Treatment of lead poisoning with an immobilized chelator comparison with conventional therapy

Lead poisoning is a global public health problem. In pregnant women it may result in developmental delays of the fetus, in children it my produce learning disability. Available chelators are nephrotoxic when eliminated as lead-chelator complexes. For safe removal of lead from the body we developed a "Lead-Hemopurifier" (L-HP), a device with an immobilized chelator. In vitro, applied to lead solutions, this device reduced the lead concentration. Applied to dogs with lead intoxication, Lead-HP-s removed lead from the blood; this was continuously replaced by lead from the bones until the skeleton was cleared from lead deposit. Treatment of lead poisoning in dogs with Lead-HP-s compared favorably with Versenate treatment of children with lead toxicity. This report demonstrates the in vivo efficiency and safety of this new detoxfication method. Methods to induce lead poisoning in dogs and procedures to identify lead released from skeletal deposits are described.     

Inorganic lead toxicology

Lead is a health hazard for all humans. Especially children under the age of six are most at risk for lead poisoning. Lead toxicity causes hematological, gastrointestinal, and neurological dysfunction. Symptoms are usually noted with blood lead greater than 2 micromoles/L. Severe or prolonged exposure may also cause chronic nephropathy, hypertension, and reproductive impairment. Lead inhibits some enzymes, alters cellular calcium metabolism, stimulates synthesis of binding proteins in kidney, brain, and bone, and slows down nerve conduction. Acute lead poisoning is relatively infrequent and results from ingestion of acid soluble lead compounds or inhalation of lead vapors but chronic exposure to low levels of the metal is still a public health issue, especially among some minorities and socioeconomically disadvantaged groups. Lead has been used since prehistoric times, and has become widely distributed and mobilized in the environment. Exposure to and uptake of this non-essential element have consequently increased. Both occupational and environmental exposures to lead remain a serious problem in many developing and industrializing countries and a public health problem of global dimensions.     

Analysis of lead in circumpulpal dentin of deciduous teeth

Absorbed lead continuously adds to the lead deposited in the vascularized circumpulpal dentin of the teeth. Thus, this dental tissue is expected to contain a lead concentration which reflects the integrated lead exposure during the time from completion of tooth formation to tooth extraction or shedding. A method has been developed to assess the lead level in the dentin surrounding the pulp chamber in deciduous teeth. Variation within the tooth is minimal, but upper medial incisors show a slightly lower lead level than do other incisors, as assessed in 714 teeth from first-grade Danish school children. This tendency was not confirmed, however, in a small number of paired teeth from the same children. The new method appears advantageous for epidemiological studies of lead neurotoxicity in children.     

Dead cattle, lead and child health

This study was carried out as part of a larger interagency investigation in response to concerns about human health following the death of three cattle from lead poisoning in an old lead mining area in Silvermines, Tipperary. Its aim was to screen for lead toxicity in the local child population. Screening consisted of measurement of blood lead concentrations and the completion of questionnaires regarding exposure to lead and general health. Pre-school and primary school children resident in four surrounding district electoral divisions (DEDs) were specifically targeted. One out of 334 (0.3%) children screened had an elevated blood lead concentration. The geometric mean lead concentration was 2.6 microg/dl which is below the intervention lead concentration of 10 microg/dl recommended by the CDC. The mean lead concentration in those aged under three years was statistically significantly higher than in those aged three years and over (3.4 microg/dl vs 2.5 microg/dl; p=0.000581). No specific health problems were identified by the questionnaires. This study concluded that the elevated environmental lead levels which were demonstrated by other agencies involved in this investigation are not currently being transferred to children. It recommends further blood screening of children in the area and ongoing education to minimise the risk of lead toxicity in the area in the future.     

Port Pirie Cohort Study: environmental exposure to lead and children's abilities at the age of four years

We studied the effect of environmental exposure to lead on children's abilities at the age of four years in a cohort of 537 children born during 1979 to 1982 to women living in a community situated near a lead smelter. Samples for measuring blood lead levels were obtained from the mothers antenatally, at delivery from the mothers and umbilical cords, and at the ages of 6, 15, and 24 months and then annually from the children. Concurrently, the mothers were interviewed about personal, family, medical, and environmental factors. Maternal intelligence, the home environment, and the children's mental development (as evaluated with use of the McCarthy Scales of Children's Abilities) were formally assessed. The mean blood lead concentration varied from 0.44 mumol per liter in midpregnancy to a peak of 1.03 mumol per liter at the age of two years. The blood lead concentration at each age, particularly at two and three years, and the integrated postnatal average concentration were inversely related to development at the age of four. Multivariate analysis incorporating many factors in the children's lives indicated that the subjects with an average postnatal blood lead concentration of 1.50 mumol per liter had a general cognitive score 7.2 points lower (95 percent confidence interval, 0.3 to 13.2; mean score, 107.1) than those with an average concentration of 0.50 mumol per liter. Similar deficits occurred in the perceptual-performance and memory scores. Within the range of exposure studied, no threshold dose for an effect of lead was evident. We conclude that postnatal blood lead concentration is inversely related to cognitive development in children, although one must be circumspect in making causal inferences from studies of this relation, because of the difficulties in defining and controlling confounding effects.     

Neonatal lead poisoning from maternal pica behavior during pregnancy

Lead toxicity has gained increasing attention in the public media because of its ubiquitous distribution in the environment and the potentially serious medical complications that it can induce, particularly in children. We present a case of an asymptomatic Hispanic woman who exhibited a unique form of pica during her pregnancy. By serendipity, she agreed to enroll into a lead screening study at our medical center when she presented to deliver her child. Her blood lead level was 119.4 microg/dL at delivery, and simultaneous measurement of the neonate's cord blood lead level was 113.6 microg/dL. The infant underwent an exchange transfusion, and the mother was treated with oral 2,3-dimercaptosuccinic acid. Both demonstrated dramatic biochemical improvement.     

Patella lead x-ray fluorescence measurements are independent of sample orientation

In vivo x-ray fluorescence bone lead measurements assess long-term lead exposure. Tibia, calcaneus, and patella are the most commonly sampled bones. Patella measurements also include lead signals from the distal femur, proximal tibia, and synovium. It is therefore important to know whether the orientation of the patella relative to the measurement system substantially affects the measured patella lead concentrations and their measurement uncertainties. This study examined whether these parameters exhibited a dependence on the orientation of the patella with respect to the measurement system, a dependence that could arise from varying nonpatella contributions. There was no effect of orientation on measured patella lead concentration, but there was a highly significant effect of orientation on the measurement uncertainty. These data do not conclusively show that there are no nonpatella contributions to a patella lead measurement; rather, that any such contributions are not a function of measurement orientation over the range of orientations considered. Further study is required if the contribution of nonpatella tissues to a patella lead XRF-measured concentration is to be fully addressed. This study also filled a gap in the literature by quantifying the within-patella (29%) and between-patella (71%) variability of measured patella lead concentrations from replicate measures of nine patellae.     

A risk evaluation of the neuropsychological effects of childhood lead toxicity

As part of a risk evaluation of the neurobehavioral toxicity of lead in children, research findings were summarized from various human epidemiological studies according to the type of design used. Irrespective of whether the research evidence being considered is from medical case series studies, case‐control, cross‐sectional retrospective cohort, or prospective longitudinal cohort research, the findings consistently support a relationship between lead exposure and cognitive impairment in children, even at lower blood levels (10 to 15 μg/dl). Furthermore, experimental research in primates suggests that these exposure levels disrupt more complex perceptual discrimination ability in subtle and permanent ways, perhaps by fundamentally disrupting attentional processes when lead alters synaptogenesis in the developing brain. If considering the research evidence in its entirety, the epidemiologic criteria are met for causality in terms of the effects of lead exposure on neurobehavioral development and attentional ability in children. We conclude that even at the 10 μg/dl blood level of lead—a level considered safe by most standards of public health policy in America today—a cause‐and‐effect relationship for neuropsychological impairment can be reasonably demonstrated. This should have significant bearing on public health policy considerations in ensuring the neuropsychological well‐being of millions of American children.     

The effect of allicin on blood and tissue lead content in mice

Previous experimental results have revealed that garlic (Alium sativum) can reduce lead toxicity and tissue lead content in lead-exposed rodents. In the present study, the effects of different doses of allicin, the main active constituent of garlic, in reducing of organ and blood lead levels were evaluated in mice exposed to 1,000 ppm of lead acetate in drinking water. Three groups of mice received allicin at doses of 12, 24, and 48 μg/kg orally (twice daily) during ongoing 14-day lead exposure. Mice were killed on experimental day 15. Allicin treatment reduced lead retention in blood and tissues. Reduction of lead concentration in blood and tissues was dose dependent. With the highest dose of allicin, the greatest rate of reduction of lead concentrations were observed in liver (73.7%), kidney (45%), brain (45%), and bone (44.4%), respectively. Liver zinc concentration was significantly reduced in all treated groups. It was concluded that allicin administered during lead exposure in mice can reduce tissue lead retention and, therefore, might have some therapeutic effect on lead poisoning.     

脑发育不同阶段慢性铅暴露对大鼠在体海马不同时间一氧化氮含量及合酶活性的影响

目的：比较脑发育不同阶段低浓度慢性铅暴露对大鼠在体海马一氧化氮含量及合酶活性的差异。方法：分别在仔鼠出生21天、42天、63天时测定对照组、断乳后暴露组、母体暴露组和持续暴露组仔鼠血铅含量和海马NO含量和NOS活性,并与对照组进行比较。结果：各暴露组在不同时间血铅含量均高于对照组（P〈0.05）。断乳后铅暴露组和持续铅暴露组NOS活性与对照组相比均有显著性差异（P〈0.05）,出生21天时明显高于对照组,而42天和63天明显低于对照组。持续暴露组NO含量与对照组相比有明显差异,出生21天时明显高于对照组,而42天和63天明显低于对照组。结论：脑发育任一阶段的慢性铅暴露均对海马NO含量和NOS活性有影响。与发育成熟海马相比,未成熟期海马对铅的神经毒性更为敏感,突触可塑性更易受损。     

Developmental effects of lead acetate on the chick embryo metanephros

The developmental effects of lead acetate were studied in the chick embryo metanephros, the third renal rudiment that acquires morphological characteristics of functioning kidney already during the prenatal life. Lead exposure was obtained by applying a lead acetate solution on the chick embryo chorioallantoic membrane at the days 9, 10 and 11 of incubation. Quantitative evaluation of the lead concentration assessed by furnace atomic absorption spectrophotometry at the days 14 and 21 of incubation demonstrated metal presence both in the chorioallantoic membrane (CAM) and in metanephros (MN). The lead concentration was higher in CAM than in MN; the metal amount was similar in the CAM of 14 and 21 day embryos, but significantly higher in the 14day embryo MN than in the 21 day embryo MN. Morphological observations on metanephros tissue of control and lead-treated embryos were performed under light, electron transmission and electron scanning microscopes. Peculiar attention was devoted to the expression of the junctional protein connexin 43, the major component of the gap junctions in the renal cells. The results indicated that lead treatment does not intervene in the general differentiation of the metanephric nephrons. The lead is reabsorbed by the proximal tubule cells that are engulfed by endocytotic vacuoles and metal deposits and show long term degenerative changes. Expression of Cx43 protein and ultrastructure of gap junctions between proximal tubule cells appeared to be unchanged. The morphological aspects of the MN corpuscles and tubules agree with the suggestion of a lead cytotoxic effect but do not corroborate, at least in this experimental model, the view of primary damage exerted by lead on the gap junctions of the renal epithelial cells.     

In vivo measurement of lead in bone using x-ray fluorescence

The factors affecting the accuracy and minimum detectable concentration of in vivo tibia lead measurement are discussed, and it is demonstrated that the use of a 109Cd source in a backscatter geometry and using the 88 keV coherently scattered photon for normalisation optimizes both criteria. The measurement is shown to be independent of variations in source-sample distance, thickness of overlying tissue and tibia size and shape. Applying the same technique in vitro to samples of human tibia and metatarsals, it is shown that the results are not significantly different (p approximately equal to 0.9) from atomic absorption spectrometry results from another laboratory. The results of Monte Carlo dose distribution calculations are presented and compared with measurements using thermoluminescent dosemeters: the mean absorbed dose to a 20 cm leg section is less than 0.1 mGy (10 mrad) and the maximum absorbed skin dose is 0.45 mGy (45 mrad). For this dose the minimum detectable lead concentration is 10 micrograms g-1. Finally, the technique has been applied to groups of normals and occupationally exposed workers, and the means have been shown to be significantly different, namely 10 and 31 micrograms g-1 respectively. In the normal subjects tibia lead correlated strongly with age (r = 0.63, p less than 0.001).     

Lead and lead toxicity in domestic and free living birds

At present, domestic and wild fauna are being exposed to aspects and factors which are foreign to the habitat in which they live. One that stands out is the enormous amount and variety of chemical compounds which, in many cases, are highly complex and which are constantly being released into the atmosphere, mainly from agricultural and industrial activity. All these substances affect some species more than others, whether they be plants or animals, from the most insignificant micro-organism to the most evolved species, among them birds. Finally, another cause of mortality in many birds is plumbism, namely death caused by the ingestion of lead. Lead has been one of the main causes of poisoning in man since ancient times due to its use in many activities although it is only recently that this toxicity has been recognized. Moreover, the use of lead pellets for shooting has resulted in the release into the environment of millions of these over many years, with serious repercussions for many bird species populations, which have ingested them either directly or indirectly. Added to this use of lead in cynegetic activities is the fate of the lead weights (sinkers or ballast) used by rod fishers, which sink to the bottom or accumulate on the banks of rivers, lakes, lagoons or reservoirs. The problem arises when these pellets or weights are ingested by birds, mainly Anatidae, which mistake them for the small stones or grit they use to triturate food in their gizzards. Small particles of lead enter the digestive tract, start dissolving in the form of lead salts, are incorporated into the bloodstream and the rest of the body, accumulate in organs like the liver or kidneys, and cause physiological or behavioural changes. When certain concentrations of lead are reached, the birds then die. If lead-poisoned birds are consumed by carrions or predators, the latter also ingest the lead so that they may also be affected or die from plumbism since, being a heavy metal, its degradation and/or elimination is very difficult. There is, therefore, no doubt that millions of birds die annually worldwide from lead poisoning (in the U.S.A., around 3?000?000), this problem being most acute in marshland. The solutions could include the introduction of legislation regulating or banning shooting, in the use of non-toxic ammunition in marshes and protected areas, the substitution of lead pellets for other non-toxic ones, such as steel, bismuth, tungsten or other suitable metals, and to go on studying other possible alternatives to end such a dramatic situation for birds all over the world.     

过氯乙烯/氧化铅填充剂在兔肾血管铸型中的应用

目的探索一种适用于兔肾血管铸型的过氯乙烯/氧化铅填充材料。方法取20%和25%过氯乙烯溶液各100mL,将20g氧化铅各一份溶于其中,配制成20%和25%的过氯乙烯/氧化铅填充剂,两种浓度的填充剂各选择6只正常家兔进行肾动脉灌注。结果20%过氯乙烯/氧化铅灌注的肾动脉显示过于密集,粗糙,欠饱满,25%过氯乙烯/氧化铅铸型标本管道饱满,粗细、疏密合理,结构显示清晰、连续、完整。结论25%过氯乙烯/氧化铅填充剂进行肾血管灌注,铸型效果好,灌注方法简便,能达到预期效果。     

An X-ray fluorescence technique for in vivo determination of lead concentration in a bone matrix.

We have previously reported the in vivo detection of lead in the skeleton of man by means of X-ray fluorescence analysis using a 740 MBq 57Co source for excitation and a 1 cm(3) Ge(Li) detector for registration of the Pb Kalpha and Kbeta radiation. The varying geometry, density and atomic composition of the tissues of interest (mainly fingers) introduce several problems in estimation of the true concentration of a given element. A two-component cylindrical finger phantom was therefore constructed from silica paraffin wax and animal bone ash. The diameter of the finger bone was estimated from X-ray examinations in two orthogonal projections. The bone mineral concentration was then estimated from the quotient of the number of coherent and Compton scattered primary photons. The lead concentration in the finger bones was then derived from a measurement on a finger phantom made of silica paraffin wax and bone ash with the same size and bone mineral concentration as the real bone. The minimum detectable lead concentration in a finger bone was 14 microgram g(-1) for 15 min measuring time. The lead concentration measured in workers from a metal industry was found to be in the range of 40-100 microgram g(-1).     

Long-term consequences of prenatal exposure to lead on brain development in rats

Administration of singe doses of lead citrate (200 mg/kg) to pregnant rats (on day 18 of pregnancy) was followed by the appearance of destructive changes in brains at age 40 days, with cysts, foci of gliocyte proliferation, pyknotic neurons, and decreases in NADH and NADPH diaphorase activities in neocortical and hippocampal neurons. Decreases in the density of neurons in the cortex and decreases in cortical thickness were also observed. The intensity of free-radical oxidation in the cortex increased three-fold, along with a 3.9-fold increase in the concentration of lipid peroxides, providing evidence of oxidative stress. The possible mechanisms by which these alterations develop are analyzed. __________ Translated from Morfologiya, Vol. 131, No. 1, pp. 27–31, January–February, 2007.     

Neoplastic transformation of human bronchial cells by lead chromate particles

Particulate hexavalent chromium (Cr(VI)) is a well-established human lung carcinogen with widespread exposure among people in occupational settings and the general public. However, no studies have examined the chromate-induced malignant transformation of human lung epithelial cells, its predominant target. Human papillomavirus-immortalized human bronchial epithelial (BEP2D) cells were used to better understand the mechanisms involved in human bronchial carcinogenesis induced by particulate chromate. We found that aneuploid cells increased in a concentration-dependent manner after chronic exposure to lead chromate. Moreover, chronic exposure to lead chromate induced BEP2D cell transformation. Transformed BEP2D cells developed through a series of sequential steps, including altered cell morphology, loss of cell contact inhibition and anchorage-independent growth. Specifically, a 5-day exposure to lead chromate induced foci formation with 0, 1, 5, and 10 microg/cm2 lead chromate inducing 0, 7, 3, and 15 foci in 10 dishes. Anchorage independence was observed in cell lines derived from these foci. These foci-derived cells also showed centrosome amplification and increases in aneuploid metaphases. Our study demonstrates that particulate Cr(VI) is able to transform human bronchial epithelial cells, and that chromosome instability may play an important role in particulate Cr(VI)-induced neoplastic transformation.     

Contribution of lead to hypertension with renal impairment

Hypertension of unknown cause is generally termed "essential." Because hypertension has long been considered a possible complication of lead poisoning and the EDTA lead-mobilization test has proved to be a sensitive indicator of excessive body stores of lead, we used this test to evaluate cumulative past lead absorption in 48 men diagnosed as having essential hypertension. Patients who had hypertension with reduced renal function (i.e., serum creatinine level greater than 1.5 mg per deciliter [133 mumols per liter]) had significantly larger amounts of mobilizable lead than did patients who had hypertension without renal impairment. The increase in mobilizable lead was not due to the renal disease itself, since 22 control patients without a history of essential hypertension but with comparable renal impairment from known causes excreted significantly less lead chelate during the three-day test. These data suggest that lead may have an etiologic role in the renal disease of some patients usually designated as having "essential" hypertension.     

Tibial lead determination by 99Tcm radiopharmaceutical x-ray fluorescence

The feasibility of measuring tibial lead concentration by x-ray fluorescence with an internal 99Tcm labelled bone-seeking radiopharmaceutical was investigated using phantoms containing known values of lead concentration and 99Tcm activity. The minimum detectable concentration (MDC) at two standard deviations based on the counts in the Kalpha1 peak of 10.9 microg Pb ml(-1) was estimated to correspond to an MDC for an individual within a range of approximately 8-15 microg Pb (g bone mineral)(-1) if the counts from all four K x-ray peaks were included. Due to its much greater dose compared to an external source, the MDC of this internal source technique would have to be reduced before it could be used for measurements of occupationally or environmentally exposed individuals other than as an adjunct for a patient undergoing a bone scan. Methods of achieving such a reduction include increasing the acquisition time and the number of HPGE detectors, and optimizing the design of their collimators.     

Alterations in consummatory behavior of mice produced by dietary exposure to inorganic lead.

Mice suckled by mothers given tap water and by mothers given a 5 mg/ml lead acetate solution during lactation were given a choice between tap water and a lead acetate solution after lactation. All offspring demonstrated an immediate aversion to the lead acetate solution. The offspring from the mothers receiving lead acetate during lactation demonstrated a greater aversion to the lead acetate solution than did the offspring from mothers receiving tap water. In addition, the lead acetate offspring drank more total fluid (tap water plus lead acetate solution) after weaning than the control offspring. The results indicate both learned and unlearned changes in motivation for fluid following ingestion of lead via the mother's milk in infancy.