Predicting rodent carcinogenicity of halogenated hydrocarbons by in vivo biochemical parameters.
Forty halogenated hydrocarbons of known rodent carcinogenicity (24 carcinogens, 16 noncarcinogens), including many promoters of carcinogenesis, nongenotoxic carcinogens, and hepatocarcinogens, were selected for study. The chemicals were administered by gavage in two dose levels to female Sprague-Dawley rats. The effects of these 40 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 operational characteristics of TS for predicting rodent cancer were sensitivity 58%, specificity 81%, positive predictivity 82%, negative predictivity 57%, and concordance 68%. The concordance for the Ames test (45%) and structural alerts (SA; 46%) was much lower. TS also outperformed the Ames test and SA in producing fewer false positives (the specificity of TS was 81% vs. only 63% for the Ames test and 57% for SA). For predicting the carcinogenicity of the most difficult halogenated hydrocarbons (Ames and SA negative chemicals), TS was capable of successfully predicting the carcinogenicity of 8 (carbon tetrachloride, chloroform, alpha-hexachlorocyclohexane, kepone, mirex, monuron, p,p'-DDE, and 2,4,6-trichlorophenol) out of 16 of these non-DNA-reactive halogenated hydrocarbon carcinogens. All 8 of these halogenated hydrocarbons were positive in either CP or CT. This evidence shows that nongenotoxic carcinogenesis is best predicted by nongenotoxic parameters such as CP or CT (components of the predictor TS).
Kitchin
K T
KT
Carcinogenesis and Metabolism Branch, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27711.
Brown
J L
JL
Kulkarni
A P
AP
D000818:Animals; D015197:Carcinogenicity Tests / Q000379:methods*; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis; D004249:DNA Damage; D005260:Female; D006846:Hydrocarbons, Halogenated / Q000633:toxicity*; D009955:Ornithine Decarboxylase / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley
D006846:Hydrocarbons, Halogenated; D003577:Cytochrome P-450 Enzyme System; D009955:Ornithine Decarboxylase