Date of Completion

7-28-2014

Embargo Period

7-22-2014

Keywords

Toxicology, Inhalation, Oxidative Stress, Risk Assessment

Major Advisor

John Morris

Associate Advisor

Jose Manautou

Associate Advisor

Urs Boelsterli

Associate Advisor

Laura Van Winkle

Field of Study

Pharmaceutical Science

Degree

Doctor of Philosophy

Open Access

Open Access

Abstract

The respiratory tract is a common toxicological target for inhaled vapors, many of which have electrophilic properties. Understanding vapor dosimetry as well as toxicant-tissue interactions is critical to interpreting toxicity data generated from rodent inhalation studies. This thesis investigates the acute respiratory tract responses to three inhaled vapors: naphthalene, diacetyl, and acrolein, all of which have distinct chemical properties and cause target organ-specific toxicities.

Male and female rats chronically inhaling naphthalene vapor develop nasal tumors. The tumor types are sex- and site-specific; female rats develop olfactory neuroblastomas and male rats develop respiratory adenomas. The proposed mode-of-action of naphthalene-induced tumorigenesis includes bioactivation to electrophilic metabolites, followed by glutathione depletion, cell death, and regenerative cell proliferation. As naphthalene produces electrophilic metabolites, the acute antioxidant effect may contribute to the sex- and site-selective response observed in chronic studies. Described herein are studies investigating the acute antioxidant effects of inhaled naphthalene on the rat nasal respiratory and olfactory airway mucosa. The results indicate that female olfactory mucosa is unable to mount an antioxidant response following naphthalene inhalation. This may explain why female rats develop olfactory neuroblastomas.

Inhalation of water-soluble electrophilic vapors often causes severe nasal injury in rats, while causing lower airway injury in humans. The absence of lower airway injury in rats is due to delivered dose of vapor to, or innate sensitivity of, these airways. Normalizing to delivered dose allows analysis of tissue sensitivity. Described herein is an approach that couples computational fluid dynamic physiologically-based pharmacokinetic airway dosimetry modeling with antioxidant/proinflammatory responses of rat upper and lower extrapulmonary airways to inhaled diacetyl and acrolein vapor. The results suggest that rat upper and lower extrapulmonary airways are of similar sensitivity to water-soluble vapors when normalized to delivered dose. This has many implications to assessing lower airway risk in mouth-breathing humans.

Two major contributions to the field are reported. 1) Sex-specific nasal antioxidant responses to inhaled naphthalene vapor may contribute to sex differences observed in chronic inhalation studies. 2) Airway-to-airway dosimetric extrapolation of toxicity data in nose-breathing rats may represent a novel approach to assess the potential of lower airway risk in mouth-breathing humans.

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