"Transgenic" mice scrutinized as faster, cheaper cancer probe The hope of faster and less expensive carcinogenicity testing is driving federal agencies to advocate the use of genetically engineered or "transgenic" mice. But whether transgenic mice, in which tumors are produced in one-fourth the time of normal laboratory mice, can provide reliable data on cancer potency is uncertain. A critical series of validation tests is nearing completion this month that will help determine whether transgenic data could become a standard tool for future regulatory screening. Scientists have long used transgenic animals for basic research, but only in recent years have researchers suggested that the animals be used for chemical safety and other regulatory tests. If the animals are proven to be effective, federal researchers can use them to begin reducing the backlog of chemicals that need to be tested. Industry, however, is concerned that data from transgenic mice could be misleading and lead to excessive regulation of their products The National Toxicology Program (NTP) conducts carcinogenicity and other toxicity tests and compiles the data for use by federal and state regulatory agencies. NTP performs bioassays on not more than 10 chemicals a year, and each "two-year" rodent bio-
Cancer bioassays using genetically modified mice are being conducted for more than 20 chemicals by researchers led by Raymond Tennant of the National Institute of Environmental Health Sciences. Photo courtesy NIEHS.
assay costs $2 million to $4 million, according to Sandy Lange, director of NTP's Liaison Office. Tests using transgenic mice can yield results in as little as six months and cost as little as $150,000. Industries also could use the animals to cut research and development costs, said Michael McClain, research adviser to the pharmaceutical company Hoffmann-La Roche. The Food and Drug Administration has already said it is willing to review data from transgenics.
Nevertheless, researchers are urging caution. The genetic alteration in transgenic mice may affect the animals metabolism or other biological processes, and tumors could result from these changes rather than from the chemical being tested. "We don't yet understand what a response from these animals means," McClain said. Transgenic animals are created by knocking out or inserting genes. A "p53-deficient" mouse, for example, has a deactivated p53 gene, which researchers believe is a critical tumor suppressor. "These are strains that are one step along the way to the development of cancer," said Roger McClellan, president of the Chemical Industry Institute of Toxicology. McClellan supports efforts by the National Institute of Environmental Health Sciences (NIEHS) to support the use of transgenic mice, "but we're a long way from being able to say that results from these are realistic predictors of human cancer risk." A new initiative sponsored by NIEHS is pushing resolution of this issue. In February, the institute invited industry and government researchers to review a proposed NTP protocol for validation tests planned to determine continued on p. 384A
Global warming may cause earlier spring, researchers say Researchers monitoring longterm changes in atmospheric carbon dioxide may have found new evidence of global warming: the earlier onset of spring in the Northern Hemisphere. A team led by Charles Keeling of the Scripps Institution of Oceanography reported in the July 11 Nature that the northern growing season now begins as much as seven days earlier than it did in the 1970s. Researchers have known for decades that atmospheric C0 2 is on the rise. But Reeling's group sees another pattern superimposed on this general upward trend: The amplitude of the seasonal C0 2 cycle—the difference between spring/summer lows (when plants take up C02) and
fall/winter highs (when they release C02)—has grown since the 1960s, increasing by 20% as measured in Hawaii and by 40% as measured in Alaska. Similar increases in amplitude show up in measurements at other locations. These larger seasonal swings are thought to result from the stimulation of plant growth by rising C0 2 levels in the atmosphere. What's more, say the researchers, the largest amplitudes seem to correspond to years when average temperatures are higher, suggesting that Northern Hemisphere plants are showing a large-scale response to temperature increases as small as 1 °C averaged over most of the NorthHemisphere.
So far there is no clear evidence of a corresponding "phase shift" in the onset of fall, which means the total growing season may or may not be getting longer, according to Timothy Whorf of Scripps, a co-author of the Nature paper. But if growing seasons are becoming longer, climate modelers may now have 3ii important bit of information to plug into their computer simulations of the global carbon cycle. These models generally have been unable to account for the annual disappearance of a significant amount of the world's carbon supply The new data may help resolve this problem said Whorf TONY REICHHARDT
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whether transgenic animals produce responses comparable to those found in standard rodent bioassays. "This effort was designed to bring everyone together before the fact to agree on what should be done and how to interpret the results," said Christopher Schonwalder, assistant to the director at NIEHS. "We wanted to pave the way for researchers, the regulated community, and regulators to accept these new methods as the basis for regulations." NIEHS researchers are currently using transgenic animals to test more than 20 chemicals with extensive databases to see if they get the results they would expect from a two-year rodent bioassay, said Raymond Tennant, chief of the Laboratory of Environmental Carcinogenesis /Mutagenesis at NIEHS. NIEHS is testing wellknown carcinogens and noncarcinogens. The tests are due to be completed this month and analysis is expected by the end of the Other laboratories in the United States Japan and the Netherlands are conducting allel tests to be compared with the NTFHS results The issue has also been taken up by an International Life Sciences Institute (ILSI) working group representing industry, academia, and regulatory agencies. The group's report, expected in November, will call for side-byside studies in which researchers test identical doses, routes of exposure, and other factors on transgenics and typical test rodents, according to David Neumann a senior ILSI scientist. The research community expects that within three to five years the issue of whether transgenic animals can be used for regulatory screening will have been decided. Researchers and regulators are hopeful. "I would hope that within 5 to 10 years [transgenics] would supplant the standard two-year bioassay for at least one species," said Ernest McConnell, a toxicology consultant and former NTP director of toxicology research and testing. Current regulations require manufacturers evaluating new drugs and chemicals to submit data from two species rvpically rats and mice PAT PHIBBS
NEWS TECHNOLO GY Presidential "green chemistry" awards promote industrial pollution prevention The first Presidential Green Chemistry Challenge Awards, presented July 11 at the National Academy of Sciences, will encourage manufacturers to take pollution prevention seriously, according to industry observers. "Major U.S. raw material manufacturers don't have many incentives to invest in the research it takes to come up with raw materials substitutes that have a more benign environmental impact," said David Liebl, director of the Great Lakes Pollution Prevention Clearing House at the University of Wisconsin-Madison. "What these awards do is tell companies that some of their competitors are having success in modifying t h e W3.V they're ducing chemicals and eliminating waste at the same time " The five award-winning projects include the development of a process that eliminated millions of pounds of waste annually in Monsanto's production of the herbicide Roundup; Dow Chemical Company's substitution of 100% carbon dioxide for ozone-depleting chlorofluorocarbons in the making of polystyrene; and the development of an economical process to substitute biodegradable thermal polyasparate for polyacrylic acid a key component of such products as disposable diapers and lenses by the Donlar Companv a small business in
suburban Chicago. Rohm and Haas received an award for a less-toxic paint to prevent barnacles from adhering to ships. The paint is far less toxic to marine organisms than existing tin-based paints and degrades more rapidly. Driving the search for the paint were government restrictions on tin-based products. The sole award for academic research went to Texas A&M University chemical engineer Mark Holtzapple for developing a technology that can convert biomass waste to animal food. The process has not yet been commercialized. Green chemistry sometimes gets snubbed as being interesting but not really commercially viable, said Paul Anastas, head of EPA's Industrial Chemistry Branch and one of the award's sponsors. "But these developments are in commerce. They're making money for companies." The awards were a joint effort of several organizations including EPA, the American Chemical Society, and the Council for Chemical Research. In addition to the public relations benefits of the awards, they also have an effect inside the company, according to Susan Turner of the American Chemical Society's government relations department. The awards show the value of environmentally beneficial efforts to officials focused on the bottom line, she says. —HARVEY BLACK
Monsanto awards pollution prevention research grant The Monsanto Company has awarded a $1 million challenge grant to SRI International, Menlo Park, Calif., to develop new technology to recover a variety of valuable chemicals in Monsanto waste streams. SRI has one year to develop a system or systems to recover sodium chloride, amino acids, and phosphorus and phosphoric acids. Last year Monsanto awarded a similar research award to SRI to develop a process to recover ammonia. SRI is still working on that technology, and completion of the recovery process is expected this fall. Monsanto went outside the company for ideas because company scientists had been unsuccessful in their attempts to develop the needed technology, said Earl Beaver, Monsanto's director of waste elimination. Monsanto has received inquiries from several companies regarding the development of their challenge award. —HARVEY BLACK
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