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29 Conclusions and Recommendations The preceding chapters have discussed a wide range of biologic markers of neuro- developmental effect. Having discussed potential biologic markers of effect (summarized in Table 29-1), we should men- tion biologic markers of exposure to vari- ous toxicants known or thought to have neurodevelopmental effects (Table 29- 2~. Experience with the study of popula- tions exposed to lead indicates that it is important to approach the study of neurodevelopmental toxicity with bat- teries of biologic markers of effect, and careful assessment of character- istics of the subjects and other poten- tial exposures. The complexity of the process being assessed is important. Assessments of simple functions can focus the site of neurotoxic deficits, but may not be as sensitive as integrated tasks. The determination of the appropri- ate set of biologic markers is an iterative - process, Unto vying assessments and reas- sessments in notentiallv exposed nonula- tions. There are several aspects of devel- oping organisms that make the assessment of possible effects of toxic exposure dif- ficult. Differentiation is not a continu- ous process; therefore, the timing of the exposure as well as dose received, deter- mine the nature and extent of effects. ~ ~ ~ ~ . 303 Consequently, epidemiologic studies can- not simply combine groups of individuals without knowledge of the developmental status of those individuals at the time of exposure. Another aspect of toxicity in devel- oping systems is that the effects may come and go. That is, subjects need to be followed longitudinally to fully characterize the neurotoxic deficits. Hence, knowledge of the developmental status of the subjects at the time of testing is also important. ~ In the following discussions of areas of research that promise to yield useful biologic markers of neurodevelopment. MODELS OF NEURODEVELOPMENT Attempts to develop mechanistic models of postnatal behavior require understand- ing of the development of the central ner- vous system and of how its components respond to a toxic insult. Radiation is useful for assessing perinatal toxicity. It interferes with normal development in two basic ways: by killing specific cell populations and by altering migration patterns of surviving cells. Those morphogenetic alterations have severe consequences, especially in microneuronal populations. Whether this model has uni- versal applicability remains to be deter-

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304 NEURODEVELOPMENTAL TOXICOLOGY TABLE 29-1 Summary of Some Markers of Central Nervous System Development Marker Usable in a Screening StudYa Usable in Population Subgroups as Secondary Assessmentb Usable Only in Studies of Special PopulationsC Remarks Growth variables: length, head size, etc. Developmental landmarks Minor physical anomalies Nerve conduction time Psychophysical measures Evoked potentials Pure-tone hearing Auditory discrimination Speech and language competence Vibratory sense Motor function Attention Visual-motor perception Psychometric intelligence Social behavior Positron emission tomographic scan Magnetic resonance . . 1magmg scan + + + Low specificity Low specificity, low sensitivity Low specificity + + + + + + + + High sensitivity, low specificity + a + =sufficiently validated and safe for application in field studies, although might warrant further refinement. b + = sufficiently demanding in terms of subject and interviewer efforts that should be used as secondary assessment in multistage assessment battery. c + =too invasive or too demanding for use on broad scale. mined. However, results with other agents and the unique biology of microneurons suggest that the model has much promise. NEUROENDOCRINE AND NEUROIMMUNOLOGIC MARKERS The nervous system has major interac- tions with other systems in the body, such as the endocrine, reproductive, and immune systems. Through complex networks of con- trol and feedback, the nervous system pro- duces changes in endocrine and immune func- tions that are important, particularly during development. Maturation of the reproductive system, for instance, is under neural control through the hypothal- amic-pituitary axis. From the perspective of research on biologic markers, those interactions provide peripheral signals of neuron action that might be directly measurable when the primary neurochemical signals are not detectable. Nervous System-Endocrine Interactions Neural signals processed through the hypothalamus control the release of gonad- otropins that regulate pituitary release of luteinizing hormone (LH) and follicle- stimulating hormone (FSH) (see discus- sions in parts of report on female or male

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CONCLUSIONS AND RECOMMENDATIONS 305 TABLE 29-2 Status of Some Markers of Exposure Agent Marker Advantages Disadvantages Lead Cadmium Mercury Blood lead concentrations Hair lead concentrations Free erythro~te protoporphyrin concentrations Tooth lead concentrations X-ray fluorescence of bone Provocative chelation response Blood cadmium concentrations Urinary cadmium concentrations Blood mercury concentrations Urinary mercury concentrations Hair mercury concentration Easily obtained Measures only recent exposures Easily obtained Subject to contamination Easily obtained, not subject Low sensitivity at lead to contamination concentrations <30 uq/dl, low Integrative marker In viva integrative Sensitive to tissue burden Easily obtained Measures excess saturation Easily obtained blood not critical target Easily obtained Easily obtained Hard to obtain Sensitivity uncertain Requires 8 hours of observation Blood not critical site Depends on metallothioneine Measures only recent exposure; Measures only recent exposure Indirect measure reproductive system). Chemical signals can be directly measured as concentrations of gonadotropins and gonadal hormones in blood and indirectly measured by secondary physiologic events (for instance, ovula- tion, luteinizing-hormone releasing hor- mone surge, and lactation). Serum prolac- tin has been measured and correlated with hypothalamic dopaminergic function, be- cause of dopamine's role as a prolactin- inhibiting factor (Memo et al., 1986~. Hyperprolactinemic states, sometimes with galactorrhea, are associated with deficiencies in hypothalamic dopaminergic neurotransmission (Ferrari and Crosig- nani, 1986~; similarly, acromegaly, a syndrome of disordered growth-hormone release, is associated with decreased hypothalamic dopamine release (Hanew et al., 1987~. Treatment of those two con- ditions involves administration of dopa- mine receptor agonists (Memo et al., 1986~. Little clinical use has been made of endocrine factors as biologic markers of neurochemical function, except in dis- orders of hypothalamic-pituitary function in which response to infused dopamine has been monitored by measuring LH and FSH (Nicoletti et al., 1986~. There should be an increased use of markers of endocrine status to make inferences of neurochemical function. Nervous System-Immune System Interactions As noted by Pert and colleagues (1985), the central nervous system and the immune system have in common many specific cell- surface recognition sites or receptors for peptides. Human peripheral monocytes might also have receptors for amino acid neurotransmitters (Malone et al., 19863. Cells of the immune systemT cells, mono- cytes, B cells, and alveolar macrophages- have been found to contain and respond to specific neuroactive peptides (Pert et al., 1985; Zhu et al., 1985~. Monocytes, a heterogeneous population of cells in blood that undergo differentiation into macrophages in the presence of particular stimulation, demonstrate chemotaxis as an important part of their function in inflammation and repair processes. In addition to the classic chemotactic stimu- li, such as bacterial material and comple- ment activation, the neuropeptides have been recently shown to elicit monocyte chemotaxis, among them opiates, substance P. bombesin, and cholecystokinin (Pert et al., 1985~. Elastin peptides also modu- late monocyte ion fluxes (Jacob et al., 1987~. Those findings indicate strong interactions and communication between the brain and cells of the immune system.

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306 It is now well known that the T4 antigen, a membrane receptor for the acquired immune deficiency syndrome (AIDS) virus, is pres- ent on some cells in the human brain (Pert et al., 1986~. The involvement of the brain in the late stages of AIDS is now a well-characterized part of the disease. Neuroleukins are a new class of growth factorspresent in muscle, brain, and other organs-that promote growth and sur- vival of spinal and sensory neurons in culture, as well as affecting B cell matur- ation (Gurney et al., 1986a,b). Neuroleu- kins are secreted by T cells in response to stimulation by such lectins as concana- valin A. Measurement of neuroleukins in bone marrow or in T cell secretions might yield a useful index of necrologic func- tion, particularly during development of the nervous and immune systems. Markers of immunologic function are accessible, and sophisticated methods for their measurement have been developed in the last decade. The possibility that monitoring some aspects of immune function could provide markers of neuroimmunologic interaction has not been explored. . . NEUROCHEMICAL MARKERS Recent Advances in Neurochemical Methods Application of the biologic-markers paradigm to studies of neurodevelopmental toxicology is restricted by the complexity and inaccessibility of many functional parts of the nervous system. Some of these problems might be overcome by examin- ing systems that are substantially con- trolled by neuronal processes, such as some aspects of endocrine and immune func- tion. In addition, major technologic advances have been made in the methods available for studying the nervous system - nOIllIlVaSlVe. .y lI1 VlVO. Computed axial tomography (CAT) has provided vast improvements in visualizing structures of organs in the body. CAT scan- ning has been heavily used in neuropsychia- tric disease, and its ability to reveal structural abnormalities in the brains of schizophrenics is among the many accom- plishments of these new techniques (Zec NEURODEVELOPMENTAL TOXICOLOGY and Weinberger, 1986). Even more exciting, however, has been the recent development of positron emission tomography (PET) and magnetic resonance imaging (MRI) tech- nologies that allow visualization of phys- iologic and biochemical processes as they occur in the brain (Battistin and Gersten- brand,1986). PET couples the fine visualization of CAT scanning with the ability to detect positrons emitted from unstable isotopes. Fluorine-18 and carbon-11 are often-used positron emitters; they can be used to tag chemicals of necrologic interest, such as drugs that bind to specific neuronal receptors or metabolic precursors of neurotransmitters (cf. Battistin and Gerstenbrand, 1986~. In addition, fluor- ine-18-tagged 2-deoxyglucose can be used to reveal the degree of cell metabolic activity in brain regions (Alavi et al., 1986~. Because neurally active cells- cells that receive neural stimuli or proc- ess signalsare metabolically active, they take up more 2-deoxyglucose and can be identified by increased density of fluorine-18 in PET scanning with fluorin- ated 2-deoxyglucose derivatives. PET scans of patients have demonstrated that schizophrenics have a higher density of dopamine receptors in basal ganglia (D.F. Wong et al., 1986) and that people with parkinsonism have a lower uptake of fluorine- 18-tagged dope (the precursor of dopamine) than control subjects (Leen- ders et al., 1986~. Interestingly, the parkinsonism patients did not show in- creased uptake of the fluorine-18-tagged postsynaptic-receptor ligand spiperone- a finding that suggests that denervation supersensitivity did not occur in these patients (Leenders et al., l 986~. The theoretical basis of quantitative interpretation of PET densitometry is controversial; however, remarkable images of regional changes in neurochemistry can be obtained with such techniques, thus overcoming (at least qualitatively) the barriers to obtaining samples of brain tissue. PET scanning appears also to have some use in diagnosis of preclinical sta~es, such as MPTP-induced brain damage (Caine et al., 1985~. MRI detects the spin resonance of some

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CONCLUSIONS AND RECOMMENDATIONS atoms and thus yields information on energy state. That is useful for studying bio- chemical reactions involving energy transfer from phosphate groups, such as adenosine triphosphate (ATP). Because many events in neurotransmission involve phosphorylation-the transfer of high- energy phosphates from ATP to proteins- this detection method is particularly attractive for the in viva study of neuro- chemistry. Some types of neuronal struc- tures, such as myelin, can be selectively imaged with MRI. MRI is applied with in- creasing frequency; it provides consider- able advantages in spatial delineation and will greatly add to information on central nervous system neurochemistry involving changes in energy state. Surrogate Cell Systems The inaccessibility of neurons has been approached ingeniously with the study of surrogate cell systems. Platelets and red cells contain some of the same bio- chemical apparatus as neurons, including receptors, high-affinity uptake, enzymes, and storage and releasing processes (Plet- scher, 1968; Murphy, 1976), and thus serve indirectly as media to assess biologic markers of events in neurons, particularly drug response. However, because of the blood-brain barrier, receptors on central nervous system neurons and peripheral 307 neurons may be different (e.g., for sero- tonin and benzodiazepine (Snyder, 1984~. Surrogate cells could not be used to char- acterize the possible differences. Platelets have binding sites for the neurotoxin MPTP (del Zompo et al., 1986~. Red cells also absorb choline by processes somewhat similar to those in neurons (Houck et al., 1988~. Red cell choline uptake has been studied in patients with disorders thought to involve deficits in central nervous system cholinergic function, such as Alzheimer's disease. The results of studies done so far are of interest, but of unknown clinical utility. The clearest example of surrogate monitoring has been the measurement of peripheral esterases in workers exposed to organophosphates (Levine et al., 1986~. Neuronal esterase, the site of action of these neurotoxins, can be studied in blood. As demonstrated by Levine and co- workers ( 1986), esterase activity in cir- culating monocytes and red cell cholines- terase activity are decreased after toxic exposures. Monocyte esterase might be an even more sensitive marker of organo- phosphate exposure than the more commonly used red cell cholinesterase (Levine et al., 1986~. Other accessible cell systems need to be evaluated for their use as sensi- tive surrogate indicators of neuronal response.

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Appendix

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