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Human Neurobehavioral Toxicology Testing W. Kent Anger Twenty-five years ago, Joseph Ruffin, a staff physician with Kaiser Steel Corporation, published a call for "Functional Testing for Behavioral Toxicity: A Missing Dimension in Experimental Environmental Toxicology" in the Journal of Occupational Medicine (Ruffin, 1963~. Since that time, the field of behavioral toxicology or, more broadly, neurotoxicology has shown a rapid growth and become one of the first independent specialty fields under the general rubric of toxicol- ogy. One result of this growth is that sufficient research has accumu- lated to allow the development of screening programs for behavioral toxicity. There are two reasons for developing standardized tests or test batteries to screen for (i.e., identify) effects of neurotoxic chemicals: (1) premarket testing or related regulatory needs and (2) development of a neurotoxicity data base. Although the former reason is a relatively recent development impacting this field, the latter has a longer history. Scientists within the field have encouraged standardization of tests (Buck et al., 1977; Dews, 1975; Morgan and Repko, 1974) and the use of reference chemicals as positive controls (Buelke-Sam, 1980; Laties, 1973~. Though never explicitly stated, the reason is to allow us to relate findings in one laboratory to findings in other laboratories or to relate findings in one country to those in other countries. The ultimate purpose is to develop enough information on a range of chemicals that general principles of neurotoxicity can be gleaned or commonalities identified. Only then can the chemical-by-chemical 69

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70 W. KENT ANGER approach to testing, now typical in this field, be replaced by a more expeditious approach. To identify the hoped-for commonalities, a data base must be assembled from research on diverse chemicals studied with common methods. This suggests the need to select standard methods to be used in research to identify neurotoxic effects. It is also consistent with the regulatory needs for pre- and postmarket screening. The selection of tests for a neurotoxicity screening battery has oc- cupied the field of neurotoxicology for several years, especially since the Environmental Protection Agency (EPA) asked the field to select neurobehavioral screening tests in 1979. In that year, the EPA spon- sored a conference in San Antonio with the purpose of identifying behavioral tests that could be used to evaluate new or untested chemicals for behavioral/nervous system effects, a primary regulatory need of the Toxic Substances Control Act (TSCA) (Geller et al., 1979~. At the end of the meeting, Weiss and Laties (1983) of the University of Rochester summed up their opinion for EPA: "This collection of papers provides the most emphatic statement so far of how essential it is for the Environmental Protection Agency to shun test [selection] standardization. . . . A behavioral analog of the Ames test. . . is an impossible dream." These comments exemplify the strong trend of opinion opposing the development of screening test batteries in the psychology community. This is especially notable among those researchers studying neurotoxic effects in adult animals. Those in the field of behavioral teratology have been more tractable on this topic, generally adopting test batteries common to several laboratories. The National Center for Toxicological Research (NCTR) collaborative laboratory study established the replicability of one such battery, as described by Buelke-Sam et al. (1985~. Those scientists conducting human neurobehavioral worksite research have also tackled the problem of battery development with enthusiasm in recent years. Several investigators in the United States are in the process of developing or validating human neurotoxicity test batteries (Otto and Eckerman, 1985~. RATIONALES FOR DEVELOPING TEST BATTERIES Two rationales can be formulated for selecting tests into a reason- ably comprehensive battery of the sort needed to assess the range of behavioral changes produced by the variety of chemicals found in the United States. The first and most comprehensive rationale would be to assess all major nervous system functions to identify all poten- tial problems that might be produced by chemical exposures. This would require a taxonomy of nervous system functions. Although

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HUMAN NEUROBEHAVIORAL TOXICOLOGY TESTING 71 such taxonomies have been developed by Carroll (1980) for cognitive functions and by Fleischman and Quaintance (1984) for a range of performance tasks, there is no widely accepted taxonomy that at- tempts to specify all nervous system functions. Of course, any such list would be too broad to accommodate in a test battery of reason- able length. The second rationale would be to select tests that would measure neurotoxic effects typically found following occupational or environmental exposures. This rationale for developing a battery of tests is likely to be an evolutionary one. That is, as certain effects replace others as the most frequently reported problems, the makeup of the battery would be altered. Neither of these approaches has been followed exclusively. Eckerman and others (GuLlion and Eckerman, 1986) developed one test battery based on eight cogrutive factors identified by Carroll (1980~. However, the battery has not been used in field evaluations. On the other hand, several approaches to He development of human neurotoxic~ty test batteries have been followed, and the resulting test batteries are undergoing field trials. The more prominent approaches are discussed next. FinIand's Institute of Occupational Health Approach Historically, the first approach to worksite neurotoxicity testing was developed at Finland's Institute of Occupational Health (FIOH) in the 1950s. Investigators at FIOH developed a test battery that is well adapted to studying the main concerns in Finnish industry, particularly exposure to a limited number of solvents. Their tests (Table 1), which have been streamlined through factor analysis over the years, reflect various psy- chological domains that can also be seen in the table (Hanrunen and TABLE 1 Finland's Institute for Occupational Health (FIOH) Test Battery Test Domain Benton Visual Retention Bourdon-Wiersma Symmetry Drawing Mira Test Reaction Time Santa Ana Wechsler Memory Scale (portions) Wechsler Adult Intelligence Scale (portions) Visual perception Visual perception Visual perception Motor performance Motor performance Motor performance Cognitive/memory Cognitive SOURCE: Hanninen and Lindstrom (1979).

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72 W. KENT ANGER Lindstrom, 1979~. The battery is now used routinely in neurotoxicity evaluations of worker groups in Finland, including prospective studies involving new workers. Problem-Based Approach The problem-based approach to worksite testing has its origins in the wide variety of neurobehavioral problems and neurotoxic chemicals found in the United States, where field investigators have typically adopted a unique battery of tests for each particular situation. The tests have been selected based on two factors: (1) the type of symp- toms reported by the exposed group to be tested and (2) the estab- lished neurotoxic effects of the chemical under study or structurally related chemicals. This general approach has led to the use of literally hundreds of different tests in various worksite studies conducted over the years Johnson and Anger, 1983) and has also been characteristic of National Institute for Occupational Safety and Health (NIOSH) research (Anger, 1985~. Approach Recommended by the World Health Organization A third approach represents a melding of the first two approaches, and was well articulated in the World Health Organization (WHO) meeting held in Cincinnati during May 1983. At that meeting, a small group of established researchers in neurotoxicology recommended a core set of tests (the Neurobehavioral Core Test Battery, or NCTB) that could be used as a basic screen to identify a broad range of neurotoxic effects, particularly for use in developing countries. Tests selected into the core set (1) had been used successfully in worksite studies (i.e., they had identified group differences produced by chemical exposures), (2) were portable, (3) required minimal training to administer, and (4) were expected to be valid and reliable in most cultures. Most of the core tests (Table 2) were well-known "paper and pencil" tests specifically chosen to avoid mechanical or other instrumentation problems (a special concern in developing countries). For the one test requiring a source of electricity (the reaction time test), the instrument selected can be operated by using batteries as well as 110- or 220-volt current. Another series of tests was identified as supplemental to the core battery. Their use was to be dependent on the chemical involved, the type of personnel available to conduct the tests, and the setting in which the tests were to be administered. The core set of tests was

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HUMAN NEUROBEHAVIORAL TOXICOLOGY TESTING TABLE 2 World Health Organization Neurobehavioral Test Battery Test Functional Domain Santa Ana A. . among Simple Reaction Time Digit Symbol Benton Visual Retention Test Digit Span Profile of Mood States (POMS) Manual dexterity Motor steadiness Attention/response speed Perceptual-motor speed Visual perception/memory Auditory memory Affect SOURCE: Johnson (1987). 73 intended to generate more uniform, more consistent data from a broad variety of occupations and neurotoxic exposure conditions. The supplemental tests were intended to provide more in-depth informa- tion based on the known effects of the chemical under study and symptoms reported by the exposed workers (Johnson, 1987~. Neurobehavioral Evaluation System Approach The Neurobehavioral Evaluation System (NES) implemented sev- eral neurobehavioral tests that had been used successfully in clinical settings or in previous field studies on IBM-PC and Portable Compaq computers. Some 17 tests were available on the NES as of 1986 (Letz and Baker). The tests are listed in the Table 3, along with the func- tions assessed. Tests are frequently added to this battery (the most recent version includes three additional tests not found in the table),1 which is following an evolutionary course dictated by current interest in the field. The NES includes variants of five of the seven WHO- NCTB tests (noted by asterisks in Table 3~. As with the problem- based model, developers of the NES recommend that the user "select tasks which are appropriate for specific exposure situations" (Baker et al., 1985~. Each of the four approaches described below is pragmatically based and used past research findings in selecting tests. Three approaches (FIOH, WHO-NCTB, NES) involve a limited battery of tests, and each battery is sensitive to important psychological functions. However, none of the batteries aspires to assess the broad range of human functions proposed above as one basis for test selection. Further, it is not clear if the functions assessed by these batteries are representa-

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74 W. KENT ANGER TABLE 3 Computer-Administered Neurobehavioral Evaluation System (NES) Domain Test Function Psychomotor Performance Symbol-Digita Coding speed Hand-Eye Coordination Coordination Simple Reaction Timea Visuomotor speed Continuous Performance Test Attention/speed Finger Tapping Motor speed Perceptual ability Pattern Comparison Visual perception Memory and learning Digit Spana Short-term memory/attention Paired-Associate Learning Visual learning Paired-Associate Recall Intermediate memory Visual Retentiona Visual memory Pattern Memory Visual memory Memory Scanning Memory processing Serial Digit Learning Learning/memory Cognitive Vocabulary Verbal ability Horizontal Addition Calculation Switching Attention Mental flexibility Affect Mood Testa Mood aVariant of WHO Core Test. SOURCE: Letz and Baker (1986). live of the range of functions that might potentially be affected by neurotoxic chemicals, the other basis for test selection noted above. To assess how well these batteries would detect the health effects typically caused by neurotoxic chemicals at low concentrations (i.e., target organ effects), the target organ health effects identified in the research literature are described, followed by a comparison of the potential of the test batteries to identify those effects. Because the batteries do not assess the broad range of human functions, it is im- portant to consider how effectively they assess health effects frequently caused by neurotoxic chemicals. There is no direct evidence on this point. Several threads of evidence do, however, provide the data to begin such an assessment. These threads, discussed in order below, demonstrate that (1) a large number of chemicals produce effects on the nervous system, and 65 of these chemicals have exposure populations in excess of one million, and (2) many nervous system-related health effects occur at lower exposure concentrations than most other effects for certain chemicals.

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HUMAN NEUROBEHAVIORAL TOXICOLOGY TESTING TARGET ORGAN EFFECTS Neurotoxic Chemicals 75 There are 60,000 (Reiter, 1980) to 100,000 (NIOSH, 1983) chemicals in commerce today. How many affect the nervous system? Anger and Johnson (1985) have reviewed major secondary reference sources in this field (American Conference of Governmental Industrial Hygienists, 1980, 1982; Clayton and Clayton, 1981; Damstra, 1978; Gosselin et al., 1976; Lazerev and Levina, 1976; Norton, 1975, revised 1980; Spencer and Schaumburg, 1980; Weiss, 1978) to identify chemicals for which there is evidence of nervous system effects. They identified just over 750 chemicals or chemical groups for which evidence of direct or indirect nervous system effects exists. It is clear that there are a large number of industrial chemicals that affect the nervous system adversely. Exposure Populations There is also evidence that people are exposed to those chemicals. In U.S. workplaces, the National Occupational Hazard Survey (NOMS) identified 200 chemicals, each of which had an estimated one million or more persons exposed. These estimates are based on statistical extrapolation from extensive sampling data and have been published by NIOSH (1977~. The number of workers exposed to each chemical is very likely inflated due to the exposure identification strategy of that survey. (The strategy was to list chemicals in work environments whether or not there was indication of actual use or exposure.) It is also obvious that many of the people in that survey were exposed to multiple chemicals and were thus counted for more than one chemi- cal. (A more recent national survey conducted by NIOSH, the Na- tional Occupational Environmental Survey [NOES], has not yet been published, but its results are expected to modify this picture consid- erably.) Cross-referencing the 750 chemicals noted above that affect the nervous system (Anger and Johnson, 1985) with the 200 chemicals to which one million or more people are exposed, by NIOSH (1977) estimate, indicates that 65 of the 200, or about one third, are also found in the list of 750 (Anger, 1986~. From these data, it is possible to conclude that a large number of U.S. workers work with chemicals that are known to affect the nervous system. These and other factors have led NIOSH to identify neurotoxic disorders as one of the 10

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76 W. KENT ANGER leading occupational problems in the United States (Centers for Dis- ease Control, 1983, 1986) and to focus efforts on their prevention. Behaviors Affected by Many Chemicals The review that identified 750 chemicals which affect the nervous system also provided an indication of the universe of nervous system- related effects that are known to be produced by industrial chemi- cals. The various behavioral deficits induced by industrial chemicals were categorized into some 120 nervous system-related effects (Anger and Johnson 1985~. Behavioral effects that have been reported as caused by 25 or more of the 750 chemicals are listed in Table 4, along with the number of chemicals with which each has been linked (in the last column). Some of the effects are vague; others are specific. Despite the lack of parallelism, which is quite predictable given the diversity in the source reports, Table 4 contains the 35 behavioral effects most frequently recognized and reported in the reference literature as occurring following exposure to industrial chemicals (Anger, 1986~. This collection of effects provides one measuring stick against which to judge the available test batteries. However, it is not clear if these neurotoxic effects are realistic concerns in the industrial environment. This would be the case if they occur at relatively low exposure levels. That is, are they target organ effects or health effects that occur at the lowest concentrations relative to other effects for a given chemical, rather than curiosities that occur only at high exposure concentrations. One line of evidence suggesting that they are target organ effects is the fact that these are cited as the basis for recommending workplace standards by one federal agency and one independent professional group. NIOSH Recommendations Over the years, NIOSH has produced 91 criteria documents on chemicals/chemical groups/physical agents (counting only once those documents that have been revised), under its mandate in the Occupational Safety and Health Act of 1970. These documents provide a review of the literature and recommend exposure maxima. The basis for the recommendation is explicitly stated in each document. A review of those documents indicates that nervous system effects have been an explicitly stated basis in about 36 of them, or approximately 40 percent. Generally, the nervous system effect was identified as one that occurred at very low concentrations and can be described as a target organ effect. The chemical/physical agents are listed in Table 5.

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HUMAN NEUROBEHAVIORAL TOXICOLOGY TESTING TABLE 4 Neurobehavioral Effects Reported Following Chemical Exposures for 25 or More Chemicals 77 Effect Of 750 Chemicalsa Motor Activity changes Ataxia Convulsions Incoordination / unsteadiness / clumsiness Paralysis Pupil size changes Reflex abnormalities Tremor/twitching Weakness Sensory Auditory disorders Equilibrium changes Olfactory disorders Pain disorders Pain, feelings of Tactile disorders Vision disorders Cognitive Confusion Memory problems Speech impairment General Anorexia Autonomic dysfunction Cholinesterase inhibition Depression of the central nervous system Fatigue Narcosis/stupor Peripheral neuropathy Affect/personality Apathy / languor / lassitude / lethargy / listlessness Delirium Depression Excitability Hallucinations Irritability Nervousness / tension Restlessness Sleep disturbances 32 89 183 62 75 31 54 177 179 37 135 37 64 47 77 121 34 33 28 158 26 64 131 87 125 67 30 26 40 58 25 39 29 31 119 NOTE: Adapted from Anger (1984, 1986), Anger and Johnson (1985). aNumbers below denote number of chemicals for which effect has been reported.

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78 W. KENT ANGER TABLE 5 Agents/Classes Cited by NIOSH Criteria Documents as Producing Nervous System Effects at Low Concentrations Chemical/Physical Agent Document No. Acrylamide Alkanes Anesthetic gases, waste Carbaryl Carbon disulfide Carbon monoxide Carbon tetrachloride Chloroform Cresol Dinitro-o-cresol Ethylene dibromide Fluorocarbon polymers, decomposition products Formaldehyde Hydrogen cyanide and salts Hydrogen sulfide Ketones Lead, inorganic/revised Malathion Mercury, inorganic Methyl alcohol Methyl parathion Methylene chloride Nitrites Noise Parathion Petroleum solvents, refined Styrene Tetrachloroethane (perchloroethane) 1,1,2,2-Tetrachloroethane Thiols (n-alkane monothiols, cyclohexanethiol, benzenethiol) Toluene 1,1,1-Trichloroethane (methylchloroform) Trichloroethylene Tungsten and cemented tungsten products Xylene Zinc oxide (77-112) (77-151) (77-140) (77-107) (77-156) (HHS 73-11000) (76-133) (75-114) (78-133) (78-131) (77-221) (77-193) (77-126) (77-108) (77-158) (78-173) (78-158) (76-205) (HHS 73-11024) (76-148) (77-106) (76-138) (78-212) (HHS 73-11001) (76-190) (77-192) (83-119) (76-185) (77-121) (78-213) (HHS 73-11023) (76-184) (HHS 73-11025) (77-127) (75-168) (76-104) NOTE: NIOSH Criteria Documents for each chemical listed in the table are available by document number (in parentheses) from NIOSH Publications, 5555 Ridge Ave., Cincinnati, OH 45213. SOURCE: NIOSH Criteria Documents.

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HUMAN NEUROBEHAVIORAL TOXICOLOGY TESTING 79 Recommendations of the American Conference of Governmental Industrial Hygienists In the United States, the earliest national sources of recommended limits for exposures to industrial chemicals were the publications of the American Conference of Governmental Industrial Hygienists (ACGIH). They have published reviews of a far larger number of chemicals than has NIOSH or any other group, and their recommendations are discussed at some length because their stated intent is to be compre- hensive in reviewing toxic chemicals in commerce in the United States (ACGIH, 1982~. The ACGIH recommendations are provided by their Threshold Limit Value (TLV) committee, composed of voting practitioners from academia and government. Persons from NIOSH and industry serve as nonvoting consultants. The ACGIH publishes annually a list of the chemicals most frequently encountered in industry for which there is documented evidence of untoward symptoms or occupational disease. For each chemical listed, exposure maxima (TLVs) are recommended (ACGIH, 1982), based on the relevant literature and the personal experience of members and consultants. The ACGIH (1982) recommended TLVs for 588 chemicals. To sup- port these recommendations, the ACGIH also published a book of documentation (ACGIH, 1980) which describes the basis for each rec- ommended TLV. Anger (1984) abstracted 36 organ systems, health effects, or other bases cited in the documentation as the most relevant information leading to the ACGIH recommendations. These presumably reflect those effects produced by low exposure concentrations. In considering only those categories labeled nervous system, unpleasant taste/odor, and eye (other than irritation), a total of 167 chemicals (roughly one-quarter of the total 588) listed through 1982 have TLVs based on these direct neurologic or behavioral effects (Anger, 1984~. This and the NIOSH criteria documents suggest that the nervous system is an important target organ for industrial chemicals in use today. To return to the 35 effects in Table 4 (produced by 25 or more of the 750 chemicals), most are also found cited under at least two chemicals in the ACGIH documentation. Thus, most of the effects in Table 4 may be presumed to occur following low-concentration exposures. An additional six effects, which were cited at least twice by ACGIH but less than 25 times in the list of 750, are also listed in Table 4. Those effects cited by ACGIH as caused by only one chemical are not included in this table.

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80 W. KENT ANGER POTENTIAL OF TEST BATTERIES TO ASSESS TARGET ORGAN HEALTH EFFECTS The data in Table 4 provide a sample of health effects occurring frequently following exposures to toxic industrial chemicals. How effectively would the test batteries noted above identify or screen for these frequently occurring effects? The 35 health effects produced by 25 or more chemicals have been repeated in Table 6 in a single col- umn. Table 6 also identifies the tests in the WHO, FIOH, and NES batteries that would presumably assess the various effects, if the sensitivity of each test and the sample size are adequate. As can be seen in Table 6, many of the motor changes would be identified by the three test batteries, and the Profile of Mood States (POMS) or mood tests found in two of the batteries would detect changes in affect. Sensory changes would be poorly identified, as would ataxia and weakness, two effects that occur frequently after toxic chemical exposure. The forte of the batteries, cognitive testing (particularly memory), is aimed at central nervous system (CNS) functions. This is based on the assumption that such effects are not reported very frequently because they are only rarely assessed with any degree of sophistication. This assumption is somewhat substantiated by past worksite research with carbon disulfide, mercury, lead, and methyl chloride. That research has identified subtle CNS deficits in worker groups exposed to concentrations that did not produce peripheral effects or other signs of frank poisoning (Anger and Johnson, 1985~. Human laboratory research on acute exposure effects of many solvents also supports this assumption (Dick and Johnson, 1986~. The WHO-NCTB, FIOH, and NES test batteries are reasonable, de- fensible, research-based approaches to the assessment of neurotoxic chemicals. Further, each battery tests for well-established health-related effects that have been accepted by the public health community in the past. They also include tests aimed at assessing the more subtle CNS deficits that occur at lower exposure concentrations than do the more frank poisoning effects that have been the focus of attention in the past. There are clearly limitations to these batteries, however. The WHO- NCTB and FIOH batteries use a test of motor performance (the Santa Ana) that has previously demonstrated differences between a group exposed to toxic chemicals and an unexposed group, but the NES hand-eye coordination test has not yet identified chemical effects. Also, only the FIOH battery and the WHO-NCTB have more than one test of coordination. The WHO-NCTB is slightly superior to both the NES and the FIOH batteries in its use of the POMS test. The FIOH battery has no test for affect, and the NES uses a mood test that

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HUMAN NEUROBEHAVIORAL TOXICOLOGY TESTING TABLE 6 Neurobehavioral Effects Reported Following Chemical Exposures 81 Tests Neurobehavioral Effects WHO NES FIOH Motor Activity changes Ataxia Convulsions Incoordination/ Santa Ana Hand-Eye Coordination Santa Ana unsteadiness / clumsiness Paralysis Pupil size changes Reflex abnormalities Tremor/twitching Weakness Sensory Auditory disorders Equilibrium changes Olfaction disorders Pain disorders Pain, feelings of Tactile disorders Vision disorders Cognitive Confusion Memory problems Speech impairment Affect/personality Santa Ana Hand-Eye Coordination Santa Ana Santa Ana Hand-Eye Coordination Santa Ana Santa Ana Benton Pattern Benton Pattern Apathy/languor/lassitude/ POMS Mood Test lethargy / listlessness Delirium Depression POMS Excitability POMS Hallucinations Irritability POMS Mood Test Nervousness/tension POMS Mood Test Restlessness POMS Sleep disturbances General Anorexia Autonomic dysfunction Cholinesterase inhibition Depression of the central nervous system Fatigue Narcosis/stupor Peripheral neuropathy Pathology Psychic disturbances Santa Ana Benton Benton POMS Santa Ana Hand-Eye Coordination Santa Ana

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82 W. KENT ANGER is based on the 65-item POMS, but it employs only 25 of those items to identify five of the six factors (all but vigor) on the POMS. The reliability and validity of the resulting test have not been assessed thoroughly, and an item-by-item analysis of the mood test indicates that it does not appear to assess some types of affect that are assessed by the POMS (and occur frequently following chemical exposures). Overall, this assessment would suggest that the WHO battery is slightly superior to the FIOH and the NES batteries, based on the criteria proposed above. However, the NES has the advantage of being ad- ministered by computer, which reduces administration costs substantially. On the negative side, some of the most frequently occurring neurotoxic effects, particularly some forms of peripheral neuropathy and affective symptoms, weakness, ataxia, and sensory effects, would be missed by all of the batteries. Of course, it is quite possible that CNS changes are correlated with some of these effects and these tests would thus perform their function of detecting health effects. A "screening" battery is developed for detection, not characterization. The established test batteries must undergo constant scrutiny. An evolutionary course of test battery development is essential when the battery is based on established health effects, because these effects may change as chemicals in use change. Further, the immense range and diversity of behavior noted above suggest that simple test batteries are inadequate for comprehensive screening. There is the danger of not detecting those effects for which the batteries lack tests. One hopes that the currently recommended test batteries noted above are designed for the problems of the future by assessing more subtle CNS effects rarely tested adequately in the past. DEVELOPMENT EFFORTS UNDER WAY The test batteries described above are not without their problems. One major problem lies in interpreting the result of these batteries. The neurobehavioral tests in the various test batteries, with only a few exceptions, are not clinical instruments. They do not have established norms based on extensive population testing. Rather, they are performance tests that provide objective measures ideally suited to test-retest (before-after) assessments. Of course, baseline (preexposure) performance data on workers exposed to chemicals almost never ex- ist. Performance data on the same tests administered to unexposed people must be used for comparison. That is, performance effects are defined, not by established norms, but by comparison data from people believed to be healthy a referent or control group. - - - r -r -

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HUMAN NEUROBEHAVIORAL TOXICOLOGY TESTING 83 An appropriate control group should consist of people who are not only unexposed to toxic chemicals, but are also similar to the exposed subjects in terms of age, education, job activities or move- ments, and socioeconomic variables. This is extremely difficult to achieve, and field researchers are virtually always concerned with the accuracy of the controls as a basis for judging the performance of the exposed gtoup. The most pervasive problem in judging the validity of group differences has been age differences between exposed and comparison groups. Therefore, the World Health Organization has recommended the development of normative data from unexposed or control subjects in five age ranges for the NCTB. This recommen- dation may be extended to the other major neurotoxicity screening batteries. The five arbitrarily selected age ranges are: 16-25,26-35, 36- 5,4 -55, and 56- 5 years. Ideally, the subjects would be employees with occupations relatively typical of those found throughout the country (or at least not atypical) and with a fairly homogeneous educational background. NIOSH is conducting such a study using the NES and the NCTB. It is the World Health Organization's intention to carry out an assessment of the NCTB in eight nations (WHO, 1987~. Because the NCTB tests were developed in western European-derivative countries (primarily Finland and the United States), the assessment is aimed at comparing the results from the U.S. and European countries with results from culturally diverse people of different countries. As of this writing, some 15 research groups had applied to participate in the assessment, although some cultural groups are not represented. If test performance in various countries/cultures is within certain ranges, the WHO-NCTB battery can be used to assess poisoning incidents or other neurotoxic exposures worldwide, and the results can be generalized to people throughout the world. Thus, data from all countries could be used to assess safe exposure concentrations of specific chemicals. This is intended to accelerate the development of a data base of chemical effects through the use of common tests. It will, in turn, advance the process of identifying chemical classes or mechanisms associated with neurotoxicity and thus lead to the ultimate goal of prediction of neurotoxicity, rather than identification through post hoc discovery of adverse health effects in humans. NOTES 1. Current information on this battery and the software to implement it are avail- able from Dr. Richard Letz, Environmental Sciences Laboratory, Mt. Sinai School of Medicine, 10 East 102nd Street, New York, NY 10029.

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84 W. KENT ANGER ACKNOWLEDGMENT AND DISCLAIMER Appreciation is extencled to Mrs. Pat Amendola and Pam Schumacher for preparation of the typescript. Mention of company or product names does not imply endorsement by NIOSH. This article is reproduced with permission from Toxicology and In- dustrial Health (Anger, 1989~. REFERENCES American Conference of Governmental Industrial Hygienists. 1980. Documentation of the Threshold Limit Values, fourth edition, 1980 (and supplemental documenta- tion for 1981 and 1982). Cincinnati, Ohio: ACGIH Publications Office. American Conference of Governmental Industrial Hygienists. 1982. Threshold Limit Values for Chemical Substances and Physical Agents in the Workroom Environ- ment with Intended Changes for 1982. Cincinnati, Ohio: ACGIH Publications Office. Anger, W. K. 1984. Neurobehavioral testing of chemicals: Impact on recommended standards. Neurobehav. Toxicol. Teratol. 6:147-153. Anger, W. K. 1985. Neurobehavioral tests used in NIOSH-supported worksite studies, 1973-1983. Neurobehav. Toxicol. Teratol. 7:359-368. Anger, W. K. 1986. Workplace exposures. Pp. 331-347 in Neurobehavioral Toxicology, Z. Annau, ed. Baltimore: Johns Hopkins University Press. Anger, W. K. 1989. Human neurobevioral toxicology testing: current perspectives. Toxicology and Industrial Health 5(2):165-180. Anger, W. K., and B. L. Johnson. 1985. Chemicals affecting behavior. Pp. 51-148 in Neurotoxicity of Industrial and Commercial Chemicals, J. L. O'Donoghue, ed. Boca Raton, Fla.: CRC Press. Baker, E. L., R. E. Letz, A. T. Fidler, S. Shalat, D. Plantamura, and M. Lyndon. 1985. A computer-based Neurobehavioral evaluation system for occupational and environ- mental epidemiology: Methodology and validation studies. Neurobehav. Toxicol. Teratol. 7:369-377. Buck, W. B., D. L. Hopper, W. L. Cunningham, and G. G. Karas. 1977. Current experimental considerations and future perspectives in behavioral toxicology. Pp. 2.1-2.10 in Behavioral Toxicology: An Emerging Discipline, H. Zenick and L. Reiter, eds. US EPA Pub. No. EPA-600/9-77-042. Research Triangle Park, N.C. Buelke-Sam, J. 1980. Standardization is not an ugly word. Neurobehav. Toxicol. 2:289-290. Buelke-Sam, J., C. A. Kimmel, and J. Adams. 1985. Design considerations in screening for behavioral teratogens: Results of the collaborative behavioral teratology study. Neurobehav. Toxicol. Teratol. 7:537-789. Carroll, J. B. 1980. Individual difference relations in psychometric and experimental cognitive tasks. L. L. Thurstone Psychometric Laboratory Report No. 163. Chapel Hill, N.C.: University of North Carolina. Centers for Disease Control. 1983. Leading work-related diseases and injuries in the United States. Morbidity and Mortality Weekly Report 32~2):2~26, 32. Centers for Disease Control. 1986. Leading work-related diseases and injuries- United States. Neurotoxic disorders. Morbidity and Mortality Weekly Report 35~8~:113- 116, 121-123. Clayton, G. D., and F. E. Clayton, eds. 1981. Patty's Industrial Hygiene and Toxicol- ogy, third revised edition. New York: John Wiley & Sons.

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