Studies of the Origins and Control of Occupational Exposure to Cytotoxic Drugs Volume 1 of 1 Sarah Roberts A thesis submitted for the degree of Doctor of Philosophy University of Bath Department of Pharmacy and Pharmacology February 2008 COPYRIGHT Attention is drawn to the fact that copyright of this thesis rests with its author. A copy of this thesis has been supplied on condition that anyone who consults it is understood to recognise that its copyright rests with the author and they must not copy it or use material from it except as permitted by law or with the consent of the author. This thesis may be made available for consultation within the University Library and may be photocopied or lent to other libraries for the purpose of consultation. Signature :……………………………………………………. Date:………………….. 1. LITERATURE REVIEW........................................................................................... 1 1.1 LITERATURE SEARCH STRATEGY .............................................................................. 1 1.2 CYTOTOXIC CHEMOTHERAPY ................................................................................... 1 1.2.1 Covalent DNA-Binding Drugs......................................................................... 3 1.2.2 Antimetabolites ................................................................................................ 7 1.2.3 Non-Covalent DNA-Binding Drugs .............................................................. 11 1.2.4 Inhibitors of Chromatin Function................................................................... 14 1.3 HEALTH EFFECTS /O CCUPATIONAL EXPOSURE RISK ............................................... 17 1.4 CYTOTOXIC RECONSTITUTION SERVICES ............................................................... 20 1.5 ROUTES OF EXPOSURE ............................................................................................ 20 1.5.1 The Preparation Process and Routes of Contamination ................................. 23 1.5.2 Pre-Contaminated Sources ............................................................................. 24 1.6 CONTROL MEASURES /R ISK MANAGEMENT /S AFE HANDLING ................................. 26 1.6.1 Engineering Controls (Biological Safety Cabinets and Isolators) ................. 30 1.6.2 Effectiveness of Personal Protective Clothing ............................................... 34 1.7 METHODS FOR MONITORING EXPOSURE TO CYTOTOXIC DRUGS ............................ 36 1.7.1 Biological Effect Monitoring ......................................................................... 37 1.7.2 Biological Monitoring .................................................................................... 37 1.7.3 Environmental Monitoring ............................................................................. 40 1.8 REMOVAL OF CONTAMINATION AND DEGRADATION /I NACTIVATION OF CYTOTOXIC DRUGS .......................................................................................................................... 43 1.9 CLOSED -SYSTEM CONTAINMENT DEVICE .............................................................. 44 1.10 SELECTION OF CYTOTOXIC MARKER DRUGS ........................................................ 47 1.10.1 Cyclophosphamide ....................................................................................... 48 1.10.2 5-Fluorouracil............................................................................................... 49 1.10.3 Methotrexate ................................................................................................ 50 1.10.4 Doxorubicin.................................................................................................. 51 1.10.5 Epirubicin ..................................................................................................... 51 1.11 INTRODUCTION TO THIS STUDY ............................................................................ 52 1.12 PROJECT STRUCTURE ............................................................................................ 54 i 2. INVESTIGATION INTO DECONTAMINATION PROCEDURES CARRIED OUT AFTER THE MANIPULATION OF CYTOTOXIC DRUGS......................... 56 2.1 INTRODUCTION ....................................................................................................... 56 2.2 OBJECTIVES ............................................................................................................ 56 2.3 STUDY DESIGN ....................................................................................................... 57 2.3.1 Design of the Questionnaire ........................................................................... 57 2.3.2 Ethics Committee Approval ........................................................................... 61 2.3.3 Research Governance Approval..................................................................... 62 2.3.4 Targets and Population Size Selection ........................................................... 63 2.3.5 Method of Distribution................................................................................... 64 2.3.6 Method of Response to the Questionnaire ..................................................... 65 2.3.7 Data Recording and Analysis ......................................................................... 65 2.4 RESULTS ................................................................................................................. 66 2.4.1 Conduct of Research ...................................................................................... 66 2.4.2 Participant Response ...................................................................................... 66 2.4.2.1 Demographics ............................................................................................. 67 2.4.3 Questionnaire Analysis and Interpretation ..................................................... 67 2.4.3.1 Concerns Regarding Cytotoxic Contamination .......................................... 68 2.4.3.2 Decontamination Procedures Used ............................................................. 69 2.4.3.3 Cleaning and Disinfection Procedure.......................................................... 69 2.4.3.4 Change in Decontamination Procedure Depending on the Drug Manipulated.............................................................................................................. 72 2.4.3.5 Purpose of the Decontamination Procedure ................................................ 72 2.4.3.6 How the Decontamination Procedure was Devised .................................... 73 2.4.3.7 Effectiveness of the Decontamination Procedure ....................................... 73 2.4.3.8 Concerns and Problems Encountered when Manipulating Cytotoxic Drugs .................................................................................................................................. 76 2.5 DISCUSSION ............................................................................................................ 78 2.6 CONCLUSION .......................................................................................................... 85 3. DEVELOPMENT AND VALIDATION OF SAMPLING/QUANTIFICATION METHODS ..................................................................................................................... 86 3.1 INTRODUCTION ....................................................................................................... 86 3.2 OBJECTIVES ............................................................................................................ 89 3.2.1 Method 1 ......................................................................................................... 89 3.2.2 Method 2 ......................................................................................................... 89 3.3 MATERIALS ............................................................................................................ 90 ii 3.4 METHOD 1 - DEVELOPMENT ................................................................................... 93 3.4.1 Selection of Drug ........................................................................................... 93 3.4.2 Drug Dilution and Reconstitution .................................................................. 94 3.4.3 Test Surface and Test Surface Coating .......................................................... 94 3.4.4 Selection of Desorbing Solution .................................................................... 95 3.4.5 Immersion and Recovery Method of Drug from the Test Surface................. 96 3.4.6 HPLC Methods............................................................................................... 96 3.5 METHOD 1 - VALIDATION ....................................................................................... 98 3.5.1 Recovery of Drug from the Test Surface ....................................................... 98 3.5.2 Retention of the Analyte ................................................................................ 98 3.5.3 Precision, Accuracy and Recovery ................................................................ 99 3.5.4 Limit of Quantification and Limit of Detection ............................................. 99 3.5.5 Linearity ....................................................................................................... 100 3.5.6 Forced Degradation Studies ......................................................................... 101 3.6 METHOD 2 - DEVELOPMENT ................................................................................