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The many ways to describe gas uptake: An extension of a PBPK model template to VOCs
Citation:
Prasad, B., A. Bernstein, D. Kapraun, AND P. Schlosser. The many ways to describe gas uptake: An extension of a PBPK model template to VOCs. Society of Toxicology 61st Annual Meeting and ToxExpo, San Diego, CA, March 27 - 31, 2022.
Impact/Purpose:
Our PBPK model template includes a variety of structures that describe inhalation uptake which allows for fast and accurate evaluation of PBPK models for inhaled gases. The addition of new features and flexible representations for the inhalation route of exposure allows the template to be applied to a broader set of chemicals that can be used by other PBPK modelers.
Description:
The many ways to describe gas uptake: An extension of a PBPK model template to VOCs In chemical risk assessment, physiologically based pharmacokinetic (PBPK) models are used to estimate internal dose metrics and human equivalent doses. They allow a user to extrapolate dose across species, administration routes, and life stages. Despite these advantages, PBPK models require an often-lengthy quality assurance (QA) review process to ensure that the model theory, structure, and data all support the stated objectives. To facilitate a faster evaluation, we created a PBPK model template using free, open-source software tools capable of describing multiple chemical-specific PBPK models using one common software implementation. A first version of the template passed a rigorous initial QA review and we demonstrated that it reproduces results of published PBPK models for various PFAS. We have now extended the template to describe gas inhalation dosimetry and replicated published results for PBPK models that include inhalation routes of exposure. The current template includes multiple options to describe gas uptake, such as the use of either a dynamic description or a steady state approximation for gas exchange, and the inclusion or exclusion of an explicit lung tissue compartment. This enables the template to match lung dosimetry for models with a variety of structures for gas uptake. Other new features were also added to the template including options for steady state vs. dynamic models for venous and arterial blood compartments, saturable and first order metabolic pathways in multiple compartments, and endogenous (or background) production. Using these new features, we reproduced concentration time course predictions from PBPK models for inhalation exposures to three voltile organic compounds (VOCs) in rats, each sourced from IRIS assessments or peer-reviewed publications. The new template gas uptake features allowed us to implement (1) steady state gas exchange with explicit lung tissue using a dichloromethane model, (2) dynamic gas exchange with explicit lung tissue using a methanol model, and (3) steady state gas exchange with no explicit lung tissue using a chloroform model. By including a variety of structures that describe inhalation uptake, our PBPK model template allows for fast and accurate evaluation of PBPK models for inhaled gases. The addition of new features and flexible representations for the inhalation route of exposure allows the template to be applied to a broader set of chemicals.