2-Tier Transgenic Bioassay Studied to Improve Carcinogenesis Testing

Toxicologists at pharmaceutical and chemical companies, government agencies, universities, and laboratories around the world are discussing and acting upon a proposal to use transgenic animals to speed up and modernize the standardized bioassay currently used to determine whether chemical compounds are likely to pose a cancer threat to humans. The proposal calls for a 6-month assay that would be an alternative to the current 2-year bioassay used to identify chemical carcinogens and assess their health risk.

Scientists have developed standardized procedures for identifying toxic and carcinogenic compounds that are hazardous to human health through exposure in food, water supply, pharmaceuticals, or other environmental sources. In the United States, the National Toxicology Program (NTP) has developed a 2-year rodent bioassay that has become the scientific standard for animal bioassays.

But the NTP rodent bioassay has many limitations. It is expensive and time-consuming, and despite years of experience in rodent testing and many scientific advances, there remain many doubts and questions in translating rodent bioassay risk findings into data that is realistic and meaningful in terms of risk to humans. For many years, there has been a search for a faster, less costly but effective means to identify chemical compounds that pose cancer risks for humans exposed to these compounds.

A volley of recent advances in the development of transgenic research animals now offers hope for achieving the goal of a speedy, efficient, effective analog perhaps eventually an alternative to the NTP 2-year bioassay for identifying human chemical carcinogens. Recently, the potential for use of transgenic rodents in toxicological testing, along with a proposal for a specific strategy to use two transgenic mouse lines in a testing procedure to complement the rodent bioassay, was published by Dr. Raymond W. Tennant and coworkers. Tennant is chief of the Laboratory of Environmental Carcinogenesis and Mutagenesis of the National Institute of Environmental Health Sciences (NIEHS), at Research Triangle Park, NC

Tennant and his colleagues describe a "decision tree" design utilizing TSG-p53® and TGAC mouse lines. He believes the use of the two lines can achieve three important objectives: speed up testing of environmental chemicals, rank potential carcinogens by relative risk to develop priority lists for conducting subsequent follow-up animal bioassays, and permit low-level dose-response testing.

Before selecting these two transgenic lines for study, the NIEHS team had also looked at the Big Blue and pim-1 transgenic mouse cell lines. "Big Blue is a mutagenesis model," says Tennant. "But if you can directly use the endpoint of interest, tumor induction, then it makes more sense to go that way than to use an indirect measure of tumorigenic potential. But the Big Blue and the Muta Mouse are the two best lines for examining tissue-specific mutagens."

Tennant, RW, French, JE and Spalding, JW. Identifying chemical carcinogens and assessing potential risk in short-term bioassays using transgenic mouse models. Environmental Health Perspectives, 103(10):942-950. October 2005.