Evaluation of a non-animal toolbox informed by adverse outcome pathways for human inhalation safety.

Introduction: This work evaluated a non-animal toolbox to be used within a next-generation risk assessment (NGRA) framework to assess chemical-induced lung effects using human upper and lower respiratory tract models, namely MucilAir™-HF and EpiAlveolar™ systems, respectively.

Methods: A 12-day substance repeated exposure scheme was established to explore potential lung effects through analysis of bioactivity readouts from the tissue integrity and functionality, cytokine/chemokine secretion, and transcriptomics.

Results: Eleven benchmark chemicals were tested, including inhaled materials and drugs that may cause lung toxicity following systemic exposure, covering 14 human exposure scenarios classified as low- or high-risk based on historical safety decisions.

A proof-of-concept multi-tiered Bayesian approach for the integration of physiochemical properties and toxicokinetic time-course data for Daphnia magna.

The use of in silico and in vitro methods, commonly referred to as New Approach Methodologies (NAMs), has been proposed to support environmental (and human) chemical safety decisions, ensuring enhanced environmental protection. Toxicokinetic models developed for environmentally relevant species are fundamental to the deployment of a NAMs-based safety strategy, enabling the conversion between external and internal chemical concentrations, although they require historical toxicokinetic data and robust physical models to be considered a viable solution. Daphnia magna is a key model organism in ecotoxicology albeit with limited and scattered quantitative toxicokinetic data, as for most invertebrates, resulting in a lack of robust toxicokinetic models.