SOURCES OF VARIABILITY IN DATA FROM A POSITIVE SELECTION LACZ TRANSGENIC MOUSE MUTATION ASSAY - AN INTERLABORATORY STUDY

Experimental features of a positive selection transgenic mouse mutatio n assay based on a lambda lacZ transgene are considered in detail, wit h emphasis on results using germ cells as the target tissue, Sources o f variability in the experimental protocol that can affect the statist ical nature of the observations are examined, with the goal of identif ying sources of excess variation in the observed mutant frequencies. T he sources include plate-to-plate (within packages), package-to-packag e (within animals), and animal-to-animal variability, Data from five l aboratories are evaluated in detail. Results suggest only scattered pa tterns of excess variability below the animal-to-animal level, but, ge nerally, significant excess variability at the animal-to-animal level, Using source of variability analyses to guide the choice of statistic al methods, control-vs.-treatment comparisons are performed for assess ing the male germ cell mutagenicity of ethylnitrosourea (ENU), isoprop yl methanesulfonate (iPMS), and methyl methanesulfonate (MMS), Results on male germ cell mutagenesis of ethyl methanesulfonate (EMS) and met hylnitrosourea (MNU) are also reported.