Mirex, a
chlorinated hydrocarbon previously used as a systemic
insecticide and
flame retardant, is a nongenotoxic hepatocarcinogen in both rats and mice. In liver,
mirex induced biochemical responses and
hyperplasia characteristic of increased cell proliferation, which is consistent with its role as a liver
tumor promoter. We have recently shown that
mirex is a potent nonphorbol
ester-type skin
tumor promoter in 7, 12-dimethylbenz[a]
anthracene (DMBA)-initiated mice. However, unlike its effect in liver, a single topical application of
mirex to skin does not induce the acute biochemical responses, such as increased epidermal
DNA synthesis and
ornithine decarboxylase activity, indicative of increased cell proliferation. Multiple topical applications of
mirex over a 1 month period induced only a minimal increase in the number of epidermal nucleated cell layers, which contrasts with definitive
hyperplasia induced by a comparable
tumor-promoting dose of 12-O-tetradecanoylphorbol-13-acetate (TPA). Collectively, these data indicated that
mirex is promoting through a novel mechanism. Further evidence that
mirex promotes
tumors through a mechanism distinct from that of the prototypical skin
tumor promoter, TPA, was obtained by examining the effect of their simultaneous co-treatment. The co-application of
mirex and TPA yielded a
tumor multiplicity greater than the sum of the responses of each promoter individually. In summary, our results demonstrate that
mirex, a carcinogenic and hyperplastic agent in liver, is also a very effective
tumor promoter in mouse skin, but suggest that
mirex operates via a novel mechanism in skin that may involve only a minimal role for enhanced cell proliferation.