This is Part 1 of a presentation on Genetic Toxicology that was given by Dr. David Kirkland to scientific staff at Health Canada in Sept. 2010. Part 2 is availabile in ppt

1. David Kirkland

6. Mutations: What Do They Do? Human Impact CV diseases e.g. atherosclerosis Aging Teratogenesis - disrupted development Decreased fertility foetal wastage Cancer Heritable defects inborn errors genetic susceptibility to disease

16. Overlay Onto Minimal Agar Mix Incubate for 2-3 Days Score Colonies Using Automated Counter Number of colonies = 7 Bacterial Culture Test Article Solution S9 Mix or Buffer Molten Soft Agar (+ his or tryp) 37 o C

19. Revertants/plate  g/plate * * p<0.01, Dunnett’s test

20. Revertants/plate  g/plate * * * *p<0.01, Dunnett’s test

22. Revertants/plate  g/plate * * * * *p<0.01, Dunnett’s test

27. Large colony mutant Small colony mutant

37. % sensitivity (+ve with carcinogen) No. of chemicals 542 246 89 353

39. % specificity (-ve results with non-carcinogens) No of chemicals 176 105 26 136

41. % specificity (-ve in both tests) No. of chemicals 105 25 136 20 96

43. No. of chemicals 20 96 % specificity (-ve in all 3 tests)

44. Sensitivity/specificity trends with in vitro assays Black = actual; red = desirable

46. 804 mammalian cell studies submitted between 1995 and 2005 (testing of 596 compounds) 219 of 804 studies positive = 27% 181 of 596 compounds positive in at least 1 in vitro clastogenicity test = 30% Data kindly provided by Peter Kasper, BfArM 242 MLA (30%) 161 CHO (20%) 71 V79 (9%) 50 CHL (6%) 280 huly (35%) Comparison of rate of positives among the cell systems currently in use 10 20 30 40 % positive huly MLA CHO V79 CHL n = 71 n = 70 n = 42 n = 18 n = 18