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OCR for page 287
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
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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)
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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
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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
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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
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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
OCR for page 293
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 levels—group 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
OCR for page 294
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OCR for page 295
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:
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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
OCR for page 297
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
OCR for page 301
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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
OCR for page 303
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OCR for page 304
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
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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
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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-
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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-
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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-
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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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LIANG YOU-XIN
In conclusion, this chapter is an attempt to convey the voice of
researchers in this region and express their willingness to accept the
roles that behavioral toxicologists can play in protecting life quality
from the deteriorating effects of behavioral hazards.
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Representative terms from entire chapter:
test battery
