title: Derivation of an inhalation reference concentration based upon olfactory neuronal loss in male rats following subchronic acetaldehyde inhalation.
abstract: Acetaldehyde inhalation induces neoplastic and nonneoplastic responses in the rodent nasal cavity. This experiment further characterizes the dose-response relationship for nasal pathology, nasal epithelial cell proliferation, and DNA-protein cross-link formation in F-344 rats exposed subchronically to acetaldehyde. Animals underwent whole-body exposure to 0, 50, 150, 500, or 1500 ppm acetaldehyde for 6 h/day, 5 days/wk for up to 65 exposure days. Respiratory tract histopathology was evaluated after 4, 9, 14, 30, and 65 exposure days. Acetaldehyde exposure was not associated with reduced body weight gain or other evidence of systemic toxicity. Histologic evaluation of the nasal cavity showed an increased incidence of olfactory neuronal loss (ONL) following acute to subchronic exposure to > or = 150 ppm acetaldehyde and increased olfactory epithelial cell proliferation following exposure to 1500 ppm acetaldehyde. The severity of the ONL demonstrated dose- and temporal-dependent behaviors, with minimal effects noted at 150-500 ppm acetaldehyde and moderately severe lesions seen in the highest exposure group, with increased lesion severity and extent as the exposure duration increased. Acetaldehyde exposure was also associated with inflammation, hyperplasia, and squamous metaplasia of the respiratory epithelium. These responses were seen in animals exposed to > or = 500 ppm acetaldehyde. Acetaldehyde exposure was not associated with increased DNA-protein cross-link formation in the respiratory or olfactory epithelium. A model of acetaldehyde pharmacokinetics in the nose was used to derive an inhalation reference concentration (RfC) of 0.4 ppm, based on the no-observed-adverse-effect level (NOAEL) of 50 ppm for the nasal pathology seen in this study.
authors.affiliation: CIIT at The Hamner Institutes for Health Sciences, Research Triangle Park, North Carolina, USA. david dorman@ncsu.edu
authors.forename: David C
authors.initials: DC
authors.lastname: Dorman
authors.forename: Melanie F
authors.initials: MF
authors.lastname: Struve
authors.forename: Brian A
authors.initials: BA
authors.lastname: Wong
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Gross
authors.forename: Carl
authors.initials: C
authors.lastname: Parkinson
authors.forename: Gabrielle A
authors.initials: GA
authors.lastname: Willson
authors.forename: Yu-Mei
authors.initials: YM
authors.lastname: Tan
authors.forename: Jerry L
authors.initials: JL
authors.lastname: Campbell
authors.forename: Justin G
authors.initials: JG
authors.lastname: Teeguarden
authors.forename: Harvey J
authors.initials: HJ
authors.lastname: Clewell
authors.forename: Melvin E
authors.initials: ME
authors.lastname: Andersen
mesh_terms: D000079:Acetaldehyde / Q000633:toxicity*; D000393:Air Pollutants / Q000633:toxicity*; D000818:Animals; D019985:Benchmarking; D049109:Cell Proliferation / Q000187:drug effects; D003432:Cross-Linking Reagents / Q000633:toxicity; D004247:DNA / Q000737:chemistry / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D019570:Inhalation Exposure; D008297:Male; D008679:Metaplasia / Q000139:chemically induced / Q000473:pathology; D009296:Nasal Cavity / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009475:Neurons, Afferent / Q000187:drug effects* / Q000473:pathology; D019055:No-Observed-Adverse-Effect Level; D009831:Olfactory Mucosa / Q000187:drug effects / Q000473:pathology; D009833:Olfactory Pathways / Q000187:drug effects* / Q000473:pathology; D011485:Protein Binding / Q000187:drug effects; D011506:Proteins / Q000737:chemistry / Q000187:drug effects; D051381:Rats; D011916:Rats, Inbred F344; D012220:Rhinitis / Q000139:chemically induced / Q000473:pathology
chemical_list: D000393:Air Pollutants; D003432:Cross-Linking Reagents; D011506:Proteins; D004247:DNA; D000079:Acetaldehyde