Cell transformation assays: are we barking up the wrong tree?

Area of Science:

• Toxicology
• Carcinogenesis
• In vitro assays

Background:

• Resurgence of interest in cell transformation assays for carcinogenicity prediction.
• Current methods primarily based on rodent carcinogenicity data.
• Need to evaluate predictivity for human carcinogens and non-genotoxic carcinogens (NGCs).

Purpose of the Study:

• Critically review literature on cell transformation assays (SHE, Balb/c 3T3, C3H10T1/2).
• Assess assay ability to detect IARC Group 1 and 2A carcinogens.
• Compare predictivity for human/rodent NGCs against genotoxicity tests.

Main Methods:

• Literature review of published studies on cell transformation assays.
• Analysis of assay performance for known human carcinogens and NGCs.
• Comparison with in vitro and in vivo genotoxicity test data.

Main Results:

• Significant number of human carcinogens lack cell transformation data across major assays.
• Ongoing validation studies do not adequately address this gap.
• Cell transformation assays detect many NGCs, but their relevance to in vivo tumorigenesis is uncertain.

Conclusions:

• Recommend including more human carcinogens and exogenous metabolic activation (e.g., S9 fraction) in validation studies.
• Relying solely on cell transformation for NGC screening is premature due to mechanistic uncertainties.
• Progress in objective scoring and development of human cell-based assays is noted.