A physiologically based pharmacokinetic (PBPK) model to align dosimetry of the isobutyl metabolic series in rats and humans

Smith, Jordan N.; Tyrrell, Kimberly J.; Weitz, Karl K.; Faber, Willem

doi:10.1016/j.yrtph.2025.105914

A physiologically based pharmacokinetic (PBPK) model to align dosimetry of the isobutyl metabolic series in rats and humans

Journal Article · Sat Jul 26 00:00:00 EDT 2025 · Regulatory Toxicology and Pharmacology

DOI:https://doi.org/10.1016/j.yrtph.2025.105914· OSTI ID:2587785

Smith, Jordan N. ^[1]; Tyrrell, Kimberly J. ^[2]; ^[2]; Faber, Willem ^[3]

Pacific Northwest National Laboratory (PNNL), Richland, WA (United States); Oregon State Univ., Corvallis, OR (United States)
Pacific Northwest National Laboratory (PNNL), Richland, WA (United States)
Willem Faber Toxicology Consulting, LLC, Victor, NY (United States)

Here, we developed a physiologically based pharmacokinetic (PBPK) model in rats and humans for the isobutyl metabolic series including isobutyl acetate, isobutanol, isobutyraldehyde, and isobutyric acid. Chemical manufactures routinely use these compounds as solvents, for chemical synthesis, as potential biofuels, de-icing fluids, and additives for food and/or fragrance in consumer products. Human exposure to isobutyl compounds can occur through inhalation or oral routes. We previously developed a PBPK model for the propyl metabolic series and utilized it as a framework to create the isobutyl PBPK model due to the chemical similarities between the two series. To support model development, we measured in vitro metabolism of isobutyl acetate in rat and human blood and liver S9 fractions. Compared to rats, humans demonstrated faster isobutyl acetate hydrolysis in liver S9 fractions, while the hydrolysis rates in blood were similar between the two species. We used concentrations of isobutyl compounds measured in air and blood from rats exposed to isobutyl acetate and isobutanol as well as other published data to further parameterize the model. Following exposure to either isobutyl acetate or isobutanol, we observed isobutanol concentrations highest among the isobutyl compounds in the blood of rats. Overall, the model accurately predicts measured time course concentrations of isobutyl acetate, isobutanol, and isobutyric acid in available data in rats and humans. Sensitivity analyses identified alveolar ventilation rates, isobutyl metabolism rates, and cardiac output as the most sensitive parameters affecting concentrations of isobutyl compounds in blood. The isobutyl PBPK model enables comparisons of internal dose metrics across various isobutyl compound exposures and species and allows for calculation of equivalent external exposures that result in the same dose metric. Regulators can employ this PBPK model to predict and align internal dose metrics of isobutyl compounds for risk assessment purposes.

View Accepted Manuscript (DOE)

Research Organization:: Pacific Northwest National Laboratory (PNNL), Richland, WA (United States)

Sponsoring Organization:: USDOE

Grant/Contract Number:: AC05-76RL01830

OSTI ID:: 2587785

Report Number(s):: PNNL-ACT-SA--10895

Journal Information:: Regulatory Toxicology and Pharmacology, Journal Name: Regulatory Toxicology and Pharmacology Vol. 163; ISSN 0273-2300

Publisher:: Elsevier BVCopyright Statement

Country of Publication:: United States

Language:: English

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