The lacI transgenic mouse mutagenicity assay: quantitative evaluation in comparison to tests for carcinogenicity and cytogenetic damage in vivo.
The detection limit of the lacI transgenic mouse mutagenicity assay lies, in practice, at approximately a 50-100% increase in mutant frequency in treated animals over controls. The sensitivity of this assay in detecting genotoxins can be markedly improved by subchronic rather than acute application of the test compound. The lacI transgenic mouse mutagenicity assay was compared quantitatively to rodent carcinogenicity tests and to presently used in vivo mutagenicity assays. With the genotoxic carcinogens tested thus far, a rough correlation between mutagenic potency and carcinogenic potency was observed: on average, to obtain a doubling in lacI mutant frequency the mice had to be treated with a total dose equal to 50 times the TD50 daily dose level. This total dose could be administered either at a high dose rate within a few days or, preferably, at a low dose rate over several weeks. This analysis also indicated that a lacI experiment using a 250-day exposure period would give a detection limit approximately equal to that of a long-term carcinogenicity study. In comparison to the micronucleus test or the chromosome aberration assay, acute studies with the presently available lacI system offered no increase in sensitivity. However, subchronic lacI studies (3-4-month exposure) resulted in an increase in sensitivity over the established tests by 1-2 orders of magnitude (shown with 2-acetylaminofluorene, N-nitrosomethylamine, N-nitrosomethylurea and urethane). It is concluded that a positive result in the lacI test can be highly predictive of carcinogenicity but that a negative result does not provide a large margin of safety.
Shephard
S E
SE
Institute of Toxicology, Swiss Federal Institute of Technology, Schwerzenbach.
Lutz
W K
WK
Schlatter
C
C
D000818:Animals; D015197:Carcinogenicity Tests; D002273:Carcinogens; D002869:Chromosome Aberrations; D005069:Evaluation Studies as Topic; D005809:Genes, Regulator; D007763:Lac Operon; D051379:Mice; D008822:Mice, Transgenic; D015162:Micronucleus Tests; D009152:Mutagenicity Tests; D009153:Mutagens
D002273:Carcinogens; D009153:Mutagens