, MI, 48674 {dagger} Haskell Laboratory for Health and Environmental Sciences, E.I. du Pont de Nemours and Company, Newark, DE, 19714 {ddagger} Department of Environmental Sciences and Engineering, School of Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599 § Lovelace Respiratory Research Institute, Albuquerque, NM, 87108 Food Safety and Toxicology, Michigan State University, East Lansing, MI, 48824 || Lyondell Chemical Company, Houston, TX, 77010

a Corresponding author: Lynn H. Pottenger, PhD, DABT, TERC, 1803 Bldg Washington St., Midland, MI 48674, T: 989-638-7036, F: 989-638-9863. lpottenger{at}dow.com

Received December 3, 2006; revision received February 14, 2007; accepted February 16, 2007


  Abstract

Chronic exposure to propylene does not result in any increased incidence of tumors, yet does increase N7-hydroxypropylguanine (N7-HPGua) adducts in tissue DNA. To investigate any potential for genotoxicity (mutagenicity or clastogenicity), male F344 rats were exposed via inhalation to up to 10,000 ppm propylene for 1, 3, or 20 days (6 hr/day; 5 days/week). The endpoints examined included gene (Hprt; splenocytes) and chromosomal (bone marrow micronucleus) mutations, and hemoglobin (hydroxypropylvaline; HPVal) adducts in systemic blood, and DNA adducts (N7-HPGua) in several tissues. Similarly exposed female and male F344 rats, implanted with BrdU minipumps, were evaluated for nasal effects (irritation via histopathology; cell proliferation via BrdU). Internal dose measures provided clear evidence for propylene exposure, with HPVal increased for all exposures; N7-HPGua was increased in all tissues from rats exposed for more than one day (except lymphocytes). Saturation of propylene conversion to propylene oxide was apparent from the adduct dose-response curves. There were no biologically significant genotoxic effects demonstrated at any exposure level, with no increases in Hprt mutant frequency, nor in bone marrow micronucleus formation. In addition, no histopathological changes were noted in rodent nasal tissues, nor any induction of cell proliferation in nasal tissues. These results demonstrate that repeated exposure of rats to high concentrations of propylene (≤10,000 ppm) does not produce evidence of local nasal cavity toxicity, nor evidence of systemic genotoxicity to hematopoietic tissue, despite the formation of N7-HPGua adducts. In addition, these data indicate that formation of N7-HPGua does not correlate with any measure of genotoxic effect, neither mutagenic nor clastogenic.

Key Words: Propylene; rat; in vivo mutation; biomarkers; DNA adducts.


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