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OCR for page 184
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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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.
Representative terms from entire chapter:
repeated exposures
