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 nasalcavity. 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 ≥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 ≥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.

Comparative Risks of Aldehyde Constituents in Cigarette Smoke Using Transient Computational Fluid Dynamics/Physiologically Based Pharmacokinetic Models of the Rat and Human Respiratory Tracts

“…Rat No-Observed-Adverse-Effect Levels (NOAELs) Inhalation Exposures Simulations were conducted at the NOAELs for nasal toxicity in rats following subchronic, 6 h/day, 5 days/week inhalation exposures for each aldehyde (0.2, 50, and 1 ppm for acrolein, acetaldehyde, and formaldehyde, respectively; Table 3) (Dorman et al, 2008a, b;Kerns et al, 1983;Monticello et al, 1996;Morgan, 1997;NAS, 2011). For acrolein and formaldehyde, steady-state, breath-by-breath tissue concentrations were reached in all respiratory compartments, except olfactory epithelium within the first 2-3 breaths.…”

“…Like acrolein, formaldehyde and acetaldehyde are highly water-soluble with varying degrees of reactivity, metabolic clearance, and tissue toxicity. Acetaldehyde and formaldehyde also produce toxicity and tumors within the respiratory tissues of chronically exposed laboratory animals (Appelman et al, 1982;Dorman et al, 2008a, b Kamata et al, 1997Morgan and Monticello, 1990;Morgan et al, 1986;Woutersen and Feron, 1987;Woutersen et al, 1984Woutersen et al, , 1986. Human exposure to all 3 aldehydes is normally associated with cigarette smoking since all are reactive byproducts of burning tobacco (Counts et al, 2005).…”

Use of Nasal Pathology in the Derivation of Inhalation Toxicity Values for Hydrogen Sulfide

“…Noncancer inhalation RfCs for other chemicals have also been based on nasal effects including damage to the olfactory epithelium (Table 2). As was the case with H 2 S, dosimetry-based alternative approaches to deriving chronic inhalation RfCs have been developed for some of these chemicals including acetaldehyde 31 and acrolein. 32 In addition, derivation of occupational toxicity values increasingly rely on the use of CFD and other computational models to predict chemical delivery to the human nose, 33 and CFD models of the complete respiratory tract have been developed 34 to support other risk assessment methods.…”

No acute effects of an exposure to 50 ppm acetaldehyde on the upper airways

“…Acetaldehyde is metabolised to acetic acid, which is the critical factor of its olfactory toxicity (Morris 1997). EVects of acetaldehyde on olfactory as well as on respiratory nasal epithelium are dose-dependent (Dorman et al 2008). Olfactory testing was used to measure possible short-term eVects of acetaldehyde.…”