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Regional Issues in the
Development of the Neurobehavioral
Core Test Battery
Renato Gilioli and Maria G. Cassitto
For many decades, occupational diseases have been the focus of
research in occupational health, with the underlying understanding
that improvement in production technologies would eventually result
in the total control of diseases as a natural consequence. Although
this concept still retains a strong validity, over the past years there
has been mounting evidence to show that along with a decrease in
traditional occupational diseases, an increase has occurred in
environmental as well as work-related diseases with new characteristics.
These clinical entities are certainly less severe but still sufficiently
incapacitating so as to need early detection arid prompt intervention.
Although these considerations mainly refer to industrialized countries,
developing countries are now facing problems very similar, or perhaps
even worse, than those encountered in the earlier stages of industri-
alization by now industrially advanced countries. These considerations
are common to all occupational health domains and even more so to
neurobehavioral toxicology. Thus, environmental and work-related
disease the problem of neurotoxic disorders presents a number of
distinctive features.
First, although it is certain that the central nervous system (CNS)
and the peripheral nervous system are the target of many industrial
and environmental chemicals, no clear-cut evidence exists of a direct
quantitative dose-effect or dose-response relationship between the
level of exposure or degree of absorption and a predictable neuro-
behavioral outcome. Second, most of the combined effects (i.e., additive,
3~2
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NEUROBEHAVIORAL CORE TEST BATTERY
313
synergistic, and antagonistic) of neurotoxic agents are still unknown
or, at best, uncertain. Many other interfering or confounding factors
are known, but their role is yet to be fully understood. The World
Health Organization (WHO) Monograph on Neurotoxic Illness Johnson
et al., 1987) explores these factors in detail and shows how much
work still has to be carried out in this direction. Third, another
central feature is individual response not only to the neurotoxic agents
but also to the behavioral instruments used. This response can be
modified by age, level of education, and cultural background. This
third issue is far from being clarified. Those factors that are relevant
within the same cultural group require much greater attention when
dealing with groups belonging to different cultures. Over the last
five years, considerable attention has been paid to this aspect and
relevant material has already been obtained. In fact, after many years
of research designs characterized by heterogeneous collection of similar
or identical but variously assembled tests, yielding heterogeneous
results, the need for unifying these methodologies has been widely
recognized. This willingness to give up at least part of one's own
research instruments for the benefit of greater uniformity and the
means of realizing it have been the object of much international ef-
fort.
INTERNATIONAL INITIATIVES
The ad hoc international initiatives discussed in this chapter were
prepared by the first International Symposium on Neurobehavioral
Methods in Occupational Health held in Como and Milan, Italy in
1982. This type of approach has proved fruitful and resulted in a
triennial series of symposia, the second held in Copenhagen (1985)
and the third in Washington, D.C. (1988~. A fourth symposium will
be held in Tokyo in 1991. These symposia are aimed at acquiring the
latest developments in neurobehavioral methods as well as disseminating
basic pertinent knowledge to developing countries in different re-
gions of the world.
In Europe, the first official meeting held by an international agency
was organized in 1983 by the Health and Safety Directorate of the
European Economic Community when experts from the then 10 member
states were convened to deal with this specific topic.
In the same period, substantial results were obtained by the WHO
Office of Occupational Health in Geneva. Along with the U.S. National
Institute for Occupational Safety and Health (NIOSH), WHO convened
an international workshop in Cincinnati in 1983 to evaluate existing
information on the neurotoxicity of workplace chemicals with a double
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RENATO GILIOLI AND MARIA G. CASSITTO
purpose: (1) to transfer, after sound critique, the already existing
knowledge to health personnel in industrialized and developing countries,
and (2) to analyze existing methodologies and foster the adoption of
common instruments. In fact, an agreement was reached on a minimum
core battery, the WHO Neurobehavioral Core Test Battery (NCTB), to
be used and validated in all countries.
To help this dissemination, WHO developed an operational guide
that describes this instrument in detail, its characteristics and admin-
istration procedures. Although the monograph (Johnson et al., 1987)
has recently been published, the guide is, at the moment, distributed
by WHO to interested groups. According to WHO-intentions, the
battery is given as a package to be used as a whole; it is short, easy to
handle, and meant to measure those functions that are more easily
impaired by exposure to neurotoxic agents namely, mood, attention,
visuomotor skills, and memory. A factor analysis performed on the
data from 950 subjects resulted in the extraction of five factors: namely,
emotional status, motor response speed, visuomotor coordination,
sustained attention, and active information processing. The commonalities
are very high and reflect important intercorrelations. The reliability
and sensitivity of this battery are not optima-l, as recognized by the
panel of experts who fostered its adoption. However, the tests chosen
have the advantage of being simple and well known and, above all,
have a minimal loading in cultural factors, which are the most important
confounders in interpreting results. The WHO panel of experts also
recommended integration of this battery with additional and more
specific tests whenever possible.
Thus, two results may be obtained: other more specific measures
can (1) increase the sensitivity of the instrument and (2) allow for the
use of tests reflecting more specifically the intellectual abilities and
emotional traits that might have been determined by the cultural
history of the subjects. This approach would still permit the performance
of highly needed multicentered studies.
VALIDATION STUDIES
To implement this program on prevention of neurotoxic disorders,
WHO in 1986 presented a program of international validation of the
WHO-NCTB aimed at regional validation and use of the instruments
and development of an international reference data bank of normal
values, if feasible, with special reference to developing countries. This
validation program is under the operational responsibility of three
oversight centers. In the United States, Kent Anger of NIOSH coordinates
domestic validation as well as that of South America and China. In
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Europe, Helena Hanninen of the Helsinki Institute of Occupational
Health and Maria Cassitto of the Milan Institute of Occupational Health
are responsible for the other countries willing to participate in the
validation program. General coordination of the entire program has
recently been assigned by WHO to the Milan center. Within this
general frame, some considerations arising out of our experience with
this program can help define its potentialities and limits in terms of
regional issues and uniformity of interventions. The first recommendation
to interested groups is to spend a practice period in one of the three
oversight centers. The underlying rationale is that the same, even
simple, tests can substantially change when different instructions are
given. Moreover, according to the testers' background, different aspects
of the tests or of the subjects' behavior will be noticed, thus creating
a totally different testing situation. Because the tests in this battery
have long been used by most groups involved in neurotoxicity stud-
ies, questions may arise as to whether there is a real need to participate
In a practice exercise.
An example should clarify this issue: One of the tests in the battery
gives measures of manual ability in terms of both speed and accuracy.
Instructions stressing either or both of these aspects will result in
different performances. A satisfactory number of correct answers
can be expected from instructions stressing accuracy, whereas a high
number of answers with many errors are obtained with instructions
stressing speed. An intermediate level of correct answers and errors
will result from the third type of instructions.
In developing countries, qualified personnel skilled in psychologi-
cal testing are generally lacking. As a result, either nurses or physi-
cians themselves will have to administer the battery. In both cases,
training is essential. Difficulties in this case are mainly financial:
travel and living expenses cannot always be covered either by the
oversight center or by the trainee. Despite these difficulties, a number
of short training courses have already been organized by the three
oversight centers to provide both theoretical and practical backgrounds
aimed at diagnosing impairments of the higher-order nervous functions
found in numerous neurotoxic disorders. Theoretical training is essential
to provide the operators with the framework within which the use of
the battery acquires meaning and usefulness.
If one is already skilled in psychological measures, the difficult
step is to move from the traditional use of testing the abilities in view
of either job fitness or cerebral dysfunction in severe neurologic dis-
eases to a more subtle analysis of the slightest functional impairments.
In fact, as is well known, minor neurobehavioral changes may be
often seen in exposed populations which can proceed to further serious
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deterioration. Similarly, unexperienced personnel must also become
so sensitive to this issue as to take into proper account even the
slightest dysfunction that can be revealed only by accurate testing.
However, it must be stressed that one has to avoid the risk of reading
the psychometric outcome as though it were equivalent to a common
analytical determination, such as blood sugar. In our courses, it has
been realized that these objectives can be attained when training not
only is theoretical but also is integrated by- testing actual cases and
protocols in which participants are asked to record the subjects' ver-
bal and operational behavior in all its aspects. Optimal training would
imply a real-life situation, but simulated cases can often be equally
effective. To help demonstrations, a videotape was produced in our
laboratory showing the entire neurobehavioral examination of a patient
at our clinic hospitalized for possible carbon disulfide intoxication.
In this way, the subject's behavior can be discussed step by step, thus
facilitating the above-mentioned change in the tester's attitude.
So far, local characteristics have been somewhat overlooked for
the advantage of uniformity and international standardization. We
believe that, once the attitude toward the instruments tends to be the
same and the interpretation of the results has common reference
guidelines, greater attention to cultural dimensions will be profitable
and will result in substantial improvements in the already existing
tests or in the development of more advanced ones. According to our
experience, we are not likely to face important cultural barriers to the
implementation of this program in our regions. Rather, the first data
coming from the validation show that, in six European countries,
there are significant differences in the attitude of the subjects toward
psychological testing in general. These differences in attitude result
in differences in the effort taken and, consequently, in the scores.
This is an important issue that must receive due consideration in all
international efforts to unify methodologies.
The only difficulty for all groups involved in the validation effort
has been with POMS (a mood measure), which is a test consisting of
a lone list of adjectives that do not always have a precise counterpart
~ ~~ . · . . ~ ~ ~ · . ~ ~ T · . _ ~ ~ ~ I · ~
in all languages. lhIS IS a test Developed In tne urea crates, ana
is interesting to realize that in other English-speaking countries, the
same adjective may have different shades of meaning. In Italian, we
had to adapt some words by interpreting them in the light of the
original meaning. In Polish, some words had to be eliminated be-
cause the precise equivalent was lacking. Further, it is worth stress-
ing the fact that other adaptation problems are easily predictable in
countries where the very perceptive structures are differently devel-
oped. As-mentioned earlier, this battery has a minor loading on
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317
strictly cultural factors as transmitted by current educational pro-
grams. The battery is basically an instrument that stimulates psychomotor
and auditory memory functions. However, at present it is not known
whether these functions can be measured with these same instruments
in countries where even the written language patterns are so percep-
tibly different. Local validation of the battery will thus become an
invaluable tool to clarify these points.
As stated earlier, the WHO-NCTB was developed with the primary
aim of screening early signs of impairment of higher nervous function.
Accordingly, when the WHO-EURO Office of Environmental Health
Service planned- multicentered studies of CNS impairments due to
chemical exposure, the WHO-NCTB became part of the epidemiological
protocol. The first investigation was devoted to the evaluation of
CNS effects in a certain number of developing countries, Poland,
Czechoslovakia, Hungary, Bulgaria, Yugoslavia, Greece, and Turkey;
Israel and Italy were also studied. In spite of unavoidable difficulties
in adaptation and implementation, the performance of the study groups
showed a good level of achievement in harmonization of the methods.
The results will be released by WHO in 1990.
Another study under advanced planning involves the use of WHO-
NCTB for the evaluation of exposure to methylmercury from seafood
consumption in countries adjacent to the Mediterranean. In this case,
the battery will probably be applied only to a specific group of sub-
jects (i.e., fishermen) after careful analysis of methylmercury accu-
mulation in their hair has shown significant levels.
As a general comment, these studies have proved to be important
steps forward in the solution of one of the major problems of
neurobehavioral studies, i.e., the standardization and more rational
use of international and national resources.
An extra effort, however, needs to be made to overcome the natu-
ral individual resistance to giving up one's research tools for the
benefit of international collaboration. This resistance often stems from
a justified consideration of one's own experience which may be just
as valid as others'. However, the inherent value of a group decision
lies in its being demonstrated by many and devoted to a common
aim.
AUTOMATED TESTING
Over the last decade, several studies have also been carried out by
our group, mainly on large populations, with different aims, includ-
ing validation of methodologies; search for subtle effects on higher
nervous functions possibly arising out of long-term, low-dose exposure
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RENATO GILIOLI AND MARIA G. CASSITTO
to industrial chemicals whose neurotoxicity is still undetermined; and
medical surveillance of populations currently at work and exposed to
known neurotoxic chemicals. All the studies mentioned share the
need for sensitive and specific instruments to be administered to as
numerous a group as possible. To this end, the increasing diffusion
of relatively inexpensive, portable microcomputers has offered an ex-
tremely useful means to acquire homogeneous data especially when
multicentered studies are needed. A number of independent groups
have faced the problem and developed ad hoc automated programs.
At the 1988 symposium in Washington, D.C., about 15 automated
systems were presented, the most widespread of which is the
Neurobehavioral Evaluation System (NES) developed at Harvard by
Baker and Letz.
A few years ago, a computerized version of six out of the seven
tests of the WHO-NCTB was set up in our institute and termed MANS
(Milan Automated Neurobehavioral System).
For practical reasons, such as the impossibility of developing new
tests in reasonable time, and the need for training testers in regular
paper and pencil form, we have chosen to adopt all but one of the
tests suggested by WHO-NIOSH because of their long and worldwide
use; further, the validation of MANS is simplified by comparison
with the paper and pencil form. In fact, the correlations found between
the paper and pencil and the MANS tests range from 0.73 to 0.79.
The use of computerized techniques will facilitate the development
of new and more adequate tests by exploiting the graphic potentiali-
ties of computers. This will probably reduce the impact of cultural
differences because words can be replaced by images having a wider
universal meaning. For the time being, MANS is available in two
languages, English and Italian, while versions in German and Greek
are in progress.
~ A first international application of MANS has been activated by
the International Commission on Occupational Health through its
Scientific Committee on Neurotoxicology and Psychophysiology to
evaluate the effects on the central nervous system of organic solvent
exposure of paint manufacturers and users. The countries participating
in the study are, at present, the United States, the United Kingdom,
West Germany, and Italy.
In general, diagnosis of the impairment of higher nervous func-
tions from environmental and industrial exposure needs a thorough
evaluation by means of clinical, neurobehavioral, and neurophysiologic
investigations. A team of professionals with qualifications in
neurotoxicologic assessment is necessary. In practice, very few teams
conforming to the proposed model exist in Europe or, to our knowl-
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NEUROBEHAVIORAL CORE TEST BATTERY
319
edge, in other countries as well. In Europe, this type of expertise has
been developed particularly in both western (Sweden, Finland, Den-
mark, Germany, and Italy) and eastern (Poland, USSR, Hungary, and
Czechoslovakia) countries. An organizational model that has proved
effective in occupational health is the self-sufficient interdisciplinary
type of institute; this model is based on availability at the institute of
all the medical, biological, bioengineering, and ergonomics specialties.
For instance, the Institute of Occupational Health of the University
of Milan has, among its different specialties, a Center of Neurotoxicology
which is composed of one neurologist, two psychologists, one physi-
cian specializing in occupational medicine, and technicians for neuro-
physiological and behavioral evaluations. The activities of the center
include (1) assessment of neurological and behavioral deficits in in-
patients of the Clinic of Occupational Medicine, hospitalized for both
diagnostic-therapeutic and compensation purposes; (2) medical sur-
veilIance of high-risk groups of workers exposed to neurotoxicants;
(3) screening early effects on the CNS in working populations exposed
to chemicals whose neurotoxicity is still under scrutiny; (4) search for
effects on the CNS in case of exposure in the general environment;
and (5) training medical students and postgraduate students in occu-
pational medicine.
NOTE
Those interested in participating in the validation program should
request the "Solicitation Proposal Document" by writing: WHO Col-
laborating Centre, University of Milan, Institute of Occupational Health,
Via San Barbara 8, Milan, Italy 20122.
APPENDIX
COMPUTERIZED VERSION (MANS) OF SIX OUT OF
THE SEVEN TESTS OF THE WHO-NCTB
The POMS contains adjectives that describe different feelings about
Tension, Anger, Depression, Vigor, Fatigue, Confusion,and Sociability.
The subject indicates the intensity of his mood state, during the week
preceding the test session, by pressing for every adjective the spacebar
connected to a five-point scale ranging from "not at all" to "extremely."
The Simple Reaction Time is performed by pressing the spacebar
as promptly as possible when a red light is shown on the screen.
Stimuli are administered at intervals varying between 1 and 5 seconds
for 6 minutes. A practical trial is given.
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RENATO GILIOLI AND MARIA G. CASSITTO
The Digit Span is presented in its traditional form. The digits
appear on the screen one at a time; a sound indicates the end of the
series after which the subject is required to repeat the digits on the
keyboard.
The Digit Serial has been addecl to evaluate the ability to memo-
rize and recall eight or nine digits. The same series is displayed for a
maximum of 12 times until the subject repeats it correctly. The pre-
sentation of the digits on the screen is the same as in the Digit Span.
The Symbol Digit based on the stimulus material used In the clas-
sic WAIS subtest, requires, in its computerized version, pairing digits
to symbols for 1.5 minutes.
The Benton Visual Recognition requires the subjects to recognize a
geometrical pattern immediately, after 5 seconds of observation, among
three over sandbar drawings presented together. The 10 critical patterns
are the same used in the Visual Retention test.
The Aiming Pursuit is performed by means of a graphic tablet. A
sheet of circles is fixed on the tablet and the program is set up in
position. The subjects have to make quick and accurate movements
to place the pen inside each circle following the pattern given on the
test sheet. The circles are larger than those in the original version of
FIeischman in order to be proportional to the stylus point.
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Representative terms from entire chapter:
core test
