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Introduction Behavior is a basic property of -living organisms as they adjust to their physical and psychological environments. It is dependent upon a multitude of biochemical and electrophysiological functions at various morphological sites within the body, particularly within the nervous system. Behavioral analysis is a process of "sampling" the integrated outputs of these various functions. The major objectives of neuro- behavioral toxicity testing are to determine whether exposure to a potentially toxic chemical produces effects on these functions that exceed the organism's ability to adjust, to assist in identifying the nature of such malfunctions, and to provide information about the effects of extended exposure (both dose and time effects) that may be used in establishing threshold limit values ("no-observed-adverse- effect levels") for purposes of human safety. Behavior is a dynamic process, however, and exposure to a toxi- cant may or may not result in behavioral change. This situation arises from the fact that toxic agents do not affect behavior directly (Russell, 1979~. In general terms, toxicants enter the body through one or more of several routes, and once within the body they combine with receptor molecules to produce an agent-receptor complex. These interactions, which may or may not be reversible, initiate a series of biochemical and electrophysiological changes that characterize the overall response to the agent. Biochemical events occurring after exposure to a toxicant have significant influence on subsequent be- havioral effects and constitute the "mechanisms of action" underly- 1

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2 INTRODUCTION ing those effects. If the linkage is direct, changes in biochemical events are related to specific changes in behavior; if the linkage is diffuse, changes in biochemical events may affect a variety of behavior patterns. In 1975, the National Research Council (NRC) report Evaluating Chemicals in the Environment, was one of the first reports to formalize the concept of "behavioral toxicology." The report identified two levels at which the effects of toxicants on the nervous system could be tested by using a variety of assays including behavioral measures. The first level of investigation involves studies designed to screen for possible behavioral abnormalities produced by chemical substances. A battery of tests is often used to assess possible effects on a wide range of behavioral processes (for example, gross and fine motor functions, vision, hearing, cognition). Studies at this level involve large numbers of subjects and use simple, rapid, and inexpensive behavior technologies. Screening strategies are suited for investigat- ing large numbers of putative toxicants in a short time. These procedures are generally not appropriate to reveal basic mechanisms, nor are they suited to assess more subtle or complex behavioral functions. The second level of analysis focuses on characterizing in more detail the basic mechanisms that are altered by substances to which the organism has been exposed. Typically, tests at this level use a smaller number of subjects who are often studied in greater detail over some lengthy period of time. The behavioral technologies that are involved are more elaborate and time-consuming, and frequently require periods of retraining. Behavioral analysis thus offers useful tools for measuring the direct action of a chemical on neural tissue. Such measures of behavior are often particularly sensitive to toxic agents, showing significant effects when no overt symptomatology is observable. They are "noninvasive," requiring no sampling of body fluids or tissues. They may be applied repeatedly to study progressive effects of contacts with toxicants, for monitoring the effectiveness of regulations established to control ad- verse exposures, and to assist in the management of patients under treatment for toxic illnesses. IDENTIFICATION OF BEHAVIORAL TOXIC AGENTS It is obviously desirable that potential dangers resulting from chemical agents in the environment be identified as early as possible. One category of critical issues certain to continue to demand attention into the next decade and, indeed, well beyond is that encompass-

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INTRODUCTION 3 ing the identification of toxic agents that affect behavior. Given the existence of a behavioral abnormality, what chemical agent, if any, is its antecedent? Given a chemical agent, what may be its behavioral consequences? Six centuries ago, Paracelsus said, "All things are poisons, for there is nothing without poisonous qualities. It is only the dose which makes a thing a poison" (Sigerist, 1958~. If Paracelsus was correct, the number of chemicals having potentially toxic effects on behavior corresponds to the number of chemicals in the environment. A first step in the risk assessment process and the establishment of threshold limit values for purposes of regulation is to define a dose- effect relationship for the particular substance under consideration. A "critical issue" needing attention arises from the fact that the "effective" dose often is not directly proportional to the "administered" dose. Methods have been suggested that enable dose-effect relations to be constructed on the basis of the former rather than the latter, thus increasing ". . . confidence in the reliability of the observed relation- ship as a starting point for extrapolation outside the experimental dose range" (O'Flaherty, 1986~. Another series of questions related to dose-effect relationships centers on increasing appreciation of the fact that different behaviors have different toxic thresholds. For example, untoward effects on cognitive processes may occur without immediately obvious behavioral symptomatologies. This puts pressure on decisions about the breadth of behavioral testing and when during the life span to test. Publication of the Proceedings of the Third International Conference on Indoor Air and Climate (Berglund et al., 1984) made it convincingly clear that potentially toxic chemicals are to be found in all human environments. Discovering these "ecological traps," defining their effects on behavior, and inventing methods for preventing them from being sprung is yet another area of critical issues for the foreseeable future. MECHANISMS AND SITES OF ACTION Behaviorally, toxic chemicals may be identified solely on the basis of their measured effects on behavior, without knowledge of the physiological mechanisms or sites of action within the body. Indeed, it is a safe generalization to state that these properties are not fully understood for most of the agents of current concern. Seeking the mechanism of action of a chemical affecting the central nervous system (CNS) is not like looking for a needle in a haystack, but rather like looking for a needle in a heap of needles. What have we to lose if we

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4 INTRODUCTION do not search for mechanisms and sites of action? Clearly there are losses for the development of our knowledge in the basic biobehavioral sciences. However, let us consider three specific questions of a more applied nature, all of which document the kinds of "critical issues" within this general area of mechanisms by which chemicals act. Can an understanding of mechanisms of action help in synthesizing new compounds for specific purposes? Yes. For example, knowledge about the nature of receptors in the CNS is being used to create molecules that are less toxic and others that are more effective as therapeutic drugs in counteracting the effects of toxic agents. Is knowledge of mechanisms of action helpful in understanding neurodegenerative disorders of toxic origin? Again, yes. Searching for the mechanisms involved toxic, viral, nutritional- is essential to the prevention and treatment of disorders such as the progressive degenerative dementias. Can the search for mechanisms of action help the diagnosis and treatment of genetically induced metabolic faults? Yes, indeed. Phenylketonuria is one example of a very significant behavioral defi- ciency associated with a genetic failure to produce a specific enzyme phenylalanine (hydroxylase), a condition that results in a block to normal metabolism in a major neurochemical pathway. Very early diagnosis of the fault can enable steps to be taken, usually dietary, to limit brain damage resulting from toxic by-products of the fault. THE MEASUREMENT OF BEHAVIOR A quarter of a century ago, a physician employed by a large indus- trial firm published a challenge in the Journal of Occupational Medicine entitled "Functional Testing for Behavioral Toxicity: A Missing Di- mension in Experimental Environmental Toxicology" (Ruffin, 1963~. The challenge is currently being met by the development of methods for measuring behavior, their standardization, and their applications. Despite the sophistication of our modern methods, questions still arise which indicate that critical issues in the measurement of behavior continue to demand attention. Many of those questions are called to our attention in this volume. The measurement of behavior was introduced into the process of risk assessment as a means of providing potentially more sensitive measures of toxicity than other properties of living organisms. As Bernard Weiss has asked: "What other discipline is in the unique position of access to a technology for tracing a progression of toxicity from early, subtle effects to clear impairment? What other perspective on toxicology can integrate such a rich configuration of endpoints?"

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INTRODUCTION 5 These rhetorical questions raise many other queries of a more spe- cific nature. A sampling of these critical issues as formulated in this volume includes: What are the advantages of measuring behavior in breadth versus depth? What should guide the selection of behaviors to be measured? Under what conditions should measuring instruments be "tai- lored" versus taken "off the shelf"? What special principles are important in developing a standardized "test battery"? What are the current shortcomings in the design of test batteries? What should be done to eliminate those deficiencies? Is it possible to develop measuring instruments that can discern functional impairment through the adaptive changes that may camouflage it? Are there limiting conditions in the anDlication calf behavioral testing in nonlaboratory settings? Why is evidence from behavioral tests often not convincing to decision makers? ~rr- One of the major developments in behavioral assessment during recent years has been the introduction of microcomputer-based testing. Evaluating the pros and cons of automated testing leads to the conclusions that this general approach to the measurement of behavior, although widely accepted and applied, will be a much debated area for some time to come. THE LIFE SPAN: WHEN TO MEASURE? A central theme of many of the most frequently raised questions we have heard is, When during the life span should neurobehavioral toxicologists apply their measurements? The unanimous answer has been, "From the womb to the tomb." The existence of critical issues at the beginning of this broad range was emphasized in 1987 by the appearance of the following statement in the journal Reproductive Toxi- cology: "The most relevant data [for female reproductive risk assess- ment] come from studies reported in humans, however, these are not generally available" (Sakai, 1987~. Clearly here is an area in need of careful study. Risks during in utero development were brought to world attention by the teratogenic horrors of the thalidomide trag- edy. Today the number of such critical agents introduced into the uterine environment is recogruzed more clearly than ever before. Scientists are now aware of the particular significance of susceptibility to toxic

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\ 6 INTRODUCTION agents during the early years of postnatal development, and so we could continue through the life span, perhaps with special consider- ation of the significant problems associated with an increasingly ag- ing population. Clearly, there is no dearth of critical issues wherever in the life span neurobehavioral toxicologists choose to search. The fact that chemicals, both natural and synthetic, may trigger long-latency, neurological, and behavioral disorders without early detection emphasizes the importance of longitudinal as well as cross- sectional studies of behavioral toxicants. Examples of this species of critical issues are also to be found among the progressive degenerative dementias. APPROACHES TO RESEARCH A number of participants in the workshop pointed out that it is not really possible to divorce questions of experimental design from those related to test selection. The discussion took several directions. One of these stressed the key role played by the objectives for which the research is designed; this led to consideration of critical requirements for the establishment of neurobehavioral test batteries. These are discussed in detail in several of the chapters included in the volume. The discussion at Canberra took a second direction in which the emphasis was, in a sense, related to the venues in which research in neurobehavioral toxicology takes place. The desirable precision of the experimental approach raises questions about extrapolation to conditions of the "real world." Research in the field has problems in establishing which among several or many variables is related to the consequent behavioral malfunctions. Research in the clinic begins with a disorder and has significant difficulties in establishing its etiology. At one time the comment was made that these three approaches are analogous to the three blind men describing an elephant: one by feeling its tail; another, its leg; and the third, its trunk. Integrating information from the three inputs must certainly be a worthy effort for the next decade. The importance of using proper control data continues to receive considerable attention. The ideal of using subjects as their own con- trols measuring behavior before, during, and after exposure may be achievable only in the laboratory. Prospective studies in the field are expensive and relatively few have been conducted. Questions then arise about what constitutes an adequate control group with which to compare those exposed occupationally or adventitiously. At Canberra, attention was called to a 1988 publication that clearly illustrates this problem (Gade et al., 1988~. Reevaluation of an earlier

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INTRODUCTION study found that original behavioral measurements leading to diag- noses of chronic toxic encephalopathy did not refer to population norms for cognitive deficits or to estimates of premorbid levels of functioning. The reevaluation concluded that the poor test performance described in the original report was a consequence of the lower level of general intelligence and education of the exposed subjects, and hence could not be attributed to solvent exposure. It should not be inferred from this one example that exposure to solvents never affects behavior. The recent reevaluation only points to shortcomings in the design of the earlier study. This example has been chosen because it has another important feature. The original diagnosis of solvent-induced dementia precipitated pressures for changes in procedures used by the industries concerned, who may now be skeptical about the value of neurobehavioral toxicology. Discussion of experimental approaches to the study of neurobehavioral toxicity inevitably leads to consideration of the roles of animal mod- els (Russell and Overstreet, 1984~. The use of such models has long characterized the early stages of pharmacological research on particular compounds. Inevitably research using such models raises questions about extrapolation of results from animals to humans. Put more precisely, the basic issue is, For what decisions is a particular animal mode valid? It is not possible to design an experiment to study the effects of potentially toxic substances or even to make systematic observations relevant to such a substance without stating or implying some underlying theoretical mode! of living organisms and how they interact with their biospheres. The "construct validity" of an animal model is determined by the closeness of fit between the two types of models, the animal and the theoretical. "Predictive validity" requires demonstration of concordance between predictions based on effects of a chemical agent on the animal model and effects of the agent on humans, in essence an ex post facto validation of the model. In considering the wide use of animal models in neurobehavioral toxicology, it seems clear that such models will continue to play critical roles in the future as they have in the past. REGIONAL REQUIREMENTS Questions of critical regional requirements are raised whenever neurobehavioral toxicology has an international audience. The questions range from the relatively simple to the exceedingly complex. For ex- ample, those participating in an international meeting in Indonesia in 1986 saw an apparatus essential to assaying for potential toxicants in the local environment that had been lying idle for months because of

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8 INTRODUCTION a lack of small replacement parts. At the other extreme are social factors that stand in the way of introducing critical changes in the chemical environment when they are sorely needed. One of the most difficult tasks in efforts to alter existing toxic conditions will continue to be that of social change, of changing human behavior patterns, attitudes, and life-styles. COMMUNICATION As the need for solutions to problems of environmental manage- ment has become perceived as critical among major social issues, more attention has been turned to questions of communication among a wide variety of groups with different capabilities and different re- sponsibilities. At the level of the present discourse, fuller communi- cation among scientific disciplines involved in environmental toxicology has begun to develop. The Canberra workshop is a splendid example of the extension of such communication at an international level. Paralleling this development is a growing recognition of the importance of multidisciplinary education and training, a critical issue deserving further attention during the decade to come. Environmental management involves more than the activities of scientists. It involves trade-offs between biological limitations and social cost and benefits. Management is achieved primarily through the imposition of regulations by legislative or administrative bodies within governments. The usual progression involves a policy-making process in which scientific research points to the existence of hazards, scientific data provide a basis for economic analyses of costs and benefits, and finally, both types of information are used by regulators. Beyond communications at all these levels is the importance, dur- ing the next decade, of communicating better with society in general. There are strong social pressures toward conformity; change usually comes slowly. Here are some examples: The city of Los Angeles has a critical need for an improved and more extensive public transport system, a need recognized generally by its inhabitants for many years. City authorities have proposed several routes for such a system. Whenever a proposal involves a particular neighborhood, the "good" local citi- zens mobilize to block its approval. Very recently, the U.S. Environ- mental Protection Agency stated ". . . that it may be forced to prohibit all gasoline- and diesel-powered vehicles in smoggy, Southern California within five years unless the federal Clean Air Act is amended to extend the deadline for meeting clean air standards" (Los Angeles Times, 1988~. Public pressures are arising in several areas of the world to shorten the time taken by responsible governmental agencies to verify

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INTRODUCTION 9 the effectiveness and dangers of new drugs for the treatment of hu- man diseases. A basic conflict arises when such pressures prevent adequate evaluations, yet the public is free to sue an agency if ad- verse effects occur or if a drug is not effective. These are but two of many examples indicating the importance of communication with the general public a need that, even if given proper attention, will not have disappeared by the year 2000. CONCLUSION Risk assessment, as defined by the NRC, involves hazard identifi- cation, close-response relationships, exposure assessment, and risk characterization (NRC, 1983~. At its present state of development, neurobehavioral toxicology has critical issues to explore In all of these areas. A 1984 report by the National Academy of Sciences (NRC, 1984) assured us once again that the knowledge and skills of neurobehavioral toxicologists are greatly needed. There is evidence that this is being increasingly recognized by regulators, who must consider neurobehavioral toxicology as ". . . the introduction of a new biological endpoint into the regulatory arena" (Buckholtz and Panem, 1986~. To achieve an integrated body of knowledge and its applications demands a multidisciplinary approach. The breadth of disciplines involved precludes all neurobehavioral toxicologists from being experts in all the relevant disciplines. However, they can be acquainted with the basic concepts and techniques so that interrelations among the specialized areas of expertise can be understood by all. Acquiring this broader perspective can begin with multidisciplinary education and training. It can be continually fostered by meetings such as the Canberra workshop, when new ideas, information, and techniques can be exchanged and examined in an environment of free and posi- tive discussion. REFERENCES Berglund, B., T. Lindall, and J. Sundell, eds. 1984. Pp. 284 in Indoor Air: Recent Advances in the Health Sciences and Technology. Stockholm: Swedish Council for Building Re- search. Buckholtz, N.S., and S. Panem. 1986. Regulation and evolving science: Neurobehavioral toxicology. Neurobehav. Toxicol. Teratol. 8:89-96. Gade, A., E.L. Mortesen, and P. Bruhn. 1988. Chronic painters' syndrome. A reanalysis of psychological test data in a group of diagnosed cases, based on comparisons with matched controls. Acta Neurol. Jour. 77:293-306. Los Angeles Times. 1988. EPA issues threat to ban gas, diesel vehicles in basin. November 29.

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10 INTRODUCTION National Research Council. 1975. Evaluating Chemicals in the Environment. Washington, D.C.: National Academy Press. National Research Council. 1983. Pp. 17-83 in Risk Assessment in the Federal Govern- ment: Managing the Process. Washington, D.C.: National Academy Press. National Research Council. 1984. Reference protocol guidelines for neurobehavioral toxicology tests. Pp.169-174 inToxicity Testing Strategies to Determine Needs and Priorities. Washington, D.C.: National Academy Press. O'Flaherty, E.J. 1986. Dose dependent toxicology. Comments on Toxicol. 1:23-34. Ruffin, J.B. 1963. Functional testing for behavioral toxicology: A missing dimension in experimental environmental toxicology. J. Occup. Med. 5:117-121. Russell, R.W. 1979. Neurotoxins: A systems approach. Pp. 1-7 in I. Chubb and L.B. Geffen, eds. Neurotoxins: Fundamentals and Clinical Advances, South Australia: Uni- versity of Adelaide Press. Russell, R.W., and D.H. Overstreet. 1984. Animal model in neurobehavioral toxicology. Pp. 23-57 in N.W. Bond, ed. Animal Models in Psychopathy. Sydney: Academic Press. Sakai, C. 1987. Female reproductive risk assessment. Reproductive Toxicol. 1:53-54. Sigerist, H.E. 1958. The Great Doctors. New York: Doubleday.