Many federal agencies have testing requirements or perform assessments of inhalation toxicity. These pose challenges as they entail consideration of both the physicochemical properties (PC) of the agent and its interaction with the complexity of the respiratory tract. Dosimetry models have proven effective to integrate PC properties with airflow parameters and airway architecture to translate dose across species. Model structures vary based on PC properties such as particles vs gases, and reactive gases vs volatile organic compounds. Recent scientific, economic, and ethical drivers have led to interest in developing human-relevant, mechanistically based approaches to testing known as new approach methodologies (NAMs). The adverse outcome pathway (AOP) framework helps to organize data on adverse effects and identify key events (KE) of pathogenesis. Starting with a molecular initiating event, pathogenesis is characterized as a signature sequence of KE observed at various levels of biological organization. The aggregate exposure pathway (AEP) framework organizes exposure data, encompassing environmental transport and transformation as well as toxicokinetic interactions within organisms leading to the target site exposure (TSE). Coupling the AEP and AOP frameworks provides a source-to-outcome continuum to enable risk-based, hazard-based, or exposure-based decision making. Alignment of TSE resulting from various exposure platforms was emphasized by the NAS for evidence integration. Multi-scale dosimetry models allow quantitative description of the interactions among PC properties, key anatomical and physiological features, and major mechanisms of ADME (absorption, distribution, metabolism, and excretion); to characterize a TSE<b> </b>and aid in vitro to in vivo extrapolation, as well as advance quantitative AOP for evaluation of response-response relationship among the KE. Multi-scale dosimetry models coupled with AOP insights can guide strategic development of an<b> </b>integrated approach to testing and assessment; useful to informing testing requirements and interpretation and synthesis of results. Modular workflows and reporting standards based on the FAIR (findable, accessible, interoperable, reusable) principles will advance dosimetry models and scientific data management to ensure utility and impact.

Modernizing inhalation risk assessment: Multi-scale mechanistic modeling, novel approach methodologies (NAMs) and modular workflows

ACS Fall 2020 Virtual Meeting

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