Predicting rodent carcinogenicity of Ames test false positives by in vivo biochemical parameters.
28 chemicals known to be mutagenic in the Ames test but not carcinogenic in rodent bioassays were selected for study. The chemicals were administered by gavage in 2 dose levels to female Sprague-Dawley rats. The effects of these 28 chemicals on 4 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. The scientific approach taken was to either experimentally find individual cancer predictors of high specificity or to mathematically create composite predictors of high specificity. 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%, 93% and 86%, respectively. For these 28 mutagenic noncarcinogens, the specificity of structural alerts (SA) 13%, 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 ke 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. 5 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 predicting human cancer may be either small or large.
Kitchin
K T
KT
Carcinogenesis and Metabolism Branch, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711.
Brown
J L
JL
Kulkarni
A P
AP
D000410:Alanine Transaminase / Q000097:blood / Q000378:metabolism; D000818:Animals; D015197:Carcinogenicity Tests; D002273:Carcinogens / Q000633:toxicity*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004249:DNA Damage; D005189:False Positive Reactions; D005260:Female; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D009153:Mutagens / Q000633:toxicity*; D009955:Ornithine Decarboxylase / Q000378:metabolism; D011237:Predictive Value of Tests; D051381:Rats; D017207:Rats, Sprague-Dawley; D012486:Salmonella typhimurium / Q000187:drug effects; D012680:Sensitivity and Specificity
D002273:Carcinogens; D009153:Mutagens; D003577:Cytochrome P-450 Enzyme System; D000410:Alanine Transaminase; D009955:Ornithine Decarboxylase