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Regional Issues in the Development of the Neurobehavioral Core Test Battery Renato Gilioli and Maria G. Cassitto For many decades, occupational diseases have been the focus of research in occupational health, with the underlying understanding that improvement in production technologies would eventually result in the total control of diseases as a natural consequence. Although this concept still retains a strong validity, over the past years there has been mounting evidence to show that along with a decrease in traditional occupational diseases, an increase has occurred in environmental as well as work-related diseases with new characteristics. These clinical entities are certainly less severe but still sufficiently incapacitating so as to need early detection arid prompt intervention. Although these considerations mainly refer to industrialized countries, developing countries are now facing problems very similar, or perhaps even worse, than those encountered in the earlier stages of industri- alization by now industrially advanced countries. These considerations are common to all occupational health domains and even more so to neurobehavioral toxicology. Thus, environmental and work-related disease the problem of neurotoxic disorders presents a number of distinctive features. First, although it is certain that the central nervous system (CNS) and the peripheral nervous system are the target of many industrial and environmental chemicals, no clear-cut evidence exists of a direct quantitative dose-effect or dose-response relationship between the level of exposure or degree of absorption and a predictable neuro- behavioral outcome. Second, most of the combined effects (i.e., additive, 3~2

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NEUROBEHAVIORAL CORE TEST BATTERY 313 synergistic, and antagonistic) of neurotoxic agents are still unknown or, at best, uncertain. Many other interfering or confounding factors are known, but their role is yet to be fully understood. The World Health Organization (WHO) Monograph on Neurotoxic Illness Johnson et al., 1987) explores these factors in detail and shows how much work still has to be carried out in this direction. Third, another central feature is individual response not only to the neurotoxic agents but also to the behavioral instruments used. This response can be modified by age, level of education, and cultural background. This third issue is far from being clarified. Those factors that are relevant within the same cultural group require much greater attention when dealing with groups belonging to different cultures. Over the last five years, considerable attention has been paid to this aspect and relevant material has already been obtained. In fact, after many years of research designs characterized by heterogeneous collection of similar or identical but variously assembled tests, yielding heterogeneous results, the need for unifying these methodologies has been widely recognized. This willingness to give up at least part of one's own research instruments for the benefit of greater uniformity and the means of realizing it have been the object of much international ef- fort. INTERNATIONAL INITIATIVES The ad hoc international initiatives discussed in this chapter were prepared by the first International Symposium on Neurobehavioral Methods in Occupational Health held in Como and Milan, Italy in 1982. This type of approach has proved fruitful and resulted in a triennial series of symposia, the second held in Copenhagen (1985) and the third in Washington, D.C. (1988~. A fourth symposium will be held in Tokyo in 1991. These symposia are aimed at acquiring the latest developments in neurobehavioral methods as well as disseminating basic pertinent knowledge to developing countries in different re- gions of the world. In Europe, the first official meeting held by an international agency was organized in 1983 by the Health and Safety Directorate of the European Economic Community when experts from the then 10 member states were convened to deal with this specific topic. In the same period, substantial results were obtained by the WHO Office of Occupational Health in Geneva. Along with the U.S. National Institute for Occupational Safety and Health (NIOSH), WHO convened an international workshop in Cincinnati in 1983 to evaluate existing information on the neurotoxicity of workplace chemicals with a double

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314 RENATO GILIOLI AND MARIA G. CASSITTO purpose: (1) to transfer, after sound critique, the already existing knowledge to health personnel in industrialized and developing countries, and (2) to analyze existing methodologies and foster the adoption of common instruments. In fact, an agreement was reached on a minimum core battery, the WHO Neurobehavioral Core Test Battery (NCTB), to be used and validated in all countries. To help this dissemination, WHO developed an operational guide that describes this instrument in detail, its characteristics and admin- istration procedures. Although the monograph (Johnson et al., 1987) has recently been published, the guide is, at the moment, distributed by WHO to interested groups. According to WHO-intentions, the battery is given as a package to be used as a whole; it is short, easy to handle, and meant to measure those functions that are more easily impaired by exposure to neurotoxic agents namely, mood, attention, visuomotor skills, and memory. A factor analysis performed on the data from 950 subjects resulted in the extraction of five factors: namely, emotional status, motor response speed, visuomotor coordination, sustained attention, and active information processing. The commonalities are very high and reflect important intercorrelations. The reliability and sensitivity of this battery are not optima-l, as recognized by the panel of experts who fostered its adoption. However, the tests chosen have the advantage of being simple and well known and, above all, have a minimal loading in cultural factors, which are the most important confounders in interpreting results. The WHO panel of experts also recommended integration of this battery with additional and more specific tests whenever possible. Thus, two results may be obtained: other more specific measures can (1) increase the sensitivity of the instrument and (2) allow for the use of tests reflecting more specifically the intellectual abilities and emotional traits that might have been determined by the cultural history of the subjects. This approach would still permit the performance of highly needed multicentered studies. VALIDATION STUDIES To implement this program on prevention of neurotoxic disorders, WHO in 1986 presented a program of international validation of the WHO-NCTB aimed at regional validation and use of the instruments and development of an international reference data bank of normal values, if feasible, with special reference to developing countries. This validation program is under the operational responsibility of three oversight centers. In the United States, Kent Anger of NIOSH coordinates domestic validation as well as that of South America and China. In

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NEUROBEHAVIORAL CORE TEST BATTERY 315 Europe, Helena Hanninen of the Helsinki Institute of Occupational Health and Maria Cassitto of the Milan Institute of Occupational Health are responsible for the other countries willing to participate in the validation program. General coordination of the entire program has recently been assigned by WHO to the Milan center. Within this general frame, some considerations arising out of our experience with this program can help define its potentialities and limits in terms of regional issues and uniformity of interventions. The first recommendation to interested groups is to spend a practice period in one of the three oversight centers. The underlying rationale is that the same, even simple, tests can substantially change when different instructions are given. Moreover, according to the testers' background, different aspects of the tests or of the subjects' behavior will be noticed, thus creating a totally different testing situation. Because the tests in this battery have long been used by most groups involved in neurotoxicity stud- ies, questions may arise as to whether there is a real need to participate In a practice exercise. An example should clarify this issue: One of the tests in the battery gives measures of manual ability in terms of both speed and accuracy. Instructions stressing either or both of these aspects will result in different performances. A satisfactory number of correct answers can be expected from instructions stressing accuracy, whereas a high number of answers with many errors are obtained with instructions stressing speed. An intermediate level of correct answers and errors will result from the third type of instructions. In developing countries, qualified personnel skilled in psychologi- cal testing are generally lacking. As a result, either nurses or physi- cians themselves will have to administer the battery. In both cases, training is essential. Difficulties in this case are mainly financial: travel and living expenses cannot always be covered either by the oversight center or by the trainee. Despite these difficulties, a number of short training courses have already been organized by the three oversight centers to provide both theoretical and practical backgrounds aimed at diagnosing impairments of the higher-order nervous functions found in numerous neurotoxic disorders. Theoretical training is essential to provide the operators with the framework within which the use of the battery acquires meaning and usefulness. If one is already skilled in psychological measures, the difficult step is to move from the traditional use of testing the abilities in view of either job fitness or cerebral dysfunction in severe neurologic dis- eases to a more subtle analysis of the slightest functional impairments. In fact, as is well known, minor neurobehavioral changes may be often seen in exposed populations which can proceed to further serious

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316 RENATO GILIOLI AND MARIA G. CASSITTO deterioration. Similarly, unexperienced personnel must also become so sensitive to this issue as to take into proper account even the slightest dysfunction that can be revealed only by accurate testing. However, it must be stressed that one has to avoid the risk of reading the psychometric outcome as though it were equivalent to a common analytical determination, such as blood sugar. In our courses, it has been realized that these objectives can be attained when training not only is theoretical but also is integrated by- testing actual cases and protocols in which participants are asked to record the subjects' ver- bal and operational behavior in all its aspects. Optimal training would imply a real-life situation, but simulated cases can often be equally effective. To help demonstrations, a videotape was produced in our laboratory showing the entire neurobehavioral examination of a patient at our clinic hospitalized for possible carbon disulfide intoxication. In this way, the subject's behavior can be discussed step by step, thus facilitating the above-mentioned change in the tester's attitude. So far, local characteristics have been somewhat overlooked for the advantage of uniformity and international standardization. We believe that, once the attitude toward the instruments tends to be the same and the interpretation of the results has common reference guidelines, greater attention to cultural dimensions will be profitable and will result in substantial improvements in the already existing tests or in the development of more advanced ones. According to our experience, we are not likely to face important cultural barriers to the implementation of this program in our regions. Rather, the first data coming from the validation show that, in six European countries, there are significant differences in the attitude of the subjects toward psychological testing in general. These differences in attitude result in differences in the effort taken and, consequently, in the scores. This is an important issue that must receive due consideration in all international efforts to unify methodologies. The only difficulty for all groups involved in the validation effort has been with POMS (a mood measure), which is a test consisting of a lone list of adjectives that do not always have a precise counterpart ~ ~~ . . . ~ ~ ~ . ~ ~ T . _ ~ ~ ~ I ~ in all languages. lhIS IS a test Developed In tne urea crates, ana is interesting to realize that in other English-speaking countries, the same adjective may have different shades of meaning. In Italian, we had to adapt some words by interpreting them in the light of the original meaning. In Polish, some words had to be eliminated be- cause the precise equivalent was lacking. Further, it is worth stress- ing the fact that other adaptation problems are easily predictable in countries where the very perceptive structures are differently devel- oped. As-mentioned earlier, this battery has a minor loading on

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NEUROBEHAVIORAL CORE TEST BATTERY 317 strictly cultural factors as transmitted by current educational pro- grams. The battery is basically an instrument that stimulates psychomotor and auditory memory functions. However, at present it is not known whether these functions can be measured with these same instruments in countries where even the written language patterns are so percep- tibly different. Local validation of the battery will thus become an invaluable tool to clarify these points. As stated earlier, the WHO-NCTB was developed with the primary aim of screening early signs of impairment of higher nervous function. Accordingly, when the WHO-EURO Office of Environmental Health Service planned- multicentered studies of CNS impairments due to chemical exposure, the WHO-NCTB became part of the epidemiological protocol. The first investigation was devoted to the evaluation of CNS effects in a certain number of developing countries, Poland, Czechoslovakia, Hungary, Bulgaria, Yugoslavia, Greece, and Turkey; Israel and Italy were also studied. In spite of unavoidable difficulties in adaptation and implementation, the performance of the study groups showed a good level of achievement in harmonization of the methods. The results will be released by WHO in 1990. Another study under advanced planning involves the use of WHO- NCTB for the evaluation of exposure to methylmercury from seafood consumption in countries adjacent to the Mediterranean. In this case, the battery will probably be applied only to a specific group of sub- jects (i.e., fishermen) after careful analysis of methylmercury accu- mulation in their hair has shown significant levels. As a general comment, these studies have proved to be important steps forward in the solution of one of the major problems of neurobehavioral studies, i.e., the standardization and more rational use of international and national resources. An extra effort, however, needs to be made to overcome the natu- ral individual resistance to giving up one's research tools for the benefit of international collaboration. This resistance often stems from a justified consideration of one's own experience which may be just as valid as others'. However, the inherent value of a group decision lies in its being demonstrated by many and devoted to a common aim. AUTOMATED TESTING Over the last decade, several studies have also been carried out by our group, mainly on large populations, with different aims, includ- ing validation of methodologies; search for subtle effects on higher nervous functions possibly arising out of long-term, low-dose exposure

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318 RENATO GILIOLI AND MARIA G. CASSITTO to industrial chemicals whose neurotoxicity is still undetermined; and medical surveillance of populations currently at work and exposed to known neurotoxic chemicals. All the studies mentioned share the need for sensitive and specific instruments to be administered to as numerous a group as possible. To this end, the increasing diffusion of relatively inexpensive, portable microcomputers has offered an ex- tremely useful means to acquire homogeneous data especially when multicentered studies are needed. A number of independent groups have faced the problem and developed ad hoc automated programs. At the 1988 symposium in Washington, D.C., about 15 automated systems were presented, the most widespread of which is the Neurobehavioral Evaluation System (NES) developed at Harvard by Baker and Letz. A few years ago, a computerized version of six out of the seven tests of the WHO-NCTB was set up in our institute and termed MANS (Milan Automated Neurobehavioral System). For practical reasons, such as the impossibility of developing new tests in reasonable time, and the need for training testers in regular paper and pencil form, we have chosen to adopt all but one of the tests suggested by WHO-NIOSH because of their long and worldwide use; further, the validation of MANS is simplified by comparison with the paper and pencil form. In fact, the correlations found between the paper and pencil and the MANS tests range from 0.73 to 0.79. The use of computerized techniques will facilitate the development of new and more adequate tests by exploiting the graphic potentiali- ties of computers. This will probably reduce the impact of cultural differences because words can be replaced by images having a wider universal meaning. For the time being, MANS is available in two languages, English and Italian, while versions in German and Greek are in progress. ~ A first international application of MANS has been activated by the International Commission on Occupational Health through its Scientific Committee on Neurotoxicology and Psychophysiology to evaluate the effects on the central nervous system of organic solvent exposure of paint manufacturers and users. The countries participating in the study are, at present, the United States, the United Kingdom, West Germany, and Italy. In general, diagnosis of the impairment of higher nervous func- tions from environmental and industrial exposure needs a thorough evaluation by means of clinical, neurobehavioral, and neurophysiologic investigations. A team of professionals with qualifications in neurotoxicologic assessment is necessary. In practice, very few teams conforming to the proposed model exist in Europe or, to our knowl-

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NEUROBEHAVIORAL CORE TEST BATTERY 319 edge, in other countries as well. In Europe, this type of expertise has been developed particularly in both western (Sweden, Finland, Den- mark, Germany, and Italy) and eastern (Poland, USSR, Hungary, and Czechoslovakia) countries. An organizational model that has proved effective in occupational health is the self-sufficient interdisciplinary type of institute; this model is based on availability at the institute of all the medical, biological, bioengineering, and ergonomics specialties. For instance, the Institute of Occupational Health of the University of Milan has, among its different specialties, a Center of Neurotoxicology which is composed of one neurologist, two psychologists, one physi- cian specializing in occupational medicine, and technicians for neuro- physiological and behavioral evaluations. The activities of the center include (1) assessment of neurological and behavioral deficits in in- patients of the Clinic of Occupational Medicine, hospitalized for both diagnostic-therapeutic and compensation purposes; (2) medical sur- veilIance of high-risk groups of workers exposed to neurotoxicants; (3) screening early effects on the CNS in working populations exposed to chemicals whose neurotoxicity is still under scrutiny; (4) search for effects on the CNS in case of exposure in the general environment; and (5) training medical students and postgraduate students in occu- pational medicine. NOTE Those interested in participating in the validation program should request the "Solicitation Proposal Document" by writing: WHO Col- laborating Centre, University of Milan, Institute of Occupational Health, Via San Barbara 8, Milan, Italy 20122. APPENDIX COMPUTERIZED VERSION (MANS) OF SIX OUT OF THE SEVEN TESTS OF THE WHO-NCTB The POMS contains adjectives that describe different feelings about Tension, Anger, Depression, Vigor, Fatigue, Confusion,and Sociability. The subject indicates the intensity of his mood state, during the week preceding the test session, by pressing for every adjective the spacebar connected to a five-point scale ranging from "not at all" to "extremely." The Simple Reaction Time is performed by pressing the spacebar as promptly as possible when a red light is shown on the screen. Stimuli are administered at intervals varying between 1 and 5 seconds for 6 minutes. A practical trial is given.

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320 RENATO GILIOLI AND MARIA G. CASSITTO The Digit Span is presented in its traditional form. The digits appear on the screen one at a time; a sound indicates the end of the series after which the subject is required to repeat the digits on the keyboard. The Digit Serial has been addecl to evaluate the ability to memo- rize and recall eight or nine digits. The same series is displayed for a maximum of 12 times until the subject repeats it correctly. The pre- sentation of the digits on the screen is the same as in the Digit Span. The Symbol Digit based on the stimulus material used In the clas- sic WAIS subtest, requires, in its computerized version, pairing digits to symbols for 1.5 minutes. The Benton Visual Recognition requires the subjects to recognize a geometrical pattern immediately, after 5 seconds of observation, among three over sandbar drawings presented together. The 10 critical patterns are the same used in the Visual Retention test. The Aiming Pursuit is performed by means of a graphic tablet. A sheet of circles is fixed on the tablet and the program is set up in position. The subjects have to make quick and accurate movements to place the pen inside each circle following the pattern given on the test sheet. The circles are larger than those in the original version of FIeischman in order to be proportional to the stylus point. REFERENCES Baker, E. L., and R. F. White. 1985. The Use of Neuropsychological Testing in the Evaluation of Neurotoxic Effects of Organic Solvents. Working Group on Chronic Effects of Organic Solvents on CNS and Diagnostic Criteria. Copenhagen: WHO Regional Office-Nordic Council of Ministers. Camerino, D., M. G. Cassitto, E. Desideri, and G. Angotzi. 1981. Behaviour of some psychological parameters in a population of a Hg extraction plant. Clinical Toxi- cology 18~11~:1299-1309. Gilioli, R., M. G. Cassitto, and V. Foa, eds. 1983. Neurobehavioral Methods in Occupational Health. Proceedings of the International Symposium on Neurobehavioral Methods in Occupational Health, Coma and Milan, 1982. Pergamon Press. Hanninen, H. 1983. Psychological test batteries New trends and developments. In Neurobehavioural Methods in Occupational Health, R. Gilioli, M. G. Cassitto, V. Foa, eds. London: Pergamon Press. Hartman, D. E. 1988. Neuropsychological Toxicology. London: Pergamon Press. Hooisma, J. 1987. Abstracts of the First Meeting of the International Neurotoxicology Association, Lunteren, The Netherlands. Johnson, B., ed. 1987. Prevention of Neurotoxic Illness in Working Populations. New York: John Wiley and Sons. Juntunen, J., ed. 1982. Occupational neurology First International Course on Occu- pational Neurology, Finland. Acta Neurologica Scandinava 66: Suppl. 92. Letz, R., and E. L. Baker. 1987. Computer-admmistered neurobehavioral testing in occupational health. In Seminars in Occupational Medicine, Vol. 1, No. 3. New York: Thieme Medical Publishers.

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NEUROBEHAVIORAL CORE TEST BATTERY 321 Lezak, M. D. 1983. Neuropsychological Assessment. New York: Oxford University Press. Lindstrom, K. 1980. Changes in psychological performances of solvent-poisoned and solvent-exposed workers. American Journal of Industrial Medicine 1:69-84. National Institute for Occupational Safety and Health. 1974. Behavioral Toxicology- Early Detection of Occupational Hazards, C. Xintaras, B. L. Johnson, I. de Groat, eds. Washington, D.C.: U.S. Department of Health, Education, and Welfare. Putz-Anderson, V., B. A. Albright, S. T. Lee, B. L. Johnson, D. W. Chrislip, B. J. Taylor, W. S. Brightwell, N. Dickerson, M. Culver, D. Zentmeyer, and P. Smith. 1983. A behavioural examination of workers exposed to carbon disulfide Neurotoxicology 4:(1~:67-78. Valciukas, J. A., R. Lilis, J. Eisinger, W. E. Blumberg, A. Fishbein, and I. Selikoff. 1978. Behavioural indicators of lead neurotoxicity: Results of a clinical field survey. Int. Arch. Occup. Environ. Hlth 4:217-236. World Health Organization. 1983. Prevention of Neurotoxic Illness in Working Populations, B. L. Johnson, ed. New York: J. Wiley & Sons. World Health Organization. 1984. Protocol for Monitoring and Epidemiological Studies on Health Effects of Methylmercury. Copenhagen: WHO Regional Office for Europe. World Health Organization, Regional Office for Europe, Commission of the European Communities. 1985. Neurobehavioral Methods in Occupational and Environmen- tal Health. Second Intemational Symposium. Environmental HeaIth Series No.6. Copenhagen. World Health Organization, Regional Office for Europe, Nordic Council of Ministers. 1985. Chronic Effects of Organic Solvents on the Central Nervous System. Environmental Health Series No. 5. Copenhagen. World Health Organization. 1986. Epidemiological Study on the Health Effects of Exposure to Organophosphorous Pesticides: Core Protocol. Copenhagen. World Health Organization. 1986. Principles and Methods for the Assessment of Neurotoxicity Associated with Exposure to Chemicals. Environmental Health Cri- teria 60. Geneva. World Health Organization, Regional Office for Europe. 1987. Organophosphorous Pesticides: An Epidemiological Study. Environmental Health Series No. 22. Copenhagen. World Health Organization/National Institute for Occupational Safety and Health. 1983. Prevention of Neurotox~c Illness in Working Populations. Proceedings of a WHO/NIOSH Workshop, Cincinnati.