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Animal Moclels: What Has Workecl and What Is Neeclecl Robert C. MacPhail Biological continuity between species is the very foundation of modern biomedical science. Animal models are therefore indispens- able in evaluating a wide range of chemicals long before significant human exposures may occur. Animal models are also critical in un- raveling disease processes, as well as identifying and evaluating prophylactic and therapeutic treatments. Animal models offer the advantage of flexibility, precision, and reproducibility, but at the same time they raise nagging questions regarding their significance and generality. It is therefore quite fitting that this volume should deal with the topic of animal models of neurobehavioral toxicity. Hanna Michalek has described an extensive series of experiments using rats as an animal model for human exposure to organophosphate (OP) compounds. Rats appear to be very useful in understanding many of the actions of OPs, and also in developing therapeutic approaches to OP intoxication. More specifically her work focuses on the recep- tor changes accompanying acute and subchronic exposures, and the importance of age and genetic variables. Although acute OP toxicity is generally considered to be an inverse function of age, there are many exceptions. It remains to be determined how important meta- bolic factors are in determining age-dependent OP toxicity. Michalek has also shown differences in cholinergic function be- tween Fischer 344 and Wistar rats. With few notable exceptions, genetic considerations have rarely been addressed in neurobehavioral toxicology. Nevertheless, there are enough data to suggest that it is ~4

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ANIMAL MODELS: WHAT HAS WORKED AND WHAT IS NEEDED ]85 entirely too simplistic to refer to "the" rat, mouse, or monkey in describing one's research. What is needed is a broad-based program of research to determine directly the extent of differences between strains of stocks of commonly used laboratory species, in terms of both the basic neurobehavioral processes and the effects of chemicals. The evidence suggests that the mechanisms underlying acute OP intoxication, and the development of tolerance, may be very general across species. Therefore, we may be justified in pursuing research with rats, with due regard of course to metabolic, age, and genetic considerations. However, a notable effect of OP exposures in humans, and several other species is delayed neurotoxicity. Organophosphate- induced delayed neurotoxicity (OPIDN) is a permanent neuromuscular disorder involving the peripheral nervous system and spinal cord that can occur after acute exposures to many OPs. The syndrome has been clearly established in a variety of species, including humans. Rats have been widely considered refractory to the development of OPIDN, so it was a great surprise to find that Long Evans rats developed the neuropathy without displaying the clinical signs (e.g., Padilla and Veronesi, 1988~. Here too, genetic variables cannot be overlooked, because no evidence of OPIDN in Fischer 344 rats was recently reported (Somkuti et al., 1988~. The adequacy of rats as a broad-based model for OP toxicity would be greatly enhanced if functional effects could be revealed in OPIDN. The work of Russell, Overstreet, and several others has shown that tolerance develops to many of the behavioral and physiological effects of OPs with continued exposure. Recent evidence suggests, however, that learning and memory impairments may be present in rodents made tolerant to OPs (McDonald et al., 1988; Upchurch and Wehner, 1987~. These findings may be of tremendous importance and warrant a thorough systematic follow-up. If such findings can be substantiated, they would point to a basic complementarily between measures of learning and memory on the one hand and performance on the other. In addition, similar effects could be looked for in exposed populations of humans. In this way a much better appreciation could be gotten of the risks associated with exposure to OP compounds. David Overstreet and Elaine Bailey have reviewed some data on animal models of dementia. They rightfully point to the importance of using several tests to evaluate learning and memory, owing to the diversity of phenomena subsumed by these terms, as well as being able to eliminate confounds in interpreting test results. They have also highlighted the importance of using pharmacological and environmental challenges in neurobehavioral toxicology research. What is now needed, in addition to a lot more data, is a systematic evaluation

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186 ROBERT C. MACPHAIL of many of these methods by using standard treatments known to affect learning and memory. Work should also focus on evaluating those chemicals that have been thought to produce learning and memory deficits in humans (e.g., volatile organic solvents, chlordane). A much better appreciation also needs to be gained of the interplay between environmental and pharmacological challenges because this would be of great benefit in both uncovering "silent" toxicity and identifying behavioral mechanisms of toxicant action. Caution must be exercised, however, in evaluating pharmacological challenge data to ensure that an altered drug effect following toxicant exposure is not due to dispositional, rather than functional, variables. Deborah Cory-Slechta has indicated two major emphases in be- havioral toxicology. One has to do with screening and risk estimation on chemicals that may compromise behavioral or neurological integ- rity. The other has to do with developing fundamental information on the behavioral actions of chemicals and chemical classes. The two emphases are not entirely distinct, although they are characteristically supported by different funding sources. Cory-Slechta also points out that much of the work in behavioral toxicology has been of a "show- and-tell" nature. Given the youthful nature of the field, this is not altogether inappropriate. There are vast numbers of chemicals that have never been adequately evaluated for neurobehavioral toxicity, and many more are coming to market each year. The field will, however, suffer in the long run from a sporadic accumulation of facts and effects. Unifying principles are badly needed to integrate the vast array of data that will be obtained in a vast number of species by using a vast number of testing paradigms. Cory-Slechta next reviews what is known about lead toxicity. Her results indicate that some lead effects are very general across species and testing laboratories. The finding that low-level lead effects on operant performance depend on the schedule is intriguing and suggests that other drug-behavior interactions may accompany lead exposures. In addition to variations in exposure, data on the consequences of the rate changes in lead-exposed rats for example, by determining how they adjust to alterations in the prevailing contingencies will be very helpful in more fully understanding the functional impact of these exposures. Beverly Kulig has reviewed much of what is known about the adequacy of animal models in better understanding the consequences of solvent exposures. The overriding theme of her chapter is evaluation of sensory, motor, and cognitive functions throughout repeated exposures. Such studies are very demanding in terms of resources and logistics, so the clarity of her results is very encouraging.

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ANIMAL MODELS: WHAT HAS WORKED AND WHAT IS NEEDED ]87 Kulig presents results to support the conclusion that different tem- poral patterns of action may emerge during repeated exposures, which depend on the particular behavior and the particular solvent under investigation. Tolerance developed to some of the effects of styrene, whereas sensitization developed to some of the effects of trichloroethylene (TCE). The TCE results are exemplary of the type of data behavioral toxicologists should be striving to collect. Prominent behavioral dis- ruptions are obtained with repeated exposure that were not apparent initially or that could not be predicted from acute exposure. (Of course, it is possible that duration of exposure could have been sub- stituted to some extent by a greater level of exposure.) Nevertheless, the results clearly indicate the feasibility of finding effects only after repeated exposures. The styrene data, on the other hand, highlight an important problem that has so far been ignored in risk assessment. What are we to make of data showing tolerance to toxicant effects? Does this mean that the organism is no longer at risk from exposure? Do we pay homage to the inherent redundancies in the nervous sys- tem that give rise to behavioral and neurological repair mechanisms, and dismiss further concerns over exposure? These questions have yet to be addressed in health and regulatory arenas, but they are by no means trivial. Kulig also points to another area of research that has escaped the understanding of the risk assessor, namely, the possible reinforcing properties of toxicant exposures. We need only look, however, at the human and animal psychopharmacology literature to appreciate how salient such an effect can become, and what dire health and economic consequences can ensue. The topic may not be restricted to organic solvents. Recent data from our laboratory (Crofton et al., 1989) indicate that a fungicide widely used in the United States, triadimefon, has many behavioral and biochemical actions in common with psychomotor stimulants, most notably methylphenidate. It remains to be determined whether triadimefon can be shown to have reinforcing properties similar to the stimulants, but my considered guess is that it will. Finally, in a masterful exercise in understatement, Kulig states that scientists working "at the human level . . . have received little help from their counterparts at the animal level in addressing the issues surrounding the possible adverse effects of long-term solvent exposures on cognitive functioning." Although I wholeheartedly endorse this position, I do not believe it is due to a lack of test methods that can be applied to the problem. There are several techniques readily available that evaluate many different aspects of cognitive function which can be applied immediately to this problem. The bigger problem has to do with the resources and logistics required to undertake long-term

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88 ROBERT C. MACPHAIL exposure and assessment studies, and the delay of reinforcement as- sociated with finding effects (if indeed they are to be gotten) only after prolonged exposure. REFERENCES Crofton, K. M., V. M. Boncek, and R. C. MacPhail. 1989. Evidence for monoaminergic involvement in triadimefon-induced hyperactivity. Psychopharmacol. 97:326-330. McDonald, B. E., L. G. Costa, and S. D. Murphy. 1988. Spatial memory impairment and central muscarinic receptor loss following prolonged treatment with organo- phosphates. Toxicol. Lett. 40(1):42-56. Padilla, S., and B. Veronesi. 1988. Biochemical and morphological validation of a rodent model of organophosphorus-induced delayed neuropathy. Toxicol. Ind. Health 4(3):361-371. Somkuti, S. G., H. A. Tilson, H. R. Brown, G. A. Campbell, D. M. Lapadula, and M. B. Abou-Donia. 1988. Lack of delayed neurotoxic effect after tri-o-cresyl phosphate treatment in male Fischer 344 rats: Biochemical, neurobehavioral and neuropathological studies. Fundam. Appl. Toxicol. 10(2):199-205. Upchurch, M., and J. M. Wehner. 1987. Effects of chronic diisopropyl fluorophosphate treatment on spatial learning in mice. Pharmacol. Biochem. Behav. 27(1):143-151.