THE PH 6.7 SYRIAN-HAMSTER EMBRYO CELL-TRANSFORMATION ASSAY FOR ASSESSING THE CARCINOGENIC POTENTIAL OF CHEMICALS

Cell transformation models have been established for studying the cell ular and molecular basis of the neoplastic process. Transformation mod els have also been utilized extensively for studying mechanisms of che mical carcinogenesis and, to a lesser degree, screening chemicals for their carcinogenic potential. Complexities associated with the conduct of cell transformation assays have been a significant factor in disco uraging broad use of this approach despite their reported good predict ivity for carcinogenicity. We previously reported that many of the exp erimental difficulties with the Syrian hamster embryo (SHE) cell trans formation assay could be reduced or eliminated by culturing these cell s at pH 6.7 culture conditions compared to the historically used pH 7. 1-7.3. We and others have shown that morphological transformation (MT) , the earliest recognizable phenotype in the multi-step transformation process and the endpoint used in the standard assay to indicate a che mical's transforming activity, represents a pre-neoplastic stage in th is model system. In the collaborative study reported here, in which ap prox. 50% of the chemicals were tested under code in one laboratory (H azelton) and the other 50% evaluated by several investigators in the s econd laboratory (P & G), we have evaluated 56 chemicals (30 carcinoge ns, 18 non-carcinogens, 8 of inconclusive carcinogenic activity) in th e SHE cell transformation assay conducted at pH 6.7 culture conditions with a standardized, Good Laboratory Practices-quality protocol. An o verall concordance of 85% (41/48) between SHE cell transformation and rodent bioassay results was observed with assay sensitivity of 87% (26 /30) and specificity of 83% (15/18), respectively. The assay exhibited a sensitivity of 78% (14/18) for Salmonella assay negative carcinogen s, supporting its value for detecting non-mutagenic carcinogens. For m aximum assay sensitivity, two exposure durations were required, namely a 24-h exposure and a 7-day exposure assay. Depending on the duration of chemical treatment required to induce transformation, insight into the mechanism of transformation induction may also be gained. Based o n the data reported here, as well as the larger historical dataset rev iewed by Isfort et al. (1996), we conclude that the SHE cell transform ation assay provides an improved method for screening chemicals for ca rcinogenicity relative to current standard genotoxicity assays.