High discordance in development and organ site distribution of tumors in rats and mice in NTP two-year inhalation studies

Abstract

The National Toxicology Program (NTP) reports 60 two-year inhalation studies in both mice and rats on single agents or closely related agents. “Cadmium and cadmium compounds” and “diesel exhaust particulates” were omitted from this analysis due to lack of results regarding a particular compound. No Ames test data were available for antimony trioxide, nickel sulfate hexahydrate, and indium phosphide. For antimony trioxide, a comet assay was used as a surrogate for the Ames test. To eliminate selection bias, all positive Ames assay test results and any statistically significant increase in lung tumor incidence over background in an NTP two-year inhalation study were accepted at face value. For the 58 compounds tested via inhalation by NTP, there is a high degree of discordance between mice and rats in the susceptibility to develop lung tumors. The causation of tumors at anatomical sites outside the lung via the inhalation route is also discordant in mice and rats, for example, 11/58 (19%) of agents tested in the NTP inhalation studies using mice and rats were negative in the Ames assay test and showed lung tumors in mice only. The ability to form lung tumors in mice in the absence of genotoxicity demonstrates that other mechanisms, for example, cytotoxicity followed by reparative cellular proliferation, might be involved. Mouse and rat data are discordant regarding the ability to induce tumors at organ sites outside the lungs—0/58 as compared with 16/58, respectively. Mice and rats display distinctly different patterns of both lung tumor development and development of tumors outside the lungs.