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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

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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

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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

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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).

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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

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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).

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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

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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.

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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.

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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.