Multiple levels of response in carcinogenicity bioassays: regulational variation among viable yellow (Avy/-) mice

Within genetically identical inbred and F1 hybrid test animal populations there exist subpopulations with different levels of sensitivity to induction of toxic endpoints, e.g., neoplasms, in response to toxicant exposure. These subpopulations differ from each other by other phenotypic characteristics as well. Presumably, these differences reflect alterations in the quantitative expression of some genes. These alterations are most probably directly or indirectly induced by subtle prenatal, neonatal or postnatal changes in endogenous microenvironmental conditions or factors. Such subpopulations have been identified within a population of agouti A/a and mottled yellow Avy/A (C3H x VY)F1 hybrid male mice. In these subpopulations differential body weight gain and formation of multiple liver adenomas in response to phenobarbital treatment were correlated with altered constitutive and inducible hepatic drug-metabolizing isozyme activities. These subpopulations could be identified by body weight as early as weaning age. In a different population of (YS x VY)F1 hybrid female mice, three phenotypes with different patterns of sensitivity to liver and lung tumor formation form visually separable phenotypic subpopulations by postnatal day 7. Two of these phenotypes, obese mottled yellow and lean pseudoagouti, are genetically identical (genotype: Avy/a), while the third phenotype, lean black a/a, differs from the others by just the Avy allele. The yellow and pseudoagouti mice, fed lindane (gamma-hexachlorocyclohexane) for 24 months, differed with respect to liver tumor incidence but had similar incidences of lung tumors. In contrast, the black mice, fed lindane, were totally resistant to both types of tumors. Analyses of phenotypic variation within other inbred or F1 hybrid populations have identified analogous subpopulations. In carcinogenicity assays this phenotypic variability can be used to mimic differential sensitivity to toxicant exposure among individuals in human populations. Data obtained from such phenotypic subpopulations should assist in improving risk assessment efforts.