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University Micrdrilms International 300 N A COMPARISON OF THE EFFECTIVENESS OF SEVERAL THIOLIC CHELATING AGENTS ON THE MOBILIZATION OF ARSENIC IN THE RABBIT. Item Type text; Thesis-Reproduction (electronic) Authors Hoover, Todd David. Publisher The University of Arizona. Rights Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author. Download date 24/09/2021 12:49:10 Link to Item http://hdl.handle.net/10150/274892 INFORMATION TO USERS This reproduction was made from a copy of a document sent to us for microfilming. While the most advanced technology has been used to photograph and reproduce this document, the quality of the reproduction is heavily dependent upon the quality of the material submitted. 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Zeeb Road Ann Arbor, Ml 48106 1321805 HOCVER, TODD DAVID A COMPARISON OF THE EFFECTIVENESS OF SEVERAL THIOLIC CHELATING AGENTS ON THE MOBILIZATION OF ARSENIC IN THE RABBIT THE UNIVERSITY OF ARIZONA M.S. 1983 University Microfilms International 300 N. Zeeb Road, Ann Arbor, MI 48106 PLEASE NOTE: In all cases this material has been filmed in the best possible way from the available copy. Problems encountered with this document have been identified here with a check mark V . 1. Glossy photographs or pages 2. Colored illustrations, paper or print 3. Photographs with dark background 4. Illustrations are poor copy 5. Pages with black marks, not original copy 6. Print shows through as there is text on both sides of page 7. Indistinct, broken or small print on several pages ^ 8. Print exceeds margin requirements 9. Tightly bound copy with print lost in spine 10. Computer printout pages with indistinct print 11. Page(s) lacking when material received, and not available from school or author. 12. Page(s) seem to be missing in numbering only as text follows. 13. Two pages numbered . Text follows. 14. Curling and wrinkled pages 15. Other _____ University Microfilms International A COMPARISON OF THE EFFECTIVENESS OF SEVERAL THIOLIC CHELATING AGENTS ON THE MOBILIZATION OF ARSENIC IN THE RABBIT by Todd David Hoover A Thesis Submitted to the Faculty of the COMMITTEE ON TOXICOLOGY In Partial Fulfillment of the Requirements For the Degree of MASTER OF SCIENCE WITH A MAJOR IN TOXICOLOGY In the Graduate College THE UNIVERSITY OF ARIZONA 19 8 3 STATEMENT BY AUTHOR This thesis has been submitted in partial fulfillment of requirements for an advanced degree at The University of Arizona and is deposited in the University Library to be made available to borrowers under rules of the Library. Brief quotations from this thesis are allowable without special permission, provided that accurate acknowledgment of source is made. Requests for permission for extended quotation from or reproduction of this manuscript in whole or in part may be granted by the head of the major department or the Dean of the Graduate College when in his judgment the proposed use of the material is in the interests of scholarship. In all other instances, however, permission must be obtained from the author. SIGNED: JO". APPROVAL BY THESIS DIRECTOR This thesis has been approved on the date shown below: /s/Y- a*.* i& i ft* H.1V. Aposhian A Date Professor of Pharmacoloy and of Cellular and Developmental Biology ACKNOWLEDGMENTS I would like to express my appreciation to the members of 1117 conmittee for their time and helpful suggestions during the course of this work. In particular I wish to thank Dr. Vasken Aposhian for his efforts in directing this research and for his continued optimism and support which have made my association with him an enjoyable experience. I also wish to thank my parents for making my first step down the long road of higher education possible. Most of all I wish to thank my wife, Laney, for her love and constant encouragement and for the many sacrifices she has so unselfishly made for my happiness. iii TABLE OF CONTENTS Page LIST OF ILLUSTRATIONS vi LIST OF TABLES viii ABSTACT ix 1. INTRODUCTION 1 Physical-Chemical Properties of Arsenic 1 Applications of Arsenic 1 Arsenic Exposures 2 Toxicity 7 Carcinogenisis . 13 Interactions with Other Metals 17 Teratogenicity 17 Genetic Effects 18 Absorption, Distribution, and Metabolism of Arsenic ... 20 Arsenic Metabolism in the Rabbit 25 Arsenic Metabolism in the Marmoset Monkey 27 Principles of Chelation 28 Chelators 30 BAL 30 DMPS 32 DMSA 35 DMPA 36 WR2721 38 2. MATERIALS AND METHODS 39 Rabbits 39 Reagents 39 Dosing Solutions 41 Instrumentation 44 Animal Studies 48 Part 1 ( As Tracer Studies) 48 Part 2 (Arsenic Content of Brain Tissue) 50 Part 3 (Effect of Arsenic Valence State) 50 Part 4 (Atonic Absorption Studies) 51 Statistics 52 iv V TABLE OF CONTENTS—Continued Page 3. RESULTS 53 Part 1 (^ As Tracer Studies) 53 Part 2 (Arsenic Content of Brain Tissue) 61 Part 3 (Effect of Arsenic Valence State) 6B Part 4 (Atomic Absorption Studies) 71 4. DISCUSSION AND CONCLUSION 75 REFERENCES 84 LIST OF ILLUSTRATIONS Figure Page IA. Arsenical compounds (R-As=0) inhibit the fontation of lipoate from dihydrolipoate (Schoolmeester and White 1980) 9 IB. Arsenic depletes lipoate, blocking acety-CoA formation and thus interfering with the Krebs cycle (Schoolmeester and White 1980) 9 2. Prevalence of skin cancer with respect to age and arsenic concentration in well water (Tseng et al. 1968) 16 3. Sites of teratogenic effects of 4 different elements on embryonic development in the golden hamster (Ferm 1972) 19 4. TLC separation and purity check of sodium arsenite and sodium arsenate 42 5. Stability check of As (+3) dosing solution 43 6. Spectrum plot of arsenic-74 produced by LKB 1282 gamria counter 45 7. Spectrum plot of arsenic-73 obtained from LKB 1282 gairma counter. 47 8. Typical recorder tracing from atomic absorption analysis 49 9. Liver arsenic-74 concentration of rab^jts 24 hours after dosing with sodium arsenite- As and 23 hours post chelator administration 54 10. Concentration of arsenic-74 in the kit^eys of rabbits receiving sodium arsenite- As and the various chelators 55 11. Percent arsenic-74 dose remaining in the lungs after chelation therapy 56 vi vii LIST OF ILLUSTRATIOJS—Continued Figure Page 12. Arsenic concentration in brain tissue following administration of various chelating agents 59 13. Percent arsenic dose excreted in the feces 24 hours after arsenic administration 60 14. Urinary arsenic-74 excretion 24 hours post arsenic dose 62 15A. Brain arsenic concentration of rabbits administered sodium arsenite and followed by saline, BAL, or DMPS 67 15B. Brain arsenic concentration of rabbits given sodium arsenite followed by fractionated doses of saline, BAL, or a peanut oil/benzyl benzoate solution 67 LIST OF TABLES Table Page I. Medicinal uses of arsenic compounds (Woolson 1975).... 3 II. Occupations with potential arsenic exposure (Costa 1980) 4 III. Estimated dietary intakes of heavy metals by food class (Qehme 1978) 6 IV. Enzymes inhibited by arsenic (Carnow 1976) 8 V. Signs and symptoms of arsenic intoxication in animals and man (Carnow 1975) 12 VI. Arsenic concentration and prevalence of warts and pigmentation (Perry et al. 1948) 16 VII. Structures of the Chelators used in this study 31 VIII. Comparison of seme of the information available about DMPS and DMPA (Aposhian 1982) 37 IX. The effect of various chelators on the concentration of arsenic-74 in tissue 58 X. Probability values for the means of various chelators tested accordind to tissue type 63 XI. Comparison of brain weight to body weight ratios for control and test animals receiving BAL 69 XII. Effect of dl-DMSA on the mobilization of arsenic-74 (+5) in the presence of excess sodium arsenite (+3) or sodium arsenate (+5) 70 XIII. Effects of arsenic oxidation state and BAL therapy on arsenic concentration in brain tissue 72 XIV. Effect of BAL therapy and arsenic oxidation state on the urinary excretion of arsenic in rabbits .... 74 viii ABSTRACT The purpose of this work was to assess the effectiveness of several thiolic carpounds and their isaners in increasing the excretion and tissue mobilization of arsenic in male New Zealand white rabbits.
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