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Background: Low-level developmental lead exposure is linked to cognitive and neurological disorders in children. However, the long-term effects of gestational lead exposure (GLE) have received little attention., Objectives: Our goals were to establish a murine model of human equivalent GLE and to determine dose-response effects on body weight, motor functions, and dopamine neurochemistry in year-old offspring., Methods: We exposed female C57BL/6 mice to water containing 0, 27 (low), 55 (moderate), or 109 ppm (high) of lead from 2 weeks prior to mating, throughout gestation, and until postnatal day 10 (PN10). Maternal and litter measures, blood lead concentrations ([BPb]), and body weights were obtained throughout the experiment. Locomotor behavior in the absence and presence of amphetamine, running wheel activity, rotarod test, and dopamine utilization were examined in year-old mice., Results: Peak [BPb] were < 1, < or = 10, 24-27, and 33-42 microg/dL in control, low-, moderate- and high-dose GLE groups at PN0-10, respectively. Year-old male but not female GLE mice exhibited late-onset obesity. Similarly, we observed male-specific decreased spontaneous motor activity, increased amphetamine-induced motor activity, and decreased rotarod performance in year-old GLE mice. Levels of dopamine and its major metabolite were altered in year-old male mice, although only forebrain utilization increased. GLE-induced alterations were consistently larger in low-dose GLE mice., Conclusions: Our novel results show that GLE produced permanent male-specific deficits. The nonmonotonic dose-dependent responses showed that low-level GLE produced the most adverse effects. These data reinforce the idea that lifetime measures of dose-response toxicant exposure should be a component of the neurotoxic risk assessment process.

Background: Essential tremor (ET) is one of the most common neurologic disorders. Aside from underlying susceptibility genes, recent studies have also begun to focus on environmental toxic factors. Yet there remains a paucity of information on such factors, making studies of environmental factors important. A recent study in New York City found blood lead concentrations to be elevated in ET cases compared with matched controls. Chronic exposure to lead produces cerebellar damage, and this could predispose individuals to develop ET., Objective: The aim of this study was to determine whether the elevation in blood lead concentrations observed in a single study in New York was similarly present in ET cases sampled from a completely different geographic region., Methods: Blood lead concentrations were measured in 105 ET cases and 105 controls at Mersin University, Mersin, Turkey., Results: The median blood lead concentration was 2.7 microg/dL in ET cases compared with 1.5 microg/dL in controls (p < 0.001). In an unadjusted logistic regression model, blood lead concentration was associated with diagnosis: odds ratio (OR) = 4.01; 95% confidence interval (CI), 2.53-6.37; p < 0.001 (i.e., each 1-microg/dL increase in blood lead concentration was associated with a 4-fold increased odds of ET). This association was more robust when cases were compared with a subsample of controls who did not share the same home environment (OR = 8.13; 95% CI, 3.05-21.65; p < 0.001). In adjusted models, results were similar., Conclusions: These data replicate those of a previous study in New York and demonstrate an association between the environmental toxicant lead and a common neurologic disorder.

Increases in peak blood lead concentrations, which occur at 18-30 months of age in the United States, are thought to result in lower IQ scores at 4-6 years of age, when IQ becomes stable and measurable. Data from a prospective study conducted in Boston suggested that blood lead concentrations at 2 years of age were more predictive of cognitive deficits in older children than were later blood lead concentrations or blood lead concentrations measured concurrently with IQ. Therefore, cross-sectional associations between blood lead and IQ in school-age children have been widely interpreted as the residual effects of higher blood lead concentrations at an earlier age or the tendency of less intelligent children to ingest more leaded dust or paint chips, rather than as a causal relationship in older children. Here we analyze data from a clinical trial in which children were treated for elevated blood lead concentrations (20-44 microg/dL) at about 2 years of age and followed until 7 years of age with serial IQ tests and measurements of blood lead. We found that cross-sectional associations increased in strength as the children became older, whereas the relation between baseline blood lead and IQ attenuated. Peak blood lead level thus does not fully account for the observed association in older children between their lower blood lead concentrations and IQ. The effect of concurrent blood level on IQ may therefore be greater than currently believed.

Recent research suggests that both uric acid and lead may be nephrotoxic at lower levels than previously recognized. We analyzed data from 803 current and former lead workers to determine whether lead biomarkers were associated with uric acid and whether previously reported associations between lead dose and renal outcomes were altered after adjustment for uric acid. Outcomes included uric acid, blood urea nitrogen, serum creatinine, measured and calculated creatinine clearances, and urinary N-acetyl-ss-d-glucosaminidase (NAG) and retinol-binding protein. Mean (+/- SD) uric acid, tibia lead, and blood lead levels were 4.8 +/- 1.2 mg/dL, 37.2 +/- 40.4 microg/g bone mineral, and 32.0 +/- 15.0 microg/dL, respectively. None of the lead measures (tibia, blood, and dimercaptosuccinic-acid-chelatable lead) was associated with uric acid, after adjustment for age, sex, body mass index, and alcohol use. However, when we examined effect modification by age on these relations, both blood and tibia lead were significantly associated (ss = 0.0111, p < 0.01 and ss = 0.0036, p = 0.04, respectively) in participants in the oldest age tertile. These associations decreased after adjustment for blood pressure and renal function, although blood lead remained significantly associated with uric acid (ss = 0.0156, p = 0.01) when the population was restricted to the oldest tertile of workers with serum creatinine greater than the median (0.86 mg/dL). Next, in models of renal function in all workers, uric acid was significantly (p < 0.05) associated with all renal outcomes except NAG. Finally, in the oldest tertile of workers, associations between lead dose and NAG were unchanged, but fewer associations between the lead biomarkers and the clinical renal outcomes remained significant (p less than or equal to 0.05) after adjustment for uric acid. In conclusion, our data suggest that older workers comprise a susceptible population for increased uric acid due to lead. Uric acid may be one, but not the only, mechanism for lead-related nephrotoxicity.

Osteoporosis is a decrease in bone mineral density (BMD) that predisposes individuals to fractures. Although an elderly affliction, a predisposition may develop during adolescence if a sufficient peak BMD is not achieved. Rat studies have found that lead exposure is associated with decreased BMD. However, human studies are limited. We hypothesized that the BMD of children with high lead exposure would be lower than the BMD of children with low lead exposure. We collected data on 35 subjects; 16 had low cumulative lead exposure (mean, 6.5 microg/dL), and 19 had high exposure (mean, 23.6 micro g/dL). All were African American; there was no difference between the groups by sex, age, body mass index, socioeconomic status, physical activity, or calcium intake. Significant differences in BMD between low and high cumulative lead exposure were noted in the head (1.589 vs. 1.721 g/cm2), third lumbar vertebra (0.761 vs. 0.819 g/cm2), and fourth lumbar vertebra (0.712 vs. 0.789 g/cm2). Contrary to our hypothesis, subjects with high lead exposure had a significantly higher BMD than did subjects with low lead exposure. This may reflect a true phenomenon because lead exposure has been reported to accelerate bony maturation by inhibiting the effects of parathyroid hormone-related peptide. Accelerated maturation of bone may ultimately result in a lower peak BMD being achieved in young adulthood, thus predisposing to osteoporosis in later life. Future studies need to investigate this proposed model.

In the last decade children's blood lead levels have fallen significantly in a number of countries, and current mean levels in developed countries are in the region of 3 Mu g/dL. Despite this reduction, childhood lead poisoning continues to be a major public health problem for certain at-risk groups of children, and concerns remain over the effects of lead on intellectual development in infants and children. The evidence for lowered cognitive ability in children exposed to lead has come largely from prospective epidemiologic studies. The current World Health Organization/Centers for Disease Control and Prevention blood level of concern reflects this and stands at 10 Mu g/dL. However, a recent study on a cohort of children whose lifetime peak blood levels were consistently less than 10 Mu g/dL has extended the association of blood lead and intellectual impairment to lower levels of lead exposure and suggests there is no safety margin at existing exposures. Because of the importance of this finding, we reviewed this study in detail along with other recent developments in the field of low-level lead exposure and children's cognitive development. We conclude that these findings are important scientifically, and efforts should continue to reduce childhood exposure. However, from a public health perspective, exposure to lead should be seen within the many other risk factors impacting on normal childhood development, in particular the influence of the learning environment itself. Current lead exposure accounts for a very small amount of variance in cognitive ability (1-4%), whereas social and parenting factors account for 40% or more.

The Baltimore Memory Study is a cohort study of the multilevel determinants of cognitive decline in 50-70-year-old randomly selected residents of specific city neighborhoods. Prior studies have demonstrated that cognitive function differs by race/ethnicity, with lower scores in minorities than in whites, but the underlying basis for these differences is not understood. Studies have differed in the rigor with which they evaluated and controlled for such important confounding variables as socioeconomic status (SES), health-related behaviors, comorbid illnesses, and factors in the physical environment. The goal of this study was to describe differences in neurobehavioral test scores by race/ethnicity, before and after control for a four-dimensional measure of SES and health-related behaviors and health conditions, in a cross-sectional analysis of first visit data. Random samples of households in the study area were selected until enrollment goals were reached. Among the 2,351 persons on whom eligibility was determined, 60.8% were scheduled for an enrollment visit; of these, 1,140 (81.3%) were enrolled and tested. These study participants were 34.3% male and 65.7% female and were from 65 Baltimore, Maryland, neighborhoods. After adjustment for age, sex, and testing technician, there were large and statistically significant differences in neurobehavioral test scores by race/ethnicity, with African-American scores lower than those for whites, for both men and women. After adjustment for individual SES (educational status, household income, household assets, and occupational status), the average difference declined by 25.8%. After additional adjustment for SES, health-related behaviors and health conditions, and blood lead, the average difference declined another 10%, but large differences persisted; African Americans had test scores that averaged 0.43 standard deviation lower than those for whites across all neurobehavioral tests. These differences were present in all cognitive domains, including tests that would not be characterized as susceptible to differential item functioning by race/ethnicity, suggesting that the results are not due to race/ethnicity-associated measurement error.

Growth deficits associated with lead exposure might be ameliorated by chelation. We examined the effect of succimer on growth in 780 children 12-33 months old who had blood lead levels of 20-44 microg/dL and were randomized to receive up to three 26-day courses of succimer or placebo in a multicenter, double-blind trial. The difference in changes in weight and height between succimer and placebo groups at 1-34 months was calculated by fitting cubic splines. The difference in height change in children on succimer compared with placebo was -0.27 cm [95% confidence interval (95% CI), -0.42 to -0.11] from baseline to 9 months, when 99% of children had completed treatment, and -0.43 cm (95% CI, -0.77 to -0.09) during 34 months of follow-up. Similar differences in weight gain were not statistically significant. Although succimer lowers blood lead in moderately lead-poisoned children, it does not have a beneficial effect on growth and may have an adverse effect.

Lead is a ubiquitous toxicant that causes tremor and cerebellar damage. Essential tremor (ET) is a highly prevalent neurologic disease associated with cerebellar involvement. Although environmental toxicants may play a role in ET etiology and their identification is a critical step in disease prevention, these toxicants have received little attention. Our objective was to test the hypothesis that ET is associated with lead exposure. Therefore, blood lead (BPb) concentrations were measured and a lifetime occupational history was assessed in ET patients and in controls. We frequency matched 100 ET patients and 143 controls on age, sex, and ethnicity. BPb concentrations were analyzed using graphite furnace atomic absorption spectrophotometry. A lifetime occupational history was reviewed by an industrial hygienist. BPb concentrations were higher in ET patients than in controls (mean +/- SD, 3.3 +/- 2.4 and 2.6 +/- 1.6 microg/dL, respectively; median, 2.7 and 2.3 microg/dL; p = 0.038). In a logistic regression model, BPb concentration was associated with diagnosis [control vs. ET patient, odds ratio (OR) per unit increase = 1.21; 95% confidence interval (CI), 1.05-1.39; p = 0.007]. BPb concentration was associated with diagnosis (OR per unit increase = 1.19; 95% CI, 1.03-1.37; p = 0.02) after adjusting for potential confounders. Prevalence of lifetime occupational lead exposure was similar in ET patients and controls. We report an association between BPb concentration and ET. Determining whether this association is due to increased exposure to lead or a difference in lead kinetics in ET patients requires further investigation.

In 1984, a 56-year-old house painter developed intractable pain in his back and other joints. After several unrevealing medical work-ups, he was found to have a high blood lead level (122 microg/dL); he has a history of scraping and sanding lead paint without adequate protective measures. The patient was hospitalized and chelated with EDTA four times over the next 5 years; each time he felt better at the end of his treatment, but he returned to largely the same working conditions. He developed hypertension in April 1989, underwent a final chelation, and retired. He was subsequently followed on a regular basis with repeated measurement of lead levels in blood and bone (using a K-x-ray fluorescence instrument) as well as clinical parameters. In 1995 his blood pressure became difficult to control despite a sequential increase in his antihypertensive medication dosages and the addition of new medications. In 1997 he began calcium supplementation and a high-calcium diet; his blood pressure declined markedly, allowing him to taper off of two of his four antihypertensive medications. This case demonstrates an occupational activity (construction) that has now become the dominant source of lead exposure for U.S. adults, the importance of a good occupational history to suspecting and making a diagnosis, the possible outcomes of chronic lead toxicity, and the importance of preventing further exposure and using proper methods to treat acute toxicity. It also highlights a current major etiologic question, that is, whether and to what degree lead exposure contributes to the development of hypertension, and raises the issue of whether lead-induced hypertension constitutes a subset of hypertension that is especially amenable to therapy with dietary calcium.

In August 1997 we performed a follow-up survey of 146 lead-poisoned children from a community near a previously active auto battery recycling smelter in Haina near Santo Domingo, Dominican Republic. Our follow-up survey confirmed a severe incidence of elevated blood lead (BPb) and erythrocyte protoporphyrin/zinc protoporphyrin (EP-ZnPP) levels. The mean BPb level was 32 micrograms/dL and the mean EP-ZnPP level was 128 micrograms/dL. The frequency distribution of BPb showed that only 9% of the children had BPb levels below the currently acceptable 10 micrograms/dL threshold level, 23% had between 10 and 19 micrograms/dL, 40% had between 20 and 39 micrograms/dL, 27% had between 40 and 99 micrograms/dL, and the remainder had > 100 micrograms/dL. These findings are significantly greater than the mean BPb and EP-ZnPP levels of 14 and 35 micrograms/dL, respectively, in a comparison group of 63 children in Barsequillo, 4 miles away. BPb frequency distributions for these groups were < 10 micrograms/dL (42%), 10-19 micrograms/dL (32%), and 20-39 micrograms/dL (16%); in the remaining 10%, BPb levels were between 40 and 99 micrograms/dL. Similarly, the corresponding frequency distribution of EP-ZnPP levels in Haina children were proportional to the severity of lead poisoning and significantly higher than those of the Barsequillo comparison group. This study reveals that at least 28% of Haina children require immediate treatment; of these, 5% with lead levels > 70 micrograms/dL are also at risk for severe neurologic sequelae, and urgent action is imperative.

We investigated blood lead (B-Pb) and mercury (B-Hg) levels and auditory sensory-neural function in 62 Andean school children living in a Pb-contaminated area of Ecuador and 14 children in a neighboring gold mining area with no known Pb exposure. The median B-Pb level for 62 children in the Pb-exposed group was 52.6 micrograms/dl (range 9.9-110.0 micrograms/dl) compared with 6.4 micrograms/dl (range 3.9-12.0 micrograms/dl) for the children in the non-Pb exposed group; the differences were statistically significant (p < 0.001). Auditory thresholds for the Pb-exposed group were normal at the pure tone frequencies of 0.25-8 kHz over the entire range of B-Pb levels, Auditory brain stem response tests in seven children with high B-Pb levels showed normal absolute peak and interpeak latencies. The median B-Hg levels were 0.16 micrograms/dl (range 0.04-0.58 micrograms/dl) for children in the Pb-exposed group and 0.22 micrograms/dl (range 0.1-0.44 micrograms/dl) for children in the non-Pb exposed gold mining area, and showed no significant relationship to auditory function.

Over the past three or four decades, there have been important advances in the understanding of the actions, exposure-response characteristics, and mechanisms of action of many common air pollutants. A multidisciplinary approach using epidemiology, animal toxicology, and controlled human exposure studies has contributed to the database. This review will emphasize studies of humans but will also draw on findings from the other disciplines. Air pollutants have been shown to cause responses ranging from reversible changes in respiratory symptoms and lung function, changes in airway reactivity and inflammation, structural remodeling of pulmonary airways, and impairment of pulmonary host defenses, to increased respiratory morbidity and mortality. Quantitative and qualitative understanding of the effects of a small group of air pollutants has advanced considerably, but the understanding is by no means complete, and the breadth of effects of all air pollutants is only partially understood.

Over the 20-year period since the first issue of Environmental Health Perspectives was published, there has been considerable progress in the understanding of the potential toxicity of exposure to lead. Many of these advances have been reviewed in published symposia, conferences, and review papers in EHP. This brief review identifies major advances as well as a number of current concerns that present opportunities for prevention and intervention strategies. The major scientific advance has been the demonstration that blood lead (PbB) levels of 10-15 micrograms/dL in newborn and very young infants result in cognitive and behavioral deficits. Further support for this observation is being obtained by prospective or longitudinal studies presently in progress. The mechanism(s) for the central nervous system effects of lead is unclear but involve lead interactions within calcium-mediated intracellular messenger systems and neurotransmission. Effects of low-level lead exposure on blood pressure, particularly in adult men, may be related to the effect of lead on calcium-mediated control of vascular smooth muscle contraction and on the renin-angiotensin system. Reproductive effects of lead have long been suspected, but low-level effects have not been well studied. Whether lead is a carcinogen or its association with renal adenocarcinoma is a consequence of cystic nephropathy is uncertain. Major risk factors for lead toxicity in children in the United States include nutrition, particularly deficiencies of essential metals, calcium, iron, and zinc, and housing and socioeconomic status. A goal for the year 2000 is to reduce prevalence of blood lead levels exceeding 15 micrograms/dL.

Lead has been shown to be associated with elevated blood pressure in males in the NHANES II survey and in numerous other studies. This study confirms the association in males aged 20 to 74 and documents a significant, although weaker, association in females as well. Prospective cardiovascular disease studies such as the Framingham study indicate that increases in blood pressure should be associated with increased risk of cardiovascular disease. Using electrocardiogram data from NHANES II, this study confirms the expected association of lead with left ventricular hypertrophy (p less than 0.01). Such an association with permanent cardiovascular changes adds weight to the blood pressure findings. The logistic risk coefficients from the Framingham study can be combined with the study's association between lead and blood pressure to examine its implication for more serious outcomes. The results suggest that a halving of the population mean blood lead level would reduce myocardial infarctions by approximately 24,000 events per year and incidence of all cardiovascular disease by over 100,000. These numbers suggest a small attributable risk compared to the vast incidence of cardiovascular disease in the U.S., but a large attributable risk compared to most environmental toxins. Several biological mechanisms have been identified, with different implications for the use of bone lead as an exposure measure.

We are prospectively examining the relation between environmental lead exposure and pregnancy outcome in cohorts of women exposed to a wide range of air lead concentrations. Titova Mitrovica, Yugoslavia, is the site of a large lead smelter, refinery, and battery factory. At midpregnancy, 602 women in T. Mitrovica and 900 women in Pristina, a non-lead-exposed control town, were interviewed. Blood was obtained for blood lead (PbB), hemoglobin, erythrocyte protoporphyrin, and serum ferritin measurements. Women were seen again at delivery, at which time maternal and umbilical cord blood samples were obtained. While many demographic and social characteristics were similar across the two towns, women in Pristina were more likely to report employment outside the home, cigarette smoking, and alcohol use during pregnancy. As expected, PbB levels were substantially higher in the smelter town. At midpregnancy, PbB geometric means were 17.1 micrograms/dL in T. Mitrovica and 5.1 micrograms/dL in Pristina; 86% of the pregnant women in T. Mitrovica, compared to 3.4% of those in Pristina, had PbB levels greater than 10 micrograms/dL. Within T. Mitrovica, distance between the home and the smelter was the most important predictor of PbB at mid-pregnancy and delivery. Husband's employment in the lead industry was associated with a significant increase in maternal PbB levels independent of place of residence. Higher maternal serum ferritin concentrations were associated with lower PbB levels, suggesting that dietary iron inhibits lead absorption. Overall, the placenta was a poor barrier to lead; the relationship between maternal PbB and umbilical cord PbB was linear across a wide range of PbB levels.

In a Congressionally mandated study carried out under the aegis of the U.S. Agency for Toxic Substances and Disease Registry (ATSDR) and summarized in this article, the authors have provided estimates of the numbers of American women of childbearing age and the numbers of American pregnant women whose lead exposure is sufficiently elevated to pose an intrauterine toxicity risk. Exposures associated with such risk were defined as blood lead (PbB) levels greater than 10, greater than 15, greater than 20, and greater than 25 micrograms/dL. Using PbB prevalence projection techniques based on the Second National Health and Nutrition Examination Survey (NHANES II), we first generated projected 1984 prevalences of these PbB levels in white and black women of childbearing age, ages 15 to 19 and 20 to 44. White women in the two age bands had rates of PbBs greater than 10 micrograms/dL of 9.2 and 9.7%, respectively. For black women, the corresponding rates were 8.2 and 19.7%, respectively. Combining these rates with standard metropolitan statistical areas (SMSAs) based 1980 Census and other population enumerations show, for example, that 4.4 million U.S. women of childbearing age are estimated to have had PbBs greater than 10 micrograms/dL. Pregnant black and white women in U.S. SMSAs are approximately 9% of the U.S. black and white childbearing age total, i.e. 3.6 million out of a 41.3 million SMSA total. Of these, 403,200 pregnant women were estimated to have PbB levels greater than 10 micrograms/dL.(ABSTRACT TRUNCATED AT 250 WORDS)

Hyperactive children were compared with a nonhyperactive control group on two measures that reflect the presence of body lead and on a lead exposure questionnaire. The overall hypothesis that was tested was that a relationship exists between hyperactivity in children and a concommitant condition of increased body lead stores. Operationally, the hypothesis was reduced to a comparison of the hyperactive group and control group on the following measures: (1) blood lead levels; (2) post-penicillamine urine lead levels; (3) scores on a lead exposure questionnaire. The designation hyperactive or nonhyperactive was arrived at by using three different measurements: a doctor's diagnosis; a teacher's rating scale; a parent questionnaire. Hyperactive children had significantly higher values on all three measures than did the controls. More than half the hyperactive children had blood lead levels in the range considered to be raised but not toxic, and 60% of post-penicillamine urine levels were in the "toxic" range. It is concluded that there is an association between hyperactivity and raised lead levels, that a large body-lead burden may exact consequencies that have hitherto been unrealized; that the definition of what is a toxic level for blood lead needs reevaluation and that physicians should look for raised lead levels in children with hyperactivity.

Current questions about lead exposure focus on the consequences of levels too low to have erupted into blatantly discernible defects. The present paper addresses two sets of interrelated problems derived from this issue. One is how to define the behavioral consequences of asymptomatic lead absorption, and the second focuses on behavioral assessment procedures. Current primary prevention programs emphasize environmental monitoring, and early detection programs emphasize lead body burden measurements. The evaluation of behavioral problems in school children as a function of body burden is rarely performed. Epidemiologic data indicate sufficient natural variability to determine the degree of association between indices of total body burden and behavior. Assessment procedures are described and research suggestions offered that sample concretely defined target behaviors in social environments.

The purpose of this study is to assess the nature and magnitude of the deleterious health effects of subclinical over-exposure to lead in children. The study stems from concerns about the impact on the health of children in city slums who ingest leaded paint without overt evidence of poisoning and the health implication of rising levels of lead in the environment from automotive emissions. The study sample was derived mainly from a registry of children on whom blood lead determinations had been made by the New York City Department of Health and was supplemented by siblings of the registry cases and children from a lead belt area who had extractions of deciduous teeth in dental clinics. Information was obtained through parental interview, medical records, and psychometric evaluation. The data show that deleterious health effects occur in children who were treated for severe lead poisoning and in children without diagnosed lead poisoning who had elevated blood leads (>/=0.06 mg-%). In the absence of diagnosed lead poisoning or elevated blood leads, excess lead exposure, measured in terms of high levels of lead in teeth, was not associated with deleterious health effects.

This report is based on an analysis of deaths in 4519 battery plant workers and 2300 lead production or smelter workers during the years 1947 to 1980. Causes were coded to the seventh (1955) revision of the International Classification of Diseases. There were significant excess deaths for "other hypertensive disease" (444-447) and "chronic nephritis" (592-594) in both cohorts, the standardized mortality ratios (SMRs) being 320 and 475, respectively, for the former causes and 222 and 265 for the latter. Proportionate mortality analysis, which adjusted for race, also showed elevated ratios, 241 and 388 for the former causes and 296 and 186 for the latter. Deaths from other hypertension-related diseases did not show comparable excesses. Renal cancer deaths were fewer than expected, SMRs being 41 and 74, respectively.

Previous human studies demonstrated that lead exposure may modify the metabolism of catecholamines and of hormones controlled by the hypothalamo-pituitary axis and may affect the kallikrein-kinin system. This paper reports unpublished data on the plasma renin activity of lead-exposed workers; these results are in agreement with those of previous human and experimental studies suggesting that the synthesis or release of renin is increased after short and moderate exposure to inorganic lead and reduced whenever the exposure is prolonged. Previous experimental investigations demonstrated that lead may act on the cardiovascular system, with effects on the renin-angiotensin system, on the reactivity to stimulation of peripheral catecholaminergic receptors, on sympathetic and vagal tone, and on reactivity to the stimulation of baroreceptors. This paper reports the results of a study on male Sprague-Dawley rats that received 0, 15, 30, and 60 micrograms/mL of lead in drinking water for 18 months. Blood pressure was increased in the rats receiving 30 and 60 ppm of lead; cardiac inotropism was augmented only in those receiving the higher dose of the metal, and heart rate was not modified. Cardiovascular responses to agonists indicated that lead exposure affects the renin-angiotensin system and induces sympathetic hyperactivity by acting on central and peripheral sympathetic junctions increasing the responsiveness to stimulation of alpha 2-adrenoreceptors and by increasing the reactivity to stimulation of cardiac and vascular beta-adrenergic and dopaminergic receptors. The cAMP-dependent availability of Ca2+ for contractile mechanisms of the cardiovascular muscle cells was affected by lead.

Fifty-eight children with an increased lead burden underwent comprehensive investigations and were reevaluated 1(1/2) to 3 years later. Of these children 23-27% were noted to have minor neurological dysfunction and various forms of motor impairment during each evaluation. While the initial psychological assessment revealed low average mental abilities in the majority of children, during follow-up examination a significant increase in certain areas of intellectual functioning was observed.

Lead subacetate (0.5g) and 1000 units of vitamin D were given three times a week to four newly-weaned rhesus monkeys. In addition, two animals received only the vitamin D. The poisoned animals had an increase in the urinary excretion of delta-aminolevulinic acid, an elevated content of lead in the blood, and a fall in hemoglobin concentration. Between 6 and 18 weeks the animals suddenly developed ataxia, nystagmus, generalized weakness, and convulsions. At this time the animals were killed by perfusion of fixative and the brain prepared for light and electron microscopic studies. Definite morphological evidence of disease was confined to the central nervous system, except for one animal which showed the characteristic renal inclusions of lead poisoning. All animals showed PAS-positive globules associated with blood vessels and an exudative edema involving the white matter of the cerebral hemispheres and cerebellum. Ultra-structurally, this appeared as a granular precipitate within an expanded extracellular space. Alterations of nerve fibers were not seen in the white matter but axonal swelling was observed in the cerebral cortex. The perikaryon and neuropil appeared normal. The control animals showed no significant cerebral changes.

When infant rhesus monkeys were exposed to lead via the addition of lead acetate (0.5-9 mg/kg body weight) to their formula or by the consumption of lead particles from lead-based surrogate mothers, they developed symptoms of lead intoxication within 6 weeks. Seizures, muscular tremors, and altered social interaction were the predominant changes. Visual impairment was also apparent in the more severely affected animals. In the animals showing obvious symptoms lead levels varied between 300 to 500 mug/100 ml of blood. Even in those animals having blood lead levels below 100 mug, hyperactivity and insomnia were observed. When the exposure to lead was eliminated, seizures subsided and visual impairment was reduced; however, the abnormal social interaction persisted. These animals also experienced a gradual decline in hematocrit and hemoglobin values during the period of examination. Liver and kidney biopsies obtained from these lead-exposed animals revealed characteristic intranuclear inclusions.When adolescent and adult monkeys were exposed to doses of lead acetate similar to those employed in the infant experiments, lead levels in excess of 200 mug/100 ml of blood were recorded. However, there were no obvious behavioral abnormalities observed. There were, however, numerous lead inclusion bodies in kidney biopsy specimens from these animals. These data suggest that, like man, the infant nonhuman primate is much more susceptible to lead intoxication than is the adult. The clinical and behavioral changes recorded in these infant rhesus monkeys suggest their use as an experimental model to evaluate lead intoxication.

There is considerable clinical evidence that excessive lead absorption causes renal failure with hypertension and predisposes individuals to hypertension even in the absence of detectable renal failure. Recent analyses of transiliac bone biopsies indicate that unsuspected elevated bone leads may reflect the cause (or contributing cause) of end-stage renal disease in 5% of the European dialysis population. In these patients, bone lead levels were four times higher than in unexposed cadavers (6 micrograms/g wet weight) and approximated levels found in lead workers (30 micrograms/g). At present, the most reliable index of the body lead burden is the CaNa2 EDTA lead mobilization test. In vivo tibial X-ray-induced X-ray fluorescence (XRF) is a more practical noninvasive technique for assessing bone lead, which should find widespread application as a diagnostic tool and for epidemiologic studies.

A brief overview of current views of child development is provided, with particular attention given to the role the child's physical and social environment plays in influencing the developmental process. Examples from the recent literature are used to illustrate how these factors can influence lead exposure and most importantly how they might interact with lead to ameliorate or exacerbate possible lead effects. An example is provided which demonstrates that failure to control adequately and to adjust the data statistically to correct for the influence of these factors can lead one erroneously to attribute cognitive and behavioral changes to lead. Finally, data from the Cincinnati Prospective Lead Study are presented to illustrate the application of structural equation modeling as a means for unraveling the complex web of sociodemographic, environmental and behavioral influences on childhood lead exposure. The latter analysis indicates that for children less than 24 months of age, lead-containing dust in the home and on the children's hands are important determinates of their blood lead levels. This relationship is influenced by the amount of maternal involvement with their child and other indices of interaction between the child and primary caregiver.

Inorganic lead produces cerebral dysfunction and clinically definable encephalopathies in man. To date there have been few studies on the biochemical changes in brain following exposure to inorganic lead. Studies correlating toxicity with behavioral and brain neurochemical changes following lead exposure have been hindered because adult laboratory animals are resistant to the central nervous system effects of lead poisoning. Such studies have been impeded by lack of suitable experimental models until Pentschew and Garro showed that brain lesions develop in neonatal rats when a pregnant rat newly delivered of her litter is placed on a 4% lead carbonate containing diet. Lead passes into the developing sucklings via maternal milk. Lead-poisoned new-borns have pronounced retardation of growth and during the fourth week of ilfe develop the severe signs of lead encephalopathy, namely, extensive histological lesions of the cerebellum, brain edema, and paraplegia. There is an approximate 85-fold increase in the lead concentration of both the cerebellum and cerebral cortex relative to controls, but edema and gross vascular changes are confined to the cerebellum. Ingested lead had little effect on RNA, DNA, and protein concentrations of developing rat cerebellum and cerebral cortex. However, there was a reduction of between 10 and 20% in the DNA content of the cerebellum around 3 weeks of age in the lead-exposed sucklings. This suggests a failure of cell multiplication in this part of the brain.A critical evaluation of this experimental approach indicated that under similar dietary conditions experimental lactating rats eat 30% less food than controls resulting in: (a) sustained loss in body weight of nursing mothers and that (b) offsprings who develop paraplegia and cerebellar damage do so after gaining access to lead containing diet. We have studied mothers' food consumption and body weight changes and blood, milk, and brain lead content; and newborns' body and brain weight changes, blood and brain lead content, and brain serotonin (5HT), norepinephrine (NE), dopamine (DA), and gamma-aminobutyric acid (GABA). We have found that a lactating mother rat eating 5% lead acetate (2.73% Pb) produced milk containing 25 ppm lead. When the mothers' diet is changed at day 16 from 5% PbAc to one containing 25 ppm Pb, and neonates allowed free access to the solid diet, the sucklings still have retarded body growth but do not develop paraplegia or grossly apparent vascular damage of the cerebellum. However, during the fourth week these animals exhibit a less severe form of "encephalopathy" consisting of hyperactivity, tremors, and stereotype behavior. Pair-fed controls coetaneous to experimental groups do not display such activities. There was no change in brain 5HT, GABA, or NE, but a 15-20% decrease in brain DA. Change in DA relative to other monoamines suggests a relationship between CNS dysfunction due to lead and DA metabolism in the brain.The experimental design as discribed provides a model of CNS dysfunction due to lead exposure without debilitating histopathologies. It is possible that our findings on increased motor activity and changes in brain dopamine may correspond to early responses to lead exposure before recognized overt signs of toxicity.

Chronic and acute lead poisoning cause overt, clinical symptoms of cardiac and vascular damage with potentially lethal consequences. Morphological, biochemical, and functional derangements of the heart have all been described in patients following exposure to excessive lead levels. Disturbances in cardiac electrical and mechanical activity and postmortem evidence of morphological and biochemical derangements of the myocardium have all been reported following excessive exposure to lead in humans. In addition, signs of vascular degeneration, abnormal vascular smooth muscle function, and altered vessel compliance have been described in humans chronically and acutely exposed to toxic lead levels. Similar cardiovascular complications have been detected following excessive lead exposure in experimental animals. Myocarditis, electrocardiographic disturbances, heightened catecholamine arrhythmogenicity, altered myocardial contractile responsiveness to inotropic stimulation, degenerative structural and biochemical changes affecting the musculature of the heart and vasculature, hypertension, hypercholesterolemia, atherosclerosis, and increased vascular reactivity to alpha-adrenergic agonists have been among the reported cardiovascular disturbances linked to lead poisoning. Less certain are the cardiovascular effects of subclinical lead poisoning. Although controversial, chronic low-level lead exposure has been linked to hypertension and other cardiovascular disturbances in both clinical and experimental studies. In general, it can be concluded that lead over a wide range of exposure intensities can induce significant changes in the function of the cardiovascular system. Evidence points to the involvement of multiple sites of action. Cardiac and vascular sites, as well as sites within the central nervous system, have all been implicated in the sequelae of cardiovascular effects. The exact pathogenic mechanisms that underlie the actions of lead in the cardiovascular system, however, have yet to be elucidated definitively.(ABSTRACT TRUNCATED AT 250 WORDS)

Lead encephalopathy was induced in developing Long-Evans rats by adding lead carbonate (4% w/w) to the diet of nursing mother immediately after delivery. The morphological and biochemical features of cerebral ontogenesis were studied in 30-day-old rats. By the 30th postnatal day, the overall effect of lead intoxication was retardation of brain growth. The mass of both the cerebral gray and white matter was appreciably reduced in the lead rats without any reduction in cell populations. While the neuronal population was preserved, the growth of neurons was reduced and their maturation retarded. The retarded neuronal growth was characterized by the limited proliferation of processes in the neuropil and by the reduction in the number of synapses per neuron. However, synaptogenesis was neither delayed nor perturbed but reduced by the limited development of neuronal dendritic fields. The myelination was altered and its cerebral content significantly reduced. The effect of lead on myelination was one of hypomyelination. The hypomyelination appears to be primarily related to retarded growth and maturation of the neuron and is not a reflection of a defect in the myelinating glia or a delay in the initiation of myelination.