Behavioral Measures of Neurotoxicity.pdf

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CONTENTS

Assessment of Animal Models: What has Worked and What is Needed

Chemical Time Bombs: Environmental Causes of Neu- rodegenerative Diseases

Behavioral Measures of Neurotoxicity

INTRODUCTION

The unanimous answer was: "From the womb to the grave". The existence of critical issues at the beginning of this broad range was highlighted in 1987 by the appearance of the following statement in the journal Reproductive Toxicology: "The most important data [for assessing female reproductive risk] come from studies reported in humans, however. these are not generally available" (Sakai, 1987). Discussion of experimental approaches to the study of neurobehavioral toxicity leads inevitably to consideration of the roles of animal models (Russell and Overstreet, 1984).

ARE NEUROTOXINS DRIVING US CRAZY? PLANETARY

OBSERVATIONS ON THE CAUSES OF NEURODEGENERATIVE DISEASES OF

OLD AGE

Leonard Kurland, Extent of Neurofibrillary Changes Expected at Age 75 in the US Population. Historically, these effects have been linked to the hepatotoxic and neurotoxic properties of methylazoxymethanol (MAM), an aglycone glycoside of cycad seed. cycasin.

ASSESSMENT OF

NEUROBEHAVIORAL TESTS NOW IN USE

Current Test Batteries and Need for Development

Descriptions of the tests were published in a separate booklet (Hanninen and Lindstrom, 1979), and some of them have spread to wider use in behavioral toxicology: the Santa Ana skill test, the Bourdon-Wiersma vigilance test, the Benton visual memory test. and selected subtasks of the Wechsler Adult Intelligence Scale (WAIS). The tests had to be minimally dependent on the subjects' culture and education.

TABLE 1 Eight Batteries for Behavioral Toxicity Testing Study 1

The Current Status of Test Development in Neurobehavioral Toxicology

This battery has undergone some validation (Baker et al., 1983), although the description of the test reliability study is not clear (Fidler et al., 1987). Validity and reliability studies were conducted by Carroll in the development of the theory. Battery sensitivity has been assessed to some extent in studies of the effects of carbon monoxide and alcohol (Foree et al., 1984).

Unless all possibilities are tested, no clear conclusions can be drawn regarding the effect of the suspected toxin. The above position regarding the usefulness of theory-based test batteries is also relevant to the question of the main targets of neurobehavioral testing. Most of the remaining barriers to test development are due to the state of knowledge in neurobiology and neuropsychology.

There is a significant possibility that the development of tests will be forced to take a back seat in favor of research focusing on the effects of the many toxic substances that have not yet been studied. 34;contemplation of the navel." Neurobehavioral toxicology must make test development at least as important as the analysis of toxic effects if it is to make further progress. This would also provide a much more comprehensive picture of the breadth of the effects of a particular toxic danger.

Human Neurobehavioral Toxicology Testing

At the end of the meeting, Weiss and Laties (1983) of the University of Rochester summarized their opinion for EPA: "This collection of papers provides the most emphatic statement yet of the imperative for the Environmental Protection Agency to avoid testing. [selection ]. Two rationales can be formulated for the selection of tests in a reasonably comprehensive battery of the kind needed to assess the range of behavioral changes produced by the variety of chemicals found in the United States. The tests were selected on based on two factors: (1) the type of symptoms reported by the exposed group to be tested and (2) the established neurotoxic effects of the chemical under study or structurally related chemicals.

The NES includes variants of five of the seven WHO-NCTB tests (noted with asterisks in Table 3). These and other factors have led NIOSH to identify neurotoxic disorders as one of the 10. In the United States, the earliest national sources of recommended exposure limits for industrial chemicals were the publications of the American Conference of Governmental Industrial Hygienists (ACGIH).

The power of the batteries, cognitive testing (particularly memory), focuses on the functions of the central nervous system (CNS). The WHO NCTB slightly outperforms both the NES and FIOH batteries in using the POMS test. It is the intention of the World Health Organization to conduct an assessment of the NCTB in eight countries (WHO, 1987).

TABLE 1 Finland's Institute for Occupational Health (FIOH) Test Battery

Neurobehavioral Tests: Problems, Potential, and Prospects

A preliminary study of the psychometric characteristics of this implementation of the NCTB has been reported (Camerino, 1987). Assume for the sake of debate that the validity of the measures averages around 0.75. In practice, a much more unfavorable base rate for the condition is likely to apply in the test population.

If it becomes possible to elaborate our understanding of the psychological processes (and perhaps as a contribution to that understanding), the use of such tests is clearly valuable. The idea of a global pool of test results may be superficially appealing, but not based on the psychometric reality of the situation. The target set by the expert system is of course the test result of the conventional test instrument.

This would simply require that the model be articulated well enough to be expressed in terms of the content of the rule base. Second, these functions must be summarized in the form of a psychological description of the general dysfunctional state resulting from neurotoxin exposure. Fourth, this needs to be translated into an evaluation system in terms of individual performance components.

ASSESSMENT OF ANIMAL MODELS

WHAT HAS WORKED AND WHAT IS NEEDED

Exposure to Neurotoxins Throughout the Life Span: Animal Models for Linking

Neurochemical Effects to Behavioral Consequences

Among the different components involved in the mechanisms of synthesis and degradation of ACh (Russell and Overstreet,. Furthermore, a large variability is evident in the response of individual females in terms of severity and duration of symptoms. Apart from the data reported by Pintor et al. 1988), the development of tolerance to the OP compound late in life has not been studied.

Strain differences are only significant in the hippocampus, where Fischer animals have lower activity levels. It is of considerable interest that marked differences in the concentrations of mAChRs have been described by Overstreet et al. 1984) for two of the above regions (hippocampus and striatum) in two selectively bred lines, Flinders sensitive line (FSL) and Flinders resistant. It is also evident that mAChR levels in the brains of the aged animals are significantly lower than in the brains of young rats.

Altered (3H)quinuclidinyl benzilate binding in rat striatum after chronic cholinesterase inhibition with diisopropylfluorophosphate. Selective breeding for differences in cholinergic function: Sex differences in the genetic regulation of sensitivity to anticholinesterase, DFP. Muscarinic receptor plasticity in the brain of senescent rats: Downregulation after repeated administration of diisopropylfluorophosphate.

TABLE 1 Effects of Subchronic Intoxication with DFP in Pregnant Rats on Gestation, Birth Statistics, and Litter Survival

Animal Models of Dementia: Their Relevance to Neurobehavioral Toxicology

Testing

Any manipulation of the animal's performance may confound the interpretation of the possible effects of that manipulation on learning. ANIMAL MODELS OF DEMENTIA: THEIR SIGNIFICANCE FOR NON-INVESTMENTAL TOXICOLOGICAL TESTING. his new digital representation of the original work was reassembled from XML files created from the original paper book, rather than page breaks matching the original; however, line lengths, word breaks, heading styles, and other betting-specific formatting cannot be typographical errors, and may have been inserted by mistake. It is not our intention here to summarize all the possible schedules that can be used.

Other researchers have now used it to study many manipulations of the cholinergic system. Our approach was to lure only three of the eight arms of a standard maze. Luring only three arms of the eight-armed maze allows for other procedural manipulations.

Some of the paradigms that can be used by neurobehavioral toxicologists to investigate the potential effects of a toxin on cognitive behavior. A measurement of the effects of a treatment on locomotor activity would be particularly useful as a simple non-manipulative task, if a researcher used a limited number of tasks to assess memory (eg, Dunnett et al., 1982). Effects of intrahippocampal injections of the cholinergic neurotoxin AF64A on open-field activity and avoidance learning in the rat.

Bridging Experimental Animal and Human Behavioral Toxicology Studies

Representative performance of a nonhuman primate responding under such a schedule is shown in Figure 5, where a separation of the effects of d-amphetamine on the learning and performance components is evident. Cumulative records illustrating the effects of the administration of d-amphetamine on the performance of a monkey working on a multiple schedule that alternated repeated acquisition or learning (L) and performance (P) components. The effects of developmental and/or direct lead exposure on FR behavior in rats.

Age of testing as a factor in the behavioral effects of early lead exposure in rats. Understandably, much of the concern about the effects of organic solvents focuses on the occupational environment where exposure can be relatively high. Until recently, most animal studies examining the neurotoxicity of organic solvents have focused either on the involvement of the nervous system in the acute lethality of these compounds or on the morphological changes that can result from chronic overexposure.

A number of factors contribute to the susceptibility of the CNS to the acute effects of organic solvents. Changes in the acute effects of trichlorethylene (TCE) on the number of short-term two-choice responses of rats during and after 18 weeks of exposure. Effects of carbon disulfide on complex nerve action potential latency measured from the caudal nerve during and after 36 weeks of exposure.

Thus, it is often difficult to obtain conclusive evidence on the identification of the causative agent(s) causing psychological changes based on the results of these studies. Effects of subacute treatment with toluene on cerebrocortical alpha- and beta-adrenergic receptors in the rat.