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Combined Actions and Interactions of Chemicals in Mixtures the Toxicological Effects of Exposure to Mixtures of Industrial and Environmental Chemicals

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Combined Actions and Interactions of Chemicals in Mixtures the Toxicological Effects of Exposure to Mixtures of Industrial and Environmental Chemicals Combined Actions and Interactions of Chemicals in Mixtures The Toxicological Effects of Exposure to Mixtures of Industrial and Environmental Chemicals Miljøministeriet Miljøstyrelsen Combined Actions and Interactions of Chemicals in Mixtures The Toxicological Effects of Exposure to Mixtures of Industrial and Environmental Chemicals FødevareRapport 2003:12 1st Edition, 1st Circulation, August 2003 Copyright: Danish Veterinary and Food Administration 400 copies Printing office: Schultz Price: DKK 320.- incl. VAT ISBN: 87-91399-08-4 ISSN: 1399-0829 (FødevareRapport) Id-number: 2003012 Publications costing money can be bought at book shops or: Danish State Information Centre Phone +45 7010 1881 www.danmark.dk/netboghandel The Danish Veterinary and Food Administration Mørkhøj Bygade 19, DK-2860 Søborg Tel. + 45 33 95 60 00, fax + 45 33 95 60 01 Web site: www.fdir.dk The Danish Veterinary and Food Administration is part of the Danish Ministry of Agriculture, Food and Fisheries. The Danish Veterinary and Food Administration is responsible for the administration, research and control within food and veterinary areas “from farm to fork”, as well as practical matters relating to animal protection (otherwise under the Ministry of Justice). Making of regulations, co-ordination, research and development, take place in the Administrations center in Moerkhoej. The 11 Regional Authorities handle the practical inspection of food and veterinary matters, including import/export etc. The central administration of The Danish Veterinary and Food Administration employ a staff of approx. 550 full-time employees, whilst the 11 regional authorities employ a further approx.1.600 full-time employees. Contents CONTENTS 3 PREFACE 6 SAMMENFATNING OG KONKLUSIONER 7 Indledning 7 Kombinationseffekter inden for forskellige effektområder 7 Risikovurdering af kemiske stoffer i blandinger 9 SUMMARY AND CONCLUSIONS 12 Introduction 12 Combined action and interaction in various effect areas 12 Risk assessment of chemicals in mixture 14 1 INTRODUCTION 17 1.1 BACKGROUND 17 1.2 OBJECTIVES AND SCOPE OF THE REPORT 17 1.3 KEY HISTORICAL DEVELOPMENTS 18 2 BASIC CONCEPTS AND TERMINOLOGY USED TO DESCRIBE THE COMBINED ACTION OF CHEMICALS IN MIXTURES 20 2.1 INTRODUCTION 20 2.2 NO INTERACTION 21 2.2.1 Simple similar action (dose addition, Loewe additivity) 21 2.2.2 Simple dissimilar action (response or effect additivity, Bliss independence) 22 2.3 INTERACTIONS 23 2.3.1 Antagonism 23 2.3.2 Synergism 23 2.3.3 Potentiation 23 2.3.4 Complex similar action 24 2.3.5 Complex dissimilar actions 24 2.4 TEST STRATEGIES TO ASSESS COMBINED ACTIONS AND INTERACTIONS OF CHEMICALS IN MIXTURES 25 2.4.1 Testing of whole mixtures 25 2.4.2 Physiologically based toxicokinetic (PBTK) modelling 25 2.4.3 Isobole methods 26 2.4.4 Comparison of individual dose response curves 29 2.4.5 Response surface analysis (RSA) 30 2.4.6 Statistical designs 30 2.5 TOXICOLOGICAL TEST METHODS 31 3 GENERAL CONCEPTS IN THE RISK ASSESSMENT OF SINGLE CHEMICALS 33 3.1 INTRODUCTION 33 3.2 STEPS IN THE RISK ASSESSMENT 33 3.3 THE ACCEPTABLE DAILY INTAKE (ADI) 35 4 APPROACHES USED IN THE ASSESSMENT AND REGULATION OF CHEMICAL MIXTURES 38 3 4.1 INTRODUCTION 38 4.2 PROCEDURES USED TO ASSESS CUMULATIVE EFFECTS OF CHEMICALS THAT ACT BY A COMMON MECHANISM OF ACTION 38 4.2.1 Hazard index (HI) 40 4.2.2 Point of Departure Index (PODI) 41 4.2.3 Toxicity equivalency factors (TEF) 41 4.2.4 Margin of exposure (MOE) 44 4.2.5 Cumulative risk index (CRI) 45 4.3 USE OF RESPONSE ADDITION (SIMPLE DISSIMILAR ACTION) IN THE RISK ASSESSMENT OF MIXTURES OF POLYCYCLIC AROMATIC HYDROCARBONS (PAH).45 4.4 APPROACH TO ASSESS SIMPLE AND COMPLEX MICTURES SUGGESTED BY THE DUTCH GROUP 48 4.4.1 Simple mixtures 48 4.4.2 Complex mixtures 49 4.5 APPROCH FOR ASSESSMENT OF JOINT TOXIC ACTION OF CHEMICAL MIXTURES SUGGESTED BY ATSDR 53 4.5.1 ATSDR strategy for noncarcinogenic effects 53 4.5.2 ATSDR strategy for carcinogenic effects 54 4.6 APPROACHES CURRENTLY USED BY REGULATORY AGENCIES IN DENMARK 55 4.6.1 Danish Working Environment Authority 55 4.6.2 The Danish Environmental Protection Agency 55 4.6.3 The Danish Veterinary and Food Administration 56 5 EXPERIMENTAL STUDIES USING SIMPLE, WELL-DEFINED MIXTURES 61 5.1 INTRODUCTION 61 5.2 CHEMICALS WITH DIFFERENT TARGET ORGANS AND/OR DIFFERENT MODES OF ACTION 61 5.2.1 Other studies 64 5.3 SAME TARGET ORGAN WITH DISSIMILAR OR SIMILAR MODES OF ACTION66 5.3.1 Nephrotoxicants with dissimilar modes of action 66 5.3.2 Nephrotoxicants with similar mode of action 67 5.4 MIXTURES OF CHEMICALS AFFECTING THE SAME TARGET ORGAN BUT WITH DIFFERENT TARGET SITES 68 5.5 CONCLUSIONS OF THE DUTCH STUDIES 68 6 INTERACTIONS IN TOXICOKINETICS 70 6.1 TOXICOKINETICS 70 6.1.1 Interactions with absorption 70 6.1.2 Interference with distribution 70 6.1.3 Interference with biotransformation 70 6.1.4 Interference with excretion 72 7 COMBINED ACTIONS IN DIFFERENT TOXICOLOGICAL EFFECT AREAS 73 7.1 LOCAL IRRITATION 73 7.1.1 Introduction 73 7.1.2 Skin irritation 73 7.1.3 Ocular irritancy 76 7.1.4 Irritancy to the respiratory tract 78 7.1.5 Conclusions 80 7.2 GENOTOXICITY 81 7.2.1 Introduction 81 7.2.2 Types of damages to the hereditary material (DNA) 82 7.2.3 Types of mutations 83 4 7.2.4 Test systems 85 7.2.5 In vitro assays 85 7.2.6 In vivo assays 88 7.2.7 Interactions between genotoxic substances 89 7.2.8 Conclusion 96 7.3 CARCINOGENICITY 97 7.3.1 Introduction 97 7.3.2 Combination effects in initiation 97 7.3.3 Combination effects in promotion 99 7.3.4 Combination effect at later stages 101 7.3.5 Anticarcinogenesis 101 7.3.6 Conclusions: Over-all effects and complex mixtures 102 7.4 REPRODUCTIVE TOXICITY 103 7.4.1 Introduction 103 7.4.2 In vitro studies for testing interaction of teratogenic compounds 104 7.4.3 Examples of interaction of reproductive toxicants in vivo 105 7.4.4 Evaluation of the in vivo studies 108 7.4.5 Conclusions 109 7.5 ENDOCRINE DISRUPTING CHEMICALS 109 7.5.1 Introduction 109 7.5.2 Examples of studies on interaction of endocrine disrupting chemicals (EDCs) 110 7.5.3 Comments on studies dealing with interactions of EDCs 113 7.5.4 The isobole method – a practical approach 115 7.5.5 Conclusion 116 7.6 NEUROTOXICITY 117 7.6.1 Introduction 117 7.6.2 Complexity of the nervous system 117 7.6.3 Developmental neurotoxicity 118 7.6.4 Consequences of adverse effects on the nervous system 119 7.6.5 Examples of interactions: Mechanisms 119 7.6.6 Examples of interactions: Agents 121 7.6.7 Conclusion 125 7.7 IMMUNOTOXICITY 125 7.7.1 Direct toxic effect on the immune system 125 7.7.2 Allergy 127 7.7.3 Patch test results with mixtures of chemicals 127 7.7.4 Experimental studies on the elicitation of allergic response to mixtures of chemicals. 128 7.7.5 Sensitisation 129 7.7.6 Conclusion 129 8 BOOKS, ARTICLES AND REPORTS 131 8.1 BOOKS 131 8.2 REVIEW ARTICLES 131 8.3 CONFERENCE PROCEEDINGS 132 8.4 REPORTS 132 9 REFERENCES 133 5 Preface This co-operation was established between the Danish Environmental Protection Agency, the Ministry of the Environment and the Institute of Food Safety and Nutrition at the Danish Veterinary and Food Administration, the Ministry of Food, Agriculture and Fisheries to summarise and evaluate the currently available scientific literature in the field of risk assessment of toxicological effects of exposures to chemical mixtures. The following co-workers at the Institute of Food Safety and Nutrition wrote the report: Mona-Lise Binderup Maiken Dalgaard Lars Ove Dragsted Alireza Hossaini Ole Ladefoged Henrik Rye Lam John Chr. Larsen (Chair) Charlotte Madsen Otto Meyer Eva Selzer Rasmussen Trine Klein Reffstrup Inge Søborg Anne Marie Vinggaard Grete Østergård A steering group followed the work and provided valuable advises and contributions. The members of the steering group were: Herman Autrup, Institute of Environmental and Occupational Medicine, Aarhus University, Linda Bagge, Danish Environmental Protection Agency, Nanna P. Brandorff, Danish Working Environment Authority Inge Kraul, Danish Environmental Protection Agency, Ole Ladefoged, Institute of Food Safety and Nutrition, Danish Veterinary and Food Administration Poul Bo Larsen, Danish Environmental Protection Agency, Inge Søborg, Institute of Food Safety and Nutrition, Danish Veterinary and Food Administration 6 Sammenfatning og konklusioner Indledning Efter gældende praksis baseres risikovurderinger af kemiske stoffer og efterfølgende reguleringsmæssige tiltag, som f.eks. klassifikation og mærkning, fastsættelse af grænseværdier såsom MRL værdier osv., generelt på data fra undersøgelser af de enkelte stoffer. Mennesker udsættes imidlertid for en lang række kemiske stoffer samtidigt, og disse stoffer kan potentielt have både sammenlignelige og forskellige effekter. Som følge heraf er myndighederne nødt til at tage stilling til sådanne kemiske “cocktails” for at sikre, at de ikke har uforudsete helbredseffekter. Kombinationseffekter herunder interaktioner mellem kemiske stoffer, f.eks. lægemidler, som gives til mennesker i store doser, har været kendt i mange år inden for farmakologien. Erfaringerne herfra er dog ikke direkte anvendelige til forudsigelse af toksiske effekter af blandinger af kemikalier i miljøet og fødevarer, hvor eksponeringsniveauerne for den generelle befolkning er relativt lave, og interaktioner, som forekommer ved høje doser, er ikke nødvendigvis repræsentative for eksponering i lav-dosis niveauet. Den umiddelbare forventning er, at eksponering til forholdsvis lave doser vil resultere i mindre grad af interaktioner, når disse primært skyldes overskridelse af forskellige tærskelværdier og mætningsfænomener, for eksempel med hensyn til metabolismen (enzymatisk aktivering/deaktivering) af stofferne i organismen.
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