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OCR for page 268
Chemical Time Bombs:
Environmental Causes of
Neurodegenerative Diseases
Peter S. Spencer
The known adverse effects of chemical substances on the human
nervous system and special sense organs probably cover the waterfront
of the combined disciplines of neurology, psychiatry, ophthalmology,
and otorhinology, not to mention significant chunks of internal medicine.
If we are truly interested in developing neurotoxicity tests with wide
applicability and utility, it will be essential to consider the wealth of
noncognitive, adverse behavioral effects induced by chemical agents
acting on the nervous system and its target organs. Thus, in setting
this goal, we must recognize, as does Roger Russell, that agents with
potential for neurotoxic effects are widely deployed in the environment
and are not limited to the well-known workplace chemicals and envi-
ronmental pollutants. Indeed, some of the most widespread and
troublesome substances are found as natural toxins of plants and
animals; witness the crippling effects of Lathyrus sativus and Manihot
escutenta (cassava) in Africa and Asia, the extraordinarily high incidence
of ciguatera neurotoxicity in the Pacific Islands, and the unsolved
worldwide problem of tetanus associated with the neurotoxin of
Clostridium bacilli. Of course, although these are everyday realities
for vast numbers of our fellow beings, they are of little consequence
to those in developed countries who generally enjoy a varied diet
and excellent hygiene, and who are understandably more concerned
about avoiding contact with potentially harmful man-made substances.
Even here, however, our professional sights are often limited to a
rather small number of well-known substances such as lead salts,
268
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ENVIRONMENTAL CAUSES OF NEURODEGENE~TIVE DISEASES 269
carbon disulfide, and n-hexane; and from this well-trodden ground,
we sometimes commit the egregious error of denouncing all metals
and solvents as neurotoxicants. Why do we seem to ignore other
important subjects, such as the often well-characterized neurotoxic
potential of therapeutic agents, which probably accounts for the ma-
jority of recognized cases of chemical neurotaxicity in developed
countries? Why do we generally fad] to consider the neurotoxic potential
of food additives and fragrance raw materials when several such
agents have been shown to produce neurobehavioral toxicity in animals
or humans. Why was the discovery of methylpheny~tetrahydropyridine
(MPTP) one of the most important neurotoxins of recent times for
many years essentially ignored by behavioral toxicologists? Because
it was perceived to be only a contaminant of a street drug and therefore
of no significance for the "real world" of occupational and environmental
neurotoxicology? Are we really prepared to be this shortsighted,
and is our vision of neurotoxicology and test method development
limited to workplace chemicals and environmental pollutants? Are
we willing to pass by the many specialties of neurobehavioral toxicology?
Fortunately, as Norman Krasnegor demonstrates, the developmental
behavioral toxicologist is better acquainted than most with the need
to protect against the adverse effects of therapeutic drugs such as
thalidomide, as wed as those associated with chemicals, environmental
pollutants, and contaminants of the food supply.
ESTABLISHING CRITERIA FOR
CHEMICAL NEUROTOXICITY
At one time or another, we have all been guilty of making sweep-
ing statements implying that certain groups of substances (e.g., met-
als, solvents, pesticides) have inherent neurotoxic properties. Such
statements are not only inaccurate but also patently misleading. We
need to develop much more critical criteria for neurotoxicity. The
problem is illustrated immediately when a chemical is labeled a neurotoxin
without any consideration of dose. Obviously, anticholinesterase
chemicals have the potential for inducing dramatic neurobehavioral
changes but, as Russell points out, the very same pharmacological
properties have been exploited (without success, it is widely acknowledged)
as symptomatic therapy for Alzheimer's disease. Thus, anticholines-
terase chemicals are not neurotoxins but, at certain doses, exert neu-
rotoxic effects. An even better example of the importance of dose is
provided by the vitamin pyridoxine, well known to be an absolute
requirement for normal metabolism. In this case, neuropathy follows
both inadequate and megavitamin intake of Vitamin B6. Obviously,
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270 - PETER S. SPENCER
pyridoxine is not a neurotoxin but, in sufficiently large dosage, the
chemical does have neurotoxic potential. Similarly, lead, mercury,
and acrylamide are not neurotoxins per se, but they are able to cause
neurobehavioral changes at certain levels of exposure.
Once this point is understood, we are in a position to proceed to
the question of connecting a specific chemical to one or more
neurobehavioral effects. Our lack of precision here is equally as mis-
leading. Consider the statement that acrylamide is a peripheral ner-
vous system (PNS) neurotoxicant. Although it is certainly true that
acrylamide has the potential to induce peripheral neuropathy in humans
and animals, it is also apparent that this is a function of dose and
duration of exposure. At certain doses, acrylamide is able to induce
encephalopathy, with confusion, disorientation, memory disturbances,
and hallucinations; at other doses, ataxia and dysarthria predominate.
Thus, acrylamide is a chemical with neurotoxic potential capable of
inducing a number of neurobehavioral effects that vary in nature
with dosage and duration of exposure. An analogous situation exists
with thallium, carbon disulfide, n-hexane, and a host of other chemicals
with neurotoxic potential. Such considerations are more, much more,
than semantic niceties; our use of language in describing chemical
neurotoxicity is often so imprecise that it serves to mislead the public
rather than to inform.
Our most dismal performance, however, is reserved for our failure
to develop solid criteria that must be met before a chemical is identified
as having neurotoxic potential in human subjects or is linked with a
human neurological or developmental disorder. Stunning examples
are provided by the diatribe over solvents and aluminum. In the
case of solvents, where specific chemical substances are clearly asso-
ciated Biologically with various types of neurological deficit, some
have been prepared to indict and convict all chemicals labeled as
solvents. Are we unaware that there are many different classes of
chemicals which make up this heterogenous group of substances,
and that the large majority of solvent chemicals has never been tested
for neurotoxic potential? Apparently, this paucity of information has
not prevented some from claiming solvent chemicals as causal of
human dementia. Equally as disturbing is the rationale for continuing
to link aluminum with the etiology of Alzheimer's disease. This idea
began when neurofilamentous accumulations induced by aluminum
were observed by light microscopy to be superficially similar to those
seen in Alzheimer's disease. Somehow, the idea continued even though
neurofilaments of experimental aluminosis were found by transmission
electron microscopy to be identical to those induced by a host of
other substances and quite distinct from the characteristic paired-
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ENVIRONMENTAL CAUSES OF NEURODEGENERATIVE DISEASES 271
helical filaments of Alzheimer's disease. More fuel was added when
dialysis dementia was linked to aluminum toxicosis, although the
clinical features and neuropathology of dialysis dementia and Alzheimer's
disease are distinctly different. Nevertheless, the idea of a link be-
tween Alzheimer's disease and aluminum toxicosis has become so
entrenched that the public is encouraged to believe it. The (nonspecific)
observation of aluminum (and other metals) in neurons and senile
plaques in Alzheimer's disease and related disorders has further en-
couraged those faithful to the aluminum hypothesis. However, as
Gerhard Winneke observes, the evidence supporting an association is
(at best) circumstantial.
This discussion, of course, is intended neither to defend solvents-
many of which may well prove to have neurotoxic potential once
they are tested- nor to imply that aluminum has no etiologic relationship
with Alzheimer's disease. Rather, it is a plea for the exercise of
extreme caution in the best tradition of scientific conservatism before
statements are made about cause-and-effect relationships between
chemical substances and human neurobehavioral effects. More spe-
cifically, it is a call for the development of a set of guidelines that
must be met before a chemical is accepted as causal of human
neurobehavioral dysfunction. Identification of those chemicals that
unequivocally fulfill criteria for a potential human neurotoxin is an
essential first step in the development and validation of neurobehavioral
test methods for chemical neurotoxicity. Such tests will require reference
compounds linked to the various types of neurobehavioral deficit
under study.
The Minamata tragedy, reviewed by Winneke, provides a graphic
illustration of the steps that should be taken before a substance is
accepted as causally responsible for human neurotoxic disease. Simply
stated, the neurological illness seen in humans and cats was reproduced
in the latter both by feeding methylmercury-contaminated fish and
by administering authentic samples of the suspect chemical agent.
Because pure methylmercury was able experimentally to induce in
cats a disorder indistinguishable from that seen in the affected feline
population of Minamata Bay, and the nature of the feline disorder
clearly paralleled the attendant human disease, it was possible to
make strong statements about cause-and-effect relationships between
methylmercury and neurodegenerative disease. Thus, in the absence
of human experimentation, the strongest foundation on which we
can rest our case for chemical neurotoxicity is the experimental induction
in animals of a disorder equivalent to that seen in human subjects
exposed to the compound under scrutiny. Such substances, of which
there are relatively few, constitute the list of chemicals with proven
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PETER S. SPENCER
human and animal neurotoxic potential (class 1 chemicals). A much
larger number of chemicals has been associated with neurobehavioral
effects in exposed humans (class 4 chemicals), but these reports are
often poorly documented exposures to mixtures of ill-defined sub-
stances that have not been subjected to experimental scrutiny either
in isolation or as a mixture. Important exceptions are the recurring
reports of consistent neurobehavioral deficits associated with certain
therapeutic agents and mixtures, where the exact chemical compositions
as well as the dose and duration of exposure are often well documented
(class 3 chemicals). Our task, of course, is to help devise experimental
methods that will detect neurotoxic effects of substances which can
then be prevented from entering the marketplace or removed therefrom.
Chemicals with neurotoxic properties recognized in experimental animal
studies constitute a group of agents suspected to possess human
neurotoxic potential (class 2~. By far the largest group of substances,
however, contains that multitude of untested chemicals which is not
known to be linked to any human neurobehavioral disorder (class 5~.
Thus, in summary, at least five categories may be recognized in our
efforts to link chemical substances with potential adverse effects on
the human nervous system, the strength of the association diminish-
ing as one descends through the list:
Class 1. Experimentally proven in animals, with similar effects in
humans
Class 2. Experimentally proven in animals, with unknown effects in
humans
Class 3. Effects observed in humans but experimental evidence unavail-
able
Class 4. Possible effects in humans but experimentally unproven
Class 5. Effects unknown in humans and untested in animals
Important consequences flow from this conservative classification.
For example, in the case of industrial solvents, the majority of which
falls into classes 4 or 5, there is no justification at the present time for
stating that solvents as a class have human neurotoxic potential. On
the other hand, because solvents are so widely employed in industry
and so little is known of their chronic neurobehavioral effects, there
is every reason to improve knowledge in this area. Another example
is the so-called Spanish Toxic Oil Syndrome, an epidemic of a new
and remarkable disease that affected thousands of people in Madrid
and its surrounds. Although epidemiological studies strongly link
the disorder to the consumption of an illicit cooking oil, until a viable
model of the disease is produced in a laboratory animal fed the suspect
agent, there is always room for a small degree of doubt.
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ENVIRONMENTAL CAUSES OF NEURODEGENE~TIVE DISEASES 273
CLASSIFYING CHEMICALLY INDUCED HUMAN
NEUROTOXIC DISORDERS
Russell argues convincingly that basic and clinical research designed
to understand the neurochemical mechanisms by which exposures to
toxicants affect behavioral indicators will lead us a long way toward
a comprehension of the enormity of our task and the design of appropriate
methods to detect, define, and even predict chemical neurotoxicity.
In other words, we cannot simply devote our research time to the
somewhat pedestrian task of developing test methods to fill the regulators'
needs. With this in mind, therefore, it is appropriate to inquire how
far we have come along the mechanistic path, where we need to
concentrate research efforts to improve understanding, and how we
should proceed in our attempts to identify the "atomic variety" of
chemical time bomb. Our first chore, however, is to understand how
to classify the adverse effects of chemical substances, first in the adult
and then during brain development.
THE MATURE NERVOUS SYSTEM
AS CHEMICAL TARGET
Although a satisfactory scientific nosology of chemicals with neu-
rotoxic properties in adult human subjects remains an elusive goal, it
is possible to offer a surprisingly useful framework for the eventual
development of a comprehensive classification system. Ideally, this
should be able to link the target of chemical attack to alterations in
neural function that explain observed neurobehavioral changes and,
in the clinical setting, provide a logical basis for prevention. One
such attempt is a 1984 classification of human neurotoxic response
that was based on cellular and subcellular targets of chemical agents.
This recognizes the following sites of functional disruption or damage:
the neuron, glial cells and myelin, nervous system vasculature, and
muscle. Points pertinent to the present discussion are readily made
by selectively considering agents that act on the mature nerve cell.
Three broad types of neuronal change induced by chemical substances
are recognized, namely, functional perturbations of the excitable
membrane, interference with neurotransmitter systems, and structural
breakdown of dendrite, perikaryon, or axon.
The first type involves direct chemical interference with the excit-
able surface membrane of neurons, the consequent changes in electrical
transmission, and the associated generation of neurobehavioral alterations.
By and large, these effects appear and reverse rapidly, and the extent
of dysfunction reflects the distribution of the chemical within the
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PETER S. SPENCER
central or peripheral nervous system. The best examples are pro-
vided by agents that interfere with the normal passage of sodium
ions across the nerve cell membrane. Some substances, such as tetro-
dotoxin (from the puffer fish) and saxitoxin (paralytic "shellfish" poison),
act as channel blockers, whereas ciguatoxin, scorpion and anemone
toxins, DDT, and pyrethroid insecticides, act to increase membrane
permeability to sodium while the membrane is in either the resting
or the active state, or both. Although the neurobehavioral effects of
these channel agents range from discomfort (circumoral and distal-
extremity paresthesias) to life-threatening dysfunction (respiratory
paralysis), the salient point for the present discussion is that they are
unlikely to have any long-lasting effects once the chemical has left
the membrane receptor. Thus, although neurotoxicity may be fatal,
agents of this type do not merit consideration as delayed-action chemical
time bombs.
The second common locus of chemical attack upon the neuron is
its neurotransmitter system, the proper regulation of which is often
an absolute requirement for normal behavior. Chemicals may interfere
with neurotransmitters at many levels, including their synthesis in
the neuronal perikaryon, transport along the axon, packaging and
release from synaptic vesicles, transport across the synaptic cleft, and
reception by the target membrane, as well as the enzymatic breakdown
or reuptake of excess transmitter in the nerve gap. Because these
exigencies (points of vulnerability) exist for each and every neurotransmitter,
the possible sites of chemical-induced perturbations are legion. Take,
for example, agents active on cholinergic pathways, a subject discussed
by Russell. Of course, the relationship between human behavioral
changes and the selective actions of chemical agents on critical
neurotransmitter systems extends far beyond the cholinergic system.
Comparable examples may be drawn for chemicals active on central
and peripheral catecholaminergic pathways. For example, monoam-
ine oxidase inhibitors that increase the duration of action of synaptic
catecholamines lead to mania, hyperreflexia, and involuntary movement.
By contrast, the antihypertensive drugs tend to induce mental de-
pression, weakness, and lethargy because they serve to deplete synaptic
catecholamines. Other agents act on serotonergic pathways (lysergic
acid diethylamide, LSD), gamma-aminobutyric acid (GABA) pathways
(picrotoxin), glutamate pathways (beta-N-oxalylamino-~-alanine, BOAA),
whereas some, such as the antipsychotics and opiates, influence a
number of different pathways.
Most of the important adverse neurobehavioral effects of chemi-
cals that perturb the function of neurotransmitter systems tend to
appear rapidly, may be life threatening, and are generally considered
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ENVIRONMENTAL CAUSES OF NEURODEGENE~TIVE DISEASES 275
to reverse without permanent sequelae. In this regard, many trans-
mitter neurotoxins are as insignificant for our present thinking as
compounds that only perturb excitable membranes. A notable exception
is the persistent buccolingual-masticatory dyskinesia and choreiform
movement of trunk and extremities (tardive dyskinesia) that often
accompanies prolonged therapy with antipsychotic drugs. These in-
voluntary movements are aggravated with emotional stress and con-
centration on motor tasks, and are intensified by the reduction or
discontinuance of therapy, possibly because of the "unmasking" of
supersensitive dopamine receptors. Chemically induced movement
disorders also routinely accompany prolonged t-dopa (dihydroxy-
phenylalanine) therapy for parkinsonism. Although these two iatrogenic
conditions probably account for a significant percentage of the disabling,
chemical-induced neurological disease seen in developed countries,
they have received little attention from neurobehavioral toxicologists
concerned with environmental toxicity. However, for the neurologi-
cally and psychologically impaired patient who faithfully follows the
doctor's prescription of t-DOPA or antipsychotics, the tardive appearance
of these neurobehavioral effects may often produce an incapacitating
or life-threatening state equal to or greater than the disease under
treatment. A distinguished Spanish neurologist recently reported
that fully 30 percent of his parkinsonian patients were found to have
a drug-induced disorder that disappeared upon cessation of treatment.
Thus, in addition to the mechanistic information available from such
data, therapeutic agents also require much more rigorous neurobehavioral
testing to predict and control the develoDm~nt of iatrn~nir n~'roln~ir:~1
and psychiatric states.
~ . . ~ ~ ~ . .
1 ne uliterent types of structural damage induced by chemical agents
constitute for present purposes a very important third class of neuronal
responses to chemical attack. Numerous chemicals and drugs are
able to induce axonal degeneration without loss of the parent neurons;
most require repetitive exposure. The neurobehavioral changes (usually
peripheral neuropathy) develop rapidly or insidiously after weeks or
months of exposure, and the disorders are reversible to the extent
that damaged axons will regenerate and reconnect with sensory and
motor targets in the peripheral nervous system. The clinical signs
and symptoms develop in a distal, symmetrical, and temporally ascendant
pattern in the extremities, with sensory loss and muscle weakness
usually predominating in clinical significance over the commonly at-
tendant autonomic dysfunction. Axonal neuropathy in humans, ani-
mals, or both, is known or (from the pattern of neurobehavioral dys-
function) suspected to occur with repetitive exposure to workplace
chemicals (e.g., acrylamide, ethylene oxide, carbon disulfide, n-hexane,
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PETER S. SPENCER
methyl n-buty} ketone, dimethylaminopropionitrile, certain organo-
phosphates), therapeutic drugs (vincristine, chIoramphenicol, thalidomide,
disulfiram, isoniazid), household chemicals (thallium, arsenic, zinc
pyridinethione), abused substances (ethanol), and natural toxins
(buckthorn). Some are painful (thallium); others are associated with
autonomic dysfunction (acrylamide), prominent pyramidal signs
(leptophos, methyl bromide), or optic nerve changes (ethambutol).
Although the molecular and cellular mechanisms underlying these
toxic effects are unknown, the resulting pattern of neurobehavioral
dysfunction is remarkably stereotyped and often readily studied in
experimental species. Clinical experience demonstrates that recovery
is usually slow, with sensory and motor deficits disappearing in the
reverse order of their appearance. Recovery of sensation and strength
is usually well advanced within months or years after cessation of
exposure to the offending agent. Sometimes, when there has been
extensive damage to ascending or descending spinal pathways, there
may be permanent sensory loss, truncal ataxia, or pyramidal signs.
The pathways involved in axonal neuropathies are also deleteriously
affected with the normal advancement of age, but late-life appearance
of neuropathy in previously recovered subjects is not recognized. In
short, the fuse of this time bomb is short, and the limited damage
associated with the explosion is largely reparable.
Perhaps the most important group of potential neurotoxins con-
sists of those that trigger degeneration and loss of nerve cells. Examples
include (1) thallium-induced lesions of the amygdala and periamygdaloid
cortex, precipitating uncinate fits and peculiar affective disorders re-
sulting from disruption of the limbic system; (2) inorganic mercury-
induced cerebellar lesions associated with intention tremor, disordered
speech, and ataxic gait; (3) lead-induced cerebral cortical damage leading
to irreversible mental retardation; (4) organomercury-induced degen-
eration of dorsal root ganglion neurons and the calcarine and cerebellar
cortex, with coincident sensory loss, tunnel vision, and ataxia; (5)
MPTP-induced degeneration of nigrostriatal neurons causing parkin-
sonism; and (6) BOAA-induced loses of pyramidal neurons eliciting
the spasticity of lathyrism. Because mature neurons are postmitotic
and therefore irreplaceable, these types of neurobehavioral deficits
are permanent. Moreover, because some neuronal groups at risk for
toxic damage also normally undergo nerve cell attrition with advanc-
ing years, the combined effects of chemical-induced damage and age-
related loss may lead to a permanent deficit that becomes relentlessly
progressive in old age. Finally, and most significantly, because these
regions of the brain are commonly endowed with a substantial func-
tional reserve, the initial loss of neurons associated with chemical
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ENVIRONMENTAL CAUSES OF NEURODEGENE~TIVE DISEASES 277
damage may be clinically silent and only unmasked years or decades
later as the deleterious effects of age deliver the coup de grace. Here
is a chemical time bomb with a very long fuse, and once it explodes,
the damage accrues relentlessly until death supervenes. Long-la-
tency neurotoxicity of this type has been associated with organo-
mercurialism, MPTP-induced parkinsonism, and the cycad-associated
neurodegenerative disorder of the western Pacific that displays facets
of amyotrophic lateral sclerosis (ALS), parkinsonism, progressive
supranuclear palsy, and senile dementia. As a result of these new
observations, a search has recently begun to identify exogenous chemicals
with neurotoxic properties that may play a key role in triggering
some of the devastating neurodegenerative diseases of later life, notably
ALS, Parkinson's and Alzheimer's diseases.
DEVELOPING NERVOUS SYSTEM
AS CHEMICAL TARGET
This is the point at which we must turn our attention to the sus-
ceptibility of the nervous system during its formative stages, the subject
of Krasnegor's incisive chapter. Because the developing nervous system
is radically different in structure from its adult counterpart, a completely
independent system must be deduced to classify the adverse effects
of chemical substances. For example, whereas the adult neuron is
postmitotic, static, and typically equipped with elaborate, branching
dendrites for the receipt of electrochemically encoded information
from neighboring nerve cells, the developing neuron divides, migrates,
and has few cellular processes in contact with those of few other
nerve cells. Similarly, during development, glial cells proliferate, their
processes are mobile, and myelin formation is prominent. These and
other factors, such as an absent blood-brain regulatory interface to
control access of chemical substances to nervous tissue, radically alter
the potential responses of the developing nervous system to chemical
attack. Whereas specific or unique abnormalities are known to be
caused by certain agents (thabdomide), structurally similar abnormalities
may result from exposure to different chemicals. Conversely, differ-
ent types of developmental anomalies may occur with a single noxious
agent. Observations such as these suggest that there are factors besides
the chemical nature of the agent which dictate the type of resulting
damage. Genotype and species are important variables, but the over-
riding factor is developmental stage. Above all else, the timing of
chemical attack appears to dictate the resulting effect.
It is well established that exposure to selected agents during
development in utero may have dramatic consequences for behavior
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PETER S. SPENCER
during postnatal maturation and young adulthood. Although behav-
ioral abnormalities may be found in the absence of structural changes,
either grossly or with a light microscope, it is a tenet of neurobiology
that some (presently undetectable) alteration for example, in synaptic
organization or neurochemical anatomy must underlie a change in
neural function. That behavioral alterations induced by chemical
agents have no structural basis whatsoever is untenable. What is
needed is for the behavioral teratologist and the neurochemical anatomist
to join forces to find out how to account for these behavioral abnormalities.
As Krasnegor points out, the recent methodological breakthrough in
studying the conceptus in the externalized uterus provides a remarkable
new window of opportunity to research these phenomena. Substances
of interest can now be studied for their neurochemical, structural,
and behavioral effects at the time of gestation (when they have their
putative action upon the developing brain), postnatally during neonatal
development, at maturity, and even in old age.
Scientific Basis for Neurobehavioral Toxicity Testing
With this broad overview of the adverse effects of chemical substances
on the human nerve cell during development and at maturity, we are
in a position to assess our understanding of molecular and cellular
mechanisms of neurotoxicity and to determine where there is a lack
of information and which type of neurobehavioral effect constitutes
the greatest threat to human health.
The mere fact that we have been able to construct a tenable basis
for understanding the action of chemical substances on the human
nerve cell is most encouraging. During development, the stage of
cellular differentiation plays a major role in dictating the resultant
structural (and probably neurobehavioral) alterations. Although a
vast amount of work needs to be devoted to this subject, at least
there is a logical basis for understanding why, for example, antimitotics
rather than sodium channel agents have devastating effects. Similarly,
in the adult, there is a satisfying mechanistic explanation for the rather
similar signs and symptoms associated with chemicals that target
one or another neurotransmitter (e.g., cholinergic) pathway even though
the xenobiotics of interest (e.g., anticholinesterases, pesticides, and
certain snake venoms) may have greatly disparate chemical struc-
tures. Far less satisfying is the current state of ignorance of the mo-
lecular and cellular mechanisms underlying neuronal and axonal de-
generation. With few exceptions, such as the well-characterized action
of diphtheria toxin on the Schwann cell, a similar state of ignorance
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ENVIRONMENTA ~ CA USES OF NE URODEGENE~TIVE DISEASES 279
exists for chemical toxins that target myelinating cells, muscle cells,
the neuroendocrine system, and the intimate vasculature of the ner-
vous system.
How can we improve understanding of the scientific basis of
neurotoxicology and create a more solid foundation on which
neurobehavioral toxicity testing can be developed? We have already
noted the extraordinary new opportunity for a multidisciplinary attack
on the effects of chemical substances on the nervous system during
both in utero and postnatal development. Similarly, there are important
opportunities for collaboration in understanding how chemicals may
modify behavior in the adult. For example, the expertise of the neu-
rophysiologist is required to explain the behavioral outcome of over-
exposure to membrane channel agents; neuropharmacologists are well
equipped to discuss the functional consequences of neurotransmitter
disruption; and neuropathologists are needed to offer a rational basis
for neurobehavioral alterations associated with structural breakdown
of the nervous system. Taken in concert, therefore, behavioral toxicologists
will greatly strengthen their science if they join forces with multi-
disciplinary teams with expertise in many areas of the neurological
sciences.
An additional collaborative opportunity for the behavioral toxi-
cologist has been opened up by the advent of positron emission
tomography (PET), a noninvasive imaging system that permits assessment
of the functional status of the human and primate brain in real time.
By careful selection of appropriate radioactive labels and their pre-
cise localization in the brain following systemic administration, the
PET specialist is able to estimate the integrity of a particular brain
region and sometimes detect lesions that are clinically silent at time
of analysis but predictive of impending disease. The best example is
the ability to detect (with a fluorodopa probe) subclinical lesions in
the substantia nigra that predict the likely onset of parkinsonism
later in life. Because subtle behavioral differences have been reported
in individuals prior to the onset of clinical parkinsonism, there is an
important opportunity for collaborative research using the methodology
of both behavioral toxicology and PET. The obvious place to start is
with MPTP-lesioned primates with fluorodopa PET evidence of
nigrostriatal damage but no clinical signs of parkinsonism. Such
animals would then be candidates for testing the behavioral effects of
brain implants designed to restore normal levels of dopamine neuro-
transmitter, as discussed by Russell. Unfortunately, even though a
bona fide primate model of human parkinsonism was available to
test the efficacy of brain transplants in restoring normal behavior, the
international neurosurgical community saw fit to proceed directly
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PETER S. SPENCER
with human experimentation on Parkinson patients. Although a few
have been helped, the results overall have been disappointing.
Our final task is to decide where the "atomic" variety of chemical
time bomb is likely to be deployed in the broad environment. Implicit
in this question is the notion of a long fuse, a surprisingly large
explosion, and a devastating, irreversible outcome. Thus, we are not
concerned here with the short-latency effects of certain chemicals on
excitable membranes or the reversible consequences of pharmacological
disruption of a neurotransmitter system. Certainly, disorders such
as drug-induced tardive dyskinesia are of considerable relevance be-
cause of their poor reversibility. Degeneration of axons and myelin
is also of some concern, because these disorders are usually either
slowly reversible (peripheral neuropathy) or irreversible (spasticity).
Yet none of these conditions can be compared to the new and fright-
ening concept of long-latency neuronal toxicity, in which the chemical
exposure purportedly occurs decades prior to the clinical appearance
of a neurodegenerative disease that is not only irreversible, but also
relentlessly progressive, totally incapacitating, and even when treated,
inevitably fatal.
Just as the drama of the potential fetotoxicity of chemical substances
unfolded as a consequence of the effects of a therapeutic drug, discovery
of the principle of long-tendency neurotoxicity has come not from
testing either workplace chemicals or widespread environmental
pollutants but rather from systematic study of high-incidence
neurodegenerative disease that in one case (MPTP) was linked to a
contaminant of a street drug and, in another, a neurotoxic plant (cycad).
Experimental animal studies confirmed the suspicion that MPTP was
responsible for inducing parkinsonism in a group of California drug
addicts. More importantly, certain individuals who were exposed to
MPTP, but who remained clinically intact, were shown by fluorodopa
PET to have sustained damage to the substantia nigra. Because this
pathway is highly susceptible to age-related neuronal attrition, these
subjects are currently being followed in the expectation that the combined
effects of toxic neuronal damage and age-related cell loss will eventually
overcome the considerable functional reserve of this pathway, whereupon
they too will develop progressive clinical parkinsonism.
An even more troubling possibility has emerged from study of a
prototypical neurodegenerative disease known as western Pacific ALS
and parkinsonism-dementia (P-D) complex. Decades of research on
this disappearing familial disease have ruled out inherited and viral
factors as causal and have clearly indicated a nontransmissible envi-
ronmental trigger. The vast majority of evidence incriminates seed
of the neurotoxic cycad plant, formerly an important source of medicine
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ENVIRONMENTAL CAUSES OF NEURODEGENE~TIVE DISEASES 28]
or food in all three areas where high-incidence ALS/P-D has been
found. Epidemiological studies of populations migrating to and from
Guam have clearly established that the disorder may be acquired
during the first 20 years of life but may remain clinically silent for up
to 35 years or more. Two ideas have been advanced to explain this
phenomenon: one (discussed above in relation to MPTP) proposes
the additive effects of subclinical, chemical-induced neuronal depletion
at the time of exposure, coupled with age-related attrition of the same
neuronal population; the other proposes the existence of one or more
chemical substances in the cycad plant that act as a "slow toxin." The
latter idea evolved from the intensive study of individual patients
with documented heavy cycad exposure in the first or second decades
of life, who developed clinical ALS less than 15 years later. Because
age-related neuronal attrition cannot possibly be involved in the eti-
ology of ALS in subjects who develop aggressive disease prior to age
30, some other explanation is needed. The slow-toxin hypothesis
proposes the existence (in cycad seed) of an agent which, after single
or multiple exposure, establishes an irreversible sequence of molecular
and cellular events that lead progressively to changes in neuronal
integrity and eventually to degeneration. Once sufficient target neurons
have undergone degeneration (perhaps 50 percent of the anterior horn
cells in the case of ALS), the previously covert disease becomes clinically
apparent. A somewhat analogous situation exists with delayed peripheral
neuropathies induced by organophosphates, except in this case the
time to onset of clinical disease is measured in weeks and, once established,
the disease is not progressive. The best analogy, however, may be
with cancer, and this consideration may provide clues as to where to
look for molecular mechanisms underlying the action of a putative
slow neurotoxin. The analogy should also be read as an indication of
the massive level of funding that is urgently needed to begin to determine
whether disorders such as Alzheimer's disease are triggered by early
exposure to exogenous chemicals.
How do these new concepts of long-latency neurotoxicity influ-
ence current concerns over workplace chemicals and environmental
pollutants? First and foremost, we must rigorously explore the con-
cept of slow neurotoxins in the hope of identifying the chemical nature
of substances that exhibit this property. Once these critical pieces of
information are in hand, we should be able to identify comparable
chemical factors throughout the human environment and recommend
steps for the prevention of exposure. Just as the Guamanian public
has been warned of the long-term hazards associated with use of
cycad seed for food and medicine, one day we may be able to advise
industry of comparable slow toxins in the workplace. Although intensive
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PETER S. SPENCER
laboratory research is mandatory to reach this goal, it is also well
worthwhile subjecting patients who develop neurodegenerative disease
at a young age to the most intensive exploration of their chemical
exposure history. Here is a very special research opportunity for the
behavioral toxicologist to work in cooperation with the neurologist;
the latter has access to the patients, whereas the former should be
uniquely equipped with a broad knowledge of the potential adverse
effects of chemical substances in all environmental loci.
The second corollary to be drawn from the new concern over long-
latency neurotoxicity is the need for collaborative behavioral and
neuroanatomical studies to identify which populations of nerve cells
are most susceptible to the aging process, and how such changes
influence behavior. Additionally, there is an absolute requirement
for research focus on chemicals that have the ability to destroy age-
sensitive neuronal populations. Compounds such as trimethyltin and
the glutamate excitotoxins are of very great interest in this regard,
but does the list also include the classical environmental pollutants
that have figured so centrally in the chapters presented in Part III of
this volume? Space permits consideration of just three: solvents,
lead, and mercury.
The neurobehavioral effects of solvents have occupied an extraor-
dinary amount of space in the recent literature although, with few
exceptions, it has been difficult to obtain consistent, clear-cut evidence
of the inherent neurotoxicity of chemicals that fall within the many
classes making up this heterogeneous collection of substances. Although
some have sought to link cementing states to occupational exposure
of often ill-defined mixtures of solvents, there is no clinical or
neuropathological evidence to suggest that these substances have the
capacity to induce long-latency neurodegenerative diseases. Certainly,
we can justifiably include certain individual solvents (e.g., n-hexane,
methyl n-butyl ketone) in class 1 substances that have established
animal and human neurotoxic potential, but the associated disorders
are largely reversible (neuropathy) or persistent (ototoxicity). Because
the structure and function of the critical cellular components of peripheral
nerves and inner ear also decline with age, elderly subjects with preexisting
neurotoxic damage to these structures may be more markedly affected
than their unexposed peers. There is also special concern over the
occupational solvent carbon disulfide because, in addition to its ability
to trigger psychosis and neuropathy, there are several reports suggesting
the tardive onset of a form of parkinsonism. With this notable excep-
tion, there is no evidence to suspect that solvents represent the types
of chemical time bombs that concern us here.
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ENVIRONMENTAL CAUSES OF NEURODEGENERATIVE DISEASES 283
In a well-written advocacy for the rigorous control of environmen-
tal levels of lead, Rice proposes that this potential neurotoxicant mer-
its special consideration because the metal has a very long half-life in
the body. Less convincing is her stand that this may result in long-
latency effects, such as a neurodegenerative disorder appearing late
in life. It is far from clear, as she proposes, that lead has a propensity
to attack age-sensitive populations of neurons. Nevertheless, because
lead is likely to be mobilized from bone in advancing age (during the
process of demineralization), the suggestion of tardive toxic and neurotoxic
effects needs to be considered seriously. A few authors have linked
lead with amyotrophic lateral sclerosis, but the case is far from proved
and the leading current proponent has recently discarded the idea.
Another solitary investigator has extrapolated experimental neuro-
pathologic observations to propose a link between lead and Alzheimer's
disease, but the idea in general is given no credence. Needleman
(1980) pointed out that the mobilization of lead from the bones of the
elderly is synchronous in some subjects with restricted intake of proteins,
calories, and other trace elements, raising the possibility that some of
the cogrutive changes in older people are an effect of lead. He concluded:
"The behavioral and biochemical status of older subjects with respect
to both lead exposure and lead mobilization could well be a fertile
area for investigation." Perhaps, one might dare to add, the potential
importance of this subject merits diverting some of the current inter-
est in lead neurotoxicity from the heroic use of statistics to uncover
minor changes of dubious significance in the intellectual performance
of young subjects with modest blood levels. Isn't the possibility of
relentlessly progressive late-life decline in intellectual performance
at least as important as the possibility of being robbed of a few IQ
points during early development?
Winneke's review of Minamata disease is also of special relevance
to long-latency neurotoxicity because of the recognition by some Japanese
authorities of clinical variants in which manifestations of toxicity worsened
after contamination had ceased or in whom the signs and symptoms
of methylmercury poisoning appeared after a delay of some years.
Em. . . ... .. . . . .. _ %, . . ~ . ~ . .
lolls was initially reported in the NY/US as M'namata disease At late on-
set, and some alleged cases have been verified at autopsy. Several
explanations have been advanced to account for this phenomenon,
including (1) the psychological condition of people who are eager to
be compensated (latent Minamata disease is not recognized in local
legal circles), (2) long-lasting but slight damage due to a minimal
amount of organic mercury remaining in the brain (unlikely in view
of data on the accumulation and metabolism of ingested mercury),
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PETER S. SPENCER
and (3) the effect of aging on latent Minamata disease. In the light of
recent understanding about long-latency neurotoxic disorders, the latter
proposal clearly merits close study.
CONCLUSION
My major goal in discussing the various points raised in the preceding
four chapters is to propose a firm scientific foundation on which to
accept substances as potential human neurotoxins and to place in
perspective the relative severity of the adverse effects induced by
chemical substances by analyzing their sites and mechanisms of action.
I have argued strongly that a comprehensive understanding of behavioral
neurotoxicology can only be achieved if we consider all types of chemical
substances that attack the nervous system. Of course these compounds
must be rigorously tested and regulated, but we will only understand
the true magnitude- and awfulness of their potential effects, and be
able to devise appropriate test methods to detect such changes, if we
are prepared to draw freely from the entire bocly of knowledge available
to the science of neurotoxicology.
REFERENCE
Needleman, H. L., ed. 1980. Low Level Lead Exposure: The Clinical Implications of
Current Research. New York: Raven Press.
Representative terms from entire chapter:
neurotoxic potential
