Neurotoxicology and Teratology 27 (2005) 497 – 504 www.elsevier.com/locate/neutera
Reversible neurobehavioral performance with reductions in blood lead levels–A prospective study on lead workers Hung-Yi Chuanga,b, Kun-Yu Chaoc,d, Song-Yen Tsaie,f,T a
Department of Occupational and Environmental Medicine, Kaohsiung Medical University Hospital, Kaohsiung City, Taiwan, ROC b Graduate Institute of Public Health, Kaohsiung Medical University, Kaohsiung City, Taiwan, ROC c Bureau of Health Promotion, Department of Health, Executive Yuan, Taiwan, ROC d Department of Family Medicine, National Taiwan University Hospital, Taipei, Taiwan, ROC e Department of Neurology, Tzu-Ai General Hospital, Shilo, Yunlin County, Taiwan, ROC f Graduate Institute of Occupational Health and Safety, Kaohsiung Medical University, Kaohsiung, Taiwan, ROC Received 10 November 2003; received in revised form 2 January 2005; accepted 10 January 2005 Available online 12 February 2005
Abstract Lead poisoning remains an occupational hazard in Taiwan. Many studies, based on crossed-section design, have focused on changes in lead-associated neurobehavioral dysfunctions that occur at increased blood lead levels. This study evaluates the changes in neurobehavioral performance of lead workers as blood levels are reduced. We tested 27 lead workers in a lead glaze factory using the computer-based and automated Chinese edition of Neurobehavioral Evaluation System 2 (C-NES II) in 1994, 1996, and 1997. The association of blood lead levels and C-NES II results were analyzed by longitudinal data analysis methods, repeated ANOVA and mixed model analyses after adjustment for potential confounders. Over these 4 years, the mean lead blood levels of workers were reduced from 26.3(SD=12.0) to 8.3(SD=6.9) Ag/dL. Based on a mixed model analysis, we found that the negative effects of exposure to lead on neurobehavioral performance can be reversed to some extent with lowering levels of blood lead. During this period, we found significant improvements in 3 subtests: finger tapping, pattern comparison reaction time, and memory. This study tentatively concluded that reversibility of the neurobehavioral performance after reduction of the lead exposure, which encourages industrial hygiene and personal health promotion to reduce their body lead burden. However, though use of NES is more sensitive to detect the changes, the chronic symptoms (using standardized questionnaire) were found to decline slowly when blood lead level is reduced, with no statistically significant difference. The result means that to avoid the lead exposure primarily is essential to prevent chronic symptoms. We conclude that the most important way to prevent and possibly reverse chronic symptoms of lead poisoning remains to be the avoidance of exposure to lead. D 2005 Elsevier Inc. All rights reserved. Keywords: Lead; Neurobehavioral evaluation system (NES); Prospective study; Reversible
1. Introduction As early as 200 years before the birth of Christ lead was known as a toxic metal and it still presents hazards today [7]. The environment has improved and clear sources of lead poisoning with high levels of the toxic metal have been T Corresponding author. Department of Neurology, Tzu-Ai General Hospital, 321-90 Shinur, Shilo, Yunlin County, Taiwan, ROC. Tel.: +886 5 587 1111x8083; fax: +886 5 587 2000. E-mail address:
[email protected] (S.-Y. Tsai). 0892-0362/$ - see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.ntt.2005.01.001
removed or contained, but sources with moderate to lower levels may be overlooked because poisoning from chronic exposure to low levels may not be readily recognized. While lead primarily targets the central and peripheral nervous system, recent investigations have focused on subclinical damage and chronic health effects without typical symptoms and signs. Studies of workers with low-to-moderate blood lead levels have reported abnormal electrophysiological parameters and neurobehavioral performances to correlate positively with increasing blood lead levels [4,14,19,22]. Identifying these subclinical changes that take place in
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workers chronically exposed to lower levels of lead is important; distinguishing reversible changes in neurological function from an irreversible one may be an even more important issue for industrial hygiene and occupational health, especially when considering what changes we hope to achieve by controlling the industrial and occupational environment. The effect of lead on mental function of people exposed to lead has been investigated since the 1920s [7], and beginning in the 1960s, neurobehavioral tests were used [10]. These tests included vocabulary and similarity subtests of the Wechsler Adult Intelligence Scale (WAIS); the digital span, paired association learning, mental control, and visual reproduction subtest of Wechsler Memory Scale (WMS); and most of the Profile of Mood State (POMS) [2–4,9,10,12]. Today, to avoid interview bias, most large-scale standardized studies use computerbased tests. One of the most widely used and promising automated tests is the Neurobehavioral Evaluation System (NES) [5,16,17]. While several studies have researched the effects of increased levels of blood lead on neurobehavior, few longitudinal or follow-up studies have focused on the effects of decrements in blood lead in lead workers. Our study follows changes in neurobehavioral performance in lead-exposed workers whose working conditions, primarily exposure to lead, were improved over a 4-year period. We recorded the mean lead blood levels and the test scores of three subtests using the Chinese edition of Neurobehavioral Evaluation System 2 (C-NES II) in 1994, 1996, and 1997. Associations were tested by longitudinal data analysis methods, repeated ANOVA and mixed model analyses after adjusting for potential confounding factors.
2. Methods 2.1. Subjects Out of 69 lead-exposed glaze factory workers, 27 male volunteers enrolled in the study that started in 1994. Each participant signed a letter of informed consent. None were found to have a history of alcoholism, drug abuse, and major neurological disorders, such as severe head injury or epilepsy. In 1996, 23 workers underwent the second followup tests. Four did not participate because they were too busy to take an hour off for the tests. In 1997, 27 workers participated in the third series of tests. Consequently, 23 workers participated in 3 repeat Chinese version-NES (CNES II) tests (1994, 1996, 1997) and 4 participated in 2 (1994 and 1997). In our preliminary study for the validation of C-NES II, we recruited 506 normal adults [26]. From these adults we randomly selected 19 non-exposed age- (F3 years) and education-matched males for healthy controls or referents in the study. The comparisons we made of the non-exposed
referents and lead workers (data tested in the first year, 1994) have been published elsewhere [28]. We list that initial data from a previous report in the present study as that data is related to this more recent 4-year study. The prospective analyses do not include data from the 19 healthy controls because they were not followed up. 2.2. Questionnaire The participants were administered a health questionnaire which included questions on the habits of smoking and consumption of alcoholic beverages and beverages containing caffeine. It also included questions on medical history, present medications and drug use. They were also given an occupational questionnaire that covered demographic information and occupational history. Before the C-NES II tests were administered, all the workers were given a subjective symptoms questionnaire, translated and modified from Hogstedt [13,27] for initial screening and later follow-up. They were questioned on acute central nervous system symptoms experienced during the present workday, chronic central nervous symptoms experienced during the previous month, and peripheral nervous system symptoms. This Chinese edition of questionnaire had been used in a previous study [8,29]. Frequency of the symptoms was rated on a four-point scale: none, less than once per week, once per week, and at least once per week. 2.3. Blood lead test Blood samples were obtained by venopuncture with leadfree disposable syringes and stored in lead-free test tubes with ethylenediamine tetraacetic acid (EDTA) as the anticoagulant. All blood lead concentrations were analyzed with a graphite furnace atomic absorption spectrophotometer (Perkin-Elmer Zeeman 5100PC) at the National Taiwan University. External quality control was carried out using the blood lead proficiency test of the United States Center for Disease Control and Prevention (USCDC) since 1985. 2.4. Neurobehavioral tests We modified the NES, version 2, into a Chinese-based batter of tests (C-NES II). The test battery was programmed by C language and its construct was almost the same as the English version except that it was displayed in Chinese. Individual changes are described under each test (see below). NES is designed to be used and administered easily by persons with no formal training in behavioral testing and little experience with the use of computer. In addition, the interviewer can handle several subjects at a time and avoid direct contact with his or her subjects. Analysis of our test results for 506 normal adults [26] and a preliminary study [15,25,27] found the C-NES II to be a valid and acceptable tool.
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2.4.1. Pretest questionnaire In the NES program, six questions are asked to find out about the testee’s visual acuity, adequacy of sleep the night before the test, physical condition, intake of caffeinated beverages and alcohol, and consumption of tobacco 24 h before the computer-based neurobehavioral performance test. 2.4.2. Finger tapping The maximum numbers of taps by the right and left index finger within 30 s were recorded. 2.4.3. Continuous performance test Five geometric forms were randomly displayed on the screen. The workers were instructed to tap the keyboard as quickly as possible when the triangle-shaped form appeared on the screen. Twelve positive stimuli occurred randomly out of 60 stimuli. The mean response time from the presentation of the stimulation and the correct response was calculated. 2.4.4. Associate learning The name and occupational pairs were not translated from the NES II but were changed into common Chinese names and occupations. Seven names and occupational pairs were displayed on the screen, one pair at a time. The workers had to memorize them and report the correct match for each pair. Then, seven questions were asked in the first cycle, and this was repeated twice. The correct answers during the three cycles were recorded. 2.4.5. Symbol–digit test Nine symbols and nine digits were paired at the top of the screen, and the subject was required to press the digits on the keyboard corresponding to a test set of the nine symbols presented in scrambled order. Three sets of nine symbol– digit pairs were presented in succession (the first was a practice set). Errors were not allowed on the practice trial, and errors on other trials above 5 times resulted in a message stressing that there should be no errors and the test would be repeated until the total errors were less than 5 throughout the trials. The symbol digit pairs varied between sets to avoid incidental learning effect. The mean response latencies for each of the 9 items in each trial were recorded. 2.4.6. Pattern comparison In this test, 3 similar geometric figures appeared on the screen simultaneously. Two of them were the same. The workers had to choose the odd figure as quickly as possible. Totally, 15 items were tested. The mean response latencies and the number of correct responses were recorded. 2.4.7. Pattern memory In this test, a geometric figure appeared for 4 s on the screen and the workers were requested to memorize its shape. Then, 3 similar geometric figures, one the same as
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the previous one, appeared on the screen simultaneously. The workers were to choose the correct one as quickly as possible. Totally, 15 items were tested. The mean response latencies and the number of correct responses were recorded. 2.4.8. Visual digit span Workers were requested to memorize digits presented sequentially, one at a time. The test consisted of two parts: in one, the subject is asked to type the digits forward; in the other, he was asked to type them backward. The numbers of digits presented increased until the workers failed to correctly type digit sets of a particular length two times in a race. The longest spans that the subject correctly typed forward and backward were recorded. 2.4.9. Switching attention The switching attention test consisted of a series of three different testing conditions. In the first testing condition (bSideQ), the subject had to respond to each of a series of large rectangles presented in succession on the screen. In each trial, the rectangle appeared on either the left or right side of the screen, and the subject had to press the button on the corresponding side of the keyboard. In the second testing condition (bDirectionQ), the subject had to respond to large arrows presented in the middle of the screen that point either to the left or to the right by pressing the left or right button on the keyboard. In the third condition (bSwitchingQ), the word bSideQ or bDirectionQ appeared immediately before each stimulus. The stimuli were arrows pointing to either the left or the right, presented on either the left or right side of the screen. The subject had to respond to each stimulus based on the response criterion signified by the word presented immediately before it on each trial. As a non-threatening form of feedback, the stimulus remained on the screen until a correct response was made. The mean latencies of correct responses for each condition were recorded. 2.4.10. Associate delayed recognition A single recall trial of the names and occupations used in the Associate Learning test was administered approximately 30 min after the initial test. The number of correct responses was recorded. 2.4.11. Mood scales The mood scales were partially changed to fit our cultural background. Initially, we translated the test items from their English version. Two hundred normal persons were tested using these items. Principal components analyzed by orthomax rotation showed that the 25 items could be explained by 4 factors: factor 1 included relaxed, calm, happy, lively, energetic, full of pep, able to think clearly, clear-headed, and able to concentrate; factor 2 included tense, nervous, on edge, sad, miserable, gloomy, and exhausted; factor 3 included angry, grouchy, furious,
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unhappy and mixed-up; and factor 4 included annoyed, badtempered, tired, and confused (unpublished data). These findings mean mood constructs in Chinese are different from those of Westerners. The 25 test items were reduced to a ten-itemed mood profile with three dimensions: tension– depression (tense, nervous, sad, miserable, and gloomy), anger (angry, grouchy, furious), and fatigue–confusion (tired, confused). The mean scores of the test items in each dimension were recorded. 2.4.12. Post-test questionnaire Two questions ascertained the frequency of computer usage and the perceived difficulty of completing the above tests. 2.5. Vocabulary test Forty vocabulary test items drawn from the standard vocabulary test published by Chinese Behavioral Science Co. in Taiwan [18] were presented to the subject who was asked to select the synonym for a test word from a set of four words. However, the workers with education years less than 6 years were excluded in this study. The number of correct answers was recorded. 2.6. Statistical analysis We compared blood lead levels and characteristics of non-exposed referents and measurements of lead workers in the first year with Student t-test. In addition, the comparison of repeated measurements in different years among lead workers was with repeated ANOVA. Furthermore, we used generalized linear mixed models (SAS 8.1 software, PROC MIXED) to analyze the longitudinal relation of repeated blood lead concentrations to each neurobehavioral test items after adjustment for age and vocabulary scores in each test [20,23]. The 19 referents did not have repeated data, thus, they were not to be included in the prospective analyses (repeated ANOVA and mixed models).
3. Results Demographic data is shown in Table 1. All subjects were male. The blood lead levels of workers were significantly decreased over the 4 years due to improved industrial and personal hygiene. There was no difference in vocabulary scores between referents and lead workers in the first year. At the initial testing, the average number of years that the participants were exposed to lead was 7.4 years (SD=5.8), ranging from 1 to 34 years. Because the 4 workers who did not participate in the second C-NES II had higher educations; mean education (in years) was lower in year 3. However, because the difference was not statistically significant, it probably did not bias our results.
Table 1 The demographic data of lead workers during a follow-up period of 4 years
BPb (Ag/dL)Ta Exposure years Age (years) Education (years) Vocabulary score
Referents
Lead workers
Year 1 (N=19)
Year 1 (N=27)
Year 3 (N=23)
Year 4 (N=27)
6.90F4.2 – 39.6F8.5 9.5F3.2 18.6F4.0
26.3F12.0 7.4F5.8 39.7F9.6 9.3F2.9 17.8F4.8
10.8F6.4 9.4F7.4 43.0F9.4 8.1F2.6 15.8F4.1
8.3F6.9 10.7F5.9 44.3F8.2 9.3F2.9 16.5F4.9
a pb0.01, Repeated ANOVA for comparison of lead workers within 4 years. T pb0.01, Student t-test for comparison of referents and lead workers in year 1.
Table 2 shows the results of the questionnaire on subjective chronic symptoms over the follow-up years. When compared to the referents, the lead workers tended to tire more easily (item 1) and had more finger tremors (item 16), possibly because lead-related jobs might involve heavier work. In addition, lead workers were found to make notes to remind themselves to do things more frequently than (item 6) the referents. The difference in total symptom questionnaire scores between the reference group members (44.41F3.17) and the lead workers in the first year (52.58F5.88) was statistically significant. During the follow-up time, there was no difference in the chronic syndromes reported by the lead workers except in item 18, sexual desire. By the time the participants took the third series of tests, blood level as well as severity of symptoms had declined. Though the total scores had reduced by year 4, repeated ANOVA did not find the differences significant. No major changes were found in chronic syndromes by repeated ANOVA to control the within and between variances of these subject along 4 years (3 tests). C-NES II neurobehavioral test results are compared in Table 3. Initially, there were no differences on the pre-test questionnaires between the referents and lead workers (data not shown). Both groups participated in the C-NES II tests under similar conditions. Still these two groups were found by Student t-test to have significant differences in finger tapping tests in year 1, with lead workers having worse scores than the referents. Using repeated ANOVA to compare the 3 repeat measurements of C-NES II of the lead workers along the 4 years, we found significant improvement in the sum of finger tapping, the latent time of pattern comparison and memory tests over the study period, meaning the finger tap counts increased and latencies decreased over time with the reduction in blood lead levels. Tables 1 and 3 show that neurobehavioral performance in workers might be reversed if blood lead levels are decreased. Consequently, we used mixed model to adjust for the effect of age and education on test scores. Since the educational level of each worker would not change from one measurement to the next, we believe their vocabulary comprehension would be a better indicator of slight changes
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Table 2 The results of chronic symptoms during a follow-up period of 4 years
Have you tired more easily than expected for the amount of activity you do?T Have you felt lightheaded or dizzy? Have you had difficulty concentrating? Have you been confused or disoriented? Have you had trouble remembering things? Have you had to make notes to remember things?T Have you had diarrhea? Have you had hallucination? Have you had cold sweating? Have you had poor digestion? Have you had sialorrhea? Have you had weakness of upper or lower limbs? Have you had oppression sensation of chest? Have you felt nausea? Have you felt anxious? Have you had tremor of fingers?T Have you had tremor of eyelids, lips or tongue? Have you had loss of sexual desire?a Have you felt irritated? Have you felt depressed? Have you had heart palpitation even when not exerting yourself? Have you had dry skin? Have you been sleeping more often than is usual for you? Have you had difficulty falling asleep? Have you been bothered by incoordination or loss of balance? Have you had difficulty tightening the button? Have you had numbness or tingling in your fingers or toes more than one day? Have you had headache? Have you had inflamed gums? Have you had unstable teeth? Total scoresT
Referents
Lead workers
Year 1 (N=19)
Year 1 (N=27)
Year 3 (N=23)
Year 4 (N=27)
1.94F0.83 1.59F0.94 1.81F0.84 1.29F0.47 1.88F1.15 1.47F0.72 1.40F0.52 1.43F0.51 1.40F0.51 1.52F0.70 1.35F0.70 1.40F0.52 1.47F0.80 1.35F0.49 1.47F0.51 1.18F0.39 1.24F0.75 1.50F0.64 1.53F0.62 1.71F1.10 1.47F0.62 1.76F1.14 1.70F0.67 1.56F0.63 1.12F0.33 1.29F0.98 1.40F0.70 1.59F0.62 1.29F0.47 1.30F0.67 44.41F3.17
2.40F1.11 1.70F1.07 2.30F1.32 1.81F1.14 2.04F1.16 2.20F1.40 1.81F1.30 1.63F1.24 1.50F0.90 1.70F1.10 1.41F0.90 1.63F0.90 1.85F1.10 1.44F1.00 1.81F1.00 1.90F1.31 1.70F1.20 1.52F0.80 1.60F1.00 1.74F1.30 1.70F1.21 1.70F1.20 1.81F1.00 2.05F1.13 1.52F1.01 1.15F0.60 1.74F1.00 2.10F1.33 1.60F1.20 1.52F1.01 52.58F5.88
2.50F1.41 1.72F1.10 1.86F0.94 1.82F1.30 2.10F1.20 2.20F1.50 1.90F1.21 1.64F1.22 1.54F1.06 1.70F1.10 1.40F1.00 2.05F1.13 2.14F1.58 1.60F1.10 2.36F1.60 1.55F1.20 1.18F0.40 2.45F1.63 2.30F1.40 1.81F1.10 1.82F1.10 2.00F1.40 1.82F1.30 2.50F1.44 1.40F1.00 1.20F0.90 1.90F1.21 1.90F1.04 1.50F1.00 1.70F1.07 55.56F5.92
2.10F1.33 1.81F1.21 1.80F1.01 1.60F1.00 1.70F0.73 2.08F1.30 1.60F1.00 1.74F1.13 1.23F0.70 1.74F1.00 1.44F0.80 1.52F1.10 1.60F0.80 1.70F1.04 1.70F1.00 1.60F1.00 1.44F0.80 1.63F1.04 1.81F1.20 1.52F0.70 1.70F1.10 1.60F0.90 1.52F0.64 2.11F1.30 1.60F1.00 1.22F0.64 1.70F1.10 1.90F1.20 1.60F1.01 1.41F0.70 49.72F5.53
a
pb0.05, Repeated ANOVA for comparison of lead workers within 4 years. T pb0.05, Student t-test for comparison of referents and lead workers in year 1.
in educational level and learning effects in each measurement. Therefore, we used vocabulary scores to adjust for the effect of the education level. The mixed model analyses are presented in Table 4, where only the subtests with significant model fitting are listed. Among neurobehavioral tests by C-NES II, finger tapping tests (both preferred and non-preferred hands) were significant inversely associated to blood lead levels after adjusting age and vocabulary scores, though the combined finger tapping counts of both hands showed a weak effect ( p=0.07) in the mixed model. Latencies of pattern comparison and memory tests were also improved over time as blood lead levels declined, though based on mixed model analysis, latency in pattern memory test was weakly related to blood lead levels ( p=0.06). The other subtests of C-NES II were not found by mixed model analysis to be significant.
4. Discussion In this prospective follow-up study of repeated test measurements, we had the rare opportunity to follow-up
blood lead levels and neurobehavioral changes in workers in a glaze plant involved in an industrial hygiene and personal health improvement over 4 years. Using a sensitive computer-based neurobehavioral test battery, we were able to test changes in neurobehavioral performance as blood levels declined. We found that some of the negative effects of lead poisoning on neurobehavioral performance in adults exposed to low to moderate levels of lead could be reversed. We found significant improvements in motor neuron functioning (finger tapping test), cognitive functioning (pattern comparison test), and memory functioning (pattern memory test) as a result of reducing blood lead levels from 26.3 (SD=12.0) to 10.8 (SD=6.4) to 8.3 (SD=6.9) Ag/dL. We found that negative effects of lead on neurobehavioral performance could be reversed when blood lead levels were reduced to around 30 Ag/dL. Using POMS to study changes in the negative effects caused by exposure to high levels of environmental lead (blood lead levels: 50–80 Ag/dL initially), Baker et al. not only found improvement of behavioral effects, they also found slight improvements on the similarities and digit– symbol recall tests [6]. Using picture completion tests on
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Table 3 The results of neurobehavioral tests during a follow-up period of 4 years
Finger tapping (count) Preferred hand Non-preferred hand Suma Continuous performance test (ms) Associate learning (count) 1st time 2nd time 3rd time Sum Pattern comparison test Corrected (count) Latencies (s)a Pattern memory test Corrected (count) Latencies (s)a Visual digit span test (count) Forward Backward Sum Associate delayed recognition test (count) Mood scales (count) Tension–depression Anger Fatigue–confusion
Referents
Lead workers
Year 1 (N=19)
Year 1 (N=27)
Year 3 (N=23)
Year 4 (N=27)
87.3F10.60T 84.3F10.50T
78.84F13.54 75.11F11.16 141.37F40.18 514.62F114.14
80.34F18.78 81.60F16.75 155.60F40.89 507.47F110.30
84.61F17.73 82.19F11.64 166.37F26.88 479.18F118.75
2.32F1.42 2.79F2.30 3.00F2.31
2.63F2.10 3.11F2.00 3.15F2.13 8.90F5.20
1.83F1.53 2.52F1.83 2.90F1.50 7.22F3.90
2.60F1.85 2.81F2.15 3.30F2.42 8.70F5.50
12.7F3.28 7.54F2.63
13.93F2.42 8.52F2.92
13.00F3.50 6.90F3.00
13.40F2.22 6.09F3.50
8.68F3.11 6.62F2.78
8.81F2.80 6.39F2.20
8.22F2.72 4.45F1.90
8.90F2.50 4.30F2.12
7.50F1.86 6.67F2.87 2.35F2.57
8.00F1.70 6.40F2.50 14.37F3.73 2.60F2.32
7.41F2.17 5.30F1.80 12.68F3.24 2.70F1.82
7.52F2.31 5.26F2.35 12.77F4.21 3.00F2.10
1.92F0.58 1.73F0.47 1.97F0.74
1.82F0.95 2.07F1.40 2.00F1.01
2.03F0.96 2.17F1.27 2.20F1.10
1.85F0.93 1.92F1.20 2.15F1.22
451.9F60.60
a
pb0.05, Repeated ANOVA for comparison of lead workers within 4 years. T pb0.05, Student t-test for comparison of referents and lead workers in year 1.
lead workers, Yokoyama et al. found that the negative effects of lead poisoning on psychological performance began to reverse when blood levels were reduced levels between 30 to 64 ug/dL [30]. Our study finds that the damage caused to subclinical neurobehavioral performance
by exposure to low to moderate levels of lead (26.3F12.0) can be reversed if the employer and employee make efforts to improve industrial hygiene and personal health. One problem that can arise from the repeated use of computer-based neurobehavioral tests is that the subjects’
Table 4 Mixed model analysis of outcome variables demonstrating a significant association with lead exposure Dependent variable
Independent variables
Coefficient
SE
p value
Model fitting
Finger tapping (preferred hand)
Intercept Age (year) BPb (Ag/dL) Vocabulary score Intercept Age (year) BPb (Ag/dL) Vocabulary score Intercept Age (year) BPb (Ag/dL) Vocabulary score Intercept Age (year) BPb (Ag/dL) Vocabulary score Intercept Age (year) BPb (Ag/dL) Vocabulary score
90.580 0.067 0.341 0.983 97.278 0.293 0.281 2.256 187.592 0.517 0.0677 5.231 3.843 0.030 0.102 -0.119 1.427 0.059 0.045 1.095
9.757 0.206 0.123 3.482 8.801 0.187 0.120 3.412 24.217 0.509 0.363 10.580 1.968 0.042 0.025 0.757 1.450 0.030 0.023 0.663
b.001 0.744 0.008 0.779 b.001 0.127 0.025 0.512 b.001 0.315 0.070 0.623 0.060 0.472 b.001 0.875 0.332 0.055 0.060 0.106
AIC= 287.253 BIC= 289.472 p-valueb0.001
Finger tapping (non-preferred hand)
Finger tapping (sum)
Pattern comparison
Pattern memory
Vocabulary score: (over 20 versus under 20 points). BPb: blood lead level (Ag/dL).
AIC= 279.456 BIC= 281.675 p-valueb0.001 AIC= 363.083 BIC= 365.332 p-value=0.005 AIC= 177.582 BIC= 179.802 p-valueb0.001 AIC= 168.601 BIC= 170.850 p-value=0.552
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previous experience with the test may affect the reliability of the results on subsequent tests, meaning that the subjects may have a better C-NES II performance the second time they were tested than the first time. Obviously, if the time interval between the testing times is short, e.g. 1 week, the performance memory is still fresh and the subject may score better as a result of his or her experience and memory on how the C-NES II operates. However, the inter-test intervals in our study were 1 year or longer. The interval between the first test and the second test in particular was 2 years. We did not see these improvements between the first and second test. Furthermore, if memory or learning had an effect in this study, results of all subtests would be consistently better in the second test and the best in the third test, not inconsistent, as they were in this study. Of course, the best way to solve this problem would have been to follow up and compare test results of a reference group. Unfortunately, the study did not follow up the referents, which is one limitation of this study. The 19 members of the reference group were not followed up because they were part of 506 people used initially to validate the C-NES II [26]. After the validation study, we did not retain personal information of the 506 people. The mixed model analyses (Table 4), therefore, did not include the 19 referents. Although we only prospectively studied the lead workers, our mixed model analyses found that the intra-individual changes among lead workers to be a relatively strong evidence that reducing blood lead levels can improve neurobehavioral responses. Blood lead level of 40 Ag/dL is widely accepted as an action level in occupationally exposed adults [7]. However, many investigations have found abnormal subclinical responses, particularly in the neurobehavioral tests, at that level. Three recent meta-analyses have reported poor performance in logical memory, Santa Ana, and block design in lead-exposed adults [11,21,24]. Dose-dependent impairment of neurobehavioral function is still arguable. One of these meta-analyses provided evidence for subtle deficits being associated with average blood lead levels between 37 and 52 Ag/dL [24]. The current BEI value of American Conference of Governmental Industrial Hygienists (ACGIH) is 30 Ag/dL [1], which is similar to our workers’ initial blood lead levels (mean=26.3, SD=12.0, range: 9–40 Ag/dL). A safe exposure level of neurobehavioral function still needs further investigation. In conclusion, our study found a tentatively potential reversibility of subtle neurobehavioral performance in lead workers as their blood lead levels declined over 4 years. Our findings should encourage employers and employees to increase their efforts to improve industrial hygiene and personal health to further reduce their body lead burden. Furthermore, uses of questionnaire-based measures found that the chronic symptoms (total scores) declined slowly (in the 4th year) after blood levels had been reduced for at least 2 years, though those changes were not statistically significant. The result means that use of questionnaires to
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detect the chronic symptoms among the moderate to low lead-exposed workers are vague. However, the subclinical signs and reversibility could be detected by the C-NES II.
Acknowledgements This work was supported by the Department of Health (DOH-87-HR-504), and National Science Council (NSC892320-B-037-045, NSC89-2314-B-037-127) in Taiwan. The authors wish to thank research assistants, Shih-Yuan Chang and Lan-Yin Mu. We also appreciate the cooperation of the participants and their employer. Part of this study was presented in the ICOH (International Congress of Occupational Health) 2000 in Singapore.
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