Application of a Hybrid CFD-PBPK Nasal Dosimetry Model in an Inhalation Risk Assessment: An Example with Acrylic Acid

Abstract

The available inhalation toxicity information for acrylic acid (AA) suggests that lesions to the nasal cavity, specifically olfactory degeneration, are the most sensitive end point for developing a reference concentration (RfC). Advances in physiologically based pharmacokinetic (PBPK) modeling, specifically the incorporation of computational fluid dynamic (CFD) models, now make it possible to estimate the flux of inhaled chemicals within the nasal cavity of experimental species, specifically rats. The focus of this investigation was to apply an existing CFD-PBPK hybrid model in the estimation of an RfC to determine the impact of incorporation of this new modeling technique into the risk assessment process. Information provided in the literature on the toxicity and mode of action for AA was used to determine the risk assessment approach. A comparison of the approach used for the current U.S. Environmental Protection Agency (U.S. EPA) RfC with the approach using the CFD-PBPK hybrid model was also conducted. The application of the CFD-PBPK hybrid model in a risk assessment for AA resulted in an RfC of 79 ppb, assuming a minute ventilation of 13.8 l/min (20 m(3)/day) in humans. This value differs substantially from the RfC of 0.37 ppb estimated for AA by the U.S. EPA before the PBPK modeling advances became available. The difference in these two RfCs arises from many factors, with the main difference being the species selected (mouse vs. rat). The choice to conduct the evaluation using the rat was based on the availability of dosimetry data in this species. Once these data are available in the mouse, an assessment should be conducted using this information. Additional differences included the methods used for estimating the target tissue concentration, the uncertainty factors (UFs) applied, and the application of duration and uncertainty adjustments to the internal target tissue dose rather than the external exposure concentration.

Inhaled aerosol particle dosimetry in mice: A review

“…nasal and laryngeal cavities). Although a complete anatomical model of the ET region of the mouse is not available, limited quantitative morphometric data have been reported and/or estimated for different areas of the URT (Gross et al, 1982;Andersen et al, 2000), as shown in Table 2.…”

“…Additional quantitative data on the mouse nasal cavity in Table 2 have been taken from other independent studies (e.g. Andersen et al, 2000).…”

Study of the Variability in Upper and Lower Airway Morphology in Sprague–Dawley Rats Using Modern Micro‐CT Scan‐Based Segmentation Techniques

“…A tool that is increasingly used to assess the respiratory function is computational fluid dynamics or CFD. This method is capable of simulating flow behavior in virtual models (Bush et al, 1998;Andersen et al, 2000;Minard et al, 2006). The challenge is to develop mathematical models that realistically reflect the respiratory physiology of the animal by accurately simulating its fluid flow conditions.…”

Toxicokinetic modeling and its applications in chemical risk assessment

“…The recent RfC documentation for VC in IRIS (US EPA, 2000a) specifically describes and uses a PBPK/PT model for standard setting and dose route extrapolations. A recent risk assessment with acrylic acid (Andersen et al, 2000) applies a PBPK model linked to computational fluid dynamic calculations of nasal airflow (Frederick et al, 1998) to derive an RfC for this compound. The Hazardous Air Pollutants Test Rule (Federal Register, 1996) invited increased efficiency/efficacy in testing by providing possible substitution of certain oral toxicity tests instead of requiring new inhalation studies, for those instances where a validated PBPK model is available to conduct extrapolations across dose-routes.…”