Modernizing Inhalation Risk Assessment Workflows: Role of Dosimetry Modeling

This presentation will provide critical concepts and background information to best position the audience to understand current methods for dosimetry adjustment and emerging model structures and extrapolation approaches that might be used to modernize inhalation risk assessment.  Fundamentals of inhalation toxicology and dosimetry will be introduced, with an emphasis on how features of airway architecture, ventilation parameters, breathing mode(s), inhalability, and cellular composition, and metabolic capacities interact with key physicochemical (PC) properties of inhaled agents such as particle size, distribution, density, solubility and reactivity, to determine the location of deposition and absorption in the respiratory tract.  Illustrations will include how these PC properties are used, together with data availability and understanding of the mode of action or potential adverse outcome pathway(s) of the inhaled agent, to encourage critical evaluation and identification of the appropriate type of dosimetry model to deploy for a given inhaled agent (i.e., aerosols, reactive gases, volatile organic compounds, and chemicals classified as “Category 2” gases by EPA dosimetry methods).  Derivation of the different default dosimetric adjustment factors and their relationship to more sophisticated model structures for these different categories of PC properties will be described.  The importance of characterizing internal dose versus exposure concentration to both refine modeling approaches and increase confidence in predictions for interspecies and in vitro to in vivo extrapolations will be stressed as requisite to provide exposure alignment across experimental platforms (human, in vivo, in vitro) for robust evidence integration in risk assessment.  A practical demonstration using the new, externally peer-reviewed EPA multiple-path particle dosimetry (MPPD) model (EPA MPPD v.2.0) will impart an understanding of historical model development and emerging data requirements, show how such models integrate anatomical, physiological and PC properties to provide reliable predictions that can be customized to different use cases, and underscore the requirement of standardized parameters for assessment workflows to be tractable in regulatory applications.

Impact/Purpose

In vitro methods are increasingly being deployed to assess the toxicity of inhaled substances, but it can be challenging to ensure their relevance to human exposure scenarios. The use of in vitro data to predict human health effects due to inhalation requires the consideration of several parameters including physicochemical (PC) properties of the inhaled substance, target exposure scenarios, anatomy of the respiratory system, and understanding of deposition and uptake mechanisms in both the respiratory tract and in vitro exposure systems. Inhaled substances are incredibly diverse and include aerosols and various gases (e.g., reactive, volatile organic compounds (VOCs), and “Category 2”), all of which possess distinct PC properties that must be considered when selecting dosimetry models to predict human exposure and inform optimization of in vitro assay conditions. This presentation is the first in a continuing education course is intended for those who conduct or interpret data from in vitro inhalation studies and New Approach Methods (NAMs). This course will introduce how various dosimetry models are applied in risk assessment workflows and how in silico approaches can be utilized to predict human exposures and improve in vitro study design.  Specifically this presentation will provide the foundational aspects of inhalation risk assessment workflows across a range of inhaled substances and demonstrate how dosimetry models provide for modernization for characterization, interspecies extrapolation and in vitro to in vivo extrapolation (IVIVE), thereby supporting increased accuracy for evidence integration across experimental platforms.

Citation

Jarabek, A. Modernizing Inhalation Risk Assessment Workflows: Role of Dosimetry Modeling. Society of Toxicology (SOT) 2025, Orlando, FL, March 16 - 20, 2025.