Environmental Neurotoxicology (1992) / Chapter Skim
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4. Testing for Neurotoxicity
4. Testing for Neurotoxicity
Pages 53-94
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From page 53... ...
(Secondary prevention of neurotoxic effects in humans is discussed in Chapter 5.) In the most effective approach to primary prevention of neurotoxic disease of environmental origin, a potential hazard is identified through premarket testing of new chemicals before they are released into commerce and the environment.
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From page 54... ...
These markers can be used in future studies of experimental animals, as well as in clinical and epidemiologic studies of humans exposed to neurotoxicants, as was proposed in Chapter 3. APPROACH TO NEUROTOXICI1Y TESTING Difficulties in Neurotoxicity Testing Neurotoxicity testing is relatively new.
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From page 55... ...
Testing strategies must take those facets of the nervous system into account, and they must consider a number of variables known to modify responses to neurotoxic agents, such as the developmental stage at which ex posure occurs and the age at which the response is evaluated. The issue of timing is complex.
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From page 56... ...
The third and final tier of neurotoxicity testing is the study of mechanisms of action of chemical agents. The decision to characterize a chemical through second-tier testing might be motiENVIRONMENTAL NEUROTOMCOLOGY vated by structure-activity relationships, existing data that suggest a chemical is neurotoxic, or reports of neurotoxic effects in humans exposed to the chemical, in addition to the results of first-tier testing.
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From page 57... ...
For example, consider a screening test for an effect produced only at high doses that is consistently correlated with a milder, presumably precursor effect that occurs at lower doses. The easily detectable effect occurring at high doses in experimental animals might never be observed in humans, whose exposure would never be extreme, but its occurrence in the animal model might indicate that low-level exposure in humans could produce a more subtle toxic effect.
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From page 58... ...
A feasible screening system must strike a balance among the amount of time and expense that society is willing to expend in testing, its desire for certainty that neurotoxic substances are being kept out of or removed from the environment, and its interest in gaining benefits from various types of chemicals. CURRENT METHODS BASED ON STRUCTURE-ACTIVITY REI^TIONSHIPS Given the overwhelming lack of epidemiologic or toxicologic data on most chemical substances and the need to develop rational strategies to prevent adverse health effects of both new and existing chemicals, attempts have been made in many subfields of toxicology to generate predictive strategies based primarily on chemical structure.
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From page 59... ...
Some in vitro tests lend themselves to computer-controlled automated operation, as do some well-developed, highly sophisticated behavioral tests (see, for example, Evans, 1989) , and that results in savings in time and expense and allows testing of large numbers of substances.
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From page 60... ...
BMAA was initially identified as an exENVIRONMENTAL NEUROTOX1COLOGY citotoxic amino acid in cultures of tissue from spinal cord and cerebral cortex. That led to experiments with primates that showed that BMAA produces motoneuronal lesions in the cortex and spinal cord.
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From page 61... ...
The toxic effects and mechanisms of anticonvulsants, excitatory amino acids, and various metals and divalent cations have been assessed with these preparations. The cerebellar granule cell culture system, for example, has been exploited recently in studies of the mechanism of atkyllead toxicity (Verity et al., 1990~.
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From page 62... ...
The possible neurotoxic impact of any chemical on any specific neurobiologic variable could, in principle, be screened with an appropriate set of in vitro tests. In practice, of course, because the number of potential neurobiologic end points to be measured is so large, screening for the effects of any agent on all of them would be prohibitively expensive in time and money.
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From page 63... ...
damage would be sufficiently general to be useful? What specific test systems or combina tions would be adequate to cover a number of different and differentially site-specific neurotoxic agents?
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From page 64... ...
It is an empirical question whether such a battery of in vitro tests could contribute importantly to neurotoxicologic screening of a broad range of environmental agents. Research needs to be done with known neurotoxic agents and related compounds to see whether culture systems can reliably identify dangerous
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From page 65... ...
Of equal importance, and perhaps more difficult, would be the evaluation of presumably nonneuroto~nc substances to preclude a high rate of false positives. One might start with a fairly inclusive set of test cultures, such as of cerebral cortex, brain stem, cerebellum, spinal cord, sympathetic ganglion neurons, and a continuous cell line, such as PC12 cells.
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From page 66... ...
Tests using species closest to humans would logically yield the data about which we could feel most confident; however, various considerations" including cost, ethics, and the extent of pre-existing data bases favor the use of small laboratory rodents, such as mice and rats, for in viva hazard identification and characterization. Table 4-4 lists commonly reported neurotoxic effects of several classes of toxic chemicals in humans and animals.
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From page 68... ...
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From page 69... ...
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From page 70... ...
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From page 71... ...
Equilibrium and muscle coordination can be measured by the length of time a rat can maintain itself on a rotating rod (Bogo et al., TABLE ~6 End Points That Might be Included in a Functional Observational Battery. In Home Cage and Open Field Manipulative Physiologic Body temperature (I)
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From page 72... ...
Because of its sensitivity to neuroactive chemicals, SCOB has greater potential for use in hazard characterization than in hazard identification. Many of the behavioral tests, and particu
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From page 73... ...
as well as damage to the spinal cord and peripheral nervous system. Procedures to characterize chemicalinduced motor dysfunction have not been used extensively in neurotoxicology.
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From page 74... ...
and can be used to assess sensory function in humans, as well as in experimental animals. Various behavioral procedures require that a learned response occur only in the presence of a specific stimulus.
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From page 75... ...
Other classically conditioned responses known to be affected by psychoactive or neurotoxic agents are the conditioned taste aversion (Riley and Tuck, 1985) and conditioned suppression (Chiba and Ando, 1976~.
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From page 76... ...
, neurophysiologic testing in experimental animals appears to produce reliable indicators of what might be expected after similar exposure of other species, including humans. That can be illustrated by a brief comparison of data from clinical and experimental studies of acrylamide neurotoxicity.
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From page 77... ...
and lead produce paranodal or segmental demyelination that is manifest in diminished conduction velocities (Spencer et al., 1975; Korobkin et al., 1975; Buchthal and Behse, 1979~. Toxic neuropathies with axonal degeneration as hallmarks exhibit mild or no decrease in mammal conduction velocities; neuropathies resulting from 'diketone precursors (LeQuesne and McLeod, 1977)
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From page 78... ...
Neurochemical Procedures Functions within the nervous system depend on synthesis of, release of, and receptor activation by specific neurotransmitENKIRONME=AL NEUROTOXICOLOGY ters among specific groups of neurons. Many neurochemical end points could be measured in neurotoxicologic studies, including effects on neurotransmitters (e.g., changes in synthesis, transport, storage, release, re-uptake, or degradation of seroton~n, norepinephrine, acetylcholine, or amino acids)
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From page 79... ...
. A variety of neurochemical probes of neuronal and glial integrity could be used to evaluate the possible neurotoxic effects of a candidate chemical in experimental animals (O'Callaghan, 1988~.
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From page 80... ...
and axonal degeneration in sensory ganglion cells (Cavanaugh and Chen, 1971~. Degeneration of the long sensory and motor axons in both the central and peripheral nervous systems is produced by OF compounds, acrylamide, and 2,5-hexanedione (Cavanaugh, 1964; Spencer and Schaumburg, 1977a,b)
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From page 81... ...
It requires a high-intensity magnetic field, and it monitors changes in nuclear magnetic moment relaxation times after the magnetic field has been applied. MRI is unique in that it uses three kinds of data to characterize anatomic information: nuclear-specific data, i.e., data specific to the nuclear magnetic moment; imaging-specific data, i.e., data specific to the way MRI is being performed; and tissue-specific data, i.e., data specific to characteristics of TABLE ~7 Areas of the Nervous System to be Used in Neuropathologic Evaluation Primary Areas Secondary Areas Cerebellum Brain stem Pituitary gland Eye, oculomotor muscles, optic nerve Spinal cord Sensory ganglia Sciatic nerve (branches from vertebral column to ankles and selected muscles it innervates)
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From page 82... ...
Taken together, the uniqueness of the anatomic and biochemical data provided by MRI and MRS suggests that the combination of the two techniques will become a powerful adjunct to neuroto~ncology both in humans and in experimental animals. PET is potentially much more sensitive.
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From page 83... ...
This section indicates how age, sex, and genetic background of subjects should be considered in neurotoxicity testing. Age at Exposure Organisms can differ in sensitivity to neurotoxicants at different ages.
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From page 84... ...
Thus, it is never safe to assume that effects observed in adults can be simply extrapolated to developing subjects. Developing organisms are not always more sensitive to toxic agents than adults; they are sometimes qualitatively different in their responses, because they are biologically different.
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From page 85... ...
It is possible that a natural decline in function uncovers a longstanding deficit. It is not easy to introduce aging as a variable in screening tests, because lifetime studies in animals are expensive.
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From page 86... ...
In practice, neurotoxicity testing is rarely required, but is usually left to the discretion of the manufacturer. Until passage of the Toxic Substances Control Act (TS CA)
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From page 87... ...
Specific neurotoxicity tests are required only for drugs that are intended to be neuroactive; for other drugs, a review for neurotoxicity is undertaken only if such effects are suspected (OTA, 1990~. FDA requires neurotoxicity testing of food additives only if neurotoxicity is suspected for a particular chemical on the basis of evidence developed in traditional toxicity testing.
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From page 88... ...
The first tier is the heart of the screening aspect of neurotoxicity testing; the later tiers might produce data of great value in advancing understanding of neurotoxic processes and how the nervous system operates, but the first tier is the first line in preventing neurotoxic disease. How are chemicals ranked for entry into the first tier?
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From page 89... ...
It appears to be the simplest, 89 most comprehensive option available and it, at a minimum, should be included in the first tier of neurotoxicity testing. Depending on the particular test, behavioral end points are often used in the detection phase of testing, because they may be global indicators of many of the sensory, motor, and integrative processes of the central and peripheral nenous systems.
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From page 90... ...
Research is needed to determine whether culture systems can reliably identify known neurotoxic agents and active related compounds and distinguish them from related, but inactive (or less active) compounds.
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From page 91... ...
91 at be .s o o son ~ bO .= ct ce 3 o o V, o o to Em 4= o ho am a Ct as V, EM a' Cal 3 V)
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From page 92... ...
Ultimately, study of the data should reveal SARs that are more generally useful than the few that are now considered well established and that will be much better substantiated and more reliable than most current conjectures. Much of the controversy over proper testing procedures arises from two intrmsically conflicting objectives: m~m~ng the incidence of false positives (substances are incorrectly identified as hazardous)
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From page 93... ...
Failure to detect a truly neurotoxic substance will expose our society to health hazards, with the potential for tragic consequences like those associated with one false negative, thalidomide. Testing for 93 characterization should expose false positives; the abandonment of an occasional new chemical on the basis of what are actually false-positive screening results is the likely cost of this process.
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