Date: Fri, 20 Aug 1999 17:49:23 -0500

Organization: TDN

Provided By:Toxic Discovery Network, Inc

The National Organization of "People Helping People"

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Science Volume 285, Number 5431 Issue of 20 Aug 1999, pp. 1190 - 1191

ANIMAL TESTING:

One Mouse's Meat Is Another One's Poison Laura Helmuth Just as government labs are gearing up for a major campaign to ferret out industrial chemicals and pollutants that mimic sex hormones, scientists have discovered that some of their favorite test subjects--lab mice--vary greatly from strain to strain in their sensitivity to the hormone estrogen. According to a report on page 1259, estrogen injected into young male mice sharply curtails testis growth and sperm production in some strains, while leaving a widely used lab strain--designated CD-1--essentially unperturbed.

The findings raise concern about whether current animal tests adequately gauge the human health risks that hormone mimics may pose. The new findings "may have significant implications," says reproductive biologist Earl Gray of the Environmental Protection Agency's (EPA's) health effects lab at Research Triangle Park, North Carolina. CD-1 has been the mouse of choice, he says, for studying hormone mimics. If CD-1 mice prove insensitive to such compounds, adds reproductive biologist Frederick vom Saal of the University of Missouri, Columbia, then "these are the last animals you'd want to use" for testing. Researchers caution, however, that they have not yet determined whether the animals show the same range of sensitivity to hormone like chemicals as they do to the real McCoy. Jimmy Spearow, a reproductive geneticist at the University of California, Davis, says he first uncovered strain-to-strain differences in hormone sensitivity in the late 1980s. Then a few years ago, he got a surprise when reading papers on the physiological effects of hormonelike chemicals in mice. "I said, 'Oh my God, they're using the most resistant strains!' " Spearow recalls. To probe further, he and colleagues implanted estrogen plugs under the skin of juvenile male mice from four strains. The capsules released doses of 17b-estradiol ranging from 0.2 to 2.0 micrograms per gram of body weight for 3 weeks.

At the lowest dose, mice from the most sensitive strain, B6, developed testes that weighed 60% less than those of control animals. In CD-1 mice, however, the same dose reduced average testis weight by just 10%. Similarly, the numbers of maturing sperm dropped precipitously at the lowest doses in sensitive strains. CD-1 mice implanted with twice the amount of estrogen necessary to stop sperm production in other strains still produced roughly 90% of normal levels of maturing sperm. Overall, the researchers report, other strains are about 16 times more sensitive to estrogen than CD-1 mice.

The findings are intriguing in part because CD-1 mice have been bred to produce large litters. Spearow speculates that the physiological factors responsible for fruitful parenthood have rendered the mice relatively impervious to outside estrogens. Indeed, after breeding two strains--S15/Jls and C17/Jls--over some 70 generations, the one Spearow selected for large litter size, S15/Jls, was less sensitive to estrogen than was the other strain. "It's a biologically plausible hypothesis," says Gray, who thinks breeding for litter size "is certainly going to affect the reproductive system somewhere."

The new data suggest to vom Saal at least that "the risk assessment process substantially underestimates variability in animal populations." Wild variation could undermine the fudge factor built into animal tests to protect human health: When setting safe exposure levels for people, researchers take the dose found to be safe in lab animals and divide it by a factor of 10--to account for variability from person to person--before setting a permissible exposure level. But the gulf between CD-1 and the most estrogen-sensitive strains is so great, vom Saal says, that it overwhelms the safety factor. "If mice have a substantial potential [genetic] variation in response to estrogen," he asks, "why shouldn't one assume an equal amount of variability in response to hormones in humans?"

Regulatory agencies plan to take no chances. The EPA is now standardizing a test battery and screening procedures that its labs, starting in about 2 years, by law must use to evaluate tens of thousands of chemicals for hormonelike activity. Says Gary Timm, senior technical adviser in EPA's office of science coordination and policy, "Certainly we're interested in using the most sensitive species or strains."