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Lead (Pb) is a neurotoxic heavy metal pollutant. Despite the efforts to reduce Pb environmental exposure and to prevent Pb poisoning, exposure in human populations persists. Studies of adults with history of childhood lead exposure have consistently demonstrated cognitive impairments that have been associated with sustained glutamate signaling. Additionally, some clinical studies have also found correlations between Pb exposure and increased proclivity to drug addiction. Thus, here we sought to investigate if developmental Pb exposure can increase propensity to alcohol consumption and relapse using an alcohol self-administration paradigm. Because Pb exposure is associated with increased glutamatergic tone, we also studied the effects on the expression of synaptic and non-synaptic glutamate transporters in brain regions associated with drug addiction such as the nucleus accumbens (NAc), dorsomedial striatum (DMS), dorsolateral striatum (DLS), and medial prefrontal cortex (mPFC). We found that while developmental Pb exposure did not increase risk for alcohol self-administration, it did play a role in relapsing to alcohol. The effects were associated with differential expression of the glutamate transporter 1 (GLT1) and the glutamate/cystine antiporter (xCT). In the NAc and DLS the expression of GLT1 was found to be significantly reduced, while no changes were found in DMS or mPFC. Contrastingly, xCT was found to be upregulated in NAc but downregulated in DLS, with no changes in DMS or mPFC. Our data suggest that lead exposure is involved in relapse to alcohol seeking, an effect that could be associated with downregulation of GLT1 and xCT in the DLS., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The relationship between the blood lead concentration and cognitive function in children and adults with different ALAD genotypes who participated in the third National Health and Nutrition Examination Survey was investigated. The relationship between blood lead and serum homocysteine concentrations was also investigated. In children 12 to 16 years old, no difference in the relationship between cognitive function and blood lead concentration between genotypes was found. In adults 20 to 59 years old, mean reaction time decreased as the blood lead concentration increased in the ALAD rs1800435 CC/CG group. This represents an improvement in performance. In adults 60 years and older, no difference in the relationship between cognitive function and blood lead concentration between genotypes was found. The serum homocysteine concentration increased as the blood lead concentration increased in adults 20 to 59 years old and 60 years and older, but there were no differences between genotypes. The mean blood lead concentration of children with the ALAD rs1800435 CC/CG genotype was less than that of children with the GG genotype.

Lead poisoning remains an occupational hazard in Taiwan. Many studies, based on crossed-section design, have focused on changes in lead-associated neurobehavioral dysfunctions that occur at increased blood lead levels. This study evaluates the changes in neurobehavioral performance of lead workers as blood levels are reduced. We tested 27 lead workers in a lead glaze factory using the computer-based and automated Chinese edition of Neurobehavioral Evaluation System 2 (C-NES II) in 1994, 1996, and 1997. The association of blood lead levels and C-NES II results were analyzed by longitudinal data analysis methods, repeated ANOVA and mixed model analyses after adjustment for potential confounders. Over these 4 years, the mean lead blood levels of workers were reduced from 26.3(SD=12.0) to 8.3(SD=6.9) microg/dL. Based on a mixed model analysis, we found that the negative effects of exposure to lead on neurobehavioral performance can be reversed to some extent with lowering levels of blood lead. During this period, we found significant improvements in 3 subtests: finger tapping, pattern comparison reaction time, and memory. This study tentatively concluded that reversibility of the neurobehavioral performance after reduction of the lead exposure, which encourages industrial hygiene and personal health promotion to reduce their body lead burden. However, though use of NES is more sensitive to detect the changes, the chronic symptoms (using standardized questionnaire) were found to decline slowly when blood lead level is reduced, with no statistically significant difference. The result means that to avoid the lead exposure primarily is essential to prevent chronic symptoms. We conclude that the most important way to prevent and possibly reverse chronic symptoms of lead poisoning remains to be the avoidance of exposure to lead.

Male Fischer 344 rats received either tap water or water containing 250 ppm lead for 90 days prior to training in either Pavlovian fear conditioning or consummatory contrast, an aversive reward reduction paradigm. In Experiment 1, lead-exposed and -unexposed rats were trained in operant chambers over a 6-min session. After 3 min elapsed, three tone-shock pairings were presented over the remainder of the session. Rats then received 7 days of extinction training in an identical procedure with only tones presented, no shocks. Lead-exposed rats exhibited greater behavioral suppression to both the contextual and auditory cues that predicted shock. In Experiment 2, rats were placed in operant chambers daily and allowed to consume either a 15% or a 5% fructose solution for 7 days. On Day 8, the rats consuming the 15% fructose solution were shifted to the 5% solution for 3 days. Lead-exposed rats did not differ from their controls in either initial consumption of either solution or in the suppression of their consumption after shifting to the 5% solution. Taken together, these findings suggest that lead impairs the extinction of fear conditioning and this finding is not due to a nonspecific increase in aversive emotionality.

Chronic developmental lead exposure is known to be associated with cognitive dysfunction in children. Impairment of the induction of long-term depression (LTD) has been reported in area CA1 and dentate gyrus (DG) of rat hippocampus following chronic lead exposure. The present study was carried out to investigate age-related alterations of LTD in area CA1 and DG of rat hippocampus following developmental lead exposure in vitro. Neonatal Wistar rats were exposed to lead from parturition to weaning via milk of dams drinking 0.2% lead acetate solution. Field excitatory postsynaptic potentials (EPSPs) were recorded in hippocampal slices at various postnatal ages: postnatal day (PND) 17-23, 27-33, and 57-63. Following low-frequency stimulation (LFS, 900 pulses/1 Hz), the average magnitude of LTD is age related. In the controls, LTD magnitude in area CA1 decreased with age, whereas in DG it increased with age. In the lead-exposed groups, the magnitude of LTD declined during development in both area CA1 and DG. The differences of LTD magnitude between the control and lead-exposed rats were 27.26 +/- 9.15% (PND 17-23), 21.59 +/- 12.93% (PND 27-33), and 16.96 +/- 9.33% (PND 57-63) in area CA1, and were 6.95 +/- 9.26%, 17.60 +/- 3.91%, and 33.63 +/- 10.47% in DG, respectively. These results demonstrated that the lead-induced impairment of LTD magnitude was an age-related decline in area CA1 and an age-related increase in area DG of rat hippocampus. Published by Elsevier Science Inc.

A cross-sectional study was performed on 275 pupils from the third and fourth grade of three elementary schools (three urban areas with different traffic conditions) in Zagreb. Lead exposure was environmental, mostly through leaded gasoline. The difference in traffic density around the schools was consistent with biological indicators of lead absorption. The aim of the study was to clarify the relationship between characteristic biological indicators of lead absorption including indicators of hematological status with some psychological functions. Lead absorption in pupils was relatively low (mean blood lead: 70.8 +/- 17.88 microgram/L). Pupils' socio-economic status was evaluated by parents' education. The results obtained indicate that gender and school were associated with both biological and psychological variables. After adjusting for age, parental education, and gender, lead appears to have no association with cognitive or psycho-motor measures. The nonstandardized regression coefficients for blood lead-as a measure of the size of lead effect on VIQ, NIQ, and IQ-were -0.016, -0.031, and -0.025, respectively, all nonsignificant.

Effects of lead exposure on behavioral development during the first month of postnatal life were examined in rhesus monkeys using a multi-item assessment scale developed for the evaluation of neonatal rhesus monkeys. Lead was administered daily beginning at day 8 postpartum at levels that produced blood lead levels of about 20 microg/dl by week 4 (n = 48); controls were treated identically but given vehicle only (n = 24). All monkeys were tested once a week for the first 4 weeks postpartum. The first principal component explained a substantial portion of the variance and was relatively consistent across ages for both groups. Analyses of the individual items and of both conceptually derived and empirically defined summary scores yielded no significant effects of lead. Furthermore, there were no systematic relationships between blood lead level and performance on the test. Correlation coefficients indicated more similarity across age for control monkeys than for lead-exposed monkeys suggesting that continuity of development, as measured by this test, was disrupted by lead. The relationship between outcome on these early assessments and later behavior will be explored in subsequent studies of these monkeys.

1. Stereotyped complex behaviours are present in a number of psychotic illnesses, neurological diseases and even can be generated in response to chemical environment (e.g., drugs or toxins). 2. The circadian rhythm of complex behaviours such as, rearing, preening, scratching and biting/licking was evaluated in an open-field situation in rats exposed to lead (2% lead acetate in drinking water for 30 days). 3. The circadian rhythm of rearing patterns showed depressions from 2 to 14 hr on day 3 and 13, and from 2-6 hr on day 23 (it elevated at 10 hr), whereas increased pattern was apparent at all test periods (except at 6 hr) on day 30. 4. Increased responses of circadian rhythm of preening behaviour were obtained at 18 hr (with decrease at 22 hr) on day 3, at 6 and 14-22 hr on day 13 and, at all the test periods on day 23 (except at 6 hr) and on day 30. 5. The rhythmic patterns of the scratching behaviour showed elevations at each test period as observed on day 3, 13, 23 and 30. The responses in lead-intoxicated rates, however, showed depressions in the light-period and augmentations in the dark-period. 6. The biting/licking behaviours indicated increased patterns of the circadian rhythm attaining a parabolic response, which were inconsistent to the scratching behaviour patterns. Amongst lead-intoxicated rats this behaviour exhibited depressed responses in light-period, whereas in dark-period it showed elevations.

Paternal exposures to exogenous agents have been reported to produce a variety of developmental defects in the offspring. In experimental animals, these effects include decreased litter size and weight, increased stillbirth and neonatal death, birth defects, tumors, and functional/behavioral abnormalities-some of these effects being transmitted to the second and third generations. The majority of experimental studies assessing nervous system function of offspring following paternal exposures have utilized rats as the experimental animal, but other species can be used. The National Toxicology Program (NTP) has initiated studies to validate the rabbit as an animal model for human reproductive toxicity, because rabbits are the smallest laboratory animal from which ejaculates can be collected repeatedly. An important part of reproductive toxicology is assessment of the reproductive ability of males following exposure, as well as developmental and functional assessment of their offspring. This article describes a pilot study and a main study to investigate the feasibility of using rabbits to assess the functional effects of paternal exposure to lead. The pilot study included seven male rabbits per group exposed for 15 weeks to lead acetate sufficient to produce 0, 50, or 110 micrograms/dl blood lead. The main study included 15 male rabbits per group exposed for 15 weeks to lead acetate to produce 0, 20, 40, and 80 micrograms/dl blood lead. At the conclusion of the exposure, male rabbits were mated with unexposed females. These females carried their litters to term, delivered, and reared their own offspring. The offspring were weighed at 5, 10, 15, 20, 25, 30, and some at 35 days of age. They were also tested for exploratory activity in a standard figure-eight "maze" for 30 min/day on days 15, 20, 25, and 30. A second assessment of exploratory behavior, along with a simple test of aversive conditioning, was attempted in the pilot study, but was judged not to be suitable for the main study. Of the 21 male rabbits that were mated in the pilot study, 16 produced viable litters (6/7, 6/7, and 4/7 in control, low- and high-lead groups, respectively), with a mean number of 6 live births/litter in each treatment group (range 2-8). Of the 60 rabbits mated in the main study, 57 produced litters, and two rabbits died giving birth. Significant postnatal deaths were observed in all groups, with about one half of the offspring dying before testing was initiated at day 15. There were no treatment-related effects on offspring weight gain through wearing. The data suggest that paternal lead exposure of rabbits may reduce figure-eight activity on day 25, the time of peak activity in the offspring.

A previous report of differential effects of catecholaminergic compounds, but not other classes of compounds, on FI (fixed interval) response rates of lead (Pb)-treated pigeons suggests that catecholamine system disturbances might play a role in lead (Pb)-induced changes in FI performance. The current study sought to extend those findings using more selective dopaminergic (DA) D1 and D2-like receptor agonists, Pb-treated rats, and additional classes of compounds. Drug-induced changes in FI performance of rats exposed chronically from weaning to 0, 50, or 150 ppm Pb acetate in drinking water were compared following the administration of drugs known to impact various neurotransmitter systems altered by Pb exposure, including the selective D2-like agonist quinpirole, the D1 agonists SKF38393 and SKF82958, the mu-opioid agonist morphine, the muscarinic cholinergic agonist arecoline, the glutamate agonist NMDA, and the noncompetitive NMDA antagonist MK-801. All drugs except NMDA significantly altered FI performance, but only the effects of DA agonists differed in control and Pb-exposed rats. Pb exposure attenuated the decrements in rates produced by D1 agonists and at 150 ppm modestly altered the rate changes associated with low doses of quinpirole. These data demonstrate functional DA alterations in response to Pb exposure and provide further evidence for the selective involvement of such effects in FI performance.

This article provides a detailed examination of lead workers' reaction times to elucidate the underlying basis for the slowing found. Seventy workers, classified as either low, medium, or high lead exposed, completed a five-choice reaction time task using response-stimulus intervals (RSIs) between 0 and 4 s. Performance was assessed by analysing the distributional properties of correct reaction times. The effect of lead on movement time was constant across the entire movement time distribution and thus simply characteristic of slowed motor reaction time. By contrast, the effect of lead on decision time became increasingly evident at higher points in the percentile distribution, particularly at the shortest RSIs. This suggests that decision slowing is due to central, not peripheral, factors and is consistent with alternative analyses showing that the incidence of decision gaps also provide a sensitive indicator of lead effects. Subsidiary analyses showed that movement and decision slowing was correlated solely with levels of blood lead, but not with zinc protoporphyrin or urinary ALA levels.

Controversy over lead's effect on children's cognition rests in part on the assumption that if such an effect exists it can be characterized by a single estimator (e.g., the same rate of decline in IQ with increasing exposure, the same neuropsychological presentation), which will be found by any study that is valid. Accordingly, efforts to resolve inconsistencies in study findings have focused almost exclusively on data analytic issues germane to bias, in particular confounding and its statistical control. Relatively little consideration has been given to the role of effect modification, i.e., the impact on effect estimation of differences in the "experimental systems" employed in human epidemiological studies. Lack of consistency in findings could be due to differences among study cohorts in exposure/toxicokinetic factors (e.g., dose, timing), differences in environmental characteristics (e.g., co-exposures, co-morbidity, developmental supports, assessment setting), or differences in the distribution of genetic characteristics that affect lead metabolism. Recent findings regarding lead's impact on the development of nervous system structure and function are consistent with the hypothesis that contextual factors affect the form in which lead toxicity is expressed and may contribute to the failure to date to identify a lead-associated "behavioral signature." Characterizing the neuropsychological effects of lead might be facilitated by greater use of a clinical "process" approach to assessment, which would permit the type of fine-grained analyses of lead-associated performance differences often employed in studies of behavioral toxicity in animal models.

We performed acoustic analyses on cries elicited from a subset of healthy babies born to the Mexico City Prospective Lead Study at 2 days (n = 75), 15 days (n = 176), and 30 days (n = 166). Lead was measured in maternal blood every 8 weeks during pregnancy from week 12 to delivery and in umbilical cord (1-38 micrograms/dL, 0.05-1.84 mumol/L). Percent nasalization and number of cries decreased in babies born to mothers with higher lead levels in the last two trimesters while median fundamental frequency increased in babies born to mothers with higher lead at 12 weeks of pregnancy, and with higher cord lead in multiple regression analysis. Decreased percent nasalization was related to increased brainstem auditory evoked response latencies and interpeak intervals in a subset of the sample. The results suggest an effect of gestational exposure to lead on apparatus innervated by cranial nerves and/or lead effect on cry mediated by lead-altered auditory function. Altered baby cry and auditory function associated with lead might contribute to developmental delays by affecting early communication between caretaker and baby.

An historical cohort study of twins, aged 6 to 15 years, found reduced cognitive performance related to subclinical exposure to lead (Pb) much earlier in life. Pairs of twins discordant for blood Pb (low-Pb twins ranged from 30-50 micrograms/dl and high-Pb twins ranged from 43-80 micrograms/dl) exhibited reduced learning of a computer-administered visual discrimination and reversal by the twin having the higher exposure. There was no evidence that sensory or motor impairment contributed to the cognitive deficit. Performance of a reference group indicated that test's validity for age-related cognitive development and the method's suitability for children of varying socio-economic or racial status. Because the reversal learning approach required only one 20-min test session and was powerful enough to document Pb-related deficits in a small sample (n = 8), it may indicate a practical method for obtaining early evidence of environmentally induced developmental delays. An advantage of the test is that it can be used with both humans and animals. Tests capable of direct comparison of behavioral data from humans and animals can guide the search for behavioral and biological mechanisms in experiments that can be done only with animals. They also can augment the clinical procedures currently used.

For a prospective study of lead exposure and early development, we recruited pregnant women from a smelter town and a nonlead-exposed town in Yugoslavia and followed them and their children through age 4. For 332 children seen at age 4, mean scores on the McCarthy Scales General Cognitive Index (GCI) in the exposed and nonexposed towns were 81.3 and 86.6, respectively; geometric mean blood lead concentrations (BPb) were 39.9 and 9.6 micrograms/dl, respectively. Potential confounders included the quality of the HOME environment; maternal age, intelligence, education, and language; birthweight and gender. These showed predictable associations with 4-year intelligence, accounting for 42.7% of the variance in GCI. Following adjustment for these variables and for concurrent Hgb, we found significant independent adverse associations between GCI and BPb's, measured at 6-month intervals since birth. At age 4, BPb accounted for an incremental 3.5% of the variance in GCI, such that the estimated loss in GCI associated with an increase in BPb from 10-25 micrograms/dl was 3.8 points. The Perceptual-Performance subscale of the McCarthy was most sensitive to Pb exposure, a result consistent with findings from prospective studies in Boston and Port Pirie.

A cohort of children who attended first grade in 1983 was identified in a Danish community with low-level lead pollution. Two groups with high and low postnatal lead exposure were generated on the basis of the dentin-lead concentration in shed deciduous incisors. At age 8 years, examination of 162 children matched according to gender and socioeconomic status had shown lead-related deficits in verbal intelligence and visuomotor coordination. Re-examination was now carried out in 141 children at age 15 years using the Wechsler Intelligence Scale for Children (WISC), Bender Visual Motor Gestalt, Trail Making, and Visual Gestalts. In general, no lead-related effects could be detected in the group. However, in children with a history of neonatal jaundice, increased lead exposure was associated with mild neurobehavioral deficits, as indicated by lower verbal IQ scores and decreased visuomotor coordination. This finding suggested that moderate neonatal hyperbilirubinemia may have precipitated an increased sensitivity to subsequent exposure to lead.

In a further follow-up study of the Cincinnati Lead Study Cohort, 253 children were administered the Wechsler Intelligence Scale for Children-Revised (WISC-R) at approximately 6.5 years of age. Postnatal blood lead concentrations were inversely associated with Full-Scale (FSIQ) and Performance IQ (PIQ). Following statistical adjustment for developmental co-factors such as maternal IQ and an assessment of the quality of caretaking in the home environment, a statistically significant relationship remained between postnatal blood lead concentrations and PIQ. Further statistical analyses suggested that averaged lifetime blood lead concentrations in excess of 20 micrograms/dL were associated with deficits in PIQ on the order of approximately 7 points when compared to children with mean concentrations less or equal to 10 micrograms/dL. These results are discussed in terms of their consistency with other similar studies as well as their internal consistency with earlier reports on this cohort. The findings of this investigation support recent initiatives in the United States to reduce the exposure of children to environmental lead.

Nursery-reared rhesus monkeys were treated with no or moderate levels of lead during the first year postpartum. Previously, the lead-treated monkeys exhibited behaviors in the nonhuman primate version of the open field (10) resembling those caused by hippocampal lesions. The current study investigated the mechanism(s) underlying these lead-related effects using a cholinergic agonist (arecoline) and antagonist (scopolamine) as pharmacological probes that were administered prior to open field testing at 5 and 6 years of age, respectively. Arecoline decreased locomotion and number of sectors entered. Scopolamine decreased defecation frequency. Neither drug interacted with prior lead treatment, indicating limited cholinergic involvement in the expression of these alterations. The lead-treated subjects continued to exhibit alterations as previously reported (10); specifically, a longer latency to enter the open field, increased frequency and duration of environmental exploration and, at 5 years of age, decreased duration of inactivity in the open field. These effects were seen four and five years after lead treatment ended and nearly three and four years after blood lead levels had declined to less than or equal to 5 micrograms/dL. Although latency to enter and duration of inactivity seem to be approaching control levels, the increased exploration does not.

This analysis examined the relationship between lead exposure as registered in whole blood (PbB) and the central auditory processing abilities and cognitive developmental status of the Cincinnati cohort (N = 259) at age 5 years. Although the effects were small, higher prenatal, neonatal, and postnatal PbB levels were associated with poorer central auditory processing abilities on the Filtered Word Subtest of the SCAN (a screening test for auditory processing disorders). Higher postnatal PbB levels were associated with poorer performance on all cognitive developmental subscales of the Kaufman Assessment Battery for Children (K-ABC). However, following adjustment for measures of the home environment and maternal intelligence, few statistically or near statistically significant associations remained. Our findings are discussed in the context of the related issues of confounding and the detection of weak associations in high risk populations.

Infant rhesus monkeys ingested 0 or 1.0 mg/kg lead acetate daily from birth to one year postpartum in dietary milk. Half the monkeys in each group were offered milk ad lib, and half were given restricted quantities. Chow was available ad lib to all monkeys. Groups of 4 monkeys interacted for 1.5 h/day, 5 days/week beginning at approximately 2 months of age. The social sessions were moved to a larger arena at about 9 months postpartum. Ongoing behavior was observed during social sessions twice weekly beginning at about 3 months of age for 28 weeks, and again beginning at about 16 months of age for 11 weeks. Play behaviors were particularly susceptible to lead; social play was more severely disrupted than nonsocial play. Lead suppressed play in both test environments during the first year postpartum while self-stimulation and fearful behaviors increased. Lead-associated alterations in behavior were still present several months following termination of lead intake. Restriction of milk resulted in increased chow consumption but had little impact on behavior. Effects of lead may have been more profound in monkeys maintained on the restricted milk diet than in monkeys given milk ad lib.

The purpose of this analysis was to determine if significant associations could be observed between prenatal/postnatal blood lead (PbB) levels and the cognitive development of 258 urban, inner-city children at 4 years of age. These children have been followed since birth with frequent assessments of general health, PbB, and neuropsychological status. The Kaufman Assessment Battery for Children (K-ABC) was administered at approximately 4 years of age. Higher neonatal PbB levels were associated with poorer performance on all K-ABC subscales. However, this inverse association was limited to children from the poorest families. Maternal PbB levels were unrelated to 4-year cognitive status. Few statistically significant associations between postnatal PbB levels and K-ABC scales could be found. However, the results did suggest a weak inverse relationship between postnatal PbB levels and performance on a K-ABC subscale which assesses visual-spatial and visual-motor integration skills. In these results we note both contradiction and accord with previously published prospective studies.

In order to establish safe exposure levels to toxic chemicals, risk assessment guidelines have been developed. These guidelines evaluate epidemiologic and animal research data on a particular chemical, as well as dose-response relationships, animal to human extrapolation and assessment of exposure levels of populations. Using the guidelines, risk characterization is established in order to determine a strategy for reducing undesirable risk to human populations. Using both human neonatal lead exposure data and results from rodent and primate studies, this review examines the possibility that behavioral measurements are sufficient to provide adequate risk assessment guidelines for lead intoxication of the developing organism. The overall trend in these data during the past 10 years has been to show that exposures to inorganic lead at levels previously considered safe have long-lasting significant alterations in behavioral measures, suggesting that central nervous system function has been altered irreversibly. The conclusion is drawn that behavioral toxicology can provide sensitive, quantitative and reliable data for risk assessment and that in the future these methodologies could be used to set exposure guidelines for other neurotoxic chemicals.

In order to improve dose-response information on neurobehavioral effects of environmental lead exposure in children, the World Health Organization, Regional Office for Europe (WHO/EURO), in collaboration with the Commission of the European Communities, initiated this international study which was planned, executed and evaluated between 1984 and 1989. Eight groups from eight European countries (Bulgaria, Denmark, Greece, Hungary, Italy, Roumania, W. Germany and Yugoslavia) took part. A common study protocol with inherent quality assurance elements was developed to achieve comparability. Blood-lead concentrations (PbB) were the main markers of exposure. The WISC (4 subtests) for psychometric intelligence, the Bender Gestalt test (GFT version) and the Trail-Making test for visual-motor integration, the Vienna Reaction Device and a delayed RT task for reaction performance, and the Needleman scales for behavior ratings served as behavioral endpoints. All individual studies taken together represent a sample size of 1879 school-age children and cover a PbB range from below 5 to about 60 micrograms/100 ml. Overall statistical evaluation of outcome was done by multiple regression analysis using a uniform confounder model. The strongest and most consistent effects occurred for the Bender Gestalt test (GFT version) and for serial choice reaction performance (Vienna Device). The degree of association with PbB was significant for these variables, although the contribution of PbB to the observed variance never exceeded 0.8%. Psychometric intelligence was also negatively affected, although the consistency of outcome between studies was poor, and the association with PbB only borderline. An effort towards risk assessment was made by calculating the proportion of children at risk, using the observed regression coefficients as well as means and standard deviations.

An attempt is made to account for the ability of severely amnesic patients to learn and retain certain tasks but not others. The hypothesis is advanced that the amnesic subject can show learning through facilitation by repetition or of simple S-R relationships not requiring cognitive mediation. Three examinations are reported. The first demonstrates that the amnesic subjects have adequate speed of access to semantic and phonological knowledge and show the same degree of improvement on retesting as controls. The second and third experiments examine different degrees of cognitive mediation in paired-associate learning. Amnesic subjects are differentially impaired relative to controls on "distant" pairs and on those that, by hypothesis, would benefit from cognitive mediation. The results are discussed in terms of a disconnection syndrome. It is suggested that at the functional level, a "cognitive mediational memory system" and a semantic memory system are disconnected in the amnesic patient. Neuropathological evidence suggests that temporal lobe and frontal lobe structures are disconnected by pathways in the fornix-mammillary body route.

The hypothesis that low level lead exposure in the fetal and early preschool years is related to neuropsychological deficit is being examined in a prospective study of development through the preschool years. Clear and consistent support for the hypothesis was not obtained in previously reported findings relating maternal and cord blood lead level (PbB) and PbB from venous samples through age three years to a series of developmental tests. It was concluded the relationship of lead level and cognitive development was primarily a function of the dependence of each on the quality of the caretaking environment. The cohort has now been examined at age four years, ten months, an age selected to assess development just prior to school age. The test used was the Wechsler Preschool and Primary Scale of Intelligence. We found statistically significant correlations between most of the PbB measures and the intelligence test scores, but these were attenuated, not statistically significant and not consistent in direction when relevant confounding variables were considered. Possible biases or threats to validity were reviewed. Effect sizes relating both prenatal and preschool lead exposure to intellectual development were small, not statistically significant, and not consistent in direction.

Two cohorts of monkeys chronically exposed to lead during the first year after birth and their controls were tested during adulthood for choice accuracy on a learning and memory task, delayed spatial alternation (DSA). Neither cohort showed significant lead-related deficits, as had been seen in a previous experiment with monkeys exposed to similar chronic levels of lead during the first year with an additional high pulse given five-six weeks after birth (18,19). On the contrary, the lead-exposed monkeys in the present experiment actually performed slightly better than controls. In the previous (pulse-chronic) study, the deficit occurred at short intertrial delays, suggesting an attentional rather than mnenomic deficit. A lead-induced decrease in attentiveness could also explain the present results. The lower level lead intoxication may have decreased attentiveness to a lesser degree, so that the monkeys were less susceptible to irrelevant stimuli and performed better.

Previous reports have suggested a relationship between the neurotoxicity of lead and hippocampal dysfunction. Therefore, a comparison between the behavioral changes induced by lead exposure and by selective destruction of hippocampal neurons should help to clarify whether the intrinsic neurons of the hippocampus are directly influenced by lead. Rats maternally and permanently exposed to lead (750 ppm in the diet as lead acetate) were tested in a radial arm maze and compared with controls and rats with ibotenic acid-induced neuronal depletion in the dorsal hippocampus. Lead-exposed groups showed an impairment in the acquisition performance of the spatial task while hippocampally damaged animals did not. When they were retested 4 weeks after the end of the original acquisition, both groups of lead-exposed and ibotenic acid-treated rats showed a significant deficit in retention. These results suggest that this deficit produced by lead can be due to the damage of the hippocampal neurons but not the impairment observed in the acquisition. We propose that the neurotoxicity of lead is not entirely due to the dysfunction of the dorsal hippocampus and that other areas of the brain should be considered. Both maternally and permanently lead-exposed rats showed a similar degree of deficit in acquisition and retention, suggesting a long-lasting effect of early lead exposure.

A prospective cohort study was conducted to assess the association between early development and low-level prenatal and postnatal lead exposure. Infants' performance between 6 and 24 months on the Mental Development Index of the Bayley Scales of Infant Development declined with increasing concentration of lead in blood, but the decline varied with children's age at exposure, level of exposure, and socioeconomic status. Within the second year of life, the performance of children in lower socioeconomic strata was adversely affected at lower levels of prenatal exposure (blood lead levels of 6 to 7 micrograms/dl) than was the performance of children in higher socioeconomic strata. However, even the performance of these advantaged infants was lower when cord blood lead level exceeded 10 micrograms/dl, well below the figure currently regarded as the maximum permissable level for young children. Exploratory analyses suggested that early postnatal blood lead levels between 10 and 25 micrograms/dl were also associated with lower Mental Development Index scores, but only among children in lower socioeconomic strata.

Gestation age and ability of the baby to self-quiet and to be consoled during the first 30 days of life decrease when mother's blood lead levels rise from 36 weeks of pregnancy to birth of child. These effects appear to be independent of the absolute lead levels of mother and child (N = 42). Since pre- and perinatal stress predicts higher maternal birth lead, further work could determine the relative contributions of undetected stress during pregnancy and elevated lead levels upon subsequent development. Several cases, not included in the statistical analyses, showed associations between cord leads greatly elevated over maternal leads and poor outcome.

A cohort of 318 children born in three Sydney hospitals between April 1982 and March 1983 were recruited into a five year prospective study designed to investigate the relationship between low level lead exposures and neurobehavioural development. Blood samples were obtained at the time of birth, then at 6 month intervals to 4 years and then at 5 years; neurobehavioural and physical measures were taken at 6 months, 12 months and hence annually to 5 years. This paper presents some of the findings from the first three years of the study and addresses the issue of the relationship between fetal exposures to lead and child development to three years. Maternal and cord blood lead levels were in range 0-29 microgram/dl with the majority less that 15 micrograms/dl. The geometric means were, respectively, 9.1 micrograms/dl and 8.1 micrograms/dl. The analyses presented do not support the hypothesis of a relationship between maternal and cord blood lead levels in this range and developmental deficits in young children to the age of three years.

Cynomolgus monkeys (Macaca fascicularis) were dosed continuously from birth onward with 100, 50, or 0 micrograms/kg/day of lead. This resulted in blood lead concentrations of 25, 15, or 3 micrograms/dl respectively before withdrawal of infant formula at 200 days of age. Blood lead concentrations declined thereafter over the next 100-150 days to steady-state concentrations of 13, 11, or 3 micrograms/dl. At seven to eight years of age, monkeys were tested on a delayed alternation task. The task required the monkey to alternate responses between two pushbuttons; each alternation was rewarded with a small amount of apple juice. After each monkey learned the task, a delay was instituted between trials. The initial delay was 100 msec, and was increased in steps to 15 sec by the end of the experiment. Treated monkeys were impaired in their ability to learn the alternation task, but were not different from controls at short delay values (1 and 3 sec). At longer delay values (5 and 15 sec), treated monkeys again exhibited impairment. At the 15 sec delay value, some individuals in both treated groups exhibited marked perseveration, responding on the same button in some instances for hours at a time. Treated monkeys were also more variable in their performance across sessions than were controls. The data are interpreted as indicative of spatial learning and short-term memory deficits in the lead-exposed monkeys.