PREDICTING RODENT CARCINOGENICITY FROM MUTAGENIC POTENCY MEASURED IN THE AMES SALMONELLA ASSAY

Many in vitro tests have been developed to identify chemicals that can damage cellular DNA or cause mutations, and secondarily to identify p otential carcinogens. The test receiving by far the most use and atten tion has been the Salmonella (SAL) mutagenesis test developed by Ames and colleagues [(1973). Proc Natl Acad Sci USA 70:2281-2285; (1975): M utat Res 31:347-364], because of its initial promise of high qualitati ve (YES/NO) predictivity for cancer in rodents and, by extension, in h umans. In addition to the initial reports of high qualitative predicti vity, there was also an early report by Meselson and Russell [in Hiatt HH et al. (1977): ''Origins of Human Cancer, Book C: Human Risk Asses sment,'' pp 1473-1481] of a quantitative relationship between mutageni c potency measured in SAL and carcinogenic potency measured in rodents , for a small number of chemicals. However, other reports using larger numbers of chemicals have found only very weak correlations. The prim ary purpose of this study was to determine whether mutagenic potency, as measured in a number of different ways, could be used to improve pr edictivity of carcinogenicity, either qualitatively or quantitatively. To this end, eight measures of SAI mutagenic potency were used. This study firmly establishes that the predictive relationship between muta genic potency in SAL and rodent carcinogenicity is, at best, weak. Whe n predicting qualitative carcinogenicity, only qualitative mutagenicit y is useful, none of the quantitative measures of potency considered i mproves the carcinogenicity prediction. In fact, when qualitative muta genicity is forced out of the model, the quantitative measures are sti ll not predictive of carcinogenicity. When predicting quantitative car cinogenicity, several possible methods were considered for summarizing potency over all experiments; however, in all cases, the relationship between mutagenic potency predictors and quantitative carcinogenicity is very weak. (C) 1997 Wiley-Liss, Inc.