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PREDICTING RODENT CARCINOGENICITY OF AMES TEST "FALSE POSITIVES" BY IN VIVO BIOCHEMICAL PARAMETERS
Citation:
Kitchin, K., J. Brown, AND A. Kulkarni. PREDICTING RODENT CARCINOGENICITY OF AMES TEST "FALSE POSITIVES" BY IN VIVO BIOCHEMICAL PARAMETERS. U.S. Environmental Protection Agency, Washington, D.C., EPA/600/J-95/093.
Description:
Twenty-eight chemicals known to be mutagenic in the Ames test but not carcinogenic in rodent bioassays were selected for study. The effects of these chemicals on four biochemical assays (hepatic DNA damage by alkaline elution (DD), hepatic ornithine decarboxylase activity (ODC), serum alanine aminotransferase activity (ALT), and hepatic cytochrome P-450 content (P450) were determined. Composite predictive parameters are defined as follows: CP = [ODC and P450], CT = [ALT and ODC], and TS = [DD or CP or CT]. The specificity (percent of rodent noncarcinogens which test negative) of DD, ODC, ALT, P450, CP, CT and TS was 100%, 46%, 89%, 86%, 93% and 86%, respectively, For these 28 mutagenic noncarcinogens, the specificity of structural alerts (SA) (13%) and three other short-term genotoxicity tests (mutation in mouse lymphoma cells (MOLY) (0%), chromosomal aberrations in Chinese hamster ovary cells (ABS) (13%), and sister chromatid exchange in Chinese hamster ovary cells (SCE) (0%) were much lower. The ge test, an experimental measure of electron attachment had a specificity of 33%. DD was the only DNA related parameter to predict well the noncarcinogenic rodent bioassay result of Ames "false positive" chemicals. Five nongenotoxic parameters (ALT, P450, CP, CT and [CP or CT] predicted the rodent bioassay result well. Depending on the prevalence of chemicals carcinogenic to humans, the problem of Ames test "false positives" for human cancer may be either small or large.