Klaus Kummerer(Editor)

Pharmaceuticalsin the EnvironmentSources, Fate, Effects and Risks

Second editionWith 91 Figures and 77 Tables

YJ Springer

Contents

Part I Introduction 1

1 Pharmaceuticals in the Environment -Scope of the Book and Introduction 3

1.1 Pharmaceuticals - A Highly Diverse Group of Chemicalswith Special Properties 3

1.2 Use and Input into the Environment 41.3 Occurrence and Fate in the Environment 61.4 Effects 71.5 Resistance 81.6 Risk and Risk Management 81.7 Conclusion 9

References 10

2 Special Characteristics of PharmaceuticalsRelated to Environmental Fate 13

2.1 Introduction 132.2 Solid State Chemistry of Pharmaceuticals 132.3 Metabolism 142.4 Molecular Structure 162.5 Ionisation 182.6 Dissociation Constant 182.7 Octanol/Water Distribution Coefficient 192.8 Sludge Sorption/Desorption (iCbiomass or JCp) 20

References 23

Part II Use and Occurence of Pharmaceuticals in the Environment 25

3 Emissions from Medical Care Units 273.1 Introduction 273.2 Cytostatic Agents 273.3 Antibiotics 293.4 Disinfectants >. 313.5 Anaesthetics 323.6 AOX (Adsorbable Organic Halogen Compounds) 333.7 Iodinated X-ray Contrast Media 35

XIV Contents

3.8 Emissions from Clinical Chemical Laboratories 373.9 Heavy Metals 38

3.9.1 Platinum 383.9.2 Mercury 393.9.3 Gadolinium : 40References 41

4 Pharmaceuticals in the Environment: Changes in the Presenceand Concentrations of Pharmaceuticals for Human Use in Italy 45

4.1 Introduction 454.2 Materials and Methods 45

4.2.1 Method of Analysis 474.3 Results and Discussion 50

References 53

5 Environmental Exposure of Antibiotics inWastewaters, Sewage Sludges and Surface Waters in Switzerland 55

5.1 Introduction 555.2 Fluoroquinolones 575.3 Macrolides 615.4 On-going and Future Research 64

Acknowledgements -. 65References 65

6 Pharmaceuticals in the Canadian Environment 676.1 Overview 676.2 Pharmaceuticals Investigated in the Canadian Environment 68

6.2.1 Therapeutic Uses 686.2.2 Therapeutic Pharmaceutical Sales in Canada 71

6.3 Sources of PhACs 726.4 Occurrence of Pharmaceuticals in the Canadian Environment 73

6.4.1 Sewage 736.4.2 Surface Water' : 766.4.3 Drinking Water 82

6.5 Regulatory Framework 856.6 Conclusions and Recommendations 86

Acknowledgements 87References 87

7 Occurrence of Human Pharmaceuticals inWater Resources of the United States: A Review 91

7.1 Introduction 917.2 Environmental Contaminant Monitoring in

Water Resources of the United States ' 927.3 Environmental Occurrence Studies of Pharmaceuticals in

Water Resources of the United States 94

Contents XV

7.3.1 Local Studies 947.3.2 Regional and National Studies 99

7.4 Summary 102References 102

8 Strategies for Selecting Pharmaceuticals to Assess AttenuationDuring Indirect Potable Water Reuse 107

8.1 Introduction 1078.2 Quantification of Pharmaceuticals in Wastewater Effluent 1088.3 Predicting Concentrations of Pharmaceuticals in Wastewater Effluent 1128.4 Attenuation of Pharmaceuticals of Interest 113

8.4.1 Surface Waters 1148.4.2 Groundwater 115

8.5 Other Pharmaceuticals and Wastewater-Derived Contaminants 1168.6 Conclusions and Recommendations for Future Research 116

References 118

9 Residues of Clofibric Acid, Ibuprofen and Diclofenac in theAquatic Environment and their Elimination in Sewage Treatmentand Drinking Water Production 121

9.1 Introduction 1219.2 Clofibric Acid, Ibuprofen and Diclofenac in Sewage Water Treatment 1249.3 Clofibric Acid, Ibuprofen and Diclofenac in Drinking Water Treatment 1289.4 Future Research Needs 130

References 130

10 Drugs in Municipal Landfills and Landfill Leachates 13310.1 Introduction 13310.2 Drugs in Landfill Leachates 13310.3 Analysis of Drugs in Landfill Leachate 134

10.3.1 Analysis of Propyphenazone, Aminopyrine and Antipyrine(Ahel and Jelicic 2001) 134

10.3.2 Procedure of Breidenich (Breidenich 2003) 13510.3.3 Procedure of Schneider et al. (2001) 135

10.4 Discussion 136References 136

11 Antibiotics in Soil: Routes of Entry, Environmental Concentrations,Fate and Possible Effects 139

11.1 Introduction 13911.2 Routes of Entry for Antibiotics into Soil 13911.3 Environmental Concentrations 141

11.3.1 Antibiotics in Sediments 14111.3.2 Antibiotics in Soil 141

11.4 Fate of Antibiotics in Soil 14311.5 Possible Effects of Antibiotics in Soil 144

XVI Contents

11.6 Summary and Outlook 145Acknowledgements .1. 146References 146

12 Use of Veterinary Pharmaceuticals in the United States 14912.1 Introduction 14912.2 Regulation 14912.3 Veterinary Drugs and Food Additives Use in Food Animals 151

12.3.1 Poultry 15212.3.2 Beef Production 15212.3.3 Dairy Cattle 15312.3.4 Swine 15312.3.5 Aquaculture (Fish and Shellfish) 154

12.4 Conclusions 154Acknowledgements 154References 154

13 Use and Environmental Occurrence ofVeterinary Pharmaceuticals in United States Agriculture 155

13.1 Introduction 15513.2 Use of Veterinary Pharmaceuticals 15513.3 Environmental Occurrence of Veterinary Pharmaceuticals 156

13.3.1 Occurrence of Veterinary Pharmaceuticals inAnimal Feeding Operations 157

13.3.2 Degradation of Veterinary Pharmaceuticals in Manure and Soil 15813.3.3 Occurrence of Veterinary Pharmaceuticals in

Surface Water and Groundwater 15813.4 Effects of Veterinary Pharmaceuticals 15913.5 Conclusions 160

Acknowledgements 161References : 161

14 Fate of Veterinary Medicines Applied to Soils 16514.1 Introduction 16514.2 Releases to the Environment 166

14.2.1 Persistence in Manure and Slurry 16614.3 Fate in Soil 167

14.3.1 Sorption in Soil 16714.3.2 Persistence in Soil 16914.3.3 Dissipation in Field 171

14.4 Transport from Soils to Water Bodies 17214.4.1 Overland Flow 17214.4.2 Drainflow , 17314.4.3 Leaching 173

14.5 Fate in Surface Waters 17414.6 Summary and Recommendations 176

Contents XVII

Acknowledgements 178

References 178

Part III Fate and Effects of Pharmaceuticals in the Environment 181

15 Pharmaceuticals as Environmental Contaminants:

Modelling Distribution and Fate 18315.1 Introduction 183

15.2 Data Evaluation 183

15.3 Generic Model 185

15.4 Regional Model 189

15.5 Site Specific Models 193

15.6 Discussion and Conclusions 193

References 194

16 Effects of Pharmaceuticals on Aquatic Invertebrates -The Example of Carbamazepine and Clofibric Acid 195

16.1 Introduction 195

16.2 Materials and Methods 197

16.3 Results and Discussion 199

16.3.1 Acute Tests 199

16.3.2 Life-Cycle-Test and Reproduction Tests 200

16.3.3 Sediments in Further Research on Pharmaceuticals 206

References 207

17 What Do We Know about Antibiotics in the Environment? 20917.1 Introduction 209

17.2 Use, Emission and Occurrence of Antibiotics in the Environment 209

17.2.1 Wastewater, Surface Water and Groundwater 210

17.2.2 Sewage Sludge, Soil and Sediment 211

17.3 Fate of Antibiotics in the Environment 212

17.3.1 Elimination 212

17.4 Effects on the Environment 214

17.4.1 Wastewater and Sewage System 214

17.4.2 Surface Water 215

17.4.3 Soil and Sediments 217

17.5 Conclusion 218

Acknowledgements 218

References , 218

18 Resistance in the Environment 22318.1 Antibiotics, Bacteria and Resistance 223

18.2 Sources for Antibiotics and Resistance in the Environment 226

18.3 Input of Resistant Bacteria into the Environment 228

18.4 Conclusion 230

References ' 230

XVIII Contents

19 Effects of Ethinyloestradiol and Methyltestosterone inProsobranch Snails 233

19.1 Introduction 23319.2 Materials and Methods .': 23419.3 Results and Discussion : 235

19.3.1 Effects on Females at Concentrations from 0.1 to 1 ug I"1 23519.3.2 Effects on Males at Concentrations from 0.1 to 1 ug I"1 24019.3.3 Effects of EE2 at Concentrations from 1 to 100 ng I"1 24019.3.4 Synopsis of Effects Data for EE2 and MT in Marisa cornuarietis 245Acknowledgements 246References 246

Part IV Risk Assessment and Risk Management 249

20 Risk Assessment of Organic Xenobiotics in the Environment 25120.1 Introduction 25120.2 Definitions 25120.3 Global Approach 255

20.3.1 Assessment Endpoints 25520.3.2 Determination of Exposures and Effects 25620.3.3 Determination of Acceptable Level in Environment -

Example of an Application: Determination of Safe Levelsfor PAHs in Urban Sewage Sludges 258

20.4 Specific Approach 26320.5 Conclusion: Application to Pharmaceuticals 266

References 267

21 Environmental Risk Assessment of Medicinal Products forHuman Use: Aspects of Its Regulations in the European Union,Canada and United States 269

21.1 Introduction 26921.2 Regulations in the United States 271

21.2.1 Categorical Exclusion (CE) 27221.2.2 Environmental Assessment (EA) 27321.2.3 Environmental Impact Statement (EIS) 27321.2.4 The Retrospective Review of Ecotoxicological Data by the

United States Food and Drug Administration (FDA)and the Final Rule 273

21.3 Regulations in the European Union 27521.3.1 The Notes for Guidance 27521.3.2 General Principles for Environmental Risk Assessment of

Medicinal Products in the European Union 27621.4 Canada 27721.5 The Action Limits 278

21.5.1 United States 27821.5.2 The European Union 279

Contents XIX

21.6 The Format and Reporting of Marketing Applications andSuggested Safety Measures in the European Union 28121.6.1 The Environmental Risk Assessment Report 28121.6.2 Suggested Safety Measures in the European Union 281

21.7 Substances Used in Medicinal Products which Destroy the Ozone Layer:The Perspectives in the European Union 28221.7.1 Solvents 28221.7.2 Development of CFC Replacements 28321.7.3 European Strategy for Phase-Out of CFC in MDIs 28421.7.4 Criteria for Determining When Sufficient Alternatives

Are Available 28621.7.5 Education Programme and Post-Marketing Surveillance 28621.7.6 Final Remarks on CFCs 287References 287

22 Environmental Risk Assessment of Pharmaceuticals in the EU -A Regulatory Perspective 289

22.1 Human and Veterinary Medicinal Products 28922.2 The EU Guidance Document on the Environmental Risk Assessment of

Medicinal Products for Human Use 29022.2.1 Scope and Structure of the

Draft Guidance Document CPMP/SWP/4447/00 29122.2.2 PEC ini t ia l and the Market Penetration Factor 29222.2.3 Base Data Set 29322.2.4 Decision Criteria 29422.2.5 Risk Characterisation 29522.2.6 Hazard Identification and Subsequent Risk Characterisation 29622.2.7 PEC Refinement 29722.2.8 Outcome 298

22.3 Veterinary Medicinal Products 29922.3.1 Phase I of the Environmental Risk Assessment for

Veterinary Medicinal Products 30022.3.2 Phase II of the Environmental Risk Assessment for

Veterinary Medicinal Products 30222.4 Feed Additives 30722.5 Immunological Products for Veterinary Use 30822.6 Medicinal Products Containing or Consisting of

Genetically Modified Organisms 308Acknowledgements 309References 309

23 The ECO-SHADOW Concept -A New Way of Following Environmental Impacts of Antimicrobials . . . 311

23.1 General Introduction .̂ 31123.2 The ECO-SHADOW Concept 31223.3 Influences of Antibiotics on Environmental Ecosystems 313

XX Contents

23.4 Future Tasks 315References 315

24 A Data-based Perspective on the Environmental Risk Assessment ofHuman Pharmaceuticals I - Collation of Available Ecotoxicity Data ... 317

24.1 Introduction 31724.2 Methods 31724.3 Results 317

24.3.1 Acute Ecotoxicity Data 31724.3.2 Chronic Ecotoxicity Data 333

24.4 Discussion 33524.5 Conclusions 340

References 340Appendix 343

25 A Data Based Perspective on the Environmental Risk Assessment ofHuman Pharmaceuticals II - Aquatic Risk Characterisation 345

25.1 Introduction 34525.2 Methodology 34725.3 Results 34825.4 Discussion 35425.5 Conclusions 358

References 359

26 A Data Based Perspective on the Environmental Risk Assessment ofHuman Pharmaceuticals III - Indirect Human Exposure 363

26.1 Introduction 36326.2 Methodology 36326.3 Results 36426.4 Discussion 36426.5 Conclusions 370

References 370

27 Plasma Concentrations of Human Pharmaceuticals asPredictors of Pharmacological Responses in Fish 373

27.1 Introduction 37327.2 Experimental 374

27.2.1 Model Description 37427.2.2 Experimental Validation of Uptake 37527.2.3 Analytical Methodology 375

27.3 Result and Discussion 37627.3.1 Model Analysis 37627.3.2 Experimental Validation 37927.3.3 Tier Testing Strategy : 38127.3.4 Mixtures 382

27.4 Conclusions 383References 385

Contents XXI

28 Using (Quantitative) Structure-Activity Relationships inPharmaceutical Risk Assessment 387

28.1 Introduction 38728.2 Types of SAR 38728.3 Use of (Q)SAR 7. -. 38828.4 Conclusion 389

References 389

29 Removal of Pharmaceutical Residues fromContaminated Raw Water Sources by Membrane Filtration 391

29.1 Introduction 391^29.2 Mobile Drinking Water Purification Units (MDWPUs) 39229.3 Experimental Details 393

29.3.1 Specifications of the Tested MDWPUs 39329.3.2 Description of the First Field Site at the Teltowkanal 39729.3.3 Description of the Second Field Site and Experimental Design 39929.3.4 Sample Storage and Analysis 400

29.4 Results and Discussion 40029.4.1 Results from the First Field-Trial at the

Teltowkanal in Berlin, Germany 40029.4.2 Results from the Second Field-Trial at the

Sewage Treatment Plant in Ruhleben (Berlin, Germany) 40129.5 Conclusions and Future Applications of MDWPUs 40729.6 Summary and Outlook 407

Acknowledgements 408References 409

30 Potential Environmental Risks by Cleaning Hair and SkinEco-Label - A Possibility to Reduce Exposure to Personal Care Products 411

30.1 Introduction 41130.1.1 Availability of Data 41130.1.2 Definitions 41130.1.3 Shampoos, Shower Gels and Foam Baths (SSBs) 41230.1.4 Legislation 413

30.2 Formulations of SSBs 41330.2.1 Functions of Ingredients 41330.2.2 Cosmetic Frame Formulations 41530.2.3 Step-Wise Approach for Selection of Ingredients of SSBs for

Further Consideration 41530.2.4 Lists of Ingredients on the Product Container 41630.2.5 Characterisation of Ingredients 41730.2.6 Ecotoxicological Evaluation of Ingredients 41830.2.7 Preliminary Risk Assessment of Ingredients 421

30.3 Eco-Labelling 42230.3.1 General Considerations 42230.3.2 Eco-Labelling for SSBs 425

30.4 Summary and Outlook 426

XXII Contents

Acknowledgements 427

References 427

Part V Need for Further Research 429

31 Risks Related to the Discharge of Pharmaceuticals

in the Environment: Further Research Is Needed 43131.1 Introduction 43131.2 Drugs in the Environment 43231.3 Assessment of Environmental Risk 432

31.3.1 Predicted Environmental Concentrations 43231.3.2 Predicted No-Effect Concentrations 43331.3.3 PEC/PNEC Comparison 433

31.4 Need for Further Research 43331.4.1 Uncertainty in Refining PEC

(Need to Assess the Environmental Fate of the Pharmaceuticals) . . . 43331.4.2 Uncertainty in Refining PNEC

(Need for Standard Toxicity Tests on Environmental Organisms) . . . 435Acknowledgements 437References 437

32 Methodological Aspects Concerning the EnvironmentalRisk Assessment for Medicinal Products - Research Challenges 439

32.1 Introduction 43932.2 Protection Goals 44032.3 Research Challenges 442

32.3.1 Veterinary Medicines: Protection Goals and Risk Models 44432.3.2 Human Medicines: Protection Goals and Risk Models 447

32.4 Pharmaceuticals in Drinking Water:A Comparison of Human and Environmental Risk Assessment 448

32.5 Discussion 455Acknowledgements 456References r. 456

33 PPCPs in the Environment:Future Research - Beginning with the End Always in Mind 463

33.1 Introduction and Background 46333.2 PPCPs as "Emerging" Pollutants? 46433.3 Drivers and Outcomes -

A Perspective from a Regulatory Agency (US EPA) 46533.4 The Logic Model - Beginning with the End Always in Mind 46533.5 Drivers, Gaps, Needs, and Outcomes 46633.6 Science Drivers 46733.7 Research and Development 46733.8 Supporting Data : 46833.9 Outcomes 468

Contents XXIII

33.10 Overarching Issues and Generalisations 47133.11 Summary of Specific Research/Knowledge Needs, Gaps,

Uncertainties, Questions, and Issues 47433.12 Needs and Gaps 475

33.12.1 Research Coordination 47533.12.2 Sources/Origins 47633.12.3 Occurrence 47833.12.4 Fate and Transport 47933.12.5 Hydrology 48033.12.6 Toxicology 48233.12.7 Analytical Chemistry 48533.12.8 Monitoring 48533.12.9 Environmental Stewardship 48733.12.10 Engineering 48833.12.11 Risk Assessment/Regulation 48933.12.12 Communication of Risk 49033.12.13 Public Outreach 49133.12.14 Fostering New Research and Research Planning 49133.12.15 Summary - and the Future 49233.12.16 Notice 493References 493

Part VI Conclusion 497

34 Conclusion 49934.1 General Remarks 49934.2 Use Patterns 49934.3 Analytical Data 50034.4 Fate and Effects 50034.5 Risk Assessment and Risk Management 50234.6 Summary 503

Subject Index 505