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SCIENCE, Vol. 251, pages 624 - 626 (8 February 1991). Dioxin Risks Revisited Armed with a new understanding of how dioxin works on the molecular level, a number of scientists are challenging EPA to change the way it does risk assessment WHEN A DISPARATE GROUP OF 38 RE- searchers and regulators from the United States and Europe got together at a recent meeting on dioxi n, they reached an agree- ment that surprised almost everyone. At the Banbury Center at Cold Spring Harbor Laboratory, they agreed that before dioxin can cause any of its myriad toxic effects, be they cancer or birth defects, it must first bind to and activate a receptor. And this unlikely agreement on how dioxin works at the molecular level-and some hurried cal- culations scribbled on a blackboard-could force a dramatic change in how the federal government assesses the risk of this and similar carcinogen s. After the decades of scientific debate that have dogged this chemical, consensus on anything seems surprising. Scientists have been struggling to figure out just how dan- gerous dioxin really is ever since it was first detected in the late 1950s as a by-product of herbicide manufacture. Animal studies have shown this ubiqui:tous pollutant to be ex- quisitely lethal, the most, potent carcino-- gen ever tested. But human effects have been notoriously diffrcult 'to pin down, as shown by the decades-long controversy over the dioxin-tainted defoliant Agent Orange. Even among highly exposed groups, like the people who lived near the chemical plant that exploded in Seveso, Italy, in 1976, the only undisputed effect until recently has been the skin disease chloracne. Just last month, however, a new epidemiologic study provided what may be the strongest link yet between high doses of dioxin and human cancer (see boxes on pp. 625 and 626). In the absence of definirive human data, the Environmental Protection Agency has assumed the worst, adopting a linear risk assessment model that posits that there is no safe level of dioxin and that its toxic effects rise proportionatel,y with dose. EPA then set a stringent acceptable intake level at 0.006 picograms per kilogram of body weight per day. By contrast, Canada and some Euro- pean countries, which dismissed the linear model as unrealistic, have'set their limits about 170 to 1700 times higher than EPA's, at 1 to 10 picograrns per kilogram per day. Yet, sighs toxicologist Michael Gallo of the Robert Wood Johnson Medical School in New Jersey, "It's the same chemical on both sides of the Atlantic." Now comes the Banbury Center meeting. Organized by Gallo, Robert Scheuplein of the Food and Drug Administration, and Cornelius van der Heijden of the National Institute for Public Health in the Nether- lands, it suddenly offered a.vay out of the morass. If receptor binding is indeed the essential first step before any toxic effects can occur, as the meeting participants agreed, then that implies there is a"safe" dose or practical "threshold" below which no toxic effects occur. And that, in turn, means that the model EPA uses is wrong. "It topples the linear multistage model," exclaims Gallo. Spurred on by the Banbury meeting, Gallo and others are now urging EPA and the other federal agencies to abandon that a d a° d _o aoi~ L w G 0 0 d rn « c d E w E will also be applicable to other carcinogens that work through receptors. "This is bigger than dioxin." EPA scientist Linda Birnbaum, director of the environmental toxicology division of EPA's Health Effects Research Laboratory in North Carolina, is no less enthusiastic. "It's a new way to do risk assessment. We can set a limit below which there cannot be an effect, on a mechanistic basis. Instead of saying we know nothing and have to extrapolate back to zero, we are saying we know a hell of a lot and can make predictions." But everything about dioxin is conten- tious, and the Banbury meeting sparked its own share of dispute. Consensus broke down on just what such a receptor-based model would predict in terms of dioxin's danger. Gallo and Scheuplein contend that the new 10-i 3 10-1z 10-1 i 10-1o 10-s 10-s Dioxin concentration 10'7 A dioxin receptor model. New findings suggest that responses to dioxin increase slowly at first but then shoot up after passing a critical concentration. model, which they use as a "default" model for lack of a better alternative, and try to predict dioxin's risk based on a molecular understanding of how the chemical works. When EPA regalators adopted the default model for carcinogens in the late 1970s, their intention was always to replace it with something morc appropriate-once they knew enough to do so. But that has rarely happened. "If we can't do it for dioxin, for which we have so much information, then we probably can't do it f<or anything," says Gallo, who thinks that this new approach model will show dioxin to be far less risky than U.S. agencies now calculate. Others, like George Lucier of the National Institute for Environmental Health Sciences (NIEHS) in North Carolina, say such speculation is premature. And Ellen Silbergeld, a toxi- cologist formerly with the Environmental Defense Fund and now at the Universin, of Maryland, thinks speculation that dioxin is less risky may be dead wrong. And even if the new model does indicate that EPA's risk number is far too conserva- tive, revising it would be horrendously dif- 624 SCIENCE, VOL. 251

ficult-espccially tbr, a molecule as politi- call charged as dioxin. Gallo calls the sub- stance a powerful "litigen," referring to the scores of laWsuits that have been filed by people alleging health effects from environ- mental exposure to dioxin. Michael Gough of the Office of Technology Assessment and author of Di oxin: Agent Orange predicts "a tremendous uproar from environmental groups and Congress." Indeed, John Moore tried to revise both the dioxin risk number and the model during his tenure as assistant administrator for pesticides and toxic sub- stances at )rPA. He was foiled both times, essentiallv because the scientific rationale wasn't strong enough. Now it may be, thanks largely to the Banbury mei:ting, says Moore, who now heads the Institute for Evaluating Health Risks in Irvine. What tipped the scale is not su much new experimental data as the accu- mulating weight of evidence. Indeed, awareness that dioxin binds to a specific receptor, known as the Ah, or aromatic hydrocarbon receptor, goes back to work done in thi: 1970s by Alan Poland of the University ol" Wisconsin. Since then, the nagging question has been whether all of dioxin's eff<:cts-including cancer-are mediated through the receptor. That question was at last laid to rest at Banbury. When researchers pooled their data, they realized that for every effect stud- ied so far, in every experimental system, binding to the receptor was the first and essential step. Indeed, no effect can occur until the reo~ptor-dioxin complex is acti- vated and transported to the cell nucleus, where it interacts with the DNA and sets off a cascade of events. Poland cautions, how- ever, that son-ieone may yet turn up an effect that is not mediated this way. What's more, says Gallo, drawing on clas- sic receptor-occupancy theory, several thousand of.~ the receptors have to be occu- pied before ar:y biological response is seen- though the exact number is a matter of considerable controversy. To Birnbaum of EPA, "The key point is that there is a dose of dioxin below which the receptor does not function, and if it is not activated, there can be no effect," though she and others shy awav from saying there is a threshold in the strict sense. The upshot, most but not all of the Banbury, participants agreed, is that the Straight line predicted by the linear multi- stage model is wrong.:Instead, the curve at its lower end looks like a hockey stick in which the response increases very slightly at low doses, along the blade, and then shoots up almost lincarly at the bend in the stick. The key question, then, is where the re- sponse shoots up in humans, which the group set our to determine in a flurry of High Dioxin Dose Linked to Cancer For two decades now a debate has been raging about whether dioxin causes cancer in humans. Animal studies have shown one form of dioxin, TCDD, to be the most powerful carcinogen ever tested, earning it a reputation as a pariah, the Darth Vader of chemicals. But human epidemiologic studies, which have been hampered by insufficient exposure data or small num- bers, have been equivocal. Over the past few years a "revisionist" school has emerged, asserting that, in the absence of any definitive cancer link in humans, dioxin must have been given a bum rap. Now, a new study by federal scientists presents what many consider the strongest evidence yet that dioxin is indeed a human carcinogen-but apparently only at exceedingly high doses. In an editorial accompanying the study, which was published in the 24 January issue of The New Dioxin sleuth. Marilyn Fingerizut ran NIOSHstudy. England Journal of Medicine, biostatistician John Bailar III of McGill University in Montreal calls it "a model of its kind. We are likely to wait a long time for appreciably better or broader evidence of the effects of TCDD on human health." In the exhaustive study, which took nearly 13 years to complete, Marilyn Fingerhut and her colleagues at the National Institute for Occupational Safety and Health examined the mortality records of essentially all U.S. chemical workers exposed to dioxin on the job from 1942 to 1984: a total of 5 172 men at 12 different plants. What sets the study apart, other than its size, is that this is probably the most highly exposed population ever studied, says Fingerhut. What's more, their exposure was well characterized. The NIOSH team measured TCDD levels in the blood serum of 253 of the workers. The result: the levels correlated well with their surrogate measure, which was how long a worker was in a dioxin-contaminated job. The workers overall had a 15% increase in mortality from all cancers. But that picture changed dramatically once the cohort was divided into a low-exposure and a high-exposure group. Low exposure was defined as working less than I year in a dioxin-contaminated job; high exposure as 1 year or more. The men in both groups had their first occupational exposure to dioxin at least 20 years earlier, allowing for a 20-year latency period for cancer. In the low-exposure group, there was no increased risk of cancer, even though those men were exposed to dioxin levels an estimated 90 times higher than the general population. By contrast, the high- exposure group, who received doses estimated to be 500 times higher than the general population's, had an almost 50% excess risk of dying of cancer. The increase was mostly in soft tissue sarcomas, a form of cancer linked to dioxin in other epidemiologic studies. But there was also an unexpected increase in cancers of the respiratory system. The study did not show a significant increase in the handfiil of other cancers that have been linked to dioxin in epidemiologic studies. "Even a study this large, with all the workers in the U.S., has limitations in size for looking at individual cancers," explains Fingerhut. The study has other limitations as well. For one, workers were exposed to other occupational chemicals, often for 20 years, and the epidemiologists could not control for their effects. Nor could they control for smoking. Fingerhut thinks neither factor is likely to explain the excess cancer risk, but she cannot definitively rule out that possibility. Nevertheless, she sees the study's outcome as very clear, writing: "The increased mortality is consistent with the status of TCDD as a carcinogen." This study probably defines the upper end of human effects, adds Fingerhut, who leaves it to others to speculate about what it means for people exposed to lower doses of dioxin. Will this study settle the dioxin controversy? Not likely, if newspaper headlines are any indication. "Extensive Study Finds Reduced Dioxin Danger," heralded The Washington Post. "High Dioxin Levels Linked to Cancer," warned The New York Times. And the study is already being cited as evidence in the flap over Monsanto's alleged falsification of its dioxin studies (see box on p. 626). Indeed, Bailar predicted that "parties on both sides of the continuing debate about the regulation of dioxin exposure will no doubt cite this work in support of their positions."  L.R S FERRC'AR)' 1991 RESEARCH NEWS 625

c citci»enc on the last day <>f the meeting. Instead of direct mr.asures of receptor bind- ing, they used a handy surrogate: the in- creased activity of the cytochrome P450 enzyme system, widely considered the most sensitive response i:o dioxin in all species. No toxic effects are known to occur at levels below those required for enzyme induction. After reviewing data on the necessary dose for enzyme induction in alll species, Gallo, Birnbaum, Scheuplein, and others took turns at the blackboard, trying to calculate what the "safe" level in humans might be. Their rough, back-of- the -envelope calculation: I to 3 picograms per kilogram per day-several hundred times higher than current U.S. standards and in the same ballpark as those set by some European countries, which ar- rived there by an entirely different method. Not so fast, says Maryland's Silbergeld, who cautions again:x "replacing one stupid model with another." For one, a receptor- based model does r ot necessarily predict a "hockey stick" curve, nor does rcceptor bind- ing necessarily implya"safe" dose, says Silbergcld, who thinks her colleagues are underestimating the intricacies of receptor theory. Nor is she convinced "that the result [of the new model] will be that different from EPA's current figure. As a scientist, I object to the EPA model. But [its predic- tions] may be very, very close, for totally irrelevant reasons." Working with EPA scientists, Gallo is now setting out to refine the risk number for dioxin. George Lucier and his colleagues at NIEHS are doing the same. The idea is to build a conceptual model of cellular re- sponses to dioxin and then turn that over to mathematicians to develop a predictive tool to estimate dioxin's risks-not just for cancer but for any toxic endpoint. William Farland, who runs the dioxin risk assessment effort at EPA, expects a "straw man" model to be complete in about a year. The next step would be to see if it passes muster with the Mons,anto Studies Under Fire The Environmental Protection Agency has launched a criminal investigation to determine whetrier Monsanto Corp. of St. Louis falsified three epidemiologic studies of its workers, which showed no increased health risks from dioxin other than the skin disease chloracnr. The investigation, which EPA is mandated to conduct in response to a petition re:questing it from the activist group Greenpeace USA, should resolve, once and for all, the allegations that have been swirling around these studies for almost a year. :EPA officials would not conflrm or deny the existence of the investigation, bu t Seience obtained internal agency memos discussing it. The EPA has not notified Monsanto that it is under investigation, but says Dan Bishop, the company's director of communications, "We hope there is one, we welcome it. It is the only way to put this matter to rest." In fact, the company wrote to EPA twice ov.-r the past few months, begging the agency to perform a scientific audit of the studies. Bishop calis the fraud allegations "bald-faced lies." The main charges are that Monsanto epidemiologists misclassified exposed work- ers as unexposed in their control group and that they omitted workers who had died of two cancers that have been linked to dioxin exposure in other epidemiologic studies. The charges first came to light last February when a plantiff's lawyer in Kemner v. Monsanto, a case involving a tank-car accident, reviewed the studies, decided they were fraudulent, and alerted the press to the alleged cover-up. That brought in Green.peace, and also Cate Jenkins, a chemist in EPA's regulatory branch. She has since mad e the Monsanto studies something of a personal crusade, petitioning EPA's Science Advisory Board to audit these and other studies, and meanwhile sending numerous copies of her memos to various environmental groups, Vietnam veterans organizations, and her friends on Capitol Hill. Jenkins maintains that Monsanto's studies have directly affected how EPA regulates dioxin. Other agency officials deny that, saying that EPA's current-and very stringent-standard for dioxin exposure is based on animal studies. Everyone Scier ee spoke with who is familiar with the Monsanto studies agrees that they are flawed, but probably not as the result of criminal intent. The scientific questions about the studies may now be moot, however, as all but six of the Monsanto workers in the three studies have been carefully reexamined as part of a larger federal study just published, which suggests that high dioxin doses can cause huuian cancer (see box on'page 625). The other questions may be tougher to resolve. When EPA completes its investigation, the agency will report to the Justice De- partment and re:commend either that they prosecute or close the case.  L.R scientific community-and if it in fact of}ers an advantage over the status quo. "This is an improvement, not a cure-all," warns Lucier. Once the model is complete, perhaps the biggest question, in terms of dioxin's danger, is the background exposure of the general population, which comes chiefly from diet but also from environmental sources. If back- ground exposure is comfortably below the practical "threshold" needed for receptor activation (point B in the figure), then there may indeed be a safe dose. But if background exposure is higher, near the "threshold" (point A), "then there is no margin for ad- •ditional exposure," says Moore. Background exposure is now estimated to be about I picogram per kilogram per day-slightly be- low the rough "safe" number the Banbuny group came up with-which may not leave much room for additional exposure. At this juncture, EPA officials are enthusi- astically embracing the new scientific ap- proach. Don Barnes, a dioxin expert and executive director of EPA's Scientific Advi- sory Board, talks of "a real breakthrough, a sea change in our view ofdioxin." In fact, the topic is deemed important enough that a special briefing is planned for EPA adminis- trator William Reilly and top agency officials. But how far is EPA likely to go if the modeling exercise does reveal that dioxin is less risky than the agencies now calculate: Gough of OTA, for one, thinks that the answer is not very far: "Dioxin is the most potent carcinogen ever tested. If they back off this one, they will open the door to every chemical manufacturer in the world" whose chemical acts in the same way. "That is a door they will reluctantly open." Gallo con- tends that the door will open just a crack, as there are less than a dozen carcinogens known to work the way dioxin does. And he predicts that the new receptor-based risk model will cut both ways: some carcinogens will turn out to be far riskier than now predicted; others, like dioxin, less risky. Moore agrees that change will not be easy. "For issues this emotional, you have to be purer than Caesar's wife anytime you propose to change the status quo. There would have to be a fair degree of support within the scientific community for it to come to pass, especially if the potential change is a`relaxing' of the number." Eric Bretthauer, EPA's assistant adminis- trator for research and development, con- cedes that "the agency hasn't traditionally relaxed numbers." But, he savs, "I think there is a willingness at the policy level to take it on. My vie-,v is we have to be open to changes in science, whatever their effect on regulatory policy." He adds, however, that "the science has to be verv clear."  LESLIE ROBERTS 626 SCIENCE, A'OL. 2,,1 4:,; .