The delta-aminolevulinate dehydratase polymorphism: higher blood lead levels in lead workers and environmentally exposed children with the 1-2 and 2-2 isozymes.

The erythrocyte delta-aminolevulinate dehydratase (ALAD) isozyme phenotypes and the blood lead levels were determined in a population of 202 lead factory workers in Germany and an environmentally exposed population of 1278 children in New York who had elevated free protoporphyrin levels. In both population, individuals with the ALAD 1-2 or 2-2 isozyme phenotype had levels of blood lead statistically higher than those individuals with the ALAD 1-1 isozyme phenotype (lead workers: P greater than 0.004; children: P greater than 0.0001). Homozygotes and heterozygotes for the ALAD2 allele who expressed the 2-2 or 1-2 isozyme phenotype had median blood lead levels that were about 9 to 11 micrograms/dl greater than similarly exposed individuals who were homozygous for the ALAD1 allele. These findings support the hypothesis that the ALAD2 polypeptide binds lead more effectively, and therefore that individuals with the ALAD2 allele may be more susceptible to lead poisoning.     

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.     

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.     

Association between aminolevulinate dehydrogenase genotype and blood lead levels in Taiwan

This study was designed to evaluate the association between the aminolevulinate dehydrogenase (ALAD) genotype and blood lead levels in a general population environmentally exposed to lead. This study population of 660 subjects was secondarily sampled from the 3000 random samples of Taiwanese general population to study the distribution of blood lead levels in the Taiwanese population. A simple assay based on the polymerase chain reaction-restriction fragment length polymorphism technique was used to determine the genotype of the ALAD gene. This study found that most of the Taiwanese population was ALAD 1-1 (95.4%). Only 4.6% (30 subjects) of population were found to be 1-2 or 2-2. It has been hypothesized that the ALAD2 allele is associated with increased absorption of lead. This study found that individuals with ALAD2 alleles had 20% higher blood lead levels than persons with ALAD1 alleles (7.83 +/- 5.95 vs 6.51 +/- 5.03 micrograms/dL). However, the difference was not statistically significant, even after adjustment for other risk factors of environmental exposure. The result supports the previous finding that individuals with ALAD2 allele had higher blood lead levels. The small sample size and large amount of variation in our study may account for the insignificant association.     

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     

The delta-aminolevulinic acid dehydratase (ALAD) polymorphism and bone and blood lead levels in community-exposed men: the Normative Aging Study

Recent research has indicated that a polymorphic variant of delta-aminolevulinic acid dehydratase (ALAD) may influence an individual's level of lead in bone and blood and, as a result, may also influence an individual's susceptibility to lead toxicity. In this study, we investigated whether this ALAD polymorphism is associated with altered levels of lead in bone and blood among 726 middle-aged and elderly men who had community (nonoccupational) exposures to lead. We measured levels of blood and bone lead by graphite furnace atomic absorption spectroscopy and a K X-ray fluorescence (KXRF) instrument, respectively. We determined the ALAD MspI polymorphism in exon 4 by a polymerase chain reaction restriction fragment length polymorphism (RFLP). Of the 726 subjects, 7 (1%) and 111 (15%) were, respectively, homozygous and heterozygous for the variant allele. The mean (SD) of blood lead (micrograms per deciliter), cortical bone (tibia) lead (micrograms per gram), and trabecular bone (patella) lead (micrograms per gram) were 6.2 (4.1), 22.1 (13.5), and 31.9 (19.5) in subjects who did not have the variant allele (ALAD 1-1), and 5.7 (4.2), 21.2 (10.9), and 30.4 (17.2) in the combined subjects who were either heterozygous or homozygous for the variant allele (ALAD 1-2 and ALAD 2-2). In multivariate linear regression models that controlled for age, education, smoking, alcohol ingestion, and vitamin D intake, the ALAD 1-1 genotype was associated with cortical bone lead levels that were 2.55 microg/g [95% confidence interval (CI) 0.05-5.05] higher than those of the variant allele carriers. We found no significant differences by genotype with respect to lead levels in trabecular bone or blood. In stratified analyses and a multivariate regression model that tested for interaction, the relationship of trabecular bone lead to blood lead appeared to be significantly modified by ALAD genotype, with variant allele carriers having higher blood lead levels, but only when trabecular bone lead levels exceeded 60 microg/g. These results suggest that the variant ALAD-2 allele modifies lead kinetics possibly by decreasing lead uptake into cortical bone and increasing the mobilization of lead from trabecular bone.     

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.     

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.     

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.     

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.     

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.     

Association Between Aminolevulinate Dehydrase Genotypes and Blood Lead Levels in Children from a Lead-Contaminated Area in Antofagasta,Chile

Childhood environmental lead exposure in the city of Antofagasta, Chile, was generated by the accumulation of recently removed lead stores derived from mining activities for a long period of time. Susceptibility to harmful lead effects may be associated with polymorphisms of delta-aminolevulinic acid dehydratase (ALAD) because of the differential binding of lead to the codified proteins. We assessed the associations and possible interactions among the following variables: blood lead levels, ALAD genotypes, and distance to the source of lead contamination in Chilean children exposed to lead contamination in Antofagasta, Chile. Ninety-three children were recruited from schools located near a lead- contaminated area. Lead blood levels were measured by atomic absorption spectrophotometry. ALAD genotypes were determined by polymerase chain reaction and restriction fragment-length polymorphism analysis. The frequency of the ALAD-2 allele was estimated at 0.054. Children with the ALAD-2 genotype had higher blood lead levels than noncarriers (p = 0.06). As expected, blood lead levels were inversely correlated with the distance from lead stores. Interestingly, ALAD-2 carriers were more frequent within the area defined by a distance of 200 m from lead deposits (27%) than in areas >200 m (5%) away. Children living within a maximum distance of 200 m from the lead stores showed higher blood lead levels in ALAD-2 carriers (geometric mean = 16.4 g/dl, range 6 to 27) than in noncarriers (geometric mean = 12.1 g/dl, range 0 to 26) without achieving statistical significance (p = 0.13). A trend for higher blood lead levels in ALAD-2 carriers compared with ALAD-1 homozygous children has been observed. Because ALAD-2 frequency was higher in subjects living within 200 m from the lead deposits, we hypothesized that a long-term selective pressure against the presence of the ALAD-1 allele is the cause of the overrepresentation of the ALAD-2 allele in children living in proximity to the recently removed lead stores.     

Effects of delta-aminolevulinic Acid dehydratase polymorphisms on susceptibility to lead in han subjects from southwestern china

This study is to determine the distribution of the delta-aminolevulinic acid dehydratase (ALAD) polymorphism among Han subjects of the Chinese population and to study whether the polymorphism in the ALAD gene modifies the toxicity of lead in lead-exposed workers. For this purpose we conducted a cross-sectional study on 156 Chinese workers who were exposed to lead in lead-acid battery and electric-flex manufacturing plants. The authors found that the allele frequencies of ALAD1 and ALAD2 were 0.9679 and 0.0321, respectively. Workers with the ALAD 1-1 genotype were associated with higher blood lead levels than those with the ALAD 1-2 genotype. Blood and urine lead levels were much higher in storage battery workers than in cable workers. The self-conscious symptom survey showed that the incidences of debilitation, amnesia and dreaminess were much higher in those had more than five years of tenure or contact with lead on the job within the ALAD 1-1 genotype subgroup. Laboratory examinations showed that serum iron and zinc levels in workers' with the ALAD 1-2 genotype were higher than those with the ALAD 1-1 genotype, especially in storage-battery workers. Correlation analysis indicated that the blood lead level negatively correlated with serum calcium, iron and zinc level. The data of this study suggest that the ALAD gene polymorphism and serum ion levels may modify the kinetics of lead in blood. Therefore, the authors recommend that an adequate intake of dietary calcium, iron, and zinc or the calcium, iron, and zinc supplementation should be prescribed to Chinese lead exposed workers.     

Polymorphism of delta-aminolevulinic acid dehydratase and its effect on blood lead levels in Thai workers

To determine the prevalence of delta-aminolevulinic acid dehydratase (ALAD) polymorphism and its effects on blood lead levels (BLLs) in Thai workers, the authors performed a cross-sectional analysis of 389 Thai workers who were exposed to lead in a battery plant. The authors collected blood for BLLs and genotypic study, and they found that the allele frequencies of ALAD1 and ALAD2 were 0.98 and 0.02, respectively. They made a comparison of BLLs between genotype by dividing the levels into 2 categories of lead exposure (high and medium magnitude of exposure) and using length of employment as a covariance. Their results showed no significant difference of BLLs between the ALAD1-1 and ALAD1-2/ALAD2-2 groups in both levels of exposure. The frequency of ALAD2 in Thai workers was low; the authors found that ALAD polymorphism had a small or only modest effect on BLLs.     

A delta-aminolevulinic acid dehydratase (ALAD) polymorphism may modify the relationship of low-level lead exposure to uricemia and renal function: the normative aging study

In this study we investigated whether a known delta-aminolevulinic acid dehydratase (ALAD) exon 4 polymorphism has a modifying effect on the association of blood or bone lead level with uricemia and indices of renal function among middle-aged and elderly men. We performed a cross-sectional study of subjects who participated between 1991 and 1995 in the Department of Veterans Affairs Normative Aging Study. Information on blood lead levels, bone lead levels (measured by K-shell X-ray fluorescence), serum uric acid, serum creatinine, estimated creatinine clearance, and ALAD polymorphism status was available in 709 subjects. Regression models were constructed to examine the relationships of serum uric acid, serum creatinine, and estimated creatinine clearance to blood or bone lead level, stratified by genotype. We also adjusted for age, body mass index, blood pressure, smoking, alcohol consumption, and ingestion of analgesic medications (n = 638). Of the 709 subjects, 7 (1%) and 107 (15%) were homozygous and heterozygous for the variant (ALAD-2) allele, respectively. The mean (range) serum uric acid and creatinine levels were 6.5 (2.9-10.6) and 1.2 (0.6-2.5) mg/dL. No significant differences were found in serum uric acid, serum creatinine, or estimated creatinine clearance by ALAD genotype. However, after adjusting for other potential confounders, we found a significant linear relationship between serum uric acid and patella bone lead (p = 0.040) among the ALAD 1-2/2-2 genotype individuals above a threshold patellar lead level of 15 micro g/g. In contrast, among the wild-type (ALAD 1-1) individuals, there was a suggestion of a significant linear relationship of serum uric acid with patella bone lead (p = 0.141), but only after a threshold of 101 micro g/g. There was evidence of a significant (p = 0.025) interaction of tibia lead with genotype (ALAD 1-1 vs. ALAD 1-2/2-2) regarding serum creatinine as an outcome, but in the same linear regression model tibia lead alone was not a significant predictor of serum creatinine. Conversely, for estimated creatinine clearance, patella lead, but not the interaction of patella lead with genotype, was a significantly independent predictor (p = 0.026). Our findings suggest that ALAD genotype may modify the effect of lead on the renal excretion of uric acid as well as overall renal function among middle-aged and elderly men who had community (nonoccupational) exposures to lead. Additional research is needed to ascertain whether this constitutes a true gene-environment interaction and, if so, its clinical impact.     

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.     

Association of renal function and delta-aminolevulinic acid dehydratase polymorphism among Vietnamese and Singapore workers exposed to inorganic lead

Objectives

To investigate the effect of δ‐aminolevulinic acid dehydratase (ALAD) polymorphisms on the association between blood lead and renal function among Vietnamese and Singaporean workers who were exposed to low to medium levels of inorganic lead, and to study the distribution of ALAD polymorphism among Vietnamese, Chinese, Malays and Indians.

Methods

A total of 459 male and female workers were studied. Blood and urine were collected for each worker in order to determine ALAD genotype, blood lead, and urinary δ‐aminolevulinic acid (ALAU). Renal function tests included urine albumin (Ualb), urine β2 microglobulin (Uβ2m), urinary α1 microglobulin (Uα1m), N‐acetyl‐glucosaminidas (NAG), and urine retinol blinding protein (RBP). A multiple regression model with interaction term was applied to fit the entire data and to explore the modifying effect of ALAD polymorphism on the relation of blood lead to each renal function parameter.

Results

ALAD1‐1 was the predominant genotype for all the ethnic groups while ALAD2‐2 was the rarest. The frequency of ALAD2 allele was higher among Malays (8.8%) and Indians (10.6%) compared to the Chinese (5.0%) and Vietnamese (4.3%). The geometric mean of blood lead for all workers was 19.0 μg/dl. The models for Uβ2m, Uα1m, and NAG showed that the ALAD1‐2/2‐2 group had higher β coefficients than the ALAD1‐1 group. Corresponding to 10 μg/dl blood lead, ALAD1‐1 homozygotes had an increment of 1.288 μg/g Cr, 1.175 mg/g Cr, and 1.995 U/g Cr for Uβ2m, Uα1m, and NAG, respectively. ALAD1‐2/2‐2 subjects had higher increments of 3.802 μg/g Cr, 2.138 mg/g Cr, and 3.89 U/g Cr for Uβ2m, Uα1m, and NAG, respectively.

Conclusion

The frequency of the ALAD2 allele is as low in Vietnamese workers as in Chinese. Workers with the ALAD2 allele appeared more susceptible to the effects of lead (especially at higher levels) on renal function.     

Lead-glazed ceramic ware and blood lead levels of children in the city of Oaxaca, Mexico

Although Mexico substantially reduced use of leaded gasoline during the 1990s, lead-glazed pottery remains a significant source of population exposure. Most previous studies of lead in nonoccupationally exposed groups in Mexico have been conducted in the Mexico City metropolitan area. Oaxaca, a poor southern state of Mexico, has a centuries-old tradition of use of low temperature lead-glazed ceramic ware manufactured mainly by small family businesses. We measured blood lead levels in 220 8-10-y-old children (i.e., not from pottery-making families) who were students in the innercity of Oaxaca and in the mothers of all children. The geometric mean blood lead level of the children was 10.5 microg/dl (+7.0/-4.3 microg/dl standard deviation; range = 1.3-35.5 microg/dl). The corresponding mean value for the mothers was 13.4 (+9.0/-5.4 microg/dl standard deviation; range = 2.8-45.3 microg/dl). We used cutoffs that were greater than or equal to 10 microg/dl, 20 microg/dl, and 30 microg/dl, and we determined that 54.9%, 10.3%, and 3.0% of the children were at or above the respective criteria. We accounted for 25.2% of the variance in blood lead levels of the children, using maternal responses to a questionnaire that assessed possible lead sources in a linear multiple-regression model. The most important factors related to lead levels were family use of lead-glazed pottery, use of animal fat in cooking, and family income. The addition of maternal blood lead level to the model increased accounted variance in blood lead to 48.0%. In logistic-regression modeling of children's blood lead levels, we used a cutoff of greater than or equal to 10 microg/dl, and we found that use of lead-glazed pottery was the most important of all questionnaire items that were predictive of blood lead levels (odds ratio = 2.98). In Oaxaca, as is the case elsewhere in Mexico, lead-glazed ceramic ware remains a significant risk factor for elevated blood lead levels in children.     

Prenatal low-level lead exposure and developmental delay of infants at age 6 months (Krakow inner city study)

The purpose of the study was to assess the neurocognitive status of 6-month-old infants whose mothers were exposed to low but varying amounts of lead during pregnancy. Lead levels in the cord blood were used to assess environmental exposure and the Fagan Test of Infant Intelligence (FTII) assessed visual recognition memory (VRM). The cohort consisted of 452 infants of mothers who gave birth to babies at 33-42 weeks of gestation between January 2001 and March 2003. The overall mean lead level in the cord blood was 1.42 microg/dl (95% CI: 1.35-1.48). We found that VRM scores in 6 month olds were inversely related to lead cord blood levels (Spearman correlation coefficient -0.16, p=0.007). The infants scored lower by 1.5 points with an increase by one unit (1 microg/dl) of lead concentration in cord blood. In the lower exposed infants (1.67 microg/dl) the mean Fagan score was 61.0 (95% CI: 60.3-61.7) and that in the higher exposed group (>1.67 microg/dl) was 58.4 (95% CI: 57.3-59.7). The difference of 2.5 points was significant at the p=0.0005 level. The estimated risk of scoring the high-risk group of developmental delay (FTII classification 3) due to higher lead blood levels was two-fold greater (OR=2.33, 95% CI: 1.32-4.11) than for lower lead blood levels after adjusting for potential confounders (gestational age, gender of the child and maternal education). As the risk of the deficit in VRM score (Fagan group 3) in exposed infants attributable to Pb prenatal exposure was about 50%, a large portion of cases with developmental delay could be prevented by reducing maternal blood lead level below 1.67 microg/dl. Although the negative predictive value of the chosen screening criterion (above 1.67 microg/dl) was relatively high (89%) its positive predictive value was too low (22%), so that the screening program based on the chosen cord blood lead criterion was recommended.     

Lead burden and psychiatric symptoms and the modifying influence of the delta-aminolevulinic acid dehydratase (ALAD) polymorphism: the VA Normative Aging Study

The authors evaluated the association between lead burden and psychiatric symptoms and its potential modification by a delta-aminolevulinic acid dehydratase (ALAD) polymorphism. Lead measurements in blood or bone and self-reported ratings on the Brief Symptom Inventory from 1991 to 2002 were available for 1,075 US men participating in the Department of Veterans Affairs (VA) Normative Aging Study. The authors estimated the prevalence odds ratio for the association between interquartile-range lead and abnormal symptom score, adjusting for potential confounders. An interquartile increment in tibia lead (14 microg/g) was associated with 21% higher odds of somatization (95% confidence interval of the odds ratio: 1.01, 1.46). An interquartile increment in patella lead (20 microg/g) corresponded to a 23% increase in the odds of global distress (95% confidence interval of the odds ratio: 1.02, 1.47). An interquartile increment in blood lead (2.8 microg/dl) was associated with 14% higher odds of hostility (95% confidence interval of the odds ratio: 1.02, 1.27). In all other analyses, lead was nonsignificantly associated with psychiatric symptoms. The adverse association of lead with abnormal mood scores was generally stronger among ALAD 1-1 carriers than 1-2/2-2 carriers, particularly regarding phobic anxiety symptoms (p(interaction) = 0.004). These results augment evidence of a deleterious association between lead and psychiatric symptoms.