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People have believed since antiquity that tiny doses of toxicants can be healthful. Now hormesis, a concept oncediscredited in scientific circles, is making a surprising comeback Sipping From a Poisoned Chalice
Dioxin and its chemical cousins are among radiation punish the body at even the small- cept of hormesis “has been taken over by the most deadly compounds on Earth. Spike est of doses. If hormesis is as pervasive as its rhetoric,” says William Farland, risk assess- a rat’s water with 10 parts per billion—the backers suggest, it could mean that regula- ment chief at the U.S. Environmental Pro- tions for many chemicals, from arsenic in tection Agency (EPA). It’s too soon, he drinking water to polychlorinated biphenyls says, to conclude that the benefits of low- pool—and there’s a 50/50 chance that the rat at Superfund sites, are too stringent. “It level exposures outweigh the risks. More- will die of liver cancer. Yet even tinier con- would fundamentally change the whole risk- centrations of dioxins fed to rats inhibit tu- abrese, a toxicologist at the University of endocrine disrupters may be more harmful ago: testing modified dioxins as an anti- that poisons or radioactivity at low doses Environ Corp. in Arlington, Virginia.
vitamins, and essential minerals exhibithormesis, as does alcohol: Moderate with higher risks of heart and liver dis- ease. Calorie restriction, the sole indis- Crusader. Edward Calabrese has spent 13 years urging
sis, proponents say: The lack of calories toxicologists to recognize that chemicals can have oppo- stresses an organism, firing up responses tosis, or programmed cell death, which pro- Massachusetts, Amherst, who over the past the 1920s and ’30s, however, because Arndt tect the body from environmental insults.
decade has doggedly compiled thousands of was an adherent of homeopathy, the notion studies indicating that infinitesimal amounts that extremely dilute solutions, often con- from cadmium to pesticides to dioxin, ap- of chemicals can help microbes, plants, and taining a few or no molecules of an active pear to have paradoxical and possibly bene- substance, are therapeutic. Hormesis, coined ficial effects on organisms. The heightened healthier. “Hormesis is on the verge of being in 1943, involves concentrations at least scientific scrutiny has generated juicy head- a milestone in the evolution of risk assess- 10,000 times higher. They “are a direct con- lines: “Whatever doesn’t kill you might ment,” adds John Doull, professor emeritus tinuation of the traditional dose response,” make you stronger,” begins an article in the at the University of Kansas Medical Center September issue of Scientific American. “A in Kansas City and the co-editor of the pre- little poison can be good for you,” declares a hormesis first caught his attention in 1985, Hormesis is alluring because it challenges reach far beyond the science. Although para- when he received a flyer for a meeting prob- the conventional wisdom that toxicants and doxical dose responses are “real,” the con- ing the question of whether low-dose radia- tion is beneficial (see sidebar, p. 378). It rang cial response that enhances normal function a bell: As a graduate student, Calabrese had abrese’s tenacity for bringing hormesis into noted that peppermint plants dosed with tiny stresses. Potential mechanisms are manifold: the scientific mainstream, they point out that amounts of phosfon, a herbicide used to stunt not all hormetic effects are beneficial. For growth, grew faster than control plants. Plot- lated immune responses, apoptosis that elim- ting growth on the y-axis against dose on the inates damaged cells that would otherwise x-axis, his data formed an inverted U-shaped become cancerous. The universal factor, ac- levels of the plastics ingredient bisphenol-A curve instead of the usual S-shaped or linear fed to pregnant mice and enlarged prostate plot for a dose-related effect (see diagram). glands in their male offspring—the reverse similar dose responses. He also won funding Cadmium and water flea fecundity
from various federal agencies, including EPA, called Biological Effects of Low Level Expo- sure (BELLE) and launched a thrice-a-year Dioxin and female rat tumors
The puzzle of hormesis. Low doses of phos-
fon, a herbicide, caused plants to grow bet- ter (below); small amounts of dioxin, a car- cinogen, reduced tumors in rats (left); and a little cadmium, a toxic metal, caused water fleas to produce more young (above). The ef- fects were reversed at higher doses.
tiny concentrations of atrazine with repro- likely also protect cells against potentially ductive deformities in frogs (Science, 1 No- vom Saal says that “if there are exceptions covered thousands: plants dosed with her- to linearity, you have to revise the system.” bicides or metals growing lusher; bacteria hormesis-like, biphasic dose responses have flourishing in the presence of tiny amounts largely been carried out only on drugs, Cal- of antibiotics; immune cells treated with abrese says. Detailed studies have focused Scientists are deeply divided, however, over arsenic proliferating faster; insects doused with pesticides or alcohol living longer and Phosfon and peppermint plant growth
producing more eggs; rats fed a little sac- charine developing fewer tumors. “We see it across the whole plant and animal king- dom” and at “essentially every endpoint,” says Calabrese. The effects, he says, are modest but consistent: typically a 30% to 60% greater response than in controls.
In his latest analysis in the February 2003 issue of Toxicological Sciences, Calabrese looked at how frequently hormesis occurs, in- cluding all the dose-response curves he could find that featured at least two doses below the established no-effects level and a control.
From 195 papers that met this criterion, he re- ported that hormetic dose-response curves outnumbered curves showing no effect at the work this way, for example. “It probably oc- banned.” Calabrese says he doesn’t think it’s curs more than we’re willing to admit,” says that black and white. “There will be circum- Richard Bond, a pharmacologist at the Uni- versity of Houston, Texas. Such effects are beneficial, and cases where any change [in a The likely explanation for hormesis, Cal- often thought to be spurious or uninforma- standard] might not be advisable,” he says.
abrese and others say, is that small doses of tive, Bond says: “We draw a line to make it Nevertheless, Calabrese argues that chemi- most harmful substances stimulate a benefi- Hormesis “emphasizes that there are thresh- dents, a statistically robust study showing of Toxicology’s annual meeting in Baltimore olds for carcinogens,” and “the economic that a toxicant cuts cancer risk would require next March, and he has been organizing in- implications … are substantial,” he wrote in lots of animals. “I’d have to have pretty con- ternational conferences on hormesis thanks a commentary in Nature earlier this year.
vincing evidence before killing 5000 ani- to a hefty grant from the U.S. Air Force, mals to prove the existence of a suppression which is interested in the phenomenon be- exactly the opposite. He says that regulators effect,” Portier says. Toxicologist David cause of issues such as cleaning up jet fuel are missing a whole suite of harmful effects spills and safety in space flight. And a jour- of chemicals that haven’t been adequately Seattle, agrees. For carcinogens, he says, “I nal that debuted this year, Nonlinearity in tested at low levels. Even if the effect appears don’t think the idea of hormesis is going to Biology, Toxicology, and Medicine, brings beneficial—faster growth, larger offspring— together on its editorial board scientists on that’s not necessarily a good thing, he points done. It’s just too expensive … you’ll never out. Obesity, for example, is associated with be able to characterize [a hormetic effect] to other diseases later in life. “Anything but the point where people think it’s real.” bullish on the prospect of their colleagues what would normally be there shouldn’t be But the spotlight on hormesis is unlikely Academy of Sciences is mulling whether to transform medicine, toxicology, and phar- ing on single endpoints—such as cancer— sponsor a study of “the science of horme- sis,” says staffer James Reisa. Calabrese will and other skeptics argue. Christopher Portier lead a roundtable on hormesis at the Society of the National Toxicology Program cites anexample from a study his group publishedin 1993 on cyclophosphamide, a cancerdrug that stops cell division. At low doses, the drug seemed to protect rats from fluvirus; all survived, unlike controls. Butwhen injected with tumor cells, these ani- Proton Guns Set Their Sights on
mals were more likely to develop cancer.
The apparent reason, Portier says, is that the Taming Radioactive Wastes
drug skewed the animals’ immune cell pop-ulation, revving up T helper cells, whichfight viruses, but reducing natural killer Once mooted as energy sources, nuclear reactors that substitute particle accelerators cells, which guard against foreign cancer for chain reactions are taking long-range aim at a new mission cells. The end result was both beneficialand harmful. “What would you do with that KUMATORI, JAPAN—On the grounds of Kyoto University’s Research Reactor Institute, work- $1.75 million experiment chamber for nuclear pound?” Portier asks. The case for the diox- ers have dug into a hillside to give a 30-year- reactions at an existing proton accelerator.
ins is murky as well. Tiny amounts of these old experimental nuclear reactor an unusual mission (CEA), and Germany’s Forschung- starts up in fall 2005, the synchrotron will fire szentrum Karlsruhe are joining forces for the when all tumors are combined do the diox- protons into the heart of the reactor, straight down the axis of a cylinder of heavy metal periment (TRADE), which will add a proton wrapped in a core of nuclear fuel. Neutrons accelerator to an experimental reactor at imal studies suggest that low doses of this dislodged from the target will hurtle into the ENEA’s Casaccia Research Center in Rome.
The three partners expect to commit to fund- Calabrese notes. But in the August issue of ing the project within this year and hope to Nature Medicine, researchers reported that at these low doses—even below those rec- tem (ADS), as it’s called, isn’t pri- acts as an endocrine disrupter in female rats, causing growth in uterine and breast tissues To take a possibly beneficial effect into account in risk assessment, an agency would have to know “how all the pieces fit togeth- er,” including mechanisms, says Farland.
EPA’s latest cancer risk assessment guide- lines encourage researchers to use that kind of data; the agency is also making an effort to integrate cancer and noncancer endpoints.
“We are certainly interested in complex dose response function,” but “we’re really trying to get at the biology that underlies the phe- Getting real. In Kyoto, Kaichiro Mishima and colleagues are
cause spontaneous cancers are rare in ro- building the first complete accelerator-driven system.

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