Can nongenotoxic carcinogens be detected with the lacI transgenic mouse mutation assay?

In a commentary in Vol. 20. No. 3, ofthis joumal, Ashby and Lcigibcl [ 19921 warned of possible confusion in the understanding of gcnotoxic and nongenotoxic carcinogens becausc thc ncw transgenic mutation assays might open thc possihility of dctecting mutagenic activitics of chemieals unrclated to their presence in the cell at the momcnt of mutation initiation. They reasoncd that carcinogcns ablc to stimulatc thc rate of ccll division I Buuerworth, 1990; Cohen and Ellwein, 19911 could aceeierate the accumulation of ··spontancous'' mutations in marker genes arising from endogenous DNA darnage IAmcs. 1989~ Loeb, 1989: Lutz. 1990]. Wehave just completed a study to investigate whcther the measurement of lad mutations in lac/ transgenic mice 1 Kohl er et al.. 1990 I could indccd be uscd to dctcct nongenotoxic carcinogens such as heptachlor and phenobarbital as "indirect mutagens.'' following a 4-month feeding period at dosc Ievels positive in thc 2-yc:ar bioassays. Di(2-cthylhcxyl)phthalatc (DEHP) was includcd in the study as a carcinogen that could, in addition to having mitogenic activity, be indirectly genotoxk via oxygen radicals from peroxis~­ mal hydrogen pcroxide. 2-Acctylaminotluorenc (2-AAI·) served as positive control for thc induction of lacl mutations. Thc stimulation of Ii ver ccll divisionwas investigated in thc samc animals, using immunohistochemistry for bromodeoxyuridinc incorporatcd into DNA. The negative rcsults. hoth for lad mutations in Ii ver DNA and for the rate of hcpatocytc division. show that thc nongcnotoxic carcinogcns investigatcd do not givc risc tu a gencrally incrcascd Ievei or mutations or a sustained gencral increasc in thc rate of ccll division.