This report contains the collective views of an international group of experts and does not necessarily represent the decisions or the stated policy of the World Health Organization. Harmonization Project Document No. 10 GUIDANCE FOR IMMUNOTOXICITY RISK ASSESSMENT FOR CHEMICALS This project was conducted within the WHO/International Programme on Chemical Safety project on the Harmonization of Approaches to the Assessment of Risk from Exposure to Chemicals. WHO Library Cataloguing-in-Publication Data Guidance for immunotoxicity risk assessment for chemicals. (IPCS harmonization project document ; no. 10) 1.Risk assessment. 2.Immunotoxins. 3.Immune system. 4.Chemicals – toxicity. 4.Environmental exposure. I.International Programme on Chemical Safety. II.Series. ISBN 978 92 4 150330 3 (NLM classification: QW 630.5.I3) © World Health Organization 2012 All rights reserved. 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Technically and linguistically edited by Marla Sheffer, Ottawa, Canada Printed by the WHO Document Production Services, Geneva, Switzerland TABLE OF CONTENTS FOREWORD ......................................................................................................................... viii ACKNOWLEDGEMENTS..................................................................................................... ix CONTRIBUTORS.....................................................................................................................x LIST OF ACRONYMS AND ABBREVIATIONS ................................................................xv EXECUTIVE SUMMARY ................................................................................................. xviii 1. INTRODUCTION TO THE GUIDANCE DOCUMENT........................................1 1.1 Purpose of this document...............................................................................................1 1.2 Scope..............................................................................................................................1 1.3 Contents .........................................................................................................................2 2. BACKGROUND ..........................................................................................................4 2.1 The immune system as a special case............................................................................4 2.2 The importance of immune challenge in detecting immunotoxicity .............................6 2.3 Dose–response relationships and thresholds..................................................................8 2.4 Induction of tolerance ....................................................................................................9 2.5 The possibilities for adverse outcomes: immune stimulation, suppression and/or misregulation................................................................................................................10 2.6 The developing immune system ..................................................................................11 2.7 Early-life exposure/later-life effects ............................................................................13 2.8 Current practices ..........................................................................................................14 2.9 Newer approaches .......................................................................................................16 3. FRAMEWORK FOR IMMUNOTOXICITY RISK ASSESSMENT FOR CHEMICALS.............................................................................................................17 3.1 Risk assessment ...........................................................................................................17 3.2 Application of risk assessment principles to immunotoxicity .....................................19 3.3 General considerations for immunotoxicity risk assessment.......................................20 3.3.1 Introduction......................................................................................................20 3.3.2 Clinical and epidemiological data....................................................................20 3.3.2.1 Clinical data.........................................................................................20 3.3.2.2 Epidemiological data...........................................................................20 3.3.3 Laboratory animal data....................................................................................22 3.3.3.1 Introduction..........................................................................................22 3.3.3.2 Considerations in evaluating immunotoxicity data..............................23 3.3.4 Local versus systemic effects...........................................................................26 3.3.5 (Ir)reversibility of effects.................................................................................27 3.3.6 Biological plausibility......................................................................................27 3.3.6.1 Characterization of the health-related database ...................................27 3.3.6.2 Weight of evidence evaluation of the health-related database.............30 iii Harmonization Project Document No. 10 3.3.6.3 “Triggers” and the need for additional data to determine immunotoxicity hazard........................................................................32 3.3.7 Dose–response relationships and thresholds....................................................34 3.3.7.1 Shape of the dose–response curve .......................................................34 3.3.7.2 Mode of action and dose metric...........................................................35 3.3.7.3 Dose–response analytical approaches..................................................36 3.3.7.4 Dose–response risk assessment output: health-based guidance values ...................................................................................................36 3.3.8 Groups at risk (developing immune system, elderly, immunocompro- mised) ..............................................................................................................37 3.3.9 Acute versus chronic exposure ........................................................................38 3.3.10 Uncertainty factors...........................................................................................38 3.3.10.1 Intraspecies uncertainty factor ..........................................................38 3.3.10.2 Interspecies uncertainty factor ..........................................................39 3.3.10.3 LOAEL to NOAEL uncertainty factor .............................................39 3.3.10.4 Subchronic to chronic uncertainty factor..........................................40 3.3.10.5 Database uncertainty factor...............................................................40 3.3.11 Exposure assessment.........................................................................................41 3.3.11.1 Exposure-related effects on severity and persistence .......................42 3.3.11.2 Exposure timing and susceptibility...................................................42 3.3.11.3 Route of exposure and local immunity .............................................43 3.3.11.4 Exposure and toxicokinetic considerations.......................................43 3.3.12 Risk characterization........................................................................................44 3.4 Entry points for immunotoxicity risk assessment........................................................45 4. ASSESSMENT OF IMMUNOSUPPRESSION......................................................49