Evaluation of the Potential Impact of Age- and Gender-Specific Lung Morphology and Ventilation Rate on the Dosimetry of Vapors

Abstract

In recent years, there have been growing concerns that due to differences, both pharmacokinetic and pharmacodynamic, between children and adults, children could be at greater risk of adverse effects following chemical exposure. The specific goal of this study was to demonstrate an approach for using physiologically based pharmacokinetic (PBPK) modeling to compare inhalation dosimetry in the adult and the child of both males and females. Three categories of gases were considered: rapidly and irreversibly reactive in the respiratory tract (ozone), relatively water-soluble and nonreactive (isopropanol), and relatively water-insoluble and nonreactive (styrene, vinyl chloride, and perchloroethylene). The nonreactive chemicals were also selected because they are metabolized in the respiratory tract. The age-related changes observed for the estimated dose metrics were a function of the physiochemical properties of the inhaled vapor and their interactions in the body. Blood concentrations estimated for all vapors, either poorly metabolized (e.g., PERC), moderately metabolized (e.g., ST), or highly metabolized vapors (e.g., IPA and VC), varied less than a factor of two between infants and adults. These changes, moreover, were confined to the first year after birth, a relatively short window compared to the total lifespan of the individual. In contrast, circulating metabolite concentrations estimated in the blood, as well as amounts metabolized in the liver and lung, appeared to be a strong function of age, due to their dependence on the maturity of the pertinent metabolic enzyme systems.