Physiologically Based Modeling of Vinyl Acetate Uptake, Metabolism, and Intracellular pH Changes in the Rat Nasal Cavity

Toxicokinetic modeling and its applications in chemical risk assessment

“…The physiological models for tissue dosimetry are more completely developed than are the models for biological response. A particularly good risk assessment example of the extension of PBPK modeling to include a more PD portion is pH control models in respiratory tract epithelial tissues following exposures to vinyl acetate (VA) (Plowchalk et al, 1997;Bogdanffy et al, 1999).…”

“…PBPK/PT models developed for these esters (Plowchalk et al, 1997;Bogdanffy et al, 1999;Andersen et al, 1999) calculate tissue dose metrics in the epithelial tissue compartments of the nose in support of estimations of cancer risks (with VA) or estimations of RfCs (with both VA and MMA). The target tissue compartments in the ester models differ from the liver compartment with the models for CH 2 Cl 2 and VCM.…”

“…With VA, each epithelial tissue layer is 10 microns thick to allow modeling with experimentally measured diffusion coefficients. This tissue compartmentalization structure leads to five to seven tissue compartments depending on the total thickness of the tissues in any region (Plowchalk et al, 1997). With MMA , tissue thickness was estimated for the three main tissue regions */the mucus, epithelial cell, and sub-mucosal regions.…”

“…Morris et al (1993) developed many of these parameters for a nasal PBPK/PT model. Plowchalk et al (1997) measured esterase activities and their distribution in the nasal epithelium and submucosal regions. The dose metrics calculated differed for these two esters.…”

“…Another advantage of the explicit construction of these models was the ability to conduct sensitivity analyses to assess the relative importance of the various model parameters in controlling achieved tissue doses. The sensitivity analysis was especially useful with VA (Plowchalk et al, 1997;Bogdanffy et al, 1999) where the model is highly non-linear due to a several potentially saturable processes, including two distinct esterase pathways, proton pumping, and the sequential arrangement of compartments within the nose. These nasal dosimetry models should play an important role in RfC estimations for a variety of chemicals of interest in the Integrated Risk Information System (IRIS) Pilot Project at the US EPA (www.epa.gov\iris\).…”