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Monograph No. 27 Aneuploidy in Chinese Hamster Ocytes Following in Vivo Treatments with Trimethoxybenzoic Compounds and Their Analogues

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Monograph No. 27 Aneuploidy in Chinese Hamster Ocytes Following in Vivo Treatments with Trimethoxybenzoic Compounds and Their Analogues ECETOC T025 17 November 1999 Monograph No. 27 Aneuploidy August 1997 European Centre for Ecotoxicology Avenue E Nieuwenhuyse 4 (Bte 6) and Toxicology of Chemicals B - 1160 Brussels, Belgium Monograph No. 27 Aneuploidy August 1997 ISSN-0773-6347-27 Brussels, August 1997 © ECETOC copyright 1997 ECETOC Monograph No. 27 © Copyright - ECETOC (European Centre for Ecotoxicology and Toxicology of Chemicals), 4 Avenue E. Van Nieuwenhuyse (Bte 6), 1160 - Brussels, Belgium. All rights reserved. No part of this publication may be reproduced, copied, stored in a retrieval system or transmitted in any form of by any means, electronic, mechanical, photocopying, recording or otherwise without the prior written permission of the copyright holder. Applications to reproduce, store, copy or translate should be made to the Secretary General. ECETOC welcomes such applications. References to the document, its title and summary contained in data retrieval systems may be copied or abstracted. The content of this document has been prepared and reviewed by experts on behalf of ECETOC with all possible care and from the available scientific information. It is provided for information only. ECETOC cannot accept any responsibility or liability and does not provide a warranty for any use or interpretation of the material contained in the publication. Aneuploidy CONTENTS SUMMARY .................................................................................................................................................... 1 1. BACKGROUND ....................................................................................................................................... 3 2. ROLE OF ANEUPLOIDY IN DISEASE ................................................................................................... 5 2.1 HUMAN DATA ............................................................................................................................. 5 2.2 ANIMAL DATA ........................................................................................................................... 10 2.3 EVALUATION ............................................................................................................................ 14 3. EVIDENCE THAT CHEMICALS CAN INDUCE ANEUPLOIDY........................................................... 15 3.1 HUMAN DATA ........................................................................................................................... 15 3.2 ANIMAL DATA ........................................................................................................................... 20 3.3 EVALUATION ............................................................................................................................ 23 4. MECHANISMS INVOLVED IN THE INDUCTION OF ANEUPLOIDY ................................................. 24 4.1 CELLULAR AND MOLECULAR EFFECTS.............................................................................. 24 4.2 MECHANISMS OF CHEMICALLY INDUCED POLYPLOIDY.................................................. 28 4.3 EVALUATION ............................................................................................................................ 29 5. METHODS FOR DETECTION OF ANEUGENS .................................................................................. 30 5.1 GENERAL PRINCIPLES ........................................................................................................... 30 5.2 EVALUATION ............................................................................................................................ 30 6. REGULATORY EVALUATION OF ANEUGENS.................................................................................. 33 6.1 REVIEW OF COORDINATED ACTIVITIES RELATED TO ANEUPLOIDY ........................... 33 6.2 REGULATORY CONTROL OF ANEUGENS ........................................................................... 33 6.3 HISTORICAL REVIEW OF REGULATORY APPROACHES TO ANEUGENS ...................... 38 6.4 EVALUATION ............................................................................................................................ 38 7. SCREENING FOR ANEUGENIC CHEMICALS.................................................................................. 40 7.1 INTRODUCTION ....................................................................................................................... 40 7.2 SCREENING STRATEGY FOR ASSESSING ANEUGENIC POTENTIAL............................. 41 7.3 PROTOCOL CONSIDERATIONS FOR ASSESSING POLYPLOIDY IN THE IN VITRO CYTOGENETIC ASSAY........................................................................................................... 45 7.4 FOLLOW-UP STRATEGY FOR CHEMICALS IDENTIFIED AS HAVING ANEUGENIC POTENTIAL .............................................................................................................................. 48 7.5 EVALUATION ............................................................................................................................ 49 8. RISK CHARACTERISATION OF ANEUGENS..................................................................................... 51 8.1 EVIDENCE INDICATING THRESHOLDS FOR THE GENOTOXIC EFFECTS OF ANEUGENS.............................................................................................................................. 51 8.2 EXTRAPOLATION FROM ANIMAL DATA TO HUMAN RISK................................................. 53 8.3 PROPOSAL FOR A UNIFIED SCHEME FOR MUTAGEN HAZARD IDENTIFICATION ....... 53 8.4 EVALUATION ............................................................................................................................ 54 9. CONCLUSIONS ..................................................................................................................................... 56 BIBLIOGRAPHY ......................................................................................................................................... 57 APPENDIX A - METHODS FOR THE DETECTION OF ANEUGENS..................................................... 69 A.1 NON-MAMMALIAN METHODS................................................................................................. 70 A.2 CELL FREE SYSTEMS (TUBULIN ASSEMBLY ASSAYS)..................................................... 71 A.3 IN VITRO MAMMALIAN CELL METHODS .............................................................................. 72 A.4 IN VIVO SOMATIC CELL METHODS ...................................................................................... 75 A.5 IN VIVO GERM CELL METHODS............................................................................................ 79 A.6 VALIDATION REQUIREMENTS FOR ANEUPLOIDY TEST METHODS............................... 87 BIBLIOGRAPHY ............................................................................................................................... 89 APPENDIX B - HISTORICAL PERSPECTIVE OF COORDINATED ACTIVITIES RELATED TO ANEUPLOIDY ............................................................................................................................................. 97 BIBLIOGRAPHY ............................................................................................................................... 99 APPENDIX C - HAZARD CLASSIFICATION SCHEMES APPLICABLE TO ANEUGENS................. 100 C.1 INTRODUCTION..................................................................................................................... 100 C.2 EEC CLASSIFICATION OF MUTAGENIC SUBSTANCES................................................... 100 C.3 CANADA.................................................................................................................................. 102 C.4 US-EPA GUIDELINES FOR MUTAGENICITY RISK ASSESSMENT .................................. 103 BIBLIOGRAPHY ............................................................................................................................. 104 APPENDIX D - REGULATORY EVALUATION OF KNOWN ANEUGENS........................................ 106 BIBLIOGRAPHY ............................................................................................................................. 108 APPENDIX E - EVALUATION OF ANEUGENIC CHEMICALS DERIVED IN PART FROM THE CEC PROGRAMME........................................................................................................................................... 109 E.1 INTRODUCTION TO DATA COMPILATION ......................................................................... 109 E.2 PRESENTATION OF THE DATA........................................................................................... 112 BIBLIOGRAPHY ............................................................................................................................. 153 APPENDIX F - REVIEW OF POLYPLOIDY INDUCING CHEMICALS ................................................ 161 BIBLIOGRAPHY ............................................................................................................................. 166 APPENDIX G - HUMAN LYMPHOCYTE CELL CYCLE DATA.............................................................. 167 BIBLIOGRAPHY ............................................................................................................................. 168 APPENDIX H - GLOSSARY ................................................................................................................... 169 MEMBERS OF THE TASK FORCE........................................................................................................
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