NTP Workshop: Animal Models for the NTP Rodent Cancer Bioassay: Stocks and Strains—Should We Switch?

Abstract

The National Toxicology Program (NTP) hosted a workshop, "Animal Models for the NTP Rodent Cancer Bioassay: Strains and Stocks-Should We Switch?" on June [16][17] 2005, at the National Institute of Environmental Health Sciences (NIEHS) in Research Triangle Park, North Carolina. The workshop's objectives were to determine (1) whether the currently used models, the F344/N rat and B6C3F1/N mouse, continue to be appropriate to identify substances that may pose a carcinogenic hazard for humans and (2) whether the NTP should consider conducting cancer bioassays using multiple strains of rats and/or mice to better capture the range of genetic variability. Workshop participants advised the NTP to discontinue using the current F344/N strain due to the recent issues with fertility, seizure activity, and chylothorax and provided several options on how the program should approach identifying and selecting a new rat model. Participants believed that the B6C3F1/N mouse is still appropriate for use by the NTP, but suggested the NTP take steps to better understand and address increases in background rates of liver tumors in this strain. Finally, the participants supported the NTP exploring the use of the multiple strain approach, although they raised many questions concerning data interpretation and feasibility. This article also outlines the NTP's next steps in pursuing the workshop recommendations.

Factors influencing mutagenic mode of action determinations of regulatory and advisory agencies

“…For example, the induction of liver tumors in male B6C3F1 mice by trichloroacetic acid, a tumor type that occurs spontaneously at high and variable frequency in male mice of this strain [117,118], played an important role in the decision by California CIC not to list this chemical as a known carcinogen. In a similar fashion, renal tubular tumors in male rats can occur secondary to markedly exacerbated spontaneous chronic progressive nephropathy and/or alpha 2u -globulin nephropathy [119], both of which are disease entities specific to rodents and as such, have unclear relevance to carcinogen risk assessment.…”

Evaluation of Potential Carcinogenicity

“…The rat strain traditionally used by the NTP, the F344/N, has been plagued with high incidence of spontaneous tumours such as leukaemia and testicular interstitial cell tumours, poor fertility and other diseases, while the Sprague Dawley rat has a high spontaneous incidence of mammary tumours. The Wistar Han rat, on the other hand, has a relatively low spontaneous tumour incidence and high survival rate (Tennekes et al, 2004;King-Hebert and Thayer, 2006).…”

Occupational exposure to vinyl chloride and risk of hepatocellular carcinoma

“…HCC and precursor lesions (i.e., hepatocellular adenoma or the so-called hepatoma [48]) are relatively common in rat and mouse strains [38,49,50] and are particularly frequent in the B6C3F1 mouse hybrid used in the US National Toxicology Program [51]. B6C3F1 mice are highly susceptible to spontaneous and chemically induced hepatocarcinogenesis [52] since they carry susceptibility alleles at hepatocarcinogen sensitivity (Hcs) loci [53].…”