Hormesis: Is there a tonic in the toxin?
By Nell Boyce, US News and World Report, Oct 18, 2004

The idea that a small amount of a dangerous substance can stimulate the body's defenses isn't new--just think of vaccines. But try arguing that this same notion can apply to toxic environmental chemicals like arsenic and dioxins and you'll quickly get written off as either a quack or an apologist for polluters. Edward Calabrese argues just that, and somehow he has managed not to be demonized for his theory.

For years, this toxicologist has quietly worked at the University of Massachusetts-Amherst to bolster the credibility of the scientific theory known as "hormesis" --the idea that exposures to chemicals or radiation at low doses can have the opposite effect than at high doses. The field has been much maligned and confused with scientifically sketchy homeopathy since 1888, when a German pharmacologist named Hugo Schulz first noted that small amounts of poison encouraged the growth of yeast. Unlike homeopathy, however, which can involve solutions so dilute that they no longer contain any trace of the active substance, hormesis happens at low but real exposures that can often approximate the actual levels of toxins people encounter every day.

These low levels rarely get tested in the lab. That's because standard toxicology tests use much higher doses to quickly but roughly extrapolate what happens in the real world. Regulators currently assume that toxins either always pose some risk at any level or that there's a threshold below which toxins won't cause health problems. But while these assumptions are used to regulate everything from mercury to pesticides, Calabrese argues that they just don't reflect the paradoxical and sometimes beneficial effects seen at low doses in the lab. "The central pillar of toxicology is the dose response," he says. "I'm telling them that they got the most fundamental aspect of their field wrong."

By sticking to the science, Calabrese has brought hormesis to a previously unimagined level of respectability, with articles in top science journals and sessions at major toxicology meetings. And he's taking the logical next step--venturing out into the messy political world of environmental regulation, where passions run high. This past summer, in Toxicology and Applied Pharmacology, he proposed the heretical idea that government regulators switch to the hormesis model to assess how environmental chemicals affect humans' health.

That idea gives fits to environmental activists. They fear it might give regulators an excuse to let toxins linger in the environment. "I don't have a quarrel with Calabrese's science," says Gina Solomon of the Natural Resources Defense Council. "But I do have a quarrel with how this can be misused in the regulatory process." For Calabrese, however, it seems like the natural extension of what he's learned over the past two decades. "People had thought about hormesis in the past, but they were very ideological," he says. "I see hormesis as intellectually interesting."

Years before he ever heard the term "hormesis," back when he was a college student, Calabrese had his first brush with what was to become his calling. In one botany experiment, he noticed something weird: A chemical that was supposed to inhibit plant growth would, at low doses, spur the growth of peppermint. The oddity got stuck in the back of his mind as he finished his Ph.D., but the zeitgeist wasn't right for this idea. Rachel Carson's environmental classic Silent Spring had come out in 1962, the first Earth Day had been held in 1970, and the environmental sciences were booming.

One day, however, the mail brought an advertisement for a meeting on radiation hormesis, the idea that radiation can kick-start the body's defenses and improve health. Reminded of his mint plants, Calabrese wondered if anyone had looked at this notion in chemicals. He decided to test the idea and began to find various examples of toxins doing some good for plants and animals at low doses.

His colleagues scoffed, arguing that it must be a rare and insignificant effect. So Calabrese and colleague Linda Baldwin did a survey of some 4,000 toxicology studies reported in science journals. They found that about 350 showed chemicals had opposite effects at low levels. And the actual prevalence could exceed that, as most of these studies weren't designed to tease out subtle effects that happen at tiny doses.

These days, most toxicologists accept Calabrese's general premise that tiny doses can have strange effects. As Linda Birnbaum, director of the experimental toxicology division of the Environmental Protection Agency and president of the Society of Toxicology, says: "Just looking at a high dose when we are killing animals or causing very overt, obvious problems may not tell us what is happening at the low-dose region. The real challenge for the next years is to understand how we approach this complexity." Still, while interest in low doses has grown, the emphasis has generally been on overlooked harms.

Calabrese courts controversy because he doesn't discount the possibility that low doses could improve health. As a result, "people tend to think of hormesis as a beneficial response," says Birnbaum, who believes it's not so simple. Low doses of certain chemicals might help some body systems while hurting others. They could, for example, help prevent cancer but also interfere with the immune system or fertility.

Calabrese doesn't disagree. "Some people describe it as a beneficial effect at low doses. I don't do that," he says. "I have tried to emphasize that there are opportunities for good and bad here." For example, he and colleagues have a study next month in Reproductive Toxicology that shows that higher levels of lead can delay puberty in mice, while lower levels can speed it up. So, should regulators try to push lead levels as low as possible, or not? "It challenges regulatory risk assessment concepts," he says.

Despite his willingness to consider that toxins can sometimes be beneficial, Calabrese seems to enjoy needling industry just as much as challenging environmentalists. He's taken industry-unfriendly positions like the notion that a single brief exposure to a carcinogen might be enough to trigger cancer, and in one political fight over the cleanup of a military site, he argued for a more rigorous cleanup than even the EPA.

But intellectually, Calabrese says, he thinks hormesis should "win." And even as he lays siege to his profession's sacred pillar, he acts surprised that anyone would feel threatened, as if this toxicology debate were like a baseball game or a bike race where everyone goes for the gusto and then shakes hands at the end. The disconnect helps explain why this scientist who is so comfortable with chemicals' paradoxical effects has trouble understanding how people on every side of a debate can find his work so alarming. "I view myself as quiet and mild-mannered," Calabrese says with a sort of mystified shrug, "but I seem to get embroiled in controversy."