Inhalation dosimetry and dose-response analysis of diacetyl, 2, 3-pentanedione, and acetoin using respiratory tract vapor uptake models.

Abstract

Objective: The objectives are to develop inhalation dosimetry models of the flavoring agents diacetyl, 2, 3-pentanedione, and acetoin to predict uptake throughout the rat and human respiratory tracts and use the results with histopathology data from 2-week, nose-only inhalation exposures in Sprague-Dawley rats to assess relationships between predicted dose and in vivo responses.

Methods: Computational fluid dynamics (CFD) models of the nasal passages were used to simulate inspiratory airflow and vapor uptake and mechanistic models of the lung airways were used to simulate vapor uptake during a breathing cycle.

Results: Diacetyl and 2, 3-pentanedione demonstrated similar uptake and wall mass flux patterns throughout the respiratory tract. Acetoin, being more soluble, was rapidly absorbed in the nasal and upper lung airways. At a 10 ppm exposure concentration and resting breathing conditions, nasal uptake of diacetyl, 2, 3-pentanedione, and acetoin was 30.9, 30.3, and 73.6% in the rat, and 8.7, 9.3, and 32.5% in the human, respectively; total respiratory tract uptake was 76.5, 76.8, and 93.0% in the rat and 79.6, 81.1, and 85.9% in the human, respectively. Wall mass flux patterns aligned with previously reported in vivo observations of histopathological effects in the rat respiratory tract following 8.75, 17.5, or 35 ppm diacetyl or 2, 3-pentanedione exposure and can be used to evaluate dose-response behavior.

Conclusions: Dose-response assessment of inhaled vapors demonstrates the utility of dosimetry models for interspecies extrapolation and chemical comparisons and how their use is an important part of risk characterization as non-animal alternatives are more widely considered.