Food chemical risk analysis

Foreword ......................................................................... xv Contributors ..................................................................... xix Preface ............................................................................ xxiii Part I. Introduction ........................................................ 1 1. Food, Chemicals and Risk Analysis ................................... 3 1.1 Introduction .......................................................... 3 1.2 Food Chemicals ................................................... 4 1.3 Characteristics of Food Chemicals ...................... 5 1.3.1 Food Additives ............................................ 5 1.3.2 Pesticide Residues ..................................... 6 1.3.3 Veterinary Residues ................................... 6 1.3.4 Environmental Contaminants ..................... 6 1.3.5 Biogenic Contaminants .............................. 7 1.3.6 Inherent Phytotoxins ................................... 8 1.3.7 Cooking and Processing Contaminants ............................................. 8 1.3.8 Food Contact Materials .............................. 8 1.3.9 Novel Foods and Novel Food Technologies .............................................. 8 1.3.10 Beneficial Food Chemicals ......................... 9 1.3.11 Toxicological Effects of Food Chemicals ................................................... 10 vi Contents This page has been reformatted by Knovel to provide easier navigation. 1.4 Risk Analysis ....................................................... 10 1.4.1 Risk Assessment ........................................ 13 1.4.2 Risk Management ...................................... 13 1.4.3 Risk Communication .................................. 14 1.5 The Nature of Risk ............................................... 14 1.6 Personal Decisions about Risks .......................... 15 1.7 The Use of Risk Analysis in Food Safety ............. 16 1.8 Uncertainty .......................................................... 16 1.9 Conclusion ........................................................... 17 Further Reading ............................................................ 18 Part II. Risk Assessment ............................................... 19 2. Food Chemical Risk Assessment ....................................... 21 2.1 Introduction .......................................................... 21 2.2 Current Approaches to Risk Assessment ............. 22 2.2.1 Hazard Identification and Prioritization ....... 22 2.2.2 Hazard Characterization ............................. 23 2.2.3 Occurrence Information .............................. 24 2.2.4 Food Consumption Data ............................ 25 2.2.5 Intake Estimation ........................................ 25 2.2.6 Risk Characterization ................................. 26 2.3 Sources of Uncertainty in Hazard Characterization .................................................. 26 2.3.1 Uncertainty Analysis ................................... 27 2.3.2 Animal Studies ........................................... 29 2.3.3 In Vitro Studies ........................................... 32 2.3.4 Human Studies ........................................... 33 2.3.5 Thresholded Toxins .................................... 34 2.3.6 Non-Thresholded Toxins ............................ 36 2.3.7 Interactions Between Food Chemicals ....... 40 2.3.8 Individual Susceptibility .............................. 41 Contents vii This page has been reformatted by Knovel to provide easier navigation. 2.4 Uncertainties in Risk Characterization ................. 42 2.4.1 Interpretation of Hazard Evaluation ............ 43 2.4.2 Variations in Food Chemical Intakes .......... 43 2.4.3 Time Integration of Intake Estimates .......... 44 2.4.4 Effect of Short-Term Variations in Food Consumption on Estimates of Intake .......... 44 2.4.5 Effect of Long-Term Variations in Food Consumption on Estimates of Intake .......... 46 2.4.6 Toxicological Significance of Dosing Period ......................................................... 46 2.4.7 Corrections for Body Weight and Age ........ 47 2.4.8 Effect of Age on Food Chemical Intakes ........................................................ 48 2.4.9 Correction Factors for Children’s Intakes ........................................................ 50 2.4.10 Alternative Correction Factors ..................... 50 2.4.11 Risk Characterization Developmental Needs ......................................................... 52 2.5 Opportunities for Development in Risk Assessment ......................................................... 52 2.6 Conclusion ........................................................... 53 References .................................................................... 54 3. Quantitative Risk Assessment ............................................ 57 3.1 Introduction .......................................................... 57 3.2 What Is QRA? Definitions .................................... 57 3.2.1 Terminology: Hazard, Risk, Safety ............. 58 3.2.2 QRA ............................................................ 58 3.3 QRA and Food Safety: UK and US Perspectives ........................................................ 59 3.3.1 Before Delaney ........................................... 60 3.3.2 The Delaney Clause ................................... 60 viii Contents This page has been reformatted by Knovel to provide easier navigation. 3.3.3 After Delaney: Diethylstilboestrol, Packaging ................................................... 60 3.3.4 The 1990s and Court Rulings ..................... 61 3.3.5 Moves to Change Delaney (Unfinished Business) .................................................... 62 3.3.6 Department of Health, Committee on Carcinogenicity Approaches ....................... 63 3.3.7 EU Approaches .......................................... 63 3.3.8 GATT, NAFTA ............................................ 64 3.4 Advantages of QRA ............................................. 64 3.4.1 VSD, De Minimis, 'Bright Lines' and Negligible Risk ............................................ 64 3.4.2 ALARA and BATNEEC ............................... 65 3.5 Safety Factor Versus Mathematical Modeling ...... 66 3.5.1 Safety Factor .............................................. 66 3.5.2 Mathematical Modeling .............................. 68 3.6 The LMS Model ................................................... 71 3.6.1 Theory ........................................................ 71 3.6.2 The LMS Model in Practice ........................ 72 3.6.3 Limitations of the Mathematical Models Used in QRA .............................................. 73 3.7 Developments in Modeling ................................... 74 3.7.1 Time-to-Tumour Models ............................. 74 3.7.2 Physiologically-Based Pharamacokinetic (PB-PK) Models ............ 76 3.7.3 Biologically Based Dose-Response (BB-DR) Models ......................................... 77 3.7.4 Benchmark Doses ...................................... 78 3.7.5 Biomarkers ................................................. 79 3.8 Future Developments in QRA .............................. 80 3.8.1 New EPA Guidelines .................................. 80 Contents ix This page has been reformatted by Knovel to provide easier navigation. 3.8.2 Linkage of PB-PK and BB-DR Models ....... 81 3.9 Conclusion ........................................................... 82 References .................................................................... 85 4. Biomarkers in Epidemiological and Toxicological Nutrition Research ............................................................... 87 4.1 Introduction .......................................................... 87 4.2 Classification of Biomarkers ................................ 88 4.3 Markers of External and Internal Exposure .......... 90 4.4 Markers of Biologically Effective Dose ................. 90 4.5 Markers of Early Biological Effects ...................... 94 4.6 Markers of Modified Structure or Function ........... 96 4.7 Markers of Individual Sensitivity ........................... 97 4.8 Selection, Evaluation and Application of Biomarkers .......................................................... 98 4.8.1 Biological Aspects ...................................... 99 4.8.2 Ethical Implications and Constraints .......... 99 4.8.3 Practical and Analytical Aspects ................ 101 4.8.4 Sensitivity and Specificity ........................... 102 4.8.5 Human Variability and Study Design .......... 103 4.9 Conclusions ......................................................... 104 Acknowledgement ......................................................... 105 References .................................................................... 105 5. Expert Systems for Hazard Evaluation ............................... 109 5.1 Introduction .......................................................... 109 5.2 Factors Influencing Biological Activity .................. 111 5.3 Making Rules for Expert Systems ........................ 114 5.3.1 Binary Trees ............................................... 115 5.3.2 Statistical Methods ..................................... 116 5.3.3 Probabilities ................................................ 118 5.3.4 Knowledge Bases ....................................... 118 x Contents This page has been reformatted by Knovel to provide easier navigation. 5.4 Representation of Chemical Structural Information .......................................................... 119 5.5 Structural Descriptors Used in Expert Systems ............................................................... 121 5.5.1 Augmented Atoms ...................................... 123 5.5.2 Atom and Bond Sequences ........................ 124 5.5.3 Ring Descriptors ......................................... 124 5.5.4 Atom Pairs .................................................. 124 5.5.5 Three-Dimensional Descriptors .................. 125 5.6 The Effects of Choosing Different Types of Descriptors .......................................................... 126 5.7 Assessment of Hazard and Risk .......................... 128 5.8 Some Examples of Expert Systems ..................... 128 5.9 The Implications of Choosing Different Types of System ............................................................ 130 5.10 Applicability of Expert Systems to Food Chemical Hazard Evaluation ................................ 131 References .................................................................... 132 6. Risk Assessment: Alternatives to Animal Testing .............. 133 6.1 Introduction .......................................................... 133 6.2 The Three Rs Concept ........................................ 134 6.3 Statistics for the Use of Animals in Food Safety Evaluation ................................................. 135 6.3.1 UK .............................................................. 135 6.3.2 Europe ........................................................ 136 6.4 Legislation Relating to Food Additive Safety Assessment ......................................................... 136 6.4.1 UK Legislation ............................................ 136 6.4.2 European Legislation .................................. 137 6.4.3 US Legislation ............................................ 138 Contents xi This page has been reformatted by Knovel to provide easier navigation. 6.5 Tests Required for Food Safety Assessment ....... 139 6.5.1 Acute Oral Toxicity Tests ........................... 139 6.5.2 Short-Term Genetic Toxicity Tests ............. 139 6.5.3 Metabolism and Pharmacokinetic Studies ....................................................... 139 6.5.4 Immunotoxicity Tests .................................. 140 6.5.5 Neurotoxicity Tests ..................................... 140 6.5.6 Reproductive and Developmental (Teratogenic) Toxicity Tests ....................... 141 6.5.7 Carcinogenicity and Chronic Toxicity Tests ........................................................... 141 6.5.8 Determination of the no Observed Adverse Effect Level .................................. 142 6.5.9 Determination of the Acceptable Daily Intake .......................................................... 142 6.6 Problems with Animal Tests ................................. 143 6.6.1 Determination of the NOAEL and the ADI ............................................................. 143 6.6.2 Use of High Doses ..................................... 144 6.7 Currently Available Alternatives ........................... 144 6.7.1 Reduction Alternatives ............................... 145 6.7.2 Refinement Alternatives ............................. 149 6.7.3 Replacement Alternatives .......................... 149 6.8 Conclusions ......................................................... 157 References .................................................................... 159 7. Molecular Modeling ............................................................. 163 7.1 Introduction .......................................................... 163 7.2 Chemical Safety Evaluation and Risk Assessment ......................................................... 165 7.3 The COMPACT Approach ................................... 168 xii Contents This page has been reformatted by Knovel to provide easier navigation. 7.4 Cytochromes P450 and Their Role in Metabolic Activation ............................................. 173 7.5 Protein Modeling .................................................. 177 7.6 Quantitative Structure-Activity Relationships ....... 179 7.7 Conclusions ......................................................... 184 Acknowledgement ......................................................... 191 References .................................................................... 191 8. Estimation of Dietary Intake of Food Chemicals ................. 195 8.1 Introduction .......................................................... 195 8.2 Intake Assessment Methods for Pesticides and Other Agricultural Chemicals ........................ 196 8.2.1 Total Diet Studies ....................................... 196 8.2.2 Food Grouping Model ................................. 197 8.2.3 Federal Biological Agency for Agricultural and Forestry Management ...... 197 8.2.4 World Health Organization Tiered Approaches ................................................ 197 8.3 Intake Assessment Methods for Food Additives .............................................................. 203 8.3.1 Analysis for Additive Usage Data ............... 203 8.3.2 Food and Nutrition Division of the French Council of Public Health Method ....................................................... 203 8.3.3 Budget Method ........................................... 203 8.3.4 Codex Proposal for Tiered Additive Intake Assessment ..................................... 204 8.4 Food Consumption Data Sources for Food Chemical EDI Assessment .................................. 206 8.4.1 Food Consumption Survey Methodology ............................................... 206 Contents xiii This page has been reformatted by Knovel to provide easier navigation. 8.4.2 Validity, Reliability and Sources of Error in Food Consumption Survey Data ............ 209 8.4.3 Food Consumption Data Required for EDI Analysis ............................................... 211 8.5 Future Trends in Food Chemical Risk Assessment ......................................................... 213 8.5.1 Probabilistic Methods in Food Chemical Intake Estimation ........................................ 213 8.5.2 Intake of Multiple Chemicals ...................... 214 8.6 Uncertainty in Intake Assessment ........................ 215 8.7 Future Needs for Dietary Intake Assessment ....... 215 References .................................................................... 216 9. Assessing Risks to Infants and Children ............................ 219 9.1 Introduction .......................................................... 219 9.2 Infants and Children – Unique Population Subgroups ........................................................... 220 9.2.1 Pharmacokinetics and Pharmacodynamics .................................... 221 9.2.2 Toxicity ....................................................... 223 9.2.3 Exposures .................................................. 224 9.3 Implications for Risk Assessment ........................ 226 9.3.1 Toxicological Considerations ...................... 226 9.3.2 Exposure Assessment ................................ 229 9.3.3 Risk Characterization ................................. 233 9.4 Other Considerations ........................................... 235 9.4.1 In Utero Exposures ..................................... 236 9.4.2 Multiple Chemical Exposures ..................... 236 9.5 Conclusion ........................................................... 237 References .................................................................... 238 xiv Contents This page has been reformatted by Knovel to provide easier navigation. 10. Dietary Chemoprevention in Toxicological Perspective .......................................................................... 240 10.1 Introduction – Nutrition and Cancer ..................... 240 10.2 Risk Assessment of Carcinogens ........................ 241 10.2.1 Threshold Approach for Non-Genotoxic Carcinogens ............................................... 241 10.2.2 Non-Threshold Extrapolation for Genotoxic Carcinogens .............................. 243 10.3 Genotoxic Substances in the Diet ........................ 243 10.4 Chemopreventive Substances in the Diet ............ 244 10.4.1 Tiered Approach for Studying Chemopreventive Agents ........................... 245 10.4.2 Mechanisms of Action ................................ 248 10.4.3 Alteration of Biotransformation Capacity .... 249 10.4.4 Nutritive Dietary Chemopreventive Agents ......................................................... 252 10.4.5 Non-Nutritive Dietary Chemopreventive Agents ........................................................ 253 10.5 The Lessons of Toxicology Transposed to Chemoprevention: Four Caveats ......................... 256 10.5.1 A First Caveat: Assessment of Antimutagenic Potential .............................. 257 10.5.2 A Second Caveat: The Threshold Concept ...................................................... 258 10.5.3 A Third Caveat: Beware of Toxicity! ........... 258 10.5.4 A Fourth Caveat: (Anti)Carcinogens Are Not Always (Anti)Mutagens and Vice Versa .......................................................... 259 10.6 Feasibility of Dietary Chemoprevention in Humans ............................................................... 260 10.6.1 Evidence from Epidemiological Studies ....................................................... 260 Contents xv This page has been reformatted by Knovel to provide easier navigation. 10.6.2 Evidence from Experimental Studies in Humans ...................................................... 260 10.6.3 More Than One Beneficial Compound: The Matrix Approach .................................. 261 10.7 Conclusion ........................................................... 262 Acknowledgements ....................................................... 262 References .................................................................... 263 11. Prioritization of Possible Carcinogenic Hazards in Food ..................................................................................... 267 11.1 Causes of Cancer ................................................ 267 11.2 Cancer Epidemiology and Diet ............................ 267 11.2.1 Dietary Fruits and Vegetables .................... 268 11.2.2 Calorie Restriction ...................................... 268 11.2.3 Other Aspects of Diet ................................. 269 11.3 Human Exposures to Natural and Synthetic Chemicals ............................................................ 270 11.4 The High Carcinogenicity Rate among Chemicals Tested in Rodents .............................. 273 11.5 The Importance of Cell Division in Mutagenesis and Carcinogenesis ........................ 274 11.6 Ranking Possible Carcinogenic Hazards ............. 276 11.6.1 Natural Pesticides ...................................... 280 11.6.2 Synthetic Pesticides ................................... 281 11.6.3 Cooking and Preparation of Food .............. 281 11.6.4 Food Additives ............................................ 282 11.6.5 Mycotoxins ................................................. 283 11.6.6 Synthetic Contaminants ............................. 284 11.7 Future Directions ................................................. 285 Acknowledgements ....................................................... 289 References .................................................................... 289 xvi Contents This page has been reformatted by Knovel to provide easier navigation. 12. Threshold of Regulation ...................................................... 296 12.1 Introduction .......................................................... 296 12.2 The Threshold of Regulation in Practice .............. 304 12.3 Advantages and Effects of the Threshold of Regulation Process ............................................. 308 12.4 Future Issues ....................................................... 311 References .................................................................... 316 13. An Approach to Understanding the Role in Human Health of Non-Nutrient Chemicals in Food ......................... 317 13.1 Introduction .......................................................... 317 13.2 Non-Nutrient Chemicals under Discussion ........... 319 13.3 A New Approach .................................................. 320 13.4 Factors Affecting the Action of Chemicals in Food .................................................................... 321 13.4.1 Bioavailability .............................................. 321 13.4.2 Products Entering the Circulation ............... 322 13.4.3 Multiple Functionality .................................. 322 13.5 The Approach ...................................................... 322 13.5.1 Phase I ....................................................... 324 13.5.2 Phase II ...................................................... 324 References .................................................................... 326 Part III. Risk Management ............................................. 329 14. The Philosophy of Food Chemical Risk Management ....... 331 14.1 Introduction – Responsibilities and Benefits ........ 331 14.2 A New Game on a Different Playing Field ............ 332 14.3 The Emerging Role of the Risk Manager ............. 333 14.4 A Glimpse into the Deliberations of the Risk Manager .............................................................. 334 14.5 Applying the Philosophy – Using the Tools .......... 335 Contents xvii This page has been reformatted by Knovel to provide easier navigation. 15. Consumer Perceptions ........................................................ 336 15.1 Introduction .......................................................... 336 15.2 Ranking the Risks ................................................ 338 15.3 Theories of Risk Perception ................................. 344 15.3.1 The Psychometric Paradigm ...................... 345 15.3.2 Relationship to Sociodemographic Variables .................................................... 348 15.3.3 The Cultural Theory of Risk ........................ 350 15.4 Risk Debates and the Importance of Trust ........... 354 15.5 Conclusion ........................................................... 357 Acknowledgement ......................................................... 359 References .................................................................... 359 16. Decision Aids ....................................................................... 362 16.1 Introduction .......................................................... 362 16.2 Risk-Benefit Analysis ........................................... 365 16.2.1 The Analytical Framework .......................... 365 16.2.2 The Scope of the Analysis .......................... 366 16.3 Assessing Impacts on Producers and Consumers .......................................................... 369 16.4 Valuing Human Health Risks ............................... 372 16.4.1 The Risk Assessment Process ................... 372 16.4.2 The Valuation Techniques .......................... 372 16.4.3 Other Valuation Techniques ....................... 375 16.5 Links to the Environment ..................................... 376 16.6 Summary and Conclusion .................................... 379 References .................................................................... 379 17. Risk Evaluation, Risk Reduction and Risk Control ............. 381 17.1 Introduction .......................................................... 381 17.2 Risk Evaluation .................................................... 381 17.2.1 Stakeholder Analysis .................................. 382 xviii Contents This page has been reformatted by Knovel to provide easier navigation. 17.2.2 Decision Analysis ....................................... 382 17.2.3 Ethical and Moral Dimensions .................... 383 17.2.4 Quantitative Risk Evaluation ...................... 384 17.2.5 Managing Uncertainty ................................ 384 17.2.6 Sensitivity Analysis ..................................... 385 17.3 Risk Reduction .................................................... 385 17.3.1 Options for Food Additive Risk Reduction ................................................... 387 17.3.2 Options for Food Contaminant Risk Reduction ................................................... 389 17.4 Risk Control ......................................................... 390 17.4.1 Risks and Regulation ................................. 390 17.4.2 Less Prescriptive Control Methods ............. 391 17.4.3 Voluntary Agreements ................................ 392 17.4.4 Codes of Practice ....................................... 392 17.4.5 Hazard Analysis Critical Control Points ......................................................... 393 17.4.6 Good Manufacturing Practice and ISO 9000 ........................................................... 396 17.4.7 Monitoring and Surveillance ....................... 396 17.5 Evaluating, Reducing and Controlling Risks – Getting the Balance Right .................................... 397 References .................................................................... 398 18. Risk Communication ........................................................... 399 18.1 Introduction .......................................................... 399 18.2 Aims of Risk Communication ............................... 399 18.3 Problems Associated with Risk Communication .................................................... 400 18.4 Implications of Models of Risk Perception and Psychological Theories for Communication ......... 402 18.5 Contents of the Risk Message ............................. 404 Contents xix This page has been reformatted by Knovel to provide easier navigation. 18.6 Information Sources ............................................ 406 18.7 Target Recipients ................................................ 408 18.8 The Role of the Media ......................................... 409 18.9 Practical Concerns in Risk Communication ......... 413 18.10 Conclusions ......................................................... 414 Acknowledgements ....................................................... 415 References .................................................................... 416 19. Regulating Food-Borne Risks ............................................. 418 19.1 Introduction .......................................................... 418 19.2 History of Food Regulation .................................. 418 19.2.1 Why Are Intentional Chemical Additives Used Today? .............................................. 422 19.3 Food Regulation in the USA ................................ 422 19.3.1 Early Regulation ......................................... 422 19.3.2 Statutory Background of Current US Food Regulation ......................................... 425 19.3.3 The Process of Regulatory Approval .......... 428 19.3.4 Local Enforcement – FDA Field Offices ........................................................ 430 19.3.5 HACCP, GLPs and Other Prevention Systems ...................................................... 431 19.4 Scientific Basis for Food Safety Evaluation .......... 433 19.4.1 Traditional Approach – the Use of Animal Data ................................................ 433 19.4.2 Safety Factor Versus Risk-Based Methods ...................................................... 435 19.4.3 Quantitative Risk Assessment of Chemical Carcinogens ............................... 437 19.4.4 Comparison with Other National Regulatory Systems ................................... 442 xx Contents This page has been reformatted by Knovel to provide easier navigation. 19.5 International Regulation of Food-Borne Substances .......................................................... 445 19.5.1 GATT .......................................................... 445 19.5.2 Codex Alimentarius Commission ............... 447 19.5.3 European Union ......................................... 448 19.6 Summary ............................................................. 449 References .................................................................... 450 Part IV. Conclusion ........................................................ 453 20. Integrated Food Chemical Risk Analysis ............................ 455 20.1 Introduction .......................................................... 455 20.2 Integrated Risk Assessment ................................ 456 20.2.1 Integrated Hazard Characterization ........... 456 20.2.2 Biomarkers – Integrated Indicators of Exposure and Effect ................................... 457 20.2.3 PB-PK Modeling – an Integrated Approach to Hazard 457 Characterization ......................................... 457 20.2.4 Integrated Exposure Analysis ..................... 457 20.2.5 Integrated Risk Characterization ................ 460 20.2.6 Comparative Risk Assessment .................. 460 20.3 Integrated Risk Management ............................... 460 20.3.1 The Role of Science in Risk Management .............................................. 462 20.3.2 Integrating Consumer Perceptions ............. 463 20.3.3 Integrating Risk Communication ................ 464 20.3.4 Regulation and Deregulation ...................... 464 20.4 Integrating Uncertainty ........................................ 465 20.5 Conclusion ........................................................... 466 References .................................................................... 466 Index ............................................................................... 467