Statistical analysis of the lacI transgenic mouse mutagenicity assay.
The transgenic mouse assay is now widely used to test chemicals for genotoxic potential. In this article, we consider statistical tests for increasing trend in mutant frequency with increasing dose, along with statistical models that may be used to describe the observed dose-response relationships. The application of these methods is illustrated using data on 2-acetylaminofluorene, di(2-ethylhexyl)phthalate, heptachlor, and sodium phenobarbital. No strong evidence of extra-binomial variation was detected at the plate level, but greater evidence was noted when the data were aggregated to the package or animal level in liver, necessitating the use of statistical methods that allow for overdispersion relative to binomial variation. Clear increase on mutant frequency induced by 2-acetylaminofluorene was detected in both liver and bladder, but no apparent trends were noted with di(2-ethylhexyl)phthalate, heptachlor, and sodium phenobarbital. The exponential model provides a good fit to the observed dose-response relationship in liver, whereas a Weibull model provides a better fit for bladder.
Fung
K Y
KY
Department of Mathematics and Statistics, University of Windsor, Ontario, Canada.
Krewski
D
D
Zhu
Y
Y
Shephard
S
S
Lutz
W K
WK
D015073:2-Acetylaminofluorene / Q000633:toxicity; D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics*; D003198:Computer Simulation; D004051:Diethylhexyl Phthalate / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D029968:Escherichia coli Proteins; D006533:Heptachlor / Q000633:toxicity; D056968:Lac Repressors; D008099:Liver / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D008957:Models, Genetic; D009152:Mutagenicity Tests / Q000706:statistics & numerical data*; D010634:Phenobarbital / Q000633:toxicity; D012097:Repressor Proteins / Q000235:genetics*; D001743:Urinary Bladder / Q000187:drug effects
D001426:Bacterial Proteins; D029968:Escherichia coli Proteins; D056968:Lac Repressors; D012097:Repressor Proteins; D006533:Heptachlor; D015073:2-Acetylaminofluorene; D004051:Diethylhexyl Phthalate; D010634:Phenobarbital