Associations of blood lead, dimercaptosuccinic acid-chelatable lead, and tibia lead with polymorphisms in the vitamin D receptor and [delta]-aminolevulinic acid dehydratase genes

A cross-sectional study was performed to evaluate the influence of polymorphisms in the [delta]-aminolevulinic acid dehydratase (ALAD) and vitamin D receptor (VDR) genes on blood lead, tibia lead, and dimercaptosuccinic acid (DMSA)-chelatable lead levels in 798 lead workers and 135 controls without occupational lead exposure in the Republic of Korea. Tibia lead was assessed with a 30-min measurement by (109)Cd-induced K-shell X-ray fluorescence, and DMSA-chelatable lead was estimated as 4-hr urinary lead excretion after oral administration of 10 mg/kg DMSA. The primary goals of the analysis were to examine blood lead, tibia lead, and DMSA-chelatable lead levels by ALAD and VDR genotypes, controlling for covariates; and to evaluate whether ALAD and VDR genotype modified relations among the different lead biomarkers. There was a wide range of blood lead (4-86 microg/dL), tibia lead (-7-338 microg Pb/g bone mineral), and DMSA-chelatable lead (4.8-2,103 microg) levels among lead workers. Among lead workers, 9.9% (n = 79) were heterozygous for the ALAD(2) allele and there were no homozygotes. For VDR, 10.7% (n = 85) had the Bb genotype, and 0.5% (n = 4) had the BB genotype. Although the ALAD and VDR genes are located on different chromosomes, lead workers homozygous for the ALAD(1) allele were much less likely to have the VDR bb genotype (crude odds ratio = 0.29, 95% exact confidence interval = 0.06-0.91). In adjusted analyses, subjects with the ALAD(2) allele had higher blood lead levels (on average, 2.9 microg/dL, p = 0.07) but no difference in tibia lead levels compared with subjects without the allele. In adjusted analyses, lead workers with the VDR B allele had significantly (p < 0.05) higher blood lead levels (on average, 4.2 microg/dL), chelatable lead levels (on average, 37.3 microg), and tibia lead levels (on average, 6.4 microg/g) than did workers with the VDR bb genotype. The current data confirm past observations that the ALAD gene modifies the toxicokinetics of lead and also provides new evidence that the VDR gene does so as well.     

Associations of renal function with polymorphisms in the delta-aminolevulinic acid dehydratase, vitamin D receptor, and nitric oxide synthase genes in Korean lead workers

We analyzed data from 798 lead workers to determine whether polymorphisms in the genes encoding delta-aminolevulinic acid dehydratase (ALAD), endothelial nitric oxide synthase (eNOS), and the vitamin D receptor (VDR) were associated with or modified relations of lead exposure and dose measures with renal outcomes. Lead exposure was assessed with job duration, blood lead, dimercaptosuccinic acid (DMSA)-chelatable lead, and tibia lead. Renal function was assessed with blood urea nitrogen (BUN), serum creatinine, measured creatinine clearance, calculated creatinine clearance and urinary N-acetyl-beta-D-glucosaminidase (NAG), and retinol-binding protein. Mean (+/- SD) tibia lead, blood lead, and DMSA-chelatable lead levels were 37.2 +/- 40.4 microg/g bone mineral, 32.0 +/- 15.0 microg/dL, and 767.8 +/- 862.1 microg/g creatinine, respectively. After adjustment, participants with the ALAD(2) allele had lower mean serum creatinine and higher calculated creatinine clearance. We observed effect modification by ALAD on associations between blood lead and/or DMSA-chelatable lead and three renal outcomes. Among those with the ALAD(1-2) genotype, higher lead measures were associated with lower BUN and serum creatinine and higher calculated creatinine clearance. Participants with the eNOS variant allele were found to have higher measured creatinine clearance and BUN. In participants with the Asp allele, longer duration working with lead was associated with higher serum creatinine and lower calculated creatinine clearance and NAG; all were significantly different from relations in those with the Glu/Glu genotype except NAG (p = 0.08). No significant differences were seen in renal outcomes by VDR genotype, nor was consistent effect modification observed. The ALAD findings could be explained by lead-induced hyperfiltration.     

Effect modification by delta-aminolevulinic acid dehydratase, vitamin D receptor, and nitric oxide synthase gene polymorphisms on associations between patella lead and renal function in lead workers

Genetic polymorphisms that affect lead toxicokinetics or toxicodynamics may be important modifiers of risk for adverse outcomes in lead-exposed populations. We recently reported associations between higher patella lead, which is hypothesized to represent a lead pool that is both bioavailable and cumulative, and adverse renal outcomes in current and former Korean lead workers. In the present study, we assessed effect modification by polymorphisms in the genes encoding for delta-aminolevulinic acid dehydratase (ALAD), the vitamin D receptor (VDR), and endothelial nitric oxide synthase on those associations. Similar analyses were conducted with three other lead biomarkers. Renal function was assessed via blood urea nitrogen, serum creatinine, measured and calculated creatinine clearances, urinary N-acetyl-beta-D-glucosaminidase, and retinol-binding protein. Mean (SD) blood, patella, tibia, and dimercaptosuccinic acid-chelatable lead values were 30.9 (16.7) microg/dl, 75.1 (101.1)and 33.6 (43.4) microg Pb/g bone mineral, and 0.63 (0.75) microg Pb/mg creatinine, respectively, in 647 lead workers. Little evidence of effect modification by genotype on associations between patella lead and renal outcomes was observed. The VDR polymorphism did modify associations between the other lead biomarkers and the serum creatinine and calculated creatinine clearance. Higher lead dose was associated with worse renal function in participants with the variant B allele. Models in two groups, dichotomized by median age, showed that this effect was present in the younger half of the population. Limited evidence of effect modification by ALAD genotype was observed; higher blood lead levels were associated with higher calculated creatinine clearance among participants with the ALAD(1-2) genotype. In conclusion, VDR and/or ALAD genotypes modified associations between all the lead biomarkers, except patella lead, and the renal outcomes.     

Associations of blood pressure and hypertension with lead dose measures and polymorphisms in the vitamin D receptor and delta-aminolevulinic acid dehydratase genes

Evidence suggests that lead and selected genes known to modify the toxicokinetics of lead--namely, those for the vitamin D receptor (VDR) and delta-aminolevulinic acid dehydratase (ALAD)--may independently influence blood pressure and hypertension risk. We report the relations among ALAD and VDR genotypes, three lead dose measures, and blood pressure and hypertension status in 798 Korean lead workers and 135 controls without occupational exposure to lead. Lead dose was assessed by blood lead, tibia lead measured by X-ray fluorescence, and dimercaptosuccinic acid (DMSA)-chelatable lead. Among lead workers, 9.9% (n = 79) were heterozygous for the ALAD(2) allele, and there were no ALAD(2) homozygotes; 11.2% (n = 89) had at least one copy of the VDR B allele, and 0.5% (n = 4) had the BB genotype. In linear regression models to control for covariates, VDR genotype (BB and Bb vs. bb), blood lead, tibia lead, and DMSA-chelatable lead were all positive predictors of systolic blood pressure. On average, lead workers with the VDR B allele, mainly heterozygotes, had systolic blood pressures that were 2.7-3.7 mm Hg higher than did workers with the bb genotype. VDR genotype was also associated with diastolic blood pressure; on average, lead workers with the VDR B allele had diastolic blood pressures that were 1.9-2.5 mm Hg higher than did lead workers with the VDR bb genotype (p = 0.04). VDR genotype modified the relation of age with systolic blood pressure; compared to lead workers with the VDR bb genotype, workers with the VDR B allele had larger elevations in blood pressure with increasing age. Lead workers with the VDR B allele also had a higher prevalence of hypertension compared to lead workers with the bb genotype [adjusted odds ratio (95% confidence interval) = 2.1 (1.0, 4.4), p = 0.05]. None of the lead biomarkers was associated with diastolic blood pressure, and tibia lead was the only lead dose measure that was a significant predictor of hypertension status. In contrast to VDR, ALAD genotype was not associated with the blood pressure measures and did not modify associations of the lead dose measures with any of the blood pressure measures. To our knowledge, these are the first data to suggest that the common genetic polymorphism in the VDR is associated with blood pressure and hypertension risk. We speculate that the BsmI polymorphism may be in linkage disequilibrium with another functional variant at the VDR locus or with a nearby gene.     

Associations of uric acid with polymorphisms in the delta-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: delta-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 microg/g bone mineral, 32.0+/- 15.0 g/dL, and 0.77+/- 0.86 microg/mg creatinine, respectively, in 798 current and former lead workers. Participants with the eNOSAsp allele had lower mean serum uric acid compared with those with the Glu/Glu genotype. Among older workers (age > or = 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 VDRB 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.     

Interaction of blood lead and delta-aminolevulinic acid dehydratase genotype on markers of heme synthesis and sperm production in lead smelter workers.

The gene that encodes gamma-aminolevulinic acid dehydratase (ALAD) has a polymorphism that may modify lead toxicokinetics and ultimately influence individual susceptibility to lead poisoning. To evaluate the effect of the ALAD polymorphism on lead-mediated outcomes, a cross-sectional study of male employees from a lead-zinc smelter compared associations between blood lead concentration and markers of heme synthesis and semen quality with respect to ALAD genotype. Male employees were recruited via postal questionnaire to donate blood and urine for analysis of blood lead, zinc protoporphyrin (ZPP), urinary coproporphyrin (CPU), and ALAD genotype, and semen samples for semen analysis. Of the 134 workers who had ALAD genotypes completed, 114 (85%) were ALAD1-1 (ALAD1) and 20 (15%) were ALAD1-2 (ALAD2). The mean blood lead concentrations for ALAD1 and ALAD2 were 23.1 and 28.4 microg/dl (p = 0.08), respectively. ZPP/heme ratios were higher in ALAD1 workers (68.6 vs. 57.8 micromol/ml; p = 0.14), and the slope of the blood lead ZPP linear relationship was greater for ALAD1 (2.83 vs. 1.50, p = 0.06). No linear relationship between CPU and blood lead concentration was observed for either ALAD1 or ALAD2. The associations of blood lead concentration with ZPP, CPU, sperm count, and sperm concentration were more evident in workers with the ALAD1 genotype and blood lead concentrations >/= 40 microg/dl. The ALAD genetic polymorphism appears to modify the association between blood lead concentration and ZPP. However, consistent modification of effects were not found for CPU, sperm count, or sperm concentration.     

δ-Aminolevulinic acid dehydratase activity,urinary δ-aminolevulinic acid concentration and zinc protoporphyrin level among people with low level of lead exposure

To evaluate the relationship of δ-aminolevulinic acid dehydratase (ALAD) activity, urinary δ-aminolevulinic acid (ALAU) level and blood zinc protoporphyrin (ZPP) concentration to low blood lead (PbB) levels, these biomarkers were determined for all subjects enrolled from a rural area of southeast China where people had low levels of exposure to lead. The mean values of PbB, ALAD, ALAU and ZPP were 67.11 μg/L (SD: 1.654, range: 10.90-514.04), 339.66 nmol ml⁻¹ h⁻¹ (1.419, 78.33-793.13), 20.64 μg/L (1.603, 2.00-326.00), and 0.14 μmol/L (3.437, 0.01-2.26), respectively. ALAD was inversely associated with low levels of PbB. ZPP was inversely related to low levels of PbB but positively related to relatively higher levels of PbB. Alcohol drinking contributed to low ALAD in men. Women had higher ZPP than men. ALAU had no significant association with PbB. In conclusion, ALAD possibly has a non-linear relation with low to moderate levels of PbB. At moderate levels of PbB, ZPP increases with increasing levels of PbB. ALAU is not suitable as an indicator for low levels of lead exposure.     

Lead and delta-aminolevulinic acid dehydratase polymorphism: where does it lead? A meta-analysis

BACKGROUND: Lead poisoning affects many organs in the body. Lead inhibits delta-aminolevulinic acid dehydratase (ALAD), an enzyme with two co-dominantly expressed alleles, ALAD1 and ALAD2. OBJECTIVE: Our meta-analysis studied the effects of the ALAD polymorphism on a) blood and bone lead levels and b) indicators of target organ toxicity. DATA SOURCE: We included studies reporting one or more of the following by individuals with genotypes ALAD1-1 and ALAD1-2/2-2: blood lead level (BLL), tibia or trabecular lead level, zinc protoporphyrin (ZPP), hemoglobin, serum creatinine, blood urea nitrogen (BUN), dimercaptosuccinic acid-chelatable lead, or blood pressure. DATA EXTRACTION: Sample sizes, means, and standard deviations were extracted for the genotype groups. DATA SYNTHESIS: There was a statistically significant association between ALAD2 carriers and higher BLL in lead-exposed workers (weighted mean differences of 1.93 microg/dL). There was no association with ALAD carrier status among environmentally exposed adults with BLLs < 10 microg/dL. ALAD2 carriers were potentially protected against adverse hemapoietic effects (ZPP and hemoglobin levels), perhaps because of decreased lead bioavailability to heme pathway enzymes. CONCLUSION: Carriers of the ALAD2 allele had higher BLLs than those who were ALAD1 homozygous and higher hemoglobin and lower ZPP, and the latter seems to be inversely related to BLL. Effects on other organs were not well delineated, partly because of the small number of subjects studied and potential modifications caused by other proteins in target tissues or by other polymorphic genes.     

重度铅污染地区儿童铅中毒的分子流行病学研究

目的：研究高暴露于铅的条件下，δ－氨基乙酰丙酸脱水酶（ALAD）和维生素D体（VDR）基因多态性对儿童铅中毒易感性的影响。方法：分析了469名严重铅暴露儿童ALAD和VDR基因多态性，血铅、锌原卟啉（ZPP）、头围、身高和体重等指标。结果：具有ALADS等位基因个体，血中ZPP水平高于不含该等位基因的个体（P＝0．017）；携带VDR B等位基因个体的头围大于仅携带b等位基因者（51.19cm和50.75cm）（P＝0．028）。结论：在高水平铅暴露儿童中，ALAD多态性可影响铅的血液毒性效应。VDR基因的遗传变异改变铅对儿童颅骨发育的作用程度。ALAD和VDR基因多态性是影响严重铅暴露条件下儿童铅中毒易感性的分子遗传学因素。     

The protective effect of delta-aminolevulinic acid dehydratase 1-2 and 2-2 isozymes against blood lead with higher hematologic parameters

Previous studies have suggested that delta-aminolevulinic acid dehydratase (ALAD) types 1-2 or 2-2 are protective against the toxicity of blood lead (PbB) when zinc protoporphyrin (ZPP) levels are low because of differential binding of lead in erythrocytes. The hypothesis is that subjects with the ALAD 1-1 genotype are more susceptible to lead exposure with impaired hematologic synthesis and therefore that iron nutrition is more important in those with the ALAD 1-1 genotype. The purpose of this study was to prove the protective effect of ALAD 1-2/2-2 against PbB with higher hematologic parameters. Data on 1,219 male workers from eight lead-using factories in the Republic of Korea were examined in this cross-sectional study. Blood samples were evaluated for PbB, ZPP, hemoglobin (Hb), and serum iron (SFe) concentrations and ALAD genotypes. The overall prevalence of the ALAD 1-2/2-2 genotype was 9.3%, which was associated with lower log ZPP (p < 0.001) and higher Hb (p = 0.014) levels. For the subjects with normal iron status (SFe levels > 60 micro g/dL), those with the ALAD 1-1 genotype were more likely to be anemic (adjusted odds ratio of 5.2; 95% confidence interval, 1.2-22.6) than those with ALAD 1-2/2-2. The study confirms the protective effects of ALAD 1-2/2-2 polymorphisms against PbB on hematologic pathways. In order to promote health and to minimize the toxicity of lead exposure more effectively, the nutritional management of iron in Korean workers should take both their ALAD genotypes and occupational lead exposures into account.     

Critical dose of lead affecting delta-aminolevulinic acid levels

To estimate the critical dose of the association between the blood lead concentration (BPb) and delta-aminolevulinic acid (ALA) levels, ALA levels in plasma (ALA-P), blood (ALA-B), and urine (ALA-U), and the activity of delta-aminolevulinic acid dehydratase (ALAD) were determined in 186 Japanese lead workers, aged 18-62 yr, with BPb levels of 2.1-62.9 g/dl. For this purpose, the benchmark dose (BMD) method, recently used in the environmental health field in place of the no-observed-adverse-effect level, was introduced into this study. The BMD was defined as the BPb level that resulted in an increased probability of abnormal change in ALA-related parameters by an excess risk (BMR) of 5% in exposed workers i.e., from P0 (abnormal probability of 5% in unexposed workers) to P0+BMR for exposed workers at the BMD. ALA-related parameters were significantly correlated with BPb. The BMDs computed from the 186 workers, after controlling for age, were 15.3-20.9 microg/dl for ALA levels, and 2.9 microg/dl for ALAD; likewise, the BMDs from the 154 workers with BPb levels of less than 40 microg/dl were 3.3-8.8 microg/dl for ALA levels, and 2.7 microg/dl for ALAD. Since the cutoff value of ALA-P, computed from the latter workers, seems to be closer to the upper normal limit in unexposed adults than does that from the former workers, it is suggested that the critical dose of BPb causing the increased levels of ALA is below 10 microg/dl. Such critical doses are necessary to promote preventive activities of adverse effects of lead.     

A comparison of different lead biomarkers in their associations with lead-related symptoms

Objectives: To evaluate whether dimercaptosuccinic acid (DMSA) -chelatable lead, an estimate of current bioavailable lead stores, is a better predictor of lead-related symptoms than are other commonly used lead biomarkers. Methods: A total of 95 male lead workers from three lead industries (one secondary lead smelting facility, one polyvinyl chloride-stabilizer manufacturing plant, and one lead-acid storage battery factory), and 13 workers without occupational lead exposure recruited from an occupational health institute, were studied. Blood lead, blood zinc protoporphyrin (ZPP), 4 h DMSA-chelatable lead (after oral administration of 10 mg/kg DMSA), urine lead, and urinary δ-aminolevulinic acid levels were evaluated as predictors of 15 lead-related symptoms, assessed by self-administered questionnaire, with linear and logistic regression controlling for covariates. Total symptoms and symptoms in three categories (gastrointestinal, neuromuscular, and general) were evaluated. Results: The mean (SD) 4 h DMSA-chelatable lead level was 288.7 (167.7) μg, with a range from 32.4 to 789 μg in the 95 lead workers. The mean (SD) in the non-exposed subjects was 23.7 (11.5) μg with a range from 10.5 to 43.5 μg. Blood lead, blood ZPP, and spot urine lead levels ranged from 21.4 to 78.4 μg/dl, 40 to 331 μg/l, and 7.5 to 153.0 μg/l, respectively, in the lead workers, and from 4.0 to 7.2 μg/dl, 27 to 52 μg/l, and 2.9 to 15.5 μg/l in the non-exposed controls, respectively. The overall mean symptom score (SD), derived as the sum of 0 or 1 point for absence or presence of 15 symptoms, of the lead workers was 3.7 (2.0), compared to 1.2 (1.5) for the non-exposed workers. DMSA-chelatable lead was the best predictor of symptom scores in both crude and adjusted analyses, compared with the other biomarkers. Lead workers with DMSA-chelatable lead values greater than the median (260.5 μg) were 6.2 times more likely to have frequent tingling or numbness of the arms or legs and 3.3 times more likely to have muscle pain than subjects with lower chelatable lead values. Three symptoms (tingling or numbness of arm or leg, muscle pain, and feeling irritation at the slightest disturbance) evidenced a dose-dependent relationship with DMSA-chelatable lead levels. Conclusions: DMSA-chelatable lead was found to be the best predictor of lead-related symptoms, particularly of both total symptom scores and neuromuscular symptoms, than were the other other lead biomarkers. Received: 27 January 1999 / Accepted: 29 January 2000     

Relationship between blood lead level and urinary ALA level in workers exposed to very low levels of lead

The relationship between blood lead (PbB) level and urinary delta-aminolevulinic acid (ALAU) level was examined in a total of 3,636 lead-exposed workers in a periodic medical examination in 1992, in accordance with the Ordinance on Prevention of Lead Poisoning. The results were consistent with previously reported results in that ALAU level was found to increase with an increase in PbB level above 22.4 micrograms/dl (1.35 as a logarithmic value) and to rise markedly above 35.5 micrograms/dl (1.55). On the contrary, the geometric means of ALAU levels appeared to decrease with an increase in PbB levels within a range between a logarithmic value of 0.15 (1.4 micrograms/dl) and 1.25 (17.8 micrograms/dl). Because the earliest sign of the adverse health effects of lead is reported to occur at a PbB level of of 20 micrograms/dl, the relationship between PbB level and ALAU level was examined at PbB levels below 20 micrograms/dl. A regression formula was obtained, Y (log ALAU (mg/l)) = -0.0570X (log PbB (microgram/dl) + 0.4099. This result indicates that ALAU level decreases with a concomitant increase in PbB level lower than 20 micrograms/dl.     

δ-氨基乙酰丙酸脱水酶基因多态性与血铅和锌原卟啉的关系

目的　探讨δ 氨基乙酰丙酸脱水酶 (ALAD)基因多态性与血铅和锌原卟啉之间的关系。方法　采样分析 370名严重铅污染区儿童的血铅、锌原卟啉和ALAD基因型。结果　ALAD1 2 / 2 2 基因型的血铅水平 (2 6 2 1± 0 5 6 1) μmol/L高于ALAD1 1基因型 (2 36 0± 0 5 96 ) μmol/L ;而锌原卟啉水平也增高 ,前者 (13 0 7± 9 38) μmol/L ,后者 (9 90± 6 30 ) μmol/L。 结论　在同样的高铅暴露条件下 ,ALAD1 2 / 2 2 基因型可影响儿童体内铅负荷水平以及铅所致血液毒性效应     

A comparison of blood lead levels between migrant and native lead workers before and after implementation of a new employment permit system for migrant workers

We compared the blood lead and other lead biomarkers between migrant and native workers with a focus on the impact of the legal employment permit system that was effective from 2003, which required employers to provide mandatory annual health examinations for migrant workers on lead biomarkers in 1997 and 2005. The mean blood lead level of migrant workers was 59.5 ± 19.4 μg/dl, yielding 47% of lead poisoning cases, which was significantly higher than that of native workers (36.8 ± 14.5 μg/dl; 11% of lead poisoning cases) in 1997 before enactment of the act. The overall mean blood ZPP levels and ALAU of migrant workers were significantly higher than those of native workers. In 2005, after new migrant worker regulations were instituted, the mean value of above lead biomarkers workers was still significantly higher than that of native workers, but the magnitude of the differences was smaller compared with the difference in 1997. We confirmed that the 2003 regulations played an important role in improving the health of migrant workers in the lead industry in terms of their blood lead levels and other lead biomarkers.     

Relationship of blood lead levels to blood pressure in exhaust battery storage workers

Several researches has focused the hypothesis that low blood lead levels could be associated with an increased risk of hypertension. To assess the relation between occupational lead exposure and elevated blood pressure a group of 27 workers, age range from 27 to 62 years, mean (SD) 36.52 (+/- 8.16) yr; length of employment mean (DS) 2.97 (+/- 1.67) yr, were recruited as study subjects. The following variables were measured: blood lead concentration (BPb), delta-Aminolevulinic Acid Dehydratase (ALAD) activity, Zinc Protoporphirin (ZPP), creatinine, hematocrit, Body Mass Index (BMI) and Systolic Blood Pressure (SBP) and Diastolic Blood (DBP) Pressure. The results showed that long term occupational exposure was related to a slight increase of systolic and diastolic blood pressure among workers who had been exposed to higher level of lead with respect to workers exposed to lower level of lead. Furthermore, blood lead concentration (BPb) and ZPP resulted higher among workers exposed to higher level of ambient lead, while in the same group of workers ALAD activity resulted more inhibited. The authors concluded long term cumulative lead exposure can significantly increase blood pressure in low level Pb exposed workers.     

The relevance of arguments for excluding ALAD from the recommended biological limit values in occupational exposure to inorganic lead (WHO 1980)

Summary Data on 394 simultaneous measurements of blood lead (PbB) and biological indicators of effect are considered with regard to dose-effect and dose-response relationships, as well as the association between the biological indicators of effect themselves. The indicators are delta-aminolevulinic acid dehydratase (ALAD) and zinc-protoporphyrin (ZPP) in blood, delta-amino-levulinic acid (ALAU) and coproporphyrin (CPU) in 24-h urine specimens. The specimens were taken from periodically controlled male workers moderately to excessively exposed to inorganic lead. In addition, data are presented on the spontaneous recovery of biological indicators in 14 male workers examined immediately after, approximately 4.5 months and 10 months after cessation of lead exposure. Highly significant (P<0.001) correlations were found between all of the indicators examined, with the following order of agreement with regard to PbB: ALAD>ZPP>ALAU>CPU. Comparative advantages of ALAD in typical (variable) occupational exposure conditions were found to include: (a) the highest sensitivity at both low and relatively high lead exposure levels, (b) better reflection of biologically active lead as opposed to PbB (particularly compared to ALAU and CPU), (c) higher specificity compared to other indicators of lead effect, and (d) generally higher reliability with regard to both biologically and methodologically induced variations. The data obtained undoubtedly demonstrate that urinary indicators ALAU and CPU are not sensitive enough for the recommended health-based occupational exposure limit, as defined by relatively low PbB concentration (WHO 1980). Despite possible theoretical considerations resulting in recommendations for ZPP and ALAU but excluding ALAD (WHO 1980), practical implications seem to be far more in favour of ALAD, which permits a maximal safety margin in preventing adverse effects in the entire work population because of its sensitivity and absence of time-lag with regard to lead exposure.Presented at the 20th International Congress on Occupational Health, Cairo, 25 September –1 October, 1981     

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 of blood lead, dimercaptosuccinic acid-chelatable lead, and tibia lead with neurobehavioral test scores in South Korean lead workers

The authors performed a cross-sectional study to evaluate associations between blood lead, tibia lead, and dimercaptosuccinic acid (DMSA)-chelatable lead and measures of neurobehavioral and peripheral nervous system function among 803 lead-exposed workers and 135 unexposed controls in South Korea. The workers and controls were enrolled in the study between October 1997 and August 1999. Central nervous system function was assessed with a modified version of the World Health Organization Neurobehavioral Core Test Battery. Peripheral nervous system function was assessed by measuring pinch and grip strength and peripheral vibration thresholds. After adjustment for covariates, the signs of the beta coefficients for blood lead were negative for 16 of the 19 tests and blood lead was a significant predictor of worse performance on eight tests. On average, for the eight tests that were significantly associated with blood lead levels, an increase in blood lead of 5 microg/dl was equivalent to an increase of 1.05 years in age. In contrast, after adjustment for covariates, tibia lead level was not associated with neurobehavioral test scores. Associations with DMSA-chelatable lead were similar to those for blood lead. In these currently exposed workers, blood lead was a better predictor of neurobehavioral performance than was tibia or DMSA-chelatable lead, mainly in the domains of executive abilities, manual dexterity, and peripheral motor strength.     

Erythrocyte deformability in workers exposed to lead.

Erythrocyte deformability and other hematological indicators were determined in 17 male workers exposed to lead at a secondary lead refinery and 13 controls. Blood lead, urine lead, urine coproporphyrin, delta-aminolevulinic acid and erythrocyte zinc protoporphyrin were determined to evaluate the degree of lead exposure in the lead workers above. For the measurement of erythrocyte deformability, the microfilter method was used. The results were summarized as follows: 1. The mean values of blood lead, urine lead, urine coproporphyrin, urine delta-aminolevulinic acid and erythrocyte zinc protoporphyrin levels in lead workers were 53.5 micrograms/100g, 141.4 micrograms/l, 115.9 micrograms/l, 12.0 mg/l and 68.9 micrograms/dl respectively, suggesting a moderate influence of lead exposure. 2. The mean values of erythrocyte count, hematocrit and hemoglobin were significantly lower in lead workers than those in controls. No significant differences were found in the mean values of mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration and corpuscular natrium and potassium between lead workers and controls. 3. Erythrocyte deformability was significantly reduced in lead workers compared with controls.