Toms River

by Dan Fagin

  This new complexity has made it much more difficult for molecular epidemiologists like Frederica Perera and Barry Finette to identify specific changes—biomarkers—within human cells that are reliable indicators of cancer risk across populations. The list of candidate biomarkers keeps growing. Some appear to alter susceptibility to particular cancers, conferring extra vulnerability or extra protection. Others are clinical indicators that hold out the promise of aiding the early diagnosis and treatment of tumors. A few can even serve as “dosimeters”—rough indicators of the extent to which someone has been exposed to a particular toxic compound.6 What almost all of these biomarkers have in common, however, is that they are helpful only some of the time. In the Fallon, Nevada, cluster investigation, for example, researchers found that all eleven local children with leukemia carried a distinctive variation in a gene called SUOX—but 40 percent of cancer-free children did too.7 An ideal biomarker for childhood leukemia would be so sensitive that every child with the biomarker would have leukemia, yet so specific that every child with leukemia would have the biomarker. After decades of intensive searching, however, it now seems likely that ideal biomarkers may never be found for leukemia and many other cancers because there are just too many possible routes to carcinogenesis. Even now, more than 160 years after Rudolf Virchow first saw malignant white blood cells through his microscope, the biochemical pathways to cancer are still mostly unmapped.

  The research that Barry Finette undertook for the Toms River families is a telling example. Working intermittently for more than ten years, whenever he had enough staff and money available to pursue it, Finette and a rotating cast of junior colleagues kept reanalyzing the Toms River blood samples that still filled two freezer shelves in his Vermont laboratory. Searching, as ever, for biomarkers that correlated to chemical exposure and cancer risk, they looked again at the HPRT gene—this time tracking the types and locations of mutations within the gene’s region of the X chromosome. They also tracked alterations in eighteen other genes involved in repairing damaged DNA or expelling toxic chemicals that invade cells. Finally, they scrutinized the children’s blood cells for biomarkers that were much larger than individual snips of DNA—so large, in fact, that they could be easily seen through an optical microscope. They were chunks of malformed chromosomes, floating free in the nucleus or reattached in the wrong place or even upside down.

  In the end, none of it worked. Finette’s biomarker studies revealed no significant differences between the DNA of Toms River children and that of children who lived elsewhere. He struggled to come up with reasons for the multiple failures. Perhaps, Finette thought, he had searched for the wrong biomarkers. Or maybe he found nothing because the chemicals in the air and water of Toms River were too insignificant to have a measurable impact on the DNA of the town’s children, even though the state’s case-control studies suggested otherwise. Or possibly those genetic abnormalities had once been present in the children’s blood cells, but were gone by the time he collected his samples in 2000, many years after local pollution was at its worst. It was even possible that the DNA defects were still there but were subtle and thus too difficult to differentiate from random variation within such a small study population. Finette had samples from just forty-three Toms River children with cancer, plus their healthy siblings, which meant that his study was only slightly larger than Jerry Fagliano’s interview study and smaller than Fagliano’s birth record study—both of which had been plagued by small case numbers.

  Whatever the reason, Finette’s ten-year search for evidence that chemical exposures in Toms River had altered the genes of the town’s children and raised their cancer risk had come up empty.8 Even the chromosome malformation study, the one Finette had been the most optimistic about, failed to turn up any associations.9 In a staggering feat of ocular stamina that ended only when the grant money for her salary ran out, a lab technician named Heather Galick had squinted into her microscope and inspected exactly 201,844 white blood cells from eighty-one children. Because each cell was on the verge of dividing and had been stained, Galick could see the chromosomes inside. She counted 466 cells—roughly one out of every four hundred she examined—that had aberrant chromosomes: translocations, loose fragments, or other signs of damage. That seemed like a lot of malformations to Finette, but the ratio of aberrant-to-healthy chromosomes in the Toms River children turned out to be almost identical to the ratio in nonresidents. In fact, the out-of-towners were slightly more likely to have malformed chromosomes, a perplexing result Finette could not explain. After a decade of work, there was very little about any of his results that he could explain.

  Linda Gillick and a few other Toms River parents got the disappointing news from Finette on a stifling July afternoon in 2010, in the same Ocean of Love office where their needle-wary children had lined up to give blood samples ten years earlier. Back in 2000, dozens of families were involved; by 2010, just three were represented around the conference table. Besides Gillick, there were Bruce and Melanie Anderson (they lived in Pennsylvania now but had made the long drive) and their former neighbor Joseph Kotran, whose daughter Lauren had survived neuroblastoma as a toddler. Most of the other families had not been in touch since the legal settlement nine years earlier. “They have other things in their lives now,” Bruce Anderson would later explain with a shrug.

  There was one other big study the Toms River families were waiting for, and many of them cared a great deal about it. Styrene acrylonitrile trimer, the obscure plastics byproduct that Floyd Genicola had discovered in the Parkway wells back in 1996, had acquired outsized importance in the Toms River drama because it was so exotic and apparently unique to the town (it had not been identified as a pollutant anywhere else). To some of the families, SAN trimer felt like an answer—maybe even the answer—to their most burning questions about the cancer cluster: Why here? Why us? Even so, there were reasons to doubt SAN trimer’s true importance: The concentrations in Parkway water were low, the compound’s health risks were unknown, and there were many other toxic exposures in town, especially back in the 1960s and 1970s. Still, “the trimer,” as they called it, retained its almost mystical hold on the families as time passed. “Really, in our hearts, we all feel it’s the cause,” explained Kim Pascarella.

  The answers on SAN trimer were supposed to come from the federal government’s National Toxicology Program, but they were painfully slow to emerge. The NTP’s first attempt at its two-year, multigenerational rat study flopped because too few rats were willing to breed, but a second try, in 2005, succeeded. After two years eating trimer-laced chow, the surviving pups were asphyxiated. Pathologists pulled thirty-two organs out of each rat, dunked the organs in formaldehyde, embedded them in wax, and cut them into more than ten thousand slides, each just five microns wide—thin enough to reveal a single layer of cells under a microscope. The slides were then scrutinized for tumors by panels of experts convened by the NTP, in a laborious process that took an additional three years and was quite contentious at times. The debates over the most ambiguous slides—the ones in which it was very hard to tell whether a dot was a tumor or a noncancerous lesion—at times sounded like a roomful of highly opinionated art critics arguing about the meaning of an abstract painting.

  The chemical’s defenders got to do their own slide review, too. Dow Chemical and the Saudi Arabian company SABIC, a petrochemical behemoth that still made plastics from acrylonitrile and styrene, had formed an organization called the SAN Trimer Association (“SANTA” was its incongruously jolly acronym) and hired their own pathologists to second-guess the judgments of the government’s reviewers. For Dow and SABIC, the stakes were high: Regulatory agencies all over the world, starting with the U.S. Environmental Protection Agency, routinely rely on NTP studies in setting limits on chemical exposures.10

  The seemingly endless review process for SAN trimer finally ground to a conclusion in early 2011, nearly fifteen years after Floyd Genicola’s triumphant unmasking of the mystery compound in th
e Parkway well field. Two groups—the NTP senior staff, and then its outside review board—would convene at the agency’s North Carolina headquarters to pass judgment on the trimer’s carcinogenicity. It was a tough call. The slides showed that, except for one type of tumor, cancer incidence among the three hundred trimer-fed rats was similar to the one hundred unexposed controls. The exception was brain and spinal tumors: Eight of the trimer-fed rats had them, compared to just one unexposed rat. That was startling because brain tumors normally were very rare in rats. They had been found in just four of the almost thirteen hundred Fischer rats used as unexposed controls in recent NTP studies. That meant that the tumor count in trimer-fed rats was almost nine times higher than expected. Even more interestingly, there seemed to be a weak yet discernible dose-response pattern in which rats fed higher doses were more likely to get tumors.11

  The Gillicks and the other families had always thought of themselves as involuntary guinea pigs in an uncontrolled experiment, which is why they had pushed so hard for the multigenerational rat study. Now its results were showing that in at least one important sense, the trimer-fed rats really did resemble the thousands of Toms River children who had been exposed prenatally to much lower levels of SAN trimer in their drinking water. In both populations, certain tumors were much less rare than expected. Further, there were suggestions in the rat study, just as there had been in Jerry Fagliano’s case-control studies of the Toms River children, that those with the greatest exposure faced the highest risk.

  Was SAN trimer truly a cancer-causer? As usual, the study population was too small to know for sure. If the pathologists had found a brain tumor in just one more high-dosed male rat—three instead of two—then the dose-response pattern would have been clear. But with just fifty male rats in that dose category, the statistical ambiguity could not be resolved.12 Nor was there any way to know whether SAN trimer caused leukemia—always the key concern in Toms River—because the type of rat the National Toxicology Program had selected for testing was prone to leukemia and thus a poor test model.13 Despite these shortcomings, there was no chance the agency was going to further delay its decision by conducting additional tests to try to clear up the ambiguities—not after a decade of work and several million dollars already spent. After arguing about the data for hours at a meeting on January 24, 2011, the NTP’s senior staff reached its verdict: equivocal evidence of carcinogenicity, the middle of five possible ranks. It was a compromise, a nuanced response to provocative but highly uncertain evidence.

  It held sway for exactly two days. When the NTP’s Board of Scientific Counselors convened on January 26 to consider the case, a raft of industry consultants were waiting to testify. Dow offered four speakers, including James Swenberg of the University of North Carolina, a former chairman of the advisory board he was now trying to influence. Batting cleanup was Joseph Haseman, a consultant who had spent thirty-three years at the NTP, most of them as its chief biostatistician. When it was his turn to speak, Haseman launched a stinging critique of the staff’s decision. Based on past precedent at NTP—precedent Haseman had established—the correct call for SAN trimer was “no evidence of carcinogenicity,” he insisted.

  The families of Toms River had no hired guns to match them. When the panel’s chairman called on the next speaker, a familiar voice—both pleading and reproachful—issued from a speakerphone. It was Linda Gillick, calling from Toms River. “I really believe our children were the real rat study,” she said, her voice crackling across the silent room. “Trying to take what really happened in Toms River and duplicate it is really impossible.… I’m just concerned that at the end of all this time, effort and money, and all the lives that have been affected and lost, we won’t come out of here with true answers.” Bruce Anderson had put his comments in a letter to the NTP. “This cannot be allowed to happen to any children again,” he wrote. “We hope that the results of this testing will lead to more proactive protection.” By that standard, the staff’s proposed finding of “equivocal evidence” could only be seen as a disappointment, the same ambiguous mush the families had been hearing from government experts for almost twenty years.

  The Board of Scientific Counselors was not interested in equivocation either, but its solution was not what Gillick or Anderson had in mind. The coup de grâce came from board member Jerry M. Rice, who had been a senior scientist at the International Agency for Research on Cancer before becoming an industry consultant and academic. The Toms River cluster, he asserted, was probably a chance occurrence—no matter what Fagliano’s case-control studies had concluded back in 2001. “It’s well known that rare events cluster in space and time,” he said, adding that “an occasional brain tumor” in rats was trivial. He proposed changing the official classification to “no evidence of carcinogenicity.” The vote came a few minutes later: six to one for Rice’s proposal, with several board members abstaining because they had business ties to Dow.

  In the back row of the room, a man named Bob Fensterheim shook hands with his expert witnesses and then left for his flight back to Washington, D.C. A former top lobbyist for the American Petroleum Institute, Fensterheim now was a consultant who specialized in helping chemical manufacturers in their battles with regulatory agencies. He ran no fewer than ten industry groups, with names like the Chlorinated Paraffins Industry Association and the Alkylphenols and Ethoxylates Research Council. His latest creation, SANTA, the SAN Trimer Association, could now fade into obscurity. Its work was done.

  In the morning, styrene acrylonitrile trimer had been a possible carcinogen, at least worthy of future study to clear up the uncertainty. By the end of the day, it was not. For the Toms River families, another door had slammed shut. Science, and scientists, had let them down so many times before that it hardly even hurt anymore.

  There is one way—one very important way—in which the passage of time has strengthened the Toms River families’ conviction that industrial chemicals played a role in their children’s illnesses: The leukemia cluster is gone.

  As he promised the families he would back in 2001, Jerry Fagliano has carefully tracked new local cases of childhood cancer, just as Linda Gillick still does at Ocean of Love. As always with a rare disease in a small population, the case counts vary so much from year to year due to chance that the underlying trend is not always clear. To smooth out this instability, Fagliano uses five-year running averages. What he has found for childhood leukemia is that incidence in Toms River, after peaking in the late 1980s, has fallen sharply since then and is now below the statewide average. When charted through 2009 (the last year that fully verified data is available), the graph looks like this:14

  It is an encouraging graph. Leukemia was the type of cancer that Fagliano’s case-control studies had most strongly associated with pollution, so if the study were valid, the number of leukemia cases presumably would fall as environmental conditions in Toms River improved. That is what seems to have happened: Rates declined at the same time the factory wound down its operations and the Parkway wells were filtered or shut down.

  It is just another correlation, not a proven cause-and-effect relationship, but in the eyes of the families, it is no coincidence. The leukemia decline, many of them believe, demonstrates that pollution was responsible for the cluster and that their activism has thus saved lives. “There are so many fewer cases than we had before all the changes that took place in this town, and that’s the way we intend to keep it,” Gillick declared at a public meeting in 2011. Jerry Fagliano is less sure about the reasons but is encouraged by the trend. “It’s somewhat comforting,” Fagliano said, “in that leukemia was the one kind of cancer that really stuck out as being elevated when we did our case-control studies. The fact that it’s come back down to normal can mean one of two things: Either the association we saw at that time was causal and we’ve removed the cause, or else we’re simply seeing a return to background rates because of chance. We hope the actions we took have made a difference for public health, but I can’t say w
e’ve proven it.”

  One reason for Fagliano’s uncertainty is that the trend for all childhood cancers, not just leukemia, is murkier. After falling steadily for a decade, there was an abrupt spike: Eight cases were diagnosed in Toms River in 2004 and nine in 2005, up from the usual four or five. Was the spike just another random consequence of the natural variability of small-number statistics? The fact that the yearly counts have fallen back somewhat since then suggests that it was. So does the fact that no one type of cancer appears to be unusually elevated—unlike in the 1980s, when leukemia incidence jumped. But 2009 was another unusually bad year, with nine cases reported in Toms River, so Fagliano’s latest five-year running averages for all types of cancer counted together look especially alarming when charted:

  The curve is likely to bend back down again soon because the last few years have been good ones: just two childhood cancer cases in 2010 and three in 2011. But those recent numbers are still unofficial and uncounted in Fagliano’s five-year running averages. Where rates will go next is anyone’s guess. “It is frustrating because the rates are so unstable that there’s only so far you can take any interpretation,” Fagliano said. “It really points to the difficulty of making sense of cancer rates in relatively small populations over relatively short periods of time. The rates are going to bounce around, even over five-year intervals. With more time, it may become clearer. Maybe.”

  So what was it, really? Was the Toms River childhood cancer cluster a mirage, an aberration, or a warning? Was it a consequence of nothing but a stunningly bad run of luck, like rolling snake eyes six times in a row? Or was it the product of pollution so horrendous and governmental neglect so extreme that the combination has never been replicated anywhere but Woburn? And what about the third possibility, the one raised by David Ozonoff’s dictum that a public health catastrophe is an effect so strong that even an epidemiological study can detect it? Could it be that the only unique thing about the Toms River and Woburn clusters is that anyone managed to recognize them?