Combined Actions and Interactions of Chemicals in Mixtures

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