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Leading change is leading creativity.

Leadership is the leading of creativity which leads to creative change. To innovate or die is the question that faces our health care future. It is no longer enough for us to operate with just our serial, mathematical thinking. We must also be concerned about the spirit and the heart and how we integrate this into whole brain thinking. The challenge for us is to constantly transform and rewire our brains through the creativity process and to rewire the processes of the places where we work. We know that we can cultivate and energize our organizations through the interplay of serial, parallel, and quantum thinking processes. But we can't wait. Health care and the world of nursing are changing rapidly. We need the creative processes to build the change needed for the future for the care of our patients.

Creativity↗

Monitoring blood lead levels in workers overexposed to occupational lead: an analysis of Israeli data.

In a retrospective cohort study, we followed the blood lead [Pb(B)] and zinc protoporphyrin (ZPP) determinations of 292 workers found to have Pb(B) levels above the biological exposure index (BEI) during 1987-1993. The results indicated that (a) 22.6% of these workers were never retested for Pb(B) during the follow-up period; (b) 38.5% of the workers tested in the first year of the follow-up continued to exhibit Pb(B) levels above the BEI (84.7% of them also had ZPP > or = 100 micrograms/dl); (c) about 25% of the remaining cohort had at least one more result above the BEI during the fourth, fifth, and sixth years of follow-up; and (d) the incidence density rate of recurrence of Pb(B) concentrations above the BEI was 0.236. We recommend the establishment of a target value lower than the BEI that should be reached before the reinstatement of the overexposed worker. In our view this target value, combined with an efficient control of industrial hygiene conditions, will decrease the rate of recurrence of overexposure.

Cohort Studies↗

The effects of CaNa(2)EDTA on brain lead mobilization in rodents determined using a stable lead isotope tracer.

Studies have demonstrated the efficacy of CaNa(2)EDTA for reducing lead (Pb) levels in blood and soft tissues, including brain. However, a concern remains that a single dose of CaNa(2)EDTA may cause a significant increase in brain Pb levels due to a redistribution of endogenous Pb. Here we utilized a rodent model of Pb exposure in combination with a sensitive stable Pb isotope tracer methodology to assess the effects of CaNa(2)EDTA chelation treatment on the redistribution of Pb in brain, blood, kidney, and bone tissues. Thirty-two adult female albino rats (n = 6-7 animals/group) were exposed to 100 microg Pb/mL in drinking water for 4 weeks. Stable (204)Pb tracer was administered via i.p. injection over 2 days prior to chelation. CaNa(2)EDTA was administered i.p. at a dose of 150 mg/kg/day for 1 to 5 days. Statistical differences were evaluated with univariate ANOVA. Under the Pb exposure and chelation treatment regimens utilized here, there was no evidence of a measurable redistribution of endogenous Pb (as total Pb or labile (204)Pb tracer) into the brain after a single CaNa(2)EDTA dose. Further, CaNa(2)EDTA was not efficacious in measurably reducing brain or bone Pb levels, although brain levels of labile (204)Pb tracer were significantly reduced after 5 days of chelation. CaNa(2)EDTA treatment was effective in significantly reducing both blood and kidney Pb levels. Overall, these data substantiate the efficacy of CaNa(2)EDTA for reducing soft tissue Pb levels, but not total brain Pb, and they do not support concern for a transient increase in brain Pb levels with treatment.

Animals↗

Efficacy of succimer chelation for reducing brain lead in a primate model of human lead exposure.

The extent to which succimer (meso-2,3-dimercaptosuccinic acid [DMSA], Chemet) reduces brain lead (Pb) levels may be a primary consideration in evaluating its efficacy for reducing neurotoxicity. Clinical research in this area has been hampered by the need to use blood Pb levels as the index of treatment efficacy, despite the fact that brain Pb level is the exposure parameter of greater relevance to cognitive outcomes. Here, a nonhuman primate model of human Pb exposure was used to determine: (1) The efficacy of oral succimer for reducing brain Pb derived from chronic or recent exposures, and (2) The extent to which blood Pb levels reflect brain Pb prior to and following chelation. Adult rhesus monkeys were chronically exposed to Pb orally for 5 weeks to reach and maintain a target blood Pb level of 35-40 microg/dL. Chelation of Pb from recent exposures was assessed using a stable (204)Pb isotope tracer administered over 4 days prior to treatment. Immediately prior to chelation, a prefrontal cortex (PFC) biopsy was collected to determine pretreatment brain Pb levels. Subsequently, monkeys were assigned to vehicle (n = 5) or succimer (n = 6, 30 mg/kg/day x 5 days followed by 20 mg/kg/day x 14 days) groups. Blood and brain PFC, frontal lobe (FL), hippocampus (H), and striatum (S) were analyzed for total Pb and (204)Pb tracer concentrations by magnetic sector inductively coupled plasma-mass spectrometry. There were no measurable differences in brain Pb concentrations between the succimer and vehicle groups, indicating that succimer treatment was not efficacious in reducing brain Pb levels. In contrast, the cessation of Pb exposure significantly reduced brain (PFC) Pb ( approximately 34%) when compared to pretreatment levels (succimer and vehicle groups). Pb concentrations also varied among brain regions (PFC > FL approximately H > S). Finally, pretreatment PFC Pb concentrations were significantly correlated with the integrated blood Pb level (AUC) over the Pb exposure period, but not with the single pretreatment blood Pb collected concurrently with the PFC biopsy. Following treatment, blood Pb levels correlated only with Pb in the PFC, and not the other brain regions measured (FL, H, S). These data indicate that, under the conditions of this study, succimer treatment did not reduce brain Pb levels beyond the cessation of Pb exposure alone. Moreover, a single blood Pb measurement may be a poor predictor of brain Pb levels, reflecting limitations in the use of blood Pb level as an indicator of treatment efficacy.

Animals↗

Influence of Ca, humic acid and pH on lead accumulation and toxicity in the fathead minnow during prolonged water-borne lead exposure.

The present study examines the influence of Ca2+ as (CaSO4), dissolved organic carbon (DOC) and pH on chronic water-borne lead (Pb) toxicity to the larval fathead minnow (Pimephales promelas) under flow-through conditions. The 30 day LC50 for low hardness basic test water (19 mg CaCO3 L(-1)) was 39 (range: 27-51) microg dissolved Pb L(-1) and was greatly increased by increasing concentrations of CaSO4 and DOC to as much as 1903 (range: 1812-1992) mug dissolved Pb L(-1). Both reduced and increased pH (6.7 and 8.1, respectively) compared to control pH of 7.4 appeared to increase Pb toxicity substantially. Whole body Pb accumulation did not reflect water chemistry and thus exhibited no correlation with Pb induced mortality. One possible explanation for this lack of correlation is that mortality occurred predominantly during the first 4-6 days of exposure, whereas Pb accumulation was determined in surviving fish at the end of 30 days of exposure. Chronic Pb exposure resulted in a general iono-regulatory disturbance affecting K+, Na+ and Ca2+ homeostasis. However, recovery of Na+ and K+ levels and reversal of effects on Ca2+ homeostasis during continued exposure strongly suggest fathead minnow can acclimate to Pb. The gills accumulate the highest Pb concentrations during chronic exposure but the skeleton contains the largest mass of Pb by contributing up to approximately 80% of whole body Pb. In conclusion, water chemistry characteristics like Ca2+ and DOC should be considered for chronic water quality criteria.

Animals↗

Lead mobilization during calcium disodium ethylenediaminetetraacetate chelation therapy in treatment of chronic lead poisoning.

It has long been established that chronic lead (Pb) poisoning is a cause of renal insufficiency. However, although easily diagnosed, there is still no treatment available that will revert this type of poisoning. We report a study performed on 56 male Wistar rats administered Pb in drinking water (500 ppm Pb acetate) over a 90-day period. Twenty-one non-Pb-exposed animals served as the control group. Seven animals from each group were killed days 60 and 90. At the end of the 90-day period, 21 of the Pb-exposed animals were treated with disodium monocalcium EDTA (50 mg/kg/d for 5 days) intraperitoneally and 21 animals were administered serum saline by the same route. Three treatment courses were administered, separated by 9 days free of treatment. Seven animals from each subgroup were killed at the end of each treatment course. Pb levels were determined in blood, urine, liver, brain, kidney, and bone. Treatment with EDTA led to a greater and more rapid reduction in Pb contents in the brain and kidney. The decrease in hepatic Pb levels in the treated group of animals was similar to that in the group administered placebo. Bone Pb levels also failed to show a response to the chelating agent. Use of EDTA appears to result in a reduction in Pb deposits in such critical organs as the kidney and brain. However, the chelating agent does not seem to have access to bone Pb deposits, such that the skeleton becomes a permanent source of poisoning for other tissues.

Animals↗

Chronic oral administration of rhamnogalacturonan-II dimer, a pectic polysaccharide, failed to accelerate body lead detoxification after chronic lead exposure in rats.

Lead is a ubiquitous heavy metal and its toxicity remains an important public health issue. In previous work, we reported that ingestion of rhamnogalacturonan-II dimer (dRGII), a pectic polysaccharide, may decrease intestinal absorption and status of Pb in rats. Here, we evaluated the potential detoxifying effect of different doses of dRGII after chronic oral Pb exposure in rats. For this purpose, six groups of ten male Wistar rats weighing 150g were treated as follows: group A received a semi-purified control diet for 6 weeks; groups B, C, D, E and F received the same diet plus 3 mg Pb (as acetate) for 3 weeks. Group B was then killed. Groups C, D, E, and F continued to receive the semi-purified control diet containing 0, 2, 6 or 18g dRGII/kg diet for 3 additional weeks. During the last 5 d, a Pb conventional balance study was performed. Rats were then anaesthetized and tissues were sampled for Pb and essential minerals assay. The results showed that residual Pb in the added dRGII was not available for absorption. However, the added dRGII failed to induce any significant increase in faecal or urinary Pb excretion. Consequently, at the end of the study the intestinal Pb absorption and balance remained unchanged in the animals receiving the different doses of dRGII. In line with this, we showed that dRGII administration was not effective in decreasing tibia or kidney Pb levels in rats. In conclusion, Pb complexed by dRGII in fruits and vegetables and fruit juice is thus mostly unavailable for intestinal absorption. However, the addition of dRGII after chronic Pb exposure does not help Pb detoxification.

Analysis of Variance↗

Histological effects and lead concentrations in tissues of adult male ringed turtle doves that ingested lead shot.

Adult male ringed turtle doves (Streptopelia risoria) were administered 0 or 4-110 mg lead shot and/or were exposed to cold temperatures (6 +/- 1 degrees C). Five of the seven doves that ingested shot and were exposed to cold died. Doves that ingested shot and were not exposed to cld (21 +/- 1 degrees C) had no mortality after 9 d, but several birds had seizures. Tissues were examined microscopically for lesion. Doves ingesting shot consistently had Pb intranuclear inclusion bodies in cells of the proximal convoluted tubules, except if death occurred 48 h after shot ingestion. In such cases as in cold-exposed, Pb-treated birds), intracytoplasmic inclusions were detected. Hemosiderin loading in kupffer cells and rarely in hepatocytes was observed in doves ingesting Pb whether they were exposed to a normal temperature or to cold. it appeared that ingestion of shot could abruptly disturb spermatogenesis in ringed turtle doves. The seminiferious tubules were often devoid of spermatozoa in doves ingesting Pb.

Animals↗

Lead content of brain tissue in diffuse neurofibrillary tangles with calcification (DNTC): the possibility of lead neurotoxicity.

Diffuse neurofibrillary tangles with calcification (DNTC) is a form of presenile dementia, characterized pathologically by fronto-temporal atrophy with neurofibrillary tangles (NFTs), neuropil threads and Fahr-type calcification, in which no senile plaques are observed. As already noted, chronic exposure to lead (Pb) might be one of the etiological factors of Fahr-type calcification. Until now, there have been no reports in which Pb concentration has been quantified in DNTC brains. We examined the concentration of Pb in fresh-frozen brain tissue and in 10% formalin-fixed brain tissue from six cases of DNTC, four cases of Alzheimer's disease, and in nine non-demented elderly controls by flameless atomic absorption spectrometry, and demonstrated a high concentration of Pb in DNTC brains. Although it remains unclear how these findings are related to the formation of NFTs, they suggest that Pb neurotoxicity may be involved in the pathogenesis of DNTC.

Aged↗

Brainstem neural conduction biomarkers in lead-exposed children of Andean lead-glaze workers.

Pediatric lead (Pb) intoxication remains a major medical challenge in some developing countries where Pb is used in glazing industries. Pb exposure is reported to induce neurophysiological and neurocognitive impairment in children. However, the threshold and level of Pb intoxication necessary to induce neuropathology have not been established. Brainstem auditory evoked responses (BAERs) have been used widely as a sensitive biomarker for Pb-induced neurotoxicity. In this field study, BAER neural conduction time was used as a biomarker for central nervous system impairment in Andean children living in areas of high Pb contamination from Pb-glazing cottage industries. The mean Pb level in blood (PbB) for 112 Pb-exposed children was 49.25 microg/dL (SD, 270 microg/dL range, 4.4-119.1 microg/dL). Although BAERs in some children showed prolongations in neural conduction times, regression analyses revealed no significant correlation between PbB levels and BAER interpeak conduction times for 112 replicate recordings (I-III, r = 0.008, P = 0.93; II-V, r = 0.13, P = 0.16; I-V, r = 0.09, P = 0.35; and I-VI, r = 0.14, P = 0.27). A subgroup of 69 children in the study area with PbB levels in the United States Centers for Disease Control and Prevention (CDC) medical intervention-emergency classifications (CDC IV and V; mean, 67.0 microg/dL, SD, 15.8 microg/dL; range, 45.1-119.1 microg/dL) showed no significant correlation between PbB and BAER interpeak interval and no significant differences in BAER than a normal subgroup (t test, P > 0.05). The results demonstrate some evidence of abnormal possibly Pb-induced neural conduction delays in some individual children but a remarkable overall neurobiological functioning in severe, chronic pediatric Pb intoxication without measurable impairment of brainstem auditory nuclei and tracts, as evidenced by neurophysiological conduction times. The findings also demonstrate the variability in the threshold level and duration of Pb exposure necessary to induce brainstem neuropathology.

Adolescent↗

The distribution of lead in milk and the fate of milk lead in the gastrointestinal tract of suckling rats.

Milk can be a significant source of lead (Pb) for young mammals, including humans. Certain essential trace elements have previously been shown to be specifically associated with particular milk components and such associations often increase bioavailability. Thus, the first goal of this study was to determine the distribution of Pb in cream, casein, and whey fractions of various milks under various conditions using 203Pb as a tracer. In rat milk almost 90% of the Pb was found to be associated with the casein micelles, regardless of: 1) whether the milk was labeled in vivo or in vitro; b) whether the milk was fresh or frozen; and c) the added concentration of Pb (over the range 0.01-75 micrograms/ml). The remainder of the Pb was approximately equally distributed between cream and whey. A virtually identical pattern of Pb distribution was observed with bovine milk. Pb added to infant formula also associated predominantly with casein micelles, although the Pb content of this fraction was significantly less than with rat and bovine milks. The second goal of the study was to determine if Pb remained associated with casein as it traversed the gastrointestinal tract of infant rats. For this purpose, rat pups aged 15-16 days were gavaged with 203Pb-labeled rat milk, and lumenal contents from the stomach and small intestine were collected 2 h later. Differential centrifugation of the homogenized lumenal contents showed that in the stomach the Pb was associated primarily with the casein curd. By the time chyme reached the distal small intestine, Pb was found predominantly in a fraction that was not precipitable by high-speed centrifugation (thus, not intact casein micelles), but was nondialyzable. We conclude that Pb in milk is protein bound and remains this way as it traverses the stomach and proximal small intestine of the infant rat.

Animals↗

Intestinal accumulation of lead salts and milk lead by suckling rats.

Absorption of lead is known to be enhanced during infancy. In this study, the sites of intestinal accumulation of Pb by suckling rats have been determined under various conditions using 203Pb as a tracer. When 203Pb was administered intragastrically (IG) as a soluble salt, accumulation occurred primarily in the duodenum, regardless of dose and vehicle. In contrast, when rat pups suckled from a dam which had received 203Pb, the only region of the small intestine showing accumulation of radioactivity was the ileum. To confirm that these differences were not related to the route of administration, rat milk was labeled with 203Pb and was then used for IG administration. Once again, accumulation (4 hr post-administration) was confined to the ileum. When the dose was increased 10-fold, milk Pb displayed some accumulation in duodenal tissue, but very much less than that of soluble Pb at the same time and dosage. At 20 hr postadministration, there was negligible 203Pb in any region of the small intestine following administration as a soluble salt, but substantial retention in ileal tissue following administration in milk. The strikingly different patterns of intestinal accumulation obtained with Pb salts as compared with milk Pb suggest different modes of absorption of Pb ingested in these two forms.

Animals↗

Blood lead and hemoglobin levels in Andean children with chronic lead intoxication.

This study investigated blood lead (PbB) and hemoglobin (HbB) levels in 88 children (42 females and 46 males; ages: 2-15 years; mean age: 7.2) with chronic Pb exposure, living in a highly Pb-contaminated Andean village at above 2800 meters. The mean PbB level for 88 venous blood samples was 43.2 microg/dl (SD: 25.1; range: 6.2 - 128.2 microg/dl) measured by ICP-MS, and 42.0 microg/dl (SD: 26.0; range: 5.0 - 130.0 microg/dl) by GFAAS analysis. The mean PbB level for the 42 females was 41.0 microg/dl and for 46 males, 45.0 microg/dl. Multiple regression analysis showed a significant gender by age interaction (R2 = 0.099; F = 4.173, p = 0.044), indicating a relationship between age and PbB level for males, but not for females. Simple regression analysis showed a statistically significant positive correlation between PbB levels and age for males (r = 0.416, p = 0.004), but not for females (r = -0.042, p = .793). The measured mean HbB level for the 88 children was 12.6 g/dl (12.5 g/dl for females and 12.8 g/dl for males) and lower than expected for children living in the Ecuadorian Andes. The mean altitude-corrected HbB level was 10.9 g/dl (10.8 g/dl for females and 11.1 g/dl for males). A significant inverse correlation between PbB and HbB levels was observed for the group of 88 children (r = -0.292, p = 0.006). Multiple regression analyses indicated no significant age and gender interaction (R2 = 0.014; F = 0.025, p = 0.876) for HbB levels. In conclusion, the results of this investigation indicate that the children in this Pb-contaminated, high altitude study area had chronic elevated PbB levels, which increased with age for males, and probable Pb-induced anemia.

Adolescent↗

[A literature review of concentrations of arsenic, lead, cadmium and mercury in body fluids and tissues for establishing normal values and detection of body burden. 4. Lead, summary of average values for As, Cd, Hg and literature references].

The last of 4 communications on metal concentrations in human body media deals with lead. It includes also a summary of mean exposure levels, critically elevated levels, and references. Publications obtained from a comprehensive data bank search from January 1980 to April 1984 are listed in tables; study groups have been assigned to the following categories: normal; exposed; and exposed, exhibiting adverse health effects. Quality and strength of evidence of analytical procedures and reported data are discussed, particularly in light of adverse health effects. General methods and individual analytical procedures were presented in the 1st communication.

Arsenic↗

Lead-protein interactions as a basis for lead toxicity.

The interaction of lead (Pb) with proteins may represent a fundamental mechanism by which Pb exerts toxicity. In this overview, various factors which influence the interaction of Pb with proteins will be discussed. Pb interacts with enzyme functional groups, and high-affinity metal-binding proteins, such as Pb-binding proteins and metallothioneins, can mediate this Pb-enzyme interaction. Many other factors influence Pb-protein interactions including ligand competition and binding affinities; protein folding and the nature of the metal-binding site; rates of protein synthesis and degradation; and intracellular localization of the ligand and metal. The remainder of this overview will focus on specific examples of important proteins known to be influenced by Pb or which hypothetically may be influenced by Pb. Gaps in knowledge and important research needs are emphasized. Many of the factors discussed play a role in the relative sensitivity of various enzymes in heme biosynthesis to Pb. Disruption of this critical pathway by Pb may result in neuropathologies and accumulation of neurotoxic heme precursors. High-affinity metal-binding proteins have been shown to play a role in mediating Pb inhibition of the octameric Zn-containing enzyme, ALA dehydratase. Knowledge of regional localization in brain and the postnatal ontogeny of the high-affinity metal-binding proteins may be pivotal in understanding Pb neurotoxicity. Other specific examples related to or potentially related to Pb toxicity which are discussed include nucleic acid binding proteins, calmodulin, protein kinase C, and carbonic anhydrase. These proteins will serve as models to understand some basic principles and differences in Pb-protein interactions.

Animals↗

Screening children exposed to lead: an assessment of the capillary blood lead fingerstick test.

We describe results of a 3-year study in which 499 paired venous and capillary blood specimens, collected by fingerstick on the same day, were analyzed for lead (BPb) and erythrocyte protoporphyrin (EP). False-positive rates (FPRs) and the proportion of false positives were calculated at four BPb thresholds. At the 100 microg/L threshold, the FPR for all data was 13%, but the proportion of false positives was only 5%. The log ratios of capillary-to-venous BPb data indicate that, with the exception of eight outliers, two subpopulations exist that follow a log-normal distribution. These two subpopulations, the "core" (n = 303) and "shifted" (n = 188) groups, on average generated a positive bias at 100 microg/L BPb of 8.6% and 30.3%, respectively. The log ratios of capillary-to-venous EP data followed a normal distribution, indicating that capillary EP is not statistically different from venous EP.

Capillaries↗

Exposure of Rana ridibunda to lead I. Study of lead accumulation in various tissues and hepatic delta-aminolevulinic acid dehydratase activity.

There are few data at present on the impact of lead (Pb) on amphibians, although declines in amphibian populations due to man-made changes in the environment have been recorded in recent years. The impact of Pb in adult frogs, Rana ridibunda, was therefore examined. Animals were exposed to 14 mg l(-1) (ppm) aqueous Pb [as Pb(NO3)2] for 4, 10 and 30 days. The chosen Pb concentration corresponded to one-tenth of the 96-h LC50 value for Pb (138.18 ppm). We measured the Pb content of the liver, kidneys, ventral skin and gastrointestinal (GI) tract, and the activity of hepatic delta-aminolevulinic acid dehydratase (delta-ALA-D). Gross morphological characteristics of the frogs were not affected by Pb accumulation in their tissues. At the end of the 30 days of exposure all tissues accumulated Pb. The accumulation of Pb in the liver, kidneys and ventral skin was correlated positively with the time of exposure. The Pb concentration in the GI tract reached a plateau at day 10 and there was no significant increase of Pb in the liver after day 10, suggesting excretion of Pb. The activity of hepatic delta-ALA-D decreased by 90% on day 30 compared to control values. The decrease of hepatic delta-ALA-D activity was correlated negatively with the concentration of Pb in liver and the time of exposure. This study suggests that the hepatic delta-ALA-D activity can be used as a biomarker of Pb intoxication for this species.

Animals↗

Lead effect on blood pressure in moderately lead-exposed male workers.

BACKGROUND: The effect of lead (Pb) and potential confounding variables on blood pressure was examined in healthy male industrial workers 20-43 years of age. METHODS: In 100 Pb workers and 51 reference subjects, the following variables were measured: blood Pb (BPb), activity of delta-aminolevulinic acid dehydratase (ALAD), erythrocyte protoporphyrin (EP), blood cadmium (BCd), serum zinc (SZn), serum copper (SCu), hematocrit (Hct), body mass index (BMI), and blood pressure. The inter-relationship of biomarkers of Pb (BPb, ALAD, EP) and BCd, SZn, SCu, Hct, BMI, age, smoking, and alcohol to systolic and diastolic blood pressure was calculated by forward stepwise multiple regression. RESULTS: There was no significant difference in blood pressure between the two groups, possibly because the reference subjects had relatively high BPb levels and significantly higher BMI (P < 0.05) as compared to the Pb workers. According to the multiple regression results in Pb workers, an increase in systolic blood pressure was significantly associated with increasing EP (P = 0.001) and BMI (P < 0.002), or alternatively with increasing BMI (P < 0.004) and decreasing ALAD (P < 0.04) and BCd (P < 0.05). An increase in diastolic blood pressure was significantly associated with increasing BMI (P < 0.009) and EP (P = 0.05) and decreasing BCd (P < 0.04). With respect to the EP range of 0.73-13.94 micromol/l erythrocytes in 100 Pb workers, an increase of 17 mm Hg in systolic and 6 mm Hg in diastolic blood pressure was found. CONCLUSIONS: Long-term cumulative Pb exposure, which is better reflected by EP than by ALAD or current BPb level, can significantly increase blood pressure in moderately Pb-exposed male workers (long-term average BPb <400 microg/l; exposure duration 2-21 years).

Adult↗