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Assessment of the Risk Potential of Reactive Chemicals with Multiple Modes of Toxic Action

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Assessment of the Risk Potential of Reactive Chemicals with Multiple Modes of Toxic Action Assessment of the Risk Potential of Reactive Chemicals with Multiple Modes of Toxic Action Angela Harder Diss. ETH No.14966 Diss. ETH No. 14966 Assessment of the Risk Potential of Reactive Chemicals with Multiple Modes of Toxic Action A dissertation submitted to the Swiss Federal Institute of Technology Zurich for the degree of Doctor of Natural Sciences presented by Angela Harder Dipl. Biotechnol., Technical University Braunschweig born on July 20, 1968 Citizen of the Federal Republic of Germany accepted on the recommendations of Prof. Dr. René P. Schwarzenbach, examiner Prof. Dr. Joop L.M. Hermens, co-examiner Dr. Paolo Landini, co-examiner Dr. Beate I. Escher, co-examiner Zurich, 2002 iii Table of Contents Summary................................................................................................................. vii Zusammenfassung................................................................................................... ix 1 General Introduction................................................................... 1 1.1 Electrophiles and their Industrial Significance ......................................................................... 1 1.2 Emissions and Exposure.......................................................................................................... 2 1.3 Human Health Risks ................................................................................................................ 3 1.4 Environmental Risk Assessment ............................................................................................. 3 1.5 Molecular Based Concepts for Ecotoxicological Effect Assessment....................................... 5 1.6 Reactions with Nucleophiles .................................................................................................... 6 1.7 Objectives and Structure of this Thesis ................................................................................... 8 1.8 Literature Cited......................................................................................................................... 9 2 Evaluation of Bacterial Biosensors for Toxicity Assessment and Mode of Action Classification of Reactive Chemicals ... 13 2.1 Introduction............................................................................................................................. 14 2.2 Design of Bacterial Biosensor Set ......................................................................................... 15 2.3 Experimental Section ............................................................................................................. 18 2.3.1 Chemicals ..................................................................................................................... 18 2.3.2 Quantification of Growth Inhibition................................................................................ 19 2.3.3 Determination of Glutathione Influence on Growth Inhibition ....................................... 20 2.3.4 Determination of the Influence of DNA Repair on Decrease of Colony-Forming Units 20 2.3.5 Induction of DNA Repair Processes ............................................................................. 21 2.3.6 Determination of Mutation Rates .................................................................................. 21 2.3.7 Determination of Cell Vitality, Glutathione Depletion, and DNA Strand Breaks ........... 21 2.4 Results and Discussion.......................................................................................................... 23 2.4.1 Toxicity of Reactive Chemicals in E. coli and Comparability of Different Endpoints .... 23 2.4.2 Evaluation of Suitable Biosensors for Assessing the Contribution of the Reaction with Glutathione to the Toxicity in E. coli...................................................................... 25 2.4.3 Evaluation of Suitable Biosensors for Assessing the Contribution of the Reaction with DNA to the Toxicity in E. coli ................................................................................ 28 2.4.4 Mode of Action Classification........................................................................................ 31 2.4.5 Transferability of Modes of Action Classification to Higher Organisms........................ 32 2.5 Literature Cited....................................................................................................................... 33 iv 3 Nucleophilic Substitution Reactions of Organochlorines and Epoxides with Biological Nucleophiles: Classification According to the Reaction Order ........................................... 37 3.1 Introduction............................................................................................................................. 38 3.2 Experimental Section ............................................................................................................. 40 3.2.1 Chemicals ..................................................................................................................... 40 3.2.2 Measurement of Hydrolysis Rate Constants ................................................................ 40 3.2.3 Measurement of Reaction Rate Constants with Glutathione........................................ 41 3.2.4 Measurement of Reaction Rate Constants with 2´-Deoxyguanosine........................... 42 3.2.5 Derivation of (Pseudo) First-Order Hydrolysis Rate Constants.................................... 42 3.2.6 Derivation of Second-Order Reaction Rate Constants with Glutathione and 2’-Deoxyguanosine ...................................................................................................... 42 3.3 Results and Discussion.......................................................................................................... 45 3.3.1 Classification of Reactions according to SN1 and SN2.................................................. 45 3.3.1.1 Organochlorines............................................................................................ 46 3.3.1.2 Epoxides ....................................................................................................... 47 3.3.2 Comparison of Experimental Rate Constants with Literature Data .............................. 51 3.4 Literature Cited...................................................................................................................... 53 4 Methods and Tools for the Prediction of the Toxicity of Electrophilic Chemicals............................................................ 57 4.1 Introduction............................................................................................................................. 58 4.2 Methods and Data Sets.......................................................................................................... 59 4.2.1 Determination of Octanol-Water Partition Coefficients................................................. 59 4.2.2 Data Sets ...................................................................................................................... 61 4.3 Results and Discussion.......................................................................................................... 61 4.3.1 Prediction of Bacterial Toxicity Using Reaction Rate Constants with Biological Nucleophiles........................................................................................................................... 61 4.3.2 Comparison of Bacterial Toxicity with Toxicity in Algae, Daphnia, and Fish................ 65 4.3.3 Hazard Assessment...................................................................................................... 70 4.4 Literature Cited....................................................................................................................... 71 5 Outlook ...................................................................................... 75 5.1 Literature Cited....................................................................................................................... 77 Acknowledgments ............................................................................................................................ 79 Curriculum Vitae ............................................................................................................................... 81 v List of Figures Fig. 1.1 Lethality of Electrophiles for the Fish Pimephales promelas compared to their Theoretical Baseline Toxicity and the Environmental Hazardous Concentration....... 4 Fig. 1.2 Species Sensitivity Distribution for Baseline Chemicals and the Reactive Chemicals Epichlorohydrin, Benzyl Chloride, and Acrolein ......................................................... 5 Fig. 1.3 Time Scale of Events from Uptake of Electrophiles to Possible Toxic Effects and Continuous Scale of Hard and Soft Tendency of Nucleophiles and Electrophiles Leading to Different Proportions of Biomarkers and Toxic Effects ............................ 6 Fig. 1.4 Synthesis of Glutathione and Chemical and Enzymatically Catalyzed Reactions with Oxidizing and Alkylating Agents and the Likely Subsequent Toxicological Effects for a Prokaryote........................................................................................................... 7 Fig. 1.5 Schematic Structure of the Thesis and Association between Results of the Chapters...................................................................................................................... 8 Fig. 2.1 Toxicokinetic and Toxicodynamic Effects from Single
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