Public, Private Health Concerns Spur Rapid Progress In Toxicology

Increasing fears about carcinogens and other poisons will fuel further growth in the already booming field, experts say The science of toxicology has come a long way in a relatively short time. Back in 1961, when a fledgling society of researchers devoted to the study of poisons and their effect on the human body was well-formed enough to merit holding an annual meeting, the group had 161 members. Next week, as the Society of Toxicology (SOT) convenes its 31st annual meeting, its membership totals more than 3,100, double what it was just seven years ago. And for the first time in its history, with attendance expected to top 4,000, the event will be held in a convention center--in this case the huge Seattle Convention Center. Another sign of the discipline's growth: At this year's meeting--which runs February 23-27--some 1,600 research advances are to be presented in platform discussions and poster sessions. That is 20 percent more than were put forth only a year ago. Accompanying this quantitative growth, however, is an equally notable qualitative broadening, stemming in large part from burgeoning demands by industry, government, and the public for more information about the chemical risks that exist around us. To empower their field's stepped-up move toward maturity, toxicologists are embracing new scientific techniques from disciplines such as molecular biology and mathematics. And the wide range of symposia to be offered at the Seattle meeting attests to the increasing sophistication and scope of concerns confronting today's toxicologists. These open sessions will focus on, for example, current controversies in cancer causation, genetic susceptibility to environ- mental agents, and protein changes as indications of toxicologic mechanisms. As for poisons in the elemental sense, toxicologists agree that it is only in the past few decades that scientists have possessed enough knowledge about human chemical and biological processes to study their deadliness in detail. Indeed, says John Frazier, an associate professor in the division of toxicological sciences at Johns Hopkins University, it's only recently that toxicologists thought of themselves as participants in a distinct field. "As far as being a study of mechanisms and quantifying risks," says Frazier, "[toxicology] has only been around since the 1960s." Now, despite its relative youthfulness, the discipline is being asked to play a mature role in shaping government policy, says University of Kansas pharmacology professor John Doull. "There are an awful lot of science questions still unanswered in toxicology," he says. "And there's tremendous pressure on toxicologists from government and from the environmental community to get the answers." He adds that as a toxicologist his professional travels rarely take him to, say, Hawaii for a convention, but "there are always a million reasons why I have to go to [Washington,] D.C." Pertinent unanswered questions, scientists say, have arisen as public and governmental interest in toxicity has progressed. Worries about long-term, high-dose exposure to chemicals on the job have been replaced by concerns over the effect of low-dose environmental exposures in the general population. Low-dose exposures carry a risk of illness that is much harder for scientists to detect and quantify. This increased interest in quantifying ever-subtler chemical risks is essentially responsible for SOT's accelerating growth. But to get the necessary answers, say scientists involved in assessing chemical risk, it's not sufficient merely to train more toxicologists. In addition, many say, current practitioners must link their science more firmly with other emerging sciences, including molecular biology and mathematical modeling. They must train their younger colleagues to take a broader, interdisciplinary approach to their investigations. They must base their research agendas on the pursuit of solutions to real-world, health-threatening problems rather than hypothetical puzzles. And they must, therefore, engage more actively in dialogue with scientists and others who are concerned generally with the subject of risk assessment--quantifying and ranking risks by statistical analysis. "Too much funding is still going into the old-fashioned safety assessment of a single chemical that doesn't address fundamental questions," says Bernard Goldstein, director of the environmental and occupational health sciences institute jointly sponsored by Rutgers University and the University of Medicine and Dentistry of New Jersey. "You can't deal with the one-in-a-million risks by safety studies." To demonstrate how the field needs to interact with other disciplines, Goldstein poses, as an example, the following problem: "Sup- pose you want to know whether benzene carries a risk all the way down to zero exposure, or [whether it] has a threshold of risk." A traditional risk assessment approach would require, he says, a statistical study of "six zillion animals"--clearly impractical. Rather, says Goldstein, "We can only answer these subtle questions by studying the mechanisms of exposure," and it is for this reason that toxicologists and the agencies that fund them need to put more emphasis on multidisciplinary investigations. Johns Hopkins' Frazier agrees: "These are broad societal problems that absolutely require interdisciplinary thinking and research. But it's extremely difficult to train somebody who can take different approaches to one problem. And we don't have a group of interdisciplinary-minded scientists who are role models. And those who do have multiple perspectives need to talk more to other people." A first step in that direction, many scientists say, is for toxicologists to try to incorporate new biological techniques more quickly into their research. "The field of toxicology needs to be dragged into the molecular age," says Ellen Silbergeld, a pathology pro- fessor in the program in toxicology at the University of Maryland's Baltimore campus. "Too much of it merely consists of hitting an animal on the head and seeing which organ falls out first." Curtis Travis, head of the office of risk analysis at the Oak Ridge (Tenn.) National Laboratory, agrees that most toxicologists receive too little training in molecular biology. He blames the problem on "an entrenched system" of funding and peer review. "There's still too much observational stuff being done," he says. "For example, in December 1990 I received the Society of Toxicology's list of Ph.D.'s looking for employment--about 300 of them. There was a one-page resume on every one, and not a single one focused on molecular toxicology. "There's nobody training them because it's not been the focus in the past. So instead of hiring toxicologists, we find people in molecular biology and bring them over to toxicology. The toxicologists are five years behind the biologists in the kinds of methods they're using." Part of the problem, says Bernard Schwetz, chief of the systems toxicity branch at the National Institute of Environmental Health Sciences (NIEHS), comes from the fact that toxicology is "sometimes too much of an applied science. So most ideas about methods come from other sciences. We need to shorten the length of time between the coming of new ideas and their incorporation into toxicology. "As a person who hires scientists, I seldom hire someone trained in toxicology. I hire immunologists and endocrinologists. We want to work at the interface of sciences, and these people bring us new tools that are far more subtle than the ones that existed 20 years ago, when I was trained." Good risk assessment demands that toxicology use the tools not only of molecular biology but also of other disciplines, especially mathematics, scientists say. Engaging in more interdisciplinary research with mathematicians and learning more mathematics themselves are a must if toxicologists are to address the subtle issues of low-dose chemical exposure, says Frazier. "Good research biochemists working in toxicology use statistics to compare predictions and hypotheses, do mechanics and kinetics," Frazier says. "But that's not the same as being able to plug that information into a model of a complete biological system including all the other factors involved, like protein-binding of the chemical in the blood. That work involves nonlinear equations. Even mathematicians can't do them in their heads. You have to deal with computer technology, numerical analysis, and so on." That kind of mathematical modeling is vital for a proper analysis of subtle toxicological effects, says Dale Hattis, research associate professor at the Clark University Center for Technology, Environment, and Development in Worcester, Mass. "Without it," he says, "even a very detailed explanation is still qualitative, a kind of `knee-bone-connected-to-the-shin-bone' thing." Hattis explains: "For example, a mechanistic description can tell you how it's possible for a football player to kick a field goal. But if you want to know why 40-yard field goals are common, why 50-yarders are rare, and why 60-yarders are all but unheard of, you need to look carefully at such numbers as how strong the muscle is and how many fibers work together. It requires strong cooperation between mathematics and biology." Demands for toxicologists to take a broader perspective come from industry as well as government, according to industry officials. Future toxicologists working in industry must be trained to take a longer-range view of the ways in which humans interact with chemicals, they say. "Regulations increasingly demand that chemical companies look outside their fences, at the whole life span of the chemicals they produce. That means a toxicologist working at a chemical company needs to be more and more involved with--the current buzzword is--life-cycle analysis," says Kathryn Rosica, director of health and safety for the Chemical Manufacturers Association in Washington, D.C. "Looking not just at how, say, solvents affect the nervous system, but also taking into account what happens to the chemical at every stage of the manufacturing process, in its end use, and when it goes to a waste facility or someone tries to incinerate it. "It involves questions so much broader than just the ones that arise at the research bench. And it asks toxicologists to talk to many other people at the company--the marketers, the industrial hygienists, the R&D people." Such an approach, Rosica says, can help industry toxicologists solve a perennial problem--how to find money for the basic mechanistic research they'd like to do. "It's often because they don't integrate themselves into the whole company," she says. "So they aren't able to explain to the business guy why the $100,000 for mechanistic studies is important to the company's needs." Looking at the bigger picture would also give researchers a better idea of the problems facing their customers, says Rosica. "If they got out from behind the research bench and went to see the chemical's end user, they might find out that, hey, auto mechanics dip a bolt into the product, then stick the bolt into their mouths before they insert it. That demands research on exposure by ingestion. If they got more of this kind of knowledge about the real world, they could make their arguments better." Toxicologists could also benefit from closer cooperation with scientists who specialize in risk assessment, scientists say. "Historically, everybody's objective has been to do quantitative risk assessment," says Johns Hopkins' Frazier. "If we can't put comparable numbers on each risk, then we're essentially comparing apples and oranges. Without a quantitative yardstick, numbers that allow for comparison, we can't decide where to put society's money--whether to work on ozone or clean up asbestos." More exchange between the two groups could mean getting those quantitative yardsticks sooner, according to some scientists. "The risk-assessment procedures we're using today depend on many assumptions because real data is lacking or supposed to be lacking," says Schwetz of NIEHS. "If those of us who generate the data about biological and chemical mechanisms don't talk to risk assessors, then they're likely to go on using models not based on the best science available." Such close cooperation between toxicology and risk assessment is another reason why future toxicologists must look beyond the horizons of their own discipline. "Toxicologists need to understand how statistical models are developed, and risk assessors need to understand how basic biological research is done and more of the biological issues involved," says the University of Maryland's Silbergeld. "There's a tremendous need for the groups to talk more often. "Right now there's often no attempt to talk, and there's certainly a lack of interdisciplinary-trained people. The situation is very worrisome. Of course, the best results would come from people who have within themselves both orientations." Beyond improving risk assessment for the benefit of society as a whole, scientists say, more communication with risk assessors also could help toxicologists get more precious research dollars. "The value of risk assessment to the development of toxicologically based research has got to be recognized," says New Jersey's Goldstein. "One of the more difficult things for toxicologists to explain is how the basic mechanistic approach of the field is a useful approach," Goldstein says. "Too often, it seems they're tempted just not to try. But the question is: How do you get to the person who holds the purse strings? Well, risk assessment is very valuable in doing that. "If you look at research on basic mechanistic questions as a way to reduce the uncertainties of analyzing risk, that helps make the argument compelling." "Using a risk-assessment orientation can help prioritize the process of doing toxicology," says Roger Mc-Clellan, president of the Chemical Industry Institute of Toxicology in Research Triangle Park, N.C. "For too long the two fields were considered country cousins. You didn't want them to get too close." But, McClellan adds: "There's a real need to recognize risk assessment as a total part of the scientific process. We ought not to think of it just for the regulatory process, but also for research needs and priority setting. Too often we get caught up studying biological mechanisms in a kind of vacuum. Using a risk-assessment orientation, we'd look at the weak spots in our understanding of real problems to set our research agenda. "Everything--better science, stronger funding, better understanding of important issues--everything follows from that."

Public, Private Health Concerns Spur Rapid Progress In Toxicology

Interested in reading more?

Become a Member of