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ToxSci Advance Access originally published online on March 6, 2007
Toxicological Sciences 2007 97(2):336-347; 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

Lynn H. Pottenger*,1, Linda A. Malley{dagger}, Matthew S. Bogdanffy{dagger}, E. Maria Donner{dagger}, Patricia B. Upton{ddagger}, Yutai Li{ddagger}, Vernon E. Walker§, Jack R. Harkema, Marcy I. Banton|| and James A. Swenberg{ddagger}

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

1 To whom correspondence should be addressed at Toxicology and Environmental Research and Consulting, The Dow Chemical Company, 1803 Building, Washington Street, Midland, MI 48674. Fax: (989) 638-9863. E-mail: lpottenger{at}dow.com.

Received December 3, 2006; 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 h/day, 5 days/week). The endpoints examined included gene (Hprt, splenocytes) and chromosomal (bone marrow micronucleus [MN]) mutations, hemoglobin (hydroxypropylvaline, HPVal) adducts in systemic blood, and DNA adducts (N7-HPGua) in several tissues. Similarly exposed female and male F344 rats, implanted with bromodeoxyuridine (BrdU) minipumps, were evaluated for nasal effects (irritation via histopathology and 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 1 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 increase in Hprt mutant frequency or in bone marrow MN 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 or 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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