Using in vitro data and PBPK models to predict inhalation toxicity
In vitro assay data can provide valuable information about the effects of substances on biological systems. However, to determine safe exposure levels in real-life situations, it is necessary to consider the translation of in vitro results to the in vivo context. In vitro to in vivo extrapolation (IVIVE) uses pharmacokinetic models to relate concentrations of substances eliciting responses in an in vitro assay to an in vivo equivalent administered dose (EAD). NICEATM applied IVIVE to a group of volatile organic compounds with abundant pharmacokinetic and in vivo toxicity data. For each chemical, EADs that would result in internal concentrations (e.g., plasma or target tissue) equivalent to in vitro activity concentrations were estimated. The in vitro activity concentrations were obtained from in vitro assays measuring different endpoints (e.g., cytochrome p450 activation, transcriptome analysis, and genotoxicity) from public resources. EAD estimates were compared to published in vivo point-of-departure (PODs) or minimal risk levels provided by the ATSDR covering multiple target organs toxicities via inhalation exposure. The impact of mechanistic relevance of in vitro assays, target organs chosen for analysis, and the concordance between in vitro and in vivo exposure regimens on IVIVE outcomes will be evaluated and discussed in a presentation (Chang et al.) at the 2024 Annual Meeting of the Society of Toxicology. For most chemicals tested, close agreements between EAD estimates and rat in vivo PODs were observed, but most EADs were at least 10-fold higher than minimum risk levels, suggesting that a “modifying factor” may need to be established to approximate minimum risk levels based on in vitro assay data. This study provides proof-of-concept case examples to illustrate the utility new approach methodologies (NAMs) in informing human risk following exposure to inhaled substances.