John F. Rosen’s research while affiliated with The Children’s Hospital at Montefiore (CHAM) and other places

Lead (Pb) poisoning remains a common disease among children despite successful public health efforts that have reduced its prevalence. Treatment options for children with blood Pb levels (BPbs) <45 micro g/dL are limited because chelation therapy is generally not indicated. Calcium (Ca) and Pb interactions are well documented. Competition for binding to Ca-binding proteins may underlie a mechanism for Pb absorption. The purpose of this study was to determine the role, if any, of supplemental Ca at reducing BPbs in moderately poisoned children. Children aged 1 to 6 years with BPbs 10 to 45 micro g/dL were enrolled in a double-blinded, placebo-controlled trial of the effects of Ca supplementation on BPbs. Children received either a Ca-containing liquid or an indistinguishable placebo. Dosage was adjusted biweekly on the basis of responses to a dietary Ca intake questionnaire to reach 1800 mg in the Ca-supplemented group. Samples for BPbs and measures to assess safety were collected before and after 3 months of supplementation and after an additional 3 months of follow-up. Bivariate and multiple regression analyses were performed. A total of 67 of 88 enrolled children with a mean age of 3.6 years completed 3 months of supplementation. There were no statistically significant differences between groups on hematologic and biochemical measures, including serum and urinary Ca, at any time points. The average compliance rate was estimated to be 80% for each group during the 3-month supplementation period. At enrollment, the average daily Ca intake in this group of inner-city children was greater than the recommended daily intake for age. Although BPbs declined during a 3-month period in both groups, Ca supplementation aimed at providing 1800 mg of Ca/day had no effect on the change in BPbs. Ca supplementation should not be routinely prescribed for mild to moderately Pb-poisoned children who are dietarily Ca sufficient.

Since 1983, the Bunker Hill Superfund site (BHSS) has been the second largest on US Environmental Protection Agency's (EPA) National Priority List for cleanup. Contaminants include millions of tons of Pb, Cd, Hg and As. In 1974, following a bag house fire, 22.1% of young children had blood lead levels >80 microg/dl. In the early 1980s to the present, EPA initiated the cleanup of exterior residential soils and the smelter complex. In 1999, The National Geological Service confirmed that heavy metal pollution had extended from BHSS to Lake Coeur d'Alene (already known earlier) all the way to the Spokane River in Washington State via water borne tributaries linking Idaho and Washington States. This report focuses on public health programs and their results initiated by Federal and State agencies at the BHSS. These programs include blood lead screening, educational programs, exploratory dust control plans, and land transactions. These programs and their results are then evaluated, assessed and critically discussed. The conclusion of this critical evaluation assessment is that the protection of public health has not been adequately addressed or protected by Federal and State agencies.

Lead poisoning in children was first recognized in its severe acute form, known as lead encephalopathy.1 This condition is characterized by seizures, coma, and — not infrequently — death, and it is associated with severe neurologic sequelae in survivors. Although lead encephalopathy has become rare in the past 15 to 20 years, the dangers of clinically asymptomatic lead poisoning in children have become increasingly clear. Longitudinal studies of development from birth to adolescence show that irreversible cognitive damage can occur with blood lead levels considerably lower than those typically associated with overt symptoms.2,3 Recognition of this problem has led . . .

The neurotoxicity of low-level long-term exposure to lead has a special relevance in children. An extensive database has provided a direct link between low-level lead exposure and deficits in the neurobehavioral–cognitive performance evidenced in childhood through adolescence. Electrophysiological studies showed that neurosensory processing may be affected by lead, with consequent decrease in auditory sensitivity and visuomotor performance. Lead disrupts the main structural components of the blood–brain barrier by primary injury to astrocytes with a secondary damage to the endothelial microvasculature. Within the brain, lead-induced damage occurs preferentially in the prefrontal cerebral cortex, hippocampus and cerebellum. Some characteristic clinical features of lead poisoning may be attributed to this specific anatomical pattern. The cellular, intracellular and molecular mechanisms of lead neurotoxicity are numerous, as lead impacts many biological activities at different levels of control: at the voltage-gated channels and on the first, second and third messenger systems. These effects could be related to lead's ability to interfere with the regulatory action of calcium in cell functions. Consequently, it may be assumed that lead acts as a chemical stressor and causes breakdown of the homeostatic cellular mechanisms. This is expressed in both the anatomical site and the neurotransmitter systems which are crucial in modulating emotional response, memory and learning. There is no threshold below which lead remains without effect on the central nervous system; thus, symptoms could simply be a clinical reflection of the brain regions preferentially involved. In integrating these physiological and clinical data, it may be suggested that the different mechanisms of low level lead neurotoxicity have a final common functional pathway.

In this study we examined potential limitations of relying exclusively on blood lead (BPb) levels to evaluate children with moderately elevated BPb levels (1.21-2.12 micromol/l, or 25-44 microg/dl).We tested the following hypotheses: 1) such children without elevated erythrocyte protoporphyrin (EP) levels (>=0.62 micromol/l or >/= 35 microg/dl) are unlikely to respond to a chelating agent with a brisk urinary Pb diuresis; 2) those with elevated EP levels, but low hematologic indices consistent with iron deficiency, are also unlikely to respond to a chelating agent with a robust urinary Pb diuresis; and 3) those with elevated EP levels and iron sufficiency are more likely to respond to a chelating agent. To test these hypotheses, we performed retrospective analyses of the relationships between EP concentrations, hematologic indices, and urinary Pb excretion ratios (uPbr) in moderately Pb-poisoned children undergoing the CaNa2EDTA lead mobilization test (Pb-MT). Data from 122 children were available. Urinary Pb excretion was limited in children with an EP <0.62 micromol/l (<35 microg/dl); only 5% (1/21) of Pb-MTs were positive (uPbr >=0.6). In children with an EP >=0.62 micromol/l, low hematologic indices, such as a mean corpuscular hemoglobin (MCH) <23 pg, were associated with relatively little Pb excretion (0/14 positive Pb-MTs). In contrast, 32% (28/87) of Pb-MTs were positive in children with an EP >/= 0.62 micromol/l and iron sufficiency (p<0.01 by chi-square comparison between groups with EP >/= 0.62 micromol/l and either MCH <23 pg or MCH >/= 23 pg). We conclude that only a minority of moderately Pb-poisoned children will demonstrate enhanced urinary Pb excretion in response to chelation therapy. Some of the predicted nonresponders can be readily identified by adding the EP and complete blood count to the panel of tests performed. Images Figure 1. A Figure 1. B

Lead characteristically perturbs processes linked to the calcium messenger system. This study was undertaken to determine the role of PKC in the Pb2+ induced rise of [Ca2+]i. [Ca2+]i was measured using the divalent cation indicator, 1,2-bis(2-amino-5-fluorophenoxy) ethane N, N,N',N'-tetraacetic acid (5F-BAPTA) and 19F-NMR in the osteoblast cell line, ROS 17/2.8. Treatment of cells with Pb2+ at 1 and 5 microM produced a rise in [Ca2+]i from a basal level of 125 nM to 170 nM and 230 nM, respectively, while treatment with phorbol 12-myristate 13-acetate (PMA) (10 microM), an activator of PKC, produced a rise in [Ca2+]i to 210 nM. Pretreatment with calphostin C, a potent and highly selective inhibitor of PKC activation failed to produce a change in basal [Ca2+]i and prevented any rise in [Ca2+]i in response to Pb2+. To determine whether Pb2+ acts directly on PKC, we measured the Pb2(+)-dependent activation of phosphatidylserine/diolein-dependent incorporation of 32P from ATP into histone and endogenous TCA precipitable proteins in the 100,000 X g supernatant from homogenized ROS 17/2.8 cells. The free concentrations of Pb2+ and Ca2+ were set using 5F-BAPTA; and [Ca2+] and [Pb2+] in the PKC reaction mixtures were confirmed by 19F-NMR. We found that Pb2+ activates PKC in the range of 10(-11)-10(-7) M, with an activation constant of 1.1 X 10(-10) M, whereas Ca2+ activates PKC in the range from 10(-8) to 10(-3) M, with an activation constant of 3.6 X 10(-7) M. These data suggest that Pb2+ activates PKC in ROS 17/2.8 cells and that Pb2+ activation of PKC mediates the documented rise in [Ca2+]i and, perhaps, other toxic effects of Pb2+.

In summary, LXRF estimates of Pb in tibial cortical bone have yielded highly relevant clinical data relating to the efficacy of chelation therapy with CaNa2EDTA in lead poisoned children; diagnostic approach(es) to childhood lead poisoning; and evaluations of exposure in children, teenagers, and adults in lead-exposed and non-lead-exposed suburban communities. It is anticipated that KXRF and LXRF estimates of Pb in bone will yield new information concerning the epidemiology of hypertension, osteoporosis, and the contribution of maternal Pb to the developing fetus. It would be premature to delineate the age-developmental time boundaries over which these two systems [KXRF, LXRF] can be viewed as operated optimally. Consequently, it is appropriate to view the two approaches as providing complementary information. All such information might, in fact, be required to obtain a complete exposure profile and a comprehensive framework for assessment of health risks.