Neurotoxin Concerns, Controversy Escalate

Scientists are realizing that substances in the environment can have devastating effects on the human nervous system For decades, neuropathologist John Olney waged a one-man crusade to have "excitotoxins," chemicals in the brain that cause nerve cells to self-destruct, removed from foods. One of the worst, he argued, was glutamate, consumed by millions as the food flavoring monosodium glutamate. But nobody really paid much mind to Olney's concerns. The Food and Drug Administration (FDA) did not agree, and in 1970 judged the additive safe. So did, in that same year, a committee from the National Academy of Sciences (NAS). But by 1980 scientists were beginning to realize that there were substances that warranted their attention. Lead in paint impaired learning. Epidemiological data revealed that Lucel-7, a substance used in making bathtubs, caused neurological damage in workers. In 1983, about 500 drug-users in San Francisco developed what appeared to be Parkinson's disease. The cause was MPTP, which the addicts had mistakenly taken as synthetic heroin. The epidemic provided important clues about environmental causes of neurodegenerative disorders. Now Olney's outcries are part of an increasing clamor from the scientific community about the need for better control and monitoring of chemicals that can damage the nervous system. Although his assertions remain controversial, the existence of neurotoxicants in foods and in the environment is no longer in doubt. "He's a first-class scientist," says Peter Spencer, director and senior scientist at the Center for Research on Occupational and Environmental Toxicology at the Oregon Health Sciences University in Portland. Spencer adds that Olney - several of whose papers, including "Brain lesions, obesity, and other disturbances in mice treated with monosodium glutamate" (Science, 164:719, 1969), have been cited hundreds of times - "deserves a lot of credit for pursuing one facet of neurotoxicology, but there are many other facets." For regulators, it is not enough to know that substances we eat, breathe, or touch might damage the nervous system. They need to know how and when and under what circumstances. And they must have tests that measure a substance's potential for doing this damage. Cancer-causing agents, for example, are easy to distinguish. They cause tumors. But neurotoxic agents have a variety of effects. They can impair behavior, vision, or hearing. They can change behavior but cause no observable changes to nerve cells. The damage can be subtle. Reflexes might be slower, eye-hand coordination slightly poorer, phone numbers harder to remember. Nor is the damage always immediate. It may become evident only years after exposure. That variety presents a bewildering array of possibilities that stymie even the best intentioned regulatory agencies seeking to screen for them. "It is not quite as conveniently defined as some of the cancer endpoints," says William Slikker, Jr., branch chief at the FDA National Center for Toxicological Research in Jefferson, Ark. Cells may not die, he says, "they may just be crimped in their cell function." The result might be a faulty memory or a learning disability. Whether the tests look for changes in behavior or changes in the biochemistry, physiology, or pathology of the tissue, "adverse changes" are the key. But how does one know where to draw the line between something like caffeine, which stimulates neurological activity, and lead, which has documented adverse effects? Or when a substance causes changes in behavior but not noticeable damage to the nerve cell? "The scientific community has not agreed on one definition of neurotoxicity," says Peter Andrews, an OTA research assistant who is working on the upcoming report on neurotoxins. In addition, each agency has a different responsibility, and thus a different idea of what counts as a neurotoxicant. Agreeing on a definition proved too tough for even the National Academy of Sciences committee charged with looking into risk assessment for neurotoxins. "They really don't address the really important question of adversity [adverse effects]," says Mary Paxton, project director for the committee. There are other questions awaiting answers. What tests should be used? At what point? And how reliable are they? "I think within the neurotoxicology community there may be a fair amount of difference of opinion about what might constitute adequate screening," says Paxton. "There's a lot of different ways of looking at it; there's validity to a number of approaches." "You have to look at each chemical on a case-by-case basis and try to reach a scientific consensus," says Mark Schaefer, project director of the OTA report. Even with lead, perhaps the most well-known neurotoxicant, it is still not clear what levels are sufficient to produce its adverse effects. That uncertainty complicates the job of the Environmental Protection Agency and FDA, which must walk a fine line between protecting the public and being overly stringent. "There's some disagreement between the EPA and the FDA on whether specific neurotoxic tests are necessary," says Schaefer. EPA is considering adding several screening tests to its approval process for pesticides. They will include neuropathological evaluations, tests of motor activity, and a "Functional Observational Battery" (FOB) that looks at behavior. FDA relies on its general toxicity tests to pick up neurotoxic effects. "I don't think anyone is ready to say we've got them [tests] and we're ready to test anything that comes down the pike," says FDA's Slikker. But there is progress, he insists. Computers have improved image analysis and cell counting to make assays more reliable. Using labeled antibodies that home in on glutamate receptors, scientists have been able to see lesions more easily and to account for damage that the body would otherwise clear away. There are also neurochemical markers that can be used as measures of toxicity. But the approach is far from perfect, warns FDA psychologist Andrew Scallet, who works with Slikker. "I don't think it would work to have an insensitive test that was very expensive to do on a routine basis," he adds. "The wave of the future is defining what would be a reasonable approach." Other organizations are working on ways to screen for neurotoxic effects in humans. The World Health Organization, for example, has proposed a crude battery of tests to assess behavioral effects, and it hopes to use these to look at neurotoxicity among residents of developing countries. Sweden has taken those tests a step further, with computerized screening protocols that are much more precise and quantitative. In 1988, NAS helped sponsor an international workshop of neurotoxicologists and psychologists to discuss behavioral testing. But even on the eve of its latest report, says Paxton, the NAS committee is still debating what can be learned from such tests. --E.P. The nation's 100 or so neurotoxicologists would like to recruit the much larger pool of neurobiologists and toxicologists into this fight. But they have been hindered by the lack of government initiative, lack of knowledge, and, until recently, lack of awareness of the importance of the problem. A few policymakers are calling for action; others say more research needs to be done. One big question to be resolved is whether this issue can garner the resources to support the necessary research. There are a few signs of optimism. Congress has declared the 1990s to be the Decade of the Brain, and neurotoxicologists hope that pledge will rival President Nixon's war on cancer as a battle cry to identify, understand, and regulate substances that harm the nervous system. In the meantime, excitotoxins, glutamate in particular, have collectively become one of the hottest topics in neuroscience. Evidence is building that excitotoxins in foods can damage the brain. And MPTP has helped neurobiologists begin to understand disease mechanisms. As part of the war on cancer, the regulatory agencies worked hard to identify and eliminate or regulate carcinogens. Tests looking at death rates and tumor development screen out potential toxins. But neurotoxins represent an even bigger challenge. They are a lot more plentiful - there's an estimated 65,000 dangerous substances lurking in our food and our environment - and, often, more insidious in the damage they cause. They can affect the body on a molecular or behavioral level and can act immediately or after a long latency (see accompanying story). So the intellectual - and financial - investment required to monitor these substances is daunting. But the penalty for not making these investments may be far more costly. Those substances are everywhere: organic solvents in the workplace, chemicals in perfumes, pesticides used on lawns, natural and added chemicals in foods, or prescribed or illegal drugs. The brain is the body's kingpyn organ; yet, once damaged or destroyed, nerve cells cannot be replaced. Already, the congressional Office of Technology Assessment (OTA) estimates that the care and treatment of neurological disorders and accompanying loss of productivity can cost the U.S. as much as $300 billion a year. No one knows how much neurotoxins contribute to that cost. The longer we live, the more evident the damage, and the more burdened the health care system will become to people with behavioral, mental, and neurological problems. "The measure of the problem is huge," says Spencer. Recognizing this, Congress asked OTA to look into the problem. Its report, "Neurotoxicity: Identifying and Controlling Poisons of the Nervous System," is due out next month. At the same time, the NAS Committee on Neurotoxicology and Models of Assessing Risk, with backing from the Agency for Toxic Substances and Disease Registry within the Public Health Service, has tackled the scientific aspects of this issue. Its findings are expected to be released by this summer. And last fall the Society for Neuroscience drew Olney away from his lab bench at Washington University in St. Louis to talk to a packed, standing-room-only audience about neurotoxicants in foods. Speaking at the society's annual meeting in Phoenix, Olney, two other scientists, and a consumer advocate presented evidence that stirred the audience and resulted in the society's agreeing to urge the FDA to pay more attention to the research being done. Officials are drafting the society's official position on the issue. Part of the problem is the public's perception of risk. "Most people don't think about excitotoxins in the diet," says Dennis W. Choi, associate professor of neurology at Stanford and one of the panelists at the meeting. "We're attempting to raise their profile to make people in the regulatory agencies aware of them." There's little doubt these substances are dangerous. In 1987, 150 people got sick after eating contaminated mussels. Four died and a dozen others suffered brain damage that caused symptoms resembling Alzheimer's disease. The poison turned out to be domoic acid, which acts at one of the brain's glutamate receptors. Spencer has demonstrated that another substance found in a legume sometimes eaten by people in Asia and Africa acts at another glutamate receptor site and causes neurological disease. In addition, Spencer hypothesizes that the high incidence of Alzheimer's-like symptoms among residents of Guam may have resulted in part because starving natives during World War II were forced to eat cycads, palm-like plants that are rich in this toxin. "A few years ago, nobody would have pegged excitotoxins as possibly being involved in Alzheimer's disease," says Choi. "The thing that makes it more insidious is that there could be a considerable [time] lag." At the neuroscience meeting Choi presented work that showed how substances in the diet that did not look like glutamate could, in the presence of cofactors, have the same lethal effects on nerve cells. At the same time that science is coming up with more definitive data, society is becoming more concerned both specifically about neurotoxicity and, in general, about product and occupational safety. "We're in a period where many issues of regulation and policy matters are once again beginning to come to the fore in a rather robust manner," says James Turner, a consumer advocate lawyer who has worked with the Food Safety Council, a group of food industry representatives, academicians, and environmentalists that reviews food safety issues. Heavy public pressure for action on such complex issues as the new drug-approval processes for AIDS and the use of the pesticide Alar has FDA on the spot. Yet Turner has observed a 20-year erosion of authority and demoralization of staff at FDA. As a result, this agency, more than others, is open to criticism that it is failing to meet this emerging regulatory challenge. "They talk a big game, but they really don't respond," says Bernard Weiss, professor of toxicology at the University of Rochester, about FDA. Like Olney, Weiss has published studies indicating that certain additives - in this case, food coloring - are toxic, but he's heard little from FDA. "They have been rather passive about neurotoxicity," he adds. Some of FDA's own scientists share that concern. At FDA's National Center for Toxicological Research in Jefferson, Ark., psychologist Andrew Scallet and his colleagues have doubts that FDA is ingesting what is being learned. "There aren't a lot of neuroscientists at the FDA headquarters," says Scallet. "We might be pitching, but there might not be very many people there catching." But headquarters has a different perspective, according to David Hattan, deputy director of the FDA Division of Toxicological Review and Evaluation. "Sometimes people in basic sciences labs may not be aware of what the full spectrum of activity of these substances may be," he says. "You have to have an appreciation of how the materials are used and compare that to how the scientific studies were done." Hattan notes, for example, that food additives are not very active, and that substances that are toxic when injected into the bloodstream are not harmful when swallowed. "I'm not sure the basic scientist has a full appreciation of all these circumstances," he adds. Current FDA guidelines for food additives do not require separate tests for neurotoxicity, says Hattan, but "our present system will pick up anything that's gross." FDA is looking at additional ways to screen for neurotoxicity, and there is some interest in shifting resources to place less emphasis on carcinogenic endpoints in testing and more on neurotoxic endpoints. "But the fact of the matter," he says, "is that there are far more people who have the training and interest in carcinogenic endpoints." Neurotoxic endpoints also are far more difficult to pin down. Federal science administrators also are bogged down in the complexities of neurotoxicants. No one really knows how best to translate what has been learned into suitable regulations. There are too many chemicals yet to be tested, too little known about neurotoxicity in general, and too many other crises. As a result, says Hattan, "it will be more difficult to get more resources allocated to [neurotoxicants]." Don't look for any quick improvement, either. "Even though people perceive this as a major problem, the level of support is not coincidental with that," agrees Hugh Tilson, director of EPA's neurotoxicology division. Last fall EPA asked for $1.5 million for a neurotoxicological initiative beginning in fiscal year 1991. But the idea was axed by the Office of Management and Budget and did not show up in last week's presidential budget request to Congress. Instead, limited research resources are being channeled into molecular biology, not neurotoxicology. The situation is not much better here in the government. The National Institute on Aging (NIA) has called for more research in mechanisms of cell death (including nerve cells), the role of trace elements in dementia, and understanding the cumulative effects of exposures to substances. But it has not directed any new support that way, according to Andrew Monjan, NIA's chief of neurobiology. "I don't think there's enough data yet to recommend policy issues," says Monjan. Those who worry about neurotoxicology face a catch-22 in seeking additional funding. Critics say the National Institutes of Health and National Science Foundation study sections don't recognize the importance of studying neurotoxicants except perhaps as a means of creating models of neurological disease. "So people in academia are not going to be reinforced for work in neurotoxicological techniques," says EPA's Tilson. "It's a major problem." But neurotoxicologists are not giving up. Tilson has cobbled together an Interagency Committee on Neurotoxicology to coordinate federal efforts in the area. This informal group is developing a reference list of neurotoxic agents. The authors of the NAS and OTA reports hope their comments will stimulate interest in the field. "All these events represent the blossoming of this discipline," says Spencer, who served on both the NAS and OTA committees. "And it's not only an issue of the public danger. You have the opportunity to use neurotoxic agents as probes to uncover new concepts of brain function and dysfunction. But until the flower is out, people cannot see its beauty - or, in this case, its horror."

Neurotoxin Concerns, Controversy Escalate

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