NAMs for closing knowledge gaps in assessment of respiratory uptake – a PARC project

Inhalation is a major route of chemical exposure for both consumers and workers. Physiologically-based kinetic (PBK) modeling is a promising tool to understand the absorption, distribution, metabolism, and excretion (ADME) of inhaled chemicals and to predict systemic concentrations of chemicals in humans. New Approach Methodologies (NAMs) can help generate essential input parameters for PBK models.
However, validated NAM-based test methods to assess uptake of inhaled chemicals are currently lacking. Reliable information on respiratory uptake is required to determine relevant exposure concentrations for evaluation of systemic effects using NAMs. This manuscript describes a project that aims to apply robust and reliable in vitro models to study cellular uptake, intracellular accumulation, absorption and systemic exposure of chemicals following inhalation.
To evaluate the robustness and predictivity of different NAM-based barrier models, to examine appropriate in vitro to in vivo scaling strategies, and to assess sensitivity and uncertainty in the resulting PBK models, the project will focus on relatively data-rich chemicals, specifically per- and polyfluoroalkyl substances (PFAS).
While some have been widely explored and others remain data-poor, the entire chemical family is of interest due to its health hazards. Therefore, the work combines experimental and modeling approaches by generating in vitro data on the [...]