Application of a hybrid CFD-PBPK nasal dosimetry model in an inhalation risk assessment: An example with acrylic acid

The available inhalation toxicity information for acrylic acid (AA) Suggest s that lesions to the nasal cavity, specifically olfactory degeneration, ar e the most sensitive end point for developing a reference concentration (Rf C). Advances in physiologically based pharmacokinetic (PBPK) modeling, spec ifically the incorporation of computational fluid dynamic (CFD) models, now make it possible to estimate the flux of inhaled chemicals within the nasa l cavity of experimental species, specifically rats. The focus of this inve stigation 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 tec hnique into the risk assessment process. Information provided in the litera ture on the toxicity and mode of action for AA was used to determine the ri sk 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-PB PK hybrid model in a risk assessment for AA resulted in an RfC of 79 ppb, a ssuming a minute ventilation of 13.8 l/min (20 m(3)/day) in humans. This va lue 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 spec ies. Once these data are available in the mouse, an assessment should be co nducted using this information. Additional differences included the methods used for estimating the target tissue concentration, the uncertainty facto rs (UFs) applied, and the application of duration and uncertainty adjustmen ts to the internal target tissue dose rather than the external exposure con centration.