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OCR for page 395
The Scope and Promise of
Behavioral Toxicology
Bernard Weiss
Behavioral toxicology (BT) has almost ceased to be a term that
arouses quizzical or bemused expressions in the more orthodox ven-
ues of its parent discipline. At the same time, its full scope and
potential remain largely unappreciated and unexploited. The range
of questions it can be used to ask and the unique perspectives it can
provide on certain issues so far exceed what has been demanded of
it. This chapter aims to illustrate or identify some of its unused
capabilities, and to indicate those that need further development. Its
special focus is how behavioral measures have expanded our previous
views, based on traditional criteria, of what constitutes toxicity, and
the nature of the new issues that this expanded perspective fosters.
Foremost among these issues is how behavioral endpoints are to be
treated in risk assessment.
Almost the entire risk assessment process is designed around can-
cer (National Research Council, 1983~. What are called systemic toxicants,
such as those acting on the nervous system, are evaluated by a wholly
different set of principles. The difference stems from a presumed
biological dichotomy. The induction of carcinogenesis is assumed to
have no threshold. A single molecular event, such as a transcription
error in DNA, can generate carcinogenesis and, it is assumed, can
arise from the action of a single molecule of a carcinogenic agent.
Systemic toxicants, in contrast, are presumed to exhibit thresholds,
perhaps at the point at which they overwhelm compensatory mechanisms.
395
OCR for page 396
396
BERNARD WEISS
This doctrine of distinct biological modes of action finds expression
in the current approaches to risk assessment.
The first step in conventional risk assessment is hazard identifica-
tion, which can be based on either epidemiological or experimental
data. This first step is crucial because of the regulatory apparatus
activated when a substance is classified as carcinogenic. The next
step, dose-response assessment, almost always is based on high-dose
animal or human data. These data are used in extrapolation modeling
to compute predictions of cancer probability at low dosages. Because
of the biological assumptions, only a zero dose of a carcinogen is
assumed to add no increment of risk. Exposure assessment estimates
the levels of the agent to which the target population is exposed.
Together with the dose-response model chosen for extrapolation, the
estimated risk of cancer can then be calculated for that population in
a step called risk characterization.
Systemic toxicants, such as those acting on nervous system tissue,
are viewed from a totally different perspective. Instead of coupling a
risk estimate with an exposure level, some arbitrary threshold is defined,
then divided by a safety factor or uncertainty factor to yield an acceptable
daily intake. Such thresholds are described as effect levels of various
kinds (Klaassenet al., 1986~. The no-observed-effect level (NOEL)
refers to an exposure level offering no statistically significant increases
in either frequency or severity of response in an exposed, compared
to a control, sample. A lowest-observed-adverse-effect level (LOAEL)
refers to the lowest exposure level producing statistically significant
increases in the frequency or severity of adverse responses. Other
effect levels are defined by similar standards.
The suitability of effect levels for risk assessment is now being
questioned in many quarters and for many reasons. First, how are
adverse effects defined? Conventionally, they include any effects
that impair function, result in lesions, or inhibit an organism's ability
to respond to additional challenges, so that effect levels depend on
the specific endpoint chosen as the critical one. Moreover, some
critics contend that these do not distinguish between reversible and
irreversible effects, between immediate and delayed effects, and between
agents that may be rapidly eliminated and those that remain in the
body for extended periods. A second objection to the effect threshold
concept is statistical. It makes use of only one point on the dose-
consequence function rather than the entire function and essentially
ignores the size of the experiment. Third, the uncertainty factors by
which the NOEL, for example, is divided to provide a safety margin
for population exposure, are also arbitrary and fail to make optimal
use of experimental data. All of these objections have encouraged
OCR for page 397
SCOPE AND PROMISE OF BEHAVIORAL TOXICOLOGY
397
speculation that the highly developed cancer model for risk assess-
ment might be adapted for systemic toxicants.
The standard risk assessment protocol derived from carcinogenesis
might be modified for neurotoxicants, with extrapolation to the origin
(zero dose, zero added risk) replaced by another function, such as a
threshold model, if the standard protocol were adequate. Neurotoxicants,
however, introduce a complication: the stage of risk characterization,
instead of becoming a matter simply of finding the intersection of
dose and risk probability, turns into a complex weighing of endpoints
and their measures. The complications are especially difficult to resolve
when the endpoints are behavioral in content. To grasp this point, it
helps to begin with a review of the history of BT and some of its
special properties.
ANTECEDENTS OF BEHAVIORAL TOXICOLOGY
Although BT arrived on the scene, at least in the United States
(Weiss and Laties, 1975), less than two decades ago, it had a plethora
of antecedents that serve to explain its unusual position in toxicology
and why it is difficult to mold into the conventional risk assessment
process.
BEHAVIORAL PHARMACOLOGY
With the introduction of the minor tranquilizing and antipsychotic
drugs in the 1950s, and the demonstration that chemotherapy could
be a legitimate option in the treatment of behavior disorders, an intense
search began for new agents
~ It was accompanied by a swelling
interest in the behavioral mechanisms underlying the clinical actions
of these drugs. These two developments combined to establish a
technology and a discipline hospitable to their goals. Behavioral
pharmacology grew out of the extensive literature of experimental
psychology, particularly that aspect of it called the experimental analysis
of behavior and associated with applications of what is known as
schedule-controlled or operant behavior (Iversen and Iversen, 1981~.
Much of the early work in behavioral pharmacology was built on the
power of coupling behavior and its consequences in prescribed ways
known as schedules of reinforcement. "By manipulating correlations
between specified behaviors, such as lever presses by rats, and the
subsequent delivery of food pellets, it was possible to generate patterns
of behavior that proved differentially sensitive to various kinds of
drugs and that also provided the basis for analyses of such differen-
tial sensitivity.
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398
BERNARD WEISS
Translating this technology into one suitable for toxicology proved
a fairly easy task because most of the questions posed to behavioral
pharmacology were essentially questions in selective toxicity. Toxi-
cology did not grapple, however, with its heritage from the central
theme of behavioral pharmacology: toxicant-behavior interactions. It
remained centered on whether a particular agent deserves to be la-
beled neurotoxic. Yet, if any single principle can be identified as the
dominant product of behavioral pharmacology, it is that the nature
of a behavioral response to a chemical challenge depends on the
characteristics of the behavioral situation. At the same time and in
the same organism, a drug might elicit one kind of response pattern,
such as an increase in rate, under one schedule, whereas it elicited a
decrease in rate under another schedule or schedule variant. On the
basis of our experience with drugs, the question ought to be how to
interpret the modifications produced by exposure. Simply specifying
schedule-controlled behavior as one component of a screening battery,
while ignoring the interaction, is unlikely to yield significant contributions
to BT as a science and could evoke considerable confusion (see MacPhail,
this volume) if the resulting data were to be used to calculate some
version of a threshold.
Some confusion already exists because of the different aims of BT
and behavioral pharmacology (Weiss, 1984~. Central nervous system
(CNS) drugs are administered therapeutically at doses great enough
to influence behavior, so that behavioral pharmacologists study high
doses either to try to detect active agents or to differentiate their
behavioral effects. A BT study might entail these aims as well, but
must always consider the importance of its findings for risk estimates,
which implies action at low doses. Wood and Cox (1986), for example,
measured the response rates of rats exposed to toluene vapor and
performing on a reinforcement schedule that maintained fairly stable
rates under control conditions. They chose to study exposure
concentrations considerably lower than those used in past investiga-
tions with rodents. They observed that toluene exposure, at levels
close to those used in experimental studies with humans, and even
approximating the threshold limit value, elevated rates above control
levels. A typical strategy for dose selection, however, would have
begun with rather high levels, would have observed rate decreases,
would then have lowered the concentration to a point at which no
rate decreases occurred, and would have missed toluene's rate-enhancing
properties at low concentrations. We do not have to rely on
neurotoxicology alone to document the futility of high doses when
the aim is risk estimation. The connection between lead exposure
and hypertension emerged from an analysis of the the Second Na-
OCR for page 399
SCOPE AND PROMISE OF BEHAVIORAL TOXICOLOGY
399
tional Health and Nutrition Examination Survey (NHANES II) data,
which showed the steepest effects at low doses. Animal data had
indicated such a relationship (Victery et al., 1982) but failed to attract
attention because the results conflicted with our stereotyped expectations.
What we find currently in most assessments of animal behavior is
an arbitrary selection of experimental parameters combined with relatively
high exposure levels. We seem to have appropriated a technology
without an appreciation of what that transfer of technology requires
to make it work.
Workplace Exposure Criteria
The first industrial hygiene legislation on record was prompted by
the manifestations of mercury poisoning in miners who worked the
famous mines at Idria. Among these manifestations are tremor and a
collection of psychological complaints. Behavioral disturbances were
also listed in descriptions of many other workplace toxicants by pio-
neers in occupational hygiene, such as Ramazzini in the eighteenth
century and Hamilton in the twentieth century. Formal recognition
was embodied in the Threshold Limit Values (TLVs) issued by the
American Conference of Governmental Industrial Hygienists (ACGIH).
Note its description of the short-term exposure limit (STEL): "the
maximum concentration to which workers can be exposed for a period
of up to 15 minutes continuously without suffering from. . . narcosis
of sufficient degree to increase accident proneness, impair self-rescue,
or materially reduce work efficiency. . . " (ACGIH, 1974~. Such a
definition of safety implies quantitative information about performance
capacity that would have to be acquired under experimental conditions.
Adequate information is sparse. Anger and Johnson (1985) estimate
that about 25 percent of the workplace chemicals for which TLVs
exist are neurotoxic, but the volume of pertinent toxicity data is far
less than warranted by such a role.
The TLVs are supposed to protect against adverse effects during a
working lifetime. For substances such as organic solvents, however,
they have been based on a combination of impressionistic clinical
data, some epidemiology, and observations of acute effects. A chronic
syndrome, described extensively in the Scandinavian literature, has
also been described. It comprises signs such as a slowing of responses,
memory difficulties, and personality disturbances. The validity of
such a syndrome has aroused robust debate, but even critics acknowledge
its confirmation in workers exposed to carbon disulfide (Grasso et
al., 1984~.
Several of the chapters in this volume describe this syndrome and
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400
BERNARD WEISS
the research programs and techniques designed to extend the scien-
tific basis for exposure standards. We must acknowledge the enormous
contributions of these programs to shaping our views of how the
criteria for workplace safety should be formulated. Yet the entire
literature suffers from an inherent conflict between eagerness to ap-
ply these views and aptness of the techniques on which these appli-
cations depend. Convenience ease of administration, standardization,
and testing time are dominant concerns and, in response, the concerns
are met by collecting a series of tests into a battery. Sometimes,
however, convenient technology can be misleading.
For example, several investigations have relied on a device called
the Optacon to assess somesthetic sensitivity. The device itself, and
the psychophysical procedures governing testing, are wholly inad-
equate for such a purpose, as so cogently discussed by Maurissen
(1988~. Another example is the various reaction time measures included
in many batteries. Again, because of unfamiliarity with the psychophysical
literature, authors may fail to specify stimulus values, despite the
body of knowledge indicating that stimulus intensity is inversely re-
lated to response latency. In fact, reaction time can be used to plot
psychophysical functions (Stebbins, 1970), so that one could question
whether some of the results with solvents, for example, represent
altered "cognitive" function or sensory deficits.
The conflict between convenience and sensitivity obstructs the
usefulness of many of these batteries for risk estimation. Is it legitimate
to argue that, because they probably yield underestimates of impaired
function, safety standards such as TLVs require the application of
uncertainty factors based on groups showing deficits attributed to
exposure? Or can the argument about sensitivity be used to question
the validity of the findings, a tactic used in toxic tort cases? Finally,
if an arbitrarily safe exposure standard is the aim of such research,
what model is to provide such a standard and what are the associ-
ated risks?
Standards in the Soviet Union
Discrepancies between the workplace and community exposure
standards accepted in the West, and those prevailing in the Soviet
Union, which tend to be much lower, have generated considerable
speculation about their sources. One source surely was the image of
virtue to be gained by USSR standards that seemed more rigorous
than those adopted by capitalist nations. Other sources should be
recognized as well, however.
The most important was the doctrine flowing from the history of
OCR for page 401
SCOPE AND PROMISE OF BEHAVIORAL TOXICOLOGY
401
Soviet science, and the overwhelming authority of I.P. Pavlov, that
measures of CNS function should play a major, even dominant, role
in assessing safety and prescribing exposure standards. Tissue damage
occupied the corresponding role in the West and still remains domi-
nant. Pavlenko (1975), discussing methods for toxic assessment of
the CNS, notes Pavlov's assertion that ". . . the animal organism as a
system is able to survive in its natural environment only if a dynamic
equilibrium is maintained between this system and its environment.
This is achieved, in higher animals, chiefly through the agency of the
nervous system and by means of reflexes." Although Western scientists
tend to view Soviet data with some skepticism, in part because the
standards of scientific publication seem to be looser in the USSR, the
Soviet approach still managed to generate enough curiosity in the
West to stimulate tests of its validity.
One aspect of Soviet doctrine that still separates it from Western
toxicology, however, is the principle that any deviation from baseline
functional parameters due to toxic exposure must be interpreted as
an adverse effect (Glass, 1975~. Western scientists may interpret such
effects as evidence of adaptation, much like the change in vital capacity
produced by physical training. Simultaneously, however, Western
toxicologists must at some time resolve which behavioral endpoints
denote toxicity. Some of the more conventional practitioners insist
that behavioral changes of a transient nature, unaccompanied by pa-
thology, do not warrant the label of toxicity. Such a narrow definition
is probably no longer tenable, but what are its limits?
Ozone occupied such an ambiguous niche not long ago. It was
recognized as a potent lower-airway irritant and as a source of pathological
changes in the lung at high doses. Questions about its toxicity at low
environmental concentrations have been answered satisfactorily only
recently. Inhalation toxicologists now can document adverse pulmonary
effects, at least as a consequence of chronic exposure, at levels permitted
by current regulations. Yet consider the problem of how to interpret
findings such as those published by Weiss et al. (1981), Tepper et al.
(1982), and Tepper and Weiss (1986~. Weiss et al. (1981) trained rats
to respond on a fixed-interval schedule of food reinforcement and
measured response rates during 6-hour exposures to ozone. They
observed a reduction in lever-pressing rate at concentrations of 0.5
ppm and above. To provide a contrast with this kind of sedentary
behavior, Tepper et al. (1982) allowed rats access to running wheels
during a 12-hour period and exposed them to ozone during the middle
6 hours. A concentration as low as 0.12 ppm, the level deemed by
the regulations issued under the Clean Air Act as what might be
considered a surrogate for an effect threshold, reduced running. This
OCR for page 402
402
100 -
o 75-
z
o
o 50-
UJ
a:
25- Legend
o REVOLUTIONS
it.
· LEVER PRESSES ~
O-
BERNARD WEISS
120-
60 -
N = 4
120
RAT 1
~~ 60
I\ 1 20
it. 60 1 i<\-
~o O
120
RAT 2
60
----I ~ 1 1 0 - 1 ~ I! 1 · · ~ 0U
0.1 0.S 0.1 0.5
OZONE ppm
·0~\ RAT 3
Cot
RAT 4
-I ~1}'-- 1~
..... . . ..
0.1 0.5
FIGURE 1 Results of an experiment In which rats pressed a lever, attached to the
inner wall of a running wheel, to release a brake that locked the wheel. After prelimi-
nary training, the rats were required to make five lever presses (a fixed-ratio 5 scheule
of reinforcements to release the brake for a period of 15 seconds. Rat 1 remained on
fixed-ratio 1. Access to the running wheel occurred during the last hour of a six-hour
period of exposure to ozone. Three of the four rats showed a reduction In both lever
presses and wheel revolutions at 0.08 ppm ozone; the Environmental Protection Agency
standard is 0.12 ppm.
SOURCE: Tepper and Weiss (1986).
reduction was largely the product of lengthened pauses between bouts
of running and can be interpreted, not as toxicity per se, but as behavioral
adaptation. That is, reduced motor activity reduces minute volume
which, in turn, reduces pulmonary uptake of ozone and, finally, the
aversive consequences of running in an ozone-enriched environment.
The later paper (Tepper and Weiss, 1986) described an experiment
in which rats pressed a lever, while in the running wheel, to release a
brake and so secure an opportunity to run. A reduction in the fre-
quency of this behavior, which can be interpreted even more directly
as avoidance of the aversive consequences of exercise, occurred at an
ozone concentration of 0.08 ppm (Figure 1~. Are these behavioral
data to be adopted as evidence of ozone toxicity at these low levels,
as they would in the USSR? Do they simply indicate that exercise is
aversive at these concentrations? This is one arena in which behavioral
observations offer a unique problem for risk assessment and regulation:
Can an exposure level that elicits avoidance of the consequences of
OCR for page 403
SCOPE AND PROMISE OF BEHAVIORAL TOXICOLOGY
403
exposure be considered an adverse functional or toxic effect (Weiss,
1989~.
Public Awareness
With the stirrings of the environmentalist movement in the United
States, public concern began to shift from the grosser aspects of toxic
damage to the more subtle ones, especially those arising as the conse-
quence of low-level, prolonged exposure. Although cancer was featured,
it was inevitable that the public would begin to ask questions about
the coupling of environmental chemicals and "mental disease," for
example. Fifteen years ago, when the Environmental Protection Agency
(EPA) was preparing to respond to what later became the Toxic Substances
Control Act, legislators in the United States were already drafting
requirements that behavioral disturbances be included among the
criteria of adverse effects. At present, several legislative initiatives
and federal agencies define and regulate chemical exposures and in-
clude behavior among the aspects of toxicity to be considered in de-
termining safety. The removal of lead from gasoline can be attributed
to the mounting evidence showing an inverse relationship between
intelligence test scores in children and indices of lead exposure. The
public, however, remains largely uneducated about such issues. Even
the media still use terms such as lead poisoning to describe the impact
of lead exposure on test scores.
Terms such as lead poisoning imply that risk and the associated
calculation of acceptable exposure standards can be defined, like cancer,
by number of cases, but the lead issue has been defined by a different
metric. The paper by Bellinger et al. (1987), whose results are supported
by several other groups, offers a clear example. They compared scores,
on the Bayley Scales of Infant Development, of three groups of children
24 months of age. The groups were differentiated by lead concentra-
tions in cord blood: low (a mean of 1.6 ~g/dL); medium (a mean of
6.5 ,ug/dL); and high (a mean of 14.5 ,ug/dL). As observed in other
chapters, a few years ago the high-lead group would have been regarded
as a low-lead group. All the groups attained scores above average on
the Bayley Scales, but the differences between the high-lead group
and the other two groups came to about 8 percent.
Given the above-average scores in the high-lead group, none of
the children could be identified as cases, for example, of mental
retardation. Also, 8 percent, although statistically significant, is a
degree of variation that is often encountered on retesting. The clearest
appreciation of this difference is found in its implications for the
community.
Figure 2 compares two distributions of intelligence test scores. The
OCR for page 404
404
BERNARD WEISS
IQ SCORE
50
0.034—
0.02 -
0.01 -
~ 0.00
m
m
o
ct
cot
0.02 -
0.01 -
70
90 110 130 lS0
, , , , , , ~
I:
/ ~
~-
,W,
a. ::.:
_... .....
....... :.
/ \
, , . . , , , . . ~
so 70 90 110 \30 150
IQ SCORE
FIGURE 2 Plot describing implications of a 5 percent shift In intelligence test scores.
The upper curve depicts the distribution of intelligence test scores for instruments such
as the Stanford-B~net and Wechsler Intelligence Scale for Children. Its mean is 100 and
its standard deviation is 15. In a population of 100 million, 2.3 million individuals will
score above 130, as shown by me stippled area In the upper tail of the distribution. If
the distribution is shifted by 5 percent, or one-third of a standard deviation, to a mean
of 95, only 990 thousand individuals will score above 130. Bell~nger et al. (1987) observed
a difference of 8 percent on the Mental Development Index of the Bayley Scales of Infant
Development, between children whose cord bloods fell into a group with a mean lead
concentration of 14.5 ~g/dL and Dose In groups with lower means.
SOURCE: Weiss (1988).
upper chart depicts a distribution with a mean of 100 (the defined
average) and a standard deviation of 15 (as found, say, on the Stanford-
Binet). In a population of 100 million, 2.3 million will score above
130. The lower chart depicts a distribution with a mean of 95, or a
reduction of 5 percent. In such a population of 100 million, only 990
thousand individuals will score above 130 (Weiss, 1988~. The impli-
OCR for page 405
SCOPE AND PROMISE OF BEHAVIORAL TOXICOLOGY
405
cations for a society are staggering. Yet, they are impossible to con-
vey with the standard model of risk assessment, which counts cases.
Toxic Torts
Litigation is exerting a significant impact on the acceptance of be-
havioral criteria of toxicity. Courts in the United States are now
evaluating suits by workers claiming injury from exposure to organic
solvents, metals, pesticides, and other neurotoxic substances. Such
claims take the form of impaired intellectual performance, impaired
sensory function, subjective complaints, and other indications of nervous
system damage. These suits are now prompting segments of industry,
which previously had tended to ignore behavioral assays in chemical
development and workplace safety, to inaugurate programs responsive
to these newer facets of toxicology. Moreover, legislation such as the
Gaydos-Metzenbaum bill is prompting further review of the impact
of subtle toxicity on worker health. Behavioral toxicology will be
forced more and more, as the legal system responds to these issues,
to make explicit the sources of its conclusions and to defend them.
Legal arguments have a way of challenging vagueness, possibly to
the disadvantage of BT and some of its practitioners, because then
we will have to offer statements about probability. When workplace
exposure is at issue, how convincingly can we argue, for an individual,
that a particular collection of signs and symptoms was a likely or
unlikely outcome of a work history? What degree or proportion of
responsibility can we allocate to the work environment and what
proportion to other factors, such as the personal habits of the individual?
The test batteries devised to assay the neurobehavioral consequences
of workplace exposure to various substances, which are the substance
of the scientific arguments advanced in toxic tort cases, convey a
great deal of ambiguity when used to support decisions about individuals.
Perhaps such ambiguity is inevitable, given the problem of multiple
chemical exposures in many work histories—complicating attempts
to extract characteristic test profiles but an emphasis on differential
exposure histories and even rudimentary dose-response analysis would
yield more effective instruments in the end.
SPECIAL CHARACTERISTICS OF
BEHAVIORAL TOXICOLOGY
One message to be extracted from this list of predecessors is that
BT is still in search of an identity. We inherited certain techniques
and viewpoints, but still have to synthesize them into a mature discipline.
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406
BERNARD WEISS
To move toward such a synthesis requires not just refinements of
borrowed technology, but a technology and viewpoint uniquely our
own. Viewpoints determine technology, so we will have to examine
those that are special to BT and imbue it with some of the properties
that make it a unique challenge for risk assessment.
Basic Themes
A review of our history distinguishes two themes, which could be
termed validation and amplification, that have emerged with the de-
velopment of BT. The validation theme is embodied in the process of
hazard identification, the first step in the conventional risk assessment
process. At this stage, in contrast to cancer, emphasis falls on estab-
lishing the spectrum of toxicity associated with a particular agent,
and the aim of research directed to such questions has been to develop
adequate screening methods. Sensitivity is a secondary goal in these
programs because extrapolation is only an implied, and not a direct,
requirement or even role for such screens (e.g., Tilson et al., 1979~.
A second type of validation embodies animal models of the kind
discussed in this volume by Russell and by Overstreet. These models
seek to mimic neurological diseases, such as parkinsonism and
Alzheimer's disease, whose etiology currently is suspected by some
to result from neurotoxic processes. Here, the validation theme takes
the form of chemically induced lesions and behavioral endpoints that
are assumed to be analogues of human function such as short-term
memory.
The second theme, which I can amplification, addresses risk estimation
directly and its ultimate goal of coupling exposure levels with risk
incidence or severity. This goal would be essentially the next step,
after hazard identification, in the risk assessment process. It may be
undertaken either as an expansion of observations where humans
served in the role of sentinels or as the successor to laboratory findings
that have documented the existence of a hazard. No entirely new
substance has yet passed through the defined phases of the conven-
tional risk assessment process. Our literature is based almost exclu-
sively on agents already defined by human exposure. Hazard iden-
tification has been pursued mainly as a validation process based on
recognized toxicants. Dose-response (and dose-effect) phases have
typically been conducted, in the laboratory, as programs to establish
validity by demonstrating such relationships. Efforts to provide a
basis for dose extrapolation to humans remain minimal.
The calculation of risk based on neurobehavioral criteria is complicated
by the variety of prototypical situations in which adverse effects might
OCR for page 407
SCOPE AND PROMISE OF BEHAVIORAL TOXICOLOGY
407
appear. Exposures may be either acute or chronic; consequences may
be either reversible or irreversible, progressive or stable. Some effects
may remain latent, only to emerge with time, perhaps in advanced
age, when the reserve capacity of the nervous system has been de-
pleted. The anesthetic properties of volatile organic solvents, for
example, represent an acute reversible situation, but consistent exposures
may lead to progressive deterioration that eventually becomes irre-
versible. Delayed irreversible effects are associated, for example, with
MPTP exposure in adults and methylmercury exposure in the fetus.
Clinical and Behavioral Criteria
For all these categories, our past evaluations of adverse effects
were based largely on clinical endpoints, still the main basis for esti-
mates of the hazards of systemic toxicants acting on organs other
than the central nervous system. The adequacy of clinical criteria for
risk assessment is questionable.
Clinical criteria are especially flawed when neurotoxicity is expressed
by a gradual, progressive erosion of functional capacity. Consider
the reasons for trying to develop and refine psychological test procedures
sensitive to the early manifestations of Alzheimer's disease. By the
time a patient comes to the attention of clinicians, he or she has
already progressed to a stage that has captured the concerns of fam-
ily members. At that point, an accurate diagnosis is not an especially
formidable challenge. Even though the currently available test proce-
dures cannot comfortably differentiate victims of the disease from
controls, except in group designs, they remain vastly superior to the
clinical examination in defining the areas and extent of functional
deficit. Their precision is certain to improve now that the vast amount
of research on the psychological deficits of Alzheimer's disease is
being embodied in potential diagnostic procedures.
One of the most cogent examples of the difference between clinical
standards and psychological test or experimental design standards is
surely lead toxicity. I discussed earlier the novel way in which the
risks of lead exposure should be formulated, an example of the way
in which the amplification process works. Cory-Slechta (this volume)
traces the progressive lowering, over the past four decades. of the
blood levels accepted as hazardous to children and detectable in animal
models. Such a progression is now evolving with methylmercury,
which currently is undergoing an amplification process. Although it
has many features in common with how our views of lead toxicity
evolved, it has distinct features of its own that make it an appealing
model. One important feature is our extensive knowledge of methyl-
OCR for page 408
408
BERNARD WEISS
mercury neuropathology. Another is our ability to trace exposure
history by the analysis of methylmercury in hair. The third is its
specific effects on special systems, such as vision. The fourth is the
narrow focus of its toxicity: unlike lead, which exerts significant ef-
fects on hematopoiesis and blood pressure, methylmercury exerts only
minimal effects beyond the nervous system. The fifth feature is the
often prolonged latency to overtly detectable effects during or following
exposure.
Methylmercury as Prototype
Most current concerns about methylmercury arise from its potency
in the developing human. Minamata suggested, and Iraq confirmed,
that the fetus and neonate are far more sensitive than the adult. Clarkson
and his colleagues, in a series of analyses based on the Iraq disaster
(e.g., Clarkson et al., 1981), now suggest that the fetus may be as
much as ten times more vulnerable than the adult to methylmercury.
Such calculations are based on the appearance of paresthesias in adults
with total body burdens of 25 mg and of retarded motor development,
of a type leading to a diagnosis of cerebral palsy, in children whose
mothers accumulated a body burden of 2.5 ma. These are clinical
criteria based on examinations conducted in rural Iraq, not on the
kind of careful neuropsychological evaluation possible in major medical
centers.
It is provocative to consider what kind of results might have emerged
from the application of what are considered to be more sensitive and
specific tests currently found in neuropsychological testing centers,
such the Bayley Scales of Infant Development used by Bellinger et al.
(1987~. Even such instruments are crude compared to the tools described
in the current literature of child development, although they offer the
virtue of standardization. Given our experience with lead, we might
predict that reliance on even these imperfect instruments could amplify
sensitivity by a factor of four or five. Research now in progress
suggests that, in fact, the developmental neurotoxicity of methylmer-
cury might have been underestimated, on the basis of clinical criteria,
by almost such a factor.
It might be equally provocative to imagine the conclusions that
would have been fostered by the kinds of schemes now envisaged for
identifying neurotoxicity and then for extending it to risk estimates.
Gross neurotoxicity in developing animals would surely have been
identified at high doses by observations of developmental disorders.
In rats, a massive study designed to evaluate reproducibility of behavioral
observations between laboratories, the Collaborative Behavioral Teratology
OCR for page 409
SCOPE AND PROMISE OF BEHA VIORAL TOXICOLOGY
409
Study (CTBS), chose 6 mg/kg, administered on gestation days 6-9 or
12-16, as the high dose on the basis of a preliminary study (Buelke-
Sam et al., 1985~. Most of the six participating laboratories would
have selected that dose, a total of 24 mg/kg, as the LOAEL, on the
basis of indices such as maternal and offspring weight gain together
with a variety of behavioral indices.
Unfortunately, the protocols included neither sensitive morpho-
logical indices nor measurements of methylmercury tissue levels, so
that a direct comparison with neurotoxic health risk estimates based
on human data is not feasible, but crude parallels can be constructed
from knowledge of levels prevailing in fish. The Food and Drug
Administration action level is 1 ppm. Most swordfish exceed this
level. Shark, an increasingly popular seafood, has an even higher
content than swordfish. Freshwater pike from the Adirondacks, because
of acid rain, typically exceed 1 ppm of methylmercury as well. Assume
that a pregnant female consumes seven fish meals, within a one-
month period, of a species at the FDA action level. If each meal
consists of 240 grams of fish, she will accumulate a body burden of
1,680 grams.
For a body weight of 70 kg, this amounts to 24 ,ug/kg, or 1/1,000 of
the rat-based LOAEL. Such a body burden is equivalent to what is
now suggested to be the human LOAEL.
However, there is another provocative feature to methylmercury
that might multiply our risk estimates even more. Spyker (1975)
maintained mice, after prenatal treatment, for a lifetime. In mice
that, until that time, had manifested no adverse effects, neurological
disorders began to appear at about 15 months of age, and even in
superficially healthy mice, behavioral testing revealed functional im-
pairment. As the mice aged, they revealed more and more disorders.
These observations are a powerful argument for longitudinal studies,
but an even more powerful argument for including such possibilities
in risk assessment. Spencer (this volume) offers a compelling argument
that earlier cycad exposure may trigger the eruption of the amyotrophic
lateral sclerosis/parkinsonism-dementia (ALS-PD) syndrome even
decades later.
Individual Differences
More than other areas of toxicology, BT is sensitive to individual
differences. Other disciplines typically model results solely as means,
or even, as in carcinogenesis, within a stochastic model that relates
total exposure in a population to number of tumors irrespective of
the distribution of exposure. Some of our sensitivity perhaps stems
OCR for page 410
410
BERNARD WEISS
from the historical junction of diagnosis with psychometrics; some of
it may stem from our laboratory experiences with allegedly homoge-
neous groups of animals whose members all seem to exhibit unique
experimental personalities, especially when we trace the development
of a process such as learning. Despite our awareness (sometimes
subliminal) of individual differences, most papers in BT, like most
papers in toxicology, assume that subjects (animal and human) come
from a uniform population and treat the data, as well as the design,
accordingly. It is not the best approach to defining the characteristics
of low-dose, chronic exposure.
Physiologists are also now question-
ing the usefulness of group analyses without the data of individual
subjects—a tradition exemplified by operant experimenters.
Even acute experiments may lead to wayward conclusions if indi-
vidual differences are ignored. Ben F. Feingold was a pioneering
pediatric allergist who formulated the hypothesis that some of the
children labeled as hyperactive were actually responding to certain
constituents of the diet (Feingold, 1975~. Although he singled out
synthetic colors and flavors, mostly because he doubted their nutritional
value, his hypothesis had roots in an extensive allergy literature, but
he never held that all children with that label suffered from excessive
sensitivity to additives.
I have reviewed the experimental data generated by the Feingold
hypothesis on several occasions (e.g., Weiss, 1982, 1986a). Two gen-
eralities arise from those data. First, Feingold was correct in prin-
ciple: some children respond adversely to colors and perhaps to
other additives. Second, the prevailing view that the Feingold hypothesis
has been disproved is mostly attributable to the naive statistics practiced
by experimenters and reviewers alike. Some flaws stem from the
assumption of a uniform population and are illustrated in Figure 3.
Assume a population comprised of 70 percent nonresponders and 30
percent responders (A). Then assume a treatment that shifts the re-
sponders by one standard deviation (B). The distribution (C) shows
the results for the sample as a whole; the difference in means is
hardly visible. The usual procedure for extrapolating animal data to
human standards imposes a safety or uncertainty factor to compensate
for wide individual differences in sensitivity. Although no one disputes
that such differences exist, that recognition exercises little influence
on experimental design and analysis. Even in the laboratory within a
group of rats of the same age and strain, we see remarkable differ-
ences in the behavioral response to toxicants such as lead and have
had to develop special statistical techniques to quantify these differ-
ences.
OCR for page 411
SCOPE AND PROMISE OF BEHAVIORAL TOXICOLOGY
.40 -
.30
O .20
o
.10
ICY
PIP
it_
O' id, , , , , , ,
4.0 8.0 12.0 16.0 20.0
A
.40 -
.30 -
2
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411
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ire
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4.0 8.0 12.0 16.0 20.0
SCORE
FIGURE 3 Hypothetical distributions showing interpretive difficulties arising from
studies of populations comprised of both responders and nonresponders. (A) Distri-
bution of scores, before toxic challenge, in a population consisting of 70 percent
nonresponders (taller distribution) and 30 percent responders (shorter distribution).
(B) Distribution of scores, shown separately for responders and nonresponders, to a
toxic challenge that displaces the responders by one standard deviation. (C) Combined
distribution, shown by heavy line, of nonresponders and responders. The difference
in means, enclosed by the vertical dotted lines, indicates that even a significant displacement
of the responders alters the mean of the distribution only slightly under these circum-
stances; only with large samples could such an effect be detected consistently.
OCR for page 412
412
BERNARD WEISS
THE REMOTE FUTURE
Behavioral toxicology first emerged as an alternative to traditional
markers of toxicity such as tissue damage and as a potential reservoir
of more sensitive methods for measuring toxicity. Impelled, per-
haps, by regulatory questions, it veered from the sensitivity issue
toward the development of techniques for the detection of neurotox-
icity. Much of it remains clasped in the identification phase of risk
assessment, a status that tends to isolate it from new advances in
behavioral and neuroscience and that negates much of its early promise.
Risk assessment is viewed as the critical coupling of toxicological
science and public policy. Behavioral toxicology surely has more to
offer this process, and much more to extract from it, than a list of
procedures. What other discipline is in the unique position of access
to a technology for tracing a progression of toxicity from early, subtle
effects to clear impairment? What other perspective on toxicology
can integrate such a rich configuration of endpoints (Weiss, 1986b)?
If BT abandons its early promise by confining itself to narrow ques-
tions of techniques for identification, it could rupture its close rela-
tionship with the major concerns of public health. The science will be
the greater victim.
ACKNOWLEDGMENT
Preparation supported in part by grants ES01247, ES01248, and
ES044929 from the National Institute of Environmental Health Sciences.
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Representative terms from entire chapter:
bernard weiss
