SCIENCE JOURNAL
By SHARON BEGLEY
Scientists Revisit Idea That a Little Poison Could Be Beneficial
The Wall Street Journal Online


Edward Calabrese still has the peppermint plants that changed his life. Or at least he has the plants' descendants, propagated from cuttings over almost 40 years.

Working with their ancestor one day as a college student, he spritzed the plant with the common herbicide Phosfon, planning to measure how much the poison stunted the plant's growth. But instead of shriveling up, the Phosfon-treated plant grew some 40% taller and leafier than untreated plants.

The herbicide had been mistakenly overdiluted, and thanks to that accident, Ed Calabrese rediscovered a paradox of toxicology that had been in the doghouse since the 1930s: Low doses of a poison can be not merely harmless, but actually beneficial.

After years on the ash heap of science, hormesis, as the paradoxical effect is called, is making a comeback. It is the talk of top science journals, and will be the subject of a roundtable at the annual meeting of the Society of Toxicology in March.

Toxicology, says Prof. Calabrese, now a professor at the University of Massachusetts, Amherst, "is undergoing a revolution."

The rebels are trying to overthrow decades of entrenched wisdom by reviving a 19th-century idea. In 1888, German scientists discovered that small amounts of poison may actually do an organism good (they were studying yeast). But that result became tainted by association with homeopathy, the largely discredited therapy that uses vanishingly small (and sometimes nonexistent) doses of supposed remedies. Hormesis seemed to stumble for good in the 1930s, when advocates promoted small doses of radium as the next elixir. Many of those who fell for this quackery wound up with cancer.

As a result, by the 1940s toxicology had settled on a simple model (at least for noncarcinogens; cancer-causing agents are more complicated). Adverse effects are directly proportional to dose -- more poison, more dire effects -- above a safe threshold. Below this no-effect level, nothing happens, say the textbooks. That, says Prof. Calabrese, "was an error of historic proportions."

It is one that he has been trying to correct ever since a conference about low levels of radiation reminded him of his long-ago peppermint plants. Combing decades of toxicology studies from labs around the world, he and his UMass collaborator, Linda Baldwin, found almost 6,000 instances of hormesis. Bacteria thrived in tiny does of antibiotics. Plants grew like Topsy with minute doses of herbicides or heavy metals such as cadmium and lead. Rats exposed to tiny doses of DDT had fewer liver tumors than unexposed rats. Mice zapped with a few X-rays live longer than unzapped animals.

That wasn't enough for most toxicologists. Thousands of experiments may have found hormetic effects, but how many did not? That challenge sent Prof. Calabrese back to the toxicological literature. Last year, he said, "we found that 40% of studies that looked for effects at these low doses found a hormetic effect." Hormesis was no aberration.

To be sure, the benefits are in the range of only 20% to 60% better growth or fewer tumors or greater longevity. That makes hormetic effects hard to distinguish from chance.

Hormesis is winning converts, however, as scientists decipher the mechanisms that underlie it. Organisms respond to poisons by unleashing molecular repair crews. Exposed to a heavy metal such as mercury, for example, cells produce toxic-clean-up proteins called metallothioneins. Exposed to X-rays that tear DNA, cells produce enzymes that stitch it up.

Sometimes, the organism overcompensates. It churns out more clean-up proteins or more seamstress enzymes than needed to repair the immediate damage. That leaves cells with extra defense against the slings and arrows of everyday life, such as natural DNA breakage.

"Hormesis makes biological sense," says Prof. Calabrese. "If the compensatory response overshoots, the organism can be left slightly better off than before the exposure."

Prof. Calabrese has received funding from the chemical industry as well as the Air Force and the Environmental Protection Agency. That doesn't mean the agencies believe him, he admits; EPA, for instance, says hormesis needs much more study before it shapes regulations.

In part, that's because some chemicals do more damage at low doses. DNA, for example, has receptors for hormones and anything masquerading as them (as an estimated 500 synthetic chemicals do). When a hormone or a mimic docks with a receptor, it alters gene activity, often for the worse. But the number of receptors is finite. If there are 1,000, then 100,000 molecules of a chemical will fill every single vacancy, but so will 50,000 or 1,000. Small doses can thus pack as big a wallop as massive ones, notes endocrinologist Frederick vom Saal of the University of Missouri, Columbia.

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