Is a chemical conundrum: how dangerous dioxin?

Residents of Times Beach, Mo., were forced to leave their town in December 1982 because the chemical dioxin was found in the soil. Thirty years later, the Environmental Protection Agency can't decide how dangerous the chemical is.

In December of 1982, the people of Times Beach, Mo., were forced to abandon their town forever because the Environmental Protection Agency found high levels of a chemical called dioxin.

At the time, dioxin was considered one of the world's most dangerous chemicals. But nearly 30 years later, the EPA still can't seem to decide just how dangerous it really is.

One reason for the decades of uncertainty is that the agency has had to shift its emphasis from a few high-level exposures like Times Beach to low-level exposures that affect millions of people. But another reason is that EPA scientists and those outside the agency have yet to agree on how to assess the risk of cancer from dioxin.

The problem is that there is no ideal study that directly answers the question: Does dioxin cause cancer at typical everyday exposure levels, and if so, how big a risk does it pose?

- Joshua Cohen, deputy director of the Center for the Evaluation of Value and Risk in Health at Tufts University

'Get Out, Don't Go Back'

The dioxin story jumped into the headlines because of an unlikely series of events in Times Beach, which was a small town just west of St. Louis on Route 66.

"It was the kind of community where mom and dad married and raised their children, and their children raised their children," says Marilyn Leistner, who was the last mayor of Times Beach.

Then one day, scientists discovered that many parts of the town were contaminated with dioxin. It turned out that waste oil, spread on the roads years earlier to keep down the dust, had been tainted with the chemical.

Suddenly the town was crawling with emergency workers, Leistner says. "People would wake up in the morning and see these men in their front yard in moon suits with head gear and the respirators," she says. "It was just like something from outer space."

Not long after the men in moon suits arrived, the Meramec River flooded, putting most of Times Beach under 10 feet of water.

And on Dec. 23, while residents were waiting for the water to recede, federal officials sent them a message saying their town had become uninhabitable.

The message, says Leistner, was: "if you live in the community, you need to get out. If you're outside of the community, don't go back. And don't take nothing with you."

A Superfund Site

Federal officials had taken a drastic step — one that was based more on a hunch than on definitive science. At the time, scientists weren't sure what dioxin did to people beyond producing the skin condition chloracne, which resembles severe acne.

They knew the chemical came from industrial processes, including chlorine bleaching at paper mills, pesticide production and waste incineration. And they knew high doses caused liver tumors in rodents.

A sign marked the entrance to the abandoned town of Times Beach, Mo., on Sept. 1, 1985.

Bill Pierce/Time & Life Pictures/Getty Images A sign marked the entrance to the abandoned town of Times Beach, Mo., on Sept. 1, 1985.

So federal officials took a cautious approach. They decided residential soil should contain less than one part per billion of dioxin. In some areas of Times Beach, levels were 100 times that high. As a result, the empty town became one of the nation's first Superfund sites.

"The first time I went to the site, I went by myself, and it was really heart-wrenching," says Gary Pendergrass, an engineer hired by the Syntex Corporation to clean up Times Beach.

"Walking around the streets, walking into the houses, many of them were like people had just simply stood up, walked out and never came back," Pendergrass says. "Plates on the tables, Christmas trees, Christmas decorations outside, and just street after street of that."

Pendergrass started the cleanup by building an earthen levy around a 10-acre site to protect it from future floods. Inside the levy, he built buildings to store soil and a massive incinerator to remove dioxin from the soil.

"It was quite an operation," Pendergrass says. It involved 300 workers at its peak, cost more than $100 million, and took until 1997 to finish. Pendergrass and his crew demolished the houses and buried the rubble. They put 265,000 tons of soil through the incinerator.

How Dangerous Is Dioxin?

And while the years ticked by, the EPA continued to try and figure out what health hazards dioxin really posed at Times Beach, Love Canal and other Superfund sites.

By this time, there were lots of studies on animals — and a growing number on people who had been exposed to dioxin in industrial accidents or on the job.

That research clarified some things about dioxin, says Joshua Cohen, deputy director of the Center for the Evaluation of Value and Risk in Health at Tufts University. Cohen was also a member of a committee assembled by the National Academy of Sciences to review the EPA's assessment of risks from dioxin.

Research in the 1980s and 1990s did a good job addressing the question of whether high-level exposures at places like Times Beach put people's health at risk, Cohen says. "I think we have the answer to that question, and the answer is yes."

So the EPA had been right to worry about Times Beach.

But by the time this became clear, the agency was finding very low levels of dioxin all over the place — and it was coming from sources like people burning trash in their backyards. That created a whole new challenge for the agency, one it still is struggling to address.

"The problem is that there is no ideal study that directly answers the question: Does dioxin cause cancer at typical everyday exposure levels, and if so, how big a risk does it pose?" Cohen says

How best to answer that question is something EPA scientists and outside researchers have been arguing about for decades. The agency's scientists have decided to extrapolate cancer risk from studies of workers exposed to high levels of dioxin, Cohen says.

"For example, at exposure levels one-tenth as high as those experienced by workers, EPA would assume that the risk is one-tenth as large," he says

On that basis, every bit of contaminated soil in the country would pose a risk.

But Cohen and many other scientists outside the EPA say that's the wrong approach for dioxin and some other chemicals.

Walking around the streets, walking into the houses, many of them were like people had just simply stood up, walked out and never came back. Plates on the tables, Christmas trees, Christmas decorations outside, and just street after street of that.

- Gary Pendergrass, an engineer hired to clean up Times Beach, Mo.

They say that because of the way these chemicals behave in the body, there's a threshold below which the risk of cancer disappears. If that's true, there would be no reason to worry about exposure in most places.

In 2006, Cohen and other members of the National Academy of Sciences committee added their voices to those already calling for the EPA to reconsider its position that dioxin risk had no threshold.

By then, the agency was knee-deep in studies of dioxin, says George Gray, a toxicologist who was in charge of the science and technology arm of the EPA at the time.

"The dioxin report, when it's just printed out on a printer, is probably 2 1/2 feet tall," Gray says. "There are huge amounts of information here that have to be assembled, assimilated, integrated and somehow put together to tell a story that the agency can use to help inform decisions it has to make. And it's hard."

Gray, who is now at George Washington University, was among those who thought EPA scientists should pay more attention to the outside researchers.

But they haven't.

A Threshold For Chemical Exposure?

Late last year, the agency released a proposal to make the acceptable level of dioxin in soil even lower. And in May of this year, EPA scientists offered their latest rejection of the threshold approach to cancer risk.

That stands in stark contrast to European regulators and the World Health Organization, who decided a decade ago that dioxin did have a safe threshold. As a result, they accept exposure levels much higher than the EPA's proposed standard.

All the arguing in the U.S. has delayed regulation for so long that it's no longer as important as it once was, says Gray.

"In many ways, our dioxin problem is going away," he says. "Emissions of dioxin are down 90 percent over the last 20 years. The biggest sources are now uncontrolled backyard burning that people are doing out in rural areas on their own. It's not industry. It's not paper mills. It's none of the traditional sources. They've cleaned up."

But the EPA's actions still could have a big effect on places like Times Beach, which is now known as Route 66 State Park.

If the agency adopts its proposed lower goal for soil, the site might have to be dug up and cleaned up all over again.

Environment

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A Chemical Nurtures New Brain Cells In Rodents

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Scientists screened nearly 1,000 chemicals and found one that nurtures new neurons in rat and mice brains. University of Texas Southwestern Medical Center biochemist Steven McKnight describes the work and explains what has to happen before the chemical can be tried in humans.

Copyright © 2010 National Public Radio®. For personal, noncommercial use only. See Terms of Use. For other uses, prior permission required.

IRA FLATOW, host:

You're listening to SCIENCE FRIDAY from NPR. I'm Ira Flatow.

Up next, the latest in the quest to replenish our ever-diminishing brain cells. What if you could take a drug, a shot or a pill that would nurture new neurons in your brain, neurons that actually worked and made your brain work better? Scientists at the University of Texas Southwestern have found a chemical that might do the job some day.

In what must have been a long and tedious effort, the researchers screened 1,000 chemicals to see whether one of them might stimulate the brains of mice to grow more brain cells, and they were actually laughed at by their colleagues who thought, ha, what kind of approach is this in this age of genetics, huh? But they said that we're going to go ahead. And they found a - they found that needle in a haystack, a chemical that worked in mice and in rats. And, of course, the obvious question is: Would it work in humans?

Joining me to tell us about that is Steven McKnight. He's professor of biochemistry and the chairman of the department at the University of Texas Southwestern Medical Center in Dallas. He's talking to us today from Montana.

Thanks for taking time out. Everybody's on their vacation today. Thanks for taking time to be with us.

Dr. STEVEN McKNIGHT (Biochemistry, University of Texas Southwestern Medical Center): No problem, Ira.

FLATOW: So why, you know - here you take a chemical approach when here we are in the age of biology and the rock stars are all these biologists and synthetic biology, is that why people were laughing at you?

Dr. McKNIGHT: No. I think they laughed at us because of the fact that the chances were pretty slim that this approach, this in vivo screening approach with chemicals injected right into the brain tissue of mice would work. So the likelihood of it working was pretty small.

FLATOW: So it was like a needle in a haystack.

Dr. McKNIGHT: I think that's a good description.

FLATOW: And what did the drug or the compound actually do?

Dr. McKNIGHT: Well, we - there were assays that are fairly straightforward to monitor the birth of new neurons in the brain of a mouse. And we're not the ones who developed that assay, but we're following the literature and knew that there was an assay. And so my associate, my postdoctoral fellow at the time, Andrew Pieper, took the risk of saying let's conduct the screen...

FLATOW: Mm-hmm.

Dr. McKNIGHT: ...and inject those compounds directly into the brain and see if we could find compounds that would enhance the formation of new neurons.

FLATOW: Now we were all taught - I certain was in biology class early on - that the brain doesn't make any new nerve cells. But that doesn't seem to be the state of the knowledge. We find out that they do, right?

Dr. McKNIGHT: No, you're exactly right. And I was the same way when I was in college 30 years ago. I was taught that you're born with all the brain cells that you have and you're never going to make any new ones, so be careful with them.

FLATOW: Mm-hmm.

Dr. McKNIGHT: And yet terrific inspirational work, primarily from a scientist by the name of Fernando Nottebohm at the Rockefeller Institute, gave evidence clear as a bell that in birds, when they need to learn a new song during their mating season, they actually make entirely new neurons in order to learn that song. So I think that was the first concrete evidence that the vertebrate brain could actually make new brain cells. In the ensuing years, over the past decade or so, it's become clear that that happens not only in birds but also in mice and rodents and even also in humans.

FLATOW: So when you injected and fed this compound into mice and rodents, you found that they - it helped preserved their brain cells, the ones that - their newborn brain cells, so to speak?

Dr. McKNIGHT: That's right. In essence, our compound - we call it - we dub it P7C3, it actually doesn't force new cells to be born. Instead, the ones that are born and are being made are protected from death.

FLATOW: Hmm.

Dr. McKNIGHT: Normally, many of them die along the pathway to become wired neurons in the brain. For reasons we don't understand, most of them don't make it. And the older an animal gets, the more of them don't make it. And for some reason, our compound, P7C3, helps preserve the livelihood - the life of these newborn cells so that they can become incorporated and actually function as neurons.

FLATOW: And so as these rodents age, they age better and their brains, too, then?

Dr. McKNIGHT: Well, you know, the one behavioral study we've done was with very old rats.

FLATOW: Right.

Dr. McKNIGHT: And when a rat is 18 or 20 months old, it begins to lose its cognitive capacity. It has a harder and harder time learning. And so we just followed the paradigm that many other scientists have used and asked the question, would our P7C3 compound, if administered the last two or three months of life, preserve cognitive capacity in these aged rats? And sure enough, it appeared to do so.

FLATOW: Wow. And did you have to inject them into the brains or could you actually feed this compound to the rats?

Dr. McKNIGHT: Well, the initial assays when we're chasing after the compound, we did have to inject them right into the brain. But this particular compound, P7C3, actually can be fed to the animals orally. It gets across their gut into the blood system and crosses the blood brain barrier. And so it ends up being a rather easy compound to use, and so we - now we don't have to any longer inject it directly into the brain.

FLATOW: Now, I'm sure everybody has asked you, how do I get my hands on this?

(Soundbite of laughter)

Dr. McKNIGHT: Well, listen. Ira, this is at least a year or two off before it would qualify for human testing. We've done this all in animals. And it's a good bit more work to know whether it is a viable approach to use in humans. And like I say, that's at least a year or two away.

FLATOW: Mm-hmm. Does it migrate to one part of the brain over another part of the brain?

Dr. McKNIGHT: We don't know the answer to that. Today, we simply measured its absorbance into the entire brain tissue of these animals. We haven't looked specifically whether it reaches some part of the brain and not others. So that's ongoing experimentation.

FLATOW: Mm-hmm. And the fact that it keeps new brain cells alive and viable, would you think that it would work in all parts of the brain where new brain cells are being produced?

Dr. McKNIGHT: That would be my guess, but we really have to dig in carefully to test that. There - we studied a region of the brain called the hippocampus that's known to produce new brain cells. So that was our focal point.

There is another part of the rat brain and the mouse brain called the subventricular zone. It also makes new neurons. And we have indications that the compound also works in that region of the brain, but we haven't carried out conclusive studies.

FLATOW: Mm-hmm. Are there any other compounds like it already out there?

Dr. McKNIGHT: Well, there are a couple of compounds that are somewhat similar in chemical nature. One of the more interesting ones is a compound that was used in Russia for decades and decades as an antihistamine. And completely by accident, Russian physicians anecdotally noticed that patients suffering from Alzheimer's disease were improving. And they traced it down to the fact that these patients were taking the antihistamine that's now called Dimebon.

So about six years ago, or five years ago, a biotechnology company in the Bay Area began performing clinical trials on this antihistamine Dimebon to ask whether it really might work to help treat Alzheimer's patients. So, that compound, Dimebon, has structural similarities to the compound that we call P7C3.

FLATOW: Mm-hmm.

Dr. McKNIGHT: And so, there's some chance that they might be working via a similar pathway.

FLATOW: Mm-hmm. And do you think yours works better?

Dr. McKNIGHT: Well, it's really hard to say until they're compared in human trials. In the mouse experiments and the rat experiments, the one that we stumbled over is considerably more potent and effective than Dimebon by maybe tenfold or 30-fold. But whether that would translate to humans is an entirely different matter.

FLATOW: How many more compounds are left for you to work your way through. You went through 1,000. How many potential more are they?

Dr. McKNIGHT: Well, Ira, there's limitations. Now that we've kind of got one, I don't think we're going to go back to the well and do another thousand or two.

FLATOW: Well, but you may have some graduate students listening today. I could do that. Right? And it would be - and what would be wrong with that?

Dr. McKNIGHT: Well, you know, I think what people are surprised by is the approach of actually doing this in living animals. It's arduous and slow, and yet if you're lucky enough to find a compound that actually works in the animal, you know, that's the ultimate goal. You want something that actually can treat a disease in a living animal. And I think that was the inspiration that Andrew Pieper brought to the project. He decided, let's see if we could get something that really worked in a living animal.

FLATOW: Mm-hmm. And with all these - and you talked about all the compounds -with so many of them, how did you screen out the ones that you were going to test and leave the other ones back in the medicine cabinet?

Dr. McKNIGHT: Okay. Well, you know, this is fairly simple, Ira. We have a compound file at the University of Texas Southwestern with maybe 200,000 compounds. So we knew we couldn't screen nearly that many.

FLATOW: Right.

Dr. McKNIGHT: So we asked our chemistry colleagues to pare down the 200,000 to 1,000 that would be representative of the chemical diversity of the entire library. So we didn't have any bias. We didn't think, oh, this one would be the one that would work in the brain or this one wouldn't. We simply preserved the chemical diversity in paring it down from 200,000 to 1,000. And then, we just blindly tested them.

FLATOW: Wow. Where did you get the money for this?

Dr. McKNIGHT: Most all the money has been provided by the National Institutes of Health via federal research grants to Andrew and to me and to others who work with us. But we have had philanthropic support from wonderful people in the Dallas community who support our research for 10 or more years.

FLATOW: Mm-hmm. So they have confidence in you, in other words.

(Soundbite of laughter)

Dr. McKNIGHT: I guess the answer to that is yes. Why that would be the case, I don't know. But we really simply got lucky this time.

FLATOW: Well, yeah. So let's say you want to continue this roll of good luck, where do you go from here now? You have a compound. You know it preserves the life of these baby neuron cells developing in the brain. Are you the one that goes on to try it out in humans or do you find a partner to try that out?

Dr. McKNIGHT: Well, we reached the point, Ira - we've made many derivatives of the P7C3 compound. We've improved it. We polished it to some measure. But the next level of actually, you know, perfecting it and getting it optimized for human trials is normally best done in the for-profit world, in a biotechnology company or in a pharmaceutical company.

FLATOW: Mm-hmm.

Dr. McKNIGHT: So I would think that over the next six months or 12 months, at some point we want to hand the baton off to the appropriately skilled professionals in that domain. It's not something that's typically done in academia. It's not that we couldn't do it. But in all likelihood, we would prefer to move it into the for-profit world for a drug company or a biotechnology company to take it into human trials.

FLATOW: This is SCIENCE FRIDAY from NPR.

I'm Ira Flatow talking with Steven McKnight of University of Texas Southwestern Medical Center in Dallas, talking about the compound that works in mice and rodents to prevent the death of brain cells. Could there be side effects to something like this that you might not - you know, unintended consequences?

Dr. McKNIGHT: Oh, that's always the case. You know, we've studied this carefully in mice for - perhaps administering it for months at a time. But unintended side effects could crop up at any time. So that's the boogeyman that always gets you as you're trying to develop a drug, discover a drug.

FLATOW: Mm-hmm.

Dr. McKNIGHT: You know, there are many pitfalls ahead of us.

FLATOW: Well, I'm asking, you know, this is just a basic question about basic research. Mice don't live very long, right? And could something crop up in the human lifetime that's, let's say, 75, 80 years, that might not show up in a mouse's life.

Dr. McKNIGHT: Absolutely. Absolutely. That's entirely possible.

FLATOW: And - but this is the standard that people - that researchers use every time they do research.

Dr. McKNIGHT: Well, you got to start somewhere, Ira.

(Soundbite of laughter)

FLATOW: So you're looking for basically a business partner at this point.

Dr. McKNIGHT: Well, that's, you know, probably in the cards, that's something we'd like to do. But, you know, in the meantime, there's lots of science for Andrew and our team to do ourselves. So there's...

FLATOW: Such as? Such as? Give us an example.

Dr. McKNIGHT: We don't know for - a really important shortcoming, Ira. We don't know what protein, what molecular target in the brain this compound P7C3 touches. We have an inkling that it's perhaps working in the energy factory of cells, mitochondria. But we don't know exactly what protein target it's tickling. And as scientists, that's what we got to nail. We've really got to understand mechanistically how is this compound working. And right now, we don't have the answer.

FLATOW: So you know it works, but you don't know how it works.

Dr. McKNIGHT: That's right. And...

FLATOW: Wow.

Dr. McKNIGHT: ...we would love to be ones to make that discovery. But now that the paper is published, I think as of today the cat's out of the bag and so other scientists are going to be able to chase after, you know, that discovery...

FLATOW: Right

Dr. McKNIGHT: ...to find out how P7C3 works and...

FLATOW: Because this compound is available to anybody...

Dr. McKNIGHT: Oh, sure.

FLATOW: ...who wants to use it. You go into the little book, open it up and order some.

Dr. McKNIGHT: Absolutely. So, you know, if we don't - if we're not the ones that make that discovery of exactly how it works, shame on us.

FLATOW: Well, that's because you got a few months lead on everybody else.

Dr. McKNIGHT: Well, we've got a bit of a lead. But, you know, the wonderful thing about science is it's a worldwide community, and if we're not the ones to discover how it works, the person or the group that does will be contributing just like we have.

FLATOW: Well, we want to thank you very much for taking time to talk with us and tell us about your discovery today. Of course, wish you good luck.

Dr. McKNIGHT: Well, thank you, Ira.

FLATOW: Because when we help you, you're going to help everybody else.

Dr. McKNIGHT: Well, we can all hope so.

FLATOW: We can all. Thank you, Dr. McKnight.

Dr. McKNIGHT: Bye-bye.

FLATOW: Steven McKnight is professor of biochemistry and chairman of the department at University of Texas Southwestern Medical Center in Dallas. And he was taking time, as other people do on this vacation period, to talk to us from his vacationing spot in Montana.

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