The use of nasal dosimetry models in the risk assessment of inhaled gases.

Nasal dosimetry models, including physiologically based pharmacokinetic (PBPK) models, computational fluid dynamics (CFD) models, and hybrid CFD-PBPK models, have played a prominent role in inhalation toxicology and the risk assessment of inhaled gases. Although different in their approach, their goals are similar: to accurately describe tissue dosimetry of inhaled gases in an anatomically accurate representation of the complex nasal geometry. These models have been useful in elucidating dose-response behavior and enabling interspecies extrapolation of regional dose that may differ between laboratory animals and humans. This issue of Toxicological Sciences includes an insightful paper by Morris and Hubbs (2009) on the use of a hybrid CFD-PBPK model to describe inhalation dosimetry of two components of butter flavoring vapors: diacetyl and butyric acid. These investigators used in vitro studies of diacetyl metabolism, nasal uptake data of inhaled diacetyl in rats, and pathology data from an in vivo study to correlate simulation results for localized tissue concentration with regional pathology scores as a basis for a quantitative risk assessment of inhaled diacetyl. Many toxic gases elicit effects in the nasal passages of rodents because the nose is the first line of defense against inhaled materials in obligate nose-breathing animals. Gases that are highly soluble or reactive in nasal tissues will be mostly absorbed in the nose with strong localized dosimetric gradients, whereas gases with low solubility or those that are not as reactive have lower and more uniform absorption rates, allowing higher concentrations to reach the lungs. Regardless of its physico-chemical characteristics, gases are transported through the nose by inhaled airstreams, which are determined by the complex shape of the nose, dividing the bulk airflow into several primary airflow streams (Kimbell et al., 1997a; Morgan and Monticello, 1990). These factors lead to distinct regional deposition patterns, which, if they can be predicted, can be useful in evaluating inhalation risk. It is these characteristics of geometry, airflow, and regional deposition that nasal dosimetry models simulate. Hybrid CFD-PBPK models use information on airflow allocation and air-phase mass transfer rates derived from CFD models (Kimbell et al., 1997a) in a compartmental division of the nasal airspace and tissues. This compartmental structure of the nose based on locations of major airflow streams and epithelial types was developed by Morris et al. (1993) and has since been used in numerous other studies of inhaled gases (Andersen et al., 1999; Bush et al., 1998; Frederick et al., 1998; Teeguarden et al., 2008). In this type of model, inspiratory nasal airflow splits into dorsal and ventral components, with the dorsal flow passing over respiratory and olfactory compartments, and the ventral stream passing over respiratory compartments (Kimbell et al., 1997a). Multiple tissue stacks are comprised of mucus, epithelial, and submucosal compartments, all based on anatomical dimensions. Vapor transfer and clearance occurs by diffusion, metabolism, and blood perfusion at the appropriate epithelial levels. Morris and Hubbs (2009) also included the trachea which was divided into two equalsized sequential stacks because responses from inhaled diacetyl were observed in the anterior and posterior trachea. Inhalation of butter flavoring vapors has caused fixed airways obstruction in food manufacturing workers and has induced necrosis and inflammation of the nasal passages, larynx, trachea, and bronchi in exposed rats. Diacetyl, a primary ingredient of butter flavoring vapors, is thought to significantly contribute to airway injury and is therefore of particular concern. In a previous study, rats were exposed by inhalation to diacetyl concentrations of 100–356 ppm for 6 h (Hubbs et al., 2008). Dose dependent effects were observed in the nose, larynx, trachea, and bronchi, indicating high absorption rates in the upper respiratory tract and proximal lower respiratory tract. Although human occupational exposure also resulted in nasal irritation, more profound effects were observed in the lung, including the lower bronchial airways. This represents a classical situation in risk assessment for highly soluble and reactive gases such as diacetyl: high solubility leads to high 1 To whom correspondence should be addressed at The Hamner Institutes for Health Sciences, 6 Davis Drive, P.O. Box 12137, Research Triangle Park, NC 27709-2137. Fax: (919) 558-1300. E-mail: [email protected].