Advisors: Eberhard O. Voit, Ph.D. (BME, Georgia Tech & Emory University)

                 Qiang Zhang, Ph.D. (Environmental Health, Emory University)

Committee:

Melissa L. Kemp, PhD (BME, Georgia Tech & Emory University)

Peng Qiu, Ph.D. (BME, Georgia Institute of Technology and Emory University)  

Mark P. Styczynski, Ph.D.  (ChBE, Georgia Institute of Technology)

Assessing the Impact of Dioxin on Human Health through Mathematical Modeling

Exposure to persistent organic pollutants (POPs) can cause a variety of adverse health effects. Lipophilic POPs like dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin; TCDD) are particularly harmful over a long time horizon because they can remain in fatty tissue for several decades after exposure. TCDD has been demonstrated to impact several organs, including the liver, which is considered the primary organ for detoxifying the effects of environmental contaminants and other xenobiotics. It is known that short-term exposure to high levels of dioxin may result in the development of skin lesions such as chloracne. Long-term exposure is associated with the impairment of cholesterol dynamics and reproductive functions.  Moreover, chronic dioxin exposure has been demonstrated to pose an immensely increased risk of developing diabetes and various cancers, often in the form of soft-tissue sarcoma, non-Hodgkin lymphoma, chronic lymphocytic leukemia, and liver cancer.

Due to the ubiquity of dioxins, all people worldwide have background exposure and a certain level of dioxins in the body. Given the high toxic potential of this class of compounds, efforts need to be undertaken to reduce current background exposure and counteract their effects. Many of the individual contributions of the impact of TCDD on human health have been documented in a host of toxicological studies. However, a comprehensive understanding of the overall impact of TCDD on the human body is required to develop countermeasures against these toxic effects.

In this dissertation I propose a computational multi-scale approach, using a “template-and-anchor” model that permits a valid integration of the various contributions of TCDD toward meaningful health risk assessments. Generically, a template is a high-level model that focuses exclusively on the main physiological components of a system and involves correspondingly few parameters and variables. It provides a coarse-grained representation of the system under investigation. Anchor models provide more elaborate views of the specific biological details characterizing the mechanisms that govern the system and are represented in the template model. Specifically, I will create a template model along with a collection of pertinent anchor models. Once the specific mathematical structure of these models is established, I will demonstrate how different concentrations of TCDD drive the input and output of each anchor model and, subsequently, the overarching template model. The overall objective of this proposal is to: (1) elucidate details of dioxin-induced changes in cholesterol dynamics (2); model the TCDD-induced effects on endocrine hormones such as estradiol to understand the mechanism by which dioxin exposure may contribute to diseases such as endometriosis; and (3) integrate all anchor models into a comprehensive template model that will allow us to assess the global effects of dioxin on the human body. The results of this work are hoped to be translatable into an overall–and possibly even personalized–human health risk assessment.