Behavioral Measures of Neurotoxicity (1990) / Chapter Skim
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Chemical Time Bombs: Environmental Causes of Neurodegenerative Diseases
Chemical Time Bombs: Environmental Causes of Neurodegenerative Diseases
Pages 268-284
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From page 268... ...
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 environmental pollutants.
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From page 269... ...
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.
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From page 270... ...
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.
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From page 271... ...
This discussion, of course, is intended neither to defend solventsmany 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.
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From page 272... ...
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.
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From page 273... ...
THE MATURE NERVOUS SYSTEM AS CHEMICAL TARGET Although a satisfactory scientific nosology of chemicals with neurotoxic 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.
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From page 274... ...
Although the neurobehavioral effects of these channel agents range from discomfort (circumoral and distalextremity paresthesias) to life-threatening dysfunction (respiratory paralysis)
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From page 275... ...
. 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.
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From page 276... ...
Moreover, because some neuronal groups at risk for toxic damage also normally undergo nerve cell attrition with advancing years, the combined effects of chemical-induced damage and agerelated 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 functional reserve, the initial loss of neurons associated with chemical
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From page 277... ...
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 susceptibility of the nervous system during its formative stages, the subject of Krasnegor's incisive chapter.
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From page 278... ...
, 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.
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From page 279... ...
By careful selection of appropriate radioactive labels and their precise 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)
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From page 280... ...
. Yet none of these conditions can be compared to the new and frightening 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.
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From page 281... ...
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 etiology of ALS in subjects who develop aggressive disease prior to age 30, some other explanation is needed.
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From page 282... ...
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 longlatency 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.
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From page 283... ...
, 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.
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From page 284... ...
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.
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