Risk Assessment of Mixture of Pesticides and Similar Substances

COT Report – Risk Assessment of Mixtures of Pesticides and Similar Substances (2002)COT Report – Risk Assessment of Mixtures FSA Committee on TOXICITY Committee on Toxicity of Chemicals in Food, Consumer Products and the Environment Risk Assessment of Mixtures of Pesticides and Similar Substances © Crown copyright 2002 Published by the Food Standards Agency September 2002 September 2002 FSA/0691/0902 Committee on TOXICITY Committee on Toxicity of Chemicals in Food, Consumer Products and the Environment Risk Assessment of Mixtures of Pesticides and Similar Substances Chairman Professor I Hughes Chairman of the Working Group on Risk Assessment of Pesticides and similar substances: Professor HF Woods © Crown Copyright Contents Page Chapter 1: Executive summary 4 Chapter 2: Introduction 11 Membership of the working group and its methods of working 13 Nomenclature 14 Chapter 3: Stakeholder concerns 15 Introduction 15 Background 15 Specific chemical concerns 16 Exposure 20 Chapter 4: Current regulation of pesticides and veterinary medicines in the 28 United Kingdom and United States of America Regulation of pesticides and veterinary medicines in the UK 28 Pesticides 28 Veterinary medicines 36 Human medicines 45 Mixed exposure in the workplace 46 Regulatory controls in the United States 47 Pesticides 47 Veterinary medicines 50 Chapter 5: Evidence of dietary exposure 54 Introduction 54 Evidence of exposure to multiple pesticide residues in the diet 55 Evidence of exposure to pesticide residues in drinking water 69 Evidence of exposure to multiple veterinary medicine residues in the diet 69 Estimation of dietary intake using food consumption data and residues data 73 Estimating cumulative and aggregate exposure 74 Chapter 6: Biomonitoring and biological effect monitoring 78 Introduction 78 Biomonitoring 78 Biological effect monitoring 81 Biomonitoring data in relation to pesticide residues in food and other sources 81 Chapter 7: Toxicology of mixtures – concepts and models 87 Introduction 87 Basic concepts of mixture toxicology 87 Risk assessment of mixtures 92 Mechanisms and causes of interactions 95 1 Committee on Toxicity of Chemicals in Food, Consumer Products and the Environment Chapter 8: Toxicology of mixtures – experimental evidence 105 Introduction 105 Experimental Studies 105 Acute effects 105 Effects on the respiratory system 107 Effects on dermal absorption and toxicity 114 Neurotoxicity 115 Nephrotoxicity 120 Haematotoxicity 121 Carcinogenicity 122 Reproductive and developmental toxicology 126 Endocrine disruption 130 Immunotoxicity 137 Cytotoxicity in vitro 143 Genotoxicity 145 Multiple endpoints 155 Other effects in vivo 158 Other effects in vitro 159 Toxic interactions in humans following exposure to mixtures of pesticides, drugs, solvents or gaseous environmental pollutants 161 Evidence of possible toxicokinetic interactions between pesticides 165 Overview 166 Chapter 9: Probabilistic methods for risk assessment 184 Introduction 184 Assessment of dietary exposure 185 Assessment of cumulative dietary exposure 191 Toxicity assessment 192 Adoption by regulatory agencies 192 Conclusions 193 Chapter 10: Conclusions 197 General issues 197 Nomenclature 197 Stakeholder concerns 198 Regulation of pesticides, veterinary medicines and human pharmaceuticals 198 Evidence of exposure 199 Toxicology of mixtures 200 Implications for assessing potential health risks for humans exposed to mixtures of pesticides and similar substances 201 Chapter 11: Recommendations 203 Regulatory 203 Surveillance 203 Research 204 Public Information 204 2 Appendices Appendix 1: Glossary and Abbreviations 205 Appendix 2: Examples of Treatment Histories 223 Appendix 3: Detected Frequencies of Occurrence of Multiple Residues on Individual Samples of Food Commodities, 1997-2000 225 Appendix 4: Estimation of population based exposure to organophosphate pesticides from food and drinking water using UK data 281 Appendix 5: Substances which are currently used in the UK both as pesticides and veterinary medicines 286 Appendix 6: List of those individuals and groups who have made written submissions or oral presentations to the Working Group 288 Appendix 7: List of those who commented on the draft report following the consultation exercise 292 Appendix 8: Membership of the Working Group on the Risk Assessment of Mixtures of Pesticides and 294 Veterinary Medicines Appendix 9: Declaration of WiGRAMP Members’ Interests 295 Appendix 10: Membership of the Committee on the Toxicity of Chemicals in Food, Consumer Products and 298 the Environment 3 Committee on Toxicity of Chemicals in Food, Consumer Products and the Environment 1. Executive summary 1.1 This report of the Committee on Toxicity of Chemicals in Food, Consumer Products and the Environment prepared at the request of the Food Standards Agency, considers the risk assessment of multiple residues of pesticides and veterinary medicines in food, and of multiple sources of exposure to these substances. A specially established working group, the membership of which is given in appendix 8, drafted the report. The terms of reference were: •To assess the potential for multiple residues of pesticides and veterinary medicines in food to modify individual toxicity of chemicals in humans – the so-called “cocktail” effect. •To evaluate what assumptions can be made about the toxicity of pesticides in combination. •To consider the potential impact of combined exposure to pesticides and veterinary medicines by different routes. •To formulate advice on the standard risk assessment procedures applicable to the safety evaluation of individual pesticides and veterinary medicines in the light of the above considerations. 1.2 The working group decided to use the terminology for combined actions of mixtures, of Cassee et al, as described in Chapters 7 and 10. It was considered to be the most practicable way of describing the various ways in which combined actions may occur. This divides combined action of toxic substances into non-interaction and interaction. Both are further subdivided (see table 1.1), non-interactive processes being divided into simple similar action, where the toxicological action of the components of the mixture are the same and simple dissimilar action, where they are different. Interactive processes are divided into potentiation, when the combined effect is greater than additive and antagonism where the combined effect is less than additive. 4 Table 1.1 Nomenclature used in this report for combined actions of components of mixtures (after Cassee et al).1 Concept Term used in report Synonym(s) Effects observed Non-interaction Simple similar action Simple joint action Concentration/dose addition Simple dissimilar action Simple independent action Effect/response addition independent joint action Interaction Potentiation Synergy, supra-additivity Greater than additive effect Antagonism Sub-additivity Less than additive effect The Structure of the Report 1.3 The introduction to the report (Chapter 2) describes in more detail than above the reasons for the establishment of the Working Group, its membership and expertise and its method of working. Chapter 3 discusses stakeholder concerns and particular groups of substances that give rise to disquiet. Chapter 4 discusses the current regulatory systems for the approval of pesticides and the marketing authorization of veterinary medicinal products in the United Kingdom (UK), and where the European Union (EU) impinges on these systems. The licensing of human pharmaceuticals and the regulation of animals feed additives is also briefly discussed. Although outside the remit of the report, occupational exposure to toxic substances is briefly discussed in the context of methods that are in place to deal with occupational exposure to mixtures of substances. The regulation of pesticides, veterinary medicinal products and (very briefly) human pharmaceuticals in the United States of America (USA) is also covered. Chapter 5 deals with exposure assessment and Chapter 6 with biological monitoring, a specific type of exposure assessment. Chapters 7 and 8 deal with the toxicology of mixtures. The theoretical concepts underlying combined actions of the constituents of mixtures is discussed, together with the experimental evidence underlying these concepts. Chapter 9 deals with probabilistic risk assessment, a tool for exposure assessment that may be needed if risk assessment is to take account of all sources of exposure as well as combined exposure to different pesticides. The Committee’s conclusions General issues 1.4 The Committee recognizes that there is concern that the regulatory system for pesticides and veterinary products found in foods does not routinely address the toxic effects of different substances in combination. 1.5 There are a number of ways in which exposure to pesticide, veterinary and other chemical residues in food might theoretically result in unexpected toxicity and these have been considered in detail in this report. It was concluded that there is evidence for limited exposure of humans to multiple residues and that such exposure occurs at low levels. There are no substantiated accounts of adverse reactions 5 Committee on Toxicity of Chemicals in Food, Consumer Products and the Environment to such exposures except under laboratory conditions. Nevertheless, it was concluded that the nature and extent of combined exposure, together with the likelihood of any adverse effects, which might result, should be evaluated when carrying out risk assessment. 1.6 Groups

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