Document OXNYwVeLkJx42kwkMmEzBqgp

.nul Institu e ot Environmental Ite m t Vaencoa More Pieces in the sensitive to dioxin at low doses. That obser vation, Lucier concedes, is "not inconsistent" with a threshold. But the bottom line, he and Dioxin Puzzle Portier argue, is that they found "lots of different dose-response curves for receptor- mediated events"--which should put an end Ten months ago it seemed there might he a "threshold"for to the notion that just because dioxin binds to a receptor, there is ipso facto a threshold. dioxin's effects; now comes evidence to the contrary "That is their interpretation," retorts Gallo, who has taken the lead in developing EPA's new receptor-based model. Though Almost halfway t h r o u g h a major re- receptor complex is "activated." he calls Lucier and Fortier's assessment of dioxin's toxicity, the infamous N ot so, say Lucier and new study "super," he thinks chemical is proving to be even more slippery Portier, who about a year ago they go too far in their inter than many scientists initially suspected. sec out to answer the dioxin pretation* At even lower Less than a year ago, some of the natron's threshold question once and for doses, he suspects, they would leading dioxin experts, including Michael all. Their strategy, which they have seen a threshold. Says Gallo, associate dean tor research at the described in late September at Gallo: "I am still convinced Robert Wood Johnson Medical School in the Dioxin '91 meeting in Re that a fixed number of recep New Jersey, and Linda Bimbaum of the search Triangle Park, was to tors have to be occupied be Environmental Protection Agency's (EPA) focus on specific biochemical fore we see a response in ani Health Effects Research Laboratory in changes believed to occur along mals." But Lucier and Po- North Carolina, urged EPA to reassess the pathway to carcinogenesis rtier's new data have made a dioxin's risk. The scientists were spurred on and see how each one responds convert out o f EPA's Bim by new evidence about how the chemical to dioxin dose. Lucier concen baum, who is playing a key acts at the molecular level, which suggested trated on the biology; Portier role in the dioxin rvalua there might be a practical "threshold" or on the modeling. tion. "We arc not sure a cer "safe" dose below which no toxic effects Lucier's group began by tain number of receptors have would occur (Science, 8 February 1991, p. feeding rats varying but ex to be activated anymore," she 624). If so, they said, then the linear model tremely low doses of dioxin ev concedes, adding that the is EPA uses to predict risk is probably off, ery 2 weeks. (The lowest was sue "is turning out to be even perhaps by a large margin. 100 picograms per kilogram per In response, last May EPA administrator day.) At the end of 30 weeks, George Lucier more complicated than peo ple thought earlier." William K. Reilly launched ah effort to build the researchers measured several simple, di The key task now, say Lucier and Portier, a new, biologically based model oxin-induced changes, such as is to determine which of the effects they have for assessing dioxin's risk. Once the activity of the cytochrome analyzed is the most representative of can complete, this will be one o f the p450 enzyme system, which cer--and thus most useful in reevaluating first times EPA has replaced its goes up in response to dioxin, dioxin's cancer risk. In the end, says Lucier, generic cancer risk model-- as well as alterations in the "Mike and I may wind up in full agreement. which assumes that risk in binding capacity of several re It may be that the receptor-mediated events creases linearly, starting with the ceptors, including the epider important to cancer do exhibit a threshold." slightest exposure--with a mal growth factor receptor, Portier is now incorporating Lucier's ani mechanistic one. But now, just which signals cells to divide. mal findings, along with data from other 5 months into this rvaluation, They also looked at more com groups studying dioxin's mechanisms, into comes new evidence from plex responses, such as cell pro a biologically based mathematical model George Lucier and Chris Por liferation and the number and similar to the one Gallo is working on with tier of the National Institute of size of precancerous lesions in EPA scientists. The goal of both exercises is Environmental Health Sciences the animals' livers. to reconstruct each step in the pathway that in North Carolina suggesting The result? Contrary to the leads from dioxin exposure to cancer, using that there is no threshold, at predictions of just 10 months all existing data and filling in the holes with least for some of dioxin's effects. ago, there was "absolutely no their best guesses. Right now the two groups The old linear model might deviation from linearity" for are working independently but exchanging not be that far offafter all. They the simple responses they mea information. Birnbaum hopes to bring them emphasize, however, that the sured, says Lucier. In other together to see which model is best or final verdict is not in yet. The linear model was first Chris Portier words, the effects increased in whether a "fusion approach" is needed. proportion to the dioxin doses Once the new model is complete--Reilly called into question by evidence from a num measured in the rats' livers. has called for it in May 1992--it should be ber of labs that dioxin, unlike many carcino But this simple linear relationship may possible to get a more accurate fix on just gens, must first bind to and activate a recep not hold for more complicated responses how risky dioxin really is. At this stage, no tor before it can cause cancer or any of its (ike cell proliferation or cancer, Lucier and one is placing any bets, not even Gallo, who other effects. The notion o f a practical Portier caution. Indeed, they are still ana just 10 months ago predicted that it would "threshold" came in, explains Gallo, because lyzing their data for cell proliferation, but so turn out ro be far less risky than EPA now it appeared that a minimum number of recep far it appears to have not a linear response but estimates. "I have no idea how it will come tors must be occupied by dioxin before the a sublinear one--in other words, it is less out," he says now. L eslie Roberts IS OCTOBER 1991 000400- RESEARCH NEWS 377 O'JiLMb