Kyu Dong Ahn

delta-Aminolevulinic acid dehydratase genotype modifies four hour urinary lead excretion after oral administration of dimercaptosuccinic acid.

OBJECTIVES: Previous research suggests that binding of lead by delta-aminolevulinic acid dehydratase (ALAD) may vary by ALAD genotype. This hypothesis was tested by examining whether ALAD genotype modifies urinary lead excretion (DMSA chelatable lead) after oral administration of dimercaptosuccinic acid (DMSA). METHODS: 57 South Korean lead battery manufacturing workers were given 5 mg/kg oral DMSA and urine was collected for four hours. Male workers were randomly selected from two ALAD genotype strata (ALAD1-1, ALAD1-2) from among all current workers in the two plants (n = 290). Subjects with ALAD1-1 (n = 38) were frequency matched with subjects with ALAD1-2 (n = 19) on duration of employment in the lead industry. Blood lead, zinc protoporphyrin, and plasma aminolevulinic acid concentrations, as well as ALAD genotype, duration of exposure, current tobacco use, and weight were examined as predictors or effect modifiers of levels of DMSA chelatable lead. RESULTS: Blood lead concentrations ranged from 11 to 53 micrograms/dl, with a mean (SD) of 25.4 (10.2) micrograms/dl. After 5 mg/kg DMSA orally, the workers excreted a mean (SD) 85.4 (45.0) micrograms lead during a four hour urine collection (range 16.5-184.1 micrograms). After controlling for blood lead concentrations, duration of exposure, current tobacco use, and body weight, subjects with ALAD1-2 excreted, on average, 24 micrograms less lead during the four hour urine collection than did subjects with ALAD1-1 (P = 0.05). ALAD genotype seemed to modify the relation between plasma delta-aminolevulinic acid (ALA) and DMSA chelatable lead. Workers with ALAD1-2 excreted more lead, after being given DMSA, with increasing plasma ALA than did workers with ALAD1-1 (P value for interaction = 0.01). CONCLUSIONS: DMSA chelatable lead may partly reflect the stores of bioavailable lead, and the current data indicate that subjects with ALAD1-2 have lower stores than those with ALAD1-1. These data provide further evidence that the ALAD genotype modifies the toxicokinetics of lead-for example, by differential binding of current lead stores or by differences in long-term retention and deposition of lead.

Associations among Lead Dose Biomarkers, Uric Acid, and Renal Function in Korean Lead Workers

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-β-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 μg/g bone mineral, and 32.0 ± 15.0 μg/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 (β= 0.0111, p < 0.01 and β= 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 (β= 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 ≤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.

Associations of Uric Acid with Polymorphisms in the δ-Aminolevulinic Acid Dehydratase, Vitamin D Receptor, and Nitric Oxide Synthase Genes in Korean Lead Workers

Recent research suggests that uric acid may be nephrotoxic at lower levels than previously recognized and that it may be one mechanism for lead-related nephrotoxicity. Therefore, in understanding mechanisms for lead-related nephrotoxicity, it would be of value to determine whether genetic polymorphisms that are associated with renal outcomes in lead workers and/or modify associations between lead dose and renal function are also associated with uric acid and/or modify associations between lead dose and uric acid. We analyzed data on three such genetic polymorphisms: δ-aminolevulinic acid dehydratase (ALAD), endothelial nitric oxide synthase (eNOS), and the vitamin D receptor (VDR). Mean (± SD) tibia, blood, and dimercaptosuccinic acid–chelatable lead levels were 37.2 ± 40.4 μg/g bone mineral, 32.0± 15.0 g/dL, and 0.77± 0.86 μg/mg creatinine, respectively, in 798 current and former lead workers. Participants with the eNOS Asp allele had lower mean serum uric acid compared with those with the Glu/Glu genotype. Among older workers (age ≥ median of 40.6 years), ALAD genotype modified associations between lead dose and uric acid levels. Higher lead dose was significantly associated with higher uric acid in workers with the ALAD1-1 genotype; associations were in the opposite direction in participants with the variant ALAD1-2 genotype. In contrast, higher tibia lead was associated with higher uric acid in those with the variant VDR B allele; however, modification was dependent on participants with the bb genotype and high tibia lead levels. We conclude that genetic polymorphisms may modify uric acid mediation of lead-related adverse renal effects.

Cross-sectional study of blood lead effects on iron status in Korean lead workers

OBJECTIVEnThis study assessed the iron status of Korean male lead workers by measuring the dietary iron intake and biochemical indices, and tested the hypothesis that a high blood lead level is associated with impaired iron function, which results in higher prevalence of iron deficiency when the route of exposure is not the gastrointestinal tract.nnnMETHODSnOne hundred eighteen lead workers and 42 non-lead workers were recruited from mandatory annual health surveillance sites for industrial workers. Blood lead, hemoglobin, and hematocrit levels were evaluated as hematologic parameters, and serum iron concentrations, total iron-binding capacity, and percentage of transferrin saturation were evaluated as iron-status parameters. Dietary iron intake was assessed by a 24-h recall method.nnnRESULTSnLead workers had significantly lower hemoglobin, hematocrit, serum iron levels, percentage of transferrin saturation, and dietary iron intake than did non-lead workers, and they had significantly higher (P < 0.01) total iron-binding capacity. The occurrence of iron-deficiency cases, as assessed by hematocrit values, was significantly higher (P < 0.001) in lead workers than in non-lead workers, and the prevalence of iron deficiency was associated with high blood lead levels (P = 0.033). The dietary iron intake was inversely associated with zinc protoporphyrin (P = 0.032).nnnCONCLUSIONSnThis study confirmed the adverse effects of high blood lead levels on hematologic pathways and the effectiveness of dietary iron intake as a secondary preventive intervention against lead toxicity. To promote health and to prevent toxic effects of lead exposure in Korean lead workers, an adequate intake of dietary iron is strongly recommended.

Associations of patella lead and other lead biomarkers with renal function in lead workers.

Objective: We sought to compare associations of patella lead, which may represent a unique cumulative and bioavailable lead pool, with other lead measures in models of renal function. Methods: Renal function measures included blood urea nitrogen, serum creatinine, measured and calculated creatinine clearances, and urinary N-acetyl-β-D-glucosaminidase (NAG) and retinol-binding protein. Results: In 652 lead workers, mean (SD) blood, patella, and tibia lead were 30.9 (16.7) &mgr;g/dL, 75.1 (101.1) and 33.6 (43.4) &mgr;g Pb/g bone mineral, respectively, and were correlated (Spearmans r = 0.51–0.74). Patella lead was associated (P < 0.05) with NAG in all lead workers. In models of effect modification by age, higher patella lead also was associated with higher serum creatinine in older participants. Similar associations were observed for blood and tibia lead. Conclusions: Associations between patella lead and adverse renal outcomes were not unique; this may be due, in part, to high correlations among the lead biomarkers in this study.

Longitudinal associations between lead dose and renal function in lead workers.

BACKGROUNDnExisting research on the lead dose range associated with nephrotoxicity in the occupational setting is inconsistent and primarily cross-sectional in design.nnnOBJECTIVEnTo determine if lead dose predicts change in renal function in a large population of current and former lead workers.nnnMETHODSnThree evaluations were performed between 1997 and 2001. Lead dose was assessed with blood and tibia lead. Renal outcomes included blood urea nitrogen, serum creatinine, and calculated creatinine clearance. We used generalized estimating equations to model change in renal function between each evaluation in relation to tibia lead at the beginning of each follow-up period and concurrent change in blood lead, while adjusting for baseline lead dose and other covariates.nnnRESULTSnAt baseline, mean (SD) age and duration of occupational lead exposure were 42.0 (9.3) and 8.8 (6.3) years, respectively, in 537 current and former lead workers followed over a mean of 2.1 years. Mean (SD) blood and tibia lead were 31.3 (14.4) microg/dl and 35.0 (37.8) microg/g bone mineral, respectively. Women (25.9%) were older and more likely to be former lead workers than men. In males, serum creatinine decreased and calculated creatinine clearance increased over the course of the study. Mean blood lead was not significantly different between evaluations 1 and 3 in either sex, however, tibia lead decreased in women. Blood and tibia lead were significantly associated with change in renal function. In males, serum creatinine decreases and calculated creatinine clearance increases were greatest in participants whose blood lead declined.nnnCONCLUSIONSnBoth acute and chronic occupational lead dose measures were associated with change in renal function measures prospectively.

Associations of Subtypes of Hemoglobin with Delta-Aminolevulinic Acid Dehydratase Genotype and Dimercaptosuccinic Acid-Chelatable Lead Levels

Hemoglobin in erythrocytes may be an important intravascular site of lead binding. We examined associations of hemoglobin subtypes A1 and A2 with delta-aminolevulinic acid dehydratase (ALAD) genotype, a protein that is another important site of erythrocyte lead binding. After oral administration of dimercaptosuccinic acid (DMSA-chelatable lead), we also examined 4-h lead excretion, which provides an estimate of bioavailable lead stores. We randomly selected 57 South Korean current lead battery manufacturing workers from two plants (N = 290 employees) and from two ALAD genotype strata (ALAD1-1 and ALAD1-2). These workers voluntarily administered 5 mg/kg oral DMSA. We frequency-matched subjects with ALAD1-1 (n = 38) to subjects with ALAD1-2 (n = 19) with respect to duration of employment in the lead industry. Blood lead levels ranged from 11 to 53 microg/dl (mean +/- standard deviation, 25.4 +/- 10.2 microg/dl). After administration of oral DMSA, workers excreted a mean lead level of 85.4 (standard deviation, 45.0 microg; range, 16.5-184.1 microg). Hemoglobin A1 and A2 ranged from 3.7% to 9.9% and 1.6% to 5.9%, respectively (mean +/- standard deviation, 6.2 +/- 1.0% and 2.7 +/- 0.8%, respectively). Subjects with ALAD1-1 had elevated mean hemoglobin A1 levels (adjusted p = .05). In addition, higher hemoglobin A1 levels were associated with higher DMSA-chelatable lead levels (adjusted p = .03). This, as well as the results of prior research, suggest that both ALAD and hemoglobin A1 may be important lead-binding sites that influence urinary lead excretion after administration of DMSA.

The effect of respiratory protection with biological monitoring on the health management of lead workers in a storage battery industry

SummaryRespiratory protection with maintenance free respirator and regular biological monitoring with the measurement of zinc protoporphyrin for one year period not only made significant decreases of biological indices indicative of lead exposure (blood lead, delta-aminolevulinic acid in urine) in a storage battery workers, but also reduced the prevalence of lead related symptoms.

Associations Between Patella Lead and Blood Pressure in Lead Workers

BACKGROUNDnTo compare associations of patella lead, a lead pool that may capture aspects of both current bioavailable and cumulative lead dose thus offering advantages over tibia or blood lead, with blood lead in models of blood pressure and hypertension and to examine effect modification by age, sex and polymorphisms of the genes encoding for the vitamin D receptor (VDR) and delta-aminolevulinic acid dehydratase (ALAD).nnnMETHODSnCross-sectional data in 652 current and former lead workers were analyzed.nnnRESULTSnBlood lead, but not patella lead, was positively associated with systolic blood pressure. Neither lead measure was associated with diastolic blood pressure or hypertension status. There was no evidence of effect modification.nnnCONCLUSIONSnIn these workers, blood lead was more relevant to elevations in blood pressure than was patella lead. Additional research will be required to determine whether patella lead assessment provides unique information on vascular risk from lead exposure.

Use of Field-Portable X-Ray Fluorescence (FPXRF) Analyzer to Measure Airborne Lead Levels in Korean Workplaces

Use of Field‐Portable X‐Ray Fluorescence (FPXRF) Analyzer to Measure Airborne Lead Levels in Korean Workplaces: Nam‐Soo Kim, et al. Institute of Environmental & Occupational Medicine, College of Medicine, Soonchunhyang University, Korea—We evaluated the possibility of applying field‐portable x‐ray fluorescence (FPXRF) analysis as a rapid, on‐site and near real‐time method for evaluating airborne lead contamination in Korean workplaces. A total of 287 airborne lead filter samples were measured in 12 lead‐using workplaces during routine industrial hygienic monitoring procedures as required by Korean government regulations. All filter samples were collected using the standard industrial hygiene sampling protocol described in NIOSH Method 7300 using closed‐face 37‐mm cassettes with preloaded cellulose ester membrane filters with a pore size of 0.8 µm. The samples were first analyzed using the nondestructive, FPXRF analytical method (NIOSH method 7702), and then subsequently analyzed using inductively coupled plasma atomic emission spectrophotometry (ICP) (NIOSH method 7300) as a reference analytical method. Pair‐wise comparison of filter samples using the paired t‐test revealed no statistically significant differences between the two methods over a wide range of airborne lead levels (0.018–0.201 µg/m3) either over the industries assessed or separately in the 12 lead‐using workplaces. Linear regression of the data between the ICP and FPXRF methods produced a slope of 1.03, a y‐intercept of 0.13 µg/sample, and a coefficient of determinant (r2) of 0.975 for all the data. For samples in the range from 0 to 100 µg, the corresponding values were 1.07, −1.20 µg/sample, and 0.925, respectively. There were no significant differences in the regression analyses of the three industry types (r2=0.964–0.982). Our data suggest that FPXRF data are highly correlated with those from the laboratory‐based ICP method in terms of accuracy, precision, and bias. Therefore, FPXRF can be used for the rapid, on‐site analysis of lead air‐filter samples for values up to 26 µg/sample prior to laboratory confirmation by the ICP method.