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Neurobehavioral Toxicity Testing in China Liang You-Xin INTRODUCTION It is hardly an overstatement that "environment" has become one of the key words of our time. A great number of different chemicals are produced for use at home, in industry, in agriculture, and in the control of diseases. It is now estimated that the universe of chemical compounds exceeds 5 million and at least 80,000 chemicals are avail- able in the open market. It is also estimated that 1,000-2,000 new chemicals enter the market yearly and consequently pass into the environment (Geyer et al., 1986~. Therefore, environmental pollution due to various kinds of chemical waste, dust, fumes, smog, and vapor has become a tangible challenge to human society. In China, along with the rapid growth of industrialization, occu- pational exposure to toxic, particularly neurotoxic, substances has expanded both in the extent of exposure and in the spectrum of toxicants. According to a nationwide investigation during 1979-1981, there were 1,031,775 workers in 51,574 enterprises exposed to lead, mercury, benzene, organophosphorus pesticides, or trinitrotoluene (TNT). The overall prevalence of occupational poisoning induced by these five chemi- cals reached 1.3 percent among a total population of 987,934 exam- ined (Table 1) (Gu et al., 1985~. The challenge has grown since the swift expansion of industrialization from urban areas to rural areas where numerous small-scale industries were built at town and village levels during recent years. By 1985, there were about 2,225,000 such 287
288 TABLE 1 Prevalence of Intoxication from Five Chemicals in Question LIANG YOU-XIN Cases of Chronic Intoxication Number Prevalence Chemicals Workers Examined (x104) (x104) (%' Lead 35.50 0.627 1.766 Mercury 6.20 0.166 2.675 Benzene 50.90 0.268 0.526 Organ op ho sph oru s pesticides 1.70 0.058 3.429 Trinitrotoluene 4.20 0.110 2.619 SOURCE: Gu et al. (1985). enterprises across the country. It was reported that 65 percent of the measured levels of chemical as well as some physical agents (e.g., noise) from 2,321 worksites exceeded the prescribed maximum al- lowable concentration (MAC) or permissible exposure level (PEL). The overall prevalence of lead, benzene, mercury, and chromium poisoning reached 6 percent, which is about fivefold greater than corresponding levels found in state-owned industries in urban areas (Yu and Gu, 1987~. From the viewpoint of protecting workers from irreversible dam- age by chemicals, particualarly neurotoxicants, approaches for early detection of reversible neurotoxicity at the subclinical stage of expo- sure are a growing concern. Over the years, scientific research on, and applications of, neurobehavioral toxicity testing have been extensively conducted in Finland, the United States, and some countries in Europe. Emphasis has been mainly on the development of a test battery for the purpose of early detection of neurobehavioral effects due to occu- pational exposure to neurotoxic agents in the working population. Helena Hanninen is regarded as one of the most respected pioneers in this field that she called "toxicopsychology." Her booklet "Behav- ioral Test Battery for Toxicopsychological Studies" (Hanninen and Lindstrom, 1979) has provided detailed information about test items, instruments, and procedures for researchers involved in behavioral studies. Other pioneering work contributed by international efforts has played a key role in the initiation of neurobehavioral toxicity testing in China. Growing numbers of Chinese researchers are showing interest in exploring the use of neurobehavioral tests and recognizing that a proper test battery may serve as one of the most useful tools in the early detection of adverse effects on the nervous system. They realize that (Weiss, 1983)
NEUROBEHAVIORAL TOXICITY TESTING IN CHINA 289 · many toxicants, including certain kinds of heavy metals, or- ganic solvents, pesticides, and air pollutants act primarily on the ner- vous system; · many poisonings, before they show overt clinical signs and symptoms, may be preceded by vague, subjective, and nonspecific psychological complaints; and · finally, there are substances whose actions, although not medi- ated directly through nervous system mechanisms, produce biochemical changes that result in distinct behavioral effects. As a result, a new era of using neurobehavioral toxicity tests for evaluating psychological effects of occupational hazards developed in China during the 1980s. The objectives of the present chapter are to provide an overview of the development of neurobehavioral toxicity testing in China and to suggest roles that these methods can play as that nation faces up to its own challenges in occupational safety and health. Case studies of exposures to carbon disulfide, lead, video display terminal (VDT) operation, and static magnetic fields serve as examples to provide readers with a better understanding of the current status and future direction of the contributions of neurobehavioral testing to meeting these challenges. OVERVIEW OF RESEARCH ACTIVITIES Carbon Disulfic3e In China, carbon disulfide (CS2) is used mainly in the production of viscose rayon fiber and cellophane films (Liang et al., 1983~. Ap- proximately 50,000 workers are reportedly exposed to CS2 in these industries. Because control measures have been relatively effective in lowering the CS2 concentration at worksites, overt CS2 poisoning due to high-level exposure is no longer a serious problem. However, the neuropsychological complaints related to long-term exposure to low levels of CS2 are not uncommon. Our pilot study on CS2 (Liang et al., 1983) was initiated by both the need for~medical surveillance in the viscose rayon industry and the use of a neurobehavioral test battery for screening the subclinical effects of milder exposure. This was the first systematic use of a neurobehavioral test battery for occupational epidemiology in the region. A battery of psychological tests involving mood states, intellectual activity, visual perception, short-term memory, and performance speed was administered to 98 male workers exposed to CS2; all were from a viscose rayon factory in Shanghai. The sample was divided into
290 LIANG YOU-XIN TABLE 2 Comparision of Behavioral Scores Between CS2-Exposed and Nonexposed Groups Mean SD Test Exposed Nonexposed P Value Similarities 6.71 + 1.59 6.40 + 1.89 >0.05 Digit span 43.10 + 7.91 44.49 + 8.16 >0.05 Digit symbol 14.26 + 8.17 17.23 + 10.79 <0.05 Block design 39.15 + 17.19 44.56 + 14.51 <0.01 Reaction time 14.41 + 3.48 10.75 + 3.62 <0.05 Santa Ana 21.90 + 4.42 25.49 + 3.70 <0.01 Finger tapping 18.52 + 2.48 20.14 + 4.63 <0.01 Total scores 148.16 + 32.08 173.65 + 31.51 <0.001 NOTE: SD = standard deviation. SOURCE: Liang et al. (1983). three groups according to the level of exposure during the past 15 years: i.e., group I, a mean exposure level of CS2 above 10 mg/m3, the present maximum allowable concentration of CS2 adopted in China; group II, approximately 10 mg/m3; and group III, below 10 mg/m3. As controls, 91 nonexposed workers from a textile machinery plant were used and matched for sex, age, and educational background. There were statistically significant differences in test scores be- tween the exposed and the control groups for most items used (Table 2~. An exposure-effect relationship was found among the three groups with different exposure levels. For example, in group I, a total score of 134.04 + 27.54 could be reliably discriminated from that of from the control group (172.83 + 30.96~; group II, a total score of 150.67 + 30.46 showed differences of a lesser magnitude; whereas group III (155.27 + 34.19) was no different from controls. These findings coin- cided with the results of neurophysiological testing in the same in- vestigation. The motor conduction velocity (MCV) and conduction velocity of slow fiber (CVSF) of ulnar nerve in the CS2-exposed group were found to be 57.2 and 44.8 m/s, respectively, values significantly lower than those of the comparison group (64.0 and 47 m/s, respec- tively; Liang et al., 1984~. The present study of CS2 not only was exploratory work toward long-term research on neurobehavioral toxicity tests, but also pro- vided information about effects of low-level CS2 exposure on the nervous system that could be used to reevaluate the safety of the current
NEUROBEHAVIORAL TOXICITY TESTING IN CHINA ~ , . _ - . . . A. 291 MAL; adopted In China. The conclusions drawn from this pilot study may be summarized as follows: . Neurobehavioral toxicity tests can be recommended as a use- ful adjunct to other conventional tools in occupational epidemiology. · Levels of CS2 of about 10 mg/m3 may be close to the minimum effect level causing changes of neurobehavioral and neurophysiologi- cal functions in an occupationally exposed population. · For purposes of safety, a proposal to amend the MAC of CS2 from 10 mg/m3 to a lower level is deemed worthy of consideration. Leac! In recent years, occupational exposure to lead has been adequately controlled to prevent the occurence of overt lead poisoning; such controls have been quite successful in many countries including China. Yet milder exposure to lead in certain occupations has been associ- ated with a series of nonspecific neurasthenic symptoms, slowed nerve conduction velocity, and impaired psychological performance indica- tive of effects on the central and peripheral nervous systems. Impaired neuropsychological performance in lead workers has also been found in the absence of peripheral nervous system effects even in workers with blood lead levels below that traditionally accepted as safe (He, 1987~. In China, occupational exposures to lead occur mainly in smelting and battery plants. According to a nationwide survey in 1979-1981, the prevalence of lead poisoning was 1.77 percent in 355,000 lead workers examined. Our research focused on clarification of the ef- fects of low-level lead exposure on neurobehavioral function: 24 workers exposed to lead from a small battery plant and 24 controls from a food product manufacturer were investigated by using an expanded neurobehavioral test battery comprised of nine test items reflecting mood state, intelligence, memory, perception, vigilance, and psychomotor performance. The exposed group had an occupational exposure to lead for periods varying from 3 to 8 years at levels in air ranging from 0.06 to 0.34 mg/m3, time weighted average (TWA) 8 hours. The average blood lead level, free erythrocyte level, and zinc proto- porphyrin level were, respectively, 59.0 + 31.1, 279.7 + 178.6, and 326.6 + 202.4 ,ug/dL. These values were significantly higher than those in the control group. The results indicated that all of the neurobehavioral tests, except pursuit aiming II, showed significant reductions in test scores for the
292 LIANG YOU-XIN TABLE 3 Scores in Asymptomatic Lead-Exposed and Nonexposed Groups Exposed Nonexposed Test (n = 24) (n = 28) P Value Digit span 45.59 ~ 9.57 53.78 + 8.45 <0.01 Digit symbol 42.59 ~ 5.97 56.35 ~ 8.35 <0.01 Aiming II 47.37 i 7.76 52.26 + 11.40 >0.05 Block design 43.15 + 8.65 55.87 + 7.18 <0.01 Mental arithmetic 46.81 + 10.93 52.73 :t 8.61 <0.01 Simple reaction time 44.83 + 12.34 54.43 + 4.34 <0.01 Choice reaction time 44.04 + 9.79 55.11 + 7.77 <0.01 Flicker fusion frequency 46.58 + 2.20 52.93 + 13.01 <0.01 Mood states 44.99 ~ 8.80 56.10 + 6.75 <0.01 Total scores 403.96 :: 35.02 489.46 + 14.14 <0.01 SOURCE: Sheng et al. (19873. r exposed and nonexpose{1 groups (Table 3) (Sheng et al-, 1987~. In considering the confounding effects of sex, age, educational back- ground, and working age, a stepwise regression analysis was used in the statistical analysis-. The results showed that the most significant factor contributing to the reduction in test scores is likely to be lead exposure. The multiple regression can be expressed as Y (total score) = 3.3138 - 1.2127x2 (lead exposure) + O.I568x4 (schooling age). Simi- lar research on lead has been conducted at Nanjing Medical College (Wang et al., 1985~. A series of neurobehaviorai tests were adminis- tered to 43 lead-exposed workers, and the same number of nonexposed workers from- a machinery factory were used as controls. The major- ity of tests were related to memory, perception, and vigilance func- tions. Scores derived from the touch memory, numeral repetition, block design, digit span, and letter cancellation tests were sigruficantly lower In exposed than in the control group. The scores of touch memory and memory quotient (M.Q.) were negatively correlated to the cumulative level of lead exposure, with correlation coefficients of r = -0.679 (p ~ 0.05) and r = -0.854p < 0.05), respectively. The study suggets that memory tasks and psychomotor tests might be used as screening indicators for early signs of central nervous system dys- function due to a low level of lead exposure. Ibe impact of low-level lead: exposure on Me development of children's intelligence has attracted great interest among behavioral research- ers. ~ follow-up study of the neuropsychological effects of such exposure has been conducted by Me Department of Child and Adolescent
NEUROBEHAVIORAL TOXICITY TESTING IN CHINA 293 Health, Shanghai Medical University (Wang, 1987) using a test bat- tery of WISC-R and additional -testing of reaction time: 157 school- age children, including 89 males and 68 females, were divided into four groups based on their PbB levelsgroup I with a PbB level of less than 10 ~g/dL; group II, 1~20 ,ug/dL; group III, 20-30 ,ug/dL; and group IV, more than 30 ~g/dL. Subjects were tested over a period of two years. Results shower! a close relationship between lead exposure level and tested variables. Children who had elevated PbB performed less well on WISC-R than their counterparts with lower PbB levels. The overall IQ values for groups I, II, III, and IV were 109, 97, 78, and 72, respectively. Confounding factors (e.g., age, sex, socioeconomic status, genetic background, parent health, and habits) were taken into account by using a stepwise regression technique. It is clearly evident that exposures to low lead levels significantly disturbed the development of intelligence as measured by all the tests administered. Reductions in perceptual organization, verbal understanding, inference, and eye-hand coordination were the most affected (Table 4~. Air pollution from industrial emissions and lead contaminants from parent's work clothes are the major sources of children's exposure. Table 5 summarizes the results of a group of nursery children sub- jected to different levels of exposure (Shen, 1988~. Preventive measures for control of industrial pollutants and worker health education to improve personal hygienic behavior are needed to minimize the risks to chil- dren from lead exposure. Results of neurobehavioral toxicity testing could provide warnings and the basic evidence for action to remove these risk factors that threaten the life quality of human beings at an early age. Simulated Video Display Terminal (VDT) Operation Video display terminals are used in a variety of occupations. It is resonated that there are approximately 8 nonillion VDT operators worldwide using more than 10 million VDT unity In Chin:` VnT llCP iC hying expanded i~ ~' ~ ~^ ~ ~ ~ ~ ^^ ~ MA LAA L~~ ~ 1 ~ ~~= TO ~11 18 ---rim n industry, agriculture, commerce, management, public service, and scientific research. Professionals in occupational health have expressed great concern over possible deleterious effects result- ing from work with ART. One of these effects involving psychologi- cal factors was the major subject of a research project first reported in 1985 (Liang et al., 1985~. Owing to the difficulty of choosing a sample of subjects from the relatively homogeneous work situation at that time, a simulated television screen inspection situation was used in our pilot study designed to discover possible links between work with screen inspection and psychological effects. It is hoped that this
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NEUROBEHAVIORAL TOXICITY TESTING IN CHINA TABLE 5 Biological Effects Among Children Exposed to Different Levels of Lead in a Nursery Near a Battery Plant 295 Exposure Age PbB PEP ZPP Rank N (yr) (llg/dL) (kg/dL) (Pg/dL) 0 20 7.46 + 0.18 9.21 + 3.18 54.32 + 23.46 59.62 + 20.44 1 9 4.57+ 0.19 16.19+ 7.78 44.27+ 24.16 55.86+ 14.75 2 24 5.60 + 0.26 23.90 + 10.65a 47.88 + 28.68 61.74 + 18.28 3 6 5.20 + 0.46 35.70 + 18.05a 161.10 + 67.51b 162.68 + 83.42a ap < 0.01. by < 0.05. SOURCE: Wang (1987). TABLE 6 Psychobehavioral Tests Used in Video Display Terminal Study Function Test Memory Intelligence Perceptual ability Attention Cognition Psychomotor performance Speed Dexterity Visual spatial ability Mood Digit span Mental arithmetic Digit symbol Figure cancelation Simple and choice reaction time Finger tapping Block design Feeling tone checklist SOURCE: Liang et al. (1984). pilot study will serve as a basis for a systematic study of VDT opera- tion in the actual work environment. Two hundred fifteen employees working in a television screen as- sembly factory and a television parts manufacturer were selected and categorized into four groups according to their job characteristics, i.e., screen inspection (full-time work with display screen), assembly work, screen inspection combined with assembly work (part-time work with display screen), and auxiliary jobs (as controls). The test battery consisted of items measuring a variety of psychological functions outlined in Table 6. The results may be summarized as follows:
296 LIANG YOU-XIN · Findings from the feeling tone checklist clearly indicated that television screen inspectors were subjected to significantly greater mental stress, mainly evident as minor fatigue (comparison with con- trols, u = 3.97, p < 0.01) · Total scores derived from the tests seemed to be affected by three major variables which, ranked in order of the magnitude of these effects, were operation time, screen inspection, and working age. The effects can be expressed as a multiple regression equation: Total score = 137.7562 - 4.0302X (screen inspection) - 6.0151X6 (operation time, hours) - 0.8954X7 (working age, years). Results of several pairs of tests were highly correlated (e.g., digit symbol and digit span, reaction time and finger tapping). This implies that the two correlated tests measure similar types of psycho- logical functions and provides a clue for selecting an appropriate combination test battery for further study. · Psychological test batteries can prove useful adjuncts to other criteria (e.g., ergonomic and hygienic indicators) for evaluation of harmful effects related to work with VDTs. Static Magnetic Fields (SMF) Various subjective symptoms and functional disturbances have been reported in workers involved in the manufacture of permanent mag- nets and those working near industrial equipment using high cur- rents, including irritability, fatigue, headache, loss of memory, bra- dycardia, tachycardia, and decreased blood pressure. To study such effects in greater detail, 63 workers exposed for 1-2 years to such environments (electrolysis of sodium choloride) were investigated by using a neurobehavioral test battery similar to those described above and an examination of the functional status of the autonomic nervous system. Results indicated that workers exposed to static magnetic fields had poorer memory than the controls. Of the 63 workers exposed to a higher level of flux density of magnetic field (median, 242 gauss; range, 103-1,975 gauss), 37 had lower scores on the digit span and digit symbol tests than the remaining 26 workers with a lesser expo- sure (median, 78 gauss, range 26-200 gauss) (p < 0.05~. These effects occured concurrently with the changes in autonomic nervous system function (Liang et al., 1984~. With advances in technology, the growing number of devices generating magnetic fields are creating new occupational health chal- lenges. In China, no regulatory standards have yet been established. Based on the results of neurobehavioral testing and other findings from medical examinations, we would tentatively recommend that occupational exposure to static magnetic fields at workplaces should
NEUROBEHAVIORAL TOXICITY TESTING IN CHINA 297 not exceed 100 gauss (0.01 T) for 8-hour whole-body exposure. This recommendation corresponds to the standard that was adopted in the USSR in 1978 (World Health Organization, 1987~. NATIONAL AND INTERNATIONAL COOPERATION A five-year program toward the development of testing methods and criteria for early detection of occupational neurotoxic illness, sponsored by the Chinese Academy of Preventive Medicine, has been in operation since 1986. Our department has been involved in imple- mentation of the neurobehavioral parts of the program. The development and validation of neurobehavioral toxicity tests are two of our major tasks. Emphasis has been placed on two activities: 1. establishing a test battery consisting of relatively simple mea- suring instruments mainly using paper and pencil, oral presentation, and performance as modes of response; and 2. creating a computer-administered neurobehavioral evaluation system for occupational epidemiology. The material that follows discusses a proposed computer-adminis- tered system consisting of the 17 test items described briefly in Table 7. Development of the battery has involved collaborative efforts at an international level. A variety of neurobehavioral and neurophysiological tests are available for evaluating effects on the working population of exposure to chemical and physical agents. However, the standardization of procedures for test administration and scoring has often been lacking. As a result, the reliability and reproducibility of some results have been less than desirable. To improve the situation, in 1983 the World Health Orga- nization (WHO) proposed a Neurobehavioral Core Test Battery (NCTB) (Johnson et al., 1987~. The goal was to develop a relatively inexpen- sive, simple, and appropriate battery to study neurobehavioral ef- fects of industrial chemicals on working populations. The U.S. National Institute for Occupational Safety and Health (NIOSH) has been des- ignated one of three oversight centers. In 1987 the Department of Occupational Health, Shanghai Medical University, was the first applicant in China to receive approval from WHO and NIOSH to participate in the NCTB project. Phase I of an evaluation program has been conducted since then in Shanghai. Its objective is to study the applicability of the NCTB to working populations generally (i.e., those not exposed to harmful agents) to establish its relatively low cultural bias and
298 LIANG YOU-XIN TABLE 7 Task Performed on the Computer-Administered System Function Test (Source) Task Intelligence Mental Arithmetic (Gon, 1981) Serial Add/Subtract (Baker et al., 1985b) Memory Visual Retention (Baker et al., 1985a) Pattern Memory (Baker et al., 1985a) Paired Associate Learning (Xi et al., 1984) Digit Span (Baker et al. 1985b) Memory Scanning (Maizlish et al., 1985) Subject is asked to add "3" to the original figure starting from "1" and indicate the answer by pressing the key, say, "4." Then add another "3" to the "4" and indicate the second answer by pressing key "7." Fifteen consecutive calculations are required. Two randomly selected digits and signals either "-" or "+" are displayed in the same location on the screen. Subject is asked to perform the indicated addition or subtraction and enter the results. Digits and signals are present for 250 ms, separated by 200 ms, with the next trial beginning immediately after the key is pressed. Fifteen performances are required. The screen presents a Benton figure for 10 s, followed by four similar figures from which subject must indicate the figure previously seen and enter the number of the correct figure within 10 s. A blocklike figure is present on the screen for 10 s, followed by three similar blocks. One of the later blocks is identical to the former one. Subject is asked to identify the figure previously seen and press key for right number within 15 s. Ten performances are required. Twelve paired-associate words are displayed on the screen at a rate of one pair per 5 s. Then 20 pairs of words which contain the 12 pairs previously seen are presented ran- domly. Subject is asked to press key "1" when anyone of the 12 presents. The subject is asked to press key recalling a forward or backward series of digits which are given through an earphone at a rate of 2 digits/s. A short list of one-digit figures is displayed on the screen for 1 s, and a figure varying from 0 through 9 is then singly presented for the same length. Subject is asked to indicate whether the single figure is included in the short list or not by pressing key "Y" or "N."
NEUROBEHAVIORAL TOXICITY TESTING IN CHINA 299 Function Test (Source) Task Continuous Recognition Memory (Maizlish et al., 1985) Memory Span (Maizlish et al., 1985) Visual Two-Letter Search Perception (Thorpe et al., 1985) Symbol-Digit Substitution (Baker et al., 1985a) Length Discrimination (Baker et al., 1985a) Psychomotor Simple Visual Reaction Performance Time (Baker et al., 1985a) Simple Auditory Reaction Time (Fang and Liang, 1987) Four-Choice Series Reaction Time (Thorpe et al., 1985) A series of three-digit figures are displayed separately at a rate of once per second. Two- thirds of the series are repeatedly present. Subject is asked to indicate whether the series repeatedly present has been previously displayed by pressing key "1" or "0." Forty-two progressively prolonged series of three- to nine-digit figures are included. Subject is asked to recall the forward series of digits, attaining 50% of the given series without mistake. Two target letters are present at the top of the screen with a string of 20 letters in the middle of the screen. Subject is asked to determine whether both letters are present in the string or not by pressing key "1" or "0." Fifteen trials are required. Nine symbols and the correspondent digits are present at the top of the screen which never disappear. Subject is asked to press the digit keys corresponding to the symbols in a test list displayed on the screen. Two different-length lines of 4.5 and 5.0 cm are presented separately at an interval varying from 0.3 to 0.7 s and lasting for 0.7 s. Sub- ject is asked to press key when the longer line appears. The target line is randomly present 25 times during 10-min trials. Subject is asked to press key when a 2 x 2 cm2 red square appears on the screen. The interval of interstimulus varies from 3 to 11 s. Sixty-four trials within 6 min are required. Hetrotones are randomly added to the regular white noise. Subject is asked to press key when the dissenting tone appears through an earphone. Subject is given a box having four light- emitting diodes in a square array. A single light of the four is lit, varying from 2 to 7 s. Subject is asked to press the correspond- ing key, thereby initiating the next trial. Table 7 continues
300 TABLE 7 Continued LIANG YOU-XIN Function Test (Source) Task Psychomotor Performance (continued) Finger Tapping (Anger, 1985) Cursor Tracing (Baker et al., 1985a) Subject rests the index finger and middle finger on a red button then taps the button as fast as possible. The number of taps is recorded during 10-s tests for five trials. Subject is asked to use a joystick to trace a large sine wave pattern on the screen. A cursor is moving horizontally at a constant rate, while the subject controls the vertical motion of the cursor with the joystick. TABLE 8 WHO Neurobehavioral Core Test Battery Test Functional Domain Tested Profile of mood states Simple reaction time Digit span Santa Ana dexterity Digit symbol Benton visual retention (recognition form) Aiming (Pursuit Aiming II) Affect Attention/response speed Auditory memory Manual dexterity Perceptual-motor speed Visual perception/memory Motor steadiness SOURCE: World Health Organization (1986). * ctetermine the feasibility of its use by personnel with limited train- ing. By following the WHO protocol for evaluating the NCTB, 282 working adults, including 135 males and 147 females, not exposed to neurotoxic chemicals were examined with the individual items outlined in Table 8. Tests were carried out by using the Chinese version of the relevant instructions and forms, but strictly guided by the original concepts and principles of the operating guide for administering the NCTB. Staff involved in the project were faculty members with medical careers and medical students from the School of Public Health, Shanghai Medical University (Chen et al., 1989~. Results from the phase I evaluation are summarized below. Mood States Results presented in Table 9 show that scores obtained for the item "vigor" decreased progressively with increasing age in both male
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302 LIANG YOU-XIN and female workers. If such statistics are to be used, they should be specified more completely: e.g., what is the F value, d.f. is in a 1-way ANOVA across "age"? There were no other significant age differ- ences in the remaining five mood states in male workers. Inspection of Table 8 shows, however, that scores for these same items increased with increasing age in female workers. Performance Tests Results of performance tests (specified in Table 8) are summarized in Table 10. Both age and sex seemed to be important factors affect- ing the visual reaction speed and eye-hand coordination. All param- eters of reaction time decreased with increasing age in both male and female groups. There was a tendency for performance speed to be faster in males than in females, particularly in the younger age groups. Strong evidence existed to show that age played a more important role than sex in affecting the test scores of Digit Span, Santa Ana Manual Dexterity, Digit Symbol, and Benton Visual Recognition tests, a tendency for test scores to increase with increasing age again being apparent in both male and female groups. By comparison, sex differences did not show a major impact. Effects of aging on the Pursuit Aiming II test were consistent with those in the other performance tests; female subjects tended to outperform males. Results of the phase I evaluation of the NCTB may be summarized as follows: . . The NCTB was shown to be an applicable tool for use across cultures in various countries. Scores derived from tests in subjects with similar, but not equal, educational background did not show significant differences. In some cases, the Profile of Mood States (POMS) seemed to be too complicated, some subjects being puzzled by equivocal adjectives as they appeared in translated version. The problem could be attributed to the inevitable modification rather than simply a translation of the original meaning. · Age is supposed to be one of the factors affecting neurobehavioral performances during the life span. Our results indicate that test per- formance peaked within the age range 16-25 years, remained rela- tively constant at 26-35 and 36-45 years, and dropped precipitously at 46-55 years. This pattern is very similar to those previously reported (Johnson et al., 1987~. Differences attributed to sex were not as marked as those re- lated to age, although some tests did show significant differences between male and female groups. For instance, Pursuit Aiming II seemed to be performed better in the younger group of female workers
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304 LIANG YOU-XIN compared with the same age groups of male workers. However, other measures (e.g., Reaction Time) were found to be performed more adequately by most age groups of male workers compared to females. Phase II evaluation, focusing on the assessment and demonstra- tion of the ability of the NCTB to identify neurotoxicity in the working population exposed to neurotoxic chemicals such as CS2 and toluene, is now being conducted. EXPECTED DIRECTIONS: BARRIERS AND RECOMMENDATIONS Developments in the Near Future Neurobehavioral tests have been used in occupational and envi- ronmental health sciences in China since the early 1980s. The imme- diate needs for the futher development of neurobehavioral tests in this country are expected to be those described below. Developing and Validating Test Methods There exist a variety of test methods derived from WAIS, WMS, WISC, and others in the repertoire of traditional psychology. Prob- lems related to these diverse test methods include insufficient stan- dardization of techniques, in both test administration and scoring, careless study design, and improper data analysis. The results are that data obtained by different investigators are not adequately reproducible and comparable. Therefore, it is imperative to develop more test batteries based on critical standardization, unification, and validation requirements. Although the WHO-NCTB has partially filled this gap, consideration must be given to validating other conven- tional methods beyond those included in the NCTB. Generating New Measuring Instruments There is a need to generate more individual devices that can be used as quantitative and objective instruments for assessing subtle changes in memory, psychomotor behavior, perception, vigilance, etc. There are very real questions about the value of self-reported symp- toms and even performance scores in groups of workers who are alert to the possible effects of suspected neurotoxins and other occu- pational hazards. Therefore, it is reasonable to develop devices to
NEUROBEHAVIORAL TOXICITY TESTING IN CHINA 305 improve test objectivity and reliability in order to minimize such contamination. To achieve this approach, interdisciplinary coopera- tion should to be encouraged. For example, we collaborated with the Shanghai Development Center of Science and Technology in devel- oping a portable electronic-based device that has the capacity to test flicker fusion frequency (FFF), tone discrimination, and reaction time. A pilot study in workers exposed to lead or organotin and workers with higher mental demands during work has shown the device's remarkable advantages in terms of steadiness, accuracy, and facilitat- ing field study (Fang and Liang, 1987~. Integration of subjective measuring instruments with relatively objective assessments might provide a better neurobehavioral test battery for use by most of the Chinese researchers in the near future. Building a Computerized Evaluation System At present there is an increasing interest in the use of computer- ized test methods, primarily because of their accuracy and objectivity. One example of a computer-based neurobehavioral evaluation system designed for use in occupational and environmental epidemiology has been described by Baker and his associates (Baker et al., 1985a). We are now involved in a joint project aimed at programming the 17 test items listed in Table 7. Because the computerized approach is new, it is understandable that questions are being raised about the role it can properly play as a substitute for more conventional meth- ods (Hanninen, 1985; Iregren, this volume). Critical validation of the computerized system is urgently required, and traditional tests should not be totally discarded until the superiority of the new ones has been satisfactorily established. Keeping abreast of developments in conventional and in computerized methods should go hand in hand. Limitations and Barriers Despite increased international contact and domestic practices, neurobehavioral toxicology is still a developing discipline. This is particularly true in the following aspects: Variation of Test Sensitivity from Study to Study Although significant differences in test scores between exposed and control groups have been reported in most investigations, the sensitivity of any one test appears to vary from study to study. For example, FFF is often taken as a behavioral test to evaluate eyestrain
306 LIANG YOU-XIN and mental fatigue; the test finds differences between exposed and control groups up to 4-6 Hz in some studies reported by European investigators (Betta et al., 1983~. We have not found differences in fusion frequency of more than 2 Hz between groups we have stud- ied. When sensitivities of measuring instruments vary during their use by different investigators, can national or international norms be established for designating impairment? Bias of Learning Effect Effects of practice (learning) have been the most annoying barri- ers, frustrating the repeated use of tests. Such effects are especially apparent in follow-up studies within a short time or in comparison studies between shifts. Two ways of overcoming this difficulty are (1) to create more test batteries that use different procedures but reflect similar behavioral functions, and (2) to partial out the learning effects by comparing their realtive magnitudes in exposed and control groups when two similar, but different, groups are used. Clearly, test batteries would have to be validated. Controlling Confounding Factors It is well known that there are more possible confounders in neurobehavioral studies than in other types of studies, and they vary from one study to another. In addition to the recognized confound- ers (e.g., age, educational background, and socioeconomic status), insidious confounders (e.g., motivation, mental status, and attitude of the examinee toward the test) must be considered and are more difficult to control. One approach to minimize such bias involves pretest interviews and preeducation. This involves the collaboration of investigators with physicians from the workers' clinic, with repre- sentatives of labor unions, or with foremen in the workshop. The purposes of such education should be to develop proper attitudes, to clarify possible misunderstandings of the real objective of testing, and to emphasize the importance of the evaluation in preventing occupational risks. Even with such precautions, questions arise about possible biases introduced by exclusion from a sample of those not willing to participate. Interpreting Results Obtained from Neurobehavioral Tests Neurobehavioral tests are used mainly as adjuncts to the conven- tional tools of medical surveillance in working populations. The pur-
NEUROBEHAVIORAL TOXICITY TESTING IN CHINA 307 poses of the surveillance are the early detection of adverse functional effects, the evaluation of a work environment, and the monitoring of existing safety regulations. The following are some challenges to these purposes: Can the results obtained only from neurobehavioral tests without subjectively supporting evidence be convincing? Can adverse neurobehavioral effects be considered as a warning signal or forerunner of irreversible damage? Can regulation of occupational exposures be based on neurobehavioral findings alone? These critical issues continue to be debated and, thus, constitute barriers to the wide use of neurobehavioral tests. Comments and Recommendations Training and Education As mentioned above, neurobehavioral toxicology is still in its in- fant stage. A number of important questions remain unanswered. For example, in general, it is not clearly known how to choose the test battery that is likely to be most specific and sensitive in revealing subtle effects induced by a given chemical at various exposure levels. It is also not entirely clear as to how test procedures may be stan- dardized to ensure proper application in this field. Finally, questions continue to be raised about how much basic science of psychology is required for a researcher in neurobehavioral toxicology. There is an urgent need for international efforts toward offering short-term courses on "Neurobehavioral Toxicology and its Field Practice" for research- ers involved in this specific area. Special priority should be given to providing opportunities for researchers working in developing countries to participate in inter- national courses or meetings. At least five international meetings on behavioral toxicology have been held since 1975. Unfortunately, few participants from developing countries attended those meetings. This situation has undoubtedly blocked intercommunication between re- searchers from developed and developing countries. It is my hope that channels of communication can be created and maintained with support from both national and international organizations. Exploring the Possibility of Combining Quantitative Biochemical Markers and Neurobehavioral Testing Too little is presently known about the modes and sites of action of toxic substances and how these relate to neurobehavioral effects. Few studies on human behavioral toxicology are supported by objec-
308 LIANG YOU-XIN five biochemical indicators, in particular, the neurotransmitter indi- cators. It has been reported that hormonal responses are specific in their behavioral effects: e.g., adrenaline relates to arousal, noradrena- line to irritation, cortisol to distress (Singer, 1983~. This suggestion implies that urinary hormonal indices may be more sensitive in re- flecting mood states than questionnaires. In a more specific example, six children with increased lead absorption among whom two were hyperirritable, one was hyperactive, and the rest were clinically ~ ,, asymptomatic were studied by Silbergeld and Chisolm (1976~. Their results showed that the urinary catecholamine metabolites, homovanillic acid (HVA) and vanillylmandelic acid (VHA), were increased five- fold in the daily output. These two reports suggest that behavior markers may provide objective indicators supporting the findings of neuro- behavioral tests. If so, I would like to encourage international collaboration to elucidate possible links between these two classes of variables. Development, Validation, and Characterization of Methods Neurotoxicology is a complicated field of research, and the neurobehavioral toxicity test, as one of the research tools of neuro- toxicology, is even more complicated. The development, validation, and characterization of a variety of neurobehavioral methods for the detector of early changes of the central nervous system still remain in an exploratory phase. Therefore, methodological studies and a more systematic approach to the testing are urgently needed. As a new explorer, I would be very appreciative if international efforts could emphasize the "basic construction" of methods of neurobehavioral toxicity tests. For example, in China, solutions pertinent to the three following matters will soon be sought: (1) standardization of neurobehavioral tests to ensure full comparability between studies; (2) systematic validation of neurobehavioral tests that have been widely used; (3) publication of an operation guide in addition to the guide for the WHO/NIOSH Neurobehavioral Core Test Battery. SUMMARY In summary, this discussion of regional factors in the development of neurobehavioral toxicity tests has focused on three broad issues. Status of Research and Development of Neurobehavioral Toxicity Tests in China Emphasis is placed on the need for neurobehavioral approaches avialable to professionals facing new challenges in the fields of occu-
NEUROBEHAVIORAL TOXICITY TESTING IN CHINA 309 pational and environmental health. Results of several case studies involving exposures to CS2, lead, VDTs, and static magnetic field only summarize the findings of our preliminary studies but show the en- thusiasm of researchers interested In applying neurobehavioral testing methods to the exploration of new fields of potential risks of toxic exposures. Expected Directions in the Development of Behavioral Tests of Neurotoxicity A two-tract system involving both manual tests and computer- administered procedures is expected to be the top choice and future direction in the development of neurobehavioral toxicity tests in our region. In comparing the Finland Test Battery, the WHO/NIOSH NCTB, and the proposed computerized system, we believe that there are advantages and disadvantages intrinsic to both manual and com- puterized systems, as well as to the two manual test batteries we have used (Table 11~. Problems and Recommendations In considering the problems we face in our region, recommenda- tions are made in two broad areas, one focusing on the basic method- ological issues of standardization, validation, and characterization of testing methods, and the second on the search for more objective supporting indicators. In addition, strengthening and improving in- ternational collaboration, aimed at benefiting researchers in develop- ing countries, is urged. TABLE 11 Comparison of Neurobehavioral Tests Used Evaluation Finnish Computerized Variables Battery NCTB System Applicability 2.0 3.0 1.0 Expenditure 2.5 2.5 1.0 Time-consuming 1.5 1.5 3.0 Acceptability 2.0 2.0 1.0 Accuracy 1.5 1.5 3.0 Culture effectiveness 1.5 3.0 1.5 Integrity 3.0 2.0 1.0 Total 14.0 15.5 11.5 NOTE: The higher the score, the teeter is the evaluation of the battery in terms of the variables used.
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