Nonconcordance of mutagenicity and carcinogenicity assays results when data from short-term mutation assays do not predict the results of 2 year bioassays. Our studies on those chemicals which produced positive mutagenicity in vitro and failed to produce carcinogenicity in NTP bioassays demonstrated the requirement for cell proliferation in the early stages of chemical exposure for positive carcinogenicity results. Chemicals which fail to cause cell proliferation also fail to cause carcinogenesis, regardless of their activity in mutagenesis assays. We have examined a number of chemicals to date and observed that the ability to cause cell proliferation and carcinogenesis is organ-specific and site-specific within an organ, and may be sex- and species-specific. For instance, the mutagenic organophosphate insecticides dichlorvos, dimethoate and dioxathion fail to produce tumors in NTP bioassays or induced cell proliferation, whereas the mutagenic organophosphate flame retardant tris (2,3-dibromopropyl) phosphate induced renal tumors and renal cell proliferation, both occurring only in the outer medulla of the kidney. Methapyrilene (MPH) was a widely used antihistamine until it was found to produce hepatocellular carcinoma and cholangiocarcinoma in Fischer 344 rats. The structurally similar antihistamine pyrilamine (PYR) was marginally or noncarcinogenic in a similar study. Male rats were treated for up to 13 weeks with feed dosed with MPH to simulate the carcinogenesis assay. Cell proliferation was quantitated by measuring the incorporation of bromodeoxyuridine (BrDU) immunohistochemically. The BrDU labeling index showed a large and sustained increase in rats treated with MPH at 250 and 1000 ppm, sustaining greater than 50% labeling in the higher dose group at 4,6, and 13 week treatment groups. PYR demonstrated no significant increase in labeling above control levels at any timepoint. Recent studies have used transgenic (Big Blue@) mice to detect in vivo mutagenesis induced by diaminotoluene isomers. Results of these studies demonstrate that administration of the carcinogenic isomer, 2,4- DAT, resulted in an increase in in vivo mutation frequency, whereas administration of the noncarcinogenic isomer, 2,6-DAT failed to do so. These results indicate that cell proliferation may be requisite for expression of chemical-induced mutagenicity in vivo and ultimately for expression of carcinogenicity. Research in our laboratory is also utilizing a transgenic in vivo mutagenesis model to determine the relationship of in vivo and in vitro mutagenicity for a series of mutagenic and nonmutagenic carcinogens and noncarcinogens.
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