The “false-positive” conundrum in the NTP 2-year rodent cancer study database

Abstract

In 1990, Ames and Gold described a conundrum of “too many carcinogens” among chemicals tested in rodent bioassays. Their proposed nongenotoxic carcinogenic mechanism was amplification of the background mutation rate via cytotoxicity induced by high doses of the test chemicals, thereby leading to increases in reparative cellular proliferation rates. Recently, we have statistically and mechanistically analyzed the entire 594-study (470 final reports) NTP 2-year rodent cancer database to better understand the conundrum posed by Ames and Gold. Our analysis provides several lines of evidence that support the contention of Ames and Gold. First, across different routes of administration, relatively phylogenetically similar rats and mice are nonetheless discordant for the development of tumors at similar organ sites. Tumor site concordance across sex within species is higher than tumor site concordance across species. Second, many chemicals negative in the Ames test nonetheless induce tumors in either rats or mice. Third, 11 out of 58 chemicals tested by the inhalation route induce lung tumors in mice and not rats, are negative in the Ames test, and exhibit hyperplasia. In 2017, Tomasetti et al. provided evidence for the clinical relevance in humans of the Ames and Gold mechanism regarding amplification of the background mutation rate by demonstrating that the majority of human tumors result from accumulated mutations due to DNA replication errors.