A PBPK Model for Evaluating the Impact of Aldehyde Dehydrogenase Polymorphisms on Comparative Rat and Human Nasal Tissue Acetaldehyde Dosimetry

Abstract

Acetaldehyde is an important intermediate in the chemical synthesis and normal oxidative metabolism of several industrially important compounds, including ethanol, ethyl acetate, and vinyl acetate. Chronic inhalation of acetaldehyde leads to degeneration of the olfactory and respiratory epithelium in rats at concentrations > 50 ppm (90 day exposure) and respiratory and olfactory nasal tumors at concentrations ≥ 750 ppm, the lowest concentration tested in the 2-yr chronic bioassay. Differences in the anatomy and biochemistry of the rodent and human nose, including polymorphisms in human high-affinity acetaldehyde dehydrogenase (ALDH2), are important considerations for interspecies extrapolations in the risk assessment of acetaldehyde. A physiologically based pharmacokinetic model of rat and human nasal tissues was constructed for acetaldehyde to support a dosimetry-based risk assessment for acetaldehyde (Dorman et al., 2008). The rodent model was developed using published metabolic constants and calibrated using upper-respiratory-tract acetaldehyde extraction data. The human nasal model incorporates previously published tissue volumes, blood flows, and acetaldehyde metabolic constants. ALDH2 polymorphisms were represented in the human model as reduced rates of acetaldehyde metabolism. Steady-state dorsal olfactory epithelial tissue acetaldehyde concentrations in the rat were predicted to be 409, 6287, and 12,634 μM at noncytotoxic (50 ppm), and cytotoxic/tumorigenic exposure concentrations (750 and 1500 ppm), respectively. The human equivalent concentration (HEC) of the rat no-observed-adverse-effect level (NOAEL) of 50 ppm, based on steady-state acetaldehyde concentrations from continual exposures, was 67 ppm. Respiratory and olfactory epithelial tissue acetaldehyde and H+ (pH) concentrations were largely linear functions of exposure in both species. The impact of presumed ALDH2 polymorphisms on human olfactory tissue concentrations was negligible; the high-affinity, low-capacity ALDH2 does not contribute significantly to acetaldehyde metabolism in the nasal tissues. The human equivalent acetaldehyde concentration for homozygous low activity was 66 ppm, 1.5% lower than for the homozygous full activity phenotype. The rat and human acetaldehyde PBPK models developed here can also be used as a bridge between acetaldehyde dose-response and mode-of-action data as well as between similar databases for other acetaldehyde-producing nasal toxicants.