Behavioral Measures of Neurotoxicity (1990) / Chapter Skim
Currently Skimming:
Bridging Experimental Animal and Human Behavioral Toxicology Studies
Bridging Experimental Animal and Human Behavioral Toxicology Studies
Pages 137-158
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From page 137... ...
One derives from the growing recognition of the need to screen for performance impairment prior to the introduction of new chemicals into the environment, as well as to provide information relating to risk assessment based on neurotoxic endpoints. The second agenda involves the more traditional role of behavioral toxicology as the scientific discipline defined above, whose goal is to understand both the behavioral and the biological mechanisms by which toxicants impact behavioral function.
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From page 138... ...
STATE OF DEVELOPMENT Although the experimental capabilities for more precisely delineating behavioral and biological mechanisms of toxicant-induced performance impairment are generally at hand, the discipline remains largely at a characterization or descriptive stage of development. Much of its scientific literature attempts little more than to ascertain whether a particular toxicant alters a particular class of behavior, or to assess performance impairments produced by a toxicant across a range of behavioral endpoints; in some cases, only the barest approximation to a hypothesis may be invoked.
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From page 139... ...
The various studies are subdivided on the basis of both the type of visual cue utilized and the developmental period of lead exposure. Plus signs show those experiments reporting an impairment of visual discrimination learning as a result of lead exposure, whereas minus signs accompany those that found no change.
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From page 141... ...
Experimental animal studies also reveal that lead impairs learning based on the acquisition of spatial discrimination and can be categorized on the basis of both the route and the developmental period of exposure. Table 2 illustrates several additional issues of importance TABLE 2 Lead-Induced Changes in Spatial Discrimination Learning Developmental Period of Lead Exposure Exposure Route Oral Intraperitoneal Pre- or postnatal +Snowdon (1973)
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From page 142... ...
Thus, different behavioral performances may exhibit quite different critical periods of exposure to a toxicant, or the critical exposure period for behavioral effects produced by a toxicant may be determined at least partly by the sensitivity of the behavioral procedure. Comparative changes in schedule-controlled behavior induced by lead exposure reveal additional aspects of its behavioral toxicity, aspects that in turn may impact on, or even underlie, other lead-induced performance effects.
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From page 143... ...
Plotting changes in FI response rate against the reported blood lead values in each study produces a similar function (Cory-Slechta, 1984~. The potential generality of the dose-effect function is evidenced by the similarity of the lead-induced changes in rates of responding that have been described in other temporally based reinforcement schedules.
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From page 144... ...
, rather than on temporal parameters, exhibit a different pattern of lead effects, another indication that its behavioral toxicity is dependent upon the environmental or behavioral context. Although high-level exposures to lead are reliably associated with decreases in response rate on ratio schedules, evidence for rate-enhancing effects at lower exposure levels is not compelling (Angell and Weiss, 1982; Barthalmus et al., 1977; Cory-Slechta, 1986; Padich and Zenick, 1977; Rice, 1988~.
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From page 145... ...
Microanalysis of FI performance reveals that if pause time can be construed as an index of timing behavior, it remains intact. However, once responding begins, response rates of lead-exposed rats greatly exceed those required by the reinforcement schedule, suggesting as one possibility, a decreased responsiveness of lead-exposed organisms to the feedback generated by their own behavior on the schedule.
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From page 146... ...
Nevertheless, the utilization by experimental animal studies of more sensitive and specific behavioral endpoints than have been incorporated into many of the human studies in this area, has led over the past five years or so to a striking correspondence between results in the two areas (shown in Figure 3) in the reported levels of lead in blood at which behavioral deficits are reported.
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From page 147... ...
One is that emerging scientific disciplines such as behavioral toxicology require reliable, systematic characterization studies as a sound base for further efforts. Proceeding to mechanistic-based studies in the absence of such information, or on the basis of unreliable information, would be premature and even counterproductive.
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From page 148... ...
Although many studies utililze a multidisciplinary approach, concurrently measuring various indices of behavioral outcome and changes in neurotransmitter levels in response to a neurotoxicant, for example, few studies undertake the types of definitive experiments required to determine the precise nature of such relationships, which then remain correlational in nature. Probably one of the primary factors constraining both the scope and the advancement of behavioral toxicology may be the preponderance of "apparatus-driven" research.
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From page 149... ...
A more complex behavioral procedure known as repeated acquisition, or acquisition of response sequences, originated partly because of such a need (Borer, 1963~. In this particular task, the organism is required to learn a new sequence of responses of fixed length during each experimental session.
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From page 150... ...
This is especially advantageous because the performance component allows the assessment of nonspecific chemical effects, as would be exemplified by changes that occur in both the learning and the performance components, whereas behavioral alterations observed exclusively in the learning component may more specifically reflect changes in learning. Representative performance of a nonhuman primate responding under such a schedule is shown in Figure 5, in which a separation of the effects of d-amphetamine on the learning and the performance components is evident.
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From page 151... ...
This is accomplished by retesting the acquisition of the learning component sequence at various time intervals following the original learning. In spite of the emphasis on toxicant and chemical-induced alterations in learning, only two studies to date have utilized the repeated acquisition baseline to evaluate to~c~cant-~nduced lear~ung deficits.
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From page 152... ...
Another strategy useful to facilitate cross-species extrapolation, that is, to bridge experimental animal and human behavioral toxicology studies, is to strongly emphasize the use of behavioral paradigms that are directly applicable to both populations. Operant schedules of reinforcement exemplify one class of such baselines.
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From page 153... ...
Thus, although admittedly difficult to train, the response sequence paradigm shows comparable baseline performance across species and evidences sensitivity both to drugs and to neurodegenerative disease. Other learning and memory paradigms with direct crossspecies applicability include procedures such as delayed alternation and delayed matching to sample.
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From page 154... ...
and Alzheimer's patients (Alz; bottom panels) working on a five-link repeated acquisition paradigm.
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From page 155... ...
1976. Auditory and Visual Discrimination Learning in Sheep Prenatally and Postnatally Exposed to Lead.
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From page 156... ...
1979. Behavioral effects of postnatal lead acetate exposure in developing laboratory rats.
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From page 157... ...
1983. Behavioral effects of chronic lead exposure in the adult rat.
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From page 158... ...
1980. Repeated acquisition of fourmember response sequences in rats.
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