Tibia lead levels and methodological uncertainty in 12-year-old children.

In vivo bone lead measurements with 109Cd-based K-shell X-ray fluorescence (XRF) have been used to assess long-term lead exposure in adults. Tibia lead levels were measured in 210 children (106 boys, 104 girls) of 11-12(1/2) years of age in a lead smelter town and in a control (nonexposed) town. Tibia lead levels, methodological uncertainties, and models of some of the factors influencing them are presented. 109Cd-based K-shell XRF tibia lead methodological uncertainty in children is comparable to that in adults.

Alteration of iron homeostasis following chronic exposure to manganese in rats.

Recent studies suggest that manganese-induced neurodegenerative toxicity may be partly due to its action on aconitase, which participates in cellular iron regulation and mitochondrial energy production. This study was performed to investigate whether chronic manganese exposure in rats influenced the homeostasis of iron in blood and cerebrospinal fluid (CSF). Groups of 8-10 rats received intraperitoneal injections of MnCl2 at the dose of 6 mg Mn/kg/day or equal volume of saline for 30 days. Concentrations of manganese and iron in plasma and CSF were determined by atomic absorption spectrophotometry. Rats exposed to manganese showed a greatly elevated manganese concentration in both plasma and CSF. The magnitude of increase in CSF manganese (11-fold) was equivalent to that of plasma (10-fold). Chronic manganese exposure resulted in a 32% decrease in plasma iron (p<0.01) and no changes in plasma total iron binding capacity (TIBC). However, it increased CSF iron by 3-fold as compared to the controls (p<0.01). Northern blot analyses of whole brain homogenates revealed a 34% increase in the expression of glutamine synthetase (p<0.05) with unchanged metallothionein-I in manganese-intoxicated rats. When the cultured choroidal epithelial cells derived from rat choroid plexus were incubated with MnCl2 (100 microM) for four days, the expression of transferrin receptor mRNA appeared to exceed by 50% that of control (p<0.002). The results indicate that chronic manganese exposure alters iron homeostasis possibly by expediting unidirectional influx of iron from the systemic circulation to cerebral compartment. The action appears likely to be mediated by manganese-facilitated iron transport at brain barrier systems.

Dietary iron, animal fats, and risk of Parkinson's disease.

BACKGROUND: Recent studies have proposed a role for diet in Parkinson's disease (PD). PD is characterized by a high deposition of iron and a low concentration of ferritin in the substantia nigra. Few data in the literature are available on the possible role of dietary iron in the development of PD. METHODS: In a population-based, case-control study, we addressed the hypothesis that high dietary iron intake was associated with PD. We assessed dietary iron intake with a semiquantitative food-frequency questionnaire in 104 PD patients and 352 control subjects, frequency matched for age and gender. We also studied the association of PD and dietary iron and animal fat intake in the presence of different iron stores measured by transferrin saturation. RESULTS: No significant differences were observed between patients' and control subjects' dietary intake of iron from food or supplements (odds ratio [OR] for the highest quartile of intake, 0.9; 95% confidence interval [95% CI], 0.6, 1.3; p for trend = 0.60). Among those with low transferrin saturation levels (lower 50%), the odds ratio for PD associated with animal fat intake was ninefold higher than the risk of those with low intake (OR, 9.0; 95% CI, 2.7-29.9). Among those with high transferrin saturation, risk of PD was two times higher (relative risk, 1.9; 95% CI, 0.5-7.2) for those who reported high intake of animal fat compared with those who reported low intake. CONCLUSION: Dietary iron intake after caloric adjustment was not associated with an increased risk of PD. However, the previously described association between animal fat intake and PD was modified by iron level stores as measured by transferrin saturation. These observations suggest that dietary fat and a systemic defect in iron metabolism may act synergistically in the process of lipid peroxidation in PD.

Hyperproduction of erythropoietin in nonanemic lead-exposed children.

Lead (Pb) poisoning has numerous effects on the erythropoietic system, but the precise mechanism whereby high dose exposure causes anemia is not entirely clear. We previously reported that Pb exposure is associated with depressed serum erythropoietin (EPO) in pregnant women residing in a Pb mining town and in a nonexposed town in Kosovo, Yugoslavia. In a prospective study, we tested the hypothesis that blood Pb concentration (BPb) may be associated with depressed EPO in children. BPb, hemoglobin (Hgb), and serum EPO were measured at ages 4.5, 6.5, and 9.5 years in 211, 178, and 234 children, respectively. At 4.5 years of age, mean BPbs were 38.9 and 9.0 microg/dl in the exposed and nonexposed towns, respectively; BPbs gradually declined to 28.2 and 6.5 microg/dl, respectively, by age 9.5 years. No differences were found in Hgb at any age. At age 4. 5 years, a positive association between BPb and EPO (beta = 0.21; p = 0.0001), controlled for Hgb, was found. The magnitude of this association declined to 0.11 at age 6.5 years (p = 0.0103) and 0.03 at age 9.5 years (p = 0.39). These results were confirmed using repeated measures analyses. We concluded that in Pb-exposed children, the maintenance of normal Hgb requires hyperproduction of EPO. With advancing age (and continuing exposure), this compensatory mechanism appears to be failing, suggesting a gradual loss of renal endocrine function due to Pb exposure.

Systemic iron metabolism and mortality from Parkinson's disease.

Six measures of systemic iron metabolism were used to predict mortality among 103 patients with Parkinson's disease and 353 controls followed in a longitudinal study. Adjusting for gender, education, ethnicity, presence of dementia, and extrapyramidal signs, transferrin receptor concentration was strongly associated with mortality in patients with PD but not controls. This increase in serum transferrin receptor concentration before death suggests that the previously observed perturbation in iron metabolism continues throughout the disease course.

Lead exposure promotes translocation of protein kinase C activities in rat choroid plexus in vitro, but not in vivo.

Lead (Pb) exposure reportedly modulates PKC activity in brain endothelial preparations, which may underlie Pb-induced damage at the blood-brain barrier. Our previous work indicates that Pb accumulates in the choroid plexus and causes dysfunction of this blood-cerebrospinal fluid (CSF) barrier. The present studies were undertaken to test the hypothesis that Pb in the choroid plexus may alter PKC activity and thus affect the functions of the blood-CSF barrier. When choroidal epithelial cells in a primary culture were exposed to Pb (10 microM in culture medium), the membrane-bound PKC activity increased by 5.2-fold, while the cytosolic PKC activities decreased, an indication of the induction of PKC translocation by Pb. The effect of Pb on cellular PKC was concentration dependent in the range of 0.1-10 microM. We further evaluated PKC activity of the choroid plexus in rats chronically exposed to Pb in the drinking water (control, 50 or 250 micrograms Pb/ml) for 30, 60, or 90 days. Two-way analysis of variance revealed a significant age-related decline of PKC activities in both cytosol and membrane of the choroid plexus. However, Pb treatment did not alter plexus PKC activities. In addition, we found that short-term, acute Pb exposure in rats did not significantly change PKC activities nor did it affect the expression of PKC isoenzymes in the choroid plexus. Our results suggest that Pb exposure may promote the translocation of PKC from cytosol to membrane in rat blood-CSF barrier in vitro, but not in vivo.

Lead exposure and intelligence in 7-year-old children: the Yugoslavia Prospective Study.

For a prospective study of lead exposure and early development, we recruited pregnant women from a lead smelter town and from an unexposed town in Yugoslavia and followed their children through 7 years of age. In this paper we consider associations between lifetime lead exposure, estimated by the area under the blood lead (BPb) versus time curve (AUC7), and intelligence, with particular concern for identifying lead's behavioral signature. The Wechsler Intelligence Scales for Children-Version III (WISC-III) was administered to 309 7-year-old children, 261 of whom had complete data on intelligence, blood lead, and relevant sociodemographic covariates (i.e., Home Observation for the Measurement of the Environment (HOME), birth weight, gender, sibship size, and maternal age, ethnicity, intelligence, and education). These showed anticipated associations with 7-year intelligence, explaining 41-4% of the variance in Full Scale, Performance, and Verbal IQ. Before covariate adjustment, AUC7 was unrelated to intelligence; after adjustment, AUC7 explained a significant 2.8%-4.2% of the variance in IQ. After adjustment, a change in lifetime BPb from 10 to 30 micro/dl related to an estimated decrease of 4.3 Full Scale IQ points; estimated decreases for Verbal and Performance IQ were 3.4 and 4.5 points, respectively. AUC7 was significantly and negatively related to three WISC-III factor scores: Freedom from Distractibility, Perceptual Organization, and Verbal Comprehension; the association with Perceptual Organization was the strongest. Consistent with previous studies, the IQ/lead association is small relative to more powerful social factors. Findings offer support for lead's behavioral signature; perceptual-motor skills are significantly more sensitive to lead exposure than are the language-related aspects of intelligence.

Altered systemic iron metabolism in Parkinson's disease.

Iron deposition in the substantia nigra in Parkinson's disease has been associated with an increase in lactoferrin receptors and a reduction in ferritin concentration. This accumulation of iron in the brain may accelerate free radical formation, lipid peroxidation, and neuronal death. Remarkably, there are few data available concerning systemic iron metabolism in Parkinson's disease. We measured total iron binding capacity and circulating iron, ferritin, transferrin, and transferrin receptors; calculated transferrin saturation; and estimated dietary iron intake in patients with idiopathic Parkinson's disease and in controls. Concentrations of circulating iron, ferritin, and transferrin as well as total iron binding capacity and transferrin saturation were significantly lower in patients than controls. There were no differences in transferrin receptors or dietary intake of iron. The decrease in levels of systemic ferritin and transferrin and the total iron binding capacity parallels observations in a Parkinson's disease brain, but the reductions in serum iron concentrations and transferrin saturation do not, and were unexpected. These results suggest the existence of a defect in the systems that regulate the synthesis of the major proteins of iron metabolism in the liver as well as the brain in Parkinson's disease that may, over time, expedite entry of iron into the brain and decrease iron in the extracellular compartment.

Blood lead and blood pressure in young children.

We examined associations between blood lead concentration (BPb) and blood pressure in 282 children age 5.5 years, residing in an exposed or unexposed town in Kosovo, Yugoslavia. Mean BPb in the exposed town was 37.3 micrograms per dl (standard deviation = 12.0 micrograms per dl) and in the unexposed town was 8.7 micrograms per dl (standard deviation = 2.8 micrograms per dl). After adjustment, a 10 micrograms per dl increase in BPb was associated with a 0.5 (95% CL = -0.2, 1.3) mmHg increase in systolic and a 0.4 (95%, CL = -0.1, 0.9) mmHg increase in diastolic blood pressure. These associations, although compatible with no relation, are similar to those observed in adults; and the data are most consistent with a small association between BPb and blood pressure.

A human in vivo model for the determination of lead bioavailability using stable isotope dilution.

Beverages stored in lead-crystal glass accumulate extraordinary concentrations of lead. We obtained a lead-crystal decanter manufactured with lead from Australia, where the ratio of 206Pb/207Pb is distinctly different from that in the United States. We sought to determine the bioavailability of crystal-derived lead, using the technique of stable isotope dilution in blood. We conducted a single-dose, nonrandomized cross-over study in which participants were admitted to the Clinical Research Center twice, 1 week apart. During the first admission, subjects ingested sherry obtained from the original bottle. During the second admission, they ingested sherry that had been stored in the crystal decanter and that had achieved a lead concentration of 14.2 mu mol/l. After ingesting decanter-stored sherry, mean blood lead rose significantly (p = 0.0003) from 0.10 to 0.18 mu mol/l, while mean 206Pb/207Pb fell from 1.202 to 1.137 (p = 0.0001). On average, 70% of the ingested dose of lead was absorbed. We conclude that lead derived from crystal glass is highly bioavailable; repeated ingestions could cause elevated blood lead concentration. The technique of stable isotope dilution lends itself to the study of the bioavailability of lead in other matrices, including soil.

Controlled study of meso-2,3-dimercaptosuccinic acid for the management of childhood lead intoxication.

We examined the efficacy and safety of meso-2,3-dimercaptosuccinic acid (DMSA) in children with markedly elevated blood lead (BPb) concentrations. Among 19 children with BPb concentrations of 50 to 69 micrograms/dl (2.41 to 3.33 mumol/L) who received a 5-day inpatient oral course of DMSA (1050 mg/m2 per day), the mean BPb concentration decreased by 61%; in four who received calcium disodium ethylenediaminetetraacetic acid (CaNa2EDTA) (1000 mg/m2 per day intravenously), it decreased by 45% (p less than 0.0007). Urinary lead excretion was comparable in both groups. Treatment with DMSA was more effective than treatment with CaNa2EDTA in restoring metabolic activity to the heme pathway and was well tolerated even among nine patients who received concomitant iron supplementation and two who had homozygous deficiency of glucose-6-phosphate dehydrogenase. On discharge, these 19 children received either no chelation therapy or DMSA, 350 or 700 mg/m2 per day for 14 days on an outpatient basis. After 14 days the mean BPb values for the no-chelation, low-DMSA, and high-DMSA groups were 73%, 66%, and 50% of the pretreatment values, respectively. We conclude that a 5-day oral course of DMSA is effective in the treatment of children with severe lead poisoning. In addition, on an outpatient basis the administration of DMSA, 700 mg/m2 per day, is capable of delaying the typical rebound in BPb values and should ultimately reduce the need for repeated hospitalizations.