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4 Neurotoxic Effects Interest in the toxicology of the nervous system has grown rapidly in recent years not only because of heightened public concern about the impact of toxic substances on human health but also because the nervous system has been shown to be especially vulnerable to chemical insult (Anger and Johnson, 1985~. The potential effects of such toxicity are quite varied, reflecting the large role played by the nervous system in regulating vital body functions and in perceiving, assessing, and responding to the external environment. Interference with these processes by overexposure to chemical and certain physical agents can produce a variety of abnormal neurobehavioral responses, some of which may be life threatening, others resulting in short-term neurobehavioral changes that disappear without a trace, and still others causing permanent or even progressive neurological or psychiatric disorders. Of special concern is the possibility that envi- ronmental exposure to certain neurotoxic agents, such as lead, may ir- reversibly compromise the normal development and capacity of the human brain. Although there are no reliable estimates of the number of persons who develop neurotoxic disorders in adult life, or of the impact of overexposure to chemical agents on the developing or aging nervous system, more than 850 chemicals are known to produce neurobehavioral disorders in humans or in animals (Anger and Johnson, 19851. The National Institute for Oc- cupational Safety and Health (NIOSH) considers neurotoxic and psycho- logical conditions 2 of the 10 leading work-related disorders, and the American Conference of Governmental Industrial Hygienists (ACGIH) has identified neurotoxicity as a basis for recommending threshold limit 105

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i06 DRINKING WATER AND HEALTH values (TLVs) for 30% of the chemicals most frequently encountered in industry for which toxicological symptoms of occupational disease have been documented (Anger, 19841. Of the 197 industrial chemicals found in a 1974 NIOSH survey as having been implicated in exposure of more than 1 million people (NIOSH, 1977), 65 are neurotoxic at some exposure concentration. The magnitude of the worldwide occurrence of neurotox- icity in humans is also demonstrated by the recent World Health Orga- nization estimate that 375,000 cases of pesticide intoxication occur annually (Almeida, 1984~. Most pesticides exhibit some neurotoxic effects. Neurotoxicology is concerned not only with the actions of chemical agents but also with biological and certain physical (e.g., radiation) agents that produce adverse effects on the developing, mature, and aging nervous system (including special sense organs as well as neuroendocrine and neuromuscular systems) and on the behavior of humans and other animals. Some neuroactive agents produce rapidly reversible changes, other com- pounds cause permanent damage, and a few may induce progressive and terminal neural deterioration. Toxic disorders of the nervous system follow overexposure to abused substances (e.g., ethanol, inhalants, narcotics), therapeutic drugs, toxic products or components of living organisms (e.g., bacteria, fungi, plants, animals), chemicals designed to affect organisms unwanted by humans (e.g., fungicides, herbicides, insecticides), industrial chemicals, chemical warfare agents, additives and natural components of foods, and certain other types of chemicals encountered in the environment (Spencer and Schaumburg, 19801. The mechanisms of action of chemical agents that lead to nervous system dysfunction are, in general, poorly understood. Some agents act directly on the nervous tissue; others induce neurological or behavioral dysfunction indirectly, for example, by induc- ing changes in electrolyte balance, in cerebral blood flow, in metabolism of glucose, or in levels of critical intermediary metabolites. Such patho- physiological changes are often expressed clinically as neurobehavioral disorders because of the peculiar sensitivity of neural tissue to disruption of body homeostasis. Principles of neurotoxic response can be founded on the biology of the nervous system during development, at maturity, and during senescence. Experimental studies and clinical experience have demonstrated that the response of the developing nervous system to chemical insult may be either quantitatively or qualitatively different from the response of the mature system (Wilson and Fraser, 1977a, pp. 50-541. Some agents that induce developmental abnormalities of neural structure (neuroteratogens) or function (behavioral teratogens) may produce no or different abnor- malities in the adult (Vorhees and Butcher, 19821. Very few studies have been conducted to examine the susceptibilities of aged subjects to toxic substances. Thus, our understanding of the biological processes that might

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Neurotoxic Effects 107 underlie differential responses in that population is limited. However, it seems reasonable to conjecture that deficits associated with old age are aggravated by those chemical agents that further impair neural centers and functions already compromised by the aging process. The House Select Committee on Aging has identified neurotoxicology as an important area of research likely to have a strong impact on the prevention and treatment of neurological disorders associated with old age (OTA, 19841. In the following paragraphs, the committee has provided a rationale for using neurotoxicity as a basis for determining acceptable levels of exposure to chemicals in community drinking water. The discussion includes a review of the structure and function of the nervous system, an outline of the significant forms and end points of neurotoxicity or end points that may serve as a basis for regulation, and the identification of susceptibilities of special populations. Later in the chapter, the types of information and research that can contribute to a risk assessment based on neurotoxicity are described, and issues relating to the use of neurotoxicity as a basis for risk assessment are discussed. THE HUMAN NERVOUS SYSTEM IN HEALTH AND DISEASE Gross Structure and Function By exploring different aspects of the vast body of knowledge on the human nervous system, one can attempt to learn how neural elements react to xenobiotic substances. Although the acquisition of such an un- derstanding begins with a study of the structural and functional organi- zation of the nervous system, the broad range of these neurotoxic effects is usually recognized first by the appearance of clinical symptoms or deficits in behavioral function. At maturity, the nervous system is separated anatomically into central and peripheral divisions. The peripheral nervous system (PNS) is com- posed of nerve cells (neurons) and their processes (axons), which conduct information to muscles and between muscles, glands, sense organs, and the spinal cord or brain. PNS axons are ensheathed by Schwann cells to form nerve fibers, which run together in bundles in peripheral and cranial nerves (I and III-XII) (Thomas and Ochoa, 19841. These nerves contain afferent (sensory) and efferent (motor) fibers, both of which are repre- sented in the somatic (voluntary) and visceral (autonomic) components of the nervous system. Somatic afferent fibers conduct information from special sense organs and sensory receptors in skin and muscles to the brain, whereas visceral afferent fibers convey impulses from the gut, heart and vessels, glands, and various organs. Somatic efferents innervate striated muscle, whereas visceral efferents supply smooth muscles of blood ves-

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i08 DRINKING WATER AND H"LTH sets, glands, heart, and gut. In toxic states involving the PNS, degeneration of sensory and motor fibers leads to peripheral neuropathies associated with sensory loss (e.g., decreased sensitivity to vibration, touch, or phys- ical orientation) and motor (muscle) weakness. Dysfunction or breakdown of autonomic fibers may precipitate abnormal sweating, cardiovascular changes, or dysfunction of the gastrointestinal tract, the urinary tract, the genitals, or other organs or systems (McLeod, 19831. Manifestations of toxic disorders of the central nervous system (CNS) depend largely on the site, nature, and extent of the induced functional or structural change. The CNS consists of those parts of the nervous system contained within the skull and vertebral column. The spinal cord receives information via afferent fibers from PNS sensory receptors in the skin, voluntary muscles, tendons, blood vessels, and glands. It transmits signals for motor function through efferent fibers and communicates information via specific pathways, which include coordination centers within the brain. The brain is responsible for initiating, receiving, and integrating signals needed to maintain internal homeostasis, cognition, awareness, memory, language, personality, sexual behavior, sleep and wakefulness, movement and locomotion, sensation, vision, audition, balance, taste, olfaction, and many other body functions (Kandel and Schwartz, 19811. The brainstem, consisting of the midbrain, pans, and medulla oblongata, receives and processes information from skin, muscles, and special sense organs (e.g., inner ear), and in turn controls motor and certain autonomic functions relayed to the periphery by way of the cranial nerves. The cerebellum and basal ganglia are required for the modulation, regulation, and coordination of muscle tone and activity. The diencephalon, including the thalamus and hypothalamus, is a relay zone for transmitting information about sensation and movement. It also contains important control mechanisms for maintaining the internal homeostasis of the body. The hypothalamus functions as the primary control center for the visceral organs and inte- grates the activity of the neuroendocrine and other systems. The cerebral hemispheres, capped by the cerebral cortex, are concerned with perceptual, cognitive, motor, sensory, visual, and other functions. The optic (cranial II) nerves and their radiations conduct visual information from the retina through the thalamus to the occipital cortex. The cerebral cortex is divided into areas responsible for sensory recep- tion, motor control, and integration or association. Visual input is received in the posterior (occipital) cortex, and auditory input is directed toward the temporal lobes. Tactile sensation is perceived in the parietal cortex. The frontal cortex is concerned with the control of movement and is associated with the parietal cortex in the unilateral (left or right) regulation of speech. The remainder of the cortex is devoted to integrative and associative functions. Beneath the cerebral cortex lies a number of other

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Neurotoxic Effects 109 structural areas, most with relatively clear functions. The basal ganglia, located at the base of the cortex, are important in the control of automatic and coordinated movement, as is the cerebellum. The limbic system con- sists of portions of the cortex and lower parts of the brain, which are involved in the control of eating, drinking, aggression, general arousal, motivation, and emotion. The primary or initial sensory areas of the brain are characterized by a receptor-topical organization; that is, the sensory receptor is represented point by point. Areas adjacent to each initial reception area in the cortex provide for an integration of the simple sensory input into successively more complex sensory perceptual organizations. One of the most thor- oughly explored of these areas is the visual system, whose initial reception area lies in the lateral geniculate ganglia of the thalamus, where a point- to-point map of the retina is organized. The somatotopic arrangement in a given portion of the retina is further organized by the orientation or angularity of the cell layers in the lateral geniculate ganglia and visual cortex as they appear in the retina. Specific neurons are responsive to edges of light and dark, angles, and cornersall of a particular size or strength. Such an organization appears well suited to the identification of complex visual stimuli (Kandel and Schwartz, 19811. The motor section in the frontal cortex controls movement throughout the body: the foot and leg are controlled at the top of the motor strip; the hand, at the top of the lateral aspect; and the face, jaw, and mouth, in most of the lateral area. An entirely separate section of the frontal cortex is devoted to the precise control of eye movements. By stimulating specific neurons in the motor area, individual muscles can be activated, whereas stimulation of several neurons can produce movements of various body parts. The motor area is generally divided into the pyramidal and extra- pyramidal systems. The pyramidal tracts descend from the frontal cortex to the spinal cord, where they regulate the activity of nerve cells controlling the skeletal muscles. The extrapyramidal pathways exert control over more general responses, such as postural adjustments, and do so through con- nection with other subcortical CNS structures, including the basal ganglia and cerebellum. The largest and least well understood area of the cortex involves as- sociative responses. The frontal association areas of the cortex govern delayed response or delayed-response alteration performance, mediated by memory. Disorders of the frontal lobe are often associated with eu- phoria, apathy, indifference, impaired judgment, recent memory, and immediate recall. When this area is removed, there are alterations of discrimination ability in a range of senses, especially when visual searching is involved. Hyperactivity, increased social aggressiveness, and inability to tolerate frustration generally occur when frontal lobe tissue is destroyed.

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DRINKING WATER AND HEALTH A different set of functions is mediated by posterior cortical association areas, which govern visual-pattern discrimination and some aspects of color vision, but not visual acuity and object recognition. Learning ability is also mediated by this cortical area. The parietal association area is concerned with perception of body image and spatial relations as well as with learning involving somatesthesia. Disorders of language and inability to perceive objects occur in patients with a damaged parietal lobe (right or left). The two hemispheres of the brain commonly have structural differences and are functionally distinct with regard to higher functions. In a greatly oversimplified but didactically useful way, the human brain consists of two halves: a left hemisphere that tends to be an intellectual, rational, verbal, and analytical thinker, and a right hemisphere that tends to be a perceiver and an emotional, nonverbal, and intuitive thinker. In principle, each hemisphere is capable of independent function, but integration of function is normally maintained by an extensive network of interconnec- tions known as the corpus callosum. Hemispheric dominance develops gradually, as evidenced by the ability of young children to develop vir- tually normal speech and language capabilities after complete removal of the left hemisphere. In adults, extensive damage to the dominant hemi- sphere results in severe functional deficits in speech functions, and re- covery is slow or absent. Moreover, there are differences in the rates at which lateralization of higher functions develops in boys and girls. Hence, in preadolescents there are sex differences in vulnerability to left hemi- sphere damage. Speech becomes fixed at an earlier age in boys, who are therefore more likely to suffer more severe and enduring language deficits after cortical injury in childhood. Cellular Structure and Function The fundamental neurocellular components are neurons and glial cells, which are associated with blood vessels and other specialized epithelial and connective tissue cells (Jacobson, 19784. Neurons have relatively small cell bodies (perikarya) and multiple, relatively short processes (den- drites), which receive information transmitted from axons of other nerve cells. In addition to dendritic processes, neurons are characteristically equipped with a single, elongated axon that conducts electrical signals between neurons, or to muscles, skin, and glands. Signals are transmitted along axons by a longitudinal spread of changes in membrane potential a difference in electrical potential that exists between the intracellular (axoplasmic) and extracellular environments. In the resting state, mem- brane potential is maintained by a high intracellular concentration of po- tassium ions and a high extracellular concentration of chloride and sodium

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Neurotoxic Effects ~ ~ ~ ions. This balance is maintained by an energy-requiring ion pump located in the cell membrane; failure of this pump in certain toxic states leads to a disturbance of transmission and intracellular edema the accumulation of abnormal amounts of fluid inside the cell. Transmission of an electrical impulse along an axon is initiated by reversing the membrane potential locally; this is achieved by a rapid influx of sodium ions via membrane channels, cessation of sodium-ion flow, and an increase in potassium-ion conductance causing the potassium ions to move out of the cell along their concentration gradient. The resulting localized change in membrane po- tential the action potentialmoves along axons by reproducing these electrical events in adjacent areas of excitable membrane. Impulse prop- agation is accelerated in myelinated nerve fibers by the concentration of electrical events on the naked axon at sites between adjacent myelinating cells (nodes of Ranvier). Toxic substances that interfere with the function of ion channels in the excitable membrane or impair the function of Ranvier nodes produce transient alterations of nerve conduction that precipitate characteristic sensory or motor phenomena (Narahashi, 19841. Axons terminate at synapses where chemically encoded information is conveyed to other neurons or effecter organs. Proven chemical neuro- transmitters (up to 50 are suspected) include acetylcholine, nonepine- phrine, epinephrine, and dopamine; putative transmitters include glycine, glutamic acid, ~y-aminobutyric acid, serotonin (5-hydroxytryptamine), his- tamine, substance P. enkephalin, and many other neuroactive peptides (Cooper et al., 1982~. Enzymes responsible for the synthesis of transmitters are manufactured in neuronal perikarya. Subsequently, with membranous and cytoskeletal elements, they move toward the nerve terminal by energy- requiring axonal transport (Brady, 1984~. Retrograde transport mecha- nisms return materials to the cell body for reprocessing (Kristensson, 1984~. Toxic substances may be specific for one or more transmitter systems, acting by changing the rate of synthesis, synaptic release, reup- take, or degradation or by interfering with the interaction of the chemical signal with the receptor surface on the dendrite or other cellular membrane (muscle or gland). Such changes are usually short lasting and reversible. By contrast, chemical agents that induce loss of CNS neurons produce irreversible damage. Degeneration of CNS axons, initiated by blockade of axonal transport or by other methods, is also commonly irreversible, except for small-diameter unmyelinated monoaminergic axons that regen- erate and elongate after injury. Glial cells in the CNS include astrocytes, oligodendrocytes, and mi- croglia (Varon and Somjen, 19791. Astrocytes are divisible into proto- plasmic and fibrous forms. They are closely associated with neurons and blood vessels, play a nutritive role in maintaining neurons and other cells, and regulate the composition of the extracellular fluid. Astrocytes have

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~ 12 DRINKING WATER AND HEALTH also been implicated in the metabolic activation of methylphenyltetrahy- dropyridine (MPTP), an agent that produces parkinsonism in humans and animals. In addition, they provide an outer cellular border around the brain and spinal cord. These two organs are surrounded by a delicate pial connective tissue and are suspended in cerebrospinal fluid (CSF), which circulates between the ventricular system of the brain and spinal cord and spaces beneath the arachnoid and aural connective tissues that encase and protect the CNS. Interruption of the normal flow of CSF during devel- opment or adult life leads to hydrocephalus, a condition resulting from the accumulation of fluid in enlarged brain ventricles or between the brain and the overlying aura (Weller et al., 19831. The oligodendrocyte, another type of glial cell, elaborates short lengths of myelin around clusters of adjacent CNS axons. Myelination begins in the fourth month of fetal life and continues until the first year of postnatal life (Pansky and Allen, 19801. Toxic substances that induce changes in oligodendrocytes or myelin in postnatal or adult states cause reversible myelin vacuolation, demye- lination, and remyelination pathological events that interrupt nerve-im- pulse transmission without disrupting the structural continuity of axons (Rasminsky, 19801. CNS injuries resulting in a loss of tissue are associated with proliferation of astrocytes, which form a glial scar. In the PNS, Schwann cells envelop many small axons to form un- myelinated fibers, or associate with and elaborate lengths of myelin (in- ternodes) around single axons. PNS myelination occurs over a time course similar to that in the CNS. Toxic conditions resulting in damage to mature PNS axons are usually reversible, since axonal regeneration, reconnection, and reactivation of denervated end organs usually follow injury. Motor denervation leads to neurogenic atrophy of voluntary muscle. Damage to Schwann cells or myelin causes localized demyelination and then re- myelination pathological changes associated with blockade and resto- ration of nerve-impulse activity, respectively (Rasminsky, 19801. Exten- sive demyelination may be accompanied by axonal loss and poor functional recovery. The adult nervous system is provided with specialized regulatory in- terfaces, known as blood-brain, blood-nerve, blood-CSF, and blood- retinal barriers, among others. Such permeability barriers are formed by tight iunctions between adjacent endothelial cells lining neural capillaries and their corresponding basal laminae (Jacobs, 19801. The barrier func- tions as a differential filter that controls the passage of various substances (including certain blood-borne toxicants) from the blood to the interstitial fluid. Certain areas of the brain and PNS are devoid of blood-nerve bar- riers, including the area postrema, hypophysis, pineal body, hypothalamic regions, subfornical organ, supraoptic crest, choroid plexus, dorsal root, and autonomic ganglia. Such regions are directly exposed to toxic and

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Neurotoxic Effects 113 other substances circulating in the blood. Experimental studies demon- strate that large doses of several glutamate analogs (excitotoxicants) induce neuronal degeneration in areas of the CNS lacking a blood-brain barrier (Olney, 1980) and that other agents (e.g., doxorubicin and large concen- trations of pyridoxine) alter the integrity or cause degeneration of sensory neurons in dorsal root ganglia (Cho et al., 1980~. The CNS and much of the PNS are also protected from exogenous agents by connective tissue sheaths, but the terminal regions of efferent PNS axons in muscle and glands may be directly exposed to noxious agents present in tissue fluid. Such agents may be selectively or nonspecifically taken up by nerve terminals and carried by retrograde transport to remote target sites in the neuronal perikaryon (for agents such as ricin) or associated synapses (for substances such as tetanospasmin) (Price et al., 1975~. Normal Developmental Structure and Function Development of the human nervous system begins during the third week of embyrogenesis (see Chapter 2 on Developmental Toxicity) (Pansky and Allen, 19801. The CNS commences as an elongated neural plate of thick- ened ectoderm. The lateral edges of the plate elevate, abut, and from the fourth week onward, fuse to form a closed tubular structure (neural tube) with a long caudal portion (the future spinal cord) and a broader cephalic segment (the future brain). The latter displays three distinct dilatations corresponding to the fore-, mid-, and hindbrain vesicles. Differential growth and migration of cell populations then mold the vesicles into more complex forms. By the fifth fetal week, the forebrain consists of the diencephalon with primordial optic vesicles, pineal gland and posterior hypophysis, and two lateral expansions the primitive cerebral hemispheres. The hemi- spheres expand rapidly and cover the brainstem, forming various spe- cialized centers including the hippocampus. During late fetal life, the surface of the cerebral hemispheres grows so rapidly that convolutions (gyri) develop on its surface. The diencephalon also gives rise to the thalamus, which contains the dorsal nuclei important for the reception and transmission of auditory impulses, and ventral nuclei, which serve as relay stations for transmitting the impulses to higher cen- ters. These and other elements form the limbic system, which is concerned with the regulation of emotional activity, visceral and memory functions, and such other activities of the hypothalamus as the regulation of body temperature. The pituitary gland (hypophysis) develops from a downward extension of the diencephalon (becoming the posterior hypophysis or neu- rohypophysis) and an ectodermal outpocketing of the primitive oralLcavity (Rathke's pouch, becoming the anterior hypophysis, or adenohypophysis). Each optic vesicle forms an optic cup, which grows out to form the optic

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~ ]4 DRINKING WATER AND HEALTH nerve and retina, and induces the surface ectoderm to invaginate and form the lens and cornea. Congenital abnormalities of the eye induced by chem- ical and other agents may lead to the development of a single eye (cyclops), no eye (anophthalmia), malformation of the iris, retinal dysplasia or her- niation, and many other conditions (Wilson and Fraser, 1977b, pp. 329- 3411. In the normal state, after the eye opens postnatally, visual impulses are conducted from the retina to the lateral geniculate body and then to the occipital cortex. The remaining portion of the brain develops from the specialization of plates of cells. In general, cells located in the basal plate form motor neurons whose axons supply cranial nerves, while the more dorsal, alar plates form the sensory relay nuclei of the brainstem (Pansky and Allen, 19801. The midbrain develops the motor nuclei of cranial nerves and relay nuclei for visual and auditory reflexes. The hindbrain comprises the met- encephalon, from which develops the pons and cerebellum, and the myel- encephalon, the forerunner of the medulla oblongata. The roof plate of the myelencephalon forms the choroid plexustuft-like imaginations that produce CSF. The cerebellum develops from the metencephalon, and by the twelfth fetal week, forerunners of the midline vermis and paired hemi- spheres are visible. Cells migrate to the surface to form the external granular layer, and at the sixth developmental month, cells migrate from this layer inward toward the differentiating Purkinje cells. The inner ear, which subserves both audition and equilibrium, develops after the third week from otic placodes, which are visible on each side of the hindbrain. During later development, each vesicle divides into a ventral portion that gives rise to the saccule and cochlear duct and a dorsal component that makes up the utricle, semicircular canals, and endolym- phatic duct. The organ of Corti, the true organ of hearing, is visible by the tenth week. At maturity, impulses are transmitted by the spiral ganglion to the brainstem via cranial nerve VIII. The semicircular canals appear at the sixth fetal week, and at maturity, impulses generated in the sensory cells of the cristae and maculae as a result of position changes of the body are carried to the brain by the vestibular fibers of cranial nerve VIII. Other special sense organs include receptors for taste, which convey information via sensory ganglia to the brainstem and cortex, and receptors for olfaction, which send impulses directly to the primary and secondary olfactory cor- tex. Development of the spinal cord is comparable to that of the brainstem. Basal plates on the ventral sides of the neural tube form motor neurons, notably anterior horn cells, while the dorsal, alar plates form sensory association areas. These receive the central axon processes of sensory neurons in dorsal root ganglia, which develop from neural-crest cells that

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Neurotoxic Effects ~15 overlie the dorsal surface of the neural tube. The peripheral axons of the sensory neurons supply sensory receptors. The motor neurons of the autonomic division of the PNS develop be- tween the ventral and dorsal plates deep in the immature spinal cord. A sympathetic branch is formed in the thoracolumbar region, and a para- sympathetic component is found in the craniosacral region. The efferent portions of both parts are composed of a chain of two neurons, whereas afferent impulses from pressure and chemoreceptors in the aorta and ca- rotid arteries ascend via axons of visceral sensory neurons in dorsal root ganglia (Mayer, 19801. Some sympathetic neurons originate from the neural crest and migrate on each side of the cord to form a bilateral chain of segmentally arranged ganglia interconnected by nerve fibers; others form the celiac and mesenteric ganglia of the aortic branches and the organ plexuses found in the heart, lungs, and gastrointestinal tract. Preganglionic efferent axons of the sympathetic chain use acetylcholine as their neu- rotransmitter. Postganglionic efferent neurons, in conjunction with the adrenal medulla, release nonepinephrine directly or through the blood- stream to effecter sites in the ciliary body of the eye, the salivary glands, bronchi, heart and blood vessels, liver, gut, kidney, bladder, and external genitalia. Preganglionic neurons of the parasympathetic system, located in the midbrain, medulla oblongata, and sacral spinal cord, also use ace- tylcholine as a neurotransmitter, as do their postganglionic counterparts located close to their effecter sites in the organs listed above. Functionally, the two divisions of the autonomic nervous system tend to counteract each other (Mayer, 19801: the sympathoadrenal system, which can discharge as a unit during rage or fright, accelerates heart rate; increases blood pressure and glucose concentration; shifts blood from the spleen, skin, and gut to the skeletal muscles; and dilates the pupils and bronchioles. By contrast, the parasympathetic system tends to conserve energy by slowing the heart rate, lowering blood pressure, stimulating gastrointestinal movements and secretions (thereby aiding nutrient ab- sorption), protecting the retina from excessive light, and emptying the urinary bladder and rectum. Synchronized discharge of parasympathetic neurons does not occur normally, but is seen during poisoning with anti- cholinesterases, which inhibit the enzyme (cholinesterase) required to ter- minate the transmitter activity of acetylcholine (Mayer, 19801. Neuroteratology and Psychoteratology Experimental studies and clinical experience have demonstrated that the response of the developing nervous system to chemical substances may be either quantitatively or qualitatively different from the response

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|28 DRINKING WATER AND H"LTH TABLE 4-2 Some Common Clinical Manifestations of Human Neurotoxicitya Function Affected Manifestation Chemical Cognitive Intelligence loss Lead saltsb Learning decrements Lead salts b Memory dysfunction Anticholinesterases Sensory Irritability Carbon disulfide Apathy/lethargy Carbon monoxide A t t e n t i o n d i f fi c u l t y A n t i c h o l i n e s t e r a s e s Illusions, delusions Ergot Dementia Aluminum Depression, euphoria Ozocerite Stupor, coma Dicyclopentadiene Sensory, special Abnormalities of: Smell Cadmium Vision Organomercury Taste Selenium Audition Toluene Balance Methyl nitrite Somatosensory Skin senses (e.g., Trichloroethylene numbness, pain) Proprioception Acrylamide Motor Muscle weakness, paralysis Organophosphates Spasticity p-N-Oxalylamino-~-alanine Rigidity MPTP Tremor Chlordecone Dystonia Manganese Incoordination Organomercury Hyperactivity Lead salts Myoclonus Toluene Fasciculation Anticholinesterases Cramps Styrene Seizures, convulsions Acetonitrile Autonomic Abnormalities of: Sweating Acrylamide Temperature control Chlordane Gastrointestinal function Lead salts Appetite/body weight Dinitrobenzene Cardiovascular control 1-Nitrophenyl-3-(3- pyridylmethyl) urea Urination Dimethylaminopropionitrile Sexual function ,B-Chloroprene Immune system Myositis, vasculitis, fibrosis Guillain Barre syndrome Spanish toxic oil Gold salts aAdapted from Lane and Routledge, 1983. bData not conclusive.

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Neurotoxic Effects 129 syndrome associated with pyridoxine megavitamin therapy (Foca, 1985), prescribed for the treatment of premenstrual tension. In developing countries, biological toxins (e.g., Clostridium botulinum, C. tetani, and Corynebacterium diphtherial, neurotoxic agents naturally present in food (e.g., cassava and Lathyrus suppl.) or as contaminants (e.g., ergot and aflatoxin), and pesticides probably account for a large number of human neurotoxic disorders. Uncontrolled cholinergic crises, sometimes leading to death, are commonplace in certain regions among agricultural and pesticide workers (Almeida, 1984), and long-lasting changes in the electroencephalograms and behavior of surviving persons have been recorded (Duffy et al., 19791. Other pesticides contain tremor- and seizure- inducing organochlorines or synthetic pyrethroids that perturb neurotrans- mission (Narahashi, 1984; Taylor et al., 19791. The worldwide problem of substance abuse, particularly abuses involving ethanol, hallucinogens, narcotics, CNS stimulants, solvents, and nitrous oxide, leads to various types of short- or long-lasting neurological dysfunction. Many other sub- stances encountered in the workplace (e.g., solvents, monomers, and catalysts) have been associated with neurological illnesses ranging from polyneuropathy to organic brain syndrome. Both of these disorders were observed in workers exposed for only a few weeks to one particularly potent industrial neurotoxicant, Lucel-7 (2-tert-butylazo-2-hydroxy-5- methylhexane) (Kurt and Webb, 19801. Among the environmental pollutants with neurotoxic potential, lead and mercury each occupy a prominent position, although the number of people in North America with overt neurotoxic disorders attributable to these sources is probably low. Potent chemical toxins are secreted by or con- tained in numerous members of the animal kingdom. Many of these agents disturb nerve conduction, and one, ciguatoxin, is a major cause of acute neurotoxicity in the Pacific among those who eat contaminated fish (Kap- lan, 19801. Others (e.g., c~-bungarotoxin and cx-latrotoxin) affect synaptic transmission. Both types can produce acute, life-threatening conditions. Some of these agents find their way into food and water consumed by humans. Some chemicals with experimentally proven neurotoxic potential in animals are used as food additives (e.g., monosodium glutamate), flavors and fragrances (e.g., 2,6-dinitro-3-methoxy-4-tert-butyltoluene), and antiseborrheic agents (e.g., zinc pyridinethione), but no cases of human neurotoxic disease from these sources have been reported. The occurrence of subclinical neurological and behavioral disorders associated with chemical substances is unknown but is believed by some to be widespread. Examples include the unre~.olved controversies about childhood cognitive impairment from environmental lead contamination and the neurobehavioral effects attributed to prolonged occupational ex- posure to a variety of industrial solvents.

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]30 DRINKING WATER AND HEALTH Methods for assessing neurotoxic diseases in humans fall outside of the scope of this document. For information on this subject, please refer to Geller et al. (1979) and Spencer and Schaumburg (1980, pp. 650-7071. Epidemiological Studies There have been several epidemiological studies of outbreaks of human neurobehavioral disorders in which chemical compounds have been im- plicated and subsequently proved to be neurotoxic in animal studies. Few of these investigations have been focused on features important to the toxicologist, such as the exposure concentration and duration, route of entry, and individual susceptibility. A notable exception was the outbreak of neuropathy induced by methyl n-butyl ketone (MBK) in an Ohio factory in 1973 (Allen et al., 1975), where an analysis of the atmosphere and exposure conditions was conducted by NIOSH. This investigation was followed by a large number of experimental animal studies that demon- strated, for example, that dermal penetration was a significant route of human exposure to MBK, that oxidative metabolism yielded a number of metabolites with neurotoxic potency, and that other solvents played a role in potentiating the neurotoxic activity of MBK (Spencer and Schaumburg, 1980~. Other notable recent outbreaks subjected to epidemiological investi- gation include occupational injuries associated with exposures to chlor- decone, dimethylaminopropionitrile, n-hexane, Lucel-7, and leptophos (Pestronk et al., 1979, 1980; Spencer et al., 1980a,b, 1985; Taylor et al., 1978; Xintaras et al., 1978~. Other major outbreaks have involved con- sumption of foodstuffs contaminated with such neurotoxic substances as hexachlorobenzene, tri-o-cresyl phosphate, methylmercury, polybromi- nated biphenyls, or thallium salts (Schaumburg and Spencer, 19801. A small outbreak of neuropathy and encephalopathy in a Japanese family followed consumption of well water contaminated with acrylamide (Igisu et al., 19751. CONTROLLED AND OTHER STUDIES Controlled studies of the human response to environmental neurotoxi- cants have been limited to acute exposure associated with short-term and presumably reversible neurobehavioral dysfunction. Some of these studies have been focused on the effects of inhaled organic solvents on manual dexterity, performance on psychological test batteries, vestibular func- tions, and other functions. Another set of data from relatively controlled situations reflects clinical experience with therapeutic drugs. Although many of these compounds are not of immediate concern, some agents

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Neurotoxic Effects 131 (e.g., anticholinesterases) used in the therapeutic setting may also appear in different forms in drinking water. STUDIES IN ANIMALS Many methods have been used to assess neurotoxicity in animals, and many types of data have been produced. Experimental studies of the adverse actions of chemical agents on the nervous system include system- atic observation and measurement of behavior, neural function, structure, and biochemistry in various laboratory animals. Behavioral toxicology and teratology are relatively recent introductions to the field, and the specific methods used in these studies are evolving rapidly. In this section, no attempt has been made to describe methodology in detail. In broad terms, behavioral toxicology deals with two groups: respondent behaviors (e.g., auditory startle response), which are elicited by a specific observable stimulus and determined primarily by the properties of the stimulus presentation, and operant behaviors (e.g., exploratory activity), which occur in the absence of an eliciting stimulus and are determined primarily by their consequences. Operant behavior is frequently condi- tioned by reward or punishment to generate a reliable quantitative baseline. Some of the test methods used in behavioral toxicology, such as the psychophysical measurement of cortical blindness induced by methyl- mercury, have been successfully used to model visual neurotoxicity in humans, whereas the findings of other tests bear an unknown relationship to human disease. However, with further refinement of methods and the ability to evaluate specific changes in relation to biochemical or functional changes in the nervous system, behavioral toxicology and teratology should be especially useful in studying human neurobehavioral disorders (such as tardive dyskinesia), which appear to be unassociated with detectable neuropathological changes. A variety of electrophysiological techniques have been used to assess the presence and extent of CNS and PNS injuries, to locate the target sites of action, and to determine the cellular and molecular mechanisms of action. These techniques include measurements of PNS sensory and motor conduction velocities, tests of sensory- and motor-evoked cortical poten- tials, electroencephalography, electromyography, and extracellular unit recordings from retinal ganglion cells. Intracellular recordings, voltage and patch clamping, and noise analysis have also been used (Fox et al., 1982; Narahashi, 19841. Several of these experimental techniques have been used in clinical situations, since they are noninvasive, sensitive, reliable, and relatively easy to use. These experimental and clinical tech- niques thus allow one to determine the contribution of pathophysiology to neurological and behavioral impairment.

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]32 DRINKING WATER AND HEALTH In experimental animals, observation and measurement of changes in neural structure have provided a solid basis for understanding human neurotoxic syndromes associated with pathological changes in the devel- oping or adult nervous system. This has been possible because the methods used to assess neurological disorders in humans have been exploited and further refined by experimental neurotoxicologists. The transmission elec- tron microscope has greatly extended the resolution of tissue detail, which used to be afforded by the light microscope. Armed with these techniques and a knowledge of neurobiological principles, one can define different patterns of neurotoxic response to chemical agents and explain how these result in human diseases that vary in expression and prognosis. With the exception of certain developmental disorders associated with chemical overexposure, there is usually an excellent correlation between the neu- rotoxic disorders of mammals and human beings. Through studies in various animal models, structural and functional changes induced by nu- merous chemical substances have been characterized. These studies have also enabled investigators to pinpoint the initial site of neurotoxic damage or dysfunction information that provides a sensitive method to assess no-effect and threshold levels for the substance of interest. With few exceptions, biochemical mechanisms underlying the neuro- toxic action of environmental chemicals are poorly understood. The best examples are the actions of certain organophosphate esters on acetylcho- linesterase, which promptly induce cholinergic toxicity, and on neuropathy target esterase (formerly called neurotoxic esterase), which is associated with the development of polyneuropathy (Davis and Richardson, 1980~. From measurements of enzyme levels in tissue and blood, one can estimate the degree of enzyme inhibition and associated neurotoxic illness. Such measurements provide a sensitive means of assessing the neurotoxic ac- tivities of agents with these properties. Biochemical studies of other dis- orders will most likely yield information on mechanisms that will, in turn, provide comparably sensitive biological markers to determine the degree of neurotoxic impairment produced by chemical agents. Data on bio- chemical changes underlying neurotoxicity also are critical for the pre- vention and treatment of such disorders. Information correlating metabolism and pharmacodynamics with neu- rotoxic properties is also sparse. The usefulness of this approach, however, was elegantly demonstrated in studies of n-hexane and methyl n-butyl ketone in rats. O'Donoghue and colleagues (1982) found that these chem- ically distinct solvents appeared to produce qualitatively identical patterns of neurotoxic disease. The neurotoxic potency of each of the agents was directly proportional to the amount of y-diketone generated~by metabolism. Such studies in rats and subsequently in humans (DiVincenzo et al., 1978; Perbellini et al., 1979, 1980) demonstrated that these agents were meta-

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Neurotoxic Effects 133 helically related and each could be converted to the proximal metabolite 2,5-hexanedione. Moreover, the onset of characteristic neurological dys- function (e.g., hindlimb weakness) was linearly related to the concentra- tion of the proximal metabolite in serum (Krasavage et al., 19801. How many other neurotoxic compounds show a linear relationship between dose and effect is unknown. I NTERSPECI ES EXTRAPOLATION There are often major differences between the degree of neurotoxic response observed in animals and that found in humans. For example, the rat is relatively refractory to such agents as organophosphates, arsenic, thallium, MPTP, and thalidomide, all of which readily produce neuro- degenerative disorders in humans. Other substances that cause neuropathy in humans, such as acrylamide (see Chapter 9), n-hexane (Spencer et al., 1980a), and carbon disulfide (Seppalainen and Haltia, 1980), also produce neuropathy in rodents. Understanding in this area is so limited that there is no reliable prescription for choosing the appropriate animal for studies intended to shed light on human susceptibility. One important exception is the choice of fowl for the study of organophosphate neuropathy (Davis and Richardson, 1980~. Once a suitable test animal has been identified and a neurotoxic dose established, then the disorder of interest will usually appear in all adult animals after a similar dose and test period have elapsed. The pattern of dysfunction and the underlying structural and functional changes are also uniform across test animals within a single species. These principles may allow the experimentalist to test much smaller numbers of animals than those used, for example, in assays of carcinogenesis. Caution is appro- priate, however, in studies focused on the establishment of threshold or low-risk levels of neurotoxic response (as is generally the case in risk assessment), where one is operating in a portion of the dose-response curve that is likely to be less steep than the region in which most exper- imental studies have been performed. These rules do not apply to neu- rotoxic disorders of the developing animal, in which response rate and type of teratogenicity are often variable. RISK ASSESSMENT Little effort has been directed toward assessing risk from exposure to chemical neurotoxicants. Because of the large number of potential health end points associated with neurotoxicants, attempts at risk assessment are substantially more complex than they are for chemical carcinogens. For example, the same substance may produce markedly different neurotoxic

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]34 DRINKING WATER AND HEALTH effects, depending on age at time of exposure. Although the susceptibility of the nervous system to toxicity is well recognized, no bioassay has been developed for identifying and regulating environmental neurotoxicants. Assessment of dose-response relationships is plagued by the usual un- certainties. Epidemiological dose-response information is extremely lim- ited, and that which does exist may not be applicable to the general population. Although some animal models are particularly accurate for assessing neurological disorders in humans, the large number of potential toxic end points greatly complicates assessment since there may not be a single threshold dose for all end points. Exposure assessment requires knowledge concerning chemical type and concentration, effect and its seventy, route and duration of exposure, and identification of high-nsk groups. Safety factors used in such assessments should reflect uncertainty due to variability within the population and variability between the population of interest and the sampled population. Until an accurate probabilistic model for risk assessment is developed, safety factors will have to be used in place of confidence limits. A more detailed discussion of risk assessment for neurotoxicants is found in Chap- ter 8. REFERENCES Allen, N., J. R. Mendell, D. J. Billmaier, R. E. Fontaine, andJ. O'Neill. 1975. Toxic polyneuropathy due to methyl n-butyl ketone. An industrial outbreak. Arch. Neurol. 32:209-218. Almeida, W. F. 1984. The dangers and the precautions. World Health Aug./Sept.:10-12. Altenkirch, H., H. M. Wagner, G. Stoltenburg, and P. S. Spencer. 1982. Nervous system responses of rats to subchronic inhalation of n-hexane and n-hexane + methyl-ethyl- ketone mixtures. J. Neurol. Sci. 57:209-219. Anger, W. K. 1984. Neurobehavioral testing of chemicals: Impact on recommended stan- dards. Neurobehav. Toxicol. Teratol. 6:147-153. Anger, W. K., and B. L. Johnson. 1985. Chemicals affecting behavior. Pp. 51-148 in J. L. O'Donoghue, ed. Neurotoxicity of Industrial and Commercial Chemicals. Vol. 1. CRC Press, Boca Raton, Fla. Brady, S. T. 1984. Basic properties of fast axonal transport and the role of fast transport in axonal growth. Pp. 13-29 in J. S. Elam and P. Cancalon, eds. Axonal Transport in Neuronal Growth and Regeneration. Plenum, New York. Cammer, W. 1980. Toxic demyelination: Biochemical studies and hypothetical mecha- nisms. Pp. 239-256 in P. S. Spencer and H. H. Schaumburg, eds. Experimental and Clinical Neurotoxicology. Williams & Wilkins, Baltimore. Cho, E. S., P. S. Spencer, B. S. Jortner, and H. H. Schaumburg. 1980. A single intravenous injection of doxorubicin (Adriamycin~) induces sensory neuropathy in rats. Neurotox- icology 1 :583-591. Cooper, J. R., F. E. Bloom, and R. H. Roth. 1982. The Biochemical Basis of Neuro- pharmacology, 4th ed. Oxford University Press, New York. 367 pp.

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Neurotoxic Effects 135 Damstra, T., and S. C. Bondy. 1980. The current status and future of biochemical assays for neurotoxicity. Pp. 820-833 in P. S. Spencer and H. H. Schaumburg, eds. Experimental and Clinical Neurotoxicology. Williams & WiLkins, Baltimore. Davis, C. S., and R. J. Richardson. 1980. Organophosphorus compounds. Pp. 527-544 in P. S. Spencer and H. H. Schaumburg, eds. Experimental and Clinical Neurotoxicology. Williams & WiLkins, Baltimore. DiVincenzo, G. D., M. L. Hamilton, C. J. Kaplan, W. J. Krasavage, and J. L. O'Don- oghue. 1978. Studies on the respiratory uptake and excretion and the skin absorption of methyl n-butyl ketone in humans and dogs. Toxicol. Appl. Pharmacol. 44:593-604. Duffy, F. H., J. L. Burchfiel, P. H. Bartels, M. Gaon, and V. M. Sim. 1979. Long-term effects of an organophosphate upon the human electroencephalogram. Toxicol. Appl. Pharmacol. 47: 161-176. Ells, J. 1984. Drugs used in tuberculosis and leprosy. Pp. 287-291 in M. N. G. Dukes and J. Ells, eds. Side Effects of Drugs Annual 8. A Worldwide Yearly Survey of New Data and Trends. Elsevier, New York. Foca, F. J. 1985. Motor and sensory neuropathy secondary to excessive pyridoxine inges- tion. Arch. Phys. Med. Rehab. 66:634-636. Fox, D. A., H. E. Lowndes, and G. G. Bierkamper. 1982. Electrophysiological techniques in neurotoxicology. Pp. 299-335 in C. L. Mitchell, ed. Nervous System Toxicology. Raven Press, New York. Geller, I., W. C. Stebbins, and M. J. Wayner, eds. 1979. Test Methods for Definition of Effects of Toxic Substances on Behavior and Neuromotor Function. Proceedings of the workshop held April 1-4, 1979, San Antonio, Texas. Report No. EPA 560/11-79-010. (Neurobehavioral Toxicology, Vol. 1, Suppl. 1.) ANKHO International Inc., Fayette- ville, N.Y. 225 pp. Ginsberg, M. D. 1980. Carbon monoxide. Pp. 374-394 in P. S. Spencer and H. H. Schaumburg, eds. Experimental and Clinical Neurotoxicology. Williams & Wilkins, Baltimore. Gopalan, C. 1950. The lathyrism syndrome. Trans. R. Soc. Trop. Med. Hyg. 44:333-338. Igisu, H., I. Goto, Y. Kawamura, M. Kato, K. Izumi, and Y. Kuroiwa. 1975. Acrylamide encephaloneuropathy due to well water pollution. J. Neurol. Neurosurg. Psych. 38:581- 584. Jacobs, J. M. 1980. Vascular permeability and neural injury. Pp. 102-117 in P. S. Spencer and H. H. Schaumburg, eds. Experimental and Clinical Neurotoxicology. Williams & Wilkins, Baltimore. Jacobson, M. 1978. Developmental Neurobiology, 2nd ed. Plenum, New York. 562 pp. Johnson, M. K. 1975a. Structure-activity relationships for substrates and inhibitors of hen brain neurotoxic esterase. Biochem. Pharmacol. 24:797-805. Johnson, M. K. 1975b. The delayed neuropathy caused by some organophosphorus esters: Mechanism and challenge. CRC Crit. Rev. Toxicol. 3:289-316. Kandel, E. R., and J. H. Schwartz, eds. 1981. Principles of Neural Science. Elsevier, New York. 733 pp. Kaplan, J. G. 1980. Neurotoxicity of selected biological toxins. Pp. 631-648 in P. S. Spencer and H. H. Schaumburg, eds. Experimental and Clinical Neurotoxicology. Wil- liams & WiLkins, Baltimore. Katcher, B. S., L. Y. Young, and M. A. Koda-Kimble, eds. 1983. Applied Therapeutics: The Clinical Use of Drugs, 3rd ed. Applied Therapeutics, San Francisco. 1619 pp. Katzman, R., and R. Terry, eds. 1983. The Neurology of Aging. F. A. Davis, Philadelphia. 249 pp.

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t36 DRINKING WATER AND HEALTH Krasavage, W. J., J. L. O'Donoghue, G. D. DiVincenzo, and C. J. Terhaar. 1980. The relative neurotoxicity of methyl-n-butyl ketone, n-hexane and their metabolites. Toxicol. Appl. Pharmacol. 52:433-441. Kristensson, K. 1984. Retrograde signaling after nerve injury. Pp. 31-43 in J. S. Elam and P. Cancalon, eds. Axonal Transport in Neuronal Growth and Regeneration. Plenum, New York. Kurt, T., and C. R. Webb, Jr. 1980. Toxic occupational neuropathyTexas. Morbid. Mortal. Weekly Rep. 29:529-530. Lane, R. J. M., and P. A. Routledge. 1983. Drug-induced neurological disorders. Drugs 26: 124-147. Langston, J. W. 1985. MPTP neurotoxicity: An overview and characterization of phases of toxicity. Life Sci. 36:201-206. Le Quesne, P. M. 1980. Acrylamide. Pp. 309-325 in P. S. Spencer and H. H. Schaumburg, eds. Experimental and Clinical Neurotoxicology. Williams & Wilkins, Baltimore. Mayer, S. E. 1980. Neurohumoral transmission and the autonomic nervous system. Pp. 56-90 in A. G. Gilman, L. S. Goodman, and A. Gilman, eds. Goodman and Gilman's The Pharmacological Basis of Therapeutics, 6th ed. Macmillan, New York. McLeod, J. G. 1983. Distal autonomic neuropathy. Pp. 543-573 in R. Bannister, ed. Autonomic Failure: A Textbook of Clinical Disorders of the Autonomic Nervous System. Oxford University Press, New York. Merigan, W. H., and B. Weiss. 1980. Neurotoxicity of the Visual System. Raven Press, New York. 274 pp. Narahashi, T. 1984. Nerve membrane sodium channels as the targets of pyrethroids. Pp. 85-108 in T. Narahashi, ed. Cellular and Molecular Neurotoxicology. Raven Press, New York. NIOSH (National Institute for Occupational Safety and Health). 1977. National Occupa- tional Hazard Survey. Vol. III. Survey Analysis and Supplemental Tables. DHEW (NIOSH) Publication No. 78-114. National Institute for Occupational Safety and Health, Cincinnati. 799 pp. (Available from National Technical Information Service, Springfield, Va., as Publication No. PB-82-229881.) NRC (National Research Council). 1982. Possible Long-Term Health Effects of Short- Term Exposure to Chemical Agents. Vol. 1. Anticholinesterases and Anticholinergics. National Academy Press, Washington, D.C. 292 pp. O'Donoghue, J. L. 1985. Neurotoxicity of Industrial and Commercial Chemicals. Vol. II. CRC Press, Boca Raton, Fla. 209 pp. O'Donoghue, J. L., W. J. Krasavage, G. D. DiVincenzo, and D. A. Ziegler. 1982. Commercial-grade methyl heptyl ketone (5-methyl-2-octanone) neurotoxicity: Contri- bution of 5-nonanone. Toxicol. Appl. Pharmacol. 62:307-316. Olney, J. W. 1980. Excitotoxic mechanisms of neurotoxicity. Pp. 272-294 in P. S. Spencer and H. H. Schaumburg, eds. Experimental and Clinical Neurotoxicology. Williams & WiLkins, Baltimore. OTA (Office of Technology Assessment). 1984. Impacts of Neuroscience A Background Paper. Publication No. OTA-BP-BA-24. Off~ce of Technology Assessment, Congress of the United States, Washington, D.C. 40 pp. Pansky, B., and D. J. Allen. 1980. Pp. 10-11 in Review of Neuroscience. Macmillan, New York. Perbellini, L., F. Brugnone, G. Pastorello, and L. Grigolini. 1979. {Jrinary excretion of n-hexane metabolites in rats and humans. Int. Arch. Occup. Environ. Health 42:349- 354.

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Neurotoxic Effects 137 Perbellini, L., F. Brugnone, and I. Pavan. 1980. Identification of the metabolites of n- hexane, cyclohexane, and their isomers in men's urine. Toxicol. Appl. Pharmacol. 53:220-229. Pestronk, A., J. P. Keogh, and J. W. Griffin. 1979. Dimethylaminopropionitrile (DMAPN) intoxication: A new industrial neuropathy. (Abstract GS-1.) Neurology 29:540. Pestronk, A., J. P. Keogh, and J. W. Griffin. 1980. Dimethylaminopropionitrile. Pp. 422- 429 in P. S. Spencer and H. H. Schaumburg, eds. Experimental and Clinical Neuro- toxicology. Williams & Wilkins, Baltimore. Powell, H. C., R. R. Myers, and P. W. Lampert. 1980. Edema in neurotoxic injury. Pp. 118-138 in P. S. Spencer and H. H. Schaumburg, eds. Experimental and Clinical Neu- rotoxicology. Williams & Wilkins, Baltimore. Price, D. L., J. Griffin, A. Young, K. Peck, and A. Stocks. 1975. Tetanus toxin: Direct evidence for retrograde intraaxonal transport. Science 188:945-947. Price Evans, D. A. 1978. Genetic studies involving drug metabolism in man. Pp. 135-155 in J. W. Gorrod and A. H. Beckett. Drug Metabolism in Man. Taylor & Francis, London. Prosen, C. A., and W. C. Stebbins. 1980. Ototoxicity. Pp. 62-76 in P. S. Spencer and H. H. Schaumburg, eds. Experimental and Clinical Neurotoxicology. Williams & Wil- kins, Baltimore. Rasminsky, M. 1980. Physiological consequences of demyelination. Pp. 257-271 in P. S. Spencer and H. H. Schaumburg, eds. Experimental and Clinical Neurotoxicology. Wil- liams & Wilkins, Baltimore. Rebert, C. S., S. S. Sorenson, R. A. Howd, and G. T. Pryor. 1982. Toluene-induced hearing loss in rats evidenced by the brainstem auditory-evoked response. Pp. 314-319 in H. N. MacFarland, C. E. Holdsworth, J. A. MacGregor, R. W. Call, and M. L. Kane, eds. The Toxicology of Petroleum Hydrocarbons. Proceedings of the Symposium, May 1982, Washington, D.C. American Petroleum Institute, Washington, D.C. Schaumburg, H. H., and P. S. Spencer. 1980. Selected outbreaks of neurotoxic disease. Pp. 883-889 in P. S. Spencer and H. H. Schaumburg, eds. Experimental and Clinical Neurotoxicology. Williams & Wilkins, Baltimore. Schaumburg, H. H., P. S. Spencer, and P. K. Thomas. 1983. Pp. 127-128 in Disorders of Peripheral Nerves. F. A. Davis, Philadelphia. Seppalainen, A. M., and M. Haltia. 1980. Carbon disulfide. Pp. 356-373 in P. S. Spencer and H. H. Schaumburg, eds. Experimental and Clinical Neurotoxicology. Williams & Wilkins, Baltimore. Shils, M. E., and E. V. McCollum. 1943. Further studies on the symptoms of manganese deficiency in the rat and mouse. J. Nutr. 26:1-19. Silverstein, A., ed. 1982. Neurological Complications of Therapy. Futura, New York. 470 PP Spencer, P. S., and J. Ochoa. 1981. The mammalian peripheral nervous system in old age. Pp. 35-103 in J. E. Johnson, Jr., ed. Aging and Cell Structure. Vol. I. Plenum, New York. Spencer, P. S., and H. H. Schaumburg, eds. 1980. Experimental and Clinical Neurotox- icology. Williams & Wilkins, Baltimore. 929 pp. Spencer, P. S., and H. H. Schaumburg. 1984. An expanded classification of neurotoxic responses based on cellular targets of chemical agents. Acta Neurol. Scand. 70(Suppl. 100):9-20. Spencer, P. S., D. Couri, and H. H. Schaumburg. 1980a. n-Hexane and methyl n-butyl ketone. Pp. 456-475 in P. S. Spencer and H. H. Schaumburg, eds. Experimental and Clinical Neurotoxicology. Williams & Wilkins, Baltimore.

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