Air Force Institute of Technology AFIT Scholar Theses and Dissertations Student Graduate Works 3-2008 Comparative Kinetics and Distribution to Target Tissues of Organophosphates Using Physiologically-Based Pharmacokinetic Modeling Rick E. Vermillion Follow this and additional works at: https://scholar.afit.edu/etd Part of the Environmental Chemistry Commons Recommended Citation Vermillion, Rick E., "Comparative Kinetics and Distribution to Target Tissues of Organophosphates Using Physiologically-Based Pharmacokinetic Modeling" (2008). Theses and Dissertations. 2841. https://scholar.afit.edu/etd/2841 This Thesis is brought to you for free and open access by the Student Graduate Works at AFIT Scholar. It has been accepted for inclusion in Theses and Dissertations by an authorized administrator of AFIT Scholar. For more information, please contact [email protected]. COMPARATIVE KINETICS AND DISTRIBUTION TO TARGET TISSUES OF ORGANOPHOSPHATES USING PHYSIOLOGICALLY – BASED PHARMACOKINETIC MODELING THESIS Rick E Vermillion, Captain, USAF AFIT/GEM/ENV/08-M20 DEPARTMENT OF THE AIR FORCE AIR UNIVERSITY AIR FORCE INSTITUTE OF TECHNOLOGY Wright-Patterson Air Force Base, Ohio APPROVED FOR PUBLIC RELEASE; DISTRIBUTION UNLIMITED The views expressed in this thesis are those of the author and do not reflect the official policy or position of the United States Air Force, Department of Defense, or the U.S. Government. AFIT/GEM/ENV/08-M20 COMPARATIVE KINETICS AND DISTRIBUTION TO TARGET TISSUES OF ORGANOPHOSPHATES USING PHYSIOLOGICALLY – BASED PHARMACOKINETIC MODELING THESIS Presented to the Faculty Department of Systems Engineering and Management Graduate School of Engineering and Management Air Force Institute of Technology Air University Air Education and Training Command In Partial Fulfillment of the Requirements for the Degree of Master of Science in Engineering Management Rick E Vermillion, BS Captain, USAF March 2008 APPROVED FOR PUBLIC RELEASE; DISTRIBUTION UNLIMITED AFIT/GEM/ENV/08-M20 COMPARATIVE KINETICS AND DISTRIBUTION TO TARGET TISSUES OF ORGANOPHOSPHATES USING PHYSIOLOGICALLY – BASED PHARMACOKINETIC MODELING Rick E Vermillion, BS Captain, USAF Approved: ____//SIGNED//_______________________ _2/25/08_ Dr. Michael L. Shelley (Chairman) Date ____//SIGNED//_______________________ __2/8/08_ David A. Smith, Lt Col, USAF (Member) Date ____//SIGNED//_______________________ __2/8/08_ Dr. Jeffery M. Gearhart (Member) Date AFIT/GEM/ENV/08-M20 Abstract A physiologically – based pharmacokinetic model has been developed to examine the effects of organophosphates on the levels of acetylcholine in different tissues throughout the mammalian body. Many organophosphate-like chemical and kinetic characteristics are tested without reference to a specific chemical. Characteristics include partition coefficients, metabolic constants, the inhibition coefficient which determines the rate free AChE is bound by an organophosphate and becomes inhibited AChE, the aging rate which determines the rate in which the bond between AChE and the organophosphate become permanent, and the regeneration rate which determines the rate where the bound AChE is separated from the organophosphate and becomes free AChE once again. Two separate exposure scenarios are tested and compared against a baseline. The baseline consists of a direct inhalation exposure which allows 100 percent of the organophosphate to enter into the blood stream via blood – gas exchange. The first exposure scenario examines the effects of bronchial scrubbing (via inhalation) of a fraction of the inhaled agent with direct absorption into bronchial tissue under different exposure conditions and compares them with the inhalation exposures. The second scenario is a study of dermal exposures and compares the levels of ACh in the different tissues with those in the inhalation (baseline) tests. Organophosphates that are absorbed directly into the bronchial tissue exhibit little variation on the levels of ACh buildup in any of the tissue groups tested when compared to the inhalation exposures. No matter what the scrubbing coefficient used, or the iv combination of the parameters (partition coefficients, inhibition coefficient, aging rate, and regeneration rate) values, the change in ACh was minimal. This suggests that the scrubbing of the chemical as it passes through the airway does not help the individual being exposed. The changes are so minor that the individual will experience the same symptoms whether bronchial scrubbing takes place or not. The results showed different behavior between inhalation and dermal exposures. The levels of ACh present in the liver, kidneys, brain, slowly perfused tissue, richly perfused tissue, and diaphragm were lower with the dermal tests. These results suggest that an individual may have additional time to don protective equipment before the levels of ACh are high enough to render the person incapable of doing so. v Acknowledgments First off, I would like to thank my wife for her continued patience and support throughout my time at AFIT. She was instrumental in helping me to relax and remember the important things in life. I would also like to thank my children for keeping my spirits high and always making me laugh. Next, I would like to express my appreciation to my thesis advisor. His patience and kindness helped me to excel, see things from a different perspective, and learn about the model building process. I would also like to thank the other members of my committee for their support and insight throughout the entire process. Their experience and knowledge was insurmountable and helped me to advance in my academic journey. Lastly, I would like to thank the faculty, staff, education technicians, and fellow students who unselfishly went out of their way to help me complete this chapter of my life. Rick E Vermillion This Note is not to be included with the Acknowledgments – it is for information only: It is prohibited to include any personal information in the following categories about U.S. citizens, DOD Employees and military personnel: social security account numbers; home addresses; dates of birth; telephone numbers other than duty officers which are appropriately made available to the general public; names, locations and any other identifying information about family members of DOD employees and military personnel. vi Table of Contents Page Abstract .............................................................................................................................. iv Acknowledgments.............................................................................................................. vi Table of Contents .............................................................................................................. vii List of Figures ......................................................................................................................x List of Tables .................................................................................................................... xii I. Introduction .....................................................................................................................1 Introduction ..................................................................................................................1 Background...................................................................................................................1 Problem Statement ........................................................................................................3 Research Question ........................................................................................................4 Investigative Questions ................................................................................................5 II. Literature Review ............................................................................................................6 What are organophosphates ..........................................................................................6 Release Mechanisms ....................................................................................................8 How do organophosphates work ..................................................................................9 Symptoms ...................................................................................................................12 Effect of different organophosphates .........................................................................15 Bronchial effects .........................................................................................................17 Acetylcholinesterase and acetylcholine levels ...........................................................19 Metabolism (Body Disposing of Agent) ....................................................................20 Aging ..........................................................................................................................21 Current Treatment Procedures ....................................................................................22 vii Lack of human subjects ..............................................................................................24 Acute verses chronic ...................................................................................................26 Problems with scaling from animals to humans .........................................................28 PBPK modeling ..........................................................................................................29