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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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272 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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274 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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276 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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278 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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280 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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282 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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284 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.