A Wistar rat strain prone to spontaneous liver tumor development: implications for carcinogenic risk assessment.

The European Union legislation considers nongenotoxic substances that only cause liver tumors in certain sensitive strains of mice as raising no concern for man. The EU legislation, however, also clearly stipulates that cases where the only available tumor data are the occurrence of neoplasms at sites and in strains where they are well known to occur spontaneously with a high incidence are relevant arguments which exclude a concern for man. We have analyzed the spontaneous liver tumor incidence in Wistar rats and in B6C3F(1) and C57Bl mice used in carcinogenicity trials at the BASF facility in Ludwigshafen, Germany, over the past 15 years and compared the spontaneous liver tumor incidence in BASF Wistar rats with those observed in rat strains employed in major European contract research organizations (CROs). The results of these analyses indicate that the incidence of spontaneous liver tumors in the BASF Wistar rat strain is very high, similar to that seen in the B6C3F(1) mouse and much higher than that seen in the C57Bl mouse and other commonly used strains of rat. The analyses also revealed signs of increasing variability and liver tumor drift in several rat strains. Moreover, the incidence of spontaneous preneoplastic liver cell foci was far higher in the BASF Wistar rat strain than reported for other rat strains in the literature. The analyses provide relevant arguments which exclude a concern for man for nongenotoxic chemicals that only tested positive for liver tumors in this sensitive rat strain.