Transformation of BALB/c-3T3 cells: V. Transformation responses of 168 chemicals compared with mutagenicity in Salmonella and carcinogenicity in rodent bioassays.
This report describes the activities of 168 chemicals tested in a standard transformation assay using A-31-1-13 BALB/c-3T3 cells. The data set includes 84 carcinogens, 77 noncarcinogens, and 7 research chemicals. Carcinogens included 49 mutagens and 35 nonmutagens; noncarcinogens included 24 mutagens and 53 nonmutagens. The transformation assay did not use an exogenous activation system, thus, all chemical responses depended on the inherent target cell metabolic capacity where metabolic activation was required. The upper dose limit was 100 milli-osmolar because the assay could not discriminate active and inactive chemicals tested above this concentration. Certain physicochemical properties resulted in technical problems that affected chemical biological activity. For example, chemicals that reacted with plastic were usually nonmutagenic carcinogens. Similarly, chemicals that were insoluble in medium, or bound metals, were usually nonmutagenic and nontransforming. Multifactorial data analyses revealed that the transformation assay discriminated between nonmutagenic carcinogens and noncarcinogens; it detected 64% of the carcinogens and only 26% of the noncarcinogens. In contrast, the transformation assay detected most mutagenic chemicals, including 94% of the mutagenic carcinogens and 70% of the mutagenic noncarcinogens. Thus, transformation or Salmonella typuimurium mutagenicity assays could not discriminate mutagenic carcinogens from mutagenic noncarcinogens. Data analyses also revealed that mutagenic chemicals were more cytotoxic than nonmutagenic chemicals; 88% of the mutagens had an LD50 < 5 mM, whereas half of the nonmutagens had an LD50 > 5 mM. Binary data analyses of the same data set revealed that the transformation assay and rodent bioassay had a concordance of 71%, a sensitivity for carcinogens of 80.0%, and a specificity for detecting noncarcinogens of 60%. In contrast, Salmonella mutagenicity assays and rodent bioassays had a concordance of 63%, a sensitivity of 58%, and a specificity of 69%. The transformation assay complemented the Salmonella mutagenesis assay in the identification of nonmutagenic carcinogens; thus, the two assays had a combined 83% sensitivity for all carcinogens and a 75% specificity for nonmutagenic noncarcinogens.
Matthews
E J
EJ
Center for Food Safety and Applied Nutrition, Food and Drug Administration, Washington, DC 20204.
Spalding
J W
JW
Tennant
R W
RW
D016475:3T3 Cells / Q000187:drug effects* / Q000473:pathology; D000818:Animals; D015197:Carcinogenicity Tests; D002273:Carcinogens / Q000737:chemistry / Q000633:toxicity*; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced* / Q000473:pathology; D007928:Lethal Dose 50; D051379:Mice; D008807:Mice, Inbred BALB C; D009152:Mutagenicity Tests; D012377:Rodentia; D012486:Salmonella typhimurium; D012680:Sensitivity and Specificity
D002273:Carcinogens