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OCR for page 347
Environmental Modulation of
Neurobehavioral Toxicity
Robert C. MacPhai!
INTRODUCTION
There is an inevitable tension in neurobehavioral toxicology re-
search between focusing experimental attention inward and outward.
This tension is largely due to a clash between those who view behavior
as a by-product of nervous system activity and those who view it as
a by-product of dynamic forces operating in the environment. My
opinion is that although both views may be justifiable, the development
of a comprehensive conceptual and empirical framework in neuro-
behavioral toxicology must promote and capitalize upon both ap-
proaches. I would like to provide evidence of the relative neglect of
environmental variables in neuroscience, the importance of environmental
variables in modifying the effects of toxicants, and a framework for
systematically determining the importance of environmental variables
in modifying the effects of toxic chemicals on acquired behavior. Fi-
nally, I would like to speculate on how that framework can be used
to address some of the important research issues in the future.
Some introductory remarks are in order concerning a framework
for describing behavior in relation to the environment. Consider, for
example, a continuum such as that shown in Figure 1 in which be-
havior is related to stimulus events. At one extreme, behavior is
represented principally as a reaction to stimuli. Such behavior is
elicited, and the procedures by which elicited behavior is acquired
and maintained involve respondent conditioning. At the other extreme,
347
OCR for page 348
346
ROBERT C ~CP~
BAR
RESPONDENT ~PON~NEOUS" OPER^NT
BEH^VIOR BEHAVIOR BEH^VIOR
FICORE 1 Relabonsh~ between behavioral response classes (R) ad con~l~g stimulus
events (S) in Me environment.
~ _ c
(Whole Animal Behavior)
Peon Caulk (Stems)
~ Clout (Rains)
Cell O~anelle
Molecules
ions
FIGURE 2 Levels of organization in the nervous system.
SOURCE: Prom Shepherd (19897
behavior is principally represented as the result of consequent gather
than antecedent) shmub. This type of behavior ~ emitted, and the
procedures by which emitted behavior ~ acquired and maintained
involve operant conditioning. Intermediate between these extremes'
the relationship between controlling stimulus events and behavior is
~dear. Wader these chc~stances, behavior is said to be spontaneous,
although ~ should be recognized that to label a behavior spontaneous
is only to affirm our ignorance regarding Us controUing variables.
An implicit assumption in neuroscience ~ that behavior ~ a by-
product of nervous system activity. Although the steadily increasing
co~orabon of behavior analysis into neuroscience research is salutary,
the lack of appreciation of the importance of the environment is not
For example, in his textbook on Neurobiology' Shepherd (1989) pre-
sented Me hierarchical scheme for nervous system organization shown
in Figure 2. Behavior, according to this scheme, represents the inte-
grated output of multiple neuronal processes and pathways. Such a
scheme implies that a neurological lesion can produce mulUple effects
OCR for page 349
MODULATION OF NEUROBEHAVIORAL TOXICITY
349
( ??Higher?? ;
-
~.
( Cognition ~
( Behaviors
-
Systems ~
-
( Nuclei
( Networks ~
, . .
-
( Neurons
( Synapses
( Molecules ~
FIGURE 3 Relationship between behavior and the nervous system: levels of progres-
sive complexity.
SOURCE: From Bloom (1988).
on behavior and, conversely, that a change in behavior can come
about because of changes in the activity of different neuronal pathways.
Although such a scheme may have substantial heuristic value, it fails
to recognize the important role the environment plays in determin-
ing behavior. Similarly, Bloom (1988) recently presented a more elaborate
organizational scheme of nervous system function. That scheme, shown
in Figure 3, also completely fails to recognize the fact that behavior
and its environmental context are for all intents and purposes insepa-
rable.
Presenting these schemes should in no way be construed as an
effort to disparage attempts to define the role of behavior in neurobi-
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350
ROBERT C. MACPHAIL
ology. It should be clear, however, that environmental consider-
ations have been largely neglected in neurobiology research. A com-
prehensive approach in neurobehavioral toxicology can come about
only by jointly defining the intrinsic and extrinsic determinants of
behavior. The reasons environmental considerations are important
in toxicology can be made clear with a few examples taken from the
literature.
MODULATION OF LETHALITY
The dramatic influence of environmental conditions on the lethal
effect of amphetamine-like drugs has been well established. Events
such as crowding, loud noise, high ambient temperature, and electric
shock can substantially increase the lethal potency of sympathomi-
metic amines. In a relatively recent demonstration, for example, Landauer
and Balster (1982) showed that the LD50 of d-amphetamine was sub-
stantially lower when mice were housed in groups of 12 than in iso-
lation (2.8 versus 82 mg/kg, respectively).
Siegel et al. (1982) showed that environmental events could also
modify heroin lethality. In this experiment, rats received a series of
escalating dosages of heroin so that they could survive an otherwise
lethal dosage. Heroin was always administered on alternate days in
a distinct environment, whereas the heroin vehicle was administered
in an equally distinct environment on intervening days. The rats
were then challenged with a much larger dosage of heroin. For half
the rats this dosage was administered in the heroin-associated envi-
ronment, whereas for the others it was administered in the vehicle-
associated environment. The same dosage of heroin was also given
to naive rats that had no history of heroin exposure. The results of
this experiment are shown in Table 1. Heroin killed almost all of the
drug-naive rats (96.4 percent). Although prior exposure to heroin
produced fewer mortalities, the degree of protection was much greater
for rats receiving heroin in the heroin-associated environment (ST)
than for those receving it in the vehicle-associated environment (DT).
This experiment showed, therefore, that environmental and chemical
variables played an equally important role in modifying heroin-in-
duced lethality.
Poulos and Hinson (1982) showed that environmental circumstances
could also profoundly modify the ability of a drug to alter a nonlethal
form of behavior. Rats repeatedly received haloperidol in one dis-
tinctive environment and vehicle in another. The regimen was designed
to induce tolerance to the cataleptic effect of haloperidol. The rats
were then treated with haloperidol in either the haloperidol-associated
OCR for page 351
MODULATION OF NEUROBEHAVIORAL TOXICITY
TABLE 1 Rat Mortality After Injection
of Heroin at 15 mg/kg
Number Mortality
Group of Rats (%)
STa 37 32.4
DTb 42 64.3
Control 28 96.4
aHeroin-association environment.
Vehicle-associated environment.
SOURCE: Siegel et al. (1982).
TABLE 2 Cataleptic Response of Each Group to Haloperidol
(1.5 mg/kg) at Each Assessment Interval (Values Are Means +
Standard Errors)
357
Duration of Cataleptic Response (s)
Time After Rats Tested in Rats Tested In
Haloperidol Drug-Associated Sal~ne-Associated
Injection Control Rats Environment Environment
25 109.8 + 16.8 22.8 + 5.4 108.7 + 16.5
50 136.8 ~ 13.5 45.8 ~ 11.3 125.8 ~ 13.6
75 169.6 + 5.7 68.3 + 15.8 157.6 + 10.9
SOURCE: Poulos and Hanson (1982).
Or the vehicle-associated environment, and the duration of catalepsy
was measured. Haloperidol was also administered to drug-naive rats.
The results are shown in Table 2. When compared to drug-naive
rats, the other rats were either almost completely tolerant or completely
intolerant to Haloperidol depending on whether they received it in
the haloperidol-associated or the vehicle-associated environment. Clearly,
then, the environment can have profound effects on the behavioral
consequences of chemical exposure.
MODULATION OF OPERANT BEHAVIOR
lethality (or survivability) and catalepsy are rather gross and glo-
bal aspects of behavior. What about more subtle aspects? To what
extent do environmental variables modulate toxicant effects on more
subtle forms of behavior? This question can best be addressed through
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352
ROBERT C. MACPHAIL
research on schedule-controlled operant behavior. Conditioned be-
.havior shoulc! offer advantages over unconditioned behavior because
of the degree to which environment-behavior relationships can be
specified. As Dews (1962) said, "To express a preference for working
with conditioned behavior Is thus merely to express a preference for
working with well~on~olled situations rawer Wan vale ones." Schedule
controlled operant behavior is particularly appropriate because of
the degree to which the relevant environmental controlling variables
can be identified, specified, and manipulated. Such a degree of
specification promotes reproducibility and sensitivity, and fosters
mechanistic approaches. The basic paradigm and Me controlling variables
are shown in Figure 4. A wealth of data exists on the importance of
each of these variables in the control over operant behavior.
Schedule-controlled operant behavior has been used extensively
and profitably in evaluating the effects of a wide range of drugs on
conditioned behavior. A fundamental concept in this research in-
volves drug-behavior interactions (Sidman, 1956), or the joint dependence
of drug effects on the drug and the variables maintaining behavior.
More than three decades of research have shown that drug-behavior
. Schedule-Controlled Behavior: Operant Paradigm
ED * R ~ sR
2. Controlling Variables:
A. SD: Discrimintative Stimuli
Qualitative difference
2. Quantitative difference
B. R: Response Effects
1. Topography
2. Ongoing rate
C. SR: Reinforcer Effects
1. Qualitative differences
2. Quantitative differences
D. R ~ SR: Schedule Effects
1. Differing schedules
2. Differing parameters of the same schedule
. SD: SR Effects
Historical Variables
1. Long term
2. Short term (context)
FIGURE 4 Operant paradigm and the variables determining schedule-controlled behavor.
Behavior (R)-occurring in a stimulus environment (SD ~ R) produces changes (hi) in that
environment. Changes that maintain or strengthen behavior are called reinforcers (SR).
OCR for page 353
MODULATION OF NEUROBEHAVIORAL TOXICITY
353
interactions prevail widely in behavioral pharmacology. In fact, re-
search is available to show that each and every variable represented
in Figure 4 has been able to modify the effects of drugs on schedule-
controlled behavior. A fundamental question to be addressed in
neurobehavioral toxicology is the extent to which the effects of expo-
sure to environmental chemicals may also be influenced by these
variables (MacPhail, 1985~.
PESTICIDES
Some of our recent work showing how schedule variables modify
the effects of pesticides is described here. Pesticides represent an
extremely diverse array of substances, many of which (e.g., insecti-
cides) are specifically designed to adversely affect the nervous sys-
tem. Although there are, in general, considerable data on organo-
phosphate, carbamate, and organochIorine pesticides, many newer
pesticides- for example, formamidine and pyrethroid insecticides and
triazole fungicides have not undergone thorough evaluation.
In one experiment, the elects of the formamidine insecticide
chlordimeform were determened on the schedule-controlled behav-
ior of pigeons (Leander and MacPhail, 1980~. Pigeons performed
under a multiple schedule in which fixed-interval reinforcement alternated
with fixed-ratio reinforcement. Figure 5 shows that chlordimeform
generally decreased overall fixed-interval responding in a dosage-
dependent manner. The decreases in overall response rate were also
accompanied by a disruption of the fixed-interval pattern of responding.
Intermediate dosages of chiordimeform produced either no change
or increases in fixed-ratio responding, while larger dosages uniformly
decreased responding. Estimates of the dosage producing a 50 per-
cent reduction in responding were, depending on the pigeon, be-
tween 30 percent and 300 percent greater for fixed-ratio than for fixed-
interval performance. These data show therefore that the particular
schedule maintaining responding can influence the magnitude of the
effect produced by chlordimeform.
In another experiment, the effects of three formamidine insecti-
cides on schedule-controlled behavior were compared (Moser and
MacPhail, 1986~. The three formamidines included chiordimeform,
amitraz, and formetanate. Formetanate was unique in that it also
contains a carbamate moiety. Rats performed under a multiple schedule
in which presentation of two fixed intervals of different length alter-
nated throughout the session. The results of this experiment are
shown in Figure 6. The three pesticides could be differentiated on
the basis of their multiplicity of effects. Chlordimeform substantially
OCR for page 354
354
ROBERT C. MACPHAIL
180
160
140
120
100
so
l i
BIRD 1413
FOR
FI / ~
_· I ~
60
In 4o
20
o o
Ct
2
0 180 - BIRD 4571
O 1"
Z 140
-O 1 20
UJ
Am.
J
80
60
40
20
O ,
BIRD 4574
\
.
\ \
\\\~
a~~
BIRD 2983
\j:_
.
. _ ~
0.625 2.S 10 40
0 1.25 5 20
\\
\\
. \
.~
0.625 2.5
o 1.25 5
MO/KG DOSE OF CHLORD.IMEFQRM
(1 ~ )
10 40
20
FIGURE 5 Schedule-dependence of the effects of chlordimeform on operant behavior.
Dosage-response functions were determined for the, effects of chlordi~meform in pi-
geons~ responding maintained with, fixed-interval (FI) or fixed-ratio (FR) reinforce-
ment. Data are plotted as percent of' vehicle-injected' control (0 mg/kg) response rates.
In absolute terms, FR response rates were much higher (2.~.8x, depending on the
pigeon) than FI response rates. Brackets at 0 mglkg represent +1 SD around the
control mean. Filled circles represent effects on FR responding and unfilled circles
represent effects on FI responding.
SOURCE: From Leander and MacPhail (1980).
OCR for page 355
MODULATION OF NEUROBEHAVIORAL TOXICITY
100
80
an 60
-
o
an
a:
1
lo:
LO
cat
i
40
20 r
80
60
40
20
o
F1 1 min
CPM ~
/ AMZ
FIT
l
~ I I ~ 1 1 1 1-' 1 1
_ F15min 1~
. . .
CDM /'
7dLh
~ IT
'*~ AMZ
r · I . . , , · . .,
0 20 40 60 80 100
MEAN PERCENTAGE
DECREASE RESPONSE RATE (+ SE)
355
FIGURE 6 Differentiation of the effects of formamidine insecticides on schedule-con-
trolled behavior. Dose-response functions were determined for chlordimeform (CDM),
amitraz (AMZ), and formetanate (FMT) on the performance of rats maintained under a
multiple fixed-interval/fixed-interval schedule of reinforcement (FI 1 min. FI 5 min).
Disruptions in response patterning (decreases in index of curvature, IOC) are plotted
as a function of corresponding decreases in overall effects. Dashed lines represent
hypothetical equivalent effects.
SOURCE: From Moser and MacPhail (1986).
disrupted the temporal pattern of responding maintained under the
long fixed interval while producing a much smaller change in overall
rate of response. Formetanate, on the other hand, selectively decreased
overall response rate while producing little disruption in the tempo-
ral pattern of responding. Amitraz produced intermediate effects.
Although the upper panel shows that differences in effect were also
obtained under the short fixed interval, it is-clear from this figure
how the schedule parameter can magnify differences in the effects of
OCR for page 356
356
ROBERT C. MACPHAIL
chlordimeform and, to a lesser extent, amitraz. The effect of formetanate,
on the other hand, did not appear to depend on the schedule param-
eter. This finding, along with the fact that overall rate but not pattern
was mainly affected, suggested that formetanate acted more like a
carbamate than a formamidine. This prediction was confirmed by
pharmacological blocking experiments showing that muscarinic receptors
were involved in the action of formetanate (Moser and MacPhail,
1987~.
An analysis of toxicant effects on fixed-interval patterns may play
an important role in neurobehavioral toxicology. A particularly dra-
matic example of the relativity of toxicant effects on fixed-interval
behavior involves the triazole fungicide triadimefon. Triadimefon
was found to increase levels of motor activity in rats (Crofton et al.,
1988; Moser and MacPhail, 1989), and to induce stereotyped behavior
in rats following large dosages (Moser and MacPhail, 1989~. These
effects suggested that triadimefon acted in a way similar to that of
the psychomotor stimulants. Because psychomotor stimulants have
been shown to disrupt temporal patterns of responding, triadimefon's
effects were determined on performance maintained under the mul-
tiple fixed-interval schedule described above (Allen and MacPhail,
1988~. Triadimefon produced a dosage-related disruption in the temporal
pattern of responding under the long fixed interval. Response pat-
terning was almost completely eliminated following the largest dos-
age. Patterning under the short fixed interval, however, was only
slightly affected by triadimefon. This selectivity of effect is remarkable
if one considers that there was no difference in the extent of temporal
patterning maintained by the two schedules under baseline conditions.
The dosage disrupting response patterning by 50 percent was estimated
to 'tee five times smaller for performance under the longifixed interval.
The effect of triadimefon was also remarkable in that overall rates
under the long fixed interval changed very little despite the dosage-
related disruption of response patterning.
Findings such as these suggest that relatively subtle environmen-
tal variables may have substantial effects on the behavioral conse-
quences of some pesticide exposures. It is tempting to speculate that
many of the other variables shown in Figure 4 could also substantially
influence the effect of formamidine and triazole pesticides on sched-
ule-controlled behavior, whereas the' importance of these variables in
modifying the effect of carbamates may be relatively negligible (see
also MacPhail,1985~. Questions remain concerning the relative importance
of these variables in determining the effects of a wide range of other
environmental chemicals.
OCR for page 357
MODULATION OF NEUROBEHAVIORAL TOXICITY
RESEARCH DESIGN
357
Research designed to evaluate environmental contributions to toxicant
effects will likely have both a practical and a fundamental impact in
neurobehavioral toxicology. In a practical sense, results such as the
above serve to define more completely optimal conditions of testing
to ensure that a toxicant's effect will be detected if indeed it exists.
Hazard identification studies could be improved greatly if sufficient
detail were given to describing and controlling the environmental
context in which behavior is evaluated. Fundamentally, however,
this type of approach is critically important not only in helping to
define the full range of effects associated with chemical exposures,
but also in determining the behavioral and neurological mechanisms
by which these effects are produced. An integrated conceptual framework
such as that shown in Figure 7 can then be used to focus research
Chemical Exposures
Nervous System
Chemistry
. .~
Behavior
Environment
FIGURE 7 Conceptual framework for relating behavior and chemical exposures to the
environment and the nervous system. Chemical exposures produce changes in ner-
vous system chemistry (A) that can then lead to behavioral changes (B). Performance
of certain behavior can also affect nervous system chemistry (C). Mutual interrelation-
ships exist between behavior and the environment in which it occurs (D,E). Environ-
mental variables can also affect nervous system chemistry without clear behavioral
concomitants (F). One important feature not readily apparent in this scheme is that
behavior operating on the environment may also alter the intensity or frequency of
exposure to environmental chemicals.
OCR for page 358
358
ROBERT C. MACPHAIL
effort as well as to assimilate new information derived from diverse
research efforts. Such information can then serve as the basis for
making informed decisions in estimating risks due to chemical expo-
sure and the steps needed to effectively and efficiently regulate expo-
sures.
REFERENCES
Allen, A. R., and R. C. MacPhail. 1988. Effects of the triazole fungicide triadimefon on
schedule-controlled behavior: Comparison with methylphenidate. Paper presented
at the annual meeting of the Association for Behavior Analysis.
Bloom, F. E. 1988. Neurotransmitters: Past, present and future. FASEB Journal 2:32-
42.
Crofton, K. M., V. M. Boncek, and L. W. Reiter. 1988. Hyperactivity induced by
triadimefon, a triazole fungicide. Fund. Appl. Toxicol. 10:459~65.
Dews, P. B. 1962. Monoamines and conditioned behavior. Pp. 143-151 in Symposium
sur les Monoamines et le Systeme Nerveux Central de Ajuriaguerra . Geneva :George
et Cie.
Landauer, M. R., and R. L. Balster. 1982. The effect of aggregation on the lethality of
phencyclidine in mice. Tox. Lett. 12:171-176.
Leander, J. D., and R. C. MacPhail. 1980. Effect of chlordimeform (a formamidine
pesticide) on schedule-controlled responding of pigeons. Neurobehav. Toxicol.
2:315-321.
MacPhail, R. C. 1985. Effects of pesticides on schedule-controlled behavior. Pp. 519-
535 in Behavioral Pharmacology: The Current Status, L. S. Seiden and R. L. Balster,
eds. New York: Alan R. Liss.
Moser, V. C., and R. C. MacPhail. 1986. Differential effects of formamidine pesticides
on fixed-interval behavior in rats. Toxicol. Appl. Pharmacol. 84:315-324
Moser, V. C., and R. C. MacPhail. 1987. Cholinergic involvement in the action of
formetanate on operant behavior in rats. Pharmacol. Biochem. Behav. 26:119-121.
Moser, V. C., and R. C. MacPhail. 1989. Neurobehavioral effects of triadimefon, a
triazole fungicide, in male and female rats. Neurotoxicol. Teratol. 11:285-293.
Poulos, C. X., and R. Hinson. 1982. Pavlovian conditioned tolerance to haloperidol
catalepsy: Evidence of dynamic adaptation in the dopaminergic system. Science
218:491~92.
Shepherd, G. M. 1989. Neurobiology. New York: Oxford University Press.
Sidman, M. 1956. Drug-behavior interaction. Ann. N.Y. Acad. Sci. 65:282-302.
Siegel, S., R. E. Hinson, M. D. Krank, and J. McCully. 1982. Heroin "overdose" death:
Contribution of drug-associated environmental cues. Science 216:43~37.
Representative terms from entire chapter:
neurobehavioral toxicity
