title: Subchronic inhalation of mixtures of cigarette smoke constituents in Xpa-/-p53+/- knock-out mice: a comparison of intermittent with semi-continuous exposure to acetaldehyde, formaldehyde, and acrolein.
abstract: We investigated whether inhaling peak concentrations of aldehydes several times daily is more damaging than semi-continuously inhaling low-dose aldehydes. We exposed Xpa-/-p53+/- knock-out mice either intermittently or semi-continuously to mixed acetaldehyde, formaldehyde, and acrolein. The intermittent regimen entailed exposure to the aldehydes 7 min every 45 min, 12 times/day, 5 days/week, corresponding to concentrations inhaled by smokers. Semi-continuously exposed animals received half the dose of aldehydes in 8h/day, 5 days/week. Some mice in each group were sacrificed after 13 weeks of exposure; the rest breathed clean air until the end of 1 year. Mice injected intratracheally with benzo[a]pyrene formed a positive control group. The nasal cavity, lungs, and any macroscopically abnormal organs of all mice were analysed histopathologically. After 13 weeks of exposure, the subacute, overall, histopathological changes induced by the inhalation differed noticeably between the intermittently and semi-continuously treated Xpa-/-p53+/- knock-out mice. After 13 weeks of mixed aldehyde exposure, atrophy of the olfactory epithelium generally appeared, but disappeared after 1 year (adaptation and/or recovery). Respiratory epithelial metaplasia of the olfactory epithelium occurred at a higher incidence at 1 year. Except for a significantly greater number of tumours observed in knock-out mice compared to wild mice (semi-continuous aldehyde exposure and controls), no differences between the semi-continuous and intermittent exposure groups were observed.
authors.affiliation: Centre for Environmental Health Research, National Institute for Public Health and the Environment, Bilthoven, The Netherlands. f.cassee@rivm.nl
authors.forename: F R
authors.initials: FR
authors.lastname: Cassee
authors.forename: C Y
authors.initials: CY
authors.lastname: de Burbure
authors.forename: B
authors.initials: B
authors.lastname: Rambali
authors.forename: W
authors.initials: W
authors.lastname: Vleeming
authors.forename: A
authors.initials: A
authors.lastname: van de Kuil
authors.forename: H
authors.initials: H
authors.lastname: van Steeg
authors.forename: P H B
authors.initials: PH
authors.lastname: Fokkens
authors.forename: J G C
authors.initials: JG
authors.lastname: van Amsterdam
authors.forename: J A M A
authors.initials: JA
authors.lastname: Dormans
authors.forename: A
authors.initials: A
authors.lastname: Opperhuizen
mesh_terms: D000079:Acetaldehyde / Q000008:administration & dosage / Q000032:analysis / Q000633:toxicity*; D000171:Acrolein / Q000008:administration & dosage / Q000032:analysis / Q000633:toxicity*; D000280:Administration, Inhalation; D000818:Animals; D001273:Atmosphere Exposure Chambers; D004202:Disinfectants / Q000008:administration & dosage / Q000032:analysis / Q000633:toxicity*; D005260:Female; D005557:Formaldehyde / Q000008:administration & dosage / Q000032:analysis / Q000633:toxicity*; D006801:Humans; D008168:Lung / Q000187:drug effects* / Q000473:pathology; D008297:Male; D008679:Metaplasia / Q000139:chemically induced; D051379:Mice; D018345:Mice, Knockout; D009831:Olfactory Mucosa / Q000187:drug effects* / Q000473:pathology; D012906:Smoke / Q000009:adverse effects* / Q000032:analysis; D013045:Species Specificity
chemical_list: D004202:Disinfectants; D012906:Smoke; D005557:Formaldehyde; D000171:Acrolein; D000079:Acetaldehyde