Chronic lead exposure in immature animals: Neurochemical correlates

Pergamon Presa

Life Sciences, Qol . 23, pp . 877-888 Printed in the II .S .A .

MINIREVIEW

CHRONIC LEAD EXPOSURE IN IMMATURE ANIMALS :

NEUROCHEMICAL CORRELATES

Tsung -hing Shih and Israel Hanin Department of Psychiatry Western Psychiatric Institute and Clinic University of Pittsburgh School of Medicine Pittsburgh, Pennsylvania 15261

Various toxins existin in the environment have deleterious effects on the central nervous system CNS) . These may range from subtle brain dysfunction to severe organic destruction (1-5) . In the case of lead poisoning, it has been reported that the immature CNS is particularly vulnerable to this substance (3,6) . Lead poisoning is due in part to the inability of developing gastrointestinal epithelial cells to reject multivalent cations such as iron, strontium and lead (7) . Chronic ingestion of lead, therefore, would greatly increase the body lead burden . Recent reports in the literature have, in fact, revealed many children with increased lead absorption (1,8) . Although a large proportion of these children show biochemical evidence of impaired hems synthesis, it is intriguing to note that few have clinical symptoms compatible with plumbism (1) . Some reports do suggest, using standard psychometric and neurophystological techniques, the existence of a significant association between asymptomatic or mild symptomatic increased lead absorption and subtle, but long-lasting, impairment in behavioral and cognitive function (9-12) . However, there also are other studies which have--not found such lead-induced deficits (13-16) . An association between lead and at least some forms of minimal brain dysfunction (MBD), or hyperactivity in children has been suggested . One early clinical study has reported that, in the absence of any apparent CNS toxicity, many children with either asymptomatic or mild lead poisoning show such behavioral abnormalities as restlessness, short attention span, easy distractibility, impulsiveness, and apparent purposeless activity (17) . All of those symptoms are typical of MBD (18,19) . In 1972, David et al . (9) reported that concentrations of lead in blood and urine were found tô bé elevated in a significantly greater proportion of children with MBD as compared with those of a control group . Most recently these same investigators reported in a pilot study that 50~ of the hyperkinetic school children tested in their studies showed marked improvement when lead-chelating medications (penicillamine plus calcium disodium edetate) were used (20) . It is not known, however, whether this subclinical degree of increased blood level of lead induces any degree of either transitory or permanent damage of the developing nervous system in the very young-. The role of lead in the induction of impaired nervous system function is difficult to determine because of the lack of sensitive neurochemical indicators of the effects of lead on the nervous system of the children (21) . Therefore, a study in animals of the effects of lead on the nervous system is important for evaluation of the possible consequences of chronic lead ingestion in children . Moreover, 0300-9653/78/0904-0877$02 .00/0 Copyright (c) 1978 Pergamon Press

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experimental proof of a causal relationship between lead poisoning and MBD is important for several reasons . First, it would add to the understanding of lead as a neurotoxic substance, and this knowledge might aid in the proper diagnosis and therapy of same cases of MBD . Second, the elucidation of the CNS toxicology of lead may be helpful in explaining the neurochemistry of hyperactivity of children, with or without lead exposure . Third, the demonstration of lead-induced hyperactivity in an animal model would allow investigation and experimentation with important implications for the understanding of neurochemical consequences of lead poisoning in MBD or hyperactivity (22) . The choice of a proper animal model for such study is essential because lead absorption differs in immature and mature animals (3,23-26) . Animal models of lead-induced hyperactivity have recently been reported in mice (27), rats (28), and monkeys (29) . Lead was provided in drinking water or food to nursing mothers or directly to pups right after birth and before weaning . These animals exhibited significant increases in motor activity (27-29), poor learning performance (30,31), altered motor responsiveness to amphetamine treatment, and an alleviation of the performance deficit by amphetamine and methylphenidate (30) . Pharmacologically, these animals responded to certain drugs in a manner parallel to that seen in children with hyperactivity (18,19, 22,32,33) . Thus, in such hyperactive mice, the increased motor activity was suppressed by the administration of amphetamines, methylphenidate, cholinergic agonists and aminergic antagonists, and was exacerbated by aminergic agonists and the anticholinergic agent, atropine (34-36) . It should be pointed out at this stage that the concept of lead-induced hyperactivity is not, as yet, uniformly accepted . Several laboratories have not been able to reproduce the behavioral observations reported in the earlier publications on this subject, particularly with respect to the studies in mice (30,37-39) . This discrepancy has prompted Loch and her coinvestigators (40,4.1) to reappraise their original report demonstrating lead-induced hyperactivity in rats (28), and to suggest that the hyperactivity is due, in fact, to an indirect effect . They have proposed that this hyperactive behavior may be a result of undernutrition induced by lead-exposure in these animals, in contradiction with the r ear ier report (42), in which they were able to demonstrate that pair fed controls do not exhibit similar increases in spontaneous activity . Recently, the latter observation has been confirmed by Wince et al . (43) who compared lead-exposed rats with pair-fed controls and demonstratéd that the lead-exposed rats animals showed a significant increase in gross motor activity . The reported similarity between behavioral and pharmacological consequences of chronic lead-exposure in mice to MBD children, or children with increased lead burden have, nevertheless, prompted relatively extended studies on the neurochemical effects of postnatal lead exposure in animals . This review is intended to survey the recent neurochemical findings of this increasingly prominent environmental toxicant, and to bring up to date available information on lead-induced neurotoxicity, primarily in mice and rats . Several important reviews on other aspects of lead toxicity have recently been published (1,6,24,44,45,79) . 1.

Effects on Monoaminer gic Systems

Effects of chronic lead exposure on the central monoaminergic function in developing animals are sumrrmrized in Table 1 .

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TABLE 1 Neurochemical Effects of Chronic Lead Exposure on Monoamineraic Functiàn . Component

Aspect Studied

Tissue

Species

Result

DA

levels

forebrain

mouse

no change

36

DA

levels

whole brain

mouse

no change

39

DA

levels

whole brain

rat

no change

DA

46,47

levels

cortex,brainstem, rat cerebellum

no change

30,48

DA

levels

cortex,brainstem, rat hypothalamus, striatum

no change

37

DA

levels

whole brain

DA

levels

striatum

20% decrease

rat

synthesis rate

20% decrease

49

DA

whole brain

mouse

no change

39

DA

turnover rate

whole brain

rat

no change

46

DA

transport (high affinity)

forebrain synaptosomes

mouse

20% decrease

36

NE

levels

whole brain

mouse

no change

39

NE

levels

forebrain

mouse

27% increase

36

NE

levels

whole brain

rat

no change

28

NE

levels

whole brain

rat

NE

levels

13% increase

46,47

cortex,brainstem, rat cerebellum

no change

30,48

NE

levels

cortex,brainstem, rat hypothalamus, striatum

no change

37

NE

levels

cortex, diencephalon

rat

no change

49

NE

levels

brainstem

rat

NE

levels

20% increase

49

brainstem

rat

NE

synthesis rate

27% decrease

50

whole brain

mouse

no change

39

NE

turnover rate

whole brain

rat

increase

46

NE

transport (high affinity)

forebrain synaptosomes

mouse

no change

36

VMA

levels

forebrain

VMA

mouse

15% increase

levels

forebrain

51

mouse

48% increase

52

rat

Reference

28,42

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TABLE 1 (continued) Component

Aspect Studied

Tissue

S sties

VMA

levels

urine

mouse

216%increase

52

HVA

levels

forebrain

mouse

41% increase

51

HVA

levels

forebrain

mouse

33% increase

52

HVA

levels

urine

mouse

265%increase

52

tyrosine

levels

whole brain

mouse

no change

39

tyrosine

transport (high affinity)

forebrain synaptosomes

mouse

15% increase

36

MAO

activity

forebrain

mouse

20% increase

51

Abbreviations :

DA NE VMA MAO -

Result

Reference

Dopamine Norepinephrine Vanillylmandelic acid Monoamine oxidase

In a group of suckling rats given chronic low levels of lead since birth, Sauerhoff and Michaelson (28,42) first found no change in whole brain NE but a 20% decrease in DA levels relative to coetaneous controls . Subsequently, the same investigators reappraised their initial findings and reported instead that no changes in either levels or turnover rate of DA, but rather, an increase in NE levels and turnover were to be found (46,47) in the brain of lead-exposed rats . Since then, a number of laboratories have reported their contradictory findings of the effect of chronic lead exposure on brain monoamine parameters . Levels of DA were not found by several investigators to be changed in mouse whole brain or forebrain(36,39) ;or in rat brain regions(30,37, 48) . Others have found a decrease in DA levels in striatum of lead-treated rats (49) . The synthesis rate of DA was not found to be changed in whole brain tissue in experimental mice (39) and forebrain synaptosome high affinity transport system for DA was diminished by 20% after chronic lead exposure (36) . Mouse whole brain NE levels have been reported to either increase by 27% (36) or to exhibit no change at all (39) after lead ingestion . Several studies (30,37,48,49) have also indicated the ineffectiveness of lead exposure in al tering NE distribution in a number of rat brain areas . However, in rat brainstem, one report indicated a 27% decrease (50) while another laboratory claimed that there was an increase (49) in NE levels of lead-treated rats . In contrast to the recent data of Michaelson and his coworkers (46),Schumann et al . (39) were unable to demonstrate any change in synthesis rate of NE in whom brain of lead-exposed mice . In addition, no change in mouse forebrain synaptosome high affinity uptake of NE was found (36) . A consistent elevation of two catecholamine metabolites, VMFI and HVA was, however, found in urine and brain of these mice (51,52) . In conjunction with the above metabolite data, a 20% increase in MAO activity was also measured (51) . This might account for the increased metabolite levels in the Mouse whole brain levels of the precursor amino acid, same tissue (51,52) . tyrosine, were not changed (39), but the synaptosome high affinity uptake for tyrosine was found to be increased by 15% (36) .

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88 1

Neurochemical Correlates of Pb Exposure

In general, the neurochemical data on the effects of chronic postnatal lead ingestion on the central monoaminergic system are intriguing, and the This disdiscrepancy between different laboratories has not been resolved . crepancy in the results might be due to differences in doses of lead, duration of exposure, when and how the lead was administered to the suckling animals, the general condition of the animals, and the age of the animals when these studies were performed. 2.

Effects on Cholinergic Systems

The effects of chronic exposure of neonatal rodents to lead on the neurochemical parameters of the Cholinergic system have been studied in both central and peripheral synaptic systems . These studies have provided most extensive information on the Cholinergic aspects of lead poisoning . The effect of lead intoxication on the central Cholinergic systan has been studied in mice and rats in terms of steady-state levels of neurotransmitter and its precursor, choline (Ch), Cholinergic en~,yme activities, rate These of neurotransmitter turnover, and synaptosamal transport mechanisms . findings are summarized in Table 2 . TABLE 2 Neurochemical Effects of Chronic Lead Exposure on Cholinergic Function . Component

Aspect Studied

Tissue

Species

Results

Reference

ACh

levels

forebrain

mouse

no change

36,56

ACh

levels

cerebellum,cortex, hippocampus,midbrain, striatum, medulla-pons

rat

no change

38,53

ACh

levels

cortex,midbrain, hippocampus, striatum

rat

no change

ACh

levels

diencephalon

rat

20% increase

ACh

levels

cortex

rat

32-48% increase

50

ACh

spontaneous release

cortical minces

mouse

40% increase

56

ACh

potassium-induced release

cortical minces

mouse

16-30% decrease

56

ACh

turnover rate in vivo

cortex

rat

35% decrease

54

ACh

turnover rate 1n vivo

hippocampus

rat

54% decrease

54

ACh

turnover rate in vivo

midbrain

rat

51% decrease

54

ACh

turnover rate in vivo

striatum

rat

33% decrease

54

Ch

levels

forebrain

mouse

no change

56

54

38,53

882

TABLE 2 .

Neurochemical Correlates of Pb Exposure

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1978

(continued)

Component

Aspect Studied

Tissue

Ch

levels

Sep ci es

Results

cortex,striatum, hippocampus

rat

no change

Ch

levels

midbrain

Ch

rat

spontaneous release

30% decrease

54

cortical minces

mouse

no change

56

Ch

potassiuminduced release

cortical minces

mouse

34-57% decrease

56

Ch

transport high affinity)

mouse

50% decrease

36

Ch

forebrain synaptosanes

transport(high affinity)

cortical minces

mouse

no change

56

Ch

transport(low affinity

forebrain synaptosomes

mouse

no change

36

Ch

transport(low affinity)

cortical minces

mouse

no change

56

ChAT

activity

forebrain

mouse

no change

56

ChAT

activity

cerebellum, diencephalon, striatum

rat

no change

38,53

ChAT

activity

medulla-pons, hippocampus, cortex

rat

14-18% increase

38,53

AChE

activity

forebrain

mouse

no change

56

AChE

activity

brainstem

rat

no change

48

AChE

activity

cortex

rat

no change

50

AChE

activity

cerebellum, cortex,hippocampus,pineal, striatum

rat

no change

38,53

AChE

activity

medulla-pons, midbrain diencephalon

rat

9-12% decrease

38,53

AChE

activity

cortex, cerebellum

rat

decrease

48

BuChE

activity

cerebellum

rat

48

BuChE

no change or increase

activity

cortex, brainstem

rat

decrease

48

ChPK

activity

forebrain

mouse

no change or increase

56

Abbreviations : AChChChATAChE-

Acetylcholine ßuChECholine ChPKCholine acetyltransferase Acetylcholinesterase

Reference 54

Butyrylcholinesterase Choline phosphokinase

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Neurochemical Correlates of Pb Exposure

88 3

In animals subjected to early lead exposure, the steady-state levels of the neurotransmitter, ACh, and its precursor, Ch, were reported to be unchanged in mouse forebrain(36~~ and in the following rat brain regions : cerebellum, hippocampus, midbrain, medulla-pons, and striatum (38,53,54) . One exception was the area of the diencephalon, in which a significant elevation of 20% was found in levels of ACh in brains of animals subjected to chronic lead exposure (38,53) . Shih and Hanin (54) and Modak et al . (38,53) found no reliable change of ACh levels in rat cortex, but Hrd~a et al . (50) reported a 32-48% increase in the same region of lead-treated rats . The steady-state levels of the precursor of ACh, Ch, were significantly reduced in rat midbrain region, but no changes were found in cortex, hippocampus and striatum of lead-treated rats (54 ) . In forebrain, synaptosomal hi h affinity transport of Ch was inhibited by 50% but low affinity system was no~ affected by lead treatment (36) . However, both high and low affinity processes of Ch transport were not changed in cor tical mince preparations of chronic lead-treated mice as compared with controls (55,56) . In studies using cortical minces from chronic lead-treated mice, Carroll et al . (56) showed an increase in spontaneous release of ACh but not of Ch ; however, the potassium-induced release of ACh and Ch in cortical minces of these same mice was significantly diminished . Furthermore, the in vivo ACh turnover rates were reported to be significantly reduced in cortex, p h pih campus, midbrain and striatum (by 35,54,51 and 33%, respectively) of lead-treated rats as compared with age-matched control rats (54) . The activity of the enzymes, ChAT, AChE, BuChE, and ChPK, has also been studied . For example, Carroll and his coinvestigators (56) found that ChPK, AChE, and ChAT activity in mouse forebrâin was not altered by lead treatment . However, Modak et al . (38,53) demonstrated differential effects of AChE and ChAT in discrete areasof rat brain ; lead treatment changed the activity of the synthetic and degradative enzymes in opposite directions . AChE had significantly lower activity in the diencephalon, medulla-pons, and midbrain in rats chronically treated with lead as compared with controls . This finding is in accord with the findings that serum AChE was decreased in man exposed to high concentrations of lead in the environment, in patients with lead poisoning, and in experimental animals treated with lead (57) . In contrast, ChAT activity was significantly increased in the cerebral cortex, hippocampus, and medulla-pons regions after chronic ingestion of lead . The decreased AChE activity correlated with the significantly increased steadystate ACh concentration in diencephalon . However, in other areas there was no correlation between enzyme activities and steady-state levels of ACh and Ch . In cortex and cerebellum of lead-treated rats, AChE activity was either not changed (38,53) or decreased (48) . Sobotka et al . (48) reported that BuChE activity in telencephalon and brainstem of leâd-éxposed rats was decreased, but in cerebellum the same enzyme activity was not changed or only slightly increased . Both clinical and experimental studies have demonstrated indirect evidence of a neurotoxic effect of chronic exposure to lead ingestion on peripheral nervous system function . Feldman et al . (58) reported that children with an increased lead burden were found 1;0 ~ibit reduced motor nerve conduction velocities as compared with normal children . Along the same line of interest, neurological surveys of lead intoxicated children have also shown impairnients in fine motor coordination(10) . This decreased nervous conduction velocity was suggested experimentally to be due to segemental demyelination and axonal degeneration of peripheral motor nerves(59,60), and to the interaction of lead with the kinetics of ACh release at the myoneuraljunction(61-64) .

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Neurochemical Correlates of Pb Exposure

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Kostial and Vouk (61) were the first to demonstrate an inhibitory effect of lead ion on synaptic transmission and on the rélease of ACh from perfused superior cervical ganglia of cats during stimulation of the preganglionic fiber . Concurrently, the presence of lead ions did not change the contractile mechanism of postganglionic nerve stimulation and the sensitivity of ganglionic cells to injected ACh . This presynaptic blocking action of lead has been confirmed _in vitro in the neuromuscular junction of frogs (62), mice and rats (63,64) U~t T-fzing electrophysiological techniques, Manalis and Cooper demonstrated in experiments perforn~ed in vitro on the isolated sciatic nerve sartorius muscle preparation of the frogtFät lead reduced the size of the endplate potential and increased the frequency of miniature end-plate potentials (62) . Similar conclusions were drawn by Silbergeld et al . (63,64) who reported their in vitro studies on rat phrenic nerve hemid~aphragm preparations treated with ~f e~ rent concentrations of lead . They showed significant decreases in force of contraction, and significant increases in latency between indirect (nerve) stimulation and the initiation of contractile response . The responses of the hemidiaphragm to direct muscle stimulation and to exogenous application of ACh or to acetyl-d-methylcholine were not affected by in vitro lead treatment . However, in the same preparation obtained from mice c~ron~caTly exposed to lead, the inhibitory effects were seen after both nerve and muscle stimulation . Therefore, chronic lead exposure induced a much weaker muscle in addition to its prejunctional blocking effect of lead . 3.

Effects on Other Putative Neurotransmitter Systems .

Studies on other CNS putative neurotransmitters and metabolites such as serotonin (5HT), 5-hydroxy-indoleacetic acid (SHIAA), y-aminobutyric acid (GABA), and other amino acids have also been reported . These findings are summarized in Table 3 . High affinity uptake for phenylalanine, glycine, leucine, GABA, and 5HT from forebrain synaptosomes was not altered between lead-treated and control mice (36) . Steady-state levels of 5HT were not changed by lead treatment in rat whole brain (42) or rat brain regions (30,48, 50), neither was the level of its metabolite, 5HIAA,found to be altered in rat brain regions(30,48) .A reduction of GABA levels was found in rat cerebellum (65) but not in rat whose brain (42), cerebral cortex or brainstem (65) . Moreover, no effect was found to be induced by chronic lead administration in neonatal rats on heart cyclic adenosine monophosphate (CAMP) production stimulated by NE (66) . TABLE 3 Neurochemical Effects of Chronic Lead Exposure on Other Putative Neurotransmitter Function . Component

Aspect Studied

Tissue

Sep ties

Results

5HT

levels

whole brain

rat

no change

Reference

5HT

levels

cortex,brainstem, cerebellum

rat

no change

5HT

transport (high affinity)

forebrain synaptosomes

mouse

no change

36

phenylalanine and glycine

transport (high affinity)

forebrain synaptosomes

mouse

no change

36

42 30,48,50

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TABLE 3 (continued) Reference

Component Aspect Studied 5HIAA

levels

Tissue

Sep ties

Results

no change

30,48

GABA

levels

whole brain

rat

no change

42

levels

GAGA

levels

GABA GABA

transport (hig affinity)

CAMP

production

Abbreviations :

4.

5HT5HIAAGABAcAMP-

cortex ,brainstem, cerebellum

rat

cortex,brainstem cérebellum

rat rat

no change decrease

65

forebrain synaptosomes

mouse

no change

36

heart

rat

no change

66

65

Serotonin 5-Hydroxy-indoleacetic acid y-Aminobutyric acid Cyclic adenosine monophosphate

Calcium-Lead Interaction

It has been demonstrated, following pretreatment in vivo or administration in vitro, that calcium ion is able to reverse andTr protect against the inF~ibition by lead of ACh release from the perfused superior cervical ganglion (61) and the neuromuscular junction (63) . Moreover, calcium deficiency potentiates lead toxicity (67) and increases lead ingestion (68,69) . Also, calcium is important in the transport of lead across the gastrointestinal tract (70), and competes with lead for incorporation into bone hydroxyapatite crystals (70) . In vitro nerve stimulated release of ACh at superior cervical ganglia (61) andt~neuromuscular junction (63,64), potassium-stimulated release of ACh and Ch from cortßcal minces (56), and the high affinity uptake process for Ch in forebrain or caudate synaptosomes (71) are significantly inhibited by lead exposure and reduced calcium concentration in the medium . Therefore, one factor in the relationship between lead and calcium appears to be via a competitive interaction with regard to chollnergic function . This interaction appears to be at sites involved in the release and uptake of ACh and its precursor, Ch . Calcium also influences lead-induced effects on central dopaminergic mechanisms . However, the effects of lead on dopaminergic function are more complicated and not directly calcium-dependent . The high affinity uptake of DA into synaptosomes is blocked by both in vitro (71) and in vivo (36) lead exposure . Silbergeld (71) has demonstratédT in synaptosome preparations j,a vitro , decreased calcium concentration does not affect DA uptake ; moreover, addition of calcium does not reverse lead-induced inhibition of DA uptake . On the other hand, lead alone had no effect on release of DA, but it, nevertheless, potentiated calcium-induced release as a result of lead-induced increases in calcium influx . Thus, the ionic mechanisms for the neurotoxic effect of lead on both cholinergic and monoaminergic functions, as reviewed in the previous three paragraphs, could be explained, at least partly, through inhibition of chol-

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inergic function via inhibition of Ch uptake ; and through enhancement of dopaminergic function, by inhibiting DA reuptake and enhancing DA release in the presence of increased calcium . Lead binds to sulfhydryl groups . It thus could be chelated by administering penicillamine and BAL (72) . Lead also binds to phosphate to form an insoluble salt of lead phosphate . It is thus responsible for the inhibition of oxidative phosphorylation in mitochondrial preparations (73) . Conclusions Although, clinically, lead poisoning is thought to cause several serious behavioral problems (1,74-77), a causal relationship between lead ingestion and behavioral dysfunction has not been shown . Neurochemical and behavioral effects of chronic postnatal lead ingestion by animals have been studied, but the literature on experimental animals in still meager . It is expected that research resolving the uncertainties about effects of lead in the areas of environmental, developmental and child health will be forthcoming in the near future . In the meantime, contradictory reports exist in the literature regarding the effect of inorganic lead ingestion on the levels and turnover rate of brain catecholamines . These inconsistent observations could probably be due to differences in the timing and ways the inorganic lead was administered to the animals, and the duration of lead exposure when the test was performed . However, there is enough evidence to suggest a general trend of elevated activity of catecholaminergic function in these experimental animals . The effects of lead exposure on the cholinergic function have been reported in a more consistent manner in the literature . Both neurochemical and electrophysiological (78) data in these animals have indicated the inhibitory function of lead on cholinergic activity . Most interestingly, available pharmacological studies have supported this concept of a neurochemical hyperfunction of the catecholaminergic system and simultaneous hypofunction of the cholinergic system following lead exposure (36) . This has prompted Silbergeld and Goldberg (55) to hypothesize the existence of an interrelated cholinergic-aminergic dysfunction in their lead-induced hyperactive mice . It should be mentioned at this point that relatively few studies have been conducted investigating the involveanent of other putative neurotransmitIt might still be some time ter systems in lead-exposed experimental animals . before a comprehensive understanding of neurochemical effects in chronic lead poisoning can be obtained . Nevertheless, the data summarized in this review should, and have already, provided a useful framework for future clinical and experimental investigations . Acknowledgements Support for some of the work described was provided by USPHS Grant MH-26320 . References 1.

National Committee on the Biological Effects of Atmospheric Pollutants . Research Council . Lead : Airborne Lead in Perspective . National Academy of Sciences, Washington, D .C ., 1972 .

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2. 3. 4. 5. 6. 7. 8. 9. 10 . 11 . 12 . 13 . 14 . 15 . 16 . 17 . 18 . 19 . 20 . 21 . 22 . 23 . 24 . 25 . 26 . 27 . 28 . 29 . 30 . 31 . 32 . 33 . 34 . 35 . 36 . 37 . 38 . 39 . 40 . 41 .

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Neurochemical Correlates of Pb Exposure

Vol . 23, No . 9, 1978

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