title: Evaluation of effects from repeated inhalation exposure of F344 rats to high concentrations of propylene.
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 (< or = 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.
authors.affiliation: Toxicology and Environmental Research and Consulting, The Dow Chemical Company, Midland, MI 48674, USA. lpottenger@dow.com
authors.forename: Lynn H
authors.initials: LH
authors.lastname: Pottenger
authors.forename: Linda A
authors.initials: LA
authors.lastname: Malley
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Bogdanffy
authors.forename: E Maria
authors.initials: EM
authors.lastname: Donner
authors.forename: Patricia B
authors.initials: PB
authors.lastname: Upton
authors.forename: Yutai
authors.initials: Y
authors.lastname: Li
authors.forename: Vernon E
authors.initials: VE
authors.lastname: Walker
authors.forename: Jack R
authors.initials: JR
authors.lastname: Harkema
authors.forename: Marcy I
authors.initials: MI
authors.lastname: Banton
authors.forename: James A
authors.initials: JA
authors.lastname: Swenberg
mesh_terms: D000475:Alkenes / Q000008:administration & dosage / Q000633:toxicity*; D000818:Animals; D000963:Antimetabolites; D001973:Bromodeoxyuridine; D049109:Cell Proliferation / Q000187:drug effects; D004247:DNA / Q000235:genetics / Q000302:isolation & purification; D018736:DNA Adducts / Q000187:drug effects; D023381:Endpoint Determination; D004912:Erythrocytes / Q000187:drug effects / Q000378:metabolism; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry; D005914:Globins / Q000302:isolation & purification / Q000378:metabolism; D006454:Hemoglobins / Q000187:drug effects / Q000378:metabolism; D006868:Hydrolysis; D007041:Hypoxanthine Phosphoribosyltransferase / Q000378:metabolism; D019570:Inhalation Exposure; D008297:Male; D015162:Micronucleus Tests; D009153:Mutagens; D009297:Nasal Mucosa / Q000473:pathology; D051381:Rats; D011916:Rats, Inbred F344; D021241:Spectrometry, Mass, Electrospray Ionization
chemical_list: D000475:Alkenes; D000963:Antimetabolites; D018736:DNA Adducts; D006454:Hemoglobins; D009153:Mutagens; D005914:Globins; D004247:DNA; C013658:propylene; D007041:Hypoxanthine Phosphoribosyltransferase; D001973:Bromodeoxyuridine