Transgenic animal mutagenicity assays

TITLE......Page 1
COPYRIGHT......Page 2
CONTENTS......Page 3
NOTE TO READERS OF THE CRITERIA MONOGRAPHS......Page 9
Objectives......Page 10
Scope......Page 11
Selection of chemicals......Page 12
Procedures......Page 13
WHO TASK GROUP ON ENVIRONMENTAL HEALTH CRITERIA FOR TRANSGENIC ANIMAL MUTAGENICITY TESTING......Page 17
ACRONYMS AND ABBREVIATIONS......Page 19
GLOSSARY......Page 22
1. SUMMARY......Page 27
PART I: OVERVIEW OF GENOTOXICITY TESTING AND TRANSGENIC ANIMAL MUTAGENICITY SYSTEMS......Page 33
2.2 Gene mutation assays in vivo using transgenes......Page 34
3.2 Generation of transgenic animals with shuttle vectors: the transfer method......Page 36
3.4 Target or reporter genes — the lac operon......Page 38
3.5 Transgene shuttle vectors......Page 39
3.6 Transgenic animal models......Page 40
4.3 Recovery of the DNA construct of the shuttle vector from the genomic DNA and in vitro packaging......Page 42
4.5 Detection and quantification of mutations......Page 44
5.1 gammacII assay (Big Blue® and Muta™ Mouse)......Page 47
5.2 gpt delta model......Page 50
5.3 The lacZ plasmid model......Page 52
5.4 Upcoming transgenic models for which no extensive data are available......Page 53
6.1 Determinants studied using transgenic mutation assays......Page 56
6.2 Criteria for valid experimental design of transgenic mutation assays......Page 58
PART II: COMPARISON OF THE LACI MODEL AND THE LACZ MODEL WITH CONVENTIONAL TEST SYSTEMS......Page 65
7.1 Aim of the comparison and criteria for the selection of data......Page 66
7.2 Choice and limitations of data......Page 67
7.3 Validity of data on transgenic animal mutation assays......Page 68
7.4 Criteria for predictivity of transgenic assays......Page 69
8. COMPARISON OF THE MUTA™ MOUSE AND BIG BLUE® ASSAYS......Page 70
9.1 The Muta™ Mouse assay and the Big Blue® mouse assay versus the mouse bone marrow micronucleus test......Page 72
9.2 The Muta™ Mouse assay and the Big Blue® mouse or rat assay versus assays using endogenous reporter genes......Page 96
9.4 Results of transgenic animal mutagenicity assays compared with results of genotoxicity assays in vitro......Page 120
10.1 Comparison of target organs in carcinogenicity studies with target organs in transgenic animal mutation assays......Page 130
10.2 Comparison of results of carcinogenicity studies with results from transgenic animal mutagenicity assays......Page 154
PART III: APPLICATIONS OF TRANSGENIC ANIMAL MUTAGENICITY STUDIES......Page 175
11.1 Studies on spontaneous mutant/mutation frequencies (in organs of non-exposed transgenic animals)......Page 176
11.2 Examination of fundamental paradigms in genetic toxicology......Page 180
11.3 Studies into the mechanism of action of mutagenicity/carcinogenicity using sequence data......Page 187
11.4 Importance of the transgenic mutation assays for studies other than genetic toxicology......Page 195
PART IV: EVALUATION, CONCLUSIONS AND RECOMMENDATIONS......Page 197
12.2 Gene mutation assay — implications for testing......Page 198
12.4 Molecular analysis and mechanistic studies......Page 200
12.5 Animal welfare and economy......Page 201
13. CONCLUSIONS......Page 203
Recommendations for future research......Page 204
REFERENCES......Page 205
Master Table Legend......Page 241
APPENDIX 2: THE CII ASSAY IN TRANSGENIC RODENT STUDIES......Page 305
RESUME......Page 313
RESUMEN......Page 319