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OCR for page 69
Human Neurobehavioral
Toxicology Testing
W. Kent Anger
Twenty-five years ago, Joseph Ruffin, a staff physician with Kaiser
Steel Corporation, published a call for "Functional Testing for Behavioral
Toxicity: A Missing Dimension in Experimental Environmental
Toxicology" in the Journal of Occupational Medicine (Ruffin, 1963~. Since
that time, the field of behavioral toxicology or, more broadly,
neurotoxicology has shown a rapid growth and become one of the
first independent specialty fields under the general rubric of toxicol-
ogy. One result of this growth is that sufficient research has accumu-
lated to allow the development of screening programs for behavioral
toxicity.
There are two reasons for developing standardized tests or test
batteries to screen for (i.e., identify) effects of neurotoxic chemicals:
(1) premarket testing or related regulatory needs and (2) development
of a neurotoxicity data base. Although the former reason is a relatively
recent development impacting this field, the latter has a longer history.
Scientists within the field have encouraged standardization of tests
(Buck et al., 1977; Dews, 1975; Morgan and Repko, 1974) and the use
of reference chemicals as positive controls (Buelke-Sam, 1980; Laties,
1973~. Though never explicitly stated, the reason is to allow us to
relate findings in one laboratory to findings in other laboratories or
to relate findings in one country to those in other countries. The
ultimate purpose is to develop enough information on a range of
chemicals that general principles of neurotoxicity can be gleaned or
commonalities identified. Only then can the chemical-by-chemical
69
OCR for page 70
70
W. KENT ANGER
approach to testing, now typical in this field, be replaced by a more
expeditious approach. To identify the hoped-for commonalities, a
data base must be assembled from research on diverse chemicals studied
with common methods. This suggests the need to select standard
methods to be used in research to identify neurotoxic effects. It is
also consistent with the regulatory needs for pre- and postmarket
screening.
The selection of tests for a neurotoxicity screening battery has oc-
cupied the field of neurotoxicology for several years, especially since
the Environmental Protection Agency (EPA) asked the field to select
neurobehavioral screening tests in 1979. In that year, the EPA spon-
sored a conference in San Antonio with the purpose of identifying
behavioral tests that could be used to evaluate new or untested chemicals
for behavioral/nervous system effects, a primary regulatory need of
the Toxic Substances Control Act (TSCA) (Geller et al., 1979~. At the
end of the meeting, Weiss and Laties (1983) of the University of Rochester
summed up their opinion for EPA: "This collection of papers provides
the most emphatic statement so far of how essential it is for the
Environmental Protection Agency to shun test [selection] standardization.
. . . A behavioral analog of the Ames test. . . is an impossible dream."
These comments exemplify the strong trend of opinion opposing the
development of screening test batteries in the psychology community.
This is especially notable among those researchers studying neurotoxic
effects in adult animals. Those in the field of behavioral teratology
have been more tractable on this topic, generally adopting test batteries
common to several laboratories. The National Center for Toxicological
Research (NCTR) collaborative laboratory study established the
replicability of one such battery, as described by Buelke-Sam et al.
(1985~. Those scientists conducting human neurobehavioral worksite
research have also tackled the problem of battery development with
enthusiasm in recent years. Several investigators in the United States
are in the process of developing or validating human neurotoxicity
test batteries (Otto and Eckerman, 1985~.
RATIONALES FOR DEVELOPING TEST BATTERIES
Two rationales can be formulated for selecting tests into a reason-
ably comprehensive battery of the sort needed to assess the range of
behavioral changes produced by the variety of chemicals found in
the United States. The first and most comprehensive rationale would
be to assess all major nervous system functions to identify all poten-
tial problems that might be produced by chemical exposures. This
would require a taxonomy of nervous system functions. Although
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HUMAN NEUROBEHAVIORAL TOXICOLOGY TESTING
71
such taxonomies have been developed by Carroll (1980) for cognitive
functions and by Fleischman and Quaintance (1984) for a range of
performance tasks, there is no widely accepted taxonomy that at-
tempts to specify all nervous system functions. Of course, any such
list would be too broad to accommodate in a test battery of reason-
able length. The second rationale would be to select tests that would
measure neurotoxic effects typically found following occupational or
environmental exposures. This rationale for developing a battery of
tests is likely to be an evolutionary one. That is, as certain effects
replace others as the most frequently reported problems, the makeup
of the battery would be altered.
Neither of these approaches has been followed exclusively. Eckerman
and others (GuLlion and Eckerman, 1986) developed one test battery
based on eight cogrutive factors identified by Carroll (1980~. However,
the battery has not been used in field evaluations. On the other hand,
several approaches to He development of human neurotoxic~ty test batteries
have been followed, and the resulting test batteries are undergoing field
trials. The more prominent approaches are discussed next.
FinIand's Institute of Occupational Health Approach
Historically, the first approach to worksite neurotoxicity testing was
developed at Finland's Institute of Occupational Health (FIOH) in the
1950s. Investigators at FIOH developed a test battery that is well adapted
to studying the main concerns in Finnish industry, particularly exposure
to a limited number of solvents. Their tests (Table 1), which have been
streamlined through factor analysis over the years, reflect various psy-
chological domains that can also be seen in the table (Hanrunen and
TABLE 1 Finland's Institute for Occupational Health
(FIOH) Test Battery
Test
Domain
Benton Visual Retention
Bourdon-Wiersma
Symmetry Drawing
Mira Test
Reaction Time
Santa Ana
Wechsler Memory Scale (portions)
Wechsler Adult Intelligence Scale (portions)
Visual perception
Visual perception
Visual perception
Motor performance
Motor performance
Motor performance
Cognitive/memory
Cognitive
SOURCE: Hanninen and Lindstrom (1979).
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72
W. KENT ANGER
Lindstrom, 1979~. The battery is now used routinely in neurotoxicity
evaluations of worker groups in Finland, including prospective studies
involving new workers.
Problem-Based Approach
The problem-based approach to worksite testing has its origins in
the wide variety of neurobehavioral problems and neurotoxic chemicals
found in the United States, where field investigators have typically
adopted a unique battery of tests for each particular situation. The
tests have been selected based on two factors: (1) the type of symp-
toms reported by the exposed group to be tested and (2) the estab-
lished neurotoxic effects of the chemical under study or structurally
related chemicals. This general approach has led to the use of literally
hundreds of different tests in various worksite studies conducted
over the years Johnson and Anger, 1983) and has also been characteristic
of National Institute for Occupational Safety and Health (NIOSH)
research (Anger, 1985~.
Approach Recommended by the
World Health Organization
A third approach represents a melding of the first two approaches,
and was well articulated in the World Health Organization (WHO)
meeting held in Cincinnati during May 1983. At that meeting, a
small group of established researchers in neurotoxicology recommended
a core set of tests (the Neurobehavioral Core Test Battery, or NCTB)
that could be used as a basic screen to identify a broad range of
neurotoxic effects, particularly for use in developing countries. Tests
selected into the core set (1) had been used successfully in worksite
studies (i.e., they had identified group differences produced by chemical
exposures), (2) were portable, (3) required minimal training to administer,
and (4) were expected to be valid and reliable in most cultures. Most
of the core tests (Table 2) were well-known "paper and pencil" tests
specifically chosen to avoid mechanical or other instrumentation problems
(a special concern in developing countries). For the one test requiring
a source of electricity (the reaction time test), the instrument selected
can be operated by using batteries as well as 110- or 220-volt current.
Another series of tests was identified as supplemental to the core
battery. Their use was to be dependent on the chemical involved, the
type of personnel available to conduct the tests, and the setting in
which the tests were to be administered. The core set of tests was
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HUMAN NEUROBEHAVIORAL TOXICOLOGY TESTING
TABLE 2 World Health Organization Neurobehavioral
Test Battery
Test
Functional Domain
Santa Ana
A. .
among
Simple Reaction Time
Digit Symbol
Benton Visual Retention Test
Digit Span
Profile of Mood States (POMS)
Manual dexterity
Motor steadiness
Attention/response speed
Perceptual-motor speed
Visual perception/memory
Auditory memory
Affect
SOURCE: Johnson (1987).
73
intended to generate more uniform, more consistent data from a broad
variety of occupations and neurotoxic exposure conditions. The
supplemental tests were intended to provide more in-depth informa-
tion based on the known effects of the chemical under study and
symptoms reported by the exposed workers (Johnson, 1987~.
Neurobehavioral Evaluation System Approach
The Neurobehavioral Evaluation System (NES) implemented sev-
eral neurobehavioral tests that had been used successfully in clinical
settings or in previous field studies on IBM-PC and Portable Compaq
computers. Some 17 tests were available on the NES as of 1986 (Letz
and Baker). The tests are listed in the Table 3, along with the func-
tions assessed. Tests are frequently added to this battery (the most
recent version includes three additional tests not found in the table),1
which is following an evolutionary course dictated by current interest
in the field. The NES includes variants of five of the seven WHO-
NCTB tests (noted by asterisks in Table 3~. As with the problem-
based model, developers of the NES recommend that the user "select
tasks which are appropriate for specific exposure situations" (Baker
et al., 1985~.
Each of the four approaches described below is pragmatically based
and used past research findings in selecting tests. Three approaches
(FIOH, WHO-NCTB, NES) involve a limited battery of tests, and each
battery is sensitive to important psychological functions. However,
none of the batteries aspires to assess the broad range of human
functions proposed above as one basis for test selection. Further, it is
not clear if the functions assessed by these batteries are representa-
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74
W. KENT ANGER
TABLE 3 Computer-Administered Neurobehavioral Evaluation
System (NES)
Domain Test Function
Psychomotor Performance Symbol-Digita Coding speed
Hand-Eye Coordination Coordination
Simple Reaction Timea Visuomotor speed
Continuous Performance Test Attention/speed
Finger Tapping Motor speed
Perceptual ability Pattern Comparison Visual perception
Memory and learning Digit Spana Short-term
memory/attention
Paired-Associate Learning Visual learning
Paired-Associate Recall Intermediate memory
Visual Retentiona Visual memory
Pattern Memory Visual memory
Memory Scanning Memory processing
Serial Digit Learning Learning/memory
Cognitive Vocabulary Verbal ability
Horizontal Addition Calculation
Switching Attention Mental flexibility
Affect Mood Testa Mood
aVariant of WHO Core Test.
SOURCE: Letz and Baker (1986).
live of the range of functions that might potentially be affected by
neurotoxic chemicals, the other basis for test selection noted above.
To assess how well these batteries would detect the health effects
typically caused by neurotoxic chemicals at low concentrations (i.e.,
target organ effects), the target organ health effects identified in the
research literature are described, followed by a comparison of the
potential of the test batteries to identify those effects. Because the
batteries do not assess the broad range of human functions, it is im-
portant to consider how effectively they assess health effects frequently
caused by neurotoxic chemicals. There is no direct evidence on this
point. Several threads of evidence do, however, provide the data to
begin such an assessment. These threads, discussed in order below,
demonstrate that (1) a large number of chemicals produce effects on
the nervous system, and 65 of these chemicals have exposure populations
in excess of one million, and (2) many nervous system-related health
effects occur at lower exposure concentrations than most other effects
for certain chemicals.
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HUMAN NEUROBEHAVIORAL TOXICOLOGY TESTING
TARGET ORGAN EFFECTS
Neurotoxic Chemicals
75
There are 60,000 (Reiter, 1980) to 100,000 (NIOSH, 1983) chemicals
in commerce today. How many affect the nervous system? Anger
and Johnson (1985) have reviewed major secondary reference sources
in this field (American Conference of Governmental Industrial Hygienists,
1980, 1982; Clayton and Clayton, 1981; Damstra, 1978; Gosselin et al.,
1976; Lazerev and Levina, 1976; Norton, 1975, revised 1980; Spencer
and Schaumburg, 1980; Weiss, 1978) to identify chemicals for which
there is evidence of nervous system effects. They identified just over
750 chemicals or chemical groups for which evidence of direct or
indirect nervous system effects exists. It is clear that there are a large
number of industrial chemicals that affect the nervous system adversely.
Exposure Populations
There is also evidence that people are exposed to those chemicals.
In U.S. workplaces, the National Occupational Hazard Survey (NOMS)
identified 200 chemicals, each of which had an estimated one million
or more persons exposed. These estimates are based on statistical
extrapolation from extensive sampling data and have been published
by NIOSH (1977~. The number of workers exposed to each chemical
is very likely inflated due to the exposure identification strategy of
that survey. (The strategy was to list chemicals in work environments
whether or not there was indication of actual use or exposure.) It is
also obvious that many of the people in that survey were exposed to
multiple chemicals and were thus counted for more than one chemi-
cal. (A more recent national survey conducted by NIOSH, the Na-
tional Occupational Environmental Survey [NOES], has not yet been
published, but its results are expected to modify this picture consid-
erably.)
Cross-referencing the 750 chemicals noted above that affect the
nervous system (Anger and Johnson, 1985) with the 200 chemicals to
which one million or more people are exposed, by NIOSH (1977)
estimate, indicates that 65 of the 200, or about one third, are also
found in the list of 750 (Anger, 1986~. From these data, it is possible
to conclude that a large number of U.S. workers work with chemicals
that are known to affect the nervous system. These and other factors
have led NIOSH to identify neurotoxic disorders as one of the 10
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76
W. KENT ANGER
leading occupational problems in the United States (Centers for Dis-
ease Control, 1983, 1986) and to focus efforts on their prevention.
Behaviors Affected by Many Chemicals
The review that identified 750 chemicals which affect the nervous
system also provided an indication of the universe of nervous system-
related effects that are known to be produced by industrial chemi-
cals. The various behavioral deficits induced by industrial chemicals
were categorized into some 120 nervous system-related effects (Anger
and Johnson 1985~. Behavioral effects that have been reported as caused
by 25 or more of the 750 chemicals are listed in Table 4, along with
the number of chemicals with which each has been linked (in the last
column). Some of the effects are vague; others are specific. Despite
the lack of parallelism, which is quite predictable given the diversity
in the source reports, Table 4 contains the 35 behavioral effects most
frequently recognized and reported in the reference literature as occurring
following exposure to industrial chemicals (Anger, 1986~.
This collection of effects provides one measuring stick against which
to judge the available test batteries. However, it is not clear if these
neurotoxic effects are realistic concerns in the industrial environment.
This would be the case if they occur at relatively low exposure levels.
That is, are they target organ effects or health effects that occur at the
lowest concentrations relative to other effects for a given chemical,
rather than curiosities that occur only at high exposure concentrations.
One line of evidence suggesting that they are target organ effects is
the fact that these are cited as the basis for recommending workplace
standards by one federal agency and one independent professional
group.
NIOSH Recommendations
Over the years, NIOSH has produced 91 criteria documents on
chemicals/chemical groups/physical agents (counting only once those
documents that have been revised), under its mandate in the Occupational
Safety and Health Act of 1970. These documents provide a review of
the literature and recommend exposure maxima. The basis for the
recommendation is explicitly stated in each document. A review of
those documents indicates that nervous system effects have been an
explicitly stated basis in about 36 of them, or approximately 40 percent.
Generally, the nervous system effect was identified as one that occurred
at very low concentrations and can be described as a target organ
effect. The chemical/physical agents are listed in Table 5.
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HUMAN NEUROBEHAVIORAL TOXICOLOGY TESTING
TABLE 4 Neurobehavioral Effects Reported Following Chemical
Exposures for 25 or More Chemicals
77
Effect
Of 750
Chemicalsa
Motor
Activity changes
Ataxia
Convulsions
Incoordination / unsteadiness / clumsiness
Paralysis
Pupil size changes
Reflex abnormalities
Tremor/twitching
Weakness
Sensory
Auditory disorders
Equilibrium changes
Olfactory disorders
Pain disorders
Pain, feelings of
Tactile disorders
Vision disorders
Cognitive
Confusion
Memory problems
Speech impairment
General
Anorexia
Autonomic dysfunction
Cholinesterase inhibition
Depression of the central nervous system
Fatigue
Narcosis/stupor
Peripheral neuropathy
Affect/personality
Apathy / languor / lassitude / lethargy / listlessness
Delirium
Depression
Excitability
Hallucinations
Irritability
Nervousness / tension
Restlessness
Sleep disturbances
32
89
183
62
75
31
54
177
179
37
135
37
64
47
77
121
34
33
28
158
26
64
131
87
125
67
30
26
40
58
25
39
29
31
119
NOTE: Adapted from Anger (1984, 1986), Anger and Johnson (1985).
aNumbers below denote number of chemicals for which effect has been reported.
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78
W. KENT ANGER
TABLE 5 Agents/Classes Cited by NIOSH Criteria
Documents as Producing Nervous System Effects at
Low Concentrations
Chemical/Physical Agent
Document No.
Acrylamide
Alkanes
Anesthetic gases, waste
Carbaryl
Carbon disulfide
Carbon monoxide
Carbon tetrachloride
Chloroform
Cresol
Dinitro-o-cresol
Ethylene dibromide
Fluorocarbon polymers, decomposition products
Formaldehyde
Hydrogen cyanide and salts
Hydrogen sulfide
Ketones
Lead, inorganic/revised
Malathion
Mercury, inorganic
Methyl alcohol
Methyl parathion
Methylene chloride
Nitrites
Noise
Parathion
Petroleum solvents, refined
Styrene
Tetrachloroethane (perchloroethane)
1,1,2,2-Tetrachloroethane
Thiols (n-alkane monothiols, cyclohexanethiol,
benzenethiol)
Toluene
1,1,1-Trichloroethane (methylchloroform)
Trichloroethylene
Tungsten and cemented tungsten products
Xylene
Zinc oxide
(77-112)
(77-151)
(77-140)
(77-107)
(77-156)
(HHS 73-11000)
(76-133)
(75-114)
(78-133)
(78-131)
(77-221)
(77-193)
(77-126)
(77-108)
(77-158)
(78-173)
(78-158)
(76-205)
(HHS 73-11024)
(76-148)
(77-106)
(76-138)
(78-212)
(HHS 73-11001)
(76-190)
(77-192)
(83-119)
(76-185)
(77-121)
(78-213)
(HHS 73-11023)
(76-184)
(HHS 73-11025)
(77-127)
(75-168)
(76-104)
NOTE: NIOSH Criteria Documents for each chemical listed in the
table are available by document number (in parentheses) from NIOSH
Publications, 5555 Ridge Ave., Cincinnati, OH 45213.
SOURCE: NIOSH Criteria Documents.
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HUMAN NEUROBEHAVIORAL TOXICOLOGY TESTING
79
Recommendations of the American Conference of
Governmental Industrial Hygienists
In the United States, the earliest national sources of recommended
limits for exposures to industrial chemicals were the publications of
the American Conference of Governmental Industrial Hygienists (ACGIH).
They have published reviews of a far larger number of chemicals
than has NIOSH or any other group, and their recommendations are
discussed at some length because their stated intent is to be compre-
hensive in reviewing toxic chemicals in commerce in the United States
(ACGIH, 1982~.
The ACGIH recommendations are provided by their Threshold Limit
Value (TLV) committee, composed of voting practitioners from academia
and government. Persons from NIOSH and industry serve as nonvoting
consultants. The ACGIH publishes annually a list of the chemicals
most frequently encountered in industry for which there is documented
evidence of untoward symptoms or occupational disease. For each
chemical listed, exposure maxima (TLVs) are recommended (ACGIH,
1982), based on the relevant literature and the personal experience of
members and consultants.
The ACGIH (1982) recommended TLVs for 588 chemicals. To sup-
port these recommendations, the ACGIH also published a book of
documentation (ACGIH, 1980) which describes the basis for each rec-
ommended TLV. Anger (1984) abstracted 36 organ systems, health
effects, or other bases cited in the documentation as the most relevant
information leading to the ACGIH recommendations. These presumably
reflect those effects produced by low exposure concentrations. In
considering only those categories labeled nervous system, unpleasant
taste/odor, and eye (other than irritation), a total of 167 chemicals
(roughly one-quarter of the total 588) listed through 1982 have TLVs
based on these direct neurologic or behavioral effects (Anger, 1984~.
This and the NIOSH criteria documents suggest that the nervous
system is an important target organ for industrial chemicals in use
today.
To return to the 35 effects in Table 4 (produced by 25 or more of
the 750 chemicals), most are also found cited under at least two chemicals
in the ACGIH documentation. Thus, most of the effects in Table 4
may be presumed to occur following low-concentration exposures.
An additional six effects, which were cited at least twice by ACGIH
but less than 25 times in the list of 750, are also listed in Table 4.
Those effects cited by ACGIH as caused by only one chemical are not
included in this table.
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80
W. KENT ANGER
POTENTIAL OF TEST BATTERIES TO ASSESS
TARGET ORGAN HEALTH EFFECTS
The data in Table 4 provide a sample of health effects occurring
frequently following exposures to toxic industrial chemicals. How
effectively would the test batteries noted above identify or screen for
these frequently occurring effects? The 35 health effects produced by
25 or more chemicals have been repeated in Table 6 in a single col-
umn. Table 6 also identifies the tests in the WHO, FIOH, and NES
batteries that would presumably assess the various effects, if the sensitivity
of each test and the sample size are adequate.
As can be seen in Table 6, many of the motor changes would be
identified by the three test batteries, and the Profile of Mood States
(POMS) or mood tests found in two of the batteries would detect
changes in affect. Sensory changes would be poorly identified, as
would ataxia and weakness, two effects that occur frequently after
toxic chemical exposure. The forte of the batteries, cognitive testing
(particularly memory), is aimed at central nervous system (CNS) functions.
This is based on the assumption that such effects are not reported
very frequently because they are only rarely assessed with any degree
of sophistication. This assumption is somewhat substantiated by past
worksite research with carbon disulfide, mercury, lead, and methyl
chloride. That research has identified subtle CNS deficits in worker
groups exposed to concentrations that did not produce peripheral
effects or other signs of frank poisoning (Anger and Johnson, 1985~.
Human laboratory research on acute exposure effects of many solvents
also supports this assumption (Dick and Johnson, 1986~.
The WHO-NCTB, FIOH, and NES test batteries are reasonable, de-
fensible, research-based approaches to the assessment of neurotoxic
chemicals. Further, each battery tests for well-established health-related
effects that have been accepted by the public health community in
the past. They also include tests aimed at assessing the more subtle
CNS deficits that occur at lower exposure concentrations than do the
more frank poisoning effects that have been the focus of attention in
the past.
There are clearly limitations to these batteries, however. The WHO-
NCTB and FIOH batteries use a test of motor performance (the Santa
Ana) that has previously demonstrated differences between a group
exposed to toxic chemicals and an unexposed group, but the NES
hand-eye coordination test has not yet identified chemical effects.
Also, only the FIOH battery and the WHO-NCTB have more than
one test of coordination. The WHO-NCTB is slightly superior to both
the NES and the FIOH batteries in its use of the POMS test. The
FIOH battery has no test for affect, and the NES uses a mood test that
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HUMAN NEUROBEHAVIORAL TOXICOLOGY TESTING
TABLE 6 Neurobehavioral Effects Reported Following Chemical
Exposures
81
Tests
Neurobehavioral Effects WHO NES FIOH
Motor
Activity changes
Ataxia
Convulsions
Incoordination/ Santa Ana Hand-Eye Coordination Santa Ana
unsteadiness / clumsiness
Paralysis
Pupil size changes
Reflex abnormalities
Tremor/twitching
Weakness
Sensory
Auditory disorders
Equilibrium changes
Olfaction disorders
Pain disorders
Pain, feelings of
Tactile disorders
Vision disorders
Cognitive
Confusion
Memory problems
Speech impairment
Affect/personality
Santa Ana Hand-Eye Coordination Santa Ana
Santa Ana Hand-Eye Coordination Santa Ana
Santa Ana
Benton Pattern
Benton
Pattern
Apathy/languor/lassitude/ POMS Mood Test
lethargy / listlessness
Delirium
Depression POMS
Excitability POMS
Hallucinations
Irritability POMS Mood Test
Nervousness/tension POMS Mood Test
Restlessness POMS
Sleep disturbances
General
Anorexia
Autonomic dysfunction
Cholinesterase inhibition
Depression of the
central nervous system
Fatigue
Narcosis/stupor
Peripheral neuropathy
Pathology
Psychic disturbances
Santa Ana
Benton
Benton
POMS
Santa Ana Hand-Eye Coordination Santa Ana
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82
W. KENT ANGER
is based on the 65-item POMS, but it employs only 25 of those items
to identify five of the six factors (all but vigor) on the POMS. The
reliability and validity of the resulting test have not been assessed
thoroughly, and an item-by-item analysis of the mood test indicates
that it does not appear to assess some types of affect that are assessed
by the POMS (and occur frequently following chemical exposures).
Overall, this assessment would suggest that the WHO battery is slightly
superior to the FIOH and the NES batteries, based on the criteria
proposed above. However, the NES has the advantage of being ad-
ministered by computer, which reduces administration costs substantially.
On the negative side, some of the most frequently occurring neurotoxic
effects, particularly some forms of peripheral neuropathy and affective
symptoms, weakness, ataxia, and sensory effects, would be missed
by all of the batteries. Of course, it is quite possible that CNS changes
are correlated with some of these effects and these tests would thus
perform their function of detecting health effects. A "screening" battery
is developed for detection, not characterization.
The established test batteries must undergo constant scrutiny. An
evolutionary course of test battery development is essential when the
battery is based on established health effects, because these effects
may change as chemicals in use change. Further, the immense range
and diversity of behavior noted above suggest that simple test batteries
are inadequate for comprehensive screening. There is the danger of
not detecting those effects for which the batteries lack tests. One
hopes that the currently recommended test batteries noted above are
designed for the problems of the future by assessing more subtle
CNS effects rarely tested adequately in the past.
DEVELOPMENT EFFORTS UNDER WAY
The test batteries described above are not without their problems.
One major problem lies in interpreting the result of these batteries.
The neurobehavioral tests in the various test batteries, with only a
few exceptions, are not clinical instruments. They do not have established
norms based on extensive population testing. Rather, they are
performance tests that provide objective measures ideally suited to
test-retest (before-after) assessments. Of course, baseline (preexposure)
performance data on workers exposed to chemicals almost never ex-
ist. Performance data on the same tests administered to unexposed
people must be used for comparison. That is, performance effects are
defined, not by established norms, but by comparison data from people
believed to be healthy a referent or control group.
- - - r -r -
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HUMAN NEUROBEHAVIORAL TOXICOLOGY TESTING
83
An appropriate control group should consist of people who are
not only unexposed to toxic chemicals, but are also similar to the
exposed subjects in terms of age, education, job activities or move-
ments, and socioeconomic variables. This is extremely difficult to
achieve, and field researchers are virtually always concerned with
the accuracy of the controls as a basis for judging the performance of
the exposed gtoup. The most pervasive problem in judging the validity
of group differences has been age differences between exposed and
comparison groups. Therefore, the World Health Organization has
recommended the development of normative data from unexposed
or control subjects in five age ranges for the NCTB. This recommen-
dation may be extended to the other major neurotoxicity screening
batteries. The five arbitrarily selected age ranges are: 16-25,26-35,
36- 5,4 -55, and 56- 5 years. Ideally, the subjects would be employees
with occupations relatively typical of those found throughout the
country (or at least not atypical) and with a fairly homogeneous
educational background. NIOSH is conducting such a study using
the NES and the NCTB.
It is the World Health Organization's intention to carry out an
assessment of the NCTB in eight nations (WHO, 1987~. Because the
NCTB tests were developed in western European-derivative countries
(primarily Finland and the United States), the assessment is aimed at
comparing the results from the U.S. and European countries with
results from culturally diverse people of different countries. As of
this writing, some 15 research groups had applied to participate in
the assessment, although some cultural groups are not represented.
If test performance in various countries/cultures is within certain
ranges, the WHO-NCTB battery can be used to assess poisoning incidents
or other neurotoxic exposures worldwide, and the results can be
generalized to people throughout the world. Thus, data from all
countries could be used to assess safe exposure concentrations of
specific chemicals. This is intended to accelerate the development of
a data base of chemical effects through the use of common tests. It
will, in turn, advance the process of identifying chemical classes or
mechanisms associated with neurotoxicity and thus lead to the ultimate
goal of prediction of neurotoxicity, rather than identification through
post hoc discovery of adverse health effects in humans.
NOTES
1. Current information on this battery and the software to implement it are avail-
able from Dr. Richard Letz, Environmental Sciences Laboratory, Mt. Sinai School of
Medicine, 10 East 102nd Street, New York, NY 10029.
OCR for page 84
84
W. KENT ANGER
ACKNOWLEDGMENT AND DISCLAIMER
Appreciation is extencled to Mrs. Pat Amendola and Pam Schumacher
for preparation of the typescript. Mention of company or product
names does not imply endorsement by NIOSH.
This article is reproduced with permission from Toxicology and In-
dustrial Health (Anger, 1989~.
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Representative terms from entire chapter:
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